PRIMARY BILIARY CIRRHOSIS AND PRIMARY SCLEROSING CHOLANGITIS

CHOLESTASIS

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PRIMARY BILIARY CIRRHOSIS AND PRIMARY SCLEROSING CHOLANGITIS Paul Angulo, MD, and Keith D. Lindor, MD

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the most common chronic cholestatic liver diseases in adults. They represent clinically distinct diseases with a presumed autoimmune basis. Both conditions are characterized by progressive destruction of bile ducts leading to chronic cholestasis and biliary cirrhosis with its consequent complications, such as portal hypertension and liver failure. Although initially perceived by clinicians as rare diseases, PBC and PSC are being increasingly diagnosed and are currently among the most common reasons for hepatic transplantation.

PRIMARY BILIARY CIRRHOSIS Primary biliary cirrhosis is a disease most often diagnosed in middle-aged women of most racial groups and is characterized by ongoing inflammatory destruction of interlobular and septa1 bile ducts leading to biliary cirrhosis. Although the term primary biliary cirrhosis has been used for several decades, this terminology conveys erroneous information because most patients do not have cirrhosis on liver biopsy when the disease is diagnosed.

From the Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota

CLINICS IN LIVER DISEASE VOLUME 3 * NUMBER 3 AUGUST 1999

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ANGULO & LINDOR

Epidemiology

Primary biliary cirrhosis occurs worldwide and predominantly in women with a female to male ratio of 9 to 1. The median onset of disease is 50 years of age, but with a wide range of 21 to 91 years. Primary biliary cirrhosis has not been described in persons younger than 20 years of age. The true prevalence and incidence of PBC is unclear, because few epidemiologic studies have been conducted. Until the early 1970s, PBC was considered a rare condition that presented with persistent jaundice and almost inevitably progressed to end-stage liver disease. A better understanding of its pathogenesis in the last two decades and some recent clinical and epidemiologic studies have modified the understanding of this condition. Primary biliary cirrhosis seems to be more common than was believed because there is now an increasing awareness of the disease and because asymptomatic patients can be identified through the widespread use of screening tests, such as serum cholesterol levels and liver biochemistries. The highest incidence and prevalence of PBC have been reported in Northern However, the reported prevalence reported is geographically quite variable, ranging from 19 cases per million population in Australiazz3to 240 cases per million population in northeastern England.lsoWhether this variation represents a true difference in prevalence or results from different methodologies used in these studies is unknown. Inconsistencies in case definition and case finding methods, as well as imprecision in defining the study area, the populations evaluated, and the date of diagnosis, particularly in the earlier reports, make the comparison of studies difficult. The estimates of annual incidence range from 21a8to 22150 per million population. The prevalence of PBC seems to increase over time, with 18 cases per million population reported in 1976,16zrising to 240 cases per million population as reported in 1994150;without a clear increase in the incidence of PBC this rise may reflect an increase in survival time for patients with PBC. Genetics The occurrence of PBC in relatives of patients with this condition, along with abnormalities of cell-mediated immunity in first-degree relatives of PBC patients,13,152 suggests a genetic association. Although no significant link between PBC and the HLA class I phenotype has been found, to class I1 HLA molecules seem to contribute to the development of this condition. The association with HLA-DR8 is the most frequently observed link found in different studies, although it is present in only about one third of cases.68,zll Conversely, the DQA1*0102 haplotype seems to be strongly associated with disease resistance.z0The association with HLA class I11 antigens whose genes code for complement components C2 and C4 and factor B has been less extensively studied. An

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increased frequency of haplotype C4B2 has been reported.32Using a genotyping method, an excess frequency of haplotype C4A*QO with a significant relative risk (RR = 184) was also found to be associated with PBC.146 Pathogenesis

Although the cause of PBC remains unknown, several lines of evidence suggest an autoimmune process. These include the presence of highly specific antimitochondrial antibodies (AMA), a frequent association with other autoimmune diseases, involvement of T cells in the destruction of the bile ducts, and numerous defects in immunologic reg217 The mechanisms and agent(s) responsible for the inflam~1ation.l~~. mation and bile duct destruction are as yet unknown. The disease seems to be triggered by an immune-mediated response to an alloantigen(s) or autoantigen(s) that leads to progressive destruction of bile ducts, chronic cholestasis, and eventual development of biliary cirrhosis. Immunohistochemical phenotyping of inflammatory cells surrounding the bile ducts shows these to be a combination of CD4 and CD8 T cells.'07 In vitro, lymphocytes from patients with PBC can induce necrosis of autologous biliary cells. Abundant evidence shows that bile duct destruction is directly induced by the cytotoxicity of CD4 and CD8 T cells in contact with biliary lesions.7s,83, lo7,236 B lymphocytes are relatively uncommon in the inflammatory reaction, although they on occasion can be seen in clusters. There does not appear to be a strong selection for specific T-cell receptors in patients with PBC.56However, intracellular adhesion molecules (e.g., ICAM-1) are strongly expressed on many epithelial cells, particularly in areas of lymphocyte damage119;these molecules may serve as accessory molecules facilitating the interaction of destructive lymphocytes and their targets. Much attention has been devoted recently to the humoral immune system, particularly in identifying the antigens recognized by the AMA.Il3, 213 These autoantibodies have been shown to be directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2), the E2 unit of the branched-chain 2-0x0-acid dehydrogenase complex (BCOADC-E2),and the E2 subunit of the 2-0x0-glutarate dehydrogenase complex (OGDC-E2) as well as to the E l subunit of PDC and protein X. All of these enzymes are located on inner mitochondrial membranes. At least one of these components usually reacts with AMA in patients with PBC. The most frequent antigen against which AMA are directed is the PDC-E2; PDC-E2-reacting antibodies are present in more that 90% of patients with PBC. The mechanisms by which AMA are developed against proteins located on the inner surface of the mitochondrial membranes are unknown; PDC-E2 or a cross-reactive molecule is overexpressed on biliary cells in PBC, predominantly at the luminal domain,

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ANGULO & LINDOR

and PDC-E2-specific CD4 T cells are present in the portal inflammatory infiltrate.213Although AMA are predominantly of the IgGl and IgG3 classes, a characteristic feature of PBC is elevated serum levels of IgM, perhaps as the result of faulty switching from IgM to IgG synthesis after exposure to an unknown antigen2” or of defective suppressor T-cell It is uncertain, however, why the lesions in PBC are confined to the small intrahepatic bile ducts when the antigens on the mitochondrial membrane are found in all tissues of the body. Evidence shows that these same antigens appear to share a common epitope with antigens in the cytoplasmic region of bile duct epithelial cells in patients with PBC.94,208 It has been reported that AMA-negative patients with PBC also have similar immunoreactive material found on the damaged bile ducts in’the absence of AMA.207The main targets of the immune reactions in PBC are the epithelial cells of interlobular bile ducts. Although most patients with PBC have AMA, these autoantibodies do not appear to be cytotoxic as suggested by (1) their persistence after liver transplantation without evidence of disease recurrence; (2) the fact that disease severity is unrelated to the antibody titer; (3) they are not always present in PBC; and (4)the development of AMA in animal models after the injection of recombinant PDC-E2 protein without bile duct destruction or inflammation.lo6 Some patients with PBC have circulating immune complexes resulting either from increased production or from a defective clearance by the reticuloendothelial system. These immune complexes could contain antigens that are in partial identical to or cross-react with epithelial antigens of bile ducts or mit~chondria.’~~ However, immune complexes are not always found in PBC, and disease severity does not correlate with defective clearance by the reticuloendothelial suggesting that complement-dependent cytotoxicity may not be directly involved in the pathogenesis of PBC. The complement system is chronically activated in patients with PBC. Serum concentration of several complement components are increased.’21 A C4 abnormality has been found in patients with PBC.32* 146, ls1, 182 This defect could contribute to the deposition of immune complexes or to defective viral clearance, leading to chronic infection and possibly triggering autoimmunity. Suppressor T-cell activity is abnormal in PBC,S9,90, 238 a phenomenon that is also found in a significant proportion of healthy first-degree relatives of PBC patients.152This defect could be responsible for the increased number of circulating B cells capable of spontaneously producing AMA in v i t r ~ .133~ ~ , Several hypotheses have been proposed to explain the immune response in PBC. Environmental factors such as bacterial infection,65, 85, 104. 120 yeast antigen@ and viral infectionss6have been incriminated. Selenium deficiency and defective sulfoxidation of certain compounds, such as bile acids, estrogen, or drugs,’” have also been proposed as the underlying mechanisms leading to the development of this condition. However, all these hypotheses are still far from established.

