M.F. Bassendine

Natural history of early primary biliary cirrhosis

BACKGROUND In 1986, we reported a group of 29 patients who were positive in serum for antimitochondrial antibody (AMA), the disease-specific marker for primary biliary cirrhosis (PBC), but who had normal liver function test results and no symptoms of liver disease. However, liver histology was diagnostic or compatible with PBC in 24 patients and normal in only two. The aims of this 10-year follow-up study were to establish whether patients with AMA have very early PBC, to assess the outlook for such patients, and to follow the progression of the disease. METHODS All patients were assessed every year at our PBC clinic: records were reviewed, cause of death verified when applicable, and current clinical and biochemical data collected, including repeat liver histology as indicated. Serum samples from the original study were located. Original and follow-up serum samples were tested by ELISA for E2 components of pyruvate dehydrogenase complex and 2-oxoglutarate dehydrogenase complex. FINDINGS Five patients died during follow-up; no deaths were attributable to liver disease. Median follow-up of patients who survived was 17.8 years (range 11.0-23.9) from first-detected AMA to the last follow-up review. Overall, 22 (76%) developed symptoms of PBC and 24 (83%) had liver function tests persistently showing cholestasis. Repeat liver biopsy samples were obtained from ten patients; among these patients PBC progressed from Scheuer grade 1 to grade 2 in two and from grade 1 to grade 3 in two. No patient developed clinically apparent cirrhosis. ELISA of baseline serum samples from 27 patients was positive in 21, all of whom had original liver histology compatible with or diagnostic of PBC. Of the six patients who tested negative, only one had an original liver biopsy sample that was compatible with PBC. INTERPRETATION This study confirms that before the advent of any clinical or biomedical indications, individuals positive for AMA do have PBC. This finding extends the natural history of PBC back in some cases for many years. What determines the eventual progression to biochemically and clinically apparent disease is not yet understood. During our study no patient developed clinically apparent portal hypertension or cirrhosis. Thus, although the finding of a solitary persistently raised AMA is confirmation of a diagnosis of PBC, patients with AMA but no other signs or symptoms of PBC seem to have slow progression of the disease.

Familial primary biliary cirrhosis reassessed: a geographically-based population study

BACKGROUND/AIMS Development of primary biliary cirrhosis in the close relatives of patients with the disease has been reported in several series, suggesting a genetic component to disease susceptibility. In this study we set out to calculate, as accurately as possible, the prevalence of familial primary biliary cirrhosis in a geographically-based population. Using local population prevalence data, we have also calculated the first-degree relative, sibling and offspring relative risks of overt primary biliary cirrhosis development. METHODS All patients with definite or probable primary biliary cirrhosis in the city of Newcastle-upon-Tyne, England, were identified by an exhaustive case-finding search and were prospectively interviewed by a single investigator. Full details of family pedigree and familial primary biliary cirrhosis history were obtained. RESULTS One hundred and seventy-three patients were identified, with 160 participating in the study. Thirteen reported a family history of primary biliary cirrhosis. In three cases, both relative pairs were within the study group. The prevalence of a positive family history of primary biliary cirrhosis was therefore 10/157 (6.4% [95% Confidence Interval 2.6-10.2%]), 8/10 cases occurring in first-degree relatives. The patients had a total of 1118 first-degree relatives (live or dead) and 468 siblings. The first-degree relative prevalence of primary biliary cirrhosis was 0.72% [0.2-1.2%] (siblings 0.41% [-0.2-1.0%]). The offspring prevalence was 1.2% [0.04-2.4%], (2.3% [0.1-4.5%] for daughters). The sibling relative risk (lambda(s)) was 10.5. CONCLUSIONS The overall prevalence of definite or probable primary biliary cirrhosis in the first-degree relatives of existing patients is <1%. The risk of disease is not, however, uniform, the highest prevalence being seen in the daughters of patients. Suspicion of disease should therefore be highest in this relative group. The calculated lambda(s) for primary biliary cirrhosis in this geographically-based study is significantly lower than previous estimates from case-note-derived case series, but similar to values seen in other autoimmune diseases.

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: A large-scale study†

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA‐DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well‐characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA‐DRB1*0801 in both groups of patients compared to population‐specific healthy controls (12% versus 4% in the UK patients, P = .00087, OR = 3.05; and 18% versus 6% in the Italian patients, P = .021, OR = 3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P = .0071, OR = 0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P = .042, OR = 0.65 in the UK patients; and 10% versus 31%, P = .00092, OR = 0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific. (HEPATOLOGY 2006;44:667–674.)

