NATAP: Liver Biopsy-pro & con

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Liver Biopsy in HCV: pro & con

All Hepatitis C Patients Should be Offered

Liver Biopsy and Treatment

BY BRUCE R. BACON, MD

F. King, MD, Endowed Chair in Gastroenterology, Professor of Internal Medicine and Director of the Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine

Or

Liver Biopsy in the Management of Hepatitis C:

Not Always Required

BY DONALD M. JENSEN, MD

Professor of Medicine, Director, Center for Liver Disease, University of Chicago Hospitals

All Hepatitis C Patients Should be Offered Liver Biopsy and Treatment

By Bruce Bacon

We are aware that in clinical medicine there are rarely such absolutes as “all,†“never†or “always.†So I begin with some exceptions to the title of my article: “All hepatitis C patients should be offered liver biopsy and treatment.†For example, I would not biopsy and have never treated anyone with hepatitis C older than 80 years of age. Also, at the other extreme of age, I think it unlikely that any pediatric gastroenterologist/hepatologist would biopsy and treat infants, toddlers or even young adolescents with hepatitis C. Patients who are actively abusing alcohol or other substances are not good candidates for successful treatment, and my advice to those individuals is to solve their substance abuse problem first and then return to deal with their hepatitis C. So, there are some groups who probably should not be treated and who are thus not considered for liver biopsy.

The 2002 NIH Consensus Development Conference on Management of Chronic Hepatitis C recommended that all patients with hepatitis C be considered for

treatment (1). With this recommendation in hand, most clinicians use information

gained from liver biopsy to help determine whether or not a patient should be treated. With patients at the extremes of age and those with active substance abuse excluded, then we can divide our hepatitis C patients into two broad groups to consider for liver biopsy and treatment. The first group includes typical patients who are in their 40s or 50s, often with mild disease, who have been infected since their teenage years. These patients often have genotype 1 with intermediate levels of HCV RNA and may have normal or slightly elevated levels of serum ALT. Many have no symptoms, and most are both motivated to have treatment and able to be compliant and adherent to prescribed doses of peginterferon and ribavirin. These patients are optimal candidates for treatment

and need to know the likelihood of a successful response to treatment. In adherent genotype 1 patients, using weight-based ribavirin, the sustained virologic response rate (SVR) is 63 percent (2). For genotype 1 patients, liver biopsy is recommended to determine disease severity; this information guides the decision for or against treatment. If patients have stage 2 or greater fibrosis, treatment is generally recommended. In patients with no fibrosis (stage 0 or 1), either treatment or “watchful waiting†are acceptable approaches. For adherent genotype 2/3 patients, SVR rates are over 90 percent. Because of this high efficacy rate in genotype 2/3 patients, some clinicians have advocated that there

is no need for liver biopsy - just treat everyone for 24 weeks. Alternatively, many investigators now treat genotype 2/3 patients with stage 3 fibrosis or cirrhosis for 48 weeks (rather than the recommended 24 weeks); for considerations of longer treatment for patients with advanced fibrosis, liver biopsy is mandatory.

The second large group of patients to consider for treatment includes those spe-

cial populations of patients who present challenges to successful treatment. These include, but are not limited to, patients with chronic renal failure, those co-infected with human immunodeficiency virus (HIV), African-Americans, and patients with cirrhosis complicated by portal hypertension and hypersplenism. Patients with chronic renal failure have reduced efficacy from treatment because ribavirin cannot be used and peginterferon monotherapy in this patient population is only effective about 20 percent of the time (3). Patients co-infected with HIV have a reduced SVR rate compared to monoinfected patients - the reasons for this reduction in SVR are unknown (4, 5). Two studies have now shown a significant reduction in SVR for African-American patients when compared to Caucasians (6, 7). Once again, the reasons for this reduction in SVR are unknown.

Finally, patients with cirrhosis complicated by hypersplenism and cytopenias offer special challenges and must be managed very carefully. However, if treatment

is successful in these patients, a substantial and dramatic success has been achieved. For all these groups of patients, liver biopsy is essential to determine significance and severity of disease in order to determine whether a course of treatment with reduced efficacy is worthwhile. It must be remembered that even a 20 percent chance of success is better than the chances with no treatment. Further, with the use of early virologic response (EVR) guidelines (continuation of therapy for the full course of therapy only in patients having a >/=2 log10 drop in HCV RNA level from baseline with the initial 12 weeks of therapy), the commitment to treatment, with its atten dant side effects, is limited to only 12 weeks if therapy is those in whom therapy is not going to work.

