Assessment of nutritional status and in vivo immune responses in alcoholic liver disease.

Nutritional status and in vivo immune responses were investigated in 30 patients with alcoholic liver disease who were drinking heavily up until emergency hospital admission. Investigations were performed on admission and after 2 wk abstention and adequate hospital diet. No relationship was found between the severity of liver disease revealed histologically and the recent quantity or total duration of alcohol intake, inadequacy of diet, or nutritional status. Skin anergy was more common in those patients with cirrhosis but did not relate to depletion in circulating T lymphocytes, poor nutritional status, or to the direct effect of alcohol toxicity. Acute alcohol toxicity did, however, produce extensive and rapidly reversible metabolic and cellular changes including reduction in serum potassium, magnesium and phosphate and depletion of all circulating lymphocyte subpopulations.

Detection of lymphocyte Fc gamma receptor-blocking factors by the EA rosette inhibition assay. Refinement of the conventional method and development of a novel flow-cytometric assay.

Serum factors which interact with human peripheral blood lymphocyte Fc gamma receptors (Fc gamma Rs) may be detected in vitro by the EA rosette inhibition assay (EARIA). This assay has been used to detect circulating immune complexes and certain alloantibodies directed against cell surface antigens situated in close proximity to Fc gamma Rs. Three main types of FcR-blocking factor have been demonstrated by the EARIA in human serum following exposure to alloantigens. A strong correlation was observed between the presence of one of these FcR-blocking factors (FcBF1) and human renal allograft survival. This factor was previously shown to bind preferentially to CD32+ B cells and to inhibit antibody synthesis. In this study we have shown that detection of FcBF1 by the EARIA depends on the type of erythrocyte and on the amount of antibody used to sensitise the erythrocytes. Furthermore, we have developed a flow-cytometric version of the EARIA which is rapid, reproducible and, most importantly, objective. Inter-laboratory comparisons using this standardised EARIA should now be possible.

Correlation between high-molecular-weight Fc gamma-receptor-blocking factors in serum and renal allograft survival.

In this study, we have demonstrated the occurrence of IgG class noncytotoxic, lymphocyte Fc gamma-receptor-blocking antibodies in a proportion of sera obtained from transfused uremic patients. The presence of these antibodies was not found to correlate with subsequent renal allograft survival. Serum fractionation studies did however reveal a striking correlation between graft survival and Fc gamma-receptor blocking mediated by a serum factor(s) with a sedimentation coefficient of greater than 19S. The precise nature of this factor remains to be clarified.

In vitro studies on lymphocyte Fc gamma receptor blocking factors in human renal transplantation.

In this study we have confirmed our earlier observation that the presence in pre-transplant serum of a high-molecular-weight lymphocyte Fc gamma receptor blocking factor correlates with improved human renal allograft survival. This factor was found to bind preferentially to B cells and to impair B cell function in vitro.

Role of the adenylate cyclase, phosphoinositidase C and receptor tyrosyl kinase systems in the control of hepatocyte proliferation by hepatocyte growth factor.

Hepatocyte growth factor (HGF) is the most potent known mitogen for hepatocytes in primary culture. However, the mechanisms through which HGF induces hepatocyte proliferation have not been defined. Here we have investigated the role of the adenylate cyclase, phosphoinositidase C and tyrosine kinase signalling systems in the control of hepatocyte proliferation by HGF using freshly isolated or cultured adult rat hepatocytes. We show that human recombinant HGF caused a dose-dependent increase in hepatocyte DNA synthesis with a maximal effect at 10 ng/mL and an EC50 of 5.9 ng/mL. HGF had no effect on hepatocyte adenylate cyclase activity or intracellular cAMP levels. Elevation of hepatocyte cAMP levels resulted in inhibition of HGF-stimulated DNA synthesis. HGF stimulated inositol phospholipid hydrolysis with a maximal effect at 25 ng/mL and potentiated the effect of vasopressin (10(-8) and 10(-9)M). HGF (100 ng/mL) caused an increase in the phosphorylation on tyrosine of an unknown hepatocyte protein with a molecular mass of 36 kDa. Thus, we have shown that HGF, like epidermal growth factor (EGF), can activate the phosphoinositidase C and tyrosine kinase systems in rat hepatocytes. As with EGF, these intracellular signalling systems may underlie HGF-induced hepatocyte proliferation.

