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Alkalosis – Causes, Symptoms, Diagnosis, Treatment

Alkalosis is excessive blood alkalinity caused by an overabundance of bicarbonate in the blood or a loss of acid from the blood (metabolic alkalosis), or by a low level of carbon dioxide in the blood that results from rapid or deep breathing (respiratory alkalosis). Alkalosis is excessive blood alkalinity caused by an overabundance of bicarbonate in the blood or a loss of acid from the blood (metabolic alkalosis), or by a low level of carbon dioxide in the blood that results from rapid or deep breathing (respiratory alkalosis).

Alkalosis is an abnormal pathophysiological condition characterized by the buildup of excess base or alkali in the body. It results in an abnormally high serum pH (arterial pH greater than 7.45), which is termed alkalemia and forms one end of the spectrum of acid-base disorders. There is generally a loss of hydrogen ions (H) or an excess of bicarbonate ions (OH), and multiple factors can cause either of these. In general, alkalosis is less life-threatening than acidosis, but severe electrolyte derangements can accompany alkalosis due to transcellular shifts, potentially resulting in rare but severe clinical disorders. Alkalosis can be either respiratory or metabolic in origin, but metabolic alkalosis is far more common than respiratory causes. This activity reviews the evaluation and management of alkalosis and highlights the interprofessional team’s role in improving care for patients with alkalosis.

Alkalosis is an abnormal pathophysiological condition characterized by the buildup of excess base or alkali in the body. It results in an abnormally high serum pH (arterial pH greater than 7.45), which is termed alkalemia and forms one end of the spectrum of acid-base disorders. There is generally a loss of hydrogen ions (H) or an excess of bicarbonate ions (OH), and multiple factors can cause either of these. In general, alkalosis is less life-threatening than acidosis, but severe electrolyte derangements can accompany alkalosis due to transcellular shifts, potentially resulting in rare but severe clinical disorders. Alkalosis can be either respiratory or metabolic in origin, but metabolic alkalosis is far more common than respiratory causes.[rx]

Causes of Alkalosis

The etiology of alkalosis can subdivide into metabolic and respiratory causes:

Metabolic

Excess loss of hydrogen ion—this occurs primarily due to gastric losses (prolonged and severe gastric aspiration, excessive emesis of gastric contents as in pyloric stenosis, congenital chloridorrhea).[rx][rx]
Increased bicarbonate in the extracellular compartment—this occurs due to excess enteral intake of bicarbonate or alkali (milk-alkali syndrome) or increased parenteral intake of nitrate or acetate. Increased renal reabsorption of bicarbonate can also cause metabolic alkalosis (severe hypokalemia, primary hyperaldosteronism, Cushing syndrome, Bartter syndrome, Gitelman syndrome, toxic ingestion of licorice, excessive chloruretic diuretic use).[rx][rx][rx][rx]
Diuretic-induced alkalosis—diuretics (loop and thiazide) that block sodium and chloride reabsorption can cause increased bicarbonate absorption at the proximal tubule leading to increased serum bicarbonate concentration, also called contraction alkalosis.

Respiratory

Low production of CO2—hypometabolic conditions like severe coma, particularly when supported by mechanical ventilation.
Excess pulmonary loss of CO2—this results in alkalosis when the production of CO2 in the body is normal (psychogenic hyperventilation, iatrogenic hyperventilation in patients on assisted mechanical ventilation or extracorporeal membrane oxygenation, early stages of salicylate overdose due to overstimulation of the respiratory center).[rx]

The body has a robust buffering system that acts to minimize pH change in the initial stages of acid-base derangements. When these buffering systems are overwhelmed, alkalosis may result.

The kidney attempts to maintain normal acid-base balance by the dual mechanisms of bicarbonate reabsorption, mainly in the proximal tubule, and bicarbonate production in the distal nephron. Reabsorption of bicarbonate is mediated by a Na-H (sodium-hydrogen) antiporter and also by the H (+)-ATPase (adenosine triphosphate-use). Influences on bicarbonate reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium concentrations in the serum. In conditions resulting in respiratory alkalosis, the kidney acts to both decrease bicarbonate reabsorption and bicarbonate production as a compensatory mechanism. This process helps maintain the pH of the extracellular compartment to neutralize the effect of the low pCO2 that is the primary derangement of respiratory alkalosis. However, the kidneys’ complex buffering mechanisms may take several days to achieve full effect, with an eventual expected fall of bicarbonate by 4 to 5 mmol/L for every 10 mmHg fall in pCO2.

On the other hand, respiratory depression resulting in increased PaCO2 occurs promptly and predictably to buffer the alkalemia resulting from metabolic conditions (while this is variable, expectations are that there will be a 0.5 mmHg increase in PaCO2 per 1 mmol/L increase in HCO). Alkalemia also causes a shift in the oxyhemoglobin dissociation curve towards the left, thus increasing hemoglobin’s affinity for oxygen and decreasing oxygen release to the tissues.[rx][rx]

When the intake of potassium is suboptimal, this can correlate with metabolic alkalosis due to intracellular sodium and proton levels rising as well as a consequent depression in aldosterone levels.[rx] When protons shift into the cellular compartment, metabolic alkalosis ensues; this is followed by respiratory center depression of respiratory drive and ultimately, the purging of bicarbonate by the kidney.

Diagnosis of Alkalosis

There are no specific histopathological features that are pathognomonic for alkalosis. However, the primary cause of alkalosis may be established by histopathological studies, especially when related to kidney or adrenal disorders.

History and Physical

Alkalosis can present with a myriad of signs and symptoms, based on the etiology of alkalosis (respiratory versus metabolic) and the primary condition leading to alkalosis.

Metabolic alkalosis can have central nervous system manifestations ranging from confusion to coma, peripheral neuropathic symptoms of tremor, tingling and numbness, muscle weakness and twitching, and arrhythmias, particularly when associated with hypokalemia and hypocalcemia.[rx] Nonhypochloremic metabolic alkalosis associates with hypertension and is usually the result of syndromes of excess mineralocorticoid production. These generally correlate with signs of volume expansion, hypertension, and hypokalemia.[rx] Persistent and projectile, non-bilious emesis in a two to six-week-old, otherwise well-appearing infant is a hallmark presentation of pyloric stenosis.

Respiratory alkalosis can have associated syncope, tremors, and signs of hyperventilation, along with chest pain and dyspnea.[rx]

Lab Test and Imaging

A blood gas analysis, preferably arterial, is needed to establish alkalosis and whether it appears to be metabolic or respiratory in origin. Ancillary blood tests are necessary; these are serum chemistries with electrolytes, blood urea nitrogen, and creatinine. While the bicarbonate concentration being high can indicate the possibility of metabolic alkalosis, it is not confirmatory, as both the carbon dioxide concentration and the concentration of H+ ions will affect the presence or absence of alkalosis. Hence, a blood gas estimate of pH and pCO2 is also needed. However, in mixed acid-base disorders, complex calculations are necessary to establish multiple disturbances and whether they are primary and/or coexistent abnormalities or compensatory buffering mechanisms.[rx]

Associated electrolyte abnormalities need to be identified, including hypochloremia, hypokalemia, and hypocalcemia. An EKG may be necessary to evaluate for arrhythmias. Urine chemistry is required to assess the kidney’s response to alkalosis. Hypertension requires assessment and other tests for hyperaldosteronism when indicated. Volume depletion also requires evaluation as a coexisting condition.

When associated with hypoxia or an increased alveolar-arterial (A-a) gradient, respiratory alkalosis requires a search for a cause of hypoxia. However, pulmonary embolism may cause respiratory alkalosis without associated hypoxia and must be ruled out before attributing hyperventilation to pain or anxiety.[rx][rx]

Treatment of Alkalosis

The appropriate management of alkalosis rests on prompt identification followed by management of the primary etiology of the alkalosis and the type of the alkalosis (metabolic, respiratory, or mixed). Specific etiologies like pyloric stenosis need surgical correction, while excessive ingestion of alkali will respond to restriction of excess intake. Alkalosis associated with conditions of excess aldosterone may need hormonal correction or replacement along with the treatment of associated hypertension. Correction of chloride responsive alkalosis caused by volume depletion is possible by replenishment of extracellular volume. Electrolyte disturbances associated with alkalosis such as hypokalemia and hypocalcemia are the chief causes of clinical deterioration in the patient and must undergo correction before the onset of life-threatening complications. Slow acid administration or dialysis with low bicarbonate baths may be necessary for emergent situations.[rx]

Treatment of respiratory alkalosis primarily targets correcting the hyperventilation (primary or iatrogenic), and apart from anxiety and pain treatment, it sometimes also requires adjustment of mechanical ventilation with intentional hypercapnia.[rx]

Complications

Alkalosis can lead to life-threatening arrhythmias (atrial and ventricular tachyarrhythmias), especially when associated with hypokalemia and hypocalcemia. These associated electrolyte abnormalities can also cause carpopedal spasms, muscle weakness, and altered mental status.[23][24]

References

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Acid-Base Disorders – Causes, Symptoms, Diagnosis, Treatment

Acid-base disorders are disturbances in the homeostasis of hydrogen ion concentration in the plasma. Any process that increases the serum hydrogen ion concentration is an acidotic process. The term acidemia is used to describe serum that is abnormally acidic, and this can be due to respiratory acidosis, which involves changes in carbon dioxide, or metabolic acidosis that is influenced by decreased bicarbonate. Metabolic acidosis is characterized by an increase in the hydrogen ion concentration in the systemic circulation that results in an abnormally low serum bicarbonate level. Metabolic acidosis signifies an underlying disorder that needs to be corrected to minimize morbidity and mortality. This activity describes the risk factors, evaluation, and management of metabolic acidosis and highlights the role of the interprofessional team in enhancing care delivery for affected patients.

Your blood needs the right balance of acidic and basic (alkaline) compounds to function properly. This is called the acid-base balance. Your kidneys and lungs work to maintain the acid-base balance. Even slight variations from the normal range can have significant effects on your vital organs. Acid and alkaline levels are measured on a pH scale. An increase in acidity causes pH levels to fall. An increase in alkaline causes pH levels to rise.

When the levels of acid in your blood are too high, it’s called acidosis. When your blood is too alkaline, it is called alkalosis. Respiratory acidosis and alkalosis are due to a problem with the lungs. Metabolic acidosis and alkalosis are due to a problem with the kidneys. Each of these conditions is caused by an underlying disease or disorder. Treatment depends on the cause.

Determining the type of metabolic acidosis can help clinicians narrow down the cause of the disturbance. Acidemia refers to a pH less than the normal range of 7.35 to 7.45. In addition, metabolic acidosis requires a bicarbonate value less than 24 mEq/L. Further classification of metabolic acidosis is based on the presence or absence of an anion gap, or concentration of unmeasured serum anions. Plasma neutrality dictates that anions must balance cations to maintain a neutral charge. Therefore, sodium (Na), the primary plasma cation, is balanced by the sum of the anions bicarbonate and chloride in addition to the unmeasured anions, which represent the anion gap. Unmeasured anions include lactate and acetoacetate, and these are often some of the main contributors to metabolic acidosis.[rx][rx][rx]

Anion gap (AG) = [Na] –([Cl] + [HCO3])

Anion gap metabolic acidosis is frequently due to anaerobic metabolism and lactic acid accumulation. While lactate is part of many mnemonics for metabolic acidosis, it is important to distinguish it is not a separate etiology, but rather a consequence of a condition.

Mnemonic for anion gap metabolic acidosis differential: CAT MUDPILES

C: Cyanide and carbon monoxide poisoning
A: Arsenic
T: Toluene
M: Methanol, Metformin
U: Uremia
D: DKA
P: Paraldehyde
I: Iron, INH
L: Lactate
E: Ethylene glycol
S: Salicylates

Non-gap metabolic acidosis is primarily due to the loss of bicarbonate, and the main causes of this condition are diarrhea and renal tubular acidosis. Additional and rarer etiologies include Addison’s disease, ureterosigmoid or pancreatic fistulas, acetazolamide use, and hyperalimentation through TPN initiation. GI and renal losses of bicarbonate can be distinguished via urine anion gap analysis:

Urine AG = Urine Na + Urine K – Urine Cl

A positive value is indicative of renal bicarbonate loss, such as renal tubular acidosis. Negative values are found with non-renal bicarbonate losses, such as diarrhea.

Interpretation Steps

Acid-base interpretation is crucial to identify and correct disturbances in acid-base equilibrium that have profound consequences on patient health. The following steps use lab values and equations to determine if a patient has metabolic acidosis and any additional acid-base disturbances.

Step 1: pH, determine if the acid-base status is acidemia or alkalemia

Blood pH is maintained within a narrow range for optimization of physiological functions. Acid-base equilibrium is achieved within a pH range of 7.35 to 7.45. Blood pH distinguishes between acidemia (pH less than 7.35) and alkalemia (pH greater than 7.45)

Step 2: CO2, determine if the disturbance is metabolic or respiratory

The pCO2 determines whether an acidosis is respiratory or metabolic in origin. For respiratory acidosis, the pCO2 is greater than 40 to 45 due to decreased ventilation. Metabolic acidosis is due to alterations in bicarbonate, so the pCO2 is less than 40 since it is not the cause of the primary acid-base disturbance. In metabolic acidosis, the distinguishing lab value is a decreased bicarbonate (normal range 21 to 28 mEq/L).

Step 3: Determine if there is an anion gap or non-anion gap metabolic acidosis

AG= Na – (Cl + HCO3)

The normal anion gap is 12. Therefore, values greater than 12 define an anion gap metabolic acidosis.

Step 4: CO2, assess if respiratory compensation is appropriate

Respiratory compensation is the physiologic mechanism to help normalize metabolic acidosis, however, compensation never completely corrects an acidemia. It is important to determine if there is adequate respiratory compensation or if there is another underlying respiratory acid-base disturbance. Winter’s formula is the equation used to determine the expected CO2 for adequate compensation.

Winter’s formula: Expected CO2 = (Bicarbonate x 1.5) + 8 +/- 2

If the patient’s pCO2 is within the predicted range, then there is no additional respiratory disturbance. If the pCO2 is greater than expected, this indicates an additional respiratory acidosis. If the pCO2 is less than expected, there is an additional respiratory alkalosis occurring.

Step 5: Evaluate for additional metabolic disturbances

A delta gap must be determined if an anion gap is present.

Delta gap = Delta AG – Delta HCO3 = (AG-12) – (24-bicarbonate)

If the gap is less than -6, then a NAGMA is present.

If the gap is greater than 6, then an underlying metabolic alkalosis is present.

If the gap is between -6 and 6 then only an anion gap acidosis exists.

Respiratory acidosis

When you breathe, your lungs remove excess carbon dioxide from your body. When they cannot do so, your blood and other fluids become too acidic.

Symptoms of respiratory acidosis

Symptoms may include fatigue, shortness of breath, and confusion.

Causes of respiratory acidosis

There are several different causes of respiratory acidosis including:

chest deformities or injuries
chronic lung and airway diseases
overuse of sedatives
obesity

Types of respiratory acidosis

There are no noticeable symptoms of chronic respiratory acidosis. This is due to the fact that your blood slowly becomes acidic and your kidneys adjust to compensate, returning your blood to a normal pH balance.

Acute respiratory acidosis comes on suddenly, leaving the kidneys no time to adjust. Those with chronic respiratory acidosis may experience acute respiratory acidosis due to another illness that causes the condition to worsen.

Diagnosis of respiratory acidosis

A complete physical examination is necessary. Diagnostic testing may include:

arterial blood gas test
metabolic panel
pulmonary function test
chest X-ray

Treatment of respiratory acidosis

A doctor should be seen immediately to treat acute respiratory acidosis, as this can be a life-threatening condition. Treatment is targeted to the cause.

Bronchodilator medications may be given to correct some forms of airway obstruction. If your blood oxygen level is too low, you may require oxygen. Noninvasive positive pressure ventilation or a breathing machine may be necessary.

To treat chronic respiratory acidosis, the underlying cause needs to be determined in order for proper treatment to take place. The cause could be an organ deformity, an infection, or some type of inflammation. Each cause may require a different treatment ranging from antibiotics to a breathing machine.

In either case, if you smoke, you will be advised to stop.

Complications of respiratory acidosis

Respiratory acidosis is serious and requires immediate medical attention. Potential complications of untreated respiratory acidosis include respiratory failure, organ failure, and shock.

Preventing respiratory acidosis

You can take steps to help prevent some of the conditions that lead to respiratory acidosis. Maintain a healthy weight. Take sedatives only under strict doctor supervision and never combine them with alcohol. Do not smoke.

Metabolic acidosis

Metabolic acidosis occurs either when your body produces too much acid, or when your kidneys are unable to remove it properly.

Symptoms of metabolic acidosis

Symptoms can include rapid breathing, fatigue, and confusion.

Causes of metabolic acidosis

There are three main types of metabolic acidosis. Diabetic acidosis, or diabetic ketoacidosis, is a buildup of ketone bodies. This is usually due to uncontrolled type 1 diabetes. Hyperchloremic acidosis is when your body loses too much sodium bicarbonate, often after severe diarrhea.

Lactic acidosis is when too much lactic acid builds up. This can be due to:

prolonged exercise
lack of oxygen
certain medications, including salicylates
low blood sugar, or hypoglycemia
alcohol
seizures
liver failure
cancer
kidney disease
severe dehydration
poisoning from consuming too much aspirin, ethylene glycol, and methanol

Diagnosing metabolic acidosis

Diagnostic testing may include serum electrolytes, urine pH, and arterial blood gases. Once acidosis is confirmed, other tests may be necessary to pinpoint the cause.

Treatment of metabolic acidosis

The underlying condition behind the acidosis must be treated. In some cases, sodium bicarbonate is prescribed to return the blood to a normal pH.

Complications of metabolic acidosis

Severe cases can lead to shock and can be life-threatening.

Alkalosis

Alkalosis is when alkaline levels are too high due to decreased carbon dioxide or increased bicarbonate. There are five kinds of alkalosis.

Symptoms of alkalosis

Symptoms of alkalosis may include:

muscle twitching, hand tremor, muscle spasms
numbness and tingling
nausea
vomiting
lightheadedness
confusion

Causes and types of alkalosis

Respiratory alkalosis is when your blood has low levels of carbon dioxide. This can be caused by a number of factors, including:

lack of oxygen
high altitude
fever
lung disease
liver disease
salicylate poisoning

When you have alkalosis your carbon dioxide levels are low. This causes your body to release more bicarbonate to return your blood pH level back to normal. This is called compensated alkalosis. Your blood pH levels will test normal, however, your kidneys are releasing more bicarbonate, compensating for the lower levels of carbon dioxide.

When your blood has too much bicarbonate, it is called metabolic alkalosis. This can happen from prolonged vomiting. Prolonged vomiting can also make you lose too much chloride. This is called hypochloremic alkalosis. Some diuretic medicines can cause you to lose too much potassium. This is called hypokalemic alkalosis.

Diagnosing alkalosis

Along with a physical exam, diagnostic testing for alkalosis may include a metabolic panel, blood gas analysis, urinalysis, and urine pH.

Treatment for alkalosis

Some medications (such as chloride and potassium) can help correct chemical losses. Further treatment will depend on the cause. Your physician will need to monitor your vital signs and create a proper plan to correct your pH imbalance.

Complications of alkalosis

In severe cases, alkalosis can lead to heart arrhythmias or coma.

References

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Acid-Base Balance – Anatomy, Mechanism, Functions

Acid-base balance is the homeostatic regulation of the pH of the body’s extracellular fluid (ECF).^[1] The proper balance between the acids and bases (i.e. the pH) in the ECF is crucial for the normal physiology of the body—and for cellular metabolism.^[1] The pH of the intracellular fluid and the extracellular fluid need to be maintained at a constant level.

The body’s balance between acidity and alkalinity is referred to as acid-base balance. The blood’s acid-base balance is precisely controlled because even a minor deviation from the normal range can severely affect many organs. The body uses different mechanisms to control the blood’s acid-base balance.

