- Email: [email protected]
Liver biopsy in chronic hepatitis C: routine or selective
AJG – November, 2001
6. Alter MJ. Hepatitis C virus infection in the United States. J Hepatol 1999;31(suppl 1):88 –91. 7. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556 – 62. 8. Liou TC, Chang TT, Young KC, et al. Detection of HCV RNA in saliva, urine, seminal fluid, and ascites. J Med Virol 1992; 37:197–202. 9. Chayama K, Kobayashi M, Tsubota A, et al. Molecular analysis of intraspousal transmission of hepatitis C virus. J Hepatol 1995;22:431–9. 10. Simmonds P. Variability of hepatitis C virus genome. Curr Stud Hematol Blood Transfus 1994;61:12–35. 11. Dienstag JL. Sexual and perinatal transmission of hepatitis C. Hepatology 1997;26(suppl 1):66S–70S. 12. Buchbinder SP, Katz MH, Hessol NA, et al. Hepatitis C virus infection in sexually active homosexual men. J Infect 1994; 29:263–9. 13. Osella AR, Massa MA, Joekes S, et al. Hepatitis B and C virus sexual transmission among homosexual men. Am J Gastroenterol 1998;93:49 –52. 14. Chiaramonte M, Stroffolini T, Lorenzoni U, et al. Risk factors in community-acquired chronic hepatitis C virus infection: A case-control study in Italy. J Hepatol 1996;24:129 –34. 15. Caporaso N, Ascione A, Stroffolini T, et al. Spread of hepatitis C virus infection within families. J Viral Hepat 1998;5:67–72. 16. Wejstal R. Sexual transmission of hepatitis C virus. J Hepatol 1999;31:92–5. 17. Meisel H, Reip A, Faltus B, et al. Transmission of hepatitis C virus to children and husbands by women infected with contaminated anti-D globulin. Lancet 1995;345:1209 –11. 18. Power JP, Davidson F, O’Riordan J, et al. Hepatitis C infection from anti-D globulin. Lancet 1995;346:372–3 (letter). 19. Ohno T, Mizokami M, Lau JYN, et al. Sexual transmission of hepatitis C virus. In: Nishioka K, Suzuki H, Mishiro S, et al, eds. Viral hepatitis and liver disease: Proceedings of the International Symposium on Viral Hepatitis and Liver Disease: Molecules today, more cures tomorrow. Tokyo: SpringerVerlag, 1994:455– 8. 20. Piazza M, Sagliocca L, Tosone G, et al. Sexual transmission of hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. A randomized controlled trial. Arch Intern Med 1997;157:1537– 44. 21. Stroffolini T, Lorenzoni U, Menniti-Ippolito F, et al. Hepatitis C virus infection in spouses: Sexual transmission or common exposure to the same risk factors? Am J Gastroenterol 2001; 96:3138 – 41. 22. Mohamed MK, Hussein MH, Massoud AA, et al. Study of the risk factors for viral hepatitis C infection among Egyptians applying for work abroad. J Egypt Public Health Assoc 1996; 71:113– 42. 23. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 1998;47:16 –20. 24. Jaeckel E, Cornberg M, Mayer J, et al. Early treatment of acute hepatitis C infection with interferon-alfa 2b monotherapy prevents development of chronic HCV infection. Hepatology 2000;32:318A (abstract).
