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α1-antichymotrypsin (α1AC) deficiency: HIgh prevalence in HCV-related cirrhosis and chronic active hepatitis (HCV)
HEPATOLOGY V o l . 22, N o . 4, P t . 2, 1 9 9 5
977
AASLD
978
A S S O C I A T I O N O F D I A B E T E S MELLITUS W I T H C H R O N I C H E P A T I T I S C VIRUS (HCV) INFECTION. AL Mason. IYN Lau*. KP Oian*. N Hoanz. DL Baudv. WE lones. FG Re~enstein, RP PerrilIo Section of Gastroenterology" and Hepatology, Alton Ochsner Medical Foundation, New Orleans, LA; *Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainsville, FL. We aimed to i) assess the prevalence of diabetes in patients with chronic HCV infection; ii) determine the prevalence of HCV in diabetics; iiil examine the genotype profile of HCV-infected diabetes. METHODS: i) A retrospective chart review of 1471 patients with viral hepatitis evaluated for the following: history of diabetes; use of oral hypoglycemics or insulin; and random glucose > 200 mg/dl. 477 patients were excluded from analysis due to hypergylcemic medication or insufficient data. ii) Anti-HCV was evaluated by EIA II in 596 consecutive sera collected for giycosylated hemoglobin determination, iii) Genotyping of all anti-HCV positive diabetic sera was achieved by restriction fragment length polymorphism of the 5' UTR cDNA generated by RT-PCR. RESULTS: i) HBV HCV No. eligible patients 465 529 No. with diabetic criteria 59 111 ~2 HBV vs. HCV % prevalence of diabetes 12.7 21.0 P< 0.001 iil 24 of 596 or 4.0% of diabetics were found to be reproducibly anti-HCV positive vs. 0.8% local donors. E2 diabetics vs. controls P< 0.001 lii) HCV genotypes in 21 diabetics vs. local and national populations.
IHCV8enotype: National % Local % Diabetics %
la 37 42
lb 30 20
2a 4 2
2b 7 4
3a 6 2 5
4 Mixed pos* ne~,* 1 10 1 4 0 4 4 2 0 9.5 5 9.5
ABSTRACTS
al-ANTICHYMOTRYPSlN (alAC) DEFICIENCY: HIGH PREVALENCE IN HCV-RELATED CIRRHOSIS AND CHRONIC ACTIVE HEPATITIS C (HCV). T D Schiano, F Kueppers, SV Bellaryi YT Wachtfogel, RM Thomas, K Rothstein and M Black. Temple University School of Medicine. Depts. of Gastroenterology, Pulmonary and Pathology. a 1AC is a serine protease and acute phase reactant present in human serum. It is homologous to a 1-antitrypsin in amino acid sequence and gene arrangement. An association between a 1-AC deficiency and cryptogenic cirrhosis and chronic HCV has been noted in aSwedish study. Recently, the NS3-4A viral protease of HCV has been identified to be a chymotrypsin-like serine protease. The ouroose of this study was to examine the frequency of a 1-AC deficiency in HCVrelated cirrhosis and in chronic HCV infection. Methods: Levels of a 1-AC were assayed by radial immunodiffusion in serum samples collected over a 2 year period. Deficient levels were considered as being below the 9 5 % confidence range (0.17 mg/ml) in healthy controls. Results: 113 patients with biopsy proven cirrhosis and 94 others with chronic HCV (PCR positive) without cirrhosis were studied. 75 blood donors without liver disease were used as a control group. Of the 113 cirrhotics, the etiology in 59 was HCV, 21 alcohol, 14 cryptogenic and 19 other causes. 20•59 (34%) patients with HCV-related cirrhosis were a 1-AC deficient as compared to 6/54 (11%) with cirrhosis of other etiologies (p < 0.001). 12/94 (13%) patients with chronic HCV without cirrhosis were aIAC deficient as compared to 0/75 of blood donors. No correlation was noted between a l - A C level and indices of hepatic synthetic function (albumin, PT) or Child's class. Conclusions: A strong association exists between a 1-AC deficiency and cirrhosis, particularly in HCV-related cirrhosis. This is independent of severity of underlying liver disease and hepatic synthetic function, a 1-AC deficiency may favor HCVmediated liver injury via an effect on the NS3-4A viral protease and in the presence of the double insult of a dysregulated inflammatory response may lead to cirrhosis.
