What Is the Likelihood That My Patient With Chronic Hepatitis C Will Develop Cirrhosis, Hepatocellular Carcinoma, and/or Hepatic Decompensation?
Seela
Ramesh,
MD
Mitchell L.
Shiffman,
MD
Approximately 4 million persons within the United States are infected with the hepatitis C virus (HCV). Chronic HCV is the most common cause of cirrhosis and hepatocellular carcinoma (HCC), and over 40% of all patients who undergo liver transplantation in the United States, Europe, Canada, Australia, and many countries have chronic HCV infection.1 Despite this, the natural history of chronic HCV has a wide spectrum. Only 4% of persons with chronic HCV develop end-stage liver disease and/or HCC and need to consider liver transplantation as a therapeutic option (Figure 1-1). To some this may not sound like a major health problem. However, with 4 million persons infected, it is anticipated that 160,000 persons will develop end-stage disease and need to consider liver transplantation within the next 1 to 2 decades. Unfortunately, only about 5000 to 6000 liver transplants are performed in the United States annually, and roughly half of these are in patients without chronic HCV. It would therefore require 50 to 65 years for all those patients with end-stage liver disease from chronic HCV to receive a liver transplant. Clearly, this is an impossible task and many of these patients will not survive the pretransplant waiting period.
Figure 1-1. The natural history of patients following chronic HCV. Numbers in parentheses reflect the percentage of the total group of persons with chronic HCV infection.
When patients first find out they have chronic HCV, the vast majority are afraid that they already have cirrhosis, will develop cirrhosis or HCC, require a liver transplant, and/or die within the next 1 to 2 years. Educating patients regarding the natural history of chronic HCV is one of the most important things that a physician can do for a patient with recently diagnosed chronic HCV. As already noted above, the vast majority of patients with chronic HCV will not develop end-stage liver disease. It is therefore imperative that the physician be able to recognize which patients with chronic HCV are at increased risk to develop cirrhosis and to counsel all patients accordingly.
The natural history of chronic HCV and cirrhosis is now well established. Our understanding of this is based upon prospective long-term natural history studies initiated in the 1970s prior to the development of interferon therapy and cross-sectional studies of patients with chronic HCV being evaluated for HCV treatment. As depicted in Figure 1-2, patients with chronic HCV can be divided into one of three groups: (1) patients who will never develop any fibrosis; (2) patients with rapid fibrosis progression who develop cirrhosis within 20 to 30 years after being exposed to HCV; and (3) patients with slow fibrosis progression who would eventually develop cirrhosis but at much slower rates, which would require 30 years or more following exposure. Many persons in this later category may endure 50 to 60 years of chronic HCV infection before they develop cirrhosis. Chronic HCV may therefore not cause morbidity or contribute to mortality in these patients until they reach the seventh or eighth decades of life. During this entire time the great majority of patients with chronic HCV infection are asymptomatic.
Figure 1-2. Fibrosis progression in patients with chronic HCV.
The use of liver biopsy and examination of liver histology has traditionally been utilized to assess the risk of developing cirrhosis. The role of liver biopsy in the assessment of patients with chronic HCV is discussed in Question 3. The largest prospective study to evaluate fibrosis progression was initiated in the 1970s prior to the identification of HCV.2 This study enrolled patients with non-A, non-B hepatitis, over 95% of whom tested positive for HCV when this assay became available in the early 1990s. After an initial liver biopsy, these patients were followed prospectively for 20 years. Repeat liver biopsy was performed after 10 and 20 years or when these patients were thought to have developed cirrhosis based upon clinical grounds. All patients with bridging fibrosis on the initial liver biopsy developed cirrhosis within 5 to 10 years. All patients with portal fibrosis also developed cirrhosis, but this required 10 to 20 years. In contrast, less than 25% of patients with no fibrosis on the initial biopsy developed cirrhosis within 20 years. It is therefore apparent that patients with any degree of fibrosis will progress and eventually develop cirrhosis. Although this may take nearly 2 decades in some patients, it remains unclear how to identify those patients who will progress. This is why it is recommended that patients with any degree of fibrosis on liver biopsy be offered treatment with peginterferon and ribavirin. Waiting until patients “declare themselves” by developing more fibrosis is not recommended since sustained virologic response following treatment with peginterferon and ribavirin has been shown to be inversely related to the degree of fibrosis on liver biopsy. In contrast, the vast majority of patients with no fibrosis on liver biopsy will not develop cirrhosis over the next 2 decades or longer. The majority of these patients have normal liver transaminases (see Question 2).
