Primary Biliary Cirrhosis: New Therapeutic Directions C. L. BERG & J. L. GOLLAN Division of Gastroenterology, Brigham and Women's Hospital, and Harvard Medical School, Boston. Massachusetts. USA

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Berg CL, Gollan JL. Primary biliary cirrhosis: new therapeutic directions. Scand J Gastroenterol 1992;27 Suppl 192:43-49. The immunologic mechanisms responsible for the development of primary biliary cirrhosis (PBC) remain poorly defined. although recent investigations have provided new clues as to the role of cellular membrane proteins such as the mitochondrial autoantigens and intercellular adhesion molecules. Additionally, new therapeutic agents have become available that markedly enhance the prospect for medical management of both hepatic and extrahepatic manifestations of PBC. Definitive therapy with ursodeoxycholic acid and/or methotrexate, and symptomatic relief of pruritus with rifampicin or metronidazole may become standard in the years ahead. The results of their use to date in the treatment of PBC are detailed in this review. Successful therapy of hepatic osteodystrophy associated with PBC has yet to be achieved, although early data suggest a role for ursodeoxycholic acid, estrogen, calcium, and vitamin D in the management of this debilitating problem. Orthotopic liver transplantation continues to be successful for the management of advanced disease (>70% 5-year survival) and will remain an essential therapeutic tool until definitive medical therapy for PBC becomes available. Key words: Antimitochondrial antibodies; hepatic osteodystrophy; methotrexate; primary biliary cirrhosis; pruritus; rifampicin; ursodeoxycholic acid John L. Gollan, M . D . , Ph. D . , Division of Gastroenterology, Brigham and Women's Hospital, 75 Francis 9, Boston, MA 02115, USA

Research during the course of the past decade has resulted in impressive advances in our understanding of the immunologic phenomena associated with primary biliary cirrhosis (PBC). Several antigens responsible for the development of characteristic antimitochondrial antibodies in this disease have now been identified. Some progress has been made with regard to therapeutic interventions, and a series of promising medical treatments have recently undergone preliminary evaluation. Despite these new and exciting developments, much information is still needed to refine our approach to definitive medical management of patients with PBC. The following contribution details recent advances that have emerged over the last several years with regard to primary biliary cirrhosis, and highlights areas of therapy that should be developed in the years ahead. CELLULAR CONSTITUENTS AND THE PATHOGENESIS OF PBC Mitochondria1 autoantigens The etiology of primary biliary cirrhosis still remains elusive, although significant strides have recently been made toward a more complete understanding of the antimitochondrial antibodies that characterize this disease. These antibodies were first observed in 1965 in the sera of patients with PBC (1). Several years lager, Berg et al. (2) identified the fact that the antibodies are directed toward

Table I. Association of antimitochondrial antibodies (AMA) with systemic disease Disease state

AMA type

Primary biliary cirrhosis

Anti-M2 Anti-M4 Anti-M8 Anti-M9

Syphilis Pseudolupus Connective tissue disease Drug-induced hepatitis Myocarditis

Anti-M1 Anti-M3 Anti-M5 Anti-M6 Anti-M7

Based on Gershwin et al. (3).

mitochondria. Subsequently, it has been recognized that while these antibodies are not specific for the diagnosis of PBC, they are relatively sensitive, being present in upwards of 85% of patients with the typical clinicopathologic profile. Antimitochondrial antibodies have been divided into nine subtypes, namely anti-M1 through anti-M9 (Table I). Of these, four have been associated specifically with PBC: antiM2, M4, M8, and M9. The remaining antibodies have been associated with various other systemic illnesses distinct from PBC. The antigens to which these antibodies are directed have been characterized with regard to trypsin sensitivity and inner- versus outer-mitochondria1 membrane location