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Clinical Features

Asymptomatic Disease Widespread use of screening laboratory tests has led to increased diagnosis of PBC at an asymptomatic stage in as many as 30% of patients with this condition. Such patients are found incidentally to have an elevated serum alkaline phosphatase level and AMA during routine health evaluations, such as for hyperlipidemia, or during investigation of an unrelated complaint, such as autoimmune diseases known to be associated with PBC.135,197 Recently, it has been found that most asymptomatic individuals with AMA and normal liver biochemistries have features in the liver biopsy diagnostic of or consistent with PBC; these patients eventually develop symptoms and laboratory abnormali155 ties of chronic chole~tasis.’~~, Symptomatic Disease Table 1 outlines symptoms and signs of PBC at presentation. 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. Fatigue, although relatively nonspecific in PBC, is the most common symptom, found in about two thirds of patients, and generally becomes worse as PBC progresses. Pruritus may occur at any point in the course of the disease, developing early, or later as the PBC evolves, or intermittently throughout the course of the disease. Pruritus is generally intermittent during the day and is most troublesome in the evening and at night. Pruritus often resolves as the disease progresses, but some patients can develop severe intractable pruritus requiring liver transplantation as the only therapeutic alternative. Jaundice occurs later in the course of the disease and is usually persistent and associated with a worse prognosis. Symptoms also may be related to fat-soluble vitamin deficiency, bone pain with or without spontaneous fractures, or an associated autoimmune disease that may sometimes

Table 1. SYMPTOMS AND SIGNS OF PRIMARY BILIARY CIRRHOSIS AT PRESENTATION Prevalence Finding

(%.)

Fatigue Pruritus Jaundice Hyperpigmenta tion Hepa tomegaly Splenomegaly Xanthelasma None

70 69

30 55 50 30 20 30

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ANGULO & LINDOR

occur in patients with PBC (Table 2). Symptoms of advanced liver disease, such as ascites, bleeding from gastroesophageal varices, and encephalopathy, usually occur late in the course of PBC. At physical examination, the most common signs are jaundice, hyperpigmentation, hepatosplenomegaly, and xanthelasma. A minority of patients are men. Symptoms appear to be less frequent than in women, and autoimmune manifestations, especially Sjogren's syndrome, are also less frequent. Otherwise, PBC in men and women is identi~a1.l~~ Associated Diseases

Many of the diseases frequently found in patients with PBC are thought to be related to disturbances in the immune mechanism. These include Sjogren's syndrome, defined by the presence of dry eyes (kerotoconjunctivitis sicca), dry mouth, and specific testing; scleroderma and variants; rheumatoid arthritis; some cutaneous disorders; and renal tubular acidosis and thyroiditis. The cause of tubular acidosis is unclear, but as in Wilson's disease, it may be related to excess copper deposition within the kidney or be caused by an undefined autoimmune process. There is an increase in malignancy in patients with PBC. An increased risk of breast cancer in women with PBC was demonstrated in two studies,7l, 235 although this finding has not been confirmed by others.77,166 Hepatocellular carcinoma is uncommon, occurring in 1%to 2% of patients, but PBC patients have a substantially increased risk of developing this disease compared with the general population.166 Gallstones can be found in as many as one third of patients with PBC, but other diseases associated with gallstones, such as inflammatory bowel disease and pulmonary interstitial fibrosis, are rarely associated with PBC.

Table 2. DISEASES ASSOCIATED WITH PRIMARY BlLlARY CIRRHOSIS Prevalence Disease

("/.I

Keratoconjuntivitis sicca Arthritis/arthropathy Scleroderma and variants Scleroderma CREST or any of its components Raynaud's disease Autoimmune thyroiditis Cutaneous disorders (lichen planus, discoid lupus, pemphigoid) Renal tubular acidosis (proximal or distal) Gallstones Pulmonary fibrosis Celiac disease

72-100 4-42 15-20 3-4 7 8 15-20 11 50-60 33 Rare Rare

CREST

=

Calcinosis, Raynaud's, Esophogeal dysmotility, Sclerodactyly, Telangiectasia.

PRIMARY BILIARY CIRRHOSIS AND PRIMARY SCLEROSING CHOLANGlTIS

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Diagnosis

The diagnosis of PBC is established by biochemical results consistent with cholestasis, the presence of serum AMA revealed by indirect immunofluorescence or immunoblotting techniques, and compatible or diagnostic liver histology. Biochemical Changes

Liver biochemical tests show a cholestatic picture. Almost all patients show increased levels of alkaline phosphatase (three to four times normal) and y-glutamyltranspeptidase (GGT). Serum aminotransferases (AST, ALT) are mildly elevated (less than three times normal); marked elevations (more than five times normal) are distinctly unusual and may suggest PBC-autoimmune hepatitis overlap syndrome or coexisting viral hepatitis.52Serum bilirubin levels are usually normal in early stages, increase slowly over the course of the disease, and may reach levels exceeding 20 mg/dL. A high serum bilirubin level, low serum albumin, and prolonged prothrombin time are all poor prognostic factors and suggest advanced disease. Serum immunoglobulins, especially IgM levels, are increased, as are serum bile acid levels, in particular cholic and chenodeoxycholic acids, as well as serum cholesterol. Serologic Diagnosis

Approximately 90% to 95% of patients with PBC have serum AMA.221The M2 antibody which is directed against the pyruvate dehydrogenase complex of the inner mitochondria1membrane has a sensitivity of 98% and a specificity of 96% in the diagnosis of PBC. Other autoantibodies found in PBC patients are rheumatoid factor (in 70% of patients), antismooth muscle (in 66% of patients), antithyroid (antimicrosomal, antithyroglobulin) (in 41% of patients), and antinuclear antibodies (in 35% of patients). Liver Histology

Liver biopsy is necessary for the final diagnosis of PBC and exclusion of other liver diseases. The initial lesion on liver biopsy is damage to epithelial cells of the small bile ducts. The most important and only diagnostic clue in many cases in ductopenia as defined by absence of interlobular bile ducts in more than 50% of portal tracts. The florid duct lesion, in which the epithelium of the interlobular and segmental bile ducts degenerate segmentally with formation of poorly defined, nocaseating epithelioid granulomas, is nearly diagnostic of PBC, but is found in a relatively small number of cases and mainly in early stages. The two most popular classification systems are those presented by Ludwig138and S c h e ~ e r ,which ' ~ ~ classify the disease in 4 stages. Both systems

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ANGULO & LINDOR

describe progressive pathologic changes, initially beginning in the portal areas surrounding the bile ducts, with the eventual development of cirrhosis. In stage 1 disease, there is inflammatory destruction of the intrahepatic bile ducts involving septa1 and interlobular bile ducts that range up to 100 km in diameter. Often these lesions are focal and are described as florid duct lesions characterized by marked inflammation and necrosis around bile ducts. The portal tracts are usually expanded by lymphocytes, with only sparse neutrophils or eosinophils seen. In stage 2 disease, the inflammation, called interface hepatitis or piecemeal necrosis, extends from the portal tract into the hepatic parenchyma. Destruction of bile ducts with proliferation of bile ductules can be seen. Stage 3 disease is characterized by scarring and fibrosis. Lymphocytic involvement of the portal and periportal areas and of the hepatic parenchyma can be seen. This stage is characterized by the presence of subsequent fibrosis, although without regenerative nodules. Stage 4 disease is cirrhosis with fibrous septa and regenerative nodules. The natural history and rate of histologic progression in PBC have been recently described using the data from 916 liver biopsies performed in 222 patients with PBC during 779 patient-years of f ~ l l o w - u p .In ' ~ this ~ series, most patients progressed, only a few patients had a prolonged course of histologic stability, and sustained stage regression, as a measure of sample variability, was very unusual. A time course Markov model was used to describe the rate of histologic progression over time (Table 3). Natural History

The natural history of PBC has been described in patients with symptoms attributable to PBC as well as in asymptomatic patients who have normal or abnormal liver biochemistries. Useful prognostic models for predicting survival in individual patients have been reported. Asymptomatic Primary Biliary Cirrhosis In 1986 Mitchison and c011eagues'~~ reported 29 patients who were AMA positive (titer equal to or greater than 1 to 40), with normal liver Table 3. TIME COURSE OF HISTOLOGIC PROGRESSION IN PRECIRRHOTIC PATIENTS WITH PRIMARY BlLlARY CIRRHOSIS Initial Histologic Stage

Rate of Progression

1 year 2 years

7 41% 62%

2 43% 62%

3 35% 50%

From Locke RG 111, Therneau TM, Ludwig J, et al: Time course of histological progression in primary biliary cirrhosis. Hepatology 23:52, 1996.