Liver Biopsy in Chronic Hepatitis C: Routine or Selective A percutaneous liver biopsy can be useful in patients with chronic hepatitis C virus (HCV) infection by providing
Editorials
3053
information regarding the stage of fibrosis and grade of inflammation. Expert consensus groups from the United States and Europe have recommended the routine performance of liver biopsy before initiation of antiviral therapy for chronic hepatitis C (1, 2). The purpose of a pretreatment liver biopsy is to distinguish patients most likely to benefit from therapy (i.e., those with moderate inflammation and advanced stages of fibrosis) from patients who may be less likely to benefit (i.e., those with mild inflammation and minimal or no portal fibrosis). A liver biopsy has been shown to be useful in determining the likelihood of progression of liver injury in chronic hepatitis C; moderate or severe inflammation and fibrosis have been associated with a more rapid progression to cirrhosis (3, 4). Most clinicians use liver biopsy to determine the urgency to treat their patients, and the current consensus guidelines recommend that only patients with significant fibrosis (Metavir stages F2 [a few septa], F3 [many septa], and F4 [cirrhosis]) should be considered for antiviral therapy (1, 2). In addition, a biopsy occasionally may yield an unexpected diagnosis or document a coexisting condition such as nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis, or significant iron loading. Finally, if current investigational methods of treating fibrosis come of age and become clinically useful, then an acceptable method of quantifying liver fibrosis becomes an essential requirement to monitor and determine endpoints of therapy. However, patients with chronic hepatitis C are not always eager to have a liver biopsy. They frequently have anticipatory anxiety, which would be expected of a procedure that is associated with pain in 30% of patients, severe complications in 0.3%, and death in 0.03% (5, 6). In a study conducted in our center, the duration of pain after biopsy extended beyond the day of the biopsy in 40% of patients, and extended for over 1 wk in a small number (I. Barnard and G. Garcia, unpublished data). In our study, 15% of patients who had a liver biopsy would not have agreed to have the procedure done if they had known how they would feel during and after the procedure. Liver biopsy also adds significant direct costs (equipment, observation time, and time of a skilled clinician and pathologist) and indirect costs (time away from work and home) to the management of patients with chronic hepatitis C. Finally, a cost-effectiveness analysis suggested that the best strategy in the management of chronic HCV infection is to offer therapy to all patients and not perform liver biopsies (7). Thus, selective rather than routine liver biopsy might be used to assist in decision making regarding therapy (e.g., the patient who prefers to defer therapy rather than undergo current therapy if no or minimal fibrosis is present). Other patients prefer an attempt to achieve a sustained virological response to antiviral therapy irrespective of whatever a liver biopsy might show, and yet other patients not only opt for therapy but also want to know their degree of hepatic fibrosis. An approach to the determination of the need for therapy because of the presence of advanced fibrosis without the
3054
Editorials
performance of liver biopsy is to find the right combination of biochemical markers, and/or other clinical and imaging findings, with high positive and negative predictive values of advanced fibrosis. In this issue Pohl and colleagues (8) propose a simple formula based on readily available tests to determine the likelihood of Metavir stage F3 or F4 fibrosis in patients with chronic hepatitis C. In their patient population, an AST/ALT ratio of ⱖ1 in combination with a platelet count of ⬍150,000/mm3 detected patients with severe fibrosis with an excellent specificity (99.1%) and positive predictive value (93.1%) but with a relatively low sensitivity (41.2%). This formula could not be used in patients with significant alcohol consumption. The combination of the two laboratory values, AST/ALT ratio ⱖ 1 and platelet count ⬍ 150,000/mm3, would result in the elimination of a liver biopsy in a relatively small number of patients (15/211 [7.1%]). The investigators were unable to distinguish patients with no or minimal fibrosis using an AST/ ALT ratio of ⬍1 and various combinations of platelet counts. Although a good model will hold true for the population in which it was developed, one cannot predict with certainty how well that model will perform in all patients with chronic hepatitis C until it is tested and shown to have general applicability. The authors suggest a decision