The three-dimensional structures of many extracellular proteins, such as the plasma proteins and membrane proteins of the body’s cells, are very sensitive to the extracellular pH.^[rx]^[rx] Stringent mechanisms, therefore, exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, proteins are denatured (i.e. their 3-D structure is disrupted), causing enzymes and ion channels (among others) to malfunction.

pH, Buffers, Acids, and Bases

Henderson–Hasselbalch equation

The Henderson–Hasselbalch equation when applied to the carbonic acid-bicarbonate buffer system in the extracellular fluids, states that:^[rx]

${\mathrm {pH}}={\mathrm {p}}K_{{{\mathrm {a}}~{\mathrm {H}}_{2}{\mathrm {CO}}_{3}}}+\log _{{10}}\left({\frac {[{\mathrm {HCO}}_{3}^{-}]}{[{\mathrm {H}}_{2}{\mathrm {CO}}_{3}]}}\right),$

where:

$pH$ is the negative logarithm (or cologarithm) of molar concentration of hydrogen ions in the ECF.
$p K a H2CO3$ is the cologarithm of the acid dissociation constant of carbonic acid. It is equal to 6.1.
$[HCO - 3]$ is the molar concentration of bicarbonate in the blood plasma
$[H 2 CO 3]$ is the molar concentration of carbonic acid in the ECF.

However, since the carbonic acid concentration is directly proportional to the partial pressure of carbon dioxide ( $P_{{\mathrm {CO} }_{2}}$ ) in the extracellular fluid, the equation can be rewritten as follows:^[rx]^[rx] $\mathrm {pH} =6.1+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{0.0307\times P_{\mathrm {CO} _{2}}}}\right),$

where:

$pH$ is the negative logarithm of molar concentration of hydrogen ions in the ECF.
$[HCO - 3]$ is the molar concentration of bicarbonate in the plasma
$P CO2$ is the partial pressure of carbon dioxide in the blood plasma.

The pH of the extracellular fluids can thus be controlled by the regulation of PCO₂ and other metabolic acids.

Acids dissociate into H⁺ and lower pH, while bases dissociate into OH⁻ and raise pH; buffers can absorb these excess ions to maintain pH.

Key Points

A basic solution will have a pH above 7.0, while an acidic solution will have a pH below 7.0.

Buffers are solutions that contain a weak acid and its a conjugate base; as such, they can absorb excess H⁺ ions or OH^– ions, thereby maintaining an overall steady pH in the solution.

pH is equal to the negative logarithm of the concentration of H⁺ ions in solution: pH = −log[H⁺].

Key Terms

alkaline: having a pH greater than 7; basic
acidic: having a pH less than 7
buffer: a solution composed of a weak acid and its conjugate base that can be used to stabilize the pH of a solution

Self-Ionization of Water

Hydrogen ions are spontaneously generated in pure water by the dissociation (ionization) of a small percentage of water molecules into equal numbers of hydrogen (H⁺) ions and hydroxide (OH⁻) ions. The hydroxide ions remain in solution because of their hydrogen bonds with other water molecules; the hydrogen ions, consisting of naked protons, are immediately attracted to un-ionized water molecules and form hydronium ions (H₃0⁺). By convention, scientists refer to hydrogen ions and their concentration as if they were free in this state in liquid water.

$2 H_{2} O ⇋ H_{3} O^{+} + {OH}^{-}$

The concentration of hydrogen ions dissociating from pure water is 1 × 10⁻⁷ moles H⁺ ions per liter of water. The pH is calculated as the negative of the base 10 logarithm of this concentration:

pH = −log[H⁺]

The negative log of 1 × 10⁻⁷ is equal to 7.0, which is also known as neutral pH. Human cells and blood each maintain near-neutral pH.

pH Scale

The pH of a solution indicates its acidity or basicity (alkalinity). The pH scale is an inverse logarithm that ranges from 0 to 14: anything below 7.0 (ranging from 0.0 to 6.9) is acidic, and anything above 7.0 (from 7.1 to 14.0) is basic (or alkaline ). Extremes in pH in either direction from 7.0 are usually considered inhospitable to life. The pH in cells (6.8) and the blood (7.4) are both very close to neutral, whereas the environment in the stomach is highly acidic, with a pH of 1 to 2.

The pH scale: The pH scale measures the concentration of hydrogen ions (H⁺) in a solution.

Non-neutral pH readings result from dissolving acids or bases in water. Using the negative logarithm to generate positive integers, high concentrations of hydrogen ions yield a low pH, and low concentrations a high pH.

An acid is a substance that increases the concentration of hydrogen ions (H⁺) in a solution, usually by dissociating one of its hydrogen atoms. A base provides either hydroxide ions (OH⁻) or other negatively-charged ions that react with hydrogen ions in solution, thereby reducing the concentration of H⁺ and raising the pH.

Strong Acids and Strong Bases

The stronger the acid, the more readily it donates H⁺. For example, hydrochloric acid (HCl) is highly acidic and completely dissociates into hydrogen and chloride ions, whereas the acids in tomato juice or vinegar do not completely dissociate and are considered weak acids; conversely, strong bases readily donate OH⁻ and/or react with hydrogen ions. Sodium hydroxide (NaOH) and many household cleaners are highly basic and give up OH⁻ rapidly when placed in water; the OH⁻ions react with H⁺ in solution, creating new water molecules and lowering the amount of free H⁺ in the system, thereby raising the overall pH. An example of a weak basic solution is seawater, which has a pH near 8.0, close enough to neutral that well-adapted marine organisms thrive in this alkaline environment.

Buffers

How can organisms whose bodies require a near-neutral pH ingest acidic and basic substances (a human drinking orange juice, for example) and survive? Buffers are the key. Buffers usually consist of a weak acid and its conjugate base; this enables them to readily absorb excess H⁺ or OH^–, keeping the system’s pH within a narrow range.

Maintaining a constant blood pH is critical to a person’s well-being. The buffer that maintains the pH of human blood involves carbonic acid (H₂CO₃), bicarbonate ion (HCO₃^–), and carbon dioxide (CO₂). When bicarbonate ions combine with free hydrogen ions and become carbonic acid, hydrogen ions are removed, moderating pH changes. Similarly, excess carbonic acid can be converted into carbon dioxide gas and exhaled through the lungs; this prevents too many free hydrogen ions from building up in the blood and dangerously reducing its pH; likewise, if too much OH^– is introduced into the system, carbonic acid will combine with it to create bicarbonate, lowering the pH. Without this buffer system, the body’s pH would fluctuate enough to jeopardize survival.

Buffers in the body: This diagram shows the body’s buffering of blood pH levels: the blue arrows show the process of raising pH as more CO2 is made; the purple arrows indicate the reverse process, lowering pH as more bicarbonate is created.

Antacids, which combat excess stomach acid, are another example of buffers. Many over-the-counter medications work similarly to blood buffers, often with at least one ion (usually carbonate) capable of absorbing hydrogen and moderating pH, bringing relief to those that suffer “heartburn” from stomach acid after eating.

Chemical Buffer Systems

Chemical buffers, such as bicarbonate and ammonia, help keep the blood’s pH in the narrow range that is compatible with life.

Key Points

The body’s acid-base balance is tightly regulated to keep the arterial blood pH between 7.38 and 7.42. Buffer solutions keep the pH constant in a wide variety of chemical actions.

A buffer solution is a mixture of a weak acid and its conjugate base, or a weak base and its conjugate acid.

The bicarbonate buffering system maintains optimal pH levels and regulates the carbon dioxide concentration that, in turn, shifts any acid-base imbalance.

Renal physiology controls pH levels through several powerful mechanisms that excrete excess acid or base.

Key Terms

bicarbonate: An alkaline, vital component of the pH buffering system of the human body that maintains acid-base homeostasis.
buffer: A solution used to stabilize the pH (acidity) of a liquid.
pH: In chemistry, a measure of the activity of the hydrogen ion concentration.

EXAMPLES

Anything that adversely affects an individual’s bloodstream will have a negative impact on that individual’s health since the blood acts as a chemical buffer solution to keep all the body’s cells and tissues properly balanced.

Acid-Base Homeostasis

Acid-base homeostasis concerns the proper balance between acids and bases; it is also called body pH. The body is very sensitive to its pH level, so strong mechanisms exist to maintain it. Outside an acceptable range of pH, proteins are denatured and digested, enzymes lose their ability to function, and death may occur.

Buffer Solution

A buffer solution is an aqueous solution of a weak acid and its conjugate base, or a weak base and its conjugate acid. Its pH changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a means of keeping pH at a nearly constant value in a wide variety of chemical applications.

Many life forms thrive only in a relatively small pH range, so they utilize a buffer solution to maintain a constant pH. One example of a buffer solution found in nature is blood. The body’s acid-base balance is normally tightly regulated, keeping the arterial blood pH between 7.38 and 7.42.

Several buffering agents that reversibly bind hydrogen ions and impede any change in pH exist. Extracellular buffers include bicarbonate and ammonia, whereas proteins and phosphates act as intracellular buffers.

The bicarbonate buffering system is especially key, as carbon dioxide (CO₂) can be shifted through carbonic acid (H₂CO₃) to hydrogen ions and bicarbonate (HCO³⁻):

$H_{2} O + {CO}_{2} ⇋ H_{2} {CO}_{3} ⇋ H^{+} + {CO}_{3}^{-}$

Acid–base imbalances that overcome the buffer system can be compensated in the short term by changing the rate of ventilation. This alters the concentration of carbon dioxide in the blood and shifts the above reaction according to Le Chatelier’s principle, which in turn alters the pH.

Renal Physiology

The kidneys are slower to compensate, but renal physiology has several powerful mechanisms to control pH by the excretion of excess acid or base. In response to acidosis, the tubular cells reabsorb more bicarbonate from the tubular fluid, and the collecting duct cells secrete more hydrogen and generate more bicarbonate, and ammonia genesis leads to an increase of the NH₃ buffer.

In its responses to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from the tubular epithelial cells, and lower the rates of glutamine metabolism and ammonium excretion.

This chart shows the pH range of a variety of common fluids. Buffering agents keep blood pH between 7.38 and 7.42. Sulfuric acid (batter acid) has the highest acidity on the chart; distilled water and saliva are neutral; and lye has the highest alkalinity on the chart.

pH range: Buffering agents keep blood pH between 7.38 and 7.42.

Regulation of H+ by the Lungs

Acid-base imbalances in the blood’s pH can be altered by changes in breathing to expel more CO₂and raise pH back to normal.

Key Points

Hydrogen ions (H+) are carried in the blood along with oxygen and carbon dioxide.

Sixty percent of the carbon dioxide is carried as dissolved bicarbonate.

A small amount of carbon dioxide is carried on the hemoglobin as carbaminohemoglobin, which is transported to the lungs for removal.

Following Le Chatelier’s principle, an imbalance in pH is returned to normal by increasing the rate of ventilation in the lungs.

To compensate for acidemia, more CO₂ is expelled, while the opposite occurs for alkalemia.

Key Terms

carbaminohemoglobin: A compound of hemoglobin and carbon dioxide. It is one of the forms in which carbon dioxide exists in the blood.
Le Chatelier’s principle: A principle that states that if a chemical system at equilibrium experiences a change in concentration, temperature, or total pressure, the equilibrium will shift in order to minimize that change.

EXAMPLES

Since maintaining normal pH is vital for life, and since the lungs play a critical role in maintaining normal pH, smokers have yet another reason to quit smoking.

Acid-base imbalance occurs when a significant insult causes the blood pH to shift out of its normal range (7.35 to 7.45). An excess of acid in the blood is called acidemia and an excess of base is called alkalemia.

The process that causes the imbalance is classified based on the etiology of the disturbance (respiratory or metabolic) and the direction of change in pH ( acidosis or alkalosis). There are four basic processes and one or a combination may occur at any given time.

Metabolic acidosis
Respiratory acidosis
Metabolic alkalosis
Respiratory alkalosis

Blood carries oxygen, carbon dioxide, and hydrogen ions (H+) between tissues and the lungs. The majority of CO₂ transported in the blood is dissolved in plasma (60% is dissolved bicarbonate).

This is a diagram of expiration that shows a person exhaling. When blood pH drops too low, the body compensates by increasing breathing to expel more carbon dioxide.

Expiration: When blood pH drops too low, the body compensates by increasing breathing to expel more carbon dioxide.

A smaller fraction is transported in the red blood cells that combine with the globin portion of hemoglobin as carbaminohemoglobin. This is the chemical portion of the red blood cell that aids in the transport of oxygen and nutrients around the body, but, this time, it is carbon dioxide that is transported back to the lung.

Acid-base imbalances that overcome the buffer system can be compensated in the short term by changing the rate of ventilation. This alters the concentration of carbon dioxide in the blood, shifting the above reaction according to Le Chatelier’s principle, which in turn alters the pH. The basic reaction governed by this principle is as follows:

$H_{2} O + {CO}_{2} ⇋ H_{2} {CO}_{3} ⇋ H^{+} + {CO}_{3}^{-}$

When the blood pH drops too low (acidemia), the body compensates by increasing breathing to expel more CO₂; this shifts the above reaction to the left such that less hydrogen ions are free; thus, the pH will rise back to normal. For alkalemia, the opposite occurs.

The Role of the Kidneys in Acid-Base Balance

The kidneys help maintain the acid–base balance by excreting hydrogen ions into the urine and reabsorbing bicarbonate from the urine.

Key Points

The kidneys maintain homeostasis through the excretion of waste products.

Acidosis causes more bicarbonate to be reabsorbed from the tubular fluid, while the collecting ducts secrete more hydrogen to generate more bicarbonate, and more NH₃ buffer is formed.

Alkalosis causes the kidney to excrete more bicarbonate as there is reduced secretion of hydrogen ions and more ammonium is excreted.

Key Terms

base: Any of a class of generally water-soluble compounds, that have a bitter taste, turn red litmus paper blue, and react with acids to form salts.
renal: Pertaining to the kidneys.

EXAMPLES

Urine testing is important because it can detect acid-base imbalances. For instance, uncontrolled diabetes results in highly acidic urine. If diabetes remains uncontrolled, the kidneys could become over-stressed and malfunction, which could lead to coma or death.

Within the human body, fluids such as blood must be maintained within the narrow range of 7.35 to 7.45, making it slightly alkaline. Outside that range, pH becomes incompatible with life; proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself.

To maintain this narrow range of pH the body has a powerful buffering system. Acid-base imbalances that overcome this system are compensated in the short term by changing the rate of ventilation.

Kidneys and Acid-Base Balance

The kidneys have two very important roles in maintaining the acid-base balance:

They reabsorb bicarbonate from urine.
They excrete hydrogen ions into urine.

The kidneys are slower to compensate than the lungs, but renal physiology has several powerful mechanisms to control pH by the excretion of excess acid or base. The major, homeostatic control point for maintaining a stable pH balance is renal excretion.

Bicarbonate (HCO₃₋) does not have a transporter, so its reabsorption involves a series of reactions in the tubule lumen and tubular epithelium. In response to acidosis, the tubular cells reabsorb more bicarbonate from the tubular fluid, and the collecting duct cells secrete more hydrogen and generate more bicarbonate, and ammonia genesis leads to an increase in the formation of the NH₃ buffer.

In response to alkalosis, the kidneys may excrete more bicarbonate by decreasing hydrogen ion secretion from the tubular epithelial cells, and lowering the rates of glutamine metabolism and ammonium excretion.

Organ Systems Involved

Every organ system of the human body relies on pH balance; however, the renal system and the pulmonary system are the two main modulators. The pulmonary system adjusts pH using carbon dioxide; upon expiration, carbon dioxide is projected into the environment. Due to carbon dioxide forming carbonic acid in the body when combining with water, the amount of carbon dioxide expired can cause pH to increase or decrease. When the respiratory system is utilized to compensate for metabolic pH disturbances, the effect occurs in minutes to hours.

The renal system affects pH by reabsorbing bicarbonate and excreting fixed acids. Whether due to pathology or necessary compensation, the kidney excretes or reabsorbs these substances which affect pH. The nephron is the functional unit of the kidney. Blood vessels called glomeruli transport substances found in the blood to the renal tubules so that some can be filtered out while others are reabsorbed into the blood and recycled. This is true for hydrogen ions and bicarbonate. If bicarbonate is reabsorbed and/or acid is secreted into the urine, the pH becomes more alkaline (increases). When bicarbonate is not reabsorbed or acid is not excreted into the urine, pH becomes more acidic (decreases). The metabolic compensation from the renal system takes longer to occur: days rather than minutes or hours.

Function

The physiological pH of the human body is essential for many processes necessary to life including oxygen delivery to tissues, correct protein structure, and innumerable biochemical reactions that rely on the normal pH to be in equilibrium and complete.

Oxygen Delivery to Tissues

The oxygen dissociation curve is a graph depicting the relationship of the partial pressure of oxygen to the saturation of hemoglobin. This curve relates to the ability of hemoglobin to deliver oxygen to tissues. If the curve is shifted to the left, there is a decreased p50, meaning that the amount of oxygen needed to saturate hemoglobin 50% is lessened and that there is an increased affinity of hemoglobin for oxygen. A pH in the alkalotic range induces this left shift. When there is a decrease in pH, the curve is shifted to the right, denoting a decreased affinity of hemoglobin for oxygen.

Protein Structure

It would be hard to overstate the importance of proteins in the human body. They makeup ion channels, carry necessary lipophilic substances throughout our mostly lipophobic body, and participate in innumerable biological processes. For proteins to complete necessary functions, they must be in the proper configuration. The charges on proteins are what allow their proper shape to exist. When pH is altered outside of the physiological range, these charges are altered. The proteins are denatured leading to detrimental changes in architecture that cause a loss of proper function.

Biochemical Processes

Throughout the human body, many chemical reactions are in equilibrium. One of the most important was previously mentioned with the equation:

H20 + CO2 <-> H2CO3<-> H+ + HCO3-

The Le Chatelier Principle states that when the variables of concentration, pressure, or temperature are changed, a system in equilibrium will react accordingly to restore a new steady state. The reaction above, states that if more hydrogen ions are produced, the equation will shift to the left so that more reactants are formed, and the system can remain in equilibrium. This is how compensatory pH mechanisms work; if there is metabolic acidosis present, the kidneys are not excreting enough hydrogen ions and/or not reabsorbing enough bicarbonate. The respiratory system reacts by increasing minute ventilation (often by increasing respiratory rate) and expiring more CO2 to restore equilibrium.[rx]

What’s normal?

A normal range for arterial pH is 7.35 to 7.45. Acidosis is a pH less than 7.35; alkalosis is a pH greater than 7.45. Because pH is measured in terms of hydrogen (H⁺) ion concentration, an increase in H⁺ ion concentration decreases pH and vice versa. Changes in H⁺ ion concentration can be stabilized through several buffering systems: bicarbonate-carbonic acid, proteins, hemoglobin, and phosphates.

Acidosis, therefore, can be described as a physiologic condition caused by the body’s inability to buffer excess H⁺ ions. At the other end, alkalosis results from a deficiency in H⁺ ion concentration. Acidemia and alkalemia refer to the process of acidosis or alkalosis, respectively, occurring in arterial blood.

Body acids are formed as end products of cellular metabolism. Under normal physiologic conditions, a person generates 50 to 100 mEq/day of acid from the metabolism of carbohydrates, proteins, and fats. In addition, the body loses base in the stool. In order to maintain acid-base homeostasis, acid production must balance the neutralization or excretion. The lungs and kidneys are the main regulators of acid-base homeostasis. The lungs release CO₂, an end product of carbonic acid (H₂CO₃). The renal tubules, with the regulation of bicarbonate (HCO₃^–), excrete other acids produced from the metabolism of proteins, carbohydrates, and fats.

Reference values for arterial blood

	Women	Men
cH⁺P	36.3–41.7 nmol l⁻¹ (pH: 7.38–7.44)	37.2–42.7 nmol l⁻¹ (pH: 7.37–7.43)
ctH⁺Ecf	−2.3–+2.7 mmol l⁻¹	−3.2–+1.8 mmol l⁻¹
pCO₂	4.59–5.76 kPa (33.8–42.4 mmHg)	4.91–6.16 kPa (36.8–46.2 mmHg)
cHCO₃⁻P	21.2–27.0 mmol l⁻¹	22.2–28.3 mmol l⁻¹

cH⁺P: conc. of (free) hydrogen ion in plasma; ctH⁺Ecf: conc. of titratable hydrogen ion in extracellular fluid (also called standard base deficit, SBD); pCO₂: tension of carbon dioxide; cHCO₃⁻P: conc. of bicarbonate in plasma.

