primary biliary cirrhosis

PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING CHOLANGITIS, AND ADULT CHOLANGIOPATHIES 1089-3261/98 $8.00 + .OO

PRIMARY BILIARY CIRRHOSIS Clinical and Associated Autoimmune Features

and Natural History

David E. J. Jones, MRCP, Oliver F. W. James, FRCP, and Margaret F. Bassendine, FRCP

Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease in which the biliary epithelial cells lining the small intrahepatic bile ducts are the target for immune mediated damage. Although rank- ing far below hepatitis viruses and alcohol-related liver diseases, PBC is an important cause of chronic liver disease worldwide, and in the western world it represents one of the most common indications for liver transplantation. Furthermore, in affected patients, the symptoms typical of the condition often have a significant effect on quality of life and patients respond poorly to treatment. In addition, PBC provides an important model for the study of autoimmunity in humans. The identification of the major autoantigens, together with the availability of liver tissue from different stages of the disease process means that aspects of the immunopathogenesis of the condition can be accurately studied, with potentially important implications for our understanding of both PBC in particular and autoimmunity in general. Current con- cepts of disease pathogenesis and increasing knowledge of the clinical course of the disease have allowed us to propose a model for the natural history of PBC from initial breakdown of self tolerance to the complications of decompensated stage IV disease when patient prognosis is significantly affected unless transplantation is performed (Fig. 1).

From the Centre for Liver Research, The Medical School, University of Newcastle upon Tyne, New Castle upon Tyne, United Kingdom

CLINICS IN LIVER DISEASE

VOLUME 2 * NUMBER 2 * MAY 1998 265

266 JONES et al

Environmental Genetic trigger(s) predisposition

Pre-Disease (Disease specific antibodies, usually AMA reacting with PDC-E2/E3BP;

Normal LFTs) 1; i ?

1 Genetic / Early Disease (Abnormal LFTs +/- symptoms)

Late Disease (Histological stage III/IV)

Decompensated Disease

Death or Transplant

I I V

Disease Recurrence? (AMA positive)

Figure 1. Natural history model of primary biliary cirrhosis.

PRIMARY BILIARY CIRRHOSIS 267

This article discusses the stages in the natural history of PBC with reference to this model.

CAUSATION

The most widely accepted hypothesis is that PBC arises in a susceptible individual as a result of exposure to one or more environmental factors. Ninety percent of affected individuals are women,", 41, 90 but the age and severity of disease at the time of diagnosis are similar in men and women.6z This apparent increase in PBC susceptibility in women mirrors a similar trend in other autoimmune diseases. Associated autoimmune diseases, especially sicca syndrome, are more common in

but as with other autoimmune diseases, the reasons for female susceptibility are unclear.

Environmental Factors

Available evidence suggests that environmental factors play an important role in triggering PBC development. Epidemiological studies have suggested marked differences in disease incidence in genetically related populations exposed to different envir~nments .~~ Regional differences in disease prevalence have long been recognized within the United Kingdom.33 More striking, however, are the differences in PBC prevalence between the native Northern European population and emigrant populations with similar origins. A recent, exhaustive, case-finding study in Newcastle, United Kingdom has suggested a disease-point prevalence of at least 24 per 100,000.66 In marked contrast, the disease prevalence has been estimated at 1.9 per 100,000 in Victoria, Australialo5 and at 2.2 per 100,000 in Ontario, Canada.'lo In both cases, the population is largely of Western European origin. Even allowing for differences in case finding protocol these studies suggest a marked, locally-variable, environmental component to the risk of PBC development.