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C. L. Berg & J . L. Gollan

(3), but only M1 and M2 have been thoroughly characterized. M1 appears to be equivalent to cardiolipin, and M2, the autoantigenic complex for PBC, has been found to consist of at least five polypeptides localized to the a-ketoacid-dehydrogenase complex of the inner mitochondrial membrane (4). No comparable antigen identification has been achieved for the other antigens characteristic of PBC (that is, M4, M8, and M9). Whereas the precise relationship of these autoantigens to the pathogenesis of PBC remains uncertain, there has been increasing recognition of patterns of antimitochondrial antibody positivity that appear to correlate with the clinical course of the disease. Four distinct patterns of antimitochondrial antibodies have been described (Table 11). Stratification of patients into one of these four groups has been shown to successfully predict clinical outcome (4-6). Analysis of stored serum suggests that the antimitochondrial antibody profile is constant despite progression of the disease and that individuals with profiles A and B typically have benign disease (without progression to histologic stages III/ IV). In contrast, 94% of individuals with profile D experience progressive disease, with the development of fibrosis and cirrhosis. Antimitochondrial antibody profile C appears to correlate with clinically ‘borderline cases’, with a slower progression to the late histologic stages than profile D. With this newly developed capability to predict the prognosis for groups of patients with PBC, all therapeutic trials should now attempt to separate the response to different regimens on the basis of the antimitochondrial antibody profile. By analyzing patients predicted to have a ‘good‘ versus a ‘poor’ prognosis individually, therapeutic benefits may become evident which could be overlooked if the patients were analyzed collectively. In addition, precise identification of the entire spectrum of antigens that appear to have prognostic implications may provide further insight into the pathogenesis of PBC.

Intercellular adhesion molecules A second class of cellular membrane proteins which may have pathophysiologic or potential therapeutic importance with regard to PBC are the intercellular adhesion molecules

(ICAMs). The induction and maintenance of T-cell cytotoxicity within the biliary epithelium requires lymphocyte adhesion to target cells and to other immune cells (7). This adhesion is mediated, in part, by the interaction of leukocyte function-associated antigen 1 and the intercellular adhesion molecules, ICAM-1 and ICAM-2. The expression of ICAM1in PBC, defined by monoclonal antibodies, shows a pattern of expression which correlates directly with the biliary structures injured in PBC (7). Thus, ICAM-1 is strongly expressed on interlobular bile ducts but not on medium-sized or large ducts. Moreover, this expression of ICAM-1 on biliary epithelial cells is limited to livers with PBC and primary sclerosing cholangitis (PSC) and is not evident in normal liver specimens. Since ICAM-1 expression is a key mediator of lymphocyte adhesion, increased expression on interlobular bile ducts in PBC (and PSC) may enhance T-cell-mediated injury to these structures. Whereas the identification of increased ICAM-1 expression does not distinguish this event as a primary or secondary phenomenon, this observation provides yet another clue to the pathogenesis of PBC. Should this increased expression of ICAM-1 be found to be a critical step in the process of ductular injury in PBC, the use of antiICAM-1 antibodies may provide a highly focused approach to the treatment of this disease. DEFINITIVE THERAPIES Definitive medical therapy for PBC has, until recently, been universally disappointing. The use of corticosteroids (8), azathioprine (9), D-penicillamine (lo), and chlorambucil (11) has resulted in marginal therapeutic success and, in the case of corticosteroids, chlorambucil and D-penicillamine, has been accompanied by an unacceptable profile of adverse effects. More favorable results have been observed with colchicine therapy (12-14); however, improvement in conventional liver function tests in response to colchicine has not been accompanied by an improvement in symptoms, liver histology, or the clinical endpoint of death or need for liver transplantation (15,16). Treatment with cyclosporine has resulted in modest symptomatic, biochemical, and histologic improvement (17); patients treated with this agent,

Table 11. Definition of antimitochondrialantibody profile on the basis of clinical outcome Profile type

Antibody characteristics

Clinical outcome


Only anti-M9 positive by ELISA

Benign clinical course, histologic progression rare


Anti-M9 and/or anti-M2 positive by ELISA

Similar to profile A


Anti-M2, anti-M4 and/or anti-M8 positive by E U S A

‘Borderline’prognosis between profile A/B and profile D


Anti-M2, anti-M4 and/or anti-M8 positive by ELISA and ClT

Histologic progression to fibrosis/cirrhosis classical course

Based on Klein et al. (4). ELISA = enzyme-linked immunosorbent assay; CFT = complement fixation test.

New Therapeutic Directions in PBC

Table 111. Definitive medical therapy for primary biliary cirrhosis Promising medical therapies

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Ursodeoxycholic acid Methotrexate