Related Testing

Arterial blood gas (ABG) sampling, is a test often performed in an inpatient setting to assess the acid-base status of a patient. A needle is used to draw blood from an artery, often the radial and the blood is analyzed to determine parameters such as pH, pC02, pO2, HCO3, oxygen saturation, and more. This allows the physician to understand the status of the patient better. ABGs are especially important in the critically ill. They are the main tool utilized in adjusting to the needs of a patient on a ventilator. The following are the most important normal values on an ABG:

pH = 7.35 to 7.45
pCO2 = 35 to 45 mmHg
pO2 = 75 to 100 mmHg
HCO3- = 22 to 26 mEq/L
O2 Sat = greater than 95%

The ability to quickly and efficiently read an ABG, especially in reference to inpatient medicine, is paramount to quality patient care.

Look at the pH
Decide whether it is acidotic, alkalotic, or within the physiological range
PaCO2 level determines respiratory contribution; a high level means the respiratory system is lowering the pH and vice versa.
HCO3- level denotes metabolic/kidney effect. An elevated HCO3- is raising the pH and vice versa.
If the pH is acidotic, look for the number that corresponds with a lower pH. If it is a respiratory acidosis, the CO2 should be high. If the patient is compensating metabolically, the HCO3- should be high as well. Metabolic acidosis will be depicted with an HCO3- that is low.
If the pH is alkalotic, again, determine which value is causing this. A respiratory alkalosis will mean the CO2 is low; a metabolic alkalosis should lend an HCO3- that is high. Compensation with either system will be reflected oppositely; for a respiratory alkalosis the metabolic response should be a low HCO3- and for metabolic alkalosis, the respiratory response should be a high CO2.
If the pH level is in the physiological range but the PaCO2 and/or bicarb are not within normal limits, there is likely a mixed disorder. Also, compensation does not always occur; this is when clinical information becomes paramount.
Sometimes it is difficult to ascertain whether a patient has a mixed disorder. This is discussed later.

Other tests that are important to perform when analyzing the acid-base status of a patient include those that measure electrolyte levels and renal function. This helps the clinician gather the information that can be used to determine the exact mechanism of the acid-base imbalance as well as the factors contributing to the disorders.[rx][rx]

References

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Enterovesical Fistula – Causes, Symptoms, Treatment

An enterovesical fistula is a pathologic connection between the bowel and the bladder. This activity reviews the evaluation, diagnosis, and treatment of this condition and highlights the role of the interprofessional team in caring for affected patients.

A fistula is an abnormal connection between two epithelial surfaces[rx]. There are some exceptions of this definition, like when the surfaces are not epithelial as in the endothelial surfaces of vascular fistulae or in the connection of gastrointestinal (GI) mucosa to a wound where no epithelial surface is included. An enterovesical fistula is an abnormal communication between the intestine and the bladder.[rx] The organ of origin of the fistula is usually stated first. Therefore, with an enterovesical fistula, the fistula usually begins from the intestine and ends to the bladder. However, the fistulization process could begin from the bladder wall and end in the intestine or other luminal structures.[rx] Most of the known and clinically encountered fistulae originate from the bowel.

The term bowel is generally used to indicate the small intestine[rx]. It is interchangeably used in the literature to refer to all intestinal (small and large) fistulas with the urinary bladder. More specific terms are also used, including jejunovesical, ileo vesical, colovesical, sigmoid vesical, or rectovesical fistulae, to indicate the specific part of the intestine involved in the fistulae[rx]. Since the colovesical fistula is by far the most common fistula between the intestine and the bladder, most of the content of this article will apply on the colovesical fistula unless it is otherwise indicated.

Causes of Enterovesical Fistula

An enterovesical fistula is a complication of an underlying disease or injury. A good understanding of the pathophysiology of the fistula formation process is essential for appropriate management and prevention. Several causes may result in this complication. Depending on the cause, the processing of developing the fistulae may range between months to years. Generally, any pathology of the wall of the bowel or bladder can lead to the development of a fistula. Other categories of causes include injury, including iatrogenic and radiation.

The common causes of enterovesical fistula are[rx]:

Diverticular disease – is by far the most common cause of enterovesical fistula. It accounts for two-thirds or more of this type of fistulae. Diverticular disease is much more common in large bowel than small bowel. Complicated diverticulitis is more likely to cause fistula than non-inflamed diverticula. Erosion of the diverticular wall with the components of inflammation and a small abscess can extend and involve the adjacent bladder wall to create the fistulous connection. An occasional increase in the luminal pressure in either side of the fistula and the continued inflammatory process will likely maintain the fistula patent.
Malignancy – is the second common cause of enterovesical fistula[rx]. It accounts for about 10% to 20% of the cases. Intestinal mucosal malignancy usually spread radially as well as circumferentially. Radial extension and destruction of normal tissue may extend to the nearby bladder wall creating an abnormal connection. Bladder malignancy can similarly cause the same fistula.
Crohn and other inflammatory diseases
Radiation[rx]: Fistula manifests after a long lag period that could extend to years. A less common cause but within the same group of patients is chemotherapy.
Injuries: Either iatrogenic injuries like in pelvic surgeries or other injuries like in traumas of the pelvis are rare causes. [rx]
Foreign bodies are a rare cause of fistula.[rx]

The occasional mistake of considering the causes of non-healing of fistula abbreviated with the mnemonic FRIENDS as causes of fistula. It is correct that most causes included in FRIENDS are known causes of fistula formation, but they include unrelated factors like epithelialization or distal obstruction. A fistula that is already formed is unlikely to heal if the tract lining epithelializes, or the distal stream of the GI tract is obstructed. However, these factors by themselves are not known to cause fistula formation.

Colovesical fistulae are the most common type of fistulous communication between the bowel and the urinary bladder. The incidence in patients with diverticular disease approximately 2%. Less than 1% of carcinomas of the colon result in fistula formation.

Colovesical fistulae are more common in males. A lower incidence in females is most likely due to the interposition of the uterus and adnexa between the bladder and the colon. In women, other types of fistulae are more common than colovesical fistulae. Women who present with colovesical fistulae are usually older or have a history of hysterectomy. Uterine atrophy or absence of the uterus may be predisposing factors.

An enterovesical fistula usually refers to a predisposing pathophysiologic process. Therefore, pathophysiology depends on the predisposing cause of the disease. This extends from acute infectious processes like in diverticulitis to the worst process as malignancy. Consequent to the development of a fistula, an additional pathophysiologic process starts as a result of the connection between two different lumens. The most affected lumen is the bladder because it is sterile. Contamination of the bladder lumen with intestinal content, especially the colonic content with high bacterial load, results in persistent infection (cystitis).

Symptoms of Enterovesical Fistula

Your symptoms will be different depending on if you have an internal or external fistula. They’re accompanied by other symptoms, including:

abdominal pain
painful bowel obstruction
fever
elevated white blood cell count
diarrhea
rectal bleeding
a bloodstream infection or sepsis
poor absorption of nutrients and weight loss
dehydration
worsening of the underlying disease

The most serious complication of GIF is sepsis, a medical emergency in which the body has a severe response to bacteria. This condition may lead to dangerously low blood pressure, organ damage, and death.

Diagnosis of Enterovesical Fistula

Histopathologic examination of the tissue involved in the fistula reflects an acute inflammatory reaction besides the original pathology of the causative disease except in injuries. The acute inflammation is caused by a combination of more than one factor, like the primary pathology causing the fistula (diverticular disease, malignancy, Crohn, among others), tissue irritation by the flow of intestinal content, and the resulting infection. Other histopathological findings like chronic inflammation from radiation or Crohn, malignancy, and or injury-related necrotic process can be identified depending on the cause of the fistula. Identifying the fistula histopathology is usually a late stage after surgical treatment and excision of the fistula and related tissue. Occasionally intraoperative diagnosis is made by biopsying incidentally identified fistulae. The frozen section is used to determine the cause of the fistula and plan the surgical treatment. The malignant fistulous tissue is treated surgically differently (usually with radical excision) than non-malignant tissue.

Like in almost all surgical diseases, signs and symptoms will involve the cause of the disease, the disease, and its complications. Occasionally fistula is the presenting finding of the underlying disease.[rx] The most common signs and symptoms are recurrent urinary tract infection and pneumaturia.[rx] Other signs and symptoms that can be identified in the history may include:

Signs and Symptoms of the Cause of the Disease

Diverticular disease: Pain and other signs and symptoms of the infectious GI malignancy; general signs and symptoms of weight loss, weakness, cachexia, poor appetite; and local signs and symptoms of intestinal obstruction, GI bleeding, change of bowel habit, and abdominal pain with possible tenderness
Inflammatory process: Lower abdominal pain/tenderness, fever, GI bleed, and alteration of bowel habit

A history of known diseases causing enterovesical fistula should raise suspicion of the problem. Pneumaturia is a highly diagnostic symptom of enterovesical fistula.[rx] On rare occasions, fecaluria (presence of fecal material in the urine) is present.[rx]

Lab Test and Imaging

Evaluation of enterovesical fistulas includes an assessment to:

Confirm the diagnosis
Characterize further the site, size, and complexity of the fistula
Identify the underlying pathology if it is unknown
Plan for management
Reevaluate and follow up progression

Several investigation modalities are available to achieve all or some of the above goals. The appropriate clinical practice is to start with simple tests, then base the rest of the investigation on the need. Confirming the diagnosis is not difficult. It is usually done with imaging.

Evaluation Modalities

In addition to the clinical evaluation that includes a comprehensive history and appropriate physical exam, the following modalities are available to evaluate enterovesical fistulas.

Imaging

Imaging with GI contrast that traverses through the fistula to the bladder provides satisfactory confirmation. On occasions, the contrast is not seen in the fistula itself but is seen in the end organ (bladder).

Small bowel follows through, or contrast enema can provide this confirmation.

CT provides more details about the tissue in the area and the fistula itself. It is helpful in planning for surgical treatment.

MRI may be needed in subtle or difficult to diagnose fistulae. It has the advantage of better soft tissue characterization. It is also useful in complex fistulas like in complicated Crohn’s.[rx]

Endoscopy

Cystoscopy, or colonoscopy in the case of colovesical fistula, is useful to identify the site of the fistula at the mucosal of the scoped organ. A small area of inflamed, red, and possibly elevated mucosa is a sign of a possible fistulous tract. Unless the fistula is very wide, it is usually difficult to visualize its lumen endoscopically.

Endoscopy can provide further information about the underlying disease, like in malignancy or Crohn’s. Fistulas might an incidental finding of endoscopy performed for other reasons. In this situation, further investigations are required.

Treatment of Enterovesical Fistula

Treatment of enterovesical fistula includes treatment of the fistula itself and the underlying disease if it is treatable. Therefore, confirming the fistula etiology should be done before planning treatment. Good clinical practice is to treat with the least aggressive treatment modality with the best success rate.

Conservative or Non-operative Approach

Medical treatment of the symptoms and possible complications like UTI can be used in selected patients. This approach can be considered in high-risk patients and severe underlying diseases. The associated complication rate from this approach is found to be low in recent studies.[rx][rx]

Medical treatment includes treating UTI and the associated symptoms, maximizing medical treatment of the underlying disease like in Crohn’s or diverticulitis, and support of the general patient’s condition.

Other conservative treatment includes non-operative measures to close the fistula like fibrin glue or other occlusive measures. The success rate of these measures is not high. They are still an option to consider in high-risk patients.

Operative Approach

The basic principle of the surgical approach is to excise the involved segment of the bowel and the fistula[rx][rx]. After the diagnosis of the fistula and the underlying disease is confirmed and further characterized, surgical treatment can be planned accordingly. Limited conservative excision of the involved intestinal segment and the fistula is recommended in operative cases of diverticular disease, limited Crohn’s, and other reversible inflammatory diseases[rx][rx]. The fistula site on the bladder wall can be over swan with an absorbable suture. The indwelling urinary catheter should be maintained for a few weeks during the healing process. More radical excision is recommended for inoperable malignancy. Oncologic excision of the intestine with partial cystectomy that includes the fistula site to a free margin is necessary[rx]. Primary closure of the bladder wall is sufficient unless the trigon is involved.

An enterovesical fistula may sometimes be identified intraoperatively while operating on the underlying disease. Dense adhesions of the intestine on the bladder are the trigger to suspect the fistula. Unless it is cancer surgery, the operative approach is usually the same. If the pathology cannot be confirmed, a frozen section of the fistula tissue is needed to rule out malignancy.

At UCSF, fistulas are treated by the UCSF Complex Abdominal Surgery Program, a high-volume service whose surgeons perform intricate and challenging abdominal procedures using state-of-the-art surgical repair. The multidisciplinary team also includes specialists in nursing, intensive care medicine, wound care, plastic surgery, pharmacology, infectious diseasese, nutritional and physical rehabilitation. Our depth and breadth of experience helps ensure that each patient receives the best possible care for ECFs.

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Enterocutaneous Fistula – Causes, Symptoms, Treatment

An enterocutaneous fistula (ECF) is an abnormal connection that develops between the intestinal tract or stomach and the skin. As a result, contents of the stomach or intestines leak through to the skin.

An enterocutaneous fistula (ECF) is an aberrant connection between the intra-abdominal gastrointestinal (GI) tract and skin/wound. Because of differences in management and significant preponderance of small intestinal and colonic fistulae, fistulae originating in the rectum, upper GI tract, or pancreas will not be discussed in this occur as a surgical complication, but can also occur due to trauma, malignancy, inflammatory bowel disease, or ischemia. This activity describes the pathophysiology, evaluation, and management of enterocutaneous fistulas and highlights the role of the interprofessional team in the management of affected patients.

A fistula is an abnormal connection between two epithelized surfaces. Fistulas can form between any two hollow spaces including blood vessels, intestine, vagina, bladder, and skin. There are three different categories used to define a fistula, anatomic, physiologic, and etiologic. Anatomically, fistulas are subdivided into two categories, internal and external. Internal fistulas are connections between two internal structures. A few examples of an internal fistula would be enterocolitis, ileosigmoid, and aortoenteric. Alternatively, external fistulas form connections between an internal structure and an external structure. Examples of this would be enterocutaneous, enter atmospherically, and rectovaginal fistulas. When categorized physiologically, the fistula is differentiated based on fluid output. Low-output fistulas drain less than 200 ml of fluid per day, high-output fistulas drain greater than 500 ml of fluid per day, and medium-output fistulas fall between the two. Etiology is the last way in which fistulas are categorized. Common etiologic categories are traumatic fistulas, surgical site fistulas, and fistulas associated with Crohn’s disease. This article will specifically cover fistulas that fall under the anatomical category of neurocutaneous fistulas.[rx][rx][rx][rx]

Causes of Enterocutaneous Fistula

It is estimated that 80% of enterocutaneous fistulas are of iatrogenic origin secondary to surgery. Surgical complications, such as enterotomies or intestinal anastomotic dehiscence, are known to be at high risk for the development of an enterocutaneous fistula. Trauma, malignancy, and inflammatory bowel disease increase risk of fistula development postoperatively. The 20% of fistulas not associated with surgery are caused by systemic diseases such as Crohn’s disease, radiation enteritis, malignancies, trauma, or ischemia.[rx][rx]

An underlying disease or surgical event usually causes intestinal fistula formation.[rx][rx] Intestinal fistula is therefore considered a complication more than a separate disease by itself.[rx][rx][rx][rx][rx] The common causes of intestinal fistula are:

Surgical Procedure – The surgical complication is the most common cause of intestinal fistula formation.[rx][rx] There are various numbers in the literature and textbooks of the percentage of intestinal fistulae caused by surgical procedures. The accurate percentage depends on many factors including patients population, surgeons’ skills, disease, and procedures complexity. Therefore, it is difficult and inaccurate to make a generalization on the percentage from the studies. Surgical procedures cause more than half of intestinal fistulas. Any practicing general surgeon realizes this extent of the impact.
Diverticular Disease – Complex diverticular disease is a common cause of fistula connecting to an intra-abdominal organ like the bladder.[rx][rx] Erosion of the diverticular wall with the components of inflammation and abscess can extend and involve the adjacent bladder wall to create the fistulous connection. An occasional increase in the luminal pressure in either side of the fistula and the continued inflammatory process will likely maintain the fistula patent.[rx]
Crohn’s Disease – Chronic inflammatory bowel diseases, especially Crohn’s disease, are a well-known cause of intestinal fistulization.[rx][rx][rx][rx] Entero-enteric, entero-colic, entero-vesical, entero-cutaneous, and peri-anal fistulae are common examples of Crohn’s fistula complication.[rx]
Malignancy – Cancer of the intestine or adjacent organs is a known cause of fistulization to and from the intestine.[rx][rx] These fistulae are also called malignant fistulae. Intestinal mucosal malignancy usually spread radially as well as circumferentially. Radial extension and destruction of normal tissue may extend to the nearby organs creating an abnormal connection.
Radiation – Radiation causes long-term chronic inflammation with poor healing and repair processes.[rx] Therefore, intestinal fistula caused by radiation manifests after a long lag period that could extend to years.
Non-Surgical Injuries and Foreign Bodies – Injuries in trauma or by a foreign body can result in non-healing abnormal connection with the intestine.[rx] There is a number of causes that are abbreviated in the mnemonic “FRIENDS” (foreign body, radiation, inflammation, epithelization, neoplasm, distal obstruction, short fistula). These are known causes of non-healing fistula. Epithelization of the fistula lining prevents its healing but does not by itself create a fistula. Similarly distal (to the fistula site) intestinal obstruction or short fistula. Failure of an intestinal fistula to heal after appropriate treatment raises the suspicion for these causes and mandates further investigation.

Symptoms of Enterocutaneous Fistula

Your symptoms will be different depending on if you have an internal or external fistula. They’re accompanied by other symptoms, including:

abdominal pain
painful bowel obstruction
fever
elevated white blood cell count
diarrhea
rectal bleeding
a bloodstream infection or sepsis
poor absorption of nutrients and weight loss
dehydration
worsening of the underlying disease

The most serious complication of GIF is sepsis, a medical emergency in which the body has a severe response to bacteria. This condition may lead to dangerously low blood pressure, organ damage, and death.

Diagnosis of Enterocutaneous Fistula

As previously mentioned, the most common cause of an enterocutaneous fistula is iatrogenic and occurs in the postoperative period. A history of trauma, inflammatory bowel disease, and oncologic surgery places patients at a high risk of developing a fistula.

Histopathologic examination of the tissue involved in the fistula reflects an acute inflammatory reaction besides the original pathology of the causative disease except in injuries. Acute inflammation is caused by a combination of more than one factor like the primary pathology causing the fistula (diverticular disease, malignancy, Crohn’s, among others), tissue irritation by the flow of intestinal content, and the resulting infection.[rx] Other histopathological findings like chronic inflammation from radiation or Crohn’s, malignancy, and or injury-related necrotic process can be identified depending on the cause of the fistula. Identifying the fistula histopathology is usually a late stage after surgical treatment and excision of the fistula and related tissue. Occasionally intra-operative diagnosis is made by biopsying incidentally identified fistulae. The frozen section is used to determine the cause of the fistula and plan the surgical treatment. Malignant fistulous tissue is treated surgically differently (usually with radical excision) than non-malignant tissue.

Postsurgical intestinal fistulae are acute with a significant, infectious, inflammatory component that may infrequently lead to sepsis. Sudden deterioration of multiple organs can be the presenting clinical picture on some of these occasions. This is the most detrimental pathological component in patients’ survival in these complications.

History and Physical

History and physical exam details in the intestinal fistula will reveal signs and symptoms of the underlying disease and complication.

Depending on the underlying disease, a variety of signs and symptoms of abdominal pain, diarrhea, fever, gastrointestinal (GI) bleed, weakness, cachexia, poor appetite, and weight loss can be variably encountered. Specific symptoms related to the organ involved in the fistula may be identified. Examples of these symptoms are recurrent UTIs, pneumaturia or fecaluria in an entero-vesical fistula.[rx] Vaginal pain, discharge, and recurrent infections are seen in recto- or colo-vaginal fistula.[rx] Skin pain, irritation, and excoriation are also seen in entero- or colo-cutaneous fistula.

The following scenario is an example of the events leading up to the development of an enterocutaneous fistula. A patient with a postoperative fever, leukocytosis, ileus, and abdominal tenderness is found to have a wound infection. The next step in treating this patient is to drain the abscess. However, one or two days after draining the abscess, enteric contents are observed in the wound. Finding enteric contents that are continually leaking into the wound establishes a diagnosis of an enterocutaneous fistula.

A helpful, commonly used acronym for remembering the factors that make fistula formation favorable and unlikely to spontaneously regress is “FRIEND.” The acronym is remembered easily with the mnemonic “the friends of the fistula.”

