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Normalization of urinary porphyrin level and disappearance of skin lesions after successful interferon therapy in a case of chronic hepatitis C complicated with porphyria cutanea tarda
uct-moment correlation coefficient). The mean levels of HCV-RNA in serum and liver were higher in Group II patients than Group I and III (not statistically significant). The mean ratio of liver to serum HCV-RNA levels was 36 (range: 1-138) and was not significantly different among the three histologic groups. We conclude that quantitation of HCV-RNA levels in liver biopsies can be accomplished with relative ease using the bDNA assay after a simple processing step. There was a signilicant correlation between serum and liver HCVRNA levels. This supports the hypothesis that serum levels reflect HCV-RNA levels in the liver. Patients with histologically less active disease and patients with fibrosis had lower levels of HCV-RNA in both liver and serum than patients with moderate to severe disease. Further analysis of the levels of HCV-RNA in liver tissue as well as serum during different stages of disease may shed light on the pathogenesis of chronic hepatitis due to HCV HCV-RNA levels in the liver may be useful in predicting and evaluating response to alpha-interferon therapy. Ester Coelho-Little, Lennox J. Jeffers, Maria Bartholomew, K. Rajender Reddy, Eugene R. Schiff and Peter J. Dailey’ Department of Hepatology, University of Miami School of Medicine, and Hepatology Section, Veterans Admistration Medical Center, Miami, FL 33101 and ‘Chiron Corporation, Emeryville, CA 94608, USA
References 1. Lau JYN, Davis GL, Kniffen J, Qian K, Urdea MS, Chan C, et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 1993; 341: 1501-4. 2. Wilber JC, Johnson PJ, Urdea MS. Reverse transcriptase-
r = 0.62, p =
. --
10‘6
10’ Serum:
10‘s
HCV Eq./ml
Fig. I. HCV RNA levels in serum and liver tissue.
PCR for hepatitis C virus RNA. In: Persing DH, Smith TF, Tenover FC, White TJ, eds. Diagnostic Molecular Microbiology: Principles and Applications. Washington DC.: American Society for Microbiology, 1993; 327-31. 3. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431-5. 4. Cox RA. The use of guanidinium hydrochloride in the isolation of nucleic acids. Methods Enzymol 1968; 12B: 120-2.
Normalization of urinary porphyrinlevel and disappearanceof skin lesions after successful interferontherapy in a case of chronic hepatitis C complicated with porphyriacutanea tarda
To the Editor:
Porphyria cutanea tarda (PCT) is characterized by photosensitivity of the skin, liver injury and hemosiderosis due to decreased activity of uroporphyrinogen decarboxylase, either acquired or inherited as an autosomal dominant trait. Recent reports clarified the relationship between hepatitis C virus (HCV) infection and PCT (l-3). We report here a case of chronic hepatitis C complicated by PCT that was successfully treated by interferon (IFN); the skin lesions disappeared and the urinary porphyrin level was normalized. A 69-year-old male was admitted to our hospital because of liver injury. He had a past history of blood transfusion during surgery for subarachnoid hemorrhage at the age of 46 and a history of alcohol intake of 50 g/day from the age of 20 to 66. His father died of hepatocellular carcinoma, but there was no family history of PCT. He consulted our dermatologist because of facial erythemas and erosions and was diagnosed with PCT and scleroderma at the age of 67 years. Since liver injury was detected, he was referred to our department. On admission, he had photosensitivity and skin lesions on the chin, neck, shoulders and chest. Laboratory findings included elevated transaminase levels (AST 393 IU/l and AST 473 IU/l) and he was positive for anti-HCV and HCV-RNA (lo4 copies!50 ~1 by reverse transcription combined with
nested polymerase chain reaction (4)), but negative for HB, antigen. The genotype of HCV was II according to the classification proposed by Okamoto et al. (5). The qualitative test for urinary porphyrin was positive and the urinary uroporphyrin level was markedly elevated (421.9 &I, control value: 14.4t8.4 &l, mean?SD). Liver biopsy revealed chronic active hepatitis, stage 2A, and the liver specimen appeared red under an ultraviolet lamp. He was treated with IFN&a for 1 year; 6 MIU per day for 4 weeks followed by the same dose 3 times per week (total dose was 1098 MIU). Four weeks after IFN treatment was initiated, serum transaminase levels decreased (AST 70 IU/I and ALT 60 IU/l) and HCV-RNA became negative and remained negative, even after IFN therapy was completed. The qualitative test for urinary porphyrin became negative 5 months after starting the IFN therapy and remained negative. The urinary uroporphyrin level after the treatment was markedly decreased to 41.3 ,@I. Liver biopsy after the treatment showed marked improvement of the inflammatory changes of the liver. Serum transaminase levels have remained within normal ranges for more than 1 year since IFN therapy was completed. Furthermore, the photosensitivity and skin lesions disappeared after the therapy. The present case provides further confirmation that HCV is related to the pathogenesis of the liver injury and PCT itself.
