Diminished Flow of Bile and Subsequent Development of a Biliary (Portal to Portal) Cirrhosis

PRIMARY BILIARY CIRRHOSIS: NEW PERSPECTIVES*

WILLIS C. MADDREY

PHILADELPHIA

Primary biliary cirrhosis (PBC) is a chronic, usually progressive, cholestatic liver disease of unknown etiology which is found predominantly in middle-aged females and is characterized by the progressive destruction and disappearance of small interlobular hepatic bile ducts (1-4). The extrahepatic bile ducts are not affected. The diagnosis of PBC is most often established between the ages of 30 and 70 years. There is no evidence that the course of PBC occurring in a male differs from that found in females (5). The diagnosis of PBC should be prominently considered in the evaluation of an adult patient with chronic cholestasis. PBC must be distinguished from extrahepatic bile duct obstruction and several other established causes of chronic cholestasis including chronic drug-induced cholestasis, primary sclerosing cholangitis, and cholestatic chronic active hepatitis. The clinical manifestations of PBC result from the destruction and subsequent loss of bile ducts, thereby leading to a diminished flow of bile and subsequent development of a biliary (portal to portal) cirrhosis. In the majority of patients with PBC, there is no evidence of cirrhosis at the time of diagnosis, and the term chronic destructive intrahepatic cholangitis is a more appropriate designation. Early descriptions of PBC emphasized the clinical and histologic features of patients with advanced disease and cirrhosis. With increasing awareness of PBC over the past three decades, the diagnosis is being made earlier in the course of the illness, and many patients are being identified in whom there are no signs or symptoms of liver disease and the only abnormalities detected are an elevated serum alkaline phosphatase level and presence of antimitochondrial antibodies. SPECULATIONS REGARDING ETIOLOGY The etiology of PBC remains unknown. The disorder has been detected in more than one member of a family suggesting a genetic predisposition (6-8). Furthermore, family members of patients with PBC have an increased incidence of circulating autoantibodies as well as an apparent increase in occurrence of other autoimmune disorders (9). No definite association with any specific HLA type has been found in patients with

* From the Department of Medicine, Jefferson Medical College, Philadelphia, Pennsyl- vania 19107.

142 PRIMARY BILIARY CIRRHOSIS 143 PBC. There are many features of PBC which suggest that there may be an underlying immunologic basis for the disorder (3). Autoantibodies including those directed against mitochondrial as well as nuclear and thyroid antigens are found in increased frequency in patients with PBC. PBC is found in association with a number of other disorders with presumed immunologic bases including Sjogren's syndrome, thyroiditis, rheumatoid arthritis, and the CREST syndrome (10-12). In an occasional patient, there is the apparent coexistence of sarcoidosis and PBC (13). The antimitochondrial antibody system has been extensively studied in patients with PBC (14-16). Antimitochondrial antibodies (AMAs) are found in greater than 95% of these patients and testing for the presence of AMAs is important in diagnosis. The role of the AMAs in the pathogenesis of PBC is uncertain. The AMAs are neither organ nor species specific. There is no apparent correlation between the titer of AMAs and disease activity. It has been suggested that there is cross reactivity between the antimitochondrial antibodies found in PBC and structural proteins found in R mutants of enterobacteriaceae thereby suggesting an infectious etiology for PBC (17). There is no evidence PBC results from deposition of immune complexes such as had been suggested earlier using less specific assays (3). Patients with PBC have been demonstrated to have an impaired sulfoxidation pathway similar to that implicated in the pathogenesis of chlorpromazine-induced liver injury (18, 19). Sulfoxide metabolites of chlorpromazine are less cholestatic and hepatotoxic than are hydroxyl metabolites. Because of the similarities between chlorpromazine-induced liver injury and PBC, the status of the sulfoxidation pathway was evaluated and found to be impaired (19, 20). It has been suggested that the inability to sulfoxidize a variety of compounds including such potent cholestatic agents as D-ring estrogen derivatives may promote intracellular accumulation of toxic products. The defect in sulfoxidation in patients with PBC was corrected by liver transplantation. CLINICAL FEATURES Most often, patients with PBC are females (90%) in mid-life who complain of progressive loss of energy and malaise. Unexplained weight loss may be found early in the illness. Late in the course, weight loss may be accelerated by the development of steatorrhea with diarrhea secondary to decreased delivery of bile salts to