Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients.

BACKGROUND: Chronic hepatitis B infection (CHB) is a major health problem in Australia and worldwide. CHB is associated with significant long-term morbidity and mortality. Well tolerated treatment is now available, however the development of resistance is common and the optimal timing of treatment is yet to be determined. Identifying the factors that influence the natural history of CHB may help determine which patients need treatment and when to start it. OBJECTIVE: To determine the demographics, clinical features and virological profile of Australian patients infected with CHB and the influence of these factors on disease activity and severity. STUDY DESIGN: Review of prospectively collected demographic, clinical and virological features of all patients positive for hepatitis B surface antigen (HBsAg) for more than 6 months who were referred to St. Vincent's Hospital liver clinics. Age, sex and ethnicity were correlated with hepatitis B e antigen status (HBeAg), HBV replication status (ALT and HBV DNA), genotype and liver histology. RESULTS: 703 chronic hepatitis B surface antigen positive patients were identified. The patients were predominantly male with an average age of 44. Eighty two percent of patients were born overseas, primarily from Asian (65%) and Mediterranean countries (14%). Two thirds (426) had an elevated ALT (median 79) at presentation. HBeAg was positive in 37%. Active viral replication, defined as abnormal ALT or positive HBVDNA, was present in 74%, 48% of whom were HBeAg negative. In a subset of 103 patients genotyped, 8% had genotype A, 29% B, 41% C and 22% D. Genotype correlated with ethnicity; patients infected with genotypes A were predominantly Caucasian, B and C were Asian, and D were Mediterranean. Of 296 (42%) patients who underwent liver biopsy, 76 (27%) had advanced fibrosis. Advanced fibrosis was associated with increasing age and Mediterranean ethnicity. CONCLUSION AND RECOMMENDATIONS: Perinatal or early childhood transmission is predominant mode of infection in Australia. Two thirds of this cohort had active replication and were at increased risk of developing cirrhosis and/or hepatoma. Advanced disease was associated with age and ethnicity. HBeAg negative CHB accounts for almost half of all those with active viral replication. This parallels the rise in this form of CHB in Asia and the Mediterranean basin. Screening should be offered to people born in, or with parents born in areas of high endemnicity. To detect the development of active disease, patients with positive HBsAg but normal ALT should have liver function tests done 6 monthly and those with elevated ALT should be referred for consideration of therapy, irrespective of HBeAg status.

Changes in hepatitis C-related liver disease in a large clinic population.

BACKGROUND: Hepatitis C virus (HCV) infection is a significant problem in the Australian community. Over the past few years, the number of patients with diagnosed hepatitis C has increased greatly. The aims of the present study were to define the clinical features of a large group of patients with chronic HCV infection and to examine changes occurring in the referral base and epidemiological characteristics of this group since analysis of the first 342 patients in 1994. METHODS: The study included 1,546 consecutive anti-HCV-positive patients who had been referred to St Vincent's Hospital from January 1990 to June 1998. Clinical and laboratory data were collected on all patients. RESULTS: Referrals from general practitioners increased from 31% to 70% of all patients between 1990-1993 and 1994-1998. A history of injecting drug use (IDU) was present in 64% of the patients. While 89% of the IDU group was Australasian born, 49% of those in the sporadic group were born overseas. Cirrhosis was found in 18% of biopsied patients. Age, infection duration, age at infection, Mediterranean or Asian origin and a history of transfusion or lack of HCV risk factors were associated with cirrhosis on univariate analysis. Patient age was the only independent predictor of cirrhosis. CONCLUSION: The majority of patients with HCV are diagnosed in general practice. A risk factor for infection is identified in 82% of patients. While our reported prevalence of cirrhosis may be an overestimate of that in the overall HCV community, the ultimate disease burden is likely to be significant.

Role of alcohol in the progression of liver disease caused by hepatitis C virus infection.

