DIAGNOSIS AND THERAPY OF CHOLESTATIC LIVER DISEASE

MANAGEMENT OF CHRONIC LIVER DISEASE

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DIAGNOSIS AND THERAPY OF CHOLESTATIC LIVER DISEASE Tousif M. Pasha, MD, and Keith D. Lindor, MD

The differential diagnosis of cholestatic liver diseases is extensive. The first part of this article covers primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), as these two diseases have many clinical, biochemical, and pathologic features that are typical of cholestatic liver diseases. Subsequently, the remainder of the differential diagnoses (Table 1) and approach to diagnosis of cholestatic liver disease are discussed. PRIMARY BlLlARY CIRRHOSIS

PBC is a chronic progressive cholestatic disease, morphologically characterized by inflammatory destruction of the interlobular and septa1 bile ducts. The cause of PBC remains unknown, but there is considerable clinical, serologic, and histologic evidence to support an autoimmune etiology.4Z, 45 The disease primarily affects middle-aged women, who present with pruritus with or without jaundice. The routine use of screening blood tests has led to early detection of PBC in the asymptomatic stage. The diagnosis is made by detecting elevated serum alkaline phosphatase levels and serum antimitochondrial antibodies (AMA). The natural history is one of slowly progressive cholestasis with liver damage, fibrosis, and cirrhosis with its concomitant complications. Symptomatic treatment includes the control of pruritus and complications resulting from cholestasis, such as steatorrhea, fat-soluble vitamin deficiency, and osteoporosis. Many different pharmacologic therapies have been used to slow the progression of PBC with variable results. Ursodeoxycholic acid (UDCA) is the most promising. Liver transplantation is the only definitive therapy for the management of end-stage PBC,’06 although the disease can recur in the transplanted liver? Survival models have been developed to aid in the timing of liver transplantation for maximizing benefit to the patient.28

From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota

MEDICAL CLINICS OF NORTH AMERICA ~~~~

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VOLUME 80 * NUMBER 5 SEPTEMBER 1996

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Table 1. DIFFERENTIAL DIAGNOSIS OF CHOLESTATIC LIVER DISEASES lntrahepatic Cholestasis

Extrahepatic Biliary Obstruction

PBC PSC Drug toxicity Acute toxicity (<3 months) Acute cholestatic hepatitis Acute hepatitis Acute cholestasis (bland) Chronic toxicity (>6 months) Chronic cholestasis (PBC-like) Sclerosing cholangitis (PSC-like) Hepatocellular diseases Alcoholic hepatitis Viral hepatitis (6, C) Autoimmune hepatitis Sarcoidosis Postoperative state Parenteral nutrition Idiopathic adult ductopenia Dubin-Johnson syndrome Rotor’s syndrome Recurrent (benign) intrahepatic cholestasis Cholestatic jaundice of pregnancy

lntraductal obstruction/abnormalities Gallstones Surgical strictures Infections AIDS (Cryptosporidium,CMV) Malignancy Malformation (atresia) Cholangiocarcinoma Extrinsic compression Malignancy (pancreatic, metastasis) Pancreatitis Lymphoma

PBC = primary biliary cirrhosis; PSC = primary sclerosing cholangitis; AIDS deficiency syndrome; CMV = cytomegalovirus.

=

acquired imrnuno-

Epidemiology and Genetics

PBC has been reported from all parts of the world and affects all races. About 95% of patients are women, and the peak age of onset is from 30 to 64 years. PBC is an uncommon disease with a reported incidence of 5.8 to 15 cases per million persons per year and an estimated prevalence of 37 to 144 cases per million pers0ns.4~There have been several reports of associations with human leukocyte antigen (HLA) class I and class I1 antigens in PBC as well as familial clustering, suggesting a genetic associationP7 Pathogenesis

Although the cause remains unknown, PBC is considered an autoimmune disease on the basis of the presence of specific AMA, a strong association with other autoimmune diseases, involvement of T cells in the destruction of the bile ducts, and numerous defects in immunologic Despite several advances in the understanding of the epitopes recognized by AMA, the mechanisms responsible for the initiation and perpetuation of the disease remain undefined. AMA are found in 90% to 95% of patients with PBC. AMA are not specific for PBC and can be found in a small percentage of patients with autoimmune drug-induced hepatitis, connective tissue diseases, PSC, syphilis, and myocarditi~.~~, 35

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Table 2. HISTOLOGIC STAGING IN PRIMARY BlLlARY CIRRHOSIS

Inflammation limited to portal triads with mononuclear infiltration Stage 1 (portal stage) Stage I1 (periportal stage) Inflammation beyond portal triads, piecemeal necrosis, small granulomas, and small duct proliferation may be seen Stage 111 (septa1stage) Bridging fibrosis connecting the portal tracts Regenerative nodules surrounded by fibrosis Stage IV (cirrhosis)

AMA were first noted to be associated with PBC in 1965.'On The AMA were initially divided into nine subtypes, anti-M1 to anti-M9, with PBC associated with anti-M2, anti-M4, anti-M8, and anti-M9. The mitochondrial antigens to which anti-M2, the most specific AMA, are directed have been characterized and localized to the E2 subunit of the pyruvate dehydrogenase complex located on the inner mitochondrial membrane.3s Cytotoxic T cells as well as B cells are found in the region of bile duct destruction, and the presence of defective suppressor cell function and increased levels of IgM, IgG, and IgA in affected patients suggests abnormalities of both cellular and humoral immunity. Their role in the pathogenesis of PBC, however, still remains unclear.74,76 Pathology The initial lesion on liver biopsy is damage to epithelial cells of the small bile ducts (50 to 100 pm diameter). Based on histologic progression, four stages60 are described (Table 2). The most important and often only diagnostic clue in many cases of PBC is ductopenia (absence of interlobular bile ducts in > 50% of portal tracts). The florid duct Zesion (Fig. l), in which the epithelium of the

Figure 1. Liver biopsy showing florid duct lesion characteristic of primary biliary cirrhosis (hematoxylin & eosin, x 250).

