Cholestatic liver diseases (CLDs) encompass a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury and ultimately end-stage liver disease. Many patients with CLD are diagnosed between the ages of 20-50 years, a particularly productive period of life professionally, biologically and in other respects; it is not surprising, thus, that CLD is often associated with impaired health-related quality of life (HRQOL) and uncertainty regarding implications for and outcomes of pregnancy. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most prominent CLDs, both having considerable morbidity and mortality and representing major indications for liver transplantation. These disorders, as a consequence of their complications (eg ascites, hepatic osteodystrophy), associated conditions (eg inflammatory bowel disease) and symptoms (eg pruritus and fatigue), can significantly impair an array of domains of HRQOL. Here we review these impactful clinical aspects of PSC and PBC as well as the topics of fertility and pregnancy.

Background. The study aims to analyze in detail the incidence, mortality using the standardized incidence ratio (SIR), and standardized mortality ratio (SMR) of hepatocellular carcinoma (HCC) in primary biliary cirrhosis (PBC), because no large case studies have focused on the detailed statistical analysis of them in Asia. Methods. The study cohorts were consecutively diagnosed at Gunma University and its affiliated hospitals. Age- or sex-specific annual cancer incidence and deaths were obtained from Japanese Cancer Registry and Death Registry as a reference for the comparison of SIR or SMR of HCC. Moreover, univariate analyses and multivariate analyses were performed to clarify predictive factors for the incidence of HCC. Results. The overall 179 patients were followed up for a median of 97 months. HCC had developed in 13 cases. SIR for HCC was 11.6 (95% confidence interval (CI), 6.2-19.8) and SMR for HCC was 11.2 (95% CI, 5.4-20.6) in overall patients. The serum albumin levels were a predictive factor for the incidence of HCC in overall patients. Conclusions. The incidence and mortality of HCC in PBC patients were significantly higher than those in Japanese general population. PBC patients with low serum albumin levels were populations at high risk for HCC.

Several studies have indicated that primary biliary cirrhosis (PBC) may be associated with increased risk of some cancers, but the results are controversial. We conducted a systematic review of studies to examine the association of PBC with cancer risk by meta-analysis. We searched the PubMed and EMBASE databases for English-language studies published before November 2011. Studies were included if they reported relative risk estimates with 95% confidence intervals (CIs) or related data for the association between PBC and cancer risk. Approximately 16,300 PBC patients from several countries were included in this analysis. Of the 3510 titles identified, 16 publications involving 17 studies meeting the inclusion criteria were included in the meta-analysis. Compared with the general population, PBC patients had a significantly higher risk of overall cancer (pooled rate ratio [RR], 1.55; 95% CI, 1.28-1.83) and hepatocellular carcinoma (HCC) (pooled RR, 18.80; 95% CI, 10.81-26.79). For stomach and pancreas cancers, the results of one study that only examined male patients with PBC indicated that PBC patients had increased risk of stomach cancer and pancreatic cancer, whereas the results of other studies of mixed-sex patients showed no significant association. Therefore, despite inconsistent results, the meta-analysis could not be conducted for assessing the association. PBC was not significantly associated with increased risk of other cancers.

The present systematic review and meta-analysis demonstrate that PBC is closely associated with a greater risk of overall cancer and HCC, but not with other cancers. The data regarding the association between PBC and risks of several cancers need to be further confirmed in future studies.

The limited information and divergent results on the prevalence, incidence, and risk factors for hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) may be due to the low prevalence of the disease and geographical and environmental differences. Therefore, we analyzed the incidence, prevalence, survival, and risk factors for HCC in patients with PBC from two European centers (389 from Barcelona, Spain, and 327 from Padova, Italy) followed up for 9.3 +/- 6.5 years. Gender, age, smoking habit, alcohol consumption, presence of hepatitis B surface antigen (HBsAg) or hepatitis C virus antibodies (anti-HCV), and advanced histological stage (III-IV) were evaluated as risk factors for tumor development. Twenty-four patients (13 from Barcelona and 11 from Padova) developed HCC. The prevalence of HCC was similar in Barcelona (3.34%) and Padova (3.36%). The incidence was 0.35 and 0.37 per 100 patient-years, respectively. Male gender, age >52 years, smoking habit, alcohol >40 g/day, HBsAg, and anti-HCV were not associated with HCC. Advanced histological stage was the only factor associated with the development of HCC (odds ratio [OR]: 5.80, 95% confidence interval [CI]: 2.34-14.38, P < 0.001). When analyzing the two series separately, male gender was associated with higher likelihood of HCC in Padova (OR: 8.09, 95% CI: 1.93-33.8, P < 0.01). The median survival after the diagnosis of HCC was 36 months.