In patients with chronic hepatitis C, alcohol consumption has been proposed as a risk factor for the progression of liver disease; however, evidence for this remains conflicting. Two hundred thirty-four anti-hepatitis C virus (HCV)-positive patients who had a liver biopsy performed within the past 24 months were studied. Demographic data and information on risk factors were recorded. A detailed lifetime alcohol consumption history was obtained. Viral studies included HCV viral titer and HCV genotype. Mean age (+/- SEM) of the group was 40.8 +/- 0.7 years. One hundred sixty-six (71%) were male. A risk factor for HCV infection was found in 195 patients (86%). Genotype distribution was: 1b: 22%; 1a: 15%; 1(nonsubtypable): 15%; 3a: 34%; and 2: 7%. Fifty (21%) patients had cirrhosis. Patients with cirrhosis were older (51.6 +/- 1.8 years) than those with chronic hepatitis (37.6 +/- 0.6 years; P = .0001), were infected at an older age (25.9 +/- 2.0 vs. 20.9 +/- 0.6 years; P = .001), and had a longer duration of infection (20.5 +/- 1.3 vs. 16.2 +/- 0.5 years; P = .0008). Patients with cirrhosis had a greater total lifetime alcohol consumption (288,765 +/- 58,115 g) than those with chronic hepatitis (189,941 +/- 15,453 g; P = .018). Cirrhotic patients also had greater total alcohol consumption during the period of infection with HCV (240,962 +/- 63,756 g vs. 146,510 +/- 12,862 g; P = .02). On multivariate analysis, subject age and total alcohol consumption were independently associated with the presence of cirrhosis. Total lifetime alcohol consumption is a risk factor for the progression of liver disease caused by HCV.

Preventing endoscopic retrograde cholangiopancreatography related sepsis: a randomized controlled trial comparing two antibiotic regimes.

Current antibiotic prophylaxis for endoscopic retrograde cholangiopancreatography (ERCP) is not standardized and may be inadequate. We aimed to evaluate the efficacy of 3 days of additional oral antibiotics in the prevention of ERCP-related sepsis. One hundred and fifty-six patients were randomized prospectively to receive either intravenous ticarcillin and clavulinic acid (Timentin; SmithKline Beecham, Dandenong, Victoria, Australia), pre-ERCP (group I) or Timentin and 3 days of oral amoxycillin and clavulinic acid (Augmentin; SmithKline Beecham, Dandenong, Victoria, Australia), group II). Blood cultures were taken 30 min after the procedure. The occurrence of sepsis, defined as a temperature over 38 degrees C, occurring in the first 7 days was recorded and the risk factors for the development of sepsis were evaluated. Four patients had significant positive blood cultures despite the prior administration of Timentin. Sepsis occurred in 10% of group I patients, but only 3% of group II patients (relative risk 3.30; 95% confidence intervals 0.74-14.8). The performance of sphincterotomy and the presence of common bile duct stones were significant risk factors for the development of sepsis. We would recommend 3 days of additional oral Augmentin after a single dose of intravenous antibiotics in patients at increased risk of sepsis, which would include those with bile duct stones and/or those undergoing a therapeutic procedure.

Preclinical trial of a bioartificial liver support system in a porcine fulminant hepatic failure model.

BACKGROUND: This study describes the pre-clinical trials of an extracorporeal bioartificial liver support system (BALSS). It includes the biochemical changes which occur in the plasma and blood of pigs with devascularized livers when the plasma is treated in a BALSS, and the testing of the system for presence or absence of infective agents, pyrogens and for toxicity. METHODS: Hepatic cells were prepared from littermate juvenile white landrace pigs with a double-step collagenase digest technique. The cell preparations were incubated with collagen-coated dextran microspheres (CDM) for 3 h and the medium was tested to determine cellular metabolic activity. Incubation continued for a further 20 h during which the hepatic cells attach to the CDM. The CDM-attached cells were inoculated into a hollow fibre bioreactor which was part of an extracorporeal liver support system. RESULTS: Hepatic cell content of the bioreactor was 6 x 10(9) +/- 3 x 10(8) cells, equivalent to those present in half a pig's liver. The system was tested in a controlled trial with the plasma of pigs with fulminant hepatic failure (FHF) due to devascularized livers. When plasma from FHF pigs was circulated through the device there was significantly less of an increase in the accumulation of ammonia, lactate and most amino acids when hepatic cells were included in the circuit compared with those in control experiments when they were excluded. Similar changes occurred in procine blood. There were few infections diagnosed and an absence of pyrogens, endotoxins and toxicity in the bioreactor contents or in the terminating reservoir or animal blood samples. CONCLUSIONS: We believe that the results, demonstrating function of the porcine hepatic cells in the circuit, together with low risks, justify a clinical trial of use of the BALSS in Australia.

Evaluation of blood donors with equivocal hepatitis C serological results.

