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Biomedical subjects

I G McFarlane

Publications and source records attributed to I G McFarlane.

At least 19 recordsLinked to original sources
PubMed2002

Characteristics of autoimmune hepatitis in patients who are not of European Caucasoid ethnic origin.

BACKGROUND: Significant diversity in disease severity has been identified for autoimmune disorders among different ethnic groups but there is a lack of data on autoimmune hepatitis (AIH) in populations other than those of European Caucasoid (EC) or Japanese extraction. AIMS: To assess the clinical features, response to therapy, and eventual outcome in AIH patients of non-EC ethnicity. METHODS: A retrospective review of a regularly updated database of patients with AIH referred to liver outpatient clinics at King's College Hospital, London, since 1983. RESULTS: Twelve patients were identified (10 female; six African, five Asian, one Arabic; median age at presentation 30 years (range 12-58)) who satisfied international criteria for type 1 (11 cases) or type 2 (one case) AIH. Nine (75%) had cholestatic serum biochemistry and three (25%) had mild biliary changes on liver biopsy without definitive features of primary biliary cirrhosis or cholangiographic evidence of primary sclerosing cholangitis. Four showed a complete biochemical response to standard prednisolone with or without azathioprine therapy, three partial, and five no response. Four have required liver transplantation for intractable disease. By comparison with 180 EC patients with definite AIH attending during the same period, the non-EC patients were younger (p<0.05), presented with cholestatic biochemistry (p=0.014), and morphological biliary features more frequently (p<0.0005) and showed a poorer initial response to standard therapy (p<0.0005). CONCLUSIONS: Clinical expression of AIH in non-EC patients seems to differ in important respects from that in EC or Japanese patients. Management of such patients is challenging and may require alternative or more aggressive treatment strategies.

Adolescent↗
PubMed2001

Management and outcome of pregnancy in autoimmune hepatitis.

BACKGROUND: There is a paucity of data in the literature on the risks associated with, and optimal management of, pregnancy in patients with autoimmune hepatitis (AIH). AIMS: To assess maternal and fetal outcomes in relation to clinical management of pregnancy in a large cohort of patients with well defined AIH. METHODS: A review of all known pregnancies in 162 females with definite AIH attending our clinics between 1983 and 1998, with respect to treatment, natural history, and outcome. RESULTS: Thirty one live births (one twin) resulted from 35 pregnancies in 18 women (seven with cirrhosis). Median age at conception was 28 years (range 18-36). Two patients presented with AIH de novo during pregnancy. At conception, in 15 pregnancies patients had been receiving azathioprine alone or (in nine) with prednisolone, in seven prednisolone alone, and in one cyclosporin. Fetal loss at > or =20 weeks' gestation occurred in two instances. Flares in disease activity occurred during four pregnancies and within three months of delivery in a further four. Among the 31 children born (median follow up 10 years) only two abnormalities have been identified: Perthes' disease in one and severe mental and physical handicap in a second who was born prematurely following decompensation of the mother's liver disease. Neither mother was receiving azathioprine. CONCLUSIONS: Successful completion of pregnancy is a realistic expectation for patients with well controlled AIH. Treatment options vary, but azathioprine appears to be generally safe and without adverse outcomes for mother or baby. Vigilance is required, however, and patients need to be monitored carefully during pregnancy and for several months post partum.

Adolescent↗
PubMed2001

Autoimmune hepatitis: Clinical manifestations and diagnostic criteria.

In 1998, the International Autoimmune Hepatitis Group--a panel of 40 hepatologists and hepatopathologists from 17 countries who have a particular interest in autoimmune hepatitis (AIH)--undertook a review, in light of subsequent experience, of the descriptive criteria and diagnostic scoring system that it had proposed in 1993 for the diagnosis of AIH. This review (published in 1999) noted that the original descriptive criteria appeared to be quite robust and required only relatively minor modifications to bring them up to date with developments and experience in diagnostic modalities for liver disease in general. Analysis of published data on the application of the original criteria in nearly 1000 patients revealed that the diagnostic scoring system had an overall diagnostic accuracy of 89.8%, with a sensitivity of 98.0%. Specificity for excluding definite AIH in patients with chronic viral hepatitis and circulating autoantibodies or patients with overlapping cholestatic syndromes was 98% to 100%, but specificity for excluding probable AIH in these disorders ranged from only 60% to 80%. Modifications, including adjustments to the weightings against biochemical and histological cholestatic features, have been made to the scoring system to improve its specificity.

Chronic Disease↗
PubMed2001

Autoimmune liver diseases.