Uncertain efficacy or unfavorable side effects

Azathioprine Colchicine Cyclosporine

Not recommended

D-PeniCihnine Glucocorticoids Chlorambucil

however, frequently develop nephrotoxicity (63%) and/or hypertension (47%), and it is probable that the frequency of these side effects will limit the useful application of this drug (Table 111). Ursodeoxycholic acid Considering the disappointing results associated with the aforementioned therapeutic modalities, it is understandable that considerable enthusiasm has accompanied recent reports (18-21) that ursodeoxycholic acid has a favorable effect on patients with PBC. Although the mechanism of action of this bile acid remains uncertain, several hypotheses have been proposed. Ursodeoxycholic acid in a dose of 1215 mg/kg/day may lead to a relative reduction of endogenous, hydrophobic bile acids at the level of the hepatocyte and biliary epithelial membranes. This replacement of native bile acids is mediated by competition between ursodeoxycholic acid and the endogenous bile acids at the site of ileal absorption (22). Replacement of these potentially toxic native bile acids, which are retained under cholestatic conditions, may thus minimize cellular membrane injury (23). Alternatively, it has been suggested that ursodeoxycholic acid is effective by means of immunomodulation (18,24). Lastly, a choleretic effect has been postulated to explain the improvement noted in cholestatic disorders in response to ursodeoxycholic acid. Subsequent to the initial uncontrolled findings presented in 1985 (25), suggesting a beneficial effect of ursodeoxycholic acid on the course of PBC, results of several large controlled trials have been reported (18-21). The most detailed data available have been reported by Poupon et al. (18). In this 2-year, multicenter, double-blind, placebo-controlled trial a total of 146 patients with PBC were enrolled; half received ursodeoxycholic acid (, whereas the others received placebo. Side effects were minimal, leading to the withdrawal of only one patient in the ursodeoxycholic acid group. Improvements in serum bilirubin, alkaline phosphatase, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), y-glutamyltransferase, cholesterol, and IgM levels were noted in the ursodeoxycholic acid group. A decrease in both the antimitochondrial antibody titer and the Mayo risk score was also evident. Symptomatic relief of pruritus was documented in some patients. Most importantly, these changes in biochemical and clinical variables were accompanied by improvement in the mean his-


tologic score of follow-up liver biopsies. Because exclusion criteria limited the number of patients with cirrhosis in this study, it is inappropriate to extrapolate these favorable results to patients with more advanced disease. In fact, the experience of Hadziyannis et al. (19) suggests that some cirrhotic PBC patients may not respond, even biochemically, to ursodeoxycholic acid. Indeed, not all reports have been as uniformly favorable. Perdigoto & Wiesner (26) recently described three noncirrhotic patients who manifested marked symptomatic and biochemical improvement in response to ursodeoxycholic acid treatment yet developed histologic progression to cirrhosis with concomitant variceal hemorrhage, despite therapy. In addition, other investigators have warned of a potential ‘escape phenomenon’ whereby initial biochemical and symptomatic improvement disappears after 1 year of therapy. The data in the above 2-year trial and our own 3to 4-year treatment experience of patients with PBC suggest that if such a phenomenon exists, it is uncommon. Moreover, we have noted that patients with PBC in whom liver function test results plateau above the normal range, while being treated with 13-15 mg/kg/day of ursodeoxycholic acid for more than 1 year, will respond with further improvement in serum chemistry when the dose of ursodeoxycholic acid is increased to 18-20 mg/kg/day (C. Berg, J. Gollan; unpublished observations). Overall, the weight of data reported to date favors ursodeoxycholic acid use in precirrhotic patients with primary biliary cirrhosis. The minimal side effects of this drug and the lack of other non-toxic, efficacious therapies lead us to recommend ursodeoxycholic acid therapy for PBC, even while data from larger-scale, longer-term trials are awaited. Methotrexate On the basis of the description of PBC as a model autoimmune disease (27), it is not surprising that various immunosuppressive agents have been evaluated in the treatment of this condition. Corticosteroids, azathioprine, cyclosporine, and penicillamine have all either failed to match the success achieved by their use in other autoimmune conditions or have been associated with serious side effects. However, it remains to be seen whether selected subsets of patients may benefit from one or more of these therapies. Recently, small, uncontrolled trials (28-31) have examined the potential role of methotrexate in preventing the progression of the hepatic lesion in PBC. Results thus far have been mixed. Weber et al. (30) treated five patients with low-dose (7.5-15 mg/week) methotrexate for 12 months. While pruritus improved markedly, persistent improvement in serum alkaline phosphatase, bilirubin, and aminotransferase levels was not documented. Similarly, comparison of hepatic histology after 12 months’ therapy with pretreatment biopsies was disappointing. The experience reported by Bergasa et al. (29), and Kaplan & Knox (31), however, is more encouraging. Uti-

