By nature, the patient with chronic cholestasis presents a difficult management problem. The pathophysiology of cholestasis includes the myriad consequences of diminished bile flow. Those substances normally excreted into bile are retained in the liver and subsequently regurgitated into the serum and tissues. Malabsorption of fat soluble vitamins and long chain triglycerides may result from decreased intraluminal concentrations of bile acids. Progressive hepatic damage may occur with the eventual development of biliary cirrhosis, portal hypertension, and liver failure. All of the above contribute to the altered hormonal and nutritional states often seen in patients with chronic cholestasis.
A recent review has discussed the diagnosis and classification of Neonatal Cholestasis;1 these aspects will not be discussed here. Those problems to be addressed in this review include the management of the following: 1) pruritis and xanthomas, 2) malnutrition and fat-soluble vitamin malabsorption, and 3) the consequences of hepatic failure, which include variceal hemorrhage and ascites. We will also discuss the new option available for patients with end stage liver disease - transplantation. A general overview of our approach to these problems may be found in the Table.
PRURITIS AND XANTHOMATA
The pruritis associated with chronic liver disease may carry with it significant morbidity. Pruritis is common in patients with congenital cholestasis, as well as in those with primary biliary cirrhosis and biliary obstruction. Cholestyramine resin has been used effectively since 1960 to relieve the itching. In addition, agents which potentially increase bile flow, such as phenobarbital, may be of use. Antihistamines, although frequently used, have little role in the management of the pruritis of cholestasis.2
The etiology of cholestatic pruritis remains obscure. The role of retained bile acids has long been questioned. Recent studies, however, have cast doubt upon this simplistic mechanism, as little correlation has been found between pruritis and serum or skin bile acid levels. 1-4 In addition, cholestyramine is efficacious in relieving the pruritis of uremia, a condition in which serum bile acid concentrations are generally low. The possibility that pruritis might result from unusual physiochemical forms of bile acids produced in hepatic disease remains unproven. Xanthomata, which often accompany pruritis, seem attributable to the elevated serum lipid values often seen in chronic cholestasis. The lesions may occur about the eyes, on the upper lip, on the neck, chest, or back. Later, the wrists, elbows, knees, ankles, and buttocks are involved. The xanthomas respond to measures which lower serum lipid and cholesterol values, such as the administration of cholestyramine resin, which binds bile acids and thus leads to the excretion of cholesterol. The xanthomas generally disappear when progressive hepatic disease results in decreased serum lipid values.5
As mentioned above, cholestyramine (8-16 g/d) can be efficacious in both the treatment of pruritis and xanthomata. Unfortunately, the resin is unpalatable and difficult to administer. Side effects of cholestyramine include constipation, hyperchloremia, and fat-soluble vitamin deficiency. Phenobarbital (3-5 mg/Kg/d) may be useful, as well, to stimulate bile flow in those patients with some degree of residual bile duct patency. Side effects of phenobarbital include initial sedation, paradoxical hyperexcitability, and addiction. In addition, the metabolism of other concomitantly administered drugs may be altered. Both phenobarbital and cholestyramine may require 2 to 4 weeks to produce the desired effects. Finally, although experimental, plasma perfusion has also been successfully used in the treatment of pruritis.6
Chronic cholestasis may have profound effects on nutrition and eventual growth. Diminished delivery of bile to the proximal small bowel results in decreased intraluminal concentrations of bile acids; fat malabsorption has been correlated with these lowered concentrations. 7 Medications such as cholestyramine, which binds bile acids and thus induces fat malabsorption, and neomycin, which may directly affect intestinal absorptive function, may further compromise absorption. Multiple other factors contribute to the malnutrition of chronic liver disease. Anorexia, be it secondary to the presence of infection, weakness, or specific nutrient deficiency (ie, zinc) is often seen. Visceral compression, attributable to organomegaly or ascites, may cause early satiety and gastroesophageal reflux. Intrahepatic retention of bile acids with subsequent hepatic dysfunction and disordered hepatic metabolism may also affect nutrient homeostasis. Glucose intolerance and insulin resistance have been noted in adults with cirrhosis.8,9 Decreased serum branched chain amino acids (valine, leucine, and isoleucine) as well as increased serum levels of aromatic amino acids (tyrosine, phenylalanine and methionine) may be seen in chronic liver disease. 10 The implications of these aberrations are unknown; however, the probability of subtle physiologic effects and nutrient interactions must be considered..