the intestine. Pruritus is an important early symptom. The exact pruritogen has not been identified. Once pruritus appears in a patient with PBC, it rarely spontaneously remits. In addition, the skin may become thickened and hyperpigmented. An enlarged liver is found in more than half of patients with PBC at the 144 WILLIS C. MADDREY time of diagnosis. Abdominal pain is unusual. Splenomegaly may be detected even in asymptomatic patients. Bone pain especially severe in the back is frequent and results from osteoporosis which may be debili- tating and associated with fractures (21-23). Once a patient enters the progressive phase of the illness, the level of serum bilirubin begins to rise, xanthelasma and xanthomata develop in patients in whom there is a retention of lipids. Evidence of hepatocellular failure along with portal hypertension, ascites, and hepatic encephalopathy are late manifestations. However, occasionally a patient with PBC will present with bleeding from esophagogastric varices in the absence of manifestations of cholestasis (24). BIOCHEMICAL AND SEROLOGIC FINDINGS The usual biochemical tests of the liver in patients with PBC reveal evidence of cholestasis. The serum alkaline phosphatase level is almost invariably increased as are the 5' nucleotidase and gammaglutamyl transpeptidase (GGTP) levels. Serum bilirubin may be normal or only slightly elevated early in the course of PBC. Serum cholesterol levels are elevated in the majority of patients with symptomatic disease. Early in the course of PBC, the HDL cholesterol level is increased and subsequently falls as the disorder progresses (25). The combination of a falling serum cholesterol level in a patient with advanced PBC associated with an increasing serum bilirubin and a decreasing serum albumin is an ominous sign indicating failure of hepatic synthesis. Aminotransferase levels are usually only slightly increased. In some patients there is evidence of coexistent pancreatic insufficiency (26). The serum IgM level is increased in approximately 75% of patients with PBC (3). There is evidence that the IgM in these patients is highly immunoreactive and contains cryoproteins. The immunoreactive IgM is produced by a small population of B cells and production presumably results from a defect in T-suppressor cell regulation (27, 28). Further- more, the immunoreactive IgM has been shown to promote spontaneous conversion ofcomplement C3 to C3b and C3c by activation ofthe classical complement pathway thereby inducing hypercatabolism of complement in patients with PBC (29, 30). The discovery of antimitochondrial antibodies (AMAs) and recognition of the high (approximately 95%) incidence of these antibodies in patients with PBC was a milestone in the development of knowledge regarding the disorder (14-16). AMAs are rarely found in patients with mechanical obstruction of the biliary tract. However, these antibodies are found in 5-15% of patients with idiopathic chronic active hepatitis, and occasionally the differentiation of the disorders is difficult. Over the past several PRIMARY BILIARY CIRRHOSIS 145 years, it has been determined that the antimitochondrial antibody system is composed of several antigens with varying disease specificities. Several antigens have been identified within the mitochondria which are targets for the AMAs. The most prevalent AMA in PBC is designated M2 and is directed against a polypeptide found in the inner membrane of the mitochondria (15, 16). In addition to the M2 antigen, patients with PBC often have antibodies to antigens designated M4 and M8. It has been noted that patients who have anti-M2 as the sole AMA detected are generally asymptomatic and have a good prognosis, whereas patients in whom antibodies to M2 are found in association with antibodies to M4 and M8 more often have evidence of progressive disease. Therefore, the subtype pattern of AMAs, while not yet in widespread use, may prove to be important in predicting the course of PBC and in the separation of PBC from other disorders. More recently, an AMA designated M9 has been identified and associated with an antigenic site on submitochondrial particles (31). Anti-M9 is often found in patients with early PBC and is generally not found in later stages of the disorder. Of note has been the detection of anti-M9 AMA in 50% of 70 relatives of eleven patients with PBC as well as in 63% of technicians who were working in an immuno- pathologic laboratory testing blood from patients with PBC (15). These observations further increase interest in a possible infectious etiology for PBC. Another antibody found in patients with PBC is an anticentromere antibody originally described in patients with scleroderma (12). The anticentromere antibody is a specialized type of antinuclear antibody which may be an important marker for patients with PBC who have the CREST syndrome. PATHOLOGY As befits the known early immunologic attack on small intralobular bile