RESEARCH ARTICLE


The Natural History of Hepatit is C Viral Infection: Clinical Evaluation and Monitoring



Matthew Chin, Christopher Hogan, Douglas Nguyen*
Division of Gastroenterology and Hepatology, University of California Irvine, Irvine, CA, United States


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© Chin et al.; Licensee Bentham Open

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the Assistant Clinical Professor of Medicine, Department of Medicine UC Irvine School of Medicine 333 City Blvd. West, Suite 400 Orange, CA 92868, United States; Tel: 714-456-6745; Fax: 714-456-7753; E-mail: douglaln@uci.edu


Abstract

Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease in the world and represents a substantial burden on global health systems and individual patient wellbeing. Routine screening for HCV in certain high-risk populations is appropriate. HCV can cause both an acute and chronic hepatitis, and manifests as a variety of hepatic and extrahepatic symptoms, largely influenced by a combination of host and viral factors. It can be difficult to predict clinical outcomes in individual cases. In those who suffer a chronic infection, progression to cirrhosis carries the risk of decompensation and hepatocellular carcinoma. The natural history of HCV infection and our understanding of risk factors that are predictive of disease progression are discussed.

Keywords: Chronic hepatitis C, Cirrhosis, Hepatocellular carcinoma, Natural history.



INTRODUCTION

Hepatitis C virus (HCV) infection is one of the most common causes of chronic liver disease, affecting as many as 185 million people worldwide [1]. Population-based representative studies administered by the National Health and Nutrition Examination Survey (NHANES) estimate that the prevalence of HCV-antibody positivity in the US between 2003 and 2010 was 1.3%, or, 3.6 million persons [2] although other studies estimate that the true prevalence may be as high as 5.1 million persons [3]. The sequelae of chronic HCV (CHC) infection include cirrhosis and hepatocellular carcinoma (HCC). In the US, HCV-related liver disease is a common diagnosis responsible for inpatient hospitalization, a leading cause of death and a frequent indication for liver transplantation [4]. Conservative estimates place the cost of the total burden of HCV-related liver disease on the medical system at more than $5 billion [5].

HCV BIOLOGY

The HCV genome is a positive-strand RNA molecule of 9,500 nucleotides which encodes a 3,000 amino acid polyprotein. This large protein undergoes post-translational processing by host and viral enzymes to form structural and nonstructural viral proteins. The polymerase enzyme of RNA viruses lack proofreading ability and are therefore unable to correct errors made during the process of replication. These nucleotide changes result in tremendous viral heterogeneity, with the exception of the 5’ terminus of the viral RNA, which is highly conserved, and, therefore, a useful target for amplification in diagnostic assays. This heterogeneity plays an important role in the pathogenesis of disease, response to treatment, and to date, has made it difficult to develop an effective vaccine [6]. Six major genotypes and more than 50 subtypes of HCV have been identified [7], having risen out of unique infection patterns, population migration, immune selection, and replication efficiency [8].

HCV TRANSMISSION AND SCREENING

Transmission is most efficiently achieved through parenteral exposure to HCV. Intravenous (IV) drug use is the most common means by which patients in the US acquire HCV, with studies suggesting that 60% of newly acquired infections occur in those who have injected illegal drugs and that up to 77% of IV drug uses are anti-HCV positive [9]. Therefore, it is broadly recommended that individuals who have ever used illicit IV drugs should be tested for HCV infection [10]. Prior to the initiation of donor screening for anti-HCV antibodies in the 1990s, blood transfusion was a major risk factor for HCV infection, with more than 10% of transfusion recipients acquiring infection [11]. Following the introduction of routine screening of blood donors, transfusion-related HCV infection has become exceedingly rare, with an estimated risk of 1 in a million per unit transfused [12]. Individuals who have received blood transfusions or organ transplant prior to 1992 should be tested for HCV [13].

Routine testing for HCV is also appropriate in patients with unexplained elevations in aminotransferase levels, hemophilia patients who received blood products before 1987 (when viral inactivation procedures were implemented), hemodialysis patients, children born to HCV-infected mothers, patients with human immunodeficiency virus (HIV) infection, healthcare workers following a needle stick injury or mucosal exposure to HCV-infected blood, or sexually intimate partners of HCV-infected patients [13]. Finally, the US Preventative Services Task Force and Center for Disease Control recommends one-time testing of all patients born between 1945 and 1965, regardless of other risk factors, citing the higher prevalence of HCV in patients of this age demographic [14].