The differential diagnosis of the three disorders that are usually classified as autoimmune liver diseases, namely autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), requires careful exclusion of other causes of chronic liver disease together with the finding of suggestive patterns of abnormalities of serum biochemical parameters, immunoglobulin isotypes and 'conventional' non-organ-specific autoantibodies. Antimitochondrial antibodies (particularly those reacting with epitopes on the E2 components of the pyruvate dehydrogenase and other 2-oxo-acid dehydrogenase complexes), and some sub-specificities of antinuclear antibodies, are virtually pathognomonic of PBC. Anti-liver-kidney microsomal antibodies reacting with defined epitopes on the cytochrome isoform P4502D6 are relatively specific for a small sub-group of (so-called 'type 2') AIH. However, most of the other serological parameters lack specificity. Additionally, within and between each disease group there is wide variability, even among patients with comparable severity of liver damage. Thus, in many cases, liver histology and/orcholangiography is still required for definitive diagnoses or for assessing stage and severity of these disorders. A number of autoantibodies that are more directly related to the liver than the 'conventional' autoantibodies are showing promise as possibly more specific diagnostic markers of AIH. Commercial tests for some of these are under development and it is hoped that they will soon become widely available.

Autoantibodies↗
PubMed2000

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland.

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.

Adult↗
PubMed1999

Pathogenesis of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is an idiopathic disorder affecting the hepatic parenchyma. There are no morphological features that are pathognomonic of the condition but the characteristic histological picture is that of an interface hepatitis without other changes that are more typical of other liver diseases. It is associated with hypergammaglobulinaemia, high titres of a wide range of circulating auto-antibodies, often a family history of other disorders that are thought to have an autoimmune basis, and a striking response to immunosuppressive therapy. The pathogenetic mechanisms are not yet fully understood but there is now considerable circumstantial evidence suggesting that: (a) there is an underlying genetic predisposition to the disease; (b) this may relate to several defects in immunological control of autoreactivity, with consequent loss of self-tolerance to liver auto-antigens; (c) it is likely that an initiating factor, such as a hepatotropic viral infection or an idiosyncratic reaction to a drug or other hepatotoxin, is required to induce the disease in susceptible individuals; and, (d) the final effector mechanism of tissue damage probably involves auto-antibodies reacting with liver-specific antigens expressed on hepatocyte surfaces, rather than direct T-cell cytotoxicity against hepatocytes.

Animals↗
PubMed1999

ANCAs away.

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Antibodies, Antineutrophil Cytoplasmic↗
PubMed1998

Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases.

OBJECTIVE: We report five cases (four male; median age 20 yr, range 14-38 yr) of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. The patients presented with jaundice, elevated serum aminotransferase and alkaline phosphatase activities, hyperglobulinemia with high immunoglobulin G (IgG) levels, circulating antinuclear and/or smooth muscle autoantibodies (> or = 1:40), and moderate to severe interface hepatitis on liver biopsy (with biliary features in four). METHODS: All five fulfilled criteria for diagnosis of "definite" autoimmune hepatitis and showed marked responses to prednisolone and azathioprine therapy, with relapses occurring during reduction or withdrawal of treatment. Cholangiographic features of primary sclerosing cholangitis were found in three patients at presentation and after intervals of 7 and 14 yr in the other two. Only two had evidence of inflammatory bowel disease. Diagnostic criteria for identifying those patients who may benefit from immunosuppressive therapy were reviewed. RESULTS: Review of the literature revealed only 11 similar cases that were sufficiently well described for comparison. However, in contrast to these and the present cases, preliminary data from other studies have suggested a marked association with ulcerative colitis and a poor response to immunosuppressive therapy. CONCLUSIONS: It is recommended that the possibility of an autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome responsive to immunosuppressive therapy should be considered in any patient presenting with a hepatitic illness with hyperglobulinemia, antinuclear or smooth muscle autoantibodies, and biliary changes on liver biopsy. Cholangiography should be considered in such patients.

Adolescent↗
PubMed1997

Alcohol dehydrogenase: a target of humoral autoimmune response in liver disease.