ducts, the earliest histologic manifestations of PBC are found within the portal triad (32, 33). Interlobular bile ducts measuring 80-100 ,um are most often involved (34). Similarities between the early lesions of PBC and the graft versus host disease have been noted (35). The predominant inflammatory cells in the portal triad consists of plasma cells and lymphocytes. Granulomas are often found (40%) around the affected bile ducts but may be found elsewhere in the hepatic parenchyma (32, 33). It has been suggested that the presence of granulomas indicates a relatively early stage of the disease and a more favorable prognosis (36). Liver biopsy findings in patients with PBC have led to a histologic classification of the disorder into four broad stages (33). The classification is quite arbitrary and features characteristic of several stages may 146 WILLIS C. MADDREY coexist in a liver biopsy. There may be a poor correlation between clinical and histologic manifestations of disease. Stage I: Focal ductular destructive lesions with damage to the small intralobular bile ducts characterize the earliest histologic abnormality. These lesions are often irregu- larly scattered throughout the liver. The damaged ducts may be surrounded by a dense infiltrate of lymphocytes and plasma cells. The infiltrating lymphocytes have been shown to be predominantly T cells with those immediately around the injured bile duct of the suppressor-cytotoxic type (37). Stage II: As the disease progresses, ductular proliferation occurs with evidence of inflammation and early fibrosis which spills over into periportal areas. Periportal inflammation, cell destruction, and cholestasis may be prominent. Stage III: Septal fibrosis is found with bridging from portal to portal areas and evidence of architectural remodeling of the liver. There is a progressive diminution in the number of identifiable bile ducts. Stage IV: The late histologic manifestation of PBC is cirrhosis with regenerative nodules. Often by this phase of the illness, the characteristic earlier features have disappeared and few intact interlobular bile ducts are found. DIAGNOSIS PBC should be considered in any patient with evidence of cholestatic liver injury. The disorder must be especially sought in the middle-aged female who has pruritus, fatigue, and an elevated serum alkaline phosphatase. The diagnosis is confirmed by finding a positive AMA test and a compatible liver biopsy in a patient in whom there is no evidence of extrahepatic bile duct obstruction. Endoscopic retrograde cholangiogra- phy may be required to conclusively demonstrate patency of the extrahepatic biliary system. Particular attention must be directed towards obtaining a history of any medications the patient may have been receiving. A prolonged, cholestatic illness similar to that of PBC has been found in patients taken phenothiazines (20). COURSE OF PRIMARY BILIARY CIRRHOSIS As a result of increased awareness of the diagnosis of PBC and the widespread use of liver biopsy and AMA tests in the evaluation ofpatients with elevated serum alkaline phosphatase levels, the diagnosis is being made in many patients who have few if any symptoms or signs of liver disease (38, 39). The course of PBC is quite variable. In some patients, there is a relentless downhill course with the development of cirrhosis and many complications of severe cholestasis. However, many patients with clinically mild or asymptomatic disease survive for more than a decade with no apparent progression (38, 39). In a follow-up study of 243 symptomatic patients, the average survival was 11.9 years which is much longer than that earlier thought usual for PBC (38). In 37 patients who PRIMARY BILIARY CIRRHOSIS 147 were asymptomatic at the time of diagnosis, there was no difference in survival over a twelve year interval for the patients with PBC when compared to that for a control population (39). Whether all asymptomatic patients will eventually progress to symptomatic PBC is unknown. PROGNOSTIC FACTORS The finding of granulomas on liver biopsy has been suggested as a factor associated with a favorable prognosis, whereas patients with con- comitant manifestations of other autoimmune disorders such as thyroiditis, Sjogren's or CREST syndrome appear to have a poor prognosis (12, 36). A rising serum bilirubin is an ominous sign as is the expected poorer prognosis in those who are older, have cirrhosis, and have a decreased serum albumin level (40-42). THERAPY In the absence of a specific effective therapy for patients with PBC, management must emphasize general support of the patient and those measures designed to relieve symptoms and minimize the effects of complications (3, 43). With the availability and relatively widespread utilization of liver transplantation in patients with advancing PBC, many of the heretofore frequent complications of the disorder such as recurrent bleeding from gastroesophageal varices and severe