Unfortunately, little is known about what environmental factors actually trigger disease development in at-risk individuals. One potential source of disease-inducing environmental exposure was identified in Sheffield, United Kingdom, where PBC prevalence within the city was related to the source of drinking water since the prevalence in the area supplied by one reservoir was 10 times higher than in the areas supplied by the other four reservoir^.^^ Extensive analysis of the water from this source failed to find any infectious or chemical factors unique to this reservoir, and studies of the relationship between water supply and PBC prevalence in other populations have failed to establish a link. The literature does contain isolated reports of factors that have triggered PBC, including interfer0n-c~'~ and chlorproma~ine,~~ but these are only likely to account for a small minority of cases. The search for more general-acting trigger factors in PBC and other autoimmune conditions

268 JONES et a1

has focused primarily on infectious organisms that, through the mechanisms of molecular mimicry and nonspecific immunostimulation, can bypass the normal mechanisms of peripheral self-tolerance.M In autoimmune hepatitis, there is evidence to suggest that hepatocyte damage can be triggered by Epstein-Barr virus infection,’O’ but such evidence is lacking in PBC. Reports suggesting that PBC patients have an increased incidence of asymptomatic bacteriurias and have antibodies in their blood reactive with antigens from the atypical mycobacterium M . gur- dunae, suggest a potential role for infection with these organismslo2 have not been ~onfirmed.~” 77 A report that human mycoplasma-like organisms can induce PBC-like lesions in mice suggests another potential infectious trigger43 in light of the established link between infection with mycoplasma and the induction of autoimmunity in animals.12

Genetic Susceptibility

Whatever event(s) trigger development of PBC, it appears that inherited factors play a significant role in determining disease susceptibility. The major evidence in support of this has come from family studies. The risk of PBC is significantly higher in close relatives of patients with the disease than in the rest of the popu1ation.l. The prevalence of PBC in first degree relatives of patients has been estimated to be as high as 6420 per 100,000 (6.4%), significantly higher than the highest reported whole population prevalence.‘j6 Based on these studies of familial disease, the sibling risk has been estimated as 100.’03 By means of compari- son, the estimated sibling risk for autoimmune diabetes is lower at 14.1°3 There are no data from twin studies in PBC, a cornerstone in the study of the balance between environmental and inherited factors in disease susceptibility, and, presumably, is a result of the low, overall disease incidence preventing collection of the requisite numbers of twin pairs to study. A single report has suggested discordant disease in monozygotic twins, confirming the view that environmental factors are important in disease de~elopment .~~

The data regarding the risk of familial disease, which appear to suggest considerable risk, must be interpreted with caution. None of the studies were population based, resulting instead from case series with the risk of selection bias. Moreover, clinical experience suggests that the diagnosis of PBC has, in the past, often been delayed or missed, a factor thought to play a role in the apparent, recent increases in disease prevalence. Presence of an existing PBC patient in the family may alert other members to the possibility of the disease, allowing earlier presentation and diagnosis and giving rise to a spuriously elevated disease prevalence in families. The final caution with regard to family studies is the possible role played by shared environment in determining shared risk. This problem is highlighted by a report of a mother and an unrelated friend, who developed PBC after nursing the daughter, who died of the disease.24 The conventional view is that PBC development


typically occurs later in life when siblings no longer live together, suggesting that it is the shared genetic background rather than the shared environment that confers risk. Even with this scenario, it is impossible to rule out a significant role for shared environmental factors, which may shape the immune repertoire early in life and play a role in disease development many years later.

Limited data are available regarding the genetic loci responsible for PBC su~ceptibility.~~ Most attention has focused on the major histocom- patibility complex (MHC) on chromosome 6. An MHC association with the class I1 allele HLA DR8 has now been demonstrated in several genotyping studied involving different population^.^^, 78* y7 Although this association is strong, the risk associated with HLA DR8 only accounts for a minority of cases. A strong association has also been demonstrated with the presence of a null allele at the C4 locus within the class I11 MHC region.64 A weaker association has been demonstrated with a promoter polymorphism at position 308 of the promoter region of the proinflammatory cytokine tumor necrosis factor-a (TNF-a) gene, also within the class I11 region.29, lf16

