“Sicca Complex” in Liver Disease

Sixty-three patients with liver disease were studied for the presence of the components of Sjögren''s syndrome. The “sicca complex” (that is, patients without arthritis) was detected in 42% of patients with active chronic hepatitis, 72% with primary biliary cirrhosis, and 38% with cryptogenic cirrhosis. One patient with active chronic hepatitis and one with primary biliary cirrhosis had rheumatoid arthritis. No evidence of Sjögren''s syndrome was detected in seven patients with alcoholic cirrhosis. It is suggested that the sicca complex and autoimmune liver disease may be part of a systemic disorder in which immunological mechanisms are concerned in the pathogenesis.     

Increased incidence of menstrual abnormalities and hysterectomy preceding primary biliary cirrhosis.

A study was performed to assess the incidence of previous hysterectomy and dilatation and curettage among women with primary biliary cirrhosis. In 87 patients with primary biliary cirrhosis hysterectomy or dilatation and curettage had been performed significantly more often than among 100 age matched normal controls and 80 age matched patients with chronic active hepatitis or alcoholic liver disease. Among the 47 patients with primary biliary cirrhosis who had undergone hysterectomy or dilatation and curettage operations had been performed at a mean of 10.7 years and 13.2 years, respectively, before the onset of disease. The main indication for hysterectomy among patients with primary biliary cirrhosis and controls was menorrhagia. These menstrual disorders may be a consequence of high concentrations of oestrogens in patients with primary biliary cirrhosis.     

Cell-mediated Immune Response in Primary Biliary Cirrhosis to a Protein Fraction from Human Bile

Cell-mediated immune responses to a protein fraction of human bile have been demonstrated, using the leucocyte migration test, in eight out of 10 patients with primary biliary cirrhosis but in only three out of nine with active chronic hepatitis. In the latter condition sensitization to a liver-specific hepatocellular antigen was found more frequently (five out of nine patients) than in primary biliary cirrhosis (two out of 10). These results, as well as the granuloma formation observed histologically, suggest that the initial bile duct lesion in primary biliary cirrhosis may be associated with a cell-mediated response to antigens—perhaps derived from bile duct epithelial cells—which may be normal constituents of hepatic bile.     

The level of steroid hormones in patients with primary biliary liver cirrhosis

The authors investigated 5 of steroid hormones in patients with primary biliary cirrhosis of the liver and healthy persons. Only cortisol was reduced in the blood of the patients with primary biliary cirrhosis. The authors consider that this reduction may be connected with the change of the activity of 17-alpha-hydroxylase of progesterone of the adrenal glands.     

Drug-induced bile duct injury

Drug-induced liver injury includes a spectrum of pathologies, some related to the mode of injury, some to the cell type primarily damaged. Among these, drug-induced bile duct injury is characterized by the destruction of the biliary epithelium following exposure to a drug. Most of the drugs associated with bile duct injury cause immune-mediated lesions to the epithelium of interlobular ducts. These share common histopathological features with primary biliary cholangitis, such as inflammation and necrosis at the expense of cholangiocytes and, if the insult persists, bile duct loss and biliary cirrhosis. Some drugs selectively target larger ducts. Such injury is often dose-dependent and thought to be the result of intrinsic drug toxicity. The histological changes resemble those seen in primary sclerosing cholangitis. This overview focuses on the clinical and pathological features of bile duct injury associated with drug treatment and on the immunological and biochemical effects that drugs exert on the biliary epithelium. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Histocompatibility Antigens in Active Chronic Hepatitis and Primary Biliary Cirrhosis

The frequency of antigens HL-A 1 (48%) and HL-A 8 (52%) in 54 patients with active chronic hepatitis from south-east England was significantly higher than in 89 control subjects from the same region (22% and 17% respectively). No correlation could be detected with the age and sex of the patients or with the presence of a particular immunological abnormality but the frequency of HL-A 1 and HL-A 8 was much lower in the nine patients who were positive for HBAg than in the 45 HBAg-negative cases. These results provide further evidence of the importance of genetic factors in active chronic hepatitis. In contrast the frequency of HL-A 1 and HL-A 8 in primary biliary cirrhosis, both in 45 patients from south-east England and in 28 patients from western Scotland, was not significantly different from that found in control groups from the same regions.     

Primary biliary cirrhosis--an attempt to evaluate the usefulness of selected tests in differential diagnosis]

Seven cases of the primary biliary cirrhosis are presented. The diagnostic problems in early stages of the primary biliary cirrhosis as well as the value of both biochemical and serologic test have been discussed with particular attention to the value of liver biopsy.     

Primary biliary cirrhosis,dark adaptometry,electro-oculography,and vitamin A state.