A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage

Background—Few studies have compared vasoactive drugs with endoscopic sclerotherapy in the control of acute variceal haemorrhage. Octreotide is widely used for this purpose, but its value remains undetermined. Aims—To compare octreotide with endoscopic sclerotherapy for acute variceal haemorrhage. Patients—Consecutive patients with acute variceal haemorrhage. Methods—Patients were randomised at endoscopy to receive either a 48 hour intravenous infusion of 50 μg/h octreotide (n=73), or emergency sclerotherapy (n=77). Results—Overall control of bleeding and mortality was not significantly different between octreotide (85%, 62 patients) and sclerotherapy (82%, 63 patients) over the 48 hour trial period (relative risk of rebleeding 0.83; 95% confidence interval (CI) 0.38 to 1.82), irrespective of Child’s grading or active bleeding at endoscopy. One major complication was observed in the sclerotherapy group (aspiration) and two in the octreotide group (pulmonary oedema, severe paralytic ileus). During 60 days of follow up there was an overall trend towards an increased mortality in the octreotide group which was not statistically significant (relative risk of dying at 60 days 1.91, 95% CI 0.97 to 3.78, p=0.06). Conclusions—The results of this study indicate that intravenous octreotide is as effective as injection sclerotherapy in the control of acute variceal bleeding, but further controlled trials are necessary to evaluate the safety of this treatment.

Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels

Background and aim: Fatigue is the commonest symptom in primary biliary cirrhosis (PBC), affecting individuals at all stages of disease. The pathogenesis of fatigue in PBC is unknown although rat models suggest a central nervous system (CNS) cause. We examined the hypothesis that a CNS abnormality related to cholestasis, rather than cirrhosis per se, underlies this symptom. Patients and methods: Fourteen patients with precirrhotic PBC (stage I–II disease), four patients with stage III–IV PBC, and 11 healthy women were studied using cerebral magnetisation contrast imaging and proton magnetic resonance spectroscopy (MRS). Results: The globus pallidus magnetisation transfer ratio (MTR), a quantifiable tissue characteristic that may be abnormal in the presence of normal magnetic resonance imaging, was significantly reduced in precirrhotic PBC patients compared with healthy controls. These measurements correlated with blood manganese levels and were more abnormal in the more fatigued subjects. There were no differences in MRS measurements between the three study groups, suggesting that the abnormal MTR was not related to hepatic encephalopathy. Conclusion: This study suggests that impairments in liver function in PBC may adversely affect the brain long before the development of cirrhosis and hepatic encephalopathy, possibly as a result of altered manganese homeostasis within the CNS.

Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease

Background—Iron overload is common in the livers of alcoholics and may play a role in disease pathogenesis. An MHC like gene, HFE,has recently been identified that is mutated in most patients with hereditary haemochromatosis (C282Y in 90% and H63D in 45% of the remainder). Aim—To examine the hypothesis that these mutations determine hepatic iron status in alcoholics and play a role in predisposition to advanced alcoholic liver disease. Methods—TheHFE gene was genotyped in 257 patients with alcoholic liver disease and 117 locally matched healthy volunteers. In addition, iron staining was scored (0–4) on biopsy specimens from fibrotic/cirrhotic patients with and withoutHFE mutations matched for age and sex. Results—Some 15.7% of fibrotic/cirrhotic patients were C282Y heterozygotes compared with 13.7% of controls (p = 0.77). One control and three patients were C282Y homozygotes. Of chromosomes without the C282Y mutation, 68/442 (15.4%) of patients’ chromosomes carried the H63D mutation compared with 36/216 (16.6%) of control chromosomes (p = 0.91). Significant (>grade 1) hepatocyte iron staining was seen in 6/23 C282Y heterozygotes and 4/26 H63D heterozygotes compared with 4/23 controls. Conclusions—Possession of a single copy of either of the two HFEmutations influences neither liver iron content nor the risk of fibrotic disease in alcoholics.

Hepatitis C virus: epidemiology and genotypes in the north east of England.

