Cases Of Primary Biliary Cirrhosis Research Articles

A Case of Primary Biliary Cirrhosis with Progressive Systemic Sclerosis

A Case of Primary Biliary Cirrhosis with Progressive Systemic Sclerosis

Case–control studies of risk factors for primary biliary cirrhosis in two United Kingdom populations

ObjectiveThe aetiology of primary biliary cirrhosis (PBC) is largely unknown. Previous studies have indicated that both environmental and genetic risk factors may be important.DesignWe undertook a large case–control study to...

A case of primary biliary cirrhosis: First report from Bangladesh

Primary biliary cirrhosis (PBC) is a rare autoimmune liver disease, not infrequent in the West, but hardly reported from the East. We report a case of PBC for the first time from Bangladesh. The patient was an elderly woman presenting with vague complaints. The diagnosis was confirmed by antibody testing and histopathology, whereas other possible causes of cirrhosis were also excluded.

The Usefulness of IgG and IgM Immunostaining of Periportal Inflammatory Cells (Plasma Cells and Lymphocytes) for the Distinction of Autoimmune Hepatitis and Primary Biliary Cirrhosis and Their Staining Pattern in Autoimmune Hepatitis–Primary Biliary Cirrhosis Overlap Syndrome

Autoimmune hepatitis (AIH)-primary biliary cirrhosis (PBC) overlap syndrome (OS) is a vaguely defined entity demonstrating features of AIH and PBC. We investigated the usefulness of IgG and IgM immunostaining for the distinction of AIH and PBC and their staining pattern in cases of possible OS. The approximate quantity of IgG+ and IgM+ periportal inflammatory cells in immunohistochemical analysis were compared in cases of AIH, PBC, and OS. AIH cases showed predominant IgG immunostaining of periportal inflammatory cells. A significant number of PBC cases also demonstrated IgG predominance rather than IgM. Six OS cases had IgG predominance, 4 had IgM predominance, and 1 was equivocal. The usefulness of IgG and IgM immunostaining is limited in PBC cases with IgM predominance for excluding AIH. IgG predominance is not specific for AIH. OS does not demonstrate either IgG or IgM predominance (P > .2) and does not help classify OS into either category.

A case of primary biliary cirrhosis associated with pernicious anemia: a case report

Primary biliary cirrhosis is often associated with autoimmune diseases. However, its association with pernicious anemia has rarely been reported.We report a case of a 68-year-old woman who presented jaundice and pruritus. Mildly elevated serum levels of alkaline phosphatase and γ-glutamyl transpeptidase were detected. The titer of anti-mitochondrial M2 anti-body was elevated. Histology of liver biopsy showed features of primary biliary cirrhosis. In addition, aregenerative macrocytic anemia was found in the full blood count. The diagnosis of pernicious anemia was established by megaloblastosis in bone marrow, atrophic gastritis without Helicobacter pylori, low level of vitamin B12 and good response to treatment regimen of vitamin B12. The association of primary biliary cirrhosis and pernicious anemia is unlikely to be casual and may be explained by autoimmune mechanism commonly shared by the diseases.

Immune-mediated bile duct injury: The case of primary biliary cirrhosis

Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T cells. Nevertheless, the condition is universally named primary biliary cirrhosis (PBC). The disease etiology and pathogenesis remain largely unknown despite the proposed lines of evidence. One twin study and numerous epidemiology reports suggest that both a susceptible genetic background and environmental factors determine disease onset while a recent genome-wide association study proposed highly significant associations with several common genetic polymorphisms in subgroups of patients. Specific infectious agents and chemicals may contribute to the disease onset and perpetuation in a genetically susceptible host, possibly through molecular mimicry. Importantly, several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and bacteria. From a pathogenetic standpoint, new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic blebs. We are convinced that the application of the most recent molecular techniques will soon provide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics.

Are transient environmental agents involved in the aetiology of primary biliary cirrhosis?

Recently a space-time clustering analysis of cases of primary biliary cirrhosis (PBC) was carried out, using population-based data from a defined geographical region of northeast England. Space-time clustering analysis is a specialised descriptive statistical technique an d is observed when excess cases are found in highly localised geographical areas for very limited periods of time. The analyses revealed the presence of highly statistically significant space-time clustering which could not be attributed to an artefactual occurrence. This finding was interpreted as providing supportive evidence for the involvement of transient environmental agents in aetiology [1]. This Special Issue of Disease Markers is dedicated to PBC and specifically the role that transient environmental factors may play in aetiology. Current knowledge is reviewed by seven selected invited experts (and associates) in the field. The aetiology of PBC is far from clear. In this Special Issue of Disease Markers, the role of transient environmental agents is reviewed by the seven invited contributors. They each provide their own perspective to the ongoing debate. The possibility that the putative transient agent might be an infection is considered by some of the reviewers. Epidemiological studies have indicated that infections may either trigger PBC or lead to progression. Reviewers also examine the putative role of other transient environmental factors, including chemical exposures, contaminated drinking water and lifestyle factors.