Twenty five patients with primary biliary cirrhosis were studied for vitamin A state. In nine patients found to have low circulating vitamin A concentrations no abnormality was found on electro-oculography or in dark adaptation. A positive correlation was found between retinol binding protein and vitamin A values (r = +0.88; p less than 0.001) and between serum albumin and vitamin A values (r = +0.75; p less than 0.001). A weaker and negative correlation was found between serum bilirubin (r = -0.47; p less than 0.05) and vitamin A values. Patients with primary biliary cirrhosis should not receive regular parenteral or even oral vitamin A supplementation unless dark adaptometry or electrooculography yields an abnormal result.     

Scleroderma and Primary Biliary Cirrhosis

Two cases of scleroderma and primary biliary cirrhosis are described. One had systemic sclerosis with primary biliary cirrhosis of six years'' duration at the stage of ductular proliferation. The other had the C.R.S.T. syndrome (calcinosis, Raynaud''s phenomenon, sclerodactyly, and telangiectases) with primary biliary cirrhosis at the florid stage. Several similar cases were found in a review of other reports, and it is suggested that the association may be due to a common “autoimmune” process.     

T cells from patients with chronic liver diseases: abnormalities in PHA-induced expression of HLA class II antigens and in autologous mixed-lymphocyte reactions

The expression of HLA Class II antigens by resting and phytohemagglutinin (PHA)-activated T cells and their functional properties in autologous mixed-lymphocyte reactions (MLR) were investigated in patients with chronic active hepatitis, with alcoholic cirrhosis, and with primary biliary cirrhosis. In all groups of patients the percentage of resting T cells expressing HLA Class II antigens was significantly higher than that in controls. The percentage of T cells which acquired HLA Class II antigens following PHA stimulation was reduced in patients with chronic active hepatitis, serum hepatitis B surface antigen (HBsAg) positive, and in those with alcoholic cirrhosis, HBsAg negative, although the level of [3H] thymidine incorporation was within normal limits. The degree of proliferation in autologous MLR with PHA-T cells was significantly reduced in patients with chronic active hepatitis, HBsAb positive, and in those with alcoholic cirrhosis, HBsAg positive. A reduced proliferation was also detected in autologous MLR with non-T cells, in patients with chronic active hepatitis, HBsAg positive. The abnormalities of autologous MLR are selective, since the proliferative and stimulatory activities of cells from patients with chronic liver diseases in allogeneic MLR were within normal ranges. The immunoregulatory role of HLA Class II antigens and of autologous MLR suggests that the abnormalities we have identified may play a role in the immunological dysfunctions underlying chronic liver diseases.     

Primary biliary cirrhosis: an epidemiological study.

A three-year study (1977-9) of primary biliary cirrhosis in the city of Sheffield disclosed 34 cases, a point prevalence of 54 per million population. Closer inspection showed an apparent clustering of cases, and the prevalence in relation to one water reservoir appeared to be more than ten times that of the other reservoirs. Nevertheless, analyses of the water showed no significant relevant differences between the reservoir serving areas with a high prevalence of cirrhosis and other reservoirs. Despite the inconclusive results of the water analyses, these findings do suggest that an environmental agent may be a cause of primary biliary cirrhosis and that further epidemiological studies may help to elucidate the cause.     

Antimitochondrial antibodies (AMA) in primary biliary cirrhosis. I. Separation of the PBC antigen activity from mitochondrial ATPase activity

Antimitochondrial antibodies are found in a variety of autoimmune liver diseases, particularly primary biliary cirrhosis. The antigen against which these antibodies are directed is localized on the inner mitochondrial membrane. Earlier work suggested that this antigen was associated with the mitochondrial ATPase. However, we have succeeded in separating the enzyme activity from the antigenic activity using gel filtration and ion-exchange chromatography. Furthermore, the antigenic activity is not affected by modulators of ATPase enzymatic activity like aurovertin or oligomycin. The antigenic activity is, however, very susceptible to reagents which block thiol groups. The mitochondrial antigen, in contrast to the ATPase enzyme, is found in high amounts in brown fat mitochondria. Identification of this antigen may help to explain why specific antimitochondrial antibodies arise in the sera of patients with primary biliary cirrhosis.Abbreviations ATPase adenosine triphosphatase - PBC primary biliary cirrhosis - AMA antimitochondrial antibodies - SMPs submitochondrial particles - CFT complement fixation test - SDS sodium dodecyl sulfate - BSA bovine serum albumin - BAT brown adipose tissue     

Hepatoimmunology: a perspective

Premises for the subspecialty of hepatoimmunology include the recognition that the liver is a lymphoid organ with unique immunological properties. These properties ensure efficient innate defence against intestinal microbes and toxins, confer a particular capacity for induction of tolerance, and provide for apoptotic disposal of redundant lymphocytes. Pathological responses within the liver are elicited when: (i) hepatotropic viruses (hepatitis virus B and C) escape immune elimination and reside in hepatocytes; (ii) the liver becomes the site of autoimmune responses directed against either hepatocytes (autoimmune hepatitis) or biliary ductules (primary biliary cirrhosis); or (iii) the liver in the course of disposal of drugs generates neoantigens that provoke adverse allergic responses. Recent advances in the understanding of the immunopathogenesis of these entities are reviewed.     