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interlobular and segmental bile ducts degenerate segmentally with formation of poorly defined, noncaseating epitheloid granulomas, is nearly diagnostic of PBC, but is found in only a relatively small number of cases, mainly in stages I and IL60

Clinical Features Asymptomatic Diseases

Widespread use of screening laboratory tests has led to increased diagnosis of PBC at an asymptomatic stage.5RSuch patients are found incidentally to have an elevated serum alkaline phosphatase level and AMA (Table 3). Liver biopsy is almost always abnormal and usually shows features consistent with PBC. Other patients are diagnosed during investigation of hypercholesterolemia or investigation of symptoms of other associated diseases.Y3 Symptomatic Diseases

The patient is usually a middle-aged woman with a complaint of fatigue or pruritus. Other symptoms include right upper quadrant abdominal pain, anorexia, and jaundice. Pruritus may occur at any point in the course of the disease and may resolve as the disease progresses. Jaundice occurs later and is usually persistent. Other features include hyperpigmentation, xanthomas, and xanthelsma. Advanced disease may present with complications of cirrhosis, such as ascites, variceal bleeding, and en~ephalopathy.9~ Steatorrhea is commonly due to bile salt deficiency but may be due to concomitant pancreatic insufficiency or celiac s p r ~ e Spontaneous .~~ bone fractures may occur because of severe ~steopenia.~~

Table 3. DIAGNOSTIC FEATURES OF PRIMARY BlLlARY CIRRHOSIS AT PRESENTATION

Asymptomatic

Routine laboratory screening-increased serum alkaline phosphatase Positive serum antirnitochondrial antibody During investigation of other diseases, e.g., hypercholesterolemia Hepatomegaly Symptomatic

Middle-aged women with pruritus followed by slowly progressive jaundice Hepatomegaly Abnormal LFTs (elevated serum alkaline phosphatase, serum bilirubin, and mild elevations of serum aspartate transarninase) Serum antimitochondrial antibody >1:40 Liver biopsy-florid duct lesion, ductopenia ERCP-norrnal intrahepatic bile ducts LFTs

=

Liver function tests; ERCP

=

endoscopic retrograde cholangiopancreatography.

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Diagnosis Biochemical Changes

Serum biochemical tests show increased serum alkaline phosphatase (three to four times normal) and gamma-glutamyltranspeptidasevalues.75Serum alanine aminotransferase and aspartate aminotransferase levels are mildly elevated; marked elevations are distinctly unusual. Serum bilirubin levels increase slowly over the course of the disease and may reach levels exceeding 20 mg/dL. A high serum bilirubin level, low albumin level, and prolonged prothrombin time are all poor prognostic factors. Serum IgM levels are usually increased, but the levels are not diagnostic. Total serum bile acid levels are increased, and serum cholesterol is variably elevated.”, 93 Serologic Diagnosis

Approximately 90% to 95% of patients have serum AMA.lQoAMA-negative patients tend to follow a course similar to that of PBC and have been labeled as AMA-negative PBC and more recently autoimmune ckolangitis. The majority (95%) of these patients have either antinuclear antibodies or anti-smooth muscle antibodies? Associated Diseases

More than 80% of patients with PBC have coexistent autoimmune disease. The connective tissue disorders, in particular scleroderma, rheumatoid arthritis,15 dermatomyositis, mixed connective diseases, sicca syndrome, and systemic lupus erythematosus as well as renal tubular acidosis and thyroiditis are frequently associated (Table 4).15,22, 8n Treatment

No specific treatment has been proven to be completely effective in patients with PBC. Specific therapies have been studied, including immunosuppressive drugs, antifibrogenic drugs, and bile acids.

Table 4. DISEASES ASSOCIATED WITH PRIMARY BlLlARY CIRRHOSIS Disease

Connective tissue disease Keratoconjunctivitis sicca Arthritidarthropathy Scleroderma and variants Autoimmune thyroiditis Cutaneous disorders (lichen planus, discoid lupus, pemphigoid) Renal tubular acidosis (proximal or distal) Gallstones Pulmonary fibrosis Celiac diseases

Prevalence (“h)

72-1 00

4-42 15-20 15-20 11 50-60

33

rare rare

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Medical Therapy

Corticosteroids were the first immunosuppressive agents to be used for treatment of PBC. Early reports and one controlled trial suggested that corticosteroid therapy led to biochemical and histologic improvements, but these benefits were overshadowed by the osteopenic effects of steroid therapy.= Azathio~ r i n e , 3chlorambucil,N ~ c y c l o ~ p o r i n and , ~ ~ ~m e t h o t r e ~ a t ehave ~ ~ been used with varying results, but their potential toxicity and marginal efficacy preclude their routine use. Colchicine, an antifibrogenic agent, has shown limited, if any, benefit in the treatment of PBC. Three placebo-controlled trials reported varying improvement in the biochemical profile and showed no histologic or symptomatic improvement? Another antifibrogenic agent, malotilate, showed only mild improvement of biochemical parameters and histology in a placebo-controlled trial in Europe and did not affect symptoms, extent of fibrosis, or survival when compared to placebo.2 Several placebo-controlled trials in patients with PBC have reported that UDCA, a hydrophilic, and hence less toxic, bile improves cholestatic biochemical parameters when used in doses of 13 to 15 mg/kg.54~85 In some series, symptomatic and histologic improvement has been noted, and long-term data suggest increased survival and delay in the need for liver tran~plantation.~~ Although UDCA is currently not approved for treatment in PBC, its use seems reasonable because the drug has minimal side effects, and there are no other safe and efficacious treatment Liver Transplantation