One important factor to remember when studying the genetic susceptibility to PBC is that the risk of autoimmunity is not restricted to PBC alone. There is an apparent susceptibility to several other autoimmune conditions, in particular a variant of Sjogrens syndrome which can be found in up to 50% of patients.96 Typical serological features of primary Sjogrens syndrome [antiRo(SSA) and antilanthanum(SSB)] are largely absent from cases of Sjogrens syndrome associated with PBC.94*y6 Isolated lacrimal dysfunction is even more common and was reported in 78% of patients in one series.28 Other autoimmune conditions are also seen frequently in PBC. Case series have emphasised the relatively high incidence (up to 20% in some series) of autoimmune thyroid disease in PBC patients.18, 26, 41* yo The CREST variant of sclerodermas2, 84 and rheuma- toid arthritis41 also complicate PBC relatively frequently. Other autoimmune associations reported less frequently include systemic lupus erythematosus (SLE),74 myaesthenia gravis,5fl autoimmune hemolytic anemia,"' idiopathic thrombocytopenic purpura (the combination of PBC with idiopathic thrombocytopenic purpura [ITP] bearing the eponym Reynold's syndrorne),7l dermatomyositis,s3 ankylosing spondylitislOO and polymy~sitis.~

NATURAL HISTORY

Since the earliest definitive descriptions of PBC, our perception of the condition has changed from being a rare disease with a poor prognosis presenting with jaundice and symptoms of liver to being a more common condition often presenting without symptoms following detection through screening with a significantly better prognosis.41, 66 To a considerable extent these changes result from earlier diagnosis leading to a change in our perception of the spectrum of disease. This spectrum

270 JONES et a1

appears to encompass subsets of patients with PBC with different natural histories.

Early Disease

Our understanding of the earliest steps in the development of PBC has been limited by the time that elapses between the postulated triggering events and the diagnosis of the disease. No representative sponta- neous animal model of PBC has been reported and this, therefore, prevents this approach to study of early disease. The authors' hypothesis is that the earliest step in the pathway of disease development is a breakdown of immune self-tolerance, brought about by a triggering event in a susceptible person, which gives rise to the autoreactive and autoantibody3 responses to mitochondrial antigens characteristic of PBC. These responses are directed against the members of the 2-oxoacid dehydrogenase family of multi-enzyme complexes, in particular the E2 component (dihydrolipoamide acetyltransferase) and E3-binding protein (Protein X) of pyruvate dehydrogenase complex (PDC-E2 and E3BP, respectively), which play a fundamental role in intermediate metabolism. Autoantibody responses are also seen, at lower frequencies, against nuclear and nuclear envelope15 autoantigens. The detection of disease-specific autoantibodies in the serum remains an important part of the diagnostic protocol for PBC, whether performed by immunofluores- cence using composite tissue or, latterly, by antigen specific enzyme linked immunosorbent assay (ELISA).36

In the earliest stage of the disease process patients have serum antimitochondrial antibodies (AMA) and histologic features typical of PBC in the absence of either cholestatic liver function tests (LFT) or typical symptoms of PBC. In a study of 29 asymptomatic AMA-positive patients with normal serum liver biochemistry, 24 were found to have histological features diagnostic of, or compatible with PBC.69 This study appeared to suggest that AMA were strongly associated with the presence of focal histological features of PBC even in the absence of metabolic sequelae. Metcalf et a1 recently reported on the outcome of these 29 patients followed-up for a median of 17.8 years.68 Five of the patients died (although none of the deaths were attributable to liver disease); 22 of 29 (76%) of the patients had developed symptoms of PBC; 24 of 29 (83%) had developed abnormal liver function tests typical of cholestasis. Ten of 29 patients had a further liver biopsy during the follow-up period, with 4 of 10 showing histological progression (2 from stage I to stage 11, 2 from stage I to stage 111). None of the patients developed clinical- or histologic-apparent cirrhosis.

These two studies confirm the view that the presence of AMA, even in the absence of cholestasis or symptoms of PBC, strongly suggests the presence, at that time, of focal histologic features of PBC, and that classical PBC will subsequently develop. This clinical situation can be regarded as the earliest identifiable stage in the development of PBC.


This observation may be of great importance in the future for the treatment of PBC. Novel immunological approaches to the treatment of autoimmunity (oral tolerization to autoantigen for example1o8) are likely to be most effective if used in the earliest stages of the autoimmune process, prior to the development of irreversible bile duct damage. The extremely strong association between the presence of AMA and the subsequent development of typical PBC suggest that this may make an ideal screening test prior to the use of immunotherapy.

