What Happens if You Don’t Get Enough Vitamin B9/Anemia is a condition that happens when you don’t have enough red blood cells to carry oxygen to your body’s tissues. One reason could be that you don’t have enough hemoglobin to make red blood cells. … You can also become anemic by not getting enough folate (vitamin B9), the natural form of folic acid found in foods.
What Causes Vitamin B9 Deficiency/Vitamin B9 is one of the B vitamins. Folic acid is a form of vitamin B-9 that can dissolve in water. It is a key ingredient in the making of the nucleic acid that forms part of all genetic material.The recommended daily intake of folate in the US is 400 micrograms from foods or dietary supplements. Folate in the form of folic acid is used to treat anemia caused by folic acid deficiency. Folic acid is also used as a supplement by women during pregnancy to prevent neural tube defects(NTD) in the baby. Low levels in early pregnancy are believed to be the cause of more than half of babies born with neural tube defects. More than 50 countries use fortification of certain foods with folic acid as a measure to decrease the rate of NTDs in the population. Long term supplementation is also associated with small reductions in the risk of stroke and cardiovascular disease.It may be taken by mouth or by injection.
Folate, distinct forms of which are known as folic acid, folacin, and vitamin B9,[rx] is one of the B vitamins.[rx] It may be taken by mouth or by injection.[rx] The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.[rx] Folate in the form of folic acid is used to treat anemia caused by folic acid deficiency.[4] Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby.[4][9] Low levels in early pregnancy are believed to be the cause of more than half of babies born with NTDs.[rx] More than 80 countries use fortification of certain foods with folic acid as a measure to decrease the rate of NTDs
Symptoms of Vitamin B9 Deficiency
Folic acid deficiency occurs when the newborn baby does not receive enough of this vitamin in the womb. A fetus that has received insufficient quantities of folic acid has strong possibilities of being born with spina bifida and may also suffer from serious defects of the nervous system.
Deficiency of folic acid may also lead to the following
anemia(macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.
Women with folate deficiency who become pregnant are more likely to give birth to low birth weight premature infants, and infants with neural tube defects.
In infants and children, folate deficiency can lead to failure to thrive or slow growth rate,
diarrhea
oral ulcers
megaloblastic anemia,
neurological deterioration.
Microcephaly
seizures
blindness and cerebellar ataxia can also be observed.
Folic acid has many roles to play in the development of bones and iron uptake by the cells. Hence its deficiency may lead to malfunctioning of the vital systems.
Recommended Intakes of Vitamin B9
Intake recommendations for folate and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) . DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:
Recommended Dietary Allowance (RDA) – Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
Adequate Intake (AI) – Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
Estimated Average Requirement (EAR) – Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
Tolerable Upper Intake Level (UL) – Maximum daily intake unlikely to cause adverse health effects.
Table 1 lists the current RDAs for folate as micrograms (mcg) of dietary folate equivalents (DFEs). The FNB developed DFEs to reflect the higher bioavailability of folic acid than that of food folate. At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable . Based on these values, the FNB defined DFE as follows:
1 mcg DFE = 1 mcg food folate
1 mcg DFE = 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods
1 mcg DFE = 0.5 mcg folic acid from dietary supplements taken on an empty stomach
For infants from birth to 12 months, the FNB established an AI for folate that is equivalent to the mean intake of folate in healthy, breastfed infants in the United States.
Recommended Dietary Allowances (RDAs) for Folate
Age
Male
Female
Pregnant
Lactating
Birth to 6 months*
65 mcg DFE*
65 mcg DFE*
7–12 months*
80 mcg DFE*
80 mcg DFE*
1–3 years
150 mcg DFE
150 mcg DFE
4–8 years
200 mcg DFE
200 mcg DFE
9–13 years
300 mcg DFE
300 mcg DFE
14–18 years
400 mcg DFE
400 mcg DFE
600 mcg DFE
500 mcg DFE
19+ years
400 mcg DFE
400 mcg DFE
600 mcg DFE
500 mcg DFE
* Adequate Intake (AI)
Food Source of Vitamin B9
Selected Food Sources of Folate and Folic Acid
Food
mcg DFE
per serving
Percent DV*
Beef liver, braised, 3 ounces
215
54
Spinach, boiled, ½ cup
131
33
Black-eyed peas (cowpeas), boiled, ½ cup
105
26
Breakfast cereals, fortified with 25% of the DV†
100
25
Rice, white, medium-grain, cooked, ½ cup†
90
23
Asparagus, boiled, 4 spears
89
22
Spaghetti, cooked, enriched, ½ cup†
83
21
Brussels sprouts, frozen, boiled, ½ cup
78
20
Lettuce, romaine, shredded, 1 cup
64
16
Avocado, raw, sliced, ½ cup
59
15
Spinach, raw, 1 cup
58
15
Broccoli, chopped, frozen, cooked, ½ cup
52
13
Mustard greens, chopped, frozen, boiled, ½ cup
52
13
Green peas, frozen, boiled, ½ cup
47
12
Kidney beans, canned, ½ cup
46
12
Bread, white, 1 slice†
43
11
Peanuts, dry roasted, 1 ounce
41
10
Wheat germ, 2 tablespoons
40
10
Tomato juice, canned, ¾ cup
36
9
Crab, Dungeness, 3 ounces
36
9
Orange juice, ¾ cup
35
9
Turnip greens, frozen, boiled, ½ cup
32
8
Orange, fresh, 1 small
29
7
Papaya, raw, cubed, ½ cup
27
7
Banana, 1 medium
24
6
Yeast, baker’s, ¼ teaspoon
23
6
Egg, whole, hard-boiled, 1 large
22
6
Vegetarian baked beans, canned, ½ cup
15
4
Cantaloupe, raw, 1 wedge
14
4
Fish, halibut, cooked, 3 ounces
12
3
Milk, 1% fat, 1 cup
12
3
Ground beef, 85% lean, cooked, 3 ounces
7
2
Chicken breast, roasted, ½ breast
3
1
* DV = Daily Value. The FDA developed DVs to help consumers compare the nutrient contents of products within the context of a total diet. The DV for folate is 400 mcg for adults and children aged 4 and older. However, the FDA does not require food labels to list folate content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.
† Fortified with folic acid as part of the folate fortification program.
The U.S. Department of Agriculture’s Nutrient Database Web site lists the nutrient content of many foods and provides a comprehensive list of foods containing folate arranged by nutrient content and by food name.
Serious kidney disease – About 85% of people with serious kidney disease have high levels of homocysteine. High levels of homocysteine have been linked to heart disease and stroke. Taking folic acid lowers homocysteine levels in people with serious kidney disease. However, folic acid supplementation does not appear to reduce the risk of heart disease-related events.
High amounts of homocysteine in the blood (hyperhomocysteinemia) – High levels of homocysteine have been linked to heart disease and stroke. Taking folic acid lowers homocysteine levels by 20% to 30% in people with normal to slightly elevated homocysteine levels. It is recommended that people with homocysteine levels greater than 11 micromoles/L supplement with folic acid and vitamin B12.
Reducing harmful effects of a medicine called methotrexate – Taking folic acid seems to reduce nausea and vomiting, which are possible side effects of methotrexate treatment.
Birth defects (neural tube defects) – Folic acid during pregnancy reduces the risk of neural tube birth defects. It is recommended that pregnant women get 600-800 mcg of folic acid per day from their diet or supplements starting 1 month before pregnancy and during pregnancy. Pregnant women with a history of neural tube birth defects are advised to get 4000 mcg of folic acid per day.
Possibly Effective for
Age-related vision loss (age-related macular degeneration) – Research shows that taking folic acid with other vitamins including vitamin B6 and vitamin B12 reduces the risk of developing age-related vision loss.
Depression – Limited research shows that taking folic acid along with antidepressants seems to improve symptoms in people with depression.
High blood pressure – Research shows that taking folic acid daily for at least 6 weeks reduces blood pressure in people with high blood pressure. But Taking folic acid with blood pressure medication does not seem to lower blood pressure more than taking only blood pressure medicine
Gum problems due to a drug called phenytoin – Applying folic acid to the gums seems to prevent gum problems caused by phenytoin. However, taking folic acid by mouth does not seem to improve symptoms of this condition.
Gum disease during pregnancy – Applying folic acid to the gums seems to improve gum disease during pregnancy.
Stroke – Taking folic acid can reduce the risk of stroke by 10% to 25% in people who live in countries that don’t fortify grain products with folic acid. But folic acid doesn’t seem to prevent strokes in most people who live in countries that do fortify grain products with folic acid.
A skin discoloration disorder called vitiligo – Taking folic acid by mouth seems to improve symptoms of vitiligo.
Cancer of the white blood cells (acute lymphoblastic leukemia) – Taking folate during pregnancy does not reduce the risk of childhood cancer of the white blood cells.
Iron deficiency – Taking folic acid with iron supplements is not more effective than taking the iron supplements without folic acid for treating and preventing iron deficiency and anemia caused by too little iron in the body.
Memory and thinking skills in older people – Most research shows that taking folic acid does not prevent decline in memory and thinking skills in the elderly.
Preventing re-blockage of blood vessels after angioplasty – There is inconsistent evidence on the benefits of taking folic acid after a procedure to widen the blood vessels. But taking folic acid plus vitamin B6 and vitamin B12 might actually interfere with healing in cases where a device (stent) is inserted in the blood vessel to keep it open.
Breast cancer – Consuming folate in the diet might lower the risk of developing breast cancer in women who also eat high amounts of methionine, vitamin B12 (cyanocobalamin), or vitamin B6 (pyridoxine), but research is not consistent. Other research suggests that taking folic acid supplements alone does not lower the risk of breast cancer.
Heart disease – Most research shows that taking folic acid alone or with other B vitamins does not reduce the risk of death or heart disease-related events in people with heart disease.
Cataracts – Research shows that taking folic acid with other vitamins including vitamin B6 and vitamin B12 does not prevent cataracts. In fact, it might increase the chance of needing to have cataracts removed.
Chronic fatigue syndrome – Daily injections of folic acid appear to have no effect on symptoms of chronic fatigue syndrome.
Diarrhea – Taking a specific nutritional supplement with added folic acid and possibly vitamin B12 does not seem to prevent diarrhea in children at risk of malnutrition. Taking this product may increase the risk of having diarrhea last more than a few days.
Preventing falls – Taking folic acid with vitamin B-12 does not seem to prevent falls in older people who are also taking vitamin D.
Fetal and early infant death – Taking folic acid during pregnancy does not seem to reduce the risk of having a baby die just before or after birth.
Toxicity from the drug lometrexol – Daily injections of folic acid appear to have no effect on symptoms of chronic fatigue syndrome.
Lower respiratory tract infections – Taking a specific nutritional supplement with added folic acid and possibly vitamin B12 does not seem to prevent infections in the lungs in children at risk of malnutrition.
Weak bones (osteoporosis) – In elderly individuals with osteoporosis, taking folic acid with vitamin B12 and possibly vitamin B6 (pyridoxine) does not seem to prevent broken bones.
Performance in older people – Taking folic acid with vitamin B-12 doesn’t seem to help older people walk better or have stronger hands.
Growths in the large intestine and rectum (colorectal adenoma) – Taking folic acid supplements does not seem to prevent growths in the large intestine or rectum.
Inherited disease called Fragile-X syndrome – Taking folic acid by mouth does not improve symptoms of fragile-X-syndrome.
Premature infants – Taking folic acid during pregnancy does not decrease the risk of having a premature baby.
Insufficient Evidence for
Acne – Limited evidence suggests that taking a specific nutritional supplement, containing vitamin B3 (nicotinamide), a compound isolated from grains (azelaic acid), zinc, vitamin B6 (pyridoxine), copper, and folic acid (NicAzel, Elorac Inc., Vernon Hills, IL) appears to reduce inflammation associated with pimples on the face.
Alzheimer’s disease – Limited evidence suggests that elderly people who consume more folic acid than the recommended dietary allowance (RDA) appear to have a lower risk of developing Alzheimer’s disease than people who consume less folic acid.
Autism – Limited research suggests taking folic acid during pregnancy might reduce the risk of autism in the child.
Beta-thalassemia – Beta-thalassemia is a disorder of the blood that results in the production of less hemoglobin, the protein that carries oxygen in the blood. Patients with beta-thalassemia usually have bone and muscle pain and have less strength. In children with this disorder, limited research suggests taking folic acid by itself, or with L-carnitine a compound similar to an amino acid from protein, might reduce bone pain and help increase strength.
Bipolar disorder – Taking folic acid does not appear to improve the antidepressant effects of lithium in people with bipolar disorder. However, taking folate with the medication valproate improves the effects of valproate.
Cervical cancer – There is some evidence that increasing folic acid and folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might help to prevent cervical cancer.
Long-term kidney disease (chronic kidney disease, CKD) – Taking folic acid might help slow kidney function decline in people with CKD. But it is not beneficial when used along with vitamin B12 (cyanocobalamin). In fact, the combination might make kidney disease worse.
Colon cancer, rectal cancer – Research suggests that taking folic acid or eating folate in the diet can reduce the risk of developing colon or rectal cancer. However, there is some research that does not suggest that taking folic acid or folate in the diet offers the same benefit. It is possible that folic acid may be more helpful for preventing colon cancer than rectal cancer or it may be more helpful for specific kinds of colon cancer.
Diabetes – Taking folic acid supplements does not seem to benefit people with diabetes.
Epilepsy – Taking folic acid does not reduce seizures in people with epilepsy.
Esophageal cancer – Research suggests that consuming more folate in the diet lowers the risk for developing esophageal cancer.
High amounts of homocysteine in the blood caused by the drug fenofibrat – Taking folic acid every other day might lower levels of homocysteine in the blood caused by the drug fenofibrate.
Stomach cancer – Research suggests that taking folic acid reduces the risk of developing some types of stomach cancer.
Gout – Early research suggests that folate might reduce the risk of gout.
Head and neck cancer – Getting more folic acid from the diet has been linked to a lower risk of head and neck cancer.
Hearing loss – Low levels of folate in the blood seem to be related to the risk for sudden hearing loss in adults. Some evidence suggests that taking folic acid daily for 3 years slows the decline of hearing loss in older people who have low folate levels. It is not clear if folic acid supplementation reduces hearing loss in people with normal folate levels.
Male infertility – Some research suggests that taking folic acid plus zinc sulfate daily can increase sperm count in men with low sperm counts.
Low birth weight – Taking folic acid during pregnancy does not prevent some babies from being born at a low birth weight but it does seem to increase the overall average of birth weights. However, some early research suggests that taking folic acid before getting pregnant might reduce the risk of having a baby that is too small even when born full term. Although this risk is not reduced in mothers that start supplementation after the baby is conceived.
Lung cancer – There does not appear to be a relationship between low levels of folic acid and lung cancer in most people.
A type of skin cancer called melanoma – Early research shows that taking folic acid might reduce the risk of melanoma.
Helping medicines used for chest pain work longer – Some evidence suggests that taking folic acid does not help medications for chest pain (nitrates) work longer.
Cleft lip – Some research suggests that taking folic acid during pregnancy lowers the risk of left lip. However, other research shows no effect.
Pancreatic cancer – Eating more than 280 mcg of folate in the diet daily is linked to a lower risk of developing pancreatic cancer. However, other research suggests that folate intake is not linked to pancreatic cancer risk.
Nerve pain (peripheral neuropathy) – There is conflicting evidence about the role of folic acid in nerve pain for people with diabetes (diabetic neuropathy). Some research suggests that taking folic acid with vitamin B6 (pyridoxine) and vitamin B12 improves some symptoms of nerve pain so that people feel happier. However, the nerves do not seem to function any better.
Cancer of the throat – Limited research suggests folic acid and folate from dietary and sources and supplements may protect against oropharyngeal cancer, a specific type of throat cancer.
Pre-eclampsia – Pre-eclampsia is marked by high blood pressure and protein in the urine during pregnancy. Limited research suggests taking folic acid supplements during pregnancy does not reduce the risk of pre-eclampsia.
Pregnancy-induced high blood pressure – Limited research suggests that taking folic acid during pregnancy does not reduce the risk of high blood pressure (gestational hypertension).
A disorder that causes a strong urge to move ones legs (restless legs syndrome; RLS) – Taking folic acid seems to reduce symptoms of restless legs syndrome. Researchers are studying whether folic acid deficiency causes restless legs syndrome.
Schizophrenia – Taking a combination of folic acid and vitamin B12 may reduce some of the negative symptoms associated with schizophrenia, but only in some patients with a specific genetic make-up. In most people, folic acid does not help with these symptoms.
Sickle-cell disease. Taking folic acid might lower homocysteine levels. However, it is not known if this will benefit people with sickle-cell disease.
Alcoholism
Liver disease
The European Food Safety Authority (EFSA), which provides scientific advice to assist policy makers, has confirmed that clear health benefits have been established for the dietary intake of folate (vitamin B9) in contributing to:
normal blood formation;
normal homocysteine;
a normal metabolism of the immune system;
normal cell division;
normal maternal tissue growth during pregnancy;
normal amino acid synthesis;
normal psychological functions;
the reduction of tiredness and fatigue;
maintanance of normal vision;
In addition, the EFSA has confirmed that supplemental folate intake increases maternal folate status, which contributes to the reduction of the risk of neural tube defects (NTD).
What is The Name of Vitamin B9/Vitamin B9 is one of the B vitamins. Folic acid is a form of vitamin B-9 that can dissolve in water. It is a key ingredient in the making of the nucleic acid that forms part of all genetic material.The recommended daily intake of folate in the US is 400 micrograms from foods or dietary supplements. Folate in the form of folic acid is used to treat anemia caused by folic acid deficiency. Folic acid is also used as a supplement by women during pregnancy to prevent neural tube defects(NTD) in the baby. Low levels in early pregnancy are believed to be the cause of more than half of babies born with neural tube defects. More than 50 countries use fortification of certain foods with folic acid as a measure to decrease the rate of NTDs in the population. Long term supplementation is also associated with small reductions in the risk of stroke and cardiovascular disease.It may be taken by mouth or by injection.
Folate, distinct forms of which are known as folic acid, folacin, and vitamin B9,[rx] is one of the B vitamins.[rx] It may be taken by mouth or by injection.[rx] The recommended adult daily intake of folate in the U.S. is 400 micrograms from foods or dietary supplements.[rx] Folate in the form of folic acid is used to treat anemia caused by folic acid deficiency.[4] Folic acid is also used as a supplement by women during pregnancy to reduce the risk of neural tube defects (NTDs) in the baby.[4][9] Low levels in early pregnancy are believed to be the cause of more than half of babies born with NTDs.[rx] More than 80 countries use fortification of certain foods with folic acid as a measure to decrease the rate of NTDs
Symptoms of Vitamin B9 Deficiency
Folic acid deficiency occurs when the newborn baby does not receive enough of this vitamin in the womb. A fetus that has received insufficient quantities of folic acid has strong possibilities of being born with spina bifida and may also suffer from serious defects of the nervous system.
Deficiency of folic acid may also lead to the following
anemia(macrocytic, megaloblastic anemia) can be a sign of advanced folate deficiency.
Women with folate deficiency who become pregnant are more likely to give birth to low birth weight premature infants, and infants with neural tube defects.
In infants and children, folate deficiency can lead to failure to thrive or slow growth rate,
diarrhea
oral ulcers
megaloblastic anemia,
neurological deterioration.
Microcephaly
seizures
blindness and cerebellar ataxia can also be observed.
Folic acid has many roles to play in the development of bones and iron uptake by the cells. Hence its deficiency may lead to malfunctioning of the vital systems.
Recommended Intakes of Vitamin B9
Intake recommendations for folate and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) . DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:
Recommended Dietary Allowance (RDA) – Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
Adequate Intake (AI) – Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
Estimated Average Requirement (EAR) – Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
Tolerable Upper Intake Level (UL) – Maximum daily intake unlikely to cause adverse health effects.
Table 1 lists the current RDAs for folate as micrograms (mcg) of dietary folate equivalents (DFEs). The FNB developed DFEs to reflect the higher bioavailability of folic acid than that of food folate. At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable . Based on these values, the FNB defined DFE as follows:
1 mcg DFE = 1 mcg food folate
1 mcg DFE = 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods
1 mcg DFE = 0.5 mcg folic acid from dietary supplements taken on an empty stomach
For infants from birth to 12 months, the FNB established an AI for folate that is equivalent to the mean intake of folate in healthy, breastfed infants in the United States.
Recommended Dietary Allowances (RDAs) for Folate
Age
Male
Female
Pregnant
Lactating
Birth to 6 months*
65 mcg DFE*
65 mcg DFE*
7–12 months*
80 mcg DFE*
80 mcg DFE*
1–3 years
150 mcg DFE
150 mcg DFE
4–8 years
200 mcg DFE
200 mcg DFE
9–13 years
300 mcg DFE
300 mcg DFE
14–18 years
400 mcg DFE
400 mcg DFE
600 mcg DFE
500 mcg DFE
19+ years
400 mcg DFE
400 mcg DFE
600 mcg DFE
500 mcg DFE
* Adequate Intake (AI)
Food Source of Vitamin B9
Selected Food Sources of Folate and Folic Acid
Food
mcg DFE
per serving
Percent DV*
Beef liver, braised, 3 ounces
215
54
Spinach, boiled, ½ cup
131
33
Black-eyed peas (cowpeas), boiled, ½ cup
105
26
Breakfast cereals, fortified with 25% of the DV†
100
25
Rice, white, medium-grain, cooked, ½ cup†
90
23
Asparagus, boiled, 4 spears
89
22
Spaghetti, cooked, enriched, ½ cup†
83
21
Brussels sprouts, frozen, boiled, ½ cup
78
20
Lettuce, romaine, shredded, 1 cup
64
16
Avocado, raw, sliced, ½ cup
59
15
Spinach, raw, 1 cup
58
15
Broccoli, chopped, frozen, cooked, ½ cup
52
13
Mustard greens, chopped, frozen, boiled, ½ cup
52
13
Green peas, frozen, boiled, ½ cup
47
12
Kidney beans, canned, ½ cup
46
12
Bread, white, 1 slice†
43
11
Peanuts, dry roasted, 1 ounce
41
10
Wheat germ, 2 tablespoons
40
10
Tomato juice, canned, ¾ cup
36
9
Crab, Dungeness, 3 ounces
36
9
Orange juice, ¾ cup
35
9
Turnip greens, frozen, boiled, ½ cup
32
8
Orange, fresh, 1 small
29
7
Papaya, raw, cubed, ½ cup
27
7
Banana, 1 medium
24
6
Yeast, baker’s, ¼ teaspoon
23
6
Egg, whole, hard-boiled, 1 large
22
6
Vegetarian baked beans, canned, ½ cup
15
4
Cantaloupe, raw, 1 wedge
14
4
Fish, halibut, cooked, 3 ounces
12
3
Milk, 1% fat, 1 cup
12
3
Ground beef, 85% lean, cooked, 3 ounces
7
2
Chicken breast, roasted, ½ breast
3
1
* DV = Daily Value. The FDA developed DVs to help consumers compare the nutrient contents of products within the context of a total diet. The DV for folate is 400 mcg for adults and children aged 4 and older. However, the FDA does not require food labels to list folate content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient.
† Fortified with folic acid as part of the folate fortification program.
The U.S. Department of Agriculture’s Nutrient Database Web site lists the nutrient content of many foods and provides a comprehensive list of foods containing folate arranged by nutrient content and by food name.
Serious kidney disease – About 85% of people with serious kidney disease have high levels of homocysteine. High levels of homocysteine have been linked to heart disease and stroke. Taking folic acid lowers homocysteine levels in people with serious kidney disease. However, folic acid supplementation does not appear to reduce the risk of heart disease-related events.
High amounts of homocysteine in the blood (hyperhomocysteinemia) – High levels of homocysteine have been linked to heart disease and stroke. Taking folic acid lowers homocysteine levels by 20% to 30% in people with normal to slightly elevated homocysteine levels. It is recommended that people with homocysteine levels greater than 11 micromoles/L supplement with folic acid and vitamin B12.
Reducing harmful effects of a medicine called methotrexate – Taking folic acid seems to reduce nausea and vomiting, which are possible side effects of methotrexate treatment.
Birth defects (neural tube defects) – Folic acid during pregnancy reduces the risk of neural tube birth defects. It is recommended that pregnant women get 600-800 mcg of folic acid per day from their diet or supplements starting 1 month before pregnancy and during pregnancy. Pregnant women with a history of neural tube birth defects are advised to get 4000 mcg of folic acid per day.
Possibly Effective for
Age-related vision loss (age-related macular degeneration) – Research shows that taking folic acid with other vitamins including vitamin B6 and vitamin B12 reduces the risk of developing age-related vision loss.
Depression – Limited research shows that taking folic acid along with antidepressants seems to improve symptoms in people with depression.
High blood pressure – Research shows that taking folic acid daily for at least 6 weeks reduces blood pressure in people with high blood pressure. But Taking folic acid with blood pressure medication does not seem to lower blood pressure more than taking only blood pressure medicine
Gum problems due to a drug called phenytoin – Applying folic acid to the gums seems to prevent gum problems caused by phenytoin. However, taking folic acid by mouth does not seem to improve symptoms of this condition.
Gum disease during pregnancy – Applying folic acid to the gums seems to improve gum disease during pregnancy.
Stroke – Taking folic acid can reduce the risk of stroke by 10% to 25% in people who live in countries that don’t fortify grain products with folic acid. But folic acid doesn’t seem to prevent strokes in most people who live in countries that do fortify grain products with folic acid.
A skin discoloration disorder called vitiligo – Taking folic acid by mouth seems to improve symptoms of vitiligo.
Cancer of the white blood cells (acute lymphoblastic leukemia) – Taking folate during pregnancy does not reduce the risk of childhood cancer of the white blood cells.
Iron deficiency – Taking folic acid with iron supplements is not more effective than taking the iron supplements without folic acid for treating and preventing iron deficiency and anemia caused by too little iron in the body.
Memory and thinking skills in older people – Most research shows that taking folic acid does not prevent decline in memory and thinking skills in the elderly.
Preventing re-blockage of blood vessels after angioplasty – There is inconsistent evidence on the benefits of taking folic acid after a procedure to widen the blood vessels. But taking folic acid plus vitamin B6 and vitamin B12 might actually interfere with healing in cases where a device (stent) is inserted in the blood vessel to keep it open.
Breast cancer – Consuming folate in the diet might lower the risk of developing breast cancer in women who also eat high amounts of methionine, vitamin B12 (cyanocobalamin), or vitamin B6 (pyridoxine), but research is not consistent. Other research suggests that taking folic acid supplements alone does not lower the risk of breast cancer.
Heart disease – Most research shows that taking folic acid alone or with other B vitamins does not reduce the risk of death or heart disease-related events in people with heart disease.
Cataracts – Research shows that taking folic acid with other vitamins including vitamin B6 and vitamin B12 does not prevent cataracts. In fact, it might increase the chance of needing to have cataracts removed.
Chronic fatigue syndrome – Daily injections of folic acid appear to have no effect on symptoms of chronic fatigue syndrome.
Diarrhea – Taking a specific nutritional supplement with added folic acid and possibly vitamin B12 does not seem to prevent diarrhea in children at risk of malnutrition. Taking this product may increase the risk of having diarrhea last more than a few days.
Preventing falls – Taking folic acid with vitamin B-12 does not seem to prevent falls in older people who are also taking vitamin D.
Fetal and early infant death – Taking folic acid during pregnancy does not seem to reduce the risk of having a baby die just before or after birth.
Toxicity from the drug lometrexol – Daily injections of folic acid appear to have no effect on symptoms of chronic fatigue syndrome.
Lower respiratory tract infections – Taking a specific nutritional supplement with added folic acid and possibly vitamin B12 does not seem to prevent infections in the lungs in children at risk of malnutrition.
Weak bones (osteoporosis) – In elderly individuals with osteoporosis, taking folic acid with vitamin B12 and possibly vitamin B6 (pyridoxine) does not seem to prevent broken bones.
Performance in older people – Taking folic acid with vitamin B-12 doesn’t seem to help older people walk better or have stronger hands.
Growths in the large intestine and rectum (colorectal adenoma) – Taking folic acid supplements does not seem to prevent growths in the large intestine or rectum.
Inherited disease called Fragile-X syndrome – Taking folic acid by mouth does not improve symptoms of fragile-X-syndrome.
Premature infants – Taking folic acid during pregnancy does not decrease the risk of having a premature baby.
Insufficient Evidence for
Acne – Limited evidence suggests that taking a specific nutritional supplement, containing vitamin B3 (nicotinamide), a compound isolated from grains (azelaic acid), zinc, vitamin B6 (pyridoxine), copper, and folic acid (NicAzel, Elorac Inc., Vernon Hills, IL) appears to reduce inflammation associated with pimples on the face.
Alzheimer’s disease – Limited evidence suggests that elderly people who consume more folic acid than the recommended dietary allowance (RDA) appear to have a lower risk of developing Alzheimer’s disease than people who consume less folic acid.
Autism – Limited research suggests taking folic acid during pregnancy might reduce the risk of autism in the child.
Beta-thalassemia – Beta-thalassemia is a disorder of the blood that results in the production of less hemoglobin, the protein that carries oxygen in the blood. Patients with beta-thalassemia usually have bone and muscle pain and have less strength. In children with this disorder, limited research suggests taking folic acid by itself, or with L-carnitine a compound similar to an amino acid from protein, might reduce bone pain and help increase strength.
Bipolar disorder – Taking folic acid does not appear to improve the antidepressant effects of lithium in people with bipolar disorder. However, taking folate with the medication valproate improves the effects of valproate.
Cervical cancer – There is some evidence that increasing folic acid and folate intake from dietary and supplement sources, along with thiamine, riboflavin, and vitamin B12, might help to prevent cervical cancer.
Long-term kidney disease (chronic kidney disease, CKD) – Taking folic acid might help slow kidney function decline in people with CKD. But it is not beneficial when used along with vitamin B12 (cyanocobalamin). In fact, the combination might make kidney disease worse.
Colon cancer, rectal cancer – Research suggests that taking folic acid or eating folate in the diet can reduce the risk of developing colon or rectal cancer. However, there is some research that does not suggest that taking folic acid or folate in the diet offers the same benefit. It is possible that folic acid may be more helpful for preventing colon cancer than rectal cancer or it may be more helpful for specific kinds of colon cancer.
Diabetes – Taking folic acid supplements does not seem to benefit people with diabetes.
Epilepsy – Taking folic acid does not reduce seizures in people with epilepsy.
Esophageal cancer – Research suggests that consuming more folate in the diet lowers the risk for developing esophageal cancer.
High amounts of homocysteine in the blood caused by the drug fenofibrat – Taking folic acid every other day might lower levels of homocysteine in the blood caused by the drug fenofibrate.
Stomach cancer – Research suggests that taking folic acid reduces the risk of developing some types of stomach cancer.
Gout – Early research suggests that folate might reduce the risk of gout.
Head and neck cancer – Getting more folic acid from the diet has been linked to a lower risk of head and neck cancer.
Hearing loss – Low levels of folate in the blood seem to be related to the risk for sudden hearing loss in adults. Some evidence suggests that taking folic acid daily for 3 years slows the decline of hearing loss in older people who have low folate levels. It is not clear if folic acid supplementation reduces hearing loss in people with normal folate levels.
Male infertility – Some research suggests that taking folic acid plus zinc sulfate daily can increase sperm count in men with low sperm counts.
Low birth weight – Taking folic acid during pregnancy does not prevent some babies from being born at a low birth weight but it does seem to increase the overall average of birth weights. However, some early research suggests that taking folic acid before getting pregnant might reduce the risk of having a baby that is too small even when born full term. Although this risk is not reduced in mothers that start supplementation after the baby is conceived.
Lung cancer – There does not appear to be a relationship between low levels of folic acid and lung cancer in most people.
A type of skin cancer called melanoma – Early research shows that taking folic acid might reduce the risk of melanoma.
Helping medicines used for chest pain work longer – Some evidence suggests that taking folic acid does not help medications for chest pain (nitrates) work longer.