ACUTE AND CHRONIC HEPATITIS

Infection with HCV can result in both acute and chronic hepatitis. Acute hepatitis following HCV exposure typically develops within 2-26 weeks, with a mean onset of 7-8 weeks [15]. More than two-thirds of patients with acute HCV are asymptomatic,16 however, in those who develop symptoms, the most commonly reported symptoms are jaundice (68%), dark urine or acholic stool (39%), nausea (34%), and abdominal pain (25%) [16]. In those who develop symptoms, the acute illness can last from 2-12 weeks. Laboratory testing during the acute phase demonstrates a highly variable degree of serum aminotransferase levels (up to 10-20 times the upper limit of normal) [17] and bilirubin concentration (often > 3-4). HCV causes approximately 20% of all cases of acute hepatitis in the US [18]. Fulminant liver failure caused by acute HCV is rare, but may be higher in those with co-infection with hepatitis B virus (HBV) [19].

Following an acute episode of HCV, the risk of chronic infection is high. Between 80-100% of patients remain HCV RNA positive and 60-80% have persistent elevation in liver enzymes [20]. Many host factors may be involved in the ability of the host to spontaneously clear the virus. These factors include the host’s age, gender, and other comorbid conditions, such as body weight, hepatic steatosis, alcohol consumption, and co-infection with HBV and/or HIV.

There is a wide variability in serum aminotransferase concentrations among patients with CHC. Up to one-third of patients may have a normal ALT, and only slight enzyme elevations are typically found in remaining patients, with only 25% having a serum ALT concentration more than twice the upper limit of normal [21]. There is generally poor correlation between aminotransferase levels and liver histology [22].

Most patients who develop CHC infection are asymptomatic or have mild, nonspecific symptoms, which may be difficult to solely ascribe to viral infection [23]. The most commonly reported symptom is fatigue, but other symptoms may also include nausea, anorexia, myalgia, arthralgia, weakness, and weight loss. Symptoms may not reliably reflect disease activity, but appear to be more common once cirrhosis develops [24].

In a subset of patients, an acute exacerbation of CHC can occur, with significant elevation of serum aminotransferase levels over the baseline in the absence of other identifiable triggers. The true incidence of this phenomenon is unknown, but may be affect approximately 10% of patients [25]. Such increases may be associated with more rapid progression of disease. In a study of 82 patients with CHC followed for a median of 36 months, a greater proportion of subjects with history of such acute exacerbations we found to have progression of fibrosis and inflammation [26].

CIRRHOSIS

The natural history of CHC is difficult to define because of the long course of the disease. A review of 111 studies demonstrated that the estimated prevalence of cirrhosis is approximately 16% (95% CI 14-90%) after 20 years of HCV infection [27]. In one case series of US patients with post-transfusion CHC who were followed for a mean of 22 years after transfusion, 51% had developed cirrhosis, 23% had active chronic hepatitis, and 5% had HCC. The mean duration of infection among patients with cirrhosis was 20.6 years [28]. Asian and European studies have demonstrated similar results [29-31].

Just as not all patients with CHC will develop cirrhosis, not all patients with cirrhosis will develop complications. In a prospective cohort of 838 patients with CHC followed for, on average, 50 months, approximately 7% of the cohort developed liver-related morbidity and mortality, and the increased mortality was confined only to those who had cirrhosis at the time of presentation.33 In a report of 200 patients with HCV cirrhosis, the most common forms of decompensation were ascites (48%), gastrointestinal bleeding (32.5%), severe bacterial infection (14.5%), and encephalopathy (5%) [32]. In a study of 384 HCV patients with compensated cirrhosis, the risk of developing decompensation was 3.9% per year [33]. The probability of survival after initial decompensation was 81.8% and 50.8% at 1 and 5 years, respectively.

HEPATOCELLULAR CARCINOMA

The mortality associated with CHC in the US is mostly associated with the consequences of decompensated end stage liver disease rather than hepatocellular carcinoma. In contrast to HBV, HCC in patients with HCV occurs almost exclusively in those with cirrhosis. Once cirrhosis secondary to CHC has developed, it is estimated that patients have a 0-3% per year risk of developing HCC [33, 34].

FACTORS PREDICTIVE OF DISEASE PROGRESSION

Both host and viral factors may be important contributors to the natural history of HCV. Faster progression of liver disease is seen in patients of male gender [35], those who acquire HCV at an older age [31], and those of higher body mass index [36]. Alcohol intake, even at very low amounts, can also promote disease progression [37, 38]. The daily use of marijuana is also a risk factor for progression of fibrosis in those with HCV, possibly through the stimulation of endogenous hepatic cannabinoid receptors [39].

The host cellular immune system to HCV may also play a role in severity of liver injury. A retrospective study of 355 patients with CHC demonstrated that African-Americans have a slower rate of progression of disease compared to non-African-Americans, possibly as a result of less immunological recognition of HCV-infected liver cells [40]. There is a correlation between severity of liver disease with human leukocyte antigen (HLA) genes; in particular, lower frequency of alleles TNFB*1, DRB1*1104, and DRB3*03 appears to be protective, while DRB1*1001 appears to be associated with worse disease severity [41]. The activity of TGF B1 and angiotensisn II have also been shown to have a significant relationship in the development of liver fibrosis [42].