The follow-up study of the AMA-positive, normal LFT cohort allows us to conclude progression of the disease in this group was extremely slow, with none of the patients apparently developing cirrhosis or dying as a result of their liver disease over a median follow-up period of 17.8 years. The median age at diagnosis of this cohort with predisease was 55 years, similar to that in most series of patients entering clinical trials, 60% of whom have late (histological stage I11 or stage IV) d i ~ e a s e . ~ ~ , ~ ~ It would thus appear that there is a subgroup of PBC patients with a less aggressive course, an observation which is compatible with the earlier report that patients presenting over age 65 years had fewer symptoms and less marked clinical features of PBC.56

Several groups have now provided evidence concerning the natural history of asymptomatic patients with abnormal LFTs (Table 1). In four long-term follow-up studies, there is a broad consensus as to outcome.2* 22, 63, 70, 76 About 40% of patients, initially asymptomatic of liver disease, will develop symptoms within 5 to 7 years. Once symptoms have developed, survival is the same as for other symptomatic patients. Life expec- tancy for those who remain asymptomatic is the same as for the general population of largely middle-aged women. For the group as a whole, survival begins to fall below that of the aged-matched general population after about 5 years of symptoms, and complications of liver disease occur in an increasing proportion. There is no accepted predictor of who will develop symptoms among the initially asymptomatic group, although stage I liver histology may carry a better long-term prognosis. This is suggested not only by our study but also by the Uppsala series of 28 asymptomatic patients with stage I disease, none of whom died

Table 1. DETAILS OF STUDIES OUTLINING THE NATURAL HISTORY OF ASYMPTOMATIC PRIMARY BlLlARY CIRRHOSIS

Time to Deaths Median Time Symptom Symptom During FU to Death

Patients Median FU Development Development Liver + Years Study in Study Years (range) Number (%) Years nonliver (range)

Mitchison et aI7O 95 5.8 (3.0-14.2) 34 (36%) 3.3 15 + 10 NA Mahl et ,Ie3 36 12.1 (1.1-19.2) 23 (64%) 3.6 NA NA Balasubaramanian 73 7.6 (2.S12.2) 33/37 (89%) NA 11 + 6 NA

et a12 Nyberg & Loof 76 56 7.4 (1.518) 21 (37%) NA 10 + I 12.7 (5-21)

From MacCarty RL, LaRusso NF, May GE, et at: Cholangiocarcinoma complicating primary sclerosing cholangitis: Cholangiographic appearances. Radiology 156:43-46, 1985; with permission.

272 TONES et al

and only 11% of whom became symptomatic during median follow-up of 7.5 years.76 In many ways this asymptomatic versus symptomatic subdivision is somewhat confusing in relation to our current appreciation of the disease; its far broader spectrum of symptoms, in particular fatigue, appears not to be stage specific (see below). The subdivision of disease in the above studies, which did indeed correlate with survival, largely revolved around the presence or absence of jaundice and the apparent discrepancy between our current view of symptoms; the apparent survival significance of their presence can be reconciled if this fact is appreciated. The presence 'of an elevated serum bilirubin is clearly associated with a poorer prognosis,8s and this clinical parameter is an important component of PBC-specific prognostic scoring systems.lW

Late Disease

In contrast to the earliest disease stages, the natural history of late disease is well documented.", 63 The development of symptoms typical of cholestasis is associated with an overall worsening of prognosis. In the untreated state, a pattern of inexorable worsening of symptoms, together with the development of complications, is associated with histologic progression by one stage every 1.5 years.61 In one 4 year follow-up study (in which only 7% of patients were asymptomatic at the outset), the frequency of cirrhosis increased from 30% to 82%, while the frequencies of both pruritus and jaundice both significantly increased (75% to 95% and 59% to 82% respectively)." Median survivals in such follow-up studies range from 5.4 yearss9 to 11.9 years.85 The apparent survival differences are likely to result both from improvements in patient management (particularly with regard to the management of disease complications, which have occurred between these studies) as well as a broad- ening of the definition of symptomatic patients to include patients with fatigue in the absence of jaundice or cholestasis who may have less severe disease. Factors identified as being associated with poor prognosis on multivariate analysis include jaundice, weight loss, hepatomegaly, splenomegaly, ascites, histologic stage, patient age, and impaired synthetic function.", 63, 85, Io9 Data from such follow-up studies have allowed the derivation of several loosely similar prognostic models,109 which have been validated in clinical and which are useful for estimating probable survival (of patients with advanced disease only) in both the research and clinical setting.