Cleft lip – Some research suggests that taking folic acid during pregnancy lowers the risk of left lip. However, other research shows no effect.
Pancreatic cancer – Eating more than 280 mcg of folate in the diet daily is linked to a lower risk of developing pancreatic cancer. However, other research suggests that folate intake is not linked to pancreatic cancer risk.
Nerve pain (peripheral neuropathy) – There is conflicting evidence about the role of folic acid in nerve pain for people with diabetes (diabetic neuropathy). Some research suggests that taking folic acid with vitamin B6 (pyridoxine) and vitamin B12 improves some symptoms of nerve pain so that people feel happier. However, the nerves do not seem to function any better.
Cancer of the throat – Limited research suggests folic acid and folate from dietary and sources and supplements may protect against oropharyngeal cancer, a specific type of throat cancer.
Pre-eclampsia – Pre-eclampsia is marked by high blood pressure and protein in the urine during pregnancy. Limited research suggests taking folic acid supplements during pregnancy does not reduce the risk of pre-eclampsia.
Pregnancy-induced high blood pressure – Limited research suggests that taking folic acid during pregnancy does not reduce the risk of high blood pressure (gestational hypertension).
A disorder that causes a strong urge to move ones legs (restless legs syndrome; RLS) – Taking folic acid seems to reduce symptoms of restless legs syndrome. Researchers are studying whether folic acid deficiency causes restless legs syndrome.
Schizophrenia – Taking a combination of folic acid and vitamin B12 may reduce some of the negative symptoms associated with schizophrenia, but only in some patients with a specific genetic make-up. In most people, folic acid does not help with these symptoms.
Sickle-cell disease. Taking folic acid might lower homocysteine levels. However, it is not known if this will benefit people with sickle-cell disease.
Alcoholism
Liver disease
The European Food Safety Authority (EFSA), which provides scientific advice to assist policy makers, has confirmed that clear health benefits have been established for the dietary intake of folate (vitamin B9) in contributing to:
normal blood formation;
normal homocysteine;
a normal metabolism of the immune system;
normal cell division;
normal maternal tissue growth during pregnancy;
normal amino acid synthesis;
normal psychological functions;
the reduction of tiredness and fatigue;
maintanance of normal vision;
In addition, the EFSA has confirmed that supplemental folate intake increases maternal folate status, which contributes to the reduction of the risk of neural tube defects (NTD).
Gunshot Wounds/Wounds are defined as a disruption of the normal structure and function of skin and underlying soft tissue that is caused by trauma or chronic mechanical stress (e.g., decubitus ulcers). Wounds can be broken down into acute or chronic, and open or closed. Wound treatment is performed according to pathology, the extent, and circumstances of the lesions. To heal, the wound needs to have a vascular supply, be free of necrotic tissue, clear of infection, and moist. General wound treatment includes surgical wound closure, open wound treatment, and plastic reconstruction of skin defects. In addition, infectious or concomitant disease prevention should be considered (e.g., antibiotic therapy, vaccines for tetanus and rabies, diabetes control).
A wound is damaged or disruption to the skin and, before treatment, the exact cause, location, and type of wound must be assessed to provide appropriate treatment.[rx][rx][rx] Each clinician will have widely differing and distinct opinions and understanding of wound care depending on their prior experience. The reason for this because of the widely differing and distinct types of wounds, each with their etiology. An ostomy nurse will have a completely different approach to wound care that will require an orthopedic surgeon who deals with trauma and both will be far different from a dermatologist who treats burn victims. Nevertheless, each of these healthcare providers is performing wound care. How do professionals then approach wound assessment when the causes are so diverse? Below are some basic questions to ask during a wound assessment to best classify and treat a wound presenting in a clinical setting.
Normal Healthy Skin of Wounds
As the interface between the environment and body, the skin has several distinct functions. It protects the underlying tissues from abrasions, the entry of microbes, unwanted water loss, and ultraviolet light damage. Tactile sensations of touch, pressure, and vibration, thermal sensations of heat and cold, and pain sensations all originate in the skin’s nervous system. The body’s thermoregulation relies on the skin’s ability to sweat and to control the flow of blood to the skin to increase or decrease heat loss. The skin’s functions are performed by three distinct tissue layers: a thin outer layer of cells called the epidermis, a thicker middle layer of connective tissue called the dermis, and an inner, subcutaneous layer. The outer layers of the epidermis are composed of flattened, cornified dead keratinocytes that form a barrier to water loss and microbe entry. These cells are derived from a basal layer of constantly dividing keratinocytes that lies next to the dermis. The epidermis does not contain nerves or blood vessels and obtains water and nutrients through diffusion from the dermis. The dermis is composed mostly of collagen fibers and some elastic fibers both produced by fibroblasts and, along with water and large proteoglycan molecules, makes up the extracellular matrix. This layer of the skin provides mechanical strength and a substrate for water and nutrient diffusion; it contains blood vessels, nerves, and cells involved in immune function, growth, and repair. The dermis also contains sweat glands, oil glands, and hair follicles. The subcutaneous layer is composed of adipocytes that form a thick layer of adipose tissue.[rx]
Types of Wounds
Each of the potential underlying causes must be addressed for the wound to heal. Before determining the underlying cause, it is important to determine what type of wound the patient has. These subclassifications can be acute or chronic.[rx][rx][rx]
1. According to the severity, a wound can be classified as
Acute
Clinicians assess acute wounds by the method of injury and damage to the soft tissues and bony structures. In crush or high impact injuries, there is an area of demarcation which is not fully recognized until sometimes as much as a week or 2 later. For this reason, it is important to determine the method of injury and to keep in mind that the wound seen is not necessarily the entirety of the wound which will be present in a week. In these cases, the patient and their family should be educated on this progression to prevent frustration and misunderstanding.
For all acute types of wounds, it is important to determine the length of time since injury (days or hours), the involvement of neurovascular supply, muscle, tendon, ligament, and bony involvement, and the likelihood of contaminants in the wound. Also of importance is when the patient had their last tetanus shot. CLinicians should start antibiotics if the wound is severely contaminated or if it is longer than 3 hours since the injury. All underlying tissue should be repaired if possible, and the wound should be irrigated to remove contaminants and bacteria.
In cases of open fracture the most used classification is Gustillo-Anderson
Type 1 – Clean wound, less than one cm with minimal soft tissue damage, adequate soft tissue coverage of bone, and no periosteal stripping
Type 2 – Wound with moderate contamination, greater than one cm with moderate soft tissue damage, adequate soft tissue coverage of bone, and no periosteal stripping
Type 3A – Wound with significant contamination, with significant soft tissue damage, adequate soft tissue coverage of bone, and periosteal stripping is present
Type 3B – Wound with significant contamination, with significant soft tissue damage, unable to cover bone with soft tissue (requiring graft), and periosteal stripping
Type 3C – Similar to type A or B, however with Arterial damage requiring repair
Chronic
If a wound becomes arrested in progression through the normal stages of inflammation and wound healing and remains open, then this becomes a chronic wound. While there is no consensus as to when a wound becomes chronic, a study by Sheehan et. al determined that in diabetic wounds, the degree of healing at 4 weeks is a strong predictor of 12 week healing, suggesting that those wounds which have not healed approximately 50% in 4 weeks are likely to have an arrested healing process, and therefore are chronic.[rx][rx]
In the chronic setting, the main goal is to identify why the wound is not healing and to fix this obstacle or obstacles.
There are a limited number of reasons a wound becomes chronic; however, once these reasons are rectified, the wound resumes its natural course of healing.
Arterial – Is there enough blood flow? Generally speaking, an ABI of less than 50 mm Hg, or an absolute toe pressure less than 30 mm Hg (or less than 50 mm Hg for persons with diabetes) indicates critical limb ischemia and predicts failure of wounds to heal.
Venous – Pressure-induced changes in blood vessel wall permeability then lead to leakage of fibrin and other plasma components into the perivascular space. Accumulation of fibrin has direct and negative effects on wound healing as it down-regulates collagen synthesis.
Infection – Underlying infectious processes including cellulitic and osteomyelitis processes will inhibit wound healing. Culturing for aerobic, anaerobic, and fungal pathogens is recommended.
Pressure – Increased pressure to the area of concern will destroy new tissue growth and prevent proper perfusion of blood to the wound site. These areas need to be offloaded to avoid pressure in the area.
Oncologic – Always biopsy areas of concern in nonhealing wounds, as this can be an atypical presentation of some types of malignancies.
Systemic – There are multiple systemic diseases which inhibit wound healing, with diabetes being the most common culprit. It has been determined that uncontrolled blood glucose levels suppresses the body’s normal inflammatory response, as well as causing microvascular disease which limits healing.
Nutrition – While serum albumin has not been found to be a good predictor of wound healing, there is some evidence that protein malnutrition, as well as insufficient levels of certain vitamins and minerals, will limit the body’s ability to heal chronic wounds.
Pharmacological – Hydroxyurea has been reported in multiple instances to cause nonhealing ulcerations.
Self-inflicted/psychosocial – There are instances where a patient is causing the ulceration, either on purpose or as a result of noncompliance. This is often the hardest factor to spot and overcome, but must always be a consideration.
2. According to level of contamination, a wound can be classified as
Clean wound – made under sterile conditions where there are no organisms present, and the skin is likely to heal without complications.
Contaminated wound – usually resulting from accidental injury; there are pathogenic organisms and foreign bodies in the wound.
Infected wound – the wound has pathogenic organisms present and multiplying, exhibiting clinical signs of infection (yellow appearance, soreness, redness, oozing pus).
Colonized wound – a chronic situation, containing pathogenic organisms, difficult to heal (i.e. bedsore).
Open
Open wounds can be classified according to the object that caused the wound
Incisions or incised wounds – caused by a clean, sharp-edged object such as a knife, razor, or glass splinter.
Lacerations – irregular tear-like wounds caused by some blunt trauma. Lacerations and incisions may appear linear (regular) or stellate (irregular). The term laceration is commonly misused in reference to incisions.[rx]
Abrasions (grazes) – superficial wounds in which the topmost layer of the skin (the epidermis) is scraped off. Abrasions are often caused by a sliding fall onto a rough surface such as asphalt, tree bark or concrete.
Avulsions – injuries in which a body structure is forcibly detached from its normal point of insertion. A type of amputation where the extremity is pulled off rather than cut off. When used in reference to skin avulsions, the term ‘degloving’ is also sometimes used as a synonym.
Puncture wounds – caused by an object puncturing the skin, such as a splinter, nail or needle.
Penetration wounds – caused by an object such as a knife entering and coming out from the skin.
Gunshot wounds – caused by a bullet or similar projectile driving into or through the body. There may be two wounds, one at the site of entry and one at the site of exit, generally referred to as a “through-and-through.”
Closed
Closed wounds have fewer categories, but are just as dangerous as open wounds:
Hematomas (or blood tumor) – caused by damage to a blood vessel that in turn causes blood to collect under the skin.
Hematomas that originate from internal blood vessel pathology are petechiae, purpura, and ecchymosis. The different classifications are based on size.
Hematomas that originate from an external source of trauma are contusions, also commonly called bruises.
Crush injury – caused by a great or extreme amount of force applied over a long period of time.
3. According to the Visuality, a wound can be classified as
Internal Wounds
Disturbance of the different regulating systems of the human body can lead to wound formation, and may include the following:
Impaired circulation – This can be from either ischemia or stasis. Ischemia is the result of reduced blood supply caused by the narrowing or blockage of blood vessels, which leads to poor circulation. Stasis is caused by immobilization (or difficulty moving) for long periods or failure of the regulating valves in the veins, which leads to blood pooling and failing to flow normally to the heart.
Neuropathy – This is seen mostly in cases of prolonged uncontrolled diabetes mellitus, where high blood sugars, derivative proteins and metabolites accumulate and damage the nervous system. The patients are usually unaware of any trauma or wounds, mainly due to loss of sensation in the affected area.
Medical illness – When chronic and uncontrolled for long periods (such as hypertension, hyperlipidemia, arthrosclerosis, diabetes mellitus, AIDS, malignancy, morbid obesity, hepatitis C virus, etc.), medical illnesses can lead to impairment of the immune system functions, diminishing the circulation and damaging other organs and systems.
External Wounds
External wounds can either be open or closed. In cases of closed wounds, the skin is intact and the underlying tissue is affected but not directly exposed to the outside environment. The following are the most common types of closed wounds:
Contusions – These are a common type of sports injury, where a direct blunt trauma can damage the small blood vessels and capillaries, muscles and underlying tissue, as well the internal organs or bone. Contusions present as a painful bruise with reddish to bluish discoloration that spreads over the injured area of skin.
Hematomas – These include any injury that damages the small blood vessels and capillaries resulting in blood collecting and pooling in a limited space. Hematomas typically present as a painful, spongy rubbery lump-like lesion. Depending on the severity and site of the trauama, hematomas can be small or large, deep inside the body or just under the skin.
Crush injuries – These are usually caused by an external high-pressure force that squeezes part of the body between two surfaces. The degree of injury can range from a minor bruise to a complete destruction of the crushed area of the body, depending on the site, size, duration and power of the trauma.
Causes of Wound
Sudden forceful fall down
Road traffic accident
Burn and injured suddenly
Falls – Falling onto an outstretched hand is one of the most common causes of wound.
Sports injuries – Many sports injury occur during contact sports or sports in which you might fall onto an outstretched hand — such as in-line skating or snowboarding.
Motor vehicle crashes – Motor vehicle crashes can cause wound. Sometimes into many pieces, and often require surgical repair.
Have osteoporosis – a disease that weakens your bones.
Eave low muscle mass or poor muscle strength – or lack agility and have poor balance (these conditions make you more likely to fall)
Walk or do other activities in snow or on the ice – or do activities that require a lot of forwarding momenta, such as in-line skating and skiing
Wave an inadequate intake of calcium or vitamin D
Football or soccer, especially on artificial turf
Rugby
Horseback riding
Hockey
Skiing
Snowboarding
In-line skating
Jumping on a trampoline
Symptoms of Wound
General signs and symptoms of a wound infection include
Increased firmness of skin or swelling around the wound bed
Increasing drainage from the wound bed
Delayed wound healing
Discoloration of the wound bed with it turning darker in color
Foul odor
Increased fragility of the wound bed
Wound breakdown /enlargement
The skin may harden or tighten in the area and red streaks may radiate from the wound. Wound infections may also cause fevers, especially when they spread to the blood.
Diagnosis of Wound
Clinicians perform wound assessment as a means for determining the appropriate treatment for an extremely diverse grouping of disease processes. Just as hypertension is not treated the same as diabetes, each of the underlying etiologies of the given wound must be identified and treated as if it were its own disease, not a blanket classification of “wound.”[rx][rx]
The initial assessment should begin with the following:
How – How was the wound created and, if chronic, why is it still open? (underlying etiology)
Where – Where on the body is it located? Is it in an area which is difficult to offload, or to keep clean? Is it in an area of high skin tension? Is it near any vital structures such as a major artery?
When – How long has this wound been present? (eg., chronic or acute)
What – What anatomy does it extend? (e.g., epidermis, dermis, subcutaneous tissue, fascia, muscle, tendon, bone, arteries, nerves)
What – What co-morbidities or social factors does the patient have which might affect which might affect their ability to heal the wound?
Is it life threatening?
All of these factors significantly affect the treatment plan moving forward. While there are many excellent biologics, skin grafts, and other options available, without the appropriate understanding of the nature of the wound the chances of healing decline significantly.
Issues of Concern
While some wounds are simple, the majority of wounds many clinicians encounter are caused by or complicated by some other issue.[rx][rx][rx][rx] These are a few of the possible complications from different wound types:
A chronic wound will have a different makeup than that of an acute wound, requiring conversion for healing.
An underlying infection will prevent wound healing even if the infection is subacute.
A damaged or constricted arterial supply will prevent appropriate blood flow to the wound.
A damaged venous supply will cause venous stasis.
Physical pressure on chronic ulceration will cause repeated damage, preventing healing.
Tests
Many minor and superficial skin and wound infections are diagnosed by a healthcare practitioner based on a physical examination, sign and symptoms, and experience. A clinical evaluation cannot, however, definitively tell the healthcare practitioner which microbe is causing a wound infection or what treatment is likely to be effective. For that, laboratory testing is required.
Laboratory Tests
Examples of common tests include
Bacterial culture – This is the primary test used to diagnose a bacterial infection. Results are usually available within 24-48 hours.
Gram stain – This is usually performed in conjunction with the wound culture. It is a special staining procedure that allows bacteria to be evaluated under the microscope. The results are usually available the same day and provide preliminary information about the microbe that may be causing the infection.
Antimicrobial susceptibility – A follow-up test to a positive wound culture, this is used to determine the bacteria’s likely susceptibility to certain drugs and helps the healthcare practitioner select appropriate antibiotics for treatment. Results are typically available in about 24 hours. This testing can identify resistant bacteria such as MRSA.
Other tests may include
KOH prep – This is a rapid test performed to detect fungi in a sample. The sample is treated with a special solution, placed on a slide, and examined under a microscope.
Fungal culture – This is ordered when a fungal infection is suspected. Many fungi are slow-growing and may take several weeks to identify.
AFB testing – This is ordered when a mycobacterial infection is suspected. Most AFB are slow-growing and may take several weeks to identify.
Blood culture – This is ordered when infection from a wound may have spread to the blood.
Molecular testing – to detect genetic material of a specific microbe
Basic metabolic panel (BMP) or Comprehensive metabolic panel (CMP) – This may be ordered to detect underlying conditions that can affect wound healing, such as a glucose test to detect diabetes.
Complete blood count (CBC) – An elevated white blood cell (WBC) count may be a sign of infection.
Treatment of Wound
Emergency Management
Pain control
Intravenous opiates are often used as patients typically in severe pain
Highly effective for management of pain
Lower side effect profile than systemic analgesia
Always calculate your toxic dose of local anesthetic to avoid local anesthetic systemic toxicity
Closed the wounds should be placed in long leg splint and can also be placed in traction
If open Fractures should receive antibiotics and should proceed to OR for irrigation/debridement.
Cleaning to remove dirt and debris from a fresh wound. This is done very gently and often in the shower.
Vaccinating for tetanus may be recommended in some cases of traumatic injury.
Exploring a deep wound surgically may be necessary. Local anaesthetic will be given before the examination.
Removing dead skin surgically. Local anaesthetic will be given.
Closing large wounds with stitches or staples.
Dressing the wound – The dressing chosen by your doctor depends on the type and severity of the wound. In most cases of chronic wounds, the doctor will recommend a moist dressing.
Relieving pain with medications – Pain can cause the blood vessels to constrict, which slows healing. If your wound is causing discomfort, tell your doctor. The doctor may suggest that you take over-the-counter drugs such as paracetamol or may prescribe stronger pain-killing medication.
Treating signs of infection including pain – pus and fever. The doctor will prescribe antibiotics and antimicrobial dressings if necessary. Take as directed.
Skin Traction (Hare or Thomas) if needed
May improve wound alignment, blood flow, and pain
Skin traction splint can cause complications if a patient with a significant injury (i.e. multi ligamentous knee injury)
Here we review only the commonly used medications that have a significant impact on healing, including glucocorticoid steroids, non-steroidal anti-inflammatory drugs, and chemotherapeutic drugs.
Glucocorticoid Steroids – Systemic glucocorticoids (GC), which are frequently used as anti-inflammatory agents, are well-known to inhibit wound repair via global anti-inflammatory effects and suppression of cellular wound responses, including fibroblast proliferation and collagen synthesis. Systemic steroids cause wounds to heal with incomplete granulation tissue and reduced wound contraction [rx]. Glucocorticoids also inhibit production of hypoxia-inducible factor-1 (HIF-1), a key transcriptional factor in healing wounds [rx].
Non-steroidal Anti-inflammatory Drugs – Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are widely used for the treatment of inflammation and rheumatoid arthritis and for pain management. Low-dosage aspirin, due to its anti-platelet function, is commonly used as a preventive therapeutic for cardiovascular disease, but not as an anti-inflammatory drug [rx]. There are few data to suggest that short-term NSAIDs have a negative impact on healing.
Opioids – Also known as narcotics, these medications are intense pain relievers that should only be used under a doctor’s careful supervision.
Topical Medications – These prescription-strength creams, gels, ointments, patches, and sprays help relieve pain and inflammation through the skin.
Calcium & vitamin D3 – To improve bones health and healing fracture. As a general rule, men and women age 50 and older should consume 1,200 milligrams of calcium a day, and 600 international units of vitamin D a day.
Glucosamine & Diacerein, Chondroitin sulfate – can be used to tightening the loose tendon, cartilage, ligament, and cartilage, ligament regenerates cartilage or inhabits the further degeneration of cartilage, ligament.
Chemotherapeutic Drugs – Most chemotherapeutic drugs are designed to inhibit cellular metabolism, rapid cell division, and angiogenesis and thus inhibit many of the pathways that are critical to appropriate wound repair. These medications inhibit DNA, RNA, or protein synthesis, resulting in decreased fibroplasia and neovascularization of wounds [rx].
Nutrition – For more than 100 years, nutrition has been recognized as a very important factor that affects wound healing. Most obvious is that malnutrition or specific nutrient deficiencies can have a profound impact on wound healing after trauma and surgery. Patients with chronic or non-healing wounds and experiencing nutrition deficiency often require special nutrients. Energy, carbohydrate, protein, fat, vitamin, and mineral metabolism all can affect the healing process [rx].
Carbohydrates, Protein, and Amino Acids – Together with fats, carbohydrates are the primary source of energy in the wound-healing process. Glucose is the major source of fuel used to create the cellular ATP that provides energy for angiogenesis and deposition of the new tissues [rx]. The use of glucose as a source for ATP synthesis is essential in preventing the depletion of other amino acid and protein substrates [rx].
Protein – is one of the most important nutrient factors affecting wound healing. A deficiency of protein can impair capillary formation, fibroblast proliferation, proteoglycan synthesis, collagen synthesis, and wound remodeling. A deficiency of protein also affects the immune system, with resultant decreased leukocyte phagocytosis and increased susceptibility to infection [rx]. Collagen is the major protein component of connective tissue and is composed primarily of glycine, proline, and hydroxyproline. Collagen synthesis requires hydroxylation of lysine and proline, and co-factors such as ferrous iron and vitamin C. Impaired wound healing results from deficiencies in any of these co-factors [rx].
Arginine – is a semi-essential amino acid that is required during periods of maximal growth, severe stress, and injury. Arginine has many effects in the body, including modulation of immune function, wound healing, hormone secretion, vascular tone, and endothelial function. Arginine is also a precursor to proline, and, as such, sufficient arginine levels are needed to support collagen deposition, angiogenesis, and wound contraction [rx][rx]. Arginine improves immune function, and stimulates wound healing in healthy and ill individuals [rx]. Under psychological stress situations, the metabolic demand of arginine increases, and its supplementation has been shown to be an effective adjuvant therapy in wound healing [rx].
Glutamine – is the most abundant amino acid in plasma and is a major source of metabolic energy for rapidly proliferating cells such as fibroblasts, lymphocytes, epithelial cells, and macrophages [rx]. The serum concentration of glutamine is reduced after major surgery, trauma, and sepsis, and supplementation of this amino acid improves nitrogen balance and diminishes immunosuppression [rx]. Glutamine has a crucial role in stimulating the inflammatory immune response occurring early in wound healing [rx]. Oral glutamine supplementation has been shown to improve wound breaking strength and to increase levels of mature collagen [rx].
Fatty Acids – Lipids are used as nutritional support for surgical or critically ill patients to help meet energy demands and provide essential building blocks for wound healing and tissue repair. Polyunsaturated fatty acids (PUFAs), which cannot be synthesized de novo by mammals, consist mainly of two families, n-6 (omega-6, found in soybean oil) and n-3 (omega-3, found in fish oil). Fish oil has been widely touted for the health benefits of omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The effects of omega-3 fatty acids on wound healing are not conclusive. They have been reported to affect pro-inflammatory cytokine production, cell metabolism, gene expression, and angiogenesis in wound sites [rx] . The true benefit of omega-3 fatty acids may be in their ability to improve the systemic immune function of the host, thus reducing infectious complications and improving survival [rx].
Vitamins, Micronutrients, and Trace Elements – Vitamins C (L-ascorbic acid), A (retinol), and E (tocopherol) show potent anti-oxidant and anti-inflammatory effects. Vitamin C has many roles in wound healing, and a deficiency in this vitamin has multiple effects on tissue repair. Vitamin C deficiencies result in impaired healing, and have been linked to decreased collagen synthesis and fibroblast proliferation, decreased angiogenesis, and increased capillary fragility. Also, vitamin C deficiency leads to an impaired immune response and increased susceptibility to wound infection [rx;rx]. Similarly, vitamin A deficiency leads to impaired wound healing. The biological properties of vitamin A include anti-oxidant activity, increased fibroblast proliferation, modulation of cellular differentiation and proliferation, increased collagen and hyaluronate synthesis, and decreased MMP-mediated extracellular matrix degradation [rx].
Vitamin E, an anti-oxidant – maintains and stabilizes cellular membrane integrity by providing protection against destruction by oxidation. Vitamin E also has anti-inflammatory properties and has been suggested to have a role in decreasing excess scar formation in chronic wounds. Animal experiments have indicated that vitamin E supplementation is beneficial to wound healing [rx, rx; rx] and topical vitamin E has been widely promoted as an anti-scarring agent. However, clinical studies have not yet proved a role for topical vitamin E treatment in improving healing outcomes [rx,rx].
Several micronutrients – have been shown to be important for optimal repair. Magnesium functions as a co-factor for many enzymes involved in protein and collagen synthesis, while copper is a required co-factor for cytochrome oxidase, for cytosolic anti-oxidant superoxide dismutase, and for the optimal cross-linking of collagen. Zinc is a co-factor for both RNA and DNA polymerase, and a zinc deficiency causes a significant impairment in wound healing. Iron is required for the hydroxylation of proline and lysine, and, as a result, severe iron deficiency can result in impaired collagen production [rx,rx;rx, rx; rx].
Normal Wound-healing Process
Phase
Cellular and Bio-physiologic Events
Hemostasis
vascular constriction
platelet aggregation, degranulation, and fibrin formation (thrombus)
Inflammation
neutrophil infiltration
monocyte infiltration and differentiation to macrophage
lymphocyte infiltration
Proliferation
re-epithelialization
angiogenesis
collagen synthesis
ECM formation
Remodeling
collagen remodeling
vascular maturation and regression
Dressing
Some of the unique features of each are described below.
The following dressings may be used on chronic or acute wounds depending on the nature of the wound.
Low or nonadherent dressings – are inexpensive and allow wound exudate to pass through into a secondary dressing while helping to maintain a moist wound environment. These dressings are specially designed to reduce adherence to the wound bed. Non adherent dressings are made from open weave cloth soaked in paraffin, textiles, or multilayered or perforated plastic films. This type of dressing is suitable for flat, shallow wounds with low exudate such as a venous leg ulcer.
Hydrocolloid dressings – are composed of adhesive, absorbent, and elastomeric components. Carboxymethylcellulose is the most common absorptive ingredient. They are permeable to moisture vapor, but not to water. Additionally, they facilitate autolytic débridement, are self-adhesive, mold well, provide light-to-moderate exudate absorption, and can be left in place for several days, minimizing skin trauma and disruption of the healing process. They are intended for use on light-to-moderate exuding, acute or chronic partial- or full-thickness wounds but are not intended for use on infected wounds. Upon sustained contact with wound fluid, the hydrocolloid forms a gel.
Foam dressings – vary widely in composition and construction. They consist of a polymer, often polyurethane, with small, open cells that are able to hold fluids. Some varieties of foam dressings have a waterproof film covering the top surface and may or may not have an adhesive coating on the wound contact side or border. Foams are permeable to water and gas, and are able to absorb light to heavy exudate. This type of dressing is frequently used under compression stockings in patients with venous leg ulcers.
Film dressings consist of a single – thin transparent sheet of polyurethane coated on one side with an adhesive. The sheet is permeable to gases and water vapor but impermeable to wound fluids. Film dressings retain moisture, are impermeable to bacteria and other contaminants, allow wound observation, and do not require a secondary dressing. Excessive fluid buildup may break the adhesive seal and allow leakage. Film dressings are intended for superficial wounds with little exudate and are commonly used as a secondary dressing to attach a primary absorbent dressing. The dressing may remain in place for up to seven days if excessive fluid does not accumulate. Film dressings have been used extensively to treat split-thickness graft donor sites.
Alginate dressings – are made from calcium or calcium-sodium salts of natural polysaccharides derived from brown seaweed. When the alginate material comes into contact with sodium-rich wound exudates, an ion exchange takes place and produces a hydrophilic gel. This hydrophilic gel is capable of absorbing up to 20 times its weight and does not adhere to the wound. This dressing can remain in place for about seven days if enough exudate is present to prevent drying. This category of dressing is best suited for moist, moderate-to-heavy exuding wounds. Alginate dressings require a secondary dressing, such as a film dressing, to hold them in place and to prevent the alginate from drying out.
Hydrofiber dressing – is composed of sodium carboxymethylcellulose fibers.[rx] The fibers maintain a moist wound environment by absorbing large amounts of exudate and forming a gel. This dressing is not intended for lightly exuding wounds. A secondary dressing is required.
Hydrogel sheets – are three-dimensional networks of cross-linked hydrophilic polymers. Their high water content provides moisture to the wound, but these dressings can absorb small-to-large amounts of fluid, depending on their composition. Depending on wound exudate levels, hydrogels may require more frequent dressing changes, every 1–3 days, compared with other synthetic dressings. Hydrogel sheets can be used on most wound types but may not be effective on heavily exuding wounds. The gel may also contain additional ingredients such as collagens, alginate, or complex carbohydrates. Amorphous hydrogels can donate moisture to a dry wound with eschar and facilitate autolytic débridement in necrotic wounds. A second dressing may be used to retain the gel in shallow wounds.
