Chronic hepatitis C with normal aminotransferase levels

Chronic hepatitis C with normal aminotransferase levels

GASTROENTEROLOGY 2004;126:1409 –1415 CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, ...

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GASTROENTEROLOGY 2004;126:1409 –1415

CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California

Chronic Hepatitis C With Normal Aminotransferase Levels AIJAZ AHMED and EMMET B. KEEFFE From the Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California

Clinical Case A 43-year-old woman is referred for management of chronic hepatitis C. After donating blood, the patient was informed that she had hepatitis C virus (HCV) infection. She initially saw her primary care physician who ordered a complete blood count, prothrombin time, and hepatic function panel. On referral evaluation, the patient has no symptoms or signs of chronic liver disease, and all of the laboratory tests arranged by her primary physician were normal.

Background Chronic hepatitis C is estimated to affect 170 million individuals worldwide, and at least 2.7 million persons in the United States are viremic with detectable HCV RNA.1 Most patients with chronic hepatitis C remain asymptomatic and without significant liver disease for 2 or more decades following infection.2 Natural history studies suggest that approximately 20% of patients with chronic hepatitis C progress to cirrhosis in the first 20 years of infection.1,2 The risk of cirrhosis in patients with persistently normal alanine aminotransferase (ALT) levels in the setting of chronic hepatitis C is even lower.3–5 Currently, liver biopsy is the most reliable method of staging the severity of hepatic fibrosis. Although peginterferon plus ribavirin combination therapy has resulted in significant improvement in the sustained virological response rate to approximately 50% overall, therapeutic efficacy remains less than optimal.6 –9 In addition, treatment is expensive (approximately $30,000/ year for drug costs alone) and associated with significant adverse effects.10

Definition of Normal ALT The criteria for a persistently normal ALT level in patients with chronic hepatitis C varies from one study to the other, with no universally accepted definition.3,4 The

absolute ALT level, number of tests performed, time interval between testing, total duration of observation, and coexisting other liver chemistry abnormalities may be crucial.3,4 The normal range for any laboratory test is typically estimated by obtaining samples from a population of “healthy” individuals (some of whom may have undiagnosed chronic hepatitis C or fatty liver), and the upper limit of the test is set at 2 standard deviations above the mean population value. In most clinical trials, patients with persistently normal ALT levels are defined on the basis of 2 or 3 normal ALT levels obtained at intervals of at least 1 month during a 6-month period of time preceding antiviral therapy.3,4

Epidemiology of HCV Infection With Normal ALT Blood Donor Population In the United States, approximately 0.4% of volunteer blood donors test positive for anti-HCV.11,12 Screening is performed with anti-HCV testing, and patients with a detectable anti-HCV undergo confirmatory testing for the presence of HCV RNA by polymerase chain reaction. Blood donor volunteers who test positive for anti-HCV are informed by blood bank personnel of their serologic status and advised to consult their personal physicians for evaluation. Routine screening of blood donors has facilitated the identification of many individuals with detectable anti-HCV who are asymptomatic and have no history of liver disease. In the blood donor population, approximately 25% of patients with chronic hepatitis C have persistently normal ALT levels.11,12 The majority of volunteer blood donors are unaware of underlying chronic hepatitis C before attempting to donate blood and, at the time of blood donation, deny a history of high-risk behavior for acquiring HCV. © 2004 by the American Gastroenterological Association

0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.02.073

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Table 1. Normal ALT: Degree of Hepatic Fibrosis Year

Author (ref)

N

Normal to minimal (%)

Mild to moderate (%)

Advanced (%)