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biochemistries and no symptoms of liver disease. Liver histology was compatible with or diagnostic of PBC in 24 patients (83%) and normal in only 2 patients. The whole cohort of patients was followed up for a median of 17.8 years (range 11 to 24), and the outcomes were recently r e ~ 0 r t e d . Twenty-four l~~ patients (83%) developed persistently abnormal liver biochemistries, and 22 (76%)developed persistent symptoms attributable to PBC, including fatigue, pruritus, and right upper abdominal discomfort. Five patients died during the follow-up period but none because of liver disease. The median time from the first positive AMA test to persistently abnormal liver biochemistries was 5.6 years (range 0.9 to 19). Four of the 10 patients who had a liver biopsy repeated during a median follow-up of 11.4 years (range 1.3 to 14.3) showed stage progression, but none of the patients in this cohort developed cirrhosis or portal hypertension during the follow-up. This study clearly shows that asymptomatic patients who are positive for AMA and have normal liver biochemistries have very early PBC. These patients may, with time, develop clinically obvious PBC, thus extending the natural history of this condition earlier in time. These patients may represent a different subgroup of patients with PBC whose natural history may differ from that of the general PBC patient population. Several reports have provided evidence regarding the natural history of asymptomatic patients who are AMA positive and have abnormal liver biochemistries consistent with cholestasis and liver histology diagnostic of or compatible with PBC. Those patients who are asymptomatic at presentation survive longer, but in most of these patients, the disease will eventually progress. Patients who remain asymptomatic for several years may have a significantly longer survival than symptomatic patients, but their life expectancy is still less than that of age- and gender-matched population. About 40% of the initially asymptomatic patients will develop symptoms of PBC within 5 to 7 years of followup. Once symptoms develop, life expectancy for these patients falls significantly and is the same as for other symptomatic patients, with a median survival of approximately 10 years.17,69,158 Unfortunately, there is no way to predict accurately which asymptomatic patients will develop symptoms of PBC; nevertheless, patients with normal serum bilirubin levels and stage I disease may certainly have a better long-term prognosis than patients with more severe liver disease at the time of diagnosis. Symptomatic Primary Biliary Cirrhosis

In contrast with asymptomatic patients, those patients with PBC who have symptoms of chronic cholestasis show a more rapid progression to end-stage liver disease and its inherent complications, and they have a worse prognosis. Several independent predictors of a poor prognosis have been identified in this group of patients with PBC, including advanced age, high serum bilirubin levels, poor synthetic function, hepa-

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tomegaly, fluid retention (edema, ascites), variceal bleeding, and advanced histologic stage (Table 4). Development of portal hypertension and its complications in patients with PBC is similar to that in other forms of cirrhosis. Most PBC patients with portal hypertension have cirrhosis in the liver biopsy; however, portal hypertension can be found in some patients with PBC with moderate to severe inflammation in the liver biopsy and without cirrhosis. Development of esophageal varices is an ominous sign that occurs in approximately one third of patients with PBC during their extended follow-up. About 40% of these patients will experience one or more episodes of variceal bleeding within the first 3 years following development of varices, and this development can be associated with a decreased survival.69 Predicting Survival in Patients with Primary Biliary Cirrhosis When untreated, PBC may follow a course that extends over a 15to 20-year period. However, in patients with serum bilirubin levels greater than 10 mg/dL, the average life expectancy is reduced to 2 years. To predict survival in patients with PBC, several prognostic models, some of which rely on Cox’s proportional hazard analysis, have been 54, 193 Of these models, the Mayo risk score- based on patient age, serum bilirubin, albumin, prothrombin time, and edema, has been cross-validated and widely used in predicting survival and in guiding physicians in patient referral for liver transplantation. These prognostic models can also be used to monitor the effect of experimental drugs in clinical trials. In using these prognostic models, however, it is worth recalling that, although all them are of undoubted help in the clinical decision-making process, none of them should replace the clinician’s judgment in determining the best time for liver transplantation in an individual patient. Treatment

Specific Therapy Many controlled and uncontrolled trials evaluating drugs with different properties in the treatment of PBC have been published. These drugs can be categorized according to their mechanisms of action as immunosuppressive, antiinflammatory, cupruretic, antifibrotic, or bile acids (Table 5). Corticosteroids. Although reports in the early 1950s described the beneficial clinical and biochemical effects of corticosteroids, only one placebo-controlled trial has been ~ 0 n d u c t e d . IThirty-six ~~ patients received prednisolone. After a year of treatment patients showed clinical and biochemical improvement as well as reduced overall inflammation

European (46)

Age Bilirubin Albumin Cirrhosis Cholestasis

Yale (1 89)

Age Bilirubin Hepatomegaly Fibrosis Cirrhosis

Age Bilirubin Albumin Prothrombin time Edema

Mayo (54)

Glasgow (72)

Age Bilirubin Ascites Variceal bleeding Fibrosis Cholestasis Mallory’s bodies

Oslo (193)

Variceai bleeding Bilirubin

Table 4. INDEPENDENT PREDICTORS OF SURVIVAL IN PATIENTS WITH PRIMARY BlLlARY CIRRHOSIS

Age Bilirubin Albumin

(93)

Australia

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ANGULO & LINDOR

Table 5. PROPERTIES OF DIFFERENT DRUGS EVALUATED IN THE TREATMENT OF PRIMARY BlLlARY CIRRHOSIS ~~

Drug

Corticosteroids Cyclosporine Azathioprine Chlorambucil D-penicillamine Methotrexate Colchicine Tacrolimus Ursodeoxvcholic acid

Immunosuppressive

Antinflammatory

Antifibrotic

X

X

X

X

in the liver biopsy. The study was continued in a single-blind manner Worsenfor a further 2 years, but mortality was similar in both ing of osteopenic bone disease is the main concern in using corticosteroids in the treatment of PBC, and corticosteroids cannot be recommended currently outside the context of prospective trials. D-penicillamine. Increased hepatic copper concentration in PBC patients prompted assessment of the potential benefit of d-penicillamine. Eight controlled trials involving more than 700 patients have been rep ~ r t e d D-penicillamine .~ was associated with a modest and transitory improvement in liver biochemistries in some studies, but this drug was not associated with any effect on survival. Furthermore, about 20% of patients developed serious side effects, and penicillamine is not used in the treatment of PBC. Colchicine. Colchicine has some antiinflammatory and antifibrotic effects. Three placebo-controlled trials involving a total of 181 patients 96, z2 Colchicine was associated with some biohave been conducted.30, chemical improvement but was without effect on symptoms related to cholestasis, on histologic progression to cirrhosis, or in improving overall The minimal toxicity of colchicine has led some physicians to recommend its use in PBC; however, based on the analysis of these studies, colchicine does not seem to be of benefit in patients with PBC. Azathioprine. Azathiopine is currently used to prevent allograft rejection and was evaluated in a large international study involving 248 patients with PBC. After the first 18 months of follow-up, no significant effects were noted on clinical course, liver biochemistries, liver histology, or survival.51With extended follow-up, and after adjustment for a slight imbalance in mean serum bilirubin between the two groups, a statistical improvement in survival was shown with this drug.%Uncertainty about the conclusions of this trial caused by the large number of withdrawals, missing data, and the initially reported negative results have made azathioprine a rarely used therapy for patients with PBC. Chlorambucil. Chlorambucil was evaluated in a small controlled trial involving 24 patients with a mean follow-up of 4.1 years.84Although improvement in liver biochemistries and reduced inflammation in the

