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.

9.3.1 DIAGNOSIS

The more accurate term for this disease is chronic nonsuppurative granulomatous cholangitis. It predominantly affects women in middle age and is frequently associated with autoimmune phenomena outside the liver (renal tubular acidosis, vitiligo, thyroiditis, sicca syndrome, CREST syndrome, rheumatoid arthritis and, less often, glomerulonephritis and vasculitis). It is therefore presumed that PBC is also an autoimmune disease, although the inciting antigen has not been identified.

PBC is rarely diagnosed at the first visit, because one-third or more of patients are asymptomatic. The biochemical pattern seen in PBC is typically cholestatic: elevated alkaline phosphatase, GGT and 5«NT, with modest elevations of the aminotransferases. An elevated bilirubin is associated with progressive, symptomatic disease, indicating a poor prognosis. The most common symptom of this illness is fatigue, very hard to define yet very distressing to the patient. Other symptoms include pruritus, xanthelasma and, later in the course of the disease, ascites, jaundice and encephalopathy. Portal hypertension occurs early in this disease, as it is presinusoidal in nature; thus, variceal hemorrhage may be a presenting symptom. Many patients with PBC present with nonhepatic associations first. Raynaud's osteoporosis, sicca syndrome and rheumatoid arthritis are the most common. Some patients with PBC have been misdiagnosed as having the chronic fatigue syndrome.

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.

Any disease that permanently and progressively damages bile ducts and is not caused by PBC may lead to secondary biliary cirrhosis, sometimes (although not usually) in the absence of overt jaundice. The most obvious cause is biliary atresia; other pediatric conditions include the various hypoplastic duct syndromes, other biliary tree abnormalities - Caroli's disease, choledochal cysts, sclerosing cholangitis - and cystic fibrosis, which causes focal biliary cirrhosis. In adults the commonest cause of secondary biliary cirrhosis is probably primary sclerosing cholangitis (PSC), although iatrogenic bile duct strictures also feature.

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.

9.5.1 DIAGNOSIS

The history in any patient is always of utmost importance. A complete drug history should be taken, including prescribed and over-the-counter drugs. A past history of cholecystectomy should never be forgotten; common bile duct stones are not unusual, even in the absence of symptoms and/or dilated bile ducts on ultrasound. Manifestations of other autoimmune disease should be sought. A history of chills and fever would make one suspect extrahepatic (nonmalignant) biliary disease.

Examination should make special note of the patient's temperature. Signs of chronic cholestasis include scratch marks, shiny nails, increased skin pigmentation, xanthelasma, xanthomatous neuropathy, and jaundice, which in its later stages takes on a greenish hue. Hepatosplenomegaly is common in PBC, PSC and biliary atresia, and with infiltrations like lymphoma.

9.5.2 LABORATORY CONFIRMATION

The standard biochemical tests are most helpful. Liver function tends to remain normal for long periods in patients with anicteric cholestasis, but the enzyme markers - alkaline phosphatase, GGT, 5«NT - are always elevated. In those with prolonged jaundice, coagulation abnormalities (correctable with vitamin K) are common. If the results of these tests confirm the clinical suspicion, then the next step is an ultrasound to look at the bile ducts. If there is jaundice associated with fever or chills, there should be no delay with the ultrasound examination of the abdomen.

9.5.3 FURTHER MANAGEMENT

Further management will depend entirely on whether the patient has dilated ducts. If the ducts are dilated, the management will be interventional. If the ducts are not dilated but there is still a suspicion that the problem lies in the extrahepatic biliary system (common bile duct stones following cholecystectomy, PSC), then an ERCP may still be indicated. In most circumstances, an ERCP is a more helpful and safer method of investigating extrahepatic biliary obstruction, although if the local expertise is not available, a percutaneous cholangiogram (PTC) may be necessary. The true value of magnetic resonance cholangiography (MRC) is yet to be assessed.

If the history, physical and ultrasound all support a diagnosis of intrahepatic cholestasis, then a liver biopsy may be indicated to make a diagnosis, if this is not already obvious at the bedside (e.g., sepsis, drug reactions). Cholestatic drug reactions may take many months to clear after the drug has been withdrawn. A clinical diagnosis of PBC needs to be confirmed by a positive anti-mitochondrial antibody test +/- a liver biopsy.

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.