OBJECTIVE: To characterise blood donors with equivocal hepatitis C serological results and to develop an algorithm for their diagnosis and follow-up. DESIGN: Prospective case survey. SUBJECTS AND SETTING: 100 consecutive blood donors referred to the St Vincent's Hospital Liver Clinic, Victoria, with equivocal hepatitis C serological results (positive result for second generation Abbott Enzyme Immunoassay 2.0, but at least one negative result on supplemental testing by first generation Abbott neutralisation assay and Abbott Supplemental Assay for antibody to specific viral antigens). OUTCOME MEASURES: Percutaneous risk factors for hepatitis C exposure, peak serum alanine aminotransferase (ALT) levels, results of alternative immunoassay (Monolisa) and polymerase chain reaction (PCR) to detect hepatitis C viraemia. RESULTS: Thirty subjects had positive results for alternative immunoassay. A risk factor was identified for 32 subjects and was significantly associated (P < 0.01) with positive results for alternative immunoassay (23/32) and PCR (11/32), abnormal ALT levels (7/32), and strong reactivity on initial immunoassay (23/32). Presence of antibodies to both structural and non-structural antigens was also associated with risk factors and positive alternative immunoassay results. CONCLUSIONS: A definitive diagnosis was possible in 87% of subjects. A diagnosis of hepatitis C infection was based on positive alternative immunoassay results together with positive PCR results or presence of a risk factor. Hepatitis C was excluded for 60% of patients. The diagnosis for the remaining 13% remained indeterminate, indicating the need for a definitive diagnostic test for hepatitis C.

Risk factors and predictors of outcome in an Australian cohort with hepatitis C virus infection.

OBJECTIVES: To define demographic and epidemiological features of an Australian population with chronic hepatitis C virus (HCV) infection and determine predictors of histological and clinical outcome. DESIGN: Cohort study. PATIENTS AND SETTING: 342 consecutive HCV antibody-positive patients referred to the liver clinic of a major metropolitan general hospital. OUTCOME MEASURES: Demographic data, serial alanine aminotransferase (ALT) levels, full blood count for all patients. Percutaneous liver biopsy in 152 patients (44%). RESULTS: 51% of patients had previously used injecting drugs, 15% had received a blood transfusion and 27% had no definite percutaneous risk factor (sporadic group). The injecting drug users (IDUs) were younger and more likely to have been born in Australia. The sporadic group were older and frequently were born in Mediterranean or Asian countries. A history of excessive alcohol use was common, particularly among IDUs (60%). Of 152 patients who had a liver biopsy, 49 had cirrhosis and 103 had chronic hepatitis. Some patients with a normal ALT level had marked necro-inflammatory activity. On univariate analysis, the presence of cirrhosis correlated with older age (P < 0.0001), lack of an identifiable risk factor (P < 0.001) and birth in a Mediterranean or Asian country (P < 0.0001). On multivariate analysis, the only significant predictor of cirrhosis was age (P < 0.001). Among patients with an identifiable percutaneous risk factor, cirrhosis was seen at a median time of 18 years after first exposure to risk, compared with 13 years in patients with chronic hepatitis (P < 0.01). Patients with clinical evidence of portal hypertension were, on average, 15 years older than those with histological cirrhosis only (P < 0.01). CONCLUSIONS: Injecting drug use is the major risk factor for chronic HCV infection in Australia. In patients with an identifiable risk factor, the most significant factor associated with a biopsy finding of cirrhosis is the time since first exposure to HCV.

Management of the chronic hepatitis B carrier.

Chronic hepatitis B is an increasingly prevalent disease in Australia, both because of inadequacies of the current vaccination program, and because of changing population demographics. Regular follow-up of these patients is indicated, particularly as we now have effective anti viral therapy available. The unfavourable disease outcome in about 30% of hepatitis B carriers warrants increased recognition and observation of this group of patients.

A transcription inhibitor specific for unwound DNA in RNA polymerase-promoter open complexes.

The kinetically component open complexes formed at prokaryotic and eukaryotic transcription start sites are efficiently nicked by the chemical nuclease activity of the 2:1 1,10-phenanthroline-copper(I) complex [(OP)2Cu+] and hydrogen peroxide. This reaction specificity has been attributed to the creation of a binding site(s) for redox-active tetrahedral (OP)2Cu+ when RNA polymerase form productive complexes with promoters. This proposal has been confirmed for the Escherichia coli lac UV-5 promoter by the demonstration that the 2:1 2,9-dimethyl-1,10-phenanthroline-copper(I) complex [(Me2OP)2Cu+], a redox-inactive isostere of (OP)2-Cu+, protects the transcription start site from scission by the chemical nuclease activity. (Me2OP)2Cu+ is also an effective inhibitor of transcription. The inhibition of transcription and the protection from scission of the open complex by (OP)2Cu+ exhibit the same dependence on the concentration of (Me2OP)2Cu+. This redox- and exchange-stable species is a previously undescribed transcription inhibitor that binds to a site generated by the interaction of RNA polymerase with the promoter. Unlike the intercalating agent proflavine, which is also an effective transcription inhibitor, it does not displace the enzyme from the promoter. The ability of (Me2OP)2Cu+ to inhibit transcription may be partially responsible for its potent cytotoxicity.