SUGGESTED MEDICAL MANAGEMENT OF THE CONSEQUENCES OF PERSISTENT CHOLESTASIS
Pubertal development is often delayed in patients with chronic liver disease. Although this is presumably secondary to malnutrition, altered hormonal metabolism may also play a part. Resistance to growth hormone has been described in patients with arteriohepatic dysplasia.11 Altered somatomedin secretion and increased prolactin secretion are seen in adults with chronic liver disease. t2 These alterations may lead to inefficient energy metabolism as well as to problems such as hypogonadism in the adult population.
SPECIFIC DEFICIENCIES NOTED DURING CHRONIC CHOLESTASIS
Fat-soluble vitamin deficiencies, often associated with specific symptoms, are seen in chronic cholestasis. Severe malabsorption of vitamin E has been documented to occur in chronic cholestasis. A progressive neuromuscular syndrome characterized by degeneration of spinal cord posterior columns and loss of myelinated axons of peripheral nerves has been associated with vitamin E deficiency. n Clinical features may include the development of areflexia by 5 to 6 years of age, with onset of broad-based gait, ataxia, and decreased proprioception and vibrioception, occurring by age 8 to 12 years. Children who are deficient in vitamin E will have low serum concentrations as well as a low ratio of serum vitamin E to total serum lipids (defined as <0.6 mg/g for children under age 12, and less than 0.8 mg/g for older patients). Reversal of the symptoms and signs of vitamin E deficiency may occur with repletion of vitamin E stores, either orally, or if need be, parenterally. Potential of full recovery is good in patients below 3 years of age; whereas those above the age of 5 may suffer irreversible neurologic injury (Sokol RJ, Guggenheim MA, personal communication). Vitamin E deficiency may be prevented by administration of large oral doses of vitamin E. It is appropriate to measure serum levels following a therapeutic trial. Those with an inadequate response should be given vitamin E parenterally.
Vitamin D deficiency, which is a well-known cause of metabolic bone disease, may be due either to low levels (secondary to malabsorption) or "functional" deficiency (secondary to decreased hydroxylation), both of which may be attributable to chronic cholestasis. Deficiencies of the other fat soluble vitamins have also been noted to occur in chronic cholestasis; these are listed in the Table.
In addition to fat-soluble vitamin malabsorption, alterations in total caloric absorption, as well as in essential fatty acid absorption, may be important. Deficiencies of the water-soluble vitamins have been reported in adults with chronic cirrhosis. Low levels of serum iron, associated with decreased transferrin synthesis and blood loss, have been described. Magnesium, potassium, phosphorus, and calcium balance may be altered. Finally, excessive accumulation of such compounds as copper is possible in chronic liver disease; these accumulations may theoretically lead to toxicity.
The initial step in the proper nutritional management of the patient with chronic cholestasis is to obtain accurate measurement of current nutritional status, as well as to document current hepatic synthetic capabilities. Height, weight, and skinfold measurements are all of use; however, weight may be falsely elevated because of fluid retention. Fat malabsorption can be quantitated, and the presence of specific vitamin deficiencies inferred through serum levels. The goal of the nutritional management of the patient with chronic cholestasis is to maximize growth while controlling manifestations of the other problems seen in chronic liver disease, such as ascites. I4 Dietary restriction is generally of little use; the diets are unpalatable and are rejected. Replacement of some dietary long chain triglycerides with supplements containing medium chain triglycerides (MCT) will maximize fat absorption. MCT-containing formulas, such as Portagen® or Pregestimil,® may be of use. Provision of adequate protein and carbohydrate calories and replacement of fat-soluble vitamins and micronutrients (calcium, phosphate and zinc) is essential. Consistent use of newer methods of enteral and parenteral feeding will help meet these requirements. IS Food rich in copper might be avoided, since this potentially toxic element requires biliary elimination. Salt restriction may be necessary in the presence of ascites, and protein restriction may be necessitated by encephalopathy.
Despite the above measures, attempts to ensure adequate nutrition and to maximize growth in the patient with chronic cholestasis may be limited by loss of hepatic synthetic function as well as by progression of hepatic disease. Iatrogenic factors, ie, drugs such as corticosteroids, given in chronic active liver disease, may also contribute to growth failure.
Ascites is frequently seen in patients in whom chronic cholestasis is associated with portal hypertension. Multiple factors interplay in the etiology of ascites: 1) hypoalbuminemia, which is not critical to ascitic formation, but may contribute;16,17 2) increased lymphatic flow, secondary to portal hypertension, may lead to peritoneal fluid collection; and 3) renal retention of sodium and water seen in chronic liver disease may contribute to the already elevated pressure in the splanchnic bed, again with ascites the end result, is. 19 j/he latter may be the most important factor.
