Correspondence
Risk Factors for Hepatocellular Carcinoma in Patients with Chronic Liver Diseases
N Engl J Med 1993; 329:1896-1898December 16, 1993
- Article
To the Editor:
In the report by Tsukuma et al. (June 24 issue)1 on the risk factors for hepatocellular carcinoma in patients with chronic liver disease, the study group was composed of patients with cirrhosis of the liver or chronic hepatitis. It is not stated whether the patients had had liver biopsies, although the criteria for enrollment, “a clinical diagnosis of chronic hepatitis or compensated cirrhosis,” suggest that biopsies were not performed in all patients.
I believe that histologic study, particularly in the patients with chronic hepatitis, could have contributed to a more accurate classification of the liver disease. It would have been of interest to know whether the subgroup of 26 patients with chronic hepatitis at enrollment in whom hepatocellular carcinoma developed had special histologic features, especially with respect to severity.
Tsukuma et al. observed that patients with chronic hepatitis who had elevated alpha-fetoprotein levels at enrollment were at significantly higher risk for liver cancer than those who had normal levels. However, I believe that these observations could be the result of more aggressive histologic features in these patients.
Although the mechanism of the increase in serum alpha-fetoprotein levels in benign liver diseases is complex and not well understood,2 this increase has been related to greater histologic activity in chronic liver diseases3,4. We have measured serum alpha-fetoprotein levels in patients with benign liver diseases who underwent liver biopsy5. Twenty-two of the 86 patients with cirrhosis (25.6 percent) had abnormal alpha-fetoprotein levels. Among the patients with chronic hepatitis, those with more aggressive histologic features who were classified as having chronic active hepatitis had higher rates of above-normal values than those classified as having chronic persistent hepatitis (40 percent vs. 6.7 percent). These results suggest that histologic findings should be taken into consideration when the serum levels of alpha-fetoprotein are evaluated.
I believe that the predictive value for the development of hepatocellular carcinoma Tsukuma et al. attributed to alpha-fetoprotein levels could be a reflection of more aggressive histologic features in affected patients.
5 ReferencesJulio Collazos, M.D.
Hospital de Galdakao, 48960 Vizcaya, Spain1
Tsukuma H ,Hiyama T ,Tanaka S , et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993;328:1797-1801
Full Text | Web of Science | Medline2
Taketa K . Alpha-fetoprotein: reevaluation in hepatology. Hepatology 1990;12:1420-1432
CrossRef | Web of Science | Medline3
Liaw YF ,Tai DI ,Chen TJ ,Chu CM ,Huang MJ . Alpha-fetoprotein changes in the course of chronic hepatitis: relation to bridging hepatic necrosis and hepatocellular carcinoma. Liver 1986;6:133-137
Medline4
Delpre G ,Gilat T . L'alpha-foeto-proteine. Gastroenterol Clin Biol 1978;2:193-214
Web of Science | Medline5
Collazos J ,Genolla J ,Ruibal A . Preliminary study of alpha-fetoprotein in nonmalignant liver diseases: a clinico-biochemical evaluation. Int J Biol Markers 1992;7:97-102
Medline
To the Editor:
Tsukuma et al. report viral hepatitis to be strongly associated with hepatocellular carcinoma. They include data on 917 patients, 677 of whom (73.8 percent) had clinical chronic hepatitis. No details of the patients' symptoms on histologic diagnosis are provided, and there is no conclusive information as to whether the infection was initially asymptomatic or clinically evident.
For an understanding of the oncogenic potential of hepatotropic viruses, it is essential to consider such viral characteristics as the degree of replication (e.g., viral titers) as well as the immunologic response, which in the case of hepatic viruses is mainly responsible for the clinical presentation (since the viruses themselves are not cytopathic).
The finding that high titers of hepatitis B core antibody seem to increase the risk of hepatocellular carcinoma is consistent with the finding that these antibodies might prevent an effective cytotoxic T-cell response to infected hepatocytes, thus increasing the likelihood of nonclearance of the virus, high rates of replication, high titers of antigen, few symptoms, and progressive disease1,2. On the other hand, high doses of virus, as occur with transfusion-associated infection, might lead to the infection of protective B cells, as is the case with hepatitis B virus, and cause the destruction of these cells by T cells specific for the hepatitis B envelope antigen3. Another possibility is that the reactive cellular response becomes exhausted, leading to viral persistence4.