PBC triggers in water reservoirs, coal mining areas and waste disposal sites: from Newcastle to New York.

Various environmental factors have been proposed as triggers of primary biliary cirrhosis (PBC), a progressive autoimmune cholestatic liver disease which is characterised by the destruction of the small intrahepatic bile ducts. Support for their pathogenic role in PBC is provided by epidemiological studies reporting familial clustering and clusters of the disease within a given geographical area. The seminal study by Triger reporting that the great majority of PBC cases in the English city of Sheffield drank water from a specific water reservoir, has been followed by studies reporting disease 'hot spots' within a restricted geographic region of the former coal mining area of Newcastle. The New York study reporting an increased risk and significant clustering of PBC cases near toxic federal waste disposal sites has added strength to the notion that environmental factors, possibly in the form of infectious agents or toxic/chemical environmental factors in areas of contaminated land, water or polluted air may play a key role in the development of the disease. This review discusses the findings of reports investigating environmental factors which may contribute to the cause of primary biliary cirrhosis.

PBC Triggers in Water Reservoirs, Coal Mining Areas and Waste Disposal Sites: From Newcastle to New York

Various environmental factors have been proposed as triggers of primary biliary cirrhosis (PBC), a progressive autoimmune cholestatic liver disease which is characterised by the destruction of the small intrahepatic bile ducts. Support for their pathogenic role in PBC is provided by epidemiological studies reporting familial clustering and clusters of the disease within a given geographical area. The seminal study by Triger reporting that the great majority of PBC cases in the English city of Sheffield drank water from a specific water reservoir, has been followed by studies reporting disease 'hot spots' within a restricted geographic region of the former coal mining area of Newcastle. The New York study reporting an increased risk and significant clustering of PBC cases near toxic federal waste disposal sites has added strength to the notion that environmental factors, possibly in the form of infectious agents or toxic/chemical environmental factors in areas of contaminated land, water or polluted air may play a key role in the development of the disease. This review discusses the findings of reports investigating environmental factors which may contribute to the cause of primary biliary cirrhosis.

Validation of Coding Algorithms for the Identification of Patients with Primary Biliary Cirrhosis Using Administrative Data

Large-scale epidemiological studies of primary biliary cirrhosis (PBC) have been hindered by difficulties in case ascertainment. To develop coding algorithms for identifying PBC patients using administrative data--a widely available data source. Population-based administrative databases were used to identify patients with a diagnosis code for PBC from 1994 to 2002. Coding algorithms for confirmed PBC (two or more of antimitochondrial antibody positivity, cholestatic liver biochemistry and/or compatible liver histology) were derived using chart abstraction data as the reference. Patients with a recorded PBC diagnosis but insufficient confirmatory data were classified as 'suspected PBC'. Of 189 potential PBC cases, 119 (60%) had confirmed PBC and 28 (14%) had suspected PBC. The optimal algorithm including two or more uses of a PBC code had a sensitivity of 94% (95% CI 71% to 100%) and positive predictive values of 73% (95% CI 61% to 75%) for confirmed PBC, and 89% (95% CI 82% to 94%) for confirmed or suspected PBC. Sensitivity analyses revealed greater accuracy among women, and with the use of multiple data sources and one or more years of data. Inclusion of diagnosis codes for conditions frequently misclassified as PBC did not improve algorithm performance. Administrative databases can reliably identify patients with PBC and may facilitate epidemiological investigations of this condition.

Familial Clustering and Genetic Background of Primary Biliary Cirrhosis in Japan

Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease. To elucidate the genetic background of PBC by investigating familial cases of PBC. Familial cases were picked out from 171 PBC patients who enrolled in this study. We analyzed them and their family members, and compared them clinically and immunogenetically to non-familial cases. Out of 171 PBC patients, ten (5.8%) were identified as familial PBC in five families. The clinical features of familial PBC were almost comparable to those of non-familial PBC. The distribution of human leukocyte antigens (HLA)-A, -B and -DR in familial PBC showed no specificity. Two new PBC patients were identified in one family in addition to the two originally enrolled PBC patients, resulting in four patients with PBC within the same family. The two new PBC patients had an identical HLA haplotype. On the other hand, one HLA-identical sister of a PBC patient in another family did not develop PBC. Primary biliary cirrhosis can exhibit familial clustering without any HLA predisposition, however, a survey of families for PBC could be useful for identifying new patients with PBC in the asymptomatic stage for earlier diagnosis and treatment.

