How Common is Diabetic Nephropathy/Diabetic Nephropathy (DN) or diabetic kidney disease is a syndrome characterized by the presence of pathological quantities of urine albumin excretion, diabetic glomerular lesions, and loss of glomerular filtration rate (GFR) in diabetics. Diabetes may be classified as type 1 (autoimmune β-cell destruction and absolute insulin deficiency), type 2 (relative insulin deficiency and resistance), and other types (eg, pancreatic disease).
Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria (>300 mg/24 hr, or 300 mg/g creatinine), a progressive decline in glomerular filtration rate (GFR), arterial hypertension, and increased cardiovascular morbidity and mortality.
Chronic kidney disease (CKD) is a type of kidney disease in which there is gradual loss of kidney function over a period of months or years.[rx][rx] Early on there are typically no symptoms.[rx] Later, leg swelling, feeling tired, vomiting, loss of appetite, or confusion may develop. Complications may include heart disease, high blood pressure, bone disease, or anemia.[rx][rx]
Pathophysiology of Diabetic Nephropathy
DN is a clinical syndrome characterised by the insistent albuminuria that should be confirmed on at least two occasions separated by 3-6 months, by continuous decline in the glomerular filtration rate (GFR), and by increased arterial blood pressure. DN is characterised by different events. The characteristic occurrence is thickening of the glomerular basement membrane (GBM). After renal damage, the thickening of the basement membrane starts, which leads to pathologic modifications in mesangial and vascular cells. It includes formation of AGEs, accumulation of polyols, and activation of protein kinase C [rx,rx]. It leads to activation of the inflammatory pathway playing a significant role in the damage of GBM [rx].
Secondly, the renal hemodynamic anomaly is similar in both types of diabetes [rx]. An initial physiologic abnormality is glomerular hyper-filtration related to intra-glomerular hypertension [rx]. This is complemented by the onset of microalbuminuria. Microalbuminuria is considered the first sign indicating the onset of DN [rx].
The exact pattern observed in the pathophysiology of DN is:
Hyperglycaemia
Thickening of GBM
Glomerular hyper-filtration
Impaired endothelial integrity
Onset of microalbuminuria
Impairment of nitric oxide transport
Loss of afferent/efferent auto-regulatory control
Continued loss of glomerular filtration capabilities
Causes of Diabetic Nephropathy
Hyperglycemia – Hyperglycemia is a significant risk factor for the development of microalbuminuria, both in type 1 and in type 2 DM [rx,rx,rx]. A reduction of 1% in HbA1c is associated with a 37% decrease in microvascular endpoints [57]. In the presence of micro- and macroalbuminuria the role of metabolic control is less defined, even though some studies showed a deleterious effect of high glucose levels on GFR [rx,rx].
Arterial Hypertension – Arterial hypertension is a main risk factor for the development of DN [rx,rx], and probably the best known relevant factor related to its progression. Analysis of UKPDS showed that every 10 mmHg reduction in systolic BP is associated with a 13% reduction in the risk of microvascular complications, with the smallest risk among those patients with systolic BP <120 mm Hg [rx].
Smoking – Smoking is a risk factor for DN [rx,rx] and might contribute to its progression [rx]. Although some studies did not confirm these observations [rx,rx], it is strongly recommended to quit smoking in any phase of DN, also aiming to reduce the associated cardiovascular and cancer risk.
Dyslipidemia – In type 2 DM, elevated serum cholesterol is a risk factor for the development of DN [rx,rx]. In type 1 DM patients increased serum triglycerides, total and LDL-cholesterol were associated with micro- and macroalbuminuria [rx,rx]. High serum cholesterol also seems to be a risk factor for GFR loss in macroalbuminuric type 1 diabetic subjects [rx].
Proteinuria – Proteinuria itself could lead to progression of DN. Proteinuria >2 g/24 h is associated with a greater risk of ESRD [rx]. Increased leakage of albumin may induce glomerular damage probably through activation of inflammatory cascades [rx]. This would be a reason to target decreased urinary albumin excretion in DN treatment.
Glomerular hyperfiltration – Elevated GFR values are present in about one third of type 2 DM patients [rx,rx] and theoretically it could cause DN due to glomerular damage [rx]. Studies led to controversial findings regarding its role as a risk factor for the development of DN [rx,rx]. Type 2 DM patients with a single-kidney more often present increased UAE levels [rx,rx]. On the other hand, type 1 DM patients with only one kidney do not have a more aggressive disease [rx]. Glomerular hyperfiltration probably plays a small role, if any, in the development of DN [rx].
Dietary factors – Increased dietary protein intake seems to be associated with the presence of higher UAE values, at least in patients with type 1 DM [rx]. In patients with type 2 DM this association has not been documented. The source of proteins in the diet also seems to be related to the presence of DN. A higher intake of fish protein is related to a lower risk of microalbuminuria in type 1 DM patients [rx]. The mechanisms involved in these findings are unknown but probably related to hemodynamic factors [rx].
Vascular disease – includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome, and vasculitis.
Glomerular disease – comprises a diverse group and is classified into:
Primary glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
Secondary glomerular disease such as diabetic nephropathy and lupus nephritis
Congenital disease such as polycystic kidney disease.
Tubulointerstitial disease – includes drug- and toxin-induced chronic tubulointerstitial nephritis, and reflux nephropathy.
Obstructive nephropathy – is exemplified by bilateral kidney stones and diseases of the prostate such as benign prostatic hyperplasia.
On rare cases – pinworms infecting the kidney can also cause nephropathy.
Nontraditional causes of CKD (CKDu) – are denoted if the common causes of CKD are not present:
CKD of unknown cause is the subject of study by the Sri Lanka Ministry of Health and the World Health Organization 2009–2012.[rx]
Mesoamerican nephropathy, a form of CKDu, is “a new form of kidney disease that could be called agricultural nephropathy”.[rx]
Autoimmune disease, such as lupus erythematosus
Infection with hepatitis B, hepatitis C or syphilis
Certain medications, such as gold salts and nonsteroidal anti-inflammatory drugs
Solid cancerous tumors or blood cancers
Symptoms of Diabetic Nephropathy
CKD is initially without specific symptoms and is generally only detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases:
Blood pressure – is increased due to fluid overload and production of vasoactive hormones created by the kidney via the renin–angiotensin system, increasing one’s risk of developing hypertension and/or suffering from congestive heart failure.
Urea accumulates – leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Due to its high systemic circulation, urea is excreted in eccrine sweat at high concentrations and crystallizes on skin as the sweat evaporates (“uremic frost”).
Potassium accumulates – in the blood (hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the glomerular filtration rate falls to less than 20–25 ml/min/1.73 m2, at which point the kidneys have decreased ability to excrete potassium.[rx]
Erythropoietin synthesis is decreased causing anemia.
Fluid volume overload – symptoms may range from mild edema to life-threatening pulmonary edema.
Hyperphosphatemia – due to reduced phosphate excretion, follows the decrease in glomerular filtration. Hyperphosphatemia is associated with increased cardiovascular risk, being a direct stimulus to vascular calcification.[rx] Moreover, circulating concentrations of fibroblast growth factor-23 (FGF-23) increase progressively as the renal capacity for phosphate excretion declines, but this adaptative response may also contribute to left ventricular hypertrophy and increased mortality in CKD patients.[rx][rx]
Hypocalcemia – due to 1,25 dihydroxyvitamin D3 deficiency (caused by stimulation of FGF-23 and reduction of renal mass),[rx] and resistance to the calcemic action of parathyroid hormone.[rx] Osteocytes are responsible for the increased production of FGF-23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D3).[rx] Later, this progresses to secondary hyperparathyroidism, renal osteodystrophy, and vascular calcification that further impairs cardiac function. An extreme consequence is the occurrence of the rare condition named calciphylaxis.[rx]
The concept of chronic kidney disease-mineral bone disorder (CKD-MBD)– [rx][rx] currently describes a broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of: (1) abnormalities of calcium, phosphorus (phosphate), parathyroid hormone, or vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength (renal osteodystrophy); and( 3) vascular or other soft-tissue calcification.[rx] CKD-MBD has been associated to poor hard outcomes.[rx]
Metabolic acidosis – (due to accumulation of sulfates, phosphates, uric acid etc.) may cause altered enzyme activity by excess acid acting on enzymes; and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia).[rx] Acidosis is also due to decreased capacity to generate enough ammonia from the cells of the proximal tubule.[rx]
Iron deficiency anemia – which increases in prevalence as kidney function decreases, is especially prevalent in those requiring haemodialysis. It is multifactoral in cause, but includes increased inflammation, reduction in erythropoietin, and hyperuricemia leading to bone marrow suppression.
People with CKD – suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with CKD and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.[rx]
Sexual dysfunction – is very common in both men and women with CKD. A majority of men have a reduced sex drive, difficulty obtaining an erection, and reaching orgasm, and the problems get worse with age. A majority of women have trouble with sexual arousal, and painful menstruation and problems with performing and enjoying sex are common.[rx]
A usual first symptom – is frequent urination at night: nocturia. Other symptoms include tiredness, headaches, a general feeling of illness, nausea, vomiting, frequent daytime urination, lack of appetite, itchy skin, and leg swelling.[rx]
swollen ankles, feet, lower legs, or hands caused by water retention
Decreased protein in the blood, particularly albumin
Natural clinical course of diabetic kidney disease
The natural history of DN is divided into five stages [rx]
Stage 1 – Renal pathology develops at the onset of diabetes. The growth of the kidney increases by several centimetres. By the time of diagnosis, the GFR and urinary albumin excretion (UAE) have been increased. It can be controlled at this level by onset of insulin.
Stage 2 – The second phase typically lasts for 5-15 years after diagnosis of diabetes. The characteristics of the second phase include: (1)GFR remains elevated due to hyperfiltration. (2)Kidneys remain hypertrophied and UAE rate stays normal.
Stage 3 – The characteristics of stage three are:
Microalbuminuria is present. It occurs in 30-50% of patients after diabetes onset, 80% of whom go on to develop overt nephropathy over 10-15 years.
GFR remains elevated or returns to normal range
Blood pressure starts to rise in 60% of patients
Histological changes-progression is as seen in stage two.
Stage 4 – This stage is also known as clinical nephropathy or overt nephropathy. The characteristic histological features of stage four are formation of the Kimmelstiel-Wilson nodule (focal glomerular sclerosis) and macroproteinuria. It can progress to nephrotic in 30% of patients or may decline in 80% depending on deterioration of GFR.
Stage 5 – As the GFR continues to decline, ESRD may develop. DN is considered the most common cause of ESRD because of associated autoimmune neuropathy and cardiac disease.
The stages of chronic kidney disease (CKD) are mainly based on measured or estimated GFR. There are five stages but kidney function is normal in stage 1 and minimally reduced in stage 2.
Categories of Diabetic Nephropathy
Category C I: Normal or near normal renal structure
These patients (35% of MA and 15% of proteinuria) had normal renal biopsies or showed very mild glomerular, tubular, interstitial and/or vascular changes.
Category C II: Typical diabetic nephropathology
These patients (30% of MA and 50% of proteinuria) had established diabetic lesions with an approximately balanced severity of glomerular, tubulo-interstitial and arteriolar changes, a picture typical of that seen in most T1DM patients with obvious light microscopic DN changes.
Category C III: Atypical patterns of renal injury
These patients (35% of MA and proteinuria) had relatively mild diabetic glomerular changes considering disproportionately severe: (a) Tubular atrophy, TBM thickening and reduplication and interstitial fibrosis (tubulo-interstitial lesions). (b) Advanced glomerular arteriolar hyalinosis commonly associated with atherosclerosis of larger vessels. (c) Global glomerular sclerosis. In C III group these patterns were present in all possible combinations.
Diagnosis of Diabetic Nephropathy
1)Enough time: At least 10 years past the onset of diabetes, but this criterion is often not verifiable in type 2.
2)Persistent albuminuria more than 300 mg in 24 hours
3)Diabetic retinopathy at the same time: Given that almost all patients with type 1 diabetes with diabetic nephropathy have retinopathy, retinopathy in patients with first and second criteria, prove the diagnosis, and lack of it virtually excluded diagnosis.