The epidemiology of hepatitis C virus (HCV) infection was studied in an English teaching hospital over an 18 month period. A total of 104 HCV antibody positive patients were referred for further investigation. They were divided into those diagnosed through screening (blood donors and intravenous drug abusers) and those diagnosed for other reasons, and their mean ages, known risk factors for HCV transmission, genotypes, and liver biopsy histology were analysed. Screened patients were significantly younger than the others. No significant difference in age was found between genotypes. Most patients genotyped (69%) were genotype 1. Intravenous drug abusers had a higher proportion of subtype 1a, and patients who acquired HCV through blood transfusion had a higher proportion of subtype 1b. Liver biopsy specimens were scored using a histological activity index for liver inflammation and fibrosis. Patients with subtype 1b had significantly more severe liver disease than other genotypes when the histological activity index scores for fibrosis were analysed (p < 0.05). Liver disease worsened significantly with age according to all three histological activity index scores (portal activity: p < 0.01, acinar activity: p < 0.001, fibrosis: p < 0.0001). Liver disease worsened with increased duration of infection (p < 0.002), and patients who also abused alcohol presented at a significantly younger age (cirrhosis, p < 0.05, hepatocellular carcinoma, p < 0.02).

Apolipoprotein ε3 allele is associated with persistent hepatitis C virus infection

Background: Host genetic factors may significantly influence the ability to clear hepatitis C virus (HCV) following infection. HCV is associated with very low density lipoproteins (VLDL) and low density lipoproteins (LDL) in the host’s circulation. Apolipoprotein E (APOE) is found in VLDL and binds to potential receptors involved in HCV entry into cells, the LDL receptor, and the scavenger receptor protein SR-B1. The APOE gene is polymorphic with three alleles coding for three isoforms: Apo-ε2, Apo-ε3, and Apo-ε4. The aim of this study was to assess if these functional polymorphisms determine disease outcome in HCV infected individuals. Methods: The APOE genotype was determined in 420 Northern European patients with evidence of exposure to HCV. Genotype and allele distribution were compared with those of 288 healthy controls and progression of liver disease and viral clearance were analysed according to APOE allele status. Results: The APOE*E2 and APOE*E4 alleles were both associated with a reduced likelihood of chronic infection (odds ratio (OR) 0.39 (95% confidence interval (CI) 0.211–0.728), p = 0.003; and OR 0.6 (95% CI 0.38–0.96), p = 0.032) and there was a notable absence of the E2E2 genotype in the HCV antibody positive group compared with the control population (p = 0.0067). Overall the genotypes carrying the E2 allele (E2,E3 and E2,E4) were associated with the equivalent of a 3–5-fold reduction in the risk of chronic HCV infection (genotype relative risk 0.36 and 0.20, respectively). Conclusion: This study indicates that functional APOE gene polymorphisms may be a determinant of outcome in HCV infection. We hypothesise that the E2 allele may protect against viral persistence via defective binding of HCV lipoviral particles to the cellular receptors involved in entry of these infectious particles.

Tumour necrosis factor-a promoter polymorphisms in primary biliary cirrhosis

Abstract Background/aims : The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives of patients, suggesting that genetic factors play a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-α has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-α gene, which may play a role in the control of TNF-α secretion, as candidate susceptibility loci in PBC. Methods : The polymorphisms at positions −238 and −308 in the TNF-α promoter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individuals. All PBC subjects were also genotyped for HLA DR8, a previously identified susceptibility locus in PBC. Results : The −308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%). However, this genotype was found significantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls ( p p =0.001 OR 3.1 [1.6–5.9]). Linkage between TNF −308 and HLA DR8 was not seen. No association was found between PBC and the biallelic −238 TNF-α polymorphism, either in the whole PBC population or the histological Stage III/IV subgroup. Conclusions : Our study provides no evidence for involvement of the TNF-α −308 or −238 promoter polymorphisms in genetic predisposition to PBC. However, the significantly increased frequency of the −308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility. The finding of different allele frequencies in PBC patients in different disease subgroups emphasises the importance of clinical phenotype/case-mix in the design of disease association studies.

Non-Hodgkin's Lymphoma and Hepatitis C Virus Infection

The hepatitis C virus (HCV) is a recently described and important cause of acute and chronic liver disease. A hallmark of HCV is its propensity to become chronic, some patients with chronic HCV progressing to cirrhosis and hepatocellular carcinoma (HCC). HCV is also lymphotrophic and we report 2 patients with HCV cirrhosis who developed non-Hodgkins lymphoma (NHL). These cases raise the possibility that chronic HCV infection of lymphocytes plays an aetiological role in this malignancy. However screening of a further 63 consecutive patients over the age of 50 years with NHL for HCV antibody by second generation enzyme linked immunoassay (ELISA) failed to identify any patients with evidence of HCV infection. This suggests that HCV is an uncommon contributory factor for the development of non-Hodgkins lymphoma in the United Kingdom.