F – Foreign body
R – Radiation
I – Inflammation or infection
E – Epithelialization of the fistula tract
N – Neoplasm
D – Distal obstruction

Lab Test and Imaging

After stabilizing the patient, the next step is to evaluate the fistula. Ultrasound, CT scan, and fistulography are three imaging modalities that can be used to help characterize a fistula. Small bowel follow-through and endoscopy studies may also be helpful. Imaging is important for determining whether or not all of the fluid traveling through the fistula is coming out of the external opening. In some cases, fluid can be partially leaking into the abdomen and can then lead to the formation of an abscess. CT scan with oral contrast is considered the single best radiologic test since it can identify the tract, abdominal leaking, intra-abdominal abscesses, distal obstruction, and foreign bodies. Fistulography is used less often but can be useful when CT or ultrasound is unavailable or inconclusive. It is performed by injecting contrast into the external opening of the fistula and taking plain film radiographs of the area.

Imaging

Imaging with GI contrast that traverses through the fistula from the intestinal lumen to the other end of the fistula confirms the presence and extent of the fistula. On occasions, the contrast is not seen in the fistula itself but is seen in the end organ (bladder, vagina, extra-abdominally)[rx][rx]. Small bowel follow-through imaging or contrast enema can provide this confirmation.

CT is often done first, especially with an acute intestinal fistula, for the high accuracy and details it provides about the fistulous organs and the entire abdominopelvic cavities. CT provides details essential for planning for surgical treatment. MRI may be needed in subtle or difficult to diagnose fistulae. It has the advantage of better soft tissue characterization. It is also useful in complex fistulas like in complicated Crohn’s disease.[rx]

Endoscopy

Colposcopy, cystoscopy, gastroduodenostomy, or colonoscopy are used to identify the site of the fistula at the mucosa of the scoped organ. A small area of inflamed, red, and possibly elevated mucosa is a sign of a possible fistulous tract. Unless the fistula is very wide, it is usually difficult to visualize its lumen endoscopically. Endoscopy can provide further information about the underlying disease like malignancy or Crohn’s. Fistulas might be an incidental finding of endoscopy performed for other reasons. In this situation, further investigations are required.

Treatment of

The first step in patient management is stabilization. Patients are at high risk for electrolyte imbalances, sepsis, and malnutrition. Controlling all three of these factors is essential for survival. Electrolyte abnormalities and fluid balance need to be monitored closely because these patients can develop severe derangements quickly. Electrolyte losses vary depending on the location of the fistula in the gastrointestinal (GI) tract and the amount of output. Any deficiencies need to be replaced. In septic patients, a source needs to be identified and appropriately treated. Sepsis is documented as being responsible for two-thirds of mortality in these patients. Intra-abdominal abscesses are common and should be high on the differential as the source of sepsis. The Surviving Sepsis Campaign guidelines should be followed when treating these patients. Most patients will need parenteral nutrition, but a subset of patients may be able to tolerate an enteral elemental diet if the fistula is distal in the GI tract and the output from the fistula is not increased by starting feeds. Either way, adequate nutrition is a well-established, essential component to treat these patients properly. Another important variable to stabilize is the output from the fistula. The fluid needs to be properly contained as not to damage the surrounding skin and to increase odds of healing. Various methods of wound care can aid in preventing skin loss, minimizing pain, and allowing the patient to function on a daily basis. Such strategies are typically similar to ostomy bag appliances, but some will require a more customized plan for containing the fistula output.

A decision then needs to be made on how to treat the fistula itself. There are some cases in which immediate surgical correction may be appropriate, but the majority of fistulas are treated non-operatively. This is because 90% of fistulas close on their own within 5 weeks of medical management. Depending on the surgeon, 2 to 3 months of will be attempted before the surgical correction of a fistula is considered. This waiting period gives the fistula an appropriate amount of time to close spontaneously. It also decreases the morbidity and mortality of surgical correction. When initiating medical management, the factors mentioned in the previous section that promotes fistula development should be evaluated. All modifiable variables should be corrected to increased chances of spontaneous closure. Low-output fistulas are more likely to close than higher output fistulas. A longer fistula tract length is associated with a higher chance of closing.

The goal of medical management is to decrease fistula output and encourage spontaneous closure. Nasogastric tubes should be avoided. In high output fistulas, proton pump inhibitors (PPIs) and H2 blockers can be used to decrease gastric secretions. Antidiarrheals, such as loperamide, are also effective in reducing the output of high-output fistulas. Octreotide, a somatostatin analog, has been extensively studied for controlling fistula output. It has been shown to decrease output, increase spontaneous closure, and decrease hospital stay, but has never been shown to decrease mortality. If a fistula has over one liter per day of output, an octreotide trial can be attempted. After 72 hours if there is a significant reduction in volume, the medication can be continued.

If the fistula does not resolve with medical management, surgical management will then be considered. Operating on fistulas is fraught with difficulties, and there is a high risk for recurrence. The surgical approach may be difficult due to previous surgeries and adhesions. The bowel must be run carefully, and extreme care must be taken to not cause any accidental enterotomies during lysis of adhesion and bowel mobilization. As long as the bowel looks healthy, the best option is to excise the fistula tract and resect a small amount of associated bowel followed by an anastomosis to reestablish bowel continuity. To decrease the recurrence rate, one must make sure to close the fascia where the fistula tract was traversing. As long as medical management, proper nutrition, and an appropriate waiting time precede the operation, permanent resolution of an enterocutaneous fistula occurs in 80% to 95% of cases.

At UCSF, enterocutaneous fistulas are treated by the UCSF Complex Abdominal Surgery Program, a high-volume service whose surgeons perform intricate and challenging abdominal procedures using state-of-the-art surgical repair. The multidisciplinary team also includes specialists in nursing, intensive care medicine, wound care, plastic surgery, pharmacology, infectious diseasese, nutritional and physical rehabilitation. Our depth and breadth of experience helps ensure that each patient receives the best possible care for ECFs.

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Intestinal Fistula – Causes, Symptoms, Diagnosis, Treatment

Intestinal Fistula/A fistula is an abnormal communication between two epithelial surfaces. This definition is not without exceptions. It is a general description to differentiate fistulae from sinuses[rx] and other forms of luminal tracts.

As the definition implies, fistula connects 2 different surfaces or lumens. It often starts from an offending site and makes its way to an adjacent lumen or surface. An intestinal fistula is a fistula that starts from the intestine. It could connect to a variety of adjacent organs or surfaces.

Fistulae are named according to the surfaces or organs they connect like the entero-vesical fistula or the entero-cutaneous fistula.[rx] The name starts with the primary organ of origin of the fistula then the surface or organ to which it connects. For example, the recto-vaginal fistula starts from the rectum and ends in the vagina. Similarly, the entero-cutaneous fistula starts from the small intestine and ends or opens to the skin.

Intestinal fistulae are a challenging surgical condition. Assessment, management, and prognosis depend on the complexity of the fistula and the underlying etiology. In this article, fistulae starting from the intestine both small and large intestine will be the focus of discussion. Details of specific fistulae will not be included.

Types of Fistula

Common examples of intestinal fistulae are

Entero-cutaneous fistula,
Enter-enteric fistula,
Entero-vesical fistula,[rx][rx]
Entero-colic fistula,
Entero-atmospheric fistula,[rx] and
Recto-vaginal fistula.[rx][rx][rx]

Causes of Intestinal Fistula

An underlying disease or surgical event usually causes intestinal fistula formation.[rx][rx] Intestinal fistula is therefore considered a complication more than a separate disease by itself.[rx][rx][rx][rx][rx] The common causes of intestinal fistula are:

Surgical Procedure – The surgical complication is the most common cause of intestinal fistula formation.[rx][rx] There are various numbers in the literature and textbooks of the percentage of intestinal fistulae caused by surgical procedures. The accurate percentage depends on many factors including patients population, surgeons’ skills, disease, and procedures complexity. Therefore, it is difficult and inaccurate to make a generalization on the percentage from the studies. Surgical procedures cause more than half of intestinal fistulas. Any practicing general surgeon realizes this extent of the impact.
Diverticular Disease – Complex diverticular disease is a common cause of fistula connecting to an intra-abdominal organ like the bladder.[rx][rx] Erosion of the diverticular wall with the components of inflammation and abscess can extend and involve the adjacent bladder wall to create the fistulous connection. An occasional increase in the luminal pressure in either side of the fistula and the continued inflammatory process will likely maintain the fistula patent.[rx]
Crohn’s Disease – Chronic inflammatory bowel diseases, especially Crohn’s disease, are a well-known cause of intestinal fistulization.[rx][rx][rx][rx] Entero-enteric, entero-colic, entero-vesical, entero-cutaneous, and peri-anal fistulae are common examples of Crohn’s fistula complication.[rx]
Malignancy – Cancer of the intestine or adjacent organs is a known cause of fistulization to and from the intestine.[rx][rx] These fistulae are also called malignant fistulae. Intestinal mucosal malignancy usually spread radially as well as circumferentially. Radial extension and destruction of normal tissue may extend to the nearby organs creating an abnormal connection.
Radiation – Radiation causes long-term chronic inflammation with poor healing and repair processes.[rx] Therefore, intestinal fistula caused by radiation manifests after a long lag period that could extend to years.
Non-Surgical Injuries and Foreign Bodies – Injuries in trauma or by a foreign body can result in non-healing abnormal connection with the intestine.[rx] There is a number of causes that are abbreviated in the mnemonic “FRIENDS” (foreign body, radiation, inflammation, epithelization, neoplasm, distal obstruction, short fistula). These are known causes of non-healing fistula. Epithelization of the fistula lining prevents its healing but does not by itself create a fistula. Similarly distal (to the fistula site) intestinal obstruction or short fistula. Failure of an intestinal fistula to heal after appropriate treatment raises the suspicion for these causes and mandates further investigation.

Pathophysiology

An intestinal fistula is a complication of an underlying disease, surgical procedure or injury. To better assess, manage, and prevent fistulae a good understanding of the pathophysiology of the fistula formation process is needed.[rx] The primary trigger of the intestinal fistula is the loss of the intestinal wall integrity in the area of the underlying disease or etiology. This will lead to perforation or penetration to an adjacent organ or surface. The process may take days, months or years depending on the underlying etiology. Iatrogenic surgical injuries may lead to intestinal fistulae with few days, while radiation may take months or years.

More complex fistulae that result after surgical procedures are formed by a leak of the intestine formation a collection of intestinal content that eventually finds its way to another organ or surface. A similar but slightly simpler process takes place in the fistula-in-and formation.[rx] An abscess in the anal area (usually formed as an infected anal crypt) finds its way or drained to the body surface. So, rather than a direct fistulous tract, postsurgical fistulae are most likely to be a leaking intestinal content that is connected to another epithelial surface. A more extreme of this example is what is practically called fistula when a bowel anastomotic leak is identified by intestinal content draining through an intra-abdominally placed drain. This is generally referred to as a controlled fistula. The same applies to pancreatic fluid observed in the drain after non-total pancreatectomy.

Symptoms of Intestinal Fistula

Your symptoms will be different depending on if you have an internal or external fistula. They’re accompanied by other symptoms, including:

abdominal pain
painful bowel obstruction
fever
elevated white blood cell count
diarrhea
rectal bleeding
a bloodstream infection or sepsis
poor absorption of nutrients and weight loss
dehydration
worsening of the underlying disease

The most serious complication of GIF is sepsis, a medical emergency in which the body has a severe response to bacteria. This condition may lead to dangerously low blood pressure, organ damage, and death.

Diagnosis of Intestinal Fistula

Histopathologic examination of the tissue involved in the fistula reflects an acute inflammatory reaction besides the original pathology of the causative disease except in injuries. Acute inflammation is caused by a combination of more than one factor like the primary pathology causing the fistula (diverticular disease, malignancy, Crohn’s, among others), tissue irritation by the flow of intestinal content, and the resulting infection.[rx] Other histopathological findings like chronic inflammation from radiation or Crohn’s, malignancy, and or injury-related necrotic process can be identified depending on the cause of the fistula. Identifying the fistula histopathology is usually a late stage after surgical treatment and excision of the fistula and related tissue. Occasionally intra-operative diagnosis is made by biopsying incidentally identified fistulae. The frozen section is used to determine the cause of the fistula and plan the surgical treatment. Malignant fistulous tissue is treated surgically differently (usually with radical excision) than non-malignant tissue.

Postsurgical intestinal fistulae are acute with a significant, infectious, inflammatory component that may infrequently lead to sepsis. Sudden deterioration of multiple organs can be the presenting clinical picture on some of these occasions. This is the most detrimental pathological component in patients’ survival in these complications.

History and Physical

History and physical exam details in the intestinal fistula will reveal signs and symptoms of the underlying disease and complication.

Depending on the underlying disease, a variety of signs and symptoms of abdominal pain, diarrhea, fever, gastrointestinal (GI) bleed, weakness, cachexia, poor appetite, and weight loss can be variably encountered. Specific symptoms related to the organ involved in the fistula may be identified. Examples of these symptoms are recurrent UTIs, pneumaturia or fecaluria in an entero-vesical fistula.[rx] Vaginal pain, discharge, and recurrent infections are seen in recto- or colo-vaginal fistula.[rx] Skin pain, irritation, and excoriation are also seen in entero- or colo-cutaneous fistula.

In the acute phase of postsurgical intestinal fistula and leak, symptoms are more severe and can be life-threatening. Sudden onset deterioration of vital signs, abdominal pain, and tenderness are common clinical findings. Depending on the type and complexity of the underlying disease and the surgical procedure fistula can be further investigated by reviewing operative notes details if the operating surgeon is not available.

Lab Test and Imaging

Evaluation of the intestinal fistula should be performed according to the acuity and complexity of the fistula. Chronic or subacute fistulae like colo-vesical, recto-vaginal, or entero-enteric fistulae can be evaluated in an outpatient sequential setting. The aim of the evaluation would be to:

Confirm the diagnosis
Characterize further the site, size, and complexity of the fistula
Identify the underlying pathology if it is unknown
Plan for management
Re-evaluate and follow up progression

A severe or acute intestinal fistula, as in a postsurgical complication, should be evaluated promptly when suspected to verify the suspicion and assess the extent of the complication.

Evaluation Modalities

In addition to the clinical evaluation that includes a comprehensive history review and appropriate physical exam, the following modalities are available:

Imaging

Imaging with GI contrast that traverses through the fistula from the intestinal lumen to the other end of the fistula confirms the presence and extent of the fistula. On occasions, the contrast is not seen in the fistula itself but is seen in the end organ (bladder, vagina, extra-abdominally)[rx][rx]. Small bowel follow-through imaging or contrast enema can provide this confirmation.

CT is often done first, especially with an acute intestinal fistula, for the high accuracy and details it provides about the fistulous organs and the entire abdominopelvic cavities. CT provides details essential for planning for surgical treatment. MRI may be needed in subtle or difficult to diagnose fistulae. It has the advantage of better soft tissue characterization. It is also useful in complex fistulas like in complicated Crohn’s disease.[rx]

Endoscopy

Colposcopy, cystoscopy, gastroduodenostomy, or colonoscopy are used to identify the site of the fistula at the mucosa of the scoped organ. A small area of inflamed, red, and possibly elevated mucosa is a sign of a possible fistulous tract. Unless the fistula is very wide, it is usually difficult to visualize its lumen endoscopically. Endoscopy can provide further information about the underlying disease like malignancy or Crohn’s. Fistulas might be an incidental finding of endoscopy performed for other reasons. In this situation, further investigations are required.

Treatment of Intestinal Fistula

Treatment of enterovesical fistula includes treatment of the fistula itself and the underlying disease.[rx] Therefore, confirming the fistula etiology should be done before planning treatment. Good clinical practice is to treat with the least aggressive and highly successful treatment modality. The treatment approach depends on many factors like condition severity, acuity, type of fistula, patient’s general condition, underlying etiology, and complications resulting from the fistula.[rx][rx][rx][rx]

Conservative or Non-Operative Approach

Medical treatment of the symptoms and possible complications like UTI, skin excoriation, dehydration, and site infection is often needed. This approach alone can be considered in high-risk patients and with severe, underlying diseases. The associated complication rate from this approach is found to be low in recent studies.[rx][rx]

Medical treatment includes treating UTI and the associated symptoms, maximizing medical treatment of the underlying disease like Crohn’s or diverticulitis, and support of the general patient’s condition.

Other conservative treatment includes non-operative measures to close the fistula like fibrin glue or other occlusive measures. The success rate of these measures is not high. They are still an option to consider in high-risk patients.

Operative Approach

The basic principle of the surgical approach is to excise the involved segment of the bowel and the fistula. After the diagnosis of the fistula and the underlying disease is confirmed and characterized, surgical treatment can be planned accordingly.[rx] Limited conservative excision of the involved intestinal segment and the fistula is recommended in operative cases of diverticular disease, Crohn’s, and other reversible inflammatory diseases. More radical excision is recommended in an operable malignancy. Oncologic excision of the intestine with partial cystectomy that includes the fistula site to a free margin is necessary.

Some fistulae, for example, enterovesical fistula, may sometimes be identified intraoperatively while operating on the underlying disease. Dense adhesions of the intestine on the bladder are the trigger to suspect the fistula. Unless it is cancer surgery, the operative approach is usually the same. If the pathology cannot be confirmed, a frozen section of the fistula tissue is needed to role out malignancy.

Operative treatment of the entero-cutaneous fistula might be different. The focus is on the intestinal part where the leak started. When the conservative treatment fails, and after medical optimization of the patient, surgical treatment is planned to excise the diseased intestinal segment with primary anastomosis when possible. The fistulous tract is debrided and drained as part of the intra-abdominal adhesiolysis and debridement. Debriding all unhealthy tissue and closing with viable, healthy tissue edges is essential for successful healing and fistula closure.

References

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Abdominal Examination – Indications, Contraindication

An abdominal examination can give diagnostic clues regarding most gastrointestinal and genitourinary pathologies and may also give insight regarding abnormalities of other organ systems. A well-performed abdominal examination decreases the need for detailed radiological investigations also plays an important role in patient management.

Function

The abdominal examination is performed with the patient lying supine. The examiner should begin by giving his or her formal introduction and then approach the patient and perform the examination from the right side of the patient. The initial steps are described as follows:

Wash hands thoroughly with soap and water. An alcohol-based sanitizer can also be used. It is essential for the examiner to ensure that his or her hands are dry and warm before starting the examination.
Identify the patient.
Briefly explain the reason for and the steps of the examination and take consent from the patient.
Inquire if the patient has any pain.
Position the patient. The patient is initially positioned at 45 degrees for comfort but a supine position is necessary for palpation of the abdomen. Keeping a pillow under the patient’s head or knees can be considered.
The ideal exposure is from the nipples to the knees, but this is sometimes not practically possible. During most clinical examinations, the exposure is from the nipples to the lower abdomen.

General Inspection:

Begin with the general inspection of the patient and then proceed to the abdominal area. This should be performed at the foot end of the bed. The general inspection can give multiple clues regarding the diagnosis of the patient, for example, yellowish discoloration of the skin (jaundice) indicates a possible hepatic abnormality. It is important to note any medical equipment for monitoring and/or treatment attached to the patient or present in the bed space. These may include catheters, pulse oximeter, oxygen mask and tubing, nasogastric tube, central lines, and total parenteral nutrition lines.

Examination of the hands and arms:

The hands should be examined for the presence of pallor and jaundice. The outstretched hands are observed for the presence of tremors. A flapping tremor (asterixis) indicates hepatic encephalopathy and may be present in cirrhosis.[rx][rx] A non-specific tremor may also indicate alcohol withdrawal. The radial pulse should be examined and the blood pressure should be recorded. The hands and arms should be examined for evidence of intravenous drug use which may be present as injection site marks. The presence of an arteriovenous fistula indicates renal replacement therapy and should be inspected and palpated.

Examination of the face and neck:

The examination should begin by asking the patient to look straight ahead. The eyes should be examined for scleral icterus and conjunctival pallor. Additional findings may be present, for example, a Kayser-Fleischer ring, a brownish-green ring at the periphery of the cornea may be seen in patients of Wilson’s disease due to excess copper being deposited at the Descemet’s membrane.[rx] The ring can be best viewed under a slit-lamp. Peri-orbital plaques due to lipid deposition called xanthelasmas may be present in chronic cholestasis. Angular cheilitis, inflammatory lesions around the corner of the mouth indicate iron or vitamin deficiency which may be due to malabsorption.[rx] The oral cavity should be examined in detail. The presence of oral ulcers may indicate Crohn’s disease or celiac disease.[rx] A pale, smooth, and shiny tongue indicates iron deficiency and a beefy, red tongue is seen in vitamin B-12 and folate deficiency. The smell of the patient’s breath is itself indicative of different disorders, for example, fetor hepaticus, a distinctive smell indicating liver disorder or a fruity breath, pointing towards ketonemia.