IL28B genotype is a known predictor of spontaneous clearance of HCV infection and has implications for a patient’s response to treatment with interferon and ribavirin, however, its effect on disease progression is unclear. Studies suggest that IL28B is not associated with fibrosis progression or risks of developing advanced liver disease; although this may be finding may be limited only with patients with non-genotype 1 infection [35-43].

The effect of viral factors on disease progression is unclear. Data on viral genotype and disease progression is contradictory. While some cross-sectional studies have shown genotype 1b HCV is overrepresented among patients with cirrhosis and HCC [44, 45], subsequent studies have failed to reproduce these results [46, 47]. Co-infection with more than one HCV genotype appears to lead to an accelerated disease course [46, 47]. Co-infection with HBV [48, 49] and/or HIV [50, 51] also predicts more rapid disease progression.

The best clinical predictor of disease progression is the amount of inflammation and fibrosis on liver biopsy. Yano et al. demonstrated those patients with mild inflammation (portal inflammation alone) and no fibrosis had only 1.2% per year risk of progression of fibrosis, while those with moderate chronic hepatitis (periportal inflammation greater than 30% of limiting plate) had a 4.6% per year risk of progression to cirrhosis [52]. 100% of patients with bridging fibrosis and severe inflammation developed cirrhosis.

CONCLUSION

An understanding of the natural history of HCV infection is an important part of the effort needed to reduce the impact of this worldwide health concern [53, 54]. There is a spectrum of clinical outcomes in those infected with HCV. Patients may develop asymptomatic self-resolving acute infection, or go on to suffer chronic infection, including the morbid consequences of cirrhosis and hepatocellular carcinoma. Certain host factors play a role in disease severity, including male gender, advanced age, elevated BMI, coinfection with HBV or HIV, and drug or alcohol use. A tremendous heterogeneity in viral characteristics is clearly important to disease severity, however, the effect of viral factors on disease progression is less understood.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology 2013; 57(4): 1333-42.
[2] Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014; 160(5): 293-300.
[3] Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int 2011; 31(8): 1090-101.
[4] Kim WR. The burden of hepatitis C in the United States. Hepatology 2002; 36(5)(Suppl. 1): S30-4.
[5] Leigh JP, Bowlus CL, Leistikow BN, Schenker M. Costs of hepatitis C. Arch Intern Med 2001; 161(18): 2231-7.
[6] Farci P, Alter HJ, Govindarajan S, et al. Lack of protective immunity against reinfection with hepatitis C virus. Science 1992; 258(5079): 135-40.
[7] Simmonds P, Alberti A, Alter HJ, et al. A proposed system for the nomenclature of hepatitis C viral genotypes. Hepatology 1994; 19(5): 1321-4.
[8] Dusheiko G, Schmilovitz-Weiss H, Brown D, et al. Hepatitis C virus genotypes: an investigation of type-specific differences in geographic origin and disease. Hepatology 1994; 19(1): 13-8.
[9] Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet 2011; 378(9791): 571-83.
[10] Wasley A, Miller JT, Finelli L. Surveillance for acute viral hepatitis--United States, 2005. MMWR Surveill Summ 2007; 56(3): 1-24.
[11] Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989; 321(22): 1494-500.
[12] Pomper GJ, Wu Y, Snyder EL. Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol 2003; 10(6): 412-8.
[13] Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49(4): 1335-74.
[14] Moyer VA. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2013; 159(5): 349-57.
[15] Marcellin P. The clinical spectrum of the disease. J Hepatol 1993; 31(1): 9-16.
[16] Gerlach JT, Diepolder HM, Zachoval R, et al. Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003; 125(1): 80-8.
[17] Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet 2008; 372(9635): 321-32.
[18] Alter MJ, Mast EE. The epidemiology of viral hepatitis in the United States. Gastroenterol Clin North Am 1994; 23(3): 437-55.
[19] Chu CM, Yeh CT, Liaw YF. Fulminant hepatic failure in acute hepatitis C: increased risk in chronic carriers of hepatitis B virus. Gut 1999; 45(4): 613-7.
[20] Barrera JM, Bruguera M, Ercilla MG, et al. Persistent hepatitis C viremia after acute self-limiting posttransfusion hepatitis C. Hepatology 1995; 21(3): 639-44.
[21] Conry-Cantilena C, VanRaden M, Gibble J, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996; 334(26): 1691-6.