Renal disease less than 5 years or after 30 years of diabetes onset
Puria, RBC or WBC cast
Serum creatinine test
Microscopic examination of urine
Progressive proteinuria
Progressive renal failure
Acute nephrotic syndrome
Acute renal failure
Macroscopic hematuria
Diagnosis is based on the measurement of abnormal levels of urinary albumin in a diabetic[rx] coupled with the exclusion of other causes of albuminuria. Albumin measurements are defined as follows:[rx]
Normal albuminuria – urinary albumin excretion <30 mg/24h;
Microalbuminuria – urinary albumin excretion in the range of 30–299 mg/24h;
Macroalbuminuria – urinary albumin excretion ≥300 mg/24h.
Incipient nephropathy is the initial presence of low but abnormal amounts of urine albumin, referred to as microalbuminuria (persistent albuminuria at level 30–299 mg/24 hours). Overt nephropathy or macroalbuminuria (persistent albuminuria at level ≥300 mg/24 hours) develops after many years in type 1 diabetes but may be present at the time of diagnosis of type 2 diabetes.
Screening for DN
Most guidelines recommend screening with a spot urine albumin/creatinine ratio (ACR; normal >30 mg/g creatinine), from either first morning (preferred) or random specimens. An abnormal result is repeated once or twice over a few months for consistency.
Renal biopsy
The routine use of renal biopsy to confirm DN is much debated. Many nephrologists do not biopsy patients with classic features such as retinopathy, duration of diabetes <10 years, slow decline in GFR, gradual progression of proteinuria, and lack of active urinary sediment
Biomarkers
There are limitations in using albuminuria as a marker of DN as many patients experience GFR loss without deterioration in albuminuria and even normoalbuminuria.[rx] In fact, histologically proven advanced diabetic glomerular lesions can develop despite normoalbuminuria.[rx] Furthermore, low-grade albuminuria is a lesser predictor of disease progression than macroalbuminuria.[rx]
Investigations for DN
Urine culture – Exclude infection
Urine microscopy – Examine for red cell cast in glomerulonephritis
Anti-DNA antibodies
Complement level – Exclusion of autoimmune disease
Rheumatoid factor
Igs; Protein electrophoretic strip – Exclude multiple myeloma
According to NICE guidelines, the following patients should be referred early to the specialist [rx]:
1) Stage 4 and 5 CKD (with or without diabetes)
2) Proteinuria together with hematuria
3) Rapidly declining GFR
4) Hypertension that remains poorly controlled despite the use of at least four antihypertensive drugs at therapeutic doses
5) People with, or suspected of having, rare or genetic causes of CKD.
Cytokines
A series of circulating markers of inflammation such as C reactive protein and interleukin 1, 6 and 18, and tumor necrosis factor are increased in DN and their levels correlate with albuminuria and progression to ESRD. In addition, hyperglycemia, TGF-β1, and angiotensin II stimulate the secretion of VEGF, causing the production of endothelial nitric oxide, vasodilation and glomerular hyperfiltration [rx].
Treatment of Diabetic Nephropathy
Treatment of diabetic nephropathy is based on some principle:
1)Tight control of hyperglycemia
2)control of blood and glomerular pressure
3)Control of dyslipidemia
4)Restriction of protein intake
5)Smoking withdrawal.
However, there are some clinical features that help in making the decision to do a renal biopsy, summarised as:
1) Short-duration type 1 diabetes
2) Autoimmune disease
3) Mild or absent retinopathy
4) Red cell casts in urine
5) Significant and persistent proteinuria
Optimal blood glucose control
Control of blood pressure at 120/70 mmHg
Avoidance of potential use of nephrotoxic drugs such as nonsteroidal Antiinflammatory Drugs (NSAIDs), aminoglycosides, etc.
Early detection and management of diabetes, especially in the setting of family history.
Potential New Therapies
There is a lot of research ongoing regarding the treatment of DN
High doses of thiamine and its derivative benfotiamine have been shown to reduce the rate of microalbuminuria in experimental diabetes nephropathy, probably due to the decrease in activation of protein kinase C, protein glycation and oxidative stress [rx].
Treatment with a protein kinase C beta inhibitor normalizes GFR, decreases albumin excretion rate, and ameliorates glomerular lesions in diabetic rodents [rx].
Pimagedine, a second-generation inhibitor of the advanced glycation end product, reduced urinary protein excretion and the decline in GFR in proteinuric type 1 diabetic patients in a randomized, placebo-controlled study [rx].
New therapeutic agents in diabetic nephropathy beyond conventional RAAS inhibition
Angiotensin receptor blocker (ARB) – In the IDNT trial, 1,715 hypertensive type 2 diabetics with nephropathy were randomly assigned to receive irbesartan, amlodipine, or placebo.[rx] Irbesartan reduced the risk of ESRD or doubling of serum creatinine by 20%–23% compared to amlodipine or placebo.
ACE inhibitor versus ARB – In the DETAIL trial, 250 type 2 diabetics with early DN were randomly assigned to enalapril or telmisartan. Combination therapy with ACEI and ARB compared with ACEI or ARB monotherapy was shown to reduce proteinuria in patients with type 1 and type 2 diabetes [rx, rx]. However, the antiproteinuric effects of combination therapy do not seem to be sufficient for the prevention of renal disease progression or death.
ACE inhibitor and ARB – Earlier studies of combination ACE inhibitor and ARB reported superiority of combination therapy for lowering albuminuria and blood pressure versus either alone, in both type 1 and 2 diabetics.[rx–rx]. ACE inhibition cannot completely inhibit the production of angiotensin II but ARBs can fully inhibit the effect of angiotensin I on AT1 and this causes the accumulation of angiotensin II that via AT2 receptor causes dilation of blood vessels and decreased cell proliferation [rx].
Abundant experimental data indicate that thiazolidinediones (TZD) – a family of anti-diabetic drugs that activate the transcription factor peroxisome proliferator activator receptor gamma (PPAR-γ), have direct renoprotective effects [rx–rx]. These effects are most probably exerted by preventing diabetes-induced renal inflammatory processes. However, clinical studies have reported controversial outcomes, with some of them reporting significant antiproteinuric effects [rx–rx], and others demonstrating insignificant effects [rx]
Glitazones – represented by rosiglitazone and pioglitazone, act through the PPR gamma system and are insulin sensitizer drugs that increase the muscle uptake of glucose and diminish the atherogenic profile of the DM patient, and could be used in renal failure [rx,rx]. Rosiglitazone has been shown to decrease UAE in type 2 diabetic patients as compared to glyburide, suggesting a beneficial effect in the prevention of renal complications of type 2 DM [rx].
Treatment of hyperglycemia in the patient with type 2 diabetes mellitus and chronic kidney disease
Renin inhibitors – Renin catalyses the rate-limiting step in the production of angiotensin II. In diabetic rats, aliskiren reduced albuminuria and glomerulosclerosis, and was more effective than perindopril in reducing interstitial fibrosis.[rx]
Repaglinide and nateglinide – [rx] have a short duration of action, are excreted independently of renal function and have a safety profile in patients with renal impairment. These drugs, like the sulfonylureas, are insulin secretagogues, but they act in different cellular membrane channels, and this brings some pharmacological properties such as quick initial action, non-prolonged action and greater effect on post-prandial glycemia.
Endothelin inhibitors – In diabetic rats, an ETA receptor blockade with atrasentan or avosentan reduced albuminuria and renal fibrosis.[rx,rx] The ASCEND trial of 1,392 type 2 diabetics with overt nephropathy examined the effect of avosentan on time to doubling of serum creatinine, ESRD, or death. Avosentan halved proteinuria but increased fluid retention, edema, and congestive heart failure, resulting in the trial being stopped early
Urotensin and vasopeptidase inhibitors – Vasopeptidase inhibitors can block ACE and neutral endopeptidase. Palosuran is a competitive antagonist of the urotensin II receptor. In diabetic patients with macroalbuminuria, a 2-week course of palosuran in addition to RAS inhibitors reduced albuminuria by 24%.[rx]
PKC inhibitors – Ruboxistaurin is a selective inhibitor of PKC-β. Animal studies with ruboxistaurin showed beneficial effects on reducing mesangial expansion, hyperfiltration, albuminuria, macrophage accumulation, and tubulointerstitial injury.[rx,rx]
Aldose reductase inhibitors – These inhibitors suppress sorbitol accumulation in tissues. Epalrestat reduced mesangial expansion and preserved renal function in diabetic rats.[rx] Another inhibitor – tolrestat – prevented glomerular hypertrophy and hyperfiltration, mesangial cell hypocontractility, and albuminuria in diabetic rats.[rx]
Phosphodiesterase inhibitors – Cilostazol inhibits phosphodiesterase III and reduces thrombospondin-1 and TGF-β expression, attenuating hyperfiltration, albuminuria, and extracellular matrix deposition in diabetic rats.[rx,rx]
Agents targeting oxidative stress – Cellular and mitochondrial ROS formation is an important contributor to the pathophysiology of DN. Targeted inhibitors of ROS generation are emerging but most have not progressed to clinical trials.
Glycosaminoglycans – Sulodexide is a mixture of 80% heparan sulfate and 20% dermatan sulfate. Sulodexide may reduce the enhanced heparan sulfate degradation in the glomerular basement membrane that occurs in DN. It has anti-inflammatory properties and inhibits the hyperglycemia-induced production of ROS, MCP-1, and IL-6 in endothelial cells.[rx]
Antifibrotic agents – Pirfenidone inhibits TGF-β production and TNF-α production in models of DN and non-DN kidney disease. The exact mechanism of action is unclear. In db/db mice with type 2 diabetes, pirfenidone reduced mesangial matrix expansion but did not affect albuminuria.[rx]
Dihydropyridine calcium channel blockers – such as amlodipine and nifedipine, may be worse proteinuria and may progress nephropathy in diabetic and non-diabetic patients. Conversely, non-dihydropyridine calcium blockers such as verapamil and diltiazem, reduce the risk of overt nephropathy and improve size selectivity in glomeruli in diabetic nephropathy
Anti-proteinuric effects of renin-angiotensin-aldosterone system inhibitors – is exacerbated with reducing sodium intake and taking other antihypertensive medications at the same time including diuretics and non-dihydropyridine calcium channel blockers.
Potential benefits of spironolactone as antagonist of aldosterone receptors – was tested in a double-blind study on 59 patients with diabetes 2 that were ever treated with ACEIs or ARBs. Spironolactone 50 mg a day were given in treatment group and another group were given placebo. Urine albumin to creatinine ratio up to 40% and systolic blood pressure 7 mmHg and diastolic blood pressure 3 mmHg were reduce in spironolactone group, whereas these parameters did not change in the placebo group [rx].
Pentoxifylline – is a non-specific phosphodiesterase inhibitor with anti-inflammatory properties; it has been used in patients with peripheral artery disease and alcoholic hepatitis. Several small studies including patients with diabetic nephropathy showed that pentoxifylline had antiproteinuric effects and reduced the rate of decline in eGFR [rx–rx]. Additional data are needed before pentoxifylline can be recommended as treatment for diabetic nephropathy.
Pirfenidone – is an oral synthetic antifibrotic agent that has demonstrated benefits in animal models of diabetic nephropathy and in patients with this syndrome by preventing the progression of renal impairment. Pirfenidone is thus a promising agent for the treatment of diabetic nephropathy, and should be further investigated and advanced [rx, rx].
Endothelin-1 (ET-1) – is a potent vasoconstrictory peptide with proinflammatory and profibrotic properties that exerts its biological effects through two receptor subtypes, namely ET(A) and ET(B). ET-1 promotes diuresis and natriuresis by local production and action through ET(B) receptors in the renal medulla, whereas activation of ET(A) receptors causes vasoconstriction, mesangial-cell proliferation, extracellular matrix production, and inflammation [rx]
Phosphate binder sevelamer carbonate – a currently used phosphate binder, was shown to significantly reduce HbA1c, fibroblast growth factor 23, and lipids, and to exhibit anti-inflammatory and antioxidant properties, independently of phosphate level reduction in patients with diabetes and early kidney disease [rx]. However, a recent trial did not show any benefits of sevelamer regarding reductions in HbA1c or albuminuria overall in patients with type 2 diabetes and diabetic nephropathy, except for very specific groups of patients [rx].
Bardoxolone methyl – is an oral antioxidant. Its structure and activity profile is similar to cyclopentenone prostaglandins that exert anti-inflammatory effects by inhibiting the nuclear factor κB pathway. Experimental data of drug-induced or ischemic acute kidney injury have shown beneficial effects [rx]. According to this trial, bardoxolone methyl therapy significantly increased estimated glomerular filtration rate (eGFR) at 1 year of follow-up, while placebo therapy did not have any effects on the eGFR [rx].