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liver biopsy were found, no effects on stage of disease were noted, and the study was too small to evaluate any benefit in terms of survival. One third of patients developed bone marrow toxicity necessitating discontinuation of the drug, making chlorambucil an unattractive drug for further evaluation. It cannot be recommended for regular use in PBC. Cyclosporine. Cyclosporine has proven effective in preventing immune-mediated rejection of transplanted human allografts. A large European study involving 349 patients with PBC, with a follow-up up to 6 years (mean 2.5) and with death or liver transplantation as the main end points, showed biochemical improvement but no effect on preventing histologic progression or patient survival.134 A multivariate analysis suggested a reduction in mortality for patients treated with cyclosporine. The use of this drug, however, is associated with a high incidence of side effects, such as hvpertension and depression of renal function, largely precluding long-ierm use of cycloiporine in treating patients with PBC. Methotrexate. Methotrexate has been reported to produce clinical, biochemical, and histologic improvement in overall inflammation and bile duct injury in one randomized and three open trials involving a small number of patients.23,48, 95, 97 However, the stage of disease and fibrosis continued to progress despite methotrexate treatment. In a recent report, long-term methotrexate therapy led to clinical remission, normalization of liver biochemistries, and improvement in histologic stage in a subgroup of five patients with PBC.98These encouraging results should be weighed against the high incidence of side effects reported.lZ7,196 Larger, controlled trials are currently under way to better define methotrexate's role in the treatment of PBC. Ursodeoxycholic Acid. Ursodeoxycholic acid (UDCA), the 7-p epimer of chenodeoxycholic acid, is the drug most widely evaluated in the treatment of PBC. Ursodeoxycholic acid occurs naturally in small quantities in human bile (< 4% of total bile acids). It was first introduced for the dissolution of radiolucent gallstones in the 1970s and was recently approved by the Food and Drug Administration for treatment of PBC. Several mechanisms of UDCA's protective actions have been proposed, such as inhibiting absorption of toxic, hydrophobic, endogenous bile salts; stabilizing hepatocyte membranes against toxic bile salts; replacing endogenous bile acids, some of which may be hepatotoxic, with the nonhepatotoxic UDCA; and reducing expression of major histocompatibility complex (MHC) class I and class I1 antigens in PBC patients. During UDCA therapy there is a variable increase of total serum bile acids. The proportion of UDCA in serum and bile increases to about 30% to 60% of the total bile Iz3 and the proportion of endogenous bile acids, such as cholic, chenodeoxycholic, deoxycholic, and lithocholic acids, consequently declines. Ursodeoxycholic acid enrichment of the bile acid pool is similar in all histological stages: and there is a correlation between the degree of enrichment and improvements in liver biochemistries and in Mayo risk score.6,lZ4 Several large, controlled trials of UDCA have shown a clear im-

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ANGULO &I LINDOR

provement in liver biochemistries and survival free of liver transplantation.* Table 6 shows the number of patients enrolled, dose of UDCA used, and main results of published controlled trials of UDCA in the treatment of PBC. All these trials showed a consistent biochemical improvement during therapy. Improvement in some histologic features, 47, ls4 and bile such as piecemeal necrosis, inflammation, chole~tasis,'~~ duct paucity and pro1iferation;lT was also found after 2 years of UDCA therapy. In patients with PBC, UDCA significantly decreases the risk of developing gastroesophageal variceslZ6and delays progression to ~irrhosis.~ Ursodeoxycholic acid therapy has also been shown conclu188, lS5Figure 1 sively to prolong survival free of liver transplantati~n.'~~, shows UDCA effects on survival in 548 PBC patientsls3enrolled in three placebo-controlled trials.81, lM During UDCA therapy, there is a significant decrease of the Mayo risk score, a cross-validated index of survival in PBCsl, ls4; with UDCA therapy, the Mayo risk score regains its validity in predicting survival, just as when used in the absence of effective therapy8 The most costeffective dose of UDCA in PBC is 13 to 15 mg/kg/d.6 This dosage can be divided into three or four doses given with meals. In patients taking cholestyramine, UDCA should be taken at least 2 hours before or after cholestyramine to ensure better intestinal absorption. Combination Therapy. The use of combination therapy with drugs that have different properties and some benefit in PBC has been evaluated in open and controlled trials. These combinations include UDCA and methotrexate, UDCA and colchicine, cyclosporin and prednisone, chlorambucil and prednisolone, UDCA and corticosteroids, and UDCA with prednisone and azathioprine. Although some biochemical benefit in the short term has been reported by adding prednisone and azathioprine in patients with a suboptimal response to UDCA,234the small number of patients enrolled as well as the short follow-up and the risk of development of drug-related side effects do not allow the recommendation any of these combinations in the treatment of PBC. Furthermore, these combinations do not seem to be more effective than UDCA used alone.5 IZ37

Complications of Chronic Cholestasis and Their Management Bone Disease. Osteopenic bone disease with its predisposition to spontaneous fracturing is a common complication of chronic cholestatic liver disease.79Although its etiology is poorly understood, osteopenia in PBC seems to be intimately related to the cholestasis itself, and in nearly all instances is related to osteoporosis rather than osteomalacia. Women with PBC lose bone mass at a rate approximately twice that seen in agematched controls,58and this accelerated bone loss results from decreased *References47, 60, 81, 123, 125, 183, 184, 185, and 219.

20 55 146 86 46 180 222 151 61

Leushner et a1 (115) Oka et a1 (169) Poupon et a1 (184, 185) Battezati et a1 (18) Turner et a1 (209) Lindor et a1 (123, 125) Heathcote et a1 (81, 183) Combes et a1 (47, 60) Vouristo et a1 (219)

Improved* Improved* Improvedt Improved* No change No change No change No change$ Imuroved

Pruritus

Improved Improved Improved Improved Improved Improved Improved Improved Imuroved

Laboratory

Improved NE Improved NE No change No change Improved Improved Imuroved

Histology

NE NE Improved NE NE Improved Improved5 Improved11 NE

Survival

‘Similar improvement in UDCA and placebo groups. +Improvement in UDCA and placebo groups, but UDCA better than placebo. SUDCA decreased progression to severe pruritus in patients with serum bilirubin less than 2 mg/dL. §Improved when combined with French and American patients. IlObserved survival improved by UDCA when compared with expected survival using the Mayo Clinic prognostic model. NE: not evaluated.

No. of Patients

Author (Ref. No.)

10-15 mg/kg/d (9 mo) 600 mg/d (6 mo) 1 S 1 5 mg/kg/d (2 y) 500 mg/d (6 mo) 11 mg/kg/d (2 Y) 13-15 mg/kg/d (4 y) 14 mg/kg/d (2 y) 10-12 mg/kg/d (2 y) 12-15 mg/kg/d (2 y)

Dose (Duration)

Table 6. PLACEBO-CONTROLLED TRIALS OF URSODEOXYCHOLIC ACID IN THE TREATMENT OF PRIMARY BlLlARY CIRRHOSIS

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ANGULO & LINDOR

cw

.........,

0

'I..

3

Placebo and UDCA

Ei 3 l3 lc

0.5

-3 'b-8

I

UDCA Placebo and UDCA

273 276

236 220

116 81

Figure 1. Probability of survival free of liver transplantation was significantly greater in patients treated for 4 years with ursodeoxycholic acid (UDCA) than in those who first received placebo and then UDCA ( P < 0.001; relative risk, 1.92; 95% confidence interval, 1.30-2.82). (Adapted from Poupon P, Lindor KD, Cauch-Dudek, K, et al: Combined analysis of the French, American, and Canadian randomized controlled trials of ursodeoxycholic acid therapy in primary biliary cirrhosis. Gastroenterology 113:884-890, 1997.)

formation rather than increased resorption of bone.91The severity and progression of bone disease can be assessed by measuring bone mineral density in different sites, particularly in the lumbar spine and femur. Dual-energy x-ray absorptiometry and dual-photon absorptiometry are noninvasive techniques that provide an excellent quantification of the bone mass. Approximately one third of patients with PBC have severe osteoporosis, with bone mineral density of the lumbar spine below the fracture threshold of 0.85 g/cm2 of bone mass at the time of referral or diagnosis of the liver disease.lZ8(The fracture threshold is the point below which fractures can occur spontaneously.)The severity of osteoporosis increases as the liver disease advances. One half of PBC patients undergoing liver transplantation have bone density values below the fracture threshold, with pathologic fractures occurring in 50% of PBC patients during the first months after liver transplantation, almost exclusively in those patients who are already osteopenic at the time of transplantation.17y Treatment of the bone disease in these patients usually includes adequate exercise and supplemental calcium and vitamin D (25,000 to 50,000 international units [IU] orally two to three times/week). Estrogens are useful in postmenopausal osteoporosis; in a small series, estrogens seemed to benefit patients with PBC.4yHowever, because of the potential