Therefore, it would be very informative to know more about the degree of viral replication and the symptoms of the patients at the beginning of the infection, to see whether patients with no history of symptoms have the same increased risk of hepatocellular carcinoma as patients with clear clinical symptoms of infection5.
5 ReferencesI. Frank Ciernik, M.D.
University of Texas Southwestern Medical Center, Dallas, TX 75235-85931
Mondelli M ,Vergani GM ,Alberti A , et al. Specificity of T lymphocyte cytotoxicity to autologous hepatocytes in chronic hepatitis B virus infection: evidence that T cells are directed against HBV core antigen expressed on hepatocytes. J Immunol 1982;129:2773-2778
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Fattovich G ,Brollo L ,Alberti A , et al. Chronic persistent hepatitis type B can be a progressive disease when associated with sustained virus replication. J Hepatol 1990;11:29-33
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Barnaba V ,Franco A ,Alberti A ,Benvenuto R ,Balsano F . Selective killing of hepatitis B envelope antigen-specific B cells by class I-restricted, exogenous antigen-specific T lymphocytes. Nature 1990;345:258-260
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Moskophidis D ,Lechner F ,Pircher H ,Zinkernagel RM . Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 1993;362:758-761
CrossRef | Web of Science | Medline5
de Franchis R ,Meucci G ,Vecchi M , et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118:191-194
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Collazos points out that the increased risk of hepatocellular carcinoma among patients with elevated alpha-fetoprotein levels could be a reflection of more aggressive histologic features in these patients. We agree with him. Akeyama et al.1 conducted a long-term follow-up study of 353 patients with chronic hepatitis or cirrhosis verified by peritoneoscopic liver biopsy. The incidence of hepatocellular carcinoma was closely associated with the histologic severity of chronic hepatitis at the time of the initial diagnosis. They further observed a higher prevalence of elevated alpha-fetoprotein levels among patients who were positive for hepatitis B surface antigen than among those who were negative, after adjustment for the severity of liver disease.
Dr. Ciernik insists that consideration of the level of replication and the immunologic response is essential for an understanding of the oncogenic potential of hepatotropic viruses. We completely agree with him, but we do not have sufficient data at present. We are also concerned with the relation of the risk of hepatocellular carcinoma and the patients' symptoms and age at the time of initial infection. The study subjects all had a clinical diagnosis of chronic hepatitis or liver cirrhosis, with abnormal results on liver-function tests; we did not include healthy carriers of hepatitis B virus or asymptomatic carriers of hepatitis C virus. Twenty-three percent had a history of blood transfusion -- a major source of hepatitis C virus infection in Japan -- and a quarter of these patients had a history of post-transfusion hepatitis. Their risk of hepatocellular carcinoma, however, was not significantly higher than 1.0. Except for these patients, we do not know when hepatitis C virus infection occurred in the patients who were positive for hepatitis C antibody. A few studies have been conducted of the long-term prognosis of asymptomatic carriers of hepatitis B virus,2,3 but little is known about the natural history of asymptomatic carriers of hepatitis C virus. It is very important to determine whether such carriers have the same risk of hepatocellular carcinoma as symptomatic patients with hepatitis C virus infection, as suggested by Dr. Ciernik.
3 ReferencesHideaki Tsukuma, M.D., M.S.
Tomohiko Hiyama, M.D.
Atsuo Inoue, M.D., Ph.D.
Center for Adult Diseases, Osaka 57, Japan1
Akeyama T ,Tsukuma H ,Miyamoto T , et al. Prognosis of chronic liver diseases: survival, incidence of hepatocellular carcinoma and its related parameters. Acta Hepatol Jpn 1987;28:1033-1039
CrossRef2
Oshima A ,Tsukuma H ,Hiyama T ,Fujimoto I ,Yamano H ,Tanaka M . Follow-up study of HBs Ag-positive blood donors with special reference to effect of drinking and smoking on development of liver cancer. Int J Cancer 1984;34:775-779
CrossRef | Web of Science | Medline3
de Franchis R ,Meucci G ,Vecchi M , et al. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118:191-194
Web of Science | Medline
