Paul J Gow

Treatment of chronic hepatitis

Viral hepatitis is the major cause of chronic liver disease worldwide. An estimated 300 million people are carriers of the hepatitis B virus, and 120 million are infected with hepatitis C. Untreated, these infections may progress to cirrhosis, liver failure, and hepatoma. Public health measures to limit new infection, including immunisation against hepatitis B and screening of blood products for hepatitis B and C viruses, have now been implemented in most developed countries and are being implemented in many developing counties. This review focuses on the treatment of chronic hepatitis B and C, which has undergone dramatic improvement in the past few years. #### Summary points Lamivudine is a safe effective antiviral drug for treating chronic hepatitis B virus infection Lamivudine is most effective in patients with substantially elevated transaminase concentrations and those with advanced cirrhosis Lamivudine treatment is hampered by the frequent development of resistance; in the near future combinations of antiviral agents may become standard treatment Ribavirin in combination with interferon is effective for selected patients with chronic hepatitis C virus infection Overall, about 30-40% of all patients can expect to be cured by this treatment, and in selected subgroups of patients cure rates of 80-90% can be achieved Treatment with interferon alfa (as part of combination therapy) reduces the risk of developing hepatocellular carcinoma and may partially reverse hepatic fibrosis The information used in the preparation of this article was based on a Medline search to identify key papers in addition to searching abstracts from the meetings of the American Association for the Study of Liver Disease and European Association for the Study of the Liver between 1997 and 2001. Search terms included hepatitis B virus, hepatitis C virus, treatment, lamivudine, tribavirin (ribavirin), interferon, pegylated interferon, and combination therapy. Of the worlds 300 million people with chronic hepatitis B, most …

Solid organ transplantation in patients with HIV infection.

Many transplant units routinely screen potential organ recipients for infection with human immunodeficiency virus (HIV), although many have not determined the appropriate reaction to a patient who is seropositive. Some units declare that HIV seropositivity excludes the option of transplantation. Of those units that do not consider seropositivity as a contraindication, few have transplanted HIV-positive patients (1). It seems that HIV-positive patients are overtly or covertly denied potentially life-saving and life-changing therapy. This attitude may be based on concerns about the likely outcome of transplanted patients and concerns that immunosuppression might adversely affect the natural history of HIV infection. The attitude was established before the development of potent and effective antiviral therapy and was sustained in a climate of incomplete and inadequate data. Is it time to re-evaluate this attitude? Published literature reports several HIV-positive patients who have undergone transplantation. Examination of sera collected before the development of HIV antibody tests in early 1980s identified several seropositive patients who underwent transplantation. Also, retrospective serum studies identified many patients who were infected by blood or organ donors at the time of transplantation. These studies permit an important, albeit limited, examination of the course of HIV infection after transplantation. Chronic liver and kidney disease commonly accompany HIV infection. Hepatitis B and C may share the same routes of transmission as HIV, thus, coinfection is common. Therefore, liver disease may accompany HIV infection. Renal disease may also be observed. HIV-associated nephropathy (HIVAN) is the most common cause of chronic renal disease in patients with HIV and occurs in up to 10% of black patients infected with HIV (2). Until the availability of highly active antiretroviral therapy (HAART) in the late 1990s, patients with HIV infection and chronic liver or renal disease were likely to die of acquired immune deficiency syndrome (AIDS) before the liver or renal disease had progressed to a stage requiring transplantation. More recently, it has been shown that potent antiretroviral therapy can reduce viral load, increased CD4 count, and prolong survival in HIV infected patients. Therefore, increasing numbers of patients with stable HIV infection may progress to end-stage liver or kidney failure. Nevertheless, attitudes to transplantation of HIV-infected patients have been slow to adjust, and many transplant centers still regard HIV infection as a contraindication to transplantation.

Etiology and outcome of fulminant hepatic failure managed at an Australian liver transplant unit

Background and Aims:  The primary aims were to identify the incidence, etiology and outcome of all adult cases of fulminant hepatic failure (FHF) presenting to the Victorian Liver Transplant Unit over the 14 year period since the Unit was established in 1988.

Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis

BACKGROUND & AIMS Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V(2) receptor antagonist, satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia. METHODS One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg (n=39), 12.5mg (n=36), 25mg (n=40) of satavaptan or placebo (n=36) for 12 weeks. Their Child-Pugh scores were 9.2+/-1.3, 8.7+/-1.7, 8.8+/-1.3, and 9.0+/-1.5, respectively. RESULTS Median time to first paracentesis was 23, 26, and 17 days with satavaptan 5, 12.5, and 25mg, respectively, versus 14 days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly (p<0.05) in all satavaptan groups versus placebo. Mean increase in ascites was 2.82+/-0.48 L/week for placebo versus 2.12+/-0.40, 2.14+/-0.33, and 2.06+/-0.40 L/week for the 5, 12.5, and 25mg of satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with satavaptan. CONCLUSIONS Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.

Review article: sarcopenia in cirrhosis--aetiology, implications and potential therapeutic interventions.

Sarcopenia (loss of muscle mass) is common in cirrhosis and is associated with poor outcomes. Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting.

A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis.

Juvenile hemochromatosis (JH) is an autosomal recessive condition that leads to significant morbidity due to early onset systemic iron overload. The majority of families with JH link to chromosome 1q and were recently found to have mutations in the HFE2 gene encoding hemojuvelin; however, several JH families have been reported to have mutations in the HAMP gene encoding hepcidin. Here, we report a multiply consanguineous family with a father and daughter showing iron overload consistent with JH. Sequence analysis of HAMP revealed homozygosity for amino acid substitution C78T due to a c.233G > A mutation. This mutation disrupts one of eight highly conserved cysteines that are believed to be critical for the function of the active enzyme. This finding adds support to the importance of the role of these conserved cysteines in the activity of hepcidin.

