Journal of Hepatology 37 (2002) 871–877 www.elsevier.com/locate/jhep
Letters to the Editor
Cutaneous thrombotic microangiopathy during treatment with Alpha-interferon for chronic hepatitis C To the Editor: Alpha interferon (a-IFN) is a glycoprotein agent used in the treatment of hematologic malignancies, metastatic melanoma, and more recently in the treatment of chronic hepatitis C, often in association with ribavirin [1,2]. In terms of renal involvement, approximately 30 cases of thrombotic microangiopathy (TMA) confirmed by renal biopsy have been attributed to treatment by a-IFN [1]. Cutaneous lesions have been recognized since 1991, most typically with a Raynaud’s syndrome and distal ischemia with necrosis of the fingers [1]. We describe for the first time two cases of non-specific skin lesions linked to a-IFN toxicity during treatment of chronic hepatitis C. The first patient was a 54-year-old woman who was hospitalized for treatment of hepatic manifestations with hepatocellular injury and cholestasis. Hepatitis C RNA by polymerase chain reaction (PCR) was positive at 5 £ 10 5 IU/ ml; the genotype was determined to be 1b, and liver biopsy revealed a histologic picture compatible with viral cirrhosis, Metavir score of A2F4 [3]. Treatment, including subcutaneous injections of pegylated a2b-IFN (Viraferon w 150 mg 0.4 ml/week) and ribavirin (Rebetol w), four capsules/day), was begun in November, 2001. Six months later the patient was referred to Dermatology for small bullous lesions occurring on otherwise normal-appearing skin, sparse on the body and predominating on the backs of the hands and feet but not involving the palms and soles. These lesions were pruriginous, and of short, 48-h duration, healing rapidly after rupture of the bullae. The second patient was a 62-year-old women treated for 7 months with pegylated aIFN plus ribavirin for chronic hepatitis C of 1b phenotype of 7 years duration. At the time of the diagnosis, hepatitis C viral RNA was positive by PCR at a level above 850 000 IU/ml and liver biopsy showed portal fibrosis and chronic hepatitis with a Metavir score of A1F2 [3]. Treatment was begun with pegylated a2b-IFN (Viraferon w, 1.5 mg/kg per week) and ribavirin (Rebetol w, four capsules/day). After 5 months of treatment, the patient developed a generalized intense pruritis, with numerous excoriated lesions. By the 8th month, these lesions were maximal on the backs of the hands and the feet. But there were no bullae, only multiple non-infected crusts, and the skin all over was normal. Blood pressure was normal in both patients. Skin biopsy revealed in both cases microthrombi of the dermal capillaries without associated inflammation, associated with sloughing of the
necrotic epidermis (Fig. 1). By immunofluorescence the lesions revealed only fibrinogen, in the absence of immunoglobulins. In both instances laboratory and clinical studies have ruled out the customary causes of microthrombi: cryoglobulinemia; problems of hemostasis (lupus anticoagulant and anticardiolipin antibodies, deficits in protein C, S or factor V Leiden); autoimmune diseases (antinuclear antibodies, antiDNA, antineutrophil cytoplasmic antibodies and other antibodies), and disseminated intravascular coagulation. Nor was there any evidence of thrombocytopenia, hemolytic anemia, or renal manifestations (hematuria, proteinuria, renal failure). The course was marked in the first patient by the persistence of some bullous lesions 1 month after discontinuation of the treatment. In the second patient there was a good response to local corticotherapy and diminution of the dose of a-IFN, but she continued to have episodes of severe pruritis.
Fig. 1. Skin biopsy showing microthrombi of the dermal capillaries (arrows). Epidermis is necrotic. Hemalun eosin saffron £ 40.
0168-8278/02/$20.00 q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.
