Cholestasis simply means failure of flow of bile. The cause of this failure can arise anywhere in the biliary system, from the liver cell down to the ampulla of Vater. For clinical purposes it is easiest to think of cholestasis as being either intra- or extrahepatic (Table 11).

Drug toxicity is the commonest cause of cholestasis occurring at the cellular level. The injury may be predictable, as with estrogens (for example), or unpredictable, as with most idiopathic drug reactions. (However, as more intracellular mechanisms become understood - e.g., the polymorphic nature of drug-metabolizing enzymes - fewer reactions will be found to be "unpredictable.") Histologically and clinically, cholestatic drug reactions can be considered as "bland" or "inflammatory." Systemic sepsis is often associated with cholestasis. Endotoxins have been shown to affect both intracellular and canalicular function. If sepsis occurs on a background of cirrhosis, the cholestasis is much more profound.

Most acute and chronic liver diseases exert a cholestatic effect via interruption of intracellular transport mechanisms or damage to the small interlobular bile ducts. Damage to small bile ducts is not at all unusual in acute and chronic hepatitis, particularly with hepatitis C. Cholestasis is also a common feature of relapsing hepatitis A, but does not carry any particular significance.

Several chronic liver diseases specifically target the intrahepatic and sometimes the extrahepatic bile ducts. The diseases of the liver that are associated with paucity of bile ducts are numerous. Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the best-known examples; other diseases that destroy bile ducts are chronic drug reactions, chronic rejection, graft-versus-host disease and chronic septic cholangitis, to name but a few.

In children, intrahepatic bile duct paucity may be syndromatic (Alagille's) or nonsyndromatic (e.g., postviral, PSC). PSC is commonly misdiagnosed as autoimmune hepatitis in children, as overt cholestasis may be absent. Cystic fibrosis may give rise to focal biliary cirrhosis as a result of inspissated bile in the ducts.

Many infiltrations may cause a biochemical cholestatic pattern of liver disease, generally anicteric - e.g., sarcoidosis, lymphomas, amyloid and granulomas of any etiology.There is a very rare condition called "benign recurrent cholestasis" whose mechanism is not understood at all. Several rare congenital conditions, often associated with secretion of abnormal bile acids, result in severe chronic cholestasis in infants. In children, total parenteral nutrition is a well-recognized cause of cholestasis that is thought to be due to the amino acid content interrupting bile acid uptake by the liver.

Diseases of the large bile ducts are generally due to stones, strictures or tumors. The AIDS epidemic has brought its own forms of cholestatic problems: fungal, protozoal and viral cholangitis. Malignant tumors causing biliary obstruction now include Kaposi's sarcoma, lymphoma, and the more common pancreatic and bile duct carcinomas.

The diagnostic hallmarks for PBC include a cholestatic serum biochemistry as described above, elevated serum cholesterol, elevated serum IgM and a positive mitochondrial antibody test. If all these features are present, a diagnostic liver biopsy is not essential. The biopsy is subject to great sampling error and all four "stages" may be seen in one specimen (Table 12).

9.3.2 MANAGEMENT

The management of PBC includes symptomatic, preventive and specific measures.

There is little one can do for the fatigue, although a sympathetic and understanding ear helps. Pruritus can generally be controlled by using the anion exchange resin, cholestyramine. There are, however, many who suffer gastrointestinal side effects from this drug, so rifampin 150 mg b.i.d. or t.i.d. can be tried instead. Ultraviolet light also helps, so that pruritus is less in the summer. A trip down south always helps in the winter!

For the most part, the complications of long-term cholestasis can be prevented, except for the osteoporosis. Once the serum bilirubin is elevated, steatorrhea may occur with subsequent malabsorption of fat-soluble vitamins. Vitamin A and D supplements are available in water-soluble form, and vitamin K is best given parenterally. The fat intake should not be reduced. Although this may reduce the steatorrhea, it will also result in massive weight loss and will not affect the serum cholesterol. Despite the hypercholesterolemia, there is no increase in incidence of ischemic heart disease in PBC. A low-cholesterol diet will not affect the high serum cholesterol as the elevation is due to failure of biliary excretion. So far nothing has been found to help the osteoporosis, which may cause wedging of the vertebrae, although calcium supplementation of the diet is always recommended in addition to vitamin D supplements.

Many specific therapies for PBC have been tried, none with resounding success. Some are definitely contraindicated - notably prednisone, because it promotes osteoporosis. Recently, treatment with ursodeoxycholic acid (UDCA) has been studied. It has very few side effects and causes a dramatic fall in all the biochemical markers for this disease, and recently has been shown to improve survival in PBC patients. Untreated, the mean survival of symptomatic PBC is 12 years. Treatment with UDCA in a dose of 13-15 mg/kg/day results in a 31% increase in survival after four years of therapy. The survival of those with asymptomatic disease is much longer. The ultimate treatment is liver transplantation; PBC patients do very well, with a 92% one-year survival rate, though recurrence in the allograft has been reported.

Primary sclerosing cholangitis is the most common cause of secondary biliary cirrhosis in adults. It affects about 10% of patients with ulcerative colitis or Crohn's colitis, although 30% of patients with PSC have no background of inflammatory bowel disease at the time of presentation. Patients are commonly asymptomatic. Just as with PBC, PSC causes presinusoidal portal hypertension, so variceal bleeding may present early - i.e., prior to the onset of jaundice (Table 13). A cholestatic enzyme pattern in any patient with liver problems should prompt the suspicion of PSC. The diagnosis is made only by ERCP, never by liver biopsy. Because liver biopsy is not helpful diagnostically it is performed only to see if the patient is cirrhotic. If PSC is suspected prior to ERCP, then antibiotic coverage should be given at the time of the procedure. Sepsis is the major complication of this disease and needs to be avoided if possible, as infection outside the liver precludes liver transplantation - the treatment of choice for decompensated disease. Prior to transplantation the only treatment available is symptomatic and/or preventive, as described for PBC. As yet there have been no therapeutic trials of any reasonable size performed in PSC and hence there is no standard therapeutic intervention, although UDCA therapy certainly leads to a fall in the serum markers of cholestasis and theoretically it should improve the bile flow.

There will always be patients in whom no diagnosis can be made immediately. In the absence of jaundice, the physician has time to observe. Granulomas of the liver are the most likely cause of a "missed" diagnosis on biopsy. Electromicroscopy may be helpful when a drug reaction is suspected.