Spontaneous paracentesis following rupture of an umbilical hernia.

Spontaneous paracentesis following a ruptured umbilical hernia is a rare but dramatic event. Only 58 cases have been recorded in the English language literature. We describe here the management and successful outcome of one such case with documented substantial paracentesis of approximately 11 L.

Gilbert's syndrome.

While Gilbert's syndrome is extremely common and benign, its pathogenesis may not be as straightforward as once believed. It has been used as a model to examine aberrations of virtually every step in bilirubin metabolism. The clinical hallmarks are of a hereditary, chronic, mild unconjugated hyperbilirubinaemia. Not infrequently subclinical haemolysis may coexist. Liver histology is normal although some minor ultrastructural abnormalities may be evident. The universal defect appears to be a reduction in hepatic bilirubin-GT activity. However, other associated abnormalities in bilirubin metabolism, which occur less consistently, suggest that this may not be the sole defect in all patients. The syndrome is almost certainly part of a spectrum which includes the Crigler-Najjar syndromes; molecular biology data suggests that there is an absence of one (or even more) GT isoenzymes in these disorders. Whether one or more genes is consistently culpable remains open to speculation. Despite the complicated pathogenesis of Gilbert's syndrome, management remains simply reassurance alone.

Hepatic extraction of morphine is impaired in cirrhosis.

Using hepatic vein catheterization this study has provided the first direct measurement of morphine hepatic extraction in 8 controls and 8 cirrhotics. The extraction ratio was 0.52 in the control group and was reduced by 25% in the cirrhotics. This reduction is due to impaired enzyme capacity rather than reduced blood flow. The effect of cirrhosis is less than that reported in similar studies of high clearance oxidized drugs and this lends support to the concept that glucuronidation may be relatively spared in cirrhosis. A discrepancy between the systemic clearance and the hepatic clearance provides indirect support for extra-hepatic metabolism of morphine.

Metoclopramide--a review.

Metoclopramide has wide applications in both clinical and experimental medicine. It is useful in the management of gastro-oesophageal reflux and gastric stasis. It is being used increasingly in the management of nausea and vomiting, and at high doses will significantly relieve the emesis that is induced by cytotoxic agents. Metoclopramide also has an important place in the investigation of the role of dopamine in physiological and pathological processes.

Hepatic vein occlusion (Budd-Chiari syndrome): problems in diagnosis and management.

Seven patients demonstrating the difficulties in diagnosis and management of hepatic vein occlusion are presented. The syndrome may present in an acute form with upper abdominal pain, abdominal swelling, ascites and tender hepatomegaly or in a chronic form, mimicking cirrhotic ascites. The clinical features, predisposing factors, liver scan and liver biopsy may all suggest the condition, but hepatic venography is essential for diagnosis and as a preliminary to treatment. It is suggested that early side to side portacaval anastomosis is the current treatment of choice.

The effects of age and chronic liver disease on the elimination of temazepam.

The pharmacokinetics of the newer 1, 4 benzodiazepine temazepam were evaluated in 16 healthy subjects aged 18-92 years and in 15 cirrhotic patients, to ascertain the effect of ageing and liver disease. The data were analysed both by classic two compartment and by non-compartmental methods. The mean elimination half-life in the control subjects was 15.5 h, considerably longer than previous estimates. No correlation was found between age and pharmacokinetic parameters. The cirrhotic group showed no statistically significant difference in the pharmacokinetic parameters nor in the urinary recovery of the dose from the control group. Temazepam plasma protein binding was assessed in a second group of 9 cirrhotics of similar severity to the main group and in matched controls. When these binding data were applied to the mean clearance data, a modest although not statistically significant, reduction in free drug clearance was observed in the cirrhotic group. This study adds further support to the observation that drugs which undergo ether glucuronidation have normal elimination patterns in patients with liver disease. Temazepam may prove to be a useful hypnotic sedative in patients with liver disease.