Polymer-based dressing – Transforming methacrylate (TMD) was compared to carboxymethylcellulose (CMC-Ag) in one study of 34 patients. The study showed that TMD, compared to CMC-Ag, was associated with lower pain scores and better patient satisfaction, but the two dressings did not differ in terms of number of dressing changes and the time to complete healing.[rx] Suprathel (a polymer-based dressing) was evaluated in a study of 72 patients, and it was compared to a polyurethane dressings (Biatain-Ibu) and a silicone dressing (Mepitel). The three dressings had similar time to re-epithelialization, but Suprathel had a significantly lower number of dressing changes compared to the two other dressings.[rx]
Crystalline cellulose dressings – Results for the comparison between CMC-Ag and TMD are presented above.[rx] Veloderm was compared to Vaseline gauze in 96 patients.[rx] The study showed that Veloderm was associated with lower time to complete healing and number of dressing changes. The two dressings did not differ in terms of incidence of exudate, peri-lesional erythema or pain intensity.[rx]Rayon dressing was compared to Veloderm in a study of 14 patients and 28 skin graft donor sites.[rx] Rayon dressing showed lower dressing adherence to wound and lower 1st day pain score; the two dressings did not differ in terms of pain beyond day 14, hyperemia, edema and pruritus.[rx]
Alginate dressings – The study evaluated the dressing materials in terms of time to healing, pain scores, clinical infections and hypergranulation. Results showed that the six types of dressings did not differ with statistical significance except in the following cases: first, the semi-permeable films (Tegaderm or Opsite) were associated with lower pain scores than any other dressing type; second, the hydrocolloid dressing (DuoDerm E) required lower time (seven days difference) to healing than all other dressings; finally, the gauze dressings (Adaptic or Jelonet) were associated with the highest incidence of clinical infections.[rx]
Alginate-based dressings – were also evaluated in three other trials; the first one compared Algisite to a keratin dressing (Keramatrix).[rx]The trial showed that Algisite was associated with higher rate of epithelialization seven days after the operation than Keramatrix in patients older than 50 years; for younger patients, the rate of epithelialization did not significantly differ.[rx] Ding et al. compared time to healing and pain scores between alginate-silver dressing and hydrofiber dressing (Aquacel-A) in 10 patients and 20 donor sites; the results showed that the alginate dressing was associated with shorter time to healing and lower pain scores.[rx]The third trial compared Algisite covered by a polyurethane dressing (Opsite) to paraffin gauze dressing; the results showed that the two dressings did not differ in terms of pain scores, time to epithelialization and the assessment of general comfort. Algisite dressings required more dressing changes (34 times) than the paraffin gauze (4 times).[rx]
Polyurethane dressings – Opsite and Tegaderm films were evaluated in Brolemann’s study, and the results were presented above. Another trial compared the Opsite dressing to a hydrofiber dressing (Aquacel-A); the results showed that Opsite was associated with lower scores of pain.[rx] The Biatain-Ibu dressing was compared to Suprathel (polymer dressing) and Mepitel (silicone dressing); the results were presented above with polymer-based dressings.[rx] Another study compared Biatain-Ibu to a gauze dressing (Jelonet), and it was reported that Biatain-Ibu was associated with lower pain and itching than Jelonet; however, the study did not report any statistical testing for the differences between interventions.[rx]
Gauze dressings – Gauze dressings were evaluated in seven trials; the results of four trials were reported earlier in this section,[rx,rx,rx,rx]and the remaining three trials were as follows one trial compared Xeroform (gauze dressing) to a multilayer dressing and showed that Xeroform was associated with longer healing time and higher pain scores than Oxyband.[rx]The second trial compared paraffin gauze to a hydrofiber dressing (Aquacel) and reported that the paraffin gauze was associated with longer re-epithelialization time and higher pain score during dressing.[rx]The last trial compared Jelonet to a multilayer dressing as a dressing over a skin graft (receiver site); the results showed that the two dressings did not affect the time to graft take, number of nursing interventions, or post-operative infections; however, they showed that Jelonet was associated with higher pain score at the time of dressing removal.[rx]
Hydrocolloid dressings – The efficacy of DuoDerm E was compared to six other dressing materials in Brolmann’s trial; the results of this trial were presented earlier in this section.[rx]In another trial, DuoDerm was compared to a silicone-based dressing (AWBAT-D); the trial showed that the two dressings did not differ in terms of pain scores, wound size or time to discharge, but the DuoDerm was associated with shorter time to re-epithelialization.[rx]
Hydrofiber dressings – The efficacy of Aquacel was studied in six trials; the results of four trials were presented earlier in the section.[rx,rx,rx,rx]One of the remaining trials compared Aquacel to carbohydrate wound dressing (Glucan II), and it showed that the two interventions did not differ in terms of time to re-epithelialization, pain scores, or donor site infection.[rx]The second trial compared two different protocols of using Aquacel; in the first protocol, Aquacel dressing was covered with gauze, while in the second one, it was covered with polyurethane film (OpSite).[rx] The trial reported that the second protocol was associated with a larger number of donor sites healing at day 14 after surgery (88% versus 67%), and it was associated with lower pain during mobility the first day after operation; the two dressings did not differ in pain scores during rest at all time-point evaluations.[rx]
Silicone dressings – Four trials evaluated the efficacy of silicone-based dressings; the result three of trials were presented earlier in this section.[rx,rx,rx] The fourth trial compared Mepitel dressing to a nylon dressing (Bridal veil) when used over a skin graft (receiver site).[rx] The results of this trial showed that Mepitel dressing was associated with less pain, easier use, and better overall experience for patients.[rx]
Keratin dressings – The efficacy of Keranatrix was evaluated in one study the results of which were presented earlier in this section.[rx]
Self-adhesive fabric dressing (Mefix) with or without fibrin sealant – One trial evaluated the difference between using Mefix alone or with a fibrin sealant; the trial showed that the use of fibrin sealant was associated with lower daily pain and incapacity scores, but it did not affect the time to dressing removal or the time to discharge for the hospital.[rx]
Multilayer (combination) dressings – The efficacy of Oxyband and Allyven was evaluated in two studies the results of which were presented earlier in this section.[rx,rx]
Nylon dressings – The efficacy of Bridal veil was evaluated in one study the results of which were presented earlier in this section.[rx]
Carbohydrate wound dressings – The efficacy of Glucan dressing was evaluated in one study the results of which were presented earlier in this section.[rx]
Negative pressure dressings – One trial compared negative pressure dressings with a conventional dressing with gauze; both dressings were used over skin grafts (receiver sites).[rx]The trial reported that the negative pressure dressing was associated with a higher percentage of graft take and shorter duration of dressing.[rx]
Complication of Wound Healing
Factors that can slow the wound healing process include
Dead skin (necrosis) – dead skin and foreign materials interfere with the healing process.
Infection – an open wound may develop a bacterial infection. The body fights the infection rather than healing the wound.
Haemorrhage – persistent bleeding will keep the wound margins apart.
Mechanical damage – for example, a person who is immobile is at risk of bedsores because of constant pressure and friction.
Diet – poor food choices may deprive the body of the nutrients it needs to heal the wound, such as vitamin C, zinc and protein.
Medical conditions – such as diabetes, anaemia and some vascular diseases that restrict blood flow to the area, or any disorder that hinders the immune system.
Age – wounds tend to take longer to heal in elderly people.
Medicines – certain drugs or treatments used in the management of some medical conditions may interfere with the body’s healing process.
Smoking – cigarette smoking impairs healing and increases the risk of complications.
Varicose veins – restricted blood flow and swelling can lead to skin break down and persistent ulceration.
Dryness – wounds (such as leg ulcers) that are exposed to the air are less likely to heal. The various cells involved in healing, such as skin cells and immune cells, need a moist environment.
Puncture Wounds/Wounds are defined as a disruption of the normal structure and function of skin and underlying soft tissue that is caused by trauma or chronic mechanical stress (e.g., decubitus ulcers). Wounds can be broken down into acute or chronic, and open or closed. Wound treatment is performed according to pathology, the extent, and circumstances of the lesions. To heal, the wound needs to have a vascular supply, be free of necrotic tissue, clear of infection, and moist. General wound treatment includes surgical wound closure, open wound treatment, and plastic reconstruction of skin defects. In addition, infectious or concomitant disease prevention should be considered (e.g., antibiotic therapy, vaccines for tetanus and rabies, diabetes control).
A wound is damaged or disruption to the skin and, before treatment, the exact cause, location, and type of wound must be assessed to provide appropriate treatment.[rx][rx][rx] Each clinician will have widely differing and distinct opinions and understanding of wound care depending on their prior experience. The reason for this because of the widely differing and distinct types of wounds, each with their etiology. An ostomy nurse will have a completely different approach to wound care that will require an orthopedic surgeon who deals with trauma and both will be far different from a dermatologist who treats burn victims. Nevertheless, each of these healthcare providers is performing wound care. How do professionals then approach wound assessment when the causes are so diverse? Below are some basic questions to ask during a wound assessment to best classify and treat a wound presenting in a clinical setting.
Normal Healthy Skin of Wounds
As the interface between the environment and body, the skin has several distinct functions. It protects the underlying tissues from abrasions, the entry of microbes, unwanted water loss, and ultraviolet light damage. Tactile sensations of touch, pressure, and vibration, thermal sensations of heat and cold, and pain sensations all originate in the skin’s nervous system. The body’s thermoregulation relies on the skin’s ability to sweat and to control the flow of blood to the skin to increase or decrease heat loss. The skin’s functions are performed by three distinct tissue layers: a thin outer layer of cells called the epidermis, a thicker middle layer of connective tissue called the dermis, and an inner, subcutaneous layer. The outer layers of the epidermis are composed of flattened, cornified dead keratinocytes that form a barrier to water loss and microbe entry. These cells are derived from a basal layer of constantly dividing keratinocytes that lies next to the dermis. The epidermis does not contain nerves or blood vessels and obtains water and nutrients through diffusion from the dermis. The dermis is composed mostly of collagen fibers and some elastic fibers both produced by fibroblasts and, along with water and large proteoglycan molecules, makes up the extracellular matrix. This layer of the skin provides mechanical strength and a substrate for water and nutrient diffusion; it contains blood vessels, nerves, and cells involved in immune function, growth, and repair. The dermis also contains sweat glands, oil glands, and hair follicles. The subcutaneous layer is composed of adipocytes that form a thick layer of adipose tissue.[rx]
Types of Wounds
Each of the potential underlying causes must be addressed for the wound to heal. Before determining the underlying cause, it is important to determine what type of wound the patient has. These subclassifications can be acute or chronic.[rx][rx][rx]
1. According to the severity, a wound can be classified as
Acute
Clinicians assess acute wounds by the method of injury and damage to the soft tissues and bony structures. In crush or high impact injuries, there is an area of demarcation which is not fully recognized until sometimes as much as a week or 2 later. For this reason, it is important to determine the method of injury and to keep in mind that the wound seen is not necessarily the entirety of the wound which will be present in a week. In these cases, the patient and their family should be educated on this progression to prevent frustration and misunderstanding.
For all acute types of wounds, it is important to determine the length of time since injury (days or hours), the involvement of neurovascular supply, muscle, tendon, ligament, and bony involvement, and the likelihood of contaminants in the wound. Also of importance is when the patient had their last tetanus shot. CLinicians should start antibiotics if the wound is severely contaminated or if it is longer than 3 hours since the injury. All underlying tissue should be repaired if possible, and the wound should be irrigated to remove contaminants and bacteria.
In cases of open fracture the most used classification is Gustillo-Anderson
Type 1 – Clean wound, less than one cm with minimal soft tissue damage, adequate soft tissue coverage of bone, and no periosteal stripping
Type 2 – Wound with moderate contamination, greater than one cm with moderate soft tissue damage, adequate soft tissue coverage of bone, and no periosteal stripping
Type 3A – Wound with significant contamination, with significant soft tissue damage, adequate soft tissue coverage of bone, and periosteal stripping is present
Type 3B – Wound with significant contamination, with significant soft tissue damage, unable to cover bone with soft tissue (requiring graft), and periosteal stripping
Type 3C – Similar to type A or B, however with Arterial damage requiring repair
Chronic
If a wound becomes arrested in progression through the normal stages of inflammation and wound healing and remains open, then this becomes a chronic wound. While there is no consensus as to when a wound becomes chronic, a study by Sheehan et. al determined that in diabetic wounds, the degree of healing at 4 weeks is a strong predictor of 12 week healing, suggesting that those wounds which have not healed approximately 50% in 4 weeks are likely to have an arrested healing process, and therefore are chronic.[rx][rx]
In the chronic setting, the main goal is to identify why the wound is not healing and to fix this obstacle or obstacles.
There are a limited number of reasons a wound becomes chronic; however, once these reasons are rectified, the wound resumes its natural course of healing.
Arterial – Is there enough blood flow? Generally speaking, an ABI of less than 50 mm Hg, or an absolute toe pressure less than 30 mm Hg (or less than 50 mm Hg for persons with diabetes) indicates critical limb ischemia and predicts failure of wounds to heal.
Venous – Pressure-induced changes in blood vessel wall permeability then lead to leakage of fibrin and other plasma components into the perivascular space. Accumulation of fibrin has direct and negative effects on wound healing as it down-regulates collagen synthesis.
Infection – Underlying infectious processes including cellulitic and osteomyelitis processes will inhibit wound healing. Culturing for aerobic, anaerobic, and fungal pathogens is recommended.
Pressure – Increased pressure to the area of concern will destroy new tissue growth and prevent proper perfusion of blood to the wound site. These areas need to be offloaded to avoid pressure in the area.
Oncologic – Always biopsy areas of concern in nonhealing wounds, as this can be an atypical presentation of some types of malignancies.
Systemic – There are multiple systemic diseases which inhibit wound healing, with diabetes being the most common culprit. It has been determined that uncontrolled blood glucose levels suppresses the body’s normal inflammatory response, as well as causing microvascular disease which limits healing.
Nutrition – While serum albumin has not been found to be a good predictor of wound healing, there is some evidence that protein malnutrition, as well as insufficient levels of certain vitamins and minerals, will limit the body’s ability to heal chronic wounds.
Pharmacological – Hydroxyurea has been reported in multiple instances to cause nonhealing ulcerations.
Self-inflicted/psychosocial – There are instances where a patient is causing the ulceration, either on purpose or as a result of noncompliance. This is often the hardest factor to spot and overcome, but must always be a consideration.
2. According to level of contamination, a wound can be classified as
Clean wound – made under sterile conditions where there are no organisms present, and the skin is likely to heal without complications.
Contaminated wound – usually resulting from accidental injury; there are pathogenic organisms and foreign bodies in the wound.
Infected wound – the wound has pathogenic organisms present and multiplying, exhibiting clinical signs of infection (yellow appearance, soreness, redness, oozing pus).
Colonized wound – a chronic situation, containing pathogenic organisms, difficult to heal (i.e. bedsore).
Open
Open wounds can be classified according to the object that caused the wound
Incisions or incised wounds – caused by a clean, sharp-edged object such as a knife, razor, or glass splinter.
Lacerations – irregular tear-like wounds caused by some blunt trauma. Lacerations and incisions may appear linear (regular) or stellate (irregular). The term laceration is commonly misused in reference to incisions.[rx]
Abrasions (grazes) – superficial wounds in which the topmost layer of the skin (the epidermis) is scraped off. Abrasions are often caused by a sliding fall onto a rough surface such as asphalt, tree bark or concrete.
Avulsions – injuries in which a body structure is forcibly detached from its normal point of insertion. A type of amputation where the extremity is pulled off rather than cut off. When used in reference to skin avulsions, the term ‘degloving’ is also sometimes used as a synonym.
Puncture wounds – caused by an object puncturing the skin, such as a splinter, nail or needle.
Penetration wounds – caused by an object such as a knife entering and coming out from the skin.
Gunshot wounds – caused by a bullet or similar projectile driving into or through the body. There may be two wounds, one at the site of entry and one at the site of exit, generally referred to as a “through-and-through.”
Closed
Closed wounds have fewer categories, but are just as dangerous as open wounds:
Hematomas (or blood tumor) – caused by damage to a blood vessel that in turn causes blood to collect under the skin.
Hematomas that originate from internal blood vessel pathology are petechiae, purpura, and ecchymosis. The different classifications are based on size.
Hematomas that originate from an external source of trauma are contusions, also commonly called bruises.
Crush injury – caused by a great or extreme amount of force applied over a long period of time.
3. According to the Visuality, a wound can be classified as
Internal Wounds
Disturbance of the different regulating systems of the human body can lead to wound formation, and may include the following:
Impaired circulation – This can be from either ischemia or stasis. Ischemia is the result of reduced blood supply caused by the narrowing or blockage of blood vessels, which leads to poor circulation. Stasis is caused by immobilization (or difficulty moving) for long periods or failure of the regulating valves in the veins, which leads to blood pooling and failing to flow normally to the heart.
Neuropathy – This is seen mostly in cases of prolonged uncontrolled diabetes mellitus, where high blood sugars, derivative proteins and metabolites accumulate and damage the nervous system. The patients are usually unaware of any trauma or wounds, mainly due to loss of sensation in the affected area.
Medical illness – When chronic and uncontrolled for long periods (such as hypertension, hyperlipidemia, arthrosclerosis, diabetes mellitus, AIDS, malignancy, morbid obesity, hepatitis C virus, etc.), medical illnesses can lead to impairment of the immune system functions, diminishing the circulation and damaging other organs and systems.
External Wounds
External wounds can either be open or closed. In cases of closed wounds, the skin is intact and the underlying tissue is affected but not directly exposed to the outside environment. The following are the most common types of closed wounds:
Contusions – These are a common type of sports injury, where a direct blunt trauma can damage the small blood vessels and capillaries, muscles and underlying tissue, as well the internal organs or bone. Contusions present as a painful bruise with reddish to bluish discoloration that spreads over the injured area of skin.
Hematomas – These include any injury that damages the small blood vessels and capillaries resulting in blood collecting and pooling in a limited space. Hematomas typically present as a painful, spongy rubbery lump-like lesion. Depending on the severity and site of the trauama, hematomas can be small or large, deep inside the body or just under the skin.
Crush injuries – These are usually caused by an external high-pressure force that squeezes part of the body between two surfaces. The degree of injury can range from a minor bruise to a complete destruction of the crushed area of the body, depending on the site, size, duration and power of the trauma.
Causes of Wound
Sudden forceful fall down
Road traffic accident
Burn and injured suddenly
Falls – Falling onto an outstretched hand is one of the most common causes of wound.
Sports injuries – Many sports injury occur during contact sports or sports in which you might fall onto an outstretched hand — such as in-line skating or snowboarding.
Motor vehicle crashes – Motor vehicle crashes can cause wound. Sometimes into many pieces, and often require surgical repair.
Have osteoporosis – a disease that weakens your bones.
Eave low muscle mass or poor muscle strength – or lack agility and have poor balance (these conditions make you more likely to fall)
Walk or do other activities in snow or on the ice – or do activities that require a lot of forwarding momenta, such as in-line skating and skiing
Wave an inadequate intake of calcium or vitamin D
Football or soccer, especially on artificial turf
Rugby
Horseback riding
Hockey
Skiing
Snowboarding
In-line skating
Jumping on a trampoline
Symptoms of Wound
General signs and symptoms of a wound infection include
Increased firmness of skin or swelling around the wound bed
Increasing drainage from the wound bed
Delayed wound healing
Discoloration of the wound bed with it turning darker in color
Foul odor
Increased fragility of the wound bed
Wound breakdown /enlargement
The skin may harden or tighten in the area and red streaks may radiate from the wound. Wound infections may also cause fevers, especially when they spread to the blood.
Diagnosis of Wound
Clinicians perform wound assessment as a means for determining the appropriate treatment for an extremely diverse grouping of disease processes. Just as hypertension is not treated the same as diabetes, each of the underlying etiologies of the given wound must be identified and treated as if it were its own disease, not a blanket classification of “wound.”[rx][rx]
The initial assessment should begin with the following:
How – How was the wound created and, if chronic, why is it still open? (underlying etiology)
Where – Where on the body is it located? Is it in an area which is difficult to offload, or to keep clean? Is it in an area of high skin tension? Is it near any vital structures such as a major artery?
When – How long has this wound been present? (eg., chronic or acute)
What – What anatomy does it extend? (e.g., epidermis, dermis, subcutaneous tissue, fascia, muscle, tendon, bone, arteries, nerves)
What – What co-morbidities or social factors does the patient have which might affect which might affect their ability to heal the wound?
Is it life threatening?
All of these factors significantly affect the treatment plan moving forward. While there are many excellent biologics, skin grafts, and other options available, without the appropriate understanding of the nature of the wound the chances of healing decline significantly.
Issues of Concern
While some wounds are simple, the majority of wounds many clinicians encounter are caused by or complicated by some other issue.[rx][rx][rx][rx] These are a few of the possible complications from different wound types:
A chronic wound will have a different makeup than that of an acute wound, requiring conversion for healing.
An underlying infection will prevent wound healing even if the infection is subacute.
A damaged or constricted arterial supply will prevent appropriate blood flow to the wound.
A damaged venous supply will cause venous stasis.
Physical pressure on chronic ulceration will cause repeated damage, preventing healing.
Tests
Many minor and superficial skin and wound infections are diagnosed by a healthcare practitioner based on a physical examination, sign and symptoms, and experience. A clinical evaluation cannot, however, definitively tell the healthcare practitioner which microbe is causing a wound infection or what treatment is likely to be effective. For that, laboratory testing is required.
Laboratory Tests
Examples of common tests include
Bacterial culture – This is the primary test used to diagnose a bacterial infection. Results are usually available within 24-48 hours.
Gram stain – This is usually performed in conjunction with the wound culture. It is a special staining procedure that allows bacteria to be evaluated under the microscope. The results are usually available the same day and provide preliminary information about the microbe that may be causing the infection.
Antimicrobial susceptibility – A follow-up test to a positive wound culture, this is used to determine the bacteria’s likely susceptibility to certain drugs and helps the healthcare practitioner select appropriate antibiotics for treatment. Results are typically available in about 24 hours. This testing can identify resistant bacteria such as MRSA.
Other tests may include
KOH prep – This is a rapid test performed to detect fungi in a sample. The sample is treated with a special solution, placed on a slide, and examined under a microscope.
Fungal culture – This is ordered when a fungal infection is suspected. Many fungi are slow-growing and may take several weeks to identify.
AFB testing – This is ordered when a mycobacterial infection is suspected. Most AFB are slow-growing and may take several weeks to identify.
Blood culture – This is ordered when infection from a wound may have spread to the blood.
Molecular testing – to detect genetic material of a specific microbe
Basic metabolic panel (BMP) or Comprehensive metabolic panel (CMP) – This may be ordered to detect underlying conditions that can affect wound healing, such as a glucose test to detect diabetes.
Complete blood count (CBC) – An elevated white blood cell (WBC) count may be a sign of infection.
Treatment of Wound
Emergency Management
Pain control
Intravenous opiates are often used as patients typically in severe pain
Highly effective for management of pain
Lower side effect profile than systemic analgesia
Always calculate your toxic dose of local anesthetic to avoid local anesthetic systemic toxicity
Closed the wounds should be placed in long leg splint and can also be placed in traction
If open Fractures should receive antibiotics and should proceed to OR for irrigation/debridement.
Cleaning to remove dirt and debris from a fresh wound. This is done very gently and often in the shower.
Vaccinating for tetanus may be recommended in some cases of traumatic injury.
Exploring a deep wound surgically may be necessary. Local anaesthetic will be given before the examination.
Removing dead skin surgically. Local anaesthetic will be given.
Closing large wounds with stitches or staples.
Dressing the wound – The dressing chosen by your doctor depends on the type and severity of the wound. In most cases of chronic wounds, the doctor will recommend a moist dressing.
Relieving pain with medications – Pain can cause the blood vessels to constrict, which slows healing. If your wound is causing discomfort, tell your doctor. The doctor may suggest that you take over-the-counter drugs such as paracetamol or may prescribe stronger pain-killing medication.
Treating signs of infection including pain – pus and fever. The doctor will prescribe antibiotics and antimicrobial dressings if necessary. Take as directed.
Skin Traction (Hare or Thomas) if needed
May improve wound alignment, blood flow, and pain
Skin traction splint can cause complications if a patient with a significant injury (i.e. multi ligamentous knee injury)
Here we review only the commonly used medications that have a significant impact on healing, including glucocorticoid steroids, non-steroidal anti-inflammatory drugs, and chemotherapeutic drugs.
Glucocorticoid Steroids – Systemic glucocorticoids (GC), which are frequently used as anti-inflammatory agents, are well-known to inhibit wound repair via global anti-inflammatory effects and suppression of cellular wound responses, including fibroblast proliferation and collagen synthesis. Systemic steroids cause wounds to heal with incomplete granulation tissue and reduced wound contraction [rx]. Glucocorticoids also inhibit production of hypoxia-inducible factor-1 (HIF-1), a key transcriptional factor in healing wounds [rx].
Non-steroidal Anti-inflammatory Drugs – Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen are widely used for the treatment of inflammation and rheumatoid arthritis and for pain management. Low-dosage aspirin, due to its anti-platelet function, is commonly used as a preventive therapeutic for cardiovascular disease, but not as an anti-inflammatory drug [rx]. There are few data to suggest that short-term NSAIDs have a negative impact on healing.
Opioids – Also known as narcotics, these medications are intense pain relievers that should only be used under a doctor’s careful supervision.
Topical Medications – These prescription-strength creams, gels, ointments, patches, and sprays help relieve pain and inflammation through the skin.
Calcium & vitamin D3 – To improve bones health and healing fracture. As a general rule, men and women age 50 and older should consume 1,200 milligrams of calcium a day, and 600 international units of vitamin D a day.
Glucosamine & Diacerein, Chondroitin sulfate – can be used to tightening the loose tendon, cartilage, ligament, and cartilage, ligament regenerates cartilage or inhabits the further degeneration of cartilage, ligament.
Chemotherapeutic Drugs – Most chemotherapeutic drugs are designed to inhibit cellular metabolism, rapid cell division, and angiogenesis and thus inhibit many of the pathways that are critical to appropriate wound repair. These medications inhibit DNA, RNA, or protein synthesis, resulting in decreased fibroplasia and neovascularization of wounds [rx].
Nutrition – For more than 100 years, nutrition has been recognized as a very important factor that affects wound healing. Most obvious is that malnutrition or specific nutrient deficiencies can have a profound impact on wound healing after trauma and surgery. Patients with chronic or non-healing wounds and experiencing nutrition deficiency often require special nutrients. Energy, carbohydrate, protein, fat, vitamin, and mineral metabolism all can affect the healing process [rx].
Carbohydrates, Protein, and Amino Acids – Together with fats, carbohydrates are the primary source of energy in the wound-healing process. Glucose is the major source of fuel used to create the cellular ATP that provides energy for angiogenesis and deposition of the new tissues [rx]. The use of glucose as a source for ATP synthesis is essential in preventing the depletion of other amino acid and protein substrates [rx].
Protein – is one of the most important nutrient factors affecting wound healing. A deficiency of protein can impair capillary formation, fibroblast proliferation, proteoglycan synthesis, collagen synthesis, and wound remodeling. A deficiency of protein also affects the immune system, with resultant decreased leukocyte phagocytosis and increased susceptibility to infection [rx]. Collagen is the major protein component of connective tissue and is composed primarily of glycine, proline, and hydroxyproline. Collagen synthesis requires hydroxylation of lysine and proline, and co-factors such as ferrous iron and vitamin C. Impaired wound healing results from deficiencies in any of these co-factors [rx].
Arginine – is a semi-essential amino acid that is required during periods of maximal growth, severe stress, and injury. Arginine has many effects in the body, including modulation of immune function, wound healing, hormone secretion, vascular tone, and endothelial function. Arginine is also a precursor to proline, and, as such, sufficient arginine levels are needed to support collagen deposition, angiogenesis, and wound contraction [rx][rx]. Arginine improves immune function, and stimulates wound healing in healthy and ill individuals [rx]. Under psychological stress situations, the metabolic demand of arginine increases, and its supplementation has been shown to be an effective adjuvant therapy in wound healing [rx].
Glutamine – is the most abundant amino acid in plasma and is a major source of metabolic energy for rapidly proliferating cells such as fibroblasts, lymphocytes, epithelial cells, and macrophages [rx]. The serum concentration of glutamine is reduced after major surgery, trauma, and sepsis, and supplementation of this amino acid improves nitrogen balance and diminishes immunosuppression [rx]. Glutamine has a crucial role in stimulating the inflammatory immune response occurring early in wound healing [rx]. Oral glutamine supplementation has been shown to improve wound breaking strength and to increase levels of mature collagen [rx].
Fatty Acids – Lipids are used as nutritional support for surgical or critically ill patients to help meet energy demands and provide essential building blocks for wound healing and tissue repair. Polyunsaturated fatty acids (PUFAs), which cannot be synthesized de novo by mammals, consist mainly of two families, n-6 (omega-6, found in soybean oil) and n-3 (omega-3, found in fish oil). Fish oil has been widely touted for the health benefits of omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The effects of omega-3 fatty acids on wound healing are not conclusive. They have been reported to affect pro-inflammatory cytokine production, cell metabolism, gene expression, and angiogenesis in wound sites [rx] . The true benefit of omega-3 fatty acids may be in their ability to improve the systemic immune function of the host, thus reducing infectious complications and improving survival [rx].
Vitamins, Micronutrients, and Trace Elements – Vitamins C (L-ascorbic acid), A (retinol), and E (tocopherol) show potent anti-oxidant and anti-inflammatory effects. Vitamin C has many roles in wound healing, and a deficiency in this vitamin has multiple effects on tissue repair. Vitamin C deficiencies result in impaired healing, and have been linked to decreased collagen synthesis and fibroblast proliferation, decreased angiogenesis, and increased capillary fragility. Also, vitamin C deficiency leads to an impaired immune response and increased susceptibility to wound infection [rx;rx]. Similarly, vitamin A deficiency leads to impaired wound healing. The biological properties of vitamin A include anti-oxidant activity, increased fibroblast proliferation, modulation of cellular differentiation and proliferation, increased collagen and hyaluronate synthesis, and decreased MMP-mediated extracellular matrix degradation [rx].
Vitamin E, an anti-oxidant – maintains and stabilizes cellular membrane integrity by providing protection against destruction by oxidation. Vitamin E also has anti-inflammatory properties and has been suggested to have a role in decreasing excess scar formation in chronic wounds. Animal experiments have indicated that vitamin E supplementation is beneficial to wound healing [rx, rx; rx] and topical vitamin E has been widely promoted as an anti-scarring agent. However, clinical studies have not yet proved a role for topical vitamin E treatment in improving healing outcomes [rx,rx].
Several micronutrients – have been shown to be important for optimal repair. Magnesium functions as a co-factor for many enzymes involved in protein and collagen synthesis, while copper is a required co-factor for cytochrome oxidase, for cytosolic anti-oxidant superoxide dismutase, and for the optimal cross-linking of collagen. Zinc is a co-factor for both RNA and DNA polymerase, and a zinc deficiency causes a significant impairment in wound healing. Iron is required for the hydroxylation of proline and lysine, and, as a result, severe iron deficiency can result in impaired collagen production [rx,rx;rx, rx; rx].
Normal Wound-healing Process
Phase
Cellular and Bio-physiologic Events
Hemostasis
vascular constriction
platelet aggregation, degranulation, and fibrin formation (thrombus)
Inflammation
neutrophil infiltration
monocyte infiltration and differentiation to macrophage
lymphocyte infiltration
Proliferation
re-epithelialization
angiogenesis
collagen synthesis
ECM formation
Remodeling
collagen remodeling
vascular maturation and regression
Dressing
Some of the unique features of each are described below.
The following dressings may be used on chronic or acute wounds depending on the nature of the wound.
Low or nonadherent dressings – are inexpensive and allow wound exudate to pass through into a secondary dressing while helping to maintain a moist wound environment. These dressings are specially designed to reduce adherence to the wound bed. Non adherent dressings are made from open weave cloth soaked in paraffin, textiles, or multilayered or perforated plastic films. This type of dressing is suitable for flat, shallow wounds with low exudate such as a venous leg ulcer.
Hydrocolloid dressings – are composed of adhesive, absorbent, and elastomeric components. Carboxymethylcellulose is the most common absorptive ingredient. They are permeable to moisture vapor, but not to water. Additionally, they facilitate autolytic débridement, are self-adhesive, mold well, provide light-to-moderate exudate absorption, and can be left in place for several days, minimizing skin trauma and disruption of the healing process. They are intended for use on light-to-moderate exuding, acute or chronic partial- or full-thickness wounds but are not intended for use on infected wounds. Upon sustained contact with wound fluid, the hydrocolloid forms a gel.
Foam dressings – vary widely in composition and construction. They consist of a polymer, often polyurethane, with small, open cells that are able to hold fluids. Some varieties of foam dressings have a waterproof film covering the top surface and may or may not have an adhesive coating on the wound contact side or border. Foams are permeable to water and gas, and are able to absorb light to heavy exudate. This type of dressing is frequently used under compression stockings in patients with venous leg ulcers.
Film dressings consist of a single – thin transparent sheet of polyurethane coated on one side with an adhesive. The sheet is permeable to gases and water vapor but impermeable to wound fluids. Film dressings retain moisture, are impermeable to bacteria and other contaminants, allow wound observation, and do not require a secondary dressing. Excessive fluid buildup may break the adhesive seal and allow leakage. Film dressings are intended for superficial wounds with little exudate and are commonly used as a secondary dressing to attach a primary absorbent dressing. The dressing may remain in place for up to seven days if excessive fluid does not accumulate. Film dressings have been used extensively to treat split-thickness graft donor sites.
Alginate dressings – are made from calcium or calcium-sodium salts of natural polysaccharides derived from brown seaweed. When the alginate material comes into contact with sodium-rich wound exudates, an ion exchange takes place and produces a hydrophilic gel. This hydrophilic gel is capable of absorbing up to 20 times its weight and does not adhere to the wound. This dressing can remain in place for about seven days if enough exudate is present to prevent drying. This category of dressing is best suited for moist, moderate-to-heavy exuding wounds. Alginate dressings require a secondary dressing, such as a film dressing, to hold them in place and to prevent the alginate from drying out.