The best therapeutic option for patients with end-stage PBC is liver transPatients with PBC are generally good candidates for liver transplantation because the majority are middle-aged without other serious illnesses. The natural history of PBC is reasonably well-known, and this facilitates patient selection and optimal timing of liver transplantation.’06Several prognostic models for PBC, including the Mayo risk model, have been developed from simple clinical measures such as serum bilirubin, which is an important variable in predicting survival. The Mayo risk model takes into account the age, serum bilirubin, serum albumin, prothrombin time, and presence or absence of edema.28 Using this model, a risk score for an individual can be calculated. Although a single risk score may not indicate if transplantation is needed, serial measurements may be helpful, and an abrupt change in the value predicts poor prognosis and suggests the need to proceed with liver transplantation. In addition to careful selection of patients, timing of liver transplantation is important to optimize outcome, decrease morbidity, and decrease cost. Although many factors must be taken into account to determine the timing of liver transplantation, there is growing evidence that transplantation earlier in the course of the disease (when the Mayo risk score is lower) rather than when the patient experiences life-threatening complications or is on life-support can improve post-liver transplantation survival.106 Indications for liver transplantation for all forms of liver disease as well as indications specific for cholestatic liver disease are listed in Table 5. Factors that need to be taken into consideration include a decrease in the quality of life, progressive cholestasis (bilirubin >10 mg/dL), deteriorating hepatic synthetic function, or intractable symptoms. Disabling fatigue; pruritus; refractory ascites; hepatic encephalopathy; or variceal bleeding not controlled by sclerotherapy, banding, or transjugular intrahepatic portocaval shunt are indications for liver

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Table 5. INDICATIONS FOR LIVER TRANSPLANTATION Indications Specific t6 Cholestatic Liver Diseases

Biochemical indications Serum bilirubin >10 mg/dL Clinical indications Intractable pruritus Progressive bone disease Recurrent bacterial cholangitis General Clinical Indications (Hepatocellular and Cholestatic Liver Disease)

Recurrent or progressive hepatic encephalopathy Refractory ascites Spontaneous bacterial peritonitis Recurrent portal hypertensive bleeding Severe chronic fatigue and weakness Development of hepatorenal syndrome Progressive malnutrition Detection of small hepatocellular carcinoma

transplantation. Liver transplantation clearly improves survival as well as quality of life; 1-year survival rates after liver transplantation are currently 85% to 90%, and in most centers, 5-year survival rates are 60% to 70%.68AMA generally persist after liver transplantation, and in long-term follow-up studies, up to 10% of patients have evidence of histologic recurrence of PBC.3 Although longer follow-up is required, preliminary data suggest that recurrent disease seems to follow a relatively benign course. (See also article by Rosen and colleagues.) Complications Pruritus is a frequent complication of cholestasis. The cause remains unknown but may be due to the accumulation of hydrophobic bile acids in the skin and excitation of nerve endings. This symptom is difficult to manage, and intractable pruritus has occasionally been an indication for liver transplantatiom4*Cholestyramine, opiate antagonists, UDCA, rifampin,@and flumecinoly6 have been used with varying success. In patients with PBC in North America, osteopenia is nearly always due to osteoporosis. These patients appear to have an accelerated rate of bone loss, but most studies suggest that osteopenia is due to decreased formation rather than to increased resorption of Estrogen therapy, especially when instituted soon after menopause, has been associated with slowing of the rate of bone loss. High-dose estrogen therapy has a theoretic risk of worsening jaundice, but this is not the case with low-dose therapy. Nevertheless, it is prudent to reassess the patient clinically and biochemically within 2 to 3 months after initiation of the estrogen therapy.I9 Most patients with PBC with fat-soluble vitamin deficiency have advanced liver disease, are jaundiced, and have a fecal fat loss in the range of 10 to 30 g/ day.87Vitamin D deficiency can be confirmed by measuring serum vitamin D levels, and when encountered, 50,000 U of vitamin D given once or twice per week is usually sufficient to correct the d e f i ~ i e n c y Vitamin .~~ A deficiency is

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uncommon and may present clinically with night blindness. Vitamin A levels can be measured, and when low, replacement with 25,000 to 50,000 U two to three times per week should be instituted, beginning at lower levels and assessing the adequacy of replacement therapy by repeat serum assays,'* because excessive vitamin A uptake has been associated with hepatotoxicity. Vitamin E deficiency has been reported in a few cases of PBC. Typically, vitamin E deficiency causes a neurologic abnormality primarily affecting the posterior columns and characterized by areflexia or loss of proprioception sense and ataxia. Replacement of vitamin E in these patients has been disappointing; nevertheless, patients with low levels of vitamin E should be started on replacement therapy, usually 100 mg twice dailyA3 Hypercholesterolemia is common, especially early in the course of the disease. The incidence of atherosclerotic heart disease is not increased in these patients, and therapy with drugs such as lovastatin is not indicated.*l In patients with cholesterol deposits in the form of xanthomas or xanthelasma, therapy with UDCA and cholestyramine may stabilize and even decrease the size of these cutaneous deposits?

