242
LETTERS TO THE EDITOR
TABLE 2 Serum levels and urinary excretion of epomediol and its main metabolite in 3 patients with intrahepatic cholestasis of pregnancy during oral epomediol administration (1200 mg/day for 15 days) Days of
Serum levels (pg/ml)
treatment
Epomediol
Metabolite M I
Urinary excretion (mg/12 h) Free Epo
Total Epo
1 2 3 5 8 10 15 Range
7.9 _+ 2.7 a 7.8 + 2.5 8.8 + 2.7 7.7 + 2.8 8.3 + 2.6 10.8 + 3.7 7.8 + 2.6 3.3-18.2
0.3 + 0.1 0.5 + 0.2 0.5 + 0.3 0.5 __+ 0.3 0.4 + 0.2 0.6 _+ 0.2 0.4 __+ 0.1 0.1-1.2
0 20.7 __+ 5.1 25.3 __+ 7.7 10.5 + 3.0 22.0 + 0.3 15.4 + 4.0 18.7 __+ 6.5 4.7-36.5
0 497 _ 100 609 _ 200 457 _+ 187 585 _+ 21 753 __+ 369 506 _ 185 210-1123
~Mean + S.E.M.
reached maximal values on the third day of treatment and remained stable throughout the 15-day treatment period, indicating an adequate intestinal absorption of epomediol (Table 2). A similar observation was done with urinary excretion of the drug. Epomediol in blood appeared largely in excess over its main metabolite. In the samples of amniotic fluid examined, only total epomediol was detected and in a concentration of 0.52/~g/ml or less. In the present pilot study, the amelioration of pruritus was greater than in a group of 9 patients who received a placebo (6) (p < 0.05, intergroup analysis of variance for non-parametric data). The lack of biochemical improvement in patients treated with epomediol could be due to the brevity of the treatment period. Alternatively, pruritus was attenuated through some extrahepa-
References I Svanborg A. A study of recurrent jaundice in pregnancy. Acta Obstet Gynaecol Scand 1954; 33: 434-44. 2 Reyes H. The enigma of intrahepatic cholestasis of pregnancy: lessons from Chile. Hepatology 1982; 2: 87-96. 3 Zuin M, Dioguardi ML, Festorazzi S, Podda M. Effects ofepomediol on bile flow and composition in normal rats and in rats with ethinyl estradiol induced cholestasis. I1 Farmaco 1981; 36: 383-9. 4 Miccio M, Orzes N, Lunazzi GC, Gazzin B, Corsi R, Tiribelli C.
tic effect of epomediol. A placebo effect seems unlikely because pruritus improved more in patients treated with the higher dose of this drug. In conclusion, epomediol can be considered a satisfactory alternative in the treatment of pruritus in patients with ICP, with the advantage of its oral administration and excellent tolerance. This study was supported by grant 467/88 from Fondecyt, Chile.
Manuel C. Gonzalez a, Joaquin Iglesias c, Claudio Tiribelli d, Jose Ribalta a, Humberto Reyes ~'b, Ismaei Hernandez b, Marcelo Bianchi b, Francisco Andrighetti b and Claudina Molina c Departamentos de aMedicina, bPreclinicas, and CObstetricia, Facultad de Medicina. Universidad de Chile (Divisidn Oriente), Hospital del Salvador, .Santiago de Chile, Chile and alstituto di Patologia Speciale Medica, Universita Degli Studi di Trieste, Trieste, Italy
Reversal of ethinyl estradiol-induced cholestasis by epomediol in the rat. Biochem Pharmacol 1989; 38: 3559-63. 5 Barrera G, Parola M. Effect of epomediol on the ATPase and adenylate cyclase activities in plasma membranes isolated from rat liver. Pharm Res Commun 1984; 16:1133-40. 6 Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arrese M, Poniachick J, Molina C, Segovia N. S-adenosyI-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results. Hepatology 1991; 13: 1084-9.