Aliskiren – an oral direct renin inhibitor, has a similar degree of blood pressure-lowering properties as other agents. In the AVOID trial, aliskiren combined with losartan was associated with a significantly greater reduction in proteinuria, but no significantly greater antihypertensive effect, than losartan monotherapy [rx]
Vitamin D therapy – has recently received attention as a potential treatment option in DN. Initial mouse studies showed that mice unable to make vitamin D or lacking vitamin D receptors had an increase in RAAS activity and even exhibited significant proteinuria.[rx]
Gene and cell-based therapy – Gene therapy involves introducing a gene into cells to increase the production of a protein of interest. A carrier or vector such as modified adenovirus is employed to deliver the gene to the nucleus where the protein coded by the gene is produced by the cellular machinery. Gene therapy targeting TGF-β/SMAD signaling has shown promise in reducing kidney injury in diabetic models. Ka et al studied Smad7 gene therapy in the db/db mouse model of type 2 diabetes. Treatment inhibited TGF-β/SMAD and NF-κB activation, resulting in a reduction in proteinuria, macrophage infiltration, inflammation, podocyte injury, and renal fibrosis.[rx]
Dyslipidemia – The most common lipid disorder in diabetes is increased triglycerides and reduced HDL. Although LDL levels in these patients is usually normal, but it has high atherogenic properties. Accompaniment of glucose intolerance or diabetes, high blood pressure, low HDL and high triglycerides, obesity and sometimes high LDL are known as metabolic syndrome, will lead to increased risk of cardiovascular disease. Therapeutic purposes by the American diabetes association are: The blood triglyceride level of less than 150 mg/dL, HDL over 60 mg/dl and LDL less than 100 mg/dL.
Protein restriction – High protein intake can increase glomerular filtration and sclerosis. Studies have shown that reducing protein intake in diabetic patients can reduce proteinuria and slow the progression of renal failure. Protein restriction can lead to decrease symptoms of uremia and delay need for dialysis. The possible mechanism of effect of protein restriction is reduced hyperfiltration in healthy nephron.
Treatment of 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 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 a 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 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 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.
Hemorrhoids Treatment /Hemorrhoids are a very common anorectal condition defined as the symptomatic enlargement and distal displacement of the normal anal cushions. They affect millions of people around the world and represent a major medical and socioeconomic problem. Multiple factors have been claimed to be the etiologies of hemorrhoidal development, including constipation and prolonged straining. The abnormal dilatation and distortion of the vascular channel, together with destructive changes in the supporting connective tissue within the anal cushion, is a paramount finding of hemorrhoidal disease[rx]. An inflammatory reaction[rx] and vascular hyperplasia[rx,rx] may be evident in hemorrhoids. This article firstly reviewed the pathophysiology and other clinical backgrounds of hemorrhoidal disease, followed by the current approaches to non-operative and operative management.
Types of Hemorrhoids
Hemorrhoids can be classified according to how severe they are
Grade 1 – Slightly enlarged hemorrhoids that can’t be seen from outside the anus.
Grade 2 – Larger hemorrhoids that sometimes come out of the anus, for example, while passing stool or – less commonly – during other physical activities. They then go back inside again on their own.
Grade 3 – Hemorrhoids that come out of the anus when you go to the toilet or do other physical activities, but don’t go back inside on their own. They can be pushed back inside, though.
Grade 4 – Hemorrhoids that are always outside the anus and can no longer be pushed back inside. Usually, a small bit of the anal lining comes out of the anus too. This is also known as rectal prolapse.
Hemorrhoid tissue, cross-section view: normal (above) and enlarged (below)
Hemorrhoids Causes
Increased pressure on the anal canal (the last section of the rectum) can cause hemorrhoids to become enlarged. Various factors might make this more likely. For example
Being overweight
Chronic constipation
Frequent diarrhea
Regularly lifting heavy objects
Pregnancy and giving birth
The risk of enlarged hemorrhoids increases with age – probably because the tissue becomes weaker over time. And hemorrhoid problems are thought to run in families too.
Age – as you get older, your body’s supporting tissues get weaker, increasing your risk of hemorrhoids
Pregnant – this can place increased pressure on your pelvic blood vessels, causing them to enlarge; read more about piles in pregnancy
Chronic diarrhea
Lifting heavy weights
Straining when passing a stool
Chronic (long-term) diarrhea can also make you more vulnerable to getting hemorrhoids.
In most cases, the symptoms of piles are not serious. They normally resolve on their own after a few days.
An individual with piles may experience the following symptoms:
A hard, possibly painful lump may be felt around the anus. It may contain coagulated blood. Piles that contain blood are called thrombosed external hemorrhoids.
After passing a stool, a person with piles may experience the feeling that the bowels are still full.
Bright red blood is visible after a bowel movement.
Bleeding when you have a bowel movement – you may see blood (usually bright red) on toilet paper or drips in the toilet or on the surface of your poo
A lump in or around your anus
A slimy discharge of mucus from your anus
A feeling of ‘fullness’ and discomfort in your anus, or a feeling that your bowels haven’t completely emptied after going to the toilet
Itchy or sore skin around your anus
Pain and discomfort after you go to the toilet
Piles can escalate into a more severe condition. This can include
Excessive anal bleeding, also possibly leading to anemia
Infection
Fecal incontinence, or an inability to control bowel movements
Anal fistula, in which a new channel is created between the surface of the skin near the anus and the inside of the anus
Strangulated hemorrhoid, in which the blood supply to the hemorrhoid is cut off, causing complications including infection or a blood clot
Diagnosis of Hemorrhoids
Internal hemorrhoid grades
Grade
Diagram
Picture
1
2
3
4
Grading
For practical purposes, internal hemorrhoids are further graded based on their appearance and degree of prolapse, known as Goligher’s classification:
First-degree hemorrhoids (grade I) – The anal cushions bleed but do not prolapse;
Second-degree hemorrhoids (grade II) – The anal cushions prolapse through the anus on straining but reduce spontaneously;
Third-degree hemorrhoids (grade III) – The anal cushions prolapse through the anus on straining or exertion and require manual replacement into the anal canal; and
Fourth-degree hemorrhoids (grade IV) – The prolapse stays out at all times and is irreducible. Acutely thrombosed, incarcerated internal hemorrhoids and incarcerated, thrombosed hemorrhoids involving circumferential rectal mucosal prolapse are also fourth-degree hemorrhoids[18].
Hemorrhoids are typically diagnosed by physical examination.[rx]
A visual examination of the anus and surrounding area may diagnose external or prolapsed hemorrhoids.[rx]
A rectal exam may be performed to detect possible rectal tumors, polyps, an enlarged prostate, or abscesses.[rx]
This examination may not be possible without appropriate sedation because of pain, although most internal hemorrhoids are not associated with pain.[rx]Visual confirmation of internal hemorrhoids may require anoscopy, insertion of a hollow tube device with a light attached at one end.[rx]
The two types of hemorrhoids are external and internal. These are differentiated by their position with respect to the pectinate line.[rx] Some persons may concurrently have symptomatic versions of both.[rx] If the pain is present, the condition is more likely to be an anal fissure or external hemorrhoid rather than internal hemorrhoid.[rx]
Rectal Examination
Your GP may examine the outside of your anus to see if you have visible hemorrhoids, and they may also carry out an internal examination called a digital rectal examination (DRE). During a DRE, your GP will wear gloves and use lubricant. Using their finger, they’ll feel for any abnormalities in your back passage. A DRE shouldn’t be painful, but you may feel some slight discomfort.
Proctoscopy
In some cases, further internal examination using a proctoscope may be needed. A proctoscope is a thin hollow tube with a light on the end that’s inserted into your anus. This allows your doctor to see your entire anal canal (the last section of the large intestine). GPs are sometimes able to carry out a proctoscopy. However, not all GPs have the correct training or access to the right equipment, so you may need to go to a hospital clinic to have the procedure.
Treatment of Hemorrhoids
Conservative
Conservative treatment typically – consists of foods rich in dietary fiber, intake of oral fluids to maintain hydration, nonsteroidal anti-inflammatory drugs, sitz baths, and rest.[rx] Increased fiber intake has been shown to improve outcomes[rx] and may be achieved by dietary alterations or the consumption of fiber supplements.[rx][rx] Evidence for benefits from sitz baths during any point in treatment, however, is lacking.[rx] If they are used, they should be limited to 15 minutes at a time.[rx] Decreasing the time spent on the toilet and not straining is also recommended.[rx]
While many topical agents and suppositories – are available for the treatment of hemorrhoids, little evidence supports their use.[rx] Steroid-containing agents should not be used for more than 14 days, as they may cause thinning of the skin.[rx] Most agents include a combination of active ingredients.[rx] These may include a barrier cream such as petroleum jelly or zinc oxide, an analgesic agent such as lidocaine, and a vasoconstrictor such as epinephrine.[rx] Some contain Balsam of Peru to which certain people may be allergic.[rx][rx]
Flavonoids – are of questionable benefit, with potential side effects.[rx][rx] Symptoms usually resolve following pregnancy; thus active treatment is often delayed until after delivery.[rx] Evidence does not support the use of traditional Chinese herbal treatment[rx].[rx]
Corticosteroid cream – If you have severe inflammation in and around your back passage, your GP may prescribe corticosteroid cream[rx], which contains steroids. You shouldn’t use corticosteroid cream for more than a week at a time as it can make the skin around your anus thinner and the irritation worse.
Painkillers – Common painkilling medication, such as paracetamol, can help relieve the pain of hemorrhoids. But if you have excessive bleeding, avoid using non-steroid anti-inflammatory drugs (NSAIDs), such as ibuprofen, as they can make rectal bleeding worse. You should also avoid using codeine painkillers as they can cause constipation. Your GP may prescribe products that contain a local anesthetic to treat painful hemorrhoids. Like over-the-counter topical treatments, these should only be used for a few days because they can make the skin around your back passage more sensitive.
Laxatives – If you’re constipated, your GP may prescribe a laxative. Laxatives are a type of medicine that can help you empty your bowels.
Injections (sclerotherapy)
A treatment called sclerotherapy may be used as an alternative to banding. During sclerotherapy, a chemical solution is injected into the blood vessels in your back passage. This relieves pain by numbing the nerve endings at the site of the injection.
It also hardens the tissue of hemorrhoid so a scar is formed. After about 4 to 6 weeks, hemorrhoid should decrease in size or shrivel up. You should avoid strenuous exercise for the rest of the day after having the injection. You may experience minor pain for a while and may bleed a little. You should be able to resume normal activities, including work, the day after the procedure.
Electrotherapy
Electrotherapy, also known as electrocoagulation, is another alternative to banding for people with smaller hemorrhoids. During the procedure, a device called a proctoscope is inserted into the anus to locate hemorrhoid.
An electric current is then passed through a small metal probe placed at the base of hemorrhoid, above the dentate line. The specialist can control the electric current using controls attached to the probe. The aim of electrotherapy is to cause the blood supplying hemorrhoid to thicken, which shrinks it. If necessary, more than one hemorrhoid can be treated during each session.
Electrotherapy can either be carried out on an outpatient basis using a low electric current, or a higher dose can be given while the person is under a general anesthetic or spinal anesthetic. Rectal bleeding is another possible side effect of the procedure, but this is usually short-lived.
Electrotherapy is recommended by the National Institute for Health and Care Excellence (NICE), and has been shown to be an effective method of treating smaller hemorrhoids.
Oral flavonoids
These venotonic agents were first described in the treatment of chronic venous insufficiency and edema. They appeared to be capable of increasing vascular tone, reducing venous capacity, decreasing capillary permeability[rx], and facilitating lymphatic drainage[rx] as well as having anti-inflammatory effects[rx].
Although their precise mechanism of action remains unclear, they are used as an oral medication for hemorrhoidal treatment, particularly in Europe and Asia. Micronized purified flavonoid fraction (MPFF), consisting of 90% diosmin and 10% hesperidin, is the most common flavonoid used in clinical treatment[rx].
The micronization of the drug to particles of less than 2 μm not only improved its solubility and absorption but also shortened the onset of action. A recent meta-analysis of flavonoids for hemorrhoidal treatment, including 14 randomized trials and 1514 patients, suggested that flavonoids decreased the risk of bleeding by 67%, persistent pain by 65% and itching by 35%, and also reduced the recurrence rate by 47%[rx]. Some investigators reported that MPFF can reduce rectal discomfort, pain and secondary hemorrhage following hemorrhoidectomy[rx].
