Jules L. Dienstag, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

As the efficacy of therapy for chronic hepatitis C improves, as acceptance of such therapy becomes more widespread, and as management of chronic hepatitis C extends from specialist hepatologists to nonspecialists, the role of liver biopsy in the management of chronic hepatitis C is being re-examined. When the role of liver biopsy was considered during the previous NIH Consensus Development Conference in 1997, pretreatment liver biopsy was endorsed as the “gold standard” for assessing the grade of liver injury and the stage of liver fibrosis in anticipation of antiviral therapy. The same recommendations appear in the consensus statement of the European Association for the Study of Liver Disease; are supported by the Centers for Disease Control, United States Public Health Service; and are implied in the consensus statement on prevention and management of hepatitis C in the Asia-Pacific region. Since that time, a series of reports have appeared either supporting or challenging the role of such histologic assessment in the management of chronic hepatitis C. In reevaluation of the value of liver biopsy, we should consider whether hepatic histology (a) provides prognostic information about the future natural history of chronic hepatitis C, (b) predicts the likelihood of response to antiviral therapy, and (c) remains the gold standard that it represented or can be supplanted by “surrogate” indicators.

Selecting patients for treatment would be easier if available therapy were uncomplicated, highly effective, simple to administer, limited in duration, and well tolerated. In patients with chronic hepatitis C, however, available therapy is far from ideal, and many factors color the decisions of individual patients and their physicians. Antiviral therapy for chronic hepatitis C requires injection therapy; side effects are common and especially difficult to accept in a population of predominantly asymptomatic persons; approximately half of treated patients fail to respond to the best therapy available; for many patients progression is so slow and limited that the decision to treat is readily postponed; and, if the steady progress in efficacy of antiviral therapy over the last decade is an indication of progress to come, many patients might fare just as well to wait until antiviral therapy improves. Perhaps, for patients with HCV genotypes 2 and 3, response to therapy is so likely that the threshold for treatment is achieved in almost all cases; however, because most patients have genotype 1, and because 60 percent of patients in this category fail to respond, pretreatment variables that shed light upon prognosis and likelihood of response to therapy are valuable for decision-making about therapy.

Although much is known about the natural history of chronic hepatitis C in large cohorts of affected persons, predicting the future course of the disease in any individual is difficult. Of the several potential prognostic variables, the most reliable appears to be histologic grade and stage, as assessed by one of several extant histologic classifications systems. Studies relying on serial liver biopsies suggest that patients with mild hepatitis and limited fibrosis progress slowly or not at all over a 10–20 year horizon, while those with moderate to severe inflammation (grade) and fibrosis (stage) progress inevitably to cirrhosis over a 20–10 year horizon, respectively. Therefore, a baseline biopsy is useful for determining the urgency of initiating therapy. Moreover, almost all instances of hepatitis C being discovered in clinical practice now represent hepatitis C virus (HCV) infections acquired one to three decades earlier, originating at a time of life when “risky” behavior occurred, even transiently. Thus, for most patients  undergoing liver biopsy for chronic hepatitis C, current biopsy includes an approximate assessment of the impact on inflammation and fibrosis of several decades of HCV infection and virus-associated liver injury. These observations have been invoked as the primary justification for recommending liver biopsy prior to embarking upon a course of antiviral therapy.

Liver biopsy is felt to be helpful in excluding other causes of liver injury that might confound interpretation of the clinical and histologic expression of HCV infection. Because some patients with chronic hepatitis C have other, concomitant causes of liver injury, a pretreatment liver biopsy to exclude such alternative factors as fat, alcohol, iron, etc. may shift clinical focus away from hepatitis C to the alternative process. Moreover, some of these factors, e.g., fat or iron, have been suggested to be cofactors in the progression of fibrosis. Another argument in favor of a pretreatment biopsy in patients with chronic hepatitis C can be made for anyone with any type of liver disorder for which treatment is an option. That is, a baseline biopsy obtained prior to committing a patient to long-term treatment preserves the value of potential subsequent histologic assessment for management decisions made in the future.

Based upon histologic prognostication, many clinicians decline to pursue therapy in patients with mild chronic hepatitis C. From a societal perspective, however, Wong et al. suggested that treatment of mild chronic hepatitis with combination interferon-ribavirin is actually cost-effective, reduces the risk of cirrhosis, and prolongs survival. The comparison strategy for this analysis was watchful waiting, with liver biopsies repeated every three years and therapy introduced for histologic progression; in addition, the calculated costs of therapy involved the combination of standard interferon with ribavirin. Although sensitivity analyses were included to address uncertainties in the many estimates required for such an analysis, this analysis was based upon costs of a previous generation of therapy, not the increased costs of contemporary therapy with pegylated interferon plus ribavirin. In addition, the benefit identified would be marginal or negligible if only one additional liver biopsy were to be performed in the future, and the analysis could not include the impact of the inevitable introduction of more effective, better tolerated treatments that would justify postponing treatment for several years.

Whether critiques of this analysis are substantial or quibbling, the perspective of individual patients and physicians may be very different and no less valid or compelling than the societal perspective adopted in this analysis. For many patients with mild disease and a likelihood of progression to cirrhosis that may be as low as 20 percent over 20 years, a viable strategy would allow postponing treatment for several years and embracing therapy without an additional liver biopsy when more highly effective treatments become available.

