Hepatocellular carcinoma in asymptomatic primary biliary cirrhosis

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.     

Hepatocellular carcinoma in primary biliary cirrhosis: a case report and review of the Japanese literature

We present a 66 year-old woman in the cirrhotic stage of primary biliary cirrhosis (PBC), who developed hepatocellular carcinoma (HCC). All serological tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) were negative. We surveyed 16 reported cases (13 females and 3 males) of PBC associated with HCC in Japan. The presence of HCV RNA was determined by the polymerase chain reaction in all of the patients, 3 of whom (19%) were HCV RNA-positive. Although patients with PBC rarely develop HCC, it is suggested that HCV infection may play a minor role in the development of HCC in Japanese patients with PBC.     

Hepatocellular carcinoma complicating biliary cirrhosis caused by biliary atresia: report of a case

A case of hepatocellular carcinoma complicating biliary cirrhosis caused by biliary atresia is reported. The patient had persistent severe jaundice with hepatosplenomegaly. A liver tumor was suspected because of the elevated serum alpha-fetoprotein and was shown by ultrasonography at 6 years of age. The tumor was treated with percutaneous ethanol injection therapy (PEIT). Nine months after initiation of PEIT, the patient died of massive bleeding from a metastatic tumor.     

Eosinophilia in primary biliary cirrhosis

OBJECTIVES: Recent studies have shown the occurrence of eosinophilia in patients with primary biliary cirrhosis (PBC). To examine whether eosinophilia is indeed a distinctive feature of PBC, we performed extensive leukocyte differential analysis using a highly sophisticated hematology instrument. We also investigated the relationship between eosinophil dynamics and clinical features of PBC including the effects of ursodeoxycholic acid (UDCA) treatment. METHODS: A flow cytometry-based blood cell analyzer (Technicon H6000) was used to examine peripheral blood eosinophil counts in 38 patients with PBC and 131 patients with various liver deseases. We also performed eosinophil quantitation in 19 PBC patients before and after administration of UDCA for 4 wk. RESULTS: Patients with PBC had significantly higher relative and absolute eosinophil counts when compared with other liver diseases (5.7 +/- 0.5% [p < 0.0001, mean +/- SEM] and 312 +/- 26 cells/microliter [p < 0.01], respectively). Twenty-one of 38 PBC patients (55%) exhibited relative eosinophilia. In patients with PBC, the eosinophil count was: 1) significantly higher in those with early histological stages (stage I-II, 6.5 +/- 0.5% vs stage III-IV, 4.4 +/- 0.7%,p < 0.05), 2) positively correlated with basophil count (p < 0.01), serum IgA levels (p < 0.05), and the degree of eosinophil infiltration in the portal tract (p < 0.01), and 3) markedly reduced by UDCA treatment (before: 5.9 +/- 0.7%, 307 +/- 37 cells/microliter; after: 2.8 +/- 0.03% [p < 0.001], 162 +/- 26 cells/microliter ?p < 0.001]). CONCLUSIONS: Eosinophilia is a common and distinctive feature of patients with PBC. UDCA ameliorates eosinophilia as well as liver function tests in PBC patients. Eosinophilia may be useful as one of the initial clues in the diagnosis of PBC, especially in its early stage.     

The geoepidemiology of primary biliary cirrhosis

Thirty-three species of fleas are recorded from the state of Tennessee. New state records are reported for two species, the pulicid fleas Euhoplopsyllus glacialis affinis and Pulex simulans. Two species of fleas with catholic feeding habits appear to be especially widespread and abundant in Tennessee. These are the pulicid Ctenocephalides felis which parasitizes cats, dogs, humans, opossums, and other medium to large sized mammals, and the hystrichopsyllid Ctenophthalmus pseudagyrtes which is associated with several species of small mammals, particularly shrews, moles, voles, and native mice. For a southeastern state, Tennessee has a relatively rich flea fauna. The figure of 33 flea species recorded here for Tennessee is higher than documented figures for other southeastern states (17 species for Alabama, 19 for Florida, 20 for Georgia, 12 for Mississippi, 18 for North Carolina, 19 for South Carolina). This is largely because several species with boreal origins inhabit the higher elevations characteristic of the Appalachian Mountains in the eastern part of the state. Although plague is not enzootic as far east as Tennessee, and murine typhus is rare of absent, suitable flea vectors inhabit the state and one abundant flea species, C. felis, is a pest because it feeds on companion animals and humans.     

Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis

We measured levels of glucose and glycated hemoglobin in the blood of three of the world's smallest nectarivorous birds, the Anna's (Calypte anna), Costa's (Calypte costae), and ruby-throated hummingbirds (Archilochus colubris). Plasma glucose levels of hummingbirds that were fasted overnight (17 mM) were higher than those in any mammal and are among the highest ever measured in a fasting vertebrate. Glucose levels in hummingbirds just after feeding were extreme, rising as high as 42 mM. The surprisingly high blood glucose concentrations in hummingbirds were accompanied by glycated hemoglobin levels that are the highest ever measured in birds but are lower than those of non-diabetic humans. How hummingbirds tolerate blood glucose levels that cause serious neurological and microvascular pathologies in diabetic humans and animals remains unknown.     

Natural history of early primary biliary cirrhosis

BACKGROUND: In 1986, we reported a group of 29 patients who were positive in serum for antimitochondrial antibody (AMA), the disease-specific marker for primary biliary cirrhosis (PBC), but who had normal liver function test results and no symptoms of liver disease. However, liver histology was diagnostic or compatible with PBC in 24 patients and normal in only two. The aims of this 10-year follow-up study were to establish whether patients with AMA have very early PBC, to assess the outlook for such patients, and to follow the progression of the disease. METHODS: All patients were assessed every year at our PBC clinic: records were reviewed, cause of death verified when applicable, and current clinical and biochemical data collected, including repeat liver histology as indicated. Serum samples from the original study were located. Original and follow-up serum samples were tested by ELISA for E2 components of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex. FINDINGS: Five patients died during follow-up; no deaths were attributable to liver disease. Median follow-up of patients who survived was 17.8 years (range 11.0-23.9) from first-detected AMA to the last follow-up review. Overall, 22 (76%) developed symptoms of PBC and 24 (83%) had liver function tests persistently showing cholestasis. Repeat liver biopsy samples were obtained from ten patients; among these patients PBC progressed from Scheuer grade 1 to grade 2 in two and from grade 1 to grade 3 in two. No patient developed clinically apparent cirrhosis. ELISA of baseline serum samples from 27 patients was positive in 21, all of whom had original liver histology compatible with or diagnostic of PBC. Of the six patients who tested negative, only one had an original liver biopsy sample that was compatible with PBC. INTERPRETATION: This study confirms that before the advent of any clinical or biomedical indications, individuals positive for AMA do have PBC. This finding extends the natural history of PBC back in some cases for many years. What determines the eventual progression to biochemically and clinically apparent disease is not yet understood. During our study no patient developed clinically apparent portal hypertension or cirrhosis. Thus, although the finding of a solitary persistently raised AMA is confirmation of a diagnosis of PBC, patients with AMA but no other signs or symptoms of PBC seem to have slow progression of the disease.     

Hepatocellular carcinoma outcomes based on indicated treatment strategy

Hepatocellular carcinoma (HCC) in Western populations historically has been associated with poor survival. In this study, we conducted a 7-year retrospective analysis of patients evaluated at our institution with HCC to determine the effects of newer treatment strategies on outcome. During the period of study, 117 patients [86 (74%) male; mean age, 59 years (range, 16-85)] were evaluated with treatment as follows: surgical resection in 22 (19%), chemoembolization with or without systemic chemotherapy in 40 (35%), systemic treatment alone in 16 (13%), orthotopic liver transplantation in 8 (7%), and supportive care only in 31 (26%). Sixty-nine patients (59%) had documented cirrhosis, with hepatitis C being the most common cause in 27 of 69 (39%). In patients receiving no treatment, median survival was just under 3 months, with only two 1-year survivors. Patients with orthotopic liver transplantation had 1-, 2-, and 3-year survival rates of 87, 87, and 58 per cent compared with 69, 52, and 43 per cent in surgically resected patients. Survival after chemoembolization was 35, 20, and 11 per cent at 1, 2, and 3 years, whereas survival after systemic chemotherapy was 30 and 15 per cent at 1 and 2 years, respectively. One-year survival was improved in noncirrhotic patients compared with cirrhotics (47% vs 29%; P < 0.05) but was no different in patients younger than 55 years compared with older patients (38% vs 38%). When possible, surgical treatment strategies offer superior survival.     

Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders

BACKGROUND: Retroviruses have been implicated in the aetiology of various autoimmune diseases. We used immunoblots as a surrogate test to find out whether retroviruses play a part in the development of primary biliary cirrhosis. METHODS: We did western blot tests for HIV-1 and the human intracisternal A-type particle (HIAP), on serum samples from 77 patients with primary biliary cirrhosis, 126 patients with chronic liver disease, 48 patients with systemic lupus erythematosus, and 25 healthy volunteers. FINDINGS: HIV-1 p24 gag seroreactivity was found in 27 (35%) of 77 patients with primary biliary cirrhosis, 14 (29%) of 48 patients with systemic lupus erythematosus, 14 (50%) of 28 patients with chronic viral hepatitis, and nine (39%) of 23 patients with either primary sclerosing cholangitis or biliary atresia, compared with only one (4%) of 24 patients with alcohol-related liver disease or alpha1-antitrypsin-deficiency liver disease, and only one (4%) of 25 healthy volunteers (p=0.003). Western blot reactivity to more than two HIAP proteins was found in 37 (51%) of patients with primary biliary cirrhosis, in 28 (58%) of patients with systemic lupus erythematosus, in 15 (20%) of patients with chronic viral hepatitis, and in four (17%) of those with other biliary diseases. None of the 23 patients with either alcohol-related liver disease or alpha1-antitrypsin deficiency, and only one of the healthy controls showed the same reactivity to HIAP proteins (p<0.0001). Our results showed a strong association between HIAP seroreactivity and the detection of autoantibodies to double-stranded DNA. HIAP seroreactivity was also strongly associated with the detection of mitochondrial, nuclear, and extractable nuclear antigens. INTERPRETATION: The HIV-1 and HIAP antibody reactivity found in patients with primary biliary cirrhosis and other biliary disorders may be attributable either to an autoimmune response to antigenically related cellular proteins or to an immune response to uncharacterised viral proteins that share antigenic determinants with these retroviruses.     

Unusual coexistence of systemic lupus erythematosus and primary biliary cirrhosis

Systemic lupus erythematosus (SLE) and primary biliary cirrhosis (PBC) are distinct clinical disorders which rarely occur in the same patient. We report on a 65-year-old woman with coexistence of both conditions. Diagnosis of SLE was ascertained by the presence of seven ACR criteria (cutaneous lesions, photosensitivity, antinuclear and anti-double-stranded-DNA antibodies, pancytopenia, arthritis, oral lesions). PBC was disclosed by clinical investigation, liver histology and highly positive antimitochondrial M2 antibodies. The most important differential diagnoses of lupus hepatitis are PBC and autoimmune hepatitis. Diagnostic criteria for these conditions are discussed, and previous reports on overlap between SLE and PBC are reviewed.     

Combined form of chronic aggressive hepatitis primary biliary cirrhosis

15 patients with primary biliary cirrhosis (PBC) and 109 patients with chronic aggressive hepatitis (CAH) have been followed. Features of PBC, namely the generalized pruritus, massive rise in alkaline phosphatase, antimitochondrial antibodies and high levels of IgM-globulins, were present in 7 patients with CAH. This group was treated with immunosuppressive drugs for 1-2 years. Clinical, biochemical, immunological and histological parameters were used to assess the therapeutic effect. The pruritus improved and there was a statistically significant reduction in the IgG-hyperglobulinemia. Some resolution of the piecemeal necroses was seen. However, in judging these changes the sampling error must be taken into account. The unknown agent attacks both the hepatocytes and the epithelial cells of the bile ducts. The immunosuppressive treatment protects the liver cells from further damage while the progressive destruction of the bile ducts remains uninfluenced. The results suggest that the smallest possible dose sufficient to suppress the activity of CAH must be selected.     

Mitochondrial antigen/antibody systems in primary biliary cirrhosis: revisited

Methods for the evaluation of the four antimitochondrial antibody subtypes in primary biliary cirrhosis - anti-M2, -M4, -M8, -M9 - are described. The importance of the application of different preparations for the demonstration of complement fixing antibodies and the detection of antibodies by ELISA or Western blotting is emphasized. Complement fixing antigens can be prepared by discontinuous isopynic sucrose density gradient centrifugation using mitochondrial subfractions derived with from beef heart (M2), rat liver (M4), or pig kidney (M8). Anti-M9 antibodies do not fix complement. For ELISA, the pyruvate dehydrogenase or the ATPase-associated antigen fraction (M2), the sulfite oxidase fraction (M4), and the chromatographically purified M8-fraction should be used. The same antigen fractions are suitable for Western blotting, but anti-M4 and anti-M8 by ELISA and Western blotting a purified fraction prepared from rat liver has to be applied. Correlating antimitochondrial antibody-subtypes with clinical condition and the natural course, there is convincing evidence that especially the presence of complement fixing antibodies against the subtypes M2, M4, and M8 is a reliable indicator for a more active course. Patients expressing only anti-M9 (without anti-M2) have biochemically all the typical features also found in classical anti-M2 positive primary biliary cirrhosis patients, but seem not to advance to late stages. Since these antimitochondrial antibody-subtypes are present even in very early stages stages without changing their pattern during the course, antimitochondrial antibody-profiles can also be taken as early prognostic parameters. The evaluation of the immunological activity by antimitochondrial antibody-subtype testing may further facilitate the decision whether therapy with ursodeoxycholic acid should be combined with steroids and/or immunosuppressive agents. The role of mitochondrial autoantigens in the induction of this chronic destructive bile duct process is also discussed. The concept is put forward that not bile ducts but naive(?) B-cells expose the different mitochondrial antigens, thereby stimulating autoreactive T-cells to provide a second signal for antibody production. The degree of breakage of tolerance to the different mitochondrial epitopes may be one crucial factor which determines the diversity of antimitochondrial antibody-subtypes in patients with primary biliary cirrhosis.     