The prevalence and incidence of HCC is similar in Spain and Italy and the advanced histological stage is the only risk factor associated with the development of HCC in PBC. The slight disparities observed between the two series might be explained by patient features on diagnosis of liver disease.

Primary biliary cirrhosis is a chronic cholestatic disease that generally appears in middle-aged women. The clinical course is slow and progressive, finally leading to cirrhosis. This disease has three forms of presentation: silent, asymptomatic and symptomatic. The silent form is characterized by the presence of antimitochondrial antibodies as the only abnormality. The silent and asymptomatic forms are less aggressive and have a slower clinical course. During the course of the disease, some patients remain asymptomatic. No distinguishing features between asymptomatic patients and those who develop symptoms have been identified. Survival is better in asymptomatic than in symptomatic patients and is excellent in patients who remain asymptomatic. The introduction of treatment with ursodeoxycholic acid has greatly prolonged the natural course of the disease. In patients with good therapeutic response, survival is similar to that in the general population. The clinical and laboratory variables associated with poor prognosis are age, bilirubinemia, albuminemia, prothrombin time, ascites, hepatic encephalopathy and advanced histological stage. Likewise, the development of varices and of hepatocellular carcinoma carries a poor prognosis. Bilirubinemia is, however, the most important variable to establish prognosis. There are distinct mathematical prognostic models that sensitively predict the probability of survival and are useful to determine disease severity in specific patients.

To characterize the clinical features of hepatocellular carcinoma (HCC) associated with autoimmune liver disease, we critically evaluated the literature on HCC associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC).

A systematic review of the literature was conducted using the Japana Centra Revuo Medicina database which produced 38 cases of HCC with AIH (AIH-series) and 50 cases of HCC with PBC (PBC-series). We compared the clinical features of these two sets of patients with the general Japanese HCC population.

On average, HCC was more common in men than in women with AIH or PBC. While many patients underwent chemolipiodolization (CL) or transcatheter arterial embolization (TAE) (AIH-series: P = 0.048 (vs operation), P = 0.018 (vs RFA, PEIT); PBC-series: P = 0.027 (vs RFA, PEIT), others refused therapeutic interventions [AIH-series: P = 0.038 (vs RFA, PEIT); PBC-series: P = 0.003 (vs RFA, PEIT)]. Liver failure was the primary cause of death among patients in this study, followed by tumor rupture. The survival interval between diagnosis and death was fairly short, averaging 14 +/- 12 mo in AIH patients and 8.4 +/- 14 mo in PBC patients.

We demonstrated common clinical features among Japanese cases of HCC arising from AIH and PBC.

Hepatocellular carcinoma (HCC) occurs with increased frequency in patients with primary biliary cirrhosis (PBC). Effectiveness of surveillance recommendations for HCC is controversial, and data are lacking in patients with PBC. In this study, we attempt to (1) establish the importance of surveillance for HCC in patients with PBC; (2) identify a target population of patients with PBC for HCC surveillance; and (3) propose surveillance recommendations for patients with PBC. We retrospectively identified 36 patients seen at the Mayo Clinic between 1976 and 2007 with a diagnosis of both PBC and HCC. Five patients (14%) were diagnosed incidentally, 17 patients comprised our surveillant population, and 14 patients were diagnosed outside a surveillance program. Patients in the surveillant population were more likely to undergo therapy (88% versus 43%; P = 0.01) and had improved survival (P = 0.002) compared with the nonsurveillant population. All cases of HCC except one were predicted to be at significant risk for HCC based on age, sex, evidence of portal hypertension, and history of blood transfusion using a previous predictive model.

