Cell-mediated Immune Responses in Chronic Liver Diseases

Studies of the cell-mediated response to liver antigens, using the leucocyte migration test, in 163 patients with various liver disorders showed that abnormal responses were almost confined to active chronic hepatitis (53% abnormal), primary biliary cirrhosis (64%), and cryptogenic cirrhosis (29%). The test was also abnormal in five out of seven patients with jaundice due to drug hypersensitivity and in one patient with acute infectious hepatitis at a time when mitochondrial antibodies were present in the serum. More of those with active chronic hepatitis on prednisone or azathioprine had normal tests than of those who were untreated, and in 8 out of 10 examined serially during therapy there was an accompanying improvement in leucocyte migration. Abnormal responses to salivary gland or kidney antigens were also found in nearly half of those with features of Sjögren''s syndrome or renal tubular acidosis as part of a multisystem involvement—this, though occurring in cryptogenic cirrhosis, was found with greater frequency in active chronic hepatitis and primary biliary cirrhosis. These cell-mediated immune responses, perhaps triggered by the initial damage to the liver from viral or other agents, may be responsible both for the perpetuation of the liver disease and, because of common surface antigens, for the damage to other organs.     

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.     

梗阻性黄疸患者经内镜逆行胰胆管造影术后胆道感染的病原菌分布、耐药性及影响因素分析

目的:探讨梗阻性黄疸患者经内镜逆行胰胆管造影(ERCP)术后胆道感染病原菌分布、耐药性以及导致术后胆道感染的影响因素。方法:选择2016年3月至2019年10月我院收治的310例行ERCP治疗的梗阻性黄疸患者,根据ERCP术后是否发生胆道感染将其分为感染组(50例)和未感染组(260例)。检测胆道感染患者病原菌种类及其耐药性,多元Logistic回归分析影响梗阻性黄疸患者ERCP术后胆道感染的影响因素。结果:ERCP术后胆道感染发生率为16.13%,大肠埃希菌、铜绿假单胞菌、粪肠球菌、屎肠球菌是主要致病菌,检出率分别为40.79%、13.16%、9.21%、6.58%。大肠埃希菌、铜绿假单胞菌对头孢类、氨基糖苷类抗生素耐药率高,粪肠球菌、屎肠球菌对利福平、喹诺酮类抗生素耐药率高,大肠埃希菌、铜绿假单胞菌、粪肠球菌、屎肠球菌均对利奈唑胺、亚胺培南敏感。多元Logistic回归分析结果显示,恶性病变、ERCP2次及以上、胆胰管汇流异常、术后胆管引流不畅是梗阻性黄疸患者ERCP术后胆道感染的危险因素(P0.05),术后预防性使用抗生素是保护因素(P0.05)。结论:梗阻性黄疸患者ERCP术后存在一定胆道感染风险,革兰氏阴性菌是主要致病菌,临床应注重对高危因素预防,有必要术后选择敏感抗生素预防性治疗。     

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.     

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.     

Amino acid composition of human liver mitochondrial membranes in normal and pathological conditions

The amino acid composition of proteins from liver mitochondrial membranes has been studied in patients with normal liver, with biliary diseases and fatty liver, with obstructive jaundice or liver cirrhosis. A characteristic pattern of the amino acid composition in patients with normal liver has been found. In the mitochondrial membranes of patients with fatty liver tryptophan and lysine were decreased while [aspartic acid plus asparagine] and [glutamic acid plus glutamine] were increased compared to their counterpart in the normal liver. In patients with obstructive jaundice of short duration (less than two months) only a slight decrease in methionine content was found, while in the case of liver cirrhosis amino acid composition was markedly changed.deceased.     