AUTOIMMUNITY AND THYROID DYSFUNCTION IN CHRONIC HEPATITIS TREATED WITH INTERFERON.Ffitima S e r e O % H Gl6ria~R Marinho~ M Raimundo~ F Ramalho and M Carneiro de Moura. Liver Unit, Department of Medicine II,Medical School o f Lisbon,Lisbon, Portugal. The aim of this study was to prospectively evaluate the development of serum autoantibodies and thyroid dysfunction during and after interferon (IFN) therapy and whether existence of autoantibodies influences the efficacy of IFN therapy in chronic hepatitis C. Ninety three patients with chronic hepatitis C were prospectively studied and completed a therapeutic trial of IFN, 3 or 6 MU, tiw, during 9 or 12 months. Serum ANA, SMLA, AMA, antithyroglobulin and/or antimicrosomal antibodies, immune complexes (IC) a~d~thyroid function (T3, T4 and TSH) were studied. Before treatment the prevalence of autoantibodies was 9.4%: ANA-3%, SMA-5.4% and anti-thyroid Abs-1%. IC were detected in 14 patients (15%). Thyroid dysfunction was present in 4.3~. None had clinical manifestations of thyroid disease. During IFN we found autoantibodies in 38% (P < 0.01). 38% developed de ncvo thyroid dysfunction (P < 0.01). Thirteen (26%) had associated abnormal TSH values; 3 patients (6%) manifested clinical thyroid disease.The prevalence of autoantibodiea and thyroid dysfunction were significantly higher in women compared to men(P < 0.01). Patients were tested for at least 6 me after IFN discontinuation, Only 3 showed auteantibodies . Thyroid dysfunction was maintained in 4 (22%), all with TSH abnormalities; 2 with hypothyroidism needed long term specific therapy. In conclusion, the detection of ANA and AML and IC was not a contraindication for IFN and had no influence on the response to IFN. Abnormal TSH values or the presence o f antdthyroid antibodies with high titers (> 1/160) were considered reason to interrupt interferon therapy.
[
9.5 19 28.5 14 * PCR positive or negative with undetermined genotype Z2 HCV genotype 2a + 2b in diabetics vs national or local controls p < 0.001 CONCLUSIONS: 1) Patients with chronic HCV infection are significantly more likely to be diabetic as compared to patients with chronic HBV infection. 2) Diabetics are significantly more likely to be anti-HCV positive compared to the general population. 3) Diabetics with HCV infection have a diminished percentage of HCV type 1 genotypes but significantly elevated prevalence of type 2 genotypes. 4,) Diabetes may be another extrahepatic disorder associated with chronic HCV infection.
979
351A
980
CHRONIC CHOLESTATIC HEPATITIS C IN IMMUNOCOMPROMISED PATIENTS. M. Bonacini, S. Govindaraian. Division GI and Liver Diseases,USC School of Medicine, Los Angeles, CA; Dept of Pathology, Rancho Los Amigos Medical Center, Downey, CA. A cholestatic variant of chronic hepatitis C has been recently described. This entity is characterized by intense pruritus usually with elevated serth'n alkaline phosphatase (AP) and bile acids (B.A.) AIM: To describe patients with HIV and HCV coinfection with marked pruritus (group A) and to evaluate eoinfeeted controls (group B), matched by peripheral CD4 counts. M E T H O D S : 14 patients with HIV and chronic hepatitis C were studied: 7 patients had pruritus (A) resistant to antihistamine therapy. Fourteen separate serum determinations were made in the 7 patients. Seven individuals without pruritus were also studied. RESULTS: All group A patients had a negative AMA and no evidence of biliary obstruction by ultrasound, ERCP or both. Medications were not substantially different in the two groups.Three group A and 6 group B patients had a liver biopsy; HAl was calculated for necroinflammatorychanges only. A B Total bili (mg/dL)® 4.5=~3.9 & 0.7±0.2 AP (IU/L) 245q-107 * 96±17 B.A.(~m/L) 189-3:115 * 24.3±12 H.A.I. score 8.3:~1.2 8.2:~3.3 CD4 (eells/~L) 162± 185 165± 185 ® all means±S.D. & p