tree for staging fibrosis and determining the need for liver biopsy. The decision regarding liver biopsy, however, is likely more complex than outlined in their algorithm. Examples of other important issues regarding whether or not to perform liver biopsy are patient preferences, cost-effectiveness strategies, presence of relative contraindications, and the finding of other laboratory abnormalities such as a high-titer antinuclear antibody with hypergammaglobulinemia or abnormal iron studies. Other investigators have studied the AST/ALT ratio in patients with chronic hepatitis C with results that are consistent with the findings of Pohl et al. (9 –11). ImbertBismut et al. (12) used a more complex formula and have achieved good performance of their model in identifying patients with or without significant fibrosis. Use of their formula could correctly classify 46% of their patients with chronic HCV infection into these two categories. However, their formula required three assays not generally performed or routinely available in patients with chronic viral hepatitis C (␣2-microglobulin, haptoglobin, and apolipoprotein A1) in addition to three routine tests (␥-globulin, ␥-glutamyltranspeptidase, and total bilirubin). One of the important endpoints and justifications for antiviral therapy in patients with chronic hepatitis C is the prevention of progression to cirrhosis and thus elimination of the risk of decompensated liver disease and hepatocellular carcinoma. As long as we continue to treat our patients with this endpoint in mind, it will be important to have dependable estimates of the degree of liver fibrosis. It is possible that specific markers of fibrosis, such as hyaluronic acid or procollagen-III peptide, will be shown to reliably
AJG – Vol. 96, No. 11, 2001
reflect the stage of hepatic fibrosis, but it is more likely that the role of these tests will be in following disease progression and the impact of antiviral therapy (13, 14). An estimate of hepatic fibrosis will be of even greater importance as the promise of generic antifibrotic therapies becomes a reality. The work of Pohl and others reassures both clinicians and patients that not everyone with chronic hepatitis C who is a candidate for antiviral therapy needs to undergo a procedure for which there is a finite complication rate, personal and societal costs, and much apprehension. Thus, we may be moving to the selective rather than the routine use of liver biopsy in patients with chronic HCV infection. Further work is needed to establish a model that accurately predicts the degree of fibrosis, including the early stages; can be generalized to all patients with chronic hepatitis C; and performs well regardless of alcohol intake. Gabriel Garcia, M.D. Emmet B. Keeffe, M.D. Division of Gastroenterology and Hepatology Stanford University School of Medicine Stanford, California
REFERENCES 1. European Association for the Study of the Liver. Consensus statement. EASL international consensus conference on hepatitis C. J Hepatol 1999;30:956 – 61. 2. National Institute of Health Consensus Development Conference. Panel statement: Management of hepatitis C. Hepatology 1997;26(suppl 1):2S–10S. 3. Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23: 1334 – 40. 4. 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;349:825–32. 5. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: Results of a prospective nationwide survey. Hepatology 2000;32:477– 81. 6. Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver biopsy: A multicenter retrospective study on 68,276 biopsies. J Hepatol 1986;2:165–73. 7. Wong JB, Bennett WG, Koff RS, et al. Pretreatment evaluation of chronic hepatitis C: Risks, benefits, and costs. JAMA 1998;280:2088 –93. 8. Pohl A, Behling C, Oliver D, et al. Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am J Gastroenterol 2001; 96:3142– 6. 9. Sheth SG, Flamm SL, Gordon FD, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998;93:44 – 8. 10. Reedy DW, Loo AT, Levine RA. AST/ALT ration ⱖ 1 is not diagnostic of cirrhosis in patients with chronic hepatitis C. Dig Dis Sci 1998;43:2156 –9. 11. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734 –9. 12. Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical
AJG – November, 2001
markers of liver fibrosis in patients with hepatitis C virus infection: A prospective study. Lancet 2001;357:1069 –75. 13. Wong VS, Hughes V, Trull A, et al. Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepat 1998;5:187–92. 14. Jeffers LJ, Coelho-Little ME, Cheinquer H, et al. ProcollagenIII peptide and chronic viral C hepatitis. Am J Gastroenterol 1995;90:1437– 40. Reprint requests and correspondence: Emmet B. Keeffe, M.D., 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509. Received June 28, 2001; accepted Aug. 10, 2001.