We established the importance of surveillance for HCC in patients with PBC. We demonstrated adequate performance of a predictive model and propose it should be refined and used to identify patients with PBC who should be screened for development of HCC. Further studies are needed so that optimal HCC surveillance recommendations in this population can be determined and included in the practice guidelines for PBC.

Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.

Hepatocellular carcinoma (HCC) occurring in a 66-year-old male patient with early stage primary biliary cirrhosis (PBC) was successfully treated by radiofrequency ablation (RFA) therapy. He was diagnosed with PBC based on the findings of pruritus, elevated serum alkaline phosphate level and positive serum antimitochondrial antibody in 2005. The serologic tests for hepatitis B surface antigen, hepatitis B surface antibody and hepatitis C virus antibody were all negative. But antibody against hepatitis B core antigen was positive. Abdominal ultrasonography and dynamic computed tomography revealed 1 hypervascular tumor, 2.6 cm in diameter, in segment V of the liver in 2007. Liver biopsy showed a moderately differentiated HCC. Non-tumorous liver was compatible with Scheuer's classification of stage II PBC. The tumor was successfully treated by RFA. This case report demonstrates that HCC can arise from precirrhotic PBC and can be successfully treated by RFA. Regular surveillance for HCC is warranted for all patients with PBC, irrespective of stage.

Although liver cirrhosis is a predisposing factor for hepatocellular carcinoma (HCC), relatively few reports are available on HCC in primary biliary cirrhosis. High plasma nociceptin (N/OFQ) level has been shown in Wilson disease and in patients with acute and chronic pain.

We report a follow-up case of HCC, which developed in a patient with primary biliary cirrhosis. The tumor appeared 18 years after the diagnosis of PBC and led to death within two years. Alfa fetoprotein and serum nociceptin levels were monitored before and during the development of HCC. Nociceptin content was also measured in the tumor tissue.

The importance and the curiosity of the presented case was the novel finding of the progressive elevation of plasma nociceptin level up to 17-fold (172 pg/mL) above the baseline (9.2+/-1.8 pg/mL), parallel with the elevation of alpha fetoprotein (from 13 ng/mL up to 3 480 ng/mL) during tumor development. Nociceptin content was more than 15-fold higher in the neoplastic tissue (0.16 pg/mg) than that in the tumor-free liver tissue samples (0.01 pg/mg) taken during the autopsy.

Results are in concordance with our previous observation that a very high plasma nociceptin level may be considered as an indicator for hepatocellular carcinoma.

The natural history of PBC is characterized by slowly progressive cholestasis with liver damage, development of cirrhosis and its complications, and death, unless the patient undergoes liver transplantation. The disease has at least three clinical presentations, each with a different course and prognosis: the silent and usually less aggressive form, the asymptomatic form, and the symptomatic form. There are no identifiable features that distinguish the asymptomatic population who will remain symptom-free from those patients who will develop symptoms. As expected, the survival is longer in asymptomatic than in symptomatic patients. Overall survival of asymptomatic PBC is shorter than for an age- and gender-matched control population, but the patients remaining asymptomatic had a survival equal to that of the general population. Natural history studies have identified several variables associated with survival, particularly age, bilirubin, albumin, prothrombin time, ascites, encephalopathy, and advanced histological stage. Development of esophageal varices and hepatocellular carcinoma can also affect survival. Serum bilirubin level is, however, the most heavily weighted prognostic variable and can be used as a simplistic prognostic index for patients with PBC. In the last two decades, natural history models have been developed that include clinical, biochemical, and histological variables, the most popular being the Mayo model. It has the advantage ofavoiding histological variables, and therefore can be applicable to a broad spectrum of patients with PBC. The models may also be used to evaluate the efficacy of different new treatments. Prognostic models based on serial measurements of the independent predictors of poor prognosis would lead to a more accurate prediction of survival; however, they probably will not replace clinical outlook.

