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Hepatitis C virus (HCV)-infection and oral lichen planus
Correspondence penia (10). The anemia caused by ribavirin is hemolytic, dose-dependent and rarely severe (4). We find it difficult to explain the anemia seen in our cases only on the basis of hemolysis, because of the disproportionately normal bilirubin and LDH levels with respect to the severity of the decrease in hemoglobin concentration. Complete aplasia of the red cell lineage, on the other hand, could not have accounted for such rapid hemoglobin decline (ª50% and ª44%, respectively, in 4 and 6 weeks). Thus, we favor the hypothesis that a combined mechanism (bone marrow pure red cell inhibition and hemolysis) was responsible for the severe anemia, and that both drugs may have contributed via an unknown interaction and to an extent which cannot be further analyzed. With the widespread use of this combination, cases of combined toxicity may become more frequent in the future. Gianfranco Tappero1, Marco Ballare´2, Massimo Farina1 and Francesco Negro3 1 Department of Internal Medicine, S. Luigi Hospital, Orbassano, and 2 Division of Gastroenterology, Hospital of Novara, Italy; 3Division of Gastroenterology, Geneva University Hospital, Geneva, Switzerland. Tel: 41 22 3729340. Fax: 41 22 3729366. e-mail: Francesco.Negro/hcuge.ch
References 1. National Institute of Health Consensus Development Conference Panel Statement: management of hepatitis C. Hepatology 1997; 26(Suppl 1): 1S–156S. 2. Patterson JL, Fernandez-Larsson R. Molecular mechanisms of action of ribavirin. Rev Infect Dis 1990; 12: 1139–46.
3. Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, Yurdaydin C, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 897–903. 4. Schalm SW, Hansen BE, Chemello L, Bellobuono A, Brouwer JT, Weiland O, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. J Hepatol 1997; 26: 961–6. 5. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 1998; 351: 83–7. 6. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996; 24: 38–47. 7. Andriani A, Bibas M, Callea F, De Renzo A, Chiurazzi F, Marceno R, et al. Autoimmune hemolytic anemia during alpha interferon treatment in nine patients with hematological diseases. Haematologica 1996; 81: 258–60. 8. Young NS. Immune pathophysiology of acquired aplastic anaemia. Eur J Haematol Suppl 1996; 60: 55–9. 9. Schattner A. The possible involvement of interferons in acquired pure red cell aplasia. Am J Hematol 1988; 27: 72–3. 10. Siciliano R, Trovato BA, Seminara G, Giustolisi V, Malaguarnera M. Interferon or hepatitis C virus induced autoimmune aplastic anemia and severe thrombocytopenia? A case report. Ann Ital Med Int 1995; 10: 193–4.
Hepatitis C virus (HCV)-infection and oral lichen planus To the Editor: Since hepatitis C virus (HCV) was identified in 1989, an increased rate of oral lichen planus (OLP) has been described in patients with chronic hepatitis C infection (1). In particular, OLP-patients from Spain, Italy and Japan were found to have increased rates of HCV infection of up to 70% (2–4). However, lack of association was reported from England and France (5,6). Since no data are at present available for Germany, we examined 127 German patients with HCV infection for OLP and 24 OLP patients for HCV infection. Three (2.4%) of 127 HCV-positive patients were clinically and histologically positive for OLP. Seventeen patients (13.3%) had hepatitis B virus markers as a consequence of earlier HBV infection. None of these had OLP. There were no statistically significant correlations between age, sex and duration of liver disease. HCV genotypes were distributed as follows: type 1: nΩ6 (4.7%); 1a: nΩ18 (14.2%); 1b: nΩ48 (37.7%); 2a: nΩ1 (0.8%); 2b: nΩ5 (3.9%); 3a: nΩ2 (1.6%); 3: nΩ22 (17.3%); 4: nΩ2 (1.6%); 4e: nΩ1 (0.8%); 5a: nΩ 1 (0.8%). In 10 patients (8.0%) we found double or triple HCV genotype infection: one patient showed type 2a/b/c infection, while others had type 1a/b (nΩ3), 2 a/b (nΩ1), 2a/c (nΩ3), 4 c/d (nΩ1) and 1/3a double infection. Only one of 24 patients with OLP was anti-HCV seropositive. The etiopathological role of HCV infection and its association with OLP are still not clear. An interesting question concerns the different geographical distributions of increased prevalence of HCV infection and the risk of developing OLP. Some studies, especially from South-
1034
ern Europe and Japan, have found a significantly higher prevalence of HCV infection in OLP patients of 27–70%. This was not the case in our study, nor in studies from England and France (5,6). In addition, the group of German patients (nΩ127) with HCV infection did not demonstrate a high prevalence of OLP (nΩ3). At present, there is no comparable study screening HCV-infected patients for OLP. The high variability of HCV, with six genotypes and several subtypes, and the different geographical distribution have been suggested as a reason for increased rates of OLP. Since different HCV genotypes may influence the clinical manifestations of HCV disease and the prognosis of interferon-alpha therapy, some studies have examined the distribution of HCV genotypes and their association with OLP. However, these studies did not prove an association between HCV genotype and OLP. Although the pathogenesis of OLP does not seem to be associated with a single causative factor, HCV may play a role in selected populations. Further studies should clarify whether HCV acts locally to develop OLP, or whether the host immune response to HCV is of importance.