Primary Biliary Cirrhosis (PBC), PBC Autoantibodies, and Hepatic Parameter Abnormalities in a Large Population of Systemic Sclerosis Patients

To investigate the diagnostic accuracy of antimitochondrial antibodies (AMA), sp100, and gp210 antibodies for primary biliary cirrhosis (PBC) in a large population of patients with systemic sclerosis (SSc); to examine concordance of these antibodies with subsets of SSc. Further, to assess the association of SSc-related antibodies with hepatic parameter abnormalities. We obtained medical records to verify the diagnoses of SSc and PBC. Sera from all participants were examined for the presence of SSc- and PBC-related antibodies, as well as for abnormalities in hepatic parameters. We examined 817 patients with SSc, of whom 16 (2%) had confirmed PBC. The sensitivity and specificity of AMA by a MIT3 ELISA for PBC were 81.3% and 94.6%, respectively. Sp100 had a sensitivity and specificity of 31.3% and 97.4%, respectively, while gp210 had an even lower sensitivity. We were able to detect all PBC cases using AMA(MIT3) and sp100 as a combined marker, resulting in a significantly improved sensitivity of 100% (p = 0.042) with an incremental decrease in specificity to 92.6%. Independent of AMA or sp100 status, there was an association of anticentromere B (CENP-B) and anti-topoisomerase antibodies (ATA) with higher alkaline phosphatase levels (p = 0.051 and p = 0.003, respectively) while anti-RNA polymerase III (anti-RNAP) was associated with lower alkaline phosphatase levels (p = 0.019) among the patients with SSc. Utilization of AMA(MIT3) and sp100 antibodies as a combined diagnostic marker leads to an improved detection of PBC in patients with SSc. CENP-B and ATA are associated with alkaline phosphatase elevation.

Large liver cell change in hepatitis B virus–related liver cirrhosis #

Large liver cell change (LLCC) refers to microscopic lesions often found in various chronic liver diseases; however, its nature is still controversial. Thirty-four formalin-fixed and 19 fresh frozen hepatitis B virus (HBV)-related cirrhosis samples were examined for the presence of LLCC, small liver cell change (SLCC), and hepatocellular carcinoma (HCC). The cell cycle checkpoint status (p21, p27, p16, Tp53), cell dynamics (proliferating cell nuclear antigen, Ki-67, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, M30), DNA damage (gamma-H2AX [H2A histone family, member X]), telomere lengths, chromosomal instability (micronuclei index), and senescence-associated beta-galactosidase (SA-beta-Gal) activity were evaluated using an in situ approach and compared to those in normal liver (n = 5) and liver with chronic cholestasis (34 cases of hepatolithiasis and three cases of primary biliary cirrhosis). In HBV-related cirrhosis, the p21, p27, and p16 cell cycle checkpoint markers were activated in normal-looking cirrhotic hepatocytes (NLCH), but diminished gradually from LLCC, SLCC, to HCC, with an increase in Tp53 expression. There was a general decrease in telomere length from NLCH, LLCC, SLCC, to HCC. Micronuclei, gamma-H2AX foci, and net cellular gain were significantly increased from normal hepatocytes, NLCH, LLCC, SLCC, to HCC. The SA-beta-Gal activity was weaker in LLCC compared to NLCH and absent in SLCC and HCC. In contrast, cholestatic LLCC showed retained expression of cell cycle checkpoint markers and decreased net cellular gain compared to adjacent normal-looking hepatocytes. HBV-related LLCC showed significantly higher Tp53 labeling index, gamma-H2AX labeling index, and micronuclei index; shorter telomere length; decreased SA-beta-Gal activity; and increased net cellular gain compared to cholestatic LLCC. The nature of LLCC is rather heterogeneous depending on the biological setting. The characteristics of HBV-related LLCC are more consistent with dysplastic rather than merely reactive hepatocytes, whereas cholestatic LLCC more likely represents reactive change with more stringent cell cycle checkpoint control.