Natural History and Prognosis Understanding of the natural history of PBC is in a state of evolution. The time of onset of the asymptomatic phase is not clear, and increasingly younger patients with mild liver test abnormalities are being detected. The disease has a slow progression with gradual development of symptoms and ultimately death from complications of biliary cirrhosis?* Earlier studies indicated that asymptomatic patients had a normal life expectancy; however, longer follow-up does not support this concl~sion.~ The overall course of the disease may exceed 10 to 15 years, but when serum bilirubin levels exceed 8 to 10 mg/dL, the average life expectancy is reduced to 2 years. Statistical survival models, as mentioned earlier, are useful in predicting survival and are particularly useful for determining the timing of liver transplantation.2*,Io6

PRIMARY SCLEROSING CHOLANGITIS PSC is a chronic cholestatic syndrome of unknown etiology characterized by diffuse inflammation and fibrosis of the intrahepatic and extrahepatic biliary ductal systems. Although the course is variable, the disease is usually progressive, advancing to biliary cirrhosis, portal hypertension, and, unless intervention with liver transplantation is accomplished, premature death from liver failure. PSC frequently occurs in association with inflammatory bowel disease, mainly chronic ulcerative colitis. The cause of PSC is unknown, and there is no adequate therapy. Similar to PBC, a variety of complications of cholestasis can occur with PSC. In addition to biliary strictures, a major complication unique to PSC is the occurrence of cholangiocarcinoma in approximately 10% of patient^.'^, Io3 Secondary sclerosing cholangitis has similar clinical characteristics as PSC but has identifiable causes (see Table l).'jl, 63

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Epidemiology

The diagnosis of PSC has increased dramatically in the last 10 to 15 years because of increased clinical awareness and utilization of diagnostic tests such as endoscopic retrograde cholangiography (ERCP), rather than a true increase in the incidence of the disease. PSC is predominantly a disease of young men. Approximately 70% of patients are male, and the average age at the time of diagnosis is 40 years.77,lo3

Pathogenesis

The cause of PSC remains unknown. A variety of mechanisms have been studied, including toxins, viral agents, and genetic and immunologic abnormalities. Absorption of toxins from an inflamed colon has been suggested as a pathogenic mechanism, but this has not yet been proven in human studies?’ Viral infections such as hepatitis A, B, and C viruses and reovirus type 3 have been studied and excluded as causes.” A role for genetic factors is supported by reports of familial occurrences of PSC and ulcerative colitis and an increased frequency of HLA B8 and HLA DR3 in patients with PSC.l4 Immunologic abnormalities include aberrant HLA expression on bile ducts, enhanced autoreactivity, and abnormalities in lymphocyte subsets.20

Clinical Presentation

Increasingly, in the last few years, patients with abnormal liver tests and without any symptoms of liver disease have been diagnosed with PSC (Tables 6 and 7). Alternatively, patients may present with pruritus, fatigue, and jaundice. Hyperpigmentation and xanthomas occur less often than in patients with PBC.’04 Approximately 70% of patients with PSC have associated inflammatory bowel disease, which usually precedes the diagnosis of PSC. The liver disease can occur after proctocolectomy, and colitis can develop several years after the onset of PSC.” Only 5% of patients with chronic ulcerative colitis have PSC. Patients may also present with episodes of fever and abdominal pain with or without jaundice (see Table 7). These recurrent episodes of cholangitis occur more frequently in patients with PSC who have undergone previous biliary tract surgery than in those who have not undergone surgery.13Some patients are diagnosed when they present with complications of advanced liver disease, such as ascites or upper gastrointestinal bleeding from varices.’03

Table 6. MODES OF CLINICAL PRESENTATION IN PATIENTS WITH PRIMARY

SCLEROSING CHOLANGITIS Asymptomatic, with abnormal liver tests Chronic cholestasis Recurrent cholangitis Complications of chronic liver disease Incidental discovery at laparotomy

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Table 7. SYMPTOMS AND SIGNS AT DIAGNOSIS IN PRIMARY SCLEROSING CHOLANGITIS Symptom or Sign Symptom Fatigue Pruritus Jaundice Weight loss Fever Sign Hepatomegaly Jaundice Splenomegaly Hyperpigmentation Xanthomas Serum alkaline phosphatase elevation Serum transaminase elevation Serum bilirubin elevation Frequency of inflammatory bowel disease Chronic ulcerative colitis Crohn’s disease

Frequency (%) 75

70 65 40 35 55 50 30 25 4

100 95 65 77 67 8

Diagnosis

The diagnosis of PSC is based on a combination of clinical, biochemical, radiologic, and, in some cases, pathologic criteria (Table 8; see Tables 6 and 7). Biochemical Tests

Almost all patients with PSC have an elevated serum alkaline phosphatase level (usually three to five times greater than normal). Similarly a majority have a mild increase in serum aspartate or alanine aminotransferase levels.56Serum bilirubin levels fluctuate, and high levels suggest progression of the diseases and complication^.'^ Of interest is the observation that tests related to copper metabolism are virtually always abnormal in patients with PSC, as with most cholestatic diseases.36