Hydrofiber dressing – is composed of sodium carboxymethylcellulose fibers.[rx] The fibers maintain a moist wound environment by absorbing large amounts of exudate and forming a gel. This dressing is not intended for lightly exuding wounds. A secondary dressing is required.
Hydrogel sheets – are three-dimensional networks of cross-linked hydrophilic polymers. Their high water content provides moisture to the wound, but these dressings can absorb small-to-large amounts of fluid, depending on their composition. Depending on wound exudate levels, hydrogels may require more frequent dressing changes, every 1–3 days, compared with other synthetic dressings. Hydrogel sheets can be used on most wound types but may not be effective on heavily exuding wounds. The gel may also contain additional ingredients such as collagens, alginate, or complex carbohydrates. Amorphous hydrogels can donate moisture to a dry wound with eschar and facilitate autolytic débridement in necrotic wounds. A second dressing may be used to retain the gel in shallow wounds.
Polymer-based dressing – Transforming methacrylate (TMD) was compared to carboxymethylcellulose (CMC-Ag) in one study of 34 patients. The study showed that TMD, compared to CMC-Ag, was associated with lower pain scores and better patient satisfaction, but the two dressings did not differ in terms of number of dressing changes and the time to complete healing.[rx] Suprathel (a polymer-based dressing) was evaluated in a study of 72 patients, and it was compared to a polyurethane dressings (Biatain-Ibu) and a silicone dressing (Mepitel). The three dressings had similar time to re-epithelialization, but Suprathel had a significantly lower number of dressing changes compared to the two other dressings.[rx]
Crystalline cellulose dressings – Results for the comparison between CMC-Ag and TMD are presented above.[rx] Veloderm was compared to Vaseline gauze in 96 patients.[rx] The study showed that Veloderm was associated with lower time to complete healing and number of dressing changes. The two dressings did not differ in terms of incidence of exudate, peri-lesional erythema or pain intensity.[rx]Rayon dressing was compared to Veloderm in a study of 14 patients and 28 skin graft donor sites.[rx] Rayon dressing showed lower dressing adherence to wound and lower 1st day pain score; the two dressings did not differ in terms of pain beyond day 14, hyperemia, edema and pruritus.[rx]
Alginate dressings – The study evaluated the dressing materials in terms of time to healing, pain scores, clinical infections and hypergranulation. Results showed that the six types of dressings did not differ with statistical significance except in the following cases: first, the semi-permeable films (Tegaderm or Opsite) were associated with lower pain scores than any other dressing type; second, the hydrocolloid dressing (DuoDerm E) required lower time (seven days difference) to healing than all other dressings; finally, the gauze dressings (Adaptic or Jelonet) were associated with the highest incidence of clinical infections.[rx]
Alginate-based dressings – were also evaluated in three other trials; the first one compared Algisite to a keratin dressing (Keramatrix).[rx]The trial showed that Algisite was associated with higher rate of epithelialization seven days after the operation than Keramatrix in patients older than 50 years; for younger patients, the rate of epithelialization did not significantly differ.[rx] Ding et al. compared time to healing and pain scores between alginate-silver dressing and hydrofiber dressing (Aquacel-A) in 10 patients and 20 donor sites; the results showed that the alginate dressing was associated with shorter time to healing and lower pain scores.[rx]The third trial compared Algisite covered by a polyurethane dressing (Opsite) to paraffin gauze dressing; the results showed that the two dressings did not differ in terms of pain scores, time to epithelialization and the assessment of general comfort. Algisite dressings required more dressing changes (34 times) than the paraffin gauze (4 times).[rx]
Polyurethane dressings – Opsite and Tegaderm films were evaluated in Brolemann’s study, and the results were presented above. Another trial compared the Opsite dressing to a hydrofiber dressing (Aquacel-A); the results showed that Opsite was associated with lower scores of pain.[rx] The Biatain-Ibu dressing was compared to Suprathel (polymer dressing) and Mepitel (silicone dressing); the results were presented above with polymer-based dressings.[rx] Another study compared Biatain-Ibu to a gauze dressing (Jelonet), and it was reported that Biatain-Ibu was associated with lower pain and itching than Jelonet; however, the study did not report any statistical testing for the differences between interventions.[rx]
Gauze dressings – Gauze dressings were evaluated in seven trials; the results of four trials were reported earlier in this section,[rx,rx,rx,rx]and the remaining three trials were as follows one trial compared Xeroform (gauze dressing) to a multilayer dressing and showed that Xeroform was associated with longer healing time and higher pain scores than Oxyband.[rx]The second trial compared paraffin gauze to a hydrofiber dressing (Aquacel) and reported that the paraffin gauze was associated with longer re-epithelialization time and higher pain score during dressing.[rx]The last trial compared Jelonet to a multilayer dressing as a dressing over a skin graft (receiver site); the results showed that the two dressings did not affect the time to graft take, number of nursing interventions, or post-operative infections; however, they showed that Jelonet was associated with higher pain score at the time of dressing removal.[rx]
Hydrocolloid dressings – The efficacy of DuoDerm E was compared to six other dressing materials in Brolmann’s trial; the results of this trial were presented earlier in this section.[rx]In another trial, DuoDerm was compared to a silicone-based dressing (AWBAT-D); the trial showed that the two dressings did not differ in terms of pain scores, wound size or time to discharge, but the DuoDerm was associated with shorter time to re-epithelialization.[rx]
Hydrofiber dressings – The efficacy of Aquacel was studied in six trials; the results of four trials were presented earlier in the section.[rx,rx,rx,rx]One of the remaining trials compared Aquacel to carbohydrate wound dressing (Glucan II), and it showed that the two interventions did not differ in terms of time to re-epithelialization, pain scores, or donor site infection.[rx]The second trial compared two different protocols of using Aquacel; in the first protocol, Aquacel dressing was covered with gauze, while in the second one, it was covered with polyurethane film (OpSite).[rx] The trial reported that the second protocol was associated with a larger number of donor sites healing at day 14 after surgery (88% versus 67%), and it was associated with lower pain during mobility the first day after operation; the two dressings did not differ in pain scores during rest at all time-point evaluations.[rx]
Silicone dressings – Four trials evaluated the efficacy of silicone-based dressings; the result three of trials were presented earlier in this section.[rx,rx,rx] The fourth trial compared Mepitel dressing to a nylon dressing (Bridal veil) when used over a skin graft (receiver site).[rx] The results of this trial showed that Mepitel dressing was associated with less pain, easier use, and better overall experience for patients.[rx]
Keratin dressings – The efficacy of Keranatrix was evaluated in one study the results of which were presented earlier in this section.[rx]
Self-adhesive fabric dressing (Mefix) with or without fibrin sealant – One trial evaluated the difference between using Mefix alone or with a fibrin sealant; the trial showed that the use of fibrin sealant was associated with lower daily pain and incapacity scores, but it did not affect the time to dressing removal or the time to discharge for the hospital.[rx]
Multilayer (combination) dressings – The efficacy of Oxyband and Allyven was evaluated in two studies the results of which were presented earlier in this section.[rx,rx]
Nylon dressings – The efficacy of Bridal veil was evaluated in one study the results of which were presented earlier in this section.[rx]
Carbohydrate wound dressings – The efficacy of Glucan dressing was evaluated in one study the results of which were presented earlier in this section.[rx]
Negative pressure dressings – One trial compared negative pressure dressings with a conventional dressing with gauze; both dressings were used over skin grafts (receiver sites).[rx]The trial reported that the negative pressure dressing was associated with a higher percentage of graft take and shorter duration of dressing.[rx]
Complication of Wound Healing
Factors that can slow the wound healing process include
Dead skin (necrosis) – dead skin and foreign materials interfere with the healing process.
Infection – an open wound may develop a bacterial infection. The body fights the infection rather than healing the wound.
Haemorrhage – persistent bleeding will keep the wound margins apart.
Mechanical damage – for example, a person who is immobile is at risk of bedsores because of constant pressure and friction.
Diet – poor food choices may deprive the body of the nutrients it needs to heal the wound, such as vitamin C, zinc and protein.
Medical conditions – such as diabetes, anaemia and some vascular diseases that restrict blood flow to the area, or any disorder that hinders the immune system.
Age – wounds tend to take longer to heal in elderly people.
Medicines – certain drugs or treatments used in the management of some medical conditions may interfere with the body’s healing process.
Smoking – cigarette smoking impairs healing and increases the risk of complications.
Varicose veins – restricted blood flow and swelling can lead to skin break down and persistent ulceration.
Dryness – wounds (such as leg ulcers) that are exposed to the air are less likely to heal. The various cells involved in healing, such as skin cells and immune cells, need a moist environment.
RestrictiveAnorexia Nervosa is the individual suffering from restrictive anorexia is often perceived as highly self-disciplined. They restrict the quantity of food, calories and often high fat or high sugar foods. They consume far fewer calories than are needed to maintain a healthy weight. This is a heartbreaking form of self-starvation.
Anorexia nervosa (AN) is classically defined as a condition in which an abnormally low body weight is associated with an intense fear of gaining weight and distorted cognitions regarding weight, shape, and drive for thinness. This article reviews recent evidence from physiology, genetics, epigenetics, and brain imaging which allow considering AN as an abnormality of reward pathways or an attempt to preserve mental homeostasis. Special emphasis is put on ghrelin-resistance and the importance of orexigenic peptides of the lateral hypothalamus, the gut microbiota and a dysimmune disorder of neuropeptide signaling. Physiological processes, secondary to underlying, and premorbid vulnerability factors—the “pondero-nutritional-feeding basements”- are also discussed.
Anorexia is a psychological and potentially life-threatening eating disorder. Those suffering from this eating disorder are typically suffering from an extremely low body weight relative to their height and body type.It is an eating disorder characterized by low weight, fear of gaining weight, and a strong desire to be thin, resulting in food restriction.Many people with anorexia see themselves as over weight even though they are in fact underweight.If asked they usually deny they have a problem with low weight.Often they weigh themselves frequently, eat only small amounts, and only eat certain foods.Some will exercise excessively, force themselves to vomit, or use laxatives to produce weight loss.
Types of Anorexia Nervosa
There are two common types of anorexia, which are as follows:
Binge/Purge Type – The person struggling with this type of eating disorder will often purge after eating. This alleviates the fear of gaining weight and offsets some of the guilt of having ingested forbidden, or highly restricted food. The compensatory purge behavior by the individual with Binge/Purge Type anorexia may purge by exercising excessively, vomiting or abusing laxatives.
Restrictive – The individual suffering from restrictive anorexia is often perceived as highly self-disciplined. They restrict the quantity of food, calories and often high fat or high sugar foods. They consume far fewer calories than are needed to maintain a healthy weight. This is a heartbreaking form of self-starvation.
Causes of Restrictive Anorexia Nervosa
Genetics – Changes in specific genes may put certain people at higher risk of anorexia. Those with a first-degree relative — a parent, sibling or child — who had the disorder have a much higher risk of anorexia.
Dieting and starvation – Dieting is a risk factor for developing an eating disorder. There is strong evidence that many of the symptoms of anorexia are actually symptoms of starvation. Starvation affects the brain and influences mood changes, rigidity in thinking, anxiety and reduction in appetite. Starvation and weight loss may change the way the brain works in vulnerable individuals, which may perpetuate restrictive eating behaviors and make it difficult to return to normal eating habits.
Transitions – Whether it’s a new school, home or job; a relationship breakup; or the death or illness of a loved one, change can bring emotional stress and increase the risk of anorexia.
Biological – Although it’s not yet clear which genes are involved, there may be genetic changes that make some people at higher risk of developing anorexia. Some people may have a genetic tendency toward perfectionism, sensitivity and perseverance — all traits associated with anorexia.
Psychological – Some people with anorexia may have obsessive-compulsive personality traits that make it easier to stick to strict diets and forgo food despite being hungry. They may have an extreme drive for perfectionism, which causes them to think they’re never thin enough. And they may have high levels of anxiety and engage in restrictive eating to reduce it.
Environmental – Modern Western culture emphasizes thinness. Success and worth are often equated with being thin. Peer pressure may help fuel the desire to be thin, particularly among young girls.
The effects of the thinness culture in media, that constantly reinforce thin people as ideal stereotypes
Professions and careers that promote being thin and weight loss, such as ballet and modeling
Family and childhood traumas: childhood sexual abuse, severe trauma
Peer pressure among friends and co-workers to be thin or be sexy.
Irregular hormone functions
Genetics (the tie between anorexia and one’s genes is still being heavily researched, but we know that genetics is a part of the story).
Other drugs may be used to intentionally cause anorexia in order to help a patient preoperative fasting prior to general anesthesia. It is important to avoid food before surgery to mitigate the risk of pulmonary aspiration, which can be fatal.
Opiates (such as morphine, heroin, oxycodone, etc.) act upon the digestive system and can reduce the physical sensation of hunger in the same way that they reduce physical sensations of pain. They also frequently cause delayed gastric emptying (gastroparesis) and can sometimes lead to changes in metabolism with long-term use.
Fear of even the slightest weight gain; taking all precautionary measures to avoid weight gain or becoming “overweight”.
Rapid, continuous weight loss.
Lanugo: soft, fine hair growing over the face and body.
An obsession with counting calories and monitoring fat contents of food.
Preoccupation with food, recipes, or cooking; may cook elaborate dinners for others, but not eat the food themselves or consume a very small portion.
Food restrictions despite being underweight or at a healthy weight.
Food rituals, such as cutting food into tiny pieces, refusing to eat around others and hiding or discarding of food.
Purging: May use laxatives, diet pills, ipecac syrup, or water pills to flush food out of their system after eating or may engage in self-induced vomiting though this is a more common symptom of bulimia.
Excessive exercise including micro-exercising, for example making small persistent movements of fingers or toes.
Perception of self as overweight, in contradiction to an underweight reality.
Intolerance to cold and frequent complaints of being cold; body temperature may lower (hypothermia) in an effort to conserve energy due to malnutrition.
Anorexia nervosa is classified under the Feeding and Eating Disorders in the latest revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5).
Relative to the previous version of the DSM (DSM-IV-TR), the 2013 revision (DSM5) reflects changes in the criteria for anorexia nervosa, most notably that of the amenorrhea criterion being removed.
Subtypes
There are two subtypes of AN
Binge-eating/purging type – the individual utilizes binge eating or displays purging behavior as a means for losing weight.It is different from bulimia nervosa in terms of the individual’s weight. An individual with binge-eating/purging type anorexia can maintain a healthy or normal weight, but is usually significantly underweight. People with bulimia nervosa on the other hand can sometimes be overweight.
Restricting type – the individual uses restricting food intake, fasting, diet pills, or exercise as a means for losing weight; they may exercise excessively to keep off weight or prevent weight gain, and some individuals eat only enough to stay alive.
Levels of severity
Body mass index (BMI) is used by the DSM-5 as an indicator of the level of severity of anorexia nervosa. The DSM-5 states these as follows
Mild: BMI of greater than 17
Moderate: BMI of 16–16.99
Severe: BMI of 15–15.99
Extreme: BMI of less than 15
Investigations of Restrictive Anorexia Nervosa
Medical tests to check for signs of physical deterioration in anorexia nervosa may be performed by a general physician or psychiatrist, including:
Complete Blood Count (CBC)– a test of the white blood cells, red blood cells and platelets used to assess the presence of various disorders such as leukocytosis, leukopenia, thrombocytosis and anemia which may result from malnutrition.
Urinalysis– a variety of tests performed on the urine used in the diagnosis of medical disorders, to test for substance abuse, and as an indicator of overall health
Chem-20 – Chem-20 also known as SMA-20 a group of twenty separate chemical tests performed on blood serum. Tests include cholesterol, protein and electrolytes such as potassium, chlorine and sodium and tests specific to liver and kidney function.
Glucose tolerance test – Oral glucose tolerance test (OGTT) used to assess the body’s ability to metabolize glucose. Can be useful in detecting various disorders such as diabetes, an insulinoma, Cushing’s Syndrome, hypoglycemia and polycystic ovary syndrome.
Serum cholinesterase test – a test of liver enzymes (acetylcholinesterase and pseudocholinesterase) useful as a test of liver function and to assess the effects of malnutrition.
Liver Function Test – A series of tests used to assess liver function some of the tests are also used in the assessment of malnutrition, protein deficiency, kidney function, bleeding disorders, and Crohn’s Disease.
Lh response to GnRH – Luteinizing hormone (Lh) response to gonadotropin-releasing hormone (GnRH) Tests the pituitary glands’ response to GnRh a hormone produced in the hypothalamus. Hypogonadism is often seen in anorexia nervosa cases.
Creatine Kinase Test (CK-Test) – measures the circulating blood levels of creatine kinase an enzyme found in the heart (CK-MB), brain (CK-BB) and skeletal muscle (CK-MM).
Blood urea nitrogen (BUN) test – urea nitrogen is the byproduct of protein metabolism first formed in the liver then removed from the body by the kidneys. The BUN test is primarily used to test kidney function. A low BUN level may indicate the effects of malnutrition.
BUN-to-creatinine ratio – A BUN to creatinine ratio is used to predict various conditions. A high BUN/creatinine ratio can occur in severe hydration, acute kidney failure, congestive heart failure, and intestinal bleeding. A low BUN/creatinine ratio can indicate a low protein diet, celiac disease, rhabdomyolysis, or cirrhosis of the liver.
Electrocardiogram (EKG or ECG)– measures electrical activity of the heart. It can be used to detect various disorders such as hyperkalemia
Electroencephalogram (EEG) – measures the electrical activity of the brain. It can be used to detect abnormalities such as those associated with pituitary tumors.
Thyroid Screen TSH, t4, t3 – test used to assess thyroid functioning by checking levels of thyroid-stimulating hormone (TSH), thyroxine (T4), and triiodothyronine (T3).
According to the American Psychiatric Association’s (APA’s) Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5), the diagnostic criteria for anorexia nervosa are as follows-
Restriction of energy intake relative to requirements leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health.
Intense fear of gaining weight or becoming fat, even though underweight.
Disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight.
The National Eating Disorders Association (NEDA) note that even without meeting all these criteria, a person may have a serious eating disorder.
Acute pharmacologic treatment of anorexia nervosa is rarely required. However, vitamin supplementation with calcium should be started in patients, and although estrogen has no established effect on bone density in patients with anorexia nervosa, estrogen replacement (ie, oral contraceptives) has been recommended for the treatment of osteopenia; the benefits and minimal effective dose of the hormone are being explored.
Types of Psychological Therapy
Various psychological therapies have proven helpful in treating patients with anorexia nervosa, including the following
These types of therapy may be beneficial for anorexia:
Family-based therapy – This is the only evidence-based treatment for teenagers with anorexia. Because the teenager with anorexia is unable to make good choices about eating and health while in the grips of this serious condition, this therapy mobilizes parents to help their child with re-feeding and weight restoration until the child can make good choices about health.
Individual therapy – For adults, cognitive behavioral therapy — specifically enhanced cognitive behavioral therapy — has been shown to help. The main goal is to normalize eating patterns and behaviors to support weight gain. The second goal is to help change distorted beliefs and thoughts that maintain restrictive eating.
Group Therapy – Group therapy allows people with anorexia nervosa to interact with others who have the same disorder. But it can sometimes lead to competition to be the thinnest. To avoid that, it’s important that you attend group therapy that is led by a qualified medical professional.
Complications of Restrictive Anorexia Nervosa
Complications can affect every body system, and they can be severe.
Physical complications include
Cardiovascular problems – These include low heart rate, low blood pressure, and damage to the heart muscle.
Blood problems – There is a higher risk of developing leukopenia, or low white blood cell count, and anemia, a low red blood cell count.
Gastrointestinal problems – Movement in the intestines slows significantly when a person is severely underweight and eating too little, but this resolves when the diet improves.
Kidney problems – Dehydration can lead to highly concentrated urine and more urine production. The kidneys usually recover as weight levels improve.
Hormonal problems – Lower levels of growth hormones may lead to delayed growth during adolescence. Normal growth resumes with a healthful diet.
Bone fractures – Patients whose bones have not fully grown yet have a significantly higher risk of developing osteopenia, or reduced bone tissue, and osteoporosis, or loss of bone mass.
Around 1 in 10 cases are fatal. Apart from the physical effects of poor nutrition, there may be a higher risk of suicide. One in 5 deaths related to anorexia is from suicide.
Newborn/Baby jaundice/Jaundice is the commonest presentation of patients with liver and biliary disease. The cause can be established in most cases by simple non-invasive tests, but many patients will require referral to a specialist for management. Patients with high concentrations of bilirubin (>100 μmol/l) or with evidence of sepsis or cholangitis are at high risk of developing complications and should be referred as an emergency because delays in treatment adversely affect prognosis.
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and whites of the eyes due to high bilirubin levels.[rx][rx] It is commonly associated with itchiness.[rx] The feces may be pale and the urine dark.[rx] Jaundice in babies occurs in over half in the first week following birth and in most is not a problem.[rx][rx] If bilirubin levels in babies are very high for too long, a type of brain damage, known as kernicterus, may occur.[rx]
Hyperbilirubinaemia is defined as a bilirubin concentration above the normal laboratory upper limit of 19 μmol/l. Jaundice occurs when bilirubin becomes visible within the sclera, skin, and mucous membranes, at a blood concentration of around 40 μmol/l. Jaundice can be categorized as prehepatic, hepatic, or posthepatic, and this provides a useful framework for identifying the underlying cause.
Types of Newborn/Baby jaundice
There are three main types of jaundice
Hepatocellular jaundice – occurs as a result of liver disease or injury.
Hemolytic jaundice – occurs as a result of hemolysis, or an accelerated breakdown of red blood cells, leading to an increase in the production of bilirubin.
Obstructive jaundice – occurs as a result of an obstruction in the bile duct. This prevents bilirubin from leaving the liver.
Others
Physiologic jaundice – Physiologic jaundice occurs as a normal response to the baby’s limited ability to excrete bilirubin in the first days of life.
Breast milk jaundice – About 2 percent of breastfed babies develop jaundice after the first week. It peaks about two weeks of age and can persist up to three to 12 weeks. Breast milk jaundice is thought to be caused by a substance in the breast milk that increases the reabsorption of bilirubin through the intestinal tract.
Breastfeeding failure jaundice – It is caused by failure to initiate breastfeeding, resulting in dehydration, decreased urine production and accumulation of bilirubin. Late preterm infants, those who are born between 34 weeks and 36 weeks, are more susceptible to this problem because they do not have the coordination and strength to maintain successful breastfeeding. However, it is also very common in full-term newborns and usually gets better once breastfeeding is established.
Jaundice from hemolysis – Jaundice may occur with the breakdown of red blood cells due to hemolytic disease of the newborn (Rh disease), or from having too many red blood cells that break down naturally and release bilirubin.
Jaundice related to inadequate liver function – Jaundice may be related to inadequate liver function due to infection or other factors.
Causes of Newborn/Baby jaundice
Hemolytic
Intrinsic causes of hemolysis
Membrane conditions
Spherocytosis
Hereditary elliptocytosis
Enzyme conditions
Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
Pyruvate kinase deficiency
Globin synthesis defect
sickle cell disease
Alpha-thalassemia, e.g. HbH disease
Extrinsic causes of hemolysis
Systemic conditions
Sepsis
Arteriovenous malformation
Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the maternal blood gives a positive indirect Coombs test)
Hemolytic disease of the newborn (ABO)
Rh disease
Hemolytic disease of the newborn (anti-Kell)
Hemolytic disease of the newborn (anti-Rhc)
Other blood type mismatches causing hemolytic disease of the newborn
Non-hemolytic causes
Breastfeeding jaundice
Breast milk jaundice
Cephalohematoma
Polycythemia
Urinary tract infection
Sepsis
Hypothyroidism
Gilbert’s syndrome
Crigler-Najjar syndrome
High GI obstruction (Pyloric stenosis, Bowel obstruction)
Conjugated (Direct) Liver causes
Infections
Sepsis
Hepatitis A
Hepatitis B
TORCH infections
Metabolic
Galactosemia
Alpha-1-antitrypsin deficiency, which is commonly missed, and must be considered in DDx
Cystic fibrosis
Dubin-Johnson Syndrome
Rotor syndrome
Drugs
Total parenteral nutrition
Idiopathic
Post-liver
Biliary atresia or bile duct obstruction
Alagille syndrome
Choledochal cyst
Drugs that may cause liver damage
Analgesics
Paracetamol
Aspirin
Non-steroidal anti-inflammatory drugs
Cardiac drugs
Methyldopa
Amiodarone
Psychotropic drugs
Monoamine oxidase inhibitors
Phenothiazines (such as chlorpromazine)
Others
Sodium valproate
Oestrogens (oral contraceptives and hormone replacement therapy)
Important risk factors for severe hyperbilirubinemia in infants at ≥ 35 weeks’ gestation
Predischarge total serum or transcutaneous bilirubin measurement in the high-risk or high–intermediate-risk zone
Lower gestational age
Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive
Jaundice observed in the first 24 hours
Isoimmune or other hemolytic diseases (e.g., G6PD deficiency)
Complete blood count and differential with a smear
Toxoplasmosis, other infections, rubella, Cytomegalovirus infection and herpes simplex (TORCH) serology
Blood culture
Hepatitis B surface antigenGlucose/serum lactate/serum amino acids/ammonia
Thyroxine, thyroid-stimulating hormone
Iron studies, ferritin
Galactosemia screen
Urine
Reducing substances
Organic acids
Bacterial culture
Urine Cytomegalovirus (positive result before four weeks of age is highly suggestive of congenital Cytomegalovirus
Conjugated bilirubin present, urobilinogen > 2 units but variable (except in children). Kernicterus is a condition not associated with increased conjugated bilirubin.
Plasma protein show characteristic changes.
Plasma albumin level is low but plasma globulins are raised due to an increased formation of antibodies.
Imaging Test
Ultrasonography – is the first line imaging investigation in patients with jaundice, right upper quadrant pain, or hepatomegaly. It is non-invasive, inexpensive, and quick but requires experience in technique and interpretation. Ultrasonography is the best method for identifying gallbladder stones and for confirming extrahepatic biliary obstruction as dilated bile ducts are visible. It is good at identifying liver abnormalities such as cysts and tumors and pancreatic masses and fluid collections, but visualization of the lower common bile duct and pancreas is often hindered by overlying bowel gas. Computed tomography is complementary to ultrasonography and provides information on liver texture, gallbladder disease, bile duct dilatation, and pancreatic disease. Computed tomography is particularly valuable for detecting small lesions in the liver and pancreas.
Cholangiography – identifies the level of biliary obstruction and often the cause. Intravenous cholangiography is rarely used now as opacification of the bile ducts is poor, particularly in jaundiced patients, and anaphylaxis remains a problem. Endoscopic retrograde cholangiopancreatography is advisable when the lower end of the duct is obstructed (by gallstones or carcinoma of the pancreas). The cause of the obstruction (for example, stones or parasites) can sometimes be removed by endoscopic retrograde cholangiopancreatography to allow cytological or histological diagnosis.
Percutaneous transhepatic cholangiography – is preferred for hilar obstructions (biliary stricture, cholangiocarcinoma of the hepatic duct bifurcation) because better opacification of the ducts near the obstruction provides more information for planning subsequent management. Obstruction can be relieved by insertion of a plastic or metal tube (a stent) at either endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography.
Magnetic resonance cholangiopancreatography – allows non-invasive visualization of the bile and pancreatic ducts. It is superseding most diagnostic endoscopic cholangiopancreatography as faster magnetic resonance imaging scanners become more widely available.
Liver biopsy – Percutaneous liver biopsy is a day case procedure performed under local anesthetic. Patients must have a normal clotting time and platelet count and ultrasonography to ensure that the bile ducts are not dilated. Complications include bile leaks and hemorrhage, and overall mortality is around 0.1%. A transjugular liver biopsy can be performed by passing a special needle, under radiological guidance, through the internal jugular vein, the right atrium, and inferior vena cava and into the liver through the hepatic veins.
Measurement of Bilirubin Levels – Bilirubin level can be checked through the biochemical method, Bilimeter or transcutaneous bilirubinometer (rx–rx).
Biochemical – The gold standard method for bilirubin estimation is the total and conjugated bilirubin assessment based on the van den Bergh reaction ([rx, rx].
Millimeter – Spectrophotometry is the base of Bilimeter and it assesses total bilirubin in the serum. Because of the predominant unconjugated form of bilirubin, this method has been found a useful method in neonates.
Transcutaneous Bilirubinometer – This method is noninvasive and is based on the principle of multi-wavelength spectral reflectance from the bilirubin staining in the skin [rx]. The accuracy of the instrument may be affected by the variation of skin pigmentation and its thickness [rx].
Clinical Approach to Jaundice – The initial step in the evaluation of any newborn for jaundice is to differentiate between physiological and pathological jaundice. A helpful algorithm as adapted by AAP (2004b) [rx] is as follows.
Dependency on Newborn Period or Preterm – Preterm intervention values are different and depend on the degree of prematurity and birth weight [rx–rx].
Evidence of Hemolysis – Onset of jaundice within 24 h, presence of pallor and hydrops, presence of hepatosplenomegaly, presence of hemolysis on the smear of peripheral blood, increased count of reticulocyte (>8%), rapid rise of bilirubin (>5 mg/dl in 24 h or >0.5 mg/dl/hr) or a family history of considerable jaundice should create a suspicion of hemolytic jaundice [rx].
Instructions and Precautionary Measure for Parents during Physiological Jaundice – The benign nature of jaundice should be explained and demonstrated to the parents. The mother should be encouraged to breast-feed her baby frequently and exclusively, at least eight to twelve times per day for initial several days, with no top feeds or glucose water whatsoever [rx–rx]. The mother should be told to bring the baby to the hospital if the color on the legs looks as yellow as the face.
Abdominal sonography – is a valuable screening test in the jaundiced patient [rx]. The demonstration of biliary ductal dilation, gallstones, hepatic mass lesion, or an enlarged or abnormally shaped pancreas directs further investigation or therapy. Sonography is noninvasive, readily available in most hospitals, does not involve radiation exposure, and is cheaper than CT or other procedures in which the bile ducts are directly opacified. It may also allow guided biopsy or drainage of lesions in the liver or pancreas. However, sonography may be technically unsatisfactory in up to 40% of cases, primarily due to obesity or to the accumulation of bowel gas, which prevents transmission of sound waves.
Hepatobiliary scintigraphy – had little to contribute to the differential diagnosis of jaundice except in the instance of neonatal hepatitis versus biliary atresia or the occasional need for objective assessment of liver size. However, the development of new radionuclide agents with improved hepatic extraction and biliary excretion, improved imaging techniques, and the application of computer assistance to the interpretation of dynamic scans have transformed HBS into an accurate modality for the diagnosis of large bile duct obstruction and may also prove useful in demonstrating intrahepatic cholestasis[rx].
Percutaneous transhepatic cholangiography – involves passage of a thin needle into the liver under fluoroscopic guidance and injection of contrast into the biliary tree [rx]. The procedure is easily available, its cost is generally less than that of ERCP, and a local anesthetic injection over the right flank is the only sedative or anesthetic medication required. Dilated ducts are opacified in 95 to 100% of cases, but even nondilated ducts are opacified in 60 to 95% of cases. A dilated, the obstructed duct may be decompressed percutaneously by the passage of a guide wire and cannula through the right flank incision.
Endoscopic retrograde cholangiopancreatography – is performed by passing a flexible fiberoptic endoscope into the patient’s duodenum, inserting a cannula into the pancreatic and common bile ducts and injecting radiopaque contrast into these structures under fluoroscopy [rx]. ERCP has the advantage of visualization and potential biopsy of the stomach and duodenum (since the scope is side-viewing. the esophagus cannot be seen). The procedure diagnoses pancreatic carcinoma in at least 90% of cases and can furnish visual (photographic and radiographic) and histologic proof of ampullary tumors.