BACKGROUND & AIMS: Liver-specific membrane lipoprotein (LSP) is a heterogeneous liver preparation that has been widely used to study autoreactivity in liver disease. The aim of this study was to identify autoantigens in LSP. METHODS: Guinea pig anti-LSP serum was used to screen a human liver complementary DNA (cDNA) library. Humoral immune responses to isolated potential autoantigens were investigated by immunoblotting in 91 pediatric patients with various liver diseases, 20 adult patients with alcoholic liver disease and 20 with autoimmune thyroid disease, 37 healthy children, and 20 healthy adults. RESULTS: A 1.6-kilobase cDNA insert isolated from the cDNA library was found to encode amino acids 61-374 of the human alcohol dehydrogenase (ADH)-gamma 1 subunit. Antibodies to this or other ADH subunits were found significantly more frequently in autoimmune liver diseases (19 of 39 patients; 49%), Wilson's disease (5 of 13 patients; 38%), and alcoholic liver disease (10 of 20 patients; 50%) than in normal controls (P < 0.0001, P < 0.005, and P < 0.05, respectively) and correlated with disease activity in autoimmune liver disease. CONCLUSIONS: ADH has been identified as a new antigenic component of the LSP using a xenogeneic antiserum to immunoprobe a human cDNA liver library and seems to be a target autoantigen in liver disease. This approach may be useful in identifying other potential autoantigens.

Adolescent↗
PubMed1997

Screening of hepatoprotective plant components using a HepG2 cell cytotoxicity assay.

Identification of the active components of plants with hepatoprotective properties requires screening of large numbers of samples during fractionation and purification. A screening assay has been developed based on protection of human liver-derived HepG2 cells against toxic damage. Various hepatotoxins were incubated with HepG2 cells in 96-well microtitre plates (30,000 cells well-1) for 1 h and viability was determined by metabolism of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS). Bromobenzene (10 mM) and 2,6-dimethyl-N-acetyl-p-quinoneimine (2,6-diMeNAPQI, 200 mM) had greater toxic effects than tert-butyl hydroperoxide (1.8 mM) or galactosamine (10 mM), reducing mean viability to 44.6 +/- 1.2% (s.e.m.) and 56.1 +/- 2.1% of control, respectively. Protection against toxic damage by these agents was tested using a crude extract of a known hepatoprotective Sri Lankan plant, Osbeckia aspera, and two pure established hepatoprotective plant compounds, (+)-catechin and silymarin (1 mg mL-1). Viability was significantly improved by Osbeckia (by 37.7 +/- 2.4%, P < 0.05, and 36.5 +/- 2.1%, P < 0.05, for bromobenzene and 2,6-diMeNAPQI toxicity, respectively). Comparable values for (+)-catechin were 68.6 +/- 2.9% and 63.5 +/- 1.1%, and for silymarin 24.9 +/- 1.4% and 25.0 +/- 1.6%. This rapid and reproducible assay should prove useful for the isolation and identification of active hepatoprotective compounds in crude plant extracts.

Bromobenzenes↗
PubMed1995

Protective effects of Osbeckia octandra against galactosamine and tert-butyl hydroperoxide induced hepatocyte damage.

Ayurvedic and other 'traditional' medical practitioners in Sri Lanka use the mature leaves of the plant Osbeckia octandra for its hepatoprotective properties. In this study the effects of an aqueous extract of Osbeckia octandra against injury induced by D-galactosamine and tert-butyl hydroperoxide (TBH) were investigated in freshly isolated rat hepatocytes. The plant extract (500 micrograms/ml) significantly reduced the inhibition of protein synthesis (as assessed by the incorporation of 14C-leucine into protein) in hepatocytes incubated for 1 h with 10 mM galactosamine by a mean of 25.6 +/- 3.6% and decreased the release of cellular lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzyme activities into the medium by 55.3% and 32.8%, respectively. With TBH, the plant extract decreased lipid peroxidation (estimated from malondialdehyde formation) by a mean of 29.9 +/- 1.1% together with a 46.8% and 54.7% decrease in the release of LDH and AST, respectively into the incubation medium. Significant protection was also obtained when the Osbeckia extract was added to the incubation medium up to 30 min after pre-exposure of the hepatocytes to either galactosamine or, to a lesser extent, TBH. The results support the use of Osbeckia as a hepatoprotective agent.

Animals↗
PubMed1995

Azathioprine for long-term maintenance of remission in autoimmune hepatitis.