Oral Calcium Dobesilate
This is another venotonic drug commonly used in diabetic retinopathy and chronic venous insufficiency as well as in the treatment of acute symptoms of hemorrhoids[rx]. It was demonstrated that calcium dobesilate decreased capillary permeability, inhibited platelet aggregation and improved blood viscosity; thus resulting in a reduction of tissue edema[rx].
A clinical trial of hemorrhoid treatment showed that calcium dobesilate, in conjunction with a fiber supplement, provided an effective symptomatic relief from acute bleeding, and it was associated with a significant improvement in the inflammation of hemorrhoids[rx].
Topical Treatment
The primary objective of most topical treatment aims to control the symptoms rather than to cure the disease. Thus, other therapeutic treatments could be subsequently required. A number of topical preparations are available including creams and suppositories, and most of them can be bought without a prescription.
Strong evidence supporting the true efficacy of these drugs is lacking. These topical medications can contain various ingredients such as local anesthesia, corticosteroids, antibiotics and anti-inflammatory drugs[rx].
Topical treatment may be effective in selected groups of hemorrhoidal patients. For instance, Tjandra et al[rx] showed a good result with topical glyceryl trinitrate 0.2% ointment for relieving hemorrhoidal symptoms in patients with low-grade hemorrhoids and high resting anal canal pressures. However, 43% of the patients experienced a headache during the treatment.
Which contains 0.25% phenylephrine, petrolatum, light mineral oil, and shark liver oil. Phenylephrine is a vasoconstrictor having a preferential vasopressor effect on the arterial site of circulation, whereas the other ingredients are considered protectants. Preparation-H is available in many forms, including ointment, cream, gel, suppositories, and medicated and portable wipes[rx]. It provides temporary relief of acute symptoms of hemorrhoids, such as bleeding and pain on defecation.
Drug Therapy
A vast industry has evolved around preparatory creams and suppositories for treating hemorrhoids. These combinations of steroids, anesthetics, antiseptics and barrier creams may be effective in temporarily relieving the acute symptoms of the haemorrhoidal disease. Patients often return to these agents if symptoms recur, not realizing that symptoms fluctuate with time and may have resolved with simple hygiene alone.
Unlike for these over-the-counter remedies, there is some evidence for the effectiveness of venotonic therapies. Oral flavonoid medication can control acute bleeding.[rx][rx]
Rubber Band Ligation
Various outpatient treatments for symptomatic hemorrhoids exist. In the UK and many other countries, rubber band ligation (RBL) is the most commonly performed of these therapies.[rx] RBL uses a device that allows a rubber band to be applied to each hemorrhoid via a proctoscope.
This band constricts the blood supply causing hemorrhoid to become ischaemic before being sloughed approximately 1–2 weeks later. The resultant fibrosis reduces any element of haemorrhoidal prolapse that may have been present. Although easy to perform, and with a short learning curve, care has to be taken to place the bands correctly to reduce the potential for severe pain.
Injection Sclerotherapy
Various sclerosant solutions have been used for injecting piles. The comparative efficacy of these solutions is unclear. Less potent solutions such as 5% phenol in almond oil are more commonly used and probably have a lower risk of mucosal necrosis. Injection treatment is simple, safe and rapid, but probably not as effective as RBL.[rx]
This treatment modality should probably be reserved for patients where bleeding is the main symptom and conservative therapy has not improved the symptoms (and other causes having been excluded). Other indications possibly include patients with a high risk of secondary hemorrhage (patients on anticoagulants and patients with advanced cirrhosis) and those who are immunocompromised.[rx],[rx]
Infrared Coagulation
Infrared coagulation consists of a direct application of infrared waves to the haemorrhoidal pedicle resulting in necrosis and sloughing of the pile. Several applications are required per hemorrhoid but each takes a few seconds. Complications and efficacy are similar to RBL with some suggesting less pain presumably related to the lower volume of tissue necrosis.[rx]–[rx] Although a potential alternative to RBL, the equipment is expensive and there is a longer learning curve.
Bipolar, direct current and radiofrequency ablation therapy
Application of low wattage bipolar diathermy results in tissue coagulation. The process takes up to 30 s and multiple applications to the same site are often required.[rx] Complications, including pain, bleeding, and fissuring, occur in around 10% of patients.
Direct current therapy has gained recent favor in the form of Ultroid therapy, although the reasons for its popularity, other than aggressive marketing, are unclear. The procedure involves the application of a probe onto the haemorrhoidal cushion and application of a low direct current for around 10 min per hemorrhoid. Results are at best equivalent to injection sclerotherapy[rx] and RBL, but with the procedure taking significantly longer.
Radiofrequency ablation cuts and coagulates haemorrhoidal tissue using less power (and hence less temperature) than other electrical equipment. A comparison with RBL suggested similar efficacy to RBL with less pain.[rx] Again equipment is expensive and the procedure has not gained universal acceptance.
Combination Therapy
Numerous combinations of therapies have been described and include RBL with injection sclerotherapy[rx]or infrared coagulation.[rx] Again, the studies are of poor quality. Indeed, the description of some therapies involves almost daily outpatient visits over a few weeks. Such an intense therapy negates the advantage of an outpatient procedure, particularly as efficacy is not clear.
With this caveat, the combination of RBL with injection sclerotherapy does make practical sense. Not only is the double therapy a ‘belt and braces’ approach but also the bolus of sclerosant below the band ligation may act to secure the band, reducing failure due to premature slippage.
Non-operative Treatment
Sclerotherapy
This is currently recommended as a treatment option for first- and second-degree hemorrhoids. The rationale of injecting chemical agents is to create a fixation of mucosa to the underlying muscle by fibrosis. The solutions used are 5% phenol in oil, vegetable oil, quinine, and urea hydrochloride or hypertonic salt solution[rx].
It is important that the injection is made into submucosa at the base of the hemorrhoidal tissue and not into the hemorrhoids themselves; otherwise, it can cause immediate transient precordial and upper abdominal pain[rx].
Misplacement of the injection may also result in mucosal ulceration or necrosis, and rare septic complications such as prostatic abscess and retroperitoneal sepsis[rx].
Antibiotic prophylaxis is indicated for patients with predisposing valvular heart disease or immunodeficiency because of the possibility of bacteremia after sclerotherapy[rx].
Rubber Band Ligation
Rubber band ligation (RBL) is a simple, quick, and effective means of treating first- and second-degree hemorrhoids and selected patients with third-degree hemorrhoids. Ligation of the hemorrhoidal tissue with a rubber band causes ischemic necrosis and scarring, leading to fixation of the connective tissue to the rectal wall.
Placement of rubber band too close to the dentate line may cause severe pain due to the presence of somatic nerve afferents and requires immediate removal. RBL is safely performed in one or more than one place in a single session[rx] with one of several commercially available instruments, including hemorrhoid ligator rectoscope[rx] and endoscopic ligator[rx] which use suction to draw the redundant tissue into the applicator to make the procedure a one-person effort.
Infrared Coagulation
The infrared coagulator produces infrared radiation which coagulates tissue and evaporates water in the cell, causing shrinkage of the hemorrhoid mass. A probe is applied to the base of hemorrhoid through the anoscope and the recommended contact time is between 1.0-1.5 s, depending on the intensity and wavelength of the coagulator[rx].
The necrotic tissue is seen as a white spot after the procedure and eventually heals with fibrosis. Compared with sclerotherapy, infrared coagulation (IRC) is less technique-dependent and avoids the potential complications of misplaced sclerosing injection[rx]. Although IRC is a safe and rapid procedure, it may not be suitable for large, prolapsing hemorrhoids.
Radiofrequency ablation
Radiofrequency ablation (RFA) is a relatively new modality of hemorrhoidal treatment. A ball electrode connected to a radiofrequency generator is placed on the hemorrhoidal tissue and causes the contacting tissue to be coagulated and evaporized[rx].
By this method, vascular components of hemorrhoids are reduced and hemorrhoidal mass will be fixed to the underlying tissue by subsequent fibrosis. RFA can be performed on an outpatient basis and via an anoscope similar to sclerotherapy. Its complications include acute urinary retention, wound infection, and perianal thrombosis. Although RFA is a virtually painless procedure, it is associated with a higher rate of recurrent bleeding and prolapse[rx].
Cryotherapy
Cryotherapy ablates the hemorrhoidal tissue with a freezing cryoprobe. It has been claimed to cause less pain because sensory nerve endings are destroyed at very low temperature. However, several clinical trials revealed that it was associated with prolonged pain, foul-smelling discharge and a high rate of persistent hemorrhoidal mass[rx]. It is therefore rarely used.
Operative Treatment
The operation is indicated when non-operative approaches have failed or complications have occurred. Different philosophies regarding the pathogenesis of hemorrhoidal disease create different surgical approaches.
Summary of different philosophies regarding the pathogenesis of hemorrhoids and related surgical approaches
Theory
Short description
Surgical approach
Sliding anal cushions
Hemorrhoids develop when the supporting tissues of the anal cushions disintegrate or deteriorate
Hemorrhoidectomy, plication
Rectal redundancy
Hemorrhoidal prolapse is associated with an internal rectal prolapse
Stapled hemorrhoidopexy
Vascular abnormality
Hyperperfusion of arteriovenous plexus within anal cushion results in the formation of hemorrhoids
Doppler-guided hemorrhoidal artery ligation
Hemorrhoidectomy
Excisional hemorrhoidectomy is the most effective treatment for hemorrhoids with the lowest rate of recurrence compared to other modalities[rx]. It can be performed using scissors, diathermy[rx,rx], or vascular-sealing device such as Ligasure (Covidien, United States)[rx,rx] and Harmonic scalpel (Ethicon Endosurgery, United States)[rx,rx]. Excisional hemorrhoidectomy can be performed safely under perianal anesthetic infiltration as an ambulatory surgery[rx,rx].
Indications for hemorrhoidectomy include failure of non-operative management, acute complicated hemorrhoids such as strangulation or thrombosis, patient preference, and concomitant anorectal conditions such as anal fissure or fistula-in-ano which require surgery[rx]. In clinical practice, the third-degree or fourth-degree internal hemorrhoids are the main indication for hemorrhoidectomy.
A major drawback of hemorrhoidectomy is postoperative pain[rx]. There has been evidence that Ligasure hemorrhoidectomy results in less postoperative pain, shorter hospitalization, faster wound healing and convalescence compared to scissors or diathermy hemorrhoidectomy[rx–rx]. Other postoperative complications include acute urinary retention (2%-36%), postoperative bleeding (0.03%-6%), bacteremia and septic complications (0.5%-5.5%), wound breakdown, unhealed wound, loss of anal sensation, mucosa prolapse, anal stricture (0%-6%), and even fecal incontinence (2%-12%)[rx–rx]. Recent evidence has suggested that hemorrhoidal specimens can be exempt from pathological examination if no malignancy is suspected[rx].
Plication
Plication is capable of restoring anal cushions to their normal position without excision. This procedure involves oversewing of hemorrhoidal mass and tying a knot at the uppermost vascular pedicle. However, there are still a number of potential complications following this procedure such as bleeding and pelvic pain[rx].
Doppler-guided hemorrhoidal artery ligation
A new technique based on doppler-guided ligation of the terminal branches of the superior hemorrhoidal artery was introduced in 1995 as an alternative to hemorrhoidectomy[rx]. Doppler-guided hemorrhoidal artery ligation (DGHAL) has become increasingly popular in Europe. The rationale of this treatment was later supported by the findings from vascular studies[rx,rx], which demonstrated that patients with hemorrhoids had increased caliber and arterial blood flow of the terminal branch of the superior rectal arteries.
Therefore, ligating the arterial supply to hemorrhoidal tissue by suture ligation may improve hemorrhoidal symptoms. DGHAL is most effective for second- or third-degree hemorrhoids. Notably, DGHAL may not improve prolapsing symptoms in advanced hemorrhoids. Short-term outcomes and 1-year recurrence rates of DGHAL did not differ from those of conventional hemorrhoidectomy[rx]. Given the fact that there is the possibility of revascularization and recurrence of symptomatic hemorrhoids, further studies on the long-term outcomes of DGHAL are still required[rx].