Treatment of Newborn/Baby jaundice
Key elements from the American Academy of Pediatrics guideline on the management of hyperbilirubinemia in the newborn at ≥ 35 weeks’ gestation[rx]
Promote and support successful breastfeeding
Establish nursery protocols for the identification and evaluation of hyperbilirubinemia
Measure the total serum or transcutaneous bilirubin level in infants with jaundice in the first 24 hours
Recognize that visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented infants
Interpret all bilirubin levels according to the infant’s age in hours
Recognize that infants at less than 38 weeks’ gestation, particularly those who are breastfed, are at higher risk of hyperbilirubinemia and require closer surveillance and monitoring
Perform a systematic assessment on all infants before discharge for the risk of severe hyperbilirubinemia
Provide parents with written and verbal information about jaundice in the newborn
Provide appropriate follow-up based on the time of discharge and the risk assessment
Treat jaundice in the newborn, when indicated, with phototherapy or exchange transfusion
The treatment options for jaundice include phototherapy further subdivided to conventional, intensive and exchange transfusion, and pharmacological treatment subdivided to phenobarbitone, intravenous immunoglobulins (IVIG), metalloporphyrins and follow up remedies [rx].
Phototherapy
Hyperbilirubinemia can be treated easily without or with a minimal adverse effect with phototherapy [rx, rx]. The efficacy of phototherapy depends on surface area exposed to phototherapy: Double surface phototherapy may be more effective than single surface phototherapy [rx]. The spectrum of light source: Special blue tubes with the mark F20T12/BB should be used rather than F20T12/B lights and Irradiance or energy output may be increased in a phototherapy unit by lowering the distance of the neonate to within 15–20 cm [rx, rx]. Continuous phototherapy is better than intermittent phototherapy. Phototherapy should not be interrupted except during breastfeeding or nappy change [rx, rx–rx].
Conventional Phototherapy
One can use conventional or fiber-optic phototherapy units provided jaundice is non-hemolytic or its progression is slow.
Intensive Phototherapy
In the circumstances including hemolytic jaundice, rapidly increasing bilirubin, or ineffectiveness of a conventional unit, using intensive phototherapy is warranted. Placing the baby on the bili-blanket and using additional overhead phototherapy units contain blue lights and then lowering the phototherapy units to within a distance of 15–20 cm are two significant remedies [rx].
Exchange Transfusion
Through exchange transfusion, bilirubin and hemolytic antibodies are removed [rx].
Rh Isoimmunization – Always, Blood using for exchange transfusion should be negative Rh isoimmunization, negative for Rh factor. O (Rh) negative packed cells suspended in AB plasma will be the best choice. O (Rh) negative whole blood or cross-matched baby’s blood group (Rh negative) may also be used in an emergency [rx, rx].
ABO Incompatibility – Only O-blood group should be used for exchange transfusion in newborns with ABO incompatibility. The best choice would be O group (Rh compatible) packed cells which are suspended in O group/AB plasma whole blood (Rh compatible with baby).
Other situations – In the case of the Cross-matched with baby’s blood group blood volume used or double volume exchange should be kept in mind.
Blood Volume Used – Partial exchange is done at birth in Rh hemolytic disease: 50-ml/kg of packed cells
Pharmacological treatment of neonatal jaundice can further be categorized into different subheadings such as phenobarbitone, Intravenous immunoglobulins, and Metalloporphyrins etc. [rx, rx–rx].
Bilirubin processing including hepatic uptake, conjugation, and its excretion are ameliorated by this agent thus helps in decreasing level of bilirubin. However,r the effect of phenobarbitone is not rapid and takes time to show. When used for 3–5 days in a dose of 5 mg/kg after birth prophylactically, it has shown to be effective in babies with hemolytic disease, extravasated blood and in pre-term without any significant side effects. There is a huge literature documenting the efficacy and mechanism of action and complications of treatment for Phenobarbital [rx–rx].
High dose IVIG (0.5–1 gr/kg) has shown to be effective in decreasing the needs of exchange transfusion and phototherapy in babies with Rh hemolytic disease [rx–rx].
Metalloporphyrins
These compounds are still experimental but showing promising results in various hemolytic and non-hemolytic settings without significant side effects [rx, rx–rx].
Fiber-optic blanket
Another form of phototherapy is a fiberoptic blanket placed under the baby. This may be used alone or in combination with regular phototherapy.
Exchange transfusion to replace the baby’s damaged blood with fresh blood
Exchange transfusion helps increase the red blood cell count and lower the levels of bilirubin. An exchange transfusion is done by alternating giving and withdrawing blood in small amounts through a vein or artery. Exchange transfusions may need to be repeated if the bilirubin levels remain high.
Adequate hydration with breastfeeding or pumped breast milk.
The American Academy of Pediatrics recommends that, if possible, breastfeeding be continued. Breastfed babies receiving phototherapy who are dehydrated or have excessive weight loss can have supplementation with expressed breast milk or formula.
Follow-up
Babies having roughly 20 mg/dl serum bilirubin and that requiring exchange transfusion should be kept under follow-up in the high-risk clinic for neurodevelopmental outcome [rx, rx]. Hearing assessment (Brainstem Evoked Response Audiometry (BAER)) should be done at 3 months of corrected age [rx].
Risk factors
Underlying conditions that may cause jaundice to include
Acute inflammation of the liver – This may impair the ability of the liver to conjugate and secrete bilirubin, resulting in a buildup.
Inflammation of the bile duct – This can prevent the secretion of bile and removal of bilirubin, causing jaundice.
Obstruction of the bile duct – This prevents the liver from disposing of bilirubin.
Hemolytic anemia – The production of bilirubin increases when large quantities of red blood cells are broken down.
Gilbert’s syndrome – This is an inherited condition that impairs the ability of enzymes to process the excretion of bile.
Cholestasis –This interrupts the flow of bile from the liver. The bile containing conjugated bilirubin remains in the liver instead of being excreted.
Crigler-Najjar syndrome – This is an inherited condition that impairs the specific enzyme responsible for processing bilirubin.
Dubin-Johnson syndrome – This is an inherited form of chronic jaundice that prevents conjugated bilirubin from being secreted from the cells of the liver.
Pseudojaundice – This is a harmless form of jaundice. The yellowing of the skin results from an excess of beta-carotene, not from an excess of bilirubin. Pseudojaundice usually arises from eating large quantities of carrot, pumpkin, or melon.
How Do You Remove Fat From Your Liver/ Fatty Liver corresponds to the presence of macrovesicular changes without inflammation (steatosis) and lobular inflammation in the absence of significant alcohol use. It can be divided into two subgroups: NAFL (Non-Alcoholic Fatty Liver) or simply Steatosis and NASH (Non-Alcoholic Steatohepatitis). NAFL is defined as the presence of hepatic steatosis with no evidence of hepatocellular injury in the form of ballooning of the hepatocytes. NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte injury (ballooning), Mallory hyaline, and mixed lymphocytic and neutrophilic inflammatory infiltrate in the perivenular area with or without fibrosis.[rx] It is important to note that NAFL is a spectrum, with NAFL being the mildest form and NASH and cirrhosis being at the other end of the spectrum. NAFL (Non-Alcoholic Fatty Liver) or simply Steatosis and NASH (Non-Alcoholic Steatohepatitis) could only be distinguished with histology and liver biopsy.[rx].
NAFLD is commonly associated with Metabolic Syndrome, obesity, diabetes, and hyperlipidemia. Nearly 80% of patients with Metabolic Syndrome have NAFLD.[rx][rx][rx]
Etiological Causes of Fatty Liver
Fat accumulates in the liver for several reasons. Most commonly, it involves increased delivery of free fatty acids (FFAs) to the liver, increased synthesis of fatty acids in the liver, decreased oxidation of FFA, or decreased synthesis or secretion of very-low-density lipoprotein (VLDL).[6][7]
Oxidative stress in the hepatocytes can activate stellate cells and lead to the production of collagen and inflammation.
Other factors that may contribute to fatty liver include:
The use of medications (e.g., tamoxifen, amiodarone, methotrexate)
Fatty liver (FL) is commonly associated with metabolic syndrome (diabetes, hypertension, obesity, and dyslipidemia), but can also be due to any one of many causes:[rx][rx]
Alcohol – Alcoholism is one of the causes of fatty liver due to the production of toxic metabolites like aldehydes during the metabolism of alcohol in the liver. This phenomenon most commonly occurs with chronic alcoholism.
Other – celiac disease,[rx] inflammatory bowel disease, HIV, hepatitis C (especially genotype 3), and alpha 1-antitrypsin deficiency[rx]
Personal and family history of diabetes, hypertension and CVD
Alcohol use: < 20 g/d (women), < 30 g/d (man)
Waist circumference, BMI, change in body weight
Hepatitis B/C infection
Liver enzymes
History of steatosis-associated drug use
Fast blood glucose, hemoglobin A1c
Serum total and HDL-cholesterol, triacylglycerol, uric acid
Undertaken due to clinical suspicion
Ultrasound
Hemochromatosis testing: Ferritin and transferrin saturation
Severe fat loss, voracious appetite, accelerated linear growth, and advanced bone age
Low-fat diet
Brunt grading and staging of nonalcoholic steatohepatitis[rx]
Symptoms of Fatty Liver
Nonalcoholic fatty liver disease usually causes no signs and symptoms. When it does, they may include:
Enlarged liver
Fatigue
Pain in the upper right abdomen
a poor appetite
weight loss
abdominal pain
Swollen belly
Enlarged blood vessels underneath your skin
Larger-than-normal breasts in men
Red palms
Skin and eyes that appear yellowish, due to a condition called jaundice
physical weakness
fatigue
abdominal pain
jaundice
confusion
an enlarging, fluid-filled abdomen
jaundice of the skin and eyes
confusion
abnormal bleeding
Possible signs and symptoms of nonalcoholic steatohepatitis and cirrhosis (advanced scarring) include:
Abdominal swelling (ascites)
Enlarged blood vessels just beneath the skin’s surface
Enlarged breasts in men
Enlarged spleen
Red palms
Yellowing of the skin and eyes (jaundice)
Diagnosis of Fatty Liver
Tests done to pinpoint the diagnosis and determine disease severity include:
Blood tests
Complete blood count
Liver enzyme and liver function tests
Tests for chronic viral hepatitis (hepatitis A, hepatitis C and others)
Celiac disease screening test
Fasting blood sugar
Hemoglobin A1C, which shows how stable your blood sugar is
Lipid profile, which measures blood fats, such as cholesterol and triglycerides
Imaging procedures
Imaging procedures used to diagnose nonalcoholic fatty liver disease include:
Plain ultrasound – which is often the initial test when liver disease is suspected.
Computerized tomography (CT) scanning – of the abdomen. These techniques lack the ability to distinguish nonalcoholic steatohepatitis from nonalcoholic fatty liver disease but still may be used.
magnetic resonance imaging (MRI)- of the abdomen. These techniques lack the ability to distinguish nonalcoholic steatohepatitis from nonalcoholic fatty liver disease but still may be used.
Transient elastography – an enhanced form of ultrasound that measures the stiffness of your liver. Liver stiffness indicates fibrosis or scarring.
Magnetic resonance elastography – which combines magnetic resonance imaging with patterns formed by sound waves bouncing off the liver to create a visual map showing gradients of stiffness throughout the liver reflecting fibrosis or scarring.
Brunt grading and staging of nonalcoholic steatohepatitis[rx]
Grading
Staging
Mild (Grade 1)
Stage 1
Steatosis (mostly macrovesicular)
Zone 3 perisinusoidal/pericellular fibrosis (focal or extensive)
Zone 3 perisinusoidal/pericellular fibrosis with associated focal or extensive periportal fibrosis
No/mild portal chronic inflammation
Moderate (Grade 2)
Steatosis-any degree
Ballooning hepatocytes-zone 3
Intra-acinar neutrophils-may be associated with zone 3 pericellular fibrosis
Stage 3
Portal and intra-acinar chronic inflammation
Zone 3 perisinusoidal/pericellular fibrosis and portal fibrosis with associated focal or extensive bridging fibrosis
Severe (Grade 3)
Panacinar steatosis
Ballooning-zone 3
Intra-acinar inflammation with scattered neutrophils
Stage 4
Neutrophils associated with ballooned hepatocytes with/without chronic inflammation
Cirrhosis
Chronic portal inflammation-mild or moderate
Treatment of Fatty Liver
Avoiding alcohol. If you have alcoholic liver disease, then giving up alcohol is the most important thing you can do. Continuing to drink may result in you getting cirrhosis or alcoholic hepatitis. Giving up alcohol is also good for people with NAFLD.
Losing weight. This is not easy for many people with fatty liver disease, so having a well-designed management plan designed by a doctor or dietitian can be beneficial. Gradual weight loss is the key, as sudden, severe weight loss can actually make the condition worse. Weight loss surgery may be recommended for some people.
Exercising. Even if this does not directly result in weight loss, it is very worthwhile as exercise has been shown to reduce insulin resistance, a key factor in fatty liver disease. Both aerobic exercise and resistance training, such as low impact weight training, will help.
Controlling your blood sugar levels.
Reducing or avoiding soft drinks and juices and processed foods rich in sugar.
Treating high cholesterol. Your doctor may suggest medicines to lower your cholesterol levels, in addition to dietary and lifestyle changes.
Avoiding medicines that may affect your liver, such as some steroids. Do not take medicines that have not been prescribed by your doctor.
Quit smoking. You will also be advised to quit smoking, to reduce your risk of heart disease.
Several drug therapies have been tried in both research and clinical settings, yet no agent has been approved by the Food and Drug Administration for the treatment of NAFLD[rx].
Vitamin E
Vitamin E, an inexpensive potent antioxidant, has been examined as a treatment agent for NAFLD in many adult and pediatric studies, with varying results. In all studies, vitamin E was well tolerated, and most studies showed modest improvements in the ultrasonographic appearance of the liver, serum aminotransferase levels and histologic findings[rx,rx,rx].
In one published series of 11 pediatric patients with NASH who received vitamin E (d-α-tocopherol), 400 to 1200 IU, ALT improved [rx–rx].
Lipid-Lowering Agents
Few small trials assessed the usefulness of lipid-lowering and cytoprotective drugs for NAFLD treatment, with varying results. In one controlled trial, gemfibrozil improved liver chemistry in 74% of NAFLD patients in the treatment group, compared with 30% of untreated control subjects with no available histologic data. So, in general, lipid-lowering agents are not used for NASH treatment[rx].
Insulin Sensitizers
The association between hyperinsulinemic insulin resistance and NAFLD provides a logical target for treatment. Two classes of drugs have been shown to correct insulin resistance: biguanides (e.g., metformin) and thiazolidinediones.
Metformin, a biguanide that reduces hyperinsulinemia and improves hepatic insulin sensitivity, reduces hepatomegaly and hepatic steatosis in ob/ob mice[rx], but results in human studies have been less impressive[rx,rx] as in human studies, although ALT improved and liver size decreased, metformin was not consistently found to improve liver histology[rx,rx].
Thiazolidinediones
These drugs modulate tissue insulin sensitivity through the peroxisome proliferator-activated receptor (PPAR)-γ signaling and improve blood glucose control. Rosiglitazone and pioglitazone are the agents widely studied in this class of drugs for the management of T2DM.
Following the controversy about increased cardiovascular events, rosiglitazone use has been much lower in recent years, with pioglitazone being the agent widely used currently. Pioglitazone has been shown to improve the hepatic insulin sensitivity and fatty acid oxidation and to inhibit hepatic lipogenesis.[rx]
There is moderate quality evidence to suggest the benefits of pioglitazone in the improvement of biochemical and histological parameters of NAFLD, although the drug use may be associated with weight gain.[rx],[rx] In combination with intense lifestyle modification, this drug should be considered in patients with NASH.
Antioxidants
Oxidative stress plays a major role in the pathogenesis of NAFLD and several investigators studied the effects of antioxidants extensively.[rx]–[rx] Vitamin E is the most studied antioxidant in this group.
Supplementation of this was associated with significant improvement in all histological parameters, such as steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis, as compared to placebo.[rx] Vitamin E is used in the dose of 800 International Units daily for patients with NASH, especially in non-diabetic cases.[rx],[rx]
Although multiple agents such as N-acetylcysteine, betaine, probucol, viusid, and silibinin (milk thistle) have been used in different trials, the use of these agents is not recommended in current clinical practice because of conflicting/insufficient evidence on the benefits.[rx]
Metformin
Although metformin use was associated with significant improvements in IR and liver transaminases (AST and ALT), the drug failed to show improvement in the histological parameters, such as steatosis, inflammation, hepatocellular ballooning and fibrosis.[rx]
However, because of the antidiabetic efficacy, metformin should be considered for patients with T2DM or even prediabetic states and NAFLD. Metformin is found to be safe, even in patients with cirrhosis, and may protect against the development of HCC in cases with T2DM and chronic liver diseases.[rx]
Ursodeoxycholate
Ursodeoxycholate (UDCA) is a hydrophilic bile acid that is associated with hepatoprotective properties. In one study, UDCA produced improvement in liver enzymes and a decrease in hepatic steatosis. The long-term benefits of UDCA and the optimal dose of UDCA remain to be established[rx].
Taurine
Taurine is believed to function as a lipotropic factor and to improve the mobilization of hepatic fat. In another single uncontrolled series, 10 children treated with taurine supplements orally had a radiologic resolution of their fatty liver[rx].
Betaine
Betaine is a hepatoprotective factor, and liver histology and aminotransferase activity were improved in ten NAFLD subjects who received betaine for one year[rx,rx].
In a recent randomized placebo-control study, 55 NASH patients received betaine (20 g daily). Patients randomized to betaine had a decrease in steatosis grade without a significant change in intragroup or intergroup differences in the NAS or fibrosis stage.
Moreover, there was no significant change in adiponectin, insulin, glucose, proinflammatory cytokines, or oxidant stress in NASH patients receiving betaine therapy[rx].
Pentoxifylline
Pentoxifylline antagonizes TNF-α and is orally available for long-term use. In two small pilot studies, ALT improved after several months of treatment at a dose of 400 mg three times a day. In addition, although the drug was well tolerated in one study, 9 of 20 subjects in the other study dropped out because of side effects, especially nausea[rx,rx].
Losartan
Angiotensin II has been implicated in hepatic stellate cell activation and matrix production[rx]. In a small pilot study of an angiotensin receptor blocker, losartan, an improvement in ALT was noted[rx].
Drugs for weight loss
Medications that help weight loss may potentially alter the pathogenic mechanisms of NAFLD and may be useful in selected patients. Most of these medications are associated with only modest weight loss benefit and several of them have been withdrawn from the market owing to undesirable side effects.
Orlistat
This medication inhibits pancreatic lipase, resulting in fat malabsorption and weight loss as a consequence. Although two previous RCTs showed some beneficial effects of orlistat in patients with NASH, it is not clear if the benefit was related to weight loss conferred by the drug or direct effect.[rx–rx] Therefore, the drug use should be selected for individual patients as per the clinician’s discretion and situation.
Lorcaserin
This is an appetite suppressant associated with about 4% weight loss in 12 months when combined with lifestyle changes.[rx] Pooled data from three lorcaserin RCTs showed that there was a modest reduction in ALT levels and improvement of cardiovascular outcomes in treated patients with NAFLD compared to placebo.[rx]
Naltrexone/bupropion combination
This drug combination is associated with a weight loss of approximately 5%. Modest reductions in hepatic aminotransferase levels were observed in patients who lost > 10% weight in 12 months with a higher dose of the combination.[rx]
Phentermine/topiramate
This combination is also associated with significant weight loss benefit and may be associated with the improvement of NAFLD.[rx]
Liraglutide
High-dose liraglutide treatment (3 mg daily) has been approved by the United States’ Food and Drug Administration and the European Medicine Agency recently for primary management of obesity in patients without diabetes.
About 8.5% weight loss has been observed in the treated patients compared to placebo in a major clinical trial, although the data on NAFLD was not available in this study.[rx] However, another recent phase 2 clinical trial reported significant improvement of liver histology when 1.8 mg liraglutide was administered to patients.[rx] Therefore, high-dose liraglutide treatment also may be associated with the same benefit.
Other novel agents
Pentoxyphylline is a competitive nonselective phosphodiesterase inhibitor which raises cyclic adenosine monophosphate and inhibits tumour necrosis factor-α. Both animal studies and clinical trials in humans showed the beneficial effects of this novel agent.[rx,rx,rx]
Although prebiotics and probiotics have been claimed to be useful in the treatment and prevention of patients with obesity and NAFLD, inadequate supporting data from high-quality clinical studies is against the recommendation of the use of these medications in normal clinical practice.[rx]
Glucagon-like Peptide-1 (GLP-1) Analogs
GLP-1 analogs are stabilized (long-acting) agonists that bind receptors for the endogenous, intestinally-secreted hormone, GLP-1. Three members of this drug class are approved in the US, including exenatide, liraglutide, and albiglutide.
They improve blood glucose control by enhancing glucose-dependent insulin secretion, slowing gastric emptying, suppressing postprandial glucagon production, and decreasing food intake through enhanced satiety. They are administered by subcutaneous injection (from twice daily to once weekly for different preparations), and they most often are used as second-line agents in conjunction with other glucose-lowering drugs or insulin.
A recent small study from Japan showed improved steatosis and NASH histology (lower NAS score) following liraglutide treatment in overweight or obese subjects with prediabetes (rx). This was associated with improved glucose tolerance and a small decrease in BMI. While these initial data are intriguing, further studies will be needed to establish whether or not liraglutide or other GLP-1 analogs can be useful in preventing or treating NAFLD.
Dipeptidyl peptidase-4 (DPP-4) inhibitors
DPP-4 inhibitors, currently sitagliptin, saxagliptin, linagliptin, and alogliptin in the US, influence glucose homeostasis by blocking the deactivation of endogenous GLP-1 and a second incretin hormone, glucose-dependent insulinotropic peptide (GIP).
Some of the effects of DPP-4 inhibitors may overlap with those of administered GLP-1 analogues (as noted above), but these drugs likely have additional actions by increasing levels of hormones other than GLP-1. DPP-4 inhibitors have the advantage of being taken orally.
Several clinical studies with sitagliptin in subjects with T2DM and NASH have shown decreases in alanine aminotransferase levels ([rx–rx] and, in two studies, improved liver histology [rx,rx].
Incretin-Based Therapy
There are two main groups of incretin-related drugs extensively studied for use in NAFLD, viz., GLP-1 analogues (e.g., exenatide, liraglutide, lixisenatide, dulaglutide and semaglutide) and dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g., sitagliptin, saxagliptin, vildagliptin, alogliptin and linagliptin).
Both classes of drugs augment the meal-related insulin secretion from the pancreas, along with extra-pancreatic effects on multiple organs that make them very useful for the management of T2DM.[rx] Use of GLP-1 analogues are associated with weight loss, and DPP-4 inhibitors are weight neutral.
Incretin-based therapy is very commonly used in overweight/obese T2DM patients, many of whom suffer from NAFLD as well. Remarkable benefits of both the conditions make this class of agents unique in managing the cases.[rx]
Surgical Treatment
Bariatric surgery is the primary surgical intervention for NAFLD in patients with an BMI more than 40 kg/m2 or of 35 kg/m2 with comorbidities[rx]. Current bariatric surgical techniques include vertical banded gastroplasty, adjustable gastric banding, Roux-en-Y gastric bypass, biliopancreatic bypass, and biliopancreatic diversion with duodenal switch. Based on a recent meta-analysis, bariatric surgery is associated with significant histologic improvements in steatosis, steatohepatitis, and fibrosis, with more than 50% of patients experiencing complete resolution of their fatty liver disease after surgery. Although these results are compelling, these observational studies showed no relationship between histologic improvement and the amount of weight loss[rx].
Risk For Fatty Liver Disease
Researchers do not know the cause of nonalcoholic fatty liver (NAFLD). They do know that it is more common in people who
Have type 2 diabetes and prediabetes
Have obesity
Are middle aged or older (although children can also get it)
Are Hispanic, followed by non-Hispanic whites. It is less common in African Americans.
Have high levels of fats in the blood, such as cholesterol and triglycerides
Have high blood pressure
Take certain drugs, such as corticosteroids and some cancer drugs
Have certain metabolic disorders, including metabolic syndrome
Lung cancer is among the most deadly cancers for both men and women (rx). Its death rate exceeds that of the three most common cancers (colon, breast, and pancreatic) combined (rx). Over half of patients diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is around 17.8% (rx). There are two main subtypes of lung cancer, small-cell lung carcinoma and non-small-cell lung carcinoma (NSCLC), accounting for 15% and 85% of all lung cancer, respectively (rx). NSCLC is further classified into three types: squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma.
Squamous-cell carcinoma comprises 25–30% of all lung cancer cases. It arises from early versions of squamous cells in the airway epithelial cells in the bronchial tubes in the center of the lungs. This subtype of NSCLC is strongly correlated with cigarette smoking (rx).
Cellular Classification of NSCLC
Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:
Squamous cell carcinoma (25% of lung cancers).
Adenocarcinoma (40% of lung cancers).
Large cell carcinoma (10% of lung cancers).
There are numerous additional subtypes of decreasing frequency.[rx]
WHO/IASLC Histologic Classification of NSCLC
Squamous cell carcinoma.
Papillary.
Clear cell.
Small cell.
Basaloid.
Adenocarcinoma.
Acinar.
Papillary.
Bronchioloalveolar carcinoma.
Nonmucinous.
Mucinous.
Mixed mucinous and nonmucinous or indeterminate cell type.
Solid adenocarcinoma with mucin.
Adenocarcinoma with mixed subtypes.
Variants.
Well-differentiated fetal adenocarcinoma.
Mucinous (colloid) adenocarcinoma.
Mucinous cystadenocarcinoma.
Signet ring adenocarcinoma.
Clear cell adenocarcinoma.
Large cell carcinoma, Variants.
Large cell neuroendocrine carcinoma (LCNEC).
Combined LCNEC.
Basaloid carcinoma.
Lymphoepithelioma-like carcinoma.
Clear cell carcinoma.
Large cell carcinoma with rhabdoid phenotype.
Adenosquamous carcinoma
Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.
Carcinomas with spindle and/or giant cells.
Spindle cell carcinoma.
Giant cell carcinoma.
Carcinosarcoma.
Pulmonary blastoma.
Carcinoid tumor
Typical carcinoid.
Atypical carcinoid.
Carcinomas of salivary gland type.
Mucoepidermoid carcinoma.
Adenoid cystic carcinoma.
Others.
Unclassified carcinoma.
Squamous cell carcinoma
Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.
Adenocarcinoma
Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.
Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.
Stage of Lung Cancer
Early disease stage I-IIIA
Stage IA
Once the histopathological diagnosis is made, if the patients generally consider fit for radical treatment these will undergo surgical intervention. Usually, lobectomy or greater resection is recommended rather than sublobar resections (wedge or segmentation).
In patients with stage I NSCLC who may tolerate operative intervention but not a lobar or greater lung resection because of comorbid disease or decreases in pulmonary functions segmentectomy/anatomical resection is recommended over non-surgical interventions.
Further management will base on the initial extent of the disease, postoperative information and on patient preference and decision. The use of pre-operative or post-operative chemotherapy or radiation therapy in stage I NSCLC is not recommended by small randomized studies.
Stage IB
The meta-analysis over review gave non-clear evidence-based for adjuvant or induction treatment in stage IB patients after radical tumor resection. Only selective patients and patients that are participating in protocols are candidates for further treatment.
Stage II
Patients with stage II are usually considered for multidisciplinary treatment strategies. The administration of postoperative radiation therapy for the improvement of survival is not recommended in patients who undergo radical resection of stage II tumor with N1 lymph node metastasis [stage II (N1) NSCLC].
In patients who undergo radical resection of stage II tumor and are in a good physical condition, adjuvant platinum-based chemotherapy should be offered between 4th and 8th week following the thoracotomy (adequate wood healing, non-residual inflammatory or infectious complications). Patients in stage II, who are not candidates for surgical approaches due to comorbidities (e.g., pulmonary risk factors), could be considered for chemo-radiotherapy strategies.
Locally advanced IIIA and selected IIIB
Patients in stage IIIA1-IIIA2 (rx) are usually operated with mediastinal lymphadenectomy followed by platinum-based of adjuvant chemotherapy. Postoperative radiation therapy alone can reduce the relapse locally without increasing survival.
Multidisciplinary management of IIIA3 and IIIA4 patients becomes crucial. Patients with proven N2involvement (IIIA3 and IIIA4) could be treated by induction chemotherapy followed by surgery followed by platinum-based chemoradiotherapy.
Stage IIIB is typically considered for concurrent chemoradiotherapy approaches. In selected cases, surgery will be incorporated within clinical trials.
Causes of Lung Cancer
Cigarette Smoking
The emergence of the lung cancer epidemic in the 20th century has no doubt been caused by cigarette smoking. The effect of pipe and cigar use on the risk of lung cancer is similar to that of light cigarette smoking.[rx],[rx] In the United States and the United Kingdom, the decline in lung cancer rates is projected to level off in 2 decades because of the slow progress in smoking cessation at present. Lung cancer will remain among the top killers for decades unless radical reductions in smoking prevalence are achieved.[rx]
Second Hand or Passive Smoking
The causal association that has been established between secondhand tobacco smoking and lung cancer can explain 1.6% of lung cancers.[rx] Results from a meta-analysis[rx] and a comprehensive review[rx] showed a relative risk between 1.14 to 5.20 in people who had never smoked but who lived with a smoker. A more recent study reported that passive smoking during childhood increased lung cancer risk in adulthood by 3.6 fold.[rx]
Diet and Food Supplements
Fruits and vegetables that are a rich source of antioxidant vitamins and other micronutrients, particularly carotenoids, are thought to benefit health by decreasing the risk of lung and other cancers.[rx]–[rx] Although some studies indicate carotenoids decrease lung cancer risk, results have been ambiguous, and some have even indicated that high-dose supplements can be harmful.
Lutein, zeaxanthin, lycopene, and α-carotene displayed a certain protective trend, yet β-cryptoxanthin showed a more consistent protective effect. There is some evidence of a protective role for vitamins C and E, but not vitamin A; no associations were observed between intakes of total or specific types of fat and lung cancer risk regardless of smoking status. In contrast, cured meat (eg, sausage, pressed duck, and cured pork), deep-fried cooking, and chili have been associated with an increased lung cancer risk.[rx]–[rx]
Alcohol
From a pooled analysis of 7 prospective studies with 399,767 participants and 3137 lung cancer cases, a slightly greater risk of lung cancer was indicated among people who consumed at least 30 g/d of alcohol than among those who abstained from alcohol.[rx]
Exercise and Physical Activity
Available data suggest that physically active individuals have a lower risk of lung cancer: moderate to high levels of leisure-time physical activity were associated with a 13% to 30% reduction in lung cancer risk.[rx]–[rx] Overall, physical activity could help to reduce lung cancer risk and mortality among heavy smokers.[rx]–[rx]
Air Pollution
Lung cancer could be one of the long-term adverse effects of cumulated exposure to ambient air pollution, such as emissions rich in various polycyclic aromatic hydrocarbon compounds, likely through oxidative stress, inflammation, induction of a procoagulatory state, and dysfunction of the autonomic nervous system.[x],[rx] The proportion of lung cancers attributable to urban air pollution in Europe is estimated to be 11%.[rx]
Occupational Exposure
Many work settings could have exposed workers to carcinogens, leading to an increased risk of lung and other cancers. Crystalline silica and chrysotile asbestos are well-known human carcinogens; as expected, workers exposed to silica dust and asbestos fiber are at a higher risk of developing lung cancer. Uranium miners and nuclear plant workers are also known to have an increased cancer risk because of exposure to radioactive particulate mass.[rx]
Lung Cancer Susceptibility Genes
Familial clustering or aggregation of lung cancer has been reported repeatedly in the past 60 years, suggesting a hereditary base to disease development.[rx]–[rx] An increased risk of lung cancer was found in the carriers of TP53 (for expansion of gene symbols, use the search tool at www.genenames.org) germline sequence variations, and carriers who smoked cigarettes are more than 3 times more likely to develop lung cancer than carriers who did not smoke.[rx]
The germline epidermal growth factor receptor (EGFR) T790M sequence variation was reported in a family with multiple cases of NSCLC.[rx] Finally, a genome-wide linkage study of 52 extended families identified a new major susceptibility locus influencing lung cancer risk at 6q23–25p.[rx] Laryngeal and throat cancers were also included in this study. Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:
History of or current tobacco use: cigarettes, pipes, and cigars.[rx]
Exposure to cancer-causing substances in secondhand smoke.[rx,rx]
Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents.[rx]
Beta carotene supplements in heavy smokers.[rx,rx]
Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.[rx]
Other Causes of Lung Cancer
Numerous other substances, occupations, and environmental exposures have been linked to lung cancer. The International Agency for Research on Cancer (IARC) states that there is some “sufficient evidence” to show that the following are carcinogenic in the lungs:[rx]
Some metals aluminumm production, cadmium and cadmium compounds, chromium(VI) compounds, beryllium and beryllium compounds, iron and steel founding, nickel compounds, arsenic and inorganic arsenic compounds, and underground hematite mining)
Some products of combustion (incomplete combustion, coal (indoor emissions from household coal burning), coal gasification, coal-tar pitch, coke production, soot, and diesel engine exhaust)
Ionizing radiation (X-radiation, gamma radiation, and plutonium)
Some toxic gases (methyl ether (technical grade), and bis-(chloromethyl) ether, sulfur mustard, MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture) and fumes from painting)
Rubber production and crystalline silica dust
There is a small increase in the risk of lung cancer in people affected by systemic sclerosis.