hyperlipidemia are avoided by liver replacement. Pruritus. Pruritus is often a major disabling feature of PBC and occurs in the majority of patients with symptomatic disease. The use of the non- absorbed quarternary ammonium exchange resin cholestyramine is usually effective in patients in whom the serum bilirubin level is less than 5 mg/dl (44). Cholestyramine apparently exerts an effect by binding to an as yet unidentified pruritogen found in bile. Colestipol hydrochloride is another ammonium binding resin which is as effective as cholestyramine in the control of pruritus. Since both of these drugs are non-specific binding agents, other medications should not be given at or near the time of resin use. In intractable pruritus, large-volume plasmapheresis may be useful and provide rapid relief (45). However, plasmapheresis is expensive and must be repeated at distressingly regular intervals. Rifampin has also been suggested to be effective in the control of pruritus in some patients with PBC although the mechanism of the effect is unknown (46). The use of ultraviolet light therapy for pruritus has largely been abandoned as has the use of methyltestosterone which has been reported to decrease pruritus but to increase jaundice (47). 148 WILLIS C. MADDREY FAT SOLUBLE VITAMIN DEFICIENCIES Administration of the fat soluble vitamins A, D, E, and K may be required in patients with PBC (48). Deficiencies of these vitamins presumably result from malabsorption. Vitamin replacement therapy should be based on serum levels since absorption of vitamins is unpredictable. Vitamin A deficiency may be associated with impaired dark adaptation (49). Overt symptoms of night blindness are unusual. Oral vitamin A therapy may be required and in some patients with vitamin A deficiency, there is coexistence of zinc deficiency which must also be corrected in order to reverse abnormal dark adaptation (49). Vitamin D deficiency is often found in patients with PBC. Serum 25-OH vitamin D levels are frequently decreased. Bone disease, characteristically osteoporosis, with pain and fractures is a major disabling problem in many patients with advanced PBC (21-23). The pathogenesis of the osteoporosis remains unknown. The bone disease found in patients with PBC is rarely vitamin D responsive osteomalacia. Vitamin D supplementation usually readily restores serum vitamin 25-OH levels to normal but restoration does not associate with reversal of bone disease (21-23). Vitamin K supplementation may be effective in reversing a prolonged prothrombin time in a patient with advanced PBC. Steatorrhea and Weight Loss: The use of medium chain triglycerides (MCT) may be useful as a high caloric, well-absorbed dietary supplement in patients with advanced cholestasis and steatorrhea (50, 51). An occasional patient, especially those with PBC and the sicca syndrome, may require pancreatic replacement therapy (26). EXPERIMENTAL THERAPIES Corticosteroids: The many features of PBC suggesting immunologically mediated damage indicate a possible role for corticosteroid therapy. However, no controlled trials have conclusively demonstrated a benefit. Corticosteroids are generally not used in these patients because of con- cern that bone disease may be accelerated (52). Azathioprine: Azathioprine was reported in a multinational prospective double-blind randomized trial to improve survival in patients with PBC (41). In this study, azathioprine apparently reduced the risk of death to 59% of that observed with placebo treatment. Side effects from the azathioprine were relatively few and minor. A prognostic index was developed based on five variables which were independently shown to indicate poor prognosis-high serum bilirubin, increasing age, presence of cirrhosis, low serum albumin, and central (Zone III) cholestasis. From application of the index, there was evidence that azathioprine slowed the PRIMARY BILIARY CIRRHOSIS 149 rate of development of PBC. The observations indicating a beneficial effect from azathioprine warrant further studies. However, clinical and histologic information regarding the patients was not provided in the initial reports. d-Penicillamine: d-Penicillamine was extensively evaluated in the treatment of PBC over much of the past decade (53). Potentially favorable actions of d-penicillamine which led to the initiation of the trials included the ability to reduce the hepatic copper level which was shown to be increased in patients with PBC as well as the established antifibrotic effects of the drug. The use of d-penicillamine has been abandoned following demonstration in several trials that the drug was often poorly tolerated and had no favorable effect on symptoms, histologic features, or survival (53). Colchicine: At present, there is enthusiasm for the use of colchicine in patients with PBC (54-56). Colchicine has been reported by three groups of investigators to have produced significant improvement of serum