The findings by epidemiological studies on the link between PBC and HCC are in general agreement with the notion that cirrhosis is a risk factor for HCC development. From the clinical perspective, this implies that in PBC patients with cirrhosis, the screening for HCC should be considered for evaluating prognosis as well as therapeutic options. At this time, it is not possible to determine whether any PBC-specific risk factors other than cirrhosis per se exist for the development of HCC. Identification of such risk factors may point to new mechanisms involved in the carcinogenesis of HCC. In order to answer the question whether the underlying mechanisms for PBC are risk factors for HCC, more aggressive clinical studies with larger patient populations are needed. Such studies should include patients with PBC as well as patients with cirrhosis of other etiologies, both have to be carefully matched for patient characteristics including race, gender, age, disease stage and period of follow-up. On the other hand, the resolution of this issue also relies on a better understanding of the molecular pathogenesis of PBC itself.

The prevalence of hepatocellular carcinoma (HCC) in primary biliary cirrhosis (PBC) is not well established, as some reports suggest a low risk, whereas others indicate that HCC may be no less frequent than in other types of cirrhosis.

We compared the incidence of HCC in a series of 140 patients with PBC (five men, 135 women, mean age 54 +/- 1.6 yr) followed-up for a mean of period of 5.6 +/- 0.4 yr with a group of patients with cirrhosis related to hepatitis C virus (HCV) who were matched for age, sex, and follow-up period. In all patients, HCC was prospectively screened by clinical, laboratory, and ultrasound procedures.

Five patients with PBC (3.6%) developed HCC. All were in stage IV of the disease. The incidence of HCC in the 45 patients with late stages of the disease (III or IV) was 11.1%, similar to that found in patients with HCV-related cirrhosis, which was 15.0%. The relative risk for HCC in late stages of PBC was of 0.812 (95% CI, 0.229-2.883) with respect to HCV-related cirrhosis. The probability for developing HCC was significantly higher in patients with HCV-related cirrhosis than in PBC patients overall (p = 0.001), but was similar in patients with HCV-related cirrhosis and in patients with PBC in stages III and IV (p = ns).

The risk for HCC in patients with late stages of PBC is similar to that in patients with HCV-related cirrhosis.

To study the natural course of primary biliary cirrhosis (PBC) in order to be able to design accurate clinical pharmacological studies and evaluate the need for liver transplantation.

A cohort of 86 patients with PBC living in northern Sweden was followed for a 10-year period during 1983-93. No patients received therapy with ursodeoxy cholic acid or other drugs during the follow-up period.

At start all patients were investigated personally by the authors. At follow-up medical notes were scrutinized and special questionnaires to the current responsible physician were applied. Endpoints were the time of dropout, liver transplantation, death or end of the study period.

At follow-up data were available for 84 patients (97%). During the study period 34 patients died, of whom 28 were symptomatic; 15 deaths had no direct connection to PBC. Nineteen deaths were related to PBC of whom two were asymptomatic, the most common cause being end-stage liver disease with liver coma. During the study period in all eight patients were subjected to liver transplantation.

The survival rate of the 32 asymptomatic PBC patients at the start of the study was the same as a sex- and age-matched standard background population. Those patients with symptomatic PBC from the beginning of study had a survival rate at 10 years of 50%, and the most ominous sign was a bilirubin greater than 35 micromol L(-1) . Liver transplantation was performed in almost 10% in this cohort until 1993. Since then, the indications and referral practice for liver transplantation has changed and is now higher.

Suggestions that breast cancer may be more common in patients with primary biliary cirrhosis (PBC) have been challenged. It has recently been proposed that total cancer rates may be higher in patients with PBC, as well as liver cancers.

To investigate these proposals on a strictly defined case series.

A total of 769 prevalent or incident PBC patients with "definite" or "probable" disease detected in a defined area of the north-east of England during 1987-94.

Cancer events and deaths were identified by obtaining information from one or more of the following sources: Office for National Statistics (ONS) Central Registers, Regional Cancer Registry, and clinical case records. Standardised cancer incidence (SIR) and mortality ratios (SMR) were calculated using the local region as the standard population.