Types of Lung Cancer
Types of Lung Cancer.
Lung Cancer Type
% of All Lung
Cancer
Anatomic Location
Squamous cell lung cancers (SQCLC)
25–30%
Arise in main bronchi and advance to the carina
Adenocarcinomas (AdenoCA)
40%
Arise in peripheral bronchi
Large cell anaplastic carcinomas (LCAC)
10%
Tumors lack the classic glandular or squamous morphology
Small cell lung cancers (SCLC)
10–15%
Derive from the hormonal Cells Disseminate into submucosal lymphatic vessels and regional lymph nodes almost without a bronchial invasion
TNM classification of lung cancer in the 6th edition (rx, rx) and proposal for the 7th edition (rx)
6th edition
Proposal for the 7th edition
T
TX
Primary tumor cannot be assessed, or evidence of malignant cells in sputum or bronchial lavage fluid but no visualization of tumor on imaging or bronchoscopy
TX
Primary tumor cannot be assessed, or evidence of malignant cells in sputum or bronchial lavage fluid but no visualization of tumor on imaging or bronchoscopy
T0
No evidence of primary tumor
T0
No evidence of primary tumor
Tis
Carcinoma in situ
Tis
Carcinoma in situ
T1
Tumor ≤ 3 cm greatest diameter, surrounded by lung tissue or visceral pleura, no bronchoscopic evidence of invasion proximal to the lobar bronchus (i.e., main bronchi are free)*1
T1
Tumor ≤ 3 cm greatest diameter, surrounded by lung tissue or visceral pleura, no bronchoscopic evidence of infiltration proximal to the lobar bronchus (i.e., main bronchi are free)*1
T1a
Tumor ≤ 2 cm greatest diameter
T1b
Tumor > 2 but ≤ 3 cm greatest diameter
T2
Tumor > 3 cm or tumor with one of the following features:
T2
Tumor > 3 but ≤ 7 cm with one of the following features:
invasion of the main bronchus, ≥ 2 cm dis tal to the carina
invasion of the visceral pleura
associated atelectasis or obstructive pneumonia extending as far as the hilus but not involving the whole lung
invasion of the main bronchus ≥ 2 cm distal to the carina
invasion of the visceral pleura
Associated atelectasis or obstructive pneumonia extending as far as the hilus but not involving the whole lung
T2a
Tumor > 3 but ≤ 5 cm greatest diameter
T2b
Tumor > 5 but ≤ 7 cm greatest diameter
T3
Tumor of any size with direct invasion of one of the following structures:
T3
Tumor > 7 cm or any tumor with direct invasion of one of the following structures:
chest wall (including tumors of the superior sulcus)
diaphragm
phrenic nerve
mediastinal pleura
parietal pericardium
chest wall (including tumors of the superior sulcus)
diaphragm
phrenic nerve
mediastinal pleura
parietal pericardium
or tumor in the main bronchus < 2 cm distal to the carina, without the involvement of the carina and without associated atelectasis or obstructive pneumonia of the whole lung
or tumor in the main bronchus < 2 cm distal to the carina, without the involvement of the carina and without associated atelectasis or obstructive pneumonia of the whole lung or satellite tumor nodule(s) in the same lobe
T4
Tumor of any size invading one of the following structures:
T4
Tumor of any size invading one of the following structures:
mediastinum
heart
great vessels
trachea
recurrent laryngeal nerve
esophagus
vertebral body
carina
mediastinum
heart
great vessels
trachea
recurrent laryngeal nerve
esophagus
vertebral body
carina
or separate tumor nodule(s) in another ipsilateral lobe
or separate tumor nodule(s) in the same lobe or tumor with malignant pleural* 2 or pericardial effusion
N
NX
Regional lymph nodes could not be evaluated
NX
Regional lymph nodes could not be evaluated
N0
No regional lymph node metastases
N0
No regional lymph node metastases
N1
Metastasis/metastases in the ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including involvement by direct extension of the primary tumor
N1
Metastasis/metastases in the ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary lymph nodes, including involvement by direct extension of the primary tumor
N2
Metastasis/metastases in the ipsilateral mediastinal and/or subcarinal lymph nodes
N2
Metastasis/metastases in the ipsilateral mediastinal and/or subcarinal lymph nodes
N3
Metastasis/metastases in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes
N3
Metastasis/metastases in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes
M
MX
Distant metastases could not be evaluated
MX
Distant metastases could not be evaluated
M0
No distant metastases
M0
No distant metastases
M1
Distant metastases, including separate tumor nodules in another pulmonary lobe
M1
Distant metastases
M1a
Separate tumor nodule(s) in a contralateral lobe; tumor with pleural*2 nodes or malignant pleural (or pericardial) effusion
M1b
Distant metastases
Symptoms and findings of lung cancer and frequency distribution of important symptoms
Symptoms and findings of endobronchial growth
Cough (8% to 75%), hemoptysis (6% to 35%), pain, wheezing (0% to 2%), poststenotic pneumonia, dyspnea (3% to 60%), stridor (0% to 2%)
Weight loss (0% to 68%), night sweats, fatigue, fever (0% to 20%)
Symptoms and findings of distant metastases
Bone pain (6% to 25%), headache, neurological or psychiatric abnormalities, paraplegia, hepatomegaly, pathological fractures
Symptoms of paraneoplastic syndromes
Cushing syndrome, syndrome of inappropriate ADH secretion, Lambert-Eaton syndrome, Perre-Marie-Bamberger syndrome, etc.
Frequency data from [rx]; ADH, antidiuretic hormone
Respiratory symptoms – coughing, coughing up blood, wheezing, or shortness of breath
Systemic symptoms – weight loss, weakness, fever, or clubbing of the fingernails
Symptoms due to the cancer mass pressing on adjacent structures – chest pain, bone pain, superior vena cava obstruction, or difficulty swallowing
If cancer grows in the airways, it may obstruct airflow – causing breathing difficulties. The obstruction can lead to accumulation of secretions behind the blockage, and predispose to pneumonia.[rx]
Depending on the type of tumor, paraneoplastic phenomena—symptoms not due to the local presence of cancer—may initially attract attention to the disease.[rx] In lung cancer, these phenomena may include hypercalcemia, syndrome of inappropriate antidiuretic hormone (SIADH, abnormally concentrated urine and diluted blood), ectopic ACTH production, or Lambert–Eaton myasthenic syndrome (muscle weakness due to auto-antibodies).
Tumors in the top of the lung, known as Pancoast tumors, may invade the local part of the sympathetic nervous system, leading to Horner’s syndrome (dropping of the eyelid and a small pupil on that side), as well as damage to the brachial plexus.[rx]
Coughing, especially if it persists or becomes intense
Pain in the chest, shoulder, or back unrelated to pain from coughing
A change in color or volume of sputum
Shortness of breath
Changes in the voice or being hoarse
Harsh sounds with each breath (stridor)
Recurrent lung problems, such as bronchitis or pneumonia
Coughing up phlegm or mucus, especially if it is tinged with blood
Coughing up blood
If the original lung cancer has spread, a person may feel symptoms in other places in the body. Common places for lung cancer to spread include other parts of the lungs, lymph nodes, bones, brain, liver, and adrenal glands.
Symptoms of lung cancer that may occur elsewhere in the body
frequent chest infections, such as bronchitis or pneumonia
a lingering cough that may start to get worse
shortness of breath
unexplained headaches
weight loss
wheezing
Diagnosis of Lung Cancer
Chest X-ray
A chest X-ray is usually the first test used to diagnose lung cancer. Most lung tumors show up on X-rays as a white-grey mass.
However, chest X-rays can’t give a definitive diagnosis because they often can’t distinguish between cancer and other conditions, such as a lung abscess (a collection of pus that forms in the lungs).
If your chest X-ray suggests you may have lung cancer, you should be referred to a specialist (if you haven’t already) in chest conditions such as lung cancer.
A specialist can carry out more tests to investigate whether you have lung cancer and, if you do, what type it is and how much it’s spread.
CT scan
A computerized tomography (CT) scan is usually carried out after a chest X-ray. A CT scan uses X-rays and a computer to create detailed images of the inside of your body. Before having a CT scan, you’ll be given an injection of a contrast medium. This is a liquid containing a dye that makes the lungs show up more clearly on the scan. The scan is painless and takes 10-30 minutes to complete.
PET-CT scan
A PET-CT scan (which stands for positron emission tomography-computerized tomography) may be carried out if the results of the CT scan show you have cancer at an early stage.
The PET-CT scan can show where there are active cancer cells. This can help with diagnosis and treatment.
Before having a PET-CT scan, you’ll be injected with slightly radioactive material. You’ll be asked to lie down on a table, which slides into the PET scanner. The scan is painless and takes around 30-60 minutes.
Bronchoscopy and Biopsy
If the CT scan shows there might be cancer in the central part of your chest, you’ll have a bronchoscopy. A bronchoscopy is a procedure that allows a doctor or nurse to remove a small sample of cells from inside your lungs. During a bronchoscopy, a thin tube called a bronchoscope is used to examine your lungs and take a sample of cells (biopsy). The bronchoscope is passed through your mouth or nose, down your throat and into the airways of your lungs.
The procedure may be uncomfortable, but you’ll be given a mild sedative beforehand to help you relax and a local anesthetic to make your throat numb. The procedure is very quick and only takes a few minutes.
Other Types of Biopsy
You may be offered a different type of biopsy. This may be a type of surgical biopsies such as thoracoscopy or a mediastinoscopy, or a biopsy carried out using a needle inserted through your skin.
Percutaneous needle biopsy
A percutaneous needle biopsy involves removing a sample from a suspected tumor to test it at a laboratory for cancerous cells.
The doctor carrying out the biopsy will use a CT scanner to guide a needle to the site of a suspected tumor through the skin.
A local anesthetic is used to numb the surrounding skin, and the needle is passed through your skin and into your lungs. The needle will then be used to remove a sample of tissue for testing.
Thoracoscopy
A thoracoscopy is a procedure that allows the doctor to examine a particular area of your chest and take tissue and fluid samples. You’re likely to need a general anesthetic before having a thoracoscopy. Two or three small cuts will be made in your chest to pass a tube (similar to a bronchoscope) into your chest. The doctor will use the tube to look inside your chest and take samples. The samples will then be sent away for tests. After a thoracoscopy, you may need to stay in the hospital overnight while any further fluid in your lungs is drained out.
Mediastinoscopy
A mediastinoscopy allows the doctor to examine the area between your lungs at the center of your chest (mediastinum). For this test, you’ll need to have a general anesthetic and stay in the hospital for a couple of days. The doctor will make a small cut at the bottom of your neck so they can pass a thin tube into your chest. The tube has a camera at the end, which enables the doctor to see inside your chest. They’ll also be able to take samples of your cells and lymph nodes at the same time. The lymph nodes are tested because they’re usually the first place that lung cancer spreads to.
Staging
Once these tests have been completed, it should be possible to work out what stage your cancer is, what this means for your treatment and whether it’s possible to completely cure cancer.
Non-small-cell lung cancer
Non-small-cell lung cancer (the most common type) usually spreads more slowly than small-cell lung cancer and responds differently to treatment. The stages of non-small-cell lung cancer are:
Stage 1
The cancer is contained within the lung and hasn’t spread to nearby lymph nodes. Stage 1 can also be divided into two sub-stages:
stage 1A – the tumor is less than 3cm in size (1.2 inches)
stage 1B – the tumor is 3-5cm (1.2-2 inches)
Stage 2
Stage 2 is divided into two sub-stages: 2A and 2B.
In stage 2A lung cancer, either
the tumor is 5-7cm
the tumor is less than 5cm and cancerous cells have spread to nearby lymph nodes
In stage 2B lung cancer, either
the tumor is larger than 7cm
the tumor is 5-7cm and cancerous cells have spread to nearby lymph nodes
cancer hasn’t spread to lymph nodes but has spread to surrounding muscles or tissue
cancer has spread to one of the main airways (bronchus)
cancer has caused the lung to collapse
there are multiple small tumors in the lung
Stage 3
Stage 3 is divided into two sub-stages: 3A and 3B.
In stage 3A lung cancer, cancer has either spread to the lymph nodes in the middle of the chest or into the surrounding tissue. This can be:
the covering of the lung (the pleura)
the chest wall
the middle of the chest
other lymph nodes near the affected lung
In stage 3B lung cancer, cancer has spread to either of the following:
lymph nodes on either side of the chest, above the collarbones
another important part of the body, such as the gullet (esophagus), windpipe (trachea), heart or into the main blood vessel
Stage 4
In stage 4 lung cancer, cancer has either spread to both lungs or to another part of the body (such as the bones, liver or brain), or cancer has caused fluid-containing cancer cells to build up around your heart or lungs.
Small-cell lung cancer
Small-cell lung cancer is less common than non-small-cell lung cancer.
The cancerous cells responsible for the condition are smaller in size when examined under a microscope than the cells that cause non-small-cell lung cancer.
Small-cell lung cancer only has two possible stages:
limited disease – cancer has not spread beyond the lung
extensive disease – cancer has spread beyond the lung
Chemotherapy combined with radiation therapy and/or surgery
Stages IIIB and IIIC NSCLC
Sequential or concurrent chemotherapy and radiation therapy
Radiation therapy dose escalation for concurrent chemoradiation
Additional systemic therapy before or after concurrent chemotherapy and radiation therapy
Radiation therapy alone
Newly Diagnosed Stage IV, Relapsed, and Recurrent NSCLC
Cytotoxic combination chemotherapy
Combination chemotherapy with monoclonal antibodies
Maintenance therapy following first-line chemotherapy (for patients with stable or responding disease after four cycles of platinum-based combination chemotherapy)
EGFR tyrosine kinase inhibitors (for patients with EGFR mutations)
ALK inhibitors (for patients with ALK translocations)
ROS1 inhibitors (for patients with ROS1 rearrangements)
BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations
Immune checkpoint inhibitor for PD-L1 expressing NSCLC.
Local therapies and special considerations
Progressive Stage IV, Relapsed, and Recurrent NSCLC
Chemotherapy
EGFR-directed therapy
ALK-directed TKI
ROS1-directed therapy
BRAFV600E and MEK inhibitors (for patients with BRAFV600E mutations)
Immunotherapy
ALK = anaplastic lymphoma kinase; BRAF = V-raf murine sarcoma viral oncogene homolog B1; EGFR = epidermal growth factor receptor; MEK = MAPK kinase 1; NSCLC = non-small cell lung cancer; PD-L1 = programmed death-ligand 1; TKI = tyrosine kinase inhibitors; TNM = T, size of tumor and any spread of cancer into nearby tissue; N, spread of cancer to nearby lymph nodes; M, metastasis or spread of cancer to other parts of body.
Drugs and corresponding targets.
Drug
Target
Type
Aflibercept (AVE0005)
VEGF
Humanize VEGFR-trap
AMG 655/Conatumumab
TRAIL-R2
Monoclonal antibody
Apomab
DR5/TRAIL-R2/TNFRSF10B
Monoclonal antibody
Axitinib
PDGFR
Tyrosine kinase inhibitor
Bendamustine
DNA (SSB and DSB)
Alkylating agent
Bevacizumab
VEGF
Monoclonal antibody
Carboplatin
DNA
Small molecule inhibitor
Cediranib
PDGFR
Tyrosine kinase inhibitor
Cediranib
VEGF
Small molecule inhibitor
CI-994
Histone deactylases (HDACs)
Small molecule inhibitor
Cisplatin
DNA
Small molecule inhibitor
Cixutumumab
IGF-IR
Monoclonal antibody
Dalotuzumab
IGF-IR
Monoclonal antibody
Docetaxel
Tubulin
Small molecule inhibitor
Entinostat
Histone deactylases (HDACs)
Small molecule inhibitor
Erlotinib
EGFR
Tyrosine kinase inhibitor
Etoposide
Topoisomerase II
Small molecule inhibitor
Figitumumab
IGF-IR
Monoclonal antibody
Gefitinib
EGFR
Tyrosine kinase inhibitor
Ifosfamide
DNA
Alkylating agent
Iniparib
PARP-1
Small molecule inhibitor
Ipilimumab
CTLA-4
Monoclonal antibody
Irinotecan
Topoisomerase I
Small molecule inhibitor
Linifinib
PDGFR
Tyrosine kinase inhibitor
Mapatumumab
DR4/TRAIL-R1
Monoclonal antibody
Medl-4736
PD-L1
Monoclonal antibody
Motesanib
PDGFR
Tyrosine kinase inhibitor
MPDL-3280A
PD-L1
Monoclonal antibody
Nintedanib
VEGFR-1/2/3, PDGFR-α/β, FGFR-1/2/3, Flt-3, Src family
Multiple target Tyrosine kinase inhibitor
nivolumab
PD-1
Monoclonal antibody
Olaparib
PARP-1
Small molecule inhibitor
Paclitaxel
Tubulin
Small molecule inhibitor
Panobinostat
Histone deactylases (HDACs)
Small molecule inhibitor
Pazopanib
VEGFR-1/2/3, PDGFR-α/β, and FGFR-1 and 3
Multiple target Tyrosine kinase inhibitor
Pemetrexed
Thymidylate Synthase
Small molecule inhibitor
Pembrolizumab/MK-3475
PD-1
Monoclonal antibody
Pivanex
Histone deactylases (HDACs)
Small molecule inhibitor
Romidepsin (Depsipeptide, FK228)
Histone deactylases (HDACs)
Small molecule inhibitor
Sorafenib
VEGFR-2/3, PDGFR-β, c-Kit, Raf, and Flt-3
Multiple target Tyrosine kinase inhibitor
Sunitinib
VEGFR-1/2/3, PDGFR-α/β, c-Kit, Flt-3, and RET
Multiple target Tyrosine kinase inhibitor
Talactoferrin
Immune-modulatory function
Glycoprotein, recombinant
Topotecan
Topoisomerase I
Small molecule inhibitor
Tremelimumab
CTLA-4
Monoclonal antibody
Veliparib
PARP-1
Small molecule inhibitor
Vinblastine
Tubulin
Small molecule inhibitor
Vinorelbine
Tubulin
Small molecule inhibitor
Vorinostat
Histone deactylases (HDACs)
Small molecule inhibitor
YM155/Sepantronium bromide
Survivin
Small molecule inhibitor
Treatment of Early Stage (stage I and Stage II) Non- Small-Cell Lung Cancer
The primary treatment for resectable and operable early stage disease (Stage I and II) is surgery [rx] which provides the best option for long-term survival [rx]. Five-year survival rates after surgical resection are 60%–80% for stage I NSCLC and 30%–50% for stage II NSCLC patients [rx]. For patients refusing surgical resection or with unresectable tumors, primary radiotherapy can be used such as stereotactic body radiotherapy (SBRT) for high-risk patients or unresectable tumors [rx].
However, post-surgery radiotherapy is not recommended for stage I and II patients [rx]. To date, adjuvant platinum-based chemotherapy was shown to be beneficial for stage II NSCLC patients [rx] and is the recommended treatment strategy for completely resected patients [rx]. Conversely, a clear benefit has so far not been proven for adjuvant chemotherapy in stage I NSCLC patients [rx].
Treatment of stage III Non- Small-Cell Lung Cancer
More than 70 % of NSCLC patients are diagnosed in advanced stages or metastatic disease [rx] (stages III and IV). Stage III NSCLC is a heterogeneous disease and varies from resectable tumors with microscopic metastases to lymph nodes to an unresectable, bulky disease involving multiple nodal locations. The 5-year OS rate varies between 10% to 15% for stage IIIA-N2 disease and 2% to 5% for stage IIIA bulky disease with mediastinal involvement. In this heterogeneous population of stage III NSCLC patients, the treatment strategies, including radiotherapy, chemotherapy, and surgical resection are determined by the tumor location and whether it is resectable.
The standard treatment consists of surgery followed by chemotherapy for patients with resectable stage IIIA NSCLC. It has been shown that the adjuvant chemotherapy significantly prolonged OS rate in clinical studies [rx–rx] and that adjuvant radiation therapy can improve control of resected stage IIIA-N2 disease [84]. Meta-analyses of numerous clinical studies showed that neoadjuvant chemotherapy provides a modest 5% to 6% improvement in survival at five years [rx].
For unresectable stage IIIA patients – standard treatment may include either a sequential or concurrent combination of chemotherapy and radiation therapy (chemoradiation), and external radiation therapy for patients who cannot be treated with combined therapy. Meta-analyses of multiple randomized clinical studies showed that platinum-based chemoradiation therapy provides a significant 10% reduction in the risk of death when compared with radiation therapy alone [rx–rx]. Several clinical investigations showed that the radical surgery in Stage IIIA patients with bulky primary tumors may provide up to 50% increase in the 5-year survival rate as compared to patients with incomplete resection [rx–rx].
Eastern Cooperative Oncology Group (ECOG) Performance Status. The ECOG scale and criteria are used to assess how a patient’s disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Treatment of Stage IV Non-Small Cell Lung Cancer
Stage IV NSCLC accounts for 40% of the newly diagnosed NSCLC patients. The choice of treatment for stage IV NSCLC patients depends on many factors including, comorbidity, PS, histology, and molecular genetic features of cancer [rx].
Standard treatment options for stage IV NSCLC disease may include palliative external radiation therapy, combination chemotherapy, combination chemotherapy and targeted therapy, and any Laser therapy or internal endoscopic radiation therapy as needed. Similar to radiation therapy, surgery could also be used in some cases to alleviate disease-related symptoms.
Chemotherapy
For NSCLC, Chemotherapy is usually well tolerated by patients with PS 0 and 1 but rarely effective in patients with a PS 3 and 4 where palliative care is preferred.
Use of chemotherapy is controversial in PS 2 NSCLC patients, which represent nearly 40% of advanced stage NSCLC patients. Chemotherapy is recommended only for PS 2 patients who are reasonably fit, and awake for more than 50 % of the day.
i. First-line Chemotherapy
The median OS is 4.5 months when no chemotherapy is given to advanced metastatic NSCLC or after failure of all treatments. Use of chemotherapy improves the 1-year OS rate from 10%–20% up to 30%–50% [rx]. A combination of two cytotoxic drugs is the recommended first-line therapy for Stage IV NSCLC patients with a PS of 0 or 1.
Platinum (Cisplatin or carboplatin)-based combination therapies yield better response and OS rates than the non-platinum combination therapies. First line platinum-based chemotherapeutics may include doublets of cisplatin or carboplatin given in combination with taxanes (paclitaxel, docetaxel, or vinorelbine), antimetabolites (gemcitabine or pemetrexed), or vinca alkaloids (vinblastine) with comparable activity [rx]. Use of single cytotoxic chemotherapy is preferred in stage IV patients with a PS of 2 due to their greater risk of toxicity and drug intolerance, comparing to patients with a PS of 0 to 1.
ii. First-line combination chemotherapy with targeted therapy
Currently, the addition of bevacizumab, an antibody targeting VEGF, to first-line doublet combination chemotherapy, is supported for the treatment of stage IV NSCLC patients with the exception (squamous carcinoma histology, brain metastasis, significant cardiovascular disease or a PS greater than 1) due to fatal bleeding concerns. The combination of bevacizumab with carboplatin and paclitaxel doublet appeared to be superior to the combination with cisplatin and gemcitabine.
EGFR Tyrosine Kinase Inhibitors (first line)
The first of the approved targeted drugs for NSCLC patients are agents that specifically block the EGFR) such as tyrosine kinase inhibitor (TKI) Erlotinib (Tarceva) and gefitinib (Iressa). Mutations of EGFRs can lead to abnormal activation of this receptor triggering uncontrolled cell growth, which may account for several subsets of cancers including NSCLC.
Evidence from several randomized clinical trials demonstrated that use of single-agent gefitinib as a first-line therapy might be recommended for patients with activating EGFR mutations, particularly for patients who have contraindications to platinum therapy. Conversely, cytotoxic chemotherapy is preferred if EGFR mutation status is negative or unknown.
Three large controlled and randomized trials showed that gefitinib or erlotinib are better than platinum combination chemotherapy as first-line treatment for stage IIIB or IV lung adenocarcinomas in nonsmokers or former light smokers in East Asia [rx,rx,rx,rx].
Maintenance Therapy Following First-Line Chemotherapy
Maintenance therapy is the treatment continuation until disease progression of cancer that has not advanced following the first-line therapy. The primary goal is to improve cancer-related symptoms, and, hopefully, improve survival time beyond that provided by the first-line therapy.
It has lately gained great interest in the treatment of advanced NSCLC (stage IIIB and stage IV) [rx]. Evidence from two randomized controlled clinical trials showed a statistically significant improvement of PFS, with the addition of pemetrexed as maintenance therapy following standard first-line platinum-based combination chemotherapy [rx–rx].
Remarkably, pemetrexed maintenance therapy appears to be effective only in patients with adenocarcinoma and large cell carcinoma as well as in patients with EGFR mutations in their tumors, but not in patients with squamous cell lung carcinoma.
Second- and Third-Line Therapies in the Treatment of Advanced NSCLC
Docetaxel (Taxotere), pemetrexed, erlotinib, and gefitinib, are currently approved as second-line therapy for patients with advanced NSCLC who have failed first-line platinum-based therapy and have an acceptable PS.
Evidence from several randomized clinical trials and meta-analyses [rx–1rx] showed that docetaxel in the second-line setting leads to better survival and quality of life (QoL) when compared to best supportive care [rx] or to single-agent ifosfamide or vinorelbine [rx].
Pemetrexed yielded similar clinical response comparing to docetaxel (a median survival of about 8 months, one-year survival of 30%, and a response rate of 10%) [rx] with better toxicity profile that may benefit older patients with a PS of 3 [rx].
Pemetrexed also provided better outcome in lung adenocarcinoma patients, whereas docetaxel treatment was more effective in lung squamous cell carcinoma patients [rx]. Erlotinib related response was more common in women with adenocarcinoma, never-smokers, or east-Asians, which is correlated with more frequent EGFR activating mutations [rx].
Standard Treatment Options for Recurrent NSCLC
Recurrent or relapsed NSCLC is a cancer that has progressed or returned following an initial treatment with surgery, radiation therapy, and/or chemotherapy. Cancer may return in the lung, brain, or other parts of the body. For NSCLC patients who have never been treated with chemotherapy, the treatment plan is similar to that of Stage IV NSCLC. For those patients who have already been treated with chemotherapy, standard treatment options may include
External palliative radiation therapy, which achieves palliation of symptoms from a localized tumor mass [rx], to relieve pain and other symptoms and improve the quality of life;
EGFR inhibitors (TKIs) in patients with or without EGFR mutations.;
EML4-ALK inhibitor (Crizotinib) in patients with EML-ALK translocations.[rx,rx];
Surgical resection of isolated cerebral metastases (for selected patients who have a very small amount of cancer that has spread to the brain) [rx];
Laser therapy or interstitial radiation therapy using an endoscope (for endobronchial lesions) [rx].
Stereotactic radiation surgery (for selected patients who cannot have surgery) [rx,rx].
Cytotoxic Chemotherapy for Recurrent NSCLC
Evidence from clinical studies showed that use of cytotoxic chemotherapy and targeted therapy may achieve objective responses, albeit with a small improvement in survival for patients with recurrent NSCLC [rx]. In some trials, platinum based chemotherapy has also been shown to achieve palliation of symptoms, which occurred more often than the objective response in patients with good PS [rx,,rx].
Treatment options for NSCLC patients whose cancer has recurred after platinum-based chemotherapy may include either new cytotoxic chemotherapy such as docetaxel [rx,rx] and pemetrexed [rx], or a targeted therapy such as erlotinib [rx], gefitinib [rx], and crizotinib for cancers with EML4-ALK translocations [rx,rx]. Patients with squamous lung carcinomas benefit more from docetaxel, whereas those with non-squamous NSCLC appeared to benefit more from pemetrexed [rx].
EGFR Inhibitors for Recurrent NSCLC
A large randomized phase III trial comparing gefitinib to placebo in recurrent NSCLC patients suggested that gefitinib might be a valid treatment for recurrent NSCLC patients with improved survival compared to placebo in never-smokers[rx], In two large randomized, placebo-controlled trials, erlotinib has also been shown to improve survival and quality of life in patients with recurrent NSCLC after first-line or second-line chemotherapy compared to placebo [rx,rx].
Moreover, erlotinib treatment also induced a greater improvement in patients’ symptoms, such as a cough, pain, and difficulty in breathing, compared to placebo [rx]. Conversely, erlotinib did not improve survival when compared to standard second-line chemotherapy with docetaxel or pemetrexed [rx], in recurrent NSCLC patients after a first-line platinum combination therapy.
ALK/MET Inhibitors for Recurrent NSCLC
Crizotinib therapy has shown improvement in survival of patients with advanced, ALK-positive NSCLC compared to standard therapies for advanced NSCLC [rx] [rx]. Similar to the kinase inhibitors already used in the clinic, such as imatinib and EGFR inhibitors, resistance to crizotinib frequently develops in patients’ tumors [rx].
These tumors might either acquire additional ALK kinase domain mutations (i.e., L1196M, C1156Y mutations) that alter drug sensitivity [rx], or other ALK alterations, including amplification, gain in copy number, and loss of ALK genomic rearrangement [rx].
Furthermore, signaling through other kinases, such as EGFR, might compensate for ALK inhibition, thereby mediating resistance to ALK inhibitors [rx]. Mutation in the KRAS gene was also shown to play a role in resistance to crizotinib and around 8 % of ALK-positive NSCLC patients were shown to harbor either a KRAS or EGFR mutation in addition [rx].
Treatment of Metastatic Lung Cancer
Many phases 3 studies have shown the superiority of systemic chemotherapy over best supportive care in patients with locally advanced and metastatic lung cancer. Platinum-based chemotherapy has been widely accepted as the standard of care.
Several randomized clinical trials, as well as meta-analyses, have suggested the superiority of platinum-based over non–platinum-based therapy.[rx],[rx] Agents such as PTX, docetaxel, gemcitabine, and vinorelbine have been incorporated into platinum-based therapy doublets and have proven to be equally effective.
Chemotherapeutic Regimens
Because of the toxicities associated with platinum-based chemotherapy, non–platinum-based regimens, in particular, taxane-based regimens, have been the focus of intense research. A recent meta-analysis compared platinum-based with non–platinum-based chemotherapy in patients with advanced NSCLC.[rx]
Epidermal Growth Factor Receptor Inhibitors
In 40% to 80% of patients with NSCLC, EGFR is overexpressed, and its overexpression is associated with a poor prognosis.[rx] During the past few years, several EGFR inhibitors have been developed that are in either the receptor TK domain or are monoclonal antibodies.