The examiner should stand behind the patient to examine the neck. It is important to palpate for lymphadenopathy in the neck and the supraclavicular region. The presence of the Virchow’s node may indicate the possibility of gastric or breast cancer.[rx]

The abdominal examination itself consists of four basic components that include inspection, palpation, percussion, and auscultation.

Four Examination Components

Inspection of the abdomen:

It is important to begin with the general examination of the abdomen with the patient in a completely supine position. The presence of any of the following signs may indicate specific disorders. Distension of the abdomen could be present due to small bowel obstruction, masses, tumors, cancer, hepatomegaly, splenomegaly, constipation, abdominal aortic aneurysm, and pregnancy. The presence of any abnormal masses may indicate umbilical hernia, ventral wall hernia, femoral hernia, or inguinal hernia, depending on the location. The patient may be asked to cough, which results in raised intraabdominal pressure, causing the hernia to become more prominent.

A patch of ecchymosis may be visible on any part of the abdomen on inspection and usually indicates internal hemorrhage. The ‘Grey Turner sign’, the ecchymosis of the flank and groin seen in hemorrhagic pancreatitis and the ‘Cullen’s sign’, that is a periumbilical ecchymosis from retroperitoneal hemorrhage or intra-abdominal hemorrhage. The presence of scars may be due to surgical or traumatic injuries (gunshot wounds or stab wounds) and pink-purple striae may indicate Cushing’s syndrome. Vein dilation may be present that indicates portal hypertension or vena cava obstruction. ‘Caput Medusa’ that are distended veins flowing away from the umbilicus,[rx] have a 90% specificity in detecting hepatic cirrhosis. Sinuses and fistulae, if present, usually occur as a result of a deep infection or an infection of a surgical tract. If a stoma is identified, various features should be noted to identify the type of stoma. These include the site and appearance of the stoma and the contents of the stoma bag.

Palpation of the abdomen:

Ensure the following before beginning the palpation:

The patient is in a supine position, with the head relaxed and the arms on the side of the body. This is necessary to completely relax the abdominal wall muscles.
The patient has mentioned if he is experiencing any pain in the abdominal area and has located the point of maximal pain.

The ideal position for abdominal examination is to sit or kneel on the right side of the patient with the hand and forearm in the same horizontal plane as the patient’s abdomen. There are three stages of palpation that include the superficial or light palpation, deep palpation, and organ palpation and should be performed in the same order. Maneuvers specific to certain diseases are also a part of abdominal palpation.

The examiner should begin with superficial or light palpation from the area furthest from the point of maximal pain and move systematically through the nine regions of the abdomen. If no pain is present, any starting point can be chosen. Several sources mention that the abdomen should first gently be examined with the fingertips. Crepitus, a crunching sensation, if present, indicates the presence of air in the subcutaneous tissue.[rx] Any irregularity in the abdominal wall may also be noted which may be due to a hernia or a lipoma.

Deep palpation should be performed in the same position of the hand and forearm relative to the patient’s abdomen but with the application of firm and steady pressure. It is important to press slowly as pressing too fast may trap a gas pocket within the intestinal lumen and distend the wall resulting in false-positive tenderness. During palpation, tenderness should be noted which may present as guarding. This may be a voluntary process, in which the patient voluntarily tightens the abdominal muscles to protect a deeper inflamed structure, or an involuntary process, where the intra-abdominal pathology has progressed to cause rigidity of the abdominal muscles. Engaging the patient in conversation may help differentiate between voluntary and involuntary guarding, as the former disappears when the attention of the patient is diverted. Tenderness in any of the nine regions of the abdomen may indicate an inflammation of the organs underneath.

Examination of the different areas of the abdomen may indicate separate disease processes. Tenderness of the epigastrium may be due to gastritis or early acute cholecystitis from visceral nerve irritation. Other signs that may be appreciated include the presence of a pulsatile mass from an abdominal aortic aneurysm or abdominal wall defects, seen in muscle diastasis. Left lower quadrant tenderness may be a presenting sign of diverticulitis in the elderly. A mass, if present may be due to a tumor of the colon, a left ovarian cyst, or ectopic pregnancy. In the elderly, constipation leading to impacted feces may also present with a mass palpated in the left lower quadrant.

In the right lower quadrant, tenderness over McBurney’s point implies possible appendicitis, inflammation of the ileocolic area that may be due to Crohn’s disease or an infection with bacteria that have a predilection for the ileocecal area such as Bacillus cereus and Yersinia enterocolitica.

If tenderness is appreciated at the McBurney’s point, the following maneuvers to identify possible appendicitis should be performed:

Rovsing’s sign: While standing on the patient’s right side, gradually perform deep palpation of the left lower quadrant. Increased pain on the right suggests right-sided peritoneal irritation.[rx]
Psoas sign: Place your hand just above the patient’s right knee and ask the patient to push up against your hand. This results in contraction of the psoas muscle which causes pain if there is an underlying inflamed appendix.[rx]
Obturator sign: This is performed by flexing the patient’s right thigh at the hip with the knee flexed and rotating internally. Increased pain at the right lower quadrant suggests inflammation of the internal obturator muscle from overlying appendicitis or an abscess.

The examiner should palpate the periumbilical area for any defect, mass, or an umbilical hernia. The patient can be asked to cough or bear down to feel for any protruding mass. The inguinal and the suprapubic area should not be missed. If an inguinal or a femoral hernia is present, a detailed examination should be done. A mass palpated in the suprapubic area may be due to a uterine pathology such as uterine fibroids or uterine cancer in females or bladder mass or distension in both males and females.

The next step is to proceed to palpation of the abdominal organs. To palpate the liver, the examiner must place the palpating hand below the right lower rib margin and have the patient exhale and then inhale. With mild pressure, the liver margin may be felt under the hand as a gentle wave. It is important to feel for any nodularity or tenderness. For palpation of the gallbladder, it is recommended that the examiner gently place the palpating hand below the right lower rib margin at the midclavicular line and ask the patient to exhale as much as possible. As the patient exhales, the palpating hand should slowly be pushed in deeper and the patient should then be asked to inhale. The sudden cessation of inspiration due to pain characterizes a positive ‘Murphy sign’ seen in acute cholecystitis.[rx] To start palpation of the spleen, the hand should be placed in the right lower quadrant and moved toward the splenic flexure. When the hand reaches the left lower rib margin and the patient should be asked to exhale and then take a deep breath in. With mild pressure, the spleen may be felt under the hand as a firm mass if splenomegaly is present. There are multiple causes of splenomegaly and must be correlated with the patient’s history and other physical findings.[rx]

A two-handed technique with the patient in the supine position is used to palpate the kidneys. To palpate the right kidney, place the left hand underneath the patient’s back pushing the kidney forward and the right hand below the right lower rib margin between the mid-clavicular line and the anterior axillary line, gently pushing down. This technique is called ‘balloting’. To palpate the left kidney, the examiner should lean onto the pateint with the left hand placed around the flank into the patient’s loin and place the right hand on the abdomen below the left lower rib margin between the mid-clavicular line and the anterior axillary line. Enlarged or cystic kidneys may be appreciated using this technique.

To estimate the size of the aorta, the patient should be asked to lie down supine and completely relax the muscles of the abdominal wall. A two-handed technique is preferred, with the left and right hands placed along the lower borders of the left and right costal margins, respectively, and the fingers pointing toward the umbilicus. A generous amount of skin should be left between the two index fingers. The aorta can be palpated as a pulsatile mass, and its width can be recorded. A width greater than 2.5 cm indicates an aneurysm and an abdominal ultrasound should be performed to further investigate it. However, an enlarged aneurysm may still not be appreciated by palpation due to body habitus.

Percussion of the abdomen:

A proper technique of percussion is necessary to gain maximum information regarding the abdominal pathology. While percussing, it is important to appreciate tympany over air-filled structures such as the stomach and dullness to percussion which may be present due to an underlying mass or organomegaly (for example, hepatomegaly or splenomegaly). To appreciate splenic enlargement, the percussion of the Castell’s point (the most inferior interspace on the left anterior axillary line) as the patient takes a deep inspiration, may be helpful. A percussion note that changes from tympanitic to dull as the patient takes a deep breath suggests splenomegaly, with an 82% sensitivity and an 83% specificity. Splenomegaly occurs in trauma with hematoma formation, portal hypertension, hematologic malignancies, infection such as HIV and Ebstein-Barr virus, and splenic infarct.[rx]

Percussion is necessary to assess the size of the liver, percussion downward from the lung to the liver and then the bowel, the examiner may be able to demonstrate the change in percussion note from resonant to dull and then tympanitic. Shifting dullness, present in ascites, should be demonstrated by percussing from the midline to the flank till the note changes from dull to resonant and then having the patient roll over on their side towards the examiner and wait for ten seconds. This allows any fluid, if present, to move downwards. The percussion should then be repeated, moving in the same direction. If the percussion note changes to resonant, shifting dullness is positive.[x][rx] With the patient sitting up, the right and left costal-vertebral angles can be percussed to determine if there is any renal tenderness as in pyelonephritis.

Auscultation of the abdomen:

The last step of the abdominal examination is auscultation with a stethoscope. The diaphragm of the stethoscope should be placed on the right side of the umbilicus to listen to the bowel sounds, and their rate should be calculated after listening for at least two minutes. Normal bowel sounds are low-pitched and gurgling, and the rate is normally 2-5/min. Absent bowel sounds may indicate paralytic ileus and hyperactive rushes (borborygmi) are usually present in small bowel obstruction and sometimes may be auscultated in lactose intolerance.[rx]

The diaphragm should be placed above the umbilicus to listen for an aortic bruit and then moved 2 cm above and lateral to the umbilicus to listen for a renal bruit. The presence of the former indicates an abdominal aortic aneurysm and the latter indicates renal artery atherosclerosis.[rx] These clinical findings must be correlated with the remaining physical examination and history to formulate a preliminary diagnosis. If there is a clinical suspicion of delayed gastric emptying, a maneuver, that is sometimes uncomfortable for the patient, may be performed. The examiner should place the stethoscope on the abdomen and hold the patient at the hips and shake him from side to side. If splashing sounds, called the ‘succussion splash’ are audible, the test is positive.[rx]

Digital rectal examination:

The abdominal examination ends with the digital rectal examination. After explaining the procedure, taking the patient’s consent, and maintaining the patient’s privacy, the rectal examination should be performed with the proper technique. The examiner should place his or her lubricated, gloved finger against the patient’s rectal sphincter muscle to dilate the sphincter and slowly slide it into the rectum palpating for hemorrhoids, fissures, or foreign bodies. The prostate for size and firmness should be assessed. Tenderness or bogginess suggests prostatitis and nodules may suggest cancer. After the finger is removed it should be inspected for signs of active bleeding or melena. Perform a Guaiac test if bleeding is suspected. Examination of the external genitalia should also be performed.

Issues of Concern

The examination of the abdomen is an essential component of all comprehensive examinations of all patients of all ages. It is performed in routine or scheduled examinations, in patients with focused or generalized trauma, in patients with non-specific complaints or specific abdominal or gastrointestinal complaints. The examination may be detailed or rapid, depending on the situation or condition necessitating the examination. However, the role of abdominal examination in the developed world has largely been replaced by imaging techniques in the past two and a half decades. A review article found that the number of CT scans performed in children visiting the emergency departments increased five-fold from 1996 to 2008.[rx] The increased reliance on radiological investigations poses multiple issues. The patient’s diagnosis, management, and eventual outcome is highly dependant on multiple technicalities such as the quality of the machine, the ability of the technician working the machine, patient artifact, and the physician’s experience in reading the investigation. An error in any of these steps may lead to under or over-diagnosis, both of which are detrimental to the patient.

An abdominal examination is helpful for the diagnosis of multiple pediatric diseases or conditions. Performing an abdominal examination in children, however, is challenging. This is partly due to difficulty in understanding the procedure and lower pain tolerance in children. Some sources mention that classic findings, such as right lower quadrant tenderness in appendicitis, may not be appreciated during pediatric abdominal examinations.[rx] Various sources and experts have still concluded that abdominal examination is still a valuable tool in the diagnosis of multiple conditions in both children and adults.

References

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Achalasia – Causes, Symptoms, Diagnosis, Treatment

Cardiospasm/Achalasia is a rare neurodegenerative motor smooth muscle motility disorder of the esophagus resulting in deranged oesophageal peristalsis and loss of lower oesophageal sphincter function that makes it difficult for food and liquid to pass into your stomach. Achalasia occurs when nerves in the tube connecting your mouth and stomach (esophagus) become damaged. As a result, the esophagus loses the ability to squeeze food down, and the muscular valve between the esophagus and stomach (lower esophageal sphincter) doesn’t fully relax — making it difficult for food to pass into your stomach.

Achalasia is a rare disorder that makes it difficult for food and liquid to pass from the swallowing tube connecting your mouth and stomach (esophagus) into your stomach.

Synonyms of Achalasia

Cardiospasm
Dyssynergia esophagus
Esophageal peristalsis
Megaesophagus
Esophageal achalasia;
Swallowing problems for liquids and solids;
lower esophageal sphincter spasm

Types of Achalasia

Achalasia Type 1 (Classic Achalasia)
- No contractility or peristalsis
- The lower esophageal sphincter fails to relax (all Achalasia types)
- Responds to Laparoscopic Heller Myotomy
Achalasia Type 2 (with esophageal compression)
- No normal peristalsis (but some pressurizations)
- The lower esophageal sphincter fails to relax (all Achalasia types)
- Responds to all treatment options
Achalasia Type 3 (Spastic Achalasia)
- No normal peristalsis
- Spastic contractions in distal esophagus (>20% of swallows)
- The lower esophageal sphincter fails to relax (all Achalasia types)
- Responds poorly to treatment

Causes of Achalasia

Dysphagia could be during the oropharyngeal or pharyngeal phases of swallowing.

A. Oropharyngeal dysphagia

It is a delay in the transit of liquid or solid bolus during the oropharyngeal phase of swallowing. It could be due to three main subgroups – (1) neurological, (2) muscular, or (3) anatomical.[rx]

Neurological causes include cerebrovascular accidents (post-stroke dysphagia), brainstem infarctions with cranial nerve involvement. Other causes include basal ganglia lesions as in Parkinson’s disease. Also, head and neck injuries and surgery, multiple sclerosis, central nervous tumor, botulism, amyotrophic lateral sclerosis, supranuclear palsy, and degenerative cervical spine disease.
Muscular causes include polymyositis, muscular dystrophy, and myasthenia gravis (a lesion at the neuromuscular junction).
Anatomical causes include Zenker diverticulum, enlarged thyroid, esophageal web, tumors, abscess, external compression by an aortic aneurysm (known as dysphagia aortic).[rx] Also, cervical discectomy and fusion may be associated with postoperative dysphagia.[rx][rx]

B. Esophageal dysphagia- could be due to mechanical obstruction, or motility disorders.

Mechanical obstruction causes include Schatzki ring, esophageal stricture, esophageal carcinoma, eosinophilic esophagitis.[rx]
Motility disorder causes include esophageal spasm, achalasia, ineffective esophageal motility, and scleroderma.

Mechanical obstruction is associated with dysphagia only to solid food, while the motility disorder causes are usually associated with solid and liquid dysphagia. The dysphagia may be intermittent (e.g., Schatzki ring, esophageal spasm) or permanent (as in esophageal stricture, carcinoma, achalasia, scleroderma, ineffective esophageal motility).[rx]

C. Rheumatological disorders

Sjogren syndrome (occurs in one-third of patients and caused by both xerostomia and abnormal esophageal motility, mainly of the proximal esophagus.
Systemic lupus erythematosus
Mixed connective tissue disease
Rheumatoid arthritis.
Systemic sclerosis (as part of the CREST syndrome)

D. Medications

Several drugs may contribute to the severity of dysphagia. The mechanisms by which these drugs may cause dysphagia include xerostomia and changes in esophageal motility. Also, the dysphagia may be secondary to the development of drug-induced esophagitis or the development of gastroesophageal reflux disease. Examples of these drugs are:

Antipsychotic (e.g., olanzapine, clozapine)
Tricyclic antidepressant
Potassium supplements
NSAIDs
Bisphosphonates
Calcium channel blockers
Nitrates
Theophylline
Alcohol
Medications with immunosuppressant effects (e.g., cyclosporin) can predispose to infective esophagitis and dysphagia
Opioids[rx]

It is important to note here that narcotic sedatives such as opioids can lead to compromise of airway due to central effects and could increase the risk of aspiration in patients with dysphagia. The use of opiates, even in low disease, in patients with psychiatric disorders or Parkinson’s disease, can develop hypercontractile or hypertensive esophageal consequences mimicking type III achalasia.

Others

Diffuse esophageal spasm.
Esophageal cancer.
Eosinophilic esophagitis[rx]
Hiatal hernia.
Parkinson disease.
Zenker diverticulum.
Multiple sclerosis.
Paterson-Kelly syndrome.
Dysphagia lusoria is a type of dysphagia that develops in childhood, due to compression of the esophagus by vascular abnormality. Usually, there is an aberrant right subclavian artery arising from the left side of the aortic arch, or a double aortic arch, or other rare anomalies.
Benign strictures.
Esophageal webs and rings
Esophageal reflux[rx]

Symptoms of Achalasia

Achalasia symptoms generally appear gradually and worsen over time. Signs and symptoms may include:

Inability to swallow (dysphagia), which may feel like food or drink is stuck in your throat
Regurgitating food or saliva
Heartburn
Belching
Chest pain that comes and goes
Coughing at night
Pneumonia (from aspiration of food into the lungs)
Weight loss
Vomiting
Trouble swallowing (dysphagia). This is the most common early symptom.
Regurgitation of undigested food.
Chest pain that comes and goes; pain can be severe.
Cough at night
Weight loss/malnutrition from difficulty eating. This is a late symptom.
Hiccups, difficulty belching (less common symptoms)

Diagnosis of Achalasia

Achalasia can be overlooked or misdiagnosed because it has symptoms similar to other digestive disorders. To test for achalasia, your doctor is likely to recommend:

Endoscopy – Approximately 2% to 4% of patients with suspected achalasia have pseudoachalasia from infiltrating malignancy or stricture.^[rx] Potential risk factors for malignancy-associated pseudoachalasia include older age at the time of diagnosis, shorter duration of symptoms, and more weight loss (12 vs 5 kg) on presentation.^[rx] Patients with 2 or more of these risk factors on presentation should undergo a careful investigation to rule out malignancy.^[rx^,^rx]
Barium esophagram – A barium esophagram is a noninvasive radiologic study that can assist with initial diagnosis or response to treatment with graded PD. A barium swallow evaluates the morphology of the esophagus and classically shows a dilated or tortuous esophagus with a narrowed LES and “bird’s beak” appearance.
Manometry – HRM is the gold standard test for the diagnosis of achalasia. Conventional manometry tracings in patients with achalasia show the absence of esophageal peristalsis and incomplete LES relaxation with residual pressures of over 10 mm Hg. HRM with esophageal pressure topography is more sensitive and specific than conventional manometry and is able to classify achalasia into 3 distinct subtypes, which can have treatment implications.^[rx] Type II achalasia has the best response to treatment, followed by type I achalasia, whereas type III achalasia is the most difficult to treat.^[rx^,^rx]
Esophageal manometry. This test measures the rhythmic muscle contractions in your esophagus when you swallow, the coordination and force exerted by the esophagus muscles, and how well your lower esophageal sphincter relaxes or opens during a swallow. This test is the most helpful when determining which type of motility problem you might have.
X-rays of your upper digestive system (esophagram). X-rays are taken after you drink a chalky liquid that coats and fills the inside lining of your digestive tract. The coating allows your doctor to see a silhouette of your esophagus, stomach, and upper intestine. You may also be asked to swallow a barium pill that can help to show a blockage of the esophagus.
Upper endoscopy. Your doctor inserts a thin, flexible tube equipped with a light and camera (endoscope) down your throat, to examine the inside of your esophagus and stomach. Endoscopy can be used to define a partial blockage of the esophagus if your symptoms or results of a barium study indicate that possibility. Endoscopy can also be used to collect a sample of tissue (biopsy) to be tested for complications of reflux such as Barrett’s esophagus.