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cholestasis-inducing effects of estrogens, these agents should be used cautiously in patients with cholestasis. Raloxifen, a selective estrogenreceptor modulator, may be a promising alternative to estrogen-replacement therapy in postmenopausal o s t e o p o r ~ s i and s ~ ~ should be evaluated in patients with PBC. Biphosphonates such as etidronate are now being Other evaluated and may be of benefit in PBC-associated osteopor~sis.~~ bisphophonates, such as residronate, alendronate, and pamidronate, may hold promise. Sodium flurodide, which enhances spinal bone density and bone formation, has been evaluated in a small but it can produce gastrointestinal side effects that preclude its wide use in PBC patients. Similarly, calcitonin, which inhibits bone resorption, does not appear to benefit patients with cholestatic osteoporosis.212 Fat-soluble Vitamin Deficiency. Most PBC patients who have fatsoluble vitamin deficiency have advanced liver disease and are jaundiced. Fat-soluble vitamin deficiency is almost always caused by malabsorption resulting from the amount of bile salt in the intestinal lumen. Nevertheless, vitamin D deficiency should be excluded in patients with PBC. When vitamin D deficiency is encountered, 50,000 IU of vitamin D given once or twice/week is usually sufficient to achieve a normal serum vitamin D level. Vitamin A deficiency causing night vision problems can sometimes occur in patients with PBC and PSC. When blood levels of vitamin A are low, replacement therapy with 25,000 to 50,000 IU, two to three times/week, should be instituted, usually beginning at lower levels and assessing adequacy of the replacement therapy by repeating serum assays and evaluation of dark adaptation if indicated. Vitamin K deficiency also occurs in patients with severe cholestasis and is manifested by an increased prothrombin time. A trial of vitamin K (5 to 10 mg) should be given to determine whether the prothrombin time improves. If it does, these patients should be maintained on a water-soluble vitamin K replacement, 5 mg/d. Deficiency of vitamin E has been reported in a few patients with PBC. Typically, vitamin E deficiency causes a neurologic abnormality primarily affecting the posterior columns and characterized by areflexia or loss of proprioception and ataxia. Despite the disappointing response to vitamin E replacement, patients with chronic cholestasis and low levels of serum vitamin E should be placed on replacement therapy, usually 100 mg twice daily. Hypercholesterolemia and Hyperlipidemia. Hypercholesterolemia and hyperlipidemia are found in as many as 85% of patients with PBC. High-density lipoprotein cholesterol levels are usually most prominently elevated in early-stage disease; however, as the disease progresses, the high-density lipoprotein cholesterol levels decrease and low-density lipoprotein increases. There does not appear to be an increased risk of atherosclerosis in these patients with hy~erlipidemia.~~ Some patients with hyperlipidemia may develop xanthelasmas, which can be troublesome. Ursodeoxycholic acid has been shown to lower the low-density lipoprotein cholesterol levels in patients with PBC and has been useful in

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some patients with ~anthelasma'~; surgical removal of these cholesterol deposits is seldom successful and should be avoided. Pruritus. The cause of pruritus remains an enigma, but some believe that it can be caused by the accumulation of bile acids in the skin, and the bile acid-binding resin, cholestyramine, was the first medication described to alleviate this symptom. Cholestyramine therapy is successful in most patients who can tolerate the unpleasant side effects of bad taste, bloating, and occasional constipation. The recommended dose is 3 to 12 g/d, and it is most effective when given before and after breakfast because this schedule allows maximal bile acid binding as the gallbladder empties. Drugs that can potentially be bound to this anion exchange resin (e.g., UDCA, thyroxine, digoxin, and contraceptive pills) should be taken several hours before or after cholestyramine. Not all patients with pruritus are helped by cholestyramine. The antibiotic rifampin is very effective in reducing the pruritus of PBC.9 The majority of patients respond, and benefit occurs within a week of the start of therapy. The starting dose is 150 mg twice a day, but higher doses are occasionally needed. Rifampin induces drug metabolizing enzymes, so caution must be taken with concurrent therapies. Treatment with UDCA can sometimes alleviate pruritus, although on occasion worsening of pruritus may occur with initiation of UDCA. In warm countries, exposure to ultraviolet light without sun-block can alleviate pruritus, and not surprisingly, pruritus of PBC is improved during the summer months. It has been hypothesized that pruritus may be related to the release of endogenous opioids.22,205 Intravenous infusion of naloxone showed a clear-cut benefit in a double-blind trialz4Recently, oral opiate receptor antagonists such as nalmefene25and n a l t r e x ~ n ehave ~ ~ ~led to impressive amelioration of pruritus in PBC, although further trials are needed to evaluate their safety better in patients with chronic cholestasis. Antihistamines are only helpful to combat the insomnia associated with pruritus by their sedative effect; pruritus is always more troublesome at night. Phenobarbital may have the same effect. Finally, pruritus of PBC is always cured by liver transplantation, and this is a viable option for those PBC patients who develop severe intractable pruritus. Steatorrhea. Steatorrhea can occur in patients with advanced PBC. Several causes have been described.l1° The most important cause is decreased bile acid delivery and insufficient micellar concentration of bile acids in the small intestine. Occasionally, exocrine pancreatic insufficiency can be found as part of the more widespread glandular dysfunction seen in some patients with PBC. Coexisting celiac sprue has been reported in a small number of patients with PBC, and bacterial overgrowth may be the cause of steatorrhea in some patients with PBC and scleroderma. Each of these causes has a specific and different treatment, and therefore it is important to determine the exact cause. Patients with decreased bile acid concentration usually benefit from substitution of medium-chain triglycerides for long-chain triglycerides and a decrease in total fat intake. Patients with exocrine pancreatic insufficiency will

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benefit from pancreatic replacement therapy; patients with celiac sprue will benefit from gluten withdrawal from the diet; and patients with bacterial overgrowth will benefit from intermittent antibiotic therapy. Liver Transplantation

The best therapeutic alternative for patients with end-stage PBC is liver transplantation. Although many factors should be taken into account to determine the timing of liver transplantation, earlier in the course of the disease as determined by the Mayo risk score rather than when the patient experiences life-threatening complications or is on life support, can improve posttransplantation Undoubtedly, the major manifestations of chronic liver disease that prompt the clinical hepatologist to consider liver transplantation for other chronic liver diseases also apply for PBC patients: the development of major complications related to portal hypertension (i.e., bleeding from gastroesophageal varices), diuretic-resistant ascites, hepatorenal syndrome, and hepatic encephalopathy. In particular, in patients with PBC, the development of complications associated with chronic cholestasis (such as a poor quality of life due to disabling fatigue, intractable pruritus, and severe muscle wasting) and persistent increases in serum bilirubin levels in the absence of hepatic malignancy often prompt the practicing clinician refer patients for liver transplantation even though they show no cirrhosis on liver biopsy. Recent data suggest that optimal survival and resource use can be achieved by performing liver transplantation in patients with PBC who have a Mayo risk score that does not exceed 7.8.'01 Liver transplantation clearly improves survival as well as quality of life; 1-year survival rates after liver transplantation are currently higher than go%, with a 5-year survival rate higher than 80% in most transplant centers. Antimitochondrial antibodies generally persist after liver transplantation, and in long-term follow-up studies as many as 10% of patients have evidence of histologic recurrence of PBC.16 However, recurrent PBC after liver transplantation seems to follow a benign course, at least during short-term follow-up. Autoimmune Cholangitis or Antimitochondrial Antibody-Negative Primary Biliary Cirrhosis

Autoimmune cholangitis or AMA-negative PBC is the term given to describe those patients who clinically, biochemically, and histologically appear to have the classical features of PBC, but without serum AMA when tested using indirect immunofluorescence or immunoblotting techniques. Most of these patients have antinuclear or antismooth muscle antibodies, and they tend to follow a clinical course and therapeutic response to UDCA similar to that of AMA-positive PBC patients.88,102, 108,154

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Furthermore, it has been demonstrated that although these patients may be distinguished by the lack of AMA in serum, the specific AMA subunit (i.e., the PDC-E2) is nevertheless expressed in the apical region of the biliary epithelium, as occurs in AMA-positive patients. This finding suggests that the pathogenesis of both conditions may be the same.*07 Interestingly, this staining reaction is found before HLA class I1 expression is detected, suggesting it may be the earliest specific lesion of PBC. Perhaps AMA-positive PBC can also be differentiated from AMAnegative PBC by serum antibodies to carbonic a n h y d r a ~ e Whether .~~ there is a different genetic susceptibility for the development of these two conditions is still uncertain. Patients with AMA-negative PBC or autoimmune cholangitis should be treated with UDCA (13 to 15 mg/kg/ d)lo2;however, when features in the liver biopsy suggest superimposed autoimmune hepatitis,2l,44 the combination of corticosteroids and UDCA should be considered. PRIMARY SCLEROSING CHOLANGITIS