Stapled Hemorrhoidopexy
Stapled hemorrhoidopexy (SH) has been introduced since 1998[rx]. A circular stapling device is used to excise a ring of redundant rectal mucosa proximal to hemorrhoids and resuspend the hemorrhoids back within the anal canal. Apart from lifting the prolapsing hemorrhoids, blood supply to hemorrhoidal tissue is also interrupted.
A recent meta-analysis comparing surgical outcomes between SH and hemorrhoidectomy, which included 27 randomized, controlled trials with 2279 procedures, showed that SH was associated with less pain, earlier return of bowel function, shorter hospital stay, earlier return to normal activities, and better wound healing, as well as a higher degree of patient satisfaction[rx].
However, in the longer term, SH was associated with a higher rate of prolapse[rx,rx,rx]. Considering the recurrence rate, cost of stapling device and potential serious complications including rectovaginal fistula[rx] and rectal stricture[rx,rx], SH is generally reserved for patients with circumferential prolapsing hemorrhoids and having ≥ 3 lesions of advanced internal hemorrhoids.
Acutely Thrombosed or Strangulated Internal Hemorrhoids
Patients with acutely thrombosed or strangulated internal hemorrhoids usually present with severely painful and irreducible hemorrhoids. The incarcerated hemorrhoids may become necrotic and drain. This situation is quite difficult to treat particularly in a case of extensive strangulation or thrombosis [rx]), or the presence of underlying circumferential prolapse of high-graded hemorrhoids.
Manual reduction of the hemorrhoid masses, with or without intravenous analgesia or sedation, might help reducing pain and tissue congestion. Urgent hemorrhoidectomy is usually required in these circumstances. Unless the tissues are necrotic, mucosa and anoderm should be preserved as much as possible to prevent postoperative anal stricture. In expert hands, surgical outcomes of urgent hemorrhoidectomy were comparable to those of elective hemorrhoidectomy[rx]. Complicated hemorrhoids. A: Strangulated internal hemorrhoid; B: Acutely thrombosed external hemorrhoid.
Acutely Thrombosed External Hemorrhoids
Acutely thrombosed external hemorrhoids often develop in patients with acute constipation, or those with a recent history of prolonged straining. A painful bluish-colored lump at the anal verge is a paramount finding (Figure [rx]. The severity of pain is most intense within the first 24-48 h of onset. After that, the thrombosis will be gradually absorbed and patients will experience less pain.
As a result, surgical removal of acute thrombus or excisional hemorrhoidectomy may be offered if patients experience severe pain especially within the first 48 h of onset. Otherwise, the conservative measure will be exercised including pain control, warm sitz baths, and avoidance of constipation or straining. A resolving thrombosed external hemorrhoid could leave behind as a residual perianal skin tag -which may or may not require a subsequent excision.
Hemorrhoids in Pregnancy
Hemorrhoids are very common during pregnancy especially in the third trimester[rx]. An acute crisis such as profound bleeding and irreducible prolapsing may be found in pregnant women with pre-existing hemorrhoids. Since hemorrhoids and its symptoms will gradually resolve after giving birth, the primary goal of treatment is to relieve acute symptoms related to hemorrhoids – mostly by means of dietary and lifestyle modification.
Kegel exercises, lying on the left side, and avoidance of constipation could reduce the episode and severity of bleeding and prolapse. A fiber supplement, stool softener, and mild laxatives are generally safe for pregnant women. Topical medication or oral phlebotonics may be used with special caution because the strong evidence of their safety and efficacy in pregnancy is lacking. In the case of massive bleeding, anal packing could be a simple and useful maneuver. Hemorrhoidectomy is reserved in strangulated or extensively thrombosed hemorrhoids, and hemorrhoids with intractable bleeding.
Hemorrhoids in Immunocompromised Patients
In general, any intervention or operation should be avoided, or performed with careful consideration in immunocompromised patients because of an increased risk of anorectal sepsis and poor tissue healing in such cases[rx]. A conservative measure is a mainstay for the treatment of hemorrhoids in this group of patients.
If required, injection sclerotherapy appeared to be a better and safer alternative to banding and hemorrhoidectomy for treating bleeding hemorrhoids[rx,rx]. Antibiotic prophylaxis is always given before performing any intervention, even a minor office-based procedure, due to the possibility of bacteremia.
Hemorrhoids in Patients with Cirrhosis or Portal Hypertension
A clinician must differentiate bleeding hemorrhoids from bleeding anorectal varices because the latter can be managed by suture ligation along with the course of varices, transjugular intrahepatic portosystemic shunt, or pharmacological treatment of portal hypertension[rx].
Since a majority of bleeding hemorrhoids in such patients is not life threatening, conservative measure with the correction of any coagulopathy is a preferential initial approach. Of note, rubber band ligation is generally contraindicated in patients with advanced cirrhosis due to the risk of profound secondary bleeding following the procedure.
Injection sclerotherapy is an effective and safe procedure for treating bleeding hemorrhoids in this situation. In a refractory case, suture ligation at the bleeder is advised. Hemorrhoidectomy is indicated when bleeding hemorrhoids are refractory to other approaches.
Hemorrhoids in Patients Having Anticoagulant or Antiplatelet drugs
Anticoagulant or antiplatelet drugs may promote anorectal bleeding in patients with hemorrhoids and increase the risk of bleeding after banding or surgery[rx].
Unless the bleeding is persistent or profound, the discontinuity of antithrombotic drugs may be unnecessary because most of the bleeding episodes are self-limited and stop spontaneously. Conservative measure is, therefore, the mainstay treatment in these patients. Injection sclerotherapy is preferential treatment for bleeding low-graded hemorrhoids refractory to medical treatment.
Rubber band ligation is not recommended in patients with the current use of anticoagulant or antiplatelet drugs due to the risk of secondary bleeding. If banding or any form of surgery for hemorrhoids is scheduled, the cessation of anticoagulant or antiplatelet drugs about 5-7 d before and after the procedure is suggested[rx].
Stapled Hemorrhoidopexy
Stapled hemorrhoidopexy, also known as a procedure for prolapse and hemorrhoids (PPH), is an alternative operation for treating advanced internal hemorrhoids. A circular staple device is used to excise a ring of redundant rectal mucosa just above hemorrhoid bundles – not hemorrhoids per se.
By doing this, prolapsing hemorrhoids will be repositioning (hemorrhoidopexy) and shrinking (due to a partial interruption of blood supply to hemorrhoid plexus). A recent systematic review of 27 randomized controlled trials demonstrated that, compared with conventional hemorrhoidectomy, stapled hemorrhoidopexy had less pain, shorter operative time, and quicker patient’s recovery of a patient, but a significantly higher rate of prolapse and reintervention for prolapse[rx].
Complications
Piles rarely cause any serious problems but sometimes they can lead to the following.
External piles (swellings that develop further down your anal canal, closer to your anus) can become inflamed and swollen; ulcers can also form on them.
Skin tags can form when the inside of a pile shrinks back but the skin remains. For more information, see our FAQ: Skin tags, below.
If mucus leaks from your anus, it can make the surrounding skin very sore.
Internal piles that prolapse (hang down) can sometimes get strangulated and lose their blood supply. If blood clot forms (thrombosis), piles can be very painful. External piles can also become thrombosed.
Sexual Disorder (or sexual malfunction) is difficulty experienced by an individual or a couple during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal or orgasm. According to the DSM-5, sexual dysfunction requires a person to feel extreme distress and interpersonal strain for a minimum of 6 months (excluding substance or medication-induced sexual dysfunction). Sexual dysfunctions can have a profound impact on an individual’s perceived quality of sexual life. The term sexual disorder may not only refer to physical sexual dysfunction, but to paraphilias as well; this is sometimes termed disorder of sexual preference.
Sexual function is an essential component of life, both in species propagation as well as the quality of life. Sexual dysfunction can lead to reduced quality of life and potentially procreative advancement. Male sexual dysfunction, especially erectile dysfunction, has been extensively studied and effective therapies are available for men with this disorder. However, female sexual dysfunction (FSD) is more complicated and significantly less is understood in comparison to male sexual dysfunction. Therefore, the present review focuses on therapies available or in development as well as challenges faced by investigators in the study of FSD. Other recent reviews articles may be useful for understanding additional aspects of FSD [rx–rx].
Types of Sexual Disorder
The spectrum of sexual dysfunction encompasses:
Decreased sexual desire—persistent or recurrent deficiency or absence of desire for sexual activity giving rise to marked distress and interpersonal difficulty;
Sexual aversion disorder—persistent or recurrent aversion and avoidance of all genital sexual contact leading to marked distress and interpersonal difficulty;
Difficulty in erection—recurrent or persistent, partial or complete failure to attain or maintain an erection until the completion of the sex act;
Difficulty in achieving orgasm—persistent or recurrent delay in or absence of orgasm, following a normal sexual excitement phase;
Premature ejaculation—persistent or recurrent ejaculation with minimal sexual stimulation, before, on or shortly after penetration and before the person wishes it, which causes marked distress.[rx]
Sexual dysfunction generally is classified into four categories
Desire disorders —lack of sexual desire or interest in sex
Arousal disorders —inability to become physically aroused or excited during sexual activity
Orgasm disorders —delay or absence of orgasm (climax)
Pain disorders — pain during intercourse
List of disorders of Sexual Disorder
DSM
The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders lists the following sexual dysfunctions:
Hypoactive sexual desire disorder (see also asexuality, which is not classified as a disorder)
Sexual aversion disorder (avoidance of or lack of desire for sexual intercourse)
Female sexual arousal disorder (failure of normal lubricating arousal response)
Male erectile disorder
Female orgasmic disorder
Male orgasmic disorder
Premature ejaculation
Dyspareunia
Vaginismus
Additional DSM sexual disorders that are not sexual dysfunctions include:
Paraphilias
PTSD due to genital mutilation or childhood sexual abuse
Other Sexual Problems of Sexual Disorder
Sexual dissatisfaction (non-specific)
Lack of sexual desire
Anorgasmia
Impotence
Sexually transmitted diseases
Delay or absence of ejaculation, despite adequate stimulation
Inability to control the timing of ejaculation
Inability to relax vaginal muscles enough to allow intercourse
Inadequate vaginal lubrication preceding and during intercourse
Burning pain on the vulva or in the vagina with contact to those areas
Unhappiness or confusion related to sexual orientation
Transsexual and transgender people may have sexual problems before or after surgery.
Persistent sexual arousal syndrome
Sexual addiction
Hypersexuality
All forms of Female genital cutting
Post-orgasmic diseases, such as Dhat syndrome, post-coital tristesse (PCT), postorgasmic illness syndrome (POIS), and sexual headache.
Causes of Sexual Disorder
Physical causes — Many physical and/or medical conditions can cause problems with sexual function. These conditions include diabetes, heart, and vascular (blood vessel) disease, neurological disorders, hormonal imbalances, chronic diseases such as kidney or liver failure, and alcoholism and drug abuse. Physical causes refer to health conditions that contribute to sexual problems or the inability to achieve satisfaction. Some of the most common physical causes for sexual disorders include:
Neurological disorders like multiple sclerosis
Fatigue, frequent headaches or chronic pain
Urinary or bowel difficulties
Surgery, especially in the pelvic area
Diseases like arthritis, diabetes or high blood pressure
Use of certain medication or recreational drugs
Injuries
Psychological causes — These include work-related stress and anxiety, concern about sexual performance, marital or relationship problems, depression, feelings of guilt, concerns about body image, and the effects of past sexual trauma.
Metabolic syndrome — a condition involving increased blood pressure, high insulin levels, body fat around the waist and high cholesterol
Parkinson’s disease
Multiple sclerosis
Certain prescription medications
Tobacco use
Peyronie’s disease — development of scar tissue inside the penis
Alcoholism and other forms of substance abuse
Sleep disorders
Treatments for prostate cancer or enlarged prostate
Surgeries or injuries that affect the pelvic area or spinal cord
Depression, anxiety or other mental health conditions
Stress
Relationship problems due to stress, poor communication or other concerns
Sexual trauma or abuse in the past
Anxiety disorder and attacks
Poor self-image and lack of confidence
Medications
Certain medications can cause changes in the level of experienced sexual desire through “non-specific effects on general well-being, energy level, and mood”. Declining levels of sexual desire have been linked to the use of anti-hypertension medication and many psychiatric medications; such as antipsychotic medications, tricyclic anti-depressants, monoamine-oxidase (MAO) inhibitors, and sedative drugs.