1997 2000 2002

Hoofnagle et al.26a Shiffman et al.13b Pradat et al.17c

223 37 66

37 63 35

63 31 63

0.5 6 2

aLiterature

review to 1997. review. cMulticenter European experience. bInstitutional

On closer questioning in one study, however, 35% of donors admitted to use of illicit parenteral drugs in the past, and 20% had exposure to blood or blood products.11 General Population It is estimated that approximately 20% of patients with chronic hepatitis C have persistently normal ALT levels.4 In published studies, the proportion of patients with chronic hepatitis C who have persistently normal ALT levels has varied from 8% to 33%.11,13–18 Although the presence of persistently normal ALT levels does not exclude the presence of advanced liver disease or even cirrhosis, the great majority of patients have histologically mild liver disease (stage 0 to 1 fibrosis).17–25 The prevalence of cirrhosis in patients with chronic hepatitis C in the setting of normal ALT levels varies from 0.5% to 6% (Table 1).13,17,26 Natural History of HCV Infection with Normal ALT One of the major problems encountered by most investigators in studying the natural history of chronic hepatitis C is the inability to identify infected patients when they are asymptomatic and have normal ALT levels. In addition, patients with chronic hepatitis C and persistently normal ALT levels have been excluded from registration clinical trials.6 – 8 These patients are difficult to diagnose, and a small proportion come to medical attention with an incidental diagnosis or, more rarely, late after the development of cirrhosis with end-stage liver disease. It has been shown that patients with chronic hepatitis C and normal ALT levels have significantly lower hepatocyte proliferation rates, lower apoptosis rates, and milder histologic damage as compared with patients with elevated ALT levels.27 In patients with normal ALT levels, the rate of fibrosis progression is much slower than those with elevated ALT levels.11,16,23,24 In a recent European retrospective collaborative trial, 864 patients with chronic hepatitis C were studied to determine the correlation between ALT levels and his-

tological findings on biopsy.17 Only 8% of patients had persistently normal ALT levels, a lower proportion compared to prior studies.13–16,18 Histological scores were determined using the METAVIR system. In the subset of patients with persistently normal ALT levels, 85% had mild liver disease (stage 0 –1 fibrosis).17 Therefore, only a small proportion (i.e., 15%) of patients with chronic hepatitis C and persistently normal ALT levels had moderate (stage 2) or advanced (stage 3 to 4) fibrosis. In contrast, among patients with elevated ALT levels, only 25% had mild liver disease; approximately 50% of patients with elevated ALT levels had stage 2 fibrosis, and about 25% had stage 3 or 4 fibrosis. A few investigators have reported that chronic hepatitis C in patients with persistently normal ALT levels is consistently associated with signs of histologic damage and histologic severity that does not differ from patients with elevated ALT levels.19,25,28 It is difficult to compare these contradictory results due to differences in study designs. Large, prospective studies are lacking in this patient population as patients with persistently normal ALT levels typically evade early diagnosis and have been excluded from registration trials. Moreover, the progression of fibrosis in patients with chronic hepatitis C can be variable and nonlinear.29 There may be rapid progression of fibrosis associated with flares of hepatitis C,29 and the factors associated with this rapid progression have varied with study designs (longitudinal versus cross-sectional studies).11,29 –33

Potential Management Strategies Whether to treat or follow expectantly patients with chronic hepatitis C and persistently normal ALT levels and/or mild histologic liver disease is unclear. The utility of liver biopsy in this patient population has not been studied in a large number of patients. The observation that patients with persistently normal ALT levels and mild necroinflammation have a slower rate of fibrosis progression has reinforced the recommendation that patients with mild disease activity and scant hepatic fibrosis can delay antiviral therapy until newer treatments

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Table 2. Normal ALT: Pros and Cons of Peginterferon Plus Ribavirin Antiviral Therapy Pros Interruption or delay in the progression of liver disease Prevention of risk of HCV-related future complications Higher sustained virological response based on larger proportion of patients with mild fibrosis No evidence of posttreatment ALT flares Favorable cost-effectiveness analyses Cons Favorable natural history without treatment Lack of large prospective treatment trials Majority of experience retrospective with limited number of patients Definition of normal ALT uncertain and variable from study to study Adverse effects of antiviral therapy