Table 8. RADIOLOGIC AND HISTOLOGIC FEATURES OF PRlMARY SCLEROSING CHOLANGITIS Radiologic Features (Cholangiographic Findings) Diffuse multifocal annular strictures of intrahepatidextrahepaticbile ducts Short bandlike strictures Diverticulum-likeoutpouchings Histologic Criteria (Ludwig Staging System) Portal stage (stage I) Portal hepatitis (limited to limiting plate) Periportal fibrosis/inflammation,beyond limiting plate Periportal stage (stage II) Septal fibrosislbridging necrosis Septal stage (stage 111) Cirrhotic stage (stage IV) Biliary cirrhosis

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Antibodies to as yet unidentified antigens present in the cytoplasm and the nucleus of neutrophils (antineutrophil cytoplasmic antibodies [ANCA]) have been described in approximately 70% of patients with PSC. The significance of this finding remains to be determined.30,9fl Radiologic Features

Cholangiography is the most important diagnostic test. ERCP is the procedure of choice.ffiIn most cases of PSC, the characteristic cholangiographic changes described can be seen (Fig. 2; see Table 8). Occasionally, these abnormalities are limited to intrahepatic ducts or localized to a small segment of the extrahepatic biliary system. Cholangiocarcinoma should be excluded, particularly in such atypical presentations.66Other diffuse liver diseases, such as hepatic metastases, advanced cirrhosis, polycystic liver disease, and lymphoma, may also produce narrowing and other deformities of the ducts. Rarely the pancreatic duct may be involved and demonstrate abnormalities suggestive of chronic pancreatitkffi Hepatic Histology

The main features in liver biopsy specimens of patients with PSC are periductal fibrosis and inflammation, bile duct proliferation alternating with ductal obliteration, and ductopenia. Fibrous-obliterative cholangiopathy is nearly diagnostic of PSC (Fig. 3); however, this is an uncommon Histologically the findings must be differentiated from other diseases, such as

Figure 2. Cholangiogram showing multiple strictures in the intrahepatic and extrahepatic bile ducts in a patient with primary sclerosing cholangitis.

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Figure 3. Liver biopsy showing fibrous-obliterativecholangiopathy characteristic of primary sclerosing cholangitis (hematoxylin & eosin, x 150).

PBC, prolonged extrahepatic obstruction, and autoimmune hepatitis. Many of these conditions have overlapping features and sometimes cannot be distinguished on purely histologic grounds?' Nevertheless, a liver biopsy is useful in establishing the diagnosis of PSC and is indispensable in staging the disease. As in PBC, the histologic abnormalities in PSC are divided into four stageP (see Table 8). Specific Treatment

Treatment directed toward suppressing hepatic inflammation and fibrosis has not proven successful. Palliative treatment of biliary strictures has variable benefit. Liver transplantation is the treatment of choice for end-stage liver disease.h9 Medical and Surgical Treatment

Penicillamine,5°c o l c h i ~ i n eazathioprine,9y ~~ cyclo~porin,'~~ conventional corticosteroids,'" and methotre~ate~~ are not of benefit in the treatment of PSC. UDCA is currently under investigation, and preliminary information suggests potential benefit. Several studies have shown biochemical improvement, and a few reports have suggested improvements in symptoms, histology, and cholangiography with UDCA.57,97 Surgical treatment, as well as endoscopic balloon dilatation and stenting, have been used to alleviate symptoms in patients with biliary strictures in certain specific ~ituati0ns.l~ These therapies are palliative and do not influence the natural progression of the disease. Biliary tract reconstructive procedures are reserved for cases in which severe jaundice and pruritus result from a dominant extrahepatic stricture not amenable to endoscopic or percutaneous

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balloon dilatation or stenting.17 Studies have shown that proctocolectomy for ulcerative colitis is not beneficial for PSC in patients with both diseases.102

Liver Transplantation Liver transplantation is the only therapeutic intervention that can be lifesaving for patients with end-stage disease and is successful in the majority of these patients. Previous operations such as colectomy or biliary tract surgery may make transplantation technically more difficult, and the need for a choledochojejunostomy in these patients increases the risk of biliary complications after tran~plantation.~~, 91 Despite this, studies suggest that the outcome of liver transplantation in patients with PSC is no different from the outcome in patients with other forms of chronic liver disease, with 5-year survival rates of 7% t0 8.%.71 The natural history of PSC is not as well defined as that for PBC. Survival models similar to those in PBC have been developed for PSC, although they have not been as well validated.lO' Indications for liver transplantation include those listed in Table 5. In general, patients with PSC should be referred early for consideration of liver transplantation, before the development of cholangiocarcinoma or advanced cholestatic liver failure. Because most patients do well after liver transplantation, aggressive surgical measures to relieve extrahepatic biliary obstruction before transplantation are generally not warranted. Most transplantation centers consider cholangiocarcinoma to be an absolute contraindication to liver transplantation because of the high risk of recurrent Concerns about recurrence of PSC have been raised. Finally, although symptoms related to inflammatory bowel disease remain quiescent after liver transplantation in patients with PSC and inflammatory bowel disease, colon cancer has been reported after liver transplantation, emphasizing the importance of continued colon cancer surveillance in these patients.38 Complications

PSC is associated with specific complications in addition to those related to advanced liver disease, such as variceal bleeding, ascites, and encephalopathy, and complications of cholestasis, such as osteopenia and fat-soluble vitamin deficiency, discussed under PBC.& The specific complications include cholangitis, dominant strictures, biliary stone disease, cholangiocarcinoma, and peristoma1 varices. Cholangitis can occur spontaneously; however, this complication almost always occurs in patients who have had previous surgical or radiologic manipulation of the biliary tree. Cholangitis may present as fevers, chills, and pain and result in life-threatening sepsis with shock. Empiric antibiotic therapy to cover commonly found organisms such as Enterobacter, Enterococcus, and Clostridium species should be started while awaiting culture results. In a patient with an otherwise stable course who develops superimposed cholangitis, performance of a cholangiogram to look for a stricture should be ons side red.'"^ Although PSC most commonly involves the entire biliary system, the presence of a dominant stricture (a high-grade, localized area of narrowing) may result in a rapid but reversible worsening of jaundice and may cause recurrent cholangitis. Cholangiography is indicated when a dominant stricture is suspected. Cholangiography may be done endoscopically or percutaneously, de-