However, the most severe decreases in sexual desire relating to psychiatric medication occur due to the use of selective serotonin reuptake inhibitors (SSRIs). In women specifically, the use of anticoagulants, cardiovascular medications, medications to control cholesterol, and medications for hypertension contributed to low levels of desire.
Hormone
Sexual desire is said to be influenced by androgens in men and by androgens and estrogens in women. Many studies associate the sex hormone, testosterone with sexual desire. Testosterone is mainly synthesized in the testes in men and in the ovaries in women. Another hormone thought to influence sexual desire is oxytocin.
Exogenous administration of moderate amounts of oxytocin has been found to stimulate females to desire and seek out sexual activity. In women, oxytocin levels are at their highest during sexual activity. In males, the frequency of ejaculations affects the libido. If the gap between ejaculations extends toward a week, there will be a stronger desire for sexual activity.
Interventions
There are a few medical interventions that can be done on individuals who feel sexually bored, experience performance anxiety, or are unable to orgasm. For everyday life, a 2013 fact sheet by the Association for Reproductive Health Professionals recommends:
Erotic literature
Recalling instances when feeling sexy and sexual (The patient is instructed to recall her physical appearance, the setting, the smells in the air, the music she was hearing, and the foods she was eating at that time and use these as ‘cues’ for feeling sexual now)
Social and Religious Views of Sexual Disorder
The views on sexual desire and on how sexual desire should be expressed vary significantly between different societies and religions. Various ideologies range from sexual repression to hedonism. Lawson various forms of sexual activity, such as homosexual acts and sex outside marriage vary by countries. Some cultures seek to restrict sexual acts to marriage.
In some societies, there is a double standard regarding the male and female expression of sexual desire. Female genital mutilation is practiced in some regions of the world in an attempt to prevent women to act on their sexual desire and engage in “illicit” sex.
Symptoms of Sexual Disorder
The total absence of sexual desire or a low sex drive
An inability to get aroused or maintain arousal for the duration of sexual activity
Recurrent ejaculation with minimal sexual stimulation
Inadequate lubrication in spite of sexual excitement
Not achieving an orgasm, after going through the normal excitement phase
Pain while having intercourse
Rx
Vaginal Dryness
Why It’s Happening – Vaginal dryness can result from hormonal changes that occur during breastfeeding or menopause. In fact, a study of 1,000 postmenopausal women published in January 2010 in the journal Menopause found that half of the postmenopausal women experience vaginal dryness.
Low Desire
Why It’s Happening – As hormones decline in the years leading up to menopause, your libido can go south, too. But low desire isn’t just a problem for older women: Half of females ages 30 to 50 have also suffered from a lack of lust, according to a national survey of 1,000 women. Low libido can result from a number of issues, including medical problems like diabetes and low blood pressure, and psychological issues like depression or simply being unhappy in your relationship. Certain medications, like antidepressants, can also be libido killers, as can hormonal contraceptives, according to a study published in June 2010 in The Journal of Sexual Medicine.
What You Can Do – There’s no one-stop solution to boost libido, so talk to your doctor, who can help you get to the root of the problem. If the issue is emotional or psychological, they may recommend seeing a therapist. “A traditional or sexual therapist can help couples evolve from having the same old conversation patterns, life habits, and sexual habits to having a sexual relationship that’s fulfilling, invigorating, and romantic,” says Worley.
Painful Sex
Rx
Why It’s Happening – As many as 30 percents of women report pain during sex, Pain can be caused by vaginal dryness, or it may be an indication of a medical problem, like ovarian cysts or endometriosis, according to The American Congress of Obstetricians and Gynecologists. Painful sex can also be related to vaginismus, a condition in which the vagina tightens involuntarily when penetrated.
What You Can Do – Talk to your healthcare provider to rule out medical issues like ovarian cysts, endometriosis, or vaginismus. If those aren’t the problem, your doctor may recommend pelvic floor physical therapy, medication, or surgery to treat the cause of pain, says Worley. “It’s important to understand that the first treatment doesn’t always work, and sometimes multiple attempts at treatment are needed before you find success,” he says.
Arousal Problems
Why It’s Happening – The inability to become aroused may be due to a number of reasons, such as anxiety or inadequate stimulation (aka, you need more foreplay). If you experience dryness or pain during sex, it can also be harder to become turned on. Hormonal changes due to menopause or a partner’s sexual issues (like erectile dysfunction or premature ejaculation) can also make it more difficult to get in the mood.
What You Can Do – Work with your healthcare provider to ID the underlying reason you can’t become aroused, recommends Worly. He or she can help connect you with the right form of treatment to correct the problem, whether that’s seeking out sexual therapy, a medication (like hormones), or treatment for your partner’s problem, he says.
Trouble Reaching Orgasm
Why It’s Happening – About 5 percent of perimenopausal women experience orgasm problems,” says Worly. Aside from hormone changes, an inability to reach orgasm may also be due to anxiety, insufficient foreplay, certain medications, and chronic diseases.
What You Can Do – Just like other forms of sexual dysfunction, it’s key to talk to your doctor to address the underlying problem before trying to treat it. In the meantime, try being more mindful while you’re getting it on by paying attention to the sensations as they happen. suggests that being mindful during sex can make it easier to achieve orgasm. It may also be useful to add a vibrator to your sexual repertoire, says Worley. “Vibrators are now sold at most pharmacies, both in the store and online, so it’s possible to buy them discreetly from the comfort of your home,” he notes.
Diagnosis of Sexual Disorder
Physical exam – This might include careful examination of your penis and testicles and checking your nerves for sensation.
Blood tests– A sample of your blood might be sent to a lab to check for signs of heart disease, diabetes, low testosterone levels, and other health conditions.
Urine tests (urinalysis) – Like blood tests, urine tests are used to look for signs of diabetes and other underlying health conditions.
Ultrasound – This test is usually performed by a specialist in an office. It involves using a wand-like device (transducer) held over the blood vessels that supply the penis. It creates a video image to let your doctor see if you have blood flow problems. This test is sometimes done in combination with an injection of medications into the penis to stimulate blood flow and produce an erection.
Psychological exam – Your doctor might ask questions to screen for depression and other possible psychological causes of erectile dysfunction.
Treatment of Sexual Disorder
Most types of sexual dysfunction can be corrected by treating the underlying physical or psychological problems. Other treatment strategies include:
Medication— When a medication is the cause of the dysfunction, a change in the medication may help. Men and women with hormone deficiencies may benefit from hormone shots, pills, or creams. For men, drugs, including sildenafil, tadalafil, vardenafil, and avanafil may help improve sexual function by increasing blood flow to the penis.
PDE5 Inhibitors – Increasing blood delivery to the genitals with the development of the first marked PDE5 inhibitor, sildenafil revolutionized the treatment of erectile dysfunction in men. The physiological mechanism responsible for relaxation of smooth muscle of cavernous tissue (both male and female) is initiated with the release of nitric oxide (NO) from adjacent nerve endings and/or endothelial cells upon mental and sensory stimuli via spinal reflex [rx].
Prostaglandins – Prostaglandins (PG) are found in virtually all tissues and organs. They are autocrine and paracrine lipid molecules, which are quickly metabolized, and participate in a variety of physiological events, including blood flow regulation. Specifically, the PG isoform PGE1 (signaling through its EP2 receptor) causes smooth muscle relaxation in the vaginal, uterine, as well as penile smooth muscle [rx]. PGE1/EP2 activation leads to increases in cAMP resulting in activation of protein kinase A, which causes smooth muscle relaxation. Prostaglandins have been used in male sexual dysfunction, especially erectile dysfunction (administered through penile injection), for some time and have displayed positive outcomes for certain women with genital sexual arousal disorder, most likely through increasing vaginal secretion and arterial smooth muscle relaxation [rx].
Nitric Oxide Donor and Combination Therapy – It is well established that the production of NO is essential in vascular relaxation to numerous stimuli. PDE5 inhibitors augment NO-initiated dilation by propagating the downstream mediator, cGMP, through the activation of guanylate cyclase. Thus, activation of the NO-NO synthase (NOS) system is a potential site for pharmacological intervention. Pacher et al., demonstrated the topical application of a NO donor, DS1, a linear polyethyleneimine-nitric oxide/nucleophile adduct, increased vaginal blood flow in anesthetized rats [rx].
Vasoactive Intestinal Peptide – Vasoactive intestinal peptide (VIP) is a polypeptide hormone containing 28 amino acid residues and is produced in many areas of the human body. VIP has potent vasorelaxant effects and has been suggested to contribute to vaginal blood flow control [rx, rx]. Like many peptidic therapies, oral administration of VIP is complicated by low bioavailability and high rate of clearance. Therefore, an alternative approach using an inhibitor of neutral endopeptidase (NEP), the primary enzyme responsible for the degradation of VIP, has been in development under the assumption that inhibition of NEP will lead to more VIP in the circulation, which can increase clitoral and vaginal blood flow when sexually stimulated [rx].
Testosterone – The use of testosterone to treat FSD has delivered mixed results. A primary concern in testosterone therapy is the long-term side effects including hirsutism, acne, and masculinization [rx]. Given the results following the Woman’s Health Initiative, replacement therapy with estrogen and progestin revealed elevation in coronary heart disease, stroke and thrombosis formation [rx], a certain amount of caution must be taken in the treatment of FSD with hormones.
Estrogen – Estrogen plays a vital role in the regulation of female sexual function. Alterations in estradiol levels can result in vaginal wall smooth muscle atrophy and increased vaginal canal acidity, ultimately leading to discomfort and stress [rx]. The findings from the Woman’s Health Initiative raised concerns on estrogen replacement therapy, however, the benefits of estrogen in normal function are well accepted. Estrogen plays a vital role in the regulation of female sexual function. Alterations in estradiol levels can result in vaginal wall smooth muscle atrophy and increased vaginal canal acidity, ultimately leading to discomfort and stress [rx].
Centrally Mediated Stimulation – The sexual response for men and women is distinct. Regarding treatment of male ED, PDE5 inhibitors have proven to be very successful, whereas in FSD similar achievements have not been made. Treating FSD through central acting mediators has recently received more attention. This area of investigation has gained momentum by recent publication demonstrating that several hypothalamic nuclei are activated in rodent sexual response [rx]. Therefore, central regulation/activation of the female sexual response could mark an alternative approach for treating FSD.
Nitric Oxide Donor and Combination Therapy – It is well established that the production of NO is essential in vascular relaxation to numerous stimuli. PDE5 inhibitors augment NO-initiated dilation by propagating the downstream mediator, cGMP, through the activation of guanylate cyclase. Thus, activation of the NO-NO synthase (NOS) system is a potential site for pharmacological intervention. Pacher et al., demonstrated the topical application of a NO donor, DS1, a linear polyethyleneimine-nitric oxide/nucleophile adduct, increased vaginal blood flow in anesthetized rats [rx].
Centrally Mediated Stimulation – The sexual response for men and women is distinct. Regarding treatment of male ED, PDE5 inhibitors have proven to be very successful, whereas in FSD similar achievements have not been made. Treating FSD through central acting mediators has recently received more attention. This area of investigation has gained momentum by recent publication demonstrating that several hypothalamic nuclei are activated in rodent sexual response [rx]. Therefore, central regulation/activation of the female sexual response could mark an alternative approach for treating FSD.
Vasoactive Intestinal Peptide – Vasoactive intestinal peptide (VIP) is a polypeptide hormone containing 28 amino acid residues and is produced in many areas of the human body. VIP has potent vasorelaxant effects and has been suggested to contribute to vaginal blood flow control [rx, rx]. Like many peptidic therapies, oral administration of VIP is complicated by low bioavailability and high rate of clearance. Therefore, an alternative approach using an inhibitor of neutral endopeptidase (NEP), the primary enzyme responsible for the degradation of VIP, has been in development under the assumption that inhibition of NEP will lead to more VIP in the circulation, which can increase clitoral and vaginal blood flow when sexually stimulated [rx].
Mechanical aids — Aids such as vacuum devices and penile implants may help men with erectile dysfunction (the inability to achieve or maintain an erection). A vacuum device (Eros) is also approved for use in women but can be costly. Dilators may help women who experience narrowing of the vagina.
Sex therapy — Sex therapists can be very helpful to couples experiencing a sexual problem that cannot be addressed by their primary clinician. Therapists are often good marital counselors, as well. For the couple who wants to begin enjoying their sexual relationship, it is well worth the time and effort to work with a trained professional.