Mathias Grote1, Peter A. Reichart1, Thomas Berg2 and Uwe Hopf2 Department of Oral Surgery and Dental Radiology, Charite´, Campus Virchow, Faculty of Medicine, Humboldt University, Berlin and 2Medical Clinic and Policlinic, Charite´, Campus Virchow, Faculty of Medicine, Humboldt University, Berlin, Germany.
1
Correspondence
References 1. Lodi G, Porter SR. Hepatitis C virus infection and lichen planus. A short review. Oral Diseases 1997; 3: 77–81. 2. Baga´n JV, Aguirre JM, del Olmo JA, Milian A, Pen˜arrocha M, Rodrigo JM, Cardona F. Oral lichen planus and chronic liver disease: a clinical and morphometric study of the oral lesions in relation to transaminase elevation. Oral Surg Oral Med Oral Pathol 1994; 78: 337–42. 3. Carrozzo M, Gandolfo S, Carbone M, Colombatto P, Brocoletti R, Garzino-Demo P, et al. Hepatitis C virus infection in Italian patients with oral lichen planus: a prospective casecontrol study. J Oral Pathol Med 1996; 25: 527–33.
4. Nagao Y, Sata M, Tanikawa K, Itho K, Kameyama T. Lichen planus and hepatitis C virus in the Northern Kyushu region of Japan. Eur J Clin Invest 1995; 25: 910–4. 5. Ingafou M, Porter SR, Scully C, Teo CG. No evidence of HCV infection or liver disease in British patients with oral lichen planus. J Oral Maxillofac Surg 1998; 27: 65–6. 6. Cribier B, Gernier C, Laustriat D. Lichen planus and hepatitis C virus infection: an epidemiologic study. J Am Acad Dermatol 1994; 31: 170–2.
Danazol therapy: an unusual aetiology of hepatocellular carcinoma To the Editor: Danazol is an inhibitor of pituitary gonadotropin with weak androgenic effects, which is currently used in the treatment of endometriosis, fibrocystic disease of the breast, idiopathic thrombocytopenic purpura and hereditary angioneurotic edema. Its hepatologic effects, such as reversible elevations of serum aminotransferase values or cholestasis hepatitis, have been well documented. A few cases of hepatocellular tumors have been reported essentially as hepatocellular adenomas (1). We report an exceptional case of hepatocellular carcinoma induced by danazol. A 34-year-old woman was treated with only danazol (400 mg daily) for 13 years for hereditary angioneurotic edema. She had no antecedent, except two cesareans in 1983 and 1988. The alcohol intake was ∞20 g/day. She was admitted in May 1997 for a mass in the right hypochondrium. The physical examination was normal except for this mass. Aminotransferases and alkaline phosphatases were normal, alphafeto protein concentration was ∞5 mg/l. Serological markers of hepatitis A, B and C were negative. Transferrin iron and serum ferritin concentrations were normal. Detection of autoantibodies was negative. Abdominal ultrasonography showed a large and heterogeneous hepatic tumor of 11¿6.5¿7 cm in segments V and VI. Abdominal tomodensitometry confirmed this hypervascular and heterogeneous tumor in segments V and VI (Fig. 1). These data
Fig. 1. Hypervascular and heterogeneous (11¿6.5¿7 cm) in segments V and VI.