HEPAT 01156
Hepatitis C virus, autoimmune liver disease and cryoglobulinaemic hepatitis Dr. Magrin and colleagues reported (J Hepatol, 1991; 13: 364-7) the association of hepatitis C virus (HCV) infection and autoimmune chronic active hepatitis (AICAH) in a group of fifteen Italian patients. On the basis
of this association and the efficacy of s-interferon treatment, the Authors hypothesized the existence of a clinically and etiologically distinct subset of AI-CAH. Another study reports evidence of geographical hetero-
LETTERS TO THE EDITOR
243
geneity in the occurrence of a n t i - H C V antibodies (antiHCV) in patients with A I - C A H (1): Italian patients with A I - C A H showed a significantly higher frequency of antiHCV and higher patient mean age than a comparable English series, particularly for the type-2 variant (49 vs. 11 years). These differences lead the Authors to wonder whether the Italian patients had true A I - C A H (1). A comparable high frequency of H C V seropositivity has been reported in another immunological disorder: i.e. mixed cryoglobulinaemia (MC) (2-4). Although different viruses, namely HBV, HCV, EBV, etc., have been suggested as causative agents of M C (5); the high rate (90%) of a n t i - H C V antibodies and H C V - R N A in our unselected M C series suggests an important pathogenetic role for this virus (6,7). M C is an immunoproliferative disorder characterized by the involvement of several organs secondary to tissue deposition of circulating immune complexes (8,9). Liver involvement is reported in 70% of patients and the clinical course and histological lindings of cryoglobulinaemic hepatitis are comparable to other forms of CAH. In the majority of M C patients, hepatitis appears during the course of the disease, but in some cases it represents the prevalent manifestation. In these instances diagnosis of M C can be done on the bases of serological alterations: mixed cryoglobulins with rheumatoid factor activity, reduced hemolytic complement activity (CHso), low C4 and normal C3 levels. Italian patients with A I - C A H or M C hepatitis share important clinico-epidemiological and serological findings (Table 1). Since mean age, female/male ratio, severity of liver damage (AST levels and cirrhosis), a n t i - H C V seropositivity are comparable in different series, it is possible that some Italian patients classified as A I - C A H or as MC, according to different Authors' approach, could have the same systemic disorder. It can be hypothesized that hepatotropic virus might trigger an immunological disor-
TABLE 1
References
(GISC). Cryoglobulinaemia and serological markers of hepatitis viruses. Lancet 1991; 338: 758-9. 6 Ferri C, Greco F, Longombardo G, et al. Antibodies against hepatitis C virus in mixed cryoglobulinaemia patients. Infection 1991; 19: 417-20. 7 Ferri C, Greco F, Longombardo G, et al. Association between hepatitis C virus and mixed cryoglobulinaemia. Clin Exp Rheumatol 1991; 9: 621-4. 8 Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinaemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 1980; 69: 287-308. 9 Ferri C, Pietrogrande M, Cecchetti R, et al. Low-antigen-content diet in the treatment of patients with mixed cryoglobulinemia. Am J Med 1989; 87: 519-24. 10 Pozzato G, Moretti M, Franzin F, et al. Severity of liver disease with different hepatitis C viral clones. Lancet 1991; 338: 509.
I Lenzi M, Johnson PJ, McFarlane IG, et al. Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity. Lancet 1991; 338: 277-80. 2 Ferri C, Marzo E, Longombardo G, Lombardini F, Greco F, Bombardieri S. Alpha-interferon in the treatment of mixed cryoglobulinemia patients. Eur J Cancer 1991; 27, Suppl 4: 81-2. 3 Casato M, Pucillo LP, Lagan~, B, Taliani G, Goffredo F, Bonomo L. Cryoglobulinaemia and hepatitis C virus. Lancet 1991; 337: 1047-8. 4 Ferri C, Greco F, Longombardo G, et al. Hepatitis C virus antibodies in mixed cryoglobulinaemia patients. Arthr Rheum 1991; 34: 1606-10. 5 Galli M, and Gruppo ltaliano per 1o Studio delle Crioglobulinemie
Autoimmune chronic active hepatitis (AI-CAH)and cryoglobulinaemic hepatitis (MC-CAH) AI-CAH Magrin et al. (15 pts) 53 (43-64) 2.0 60% 2.8 (1.5-8) 60% 20% 20% n.a. n.a. 100%* 67%
MC-CAH Lenziet al. (80 pts) 55 (21-81) 3.2 45% 3.0 (0.6-19) n.a. 59% 41% n.a. n.a. 66%** n.a.