Gefitinib is the first targeted therapy to be registered and later approved by the Food and Drug Administration (FDA) for use in lung cancer.[rx]Unfortunately, the results from two phase 3 randomized trials of gefitinib failed to show a survival benefit for gefitinib vs placebo. The Iressa Survival Evaluation in Lung Cancer trial was a randomized phase 3 study comparing daily therapy with 250 mg of gefitinib vs placebo.[rx]
Sequence Variations in EGFR and Response to EGFR-TK Inhibitors
The observation that certain subgroups of patients, particularly female patients, those who have never smoked, those who have adenocarcinoma histology, and those who are of Asian descent, have a higher response rate and clinical benefit with gefitinib and erlotinib therapy prompted research to elucidate the molecular mechanism responsible for this increased response. Three research groups have presented studies showing a positive relationship between the presence of activating mutations in the EGFR TK domain and clinical response to gefitinib.[rx]–[rx]
Vascular Endothelial Growth Factor Inhibitors
Vascular endothelial growth factor (VEGF) binds to the VEGF receptors (VEGFRs) VEGFR1 (FLT1) and VEGFR2 (kinase insert domain-containing receptor) on vascular endothelial cells. Activation of VEGFR2 alone is necessary and sufficient to affect the VEGF-induced processes of mitogenesis, angiogenesis, and vascular permeability.
Previous attempts to combine chemotherapy and targeted therapy in lung cancer have been unsuccessful. In fact, several negative studies have compared standard chemotherapy doublet and targeted therapy (including agents such as EGFR inhibitors, antisense molecules, and immune modulators) to first-line regimens. Eastern Cooperative Oncology Group trial E4599[rx]
Stereotactic RT
Stereotactic RT techniques include fixation, ultraprecise treatment planning, RT directed to gross disease alone, and high doses per fraction. They are used to treat small lung tumors (T1-2, N0, M0). In a study of 257 patients, the local control rate was 92% and the 5-year survival rate was 81% for a biologically effective dose of 100 Gy or more. Pulmonary complications (grade, >2) occurred in 5.4% of patients.[rx]
Hadron Therapy
A hadron is a subatomic particle (proton, neutron, or heavy ion) composed of quarks that are influenced by a strong nuclear force. Potential advantages of hadron RT compared with conventional RT (x-rays and electrons) include higher relative biologic effectiveness, higher linear energy transfer, lower oxygen-enhancement ratio, and excellent dose distribution. The major disadvantages of hadron therapy are its complexity and extremely high cost.
Treatment of Second Primary Tumor
A second primary cancer is a separate cancer arising in a patient who had another cancer in the past. Second or higher order primary tumors account for about 6 to 10% of all cancer diagnoses, and are the fifth most commonly diagnosed cancer in Western countries. The risk of developing a second primary cancer may increase with the use of cancer therapies, such as chemotherapy and radiation therapy.
However, it is crucially important to remember that this cancer therapy-related risk is minimal when compared to the benefits of treating the original primary cancer. Patients with lung cancer are at high risk of developing second primary lung cancers. However, it may be difficult to accurately determine whether the new tumor is a second primary cancer or metastasis from original cancer.
Studies have shown that in the majority of lung cancer patients the new lesion is a second primary tumor. When the original primary tumor has been surgically removed, surgical resection of second primary tumors may achieve a 5-year survival rate of 60%, with a comparable expected operative morbidity and mortality to the primary surgery. Tumors 2 cm or smaller are associated with significant positive long-term prognostic factors for survival and freedom from recurrence following resection of the second primary cancer [rx–rx]
Treatment of Brain Metastases
Brain metastases are a common problem in lung cancer patients and a significant cause of morbidity and mortality. Brain metastases are found in about 80% of SCLC and 30% NSCLC at two years from diagnosis [rx,rx]. Among the various histologies of NSCLC, the incidence of brain metastases in patients with adenocarcinoma and large cell carcinoma is greater than in patients with squamous cell carcinoma [rx,rx].
The median survival for untreated lung cancer patients with brain metastases is 4 to 7 weeks [rx–rx]. The treatment may be for the relief of symptoms or therapeutic strategies. Treatment options for lung cancer patients with brain metastases may include Whole Brain Radiotherapy (WBRT), surgical resection, Stereotactic Radiosurgery (SRS), Systemic therapy and Radiosensitization, or a combination of these various treatment modalities.
Whole Brain Radiotherapy (WBRT)
WBRT is the standard of care for cerebral metastasis in lung cancer patients. Several randomized trials have assessed numerous WBRT dose and fractionation schedules but showed no significant difference in either survival times, or symptomatic response rates and duration.
Nevertheless, the results of these trials have suggested better palliative effects from the more prolonged schedules and the choice of dose fractionation schedule should be based on patients’ prognosis [rx].
Additionally, a systematic imaging study of dose-response based on tumor size and histology, following WBRT (30 Gy in 10 fractions) [rx], showed an improved response rate for smaller tumors without necrosis. The complete response rate was 37% for SCLC, 25% for squamous cell carcinoma, and 14% for non-breast adenocarcinoma.
Surgery
In patients with multiple brain metastases, surgery is typically limited to the resection of the dominant, symptomatic lesion. Various studies have shown that surgery combined with adjuvant WBRT or stereotactic radiosurgery (SRS) has similar survival outcome in patients with multiple lesions compared with patients with single brain metastasis or a single lesion [rx–rx].
About 50% of patients treated with resection and postoperative radiation therapy develop recurrence in the brain [118]. Few patients with recurrent brain metastasis and good PS, but without progressive metastases outside of the brain, may be treated with surgery or stereotactic radiation surgery [rx,rx]. However, most patients with recurrent brain metastasis may be treated with additional radiation therapy, albeit with a limited palliative benefit [rx].
Stereotactic Radiosurgery (SRS) with and without WBRT
Stereotactic radiosurgery (SRS) is a form of non-invasive radiation therapy that focuses on high-power energy on a precisely defined small target (e.g. the center of the tumor). The suggested mechanisms of SRS-induced tumor killing are radiation-induced DNA damage, endothelial cell apoptosis, microvascular dysfunction, and induction of T-cell response against the tumor [rx–rx].
Because of the generally small size and well-defined margin of brain metastases at presentation [rx,rx], SRS may be an effective alternative to surgery for up to four small brain metastases (up to 4 cm in size) [rx].
Systemic Therapy and Radiosensitization
In 30–70% of patients with single brain metastasis, lung cancer is the primary disease [rx]. Generally, most chemotherapeutic agents are unable to cross the blood-brain barrier reach the CNS. However, the endothelium leakiness of the tumor vessels, which may disrupt the blood-brain barrier, is well documented in human cancer, particularly in case of macroscopic metastases or relapsed disease.
In keeping, several small phase II studies demonstrated that chemotherapy alone yields response rates of brain metastases of 43%–100% and 0%–38% for metastases from SCLC and NSCLC, respectively [rx]. However, combining chemotherapies (thalidomide, teniposide, topotecan, paclitaxel, and cisplatin) to WBRT did not demonstrate survival benefit although some showed enhanced response rates [rx–rx].
Radiosensitizing agents, such as motexafin gadolinium (Xcytrin) and efaproxyn (efaproxiral or RSR-13), may increase oxygen levels in the tumor and therefore enhance its sensitivity to radiation therapy.
Role of Angiogenesis Inhibitors in NSCLC
Angiogenic pathways provide an important target in NSCLC treatment since they foster tumor growth through the development of new blood vessels. The complex process of angiogenesis is regulated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), as well as angiopoietins [rx].
Currently, only the monoclonal antibody bevacizumab, targeting circulating VEGF, is approved for first-line treatment of advanced NSCLC in combination with platinum-based chemotherapy [rx]. Several anti-angiogenic agents are under clinical investigation, including sorafenib and sunitinib.
Other Molecular Targeted Agents, under Clinical Evaluation for NSCLC Treatment
Talactoferrin
The glycoprotein lactoferrin was first described as an iron-binding protein in breast milk and shows immune-modulatory functions [rx,rx]. The human recombinant lactoferrin, talactoferrin, is given orally, and is able to recruit immature dendritic cells (DC) into the gut-associated lymphoid tissue, where cross-presentation of tumor antigens and subsequent DC maturation can occur [rx].
Preclinical data also showed an increase in splenic NK cell activity and inhibition of NSCLC tumor growth with lactoferrin [rx]. A double-blind, placebo-controlled phase II study using lactoferrin as monotherapy showed improved OS (median 6.1 vs, 3.7 months after a follow-up of 15.2 months).
When combining with chemotherapy (carboplatin and paclitaxel) in treating advanced stage IIIB/IV NSCLC patients, lactoferrin also showed a promising trend for disease-control rates in the intention-to-treat and evaluable population [rx].
Insulin-like Growth Factor Inhibitors
The insulin-like growth factor system (IGF system) comprises two receptors: Insulin-like growth factor 1 receptor (IGF-IR) and IGF-IIR with their respective ligands: Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) and six high-affinity IGF binding proteins (IGFBP) that function as carrier proteins for these ligands. IGF 1 and 2 are involved in the regulation of the development and growth of somatic tissues, as well as carbohydrate metabolism [rx,rx].
The IGF signaling pathway promotes cell growth by stimulating cell proliferation and differentiation. Additionally, IGF-IR, but not IGF-IIR, signaling inhibits apoptosis [rx]. These ligands bind to the extracellular domain of the IGF receptor 1 (IGF-1R), which is expressed on many normal human cells [rx,rx], and overexpressed in many cancers, including lung cancer. Furthermore, increased IGF-1 levels, and decreased IGFBP-3/4 level correlate with a higher risk of lung cancer [rx,rx].
Histone Deacetylase Inhibitors
Histones are nuclear structural enzymes and, as part of the chromatin, are involved in nucleosomal DNA organization and gene regulation. Conformational changes in DNA structure are regulated by histone acetylation and deacetylation, a mechanism that is often affected in tumor cells [rx].
Histone deacetylases (HDACs) are involved in chromatin condensation and repression of gene expression and are frequently overexpressed in many cancers [rx]. Contrary to genetic mutations, the epigenetic modifications induced by HDACs are reversible, and therefore, HDACs are an attractive target for cancer therapy [rx].
Various HDAC inhibitors have been developed and shown to modulate the acetylation status of several important cellular proteins involved in tumor cell growth and proliferation, including p53, HSP90, STAT3, subunits of NFκ-B and α-tubulin [rx,rx,rx].
Pro-Apoptotic Agents
Apoptosis has long been known as a hallmark of cancer, and cancer cells exploit both upregulations of antiapoptotic as well as downregulation of pro-apoptotic mechanisms [rx,rx]. Novel pro-apoptotic drugs are currently being investigated for the treatment of NSCLC. To date, both Mapatumumab, a high-affinity monoclonal antibody against the death receptor DR4/TRAIL-R1, and a pro-apoptotic agent apomab did not show clinical benefit as monotherapy or in combining with chemotherapies (carboplatin and paclitaxel) in clinical trials [rx,rx] [rx] [rx,rx].
A number of other new pro-apoptotic agents, such as Conatumumab (targeting DR1) and YM155 (targeting survivin), are currently under clinical investigation for the treatment of NSCLC and have shown synergistic effects in combination with chemotherapy [rx,rx,rx].
Immunotherapy
Immune Checkpoint Inhibitors
CTLA4
Tumors ascribe certain immune-checkpoint pathways as a chief mechanism of immune resistance, particularly against T cells that are specific for tumor antigens. Several of these immune checkpoints are initiated by ligand-receptor interactions, and thus are amenable to inhibition by antibodies or modulated by recombinant forms of ligands or receptors [rx]. Two monoclonal antibodies, ipilimumab and tremelimumab, have been used successfully in NSCLC against the cytotoxic T-lymphocyte-associated antigen (CTLA-4), an inhibitory T-cell co-receptor found on activated T-cells and regulatory T-cell subsets [rx,rx].
A multicenter double-blind phase II trial showed that the combination of ipilimumab and chemotherapy (carboplatin or paclitaxel) significantly improved the immune-related PFS in advanced stage IIB/IV NSCLC patients with squamous cell carcinoma (without prior chemotherapy) [rx,rx]. Tremelimumab has also been tested in a randomized, phase II trial as maintenance after first-line chemotherapy, compared to best supportive care. However, the results of this trial showed no improvement in PFS [rx].
PD-1 and PD-L1
The immune-checkpoint receptor, programmed death-1 (PD-1), is a promising target, for stimulation of antitumor immune responses by the patient’s own immune system. Unlike CTLA4, the main role of PD-1 is to control the activity of T cells in peripheral tissues at the time of an inflammatory response to infection and to limit autoimmunity [rx–rx]. This translates into a major immune resistance mechanism within the tumor microenvironment [rx–rx].
Another interesting immunotherapeutic option is the direct targeting of PD-1 ligands (PD-L1), B7-H1/PD-L1 and B7-DC/PD-L2. It has been shown that B7-H1/PD-L1 is selectively upregulated in many human cancers including lung cancer [rx,rx]. An encouraging phase I study showed the clinical activity of PD-L1 blocking agents in NSCLC [rx,rx].
A dose-escalation study testing a monoclonal antibody against PD-1 (MDX-1106) in the treatment of refractory metastatic solid tumors (melanoma, renal cell cancer, colon cancer, NSCLC), showed objective responses in five of 49 NSCLC patients [rx].
Vaccine Therapy for NSCLC
Vaccination against pathogens is one of the most important developments in modern medicine and saves millions of lives each year. For advanced NSCLC patients, median OS is about one year, and only 3.5 % survive five years after diagnosis, despite the addition of new therapies to standard chemotherapy [rx].
Therefore, vaccinations for solid tumors, either preventive (for tumors related to infections such as human papillomavirus-associated cervical cancer [rx]) or therapeutic (breaking tolerance and achieving llong-lastingresponse in tumors such as ipilimumab (anti-CTLA-4) in advanced melanomas [rx,rx]), have long been seen as the ultimate treatment option for cancer patients.
Types of vaccine Therapy for NSCLC.
BEC2/BCG
glycosphingolipid GD3
vaccine
Combines a monoclonal antibody
that mimics the glycosphingolipid
GD3 with the adjuvant bacillus
Calmette-Guerin
Belagenpumatucel-L
Allogeneic vaccine
Four irradiated lung cancer cell lines and an antisense plasmid against TGF-beta
CimaVax EGF
EGF vaccine
Cyclophosphamide and EGF
CRS-207
Mesothelin vaccine
Genetically-engineered Listeria monocytogenes
INGN-225
p53 vaccine
Produced from patients’ autologous peripheral blood mononuclear cells (PBMCs)
L-BLP25/emepepimut-S
MUC-1 vaccine
Synthetic peptide derived from the mucin 1
MAGE-A3
Melanoma-associated antigen A3 vaccine
Tumor-specific antigen Mage-A3
PRAME
PRAME vaccine
Recombinant PRAME protein combined with the AS15 Adjuvant System
TG4010
MVA-MUC1-IL2 vaccine
Modified vaccinia Ankara encoding human MUC-1 antigen and interleukin-2
A. MUC1
Mucin-1 (MUC1) is a glycoprotein present on normal epithelial tissue and in various cancers, including NSCLC [rx,rx]. A mutated MUC1protein overexpressed in cancer cells shows aberrant glycosylation pattern that is antigenically different from wild-type protein expressed on normal epithelial cells [rx]. L-BLP25 is a synthetic vaccine against the core peptide of MUC1 combining the peptide with cyclophosphamide as an adjuvant [rx,rx]. Recently updated data from a phase IIB randomized study treating stage IIIB/IV NSCLC patients with L-BLP25 showed significant improvement in the vaccine group comparing to the supportive group (3-year survival rates: 31 vs. 17 % [rx])
B. EGF
CimaVax EGF is a new vaccine that is being developed for NSCLC treatment. This vaccine is made up of low dose cyclophosphamide and EGF. It works as an immunoadjuvant to reduce the inhibition of T-suppressor cells and to stimulate the production of anti-EGF antibodies that may inhibit EGF binding EGFR on cancer cells, and consequently decrease cancer cells growth [rx,rx,rx,rx].
A phase I study showed that the production of anti-EGF antibodies and serum EGF levels after use of the EGF-based vaccine, correlate with increased survival rates in NSCLC patients [rx].
C. Melanoma-associated antigen (MAGE)
Melanoma-associated antigen A3 vaccine (MAGE-A3) uses a tumor-specific antigen, which is expressed in 35 % of NSCLC, most frequently in squamous cell carcinomas [rx]. It ranges from 16 % in stage IA to 48 % in stage IIIB and may be associated with poor prognosis [rx,rx,rx]. The MAGE-A3 vaccine, initially developed for metastatic melanoma patients, showed a positive sign of activity after 28 months in a phase II adjuvant therapy study in early-stage NSCLC [rx]. Prior to treatment, the NSCLC tumors were analyzed by gene expression profiling to identify a gene signature that correlates with the clinical activity of the vaccine [rx].D. TGF beta
E. PRAME
Another important tumor antigen for vaccine therapy is PRAME (preferentially expressed antigen of melanoma), which has recently been shown to contribute to carcinogenesis in NSCLC [rx]. As the name suggests, it was first detected in a melanoma patient [rx], and is expressed in a variety of tumors [rx].
PRAME seems to function via the suppression of the retinoic acid receptor (RAR), a signaling pathway which regulates cell death and cell cycle [rx,rx].
Overexpression of PRAME might be used by tumor cells to escape suppressive RAR signaling, thereby fostering tumor-progression [rx]. Clinical data suggests that poor clinical outcome of some patient subpopulations correlates with PRAME expression in neuroblastoma [rx] and breast cancer [rx–rx].
Targeted Therapies in SCLC
VEGF inhibitors
Inhibition of circulating VEGF with bevacizumab has been studied in ES-SCLC. Chemotherapy naïve patients treated with cisplatin, irinotecan, and bevacizumab, showed an ORR of 75 %, a median OS of 11.6 months, and a median PFS of 7.0 months [rx]. A study investigating cisplatin, etoposide, and bevacizumab in previously untreated ES-SCLC patients showed that a higher baseline level of vascular cell adhesion molecule (VCAM) was associated with a higher risk of progression or death, compared to lower levels of VCAM, but no other biomarkers could be correlated with treatment outcome [rx].
EGFR inhibitors
Mutation of the EGFR is less frequent in SCLC compared to NSCLC, and only around 4% of patients were shown to harbor the mutation [rx]. In a phase II study, patients were stratified according to chemosensitive or chemo-refractory relapsed SCLC and treated with gefitinib. However, the abovementioned study could not demonstrate a gefitinib benefit for SCLC patients [rx].
Bendamustine
This cytotoxic agent causes DNA breaks through its alkylating activity. Compared with other alkylating agents, bendamustine causes more extensive and durable DNA single- and double-strand breaks [rx]. Combining bendamustine with carboplatin in treating ES-SCLC [rx], the ORR was 72.7 %, with a median TTP of 5.2 months and median survival time of 8.3 months. As a single agent in second- and third-line setting in patients with relapsed/refractory SCLC, Bendamustine is well tolerated and effective agent [rx].
Immunotherapy
To date, only a few studies have evaluated immunotherapy in the treatment of SCLC [rx]. The BEC2/BCG vaccine combines a monoclonal antibody that mimics the glycosphingolipid GD3, which is selectively expressed in SCLC, with the adjuvant bacillus Calmette-Guerin [rx].
The BEC2/BCG vaccine has been demonstrated to develop antibodies against GD3 in Melanoma patients. In an early clinical study, although only 30% of the SCLC patients (5/15, ES/LS-SCLC=8/7) developed measurable anti-GD3 antibodies, the median OS was 20.5 months (relapse-free survival was longer in patients who developed measurable anti-GD3 antibodies) ,[rx,[rx]].
Palliative Care for Patients with Lung Cancer
A high percentage of lung cancer patients suffers from substantial symptom burden, including fatigue, loss of appetite and weight loss, as well as dyspnea, hemoptysis, and chest pain [rx]. Better quality of life, lower depressive symptoms, higher median survival and fewer needs on aggressive end-of-life care were observed in patients receiving early palliative care combined with standard oncologic care compared to standard oncologic alone for metastatic NSCLC.[rx]. Megestrol acetate (MA), an appetite stimulant, is one of the supporting treatments that have shown success in treating cancer-related anorexia (CRA) and improve quality of life.
Mesothelin
Mesothelin is an immunogenic glycoprotein specifically overexpressed in malignant mesothelioma, NSCLC, ovarian, and pancreatic cancers [rx]. CRS-207 is a genetically-engineered, double-deleted bacteria Listeria monocytogenes strain expressing the human mesothelin [rx]. Phagocytic cells, such as macrophages and dendritic cells, take up CRS-207, and mesothelin is subsequently expressed and processed through the MHC I presentation pathway.
This process is predicted to activate T cells in order to attack mesothelin-positive mesothelioma cells. In preclinical studies, CRS-207 was shown to elicit anti-mesothelin cell-mediated immunity [rx]. In a phase I dose-escalation study treating patients with advanced mesothelin expression and treatment-refractory cancers, with CRS-207, mesothelin-specific T-cell responses were in one of five patients with mesothelioma, with 15 months or more survival after the first dose [rx]. Patients who received sequential CRS-207 treatment with prior immunotherapy or subsequent local radiation therapy benefited the most. CRS-207 is currently investigated in combination with first-line chemotherapy in mesothelioma patients.
WT1 analog peptide vaccine
The transcription factor Wilms’ tumor suppressor gene 1 (WT1) is frequently overexpressed in mesothelioma and other solid and hematopoietic tumors [rx]. Recently, a multivalent WT1 peptide analog vaccine was developed [rx]. A CD-4+ T-cell proliferation to WT1-specific peptides was seen in six of nine patients, and a CD8+ T-cell response was detected in six of six HLA-A0201 patients in an early study investigating the WT1 peptide analog vaccine in MM and NSCLC patients. Stimulated T-cells also showed cytotoxicity against WT1 positive cells [rx]. A subsequent randomized phase II study is currently investigating the adjuvant WT1 analog peptide vaccine in MM patients who have completed combined modality therapy [rx].
Dendritic cell vaccine
Dendritic cells (DCs) are the most potent antigen-producing cells, capable of sensitizing T cells to both new and recall antigens. DC-based cancer immunotherapy is aimed at using these cells to prime specific antitumor immunity through the generation of effector cells that attack and kill tumors. Dendritic cells can be matured using a standard cytokine cocktail and pulsed with autologous tumor cell lysates, which presents a source of tumor antigens for immunotherapy [rx].
How Do You Get Rid of Smell Down There/ Vaginal odor is any odor that originates from the vagina. It’s normal for your vagina to have a slight odor. But, a strong vaginal odor, for instance, a “fishy” smell might be abnormal and could indicate a problem. The abnormal vaginal odor that happens because of infection or another problem is usually associated with other vaginal signs and symptoms such as itching, burning, irritation or discharge.
Having a healthy vagina is extremely important to overall health, healthy births, and healthy marriages, and vaginal odor can be a signal that there might be a health issue at play. How this affects a woman’s self-esteem is another side effect, not to mention how it can affect her relationship with her significant other due to the impact it may have on their sex life.
Causes of Vaginal Odor
Common causes of abnormal vaginal odor include
Bacterial vaginosis
Poor hygiene
A retained or forgotten tampon left in place for several days
Trichomoniasis
Rectovaginal fistula (an abnormal opening between the rectum and vagina that allows feces to leak into the vagina)
Cervical cancer
Vaginal cancer
Vaginal Secretions
Perspiration
pH imbalance
Menstruation
Sexual Intercourse
Infection
Symptoms of Vaginal Odor
A bad smell could be due to genital infection or disease. Clues include:
Treatment is typical with the antibiotics metronidazole or clindamycin. They can be either given by mouth or applied inside the vagina. About 10% to 15% of people, however, do not improve with the first course of antibiotics and recurrence rates of up to 80% have been documented. Recurrence rates are increased with sexual activity with the same pre-/posttreatment partner and inconsistent condom use although estrogen-containing contraceptives decrease recurrence. When clindamycin is given to pregnant women symptomatic with BV before 22 weeks of gestation the risk of pre-term birth before 37 weeks of gestation is lower.
Other antibiotics that may work include macrolides, lincosamides, nitroimidazoles, and penicillins.
Bacterial vaginosis is not considered a sexually transmitted infection, and treatment of a male sexual partner of a woman with bacterial vaginosis is not recommended.
Probiotics
A 2009 Cochrane review found tentative but insufficient evidence for probiotics as a treatment for BV.A 2014 review reached the same conclusion. A 2013 review found some evidence supporting the use of probiotics during pregnancy
If you’re concerned about an abnormal or long-standing vaginal odor, please see your doctor, especially if you have other signs and symptoms, such as itching, burning, irritation, or weird discharge.
In order to prevent having a malodourous vagina, here are a few tips to help everyone
Wash your genital area – Even though the vagina will clean itself inside your body with natural secretions, during your regular baths or showers, use a very small amount of mild, unscented soap and lots of water to wash the area. It’s better to not use perfumed soaps, gels, and antiseptics as these can affect the healthy balance of bacteria and pH levels in the vagina and cause irritation, which may lead to inflammation. During your period, wash the area more than once a day. Also, wash after intercourse – I don’t mean after each “round” but do not make it a habit to wait hours after sexual activity to clean up. It’s also important to note that keeping the perineal area (between the vagina and anus) clean is essential too.
Avoid douching – All healthy vaginas contain nature-approved bacteria and yeast. The normal acidity of your vagina helps to keep these bacteria and yeast in check. A douche flush water up into the vagina and then out, clearing any and all vaginal secretions. All douching does is washes out the vagina – including all the healthy stuff thus affecting the natural balance of your vagina.
Practice safe sex. In this era of all sorts of sexually transmitted infections, this point cannot be overstressed!
Organisms that cause chlamydia, gonorrhea, genital herpes, genital warts, syphilis, and HIV are all transmitted through sex.
Abstinence is still the only fool-proof way to avoid these infections. Where you cannot abstain, if you are unmarried, ensure you have only one partner with whom you are having protected intercourse with. A simple trick to abstinence is telling your prospective sexual partner that you both need to get tested and certified in order to ensure that you are both clear of any infections before any rolling in the hay can take place!
Practice gentle hygiene
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Showering after exercise to remove sweat and using fragrance-free soap on just the vulva may help to reduce vaginal odor.
Safe, gentle vaginal hygiene practices can reduce vaginal odor. Some strategies include
Wiping front to back: This prevents fecal matter from getting into the vagina.
Urinating immediately after sex.
Using a gentle, fragrance-free soap on the vulva only. Inserting soap into the vagina can alter vaginal pH, causing infections and a foul odor.
Changing underwear daily, or when underwear is sweaty or soiled.
Washing underwear in unscented products.
Showering after sweating or exercise as trapped sweat can increase vaginal odor.
Washing the vulva with water if there is an unpleasant odor. Between showers, women can use a washcloth to gently wipe down the area, removing sweat and other sources of odor.
Tips for preventing future odor
Once you eliminate the unusual vaginal odor, keep these tips in mind for preventing another problem later
Consider probiotics. Probiotics, which are good-for-you bacteria, can help maintain the pH balance in your vagina. Probiotic-rich foods include yogurt, kombucha, and unpasteurized sauerkraut.
Maintain a healthy diet. Aim to eat a balanced diet with plenty of fruits, vegetables, whole grains, and lean proteins. A balanced diet makes for a healthy body, and that includes your vagina.
Stay hydrated. Drinking plenty of water is good for more than just your skin. It can help your vagina’s overall health, too, by encouraging healthy sweating and fluid release.
Avoid douches and scrubs. You might think they’ll help eliminate bad bacteria, but they also eliminate the good bacteria. Let your body work out the bacteria ratios, and skip these unnatural washes.
Wash your vagina before and after intercourse. Sex introduces bacteria, as well as foreign substances like lubrication and spermicide from condoms. Wash before and after sex to help maintain natural bacteria levels.
Cut out tight clothes. Clothes that are too tight don’t let your vagina and groin area breathe. Getting plenty of oxygen is vital to good vaginal health.
Wear cotton panties. Cotton panties wick away excess moisture from sweating or discharge. Synthetic fabrics are not as good at this.
What is the best painkiller for a toothache/ Dental Pain also is known as dental pain is a pain in the teeth and/or their supporting structures, caused by dental diseases or pain referred to the teeth by non-dental diseases? Common causes include inflammation of the pulp, usually in response to tooth decay, dental trauma, or other factors, dentin hypersensitivity (short, sharp pain, usually associated with exposed root surfaces), apical periodontitis (inflammation of the periodontal ligament and alveolar bone around the root apex), dental abscesses (localized collections of pus, such as apical abscess, pericoronal abscess, and periodontal abscess), alveolar osteitis (“dry socket”, a possible complication of tooth extraction, with loss of the blood clot and exposure of bone), acute necrotizing ulcerative gingivitis (a gum infection, also called “trench mouth”), temporomandibular disorder and others.
A toothache is the most common cause of oral pain [rx]. Although fractured teeth and exposed dentin may produce dentin hypersensitivity and cause dental pain [rx], untreated dental decay has been reported as the most important reason for a toothache which can impact routine daily activities such as eating, studying, concentrating on delicate tasks, and so on [rx–rx]. Several investigations that studied the impact of dental and facial pain emphasized that tooth and mouth diseases directly influence the quality of life in a community [rx, rx].
A wide range of toothache prevalence has been reported from 5% to 88% [rx–rx]. Dental pain has been confirmed as a public health problem [rx]. A recent investigation of children and adolescents revealed that overall, about one-tenth of patients complaining of pain suffered from a toothache [rx].
Causes of Dental Pain
Infection
Gum disease
Grinding teeth (bruxism)
Tooth trauma
An abnormal bite
Tooth eruption (in babies and school-age children)
A toothache in or around a tooth or several teeth caused by different factors can lead to crippling pain.
Gum inflammation
Gum disease
Tooth decay
Damaged tooth filling
Abscessed tooth
Infected gums
Tooth fracture
Even teeth grinding
Severe, persistent gum pains;
Pain when you open your mouth wide;
Migraines and fevers caused by mouth pains;
Consistent bad tasting fluids draining from your gum.
Toothaches are sometimes sharp, dull, intermittent or persistent. To feel the pain in some instances, you have to press against the tooth or gum.
TMJ/TMD (Temporomandibular Joint Disorder), sinus or ear infections, and tension in the facial muscles can cause discomfort that resembles a toothache, but often these health problems are accompanied by a headache.
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Pain around the teeth and the jaws can be symptoms of heart disease such as angina. If your dentist suspects a medical illness could be the cause of your toothache, he or she may refer you to a physician
Symptoms of Dental Pain
Because the symptoms of a toothache may resemble other medical conditions or dental problems, it can be difficult to diagnose the cause without a complete evaluation by your dentist. If you notice pus near the source of the pain, your tooth may have become abscessed, causing the surrounding bone to become infected. Or the pus could indicate gum disease, which is usually characterized by inflammation of the soft tissue, bleeding gums and abnormal loss of bone surrounding the teeth.
Contact your dentist immediately if you have any of the following symptoms:
Fever
Difficulty breathing or swallowing
Swelling around the tooth area
Pain when you bite
A foul-tasting discharge
Continuous lasting pain
While tooth decay is often the primary cause of a toothache, it’s important for you to have a complete oral examination to determine the cause. Other causes of a toothache can include the following.