Treatment of Achalasia

Achalasia treatment focuses on relaxing or stretching open the lower esophageal sphincter so that food and liquid can move more easily through your digestive tract.

Specific treatment depends on your age, health condition and the severity of the achalasia.

Nonsurgical treatment

Nonsurgical options include:

The management plan. may include (i) elimination of certain food consistencies from the diet. (ii) adjustment of meal bolus seizes and (iii) use of techniques such as chin-tuck, head-turn, and supraglottic maneuvers to help in minimizing/preventing aspiration. Also, strengthening and coordinating muscles involved in swallowing. Gastroscopy tubes may be indicated in patients who fail to respond to the above-stated measures.[rx]
Pneumatic dilation. A balloon is inserted by endoscopy into the center of the esophageal sphincter and inflated to enlarge the opening. This outpatient procedure may need to be repeated if the esophageal sphincter doesn’t stay open. Nearly one-third of people treated with balloon dilation need repeat treatment within five years. This procedure requires sedation.
Botox (botulinum toxin type A). This muscle relaxant can be injected directly into the esophageal sphincter with an endoscopic needle. The injections may need to be repeated, and repeat injections may make it more difficult to perform surgery later if needed. Botox is generally recommended only for people who aren’t good candidates for pneumatic dilation or surgery due to age or overall health. Botox injections typically do not last more than six months. A strong improvement from the injection of Botox may help confirm a diagnosis of achalasia.
BT injection. for achalasia is an effective short-term therapy. BT injection into the LES locally inhibits the release of acetylcholine, causing relaxation of the smooth muscle, which allows for easier passage of food bolus into the gastric body.
Balloon dilation. In this non-surgical procedure, you’ll be put under light sedation while a specifically designed balloon is inserted through the LES and then inflated. The procedure relaxes the muscle sphincter, which allows food to enter your stomach. Balloon dilation is usually the first treatment option in people in whom surgery fails. You may have to undergo several dilation treatments to relieve your symptoms, and every few years to maintain relief.
Stretching the esophagus (pneumatic dilation). The doctor inserts a balloon in the valve between the esophagus and stomach and blows it up to stretch the tight muscles. You might need this procedure several times before it helps.

Medication.

Muscle relaxants – such as nitroglycerin (Nitrostat) or nifedipine (Procardia) before eating. These medications have limited treatment effects and severe side effects. Medications are generally considered only if you’re not a candidate for pneumatic dilation or surgery, and Botox hasn’t helped. This type of therapy is rarely indicated.
Sublingual nifedipine – significantly improves outcomes in 75% of people with mild or moderate disease. It was classically considered that surgical myotomy provided greater benefit than either botulinum toxin or dilation in those who fail medical management.^[rx] However, a recent randomized controlled trial found pneumatic dilation to be non-inferior to laparoscopic Heller myotomy.^[rx]
Pharmacotherapy-nitrates, calcium-channel blockers – (e.g., nifedipine 10 to 20 mg sublingual 15 to 30 minutes before meals). It acts by lowering the lower esophageal sphincter resting pressure. Nitrates, calcium channel blockers, and phosphodiesterase-5 inhibitors to reduce the lower esophageal sphincter (LES) pressure.
Calcium channel blockers – inhibit the entry of calcium into the cells blocking smooth muscle contraction, leading to a decrease in LES pressure. Hypotension, pedal edema, headache, the rapid development of tolerance, and incomplete symptom improvement are limiting factors to its use. Nitrates increase nitric oxide concentrations in smooth muscles, causing an increase in cyclic adenosine monophosphate levels, which leads to smooth muscle relaxation. These treatments are less effective, provide only short-term relief of symptoms, and are primarily reserved for patients who are waiting for or who refused more definitive therapy, such as pneumatic dilatation or surgery.[rx][rx]
Scopolamine – also known as hyoscine Devil’s Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion and sickness, achalasia, and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva.^[rx] When used by injection, effects begin after about 20 minutes and last for up to 8 hours.^[rx] It may also be used orally and as a transdermal patch.^[rx]

Surgery

Surgical options for treating achalasia include:

Peroral endoscopic myotomy (POEM) – is an effective minimally invasive alternative to laparoscopic Heller myotomy to treat achalasia at limited centers.[rx] Dissection of the circular fibers of the LES is achieved endoscopically, leading to relaxation of the LES; however, the risk of gastroesophageal reflux is high because it does not include an antireflux procedure. Esophagectomy is the last resort.
Heller myotomy. The surgeon cuts the muscle at the lower end of the esophageal sphincter to allow food to pass more easily into the stomach. The procedure can be done noninvasively (laparoscopic Heller myotomy). Some people who have a Heller myotomy may later develop gastroesophageal reflux disease (GERD). To avoid future problems with GERD, a procedure known as fundoplication might be performed at the same time as a Heller myotomy. In fundoplication, the surgeon wraps the top of your stomach around the lower esophagus to create an anti-reflux valve, preventing acid from coming back (GERD) into the esophagus. Fundoplication is usually done with a minimally invasive (laparoscopic) procedure.
Peroral endoscopic myotomy (POEM). In the POEM procedure, the surgeon uses an endoscope inserted through your mouth and down your throat to create an incision in the inside lining of your esophagus. Then, as in a Heller myotomy, the surgeon cuts the muscle at the lower end of the esophageal sphincter. POEM may also be combined with or followed by later fundoplication to help prevent GERD. Some patients who have a POEM and develop GERD after the procedure are treated with daily oral medication.

References

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Esophageal Peristalsis – Causes, Symptoms, Treatment

Esophageal Peristalsis/Achalasia is a rare neurodegenerative motor smooth muscle motility disorder of the esophagus resulting in deranged oesophageal peristalsis and loss of lower oesophageal sphincter function that makes it difficult for food and liquid to pass into your stomach. Achalasia occurs when nerves in the tube connecting your mouth and stomach (esophagus) become damaged. As a result, the esophagus loses the ability to squeeze food down, and the muscular valve between the esophagus and stomach (lower esophageal sphincter) doesn’t fully relax — making it difficult for food to pass into your stomach.

Achalasia is a rare disorder that makes it difficult for food and liquid to pass from the swallowing tube connecting your mouth and stomach (esophagus) into your stomach.

Synonyms of Achalasia

Cardiospasm
Dyssynergia esophagus
Esophageal peristalsis
Megaesophagus
Esophageal achalasia;
Swallowing problems for liquids and solids;
lower esophageal sphincter spasm

Types of Achalasia

Achalasia Type 1 (Classic Achalasia)

No contractility or peristalsis
The lower esophageal sphincter fails to relax (all Achalasia types)
Responds to Laparoscopic Heller Myotomy

Achalasia Type 2 (with esophageal compression)

No normal peristalsis (but some pressurizations)
The lower esophageal sphincter fails to relax (all Achalasia types)
Responds to all treatment options

Achalasia Type 3 (Spastic Achalasia)

No normal peristalsis
Spastic contractions in distal esophagus (>20% of swallows)
The lower esophageal sphincter fails to relax (all Achalasia types)
Responds poorly to treatment

Causes of Achalasia

Dysphagia could be during the oropharyngeal or pharyngeal phases of swallowing.

A. Oropharyngeal dysphagia

It is a delay in the transit of liquid or solid bolus during the oropharyngeal phase of swallowing. It could be due to three main subgroups – (1) neurological, (2) muscular, or (3) anatomical.[rx]

Neurological causes include cerebrovascular accidents (post-stroke dysphagia), brainstem infarctions with cranial nerve involvement. Other causes include basal ganglia lesions as in Parkinson’s disease. Also, head and neck injuries and surgery, multiple sclerosis, central nervous tumor, botulism, amyotrophic lateral sclerosis, supranuclear palsy, and degenerative cervical spine disease.
Muscular causes include polymyositis, muscular dystrophy, and myasthenia gravis (a lesion at the neuromuscular junction).
Anatomical causes include Zenker diverticulum, enlarged thyroid, esophageal web, tumors, abscess, external compression by an aortic aneurysm (known as dysphagia aortic).[rx] Also, cervical discectomy and fusion may be associated with postoperative dysphagia.[rx][rx]

B. Esophageal dysphagia- could be due to mechanical obstruction, or motility disorders.

Mechanical obstruction causes include Schatzki ring, esophageal stricture, esophageal carcinoma, eosinophilic esophagitis.[rx]
Motility disorder causes include esophageal spasm, achalasia, ineffective esophageal motility, and scleroderma.

Mechanical obstruction is associated with dysphagia only to solid food, while the motility disorder causes are usually associated with solid and liquid dysphagia. The dysphagia may be intermittent (e.g., Schatzki ring, esophageal spasm) or permanent (as in esophageal stricture, carcinoma, achalasia, scleroderma, ineffective esophageal motility).[rx]

C. Rheumatological disorders

Sjogren syndrome (occurs in one-third of patients and caused by both xerostomia and abnormal esophageal motility, mainly of the proximal esophagus.
Systemic lupus erythematosus
Mixed connective tissue disease
Rheumatoid arthritis.
Systemic sclerosis (as part of the CREST syndrome)

D. Medications

Several drugs may contribute to the severity of dysphagia. The mechanisms by which these drugs may cause dysphagia include xerostomia and changes in esophageal motility. Also, the dysphagia may be secondary to the development of drug-induced esophagitis or the development of gastroesophageal reflux disease. Examples of these drugs are:

Antipsychotic (e.g., olanzapine, clozapine)
Tricyclic antidepressant
Potassium supplements
NSAIDs
Bisphosphonates
Calcium channel blockers
Nitrates
Theophylline
Alcohol
Medications with immunosuppressant effects (e.g., cyclosporin) can predispose to infective esophagitis and dysphagia
Opioids[7]

It is important to note here that narcotic sedatives such as opioids can lead to compromise of airway due to central effects and could increase the risk of aspiration in patients with dysphagia. The use of opiates, even in low disease, in patients with psychiatric disorders or Parkinson’s disease, can develop hypercontractile or hypertensive esophageal consequences mimicking type III achalasia.

Others

Diffuse esophageal spasm.
Esophageal cancer.
Eosinophilic esophagitis[rx]
Hiatal hernia.
Parkinson disease.
Zenker diverticulum.
Multiple sclerosis.
Paterson-Kelly syndrome.
Dysphagia lusoria is a type of dysphagia that develops in childhood, due to compression of the esophagus by vascular abnormality. Usually, there is an aberrant right subclavian artery arising from the left side of the aortic arch, or a double aortic arch, or other rare anomalies.
Benign strictures.
Esophageal webs and rings
Esophageal reflux[rx]

Symptoms of Achalasia

Achalasia symptoms generally appear gradually and worsen over time. Signs and symptoms may include:

Inability to swallow (dysphagia), which may feel like food or drink is stuck in your throat
Regurgitating food or saliva
Heartburn
Belching
Chest pain that comes and goes
Coughing at night
Pneumonia (from aspiration of food into the lungs)
Weight loss
Vomiting
Trouble swallowing (dysphagia). This is the most common early symptom.
Regurgitation of undigested food.
Chest pain that comes and goes; pain can be severe.
Cough at night
Weight loss/malnutrition from difficulty eating. This is a late symptom.
Hiccups, difficulty belching (less common symptoms)

Diagnosis of Achalasia

Achalasia can be overlooked or misdiagnosed because it has symptoms similar to other digestive disorders. To test for achalasia, your doctor is likely to recommend:

Endoscopy – Approximately 2% to 4% of patients with suspected achalasia have pseudoachalasia from infiltrating malignancy or stricture.^[rx] Potential risk factors for malignancy-associated pseudoachalasia include older age at the time of diagnosis, shorter duration of symptoms, and more weight loss (12 vs 5 kg) on presentation.^[rx] Patients with 2 or more of these risk factors on presentation should undergo a careful investigation to rule out malignancy.
Barium esophagram – A barium esophagram is a noninvasive radiologic study that can assist with initial diagnosis or response to treatment with graded PD. A barium swallow evaluates the morphology of the esophagus and classically shows a dilated or tortuous esophagus with a narrowed LES and “bird’s beak” appearance.
Manometry – HRM is the gold standard test for the diagnosis of achalasia. Conventional manometry tracings in patients with achalasia show the absence of esophageal peristalsis and incomplete LES relaxation with residual pressures of over 10 mm Hg. HRM with esophageal pressure topography is more sensitive and specific than conventional manometry and is able to classify achalasia into 3 distinct subtypes, which can have treatment implications.^[rx] Type II achalasia has the best response to treatment, followed by type I achalasia, whereas type III achalasia is the most difficult to treat.
Esophageal manometry. This test measures the rhythmic muscle contractions in your esophagus when you swallow, the coordination and force exerted by the esophagus muscles, and how well your lower esophageal sphincter relaxes or opens during a swallow. This test is the most helpful when determining which type of motility problem you might have.
X-rays of your upper digestive system (esophagram). X-rays are taken after you drink a chalky liquid that coats and fills the inside lining of your digestive tract. The coating allows your doctor to see a silhouette of your esophagus, stomach, and upper intestine. You may also be asked to swallow a barium pill that can help to show a blockage of the esophagus.
Upper endoscopy. Your doctor inserts a thin, flexible tube equipped with a light and camera (endoscope) down your throat, to examine the inside of your esophagus and stomach. Endoscopy can be used to define a partial blockage of the esophagus if your symptoms or results of a barium study indicate that possibility. Endoscopy can also be used to collect a sample of tissue (biopsy) to be tested for complications of reflux such as Barrett’s esophagus.

Treatment of Achalasia

Achalasia treatment focuses on relaxing or stretching open the lower esophageal sphincter so that food and liquid can move more easily through your digestive tract.

Specific treatment depends on your age, health condition and the severity of the achalasia.

Nonsurgical treatment

Nonsurgical options include:

The management plan. may include (i) elimination of certain food consistencies from the diet. (ii) adjustment of meal bolus seizes and (iii) use of techniques such as chin-tuck, head-turn, and supraglottic maneuvers to help in minimizing/preventing aspiration. Also, strengthening and coordinating muscles involved in swallowing. Gastroscopy tubes may be indicated in patients who fail to respond to the above-stated measures.[rx]
Pneumatic dilation. A balloon is inserted by endoscopy into the center of the esophageal sphincter and inflated to enlarge the opening. This outpatient procedure may need to be repeated if the esophageal sphincter doesn’t stay open. Nearly one-third of people treated with balloon dilation need repeat treatment within five years. This procedure requires sedation.
Botox (botulinum toxin type A). This muscle relaxant can be injected directly into the esophageal sphincter with an endoscopic needle. The injections may need to be repeated, and repeat injections may make it more difficult to perform surgery later if needed. Botox is generally recommended only for people who aren’t good candidates for pneumatic dilation or surgery due to age or overall health. Botox injections typically do not last more than six months. A strong improvement from the injection of Botox may help confirm a diagnosis of achalasia.
BT injection. for achalasia is an effective short-term therapy. BT injection into the LES locally inhibits the release of acetylcholine, causing relaxation of the smooth muscle, which allows for easier passage of food bolus into the gastric body.
Balloon dilation. In this non-surgical procedure, you’ll be put under light sedation while a specifically designed balloon is inserted through the LES and then inflated. The procedure relaxes the muscle sphincter, which allows food to enter your stomach. Balloon dilation is usually the first treatment option in people in whom surgery fails. You may have to undergo several dilation treatments to relieve your symptoms, and every few years to maintain relief.
Stretching the esophagus (pneumatic dilation). The doctor inserts a balloon in the valve between the esophagus and stomach and blows it up to stretch the tight muscles. You might need this procedure several times before it helps.

Medication.

Muscle relaxants – such as nitroglycerin (Nitrostat) or nifedipine (Procardia) before eating. These medications have limited treatment effects and severe side effects. Medications are generally considered only if you’re not a candidate for pneumatic dilation or surgery, and Botox hasn’t helped. This type of therapy is rarely indicated.
Sublingual nifedipine – significantly improves outcomes in 75% of people with mild or moderate disease. It was classically considered that surgical myotomy provided greater benefit than either botulinum toxin or dilation in those who fail medical management.^[rx] However, a recent randomized controlled trial found pneumatic dilation to be non-inferior to laparoscopic Heller myotomy.^[rx]
Pharmacotherapy-nitrates, calcium-channel blockers – (e.g., nifedipine 10 to 20 mg sublingual 15 to 30 minutes before meals). It acts by lowering the lower esophageal sphincter resting pressure. Nitrates, calcium channel blockers, and phosphodiesterase-5 inhibitors to reduce the lower esophageal sphincter (LES) pressure.
Calcium channel blockers – inhibit the entry of calcium into the cells blocking smooth muscle contraction, leading to a decrease in LES pressure. Hypotension, pedal edema, headache, the rapid development of tolerance, and incomplete symptom improvement are limiting factors to its use. Nitrates increase nitric oxide concentrations in smooth muscles, causing an increase in cyclic adenosine monophosphate levels, which leads to smooth muscle relaxation. These treatments are less effective, provide only short-term relief of symptoms, and are primarily reserved for patients who are waiting for or who refused more definitive therapy, such as pneumatic dilatation or surgery.[rx][rx]
Scopolamine – also known as hyoscine Devil’s Breath, is a natural or synthetically produced tropane alkaloid and anticholinergic drug that is formally used as a medication for treating motion and sickness, achalasia, and postoperative nausea and vomiting. It is also sometimes used before surgery to decrease saliva.^[rx] When used by injection, effects begin after about 20 minutes and last for up to 8 hours.^[rx] It may also be used orally and as a transdermal patch.^[rx]

Surgery

Surgical options for treating achalasia include:

Peroral endoscopic myotomy (POEM) – is an effective minimally invasive alternative to laparoscopic Heller myotomy to treat achalasia at limited centers.[rx] Dissection of the circular fibers of the LES is achieved endoscopically, leading to relaxation of the LES; however, the risk of gastroesophageal reflux is high because it does not include an antireflux procedure. Esophagectomy is the last resort.
Heller myotomy. The surgeon cuts the muscle at the lower end of the esophageal sphincter to allow food to pass more easily into the stomach. The procedure can be done noninvasively (laparoscopic Heller myotomy). Some people who have a Heller myotomy may later develop gastroesophageal reflux disease (GERD). To avoid future problems with GERD, a procedure known as fundoplication might be performed at the same time as a Heller myotomy. In fundoplication, the surgeon wraps the top of your stomach around the lower esophagus to create an anti-reflux valve, preventing acid from coming back (GERD) into the esophagus. Fundoplication is usually done with a minimally invasive (laparoscopic) procedure.
Peroral endoscopic myotomy (POEM). In the POEM procedure, the surgeon uses an endoscope inserted through your mouth and down your throat to create an incision in the inside lining of your esophagus. Then, as in a Heller myotomy, the surgeon cuts the muscle at the lower end of the esophageal sphincter. POEM may also be combined with or followed by later fundoplication to help prevent GERD. Some patients who have a POEM and develop GERD after the procedure are treated with daily oral medication.

References

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Autoimmune Hepatitis – Causes, Symptoms, Treatment

Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause that is characterized by a loss of immune tolerance against liver antigens, resulting in progressive destruction of the hepatic parenchyma and histologically by interface hepatitis, serologically by the presence of non-organ specific autoantibodies, biochemically by elevated aminotransferases and serum IgG, and clinically by the response to immunosuppressive treatment in the absence of other known causes of liver disease. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. Chronic hepatitis occurring predominantly in young women with arthralgias, myalgia, hepatosplenomegaly, amenorrhea, skin rashes, fluctuating course, and invariably fatal outcome Autoimmune hepatitis may present concurrently with other autoimmune diseases like Graves disease, rheumatoid arthritis, celiac disease, type I diabetes, ulcerative colitis, hemolytic anemia, and immune thrombocytopenia.

Synonyms of Autoimmune Hepatitis

AIH
autoimmune chronic active hepatitis
lupoid hepatitis

Types of Autoimmune Hepatitis

There are two known types of autoimmune hepatitis.

Type 1 – is distinguished by the presence of anti-smooth muscle antibodies (ASMA) with or without anti-nuclear antibodies (ANA).
Type 2 – autoimmune hepatitis presents with positive anti-liver/anti-kidney microsome (anti-LMK) type 1 antibodies or anti-liver cytosol (anti-LC) type 1 antibodies.