There were 97 cancer events during 1987-96. SIR from cancer registrations for all cancers was 1.7 (95% confidence interval (CI) 1.3 to 2.2), for liver cancer was 74 (95% CI 32 to 146), and for breast cancer was 1.1 (95% CI 0.4 to 2.4). SMR for all cancers was 1. 8 (95% CI 1.4 to 2.4), for liver cancer was 39 (95% CI 20 to 68), and for breast cancer was 0.4 (95% 0.1 to 1.6). The results were similar after excluding the first year of follow up after PBC diagnosis.

There was some evidence of a small increase in overall cancer incidence and mortality in PBC patients. With the exception of liver cancer, it is unlikely that there is a high excess incidence for PBC patients from any cancer at a particular site, and specifically breast cancer.

We report an autopsy case of hepatocellular carcinoma (HCC) with sarcomatous change arising in the context of primary biliary cirrhosis (PBC) in a 79-year-old man. Primary biliary cirrhosis was diagnosed (stage I according to Scheuer's classification) by findings on blood biochemical analysis, laparoscopy, and liver biopsy at age 69 years. Five years later, (at age 74 years), a mass lesion was detected in the S6 region of the liver by abdominal ultrasonography, and target biopsy revealed well differentiated HCC. Blood biochemistry, ultrasonography, and computed tomography findings showed that the PBC had progressed to stage IV (cirrhotic stage). Percutaneous ethanol injection therapy (PEIT) was administered to the HCC several times over a 5-year period; however, the patient died of liver failure in February, 1994 (at age 79 years). Viral markers for hepatitis B and C were negative during the course, and hepatitis C virus RNA was not detected by polymerase chain reaction. Autopsy findings showed liver cirrhosis and diffuse involvement of spindle-shaped sarcomatoid cells in the liver, particularly in the S6 region, associated with several nodules of trabecular HCC cells. A zone of transition between the sarcomatoid cells and the trabecular hepatocellular carcinoma cells was observed. The sarcomatoid cells were diffusely disseminated in the peritoneal cavity and had metastasized to multiple organs. Immunohistochemically, the cells were positive for fibrinogen, as were the coexisting trabecular hepatocellular carcinoma cells. The HCC had been treated several times with PEIT. Of interest, PEIT may be an important factor in this type of tumor progression.

In 1979 death rate registration for primary biliary cirrhosis (PBC) became available in The Netherlands. In the 14-year period 1979-92, 417 persons died of and 179 with PBC. We investigated secondary causes of death using standardized mortality ratios (SMR) (1.0 as reference, P < 0.001 regarded as significant).

Median age was 70-74 (35 to > 85) years. Secondary causes of death originated from the circulatory, digestive, and respiratory tracts and malignancies. Younger persons (< 60 years), dying of PBC, more often died with "toxicity related to immunosuppression' than older persons (P < 0.01). Younger persons (< 60) dying with PBC, more often died of hepatocellular carcinoma (HCC) than older ones (P < 0.05). In patients with PBC the frequency of HCC (SMR, 25.5; P < 0.0001) and diseases of the musculoskeletal system/connective tissue (SMR, 5.1; P < 0.0001) was higher than in the general population. Malignancies in general (SMR, 0.7), pancreatic carcinoma (SMR, 2.5), breast cancer (SMR, 0.1) and diseases of the circulatory system (SMR, 0.8) differed but not significantly (P < 0.05 - < 0.01). No difference existed in the localization of malignancies in patients dying of as compared with those dying with PBC.

Deaths occurred predominantly in the older age classes, with an age-related difference in some associated disorders. Patients with PBC showed an increased risk of HCC and diseases of the musculoskeletal system. Similar studies from different countries are needed.

We report herein the case of a 69-year-old woman in whom hepatocellular carcinoma (HCC) arising in the precirrhotic phase of primary biliary cirrhosis (PBC) was successfully managed by a right hepatic lobectomy. The patient, who had never received a blood transfusion, had a 4-year history of asymptomatic PBC of Scheuer's histological classification stage II. Abdominal computed tomography (CT) revealed a mass measuring 4.0 cm in the right hepatic lobe, and a right hepatic lobectomy was performed in consideration of her good liver function and the deep location of the tumor in the right lobe. The patient has remained well without any evidence of recurrent disease for 4 years since her operation. A review of the literature revealed only two cases of successful partial hepatectomy, but none of major hepatectomy. Most of the reported cases had been treated with transcatheter arterial embolization (TAE) and were associated with poor survival. Our experience of this patient indicates the potential value of hepatectomy as an alternative to TAE in selected patients with resectable disease and good hepatic function.