tumor
suggested a malignant tumor. Resection of segments V and VI was performed in October 1997. At histological examination the tumor was composed of many malignant hepatocytes with large nuclei, many acini and a few peliosis lesions. Bile was accumulated in these acini. Mitotic activity was weak. This tumor was a well-differentiated hepatocellular carcinoma developed on a non-cirrhotic liver. The hypothesis of hepatocellular carcinoma induced by danazol was accepted in the absence of other etiology. The danazol therapy was stopped. The patient remained in excellent condition during the 2 months after the surgery. This report of a 34-year-old woman with hereditary angioneurotic edema is the third case in the literature of hepatocellular carcinoma induced by long-term danazol treatment. Danazol, an inhibitor of pituitary gonadotropin is a derivative of C17 ethinyltestosterone with weak androgenic effects. It is used in treatment of hereditary angioneurotic edema, a disease characterized by deficiency of C1 esterase inhibitor. Danazol increased the hepatic synthesis of this inhibitor. Mild reversible elevations of serum aminotransferase values were often observed in patients who were taking danazol. Cholestasis hepatitis and hepatosplenic peliosis have also been documented (2). Danazol may lead to the development of primary livers tumors such as hepatocellular adenoma (1). It has rarely been implicated in the development of hepatocellular carcinoma; indeed, only two cases have been described in the literature (3,4). The exact mechanism is not clear; it may play a role in the promotion and initiation steps of carcinogenesis. This observation was similar to the two other cases as regards the young age of the three patients (age between 30 and 50 years). In two cases biochemical tests and the alpha-feto protein concentration were normal. Tumors were always large with a diameter between 7 to 11 cm. Histologically there were some well-differentiated hepatocellular carcinomas. However, a few differences characterized our observation: the long duration of treatment (13 years) and the absence of clinical signs. The treatment was always a partial resection of the liver because discontinuation of the drug alone failed to cause regression of the tumor. The post-operative course was not well known, justifying regular ultrasonographic control. When long-term danazol therapy is required, ultrasonography may be useful for early tumor detection. Delphine Crampon1, Raphae¨lle Barnoud2, Magali Durand1, Denise Ponard3, Claude Jacquot4, Jean-Jacques Sotto5, Christian Letoublon6 and Jean-Pierre Zarski1 1 Department of Hepatogastroenterology, 2Department of Anatomopathology, 3Laboratory of Immunology, 4Department of Anesthesia, 5De-
1035
References 1. National Institute of Health Consensus Development Conference Panel Statement: management of hepatitis C. Hepatology 1997; 26(Suppl 1): 1S–156S. 2. Patterson JL, Fernandez-Larsson R. Molecular mechanisms of action of ribavirin. Rev Infect Dis 1990; 12: 1139–46.
3. Di Bisceglie AM, Conjeevaram HS, Fried MW, Sallie R, Park Y, Yurdaydin C, et al. Ribavirin as therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 897–903. 4. Schalm SW, Hansen BE, Chemello L, Bellobuono A, Brouwer JT, Weiland O, et al. Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C. J Hepatol 1997; 26: 961–6. 5. Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group. Lancet 1998; 351: 83–7. 6. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol 1996; 24: 38–47. 7. Andriani A, Bibas M, Callea F, De Renzo A, Chiurazzi F, Marceno R, et al. Autoimmune hemolytic anemia during alpha interferon treatment in nine patients with hematological diseases. Haematologica 1996; 81: 258–60. 8. Young NS. Immune pathophysiology of acquired aplastic anaemia. Eur J Haematol Suppl 1996; 60: 55–9. 9. Schattner A. The possible involvement of interferons in acquired pure red cell aplasia. Am J Hematol 1988; 27: 72–3. 10. Siciliano R, Trovato BA, Seminara G, Giustolisi V, Malaguarnera M. Interferon or hepatitis C virus induced autoimmune aplastic anemia and severe thrombocytopenia? A case report. Ann Ital Med Int 1995; 10: 193–4.