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C. L. Berg 13J . L . Gollan

Several recent trials have examined the potential efficacy of the antibiotic rifampicin for controlling the pruritus of PBC (35-38). Rifampicin has been recognized to increase hepatic microsomal enzyme activities (39), and thus suggested modes of action (36) include: 1) enhanced microsomal sulfoxidation of di- and mono-hydroxy bile acids, leading to increased elimination by urinary excretion, and 2) enhanced metabolism of non-bile acid pruritogenic substances. Two recent trials of long-term administration of rifampicin to pruritic PBC patients, in the absence of other antipruritic compounds, have reported favorable results (35,36). Podesta et al. (35) utilized a dose of 300 mg orally twice daily in a prospective cross-over study in 14 patients. Response to therapy was assessed using a daily patient log of symptoms; complete relief of pruritus was noted in 79% of the patients during rifampicin therapy, with partial improvement noted in the other patients. A response was evident within 7 days of therapy and was maintained over an 8-month period, during a second, open-label period of therapy. Similarly, favorable results have been reported recently by Bachs et al. (36) using a dose of 10 mg/kg/day. As in the prior report, symptomatic relief was observed in all treated patients within 14 days and persisted throughout the period (mean, 14.4 months) of therapy. In both studies, longterm treatment was associated with significant side effects in -10% of patients. Two individuals developed marked elevation in transaminases, which resolved with discontinuation of rifampicin, and one patient developed an allergic reaction characterized by eosinophilia, cutaneous rash, and EXTRAHEPATIC MANIFESTATIONS O F PBCfacial edema. Whereas toxic hepatitis is reported in -1% of THERAPEUTIC MODALITIES patients treated with rifampicin, these cases suggest the need PBC is associated with a plethora of extrahepatic mani- for careful monitoring of PBC patients treated with this festations, and recent progress in the management of these drug, since they may be predisposed to hepatic toxicity. vexing problems has been most promising with regard to the Overall, however, these findings are most encouraging and suggest the need for larger clinical trials to define the role control of pruritus and hepatic osteodystrophy. for this drug in cholestatic pruritus. Our own experience suggests (albeit indirectly) that the Pruritus Conventional therapy for the control of pruritus has cen- beneficial effects of rifampicin on pruritus may not be due tered on the use of cholestyramine, ursodeoxycholic acid, solely to the hepatic metabolism of deleterious bile salts but histamine antagonists, androgenic steroids, and pheno- rather may be due to altered bacterial metabolism of bile barbital. As with any condition in which a multiplicity of acids in the gut lumen of cholestatic patients. This hypothesis therapies exist, all of the above agents have been applied is based on our observation that metronidazole is efficacious with only limited success. The lack of a consistently suc- in controlling refractory pruritus in patients with PBC (C. cessful therapeutic agent for the pruritus of PBC is largely Berg, S. Zucker, M. Carey, J. Gollan; unpublished obserrelated to our poor understanding of the pathogenesis of vations). Pulse therapy with metronidazole, 250 mg orally this debilitating symptom. Several hypotheses have been three times daily for 1 week has resulted in the prompt proposed, which center on the role of 'toxic' bile salts as the resolution of pruritus associated with PBC, which was refracagents responsible for the development of pruritus. One tory to both ursodeoxycholic acid and cholestyramine (16model postulates that retained bile salts, particularly the 20 g/day). Symptoms typically have returned in 4-6 weeks dihydroxy and unconjugated forms, accumulate in the skin after cessation of therapy (presumably coincident with bacand lead to the excitation of cutaneous nerve endings (33). terial recolonization of the intestinal lumen) and have reproAlternatively, Ghent (34) has postulated that high con- ducibly responded to additional short courses of metronicentrations of bile salts in the liver lead to hepatic membrane dazole. Evaluation of the effects of metronidazole (and disruption, which in turn results in the release of some, as other antibiotics) on pruritus in other cholestatic conditions is in progress. Thus, it remains to be seen whether antiyet unidentified, compound that initiates pruritus.

lizing a dose of 15 mg/week, both groups documented improvement in pruritus, liver function test results, and, most importantly, hepatic histology. Interestingly, ALAT levels were found to increase initially in both trials but then declined progressively as therapy continued. The presence of this rise in ALAT during the initial months of therapy has been noted to be indicative of a favorable long-term response (28). A review by Kaplan (28) of 32 treated patients suggests that such favorable improvement is limited to those patients without cirrhosis at the time of initiation of methotrexate therapy. Substantial concern with regard to potential side effects of methotrexate therapy has tempered enthusiasm while the results of larger on-going trials are in progress (32). Since dose-related hepatotoxicity associated with methotrexate has been documented when the drug has been used in the treatment of various other illnesses, the use of a potentially hepatotoxic drug in patients with underlying chronic liver disease clearly must be viewed with caution. Fortunately, in the small, short-term studies reported to date, this concern has not been borne out. However, documented toxicity has included the development of interstitial pneumonitis (28,31) and bone marrow suppression (31). Thus, while preliminary, short-term trials utilizing methotrexate in the management of primary biliary cirrhosis are encouraging. endorsement of this therapy except in clinical trials must await the results of prospective, randomized, long-term studies.