Four subtypes of autoimmune hepatitis are recognized, but the clinical utility of distinguishing subtypes is limited.

Type 1 AIH – Positive ANA and SMA,^[rx] elevated immunoglobulin G (classic form, responds well to low dose steroids);
Type 2 AIH – Positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3;
Type 3 AIH – Positive antibodies against soluble liver antigen^[14] (this group behaves like group 1)^[15] (anti-SLA, anti-LP)
AIH -with no autoantibodies detected – (~20%)(of debatable validity/importance)

Causes of Autoimmune Hepatitis

There is no specific evidence of the cause. Sixty percent of patients have chronic hepatitis but without serologic evidence of a viral infection. The disease is associated with anti-smooth muscle autoantibodies. [rx]

AIH occurs when your immune system mistakes your liver cells for foreign aggressors and creates antibodies to attack them. Doctors don’t know precisely why this occurs. However, certain risk factors have been identified, including:

autoimmunity – the process of your immune system making autoantibodies, which ‘attack’ and damage your body’s own cells and organs
environmental triggers – causes starting outside of the body; for example getting a virus, taking certain medications, or coming into contact with other toxins
genetic predisposition – inheriting genes that may make it easier for a trigger to set off the disease.
a family history of AIH
history of bacterial or viral infections
being female
the use of certain medications, such as minocycline

Other autoimmune conditions can cause symptoms of liver disease and are also associated with the development of AIH. These diseases include:

Grave’s disease
thyroiditis
ulcerative colitis
type I diabetes
rheumatoid arthritis
scleroderma
inflammatory bowel disease (IBD)
systemic lupus erythematosus
Sjögren’s syndrome

Symptoms of Autoimmune Hepatitis

Signs and symptoms in people with autoimmune hepatitis range from mild to severe depending on the amount of liver damage present. Symptoms are generally due to scarring of liver tissue (cirrhosis). Some people have no symptoms at first and are diagnosed after being evaluated for another health problem.^[rx] Some of the most common signs and symptoms in people with autoimmune hepatitis may be nonspecific and include:^[rx]^[rx]^[rx]^[rx]

Most patients have nonspecific symptoms: fatigue, anorexia, nausea, weight loss, jaundice, pruritus, and amenorrhea
Clinical manifestations of autoimmune hepatitis depend on how acute liver disease is at presentation, the stage of inflammation, or the complication of liver cirrhosis.
The most common features of autoimmune hepatitis are fatigue, malaise, jaundice, abdominal pain, and sometimes, arthralgias.
Fatigue (the most common symptom reported).
Nausea.
Loss of appetite.
Diarrhea.
Jaundice (yellowing of the skin and whites of the eyes).
Loss of brain function (hepatic encephalopathy).
Fluid in the abdomen (ascitesb).
Swelling of the legs (edema).
Easy bruising and bleeding.
An enlarged spleen (splenomegaly).
Gallstones.
Itchy skin (pruritis) or skin rashes.
Joint pain.
Vomiting.
Dark urine.
Pale or gray-colored stools.
Absence of menstrual periods in women (amenorrhea).

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
100% of people have these symptoms
Increased circulating IgG level		0003237
80%-99% of people have these symptoms
Anti-liver cytosolic antigen type 1 antibody positivity		0030909
Antineutrophil antibody positivity		0003453
Antinuclear antibody positivity		0003493
Elevated hepatic transaminase	High liver enzymes	0002910
Liver kidney microsome type 1 antibody positivity		0030908
Smooth muscle antibody positivity		0003262
30%-79% of people have these symptoms
Abdominal pain	Pain in stomach [ more ]	0002027
Arthralgia	Joint pain	0002829
Chronic fatigue	Chronic extreme exhaustion	0012432
Depressivity	Depression	0000716
Spider hemangioma		0012522
5%-29% of people have these symptoms
Acute hepatitis	Acute liver inflammation	0200119
Anxiety	Excessive, persistent worry and fear	0000739
Arthritis	Joint inflammation	0001369
Ascites	Accumulation of fluid in the abdomen	0001541
Cirrhosis	Scar tissue replaces healthy tissue in the liver	0001394
Diffuse hepatic steatosis		0006555
Gastrointestinal hemorrhage	Gastrointestinal bleeding	0002239
Glomerulonephritis		0000099
Increased total bilirubin	High bili total	0003573
Jaundice	Yellow skin [ more ]	0000952
Sclerosing cholangitis		0030991
Splenomegaly	Increased spleen size	0001744
Thyroiditis	Thyroid gland inflammation	0100646
Ulcerative colitis		0100279
Vitiligo	Blotchy loss of skin color	0001045
1%-4% of people have these symptoms
Fulminant hepatitis		0004787
Hepatocellular carcinoma		0001402
Viral hepatitis		0006562

Diagnosis of Autoimmune Hepatitis

A multi-pronged approach is used to make a diagnosis. This approach includes determining symptoms, laboratory tests, and biopsies, as no single diagnostic test is pathognomonic for autoimmune hepatitis. Marked elevation of serum transaminases (AST, ALT) and gamma-globulin is common; elevation in alkaline phosphatase is less common. The serum levels of AST, ALT, and gamma globulin reflect disease severity and immediate prognosis at presentation.

Diagnosis is based on combinations of clinical, laboratory, and histological features
Revised diagnostic International Autoimmune Hepatitis Group (IAHG) scoring system (rx):
- Complex system evaluating 11 clinical, laboratory, and histological factors
- For research purposes – not designed for clinical practice
Simplified diagnostic IAHG scoring system (rx):
- Simple system evaluating 4 laboratory and histological factors: serum autoantibodies, IgG, liver histology and viral hepatitis serology
- Cutoff values for probable and definite AIH are 6 points (88% sensitivity and 97% specificity) and 7 points (81% sensitivity and 99% specificity), respectively
AIH subtypes depend on autoantibody serology:
- Type 1: positive for antinuclear antibody (ANA) or anti-smooth muscle antibody (SMA); 10% have other autoimmune disorders
- Type 2: positive for anti-liver-kidney microsomal (LKM) antibody or anti liver cytosol type 1 (LC1) antibody-positive; often presents with acute or fulminant hepatitis; 17% have other autoimmune disorders
About 10% of AIH shows coexisting features of the immune-mediated biliary disease (overlap syndrome) or are associated with atypical features (variant syndrome)
- Overlap syndrome: AIH primary biliary cirrhosis and AIH primary sclerosing cholangitis
- Variant syndromes: seronegative AIH and antimitochondrial antibody (AMA) positive AIH

Laboratory

Serum autoantibodies(rx):
- ANA – positive in 75% of type 1 AIH; not associated with disease course or outcome
- Anti-SMA – positive in 95% of type 1 AIH; not associated with disease course or outcome
- Anti-LKM – diagnostic for type 2 AIH; associated with younger age at presentation, fulminant hepatic failure, and partial IgA deficiency
- Anti-LC1 – diagnostic for type 2 AIH; associated with more severe inflammation and rapid progression to cirrhosis
- Anti soluble liver antigen (SLA) / live pancreas (LP) – positive in 20 – 50% of AIH; associated with more severe disease, treatment dependence, relapse after drug withdrawal, and need for transplantation
Serum immunoglobulin G (IgG) – not only a diagnostic marker but also a marker for monitoring treatment response (rx)
Autoantibodies – A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased immunoglobulin G level. The presence of anti-mitochondrial antibody is more suggestive of primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value.^[rx]
Blood tests – Testing a sample of your blood for antibodies can distinguish autoimmune hepatitis from viral hepatitis and other conditions with similar symptoms. Antibody tests also help pinpoint the type of autoimmune hepatitis you have.
Liver function tests – These check for inflammation or damage to your liver.
Coagulation panel – This test looks at how well the clotting proteins are working.
Electrolyte panel – Checks to see if you have an electrolyte imbalance.
Other liver tests – These are done to check for other possible types of liver disease.
CT scan – This is more detailed than a standard X-ray. It can show detailed images of any part of the body, including the bones, muscles, fat, and organs. It uses both X-rays and computer technology to make horizontal images (often called slices) of the body.
MRI – This test makes detailed pictures of organs and structures inside your body. It uses a magnetic field and pulses of radio wave energy. A dye may be shot or injected into your vein. The dye helps the liver and other organs in the belly to be seen more clearly on the scan.
Ultrasound – This uses high-frequency sound waves to create a picture of the organs. It can also check blood flow in blood vessels.
Liver biopsy – Doctors perform a liver biopsy to confirm the diagnosis and to determine the degree and type of liver damage. During the procedure, a small amount of liver tissue is removed, using a thin needle that’s passed into your liver through a small incision in your skin. The sample is then sent to a laboratory for analysis.
Anti-liver cytosol type I, anti-soluble liver antigen (SLA) antibodies, and perinuclear antineutrophil cytoplasmic antibodies (pANCA) can also be associated with autoimmune hepatitis. [rx]Conversely, anti-mitochondrial antibodies are more commonly seen with primary biliary cirrhosis and are usually absent in autoimmune hepatitis; however, they can be present in those with overlapping syndromes. Atypical perinuclear antineutrophil cytoplasmic antibodies are commonly associated with type-1 autoimmune hepatitis and primary sclerosing cholangitis. Anti-LKM1 is common in type-1 autoimmune hepatitis and mainly observed in children.
Anti-SLA antibodies – are more useful from a prognostic standpoint as these are associated with more severe disease, treatment failure, and higher relapse rates. A liver biopsy is required for both diagnosis and staging of autoimmune hepatitis.

Treatment Of Autoimmune Hepatitis

Treatment (which is based on supportive care) is as follows

Antiviral medications (if virus causes)
Antibiotics, (if bacteria cause)
Steroids are used to reduce brain swelling
Sedatives for restlessness
Acetaminophen for fever
Occupational and physical therapy (if the brain is affected post-infection)

Medications

autoimmune hepatitis is a rare condition with no randomized controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide, and rituximab.^[rx]

Corticosteroids – are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like autoimmune hepatitis. Because most patients respond to corticosteroids or glucocorticoid immunosuppressant treatment, this condition is now also referred to as steroid-responsive autoimmune hepatitis. Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days or prednisone is usually administered orally at 2 mg/kg/day (up to a maximum of 60 mg/day), azathioprine is administered at the initial dose of 1 mg/kg/day, which can be further increased up to 2.5 mg/kg/day until sustained biochemical remission is achieved.[rx]
Budesonide – has been shown to be more effective in inducing remission than prednisone, and result in fewer adverse effects.^[17]
Immunoglobulin infusion(IVIG) – Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune hepatitis[rx] [rx] Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.[rx][rx]
Plasmapheresis – can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual. [rx]
Biological Drugs – Rituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.[rx]
Anti Seizure Drugs – management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of autoimmune hepatitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects.[rx] Gradual reduction of autoimmune hepatitis is possible during follow-up and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx][rx]
Benzodiazepines and electroconvulsive therapy – have been utilized to treat catatonia. Abnormal movements associated with this autoimmune hepatitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine. ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx][rx]
Antiviral Medication – Herpes simplex encephalitis is the commonest autoimmune hepatitis. Any patient who presented with clinical features of autoimmune hepatitis should be treated empirically with IV acyclovir, pending the result of autoimmune hepatitis results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of autoimmune hepatitis is often due to autoimmune hepatitis triggered by autoimmune hepatitis. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary autoimmune hepatitis.[rx]
Liver transplant – When medications don’t halt the progress of the disease or you develop irreversible scarring (cirrhosis) or liver failure, the remaining option is a liver transplant. During a liver transplant, your diseased liver is removed and replaced with a healthy liver from a donor. Liver transplants most often use livers from deceased organ donors. In some cases, a living donor liver transplant can be used. During a living donor liver transplant, you receive only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.

Current Alternative Treatments

Although conventional treatment with steroids ± azathioprine allows achieving remission in most patients, in cases of initial treatment failure or multiple relapses during tapering or discontinuation attempts, alternative therapies are often proposed.

Cyclosporine (CSA) is a powerful immunosuppressant that has been successfully used in patients with JAIH as a short-term initial treatment alternative to steroid-azathioprine or as a salvage treatment (rx, rx). The main side effects of CSA include nephrotoxicity, arterial hypertension, and gastrointestinal and neurological toxicity. Minor but frequent side effects are Hypertrichosis and gum hypertrophy; although transient they occasionally can influence adherence to treatment. Since 1985, the use of CSA has been documented in 133 adults with autoimmune hepatitis. CSA was used as salvage therapy and showed an overall positive response of any degree in about 93% of patients and a negative response, defined as no response, non-compliance, or drug intolerance in 7% (rx, rx).

Regarding pediatric patients, there are only five major publications in which CSA is mostly administered for short periods, mainly to induce remission, as a bridge to conventional treatment (rx, rx).

Furthermore, the effectiveness of CSA was similar to steroids as salvage therapy in children with JAIH and liver failure (rx). Prolonged CSA treatment for autoimmune pediatric liver disorders was first reported in 2004 with an excellent safety profile (rx), confirmed also in a recent follow-up study (rx).

A recent meta-analysis by Zizzo et al. confirmed that CSA has the highest short-term response rate (86%) in conventional treatment-refractory children with autoimmune hepatitis (rx).

Besides CSA, a wide range of immunosuppressive drugs has been used in small series of children (rx).

Mycophenolate Mofetil (MFM) is the second most effective drug for conventional treatment-refractory children with JAIH after cyclosporine (36% remission rate at 6 months) (rx). The main concern is the use of MMF is the lack of knowledge regarding its therapeutic range and toxic threshold; moreover, MFM is more expensive than azathioprine and is absolutely contraindicated during pregnancy.

Recently, Budesonide, a corticosteroid with potentially fewer side effects than other glucocorticoids, emerged as an alternative first-line treatment in association with azathioprine. When comparing the effects of budesonide vs. prednisone, both in combination with azathioprine, budesonide did cause fewer side effects than prednisone; however, after 12 months, only 46% of the patients treated with budesonide achieved complete remission (rx). The low proportion of remission observed in this study does not support its use as a first-line treatment of AIH (rx, rx).

mTOR inhibitors as sirolimus or everolimus have been used as salvage therapy with good results in few published adult patients (rx, rx).

Liver transplantation represents a therapeutic option for a small proportion of patients under two main circumstances: patients presenting with acute liver failure that does not respond to salvage therapy with rescue immunosuppression, and patients with cirrhosis with end-stage liver disease.

Next steps

Tips to help you get the most from a visit to your healthcare provider:

Know the reason for your visit and what you want to happen.
Before your visit, write down questions you want answered.
Bring someone with you to help you ask questions and remember what your provider tells you.
At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
Ask if your condition can be treated in other ways.
Know why a test or procedure is recommended and what the results could mean.
Know what to expect if you do not take the medicine or have the test or procedure.
If you have a follow-up appointment, write down the date, time, and purpose for that visit.
Know how you can contact your provider if you have questions.

References

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Autoimmune Chronic Active Hepatitis – Symptoms, Treatment

Autoimmune Chronic Active Hepatitis/Autoimmune hepatitis refers to chronic and progressive inflammation of the liver from an unknown cause that is characterized by a loss of immune tolerance against liver antigens, resulting in progressive destruction of the hepatic parenchyma and histologically by interface hepatitis, serologically by the presence of non-organ specific autoantibodies, biochemically by elevated aminotransferases and serum IgG, and clinically by the response to immunosuppressive treatment in the absence of other known causes of liver disease. The proposed mechanism for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger, and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver. Chronic hepatitis occurring predominantly in young women with arthralgias, myalgia, hepatosplenomegaly, amenorrhea, skin rashes, fluctuating course, and invariably fatal outcome Autoimmune hepatitis may present concurrently with other autoimmune diseases like Graves disease, rheumatoid arthritis, celiac disease, type I diabetes, ulcerative colitis, hemolytic anemia, and immune thrombocytopenia.

Synonyms of Autoimmune Hepatitis

AIH
autoimmune chronic active hepatitis
lupoid hepatitis

Types of Autoimmune Hepatitis

There are two known types of autoimmune hepatitis.

Type 1 – is distinguished by the presence of anti-smooth muscle antibodies (ASMA) with or without anti-nuclear antibodies (ANA). This is the most common type in the United States, accounting for 96% of the AIH cases in North America, has a female to male ratio of 4 to 1, and a great response to corticosteroids. It is characterized by the presence of antinuclear antibody (ANA) and anti-smooth-muscle antibody (ASMA).
Type 2 – autoimmune hepatitis presents with positive anti-liver/anti-kidney microsome (anti-LMK) type 1 antibodies or anti-liver cytosol (anti-LC) type 1 antibodies. This type occurs most often in Europe and the patients tend to be younger (usually less than 14 years old), have more severe disease, worse response to corticosteroids, and relapse more often. Type 2 AIH accounts for only 4% of the AIH cases in North America. It is characterized by the presence of anti-liver kidney microsomal antibody type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies.

Four subtypes of autoimmune hepatitis are recognized, but the clinical utility of distinguishing subtypes is limited.

Type 1 AIH – Positive ANA and SMA,^[rx] elevated immunoglobulin G (classic form, responds well to low dose steroids);
Type 2 AIH – Positive LKM-1 (typically female children and teenagers; disease can be severe), LKM-2 or LKM-3;
Type 3 AIH – Positive antibodies against soluble liver antigen^[14] (this group behaves like group 1)^[15] (anti-SLA, anti-LP)
AIH -with no autoantibodies detected – (~20%)(of debatable validity/importance)

Subclassifications

1.Type 1 autoimmune hepatitis

Characterized by SMA and/or ANA
Ancillary markers (i.e., atypical pANCA [frequently present] and anti-SLA [16%])
Most common type in the United States and affecting all ages, including infants. Most (78%) patients women (female-to-male ratio, 3.6:1)
Concurrent ulcerative colitis cholangiography to exclude PSC
Acute onset in 40% and rarely, acute severe (fulminant) presentation. Implicated HLA: DRB1^∗0301 (northern European), DRB1^∗0401 (northern European), DRB1^∗0404 (Mexican), DRB1^∗0405 (Japanese), DRB^∗1301 (South American), DRB1^∗1501 (protective)
Implicated polymorphic autoimmune promoters (all North American): TNFA-308^∗A, CTLA4^∗G, TNFRSF6^∗G, MICA^∗008
Target autoantigen unknown
DRB1^∗0301 (principal susceptibility allele) and DRB1^∗0401 (secondary but independent susceptibility allele) in white North American and northern European patients
Cirrhosis at presentation in 25% indicating subclinical aggressive stage
Concurrent extrahepatic immune diseases in 38%, including the following:

▪Autoimmune thyroiditis (12%) ▪Graves’ disease (6%) ▪Ulcerative colitis (6%) ▪Rheumatoid arthritis (1%) ▪Pernicious anemia (1%) ▪Systemic sclerosis (1%) ▪Coombs-positive hemolytic anemia (1%) ▪Idiopathic thrombocytopenic purpura (1%) ▪Leukocytoclastic vasculitis (1%) ▪Nephritis (1%) ▪Erythema nodosum (1%) ▪Fibrosing alveolitis (1%)

2.Type 2 autoimmune hepatitis

Characterized by anti-LKM1
Ancillary marker (i.e., anti-LC1 [32%]); no atypical pANCA
Affects mainly children (age range, 2 to 14 years)
Of Europeans with type 2 autoimmune hepatitis, adults comprising 20%
Anti-LKM1 in only 4% of North American adult patients
Commonly associated with concurrent immune diseases, including vitiligo, insulin-dependent diabetes mellitus, and autoimmune thyroiditis
Frequent organ-specific autoantibodies (antibodies to parietal cells, thyroid, or islets of Langerhans)
Acute or acute severe (fulminant) presentation possible
DQB1^∗0201 principal genetic risk factor in strong linkage disequilibrium with DRB1^∗07 and DRB1^∗03
Cytochrome monooxygenase, CYP2D6, the target autoantigen
Five antigenic sites located within recombinant CYP2D6; amino acid sequence between positions 193 and 212 main epitope of anti-LKM1
Homologies between recombinant CYP2D6 and genome of hepatitis C virus, cytomegalovirus, and herpes simplex virus type 1
Anti-LKM1 in 10% with chronic hepatitis C in Europe but rare in United States
Equally responsive to corticosteroid therapy as type 1 autoimmune hepatitis