Hepatitis C virus (HCV)-infection and oral lichen planus To the Editor: Since hepatitis C virus (HCV) was identified in 1989, an increased rate of oral lichen planus (OLP) has been described in patients with chronic hepatitis C infection (1). In particular, OLP-patients from Spain, Italy and Japan were found to have increased rates of HCV infection of up to 70% (2–4). However, lack of association was reported from England and France (5,6). Since no data are at present available for Germany, we examined 127 German patients with HCV infection for OLP and 24 OLP patients for HCV infection. Three (2.4%) of 127 HCV-positive patients were clinically and histologically positive for OLP. Seventeen patients (13.3%) had hepatitis B virus markers as a consequence of earlier HBV infection. None of these had OLP. There were no statistically significant correlations between age, sex and duration of liver disease. HCV genotypes were distributed as follows: type 1: nΩ6 (4.7%); 1a: nΩ18 (14.2%); 1b: nΩ48 (37.7%); 2a: nΩ1 (0.8%); 2b: nΩ5 (3.9%); 3a: nΩ2 (1.6%); 3: nΩ22 (17.3%); 4: nΩ2 (1.6%); 4e: nΩ1 (0.8%); 5a: nΩ 1 (0.8%). In 10 patients (8.0%) we found double or triple HCV genotype infection: one patient showed type 2a/b/c infection, while others had type 1a/b (nΩ3), 2 a/b (nΩ1), 2a/c (nΩ3), 4 c/d (nΩ1) and 1/3a double infection. Only one of 24 patients with OLP was anti-HCV seropositive. The etiopathological role of HCV infection and its association with OLP are still not clear. An interesting question concerns the different geographical distributions of increased prevalence of HCV infection and the risk of developing OLP. Some studies, especially from South-
1034
ern Europe and Japan, have found a significantly higher prevalence of HCV infection in OLP patients of 27–70%. This was not the case in our study, nor in studies from England and France (5,6). In addition, the group of German patients (nΩ127) with HCV infection did not demonstrate a high prevalence of OLP (nΩ3). At present, there is no comparable study screening HCV-infected patients for OLP. The high variability of HCV, with six genotypes and several subtypes, and the different geographical distribution have been suggested as a reason for increased rates of OLP. Since different HCV genotypes may influence the clinical manifestations of HCV disease and the prognosis of interferon-alpha therapy, some studies have examined the distribution of HCV genotypes and their association with OLP. However, these studies did not prove an association between HCV genotype and OLP. Although the pathogenesis of OLP does not seem to be associated with a single causative factor, HCV may play a role in selected populations. Further studies should clarify whether HCV acts locally to develop OLP, or whether the host immune response to HCV is of importance.
Mathias Grote1, Peter A. Reichart1, Thomas Berg2 and Uwe Hopf2 Department of Oral Surgery and Dental Radiology, Charite´, Campus Virchow, Faculty of Medicine, Humboldt University, Berlin and 2Medical Clinic and Policlinic, Charite´, Campus Virchow, Faculty of Medicine, Humboldt University, Berlin, Germany.
1
Correspondence
References 1. Lodi G, Porter SR. Hepatitis C virus infection and lichen planus. A short review. Oral Diseases 1997; 3: 77–81. 2. Baga´n JV, Aguirre JM, del Olmo JA, Milian A, Pen˜arrocha M, Rodrigo JM, Cardona F. Oral lichen planus and chronic liver disease: a clinical and morphometric study of the oral lesions in relation to transaminase elevation. Oral Surg Oral Med Oral Pathol 1994; 78: 337–42. 3. Carrozzo M, Gandolfo S, Carbone M, Colombatto P, Brocoletti R, Garzino-Demo P, et al. Hepatitis C virus infection in Italian patients with oral lichen planus: a prospective casecontrol study. J Oral Pathol Med 1996; 25: 527–33.
4. Nagao Y, Sata M, Tanikawa K, Itho K, Kameyama T. Lichen planus and hepatitis C virus in the Northern Kyushu region of Japan. Eur J Clin Invest 1995; 25: 910–4. 5. Ingafou M, Porter SR, Scully C, Teo CG. No evidence of HCV infection or liver disease in British patients with oral lichen planus. J Oral Maxillofac Surg 1998; 27: 65–6. 6. Cribier B, Gernier C, Laustriat D. Lichen planus and hepatitis C virus infection: an epidemiologic study. J Am Acad Dermatol 1994; 31: 170–2.