977
AASLD
978
A S S O C I A T I O N O F D I A B E T E S MELLITUS W I T H C H R O N I C H E P A T I T I S C VIRUS (HCV) INFECTION. AL Mason. IYN Lau*. KP Oian*. N Hoanz. DL Baudv. WE lones. FG Re~enstein, RP PerrilIo Section of Gastroenterology" and Hepatology, Alton Ochsner Medical Foundation, New Orleans, LA; *Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainsville, FL. We aimed to i) assess the prevalence of diabetes in patients with chronic HCV infection; ii) determine the prevalence of HCV in diabetics; iiil examine the genotype profile of HCV-infected diabetes. METHODS: i) A retrospective chart review of 1471 patients with viral hepatitis evaluated for the following: history of diabetes; use of oral hypoglycemics or insulin; and random glucose > 200 mg/dl. 477 patients were excluded from analysis due to hypergylcemic medication or insufficient data. ii) Anti-HCV was evaluated by EIA II in 596 consecutive sera collected for giycosylated hemoglobin determination, iii) Genotyping of all anti-HCV positive diabetic sera was achieved by restriction fragment length polymorphism of the 5' UTR cDNA generated by RT-PCR. RESULTS: i) HBV HCV No. eligible patients 465 529 No. with diabetic criteria 59 111 ~2 HBV vs. HCV % prevalence of diabetes 12.7 21.0 P< 0.001 iil 24 of 596 or 4.0% of diabetics were found to be reproducibly anti-HCV positive vs. 0.8% local donors. E2 diabetics vs. controls P< 0.001 lii) HCV genotypes in 21 diabetics vs. local and national populations.
IHCV8enotype: National % Local % Diabetics %
la 37 42
lb 30 20
2a 4 2
2b 7 4
3a 6 2 5
4 Mixed pos* ne~,* 1 10 1 4 0 4 4 2 0 9.5 5 9.5
ABSTRACTS
al-ANTICHYMOTRYPSlN (alAC) DEFICIENCY: HIGH PREVALENCE IN HCV-RELATED CIRRHOSIS AND CHRONIC ACTIVE HEPATITIS C (HCV). T D Schiano, F Kueppers, SV Bellaryi YT Wachtfogel, RM Thomas, K Rothstein and M Black. Temple University School of Medicine. Depts. of Gastroenterology, Pulmonary and Pathology. a 1AC is a serine protease and acute phase reactant present in human serum. It is homologous to a 1-antitrypsin in amino acid sequence and gene arrangement. An association between a 1-AC deficiency and cryptogenic cirrhosis and chronic HCV has been noted in aSwedish study. Recently, the NS3-4A viral protease of HCV has been identified to be a chymotrypsin-like serine protease. The ouroose of this study was to examine the frequency of a 1-AC deficiency in HCVrelated cirrhosis and in chronic HCV infection. Methods: Levels of a 1-AC were assayed by radial immunodiffusion in serum samples collected over a 2 year period. Deficient levels were considered as being below the 9 5 % confidence range (0.17 mg/ml) in healthy controls. Results: 113 patients with biopsy proven cirrhosis and 94 others with chronic HCV (PCR positive) without cirrhosis were studied. 75 blood donors without liver disease were used as a control group. Of the 113 cirrhotics, the etiology in 59 was HCV, 21 alcohol, 14 cryptogenic and 19 other causes. 20•59 (34%) patients with HCV-related cirrhosis were a 1-AC deficient as compared to 6/54 (11%) with cirrhosis of other etiologies (p < 0.001). 12/94 (13%) patients with chronic HCV without cirrhosis were aIAC deficient as compared to 0/75 of blood donors. No correlation was noted between a l - A C level and indices of hepatic synthetic function (albumin, PT) or Child's class. Conclusions: A strong association exists between a 1-AC deficiency and cirrhosis, particularly in HCV-related cirrhosis. This is independent of severity of underlying liver disease and hepatic synthetic function, a 1-AC deficiency may favor HCVmediated liver injury via an effect on the NS3-4A viral protease and in the presence of the double insult of a dysregulated inflammatory response may lead to cirrhosis.