our series (42 pts) 61 (40-77) 2.8 30% 3.2 (1.1-14) 15% 26% n.a. 6.5 (0.2-25) 95% 97%* 86%
Age" F/M ratio Cirrhosis AST ANA ASMA Anti-LKM-I Cryocrit % Low CHso Anti-HCV HCV-RNA (PCR +) "Mean values (range). *Detected by Second Generation Ortho EL1SA and RIBA-2. **Detected by Ortho ELISA-I, RIBA-I and UBI EL1SA. AST=aspartate aminotransferase activity as multiple of upper limit of normal values; n.a.= not available. der with a variety of clinical patterns: from the isolated C A H to A I - C A H , with a possible association of systemic features, and finally the typical mixed cryoglobulinaemic syndrome. Hypothetically, a variable genetically induced host response a n d / o r the presence of different hepatitis C viral clones (10) could explain these different patterns. In conclusion, future studies on ' a u t o i m m u n e ' liver disease or 'cryoglobulinaemic' hepatitis should include a complete assessment (anti-nuclear, anti-smooth-muscle and a n t i - L K M 1 antibodies, circulating mixed cryoglobulins, complement levels) to better define possible patient subsets. C l o d o v e o Ferri a, Giovanni L o n g o m b a r d o a, Luca La Civita a, Stefano Bombardieri ~, Francesco Greco b, Peter Highfield c and T i m o t h y Corbishley c °Rheumatology and Clinical Immunology Unit, Universityof Pisa, bBIood Center, Ospedale S. Chiara, Pisa, Italy and ~Molecular Biology Section, Wellcome Diagnostic, Beckenham, United Kingdom
LETTERS TO THE EDITOR
TABLE 2 Serum levels and urinary excretion of epomediol and its main metabolite in 3 patients with intrahepatic cholestasis of pregnancy during oral epomediol administration (1200 mg/day for 15 days) Days of
Serum levels (pg/ml)
treatment
Epomediol
Metabolite M I
Urinary excretion (mg/12 h) Free Epo
Total Epo
1 2 3 5 8 10 15 Range
7.9 _+ 2.7 a 7.8 + 2.5 8.8 + 2.7 7.7 + 2.8 8.3 + 2.6 10.8 + 3.7 7.8 + 2.6 3.3-18.2
0.3 + 0.1 0.5 + 0.2 0.5 + 0.3 0.5 __+ 0.3 0.4 + 0.2 0.6 _+ 0.2 0.4 __+ 0.1 0.1-1.2
0 20.7 __+ 5.1 25.3 __+ 7.7 10.5 + 3.0 22.0 + 0.3 15.4 + 4.0 18.7 __+ 6.5 4.7-36.5
0 497 _ 100 609 _ 200 457 _+ 187 585 _+ 21 753 __+ 369 506 _ 185 210-1123
~Mean + S.E.M.
reached maximal values on the third day of treatment and remained stable throughout the 15-day treatment period, indicating an adequate intestinal absorption of epomediol (Table 2). A similar observation was done with urinary excretion of the drug. Epomediol in blood appeared largely in excess over its main metabolite. In the samples of amniotic fluid examined, only total epomediol was detected and in a concentration of 0.52/~g/ml or less. In the present pilot study, the amelioration of pruritus was greater than in a group of 9 patients who received a placebo (6) (p < 0.05, intergroup analysis of variance for non-parametric data). The lack of biochemical improvement in patients treated with epomediol could be due to the brevity of the treatment period. Alternatively, pruritus was attenuated through some extrahepa-
References I Svanborg A. A study of recurrent jaundice in pregnancy. Acta Obstet Gynaecol Scand 1954; 33: 434-44. 2 Reyes H. The enigma of intrahepatic cholestasis of pregnancy: lessons from Chile. Hepatology 1982; 2: 87-96. 3 Zuin M, Dioguardi ML, Festorazzi S, Podda M. Effects ofepomediol on bile flow and composition in normal rats and in rats with ethinyl estradiol induced cholestasis. I1 Farmaco 1981; 36: 383-9. 4 Miccio M, Orzes N, Lunazzi GC, Gazzin B, Corsi R, Tiribelli C.