Hepatocellular carcinoma is an uncommon complication of primary biliary cirrhosis. Hepatocellular carcinoma occurs generally in the end stage of the disease. We report a case of asymptomatic primary biliary cirrhosis complicated by a hepatocellular carcinoma in a 66 year-old man.

This review discusses the etiological association of hepatitis C virus with hepatocellular carcinoma and recent progress in the understanding of early histopathological changes that occur in cirrhotic livers leading to hepatocarcinogenesis. In some parts of the world (for example Japan) hepatitis C virus infection is becoming a more important etiological factor in the pathogenesis of hepatocellular carcinoma than infection with hepatitis B virus. Biopsy-proven adenomatous hyperplasia often progresses to hepatocellular carcinoma and adenomatous hyperplasia should be treated as a potentially malignant lesion.

A 57 year old man with auto-immune chronic active hepatitis, regularly treated with immunosuppressive therapy, had hepatocellular carcinoma (HCC) 10 years after diagnosis of the hepatitis. Assays of the hepatitis C virus antibodies against capsid and non-structural proteins revealed seronegativity in serial serum samples of this patient stored in the previous 10 years during follow up. The seronegative hepatitis C antibodies excluded hepatitis C virus as the cause of the HCC. The occurrence of HCC in this case suggests the necessity of surveillance for early detection of liver cancer in patients with auto-immune chronic active hepatitis undergoing long-term immunosuppressive therapy.

Improved immunosuppressive regimens, better postoperative intensive care and judicious patient selection have all resulted in increased patient survival following orthotopic liver transplantation (OLT), which has become the preferred option for most patients with end-stage primary biliary cirrhosis (PBC). As with most other clinical series, PBC is now the most common indication for OLT in the King's College hospital and Cambridge programmes. To date (30 July 1990), 129 patients with PBC have been transplanted, with overall actual 1 and 5 year survival rates of 65 and 63% respectively. When patients transplanted since 1985 are considered, both the 1 and 2 year survival rates are 78%. Immediate operative mortality was 4.5%, generally due to uncontrollable bleeding, while further mortality within 30 days of operation--mainly consequent upon infection and multi-organ failure--has fallen from 40% prior to 1985 to 9% since 1988. Thirteen per cent of patients have been retransplanted for vanishing bile duct syndrome, manifest in this series invariably within the first 6 months following OLT. Although rehabilitation in this series was excellent, a significant percentage of cases have continuing problems with metabolic bone disease, hypertension and renal impairment, mainly due to cyclosporin toxicity.

A survey of Japanese autopsy cases of primary biliary cirrhosis disclosed that hepatocellular carcinoma is apparently becoming a better recognized complication of the advanced stage of primary biliary cirrhosis. Six autopsy cases (five women and one man) of primary biliary cirrhosis associated with hepatocellular carcinoma were obtained from several Japanese institutions and examined. All cases were in an established cirrhotic stage of primary biliary cirrhosis. Hepatocellular carcinoma was incidentally found at autopsy in four cases and, in these, the carcinomas were small in size and number. The other two cases showed advanced hepatocellular carcinoma and one case showed extrahepatic metastasis. Histologically, all cases showed well-differentiated hepatocellular carcinomas. Fatty changes or bile plugs were frequently seen within the tumors. Mallory body clusters and focal deposition of copper-binding protein were consistently found in cirrhotic liver tissues and also in the carcinoma tissues of almost all cases. The presence of atypical adenomatous hyperplasia in the peripheries of some carcinomas suggested that hepatocellular carcinoma in primary biliary cirrhosis may evolve through multiple steps.