Disease Heterogeneity and Progression

These studies suggest that there is a wide spectrum of PBC ranging from the patients presenting with isolated AMA, who have an essentially normal prognosis, to patients presenting with jaundice and pruritus in whom PBC is a rapidly progressive, fatal disorder. It would appear,


therefore, that in addition to the environmental and genetic factors which determine disease onset, there must be factors which determine the rate of disease progression. Appreciation of the disease spectrum is important for planning trials of therapy in PBC, as inclusion of patients similar to the group the authors have identified with a very low risk of progression will affect analysis of any therapeutic benefit.

Few data are currently available regarding factors which may determine the risk and rate of progression in PBC. Attempts have been made to address the question of whether AMA are of prognostic value in PBC.91 Provocative findings have been reported by Berg et a1 suggesting that the presence of AMA reacting with complement fixing antigens- M4 and M8-may herald a more progressive course of PBC,51,107 while AMA reacting with an outer membrane-associated antigen on liver mitochondria-M9-may be associated with a benign p rogn~s i s .~~ These retrospective observations have now been evaluated in a multicenter prospective study started in 1985.52 Forty four of 177 (25%) patients with early (histologic stage I stage 11) disease developed late-stage PBC over a 10 year follow-up; 43 of them had antiM8 and antiM4 antibodies, suggesting that this AMA-profile may help to identify patients at risk of an aggressive course. The biochemical identity of these putative nonM2 mitochondria1 autoantigens presently is unknown,2°, 79 and these potentially important findings in relation to prognosis have not been confirmed. Since the identification of the M2 antigens reacting with AMA as components of the 2-oxoacid dehydrogenase family of multienzyme complexes3 the question of whether the presence or titer of AMA to specific components of these complexes (e.g., PDC-E2 and PDC-E3BP) is of prognostic value has also been looked at. PBC patients with histological stage I disease have a lower incidence of autoantibodies to each M2 protein, compared with more advanced disease (IgG, p < 0.05) but there was no correlation between the presence of IgG of IgM antibodies to the M2 polypeptides and established prognostic markers in PBC (serum bilirubin and albumin levels).73 By contrast we found that the titer of IgG autoantibodies to biochemically purified PDC-E2 and PDC-E3BP (Protein X) correlated with histologic stage (p < 0.04) and prognostic biochemical variables, higher serum bilirubin and lower albumin levels (p = 0.038 and 0.028, re~pectively).~~ This result has not been confirmed using quantitative EIA methods with recombinant PDC-E2 as and there is certainly no suggestion that the levels of AMA are useful in predicting disease progression in an individual patient. Similarly, it does not appear that PBC patients with antinuclear autoantibodies (ANA) against nuclear envelope or nuclear dot proteins have different clinical profiles to those without them15, 93; the main utility of these PBC-specific ANA is in the diagnosis of patients with low titre or undetectable AMA.

There may be a genetic basis to explain the marked interindividual variation in disease progression. We have recently demonstrated that the TNFa-308 promoter polymorphism genotype TNFZ/TNFZ106 and the MHC class I1 allele HLA DR8 (Jones et al, unpublished data, 1997) are

274 JONES et al

present more frequently in patients with advanced disease than in patients with early disease. The risk and rate of disease progression remains an area of considerable interest, as the identification of patients at high risk of cirrhosis would allow clinicians to stratify therapy and target more aggressive treatment (e.g., meth~trexate~~) to this at risk subgroup.

