Chronic hepatitis : morbidity and mortality in patients and their children

The spread of Hepatitis C Virus (HCV) infection started in Sweden in the end of the 1960s with a culmination in the 1970s, most likely due to increased injection drug use. Mandatory notification of acute and chronic HCV infection in Sweden started in 1990. The estimated prevalence of viremic HCV infection in Sweden is 35,000-45,000. Even though the prevalence is estimated to decrease during the next decade it is believed that the disease burden of HCV-related cirrhosis and HCC will increase. HCV is a global health problem with world prevalence of viremic HCV infection assessed to be 118.9 million. HCV infection has a quiescent progression where most individuals have only mild symptoms until decompensated cirrhosis. Approximately 5-30% patients develop cirrhosis in 20 to 30 years. The natural history of HCV infection in pregnancy and in infants is not well studied. The aim of this thesis was to study morbidity and mortality of individuals infected with HCV and/or B virus and in children of HCV infected mothers.

In paper I the standardized incidence ratios (SIR) for hepatocellular cancer (HCC) were studied in individuals notified with HBV and HBV-HCV dual infection. In the HBV cohort (n=9,646), individuals infected with HBV in 40-49 years had 47 times increased risk of developing HCC compared with general population. In the HBV-HCV cohort (n=1,697), individuals with co-infection for 20-29 years had 34 times increased risk of developing HCC. This established the excessive risk of developing HCC in individuals with HBV and in those co-infected with HBV and HCV compared with the general population.

Mortality and cause of death was studied in paper II. The standardized mortality ratio (SMR) demonstrated a 6 times excess mortality in the HCV cohort (n=34,235) compared with the general population, and 36 times excess mortality from liver disease. Deaths from illicit drugs and external reasons were common in young adults. In paper III the odd ratio (OR) for the outcome of pregnancy of HCV infected mothers, compared with mothers in the general population Mothers with HCV infection (n=9,599) had increased risk for several adverse pregnancy outcomes. They had 7 times excessive risk of their pregnancy terminating in stillbirth and almost two times increased risk for late neonatal death. Paper IV, demonstrated excessive mortality in children (n=19,097) of mothers (n=9,599) with HCV infection compared with the general population. From 1 to 4 weeks, the adjusted hazard ratio (HR) was 2.26 and from 1 to 6 months the HR was 2.63. From age 15 to 20 years of age HR was 2.50 and from year 20 and onward the HR was 3.16.

To conclude: HBV and HVB-HCV infected individuals have an excessive risk of developing HCC. Drug related mortality in the HCV-cohort was high. Liver related mortality was high in all cohorts. Mothers with HCV are in risk of adverse outcome of pregnancy. Children of mothers with HCV infection have an increased risk of dying in the perinatal period, within 6 months of living or after their teenage years.

List of scientific papers

I. Davídsdóttir L, Duberg AS, Törner A, Aleman S, Bäck E, Ekdahl K, Blaxhult A, Ekbom A, Hultcrantz R. Hepatocellular carcinoma in individuals with HBV infection or HBV–HCV co-infection in a low endemic country. Scand J Gastroenterol. 2010 Aug; 45(7-8):944-52.
https://doi.org/10.3109/00365521003770251

II. Duberg AS, Törner A, Davidsdóttir L, Aleman S, Blaxhult A, Svensson A, Hultcrantz R, Bäck E, Ekdahl K. Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study. J Viral Hepat. 2008 Jul; 15(7):538-50.
https://doi.org/10.1111/j.1365-2893.2008.00982.x

III. Lóa Davidsdóttir, Soo Aleman, Anders Ekbom, Matteo Bottai, Ann-Sofi Duberg, Rolf Hultcrantz. Increased risk for stillbirths in infants born to mothers with hepatitis C, a nationwide study of 19,072 infants. [Manuscript]

IV. Lóa Davidsdóttir, Soo Aleman, Anders Ekbom, Matteo Bottai, Ann-Sofi Duberg, Rolf Hultcrantz. Increased mortality in children of mothers with hepatitis C virus infection in Sweden, a national cohort study. [Manuscript]