The northern part of Sweden is sparsely populated and must be regarded as a rural region. An investigation into the incidence and prevalence of primary biliary cirrhosis was conducted and the course of the disease was followed. In total, 111 patients with primary biliary cirrhosis were identified for the 10-yr period 1973 to 1982 in the northern health region of Sweden. The mean annual incidence amounted to 13.3 per million and the point prevalence was 151 per million, which is the highest reported so far. There was a significantly higher prevalence in the most northern county of Sweden, both with respect to total number of primary biliary cirrhosis patients and symptomatic patients. Asymptomatic patients amounted to 37%. During the study period 25 patients out of the 111 died (23%), 14 as a direct consequence of the liver disease. Three patients died of primary hepatocellular carcinoma, one having an asymptomatic liver disease without cirrhosis. Primary biliary cirrhosis seems to be more common in Sweden, especially in the northern part, than it is elsewhere. A high frequency of extrahepatic symptoms (85%), mainly musculoskeletal, was recorded. These symptoms may lead to the first contact with the health service, rather than signs of liver disease. Thus, an increasing number of patients are diagnosed with asymptomatic liver disease, who must be followed to check for the eventual development of symptoms.

The most important condition associated with hepatocellular carcinoma is chronic hepatitis B virus infection. This article summarizes the information linking hepatocellular carcinoma with conditions other than hepatitis B virus infection.

The major risk factors for HCC are outlined in Table 2. Each factor may contribute to the multistep process of hepatocarcinogenesis. Hepatitis B virus and aflatoxins are the principal aetiological candidates and may be considered as initiators of the malignant state (see Figure 1). The majority of HCC arises via the cirrhotic pathway; the associated changes in the hormonal milieu may alter the handling of environmental carcinogens and the rounds of cell proliferation may increase sensitivity to sub-threshold doses of carcinogens. Exogenous androgens and oestrogens may operate through a similar mechanism to promote clonal expansion of preneoplastic cells. The importance of identifying the major aetiological factors lies in the possibility of prevention. The prognosis of HCC is dismal and it represents a major scourge in developing Third World countries. It is encouraging to think that the majority of cases could be prevented by the widespread use of hepatitis B vaccines and the development of intervention programmes against aflatoxin contamination of foodstuffs.

To determine whether primary biliary cirrhosis differed in men and women we reviewed the presenting features and clinical course of 39 men and 191 women with primary biliary cirrhosis followed at this unit between 1970 and 1984. Age and severity of disease at time of diagnosis were similar in both groups. Pruritus was significantly less common in men than in women both at diagnosis and throughout the period of follow up (p less than 0.01). The difference in incidence of pruritus at diagnosis was most evident when the male group were compared with a group of premenopausal women, an observation which is consistent with involvement of sex steroid metabolism in the origin of pruritus. Skin pigmentation was also less marked in men at diagnosis (p less than 0.05). Autoimmune associated conditions, especially sicca syndrome, were more common in women. Survival was similar among men and women although hepatoma developed significantly more frequently in male patients (p less than 0.01).

A 27 year old woman with hepato-lenticular degeneration (Wilson's disease) was found to have primary hepatocellular carcinoma (PHC) three and a half years after she was started on treatment with D-penicillamine. The tumour was resected since when she has remained well. Her liver function tests were normal throughout the course of her disease. The available literature is reviewed and possible mechanisms for this association proposed.

Serial estimations of serum alpha-fetoprotein in 130 white patients from the United Kingdom with primary biliary cirrhosis who were followed for periods of 1-52 mo revealed 5 cases of hepatocellular carcinoma; all were subsequently confirmed histologically. At the time alpha-fetoprotein was first noted to be elevated, none had signs or symptoms of tumor development. Of the 52 patients who died during the follow-up period, hepatocellular carcinoma was the cause of death in 3 (33%) of the 9 men, and 2 (5%) of the 43 women. Allowing for the marked predominance of women among patients with primary biliary cirrhosis, hepatocellular carcinoma may be no less frequent in primary biliary cirrhosis than in other types of cirrhosis.

