Hepatocellular carcinoma: prevention, detection and treatment … in the real world

Hepatocellular carcinoma (HCC) is an important cause of death worldwide and an increasing problem in Western countries. In Australia and the USA an increase in the incidence of HCC over the past three decades has been documented. This has been attributed both to immigration from areas endemic for hepatitis B and to a cohort of individuals with chronic hepatitis C originally infected 20– 40 years ago and now progressing through cirrhosis to HCC. The future is no brighter: the hepatitis C epidemic shows no signs of abating whereas non-alcoholic fatty liver disease (NAFLD) related to diabetes and obesity looms as a potential second wave of cirrhosis and HCC in developed countries. HCC generally arises in patients with cirrhosis on a background of chronic viral hepatitis, alcohol excess or other chronic liver diseases (NAFLD or haemochromatosis, for example). These diseases are opportunities for intervention and, through this, prevention of HCC both at an individual and at a population level. Effective hepatitis B vaccination programmes can prevent vertical and horizontal transmission leading to a reduction in HCC incidence. This has been documented in Taiwan where the incidence of childhood HCC declined following implementation of targeted (1984) and then universal (1986) neonatal vaccination. In Australia, universal neonatal hepatitis B vaccination is recommended with catch-up vaccination of preadolescents (10–13 years of age) not immunized at birth. Effective immunization against hepatitis C is not yet available, but screening of blood products has minimized transmission by this route and harm reduction strategies, such as needle exchange programmes, may help to decrease transmission among i.v. drug users. Likewise, strategies to reduce alcohol abuse and obesity in the community, if effective, would be expected to reduce the future incidence of HCC. Worldwide, hepatitis B is the most important cause of HCC and, in some regions, dietary aflatoxin exposure is a key cofactor. Public health measures to reduce aflatoxin exposure and chemopreventative agents to counteract the effects of this toxin are currently being evaluated. Treatment options for chronic viral hepatitis have improved dramatically over the past decade and provide an opportunity for intervention at a second stage in the pathogenesis of HCC. The combination of pegylated interferon and ribavirin achieves sustained response rates of approximately 50–55% in chronic hepatitis C. Sustained response in non-cirrhotic patients should prevent progression to cirrhosis and HCC provided other causes of liver injury, such as alcohol abuse and coinfection with hepatitis B, are also eliminated. Treatment of cirrhotic patients with hepatitis C may also reduce subsequent progression to HCC presumably by reducing ongoing hepatocellular injury, regeneration and repair and possibly through a direct antiproliferative effect of interferon. In chronic hepatitis B, treatment with nucleoside analogues is effective in suppressing viraemia, reducing inflammatory activity and slowing the progression of fibrosis. The nucleoside analogues lamivudine, adefovir and entecavir are now available for treatment of hepatitis B in Australia. Long-term treatment with entecavir appears to reduce the development of HCC in the infected woodchuck model of hepatocarcinogenesis. In humans, a prospective randomized controlled study of lamivudine in advanced hepatitis B fibrosis or established cirrhosis has shown a reduction in HCC occurrence from 7.4% in the control group to 3.9% in the treated group (P = 0.047). Probably, such benefits will be seen in treatment regimes using other agents. Likewise, prevention of cirrhosis by venesection in patients with haemochromatosis and, hopefully, future interventions in NAFLD will further reduce the incidence of HCC in other groups at risk. Although elimination of HCC through prevention and treatment of chronic liver disease should be the goal, the full impact of such strategies may be decades away. Early detection of HCC remains an important focus in the management of patients with advanced liver disease. Surveillance for HCC, generally by 6-monthly hepatic ultrasound and monitoring of a-fetoprotein, identifies smaller lesions that are more amenable to treatment and may result in a survival advantage though further evidence for the latter is required. Despite uncertainties regarding the benefits, HCC surveillance has been widely adopted by gastroenterologists. Offered the choice and provided with appropriate information, most cirrhotic patients will opt for surveillance.