SYMPTOMS OF PRIMARY BlLlARY CIRRHOSIS

Fatigue

Profound fatigue, which can often adversely affect patient quality of life is an often underdiagnosed symptom of PBC. In an unpublished survey by the United Kingdom-PBC support group (personal communi- cation, 1997) fatigue was voted the worst of all symptoms associated with the disease. Early case series reported fatigue as a symptom in only a small proportion of patients. A demographic study in Ontario, Canada, in which patients reported their own symptoms by questionnaire, reported fatigue to be a symptom in greater than 80% of patients."O This apparent discrepancy would tend to suggest that the previous low- reporting of fatigue as a symptom of PBC results, perhaps, from physi- cian bias in the appreciation of symptoms and their significance. The mechanism of fatigue development in PBC is not known, although a preliminary report has shown an association between fatigue severity and parameters of depression.1° There is no association between fatigue and disease stage, nor by implication is there a link between symptoms and prognosis (of the type seen with cholestatic symptoms) where fatigue is the only symptom. Data regarding the impact of fatigue on patient quality of life in PBC are not least because of a lack of properly validated PBC specific fatigue measurement tools. Difficulties in fatigue severitv assessment have also prevented assessment of im- " provement in this symptom in response to therapy in controlled trials in PBC.

Pruritus

Clinical descriptions of PBC have emphasized the importance of pruritus as a presenting feature of symptomatic disease. Approximately 50% of patients in most symptomatic series present with isolated pruritus, with a smaller percentage presenting with a combination of pruritus and cholestatic Pruritus of PBC is often worse at night, affecting sleep, and may contribute to a patient's fatigue. In one series of 100 patients, 5 initially presented with pruritus during pregnancy that failed to resolve following delivery.y0 The theories regarding cause and therapeutic approaches to pruritus in PBC are outlined in detail else- where in this issue.


Jaundice

Cholestatic jaundice is seen less commonly as a presenting feature in PBC, typically developing after the onset, or less commonly at the same time as pruritus. Following the initial development of jaundice, a progressive rise in the serum bilirubin is seen; this is an important prognostic indicator in PBC.5* 21, 75, 88, lo9 Ursodeoxycholic acid (UDCA) therapy, which has been shown to improve surviva160 has a particularly marked lowering effect on the serum bilirubin, an effect which is out of proportion to the less marked effects on prognosis.45 Care should be taken in interpreting the significance of absolute serum bilirubin levels in patients taking UDCA. In the later stages of the disease, when jaundice is progressive, it can be accompanied by significant skin pigmentation which can be distressing to patients.

Abdominal Pain

Unexplained abdominal pain has been reported as a symptom in between 7%" and 17%55 of PBC patients in case series. This is typically right upper quadrant discomfort, is not related to histological stage and fails to respond to UDCA therapy. Cholelithiasis is an important differential diagnosis because of its high incidence in PBC.92

COMPLICATIONS OF PRIMARY BILIARY CIRRHOSIS

The complications of PBC can be subdivided into metabolic sequelae and complications of cirrhosis.

Metabolic Sequelae

Stea torrhoea

Steatorrhoea is a feature of advanced PBC and typically is seen at the stage where patients are markedly jaundiced. Where present, it contributes significantly to the weight loss often seen with advanced disease. The primary pathological mechanism is failure of fat absorption secondary to low intestinal bile salt levels and to bile secretory failure.s4, 86 It has also been suggested that pancreatic hyposecretion may play a part in fat malabsorption and weight loss in some patients. If marked steatorrhoea is present, this can lead to abnormalities in fat soluble vitamin absorption and systemic deficiency. Deficiency of vitamin A may cause visual problems104 and vitamin D malabsorption may contribute to metabolic bone disease.14 Subclinical vitamin E deficiency also may be seen.42 Patients with advanced PBC, particularly where

276 JONES et a1

overt steatorrhoea is present, should have parenteral fat soluble vitamin supplementation.

Hypercholesterolaemia

An association between high serum cholesterol levels and PBC has been appreciated since the earliest clinical descriptions of the condition which emphasized the presence of xantholasmata. Serum cholesterol levels are elevated in over 50% of patients in a series of symptomatic cases.9o PBC patients do not appear to be at increased risk of death from atherosclerosis related disease.I7 This may be because of the relative proportions of the different lipoproteins. PBC patients, particularly in the early phase of the disease, have mild elevation of low and very low density lipoproteins (LDL & VLDL), but significant elevation of high density lipoprotein (HDL).37, 40 PBC patients also appear to have only low levels of serum lipoprotein; elevated levels of lipoprotein appear to be associated with increased risk of coronary artery disease.31 UDCA therapy reduces total cholesterol levels, the predominant effects being on LDL and VLDL. HDL levels are relatively stable on UDCA therapy.81