A clinicopathological review of 100 cases of primary malignant tumours of the liver.

One hundred cases of primary malignant tumour of the liver coming to necropsy in the period 1900-1969 have been reviewed. The overall tumour incidence was 0.46% of all necropsies. The overall tumour incidence in hepatic cirrhosis was 12.3%, but the corresponding male and female incidences were 17.5 and 4.4% respectively. There was no significantly increased tumour incidence in haemochromatosis. An increasing incidence of primary malignant tumours of the liver has been noted since 1940 and appears to be due to a corresponding increase in incidence of hepatic cirrhosis. Hepatocellular carcinomas outnumbered cholangiocarcinomas by 8 to 1, were more common in males than females (6 to 1), and in 77% of cases occurred in cirrhotic livers. Tumours supervened as a complication of macronodular or predominantly macronodular cirrhotic patterns.

Mallory's ('alcoholic') hyaline in primary biliary cirrhosis.

Mallory's (;alcoholic') hyaline has been found in hepatocytes in 18 of 70 patients with primary biliary cirrhosis. These inclusions have previously been noted in only three cases of primary biliary cirrhosis. Current views on the nature of Mallory's hyaline are briefly discussed.

Hepatic cirrhosis: a clinico-pathological review of 520 cases.

A clinico-pathological review of 520 patients with hepatic cirrhosis coming to necropsy at the Western Infirmary, Glasgow over the period 1900-69 is reported. There has been an overall increase in incidence of cirrhosis since the 1940s, and this has been largely due to a rise in female incidence. A similar trend in the period 1940-71 has been confirmed at a national level in data abstracted from the Annual Reports of the Registrar General for Scotland. The mean age at death has risen for both sexes. Aetiologically, the cirrhosis was alcoholic in 18.5%, posticteric in 10.4%, cryptogenic in 61.9%, and haemochromatosis was diagnosed in 7.5%. Primary malignant tumours of liver supervened in 12.3%. The causes of death and the morphological patterns of the cirrhosis are reviewed.

Hepatic vein lesions in alcoholic liver disease: retrospective biopsy and necropsy study.

Obliteration of the terminal hepatic venules with perivenular fibrosis (phlebosclerosis) is a well recognised feature in alcoholic liver disease. Veno-occlusive lesions with intimal obliteration of hepatic veins and a lymphocytic phlebitis of hepatic veins may also be present. We looked for these lesions in 256 liver biopsies and 50 livers obtained at necropsy from patients with alcoholic liver disease. Phlebosclerosis was a universal finding in alcoholic hepatitis and cirrhosis and showed increasing severity with progressive liver injury. Veno-occlusive lesions, however, were found in only 25 of 256 (9.8%) of biopsies and 11 of 50 (22%) of livers obtained at necropsy, showing alcoholic hepatitis or cirrhosis: lymphocytic phlebitis was found in 10 of 256 (3.9%) and two of 50 (4%), respectively. Moreover, veno-occlusive lesions were generally mild. The prevalence of veno-occlusive lesions and lymphocytic phlebitis was considerably less than has been previously documented. Phlebosclerosis may have a different mechanism and be a more important contributory factor in progressive liver injury.

Liver membrane antibodies in alcoholic liver disease. II. Antibodies to ethanol-altered hepatocytes.