The Irony of Treating Wilson’s Disease The evolution of life on earth was dependent upon the ability of organisms to utilize oxygen, a task made possible by the oxidation-reduction reactions facilitated by trace metals such as iron and copper capable of electron exchange. Studies in yeast and more recent revelations about comparable systems in humans indicate that complex homeostatic mechanisms exist for these trace elements, and that copper proteins play a critical role in the transfer and transport of iron (1). Human diseases such as Wilson’s disease, aceruloplasminemia, and genetic hemochromatosis have taught us much about the normal pathophysiology of copper and iron by defining the specific parts of the homeostatic mechanisms that go awry in these disorders. The interesting interdependence of these trace elements is highlighted by the findings of elevated iron in the livers of penicillaminetreated patients with Wilson’s disease by Shiono et al. (2). Shiono and colleagues’ report in this issue focuses on four male patients with Wilson’s disease with an initial reduced level of serum ceruloplasmin who later underwent a follow-up biopsy. In these four, normal hepatic iron content and hepatic iron indexes were present at the outset, though two were reported to have histochemically detectable iron. After treatment with D-penicillamine the level of ceruloplasmin was reduced and the hepatic iron increased in all of these individuals. In two patients, this iron accumulation was accompanied by an increased serum ferritin. What accounted for the increased hepatic iron in these individuals? The possibilities include increased absorption of iron by enterocytes with subsequent storage in the liver, reduced efflux of hepatocellular iron or increased red cell turnover and recycling of iron, or a combination of these. The presence of hemolysis was reported in only one of these patients before treatment, and presumably did not occur in the others. The critical link is most probably the reduced efflux of iron from the liver because of the inhibition of copperdependent protein function. The normal levels of hepatic iron before D-penicillamine treatment suggest that the subsequent increase in hepatic iron content was indeed iatrogenic. Hepatic iron deposition after long term treatment specific
Editorials
3055
for Wilson’s disease appears only in one other report of a patient with proven Wilson’s disease without hemochromatosis (3). The sex of this patient was not revealed in the report. The liver biopsy from this patient, performed after 15 yr of combination treatment with penicillamine and zinc, contained iron-laden hepatocytes in contrast to the initial biopsy, in which histochemically detectable iron was absent. The authors initially postulated that the iron deposition was due to an excess loss of copper due to penicillamine treatment; however, they then excluded this hypothesis because of the increase in hepatic copper over time from 480 to 1028 g/g dry weight liver. I believe their initial hunch was correct. How could D-penicillamine treatment or penicillamine and zinc treatment cause iron retention? The answer most likely lies in the induction of a relative intracellular copper deficiency from synthetic pools despite the overall overload of copper within the hepatocytes of these patients. This localized copper deficiency could lead to failure of incorporation of copper into cuproproteins, thereby reducing their activity. In particular, proteins that participate in ferroxidase reactions that render iron available for transfer across membranes by transporter molecules or for transport in association with proteins such as transferrin are likely affected. The copper proteins thus far identified as pivotal in iron metabolism include ceruloplasmin and its membrane-bound homologue hephaestin (for review, see Ref. 4). Other copper transfer proteins or chaperones exist in cells, and it is possible that these may be affected by chelation therapy, but the ultimate effect would be failure to deliver copper to the synthetic sites for ferroxidase proteins. These ferroxidase active proteins are thought to accelerate iron efflux by the newly identified basolateral iron transport protein ferroportin or IREG1 (5) by accelerating the change from Fe⫹2 to Fe⫹3 for its binding to transferrin. When ceruloplasmin is entirely absent, as in the rare disorder aceruloplasminemia, there is iron retention by many organs, including the liver (6). In the patients in Shiono et al.’s report (2) and the previous report of the single patient by Luca et al. (3), the presence of circulating ceruloplasmin, as low as the initial level was in these patients with Wilson’s disease, was obviously adequate for preventing the iron accumulation seen in aceruloplasminemia. However, in these individuals, treatment with penicillamine or penicillamine and zinc reduced serum ferroxidase activity, and most likely reduced tissue ferroxidase activity, thus leading to hepatocellular iron accumulation. Is this reduction of ferroxidase activity a natural consequence of treating all patients with Wilson’s disease, or a consequence of overtreatment? From my experience, the answer would be the latter. The initial dosage of penicillamine utilized by these investigators, 1200 mg, though within the range of acceptable dosages for patients with Wilson’s disease, was never adjusted downward based on objective parameters. Rather, the same dosage was later reduced empirically to 600 mg/day. Herein most likely lies the problem.