bilirubin, alkaline phosphatase, and aminotransferase levels (54-56). Colchicine may favorably affect the course of PBC through its anti- inflammatory effects or through inhibition of intracellular microtubule assembly. Colchicine has anti-inflammatory properties as has been demonstrated in its use in patients with gout and familial Meditteranean fever. Furthermore, colchicine apparently reduces fibrosis by inhibition of collagen synthesis and by increasing collagenase activity. In one study, four years after entry, the cumulative mortality from liver disease was 21% in patients with PBC treated with colchicine as compared to 47% in patients who received placebo (p < 0.05) (54). However, in these studies, no histologic improvement was noted in the disease nor were there any effects on symptoms. One major advantage of colchicine therapy is its low instance of toxicity. Dose-related diarrhea is the only frequent side effect of the drug. Ursodeoxycholic acid: Ursodeoxycholic acid (UCDA) is a hydrophilic bile acid which has proven useful in the dissolution of gallstones and is apparently free of hepatotoxic effects (57). UCDA therapy is under investigation in patients with PBC because of a presumed anti-inflammatory effect. The presumed mechanism of action of UCDA is through replacement of toxic, endogenous bile acids which accumulate within hepatocytes as a result of diminished bile flow with non-toxic UCDA. In preliminary studies of UCDA therapy in patients with PBC, the incidence and severity of pruritus was reduced, and there were improvements in serum bilirubin, aminotransferases, alkaline phosphatase, and GGTP levels (58). In several patients discontinuation of UCDA was followed by deterioration of liver biochemical tests. However, thus far there have 150 WILLIS C. MADDREY been no studies conclusively demonstrating improvement in histologic evidence of liver disease nor improvement in long-term survival in those patients receiving UCDA. Multicenter trials are in progress. Cyclosporin A: Cyclosporin A is under investigation as a treatment in patients with PBC (59). Cyclosporin A has been used extensively and successfully in the treatment and prevention of rejection following liver transplantation. The drug has been demonstrated to inhibit T helper cell function. In a preliminary study, decreases in serum alkaline phosphatase and GGTP levels were found in patients with PBC receiving cyclosporin A (59). However, there are many side effects of cyclosporin A which may limit its usefulness as a therapeutic agent. Of most importance are established increases in serum creatinine and renal failure. Other side effects include accentuation of hypertension, thrombocytopenia, hirsut- ism, headaches, and paresthesias. Methotrexate: Methotrexate therapy, given orally and in low-dose, has been reported to lead to improvement in biochemical and clinical manifestations of PBC (60). One possible favorable action of methotrexate is through inhibition of interleukin-1 thereby reducing the number of activated T cells which may be important in causing bile duct damage. Much further study will be required to establish a role for methotrexate therapy. LIVER TRANSPLANTATION IN PRIMARY BILIARY CIRRHOSIS Patients with PBC are considered especially good candidates for hepatic transplantation, and most patients with advanced PBC should be at least considered for transplantation (61, 62). The progressive deterio- rating course of PBC once clinically apparent jaundice and other signs of liver disease appear is relatively well-established and somewhat pre- dictable. These patients often are middle-aged women with no evidence of irreversible damage in other organ systems. Indications for liver transplantation in PBC include advanced symptomatic disease, rising serum bilirubin, bleeding from esophagogastric varices, severe metabolic bone disease, and muscle wasting. As the results from liver transplantation have improved in patients with PBC, transplantation is being considered much earlier in the course of the disorder. For many patients with PBC, liver transplantation offers an opportunity to return to a prolonged, productive life. Projected five year survivals of 66% or more are being reported (62). Apparent recurrence of PBC in the transplanted liver has been reported but this is difficult to distinguish because of the similarities between the histologic findings of PBC and those of graft versus host disease (63). PRIMARY BILIARY CIRRHOSIS 151 REFERENCES