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New Therapeutic Directions in PBC

biotics represent a new and effective therapy for pruritus associated with PBC and other cholestatic diseases. Lastly, recent studies in which the use of opioid antagonists produced marked improvement in the pruritus associated with chronic cholestasis (40) suggest a potential therapeutic role for this class of compounds. While naloxone, the agent used by Rergasa et al. (40), can only be administered parenterally. other oral opioid antagonists may be useful in the treatment of pruritus. The mechanism of action by which these compounds are effective remains unknown but is the subject of active on-going investigation and may provide insight into the pathophysiology of pruritus.

Hepatic osteodystrophy Even though incapacitating bone pain and fractures are frequently associated with advanced PBC, the mechanisms underlying the bone disease that accompanies PBC remains poorly defined. The term hepatic osteodystrophy has been coined to describe the bone disease that appears to have characteristics of both osteoporosis and osteomalacia (41), although features of the former tend to predominate. Various treatment regimens have been proposed, which have focused primarily on calcium and/or vitamin D supplementation. Unfortunately, this approach alone has been less than uniformly successful. Several recent trials, however, indicate that increased bone mass (or, at least, a reduction in the rate of decrease in bone mass) may result in patients with PBC being treated with estrogen supplementation (42), calcitonin (43), or ursodeoxycholic acid therapy (44,45). While no long-term clinical endpoint has been evaluated in these studies, the preliminary findings with regard to bone density merit further attention. Estrogen therapy has generally been avoided by hepatologists caring for patients with PBC, since estrogens have been implicated in the impairment of biliary excretion and can cause cholestasis per se in normal individuals (41). On the other hand, estrogens have been an important therapeutic modality in the management of postmenopausal osteoporosis. Crippin et al. (42) recently reported a retrospective review of lumbar spine mineral density measurements in patients with PBC and correlated these data with menopausal status and estrogen supplementation. Estrogen supplementation was found to increase bone density slightly over a 1-year period. Importantly, estrogen therapy did not appear to aggravate cholestasis in patients. While this preliminary observation needs to be confirmed in larger, randomized, prospective trials, our own personal bias has been toward the use of estrogen supplementation in postmenopausal women with PBC. To avoid potential confusion with regard to the interpretation of liver function tests in patients being treated with drugs, such as ursodeoxycholic acid therapy, our practice has been to wait until a stable biochemical base line has developed after ursodeoxycholic acid administration before initiating estrogen supplementa-


tion. To date, no clear advantage of oral versus transdermal estrogen therapy is apparent. Depressed serum osteocalcin levels have been documented in PBC (44), suggesting diminished osteoblast activity and therefore impaired bone formation. The decrease in osteocalcin levels appears to be unrelated to the stage or duration of PBC. Interestingly, ursodeoxycholic acid therapy in PBC patients was associated with an increase in serum concentrations of osteocalcin and normalization of levels in 30% of the treated individuals (44).However, no data on concomitant bone density measurements are yet available on these patients. Crippin et al. (45) also noted a trend toward diminished bone loss, as measured by lumbar spine bone density, in PBC patients treated with ursodeoxycholic acid for 12 months. Whereas neither of these studies is sufficient to recommend the use of ursodeoxycholic acid in PBC solely for the treatment of hepatic osteodystrophy. these apparent effects on bone mass, together with the other beneficial hepatic effects, further strengthen the case for ursodeoxycholic acid treatment of PBC. Calcitonin also has been used in the management of postmenopausal osteoporosis. This drug, which inhibits osteoclast activity and thus may reduce osteoclast-induced bone resorption, has been used only in small numbers of patients with PBC. Reports on the efficacy of calcitonin in these patients are conflicting (43,46), and the beneficial results reported may merely be secondary to concomitant calcium and vitamin D administration. On the basis of the conflicting data in such a small number of patients with PBC, the administration of calcitonin for the treatment of hepatic osteodystrophy cannot yet be recommended.