Primary sclerosing cholangitis is a chronic cholestatic syndrome of unknown etiology, frequently associated with inflammatory bowel disease (IBD) and characterized by diffuse fibrosing inflammatory destruction of the intra- and/or extrahepatic biliary duct system. Although the course of the disease is be highly variable, PSC often follows a progressive course leading to biliary cirrhosis and its inherent complications of portal hypertension and liver failure unless liver transplantation is performed. Epidemiology In contrast to PBC, PSC has a male predominance of 2 to 1, with median onset at 40 years but with a wide range of 1 to 90 years. There have been no epidemiologic studies of he prevalence of PSC in any general population group. The presence of PSC in the United States has not been studied directly, but because approximately 70% of patients with PSC will have ulcerative colitis, and it is known that there is a 3% to 7.5% prevalence of PSC in patients with ulcerative colitis, estimates of the prevalence can be made. The prevalence of ulcerative colitis ranges from 40 to 225 cases per 100,000 population, so the prevalence of PSC in the United States can be estimated to be between 2 and 7 cases per 100,000 population. Similarly, an epidemiological study from Sweden showed the prevalence of ulcerative colitis and PSC to be 171 cases per 100,000 population and 6.3 cases per 100,000 population, re~pective1y.l~~ These figures, however, underestimate the true prevalence of PSC; the prevalence of PSC in ulcerative colitis is likely to be higher than estimated because some patients with PSC will have normal liver biochemis-

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tries and approximately 30% of patients with PSC will not have ulcerative colitis. It is apparent that PSC is more common than previously suspected, and the actual prevalence may be higher than here reported.

Pathogenesis

The cause of PSC is unknown. However, a number of factors have been proposed that might cause recurring damage to the bile ducts and lead to development of the disease. These factors can be separated into immune and nonimmune mechanisms. lmmune and Genetic Mechanisms

Several cellular and humoral immune alterations support an immunologic disturbance as the underlying cause of PSC. Cellular immune factors may play a role, as suggested by the composition of the portal infiltrate, which is made up mainly of CDCpositive T lymphocyte^.^^, 224 T lymphocytes surrounding the bile ducts in patients with PSC express interleukin-2 receptors or HLA DR as evidence of activation.224The presence of HLA class I1 molecules on biliary epithelium suggests that these cells can present the putative antigen(s) to class I1 restricted lymphocytes, thereby initiating an inflammatory response.34,42 An immunemediated mechanism underlying the development of this disease has also been supported by the findings in an experimental model of immune-mediated cholangitis210and shared antibodies against colonic and biliary epithelial antigens.145The HLA class I1 expression on biliary duct epithelium in PSC is not disease specific; it may occur in other liver diseases such as PBC and might represent a secondary response to inflammation. Patients with PSC frequently have elevated levels of immunoglobu237 The lins, including a variety of non-organ-specific autoantib~dies.~, relevance of these autoantibodies to the pathogenesis of PSC remains uncertain, but they may be merely markers of immune reactions occurring in this condition, and some may be associated with underlying IBD. An antineutrophil cytoplasmic antibody (ANCA) originally detected in serum from patients with ulcerative colitis was subsequently identified in a high proportion of patients with PSC.57However, ANCA have also been detected in serum from patients with other autoimmune liver diseases such as autoimmune hepatitis and PBC.I6O The occurrence of PSC in members of the same family and definite HLA association suggests a genetic predisposition for developing this condition. Susceptibility to PSC seems to be determined by 150, 151; the HLA DRB1*0301 (DR3) and DRB3*0101 (DRw52a) alleles149, DRB1*0401 (DR4) allele may be a marker of more rapid disease progre~sion.~, 148

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Nonimmune Mechanisms The close association between PSC and IBD have led to the hypothesis that chronic portal bacteremia might cause chronic biliary tract infection, inflammation, portal fibrosis, and ultimately PSC. Furthermore, hepatobiliary lesions similar to those seen in humans with PSC were found in an animal model of small bowel bacterial overgrowth.16,'17 In this model, increased intestinal permeability resulted in the absorption of a bacterial cell wall product, peptidoglycan-polysaccharide, which activated Kupffer's cells in the liver, leading to a significant increase in plasma tumor necrosis factor (TNF) levels compared with controls. The administration of pentoxifylline suppressed TNF released by Kupffer 's cells, reduced plasma levels of TNF, and prevented liver damage.'18 These lines of evidence suggest portal bacteremia as a potential antigen source in genetically predisposed individuals. However, the relevance of absorption of intestinal bacteria endotoxins through a diseased bowel mucosa to the pathogenesis of PSC is unclear. Primary sclerosing cholangitis may exist without any evidence of IBD, it may present several years before the bowel disease or long after colectomy, and colectomy is not associated with any effect on the course of PSC. Furthermore, early investigations in patients with PSC have not shown evidence of portal 218 Although vein phlebitis, the typical feature of portal ba~teremia.'~~, these findings do not completely exclude a possible role of portal bacteremia as a contributing pathogenic factor in PSC, this mechanism has not yet been established. Cholangitis caused by cytomegalovirus in immunocompromised patients has a cholangiographic picture similar to PSC.41However, there are no data to suggest the same mechanism in immunocompetent subject~.'~~ Hepatotoxic bile acid metabolites, such as lithocolic acid formed from chenodeoxycholic acid by bacterial 7-a-dehydroxylation in the colon, are hepatotoxic in animals.'76 However, no major abnormalities have been found in the composition and concentration of bile acids in the bile and portal blood of patients with either PSC or IBD.199 The bile ducts are supplied by the hepatitic arterial tree. Accidental damage occurring during surgery or as a complication of cytotoxic drug infusion in the hepatic artery can lead to a form of sclerosing cholangitis similar to PSC.'39However, there is no pathological data suggesting that ischemic damage to a bile duct is a cause of PSC. Although major advances in the understanding of PSC have been made in the last decade, much work remains to uncover its causes and better understand the genetic and immunologic basis of this condition.

Clinical Manifestations The clinical manifestations of PSC can be highly variable, and patients may be either asymptomatic or symptomatic. In the early 1980s,

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PSC was frequently diagnosed in patients with symptoms and signs of chronic cholestasis or in patients with manifestations of end-stage liver disease; asymptomatic patients were rare (7Y0-10%).~~, 227 However, the increasing use of endoscopic retrograde cholangiopan-creatography (ERCP) in the last two decades, particularly in patients with asymptomatic elevation of alkaline phosphatase or y-glutamyltransferase, has led to diagnosing this condition in a high proportion of patients without clinical manifestations of liver disease. Recent series have reported that 15% to 45% of PSC patients are asymptomatic at the time of diagno228, Although these patients can remain free of symptoms and s ~ s .I7O,~ ~ completely well for some years, the disease can follow a progressive course, as estimated by the progression of changes seen on liver biopsy and cholangiography.Not surprisingly, as many as 17%of asymptomatic patients with PSC have cirrhosis on liver biopsy at the time of diagnos~s.~~ Table 7 shows the most common symptoms and signs found in patients with PSC. The disease may sometimes present with periodic remissions and exacerbations. The most common manifestations are fatigue, jaundice, pruritus, and abdominal pain; ascites, bleeding from 55, 63, 195 gastroesophageal varices, and acute cholangitis are less frequent.43, As in PBC, the nonspecific complaint of fatigue is common in patients with PSC, but often it is not considered as a manifestation of PSC. It has recently been suggested that altered serotoninergic transmission in the brain could explain this symptom.203Hyperpigmentation, xanthomas, and xanthelasma can occur, but these manifestations are less common than in PBC patients.229 Presenting symptoms in PSC can sometimes be related to portal hypertension or liver failure. Development of gastroesophageal varices, ascites, and encephalopathy do not differ from other liver diseases. Patients with PSC and ulcerative colitis who undergo colectomy with an ileal stoma can develop a unique complication, the development of peristomal varices that have a high rate of bleeding and almost always occur in patients with gastroesophageal varices. Bleeding occurs from the peristomal mucocutaneous junction, and local treatment usually fails. These patients frequently experience rebleeding episodes during followup.230A portosystemic shunt can prevent rebleeding from peristomal varices, but because these patients often suffer from end-stage liver disease, liver transplantation is often the most appropriate treatment. When required, a surgical procedure less susceptible to variceal formation, such as ileoanal anastomosis, is preferred.99 Patients with PSC are at high risk for acute and recurrent episodes of bacterial cholangitis. In these patients, choledocholithiasis, dominant stricture, or bile duct cancer should be considered as the precipitating factor and should prompt cholangiography. In addition to extraction of stones and balloon dilatation with or without stenting, broad-spectrum antibiotics therapy is necessary. Like patients with PBC, patients with PSC have an increased prevalence of associated disorders. The associated conditions are ulcerative

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colitis (in 70%-75% of patients), Crohn’s colitis (in 5%-8% of patients), pancreatitis (in 10%-25% of patients), and diabetes mellitus (in 5%-10% of patients). Ulcerative colitis in patients with PSC often shows extensive involvement of the colon but, paradoxically, often follows a relatively benign course.64Rare associations with PSC include sicca syndrome, Riedel’s thyroiditis, retroperitoneal fibrosis, celiac disease, and autoimmune hemolytic anemia. Diagnosis The diagnosis of PSC is based on a combination of clinical (Table 7), biochemical, radiologic, and, in some cases, pathologic finding.