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DISCUSSION Paterson (Chicago): Thank you very much, Dr. Maddrey. I must say that is a mind- boggling set of perspectives you laid out. I want to ask two questions. Is anything known about the nature of the presumed definitive antigen which represents the moiety in the target cell; and if so, is there an animal model that has been developed for this disease or attempts made in that direction? Maddrey: There is no animal model of primary biliary cirrhosis (PBC) yet known. There is some presumed evidence that the target antigen is on the bile ductular epithelium. Current emphasis is on an HLA protein that might be similar to that of an infectious agent. There are a lot of might-be's in there and we do not yet know the target. Paterson (Chicago): Do the lymphocytes of patients early in this disease when cultured in the presence of that protein or the target cells undergo proliferation? Maddrey: Unfortunately there are variable results. There are several studies. However none are conclusive. Nolan (Buffalo): Will, that was a wonderful presentation as always. I wonder why you didn't mention methotrexate as being a possible new therapy that seems to show promise in this disease. Maddrey: Only for limits of time. Methotrexate to my knowledge has only been tried in ten patients with PBC. We have a small study. I'm a little fearful of mentioning these potentially toxic drugs until they've had at least a one year experience. 154 WILLIS C. MADDREY Clifton (Iowa City): That was a great paper. Will, I thought I heard you say something to the effect that you were using ursodeoxycholic acid because chenodeoxycholic acid might be playing some deleterious role. In the gall stone study in which chenodeoxycholic acid was the major agent, was there any evidence of biliary cirrhosis developing in patients taking this agent over a period of several years? Maddrey: No, there was not, Jim. The situation in that is quite different though. The concentration of bile acids within the liver cells in patients in the gall stone study is miniscule compared to the grossly obvious accumulations in PBC. It turns out that ursodeoxycholic acid does not change the total concentration of bile acids within the hepatocyte. As you recall in the gallstone study, there was a small but real incidence of hepatic injury as evidenced by elevated aminotransferase levels which led to a preference for ursodeoxycholic acid everywhere in the world except in the United States where chenodeoxycholic acid was the only licensed drug. Smith (Rochester): Does the disease recur in the transplanted liver? Maddrey: We do not think this disorder recurs after liver transplantation. Sir Roy Calne and his group in England did report histologic evidence, in several patients, of an illness that looks similar. The problem is graft-versus-host in the post-transplant situation and PBC are almost identical histologically. Therefore the question is, are we seeing a chronic rejection reaction or are we seeing a recurrence of disease. The good news is that five to ten years down the way in the patients that we are following, the full syndrome of PBC has not redeveloped. Fleming (Jacksonville): I thoroughly enjoyed that excellent review. You mentioned the potential of vitamin A deficiency in patients with PBC. I suspect you omitted comments about the dangers of chronic vitamin E deficiency only because of time. We have seen, and I'm sure you have, the posterior-lateral column and cerebellar signs in patients with advanced progressive PBC and vitamin E deficiency. Maddrey: Yes, Dr. Fleming, we surely have. We have reviewed 60 patients and will have a paper this month on this. We also have been using vitamin E supplementation to prevent neurological deterioration which was so clearly first shown in children with malabsorption, but has been seen now in several adults first described from the Mayo Clinic. Santos (Baltimore): Willis, you mentioned the liver transplants. One would wonder what would happen if one gave the patient cyclosporin with the early disease. This is the same treatment that you used to keep the liver in. Chlorambucil is a lousy immunosup- pressant. Has that ever been done or thought of? Maddrey: The Mayo Clinic is carrying out a cyclosporin study right now and showing some rather remarkable effects. My problem with it is the 20% nephrotoxicity from cyclosporin that we get into in the post transplant situation. Santos (Baltimore): But, Tom Starzl has problems with cyclosporin also. At any rate I raise that question. Maddrey: So therefore you choose at what time of the illness you have your problems. Cahill (Bethesda): There are at least 600 newly diagnosed diabetic children in the world now on full immunosuppressive doses of cyclosporin, holding the progression of their Beta- cell destruction in check and thereby sparing, in many, insulin therapy. I agree with Dr. Santos that there is no doubt that the liver doesn't get the recurrent disease because of the immunosuppression. In discordant identical twins, one with diabetes, the other without, transplanted Beta cells from normal to diabetic are subsequently destroyed, thanks to the persisting immune memory to destroy Beta cells. They are therefore put on immunosuppression even though they are identical twins. My guess is cyclosporin will provide dramatic results in your disease. Maddrey: Well, we'll see.