Liver biopsy would be less important were other clinical or laboratory tests available that could predict reliably the grade of inflammatory injury or the stage of fibrosis; however, to date, no such surrogates have been validated. Weighing against liver biopsies are the high costs of the procedure as well as its invasive nature and associated risks. Because most patients referred for evaluation have moderate to severe chronic hepatitis on liver biopsy, and because liver biopsies have been found by some investigators to have a limited impact on decision-making about treatment, the importance of a pretreatment liver biopsy might be questioned. Even the assumption that liver biopsy would be valuable for excluding other diagnoses in patients with chronic hepatitis C could not be confirmed by Saadeh et al. Nevertheless, these investigators marshaled data to support the utility of pretreatment liver biopsy by showing limited sensitivity and specificity of nonhistologic approaches, none of which was adequately predictive of  histologic findings in the large majority of patients. Predicting the presence of cirrhosis is especially challenging; cirrhosis can be present in up to half of well compensated patients with chronic hepatitis C, and neither a single test nor a combination of clinical and laboratory features has been shown to have sufficient predictive value for the presence of cirrhosis. Given the implications of cirrhosis for surveillance and management, baseline biopsy takes on special importance.

On the other side of the coin, baseline biopsies have been reported to demonstrate unexpectedly mild liver disease in some patients referred for treatment, including persons with hemophilia and with injection drug use, and the more publicized women who received contaminated anti-D immune globulin in Ireland and Germany. Thus, nonhistologic assessments have neither the sensitivity nor the specificity to replace liver biopsy in the initial assessment of suitability for treatment. Another area of potential controversy is the subset of patients with chronic hepatitis C but persistently normal aminotransferase activities. Anecdotal reports have appeared to show that some of these patients have histologically very severe or advanced liver disease, suggesting that all such patients require liver biopsy to unearth clinically subtle but advanced liver disease.

When group data are evaluated, however, the preponderance of evidence suggests that severe liver injury is the marked exception in such patients. Moreover, among patients with chronic hepatitis C and persistently normal aminotransferase levels, histologic activity, as monitored by sequential liver biopsies over more than half a decade, does not progress. Therefore, and because the last NIH Consensus Development Conference in 1997 failed to identify any benefit of  therapy in this subgroup, many authorities are reluctant to pursue liver biopsy in patients with normal aminotransferase activity.

Although other predictors of responsiveness to therapy exist, the degree of fibrosis has also been shown to be an independent inverse predictor of response to therapy. On the other hand, the negative predictive value of fibrosis or cirrhosis is too low to justify withholding therapy, and the need for therapy may be more compelling in this group of patients who have more advanced disease.

For contemporary antiviral therapy of chronic hepatitis C, pretreatment liver biopsy provides important information about prognosis and the need for early treatment and should be retained. Future research should focus on delineating how broadly histologic assessment should be implemented and whether other clinical features suffice to supplant liver biopsy under certain circumstances. Because liver biopsy is invasive, the search for noninvasive laboratory markers of necroinflammatory activity, fibrosis, and cirrhosis should command a high priority, as should the quest for genetic markers associated with accelerated disease progression.

 References

1. National Institute of Health Consensus Development Conference Panel Statement: Management of hepatitis C. Hepatology 1997;26:2S–10S.

2. Perrillo RP. The role of liver biopsy in hepatitis C. Hepatology 1997;26:57S–61S.

3. Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: The Knodell histology activity index and beyond. Hepatology 2000;31:241–6.

4. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825–32.

5. Yano M, Kumada H, Hage M, Ikeda K, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23:1334–40.

6. Wong JB, Koff RS, International Hepatitis Interventional Therapy Group. Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C: A cost-effectiveness analysis. Ann Intern Med 2000;133:665–75.

7. Fontaine H, Nalpas B, Poulet B, Carnot F, Zylberberg H, Brechot C, Pol S. Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C. Human Pathology 2001;32:904–9.

8. Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D, Easley K. The role of liver biopsy in chronic hepatitis C. Hepatology 2001;33:196–200.

9. Poynard T, Ratziu V, Benmanov Y, Di Martino V, Bedossa P, Opolon P. Fibrosis in patients with chronic hepatitis C: Detection and significance. Seminars Liver Dis 2000;20:47–55.

10. Mathurin P, Moussalli J, Cadranel J-F, Thibault V, Charlotte F, Dumouch P, Cazier A, Huraux J-M, Devergie B, Vidaud M, Opolon P, Poynard T. Slow progression rate of fibrosis in hepatitis C virus patients with persistently normal alanine transaminase (sic) activity. Hepatology 1998;27:868–72.

11. Persico M, Persico E, Suozzo R, Conte S, De Seta M, Coppola L, Palmentieri B, Sasso FC, Torella R. Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels. Gastroenterology 2000;118:760–4.

12. Martinot-Peignoux M, Boyer N, Cazals-Hatem, D, Pham B-N, Gervais A, Le Breton V, Levy S, Degott C, Valla D-C, Marcellin P. Prospective study on anti-hepatitis C virus-positive patients with persistently normal serum alanine transaminase (sic) with or without detectable serum hepatitis C virus RNA. Hepatology 2001;34:1000–5.