Behavioral treatments — These involve various techniques, including insights into harmful behaviors in the relationship, or techniques such as self-stimulation for treatment of problems with arousal and/or orgasm.
Psychotherapy — Therapy with a trained counselor can help a person address sexual trauma from the past, feelings of anxiety, fear, or guilt, and poor body image, all of which may have an impact on current sexual function.
Education and communication — Education about sex and sexual behaviors and responses may help an individual overcome his or her anxieties about sexual function. Open dialogue with your partner about your needs and concerns also helps to overcome many barriers to a healthy sex life.
Providing education –Education about human anatomy, sexual function, and the normal changes associated with aging, as well as sexual behaviors and appropriate responses, may help a woman overcome her anxieties about sexual function and performance.
Enhancing stimulation – This may include the use of erotic materials (videos or books), masturbation, and changes in sexual routines.
Providing distraction techniques –Erotic or non-erotic fantasies; exercises with intercourse; music, videos, or television can be used to increase relaxation and eliminate anxiety.
Encouraging non-coital behaviors –Non-coital behaviors (a physically stimulating activity that does not include intercourse), such as sensual massage, can be used to promote comfort and increase communication between partners.
Minimizing pain – Using sexual positions that allow the woman to control the depth of penetration may help relieve some pain. Vaginal lubricants can help reduce pain caused by friction, and a warm bath before intercourse can help increase relaxation.
Alprostadil self-injection – With this method, you use a fine needle to inject alprostadil (Caverject Impulse, Edex) into the base or side of your penis. In some cases, medications generally used for other conditions are used for penile injections on their own or in combination. Examples include papaverine, alprostadil, and phentolamine. Often these combination medications are known as mix (if two medications are included) or trimix (if three are included).
Alprostadil urethral suppository – Alprostadil intraurethral (Muse) therapy involves placing a tiny alprostadil suppository inside your penis in the penile urethra. You use a special applicator to insert the suppository into your penile urethra. The erection usually starts within 10 minutes and, when effective, lasts between 30 and 60 minutes. Side effects can include pain, minor bleeding in the urethra and formation of fibrous tissue inside your penis.
Penile implants – This treatment involves surgically placing devices into both sides of the penis. These implants consist of either inflatable or malleable (bendable) rods. Inflatable devices allow you to control when and how long you have an erection. The malleable rods keep your penis firm but bendable.
Exercise– Recent studies have found that exercise, especially moderate to vigorous aerobic activity, can improve erectile dysfunction. However, benefits might be less in some men, including those with established heart disease or other significant medical conditions.
Psychological counseling– If your erectile dysfunction is caused by stress, anxiety or depression — or the condition is creating stress and relationship tension — your doctor might suggest that you, or you and your partner, visit a psychologist or counselor.
Testosterone replacement – Some men have erectile dysfunction that might be complicated by low levels of the hormone testosterone. In this case, testosterone replacement therapy might be recommended as the first step or given in combination with other therapies that are following.
Androgen therapy
Estrogen therapy
Phosphodiesterase inhibitors
Testosterone replacement therapy
Tibolone
Potential and Current Therapeutic Options Available for the Treatment of Female Sexual Dysfunction
Improves vaginal dryness and overall sexual function
CNS
Dopaminergic agonist
Apomorphine
Bupropion
(Uprima®, Tap)
(Wellbutrin XL®, GlaxoSmithKline)
Binds to D receptors; increases sexual responsiveness
Synthetic α-melanocortin- stimulating hormone
Bremelanotide
(PT-141®, Palatin)
Binds to MC4 receptors; contributes to VSM relaxation
The specific management involves the following stages
Helping the woman develop more positive attitudes towards her genitals – After fully describing the female sexual anatomy, the therapist needs to encourage the woman to examine herself with a hand mirror on several occasions. Extremely negative attitudes (especially concerning the appearance of the genitals, or the desirability of examining them) may become apparent during this stage, possibly leading to failure to carry out the homework. Some women find it easier to examine themselves in the presence of the partners; others may only get started if the therapist helps them do this first in the clinic. If this is necessary a medically qualified female therapist is to be involved.
Pelvic muscle exercises – These are intended to help the woman gain some control over the muscles surrounding the entrance to the vagina. If she is unsure whether or not she can contract her vaginal muscles she may be asked to try to stop the flow of urine when she next goes to the toilet. The woman can later check that she is using the correct muscles by placing her finger at the entrance to her vagina where she needs to be able to feel the muscle contractions. Subsequently, she is advised to practice firmly contracting these muscles for an agreed number of times (e.g. 10) several times a day.
Vaginal penetration – Once the woman has become comfortable with the external genital anatomy she is advised to explore the inside of her vagina with her fingers. This is partly to encourage familiarity and partly to initiate vaginal penetration. Negative attitudes may also become apparent at this stage (e.g. concerning the texture of the vagina, its cleanliness, fear of causing damage, and whether it is ‘right’ to do this sort of thing). The rationale for any of these objections is to be explored. At a later stage, the woman might try using two fingers and moving them around. Once she is comfortable inserting a finger herself, her partner needs to begin to do this under her guidance during their homework sessions. A lotion (e.g. K-Y or baby lotion) can make this easier. Graded vaginal dilators can be used. However, clinical experience has shown that the use of fingers is just as effective.
Vaginal containment – When vaginal containment is attempted the pelvic muscle exercises and the lotion are used to assist in relaxing the vaginal muscles and making penetration easier. This is often a difficult stage and the therapist, therefore, needs to encourage the woman to gain confidence from all the progress made so far. Persisting concerns about possible pain may need to be explored, including how the woman might ensure that she retains control during this stage.
Movements during containment – Once containment is well established the couple is asked to introduce movement during containment, with preferable women starting the movements first. With this, the general programme of sex therapy is completed and now the treatment needs to include superimposition of treatment for specific sexual dysfunctions.
Steps in the management of vaginismus – Treatment is to be individualized for each woman and/or partner, whenever possible with their input. The psychological issue, as well as interpersonal issues,s need to be addressed first. The sex education needs to focus on clarifying normal sexuality and reducing negative attitude towards sex. Besides the use of general relaxation exercises, the relaxation procedure needs to focus on teaching women to relax muscles around the inner thigh and pelvic area. The specific behavioral management is to be followed.
Other oral Erectogenic Agents
Trazodone – One of the earliest drugs used in erectile dysfunction was trazodone. Trazodone and its active metabolite have an antagonistic effect on 5HT2C receptors and may also have adrenoceptor antagonistic action. Available data suggest that trazodone is more efficacious than placebo in mixed and psychogenic erectile dysfunction.
Yohimbine – It is an α2-adrenergic blocker. Before the introduction of sildenafil, yohimbine was the most widely used oral medication for management of erectile dysfunction. Available evidence suggests that it is more efficacious than placebo.
Apomorphine – Apomorphine is a dopamine agonist (D1 & D2 receptors) and its sublingual form (Apo-SL) is a new central initiator of erection and has been found to be effective in various types of erectile dysfunction. Recent studies show that sublingual apomorphine has a safe cardiovascular profile and thus making it a new treatment option for patients with concomitant disease including cardiovascular disease and diabetes mellitus.
Phentolamine – Oral phentolamine mesylate, is a competitive inhibitor of α- adrenergic receptor. It also has the advantage of lack of interaction with nitrates and hence has been suggested as an alternative to the treatment of erectile dysfunction in patients with the cardiac illness.
L-arginine – L-arginine is the precursor of Nitric Oxide (NO) and has been shown to improve erections in 40% of patients.
Remedies for Female Sexual Dysfunction
Some of the most commonly recommended home remedies for improving sexual disorders include:
A mixture of milk (250 ml), to which drumstick flowers (10 to 15 grams) have been added
A combination of pistachios, dried dates, quince seeds, and almonds, which have all been blended together.
Eating 100 grams of dried dates on a regular basis
Herbs, such as kava-kava, ginkgo biloba, chives, diffuse, arginine, lepidium meyenii and damiana
Natural therapies, like full body massages and hot baths.
Aromatherapy using essential oils like clary sage, rose, jasmine and lavender
Chewing on a few pieces of garlic or increasing the amount of garlic consumed through meals
In case the sexual disorder is a result of a medical condition, then it may be necessary to first address that. Medical treatment may also be used in case home remedies do not prove to be very effective. Some of the medication or therapies suggested for curing sexual disorders in men and women include:
Diet for Sexual Disorders
Given below are some of the food items that should be included in a diet for better sexual health:
Alfalfa sprouts
Avocado
Garlic
Ginger
Nuts
Olive oil
Onions
Salmon
Similarly, there are certain foods that may aggravate sexual disorders and therefore should be strictly avoided by individuals who do have problems or are undergoing treatment. Some of the foods that should be consumed in limited quantities or preferably not at all include:
Red meat
Caffeinated beverages like tea, coffee, and aerated drinks
Alcohol
Sweets and sugary items
Starchy food, such as processed or packaged items
There are some alternative health care practitioners who refer to Vitamin E as the sex vitamin as it helps in the production of sex hormones. They believe it improves sexual attraction, desire, and moods. Hence, increasing the intake of these vitamins can reduce sexual disorders considerably.
Outdoor exercise is any bodily activity that enhances or maintains physical fitness and overall health and wellness.It is performed for various reasons, including increasing growth and development, preventing aging, strengthening muscles and the cardiovascular system, honing athletic skills, weight loss or maintenance, and also for enjoyment. Many individuals choose to exercise publicly outdoors where they can congregate in groups, socialize, and enhance well-being.
Physical exercises are generally grouped into three types, depending on the overall effect they have on the human body
Aerobic exercise is any physical activity that uses large muscle groups and causes the body to use more oxygen than it would while resting. The goal of aerobic exercise is to increase cardiovascular endurance. Examples of aerobic exercise include running, cycling, swimming, brisk walking, skipping rope, rowing, hiking, playing tennis, continuous training, and long slow distance training.
Anaerobic exercise, which includes strength and resistance training, can firm, strengthen, and tone muscles, as well as improve bone strength, balance, and coordination. Examples of strength moves are push-ups, pull-ups, lunges, and bicep curls using dumbbells. Anaerobic exercise also includes weight training, functional training, eccentric training, interval training, sprinting, and high-intensity interval training increases short-term muscle strength.
Flexibility exercises stretch and lengthen muscles. Activities such as stretching help to improve joint flexibility and keep muscles limber The goal is to improve the range of motion which can reduce the chance of injury.
Physical exercise can also include training that focuses on accuracy, agility, power, and speed.
Sometimes the terms ‘dynamic’ and ‘static’ are used. ‘Dynamic’ exercises such as steady running, tend to produce a lowering of the diastolic blood pressure during exercise, due to the improved blood flow. Conversely, static exercise (such as weight-lifting) can cause the systolic pressure to rise significantly (during the exercise).
The Benefits of Outdoor Exercise
There is no debating the health benefits of daily exercise. The U.S. Centers for Disease Control and Prevention, the American College of Sports Medicine, and the Surgeon General’s Report on Physical Activity and Health all agree that we need at least 30 minutes of moderate to intense physical activity every day. The good news is that you don’t have to work out in a gym to get in shape. Outdoor exercises are just as effective, can be more fun, and have some appealing advantages.
Reasons to Take Your Workouts Outside
Outdoor fitness can be a structured exercise program that takes advantage of the natural terrain of the outdoors to get you in shape, or it can be as simple as taking a brisk walk outside. Outdoor fitness can take many forms: Raking leaves, for example, is considered moderate physical activity. If you weigh about 135 pounds, you can burn close to 250 calories by raking leaves for an hour.
Whichever way you choose to exercise outside, there are numerous benefits
No membership fees – The outdoors belongs to all of us. “You don’t need any special equipment — the outdoors is available wherever you are, just outside your door,” says Tina Vindum, the author of Tina Vindum’s Outdoor Fitness: Step Out of the Gym into the Best Shape of Your Life and the first outdoor fitness instructor accredited by the American Council on Exercise.
The air is cleaner – The Environmental Protection Agency estimates that indoor air is more than twice as polluted as outdoor air.
A free daily dose of D – Scientists recommend outdoor exercise as a way to get your vitamin D through sunlight. This is especially important if you are overweight — a recent study found that people who are overweight are almost twice as likely to be deficient in vitamin D.