tic effect of epomediol. A placebo effect seems unlikely because pruritus improved more in patients treated with the higher dose of this drug. In conclusion, epomediol can be considered a satisfactory alternative in the treatment of pruritus in patients with ICP, with the advantage of its oral administration and excellent tolerance. This study was supported by grant 467/88 from Fondecyt, Chile.
Manuel C. Gonzalez a, Joaquin Iglesias c, Claudio Tiribelli d, Jose Ribalta a, Humberto Reyes ~'b, Ismaei Hernandez b, Marcelo Bianchi b, Francisco Andrighetti b and Claudina Molina c Departamentos de aMedicina, bPreclinicas, and CObstetricia, Facultad de Medicina. Universidad de Chile (Divisidn Oriente), Hospital del Salvador, .Santiago de Chile, Chile and alstituto di Patologia Speciale Medica, Universita Degli Studi di Trieste, Trieste, Italy
Reversal of ethinyl estradiol-induced cholestasis by epomediol in the rat. Biochem Pharmacol 1989; 38: 3559-63. 5 Barrera G, Parola M. Effect of epomediol on the ATPase and adenylate cyclase activities in plasma membranes isolated from rat liver. Pharm Res Commun 1984; 16:1133-40. 6 Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arrese M, Poniachick J, Molina C, Segovia N. S-adenosyI-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a randomized, double-blind, placebo-controlled study with negative results. Hepatology 1991; 13: 1084-9.
HEPAT 01156
Hepatitis C virus, autoimmune liver disease and cryoglobulinaemic hepatitis Dr. Magrin and colleagues reported (J Hepatol, 1991; 13: 364-7) the association of hepatitis C virus (HCV) infection and autoimmune chronic active hepatitis (AICAH) in a group of fifteen Italian patients. On the basis
of this association and the efficacy of s-interferon treatment, the Authors hypothesized the existence of a clinically and etiologically distinct subset of AI-CAH. Another study reports evidence of geographical hetero-
LETTERS TO THE EDITOR
243
geneity in the occurrence of a n t i - H C V antibodies (antiHCV) in patients with A I - C A H (1): Italian patients with A I - C A H showed a significantly higher frequency of antiHCV and higher patient mean age than a comparable English series, particularly for the type-2 variant (49 vs. 11 years). These differences lead the Authors to wonder whether the Italian patients had true A I - C A H (1). A comparable high frequency of H C V seropositivity has been reported in another immunological disorder: i.e. mixed cryoglobulinaemia (MC) (2-4). Although different viruses, namely HBV, HCV, EBV, etc., have been suggested as causative agents of M C (5); the high rate (90%) of a n t i - H C V antibodies and H C V - R N A in our unselected M C series suggests an important pathogenetic role for this virus (6,7). M C is an immunoproliferative disorder characterized by the involvement of several organs secondary to tissue deposition of circulating immune complexes (8,9). Liver involvement is reported in 70% of patients and the clinical course and histological lindings of cryoglobulinaemic hepatitis are comparable to other forms of CAH. In the majority of M C patients, hepatitis appears during the course of the disease, but in some cases it represents the prevalent manifestation. In these instances diagnosis of M C can be done on the bases of serological alterations: mixed cryoglobulins with rheumatoid factor activity, reduced hemolytic complement activity (CHso), low C4 and normal C3 levels. Italian patients with A I - C A H or M C hepatitis share important clinico-epidemiological and serological findings (Table 1). Since mean age, female/male ratio, severity of liver damage (AST levels and cirrhosis), a n t i - H C V seropositivity are comparable in different series, it is possible that some Italian patients classified as A I - C A H or as MC, according to different Authors' approach, could have the same systemic disorder. It can be hypothesized that hepatotropic virus might trigger an immunological disor-
TABLE 1
References
(GISC). Cryoglobulinaemia and serological markers of hepatitis viruses. Lancet 1991; 338: 758-9. 6 Ferri C, Greco F, Longombardo G, et al. Antibodies against hepatitis C virus in mixed cryoglobulinaemia patients. Infection 1991; 19: 417-20. 7 Ferri C, Greco F, Longombardo G, et al. Association between hepatitis C virus and mixed cryoglobulinaemia. Clin Exp Rheumatol 1991; 9: 621-4. 8 Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinaemia: clinical aspects and long-term follow-up of 40 patients. Am J Med 1980; 69: 287-308. 9 Ferri C, Pietrogrande M, Cecchetti R, et al. Low-antigen-content diet in the treatment of patients with mixed cryoglobulinemia. Am J Med 1989; 87: 519-24. 10 Pozzato G, Moretti M, Franzin F, et al. Severity of liver disease with different hepatitis C viral clones. Lancet 1991; 338: 509.