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pending on the location of the stricture; identified strictures can be dilated using a balloon catheter. Some strictures may require stenting for 3 to 6 months after dilation to maintain bile duct patency.I7Cytologic brushings should be obtained to exclude cholangiocarcinoma. Biliary stone disease is a common complication in PSC, occurring in a fourth of the patients; the stones are usually confined to the gallbladder.9Worsening of liver tests or the onset of pruritus or cholangitis may be the presenting feature of choledocholithiasis. ERCP is useful in establishing the diagnosis as well as for sphincterotomy and stone extraction. Cholangiocarcinoma is the most devastating and lethal complication of PSC and occurs in 10% to 15% of patients.88,94 Risk factors have not been studied in detail, but most patients with cholangiocarcinoma have advanced liver disease, long-standing ulcerative colitis and progressive changes on cholangiography. Other clues to the diagnosis include a rapid, persistent increase in jaundice and marked elevation of serum alkaline phosphatase levels. Repeated attempts at brushing for cytology help to distinguish between benign and malignant strictures. The overall median survival is approximately 5 months, and liver transplantation is seldom successful in these ~atients.9~ Patients who have undergone proctocolectomy for associated chronic ulcerative colitis and an ileostomy may develop varices around the ostomy stoma as a manifestation of portal hypertension. These varices are painful and may bleed severely and require blood transfusions. Local measures to control bleeding generally fail. The bleeding can be reversed by lowering the portal pressure, ideally by liver transplantation.Io2 Prognosis The prognosis of PSC varies considerably from patient to patient, and information regarding the natural history is slowly evolving. In general, PSC is a progressive disease with a median survival of 10 to 12 years from diagnosis, and both symptomatic and asymptomatic patients have reduced survival compared to age-matched, sex-matched, and race-matched U.S. p o p ~ l a t i o n s As .~~ mentioned earlier, models to predict survival and aid in the timing of liver transplantation have been developed, and these generally take into account the age, bilirubin levels, histologic stage, and presence or absence of splenomegaly. These models, however, require cross-validation before their true utility is known.'Ol DIFFERENTIAL DIAGNOSIS OF CHOLESTATIC LIVER DISEASES Other diseases that need to be considered in the patient with cholestasis have been listed in Table 1 and are briefly discussed. Familial Diseases Dubin-Johnson syndrome, also called chronic idiopathic jaundice, is an autosomally inherited disorder in which there is a defect in the excretion of bilirubin. Classically, the sulfobromophthalein (Bromsulphalein) elimination is

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delayed. Affected patients may be asymptomatic, have vague constitutional symptoms, or present with jaundice for the first time when using oral contraceptives. The patient typically does not have an elevation of the serum alkaline phosphatase level and requires no treatment. The prognosis is excellent.'08 Another rare syndrome inherited as an autosomal recessive trait is Rotor's syndrome which is associated with impairment of hepatic storage capacity. There is no pigment in the liver cells, and the Bromsulphalein elimination curve is normal.'M Benign Familial Recurrent Cholestasis

This is a rare syndrome characterized by recurrent attacks of pruritus and jaundice. During the attack, serum alkaline phosphatase levels increase, and the liver biopsy specimen shows features of cholestasis. The cholangiogram is normal, however, and remission is the rule. Cirrhosis does not develop, and the prognosis is excellent." lntrahepatic Cholestasis of Pregnancy

This is the second most common cause of jaundice in pregnancy, after viral hepatitis. It occurs in the second or third trimester of pregnancy and presents typically with pruritus and later jaundice. The syndrome lasts for the duration of the pregnancy and resolves within 2 to 4 weeks of delivery, with no longterm s e q ~ e l a e . ~ ~ This condition may be recurrent, is known to occur in families, and is associated with cholestasis seen with oral contraceptives and so-called benign recurrent cholestasis. The cause is thought to be increased sensitivity of the bile ducts to estrogen52and is treated with UDCA.79(See also the article by Wolf.) Drug-Induced Cholestasis

Drugs and chemical agents can produce not only cholestatic liver injury, but also liver injury resembling acute hepatitis, cholestatic hepatitis, chronic hepatitis, and granulomatous hepatitis6,33 Based on the mechanism of liver injury, two major types of chemical hepatotoxicity have been recognized: direct toxic injury and idiosyncratic damage. Direct toxic injury most likely results in hepatocellular damage; has a short latency period and a predictable and doserelated toxicity; and generally lacks extrahepatic manifestations such as arthralgia, fever, rash and eosinophilia. Idiosyncratic reactions do not have a predictable or dose-related toxicity; have a variable latency period between exposure and effect; may have extrahepatic manifestations; and can have a variety of different hepatic histopathologic responses, depending on the toxin?3 Generally, there is a history of drug or chemical exposure that helps in the diagnosis. A list of offending agents is presented in Table 9. Acute forms of liver toxicity are seen most commonly. In acute cholestatic hepatitis, seen for example with chlorpromazine toxicity, pruritus and jaundice develop 1 to 4 weeks after treatment. Liver biopsy shows cholestasis; bile plugs in dilated biliary canaliculi; and a dense portal infiltrate of polymorphonuclear leukocytes, eosinophils, and mononuclear cells?' Chronic forms of toxicity with syndromes