Clinical and pathological observation on 60 cases of primary biliary cirrhosis

目的 分析原发性胆汁性肝硬化(PBC)的临床和病理特征有助于该病的早期诊断和治疗.方法 回顾分析60例PBC患者资料.结果 患者中女性47例,主要表现为黄疸、乏力、瘙痒.多数患者-γ-谷氨酰转肽酶(GGT)与碱性磷酸酶(ALP)显著增高,血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、总胆红素(TBil)、直接胆红素(DBil)不同程度升高;66.7%患者免疫球蛋白IgM增高;75%抗线粒体抗体M2亚型(AMA-M2)阳性,是PBC的重要特征.28.17%gp210阳性且男性略多.35例肝穿PBC Ⅰ～Ⅱ期16例,Ⅲ～Ⅳ期19例,统计学显示IgM在PBC Ⅰ～Ⅱ期增高明显(P＜0.05).结论 PBC中年女性多见,应结合临床、生化、免疫学及病理检查及时诊断,IgM有助于早期诊断。

A Case of Primary Biliary Cirrhosis in Association with an Overlap Syndrome of Systemic Sclerosis and Systemic Lupus Erythematosus

A Case of Primary Biliary Cirrhosis in Association with an Overlap Syndrome of Systemic Sclerosis and Systemic Lupus Erythematosus

Primary biliary cirrhosis, similar to that in human beings, in a male C57BL/6 mouse infected with Helicobacter Pylori

We report a case of primary biliary cirrhosis (PBC) that occurred in a 24-month-old male C57BL/6 mouse infected with Helicobacter pylori (H. pylori). Microscopically, the portal tract in the liver showed nonsuppurative destructive cholangitis with variable cytologic distortion of the epithelial cells and peribiliary lymphoplasmacytic infiltration. Immunohistochemistry using alpha-smooth muscle actin demonstrated fibrous bands associating with the wall of vasculature. The level of serum antivacuolating toxin IgG in this mouse showed the highest value (optical density=2.1470) of the H. pylori-infected group (n=13) (optical density=1.7168+/-0.1759, mean+/-SD). Spontaneously developed PBC-like lesions in C57BL/6 mice have been reported by several authors. However, this case strikingly resembles human PBC with its characterized histological features. Therefore, we propose that the increase in vacuolating toxin caused by H. pylori infection may be related to the development of PBC by molecular mimicry.

AMA Negative Primary Biliary Cirrhosis (PBC) and Small Duct Primary Sclerosing Cholangitis (PSC) Overlap Syndrome

Purpose: Overlap syndromes of two autoimmune liver diseases are not uncommon and usually involve autoimmune hepatitis with either PBC or PSC. We describe a case of AMA negative PBC and small duct PSC overlap syndrome, an extremely rare cause of autoimmune liver disease. Case Report: A 58 year old male was referred for evaluation of elevated liver enzymes: total bilirubin 2.4 mg/dL, alkaline phosphatase 630 IU/L, AST 262 IU/L, and ALT 447 IU/L. These were associated with fever, night sweats, dark urine, and pruritis. Serologies revealed an elevated pANCA (1:1280) but negative ANA, AMA, and ASMA. Complete serologic evaluation, including viral and metabolic serologies, was otherwise negative. Abdominal ultrasound revealed a normal liver and gallbladder. MRCP revealed normal intrahepatic ducts, common hepatic duct, and common bile duct. No strictures or irregularities of the biliary tree were identified. Liver biopsy revealed features of both PBC and PSC: portal hepatitis, a florid duct lesion, granulomas, and loss of small bile ducts. There was also concentric periductal fibrosis (“onion skinning”), affecting multiple small bile ducts. Trichrome and reticulin stains noted periportal fibrosis. A repeat AMA was performed using the more specific mitochondrial M2 test; this was also negative. The patient was assigned the diagnosis of AMA negative PBC and small duct PSC overlap syndrome. He was started on ursodeoxycholic acid 1200 mg daily in divided doses. Liver enzymes returned to normal within 6 months of therapy and he has had no further symptoms. The patient had undergone a screening colonoscopy 1 year prior to the elevated liver enzymes. This had revealed a hyperplastic colon polyp with normal appearing colon mucosa. Discussion: Overlap syndromes are noted in approximately 18% of patients with autoimmune liver disease and usually involve autoimmune hepatitis and either PBC or PSC. The very rare variant of PBC and PSC overlap syndrome has been reported in 4 cases in the literature. Our patient with features of both AMA negative PBC and small duct PSC represents an additional case of this extremely rare overlap syndrome.