Exercise for your mind – When you exercise outdoors, your mind becomes aware of the changing terrain. Whether you use the hills, the sand on a beach, or a winding path, your mind has to focus differently than it would on a flat gym floor,” notes Vindum.
Getting Started With Outdoor Exercise
If you have any health issues, talk to your doctor before starting an outdoor fitness program. “I tell my people to have a goal in mind, start slowly, and work up to their potential. Outdoor exercise can be adapted to anyone’s level of fitness,” advises Vindum.
Here are guidelines to get you going
Exercise early – “People can always find more excuses to avoid exercising outdoors at the end of the day,” says Vindum. In the morning your energy is higher, the air is generally cleaner, the temperature is lower, and you will feel better all day long.
Avoid temperature extremes – Although your body can adapt to colder or warmer weather, you should avoid exercising outside in extreme heat or cold.
Don’t get burned – Although some sun is good for you, too much sun is not. “Always protect yourself with a good sunscreen, and wear sunglasses and a hat with a brim,” advises Vindum.
Drink enough water – If you drink about 8 to 10 ounces of water 30 minutes before doing outdoor exercises, it should hydrate you sufficiently for a 30-minute workout. You don’t need water with electrolytes in most cases,” says Vindum. Remember that you can lose water through sweating even in cooler weather, and you may start to get dehydrated before you feel thirsty.
Get some good gear – Take advantage of the new technology that has gone into shoe treads and waterproof, breathable clothing material,” advises Vindum.
Make outdoor exercises part of your lifestyle – You can learn exercises that use only bodyweight and gravity and do them while you are walking to the post office, Vindum says. Think about walking instead of driving. Plan outdoor activities with your family. Go for a hike instead of a drive.
“Why would you need bottled aromatherapy when you can go outside and smell nature? Outside exercise uses all your senses and connects your body and mind. As you become more physically fit, your mind also becomes more aware.
Six benefits of exercising in the great outdoors.
Exercising outdoors – provides an opportunity to be physically active in a constantly changing environment. The more challenging the terrain, the harder the body has to work to sustain an efficient work rate. Cardio machines in the gym can provide numerous benefits, but doing the same movement pattern over and over again could potentially cause an overuse injury. Walking, hiking or running on terrain that is constantly changing teaches the body how to adapt to a changing environment. In addition, a constantly changing surface can enhance the strength of your connective tissue, which may help you avoid certain injuries.
Wind resistance – can help you burn more calories. When running or cycling outdoors, you may have to deal with the wind, which can offer natural resistance. A strong headwind can help you burn more calories, as you have to work harder to overcome the resistance. A good tailwind can help you move a little faster, which activates the larger type II muscle fibers responsible for strength and definition.
Exercising outdoors – is a great way to save money. There are many benefits of going to a gym or fitness studio, but if you need to manage your expenses, exercising outdoors is one option to save a few dollars. While going to a gym or studio can provide extra motivation to train, if you have a strong drive and motivation to reach your fitness goals, then exercising outdoors might be a good money-saving option.
Using your local park – running on a nearby trail or simply walking around your neighborhood are all great ways to meet your neighbors. While exercise can enhance your physical health, being connected with your community, and having a number of positive relationships can help improve your mental health as well. Put your phone down or close your laptop and go outside and move around in your community to enhance your real-life social network.
Going outdoors – gives you the opportunity to turn your exercise time into family time. There is nothing wrong with dropping your kids off at the daycare to take your favorite group fitness class, but it’s also important to exercise with your kids and show them that physical activity can be fun. Playing at the playground, going for a hike, riding bikes, or playing a sport are a few ways to be active with your kids. Playing at a park together might not be as good a workout as your favorite circuit class, but chasing your kids around and climbing the playground equipment can help you build up a good sweat.
There is quantifiable research suggesting – that outdoor exercise provides greater benefits than sweating indoors. In one study, the researchers found that exercising outdoors “was associated with greater feelings of revitalization, increased energy and positive engagement, together with decreases in tension, confusion, anger and depression. Participants also reported greater enjoyment and satisfaction with outdoor activity.
Dental care is part of oral hygiene and involves the removal of dental plaque from teeth with the intention of preventing cavities (dental caries), gingivitis, and periodontal disease. People routinely clean their own teeth by brushing and interdental cleaning and dental hygienists can remove hardened deposits (tartar) not removed by routine cleaning. Those with dentures and natural teeth may supplement their cleaning with a denture cleaner.
Brush twice a day after meals
Teaching yourself and your kids to brush in a proper manner can go a long way to keep teeth in good health. Develop a habit of brushing each part of your teeth at least for a count of ten brush strokes. First, start with the outer surfaces of your upper teeth. Then go on to the outer surfaces of your lower teeth. Do the same for the inner surfaces. Finally, brush along the chewing surfaces of your teeth. Remember to brush along the gum line, the place where the gum joins the teeth. Keep your brushes at a 45-degree angle to the gum line with your toothbrush bristles pointing towards the teeth. It takes about two to five minutes to properly brush all your teeth. One simple way of ensuring that you or the kids brush for an adequate amount of time is to make it a habit to do it for the duration of one whole song on your music player.
Floss regularly
Our mouths are filled at all times with bacteria that are looking for places where they can deposit themselves and form a colony. One of the places that don’t get addressed by mere brushing is between the teeth. This is also where stuff like jam or peanut butter goes and deposits itself making these nooks and crannies all the more attractive to bacteria. Make sure that you floss on a daily basis to clean out these hard-to-reach places between your teeth.
Use mouthwash
Antibacterial mouthwash can help fight bacterial build-up in your mouth to a very large extent. Fluoride-based mouthwashes also help in strengthening the teeth. The best time to rinse your mouth with mouthwash is just before going to bed, as it will protect your teeth and mouth all through the night. Make sure you teach the children how to rinse their mouth with mouthwash without swallowing it.
Schedule a visit to the dentist
Summers are a fun time. You may want to put off a dentist visit till later, but it is better that you schedule a visit now. Any potential damage that can be detected early will be helpful in preserving the lifelong health of your teeth. Cavities or plaque build-up that is left unattended can develop into serious problems. It is recommended that you have a thorough dental checkup once every six months.
Water is the drink of choice
As mentioned in my blog last week, the importance of water during a hot summer holiday is vital for our overall health but it also provides a vital role for our oral health too. We should avoid regular consumption of drinks with high sugar and acidic content such as sports drinks or fruit juices which increase the chance of dental decay and enamel erosion. A word of caution on drinking tap water abroad though, to reduce the risk of picking up a tummy bug, bottled water is probably the better option.
Limit your sugary foods
Our summer holidays are usually the time where we eat more excessively than usual, which more often than not, makes for a high-in-sugar diet. During the holidays we are more likely to “graze” but we must remember to keep this to a minimum. It is better for our teeth and general health to stick to three meals a day instead of having seven to ten of these “snack-attacks”, which can cause dental decay and erosion, the loss of tooth enamel, which if worn away the dentine underneath is exposed and your teeth can look discolored and become sensitive.
Protect your lips
While basking in the sun, many of us will sensibly apply suntan lotion to protect ourselves against the sun’s rays, in a bid to help prevent such diseases as skin cancer but what many people fail to realize is the importance of protecting our lips. With the skin on our lips being thin and particularly vulnerable due to the lack of melanin, shielding our lips from the sun on holiday is essential as prolonged exposure could lead to forms of oral cancer.
Pack your dental first aid kit
This is a crucial piece of equipment to take on holiday. Often small and inexpensive, there are many dental first aid kits in the market and the majority of them contain everything you would need in a dental emergency. No matter how careful we are, accidents do happen so make sure you are prepared for any eventuality.
Regulate your alcohol consumption
It’s easy to get carried away, but there a certain holiday luxury that you should be particularly careful of – and one of these is alcohol. Regular consumption of sweet cocktails and fizzy alcoholic drinks can result in tooth decay…not exactly the holiday souvenir you were hoping for. And with alcohol being a leading cause of oral cancer we must make sure that we drink responsibly.
Take your spare dentures
This may come as a surprise but many sets of dentures are lost by their owners on holiday so taking a spare pair is always a good idea. Most dentures on holiday are lost through being sick, following a bout of seasickness or food poisoning for example, with the owner not realizing that their dentures have slipped out, more often than not either overboard, or down the toilet.
Better sleeping tricks is a naturally recurring state of mind and body, characterized by altered consciousness, relatively inhibited sensory activity, inhibition of nearly all voluntary muscles, and reduced interactions with surroundings. It is distinguished from wakefulness by a decreased ability to react to stimuli, but is more easily reversed than the state of being comatose.
Sleep occurs in repeating periods, in which the body alternates between two distinct modes: REM sleep and non-REM sleep. Although REM stands for “rapid eye movement”, this mode of sleep has many other aspects, including virtual paralysis of the body. A well-known feature of sleep is the dream, an experience typically recounted in narrative form, which resembles waking life while in progress, but which usually can later be distinguished as fantasy.
Better Sleeping Tricks; How Way You Can Sleep Better?
LOSE CONTROL
Of all the things you have power over in your life, sleep isn’t one of them. No amount of wishing, hoping or willing can make it happen. As soon as you accept that it’s out of your control, you’ll spend less time worrying about it. It’s like traffic during your morning commute, you can either let it drive you nuts daily or know that it’s just a part of life—some days will be smoother than others.
SET A BEDTIME
You set an alarm to get up every morning, but punctuality for going to bed is just as important. While you don’t have to set a nightly alarm, pick an hour for shutting down every night and stick to it—on weekends too. Your body needs routine.
TAKE A BATH
The Sandman comes when the body’s temperature drops. Exaggerate that effect with a toasty bath or shower then lie down and let your body heat get low.
BLACK OUT
Even the smallest amount of light can disturb slumber. That means TVs, computers, and even hallway lights should be switched to the off position until you’ve landed safely on the other side of morning.
DROWN OUT NOISE
Putting your iPod on shuffle isn’t the best idea for drowning out your partner’s snoring. You never know when a jolting party anthem will come up. Instead, sleep with a fan on or invest in a sound machine that can produce white noise to block the racket of the outside world.
BE COOL
Cold is sleep’s partner in crime. So lower your thermostat a bit—and save money on your heat while you’re at it—then pile on the blankets. A colder bedroom means your body will function at calmer, more restful speeds.
EAT LIGHT
Heavy eating or drinking before bed increases your chances of indigestion or frequent trips to the bathroom. A light dinner about two hours before bedtime can help you sleep more soundly.
NO SMOKING OR DRINKING
A night of debauchery every now and then is fine but don’t make a habit of a glass of wine and a smoke before bed. Alcohol and nicotine are stimulants that can not only keep you wide-eyed, but also interrupt a peaceful night’s sleep.
PILLOWS
The pillow is like a sports bra; it’s the most important equipment for working out your z’s. Make sure that your pillows are supportive, comfortable, and suited to your sleeping position tendencies. The pillows of a stomach sleeper and a fetal position person don’t have to look the same.
KICK THE PETS OUT
Midnight hairballs, dogs dreaming of digging—need we say more? As adorable as they are, your pets are not sleep’s best friends. They’re just as prone to be woken up—and thus wake you up—by the little things that go bump in the night.
KILL THE PAIN
If a minor ache or pain is keeping you awake don’t fight it. Do whatever you need to make it better, whether it’s popping some Ibuprofen or getting to a doctor.
AVOID CAFFEINE
It’s fine that you can’t get through the day without your morning latte, but make it a rule that no caffeine touches your lips after sundown.
JUST BREATHE
Stop concentrating on the laundry list of concerns in your head and focus on your breath. Deep and slow or short and shallow, the sound of your inhales and exhales can be a lullaby to sooth you into slumber.
STAY CALM
When sleeplessness strikes, don’t freak out—that will only delay the process further. Give yourself a break. So what if you’re having a sleepless night? It’s not the end of the world. By thinking, ‘Great, I can’t sleep. I’m going to be worthless tomorrow,’ you’re creating a self-fulfilling prophecy. Relax and trust that there will be plenty of sleep-filled nights in your near future.
DON’T COMPENSATE
There is no such thing as making up for lost sleep except for getting back on your regular schedule. Naps, going to bed super early, or sleeping late may seem like the natural fixes to a sleepless night, but they actually send your body mixed messages. Keep your sleep schedule calibrated for your life, not a random late night or a short bout of insomnia.
cGMP availability; mediates vascular smooth muscle (VSM) relaxation