249
Correspondence
Hajime Takikawa, Ryo Yamazaki, Sadashi Shoji, Kazuhiko Miyake and Masami Yamanaka Department of Medicine, Teikyo University School of 2-1 I-I, Itabashi-ku, Tokyo 173, Japan.
Medicine, Kaga
References 1. Herrero C, Vincente A, Bruguera M, Eracilla MG, Barrera JM, Vidal J, et al. Is hepatitis C virus infection a trigger of porphyria cutanea tarda? Lancet 1993; 341: 788-9. 2. Ph.Lacour J, Bodokh I, Castanet J, Berkri S, Ortonne JP Porphyria cutanea tarda and antibodies to hepatitis C virus. Br J Dermatol 1993; 128: 121-3.
3. DeCastro M, Sanchez J, Herera JP, Chives A, Duran R, Garcia-Buey L, et al. Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 1993; 17: 551-7. 4. Okamoto H, Okuda S, Sugiyama Y, Yotsumoto S, Tanaka T, Yoshizawa H, et al. Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5’-noncoding region. Jpn J Exp Med 1990; 60: 215-22. 5. Okamoto H, Sugiyama Y, Okuda S, Kurai K, Akahane Y, Sugai Y, et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers. J Gen Virol 1992; 73: 673-9.
Augmented endogenous nitric oxide production in partial portal vein-ligated rats To the Editor:
We have investigated the role of endothelium-derived nitric oxide (EDNO) on the hyperdynamic circulation in rats with cirrhosis and rats with partial portal vein ligation by measuring nitrate ions (NOT) in serum and urine samples. Because the body oxidizes EDNO to NOT (l), measurement of the serum concentration and the urinary excretion of NO; may be a stable index for EDNO production (2).
r-p
7
20
1.
I31 B
P
lb 10 6 0 oollml
anhod*
Shun
PVL
Fig. 1. Serum nitrate concentrations and urinary excretion of nitrate in rat groups of liver cirrhosis (cirrhosis), portal vein ligation (PVL) and the respective control (controland
250
Cirrhosis was induced by administration of thioacetamide (200 mg/ kg) for 14 weeks in rats (3). Systemic and splanchnic hemodynamics and splenic-systemic shunting were determined by tracer microspheres under anesthesia with pentobarbital (4). The concentration of NO; was measured using high-performance liquid chromatography with an anion-column (IC-Pak A, Waters) (2). While marked hepatosplenomegaly was seen in the thioacetamidetreated rats, the weight of the liver was not influenced by the portal vein ligation. Thioacetamide-treated rats had characteristics of cirrhosis, but portal vein ligation rats showed no obvious changes either micro- or macroscopically. Rats with cirrhosis and rats with portal vein ligation showed a systemic hyperdynamic circulation with a significant increase in cardiac index (+24.2%, p
References 1. Lau JYN, Davis GL, Kniffen J, Qian K, Urdea MS, Chan C, et al. Significance of serum hepatitis C virus RNA levels in chronic hepatitis C. Lancet 1993; 341: 1501-4. 2. Wilber JC, Johnson PJ, Urdea MS. Reverse transcriptase-
r = 0.62, p =
. --
10‘6
10’ Serum:
10‘s
HCV Eq./ml
Fig. I. HCV RNA levels in serum and liver tissue.
PCR for hepatitis C virus RNA. In: Persing DH, Smith TF, Tenover FC, White TJ, eds. Diagnostic Molecular Microbiology: Principles and Applications. Washington DC.: American Society for Microbiology, 1993; 327-31. 3. Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431-5. 4. Cox RA. The use of guanidinium hydrochloride in the isolation of nucleic acids. Methods Enzymol 1968; 12B: 120-2.