Hypercholesterolemia Hypercholesterolemia is recognized as a hallmark of cholestatic liver disease in general, and particularly of PBC. In fact, initial clinical reports often emphasized the lipid abnormalities present in the disease, and the term ‘xanthomatous biliary cirrhosis’ (47) was often applied in the 1930s. Early in the course of PBC mildly elevated very low density lipoproteins (VLDL) and low-density lipoproteins (LDL) are noted in conjunction with elevations of highdensity lipoproteins (HDL) (48). In later stages of the disease, however, HDL fall and markedly elevated LDL are observed (48). These latter lipid changes would merit dietary and medical therapy in individuals without PBC in an effort to decrease the risk of atherosclerotic disease. A recent report (48) suggested that the serum lipid changes associated with progressive PBC are not, in fact, associated with an increased risk of atherosclerotic death. Although that study suffered from its reliance on death certificates for the ‘cause of death’, the recommendation that patients with hyperlipidemia in the setting of PBC not be subjected to specific treatment for hypercholesterolemia appears justified, at least until further studies are published.



L. Berg & J . L. Gollan

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HEPATIC TRANSPLANTATION Definitive medical therapy for the management of hepatic disease in PBC remains elusive, and hence hepatic transplantation continues to play a significant role in the management of patients with advanced disease. In the United States PBC has been the second most common indication for liver transplantation in adults in recent years (49). Indications for transplantation in the management of PBC vary between centers but generally include hepatic failure, hepatic osteodystrophy, and refractory variceal bleeding. The reported 5-year postransplantation survival rate is 70% (49), significantly exceeding that predicted by statistical models developed to calculate survival in the absence of transplantation. While such statistical models are imperfect, there is little doubt that long-term survival is greatly improved by using hepatic transplantation in selected patients with endstage PBC. PBC patients who undergo transplantation have generally experienced a marked improvement in quality of life, as both hepatic and extrahepatic manifestations of the disease resolve with transplantation (49). O n e exception to this general statement, however, relates t o hepatic osteodystrophy (41,50). Immobilization and glucocorticoid administration after transplantation may contribute to the development of newly symptomatic metabolic bone disease or the worsening of preexisting symptoms. The symptoms eventually improve with time in most patients, although osteodystrophy remains a source of long-term disability in a limited number of patients despite normal hepatic function. Nonetheless, in the Pittsburgh experience (51), more than 90% of patients with PBC who have undergone hepatic transplantation have returned to at least part-time employment. Enthusiasm about the favorable clinical outcome experienced by patients with PBC who elected to undergo liver transplantation was tempered initially by the prospect of recurrent PBC in the allograft (52). This prospect, however, has generally not been borne out by recent experience (49,53). In a histologic review by Demetris et al. (54) of allograft specimens from 106 patients transplanted for PBC no cases of recurrent disease were identified, despite the persistence of serum M2 autoantibodies after transplantation (55). Whether this apparent lack of recurrent disease is due to immunomodulation in response to posttransplantation immunosuppressive regimens or the lack of disease-specific autoantigens expressed in the allograft remains to be elucidated (56).

REFERENCES 1. Walker J, Doniach D, Roitt 1, et al. Serologic tests in diagnosis of primary biliary cirrhosis. Lancet 1965;1:827-31. 2. Berg P, Doniach D, Roitt I. Mitochondria1antibodies in primary biliary cirrhosis. I. Localization of the antigen to mitochondrial membranes. J Exp Med 1967;126:277-90. 3. Gershwin M, Coppel R, Mackay I. Primary biliary cirrhosis and

mitochondrial autoantigens-insights from molecular biology. Hepatology 1988;8:147-51. 4. Klein R, Kloppel G, Garbe W, et al. Antimitochondrial antibody profiles determined at early stages of primary biliary cirrhosis differentiate between a benign and a progressive course of the disease. J Hepatol 1991;12:21-7. 5. Monteiro E, Freitas J , Baptista A, et al. Antimitochondrial antibody profiles and prognosis of primary biliary cirrhosis in a Portuguese population [abstract]. Hepatology 1991 ;14:l95A. 6. Berg P, Klein R. Clinical and prognostic relevance of different mitochondrial antibody profiles in primary biliary cirrhosis (PBC). Molec Aspects Med 1985;8:235-47. 7. Adam D, Hubscher S, Shaw J , et al. Increased expression of intracellular adhesion molecule 1 on bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 1991 ; 14:42631. 8. Combes B. Prednisolone for primary biliary cirrhosis-good news, bad news [editorial]. Hepatology 1989;10:511-3. 9. Crowe J , Christensen E, Smith M, et al. Azathioprine in primary