Danazol therapy: an unusual aetiology of hepatocellular carcinoma To the Editor: Danazol is an inhibitor of pituitary gonadotropin with weak androgenic effects, which is currently used in the treatment of endometriosis, fibrocystic disease of the breast, idiopathic thrombocytopenic purpura and hereditary angioneurotic edema. Its hepatologic effects, such as reversible elevations of serum aminotransferase values or cholestasis hepatitis, have been well documented. A few cases of hepatocellular tumors have been reported essentially as hepatocellular adenomas (1). We report an exceptional case of hepatocellular carcinoma induced by danazol. A 34-year-old woman was treated with only danazol (400 mg daily) for 13 years for hereditary angioneurotic edema. She had no antecedent, except two cesareans in 1983 and 1988. The alcohol intake was ∞20 g/day. She was admitted in May 1997 for a mass in the right hypochondrium. The physical examination was normal except for this mass. Aminotransferases and alkaline phosphatases were normal, alphafeto protein concentration was ∞5 mg/l. Serological markers of hepatitis A, B and C were negative. Transferrin iron and serum ferritin concentrations were normal. Detection of autoantibodies was negative. Abdominal ultrasonography showed a large and heterogeneous hepatic tumor of 11¿6.5¿7 cm in segments V and VI. Abdominal tomodensitometry confirmed this hypervascular and heterogeneous tumor in segments V and VI (Fig. 1). These data
Fig. 1. Hypervascular and heterogeneous (11¿6.5¿7 cm) in segments V and VI.
tumor
suggested a malignant tumor. Resection of segments V and VI was performed in October 1997. At histological examination the tumor was composed of many malignant hepatocytes with large nuclei, many acini and a few peliosis lesions. Bile was accumulated in these acini. Mitotic activity was weak. This tumor was a well-differentiated hepatocellular carcinoma developed on a non-cirrhotic liver. The hypothesis of hepatocellular carcinoma induced by danazol was accepted in the absence of other etiology. The danazol therapy was stopped. The patient remained in excellent condition during the 2 months after the surgery. This report of a 34-year-old woman with hereditary angioneurotic edema is the third case in the literature of hepatocellular carcinoma induced by long-term danazol treatment. Danazol, an inhibitor of pituitary gonadotropin is a derivative of C17 ethinyltestosterone with weak androgenic effects. It is used in treatment of hereditary angioneurotic edema, a disease characterized by deficiency of C1 esterase inhibitor. Danazol increased the hepatic synthesis of this inhibitor. Mild reversible elevations of serum aminotransferase values were often observed in patients who were taking danazol. Cholestasis hepatitis and hepatosplenic peliosis have also been documented (2). Danazol may lead to the development of primary livers tumors such as hepatocellular adenoma (1). It has rarely been implicated in the development of hepatocellular carcinoma; indeed, only two cases have been described in the literature (3,4). The exact mechanism is not clear; it may play a role in the promotion and initiation steps of carcinogenesis. This observation was similar to the two other cases as regards the young age of the three patients (age between 30 and 50 years). In two cases biochemical tests and the alpha-feto protein concentration were normal. Tumors were always large with a diameter between 7 to 11 cm. Histologically there were some well-differentiated hepatocellular carcinomas. However, a few differences characterized our observation: the long duration of treatment (13 years) and the absence of clinical signs. The treatment was always a partial resection of the liver because discontinuation of the drug alone failed to cause regression of the tumor. The post-operative course was not well known, justifying regular ultrasonographic control. When long-term danazol therapy is required, ultrasonography may be useful for early tumor detection. Delphine Crampon1, Raphae¨lle Barnoud2, Magali Durand1, Denise Ponard3, Claude Jacquot4, Jean-Jacques Sotto5, Christian Letoublon6 and Jean-Pierre Zarski1 1 Department of Hepatogastroenterology, 2Department of Anatomopathology, 3Laboratory of Immunology, 4Department of Anesthesia, 5De-
1035