Parameter
Dentin hypersensitivity:
Reversible pulpitis:
Irreversible pulpitis
Pulp necrosis
Apical periodontitis
Periodontal abscess
Pericoronitis
Myofascial pain
Maxillary sinusitis
Site
Poorly localized
Poorly localized
Variable; localized or diffuse
No pain
Well localized
Usually well localized
Well localized, associated with a partially impacted tooth
Diffuse, often over many muscles
Back teeth top jaw
Onset
Gradual
Variable
Variable
From the pain of reversible pulpitis to no pain in days
Gradual typically follows weeks of thermal pain in the tooth
Sudden, no episode of thermal sensitivity
Sudden
Very slow; weeks to months
Sudden
Character
Sharp, quickly reversible
Sharp, shooting
Dull, continuous pain. Can also be sharp
No pain
Dull, continuous throbbing pain
Dull, continuous throbbing pain
Sharp, with continuous dull
Dull, aching
Dull, aching, occasional thermal sensitivity in back top teeth
Radiation
Does not cross the midline
Does not cross the midline
Does not cross the midline
N/A
Does not cross the midline
Little, well localized
Moderate, into jaw/neck
Extensive, neck/temple
Moderate, into other facial sinus areas
Associated symptoms
The patient may complain of receding gums and/or toothbrush abrasion cavities
Can follow restorative dental work or trauma
Follows period of pain that does not linger
Follows the period of spontaneous pain
The tooth may feel raised in the socket
May follow the report of something getting “stuck” in gum
Tooth eruption (“cutting”) or impacted tooth
Tension headaches, neck pain, periods of stress or episode of mouth open for long period
Hypersensitivity as long as the stimulus is applied; often worse in cold weather
Pain as long as the stimulus is applied
Lingering pain to hot or cold or spontaneous pain
The absence of pain following days or weeks of intense, well-localized pain
Pain on biting following constant dull, aching pain development
Dull ache with an acute increase in pain when the tooth is moved, minimal thermal sensitivity
Constant dull ache without the stimulus
Spontaneous, worse with eating, chewing, or movement of jaw
Spontaneous, worse when head is tipped forward
Exacerbating and relieving factors
Exacerbating: thermal, particularly cold
Exacerbating: thermal, sweet
Simple analgesics have little effect
Prolonged heat may elicit pain
Same as irreversible pulpitis, or no response to cold, lingering pain to hot, pain with biting or lying down
Tapping tooth makes worse, the cleansing area may improve pain
The cleansing area can improve pain
Rest or ice makes pain better, movement and chewing make it worse
Tilting head forward, jarring movements (jumping) make pain worse
Severity
Less severe than pulpitis
Severe, for short periods
Variable; pain dissipates until periapical tissue affected
Severe
Severe
Severe
Mild to severe
Mild to moderate
Mild to severe
Effect on sleep
None
None usually
Disrupts sleep
None
Disrupts sleep
Variable, can disrupt sleep
If moderate to severe will disrupt
Unusual
Unusual
Treatment of Dental Pain
Acetaminophen
An over-the-counter medicine like acetaminophen is useful in treating toothaches, and it’s the most common medications given after dental treatment, according to the American Dental Association. The National Institutes of Health notes that acetaminophen is an analgesic and changes the way your body perceives pain, which is what makes an ache tolerable.
NSAIDs
Toothaches are often accompanied by inflammation, swelling, and redness of the gums, or irritation to other parts of the mouth.
These symptoms may benefit from taking an anti-inflammatory, such as naproxen or ibuprofen, Etoricoxib as a single dosage with metronidazole and PPI (or any of the other nonsteroidal anti-inflammatory drugs (NSAIDs). You should only take one of these medications if you know for certain that you have no allergies to the ingredients, and you should always ensure you take an NSAID with food to avoid irritation to the stomach.
Holding an ice pack or a package of frozen peas to the outside of your face can be surprisingly helpful. The cold helps numb the pain. Apply the ice for a few minutes at a time and then take a break.
Topical Medication
Products such as benzocaine applied directly to the tooth can also provide you with some short-term relief from pain. Your dentist may recommend Colgate Orabase 20% Benzocaine for this purpose, as it contains 20% Benzocaine to provide clinically proven pain relief for mouth irritations.
Ice Packs
Avoid Hard Foods
Toothaches are frequently caused either by a broken tooth or a dental cavity, so until you are sure of the reason for your pain, it’s best to take precautions. While you’re waiting for and directly after toothache treatment, sticking to soft foods will help you to avoid further damage to brittle or sensitive teeth.
Keep it Clean
It is essential to maintain good dental hygiene even when you have a toothache. If it’s too painful to perform your regular daily brushing and flossing, try a product such as Colgate Peroxyl Mouth Sore Rinse. The bubbling action cleans and alleviates discomfort to promote healing. It’s not always convenient to get the treatment you require at the time you need it, but these options will help reduce the pain enough to see you through until you can get professional help.
Home Remedies for a Toothache
Cloves
Cloves contain a chemical called eugenol. Eugenol is an anesthetic chemical, means it numbs the nerves and stops the sensation of pain. Eugenol also has antiseptic properties that help kill germs. You can also use Clove oil to treat the pain. Just dab a small cotton ball and rub the oil on the tooth which has pain. You can use the clove or clove oil remedy up to 3 times a day, Eugenol can be poisonous if consumed in high amounts.
Asafoetida (Hing)
For this, you will need a tablespoon of orange juice as well. Just mix a pinch of Asafoetida in the orange juice and dab a cotton ball in the mix. Place this cotton ball on the painful teeth or the jaw for 5 to 10 minutes. This remedy works immediately in reducing pain and hence it is very popular.
Ice Cube
Massage the jaws near the painful teeth for 3 to 4 times in a day with an Ice cube. A 5-minute massage with Ice cube can significantly lower the inflammation and pain.
Salt mouthwash
A toothache caused by mild infection or injury will be reduced by time. To fasten this process, mix 1 tablespoon of salt in a cup of lukewarm water. Now take a gulp of this water in your mouth and squish it over the painful area. Repeat this 2-3 three times and the pain will be eased off.
Garlic
Garlic has antibiotic properties and the ability to fight various types of infection. If your toothache is due to some type of infection, and cure the pain. You can simply chew a clove of Garlic or you can mash the garlic clove to make a paste and apply the paste on the tooth. Garlic has Elicin, a chemical which is a potent antibiotic. Remember to use fresh garlic or freshly made garlic paste.
Instant Relief from Toothache
A mouth rinse with alcohol (Hard drinks like whiskey or vodka) provides instant relief from a toothache. Alcohol numbs the nerve fibers in the jaws immediately and prevents the sensation of pain.
Should you go see a Dentist?
Yes, you should see a doctor, if the pain lasts more than a day. If the pain is not resolved and persistent, you should visit a Dentist. Upon inspection and diagnosis of the problem, a dentist may advise you to go for many Orthodontal procedures such as tooth extraction, root canal surgery or if the tooth has a cavity; get a filling done. The longer you avoid to visit the doctor, the worse pain will get.
If a toothache isn’t treated properly, the dental pulp can eventually become infected. This can lead to serious dental problems with severe and throbbing pain.
Allopathic treatment for a toothache
The treatment for a toothache will depend on the reason for the pain. Your dentist will observe your teeth, jaws and may carry out an X-ray to try to rectify the cause of pain. Some of the commonly practiced medicines and procedures are listed below:
Hydrogen Peroxide
Dip a Q-tip in the Hydrogen peroxide and apply it to the affected tooth. This will clean the area around and help in numbing the pain for some time. Keep the hydrogen peroxide for 2-3 minutes in the mouth, then rinse it off with clean water. Do not swallow it
Painkillers
You can take painkillers such as Acetaminophen or Ibuprofen orally to control tooth pain. If the patient is an adult then aspirin can be given to him. Aspirin is not advised to children to reduce the tooth pain.
Dental Filling
A dentist will clean the decayed area (cavity) and fill it with a filling substance.
In some cases, the filling gets loose due to wear-and-tear over time, Then the dentist will remove old filling and replace it with a new one.
Root Canal
Root canal treatment is administered when the dental pulp is severely infected and damaged. It is a serious surgical procedure. Depending on your teeth condition, root canal treatment can take up to 2-5 sessions with a dentist if. In this procedure, a dentist will completely remove the infected dental pulp then fill the teeth with a special type of filling. The doctor will also seal the treated tooth with a dental crown and cap to prevent future infections.
Dental Implants
Many times the decay occurs on a critical area of teeth and it becomes difficult to treat it by above-discussed methods. Then the doctor will have to remove the affected teeth. The doctor will fix a dental implant to replace the removed tooth.
Preventing Toothache
The best way to prevent getting a toothache and many other dental problems; is to keep your gums and teeth as healthy as possible. To maintain good health of teeth and gums, you should follow these steps:
Brush twice
Use a toothpaste that contains fluoride to brush your teeth twice every day. The best times to brush, as usual; are before breakfast in the morning and before going to bed at night. Gently brush your gums and tongue as well.
Dental Floss
Sometimes, the bristles of a toothbrush are not capable of cleaning the teeth thoroughly. Just use a thin dental floss to remove dirt from in-between the teeth. If you feel like it, use a freshening mouthwash.
Control Sugar intake
Avoid the consumption of sugary foods and drinks. Sugar residues on teeth and gums can encourage the growth of bacteria and trigger the infection.
Avoid Tobacco
Chewing of Smoking tobacco can cause tooth decay and oral cancer. Tobacco can worsen many dental problems.
Examine Regularly
Visit your Dentist at regular intervals to get your teeth tested. Well, the gap between check-ups can vary, depending on the health and condition of your teeth. Go for check up at every 6 months, and prevent decay or other dental problems.
Which Painkiller is Best For Period Pain/ Period pain is the regular discharge of blood and mucosal tissue (known as menses) from the inner lining of the uterus through the vagina. The first period usually begins between twelve and fifteen years of age, a point in time known as menarche. However, periods may occasionally start as young as eight years old and still be considered normal.[2] The average age of the first period is generally later in the developing world, and earlier in the developed world. The typical length of time between the first day of one period and the first day of the next is 21 to 45 days in young women, and 21 to 31 days in adults (an average of 28 days). Bleeding usually lasts around 2 to 7 days. Menstruation stops occurring after menopause, which usually occurs between 45 and 55 years of age. Periods also stop during pregnancy and typically do not resume during the initial months of breastfeeding.
How Can I Relief From Menstrual Pain/ Period Pain
Non-Steroidal Anti-Inflammatory Drugs
The different formulations of NSAIDs have similar efficacy for dysmenorrhoea, and pain relief is achieved in most women. Between 17% and 95% (mean 67%) of women achieve pain relief with an NSAID.[rx]Compared with placebo treatment, the number needed to treat is 2.1 for at least moderate pain relief over three to five days.[rx]
Gastrointestinal effects (nausea, vomiting, and/or diarrhea) are of particular concern with NSAIDs. Effects are generally tolerable, but when treating women with risk factors for NSAID induced ulceration, the potential risks and benefits of using an NSAID should be considered.
If an NSAID is offered in this situation, a gastroprotective agent may be useful. Women with a history of gastroduodenal ulcer, gastrointestinal bleeding, or gastroduodenal perforation should probably seek alternatives.
COX 2 Specific Inhibitors
A review of the newest generation of anti-inflammatories has shown that COX 2 (cyclooxygenase-2) specific inhibitors are effective for dysmenorrhoea. Questions about the cardiovascular and cardioprotective safety of COX 2 inhibitorsw10 remain unresolved, however, and these drugs have been withdrawn from use in many countries.
Oral Contraceptives
Good quality clinical trials of oral contraceptives for dysmenorrhoea are lacking.[rx] One recent RCT found that low dose (or combined) oral contraceptives significantly reduced pain compared with placebo. Another recent trial found, however, that although a reduction in dysmenorrhoea was reported in the group who received the oral contraceptive, a similar reduction occurred in the group who took a placebo, with no significant differences between the two groups.
In an open clinical trial of a combined oral contraceptive involving 100 000 women, 65% (23 500 women) of those who had dysmenorrhoea as a pre-existing condition felt relief from dysmenorrhoea as a result of treatment. Therefore, despite a lack of many high-quality RCTs in this area, there is some evidence in general populations that combined oral contraceptives can effectively treat dysmenorrhoea.
Levonorgestrel-Releasing Intrauterine System
The levonorgestrel-releasing intrauterine system releases levonorgestrel (20 μ/day) into the uterine cavity for at least five years, thus preventing the thickening of the lining of the uterus. Up to 50% of women using it become amenorrhoeic after 12 months and reduction in dysmenorrhoea was spontaneously reported by women in non-randomised studies.[rx]
The levonorgestrel-releasing intrauterine system has also been shown to be effective in reducing dysmenorrhoea in an RCT of women with endometriosis after one year.[rx] It should be noted that non-hormone intrauterine devices may result in dysmenorrhoea and may require removal if adequate pain relief is not provided with analgesics.
Combined Drug Treatments and Less Common Drug Treatments
A combination of analgesics and the oral contraceptive or the Mirena intrauterine device is also an option in cases that do not respond to a single treatment. For the small percentage of patients who do not respond to these treatments or to combination treatment, other options exist.
Herbal products or medicines, and dietary supplements the evidence[rx][rx]
Thiamine
One study has shown that 100 mg of thiamine (vitamin B-1) taken daily may be an effective cure for dysmenorrhoea: 87% of patients were cured up to two months after treatment.
Pyridoxine and magnesium
Some evidence also exists that pyridoxine (vitamin B-6) supplements, taken alone or with magnesium, can reduce pain, but more research is needed to confirm this. Magnesium may also be an effective treatment. Women in some trials of magnesium experienced a reduction in period pain and a lowering of prostaglandins in their blood.
The therapeutic dose is unclear, however, as magnesium supplements were used several ways (daily or during pain). In addition, some women stopped taking magnesium during the trials, possibly owing to lack of benefit or due to adverse effects such as constipation.
Fish oil
The use of fish oil capsules (omega 3 fatty acids) may also reduce pain, although more research is needed; adverse effects associated with fish oil treatment were mild and included nausea and worsening of acne.
Progestogens and Antiprogestogens
Progestogens such as medroxyprogesterone acetate and gestrinone induce anovulation with resulting amenorrhoea and therefore can successfully treat the symptoms of dysmenorrhoea in women with endometriosis.[rx],[rx]
Gonadotrophin Releasing Hormones and Danazol
Gonadotrophin-releasing hormones and danazol confer the same degree of pain relief.[rx] The side effect profiles of these treatments are different, however, with danazol having more androgenic side effects, while gonadotrophin releasing hormones tend to produce more hypo-oestrogenic symptoms. Further studies are also required to establish the optimal supplementation or “add back” regimen of estrogen for limiting adverse effects.[rx]
Calcium Channel Blockers
Calcium antagonists can reduce myometrial activity and relieve dysmenorrhoea by controlling the cytoplasmic concentration of free calcium and thereby the contractions of the uterine muscle. None, however, are licensed for this indication.[rx]
Alternative Therapies
In all, 10-20% of women with primary dysmenorrhoea do not respond to treatment with NSAIDs or oral contraceptives. In addition, some women have contraindications to these treatments. Consequently, researchers have investigated many alternatives to drug treatments.
Herbal Products or Medicines, and Dietary Supplements
Herbal and dietary therapies are popular as they can be self-administered and are available from health shops, chemists, and supermarkets. This availability, although helpful, can create problems with the control of dosage, quality, and drug interactions.
Systematic reviews and RCTs of herbal and dietary supplements have shown that thiamine, pyridoxine, magnesium, and fish oil may be effective in relieving pain, although some of these may be associated with adverse effects (see box).[rx],[rx] A Bandolier review found evidence from three small RCTs that vitamin E was effective in treating dysmenorrhoea, but it advises caution in use owing to potential adverse effects when used in high doses.[rx]
Dietary changes
One RCT has shown a significant association between a low-fat vegetarian diet and a reduction in symptoms (perhaps by influencing prostaglandin metabolism), but the trial was too small (33 women) to give conclusive results.[rx]
Exercise
Physical exercise may reduce dysmenorrhoea. Current studies have too many methodological flaws, however, to be able to confirm results. It is hypothesized that exercise works by improving blood flow at the pelvic level as well as stimulating the release of β endorphins, which act as non-specific analgesics.
Transcutaneous Electrical Nerve Stimulation
Transcutaneous electrical nerve stimulation (TENS) involves stimulation of the skin using current at various pulse rates (frequencies) and intensities to provide pain relief.
A Cochrane systematic review found limited evidence from small trials that high frequency transcutaneous electrical nerve stimulation reduces pain[rx]; 42-60% of patients had at least moderate relief, and less use of additional analgesics was needed in one RCT.
Acupuncture
Acupuncture excites receptors or nerve fibers, which, through a complicated interaction with serotonin and endorphins, block pain impulses. A Cochrane systematic review found one RCT showing that acupuncture significantly reduces pain, but more research is needed to confirm this finding.[rx]
Heat
Heat therapy has been a traditional home remedy for dysmenorrhoea. One RCT has compared its use with the NSAID ibuprofen.[rx] The heat patch (39°C) used for 12 hours a day was found to be as effective as ibuprofen (400 mg three times a day) and more effective than placebo in reducing pain.
Women using both the heat patch and ibuprofen experience the most pain relief. Another RCT found a heat wrap was better than paracetamol for pain relief over an eight hour period.[rx]
Spinal Manipulation
A Cochrane systematic review of five RCTs found no significant difference between spinal manipulation and placebo manipulation.[rx]
Many women experience some levels of discomforts during periods. Fortunately, the symptoms can be prevented or reduced by taking the right foods.
Many factors are said to contribute to the discomforts during your period which manifests as inflammation (pain), bloating, fatigue, mood swings, cramps, headaches, and digestive issues.
Proteins and Fats
When you consume healthy carbs with plenty of good proteins, the pancreas responds by secreting a measured amount of insulin and fats which in turn causes the glucose from the meal enters your blood slowly.
Therefore, taking proteins foods such as eggs along with pure butter for your breakfast can help stabilize blood sugar as well as make you feel less hungry throughout the morning. Take more protein foods for lunch and dinner too and don’t forget to consume lots of veggies for every major meal.
Coconut Oil
Unstable blood glucose causes you to experience mood swings during your period. High glucose levels promote inflammation. Taking 1 tablespoon coconut oil, 3 X per day can help stabilize your blood sugar.
Green Vegetables
Green vegetables offer antioxidants phytonutrients, including carotenoids, bioflavonoids, lignins, and stilbenes, all of which also help reduce inflammation. Magnesium that’s located at the center of chlorophyll also acts as an anti-inflammatory.
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Studies have shown that dietary magnesium insufficiency is more common in adolescent girls and women, and worsens with age.
Cramps, headache, pain in certain parts of the body or the whole body is a sign of inflammation – C – reactive protein (CRP) levels are always high. CRP is a protein, also called a marker of inflammation, produced by the liver when there is inflammation in the body. All phytonutrients, magnesium (balanced by calcium), and potassium are thought to increase nitric oxide levels, a vital compound for relaxing your muscle and dilate your blood vessel. Magnesium and potassium also help relax the muscle and via their parasympathetic pathways.
The point I would like to make here is that taking green veggies while on period may help prevent or reduce headaches and cramps. Dark green vegetables are loaded with vitamin K, which coagulates blood and prevents excess bleeding.
Colorful Vegetables and Fruits
Colorful fruits and veggies are loaded with significant amounts of antioxidant and anti-inflammatory phytonutrients that include carotenoids, polyphenols, bioflavonoids. Lignins, and stilbenes. Vitamin C in and citric acid also contribute to antioxidant properties in fruit. Many veggies are also loaded with vitamin C. All these antioxidant and anti-inflammatory phytonutrients and organic acids can reduce menstrual cramps and headaches. Fruits and vegetables also provide fiber and water, which can help reduce bloating and reduce pain.
Omega-3 Fatty Acids
Prostaglandins, a group of hormone-like substances in the body, are responsible for muscle contractions and menstrual pain, hence inflammation. One way to calm down their effects is by taking foods high in anti-inflammatory omega-3 fatty acids that include salmon, walnuts, and flaxseed.
Alternatively, if you think you are lacking omega-3 via food intakes you may consume it in the form of dietary supplements. Krill oil, fish oil, mussel oil, and cod liver oil are good sources of omega-3. They are also loaded with vitamin A and D, both of which are potent antioxidants and involve in many vital physiological processes.
Pineapple
At any point in their life, women may experience dysmenorrhea that’s characterized by painful cramps that may occur immediately before or during the menstrual period. One of the ways to relieve the painful period pain is by consuming pineapple.
A painful period is sometimes thought to be a result of scanty menstrual flow with bright red or dark red blood. Consuming pineapple is said to help ease this condition. Pineapple increases your blood flow and reduces the pain.
Moderation is the key to wise eating habits.
Eat pineapple moderately while menstruating, unless you want to induce your period.
Tips: Most pineapple sold in grocery stores or organic outlets taste sour. One of the reasons behind the sour taste is because the pineapple is harvested in its unripe form. It ripens a little bit while shipped and in storage that can take several weeks before you buy it.
Sprinkling a little salt (preferably Himalayan salt) on sliced pineapples not only help reduce the sourness but increase sweetness.
Water
Water retention during periods is experienced by many women and it is usually not a pleasant one. The most common cause of water retention is hormonal changes and imbalance which due to the increase of estrogen that starts slowly in the premenstrual stage and is excessive in the follicular stage.
Another possible reason why many women experience water retention during periods is that they don’t drink enough water. Therefore, a simple remedy by drinking enough water throughout the day can help decrease water retention.
Taking diuretic foods is another way of reducing water retention. There are many diuretic foods you can consume, including cranberries, grapes, watermelon, cucumber, celery, parsley, lemon, lime, tomatoes, pumpkin, asparagus, onion, Brussel sprouts, beets, artichoke, lettuce, cabbage, and watercress.
Herbal teas such as corn silk, dandelion leaves, and juniper berries tea can also help reduce water retention.
Herbal Teas
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Herbs like chamomile, lemon grass, sensitive plant, and chrysanthemum are natural relaxants. These herbs help relax your muscle and nervous system as well as promoting better digestions.
A beverage made of fresh cacao powder which offers high antioxidant and anti-inflammatory phytonutrient contents is not categorized as a tea. However, this beverage can help many issues associated with painful periods, including inflammation, fatigue, indigestion, mood swings, and headaches.
An herbal tea made by combining ginger, clove and a little turmeric can help reduce your painful period as it is high in antioxidants and anti-inflammatory phytonutrient contents.
Herbs you can add to your diet for Period Pain / Menstrual Pain
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These herbal remedies contain anti-inflammatory and antispasmodic compounds that experts believe can reduce the muscle contractions and swelling associated with menstrual pain.
Herb or supplement
Dosage
Does it work?
chamomile tea
Sip two cups of tea per day a week before your period. You may benefit more if you drink it every month.
Drinking chamomile tea increases urinary levels of glycine, which helps relieve muscle spasms. Glycine also acts as a nerve relaxant.
fennel seeds
When your period starts, take 30 mgs of fennel extract four times a day for three days.
One study looked at girls 15 to 24 years old. The group that took the extract reported feeling relief. The placebo group reported none.
cinnamon
Take 420 mg of cinnamon capsules twice a day during the first three days of your period.
In 2015, women who took cinnamon capsules in a study reported less bleeding, pain, nausea, and vomiting compared to the placebo group.
ginger
Try grating a small piece of ginger into hot water for a warm cramp-relieving drink.
One study found that 250 mg of ginger powder four times a day for three days helped with pain relief. It also concluded ginger was as effective as ibuprofen.
pcycenogenol
Take 60 mg of pycenogenol per day during your cycle. This can help with more moderate menstrual pain.
One study found that women who took 60 mg of pycenogenol per day during their cycle reported less pain. According to the study, the benefits increase as you take the pill and continue even after you stop.
dill
Try 1,000 mg of dill for five days, two days before your cycle.
A study concluded 1,000 mg dill was as effective for easing menstrual cramps as mefenamic acid, an over-the-counter drug for menstrual pain.
How diet and exercise can help in the long run for Period Pain
Maintaining a healthy diet and keeping up a regular exercise regime can go a long way to preventing menstrual pain. One study found significant differences between period pain in women who maintained a healthy lifestyle and those who didn’t. Read on for specific diet and exercise tips.
Diet
Generally, a diet geared toward decreasing menstrual pain should be high in minimally processed foods, fiber, and plants.
Give these foods a try
papaya (rich in vitamins)
brown rice (contains vitamin B-6, which may reduce bloating)
walnuts, almonds, and pumpkin seeds (rich in manganese, which eases cramps)
olive oil and broccoli (contain vitamin E)
chicken, fish, and leafy green vegetables (contain iron, which is lost during menstruation)
flaxseed (contains omega-3s with antioxidant properties, which reduce swelling and inflammation)
Boron
This mineral helps your body absorb calcium and phosphorus. It also reduces menstrual cramps: A study that looked at 113 university students found that boron reduced the intensity and length of menstrual pain. Foods with high concentration of boron include:
avocados
peanut butter
prunes
chickpeas
bananas
You can also take boron supplements, if your diet doesn’t provide enough. However, you should consult your doctor before taking boron supplements.
How much water should you drink based on your weight? Water to Drink is the second most popular beverage in the U.S. after soft drinks. This is a scary stat, since sugary soda is a huge health hazard, upping the risk of obesity, stroke, and other heart problems. However, these dangers can be avoided if people choose to drink water, which doesn’t have negative side effects
Everywhere around us we see people sipping bottled water. In healthy people, the fluid balance is strictly regulated via osmoregulation by the hormone vasopressin and the kidneys, in combination with the thirst mechanism and drinking. Fluid intake comes from food, metabolism, and beverages, including water. People lose fluid via the skin, respiration, fecal fluid and urinary output. The obligatory urine volume is determined by maximal renal concentrating ability and the solute load which must be excreted. Under normal circumstances of diet, exercise, and climate the minimal urine output for healthy subjects is about 500 ml/day. Intake of more than 500 ml of fluids per day will result in the excretion of solute-free water. The recommended total daily fluid intake of 3,000 ml for men and of 2,200 ml for women is more than adequate. Higher fluid intake does not have any convincing health benefits, except perhaps in preventing (recurrent) kidney stones.[rx]
Symptoms of Dehydration/Water to Drink
The urine will be dark yellow
The usual color of the urine should be light yellow-amber, and if you don’t have enough water, then the kidneys will excrete more waste in the urine like blood cells, toxins, and proteins that results in darker urine. The urine can be dark also when you consume some meds, beets, B-Vitamins, food coloring, asparagus, and blackberries. In case you notice changes in the color of your urine, you should increase the consumption of water and observe the color if it becomes lighter. If the urine stays darker for a longer period of time, then it may denote health problems like gallstones or hepatitis.
Your Urine Output is Reduced
Most people urinate between 6-7 times within a 24-hour period. When you don’t drink enough water, there is less fluid available to replace the fluids being excreted from the body. The kidneys attempt to retain as much fluid as possible to prevent dehydration. If you urinate less than 6 times a day, consider your water intake and increase if necessary.
Lack of water in the body causes constipation. If you don’t drink enough water, your body will absorb water from wherever it can, including the colon. An insufficient amount of water in the large intestine will lead to harder stools. So, consuming a lot of water is important if you want to prevent or treat constipation.
Constipation can also be caused by physical inactivity, hypothyroidism, intestinal inflammation and dysbiosis, food sensitivities and stress.
Dehydration can lead to an irritated, inflamed, itching and sensitive skin. In severe cases, the skin can even become red with cracks and bleeds. The lack of water also causes the appearance of wrinkles. So, you should drink more water to revitalize your skin.
Dehydration can cause your body to become confused and receive mixed signals about hunger. You may think you need to eat when really you just need water. This is how not drinking enough water can lead to overeating.
Believe it or not, feeling thirsty for water is a sign that you are already slightly dehydrated. A dry mouth often occurs with thirst and signifies that the mucus membranes in the body need hydration. The only way to resolve thirst and a dry mouth is to drink water throughout the day.
Not drinking enough water can cause the body absorb water from other tissues in order to compensate for the lack of the fluids. For this reason, the brain tissue loses some of its moisture and shrinks, pulling away from the skull, triggering the pain receptors and resulting in a headache. When you don’t consume enough water, the blood volume drops and then reduces the amount of oxygen which is carried in the brain. The blood vessels, in response to this, will dilate and the headache will intensify.
One study conducted in 2011 showed that mild dehydration can cause fatigue, lower energy, and tiredness. Once the body lacks water, the heart needs to work harder in order to push the oxygen and nutrients through the body, thus when you feel tired, skip our coffee, (it is dehydrating) and drink water. Water should not be substituted with soda, tea, coffee, and sports drinks.
Water is extremely necessary to keep your bones and joints working properly. It helps nutrients move through your blood and into your joints, and it allows waste products to move out of your joints. Without water, your joints can become dry and rub together, causing pain.
Weak immune system
Dehydration can case an increase of toxin concentration in the blood and this can weaken the immune system. It is highly important to drink enough amounts of water in order to eliminate the toxins and help the immune system defend from infections.
Dietary reference intakes (adequate intakes) for total water set by the European Food Safety Authority (EFSA) and the Institute of Medicine (IOM)
The Institute of Medicine’s Water Intake Recommendations*.
Age (years)
Total Daily Water Needs**
Total Fluid Intake Including Water
Children
1–3
6c (1300mL)
4c (900mL)
4–8
7c (1700mL)
5c (1200mL)
Adolescents
Males
9–13
10c (2400mL)
8c (1800mL)
14–18
14c (3300mL)
11c (2600mL)
Females
9–13
9c (2100mL)
7c (1600mL)
14–18
10c (2300mL)
8c (1800mL)
Adults
Males
19+
16c (3700mL)
13c (3000mL)
Females
19+
11c (2700mL)
9c (2200mL)
*Adequate Intake (AI) for total water and total fluid intake including water in cups (c) and milliliters (mL). 1 cup = 8 fluid ounces; 1000mL = 33.8 fluid ounces.
**Total water needs is the sum of plain drinking water and water from formulas, beverages, and foods consumed.
Roughly 60 percent of the body is made of water. Drinking enough H2O maintains the body’s fluid balance, which helps transport nutrients in the body, regulate body temperature, digest food, and more.
Calorie control
Forget other diet tricks—drinking water could also help with weight loss. Numerous studies have found a connection between water consumption and losing a few pounds . The secret reason? Water simply helps people feel full, and as a result consume fewer calories.
Muscle fuel
Sweating at the gym causes muscles to lose water. And when the muscles don’t have enough water, they get tired . So for extra energy, try drinking water to push through that final set of squats.
Clearer skin
Certain toxins in the body can cause the skin to inflame, which results in clogged pores and acne . While science saying water makes the skin wrinkle free is contradictory, water does flush out these toxins and can reduce the risk of pimples.
Kidney function
Our kidneys process 200 quarts of blood daily, sifting out waste and transporting urine to the bladder. Yet, kidneys need enough fluids to clear away what we don’t need in the body. Let’s drink to that!
Productivity boost
In order to really focus, a glass of water could help people concentrate and stay refreshed and alert.
Move over coffee—water can help fight those tired eyes too . One of the most common symptoms of dehydration is tiredness. Just another reason to go for the big gulp!
Hangover help
If booze has got the best of you, help a hangover with a glass of water to hydrate the body and stop that pounding headache.
A little water can really go a long way. Aching joints and muscle cramps and strains can all occur if the body is dehydrated .
Keep things flowing
Nobody wants to deal with digestion issues. Luckily, drinking enough water adds fluids to the colon which helps make things, ahem, move smoothly.
Sickness fighter
Water may help with decongestion and dehydration, helping the body bounce back when feeling under the weather. Just beware—drinking fluids hasn’t been scientifically proven to beat colds in one swoop, so don’t swap this for a trip to the doctor or other cold remedies.
Brain boost
A study in London found a link between students bringing water into an exam room and better grades, suggesting H2O promotes clearer thinking. While it’s unclear if drinking the water had anything to do with a better score, it doesn’t hurt to try it out!
Increases Energy & Relieves Fatigue
Since your brain is mostly water, drinking it helps you think, focus and concentrate better and be more alert. As an added bonus, your energy levels are also boosted!
Promotes Weight Loss
Removes by-products of fat, reduces eating intake (by filling up your tummy if consumed prior to meals), reduces hunger (hello natural appetite suppressant!), raises your metabolism and has zero calories!
Flushes Out Toxins
Gets rid of waste through sweat and urination which reduces the risk of kidney stones and UTI’s (urinary tract infections).
Improves Skin Complexion
Moisturizes your skin, keeps it fresh, soft, glowing and smooth. Gets rid of wrinkles. It’s the best anti-aging treatment around!
Maintains Regularity
Aids in digestion as water is essential to digest your food and prevents constipation.
Boosts Immune System
A water guzzler is less likely to get sick. And who wouldn’t rather feel healthy the majority of the time? Drinking plenty of water helps fight against flu, cancer and other ailments like heart attacks.