For the typical motivated, compliant patient, biopsy is necessary to guide treatment decisions. Treatment should be offered to all patients. Patients with genotype 1 and mild disease can be offered treatment, but may decline. Similarly, in special populations of difficult-to-treat patients, biopsy is very helpful to determine the need for treatment in these patients with a reduced chance of success. Unfortunately, the various noninvasive tests of hepatic fibrosis are not sufficiently accurate to replace staging acquired by liver biopsy. We all look

forward to the day when treatment efficacy is improved in genotype 1 patients and side effects of treatment are minimized. We hope that day will come within

R E F E R E N C E S

1. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002- June 10-12, 2002. Hepatology 2002; 36:S3-S20.

2. McHutchison JG, Manns M, Patel K, Poynard T, KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ, Albrecht JK; International Hepatitis Interventional Therapy Group. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002; 123:1061-1069.

3. Meyers CM, Seeff LB, Stehman-Breen CO, Hoofnagle JH. Hepatitis C and renal disease: An update. Am J Kidney Dis 2003; 42:631-657.

4. Laguno M, Murillas J, Blanco JL, ez E, Miquel R, -Tapias JM, Bargallo X, -Criado A, de Lazzari E, Larrousse M, Leon A, Lonca M, Milinkovic A, Gatell JM, Mallolas J. Peginterferon alfa-2b plus ribavirin

compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004; 18:F27-36.

5. Torriani FJ, - M, Rockstroh JK, Lissen E, - J, Lazzarin A, Carosi G, Sasadeusz J, Katlama C, Montaner J, Sette H Jr, Passe S, De Pamphilis J, Duff F, Schrenk UM, Dieterich DT; APRICOT Study Group. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438-450.

6. Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treatment Group. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004; 350:2265-2271.

7. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004; 39:1702-1708.

Liver Biopsy in the Management of Hepatitis C: Not Always Required

BY DONALD M. JENSEN

The liver biopsy has long held a sacred place with hepatologists, but recently

its role and application in hepatitis C has been questioned. The liver biopsy provides much useful information that is difficult to obtain with precision by other means. The ability of hepatopathologists to grade the amount of inflammation and stage the degree of fibrosis has improved our understanding of the natural

history of hepatitis C and the extent to which viral, host and environmental factors

affect disease progression. In addition, the biopsy is able to assess concomitant

disorders such as steatosis, steatohepatitis (alcoholic and nonalcoholic), iron overload and autoimmune hepatitis, which may affect both the decision and effectiveness of the planned treatment. Many clinicians find the results from a liver biopsy helpful in counseling patients about prognosis and potential response to treatment. Some find that knowledge of aggressive histologic disease might even influence treatment decisions such as use of growth factors versus ribavirin or interferon dose reductions for cytopenias. Finally, the findings from a liver biopsy may prove useful in the decision to delay or avoid therapy in some patients with very mild or absent histologic disease and a difficult-to-treat viral genotype.

Regardless, not every hepatitis C patient should have a liver biopsy.

First, there is the attendant risk and discomfort. It has been estimated that the mortality rate of a percutaneous liver biopsy approaches 0.03 percent (1). Operator experience and expertise is likely important in limiting patient anxiety and minimizing complications and this fact alone may influence the decision to perform a biopsy if the clinician feels uncomfortable with the technique.

Radiologists have assumed a greater role as biopsy operators at some centers, but may use biopsy guns with an inadequate core sample size. It has been estimated that a minimally “adequate†liver biopsy core is at least 2.0 cm in length and 1 mm in width (2). In spite of this recommendation, and despite the fact that the liver biopsy is considered the gold standard to which all noninvasive tests are compared, the biopsy is hardly perfect. Even when cirrhosis is confirmed at autopsy, a single liver biopsy performed immediately prior to the autopsy was only able to confirm cirrhosis in 80 percent of cases (3). In a more recent study, Ratziu and colleagues compared the results obtained from two liver biopsy cores in a cohort of nonalcoholic fatty liver disease patients (4). They demonstrated that 35 percent of patients with bridging fibrosis on one of the biopsy samples had only mild or no fibrosis on the other paired sample. In addition to sampling problems, there is a well-known variability in the interpretation of biopsy activity and staging between pathologists.

Rapid advances have occurred in the past few years regarding surrogate fibrosis markers as an alternative to biopsy staging. These include readily available tests: platelet count, AST/ALT ratio, AST to platelet count ratio index (APRI), GGT, cholesterol, and haptoglobin (5, 6) as well as assays using combinations of more experimental serum markers (7) and transient elastography (8). In general, these surrogate tests are quite good (75-85 percent accuracy) in the detection of very low (Metavir F0-F1) and very high (Metavir F3-F4)

fibrosis scores, but are less able to differentiate between intermediate stages of disease. However,

these are exactly the two histologic extremes (very mild versus very advanced fibrosis) that are of most interest for treatment decisions.

In general, a liver biopsy is probably not required when knowledge of biopsy results will not affect management decisions. Performance of a liver biopsy should not become a gatekeeper for therapy. As an example, patients with signs of endstage or decompensated cirrhosis do not generally require a liver biopsy to assess their therapeutic options.