Owing to recent findings of certain unusual sex steroid binding in liver disease--particularly an allosteric biphasic pattern (pattern A) unique to the serum of patients with hepatocellular carcinoma--the serum binding characteristics for 5 alpha-dihydrotestosterone were examined in serum samples from six patients with primary biliary cirrhosis who had developed hepatocellular carcinoma. In all serum samples taken after the development of tumour pattern A binding only was obtained, and in four cases in which earlier samples were also examined there was a transformation from the normal, non-specific binding pattern, or an allosteric plateau pattern seen in non-malignant liver disease (designated D and C respectively), to pattern A coincident with the rise in serum alpha fetoprotein. In one patient chemotherapy leading to a fall in alpha fetoprotein abolished pattern A binding, showing further its close association with tumour growth. The value of pattern A binding as a tumour marker in hepatocellular carcinoma warrants further study.

Primary biliary cirrhosis is characterized by abnormalities in both cellular and humoral immunity. It is associated with presumably autoimmune diseases such as Sjögren's syndrome, rheumatoid arthritis, and scleroderma. Sjögren's syndrome and scleroderma have been noted to have an increased frequency of malignancy. Of 208 patients with primary biliary cirrhosis, followed for one month to 15.9 years, extrahepatic malignancies developed in 11, six of whom were women with breast cancer, and one with hepatocellular carcinoma. The incidence of breast cancer was 4.4 times (p less than 0.01) the incidence expected from the rate prevailing in the same age range in a comparable normal population. The incidence of cancer in sites other than the breast and of primary hepatocellular tumor was not significantly increased.

A male patient with Wilson's disease developed a hepatocellular carcinoma after treatment for nine years with D-penicillamine. Examination at necropsy showed that excess liver copper had been effectively removed. As copper has been shown to protect against chemically induced hepatocellular carcinoma in rats, this may be the reason for the extreme rarity of hepatocellular carcinoma in patients with Wilson's disease and possibly in other liver diseases with hepatic copper overload.

In a retrospective review of 85 patients with primary biliary cirrhosis (PBC), 10 (11.8%) were noted to have extrahepatic malignant neoplasm. In seven female patients the tumour developed within a mean of 3.5 yr after the clinical onset of PBC. This observed number of tumours, 3.5 times more common than the expected age-adjusted incidence, was statistically significant at the 0.5% level.

In a group of 50 patients seen with primary liver cell carcinoma over a period of five years, 38 had cirrhosis. In four patients the cirrhosis was due to autoimmune chronic active hepatitis. None of the patients had markers of hepatitis B virus infection, but in three of the four, serum autoantibodies were present. Coexisting autoimmune disease was present in two. Corticosteroids induced remission in all patients, and the liver disease appeared quiescent at the time primary liver cell carcinoma developed.

The occurrence of hepatocellular carcinoma in HBsAg-negative chronic active hepatitis is described in two patients. signs of the tumour appeared 18 years and nine years after the first clinical signs of chronic active hepatitis, although in one patients analysis of stored sera showed the serum alpha-fetoprotein levels had been rising over the previous 33 months. Female preponderance in HBsAg-negative chronic active hepatitis may partly account for the rarity of this complication, and the occurrence of hepatocellular carcinoma may also be a reflection of the better survival now being obtained in HBsAg-negative chronic hepatitis.

The ubiquitous problem of cirrhosis may be complicated by the development of primary liver cell carcinoma, with rates of incidence so high in certain parts of the world as to make it a candidate for the most common cancer in humans. When cirrhosis reaches the macronodular stage, the risk of developing liver cell carcinoma increases, and at this point liver cell dysplasia may be seen in biopsy. Alcoholics, who classically have a micronodular cirrhosis, may attain the macronodular pattern through better clinical management, abstinence, and longer survival. Hepatitis B-related cirrhosis, on the other hand, is most often macronodular. Recent DNA hybridization studies strongly favor a viral role in oncogenesis, and this possibility is supported by the serologic and epidemiologic evidence complied in the last decade. Liver cell malignant tumors tend to recapitulate the characteristics of normal liver, namely, growth in cords, uniformity of cytologic appearances, and bile production, but also present distinctive histologic and immunohistochemical patterns that are unique to a malignant liver cell population. The other primary malignant tumors of the liver, arising in bile ducts, blood vessels, and mesenchymal elements, all carry their individual epidemiology and morphology, but in general invoke, as does liver cell carcinoma, the concept of a series of step by step cell-carcinogen and cell-carcinogen interactions by which normal cells give rise to malignant populations.