biliary cirrhosis: a preliminary report of an international trial. Gastroenterology 1980;78:1005-1 0. 10. James 0. D-penicillamine for primary biliary cirrhosis. Gut 1985;26:109-13. 11. Hoofnagle J , Davis G, Schafer D, et al. Randomized trial of chlorambucil for primary biliary cirrhosis. Gastroenterology l986;9l:1327-34. 12. Kaplan M, Alling D, Zimmerman H, et al. A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 1986;315:1448-54. 13. WarnesT, Smith A, Lee F, et al. A controlled trial of colchicine

in primary biliary cirrhosis. Trial design and preliminary report. J Hepatol 1987;5:1-7. 14. Bodenheimer H, Schafner F, Pezzullo J. Evaluation of colchicine therapy in primary biliary cirrhosis. Gastroenterology 1988;95:124-9. 15. Warnes T. Colchicine in primary biliary cirrhosis. Aliment Phar-


macol Ther 1991;5:321-9. 16. Zifroni A, Schaffner F. Long-term follow-up of patients with primary biliary cirrhosis on colchicine therapy. Hepatology 1991;14:99&3. 17. Wiesner R , Ludwig J, Lindor K, et al. A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis. N Engl J Med 1990;322:1419-24. 18. Poupon R , Balkau B, Eschwege E, et al. A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. N Engl J Med 1991;324:1548-54. 19. Hadziyannis S , Hadziyannis E, Makris A. A randomized controlled trial of ursodeoxycholic acid therapy in primary biliary cirrhosis [abstract] Hepatology 1989;10:580. 20. Leuschner U , Fischer H, Kurtz W, et al. Ursodeoxycholic acid in primary biliary cirrhosis: results of a controlled double-blind trial. Gastroenterology 1989;97:1268-74. 21. Combes B, Carithers R, McDonald M, et al. Ursodeoxycholic acid therapy in patients with primary biliary cirrhosis [abstract]. Hepatology 1991;14:91A. 22. Stiehl A, Raedsch R, Rudolph G. Acute effects of ursodeoxycholic acid and chenodeoxycholic acid on the small intestinal absorption of bile acids. Gastroenterology 1990;98:424-8. 23. Hofman A. Bile acid hepatotoxicity and the rationale of UDCA therapy in chronic cholestatic liver disease: Some hypotheses.

Supported in part by grants DK34854 and DK36887 from the National Institutes of Health. C. L. Berg was supported by an Institutional National Research Service Award, DK07533, from NIDDK.

In: Paumgartner G, Stiehl A, Barbara L, et al., editors. Strategies for the treatment of hepatobiliary diseases. Dordrecht: Kluwer Academic Publishers, 1989:1>33. 24. Abe K , Nakadate I, Shimotono H, et al. Ursodeoxycholic acid modulates cytokine production in primary biliary cirrhosis [abstract]. Gastroenterology 1992;102:A770.

New Therapeutic Directions in PBC 25. David R, Kurtz W, Strohm W, et al. Die wirkung von urso-

desoxycholsaure bei chronischen leberkrankheiten [abstract]. Z Gastroenterol 1985;23:420. 26. Perdigoto R, Wiesner R. Progression of primary biliary cirrhosis with ursodeoxycholic acid therapy. Gastroenterology 1992;

Scand J Gastroenterol Downloaded from by University of British Columbia on 10/29/14 For personal use only.

102:1389-91. 27. Gershwin M, Mackay I. Primary biliary cirrhosis: paradigm or paradox for autoimmunity. Gastroenterology 1991;100:822-33. 28. Kaplan M. Methotrexate after five years in primary biliary cirrhosis [abstract]. Gastroenterology 1992;102:A829. 29. Bergasa N , Hoofnagle J, Axiotis C, et al. Oral methotrexate for