Highly successful therapy might also make knowledge of liver biopsy findings less pertinent to the decision to treat or not to treat. Genotype 2 and 3 patients have a high sustained virologic response (SVR) with as little as 24 weeks of treatment and 800 mg of ribavirin, which approaches 80 percent (9). Genotype 2 patients can probably be well-managed without a liver biopsy - at least those who are treatment candidates - since the SVR rate exceeds 90 percent (10). The same can be said for most genotype 3 patients (SVR approximately 79

percent). Until there is prospective data demonstrating that the presence of significant steatosis leads to more rapid fibrosis progression (11) which responds to a more intensive course of therapy, genotype 3 subjects could probably continue to be offered treatment without a baseline liver biopsy.

Somewhat controversial is the situation of older genotype 1 patients with a long

history of HCV infection and low scores for non-invasive fibrosis markers (F0-F1).

They may appropriately be managed without a liver biopsy unless the patient

desires knowledge of the histologic stage. Nevertheless, these patients will still require close clinical monitoring since their disease may accelerate with little in the way of outward signs and symptoms. It has been suggested that patients with

mild chronic hepatitis C, in whom it was elected to defer therapy, should probably

undergo liver biopsy every three to five years in order to assess disease progression.

Wong and Koff suggest that initial empiric treatment of mild chronic hepatitis

C is more cost-effective than periodic liver biopsy every three years, and should

reduce future risk of cirrhosis and prolong life (12). Since this study was published, improvements in treatment outcome should further favor immediate initial treatment over periodic liver biopsy.

Finally, there are some situations in which a liver biopsy poses a greater than

normal risk of bleeding. One may consider the use of noninvasive fibrosis makers in lieu of a liver biopsy in selected cases. This option may be considered in the uncooperative subject, in a patient with a history of bleeding complications from other invasive procedures and in some patients with renal insufficiency. However, many of these latter patients may safely undergo liver biopsy via the transvenous approach and/or with the use of clotting factor concentrates or DDAVP.

While the liver biopsy is a useful diagnostic tool that provides essential clinical

information, it is not a perfect test. Many patients with chronic hepatitis C may be

quite effectively managed without this data. The NIH Consensus Conference

realized that liver biopsy was not essential in all hepatitis C patients:

since a favorable response to current antiviral therapy occurs in 80

percent of patients infected with genotype 2 or 3, it may not always

be necessary to perform liver biopsy in these patients to make a decision

to treat (13).

Likewise, the AASLD Practice Guideline on Hepatitis C stated that:

regardless of the level of the ALT, a liver biopsy should be done when the results will influence whether treatment is recommended, but a biopsy is not mandatory to initiate therapy (14).

As noninvasive surrogate tests become better standardized, and therapies more

effective, the role of a baseline pretreatment liver biopsy will likely find a diminishing role.

R E F E R E N C E S

1. Dienstag J: The role of the liver biopsy in chronic hepatitis C. Hepatology 2002;36:S161-S171

2. Guido M, Rugge M: Liver biopsy sampling in chronic hepatitis. Semin Liver Dis 2004;24:89-97.

3. Abdi W, Millan J, Mezey E: Sampling variability on percutaneous liver biopsy. Arch Int Med. 1979;139:667-669

4. Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T: Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898-1906.

5. Forns X, Ampurdanes S, Llovet J, Aponte J, Quinto L, ez-Bauer E, Bruguera M, -Tapias J, Rodes J:Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology

2002;36:986-992.

6. Lok A, Ghany M, Goodman Z, E, Everson G, Sterling R, Everhart J, K, Bonkovsky H, DiBisceglie A, Lee W, T, Dienstag J, Morishima

C: Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: Results of the HALT-C cohort. Hepatology 2005;42:282-292.

7. Patel K, Gordon S, son I, Hezode C, Oh E, K, Pawlotsky J, McHutchison: Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis

C patients. J. Hepatol 2004;41:935-942..

8. Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Ledinghen V: Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment

of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-350.

9. Hadzyannis S, Sette H, T, Balan V, Diago M, Marcellin P, Ramadori G, Bodenheimer H, Berstein D, Rizzetto M, Zeuzem S, Pockros P, Lin A, Ackrill A: Peginterferon alfa-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Int Med 2004;

140:346-355.

10. Zuezem S, Hultcrantz R, Bourliere M, et al: Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotype 2 or 3. J Hepatol 2004;40:993-999.

11. Fartoux L, Chazouilleres O, Wendum D, Poupon R, Serfaty L: Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. Hepatology

2005;41:82-87.

12. Wong J and Koff R: Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C. Ann Int Med 2000;133:665-675.

13. National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C: June 10-12, 2002. Hepatology 2002;36(suppl 1):S3-S20.

14. Strader D, T, D and Seeff L: Diagnosis, Management, and treatment of hepatitis C. Hepatology 2004;39:1147-1171.