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Letters to the Editor
The purpose of our communication is to describe cutaneous TMA occurring during the course of treatment of hepatitis C. The majority of thrombotic complications have been described in the course of hematologic malignancies treated with a-IFN [1]. The causal role of a-IFN was recently demonstrated by the recrudescence of renal lesions after restarting treatment [1]. One report has described cutaneous thrombotic lesions contemporaneous with a renal TMA in chronic myeloid leukemia [2]. The lesions were, as in our two patients, papular skin lesions on the lower extremities, and not those of ischemia or emboli. The complications linked to a-IFN treatment occur primarily during the course of long-term treatment, with elevated doses of a-IFN, and have almost exclusively been described in malignancies [1]. Only two cases of renal TMA have been described during high dose of a-IFN treatment of hepatitis C [4,5]. The classic causes of microthrombi in hepatitis C are principally type II cryoglobulins, with a predilection for the kidney and skin [6]. Cryoglobulins were ruled out in our patients, either initially or after systematic laboratory examination. There are several possible pathophysiologic mechanisms by which a-IFN might lead to TMA with involvement of the vascular endothelium. This treatment might possibly lead to induction of pathogenic antiphospholipid antibodies [7], but several studies, including our own, fail to confirm this hypothesis. Other immunologic mechanisms have been proposed: the presence of anti-endothelial cell antibodies and anti-von Willebrand factor, or overexpression of class I antigens of the human histocompatibility system, rendering the cells vulnerable to a cytotoxic response [8]. In the literature, the TMA is almost always renal, as revealed by renal insufficiency and hypertension, with a poor prognosis. The cutaneous lesions described have almost always been related to Raynaud’s syndrome or distal ischemia with necrosis of the extremities [1]. Histologic descriptions are derived primarily from amputation specimens and show vascular occlusions. In our two patients, there was a cutaneous TMA analogous to renal TMA, as opposed to the lesions of thrombosis in distal ischemic lesions, for which there was neither clinical evidence in terms of Raynaud’s-like symptoms nor histologic evidence in terms of epidermal thinning and dermal atrophy. Rather, the lesions were non-specific thrombotic cutaneous lesions. These results serve to emphasize the following points: 1) the indispensable role of skin
biopsy in cutaneous lesions arising during the course of treatment by a-IFN. 2) The interpretation of this first symptom of TMA: Does it represent an isolated lesion or the first symptom of a diffuse systemic TMA? 3) The importance of complete cessation of a-IFN treatment because of the renal and systemic risks of this complication. These questions are becoming more and more important as the antiviral treatment of chronic hepatitis C becomes more generalized.
Caroline Creput 1, Nicole Auffret 2, Didier Samuel 3, Raymond Jian 4, Gary Hill 1, Dominique Nochy 1 1 Department of Pathology, Hoˆpital Europe´en Georges Pompidou, 20 rue Leblanc, F-75908 Paris Cedex 15, France, 2Department of Dermatology, Hoˆpital Europe´en Georges Pompidou, Paris, France, 3Department of Hepatology, Paul Brousse Hospital, Villejuifm, France, 4Department of Gastroenterology, Hoˆpital Europe´en Georges Pompidou, 20 rue Leblanc, F-75908 Paris Cedex 15, France
References [1] Zuber J, Martinez F, Droz D, Oksenhendler E, Legendre C. Alpha-interferon-associated thrombotic microangiopathy: a clinicopathologic study of 8 patients and review of the literature. Medicine 2002;81:321–331. [2] Honda K, Ando A, Endo M, Shimizu K, Higashihara M, Nitta K, et al. Thrombotic microangiopathy associated with alpha-interferon therapy for chronic myelocytic leukemia. Am J Kidney Dis 1997;30:123–130. [3] The French Metavir Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology 1994;20:15–20. [4] Ubara Y, Hara S, Takedatu H, Katori H, Yamada K, Yoshihara K, et al. Hemolytic uremic syndrome associated with beta-interferon therapy for chronic hepatitis C. Nephron 1998;80:107–108. [5] Iyoda K, Kato M, Nakagawa T, Kakiuchi Y, Sugiyasu Y, Fujii E, et al. Thrombotic thrombocytopenic purpura developed suddenly during interferon treatment for chronic hepatitis C. J Gastroenterol 1998;33:588–592. [6] Cacoub P, Lunel F, Musset L, Opolon P, Piette JC. Hepatitis C virus and cryoglobulinemia. N Engl J Med 1993;328:1121–1124. [7] Piette JC, Papo T. Potential role for antiphospholipid antibodies in renal thrombotic microangiopathy induced by interferon-alpha. Nephrol Dial Transplant 1995;10:1781. ¨ berg K. Autoimmunity after alpha-interferon [8] Ro¨ nnblom L, Alm G, O therapy for malignant carotid tumors. Ann Intern Med 1991;115:178– 183. PII: S0 168-8278(02 )00 302-1
Hepatic mucosa-associated lymphoid tissue (MALT) lymphoma associated with hepatitis C To the Editor: Extranodal mucosa-associated lymphoid tissue (MALT)type lymphomas develop in organs normally devoid of lymphoid tissue, and they are thought to be triggered by chronic antigenic stimulation associated with inflammation
or autoimmune disease, such as Helicobactor pylori infection in the stomach, and Hashimoto’s thyroiditis in the thyroid, and Sjo¨ gren’s syndrome in the salivary glands. Primary MALT-type lymphoma of the liver is uncommon, and there have been just ten English language reports of primary