Detection of Helicobacter in the liver of patients with chronic cholestatic liver diseases.

Helicobacter species were identified in human liver tissues by PCR. Biopsies were obtained from patients with primary sclerosing cholangitis, primary biliary cirrhosis and noncholestatic liver cirrhosis. One set of Helicobacter genus-specific primers and two different primer sets for Helicobacter pylori were used in the PCR-assays. Using Helicobacter genus-specific primers 80% (8/10) of patients with primary sclerosing cholangitis and 90% (9/10) of patients with primary biliary cirrhosis were positive. Seven of these 17 samples were positive using two different primers for H. pylori and Southern blot hybridization. Among the non-cholestatic liver cirrhosis controls, only one sample was positive in the Helicobacter genus-specific PCR-assay. Significantly higher values of alkaline phosphatases and prothrombin complex was found for the patients positive for Helicobacter genus. In conclusion, gene sequences of Helicobacter species and H. pylori were detected in human liver tissue using PCR and DNA hybridization in patients with a cholestatic liver disease, but rarely in noncholestatic liver cirrhosis.     

Copper and Manganese Concentrations in Biliary Cirrhosis of Liver

The presence of large amounts of copper in the liver in primary biliary cirrhosis has been confirmed; a similar increase is not found in cases of long-standing extrahepatic biliary obstruction. The serum caeruloplasmin levels are raised in primary and secondary biliary cirrhosis, but this increase does not appear to be related to the degree of increase of hepatic copper. The manganese content of the liver is slightly raised in both these conditions.The reason for the increased metal content in these circumstances cannot yet be determined, and the effects are not yet understood.     

Fibrinolysis in Cholestatic Jaundice

The fibrinolytic system was studied in primary biliary cirrhosis (16 patients) and large bile duct obstruction (10 patients, nine of whom had carcinoma). Plasma fibrinolysis (plasminogen activator activity) was decreased and fibrinogen increased in both groups of patients, particularly in those with large duct obstruction. These changes were related to the degree of cholestasis. Plasminogen activator activity was inversely related to serum triglyceride levels in patients with primary biliary cirrhosis. Urokinase inhibitors were decreased in both groups and antiplasmins increased in patients with large duct obstruction; fibrin/fibrinogen degradation products were normal in primary biliary cirrhosis and moderately increased in large duct obstruction. None of these fibrinolytic indices was related to the degree of cholestasis. Fibrinolytic activity and fibrinogen returned almost to normal levels after palliative surgery in the three patients with large duct obstruction who were studied. The decreased plasma fibrinolysis and increased fibrinogen may be due to altered lipid metabolism in cholestatic jaundice. In patients undergoing surgery for large duct obstruction there may be an increased risk of thrombosis.     

An association between α1-antitrypsin phenotype and chronic liver disease

Summary The phenotypes of alpha-1-antitrypsin have been analyzed by isoelectric focusing on polyacrylamide gels in 232 healthy Japanese blood donors and in 240 Japanese patients with chronic liver diseases: 69 with chronic active hepatitis, 122 with liver cirrhosis, 41 with hepatocellular carcinoma and 8 with primary biliary cirrhosis. The liver cirrhosis patients had a gene frequency of 0.07 forPI ^* M3, which was significantly higher (P<0.01) than that (0.03) in blood donors. The gene frequency of PI ^* M3 was significantly increased in cryptogenic liver cirrhosis (P<0.05), and there was a tendency toward an increased frequency of PI ^* M3 in post-transfusion groups, and in primary biliary cirrhosis. There were also tendenciestoward increased frequencies of PI ^* M3 in cryptogenic and post-transfusion groups of patients with chronic active hepatitis. The present study indicates that PI ^* M3 is a genetic or predisposing factor for chronic liver diseases, especially for cryptogenic and/or non A-non B viral chronic liver disease and also for primary biliary cirrhosis.     