BACKGROUND: In most patients with autoimmune hepatitis, remission can be maintained with prednisolone, usually in combination with azathioprine, but the majority of patients have a relapse when treatment is stopped and therefore require long-term therapy. Because prolonged corticosteroid therapy may have serious toxic effects, in 1984 we undertook a controlled trial of maintenance therapy with azathioprine alone. None of the 25 patients in that trial had relapses during the follow-up period of one year. We have now followed these 25 patients for 10 years and have treated an additional 47 patients in a similar manner. METHODS: The 72 patients (median age, 47 years; range, 14 to 71) had been in complete remission for at least one year with 5 to 15 mg of prednisolone per day and 1 mg of azathioprine per kilogram per day. The dose of azathioprine was increased to 2 mg per kilogram per day, and the prednisolone was gradually withdrawn. Remission was defined as the absence of symptoms suggestive of a relapse and serum globulin and aspartate aminotransferase concentrations within the normal range, with or without a liver biopsy showing only minimal inflammation. RESULTS: Sixty patients (83 percent) remained in remission while receiving azathioprine alone for a median of 67 months (range, 12 to 128). Of 48 follow-up liver biopsies in 42 patients, 45 showed inactive or minimal disease, and 3 showed moderate disease (2 after one year of therapy and 1 after eight years). After the prednisolone had been withdrawn, 26 patients lost their cushingoid facies, and 32 patients lost weight (median loss, 6.4 kg; range, 1.5 to 22.3). The most common adverse effect was arthralgia (in 38 patients). With the higher dose of azathioprine, four patients had myelosuppression, defined as a decrease in the leukocyte and platelet counts to less than 4000 and 150,000 per cubic millimeter, respectively. Two of these patients (both with pancytopenia) relapsed when the azathioprine was withdrawn; in the other two, remission was maintained with the resumption of prednisolone. Lymphopenia developed in 32 of 56 patients treated with 2 mg of azathioprine per kilogram per day for more than two years. During follow-up, nine patients died: one of liver failure and eight of causes not directly related to their liver disease. CONCLUSIONS: Many patients with autoimmune hepatitis who have been in complete remission for at least one year with prednisolone and azathioprine can remain in remission with a higher dose of azathioprine alone.

Adolescent↗
PubMed1995

Effects of ribavirin on intrahepatic and extrahepatic expression of hepatitis C virus in interferon nonresponsive patients.

Response to ribavirin therapy (1,000-1,200 mg/day for 6 months) was evaluated in nine patients with chronic hepatitis C virus (HCV) infections who had previously failed to respond to a 6-month course of alpha-interferon. All had chronic active hepatitis with elevated serum aminotransferase activities (mean +/- SD = 138 +/- 66IU/I). During ribavirin therapy, three showed a complete response (normalized serum aminotransferase), although in one patient this returned to the pretreatment level 2 months after treatment was stopped. Three others showed a partial response (serum aminotransferase reduction by > or = 50%) and the remainder showed no response. There were no consistent changes in HCV-RNA (positive strand) in serum, liver, or peripheral blood mononuclear cells during therapy, but two patients lost HCV-RNA from serum and three of five patients with negative strand HCV-RNA in their livers lost this putative replicative form of the virus. The findings suggest that ribavirin may exert its effects by suppressing viral replication rather than by eradicating the virus, at least in this group of patients, and that the drug may have some benefit in selected cases of chronic hepatitis C that are resistant to interferon. However, peripheral blood mononuclear cells represent a major extrahepatic reservoir of HCV and the present regimen of ribavirin therapy did not significantly affect this situation. More prolonged therapy may be required to eradicate the virus from this large pool of cells with the potential to continually reinfect the liver.

Adult↗
PubMed1995

Hepatitis C virus infection in Schistosomiasis mansoni in Brazil.

The involvement of the hepatitis C virus (HCV) in the severity of liver disease in chronic schistosomiasis was investigated in 215 Brazilian patients with S. mansoni infections, but without evidence of hepatitis B surface antigen (HBsAg). Forty-three had hepatointestinal (HIS) and 172 had hepatosplenic schistosomiasis (HSS), and 135 had compensated (HSSC), and 37 had decompensated (HSSD) liver disease. Fifty-two (24%) were found to have evidence of HCV infection (seropositive for anti-HCV antibodies and/or HCV-RNA). These comprised 35 (95%) of the 37 with HSSD, 16 (12%) of the 135 with HSSC, and 1 (2.4%) of the 43 with HIS, compared with only 1 (2%) of 50 control patients without S. mansoni. Testing of matched liver tissue and peripheral blood mononuclear cells (PBMCs) from 25 patients (6 HSSC and 19 HSSD) with HCV infections showed that 17 (68%) had "active" viral infections, in that negative strand HCV-RNA (the presumed replicative intermediate of the virus) could be detected in liver and/or PBMCs. Among these 25, negative strand HCV-RNA was found in 16 (84%) of the 19 with chronic active hepatitis, but in only 1 (17%) of the 6 with mild or inactive disease (P < 0.01). HCV-RNA was detected in matched spleen specimens from 9 of 10 patients (all of whom were also positive in PBMCs), suggesting that the spleen is an important extrahepatic reservoir of the virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