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Table 9. LIST OF COMMON DRUGS THAT MAY CAUSE CHOLESTASIS

Acute cholestatic hepatitis Azathioprine Captopril Chlorpromazine Chlordiazepoxide Cyclosporin Erythromycin Gold salts Acute cholestasis-bland Oral contraceptives and estrogen Anabolic steroids and androgens Granulomatous hepatitis Allopurinol Carbamazepine Hydralazine Penicillin Quinidine Sulfonamides PBC

=

Mixed hepatitis Amitriptyline Benoxaprofen Carbamazepine Cimetidine Dapsone lmipramine Quinidine Ranitidine Sulfonamides Sulindac Chronic cholestasis (PBC-like) Chlorpromazine Ajmaline Sclerosing cholangitis 5-fluorouracil or floxuridine

Primary biliary cirrhosis.

resembling PBC developing several months after acute cholestasis have also been described. The AMA tests are usually negative, and on liver biopsy the characteristic florid duct lesion is not seen. In a few instances, secondary biliary cirrhosis has been reported. The prognosis is generally good. A condition similar to cholestasis seen in pregnancy can occur following the use of oral contraceptives. The liver tests return to normal after withdrawal of the drug, and chronic liver disease does not result. Histopathology shows cholestatic features without portal inflammation.= Intrahepatic arterial infusion of floxuridine for therapy of hepatic metastatic carcinoma is associated with a high incidence of injury to the biliary tree, causing biliary sclerosis. The lesions consist of edema and blebs on the ductal epithelial surface causing distortion of the lumen and resemble cholangiographic lesions in PSC. Clinical features include jaundice, anorexia, upper abdominal pain, and weight loss.61(See also the article by Moseley.) Biliary Obstruction In adults, the most common causes of secondary biliary cirrhosis are postoperative biliary strictures or gallstones, usually with superimposed infectious cholangiti~.~~ Other causes include biliary strictures from chronic pancreatitis; extrinsic compression of bile ducts by lymphoma or metastatic carcinoma70;and rare infestation with parasites such as Clonorckis sinensis, Opisthorckis viverrini or 0.felineus, and Fasciola hepatica occurring in inhabitants of China and Southeast Asia.86Malignant tumors of the common bile duct or pancreas rarely cause biliary cirrhosis because the patients do not live long enough to develop cirrhos k Z 5In general, it takes at least 6 to 12 months of partial or complete obstruction of the common bile duct or its major branches to result in cirrhosis. In biliary obstruction, fever or right upper quadrant pain (cholangitis) or biliary colic typically occurs with jaundice and pruritus, which are common

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presenting symptoms as well. A cholestatic biochemical profile shows elevated serum alkaline phosphatase and gamma glutamyltranspeptidase levels, conjugated hyperbilirubinemia, and moderate elevation of serum aminotransferase levels. The AMA test, however, is usually negative, and cholangiography usually demonstrates the underlying pathology. Liver biopsy shows periportal bile infarcts, proliferation and dilation of the portal bile ducts and ductules, accumulation of polymorphonuclear leukocytes around bile ducts, and, ultimately, expansion of the portal tracts and fibrosis. Early relief of obstruction to the bile flow (either surgical or endoscopic) is important in preventing secondary biliary cirrhosis. Decompression improves the outcome, even in patients with established cirrhosis. Failure to do so leads to progressive end-stage liver disease.2h Secondary Sclerosing Cholangitis

PSC should be the major working diagnosis in a young man with chronic cholestasis and inflammatory bowel diseases, as discussed previously. Secondary sclerosing cholangitis can be seen in a variety of conditions. Increasingly, acalculous cholecystitis and sclerosing cholangitis with or without papillary stenosis caused by Cryptosporidium species, cytomegalovirus, and Microsporidia have been described in patients with acquired immunodeficiency syndrome (AIDS). Treatment is not satisfactory.12 Other conditions that may have cholangiographic features of PSC include postsurgical strictures, cholangiocarcinoma, hepatic arterial injury (caused by 5- ' fluorouracil, floxuridine, or thiabendazole), and other malignancies such as lymphoma and metastatic carcinoma?' Sarcoidosis

Chronic cholestatic sarcoidosis, found particularly in young African-American men, can present with features that are histologically similar to PBC and in some cases similar to PSC. Granulomatous destruction of small ducts is a hallmark of this condition. The granulomas are typically large and well-defined, in contrast to the small and poorly defined granulomas seen in PBC. Most of these patients have hilar adenopathy on chest roentgenograms and other features of sarcoidosis but do not have AMA.27 Autoimmune Hepatitis

Some patients with autoimmune hepatitis may be confused with those with PBC, especially patients with autoimmune hepatitis who also have AMA, usually in low titers of 1:40or less. About 95%, however, have antinuclear antibodies and anti-smooth muscle antibodies in the serum and on liver biopsy; these patients rarely have destruction of bile ducts. Pruritus is less common, and the serum alkaline phosphatase level is not high. In 2% to 3% of cases, it may be impossible to differentiate autoimmune hepatitis from PBC, and under these circumstances a trial of immunosuppressive therapy brings about a dramatic response in patients with autoimmune hepatitis. An overlap syndrome with features of both PBC and autoimmune hepatitis has been described in which

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the patients have typical histologic features of granulomatous cholangitis seen in PBC and high titers of AMA as well as antinuclear antibodies. UDCA and immunosuppressive drugs have been used for treatment with some success.*6 (See also the article by Czaja.)