Pruritus and Jaundice

The records of 147 patients who had pruritus and jaundice (11% of a series of 1262 patients with jaundice) were reviewed in an effort to delineate more clearly the etiology of jaundice associated with pruritus.Fifty-two had obstructive jaundice caused by neoplasm, 51 had obstructive jaundice not caused by neoplasm, 42 had pruritus associated with hepatogenous jaundice, and two had jaundice and pruritus associated with a lymphoma.Pruritus occurred in 17% of all patients with non-neoplastic obstructive jaundice and in 45% of patients with neoplastic obstructive jaundice. Hepatogenous jaundice was the cause of pruritus in almost one-third of the patients in this series-occurring in 20% of patients with infectious hepatitis and in 7% of patients with cirrhosis.This large series confirms the clinical impression that pruritus occurs most often in association with extrahepatic biliary obstruction, and as well re-emphasizes the common association of pruritus with hepatogenous jaundice.     

Diagnosis of icteric-type hepatocellular carcinoma by fine needle aspiration: a case report

BACKGROUND: Bile duct invasion is very rare in patients with hepatocellular carcinoma (HCC). It usually presents difficult problems with the clinical differential diagnosis. Moreover, another difficulty might arise when an obstructive jaundice patient is found to have past history of 2 separate malignancies. Fine needle aspiration (FNA) becomes the method of choice for clarification of the bile duct tumor thrombus. CASE: A 72-year-old man presented with progressive obstructive jaundice for 1 month. Past history revealed the occurrence of 2 distinct malignancies during the previous 3 years; they had been resected successfully. Initial imaging studies, including abdominal sonography and computed tomography, were negative for the liver. However, FNA demonstrated clusters of pleomorphic and hyperchromatic cancer cells with an increased nuclear/cytoplasmic ratio proliferating in a vague trabecular pattern with some appearance of sinusoids. Multinucleated giant cells were seen. No bile duct epithelial cells were seen. The diagnosis of the third separate malignancy, moderately differentiated HCC, was made. CONCLUSION: To our knowledge, this is the first report of icteric-type HCC diagnosed by FNA although the primary lesion was undetectable on routine, noninvasive examinations. FNA cytology is an accurate and minimally invasive method for early confirmation of biliary HCC thrombi.     

Predisposing Factors in Adverse Reactions to Drugs

Predisposing factors were sought in 118 patients who developed adverse drug reactions in hospital. Significantly more patients of 60 years and over, and more women than men, developed adverse drug reactions. Patients with reactions had more drugs before the development of the reaction than patients who did not develop reactions. A previous adverse drug reaction and a history of allergic disease were significant factors, while a history of jaundice or the presence of diabetes mellitus and renal disease was not.     

Chronic Cholangitides: Aetiology,Diagnosis, and Treatment

A number of different chronic diseases affect the intrahepatic bile radicles or cholangioles. They include primary and secondary sclerosing cholangitis, primary biliary cirrhosis, chronic cholestatic drug jaundice, atresia, and carcinoma. Aetiological factors include infection, immunological changes, hormones, and congenital defects.Patients with chronic cholestasis have decreased bile salts in the intestinal contents and suffer from a bile salt deficiency syndrome. Failure to absorb dietary fat is managed by a low-fat diet and by medium-chain trigly-cerides which are absorbed in the absence of intestinal bile salts. Fat-soluble vitamin deficiencies are prevented by parenteral vitamins A, D, and K₁. Calcium absorption is defective, and improvement may follow intramuscular vitamin D, medium-chain triglycerides, a low-fat diet, and oral calcium supplements.In partial intestinal bile salt deficiency the anionic bile-salt-chelating resin cholestyramine controls pruritus though steatorrhoea increases. Pruritus associated with total lack of intestinal bile salts is managed by methyl-testosterone or norethandrolone, though the jaundice increases.     

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.     

Risk factors for development of flucloxacillin associated jaundice.