[22] Haber MM, West AB, Haber AD, Reuben A. Relationship of aminotransferases to liver histological status in chronic hepatitis C. Am J Gastroenterol 1995; 90(8): 1250-7.
[23] Merican I, Sherlock S, McIntyre N, Dusheiko GM. Clinical, biochemical and histological features in 102 patients with chronic hepatitis C virus infection. Q J Med 1993; 86(2): 119-25.
[24] Shakil AO, Conry-Cantilena C, Alter HJ, et al. Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virulogic, and histologic features. The hepatitis C study group. Ann Intern Med 1995; 125(5): 330.
[25] Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992; 327(27): 1899-905.
[26] Sagnelli E, Pisaturo M, Stanzione M, et al. Clinical presentation, outcome, and response to therapy among patients with acute exacerbation of chronic hepatitis C. Clin Gastroenterol Hepatol 2013; 11(9): 1174-1180.e11.
[27] Villano SA, Vlahov D, Nelson KE, Cohn S, Thomas DL. Persistence of viremia and the importance of long-term follow-up after acute hepatitis C infection. Clin Gastroenterol Hepatol 1999; 29(3): 908-14.
[28] Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995; 332(22): 1463-6.
[29] Kiyosawa K, Sodeyama T, Tanaka E, et al. Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 1990; 12(4 Pt 1): 671-5.
[30] Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The obsvirc, metavir, clinivir, and dosvirc groups. Lancet 1997; 349(9055): 825-32.
[31] Zarski JP, Mc Hutchison J, Bronowicki JP, et al. Rate of natural disease progression in patients with chronic hepatitis C. J Hepatol 2003; 38(3): 307-14.
[32] Planas R, Ballesté B, Alvarez MA, et al. Natural history of decompensated hepatitis C virus-related cirrhosis. A study of 200 patients. J Hepatol 2004; 40(5): 823-30.
[33] Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112(2): 463-72.
[34] Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology 1999; 29(4): 1311-6.
[35] Marabita F, Aghemo A, De Nicola S, et al. Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection. Hepatology 2011; 54(4): 1127-34.
[36] Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999; 29(4): 1215-9.
[37] Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998; 27(6): 1730-5.
[38] Pessione F, Degos F, Marcellin P, et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology 1998; 27(6): 1717-22.
[39] Hézode C, Zafrani ES, Roudot-Thoraval F, et al. Daily cannabis use: a novel risk factor of steatosis severity in patients with chronic hepatitis C. Gastroenterology 2008; 134(2): 432-9.
[40] Wiley TE, Brown J, Chan J. Hepatitis C infection in African Americans: its natural history and histological progression. Am J Gastroenterol 2002; 97(3): 700-6.
[41] Asti M, Martinetti M, Zavaglia C, et al. Human leukocyte antigen class II and III alleles and severity of hepatitis C virus-related chronic liver disease. Hepatology 1999; 29(4): 1272-9.
[42] Powell EE, Edwards-Smith CJ, Hay JL, et al. Host genetic factors influence disease progression in chronic hepatitis C. Hepatology 2000; 31(4): 828-33.
[43] Bochud PY, Bibert S, Kutalik Z, et al. IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes. Hepatology 2012; 55(2): 384-94.
[44] Nousbaum JB, Pol S, Nalpas B, Landais P, Berthelot P, Bréchot C. Hepatitis C virus type 1b (II) infection in France and Italy. Ann Intern Med 1995; 122(3): 161-8.
[45] Hatzakis A, Katsoulidou A, Kaklamani E, et al. Hepatitis C virus 1b is the dominant genotype in HCV-related carcinogenesis: a case-control study. Int J Cancer 1996; 68(1): 51-3.
[46] Bonis PA, Tong MJ, Blatt LM, Conrad A, Griffith JL. A predictive model for the development of hepatocellular carcinoma, liver failure, or liver transplantation for patients presenting to clinic with chronic hepatitis C. Am J Gastroenterol 1999; 94(6): 1605-12.
[47] Benvegnù L, Pontisso P, Cavalletto D, Noventa F, Chemello L, Alberti A. Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis. Hepatology 1997; 25(1): 211-5.
[48] Roudot-Thoraval F, Bastie A, Pawlotsky JM, Dhumeaux D. Epidemiological factors affecting the severity of hepatitis C virus-related liver disease: a French survey of 6,664 patients. Hepatology 1997; 26(2): 485-90.
[49] Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME, Raimondo G. Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 1999; 341(1): 22-6.
[50] Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology 1999; 30(4): 1054-8.
[51] Monga HK, Rodriguez-Barradas MC, Breaux K, et al. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 33(2): 240-7.
[52] Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996; 23(6): 1334-40.
[53] Seeff LB. Natural history of hepatitis C. Hepatology 1997; 26(3)(Suppl. 1): 21S-8S.
[54] Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998; 28(6): 1687-95.