Hepatitis C

Progression of untreated disease

Chronic hepatitis C infection is associated with a significant risk of progression to cirrhosis and hepatocellular carcinoma (HCC).^{3, 84} Quantifying the magnitude of risk of progression to cirrhosis and HCC with time is difficult as outcomes are strongly influenced by study design and the characteristics of the population sampled.^{3, 84} 2++

A systematic review of 57 studies (both cross-sectional and longitudinal) which included liver clinic, post-transfusion, blood donor and community based patients, calculated the following estimates for the risk of progressing to cirrhosis after 20 years:³ 2++

• liver clinic: 22% (95% CI 18-26%)
• post-transfusion: 24% (95% CI 11-37%)
• blood donor: 4% (95% CI 1-7%)
• community based: 7% (95% CI 4-10%).

Due to the selection biases inherent in the cross-sectional liver clinic data, the community based cohort studies may be the most representative of true disease progression at a population level. The community based cohorts indicate that in those who acquire HCV infection in young adulthood, less than 10% will develop cirrhosis within 20 years. Older age at HCV acquisition, male gender and heavy alcohol consumption were associated with more rapid disease progression.³ 2++

The mean time from HCV infection to the development of HCC also shows considerable variation between studies, ranging from 9 to 31 years in one systematic review.⁸⁴ Virtually no cases of HCC occur during the first decade after HCV infection, most are detected after 20 years of infection.⁸⁴ 2++

Patients with established HCV related cirrhosis have a seven per cent risk of developing HCC, by five years follow up.^{85, 86} 2+

Patients with established CHC related cirrhosis are also at risk of complications such as ascites, gastrointestinal bleeding and hepatic encephalopathy.^{85, 86} The cumulative probability of all forms of decompensation in cirrhotic patients who remained tumour free was 18% at five years in one study, with an overall five year survival rate of 91%.⁸⁶ 2+

Age, gender and ethnicity

Increasing age at time of infection with HCV is associated with more rapid progression of liver fibrosis and reduced time from infection to cirrhosis.^87-89 Age over 40 years at time of infection is particularly associated with more rapid progression.^{88, 89} 3

Three cohort studies reported that men infected with HCV are more likely to progress to advanced stages of hepatic fibrosis than women.^{88, 90, 91} 3

Variations in disease progression have been observed in patients of different race. Two cohort studies demonstrated that disease progressed less rapidly in African-American than non African-American patients.^{92, 93} The likely rate of progression in these patients should be considered when deciding whether to proceed with antiviral therapy. 2+

Body weight

Studies have identified Body Mass Index (BMI)>25 as being associated with hepatic steatosis (see the Overweight section).

Tobacco smoking

Smoking is an independent risk factor for the progression of hepatic inflammation and fibrosis in patients with CHC.^{94, 95} No data were identified on the impact of stopping smoking. 3

Alcohol

Heavy alcohol consumption in patients infected with CHC is associated with more severe liver disease including cirrhosis, endstage liver disease and hepatocellular cancer.^{96, 97} Average alcohol intake of more than six UK units per day is associated with more rapid progression of liver fibrosis.^{87, 88, 91} Even moderate amounts of alcohol (within government recommended guidelines) have been associated with increased liver fibrosis compared to those who abstain.^{88, 98} 2+ 2++

Alanine aminotransferase

Approximately 25% (range 10-40%) of patients with CHC have persistently normal serum alanine aminotransferase (PNALT). Such patients are more likely to be female and have mild disease.¹⁰⁰ Although there is a substantial overlap between patients with PNALT and patients with mild liver disease, the terms are not synonymous and the groups are regarded separately for treatment purposes (see the Patients with mild chronic hepatitis and Patients with persistently normal ALT levels sections). The definition of ‘persistently normal’ varies in the literature with ALT measurements made every two to three months for time periods ranging between 6 and 18 months.¹⁰⁰ Flares in ALT can still occur in 21.5% of patients after being normal for 12 months.¹⁰¹ There is no association with hepatitis C genotype or viral load.¹⁰⁰ 1- 2-

Progression of liver fibrosis is slower in patients with PNALT than in patients with elevated ALT.¹⁰² In patients with untreated mild liver disease the progression to moderate or severe disease during follow up of 5.6 years is five per cent in patients with PNALT and 24% in patients with elevated ALT. 2++

Routine liver biopsy is not believed to be indicated unless specific information is required in selected patients.¹⁰⁰ 1-

Good practice points

HIV co-infection

There is an increased rate of progression to endstage liver disease in patients with HIV and HCV co-infection compared to those with HCV mono-infection (relative risk; RR 6.14, 95% CI 2.86 to 13.2).¹⁰³ Median time to cirrhosis in patients with co-infection is 26 years, compared to 38 years in those with HCV mono-infection.¹⁰³ Patients with HCV infection with mild immunodepression as a result of HIV also have more severe liver disease than those with HCV mono-infection.¹⁰⁴ There is a marked increase in liver related mortality in patients with CHC and HIV co-infection (RR 17.5).¹⁰⁵ 1+ 2+

Effective anti-HIV therapy and the associated immune recovery may limit HCV liver disease progression.¹⁰⁶ 2++

Co-infection with hepatitis a or b viruses

Vaccination against hepatitis A and B is recommended in people with HCV.¹⁰⁷ A consensus report on the treatment of hepatitis recommended vaccination for hepatitis B but not hepatitis A.¹⁰⁸ One case study of patients with HCV who contracted hepatitis A reported a very high level of fulminant hepatitis.¹⁰⁹ 4

Antibody response to hepatitis B vaccination is reduced in patients with chronic HCV.¹¹⁰ 3

Patients who are infected with HCV who have serological evidence of current or past infection with hepatitis B virus (HBV) are more likely to have advanced liver disease.^{90, 111, 112} 3

Good practice points

Iron status

Patients with CHC can have elevated iron stores, but there is debate over whether this has any influence on the disease. Serum ferritin and transferrin saturation are increased in 20-60% of patients and correlate with serum ALT, suggesting they are markers of inflammation. There is a poor correlation with hepatic iron concentration (HIC).¹¹³ HIC is rarely significantly elevated in pre-cirrhotic patients. Twenty to fifty per cent of patients with cirrhosis will have elevated HIC but this is also a common finding in patients with cirrhosis due to hepatitis B and alcoholic liver disease.¹¹³ 4

It is uncertain whether hepatic iron excess as a single factor has any influence on response to treatment with IFN alone.¹¹³ 4

No evidence was found that iron depletion (by venesection) has any influence on the virus or the activity of liver disease.¹¹³ There is preliminary evidence from four small RCTs that venesection on selected patients with markers of iron excess prior to IFN monotherapy may improve the SVR.^{113, 114} 4 1-

HCV genotype

No consistent link between HCV genotype and disease progression has been demonstrated in several cohort studies.^{87, 90, 91, 115, 116} 2+

Cryoglobulinaemia

A poor quality meta-analysis of the influence of cryoglobulinaemia suggested that cirrhosis is diagnosed more frequently in patients with cryoglobulinaemia.¹¹⁷ 1-