Using an indirect immunofluorescence technique, circulating liver membrane antibodies against normal rabbit hepatocytes and ethanol-altered rabbit hepatocytes have been sought in a series of patients with histologically confirmed alcoholic liver disease. Liver membrane antibodies against normal hepatocytes were found in 18 (28%) of the 65 sera examined, but with ethanol-altered hepatocytes as substrate liver membrane antibodies were found in 48 (74%) of the sera. Isolation of F(ab')2 fragments confirmed that the positive results were due to antibody binding. Liver membrane antibodies against ethanol-altered hepatocytes are peculiar to alcoholic liver disease, and there is a similar incidence in the various histological types of alcoholic liver disease. Absorption studies suggest that the liver membrane antibodies are directed against new or altered antigens which are not present in normal hepatocytes. These new or altered antigens may also appear after pretreatment with other primary alcohols and seem likely to be induced by a haptenic effect of the alcohol or a metabolic break-down product. These studies represent a novel approach to the further investigation of the possible role of immunological mechanisms in alcohol-induced liver injury.

Unusual variant of primary sclerosing cholangitis.

Two cases of primary sclerosing cholangitis are described, in which the characteristic bile duct lesions were unusual because there was an exuberant and exaggerated fibrous replacement of the ducts which produced dense fibrotic scars in portal tracts.

Expression of tissue polypeptide antigen (TPA) in fetal and adult liver: changes in liver disease.

The distribution of tissue polypeptide antigen (40 kD molecular weight) in normal adult and fetal liver, and in liver disease was investigated and compared with the distribution of low and high molecular weight cytokeratins. In normal liver tissue polypeptide antigen was found only in bile duct epithelium; this distribution is similar to that of high molecular weight cytokeratin, but differs from that of low molecular weight cytokeratins. In liver disease it was found in areas of ductular transformation; in Mallory's bodies; and in alcoholic liver disease and primary biliary cirrhosis in some hepatocytes that did not contain Mallory's bodies.

Serological and histological diagnosis of primary biliary cirrhosis.

A simple immunofluorescence test for antibody to a mitochondrial antigen present in many tissues is a reliable method of distinguishing most cases of primary biliary cirrhosis from jaundice due to extrahepatic biliary tract obstruction. Of 30 cases diagnosed as primary biliary cirrhosis, 26 had antimitochondrial antibody whereas none of 77 cases with jaundice due to extrahepatic bile duct obstruction showed this serological abnormality. The antibody was also found in the serum of three of 42 patients who had other forms of cirrhosis and in two of 266 patients with no evidence of liver disease.Clinical, biochemical, and serological findings favour the view that primary biliary cirrhosis is a real entity which, in our present state of knowledge, cannot be defined clearly by any single method of investigation. In particular, the liver may show a variety of histological appearances which, interpreted without regard to the other features of the case, may lead to errors in diagnosis.

A case of longstanding primary sclerosing cholangitis.

A 45-year-old man is described in whom there is currently ERCP and histological evidence of primary sclerosing cholangitis (PSC). A liver biopsy obtained 29 years ago shows similar histological features confirming that he had PSC at that time. This case indicates that PSC may follow a relatively benign course.

Sensitisation to Mallory bodies (alcoholic hyalin) in alcoholic hepatitis.

Using a leucocyte migration inhibition test sensitisation to Mallory bodies (alcoholic hyalin) was found in a statistically significant 41% of 17 patients with alcoholic hepatitis. Patients with alcohol-induced fatty liver and cirrhosis did not demonstrate sensitisation. Mallory bodies are a characteristic feature of alcohol-induced liver damage, and immunological sensitisation to them might lead to liver cell death and cell progression of the hepatitis process.

Post-infantile giant cell hepatitis: histological and immunohistochemical study.