primary biliary cirrhosis: preliminary report [abstract]. Gastroenterology 1991;100:A720. 30. Weber P, Scheurlen M, Wiedmann K. Methotrexate ameliorates disease in patients with early primary biliary cirrhosis [abstract]. Gastroenterology 1991;100:A810. 31. Kaplan M, Knox T. Methotrexate for biliary cirrhosis [letter]. Gastroenterology 1992;102: 1824. 32. Hoofnagle J, Bergasa N. Methotrexate therapy of primary biliary cirrhosis: promising but worrisome [editorial]. Gastroenterology 1991;101: l44(&2. 33. Garden J , Ostrow J, Roenigk H. Pruritus in hepatic cholestasis. Pathogenesis and therapy. Arch Dermatol 1985;121:1415-20. 34. Ghent C. Pruritus of cholestasis is related to effects of bile salts on the liver not the skin. Am J Gastroentrol 1987;82:117-8. 35. Podesta A , Lopez P, Terg R. et al. Treatment of pruritus of primary biliary cirrhosis with rifampicin. Dig Dis Sci 1991;36:21&20. 36. Bachs L, Pares A , Elena M, et al. Effectsof long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology 1992;lO2:2O77-80. 37. Ghent C, Carruthers G . Treatment of pruritus in primary biliary cirrhosis with rifampin. Gastroenterology 1988;94:488-93. 38. Bachs L, Pares A , Elena M. et al. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet 1989;1:574-6. 39. Ohnhaus E, Gerber-Taras E, Park B. Enzyme inducing drug

combinations and their effects on liver microsomal enzyme activity in man. Eur J Clin Pharmacol 1983;24:247-50. 40. Bergasa N , Talbot T, Alling D, et al. A controlled trial of naloxone infusions for the control of pruritus of chronic cholestasis. Gastroenterology 1992;102:544-9. 41. Maddrey W. Bone disease in patients with primary biliary cirrhosis. In: Popper H, Schaffner F. editors. Progress in liver diseases. Philadelphia: W. B. Saunders Company, 199053754.

42. Crippin J , Jorgensen R, Dickson E, et al. Hepatic oste-


odystrophy in primary biliary cirrhosis: the effects of estrogen administration [abstract]. Gastroenterology 1992;102:A796. 43. Floreani A , Chiaramonte M, Giannini S, et al. Longitudinal study on osteodystrophy in primary biliary cirrhosis (PBC) and a pilot study on calcitonin treatment. J Hepatol 1991;12:21723. 44. Palamarou-Vogiatzi C, Georgiou E, Proukakis C, et al. Oste-

ocalcin levels before and after ursodeoxycholic acid (UDCA) therapy in primary biliary cirrhosis (PBC) [abstract]. Hepatology 1990; 12:841. 45. Crippin J, Jorgensen R, Dickson E, et al. The effect of ursodeoxycholic acid compared to placebo on lumbar spine bone density in patients with primary biliary cirrhosis [abstract]. Gastroenterology 1991;100:A732. 46. Camisasca M, Grandinetti G , Crosignani A, et al. Calcitonin therapy for osteodystrophy associated to primary biliary cirrhosis [abstract]. Gastroenterology 1991;100:A726. 47. Thannhauser S, Magendantz H. Different clinical groups of xanthomatous diseases: clinical physiological study of 22 cases. Ann Intern Med 1938;11:1662-45. 48. Crippin J, Lindor K, Jorgensen R, et al. Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis: what is the risk? Hepatology 1992;15:858-62. 49. Tzakis A , Carcassonne C, Todo S, et al. Liver transplantation. Semin Liver Dis 1989;9:144-8. 50. Hay J , Dickson E, Wiesner R, et al. Long-term effects of orthotopic liver transplantation on the osteopenia of primary biliary cirrhosis [abstract]. Hepatology 1990;12:838. 51. Markus B, Dickson E, Grambsch P, et al. Efficacy of liver transplantation in patients with primary biliary cirrhosis. N Engl J Med 1989;320:1709-13. 52. Neuberger J , Portmann B, MacDougall B. et al. Recurrence of primary biliary cirrhosis after liver transplantation. N Engl J Med 1982;306:1-4. 53. Gouw A , Haagsma E, Manns M, et al. Recurrence of primary biliary cirrhosis after liver transplantation'? [abstract]. Gastroenterology 1992;102:A8 14. 54. Demetris A , Markus B, Esquivel C, et al. Pathologic analvsis of liver transplantation for phmary biliary cirrhosis. fiepatology 1988:8 :939-47.

55. Haagsma E, Manns M, Klein R, et al. Studies of antimitochondria1 antibodies in primary biliary cirrhosis before and after orthotopic liver transplantation. Hepatology 1987;7:12933. 56. Mackay I, Gershwin M. Primary biliary cirrhosis: current knowl-

edge, perspectives, and future directions. Semin Liver Dis 1989;9: 149-57.

Primary biliary cirrhosis: new therapeutic directions.

The immunologic mechanisms responsible for the development of primary biliary cirrhosis (PBC) remain poorly defined, although recent investigations ha...
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