Population-based studies have identified several risk factors associated with the development of cirrhosis.3 These include acquiring HCV at a later age, obesity, human immunodeficiency virus (HIV) coinfection, and having a concomitant liver disease such as HBV coinfection, hemochromatosis, nonalcoholic steatohepatitis, or being homozygous or heterozygous for alpha-1-antitrypsin deficiency. Regular alcohol use is frequently listed as a factor that accelerates the progression of chronic HCV to cirrhosis and increases the risk of developing HCC. While this is likely to be correct for persons who consume more than 6 alcoholic beverages per day, it remains unclear and controversial whether smaller amounts of alcohol, 1 drink per day or less, impact the natural history of chronic HCV.4
A genetic test has recently been developed that may allow physicians to identify those patients with chronic HCV who will develop fibrosis progression.5 This genetic test is performed on whole blood and assesses for certain single nucleotide polymorphisms (SNPs) in 7 genes, some of which are related to hepatic inflammation and fibrosis. The pattern of SNPs in these 7 genes is then converted into a numerical score that correlates with the risk of developing advanced fibrosis and cirrhosis. The Cirrhosis Risk Score (CRS) will soon be commercially available and can be utilized to identify patients who will progress to cirrhosis. Patients with a high CRS need not undergo a liver biopsy and can simply be considered for HCV treatment.
The natural history of cirrhosis in patients with chronic HCV has been evaluated in prospective clinical trials conducted over several decades prior to the availability of interferon.6 In one of these studies, 380 patients with a Child-Pugh-Turcotte (CPT) score of 6 or less and without any prior complications of cirrhosis were followed for up to 10 years. Overall, over 80% of these patients were alive after 10 years of follow-up. In contrast, patients who had either a decline in the CTP score or developed complications of cirrhosis had a marked decline in survival; approximately 50% of patients with decompensated cirrhosis died within 5 years and only 30% remained alive after 10 years. Thus, patients should be referred to a liver transplant program as soon as they develop a CPT score of 7 or greater and/or if a complication of cirrhosis such as variceal hemorrhage, ascites, hepatic encephalopathy, or HCC develops. Approximately 3% to 5% of patients with stable cirrhosis will develop complications of cirrhosis and another 1% to 3% will develop HCC on an annual basis. Thus, after 5 years of following a group of patients with stable cirrhosis, 20% would be expected to have developed hepatic decompensation and 10% to have developed HCC. Thus, patients with chronic HCV and cirrhosis need to be monitored at periodic intervals for evidence of hepatic decompensation and to screen for HCC. In our own practice we see these patients every 3 to 6 months to assess liver function and to screen for HCC. The latter is discussed in Question 39.
In summary, the vast majority of patients with chronic HCV develop progressive fibrosis and a significant proportion will develop cirrhosis. Assessing the degree of fibrosis by performing a liver biopsy is very helpful in assessing this risk and counseling patients. The cirrhosis risk score may prove to be very useful in identifying patients with significant risk for developing cirrhosis and reduce the need for liver biopsy. Approximately 3% to 5% of HCV patients with stable cirrhosis are at risk to develop hepatic decompensation per year; another 1% to 3% will develop HCC. As a result, monitoring and screening patients with HCV and cirrhosis on a regular basis are imperative. Since patients with any degree of fibrosis are at risk to progress, all such patients should be considered candidates for treatment with peginterferon and ribavirin.
References
1. Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36(5 Suppl 1):S30-S34.
2. Yano M, Kumada H, Kage M, et al. The long term pathological evolution of chronic hepatitis C. Hepatology. 1996;23:1334-1340.
3. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:825-832.
4. Monto A, Patel K, Bostrom A, et al. Risks of a range of alcohol intake on hepatitis C–related fibrosis. Hepatology. 2004;39:826-834.
5. Huang H, Shiffman ML, Friedman S, et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology. 2007;46:297-306
6. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated and cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463-472.