6. Alter MJ. Hepatitis C virus infection in the United States. J Hepatol 1999;31(suppl 1):88 –91. 7. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556 – 62. 8. Liou TC, Chang TT, Young KC, et al. Detection of HCV RNA in saliva, urine, seminal fluid, and ascites. J Med Virol 1992; 37:197–202. 9. Chayama K, Kobayashi M, Tsubota A, et al. Molecular analysis of intraspousal transmission of hepatitis C virus. J Hepatol 1995;22:431–9. 10. Simmonds P. Variability of hepatitis C virus genome. Curr Stud Hematol Blood Transfus 1994;61:12–35. 11. Dienstag JL. Sexual and perinatal transmission of hepatitis C. Hepatology 1997;26(suppl 1):66S–70S. 12. Buchbinder SP, Katz MH, Hessol NA, et al. Hepatitis C virus infection in sexually active homosexual men. J Infect 1994; 29:263–9. 13. Osella AR, Massa MA, Joekes S, et al. Hepatitis B and C virus sexual transmission among homosexual men. Am J Gastroenterol 1998;93:49 –52. 14. Chiaramonte M, Stroffolini T, Lorenzoni U, et al. Risk factors in community-acquired chronic hepatitis C virus infection: A case-control study in Italy. J Hepatol 1996;24:129 –34. 15. Caporaso N, Ascione A, Stroffolini T, et al. Spread of hepatitis C virus infection within families. J Viral Hepat 1998;5:67–72. 16. Wejstal R. Sexual transmission of hepatitis C virus. J Hepatol 1999;31:92–5. 17. Meisel H, Reip A, Faltus B, et al. Transmission of hepatitis C virus to children and husbands by women infected with contaminated anti-D globulin. Lancet 1995;345:1209 –11. 18. Power JP, Davidson F, O’Riordan J, et al. Hepatitis C infection from anti-D globulin. Lancet 1995;346:372–3 (letter). 19. Ohno T, Mizokami M, Lau JYN, et al. Sexual transmission of hepatitis C virus. In: Nishioka K, Suzuki H, Mishiro S, et al, eds. Viral hepatitis and liver disease: Proceedings of the International Symposium on Viral Hepatitis and Liver Disease: Molecules today, more cures tomorrow. Tokyo: SpringerVerlag, 1994:455– 8. 20. Piazza M, Sagliocca L, Tosone G, et al. Sexual transmission of hepatitis C virus and efficacy of prophylaxis with intramuscular immune serum globulin. A randomized controlled trial. Arch Intern Med 1997;157:1537– 44. 21. Stroffolini T, Lorenzoni U, Menniti-Ippolito F, et al. Hepatitis C virus infection in spouses: Sexual transmission or common exposure to the same risk factors? Am J Gastroenterol 2001; 96:3138 – 41. 22. Mohamed MK, Hussein MH, Massoud AA, et al. Study of the risk factors for viral hepatitis C infection among Egyptians applying for work abroad. J Egypt Public Health Assoc 1996; 71:113– 42. 23. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 1998;47:16 –20. 24. Jaeckel E, Cornberg M, Mayer J, et al. Early treatment of acute hepatitis C infection with interferon-alfa 2b monotherapy prevents development of chronic HCV infection. Hepatology 2000;32:318A (abstract).