Variants

1.Overlap syndrome with PBC

Defined by features of autoimmune hepatitis, antimitochondrial antibodies (AMA), and histologic findings of bile duct injury or loss
Most (88%) patients with AMA titers up to 1:160; seropositivity for antibodies to M2 autoantigens rare (8%) (see Chapter 14)
AMA reactivity possibly false because of confusion with anti-LKM1 by IIF
Empiric treatment (3 to 6 months) with prednisone alone (20 mg daily) or prednisone (10 mg daily) plus azathioprine (50 mg daily) effective if autoimmune features predominant and alkaline phosphatase level less than twice the upper limit of normal (ULN)
Prednisone (20 mg daily) combined with ursodeoxycholic acid (13 to 15 mg/kg daily) if PBC features predominant, alkaline phosphatase level more than twice the ULN, and/or florid duct lesions on histologic examination

2.Overlap syndrome with PSC

Defined by features of autoimmune hepatitis, cholestatic biochemical changes, histologic evidence of cholestasis including bile duct injury or loss, and abnormal bile ducts by endoscopic retrograde cholangiography (ERC) or magnetic resonance cholangiography (MRC)
Cholangiography required for diagnosis if inflammatory bowel disease present
Histologic features of bile duct injury, portal edema, and/or ductopenia and normal cholangiogram compatible with small duct PSC
Clues to diagnosis: inflammatory bowel disease, suboptimal response to corticosteroid therapy, and/or rising serum alkaline phosphatase level
Empirical therapy with prednisone (20 mg daily) and ursodeoxycholic acid (13 to 15 mg/kg daily) justified
Children with autoimmune hepatitis and abnormal cholangiograms in the absence of inflammatory bowel disease (“autoimmune sclerosing cholangitis”) typically respond to corticosteroid therapy but have shorter transplant-free survival than patients with normal bile duct biliary changes by MRC in 8% of adults with classic autoimmune hepatitis, but similar frequency by MRC in non-autoimmune liver diseases and may incorrectly implicate PSC

3.Autoimmune hepatitis and chronic viral hepatitis

Concurrence of active viral hepatitis, high-titer autoantibodies, and histologic features of interface hepatitis with or without portal plasma cell infiltration
Definite or probable autoimmune hepatitis by diagnostic scoring systems defining autoimmune predominant disease with background coincidental viremia
Nondiagnostic autoimmune features by diagnostic scoring systems with active viremia defining viral predominant disease with coincidental autoimmune findings
Immune manifestations common in chronic viral hepatitis, including SMA in 11%, ANA in 28%, diverse autoantibodies in 62%, and concurrent immune disease in 23%
SMA and ANA titers typically low in chronic viral hepatitis (up to 1:80 in 89%, 1:160 or higher in 11%; 1:320 or higher rarely
Concurrent positivity for SMA and ANA in only 4% of patients with chronic viral hepatitis
Median serum titers of SMA and ANA in classical autoimmune hepatitis of 1:160 and 1:320, respectively; 60% with concurrent SMA and ANA; and only 6% with isolated titers up to 1:8
Liver tissue evaluation essential in discriminating predominantly autoimmune from predominantly viral hepatitis
Moderate to severe portal plasma cell infiltration (66% versus 21%), acinar (lobular) inflammation (47% versus 16%), and interface hepatitis (23% versus 0%) more common in autoimmune-predominant disease
Portal lymphoid aggregates (49% versus 10%), steatosis (72% versus 19%), and bile duct damage or loss (91% versus 20%) more frequent in viral-predominant (chronic hepatitis C) disease (Fig. 5.4)
The treatment administered according to the prevailing condition: corticosteroids for autoimmune-predominant disease and peginterferon and ribavirin for viral-predominant disease (chronic hepatitis C)
Treatment results assessed at 3 months, and therapy changed if response poor

4.Autoimmune hepatitis with the cholestatic syndrome

Heterogeneous syndrome with composite features of autoimmune hepatitis and AMA-negative PBC or small duct PSC
ANA and/or SMA typically present in women with cholestatic biochemical changes, normal cholangiogram, absent AMA, and/or histologic findings of bile duct injury or loss
Possible resemblance to mainly PBC or autoimmune hepatitis
Variable response to empirical therapy with corticosteroids, ursodeoxycholic acid, or both
Possible therapy-induced improvements in clinical and laboratory findings but not in histologic changes

5.Cryptogenic (autoantibody-negative) chronic hepatitis

Satisfies international criteria for diagnosis of autoimmune hepatitis but lacks conventional autoantibodies (SMA, ANA, anti-LKM1)
Similarities in age, female predominance, frequency of concurrent immune diseases, histologic features, the occurrence of HLA B8, DRB1^∗03 and A1-B8-DRB1^∗03, and laboratory findings to classic autoimmune hepatitis
As responsive to corticosteroid treatment as in autoantibody-positive patients
Possibly representing a form that has escaped detection by conventional serologic markers
Conventional autoantibodies possibly appearing late, or possible presence of nonstandard autoantibodies (atypical pANCA, anti-SLA)
Must be distinguished from inactive cryptogenic cirrhosis and liver disease associated with celiac disease (i.e., negative for IgA antibodies to tissue transglutaminase or endomysium)Should be considered “autoantibody-negative autoimmune hepatitis” and treated with conventional corticosteroid regimens

Causes of Autoimmune Hepatitis

There is no specific evidence of the cause. Sixty percent of patients have chronic hepatitis but without serologic evidence of a viral infection. The disease is associated with anti-smooth muscle autoantibodies. [rx]

AIH occurs when your immune system mistakes your liver cells for foreign aggressors and creates antibodies to attack them. Doctors don’t know precisely why this occurs. However, certain risk factors have been identified, including:

autoimmunity – the process of your immune system making autoantibodies, which ‘attack’ and damage your body’s own cells and organs
environmental triggers – causes starting outside of the body; for example getting a virus, taking certain medications, or coming into contact with other toxins
genetic predisposition – inheriting genes that may make it easier for a trigger to set off the disease.
a family history of AIH
history of bacterial or viral infections
being female
the use of certain medications, such as minocycline

Other autoimmune conditions can cause symptoms of liver disease and are also associated with the development of AIH. These diseases include:

Grave’s disease
thyroiditis
ulcerative colitis
type I diabetes
rheumatoid arthritis
scleroderma
inflammatory bowel disease (IBD)
systemic lupus erythematosus
Sjögren’s syndrome

Symptoms of Autoimmune Hepatitis

Signs and symptoms in people with autoimmune hepatitis range from mild to severe depending on the amount of liver damage present. Symptoms are generally due to scarring of liver tissue (cirrhosis). Some people have no symptoms at first and are diagnosed after being evaluated for another health problem.^[rx] Some of the most common signs and symptoms in people with autoimmune hepatitis may be nonspecific and include:^[rx]^[rx]^[rx]^[rx]

Most patients have nonspecific symptoms: fatigue, anorexia, nausea, weight loss, jaundice, pruritus, and amenorrhea
Clinical manifestations of autoimmune hepatitis depend on how acute liver disease is at presentation, the stage of inflammation, or the complication of liver cirrhosis.
The most common features of autoimmune hepatitis are fatigue, malaise, jaundice, abdominal pain, and sometimes, arthralgias.
Fatigue (the most common symptom reported).
Nausea.
Loss of appetite.
Diarrhea.
Jaundice (yellowing of the skin and whites of the eyes).
Loss of brain function (hepatic encephalopathy).
Fluid in the abdomen (ascitesb).
Swelling of the legs (edema).
Easy bruising and bleeding.
An enlarged spleen (splenomegaly).
Gallstones.
Itchy skin (pruritis) or skin rashes.
Joint pain.
Vomiting.
Dark urine.
Pale or gray-colored stools.
Absence of menstrual periods in women (amenorrhea).

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms	Other Names	Learn More: HPO ID
100% of people have these symptoms
Increased circulating IgG level		0003237
80%-99% of people have these symptoms
Anti-liver cytosolic antigen type 1 antibody positivity		0030909
Antineutrophil antibody positivity		0003453
Antinuclear antibody positivity		0003493
Elevated hepatic transaminase	High liver enzymes	0002910
Liver kidney microsome type 1 antibody positivity		0030908
Smooth muscle antibody positivity		0003262
30%-79% of people have these symptoms
Abdominal pain	Pain in stomach [ more ]	0002027
Arthralgia	Joint pain	0002829
Chronic fatigue	Chronic extreme exhaustion	0012432
Depressivity	Depression	0000716
Spider hemangioma		0012522
5%-29% of people have these symptoms
Acute hepatitis	Acute liver inflammation	0200119
Anxiety	Excessive, persistent worry and fear	0000739
Arthritis	Joint inflammation	0001369
Ascites	Accumulation of fluid in the abdomen	0001541
Cirrhosis	Scar tissue replaces healthy tissue in the liver	0001394
Diffuse hepatic steatosis		0006555
Gastrointestinal hemorrhage	Gastrointestinal bleeding	0002239
Glomerulonephritis		0000099
Increased total bilirubin	High bili total	0003573
Jaundice	Yellow skin [ more ]	0000952
Sclerosing cholangitis		0030991
Splenomegaly	Increased spleen size	0001744
Thyroiditis	Thyroid gland inflammation	0100646
Ulcerative colitis		0100279
Vitiligo	Blotchy loss of skin color	0001045
1%-4% of people have these symptoms
Fulminant hepatitis		0004787
Hepatocellular carcinoma		0001402
Viral hepatitis		0006562

Diagnosis of Autoimmune Hepatitis

A multi-pronged approach is used to make a diagnosis. This approach includes determining symptoms, laboratory tests, and biopsies, as no single diagnostic test is pathognomonic for autoimmune hepatitis. Marked elevation of serum transaminases (AST, ALT) and gamma-globulin is common; elevation in alkaline phosphatase is less common. The serum levels of AST, ALT, and gamma globulin reflect disease severity and immediate prognosis at presentation.

Diagnosis is based on combinations of clinical, laboratory, and histological features
Revised diagnostic International Autoimmune Hepatitis Group (IAHG) scoring system (rx):
- Complex system evaluating 11 clinical, laboratory, and histological factors
- For research purposes – not designed for clinical practice
Simplified diagnostic IAHG scoring system (rx):
- Simple system evaluating 4 laboratory and histological factors: serum autoantibodies, IgG, liver histology and viral hepatitis serology
- Cutoff values for probable and definite AIH are 6 points (88% sensitivity and 97% specificity) and 7 points (81% sensitivity and 99% specificity), respectively
AIH subtypes depend on autoantibody serology:
- Type 1: positive for antinuclear antibody (ANA) or anti-smooth muscle antibody (SMA); 10% have other autoimmune disorders
- Type 2: positive for anti-liver-kidney microsomal (LKM) antibody or anti liver cytosol type 1 (LC1) antibody-positive; often presents with acute or fulminant hepatitis; 17% have other autoimmune disorders
About 10% of AIH shows coexisting features of the immune-mediated biliary disease (overlap syndrome) or are associated with atypical features (variant syndrome)
- Overlap syndrome: AIH primary biliary cirrhosis and AIH primary sclerosing cholangitis
- Variant syndromes: seronegative AIH and antimitochondrial antibody (AMA) positive AIH

Laboratory

Serum autoantibodies(rx):
- ANA – positive in 75% of type 1 AIH; not associated with disease course or outcome
- Anti-SMA – positive in 95% of type 1 AIH; not associated with disease course or outcome
- Anti-LKM – diagnostic for type 2 AIH; associated with younger age at presentation, fulminant hepatic failure, and partial IgA deficiency
- Anti-LC1 – diagnostic for type 2 AIH; associated with more severe inflammation and rapid progression to cirrhosis
- Anti soluble liver antigen (SLA) / live pancreas (LP) – positive in 20 – 50% of AIH; associated with more severe disease, treatment dependence, relapse after drug withdrawal, and need for transplantation
Serum immunoglobulin G (IgG) – not only a diagnostic marker but also a marker for monitoring treatment response (rx)
Autoantibodies – A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased immunoglobulin G level. The presence of anti-mitochondrial antibody is more suggestive of primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value.^[rx]
Blood tests – Testing a sample of your blood for antibodies can distinguish autoimmune hepatitis from viral hepatitis and other conditions with similar symptoms. Antibody tests also help pinpoint the type of autoimmune hepatitis you have.
Liver function tests – These check for inflammation or damage to your liver.
Coagulation panel – This test looks at how well the clotting proteins are working.
Electrolyte panel – Checks to see if you have an electrolyte imbalance.
Other liver tests – These are done to check for other possible types of liver disease.
CT scan – This is more detailed than a standard X-ray. It can show detailed images of any part of the body, including the bones, muscles, fat, and organs. It uses both X-rays and computer technology to make horizontal images (often called slices) of the body.
MRI – This test makes detailed pictures of organs and structures inside your body. It uses a magnetic field and pulses of radio wave energy. A dye may be shot or injected into your vein. The dye helps the liver and other organs in the belly to be seen more clearly on the scan.
Ultrasound – This uses high-frequency sound waves to create a picture of the organs. It can also check blood flow in blood vessels.
Liver biopsy – Doctors perform a liver biopsy to confirm the diagnosis and to determine the degree and type of liver damage. During the procedure, a small amount of liver tissue is removed, using a thin needle that’s passed into your liver through a small incision in your skin. The sample is then sent to a laboratory for analysis.
Anti-liver cytosol type I, anti-soluble liver antigen (SLA) antibodies, and perinuclear antineutrophil cytoplasmic antibodies (pANCA) can also be associated with autoimmune hepatitis. [rx]Conversely, anti-mitochondrial antibodies are more commonly seen with primary biliary cirrhosis and are usually absent in autoimmune hepatitis; however, they can be present in those with overlapping syndromes. Atypical perinuclear antineutrophil cytoplasmic antibodies are commonly associated with type-1 autoimmune hepatitis and primary sclerosing cholangitis. Anti-LKM1 is common in type-1 autoimmune hepatitis and mainly observed in children.
Anti-SLA antibodies – are more useful from a prognostic standpoint as these are associated with more severe disease, treatment failure, and higher relapse rates. A liver biopsy is required for both diagnosis and staging of autoimmune hepatitis.
Liver Enzyme Abnormalities – Elevation of liver transaminases less than 500 UI/L with normal alkaline phosphatase is typical. Liver transaminase elevation to 1,000 UI/L resembling acute viral hepatitis and liver ischemia is less common but can occur. An elevation of alkaline phosphatase that is disproportional to transaminase ALT or AST elevation with alkaline phosphatase to ALT or AST ratio of ≥3 is unusual and should prompt investigation of other causes of liver disease such as drug-induced disease, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Individuals with AIH may concomitantly have features of other autoimmune liver diseases such as PSC or PBC, termed overlap syndrome. The overlap syndrome of AIH with PBC or AIH with PSC will be discussed separately further in this chapter.
Gamma Globulin Elevation – Gamma globulin elevation occurs in 80% of the cases. There is a polyclonal elevation in immunoglobulin (Ig), with a predominant IgG elevation. Along with liver transaminases, gamma globulin levels are important markers of disease activity.

Treatment Of Autoimmune Hepatitis

Treatment (which is based on supportive care) is as follows

Antiviral medications (if virus causes)
Antibiotics, (if bacteria cause)
Steroids are used to reduce brain swelling
Sedatives for restlessness
Acetaminophen for fever
Occupational and physical therapy (if the brain is affected post-infection)

Medications

autoimmune hepatitis is a rare condition with no randomized controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide, and rituximab.^[rx]

Corticosteroids – are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like autoimmune hepatitis. Because most patients respond to corticosteroids or glucocorticoid immunosuppressant treatment, this condition is now also referred to as steroid-responsive autoimmune hepatitis. Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days or prednisone is usually administered orally at 2 mg/kg/day (up to a maximum of 60 mg/day), azathioprine is administered at the initial dose of 1 mg/kg/day, which can be further increased up to 2.5 mg/kg/day until sustained biochemical remission is achieved.[rx]
Budesonide – has been shown to be more effective in inducing remission than prednisone, and result in fewer adverse effects.^[17]
Immunoglobulin infusion(IVIG) – Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune hepatitis[rx] [rx] Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.[rx][rx]
Plasmapheresis – can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual. [rx]
Biological Drugs – Rituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.[rx]
Anti Seizure Drugs – management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of autoimmune hepatitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects.[rx] Gradual reduction of autoimmune hepatitis is possible during follow-up and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx][rx]
Benzodiazepines and electroconvulsive therapy – have been utilized to treat catatonia. Abnormal movements associated with this autoimmune hepatitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine. ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx][rx]
Antiviral Medication – Herpes simplex encephalitis is the commonest autoimmune hepatitis. Any patient who presented with clinical features of autoimmune hepatitis should be treated empirically with IV acyclovir, pending the result of autoimmune hepatitis results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of autoimmune hepatitis is often due to autoimmune hepatitis triggered by autoimmune hepatitis. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary autoimmune hepatitis.[rx]
Liver transplant – When medications don’t halt the progress of the disease or you develop irreversible scarring (cirrhosis) or liver failure, the remaining option is a liver transplant. During a liver transplant, your diseased liver is removed and replaced with a healthy liver from a donor. Liver transplants most often use livers from deceased organ donors. In some cases, a living donor liver transplant can be used. During a living donor liver transplant, you receive only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.

Most Common Treatment Options for Autoimmune Hepatitis

	Combination Treatment Prednisone + Azathioprine	Combination Treatment Budesonide + Azathioprine	Prednisone Monotherapy
Induction
Week 1	30 mg/d + 50 mg/d	9 mg/d + 50 mg/d	Prednisone 60 mg/d
Week 2	25 mg/d + 50 mg/d	9 mg/d + 50 mg/d	Prednisone 40 mg/d
Week 3	20 mg/d + 50 mg/d	6 mg/d + 50 mg/d	Prednisone 30 mg/d
Week 4	15 mg/d + 50 mg/d	6 mg/d + 50 mg/d	Prednisone 20 mg/d
Maintenance
First 12 months	Prednisone 10 mg/d + Azathioprine 50 mg/d	Budesonide 6 mg/d + Azathioprine 50 mg/d	Prednisone 20 mg/d or less for at least 24 months
12-24 months	Prednisone taper 2.5 mg/week until withdrawal. Thereafter azathioprine monotherapy 50-100 mg/day	Consider budesonide taper until withdrawal. Thereafter azathioprine monotherapy 50-100 mg/day
Treatment Withdrawal
	After 24 months of complete remission OR Liver biopsy showing absence of inflammation	Same	Same
Indication
	Preferred over prednisone monotherapy as fewer side effects	Potential frontline therapy Patients with obesity, acne, diabetes, and hypertension may benefit	Reserved for patients who cannot take azathioprine
Disadvantages
	Side effects of prednisone, although less often and less severe than high-dose prednisone	Expensive Fewer studies showing efficacy	Severe corticosteroid-induced side effects

Induction Phase

In the induction phase, prednisone 30 mg per day plus azathioprine 50 mg per day is started for 1 week. This is followed by a prednisone taper over the course of 4 weeks with a fixed azathioprine dose of 50 mg per day to achieve a dose of prednisone 10 mg per day plus azathioprine 50 mg per day as shown in Table 5.

Should budesonide plus azathioprine be selected, induction is achieved with a combination of budesonide 3 mg three times daily plus azathioprine 50 mg per day for 2 weeks, followed by a budesonide 3 mg twice daily thereafter.

Maintenance Phase

For those receiving prednisone plus azathioprine, the maintenance phase begins typically after 4 weeks, when the dose of prednisone 10 mg per day plus azathioprine 50 mg per day is started. This dose is continued for at least 1 full year. The daily maintenance dose of prednisone should remain fixed, as dose titration according to liver transaminases or alternate day schedules of prednisone are associated with incomplete histological improvement despite laboratory improvement.

After 1 year of controlled disease, consideration can be given to withdrawal of prednisone while continuing azathioprine. Thereafter azathioprine monotherapy is continued for long-term maintenance. Patients can often be maintained on doses of azathioprine monotherapy of 50 mg per day to 100 mg per day with normal liver enzymes. Azathioprine doses of less than 100 mg per day have the advantage of less toxicity, particularly less leukopenia. Table 5 shows the medical regimen for AIH.

If budesonide is used, the maintenance dose is 6 mg twice daily in combination with azathioprine 50 mg per day. One may consider tapering budesonide while maintaining azathioprine 50 mg per day to 100 mg per day (azathioprine monotherapy) after 12 months, but there are currently no studies on the long term effect of azathioprine monotherapy after budesonide plus azathioprine combination.