Radiologic Features (CholangiographicFindings) Diffuse multifocal annular strictures of intrahepatic or extrahepatic bile ducts Short bandlike strictures Diverticulum-like outpouchings Histologic Criteria (Ludwig Staging System) Portal stage (stage I) Portal hepatitis (limited to limiting plate) Periportal stage (stage 11) Periportal fibrosis/inflammation beyond limiting plate Septal stage (stage 111) Septal fibrosing/bridging necrosis Cirrhotic stage (stage IV) Biliary cirrhosis Biochemical Tests

Almost all patients with PSC have elevated serum alkaline phosphatase levels, usually three to five times normal. Similarly, most have a mild increase in serum AST or ALT. Serum bilirubin levels fluctuate, but high levels suggest progression of the disease or development of complications such as cholangiocarcinoma or dominant strictures with or without cholangitis. Tests related to copper metabolism are almost always abnormal in patients with PSC.73Several non-organ-specific autoantibodies can be found in patients with PSC, in particular ANCA, but none of them is disease specific.73, 237 Radiologic Features

Cholangiography is the most important diagnostic test. Endoscopic retrograde cholangiopancreatography is the procedure of but in some patients with extensive involvement of the common bile duct in whom ERCP is unsuccessful, percutaneous transhepatic cholangiography for visualization of the distal intrahepatic bile ducts is indicated. In

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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 Inflammatory Bowel Disease Ulcerative colitis Crohn’s disease

Frequency (%) 75 70 65 40

35

55 50 30 25 4

70-75 5-8

most cases of PSC the characteristic cholangiographic changes described in Figure 2 can be seen. Although highly suggestive of PSC, these cholangiographic features are not unique to PSC. Other diffuse liver diseases, such as hepatic metastasis, advanced cirrhosis, polycystic liver disease, and lymphoma, may produce similar deformities of the bile ducts, and they should be excluded. Rarely, the pancreatic duct may be

Figure 2. Cholangiograrn showing multiple strctures in the intrahepatic and extrahepatic bile ducts in a patient with primary sclerosing cholangitis. (Adapted from Pasha TM, Lindor KD: Diagnosis and Therapy of Cholestatic Liver Disease. Med Clin North Am 80:1005, 1996.)

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involved and demonstrate abnormalities suggestive of chronic pancreatitis. Hepatic Histology Although features in the liver biopsy in patients with PSC can be seen in other conditions, such as PBC, chronic hepatitis, and prolonged extrahepatic obstruction, 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 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. Fibro-obliterative cholangiopathy, although nearly diagnostic of PSC, is an uncommon finding. Terminology of Duct Disease in PSC The variations of presence or absence of IBD, cholangiographic, and histologic findings have led to the use of different diagnostic terms as defined in Table 8.l4O Malignancy

The most lethal biliary complication of PSC is the development of cholangiocarcinoma.Originally described as a complication of ulcerative colitis, cholangiocarcinoma seems to be related to the presence of PSC in patients with colitis rather than to the colonic disease per se.I9OTumors arise most frequently around the common hepatic bile duct and its bifurcation. The prevalence of the tumor in PSC varies from 4% to 20%, as shown in several cohort and case-control studies.29,35, 37, 82, 194 The autopsy prevalence is much higher, with cholangiocarcinoma reported A recent in 30% to 42% of patients with PSC undergoing autopsy.1,37,43,191 report from a transplant center shows that cholangiocarcinoma may develop in one third of patients with PSC if follow-up is extended long enough.61A large clinical experience has reported an annual incidence l~~ PSC appears to be an independent risk factor of 1%or 1 e ~ s .Moreover,

Table 8. TERMINOLOGY OF BILE DUCTS DISEASE IN PRIMARY SCLEROSING CHOLANGITIS (PSC)

Presence of IBD

Cholangiography

Liver Biopsy

+

Not diagnostic

Typical findings

Small-duct PSC (pericholangitis)

+/-

Typical findings

Typical findings

Classic PSC (global PSC) (90%)

Diagnostic Term (= 10%)

IBD: inflammatory bowel disease.

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for developing colorectal dysplasia or cancer in ulcerative colitis,8°,165 although this finding is still contr~versial.~~, Hence, PSC is a condition harboring a broad neoplastic potential with increased susceptibility for the development of both biliary and colon cancer. The prevalence of unsuspected hepatobiliary malignancy, in particular cholangiocarcinoma, in explanted livers of patients with PSC undergoing liver transplantation varies from 0% to 44% (overall mean 6.8%, 49 out of 711 patients reported) despite an exhaustive pretransplant diagnostic approach.* The prognosis for patients with PSC and cholangiocarcinoma is very poor, with a reported survival shorter than 12 months from the time of diagnosis in most patients.z6,37, 191 Liver transplantation is not an effective therapeutic alternative for most patients because the high probability of tumor recurrence during the first few months posttransplantation is associated with a high mortality rate.z,3, 63, 147, 159 The cumulative posttransplant survival in patients with known or incidental cholangiocarcinoma in the explanted liver is significantly shorter than in patients without cholangiocarcinoma.z,202 The diagnosis of bile duct carcinoma in the setting of PSC presents a difficult challenge. Older age, longer duration of IBD,191 and smoking behaviorz6have been associated with an increased risk for development of cholangiocarcinoma in patients with PSC. Although the presence of cholangiocarcinoma often portends a rapid clinical decline with marked and progressive cholestasis, clinical features lack predictive value and do not permit accurate diagnosis of the tumor. Thus, not surprisingly, metastatic disease is present in more than 50% of patients at the time of diagnosis.37 A suspicion of cholangiocarcinoma should arise when a dominant biliary stricture is found during ERCP or percutaneous transhepatic cholangiography. However, similar imaging findings can be found in patients with PSC without cholangiocarcinoma. Imaging studies, such as ultrasonography and CT scan, have a low sensitivity in diagnosing cholangiocarcinoma in its early stages. A combination of imaging procedures may have a greater diagnostic accuracy,4O particularly when imageguided biopsies are taken. Brushings of dominant biliary strictures should be performed during ERCP,although biliary cytology has a low sensitivity in the diagnosis of cholangiocarcinoma in its early stages. Difficulties inherent in imaging and cytologic modalities have led to a clinical impetus to find effective alternatives for the diagnosis of cholangiocarcinoma.Some tumor markers have been evaluated recently, of which carbohydrate antigen 19-9 (CA 19-9), a sialylated lacto-N-fucopentaose I1 epitope related to the Lewis blood group antigen has been widely studied in the diagnostic evaluation of suspected cholangiocarcinoma in patients with PSC. A threshold value of 100 U/mL was shown to be 89% sensitive and 86% specific in detecting cholangiocarcinoma in PSC.165Serologic screening with an index equal to or greater than 400 units for the two tumor *References 2,3, 61, 63, 70, 109, 147, 159, 163, and 202.

