Review
Diagnosis and Management of Cholestatic Liver Disease

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Cholestasis (slowing of bile flow) may be acute or chronic and affect any age group. In infants and children the causes often are congenital or inherited and as a result of improved management some affected children now survive to adulthood. Although jaundice is a hallmark of cholestasis it may be absent, particularly in adults with chronic cholestatic liver disease most of whom are entirely asymptomatic. A detailed history and physical are crucial to the diagnosis and noninvasive radiologic tests (ultrasound, computerized tomography scan, and magnetic resonance cholangiography) greatly facilitate diagnosis, particularly when the cause is extrahepatic. Only if sufficient portal tracts (>10) are present on liver biopsy examination can this test reliably evaluate damage to the small bile ducts. Therapy should address both the cause and the consequences of retained bile acids within the liver, and diminished delivery of bile to the gastrointestinal tract. Therapies should address symptoms, mostly pruritus and prevention, particularly osteoporosis and osteomalacia. Portal hypertension can be an early event in chronic cholestatic liver disease, sometimes occurring before the development of cirrhosis. Ursodeoxycholic acid improves the biochemical markers of cholestasis regardless of cause and may delay liver disease progression; only liver transplant is potentially curative.

Section snippets

Approach to Cholestasis

The first approach is always the history, which often is very pertinent in both acute and chronic cholestasis. Jaundice is confined predominantly to those with acute or acute-on-chronic cholestasis because end-stage chronic disease rarely is seen because liver transplant supervenes. A thorough drug history is imperative. Any medications taken within 6 weeks of presentation may be incriminated and only one dose may be sufficient to initiate disease, but a 1-time medication often is forgotten

Further Investigations in Cholestasis

Ultrasonography revolutionized the diagnostic work-up of apparent cholestasis because it could clearly distinguish intrahepatic vs extrahepatic biliary tract disease. However, although ultrasound is an excellent technique, it is very technician- and interpreter-dependent, whereas computerized tomography scan is less technician-dependent. For this reason, computerized tomography is frequently the test of first choice, even though it is not as good as ultrasonography at delineating the biliary

Visualization of the Bile Ducts: Endoscopic Retrograde Cholangiopancreatography Versus Magnetic Resonance Cholangiopancreatography

The gold standard for visualizing the extrahepatic biliary system is endoscopic retrograde cholangiography, but even in good hands it carries a significant complication rate.9 Around 3%–5% will develop some degree of pancreatitis. In individuals in whom the need for a therapeutic maneuver is not anticipated, magnetic resonance cholangiopancreatography (MRCP) is the safer option. The sensitivity and specificity of MRCP compared with endoscopic retrograde cholangiopancreatography (ERCP) has been

Physiology and Pathophysiology

Both inherited and acquired liver diseases may cause intrahepatic cholestasis. It is the identification of the many genetic causes so prevalent in the pediatric population that has facilitated our understanding of intrahepatic bile flow. Intrahepatic cholestasis may be caused by disease at the subcellular level or be caused by abnormalities of canalicular transport or motility or from damage to small biliary ductules. Cloning of the canalicular transporters in the early 1990s identified several

Cholestasis in Children

There are many other inherited causes of cholestasis that, fortunately, are very rare; such as the zinc-storage disorder described in children of Ojibwe origin.18 This causes a marked cholestatic jaundice and liver failure found to recur after liver transplantation. The exact cause for this storage disorder remains unknown. Another chronic cholestatic disease of North American Indian children of Cree extraction reported from Northern Quebec has been shown to be caused by a mutation of the

Cholestasis in Adults

Prescription drugs, over-the-counter drugs, and herbal remedies are the most common causes of acute cholestasis in adults, which may sometimes progress to a chronic vanishing bile duct syndrome.26 Thus, drugs may induce cholestasis at the subcellular, the canalicular, or the ductal level.

ICP is also a very heterogeneous condition, therefore different biochemical patterns may be observed. It has long been recognized that there is a genetic component to ICP because the disease is much more common

Consequences of Cholestasis and Its Treatment

Treatment both of the consequences of the retention of hydrophobic bile acids within the liver and the effects of diminished quantities of bile acid reaching the bowel is necessary. The retention of bile acids within the hepatocyte has a detergent effect on the intracellular membranes and promotes hepatocyte apoptosis and hepatic fibrosis. Retention of the biliary lipids normally excreted in bile causes hypercholesterolemia and xanthoma. Pruritus is the most frequent complication of bile

Symptomatic Treatment

The most prevalent symptom of cholestasis (even if anicteric) is pruritus, a symptom that often is underappreciated by physicians but when severe may cause marked sleep disturbance and sometimes cause the patient to even contemplate suicide. Thus pruritus should never be ignored. The first line of treatment is the anion-exchange resin, the best-known being cholestyramine. This agent often gives rise to gastrointestinal disturbance and is poorly tolerated by some but is effective in 80%. It

Preventive Strategies

Osteomalacia and/or osteoporosis are associated with severe chronic cholestatic liver disease (eg, that caused by PBC and PSC). Osteomalacia is seen only when there is profound icteric cholestasis with inadequate calcium and vitamin D supplementation. Calcium supplementation also benefits those with osteoporosis, with the addition of bisphosphonates when necessary.40 In individuals with chronic (even anicteric) cholestatic liver disease, screening for bone mineral density should be routine at

Specific Therapies

Although many of the genetic mutations responsible for the several forms of congenital cholestatic liver disease have been described, gene therapy is still only a hope for the future. There are a few specific therapies for cholestatic liver disease, they include antibiotics for bacterial cholangitis and corticosteroids for autoimmune cholangitis. Nonspecific therapies that promote bile flow—namely hydrophilic bile acids (eg, ursodeoxycholic acid [(UDCA]),42 make physiologic sense. UDCA leads to

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