Testosterone therapy increases muscle mass in men with cirrhosis and low testosterone: A randomised controlled trial

BACKGROUND & AIMS Low testosterone and sarcopenia are common in men with cirrhosis and both are associated with increased mortality. Whether testosterone therapy in cirrhosis improves muscle mass and other outcomes is unknown. METHODS We conducted a 12-month, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in 101 men with established cirrhosis and low serum testosterone (total testosterone <12nmol/L or free testosterone <230pmol/L) in a single tertiary centre. Body composition was assessed using dual-energy X-ray absorptiometry at baseline, 6 and 12months. RESULTS At study completion, appendicular lean mass was significant higher in testosterone-treated subjects, with a mean adjusted difference (MAD) of +1.69kg, (CI +0.40; +2.97kg, p=0.021). Secondary outcomes included a substantially higher total lean mass in the active group (MAD +4.74kg, CI +1.75; +7.74kg, p=0.008), matched by reduced fat mass (MAD -4.34kg, CI -6.65; -2.04, p<0.001). Total bone mass increased (MAD +0.08kg, CI +0.01; +0.15kg, p=0.009) as did bone mineral density at the femoral neck (MAD +0.287points, CI +0.140; +0.434, p<0.001). Haemoglobin was higher with testosterone therapy (MAD +10.2g/L, CI +1.50; +18.9g/L, p=0.041) and percentage glycosylated haemoglobin (HbA1c) lower (MAD -0.35%, CI -0.05; -0.54, p=0.028). Mortality was non-significantly lower in testosterone-treated patients (16% vs. 25.5%, p=0.352). There was no increase in adverse events in testosterone-treated subjects. CONCLUSION Testosterone therapy in men with cirrhosis and low serum testosterone safely increases muscle mass, bone mass and haemoglobin, and reduces fat mass and HbA1c. This is the first evidence-based therapy for sarcopenia in cirrhosis and thus requires larger-scale investigation into its potential impact on mortality. LAY SUMMARY Both low testosterone and muscle wasting are associated with increased risk of death in men with severe liver disease. Administering testosterone to men with liver disease who have low testosterone levels significantly increases their muscle mass. In addition, testosterone has non-muscle beneficial effects which may be able to increase survival in this population. CLINICAL TRIAL NUMBER Australian New Zealand Clinical Trials Registry trial number ACTRN 12614000526673.

Characteristics of hepatocellular carcinoma in cirrhotic and non-cirrhotic non-alcoholic fatty liver disease

AIM To determine characteristics and prognostic predictors of patients with hepatocellular carcinoma (HCC) in association with non-alcoholic fatty liver disease (NAFLD). METHODS We reviewed the records of all patients with NAFLD associated HCC between 2000 and 2012. Data collected included demographics; histology; presence or absence of cirrhosis, size and number of HCC, alpha-fetoprotein, body mass index (BMI), and the presence of diabetes, hypertension, or dyslipidaemia. RESULTS Fifty-four patients with NAFLD associated HCC were identified. Mean age was 64 years with 87% male. Fifteen percent (8/54) were not cirrhotic. 11%, 24% and 50% had a BMI of <25 kg/m2, 25-29 kg/m2 and ≥30 kg/m2 respectively. Fifty-nine percent were diabetic, 44% hypertensive and 26% hyperlipidaemic. Thirty-four percent of the patients had ≤1 of these risk factors. Non-cirrhotics had a significantly larger mean tumour diameter at diagnosis than cirrhotics (P=0.041). Multivariate analysis did not identify any other patient characteristics that predicted the size or number of HCC. CONCLUSION HCC can develop in NAFLD without cirrhosis. At diagnosis such tumours are larger than those in cirrhotics, conferring a poorer prognosis.

Liver transplant recipient selection: MELD vs. clinical judgment

Minimization of death while waiting for liver transplantation involves accurate prioritization according to clinical status and appropriate allocation of donor livers. Clinical judgment in the Liver Transplant Unit Victoria (LTUV) was compared with Model for End‐Stage Liver Disease (MELD) in a retrospective analysis of the LTUV database over the 2‐year period August 1, 2002, through July 31, 2004. A total of 1,118 prioritization decisions occurred. Decisions were concordant in 758 (68%), comparing priorities assigned by clinical judgment with those assigned by MELD, P < 0.01. A total of 263 allocation decisions occurred. Decisions were concordant in 190 (72%) and 203 (77%) of the cases, comparing donor liver allocation with prioritization by MELD and clinical judgment, respectively. Of the 52 patients allocated a liver, only 23 would have been allocated on the basis of MELD while 29 had been prioritized on the waiting list in the week prior to transplantation. A total of 10 patients died on the waiting list in the 2‐year period (annual adult waiting list mortality is 9.3%). Patients who subsequently died waiting were 3 times as likely to be prioritized by MELD as clinical judgment (29% vs. 9%, respectively). One half (3 of 6) of the patients who could have received a donor liver but who died waiting would have been allocated the organ on the basis of MELD. In conclusion, an allocation process based on MELD rather than clinical judgment would significantly alter organ allocation in Australia and may reduce waiting list mortality. (Liver Transpl 2005;11:621–626.)

Risk factors for liver transplantation waiting list mortality

Background and Aim:  The gap between the demand for liver transplantation and organ donation rates has a major impact on waiting list mortality. Understanding the risk factors that predict liver transplant waiting list death may help optimize organ allocation policy and reduce waiting list deaths.