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markers CA 19-9 and carcinoembryonic antigen was shown to be 86% accurate in detecting cholangiocarcinoma and to have a 100% specificity and positive predictive value, but with a sensitivity of only 67%.lS7 Unfortunately, these markers have limited ability to detect cholangiocarcinoma at a stage early enough to allow successful resection. Although patients with cirrhotic stage PSC may also be at risk for developing hepatocellular carcinoma, this malignancy occurs infre76 Even though it is rare, there may be a unique predisposition quentlyZ6, for the development of the fibrolamellar variant of this tumor in PSC.200 Complications of Chronic Cholestasis and Their Management As occurs in patients with PBC, patients with PSC are at risk of developing complications inherent to the chronic cholestatic process, such as fat-soluble vitamin deficiency, pruritus, hyperlipidemia, and steatorrhea. Osteoporosis as defined by a T-score below -2.5 or bone mineral density below the fracture threshold of 0.85 g/cm2 of bone mass occurs less commonly than in PBC (loo/, versus 35% of patients).1° This difference can be explained, at least in part, by the fact that PSC occurs more commonly in young men; in men, the bone mass is normally higher, and the rate of bone lose is normally less than in women. Osteoporosis in PSC should be suspected in older patients and in those with longer duration of IBD and more advanced liver disease.lo Although most patients with PSC have ulcerative colitis, which can increase the risk of osteoporosis, the colitis in these patients is usually quiescent, and only few patients require corticosteroid therapy. The severity of bone disease in PSC, however, seems to increase as the liver disease advances, and approximately 50% of patients undergoing liver transplantation have bone density below the fracture threshold, as occurs in patients with PBC.l0,*O These osteopenic PSC patients have an increased risk for development of pathologic fractures following liver tran~plantation.'~~ Medical Therapy Several drugs, such as UDCA,131,153, 201, 214 c~lchicine,'~~ cy~losporin,2~~ methotrexate,lo5 d-penicillamine,"' tacrolimus (FK506),2I6 corticosteroids,38,16' azathioprine,92,220 pentoxifylline,28 and nicotine," alone or in I3O have been evaluated in the treatment of PSC. combination therapy,lZ9, Only a few controlled trials have been reported and, unfortunately, none of these drugs has shown convincing evidence of benefit (Table 9). The drug that has received the most study in PSC has been UDCA. In most trials, UDCA at doses varying from 10 to 15 mg/kg/d has been shown to improve liver biochemistries, at least in the short term. In the largest randomized controlled trial of UDCA (13 to 15 mg/kg/d) there

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Table 9. DRUGS EVALUATED IN THE TREATMENT OF PRIMARY SCLEROSING CHOLANGITIS Drug (reference no.) Controlled Trials UDCA (131,153, 201, 214)

Colchicine (174) Cyclosporin (231) Methotrexate (105) D-penicillamine (111) Uncontrolled Trials Tacrolimus (FK506) (216) Corticosteroids (38, 161)

Azathioprine (92, 220) Pentoxifylline (28) Nicotine (11) Combination Therapy UDCA + Methotrexate (129) Corticosteroids + Colchicine (130)

Properties

Immunosuppressive Antiinflammatory Antifibrotic Antiinflammatory Immunosuppressive Immunosuppressive Cupruretic Immunosuppressive Immunosuppressive Immunosuppressive Antiinflammatory Immunosuppressive TNF inhibitor Immunosuppressive (?) Compared With UDCA alone Historical controls

Therapeutic Benefit

Biochemical histology (?) None None Biochemical histology (?) None Biochemical Clinical, biochemical histology None None None Similar to UDCA Biochemical improvement

UDCA: Ursodeoxycholic acid.

was improvement in laboratory tests in patients randomly assigned to UDCA compared with those in the placebo group, but this improvement was not accompanied by beneficial changes in clinical outcomes after as ' ~ ~ lack of long-term benefit of UDCA much as 6 years of f ~ l l o w - u p . The in PSC patients contrasts with that seen in patients with PBC. In the absence of a clinical response, it is difficult to recommend the routine use-of UDCA in patients with PSC. A small controlled trial using a higher dose of UDCA (20 mg/kg/d) showed improvement in liver biochemistries as well as improvement in liver histology after 2 years of treatment compared with placebo.153Determining whether this histologic improvement translates into significantly improved long-term outcome will require further large, controlled trials of higher dose UDCA. Drugs that look promising, in addition to high-dose UDCA, include corticosteroids and tacrolimus. However, these are also the drugs for which the fewest patients have been studied. These two drugs, and in particular tacrolimus, can be associated with significant side effects that may preclude their use as long-term therapy. The marginal biochemical improvement achieved with methotrexatelo5seems outweighed by the frequent side effects.lZ9None of the combinations tested look more I3O promising than any of the individuai Further advances in the understanding of PSC will lead to therapy more specifically targeted to the site of initial damage, that is, the bile duct epithelium. At this time, no specific medical therapy aimed at

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disrupting disease progression is available and of these drugs can be recommended outside prospective trials. Liver Transplantation

Primary sclerosing cholangitis is one of the most common indications for liver transplantation in the United States.'Oo The cumulative 1-year survival rate after liver transplantation in the United States is now greater than 85%; in recent years; many programs have achieved a 90% to 97% 1-year survival rate and a better than 85% 5-year survival rate. Actuarial patient survival after liver transplantation is significantly better than the survival rate of patients treated with nontransplantation biliary surgery'91or the predicted survival from prognostic models.70,191 Liver transplantation should be considered before the disease is too advanced because PSC patients with a low (<4.4) Mayo risk score have a significantly better long-term survival after transplantation than those patients with a higher (> 5.3) Mayo risk score.'@ Indications for liver transplantation in PSC are similar to those for PBC and other chronic liver diseases: the development of major complications related to portal hypertension and liver failure; the development of complications associated with chronic cholestasis (poor quality of life, disabling fatigue, intractable pruritus, severe muscle wasting); the development of chronic or recurrent bacterial cholangitis; and persistent increases in serum bilirubin levels in the absence of cholangiocarcinoma. Often these conditions prompt the practicing clinician to consider referral for liver transplantation even in those patients without cirrhosis on liver biopsy. Patients with PSC have a significantly higher rate of development of nonanastomotic biliary strictures after liver transplantation, and some patients can also develop features consistent with PSC on posttransplant liver suggesting that PSC can recur after liver transplantation. Although no definitive criteria for the diagnosis of disease recurrence have yet been established, if PSC recurs, it does not seem to have an aggressive course.7o Natural History and Prognostic Models

The natural history of PSC is less well understood than that of PBC. The median reported survival in patients with PSC is 10 to 12 years from the time of diagnosisB. 228 although an active search for PSC in screening programs may lead to the identification of patients in an early 14' stage of disease who can expect a significantly longer survival.36* The disease, however, generally follows a progressive course, and most asymptomatic patients eventually develop symptoms of chronic cholestasis and biliary cirrhosis with its consequent complications.lsOSeveral variables, such as older age, elevated serum levels of bilirubin, albumin,

PRIMARY BILIARY CIRRHOSIS AND PRIMARY SCLEROSING CHOLANGITIS

559

and AST, hepatosplenomegaly, variceal bleeding, presence of IBD, and histologic stage, have been identified as independent risk factors indicating a poor prognosis (Table 10). To predict survival in an individual PSC patient, prognostic index formulas that rely on Cox’s proportional hazards analysis, with and without histologic stage as a variable, have also been reported.35,55, 63, lo3,228 Recently, the Child-Pugh classification has been evaluated as a prognostic indicator for survival in PSC.198The study demonstrates that the age-adjusted Child-Pugh model predicts survival before liver transplantation with accuracy similar to the Mayo PSC model; it has the advantage of not requiring complex mathematical computations, and it has been used in formulating minimal listing criteria for liver transplantation for the United Network for Organ Sharing.137

SUMMARY

Primary biliary cirrhosis and primary sclerosing cholangitis are the most common chronic cholestatic liver diseases in adults that lead to biliary cirrhosis and its inherent complications such as portal hypertension and liver failure. Although important advances in the understanding of the pathogenesis of these conditions have been accomplished in the last two decades, much work is needed to uncover the interaction of genetic and immunologic mechanisms involved in their pathogenesis. Ursodeoxycholic acid at dosage of 13 to 15 mg/kg/d is the only agent that can currently be recommended in the treatment of PBC. No medical therapy aimed at disrupting disease progression is available for patients with primary sclerosing cholangitis, although several agents with different properties are currently under evaluation. Liver transplantation is the treatment of choice for patients with primary biliary cirrhosis and primary sclerosing cholangitis with end-stage liver disease.

Table 10. INDEPENDENT PREDICTORS OF SURVIVAL IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS Mayo (228)

King’sCambridge

(63)

Multicenter (55)

Norway (193)

New Mayo Model (103)

Age Age Age Age Histologic stage Histologic stage Histologic stage Bilirubin Bilirubin Hepatomegaly Bilirubin

Age Bilirubin Albumin

Hemoglobin Splenomegaly Inflammatory Alkaline bowel disease phosphatase

AST Variceal bleeding

AST: aspartate aminotransferase

Splenomegaly

Swedish

(35) Age Bilirubin Histologic stage

560

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Keith D. Lindor, MD Division of Gastroenterology and Hepatology Mayo Clinic 200 First Street SW Rochester, MN 55905 e-mail: lindor.keith9mayo.edu