超声对原发性胆汁性肝硬化合并自身免疫性甲状腺炎的诊断价值和相关性分析

摘要 目的：探讨超声对原发性胆汁性肝硬化合并自身免疫性甲状腺炎的诊断价值以及相关性。方法：选取2017年1月~2019年12月我院收治的90例原发性胆汁性肝硬化合并自身免疫性甲状腺炎患者为研究组,根据患者病情的不同将其分为早期组（n=48）和晚期组（n=42）。另选取50例健康志愿者为对照组,对所有患者进行超声诊断,比较两组患者的门静脉血流参数、肝动脉血流参数、肝中静脉血流参数以及脾静脉血流参数。结果：晚期组的门静脉主干内径（portal vein diameter,PVD）明显高于早期组和对照组（P<0.05）,晚期组的平均流速（portal vein velocity,PVV）明显低于早期组和对照组（P<0.05）,三组患者的门静脉血流量（perceptual video quality,PVQ）差异无统计学意义（P>0.05）。晚期组的肝动脉内径（hepatic artery inner diameter,HAD）、阻力指数（resistance index,RI）、收缩期峰值流速（peak systolic velocity/end diastolic velocity,HAVmax）、血流量（blood flow,HAQ）均明显大于对照组（P<0.05）。晚期组的肝中静脉内径（middle hepatic vein diameter,MHAD）、最高平均流速（maximum average flow rate ,MHV Vm）、最大血流量（maximum blood flow,MHVQ）均较早期组和对照组减少（P<0.05）。晚期组的脾静脉内径（splenic vein diameter,SVD）明显高于对照组和早期组（P<0.05）,晚期组的脾静脉平均流速（splenic vein mean flow rate,SVm）、脾静脉血流量 (splenicveinflow, SVF)与对照组、早期组相比差异无统计学意义（P>0.05）;经过相关性分析肝脏超声指标与甲状腺超声指标均呈现正相关关系（P＜0.05）。结论：超声在原发性胆汁性肝硬化合并自身免疫性甲状腺炎患者中应用具有很高的价值,通过对原发性胆汁性肝硬化超声指标推测自身免疫性甲状腺炎病情程度,患者的超声图像具有一定的特征性,可以用以患者的诊断和病因分析,值得在临床中应用推广。     

Deletion of kif3a in CK19 positive cells leads to primary cilia loss,biliary cell proliferation and cystic liver lesions in TAA-treated mice

Background & aimsLoss of primary cilia in epithelial cells is known to cause cystic diseases of the liver and kidney. We have previously shown that during experimental and human cirrhosis that primary cilia were predominantly expressed on biliary cells in the ductular reaction. However, the role of primary cilia in the pathogenesis of the ductular reaction is not fully understood.MethodsPrimary cilia were specifically removed in biliary epithelial cells (BECs) by the administration of tamoxifen to Kif3a^f/f;CK19^CreERT mice at week 2 of a 20-week course of TAA treatment. Biliary progenitor cells were isolated and grown as organoids from gallbladders. Cells and tissue were analysed using histology, immunohistochemistry and Western blot assays.ResultsAt the end of 20 weeks TAA administration, primary cilia loss in liver BECs resulted in multiple microscopic cystic lesions within an unaltered ductular reaction. These were not seen in control mice who did not receive TAA. There was no effect of biliary primary cilia loss on the development of cirrhosis. Increased cellular proliferation was seen within the cystic structures associated with a decrease in hepatocyte lobular proliferation. Loss of primary cilia within biliary organoids was initially associated with reduced cell passage survival but this inhibitory effect was diminished in later passages. ERK but not WNT signalling was enhanced in primary cilia loss-induced cystic lesions in vivo and its inhibition reduced the expansion of primary cilia deficient biliary progenitor cells in vitro.ConclusionsTAA-treated kif3a BEC-specific knockout mice had an unaltered progression to cirrhosis, but developed cystic lesions that showed increased proliferation.     

Use of Computer-assisted Model in Diagnosis of Drug Hypersensitivity Jaundice

Of 374 patients with jaundice seen in the liver unit over a four-year period 21 were finally thought to be hypersensitive to one of seven different drugs. The clinical, laboratory, and histological features were often difficult to distinguish from those of viral hepatitis, tumour of the extrahepatic biliary tree, or primary biliary cirrhosis. A computer-assisted diagnostic model made use of minor differences, and made a correct diagnosis in all patients. Even when information about drug ingestion was left out it was still correct in 81% of patients. Sixty-four other patients gave a history of ingestion of potentially hepatotoxic drugs of whom 62 were correctly diagnosed by the computer. In the complete series of 374 patients only two were incorrectly computed to have drug jaundice when there was no history of drug ingestion.Two additional patients became jaundiced after exposure to drugs, but were found to have primary biliary cirrhosis.