with greater efficacy and fewer side effects become available.11,16,23,24 On the other hand, some patients with mild disease are not interested in the wait and watch approach. For example, a health care provider (e.g., surgeon, nurse), a prospective mother planning pregnancy, or an individual with nonhepatic manifestations of chronic hepatitis C such as cryoglobulinemia may want to pursue antiviral therapy to eradicate HCV infection irrespective of the degree of hepatic fibrosis. The results of peginterferon plus ribavirin registration trials have supported this approach by demonstrating a significantly higher sustained virological response among patients with minimal or no fibrosis (57%) compared with those with bridging fibrosis or cirrhosis (44%).6 Therefore, preemptive treatment of mild disease may be more efficacious than delaying treatment until progression to more advanced liver disease. On the other hand, the majority of patients with persistently normal ALT levels will not progress to advanced liver disease over the next 1–2 decades, based on available natural history studies, and can safely await newer therapy (Table 2). The 1997 National Institutes of Health (NIH) Consensus Development Conference on Hepatitis C concluded that treatment of chronic hepatitis C in the setting of persistently normal ALT levels was not beneficial, and should not routinely be undertaken.34 In 2002, the second NIH Consensus Development Conference on Hepatitis C recommended that patients with persistently normal ALT levels and minimal or no fibrosis on liver biopsy should be reassured of a favorable prognosis, undergo periodic monitoring, and may not need antiviral therapy in light of the adverse effects of treatment.5 However, it was also stated, with support from an European consensus conference,35 that decisions to treat such patients should be individualized, and based on patients’ preferences and willingness or unwillingness to

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Table 3. Normal ALT: Factors to Consider in Individualized Management of Chronic Hepatitis C HCV genotype (better response with genotypes 2 or 3 vs. genotype 1) Serum HCV RNA level (better response with less than vs. greater than 1 ⫻ 106 IU/mL) Histologic stage of disease (better response with stage 0–1 vs. stage 3–4) Patient motivation and preference Complications and symptoms of HCV infection Quality of life Presence of comorbid illnesses Age Disease duration

undergo initial and/or follow-up liver biopsies to assess disease progression.5 According to the NIH consensus statement, the decision to treat patients with persistently normal ALT levels should take into account several predictive factors that may influence the outcome of therapy, such as genotype, viral load, and presence of hepatic fibrosis, as well as general considerations, such as patient preferences and motivation for therapy, symptoms, quality of life, severity of comorbid illnesses, patient age, and disease duration (Table 3). In contrast to the data presented at the 1997 NIH consensus conference, it is now apparent that ALT levels appear to have no effect on the likelihood of response to antiviral therapy for chronic hepatitis C.36 In patients with persistently normal ALT levels, the sustained virological response with interferon monotherapy and standard interferon plus ribavirin combination therapy appear to be comparable to reported studies in patients with elevated ALT levels (Table 4).36 – 40 Zeuzem et al.41 recently reported preliminary results of a an international, multicenter, randomized controlled study using peginterferon alfa-2a 180 ␮g/week plus ribavirin 800 mg/day combination therapy for either 24 or 48 weeks in HCV-infected patients with persistently normal ALT levels and demonstrated treatment efficacy comparable to previous trials in patients with elevated ALT levels.6 –9 The overall sustained virological response was 30% and Table 4. Normal ALT: Response to Interferon Plus Ribavirin Antiviral Therapy Year

Author (ref)

N

ALT

Sustained virological response (%)

2000 2001 2001 2002 2002

Gordon et al.36 Lee et al.37 Di Bisceglie et al.38 Jacobson et al.39 Sponseller et al.40

44 19 24 56 24

⬍1.3 ⬍1.5 Normal Normal Normal

36 47 25 32 50

NOTE. Standard interferon, 3 million units 3 times per week. Table adapted from Bacon et al.4