T cell responses to natural human proteins in primary biliary cirrhosis

The study of T cell responses to autoantigens in human autoimmunity has been hampered by difficulties, firstly in identifying significant autoantigens, and secondly in the purification of authentic human proteins in sufficient quantities to allow characterization of antigen-specific T cell responses. In this study we have purified a human autoantigen, pyruvate dehydrogenase, retaining its enzymatic activity, and characterized autoreactive T cell responses to it in a human autoimmune disease, primary biliary cirrhosis. T cell responses to a mixture of the E2 and protein X subunits of human pyruvate dehydrogenase complex are seen in most affected patients, but in only a small minority of normal and chronic liver disease controls. By contrast, responses to whole pyruvate dehydrogenase complex occur with equal frequency in both groups. This suggests that responses to the E2 component/protein X of pyruvate dehydrogenase complex play a role in the pathogenesis of primary biliary cirrhosis. The availability of significant quantities of the human autoantigen in primary biliary cirrhosis makes this condition an interesting model in which to study true autoreactive human T cell responses.     

Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by an immune-mediated destruction of intrahepatic small bile ducts. Apoptosis, a unique pattern of cell death, has been suggested to be responsible for the biliary destruction in PBC. To address this issue, we attempted to detect the apoptosis of biliary epithelial cells by in situ nick-end labeling and by the expression of apoptosis-related proteins using immunohistochemistry in patients with various hepatobiliary diseases, including PBC. The data was noteworthy for several reasons. First, apoptosis was occasionally detected on biliary cells in all liver specimens; however, the positive rate was high in PBC and relatively low in other livers. Strong expression of CD95 was frequently observed in the epithelial cells of the injured bile ducts of PBC, which accompanied high intensity CD95 ligand-expressing mononuclear cells. Perforin and granzyme B immunoreactivities were occasionally found on the bile ducts in control liver diseases as well as PBC, but granzyme B-positive biliary cells were prominent in PBC. In contrast, Lewis Y expression, as detected using BM-1 antibody, was consistently present in the injured bile ducts of PBC. These data suggest that apoptosis, via the perforin/granzyme B pathway, may be associated with the degrading fraction of cell cycle regulation in the small-sized biliary tree under physiological and pathological liver conditions. Moreover, enhanced apoptosis, mediated by CD95/CD95 ligand interaction, may contribute to the bile duct injury and loss observed in PBC.     

Clinicopathological study of primary biliary cirrhosis negative for antimitochondrial antibodies

Primary biliary cirrhosis (PBC) is characterized by the occurrence of antimitochondrial antibodies (AMA) and the progressive destruction of intrahepatic bile ducts, followed by biliary cirrhosis. However, there are about 5% of PBC patients who show clinicopathological features of PBC but are negative for AMA. In this study, clinicopathological features, as well as antibody reactivity against recombinant (r)-mitochondrial polypeptides, were examined in 30 AMA negative PBC patients and 38 AMA positive PBC patients, in whom the presence of AMA had been determined by indirect immunofluorescence (IF). There were few differences in the clinical and serological features between both groups. Histopathologic features, including staging, bile duct lesions and granuloma, were also similar in both groups. Among the 30 IF-tested AMA negative patients, 29 were also negative against beef heart mitochondrial proteins, but 24 reacted to one or more of the following r-polypeptides, as determined by immunoblotting: E1 alpha of pyruvate dehydrogenase complex, the E2 subunit of pyruvate dehydrogenase complex, and the branched-chain 2-oxo-acid dehydrogenase complex. The remaining six AMA-negative patients were asymptomatic, and histologically resembled having stage 1 of the disease, with relatively mild lymphocytic piecemeal necrosis. One case was positive for anti-smooth muscle antibody. The other clinicopathological features of these patients were similar to those of other AMA negative patients. The present study found that a majority of the AMA-negative patients fulfilling other clinicopathological criteria of PBC, had features similar to the AMA-positive PBC patients, and that a majority of IF AMA-negative patients were positive for r-polypeptides of the 2-oxo-acid dehydrogenase complex. It seems that nearly all the AMA negative patients possess a broad spectrum of antibody profile of AMA, in addition to clinicopathological and serological features.