Human leukocyte antigen polymorphisms in italian primary biliary cirrhosis: A multicenter study of 664 patients and 1992 healthy controls

Genetic factors are critical in determining susceptibility to primary biliary cirrhosis (PBC), but there has not been a clear association with human leukocyte antigen (HLA) genes. We performed a multicenter case-control study and analyzed HLA class II DRB1 associations using a large cohort of 664 well-defined cases of PBC and 1992 controls of Italian ancestry. Importantly, healthy controls were rigorously matched not only by age and sex, but also for the geographical origin of the proband four grandparents (Northern, Central, and Southern Italy). After correction for multiple testing, DRB1*08 [odds ratio (OR), 3.3; 95% confidence interval (CI), 2.4-4.5] and DRB1*02 (OR 0.9; 95% CI 0.8-1.2) were significantly associated with PBC, whereas alleles DRB1*11 (OR 0.4; 95% CI 0.3-0.4) and DRB1*13 (OR 0.7; 95% CI 0.6-0.9) were protective. When subjects were stratified according to their grandparental geographical origin, only the associations with DRB1*08 and DRB1*11 were common to all three areas. Associated DRB1 alleles were found only in a minority of patients, whereas an additive genetic model is supported by the gene dosage effect for DRB1*11 allele and the interaction of DRB1*11,*13, and *08. Lastly, no significant associations were detected between specific DRB1 alleles and relevant clinical features represented by the presence of cirrhosis or serum autoantibodies. In conclusion, we confirm the role for HLA to determine PBC susceptibility and suggest that the effect of HLA is limited to patient subgroups. We suggest that a large whole-genome approach is required to identify further genetic elements contributing to the loss of tolerance in this disease.

Plasma Adiponectin Levels in Primary Biliary Cirrhosis: A Novel Perspective for Link Between Hypercholesterolemia and Protection Against Atherosclerosis

Hypercholesterolemia is a common finding in primary biliary cirrhosis (PBC), but the risk of cardiovascular events in PBC patients is not increased in respect to the general population. High serum adiponectin levels appear to play a protective role in the development of either metabolic syndrome or cardiovascular disease. To investigate factors potentially preventing atherosclerosis in PBC patients. Circulating levels of adiponectin, resistin, leptin, and tumor necrosis factor-alpha (TNF-alpha) were measured in 137 consecutive PBC patients (125 women, 12 men; mean age 61.6 +/- 12.3 yr), 137 sex- and age-matched healthy controls, and 30 female patients with nonalcoholic steatohepatitis (NASH) and associated metabolic syndrome. The body mass index (BMI) was comparable in the three groups, whereas total cholesterol was significantly higher in both PBC and NASH cases than in controls (221.6 +/- 50.5 mg/dL in PBC vs 221.7 +/- 39.7 mg/dL in NASH vs 209.8 +/- 39.2 mg/dL in controls, P < 0.05). Serum concentrations of adiponectin, resistin, and leptin were significantly higher in PBC patients than in either NASH cases or controls (P < 0.05). Among the PBC patients, only adiponectin correlated positively with histological progression of the disease (P= 0.001) and negatively with BMI (P= 0.01). Logistic regression analysis revealed that adiponectin correlated independently with age, BMI, Mayo score, and gamma-glutamyl transpeptidase. The high adiponectin concentrations observed in PBC patients should be regarded as a possible protective factor against atherogenesis. The search for further protective factors should be encouraged.

Primary biliary cirrhosis following lactobacillus vaccination for recurrent vaginitis

Antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex, PDC-E2, and other mitochondrial 2-oxoacid dehydrogenases (AMA-M2) are the hallmark for diagnosis of primary biliary cirrhosis (PBC). AMA-M2 formation as an early step in the pathogenesis of PBC has recently been assumed to be triggered by bacterial mimics of the E2 subunit and certain reactant xenobiotics. We report a case of symptomatic PBC diagnosed after sequential immunization with a lactobacillus vaccine for recurrent vaginitis over years. Serum AMA-M2 specificity of the patient was evaluated by indirect immunofluorescence, immunoblotting and ELISA. Serum antibody responses against pyruvate dehydrogenase complex-E2 subunit (PDC-E2(212-226)), the major PBC-specific mitochondrial autoepitope, and microbial mimics revealed cross-reactivity with beta-galactosidase of Lactobacillus delbrueckii (LACDE BGAL(266-280)) which shows a high local homology with that of Lactobacillus species administered via the vaccine. The relative affinity of antibody reactivity to LACDE BGAL(266-280) was significantly higher than that against human PDC-E2(212-226). We conclude that lactobacillus vaccination therapy may be another culprit for the development of PBC in genetically susceptible women.