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52% for the 24-week and 48-week treatment groups, respectively, versus 0% for an untreated control group.41 For patients with genotype 1, the sustained virological response was 13% in the 24-week treatment group and 40% in the 48-week group; for patients with genotypes 2 and 3, the sustained virological response was 72% and 78% in the 24-week and 48-week groups, respectively. Patients who relapsed after completion of treatment were noted to have mild, transient ALT elevations; only one patient had a posttreatment flare with ALT levels greater than 10 times upper limit of normal. In a related study, patients in the untreated control group were followed for 72 weeks to study the short-term natural history of patients with persistently normal ALT levels in the setting of chronic hepatitis C.42 Transient elevation of ALT levels were noted in over 50% of control patients. This is an important observation and provides further data suggesting that the definition of persistently normal ALT levels in HCV population be reevaluated. Cost-Effectiveness and Quality of Life in Patients With Normal ALT A significant impairment in health-related quality of life was noted in a broad spectrum of patients with chronic hepatitis C when compared with healthy controls.43 In this report, there were no differences in quality of life between HCV patients with persistently normal ALT levels versus those with elevated ALT levels.43 In another study, the issues of quality of life and costeffectiveness were analyzed using a computer-based program in a simulated population of patients with chronic hepatitis C and histologically mild liver disease.44 Comparison was made between preemptive standard interferon plus ribavirin combination therapy without a liver biopsy, watchful waiting with a biopsy every 3 years, and combination therapy initiated only on evidence of moderate to severe histologic findings, and no treatment. It was demonstrated that preemptive treatment with interferon plus ribavirin reduces the future risk of cirrhosis to 16% as compared with 27% with no treatment, or 18% with watchful waiting and biopsy every 3 years. Preemptive immediate treatment should increase life expectancy by 1.0 quality-adjusted life-year as compared to watchful waiting with serial biopsies. In addition, preemptive treatment provided a saving of $5100 over the patient’s lifetime when compared to watchful waiting with repeated liver biopsies.44 Liver Biopsy in Patients With Normal ALT The issue of whether patients with chronic hepatitis C and persistently normal ALT levels should undergo a liver biopsy remains controversial. It is difficult

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Table 5. Normal ALT: Routine Versus Selective Liver Biopsy Benefits of Routine Liver Biopsy Gold standard for grading and staging the severity of liver disease to assist in the timing of antiviral therapy, especially in patients with genotype 1 who have a lower sustained virological response and require longer duration of therapy Diagnosis of coexisting liver diseases (uncommon) Identification of the small number of patients with cirrhosis who may benefit from screening for hepatocellular carcinoma Basis for Selective Liver Biopsy High sustained virological response rate in patients with genotypes 2 and 3, making routine liver biopsy optional Invasive procedure with risk of complications Favorable cost-effectiveness analysis to treat without biopsy Patient preference to not undergo biopsy, with or without treatment

to recommend a liver biopsy on a routine basis to patients with persistently normal ALT levels since the progression rate of fibrosis, although somewhat variable, is generally slow.27 On the other hand, information obtained from a liver biopsy may provide useful data to help decide between monitoring and antiviral therapy (Table 5). The option of performing a liver biopsy should be discussed with all patients who have persistently normal ALT levels in the setting of chronic hepatitis C. A liver biopsy may be useful in patients with persistently normal ALT levels who are interested in conservative management and express the desire to defer antiviral therapy. Patients with histologically mild liver disease can be reassured, while the small proportion of patients with more significant histological findings who may benefit from antiviral therapy can be identified. Patients who opt against liver biopsy must understand that there is a small risk, i.e., approximately 15% based on the data of Pradat et al.,17 that they may have moderate to advanced liver disease despite persistently normal ALT levels. Patients who wish to undergo antiviral therapy, particularly those with genotype 2 or 3, may quite reasonably opt not to have a liver biopsy before starting antiviral therapy based on the high sustained virological response rate of 75%– 80%.6 – 8 Thus, liver biopsy should be used selectively rather than routinely in patients with chronic hepatitis C, especially those with normal ALT levels. The indication for liver biopsy, as well as the potential benefits of antiviral therapy, needs further study in this subset of patients.