Liver Biopsy in Chronic Hepatitis C: Routine or Selective A percutaneous liver biopsy can be useful in patients with chronic hepatitis C virus (HCV) infection by providing
Editorials
3053
information regarding the stage of fibrosis and grade of inflammation. Expert consensus groups from the United States and Europe have recommended the routine performance of liver biopsy before initiation of antiviral therapy for chronic hepatitis C (1, 2). The purpose of a pretreatment liver biopsy is to distinguish patients most likely to benefit from therapy (i.e., those with moderate inflammation and advanced stages of fibrosis) from patients who may be less likely to benefit (i.e., those with mild inflammation and minimal or no portal fibrosis). A liver biopsy has been shown to be useful in determining the likelihood of progression of liver injury in chronic hepatitis C; moderate or severe inflammation and fibrosis have been associated with a more rapid progression to cirrhosis (3, 4). Most clinicians use liver biopsy to determine the urgency to treat their patients, and the current consensus guidelines recommend that only patients with significant fibrosis (Metavir stages F2 [a few septa], F3 [many septa], and F4 [cirrhosis]) should be considered for antiviral therapy (1, 2). In addition, a biopsy occasionally may yield an unexpected diagnosis or document a coexisting condition such as nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis, or significant iron loading. Finally, if current investigational methods of treating fibrosis come of age and become clinically useful, then an acceptable method of quantifying liver fibrosis becomes an essential requirement to monitor and determine endpoints of therapy. However, patients with chronic hepatitis C are not always eager to have a liver biopsy. They frequently have anticipatory anxiety, which would be expected of a procedure that is associated with pain in 30% of patients, severe complications in 0.3%, and death in 0.03% (5, 6). In a study conducted in our center, the duration of pain after biopsy extended beyond the day of the biopsy in 40% of patients, and extended for over 1 wk in a small number (I. Barnard and G. Garcia, unpublished data). In our study, 15% of patients who had a liver biopsy would not have agreed to have the procedure done if they had known how they would feel during and after the procedure. Liver biopsy also adds significant direct costs (equipment, observation time, and time of a skilled clinician and pathologist) and indirect costs (time away from work and home) to the management of patients with chronic hepatitis C. Finally, a cost-effectiveness analysis suggested that the best strategy in the management of chronic HCV infection is to offer therapy to all patients and not perform liver biopsies (7). Thus, selective rather than routine liver biopsy might be used to assist in decision making regarding therapy (e.g., the patient who prefers to defer therapy rather than undergo current therapy if no or minimal fibrosis is present). Other patients prefer an attempt to achieve a sustained virological response to antiviral therapy irrespective of whatever a liver biopsy might show, and yet other patients not only opt for therapy but also want to know their degree of hepatic fibrosis. An approach to the determination of the need for therapy because of the presence of advanced fibrosis without the
3054
Editorials
performance of liver biopsy is to find the right combination of biochemical markers, and/or other clinical and imaging findings, with high positive and negative predictive values of advanced fibrosis. In this issue Pohl and colleagues (8) propose a simple formula based on readily available tests to determine the likelihood of Metavir stage F3 or F4 fibrosis in patients with chronic hepatitis C. In their patient population, an AST/ALT ratio of ⱖ1 in combination with a platelet count of ⬍150,000/mm3 detected patients with severe fibrosis with an excellent specificity (99.1%) and positive predictive value (93.1%) but with a relatively low sensitivity (41.2%). This formula could not be used in patients with significant alcohol consumption. The combination of the two laboratory values, AST/ALT ratio ⱖ 1 and platelet count ⬍ 150,000/mm3, would result in the elimination of a liver biopsy in a relatively small number of patients (15/211 [7.1%]). The investigators were unable to distinguish patients with no or minimal fibrosis using an AST/ ALT ratio of ⬍1 and various combinations of platelet counts. Although a good model will hold true for the population in which it was developed, one cannot predict with certainty how well that model will perform in all patients with chronic hepatitis C until it is tested and shown to have general applicability. The authors suggest a decision tree for staging fibrosis and determining the