Causes, associated exposures, and outcomes of cirrhosis and hepatocellular carcinoma in Malawi: an observational cohort and case-control study.

Abstract

BACKGROUND African countries have the highest age-standardised mortality from liver disease. We studied patients with cirrhosis and hepatocellular carcinoma in Malawi to ascertain the causes, associated exposures, and outcomes after discharge, and identify opportunities for intervention strategies. METHODS In this case-control cohort study, we recruited patients aged 16 years or older who met the study definitions for cirrhosis or hepatocellular carcinoma from the Queen Elizabeth Central Hospital in Blantyre, Malawi. In the cirrhosis group, we excluded patients with a liver stiffness greater than 12 kPa if a cause of potential false elevation of liver stiffness was identified and a liver ultrasound did not show signs of cirrhosis; people with extrapulmonary tuberculosis or other non-hepatic causes of ascites; and pregnant people. In the hepatocellular carcinoma group, we excluded those with an extrahepatic malignancy or ultrasound features consistent with liver metastases, pregnant people, and indeterminate lesions as determined by consultant radiologists on serial ultrasounds. Research nurses identified potential participants on medical and surgical wards, the medical outpatient clinic, and endoscopy unit, using systematic case notes review and clinician referral during weekdays. Patients were followed up for 6 months. A community sample was recruited from the catchment area of the hospital to estimate the general population prevalence of diseases and exposures potentially associated with liver disease. For hepatitis B and C, we conducted a serological survey in individuals aged 16 years or older who were randomly selected from a census, and we randomly selected a proportion of individuals who were HBsAg positive or HBsAg negative to estimate the general population prevalence of HIV, alcohol, smoking, diabetes, hepatitis D and E, and autoimmune hepatitis serological markers. We estimated population attributable fractions (PAFs) for cirrhosis and hepatocellular carcinoma using community controls and the serological survey. PAFs were estimated from logistic regression models adjusted for age and sex, using the Bruzzi method with percentile bootstrap confidence intervals. FINDINGS Between Nov 1, 2017, and April 30, 2019, we prospectively screened 708 patients and enrolled 138 diagnosed with cirrhosis and 78 diagnosed with hepatocellular carcinoma. Patients had a median age of 40 years (IQR 35-51), 134 (62%) were male, and 82 (38%) were female. In those with hepatocellular carcinoma, median tumour size was 13·2cm (10·2-17·3) and median survival was 40 days (95% CI 30-51). The community sample comprised 3258 individuals with hepatitis B and 1661 with hepatitis C identified from the serological survey, and 120 individuals negative for HBsAg and 94 people who were HBsAg positive from the serological survey to estimate the general population prevalence of HIV, alcohol, smoking, diabetes, hepatitis D and E, and autoimmune hepatitis serological markers. At 6 months, 83 (60%) of 130 patients with cirrhosis and six (8%) of 78 patients with hepatocellular carcinoma were still alive. Hepatitis B was the main attributable cause of cirrhosis (PAF 25·3% [17·5-33·3]) and hepatocellular carcinoma (73·1% [62·6-82·9]). HIV was the second leading attributable exposure associated with cirrhosis (22·2% [12·2-32·2]) and hepatocellular carcinoma (18·0% [4·8-30·9]); the association persisted after adjusting for hepatitis B virus co-infection. For hepatocellular carcinoma (but not cirrhosis), smoking (23·6% [8·9 to 37·2]) and alcohol (14·5 [-0·2 to 28·4]) were secondary attributable exposures. Autoimmune hepatitis (five [4%] patients), primary biliary cholangitis (four [3%] patients), and hepatitis C (two [1%] patients) were uncommon causes of cirrhosis, and no patients in either group had hepatitis D or E viraemia. INTERPRETATION Hepatitis B is the leading cause of cirrhosis and hepatocellular carcinoma in Malawi. HIV was diagnosed at a much higher rate among patients with cirrhosis and hepatocellular carcinoma than community controls; it is uncertain whether the relationship is causal or influenced by confounding. Alcohol and smoking are modifiable exposures associated with hepatocellular carcinoma. Hepatocellular carcinoma and cirrhosis are diagnosed at an advanced stage, with a poor prognosis. Community screen-and-treat programmes for hepatitis B could substantially reduce liver-related mortality in this region. FUNDING Wellcome Trust, Bill and Melinda Gates Foundation, and German Federal Ministry of Economic Cooperation and Development.