Viral Hepatitis

Hepatitis C has been associated with chronic cholestasis, although the usual biochemical abnormalities reflect hepatocellular damage. Liver biopsy occasionally shows granulomatous inflammation around bile ducts, but most patients have antibodies to hepatitis C virus and the absence of AMA.

Alcoholic Hepatitis

Patients with alcoholic hepatitis can present with clinical and biochemical features of cholestatic liver disease. Alcoholic hepatitis may also coexist with other liver diseases, and hence a detailed history of alcohol intake should be obtained. Other clues to suspected alcoholic disease include the detection of Mallory bodies and central hyaline sclerosis in liver biopsy specimens. Imaging studies may detect a fatty liver and normal biliary system. Serologic tests are negative.51

Cystic Fibrosis

With advances in therapy of lung and pancreatic diseases in patients with cystic fibrosis, 60% or more of children with cystic fibrosis are surviving to adulthood.81Patients may have neonatal jaundice that generally resolves only to recur later in life. Histologic examination of the liver shows mucus-plugged cholangioles without significant parenchymal damage; consequently, portal hypertension is a prominent manifestation, whereas liver failure is rare. Focal biliary fibrosis may be present and is thought to be secondary to biliary obstruction. About a third of patients have abnormalities of the gallbladder or cystic duct. Prognosis is still largely determined by complications of pulmonary disease. There are reports of successful orthotopic liver transplantation for patients with advanced liver disease because of cystic fibrosis.lR

Idiopathic Adulthood Ductopenia

This unusual syndrome occurs in individuals who have normal cholangiograms, negative AMA tests, and no associated inflammatory bowel disease. They present with chronic cholestasis and on liver biopsy have ductopenia. Although this disease appears distinct from PSC and PBC, the natural history remains unknown.64

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APPROACH TO A PATIENT WITH CHOLESTATIC LIVER DISEASE The evaluation of adult patients with a cholestatic liver biochemical profile can be challenging. With the increasing use of screening laboratory tests, patients without symptoms and with mild elevations of serum alkaline phosphatase and gamma-glutamyltranspeptidase levels are being detected. When a patient presents with a cholestatic biochemical profile, with or without jaundice, it usually results from one of two major disease processes: biliary obstruction (intrahepatic or extrahepatic) or parenchymal liver disease. When jaundice is present, the first step is to determine if it is due to hemolysis or hepatobiliary disease. This is easily accomplished by measuring direct and indirect fractions of bilirubin. Jaundice associated primarily with unconjugated bilirubin indicates a hemolytic disorder. The initial approach to a patient who presents with a cholestatic liver enzyme profile (predominant elevations in serum alkaline phophatase and gamma-glutamyltranspeptidase levels, with or without conjugated hyperbilirubinemia and mild aminotransferase elevations) must be determined by the clinical pre~entation.~'Obtaining a careful history, performing a careful physical examination, and performing routine biochemical tests provide valuable information such that an experienced clinician can predict the nature of cholestasis in many cases.83 More importantly, the results of the clinical evaluation can direct the physician to a logical progression of imaging studies, serologic tests, and histologic evaluation. A general algorithm for the evaluation of a patient with a cholestatic biochemical profile is shown in Figure 4. The clinical evaluation should focus on distinguishing between hepatocellular, intrahepatic, and extrahepatic causes of liver disease (see Table 1).Extrahepatic causes should be excluded early because they are potentially reversible and failure to do so may result in complications such as recurrent cholangitis or secondary biliary cirrhosis. Biliary imagingR2with ultrasound or computed tomography (CT) scanning provides valuable information, regarding not only the presence of dilated bile ducts but also focal or diffuse parenchymal liver disease. Ultrasound is more sensitive than CT in detecting gallstones, whereas CT scan is better in visualizing pancreatic diseases. Both procedures are not sensitive for detecting intraductal stones. Although both procedures provide valuable clues to the cause of biliary obstruction, definitive diagnosis often remains in doubt. In these cases, a cholangiogram, either percutaneous or endoscopic, should be The endoscopic approach is preferred for several reasons: The duodenum, which is a common site for tumors causing biliary obstruction, can be inspected; the pancreatic duct can be visualized; the intrahepatic bile ducts may be sclerotic, making percutaneous cholangiography difficult; and therapeutic measures can be employed if necessary. If these investigations provide no clues, the next step is to proceed with a percutaneous liver biopsy, which often suggests the nature of liver disease (e.g., PBC, acute or chronic hepatitis, biliary tract disease, granulomatous hepatitis). (See also the article by Moseley.) SUMMARY The majority of cholestatic liver diseases can be diagnosed with a carefully performed history taking, physical examination, and appropriate imaging stud-

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Elevated alkaline phosphatase, gamma-glutamyltranspeptidase, with or without elevated conj. bilirubin

computed tomography of abdomen

(ductal dilatation or focal lesion)

1 I

I

J. Biopsy/brushingof lesion if indicated

1

1

I

1

I

I

i

Liver biopsy I

Figure 4. A diagnostic approach to cholestatic liver disease. US = ultrasound; ERCP = endoscopic retrograde cholangiopancreatography; PTC = percutaneous transhepatic cholangiography.

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ies. In a minority of cases, however, liver biopsy may be necessary to establish the diagnosis. In addition to the treatment of the specific liver disease, therapy should address the management of complications unique to cholestasis and progressive liver failure.

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