I Lenzi M, Johnson PJ, McFarlane IG, et al. Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity. Lancet 1991; 338: 277-80. 2 Ferri C, Marzo E, Longombardo G, Lombardini F, Greco F, Bombardieri S. Alpha-interferon in the treatment of mixed cryoglobulinemia patients. Eur J Cancer 1991; 27, Suppl 4: 81-2. 3 Casato M, Pucillo LP, Lagan~, B, Taliani G, Goffredo F, Bonomo L. Cryoglobulinaemia and hepatitis C virus. Lancet 1991; 337: 1047-8. 4 Ferri C, Greco F, Longombardo G, et al. Hepatitis C virus antibodies in mixed cryoglobulinaemia patients. Arthr Rheum 1991; 34: 1606-10. 5 Galli M, and Gruppo ltaliano per 1o Studio delle Crioglobulinemie
Autoimmune chronic active hepatitis (AI-CAH)and cryoglobulinaemic hepatitis (MC-CAH) AI-CAH Magrin et al. (15 pts) 53 (43-64) 2.0 60% 2.8 (1.5-8) 60% 20% 20% n.a. n.a. 100%* 67%
MC-CAH Lenziet al. (80 pts) 55 (21-81) 3.2 45% 3.0 (0.6-19) n.a. 59% 41% n.a. n.a. 66%** n.a.
our series (42 pts) 61 (40-77) 2.8 30% 3.2 (1.1-14) 15% 26% n.a. 6.5 (0.2-25) 95% 97%* 86%
Age" F/M ratio Cirrhosis AST ANA ASMA Anti-LKM-I Cryocrit % Low CHso Anti-HCV HCV-RNA (PCR +) "Mean values (range). *Detected by Second Generation Ortho EL1SA and RIBA-2. **Detected by Ortho ELISA-I, RIBA-I and UBI EL1SA. AST=aspartate aminotransferase activity as multiple of upper limit of normal values; n.a.= not available. der with a variety of clinical patterns: from the isolated C A H to A I - C A H , with a possible association of systemic features, and finally the typical mixed cryoglobulinaemic syndrome. Hypothetically, a variable genetically induced host response a n d / o r the presence of different hepatitis C viral clones (10) could explain these different patterns. In conclusion, future studies on ' a u t o i m m u n e ' liver disease or 'cryoglobulinaemic' hepatitis should include a complete assessment (anti-nuclear, anti-smooth-muscle and a n t i - L K M 1 antibodies, circulating mixed cryoglobulins, complement levels) to better define possible patient subsets. C l o d o v e o Ferri a, Giovanni L o n g o m b a r d o a, Luca La Civita a, Stefano Bombardieri ~, Francesco Greco b, Peter Highfield c and T i m o t h y Corbishley c °Rheumatology and Clinical Immunology Unit, Universityof Pisa, bBIood Center, Ospedale S. Chiara, Pisa, Italy and ~Molecular Biology Section, Wellcome Diagnostic, Beckenham, United Kingdom