Bone Disease

PBC is relatively frequently complicated by metabolic bone disease once overt cholestasis has Osteoporosis is the most common metabolic bone disease complicating PBC,65 although osteomalacia can occur and is a result of vitamin D malabsorption. Osteomalacia is rare, as risks of prolonged vitamin D deficiency have become appreciated. The severity of osteoporosis is related to the intensity and duration of jaundice.65 Genetic factors may play a role in determining relative risk of osteoporosis de~elopment .~~ Therapy with UDCA58 and calcitonin9 has not been shown to be effective and trial data regarding the use of bisphosphonates are awaited. Retrospective studies have suggested a lower incidence of osteoporosis in women taking hormone replacement therapy (HRT).I6 Prospective trial data are awaited, and the possibility of worsening cholestasis secondary to oestrogen therapy should be borne in mind. Despite initial deterioration caused by poor mobility and drug therapy, osteoporosis improves after orthotopic liver transplantati~n.~~

Renal Tubular Acidosis

Renal tubular acidosis (RTA) has been demonstrated, in an incom- plete form, in up to 30% of PBC patientsa0 Dysfunction is limited to the distal tubules, suggesting that PBC patients suffer from type I1 or classical RTA. Close correlations have been demonstrated between both abnormal copper metabolism and serum bilirubin and the degree of RTA.80 These findings suggest that the renal acidifying defect in PBC may be caused by reduced excretion by the liver of agents (copper and bile salts being the most obvious candidates) that are accumulated in the renal


tubular cells. Symptomatic acidosis from RTA is extremely rare in PBC patients.

Complications of Advanced PBC

Portal Hypertension and Oesophageal Varices

The development of portal hypertension and its accompanying complications is not uncommon in end-stage disease. In an early series, variceal haemorrhage was a presenting feature in a number of patients, although with earlier diagnosis this is now less common. Portal hypertension typically accompanies the development of cirrhosis, although it is seen, uncommonly, in precirrhotic disease resulting from nodular regenerative hyperpla~ia.'~ In this respect, it should be remembered that the disease is not necessarily homogeneous within the liver. The management of acute variceal hemorrhage and secondary bleed preven- tion raise no PBC specific issues. The conventional view is that PBC patients tolerate variceal hemorrhage reasonably well with good mainte- nance of synthetic function; however, data to back up this view are limited. PBC patients appear to tolerate surgical shunt surgery Data regarding the use of Trans-jugular intrahepatitis porto-systemic shunting (TIPSS) specifically in PBC are not as yet available. UDCA therapy may have a beneficial effect, reducing portal hyperten~ion~~ and delaying the onset of v a r i c e ~ . ~ ~

Hepa tocellular Carcinoma

Hepatocellular carcinoma (HCC) can complicate cirrhosis of any cause. Previously published reports of HCC risk in PBC, which consist of relatively small case series, have suggested that the risk of HCC development in PBC is relatively low. A recently completed follow-up study of 667 patients (273 with advanced disease, followed-up for a median of 88 months following the diagnosis of advanced disease) was performed to ascertain the actual risk of HCC development in PBC.46 No cases of HCC were seen in patients with stage I or I1 disease at their last biopsy, suggesting that only low levels of vigilance are needed for such patients. The overall HCC incidence was 2.4% and 5.9% in the patients with advanced disease. The incidence of HCC in male patients with advanced disease was 20%, compared with 4.1% in the equivalent female group. HCC played a part in 46% of the deaths seen during follow-up in male patients with advanced disease and 8.3% in females. This study confirms the view that the overall incidence of HCC in PBC is low, but suggests that the risk is appreciable in the subgroup of men with advanced disease. This fact should be borne in mind when making decisions regarding the timing of transplantation. Another recent epidemiological study in the Netherlands has confirmed that patients with PBC show an increased risk of HCC and that younger persons (less than

278 JONES et al

60 years) diagnosed with PBC died of HCC more often than older patients (p < 0.05).98

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