need for liver biopsy. The decision regarding liver biopsy, however, is likely more complex than outlined in their algorithm. Examples of other important issues regarding whether or not to perform liver biopsy are patient preferences, cost-effectiveness strategies, presence of relative contraindications, and the finding of other laboratory abnormalities such as a high-titer antinuclear antibody with hypergammaglobulinemia or abnormal iron studies. Other investigators have studied the AST/ALT ratio in patients with chronic hepatitis C with results that are consistent with the findings of Pohl et al. (9 –11). ImbertBismut et al. (12) used a more complex formula and have achieved good performance of their model in identifying patients with or without significant fibrosis. Use of their formula could correctly classify 46% of their patients with chronic HCV infection into these two categories. However, their formula required three assays not generally performed or routinely available in patients with chronic viral hepatitis C (␣2-microglobulin, haptoglobin, and apolipoprotein A1) in addition to three routine tests (␥-globulin, ␥-glutamyltranspeptidase, and total bilirubin). One of the important endpoints and justifications for antiviral therapy in patients with chronic hepatitis C is the prevention of progression to cirrhosis and thus elimination of the risk of decompensated liver disease and hepatocellular carcinoma. As long as we continue to treat our patients with this endpoint in mind, it will be important to have dependable estimates of the degree of liver fibrosis. It is possible that specific markers of fibrosis, such as hyaluronic acid or procollagen-III peptide, will be shown to reliably
AJG – Vol. 96, No. 11, 2001
reflect the stage of hepatic fibrosis, but it is more likely that the role of these tests will be in following disease progression and the impact of antiviral therapy (13, 14). An estimate of hepatic fibrosis will be of even greater importance as the promise of generic antifibrotic therapies becomes a reality. The work of Pohl and others reassures both clinicians and patients that not everyone with chronic hepatitis C who is a candidate for antiviral therapy needs to undergo a procedure for which there is a finite complication rate, personal and societal costs, and much apprehension. Thus, we may be moving to the selective rather than the routine use of liver biopsy in patients with chronic HCV infection. Further work is needed to establish a model that accurately predicts the degree of fibrosis, including the early stages; can be generalized to all patients with chronic hepatitis C; and performs well regardless of alcohol intake. Gabriel Garcia, M.D. Emmet B. Keeffe, M.D. Division of Gastroenterology and Hepatology Stanford University School of Medicine Stanford, California
REFERENCES 1. European Association for the Study of the Liver. Consensus statement. EASL international consensus conference on hepatitis C. J Hepatol 1999;30:956 – 61. 2. National Institute of Health Consensus Development Conference. Panel statement: Management of hepatitis C. Hepatology 1997;26(suppl 1):2S–10S. 3. Yano M, Kumada H, Kage M, et al. The long-term pathological evolution of chronic hepatitis C. Hepatology 1996;23: 1334 – 40. 4. 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;349:825–32. 5. Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: Results of a prospective nationwide survey. Hepatology 2000;32:477– 81. 6. Piccinino F, Sagnelli E, Pasquale G, et al. Complications following percutaneous liver biopsy: A multicenter retrospective study on 68,276 biopsies. J Hepatol 1986;2:165–73. 7. Wong JB, Bennett WG, Koff RS, et al. Pretreatment evaluation of chronic hepatitis C: Risks, benefits, and costs. JAMA 1998;280:2088 –93. 8. Pohl A, Behling C, Oliver D, et al. Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am J Gastroenterol 2001; 96:3142– 6. 9. Sheth SG, Flamm SL, Gordon FD, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol 1998;93:44 – 8. 10. Reedy DW, Loo AT, Levine RA. AST/ALT ration ⱖ 1 is not diagnostic of cirrhosis in patients with chronic hepatitis C. Dig Dis Sci 1998;43:2156 –9. 11. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734 –9. 12. Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical
AJG – November, 2001
markers of liver fibrosis in patients with hepatitis C virus infection: A prospective study. Lancet 2001;357:1069 –75. 13. Wong VS, Hughes V, Trull A, et al. Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepat 1998;5:187–92. 14. Jeffers LJ, Coelho-Little ME, Cheinquer H, et al. ProcollagenIII peptide and chronic viral C hepatitis. Am J Gastroenterol 1995;90:1437– 40. Reprint requests and correspondence: Emmet B. Keeffe, M.D., 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509. Received June 28, 2001; accepted Aug. 10, 2001.