AIM: To determine the composition of the inflammatory infiltrate and to check for the presence of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in nine cases of post-infantile giant cell hepatitis. METHODS: The clinical, serological, and histological features of the nine cases were reviewed. Immunohistochemistry was used on liver biopsy specimens from six cases to: (i) characterise the lymphocytic infiltrate; (ii) assess the monocyte/macrophage response; (iii) detect "activated" perisinusoidal cells; and (iv) detect CMV and EBV antigens. Electron microscopic examination was carried out in two cases. RESULTS: Four patients had serological features suggestive of autoimmune chronic active hepatitis; in the other five cases the aetiology was obscure. Two patients presented with neurological symptoms. Hepatitis resolved completely in one patient; two patients showed clinical improvement; and one remained stable. Cirrhosis developed in three patients, one of whom proceeded to liver transplantation, and three patients died. Portal inflammation was present in all cases and lymphocytic piecemeal necrosis in eight cases, but intra-acinar inflammation associated with hepatocyte necrosis was observed in only five cases. The inflammatory infiltrate was composed predominantly of T lymphocytes; an increase in monocyte/macrophage cells was also observed. Mallory bodies, often with associated neutrophilic infiltrate, were present in four cases, and bilirubinostasis was a feature in four cases. "Activated" perisinusoidal cells were present, especially in relation to areas of inflammation, necrosis, and fibrosis. There was severe fibrosis or cirrhosis in five cases. Paramyxoviral nucleocapsids were not seen in the two cases examined ultrastructurally. CONCLUSIONS: Post-infantile giant cell hepatitis should be viewed as a heterogeneous clinical and aetiological entity encompassing cases of hepatitis with extensive giant cell hepatocyte transformation.

Non-alcoholic steatohepatitis: a common cause of progressive chronic liver injury?

AIM: To investigate the natural history of patients with non-alcoholic steatohepatitis by means of a prospective histological study. METHODS: One thousand five hundred and seventy one patients underwent liver biopsy at the Western Infirmary in Glasgow during the 10 year period 1985 to 1994. All biopsies were reported by a single pathologist: 62 were confirmed as having non-alcoholic steatohepatitis and prospective follow up was conducted in 1999. Repeat liver biopsy was carried out where appropriate to assess disease progression. RESULTS: Initial biopsy scores for the 62 patients (20 men; mean age at biopsy, 52 years) showed a mean of 1.85, 1.39, and 0.5 for necroinflammation, fibrosis, and iron stores, respectively. Forty six were traceable and invited for review, and 26 attended (six men; mean age at initial biopsy, 49.9 years) at a mean of 8.7 years after the initial liver biopsy. No patients had symptoms or signs of chronic liver disease. Four patients had normal liver function tests, one had cirrhosis; the remaining 21 were invited to have a repeat biopsy. Seven patients agreed, a mean 8.2 years after the initial biopsy, and repeat biopsy scores showed no significant difference over this time period, with mean scores of 1.71 (initial score, 2.14), 1.43 (initial score, 0.71), and 0.14 (initial score, 0) for necroinflammation, fibrosis, and iron stores, respectively. CONCLUSION: In this series of patients with non-alcoholic steatohepatitis, with a mean clinical follow up of 8.7 years, and a histological follow up of 8.2 years, there was no evidence of progressive chronic liver injury.

A comparative study of some commercially available tests for rheumatoid factor.

Seven commercially available screening tests for rheumatoid factor and two quantitative tests have been compared with the standard Rose-Waaler test in a series of 477 sera from patients with various joint diseases. Markedly different results were obtained, and on the basis of our findings suggestions are made as to what we consider to be the most satisfactory currently available tests.

Serum protein levels in primary biliary cirrhosis.

Serum levels of albumin, transferrin, alpha(2)-macroglobulin, beta(1)C/beta(1)A, IgA, IgG, and IgM have been determined in 73 patients with primary biliary cirrhosis and in age- and sex-matched controls. A highly significant fall in albumin was demonstrated, and there were highly significant increases in alpha(2)-macroglobulin and all three immunoglobulin levels. Transferrin and beta(1)/Cbeta(1)A levels were unchanged. No significant correlations were found between the titre of antimitochondrial antibody, the duration of symptoms, and any of the serum proteins estimated. A highly significant positive correlation was present between serum albumin and transferrin levels in both patient and control groups.

Serological markers of hepatitis B in patients with alcoholic liver disease: a multi-centre survey.

In a study of 195 patients derived from five centres in northern Britain and with histologically confirmed alcoholic liver disease we have found an increased prevalence of serological markers of hepatitis B. This increased prevalence was found in each of the five centres; the overall frequency ranged from 11% sero-positivity in fatty liver, 12% in alcoholic hepatitis and 27% in cirrhosis.