AUTOIMMUNITY AND THYROID DYSFUNCTION IN CHRONIC HEPATITIS TREATED WITH INTERFERON.Ffitima S e r e O % H Gl6ria~R Marinho~ M Raimundo~ F Ramalho and M Carneiro de Moura. Liver Unit, Department of Medicine II,Medical School o f Lisbon,Lisbon, Portugal. The aim of this study was to prospectively evaluate the development of serum autoantibodies and thyroid dysfunction during and after interferon (IFN) therapy and whether existence of autoantibodies influences the efficacy of IFN therapy in chronic hepatitis C. Ninety three patients with chronic hepatitis C were prospectively studied and completed a therapeutic trial of IFN, 3 or 6 MU, tiw, during 9 or 12 months. Serum ANA, SMLA, AMA, antithyroglobulin and/or antimicrosomal antibodies, immune complexes (IC) a~d~thyroid function (T3, T4 and TSH) were studied. Before treatment the prevalence of autoantibodies was 9.4%: ANA-3%, SMA-5.4% and anti-thyroid Abs-1%. IC were detected in 14 patients (15%). Thyroid dysfunction was present in 4.3~. None had clinical manifestations of thyroid disease. During IFN we found autoantibodies in 38% (P < 0.01). 38% developed de ncvo thyroid dysfunction (P < 0.01). Thirteen (26%) had associated abnormal TSH values; 3 patients (6%) manifested clinical thyroid disease.The prevalence of autoantibodiea and thyroid dysfunction were significantly higher in women compared to men(P < 0.01). Patients were tested for at least 6 me after IFN discontinuation, Only 3 showed auteantibodies . Thyroid dysfunction was maintained in 4 (22%), all with TSH abnormalities; 2 with hypothyroidism needed long term specific therapy. In conclusion, the detection of ANA and AML and IC was not a contraindication for IFN and had no influence on the response to IFN. Abnormal TSH values or the presence o f antdthyroid antibodies with high titers (> 1/160) were considered reason to interrupt interferon therapy.
[
9.5 19 28.5 14 * PCR positive or negative with undetermined genotype Z2 HCV genotype 2a + 2b in diabetics vs national or local controls p < 0.001 CONCLUSIONS: 1) Patients with chronic HCV infection are significantly more likely to be diabetic as compared to patients with chronic HBV infection. 2) Diabetics are significantly more likely to be anti-HCV positive compared to the general population. 3) Diabetics with HCV infection have a diminished percentage of HCV type 1 genotypes but significantly elevated prevalence of type 2 genotypes. 4,) Diabetes may be another extrahepatic disorder associated with chronic HCV infection.
979
351A
980
CHRONIC CHOLESTATIC HEPATITIS C IN IMMUNOCOMPROMISED PATIENTS. M. Bonacini, S. Govindaraian. Division GI and Liver Diseases,USC School of Medicine, Los Angeles, CA; Dept of Pathology, Rancho Los Amigos Medical Center, Downey, CA. A cholestatic variant of chronic hepatitis C has been recently described. This entity is characterized by intense pruritus usually with elevated serth'n alkaline phosphatase (AP) and bile acids (B.A.) AIM: To describe patients with HIV and HCV coinfection with marked pruritus (group A) and to evaluate eoinfeeted controls (group B), matched by peripheral CD4 counts. M E T H O D S : 14 patients with HIV and chronic hepatitis C were studied: 7 patients had pruritus (A) resistant to antihistamine therapy. Fourteen separate serum determinations were made in the 7 patients. Seven individuals without pruritus were also studied. RESULTS: All group A patients had a negative AMA and no evidence of biliary obstruction by ultrasound, ERCP or both. Medications were not substantially different in the two groups.Three group A and 6 group B patients had a liver biopsy; HAl was calculated for necroinflammatorychanges only. A B Total bili (mg/dL)® 4.5=~3.9 & 0.7±0.2 AP (IU/L) 245q-107 * 96±17 B.A.(~m/L) 189-3:115 * 24.3±12 H.A.I. score 8.3:~1.2 8.2:~3.3 CD4 (eells/~L) 162± 185 165± 185 ® all means±S.D. & p