The Irony of Treating Wilson’s Disease The evolution of life on earth was dependent upon the ability of organisms to utilize oxygen, a task made possible by the oxidation-reduction reactions facilitated by trace metals such as iron and copper capable of electron exchange. Studies in yeast and more recent revelations about comparable systems in humans indicate that complex homeostatic mechanisms exist for these trace elements, and that copper proteins play a critical role in the transfer and transport of iron (1). Human diseases such as Wilson’s disease, aceruloplasminemia, and genetic hemochromatosis have taught us much about the normal pathophysiology of copper and iron by defining the specific parts of the homeostatic mechanisms that go awry in these disorders. The interesting interdependence of these trace elements is highlighted by the findings of elevated iron in the livers of penicillaminetreated patients with Wilson’s disease by Shiono et al. (2). Shiono and colleagues’ report in this issue focuses on four male patients with Wilson’s disease with an initial reduced level of serum ceruloplasmin who later underwent a follow-up biopsy. In these four, normal hepatic iron content and hepatic iron indexes were present at the outset, though two were reported to have histochemically detectable iron. After treatment with D-penicillamine the level of ceruloplasmin was reduced and the hepatic iron increased in all of these individuals. In two patients, this iron accumulation was accompanied by an increased serum ferritin. What accounted for the increased hepatic iron in these individuals? The possibilities include increased absorption of iron by enterocytes with subsequent storage in the liver, reduced efflux of hepatocellular iron or increased red cell turnover and recycling of iron, or a combination of these. The presence of hemolysis was reported in only one of these patients before treatment, and presumably did not occur in the others. The critical link is most probably the reduced efflux of iron from the liver because of the inhibition of copperdependent protein function. The normal levels of hepatic iron before D-penicillamine treatment suggest that the subsequent increase in hepatic iron content was indeed iatrogenic. Hepatic iron deposition after long term treatment specific
Editorials
3055
for Wilson’s disease appears only in one other report of a patient with proven Wilson’s disease without hemochromatosis (3). The sex of this patient was not revealed in the report. The liver biopsy from this patient, performed after 15 yr of combination treatment with penicillamine and zinc, contained iron-laden hepatocytes in contrast to the initial biopsy, in which histochemically detectable iron was absent. The authors initially postulated that the iron deposition was due to an excess loss of copper due to penicillamine treatment; however, they then excluded this hypothesis because of the increase in hepatic copper over time from 480 to 1028 g/g dry weight liver. I believe their initial hunch was correct. How could D-penicillamine treatment or penicillamine and zinc treatment cause iron retention? The answer most likely lies in the induction of a relative intracellular copper deficiency from synthetic pools despite the overall overload of copper within the hepatocytes of these patients. This localized copper deficiency could lead to failure of incorporation of copper into cuproproteins, thereby reducing their activity. In particular, proteins that participate in ferroxidase reactions that render iron available for transfer across membranes by transporter molecules or for transport in association with proteins such as transferrin are likely affected. The copper proteins thus far identified as pivotal in iron metabolism include ceruloplasmin and its membrane-bound homologue hephaestin (for review, see Ref. 4). Other copper transfer proteins or chaperones exist in cells, and it is possible that these may be affected by chelation therapy, but the ultimate effect would be failure to deliver copper to the synthetic sites for ferroxidase proteins. These ferroxidase active proteins are thought to accelerate iron efflux by the newly identified basolateral iron transport protein ferroportin or IREG1 (5) by accelerating the change from Fe⫹2 to Fe⫹3 for its binding to transferrin. When ceruloplasmin is entirely absent, as in the rare disorder aceruloplasminemia, there is iron retention by many organs, including the liver (6). In the patients in Shiono et al.’s report (2) and the previous report of the single patient by Luca et al. (3), the presence of circulating ceruloplasmin, as low as the initial level was in these patients with Wilson’s disease, was obviously adequate for preventing the iron accumulation seen in aceruloplasminemia. However, in these individuals, treatment with penicillamine or penicillamine and zinc reduced serum ferroxidase activity, and most likely reduced tissue ferroxidase activity, thus leading to hepatocellular iron accumulation. Is this reduction of ferroxidase activity a natural consequence of treating all patients with Wilson’s disease, or a consequence of overtreatment? From my experience, the answer would be the latter. The initial dosage of penicillamine utilized by these investigators, 1200 mg, though within the range of acceptable dosages for patients with Wilson’s disease, was never adjusted downward based on objective parameters. Rather, the same dosage was later reduced empirically to 600 mg/day. Herein most likely lies the problem.