Normalization of urinary porphyrinlevel and disappearanceof skin lesions after successful interferontherapy in a case of chronic hepatitis C complicated with porphyriacutanea tarda
To the Editor:
Porphyria cutanea tarda (PCT) is characterized by photosensitivity of the skin, liver injury and hemosiderosis due to decreased activity of uroporphyrinogen decarboxylase, either acquired or inherited as an autosomal dominant trait. Recent reports clarified the relationship between hepatitis C virus (HCV) infection and PCT (l-3). We report here a case of chronic hepatitis C complicated by PCT that was successfully treated by interferon (IFN); the skin lesions disappeared and the urinary porphyrin level was normalized. A 69-year-old male was admitted to our hospital because of liver injury. He had a past history of blood transfusion during surgery for subarachnoid hemorrhage at the age of 46 and a history of alcohol intake of 50 g/day from the age of 20 to 66. His father died of hepatocellular carcinoma, but there was no family history of PCT. He consulted our dermatologist because of facial erythemas and erosions and was diagnosed with PCT and scleroderma at the age of 67 years. Since liver injury was detected, he was referred to our department. On admission, he had photosensitivity and skin lesions on the chin, neck, shoulders and chest. Laboratory findings included elevated transaminase levels (AST 393 IU/l and AST 473 IU/l) and he was positive for anti-HCV and HCV-RNA (lo4 copies!50 ~1 by reverse transcription combined with
nested polymerase chain reaction (4)), but negative for HB, antigen. The genotype of HCV was II according to the classification proposed by Okamoto et al. (5). The qualitative test for urinary porphyrin was positive and the urinary uroporphyrin level was markedly elevated (421.9 &I, control value: 14.4t8.4 &l, mean?SD). Liver biopsy revealed chronic active hepatitis, stage 2A, and the liver specimen appeared red under an ultraviolet lamp. He was treated with IFN&a for 1 year; 6 MIU per day for 4 weeks followed by the same dose 3 times per week (total dose was 1098 MIU). Four weeks after IFN treatment was initiated, serum transaminase levels decreased (AST 70 IU/I and ALT 60 IU/l) and HCV-RNA became negative and remained negative, even after IFN therapy was completed. The qualitative test for urinary porphyrin became negative 5 months after starting the IFN therapy and remained negative. The urinary uroporphyrin level after the treatment was markedly decreased to 41.3 ,@I. Liver biopsy after the treatment showed marked improvement of the inflammatory changes of the liver. Serum transaminase levels have remained within normal ranges for more than 1 year since IFN therapy was completed. Furthermore, the photosensitivity and skin lesions disappeared after the therapy. The present case provides further confirmation that HCV is related to the pathogenesis of the liver injury and PCT itself.
249
Correspondence
Hajime Takikawa, Ryo Yamazaki, Sadashi Shoji, Kazuhiko Miyake and Masami Yamanaka Department of Medicine, Teikyo University School of 2-1 I-I, Itabashi-ku, Tokyo 173, Japan.
Medicine, Kaga
References 1. Herrero C, Vincente A, Bruguera M, Eracilla MG, Barrera JM, Vidal J, et al. Is hepatitis C virus infection a trigger of porphyria cutanea tarda? Lancet 1993; 341: 788-9. 2. Ph.Lacour J, Bodokh I, Castanet J, Berkri S, Ortonne JP Porphyria cutanea tarda and antibodies to hepatitis C virus. Br J Dermatol 1993; 128: 121-3.
3. DeCastro M, Sanchez J, Herera JP, Chives A, Duran R, Garcia-Buey L, et al. Hepatitis C virus antibodies and liver disease in patients with porphyria cutanea tarda. Hepatology 1993; 17: 551-7. 4. Okamoto H, Okuda S, Sugiyama Y, Yotsumoto S, Tanaka T, Yoshizawa H, et al. Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5’-noncoding region. Jpn J Exp Med 1990; 60: 215-22. 5. Okamoto H, Sugiyama Y, Okuda S, Kurai K, Akahane Y, Sugai Y, et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers. J Gen Virol 1992; 73: 673-9.
Augmented endogenous nitric oxide production in partial portal vein-ligated rats To the Editor:
We have investigated the role of endothelium-derived nitric oxide (EDNO) on the hyperdynamic circulation in rats with cirrhosis and rats with partial portal vein ligation by measuring nitrate ions (NOT) in serum and urine samples. Because the body oxidizes EDNO to NOT (l), measurement of the serum concentration and the urinary excretion of NO; may be a stable index for EDNO production (2).
r-p
7
20
1.
I31 B
P
lb 10 6 0 oollml
anhod*
Shun
PVL
Fig. 1. Serum nitrate concentrations and urinary excretion of nitrate in rat groups of liver cirrhosis (cirrhosis), portal vein ligation (PVL) and the respective control (controland
250
Cirrhosis was induced by administration of thioacetamide (200 mg/ kg) for 14 weeks in rats (3). Systemic and splanchnic hemodynamics and splenic-systemic shunting were determined by tracer microspheres under anesthesia with pentobarbital (4). The concentration of NO; was measured using high-performance liquid chromatography with an anion-column (IC-Pak A, Waters) (2). While marked hepatosplenomegaly was seen in the thioacetamidetreated rats, the weight of the liver was not influenced by the portal vein ligation. Thioacetamide-treated rats had characteristics of cirrhosis, but portal vein ligation rats showed no obvious changes either micro- or macroscopically. Rats with cirrhosis and rats with portal vein ligation showed a systemic hyperdynamic circulation with a significant increase in cardiac index (+24.2%, p