Hepatitis C clinical features and diagnosis

Hepatitis C is a single-stranded RNA virus from the Flaviviridae family (pictured in Figure 1). Chronic infection with hepatitis C virus (HCV) predominantly affects the liver and is a leading cause of chronic liver disease and liver cancer worldwide.

Although significant advances in the understanding and treatment of HCV have been made in the past 10 years, and the infection is now considered curable, national awareness of HCV is low and many carriers remain undiagnosed.

Epidemiology

The World Health Organization estimates that approximately 170 million people in the world are chronically infected with HCV — accounting for 3% of the population. The Health Protection Agency recently estimated that some 216,000 people in the UK could be affected by the virus, yet by 2012 just 95,000 people had been diagnosed.¹

These figures suggest that HCV infection is hugely under-diagnosed and most people who carry the virus are unaware of it. The reasons for this are multifactorial and efforts are being made to raise awareness of HCV among healthcare professionals and the general public.

Transmission

HCV is a blood-borne virus and so is transmitted primarily via the transfer of blood (or blood products) between people (see Box 1).

According to the WHO, around 90% of people from developed countries who have chronic HCV infection either have a history of intravenous drug misuse or received a blood transfusion before routine screening of blood products for HCV began in 1991. Although this practice has practically eradicated HCV infection by blood transfusion in the UK, not all countries do this and people who receive blood transfusions abroad may still be at risk of contracting the virus. Sexual transmission of HCV is relatively low, as is perinatal transmission.

The acute phase

About 50–90% of patients will be asymptomatic² following infection with HCV and so it is relatively uncommon to encounter patients during the acute phase. For patients who do develop symptoms, they are usually non-specific, such as decreased appetite, fatigue, abdominal pain, jaundice and flu-like symptoms.

Patients who become symptomatic in the acute phase are more likely to clear the virus spontaneously. Although they will have developed antibodies to HCV, such patients do not require pharmacological treatment and should not suffer any long-term complications. Acute HCV infection rarely leads to acute liver disease or liver failure.

Chronic infection

Although some patients may spontaneously clear the virus, approximately 85% of those infected with HCV will subsequently develop chronic infection — most developing chronic disease. Following exposure to the virus, it can take several weeks for serum alanine aminotransferase and aspartate transferase levels rise.Persistent, chronic inflammation of the hepatic cells can lead to fibrosis, and erratic hepatic cell regeneration causes the formation of small nodules that disrupt the architecture of the liver, i.e. cirrhosis.

Hepatitis C is often referred to as “the silent killer”because it can take 20–50 years for the disease to progress(see Figure 2). The progression of HCV is variable and each individual is affected differently by the virus. Not all those infected will develop serious complications and the severity of liver damage varies greatly between patients who do (see Box 2).

Cirrhosis will develop in approximately 20% of patients over a period of 20–25 years and the complications associated with cirrhosis are the main cause of HCV-related death. When the functional capacity of the liver is affected, patients experience the signs and symptoms of end-stage liver disease, such as jaundice, ascites, gastro-oesophageal varices, encephalopathy, coagulopathy and pruritus. Certain patient factors, such as high alcohol intake, diabetes, immunosuppression, obesity and co-infection with other viruses such as hepatitis B or HIV^3,4 have been found to be associated with the faster progression of cirrhosis.

Chronic HCV infection is also thought to be responsible for 50–76% of all liver cancers and is the most common reason for liver transplantation in Europe andNorth America. Although primarily a disease of the liver,HCV infection can cause extra-hepatic complications such as cryoglobulinaemia and porphyria cutanea.

Diagnosis

HCV infection is diagnosed by the detection of HCV antibodies (anti-HCV) and the presence of HCV RNA int he blood.

When HCV infection is first suspected, a serological test for anti-HCV is performed. It can take up to three months for antibodies to reach a detectable level after infection and so a negative result within this time does not rule out a diagnosis of HCV infection. Similarly, a positive result does not confirm chronic HCV infection because the patient may have spontaneously cleared the virus during the acute phase of infection.

Blood samples that test positive for anti-HCV are then tested for HCV RNA, which indicates viraemia.

Six main genotypes of HCV RNA have been identified. Genotype 1 is the most prevalent type in the western world, and in the UK around 90% of patients affected by HCV have the genotypes 1 or 3. Various qualitative and quantitative assays for HCV RNA are available and quantitative assays tend to be more frequently used. It is important to know which assay has been used and what the lower limit of detection is for each one to interpret results accurately.

Measuring the level of HCV RNA in the blood and identifying HCV genotype can guide treatment choice and predict response to treatment. Strict stopping rules(futility rules) must be adhered to during treatment, particularly when directly acting antivirals are used. The incorporation of directly acting antivirals into clinical practice has emphasised a need for rapid access to HCVRNA results and encourages the use of highly sensitive assays (ideally with a lower limit of detection of 15iu/ml)for treating patients safely and effectively.

Testing

Venepuncture is the gold standard for HCV testing; however, dried-blood spot testing can also be used as an alternative for patients with poor venous access, those who are needle phobic or when the equipment and expertise required for venepuncture are unavailable. The NationalInstitute for Health and Care Excellence public health guidance⁵ (December 2012) addresses ways to promoteand increase testing for viral hepatitis.

Some community pharmacies have been involved in pilot HCV testing schemes — offering dried-blood spot testing to those at a high risk of contracting the virus, e.g. intravenous drug misusers — and early results of these have been promising.

Box 2: Disease severity

Assessing the severity of liver disease in patients with hepatitis C is needed to determine prognosis and for planning treatment. Liver biopsies were used traditionally to provide this information but alternative, non-invasive methods to assess liver fibrosis have now been developed. These include measuring serological markers and transient elastography (eg, FibroScan)and have been evaluated extensively in patients with chronic hepatitis C. A FibroScan assesses the extent of liver fibrosis by generating a mechanical pulse at the surface of the skin which propagates through the liver. The velocity of the pulse is measured by ultrasound and correlates directly with the stiffness of the liver, which in turn reflects the degree of fibrosis.

References

1 Health Protection Agency. Hepatitis C in the UK. August 2012.www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317135237219(accessed 10 April 2013).

2 European Association for the Study of the Liver. Management of hepatitisC virus infection. Journal of Hepatology 2011;55:245–64.

3 Alter M. Epidemiology of hepatitis C in the west. Seminars in LiverDisease 1995;15:5–14.

4 National Institutes of Health. Consensus statement on management of hepatitis C. National Institutes of Health Consensus and State-of-the-Science Statements 2002;19:1–46.

5 National Institute for Health and Care Excellence. Hepatitis B and C: Ways to promote and offer testing to people at increased risk of infection December 2012. www.nice.org.uk/ph43 (accessed 10 April 2013).