Recommended Management Strategy It may be prudent to recommend expectant management without the use of current antiviral therapy to patients with persistently normal ALT levels and/or mild

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Evolution of Case Initial Evaluation

Figure 1. Normal ALT: individualized management of chronic hepatitis C.

liver disease confirmed by liver biopsy.4,5 However, patients with biopsy-proven moderate or advanced liver disease should be encouraged to undergo treatment.4,5 On the other hand, patients with mild liver disease have a significantly better sustained virological response with antiviral therapy compared with those with more advanced liver disease.6 Furthermore, preemptive use of antiviral therapy in patients with mild liver disease may be cost-effective, improve quality of life, and prolong life.44 Thus, it remains controversial whether a patient with chronic HCV infection with persistently normal ALT levels should undergo liver biopsy, or whether a patient with mild histological disease by liver biopsy should be treated. It appears that the sustained virological response for patients with persistently normal ALT levels who undergo treatment, however, are comparable to those with elevated ALT levels in the absence of advanced fibrosis (Table 4).36 – 41 In summary, the decision regarding whether to treat or follow conservatively patients with chronic hepatitis C and persistently normal ALT levels should be individualized based on the presence or absence of factors predicting a successful outcome, as well patient preferences and general medical condition (Table 3) and should follow standard treatment guidelines (Figure 1).

A review of medical records on this 43-year-old woman with chronic hepatitis C revealed normal ALT levels on an annual basis over the previous 5 years. She most likely acquired HCV infection 25 years ago at the age of 18 as a result of injection drug use over a 1-year period, and she reported a history of jaundice at that time. No other risk factors were identified. She drank alcohol only rarely on special social occasions. She had no comorbid medical conditions. She worked full-time as an accountant and was a single mother, and exercised 5 days per week. Viral studies confirmed HCV infection with a serum HCV RNA level of 560,000 IU/mL and genotype 1b. Hepatitis A and B serologies were consistent with lack of immunity, and she underwent hepatitis A and B vaccination. The patient was unsure whether to proceed with antiviral therapy to eradicate HCV infection or defer treatment to maintain her active lifestyle. The efficacy, duration, and adverse effects of peginterferon plus ribavirin therapy were discussed with the patient. The role of liver biopsy and it complications were also reviewed. She ultimately requested a liver biopsy to facilitate a decision regarding management options, and biopsy showed mild histologic liver disease with grade 1 inflammation and stage 0 fibrosis. Subsequent Management Conservative management without antiviral therapy was recommended to the patient, based on the presence of mild histologic liver disease, excellent quality of life with lack of symptoms, and a demanding work and home schedule. The importance of continuing her healthy lifestyle was also stressed. She was given the option of a follow-up liver biopsy in 5 years, based on the expected slow progression of her liver disease.

Conclusion Persistently normal ALT levels are found in approximately 20% of patients with chronic hepatitis C. In this subset of patients, the disease is generally but not always mild, and the natural history is likely to be benign over the next 1–2 decades. The role of liver biopsy and long-term benefits of peginterferon plus ribavirin combination therapy needs to be further evaluated in these patients, but preliminary data suggests that the response to antiviral therapy is similar to the response in patients with elevated ALT levels. In addition, the definition of normal ALT levels in chronic hepatitis C needs re-evaluation. Pending data from future studies, empha-

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sis should be placed on individualizing management in this patient subpopulation.

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randomized, controlled study for the treatment of patients with chronic hepatitis C and persistently normal ALT levels with peginterferon alfa-2a (40 KD) (PEGASYS®) and ribavirin (COPEGUS姝) (abstr). Hepatology 2003;38:208A. 42. Shiffman M, Diago M, Tran A, Pockros P, Reindollar R, Prati D, Lamour F, Lardelli P, Zeuzem S. Natural history of patients with chronic hepatitis C and persistently normal alanine aminotransferase levels: data from the multinational Pegasys姝 study (NR 16071) (abstr). Hepatology 2003;38:434A. 43. Wagner MV, Lee JH, Friedl R, Wolfgang J, Kronenberger B, Sarrazin C, Zeuzem S. Impaired quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels. (abstr). Hepatology 2003;38:454A. 44. Wong JB, Koff RS. Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C. A cost-effectiveness analysis. Ann Intern Med 2000; 133:665– 675.

Address reprint requests to: Emmet B. Keeffe, M.D., Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, California 94304-1509. e-mail: [email protected]; fax: (650) 498-5692.