Regardless of the mechanism, the management of ascites is a significant problem in children with chronic liver disease. Effective therapy must be aimed at the altered renal handling of salt and water seen in liver disease. Generally, a limitation of dietary sodium intake to 1 to 2 mEq/Kg/day is first undertaken. Fluid restriction is generally not required in patients with adequate urine output and in whom hyponatremia is absent. Sodium restriction may be insufficient. Therefore, diuretics may be needed; the goal is to inhibit renal sodium retention. Spironolactone, an inhibitor of aldosterone, in the dose of 2 to 3 mg/Kg/d, is often useful and offers the advantage of potassium sparing. Response generally occurs within 70 to 96 hours and may be monitored by an elevation in the urine sodium: potassium ratio. If response remains inadequate, an additional diuretic agent with a proximal tubule site of action is then added; these include the thiazides, furosemide, and ethacrynic acid. Complications of diuretic therapy may include hypokalemia, hyponatremia, and less frequently, azotemia, and encephalopathy. Careful follow-up includes monitoring of serum and urine electrolyte concentrations.20,21 Paracentesis is not indicated, except as a diagnostic measure.
PORTAL HYPERTENSION-VARICEAL HEMORRHAGE
Chronic cholestasis is often associated with the presence of portal hypertension and subsequently with the development of esophageal varices. Episodes of gastrointestinal hemorrhage in patients with chronic liver disease secondary to variceal bleeding must be added to the list of expected complications. The differential diagnosis in these patients must also include gastritis, Mallory-Weiss tears, and peptic ulcer disease. As the therapy of these conditions differs from that of variceal hemorrhage, rapid differentiation is essential.22,23 When variceal hemorrhage is established, lavage of the stomach is carried out, generally with saline. Volume replacement is given as needed, with care to avoid overadministration of sodium or of volume, which might worsen variceal hemorrhage. Vasopressin is administered intravenously if bleeding continues; this drug is a nonselective vasoconstrictor which reduces splanchnic blood flow, thereby lowering portal pressure. After a bolus of 0. 3 U/Kg (maximum 20 U) diluted in 2 cc/Kg of 5% dextrose over 10 to 20 minutes, a continuous infusion of 0.2 to 0.4 U/1.73 mp 2/ min is administered and continued for 12 to 24 hours, if needed. The dose may then be tapered. If bleeding does not respond or if massive hemorrhage occurs, a SengstakenBlakemore tube may be placed to provide balloon tamponade of varices. Complications of this mode of therapy include pulmonary aspiration, esophageal rupture, and suffocation. Finally, sclerotherapy is finding a place in the management of bleeding varices, and may be useful for long- tenu control of bleeding. 24,25 This technique, in which a sclerosing agent such as ethanol or sodium tetradecyl sulfate is injected into or around esophageal varices via an endoscope, is generally performed after the patient's medical condition has stabilized. Subsequent injections (biweekly, for example) are then required. The procedure is generally safe, however, possible complications include esophageal stricture and perforation.
Surgical methods of controlling hemorrhage include shunting procedures,26,27 which may, however, precipitate encephalopathy and worsen hepatic function, and transthoracic ligation of esophageal varices.28,29 Shunting procedures are technically difficult in young children, carry a high mortality if done on an emergent basis, and make future hepatic transplantation difficult.
Liver transplantation must be considered in patients with chronic cholestasis and subsequent hepatic failure. This alternative must be strongly considered in those patients in whom the risks of complications from liver disease outweigh the risks of surgery. With the use of Cyclosporin A, an immunosuppressive agent in use since 1980, survival rates of over 65%, 30 as opposed to 35% prior to 1980, have been reported. Thus, hepatic transplantation offers an important, and often life-prolonging, alternative to the patient with chronic liver disease as well as to the patient with metabolic diseases such as alpha- 1-antitrypsin deficiency, tyrosinemia, and Wilson's disease. Availability of donor organs, however, continues to be a limiting factor in pediatric transplantation. Hopefully, adequate public education and efficient organ procurement networks will help alleviate this problem.
The management of children with chronic cholestasis must address many issues. With early and aggressive dietary and pharmacologic intervention, however, adequate growth and development can be maintained in many patients. In the most severely affected patients, this growth may allow eventual successful, and life-saving liver transplantation.
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SUGGESTED MEDICAL MANAGEMENT OF THE CONSEQUENCES OF PERSISTENT CHOLESTASIS