OBJECTIVES--To identify risk factors predisposing to the development of flucloxacillin associated jaundice. DESIGN--Case-control study. Medical records of cases and controls were reviewed and information recorded on standard data collection forms. SETTING--Alfred Hospital recruiting subjects from Melbourne, Sydney, and Brisbane. SUBJECTS--Cases were defined as patients who had developed jaundice within eight weeks of stopping flucloxacillin, biochemical test results suggesting cholestasis, normal calibre bile ducts, and not been taking recognised hepatotoxic drugs. 51 of the 53 patients referred were included in the study. Four controls for each case were randomly selected from the patient register of the prescribing doctor. These were defined as patients who had been prescribed flucloxacillin without developing jaundice. MAIN OUTCOME MEASURES--Demographic characteristics, medical history, indication for flucloxacillin, dose, route and duration of treatment, other drugs, smoking, and previous drug allergies or use of flucloxacillin. RESULTS--Increasing age and a prolonged duration of flucloxacillin treatment were found to be risk factors for the development of jaundice. Patients aged over 55 years had an odds ratio of 18.61 (95% confidence interval 5.16-67.17) compared with patients under 30. The odds ratio for patients prescribed flucloxacillin for over 14 days was 7.13 (2.90 to 17.58) compared with patients treated for 14 days or less. Dose and route of administration were not related to the risk of jaundice. CONCLUSIONS--Older patients and those receiving flucloxacillin for longer than two weeks are at a substantially greater risk of jaundice. Careful consideration of the risk-benefit ratio is required when flucloxacillin is used in these settings.     

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.     

Lack of benefit of ursodeoxycholic acid in drug-induced cholestasis in the rat.

The administration of ursodeoxycholic acid (UDCA) has been reported to improve cholestasis in patients with primary biliary cirrhosis or sclerosing cholangitis. In the present study, we tested the hypothesis that UDCA similarly might reduce cholestasis induced by drugs. Rats were treated with three different drugs reported to induce cholestasis: 17 alpha-ethynylestradiol, alpha-napthylisothiocyanate, and cyclosporine A. UDCA administration (0.4.g/day-1.k-1 before and during administration of the cholestatic drug) did not improve survival, food intake, or serum indicators of cholestasis in any of these three animal models of cholestasis. To the extent that drug-induced cholestasis in rats mimics the human situation, we conclude that UDCA probably will not be beneficial in drug-induced cholestasis in humans.     

Breast cancer in women with primary biliary cirrhosis.

The occurrence of extrahepatic malignancy was studied in 195 unselected patients who satisfied predetermined biochemical, immunological, and histological criteria for the diagnosis of primary biliary cirrhosis. The incidence of breast cancer in women with primary biliary cirrhosis was found to be significantly higher than in an age and sex matched control population from the same well defined geographical area (p less than 0.0015). The association of breast cancer and primary biliary cirrhosis remains unexplained, though diminished immunological surveillance, fat soluble vitamin deficiency, or endocrine dysfunction may play a part.     

The Diagnosis and Management of Jaundice

Although the problems of at least 80% of patients presenting with jaundice lend themselves to accurate diagnosis by conventional clinical and laboratory findings, the remainder present an ever-increasing problem. The widespread and often indiscriminate use of many drugs has made the diagnosis of jaundice more difficult. It is now well established that many of these substances may effect liver function in a very selective fashion, resulting in a pattern of laboratory findings similar to those usually associated with surgical lesions of the biliary tree.By reviewing the newer concepts of bilirubin metabolism, the physician is in a better position to avoid these pitfalls. Since 1953, when the role of the liver in conjugation of bilirubin with glucuronic acid was defined, considerable revision in our previous concepts of bilirubin metabolism has taken place. The enzymatic activity of glucuronyl transferase and the conditions which arise in the presence of a deficiency of this enzyme have now defined a whole series of previously poorly understood jaundiced states.The problem presented by the jaundiced newborn is discussed at some length. Similarly, jaundice of long standing in the elderly debilitated adult is also discussed. The author feels that laparotomy with liver biopsy and/or cholangiography are of definite value in the management of these problems.     

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.     

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     

“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.     

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.