in Chronic Hepatitis C Virus Infection

Transcription

1 CASE REPORT Membranoproliferative Glomerulonephritis and Leukocytoclastic Vasculitis without Cryoglobulin in Chronic Hepatitis C Virus Infection Ayako NAKAJIMA, Masayuki ADACHI, Michi TANAKA, Akira SUWA, Yoshihiro YASUKI*, Hiroyuki IMAEDA** and Shinichi INADA Abstract The etiopathogenesis of extrahepatic manifestations including vasculitis in the context of HCVinfection is still unknown.wereport a case with lethal extrahepatic manifestations due to chronic hepatitis C virus (HCV) infection. The patient presented leukocytoclastic vasculitis, sensorimotor neuropathy and membranoproliferative glomerulonephritis with positive rheumatoid factor but lacked cryoglobulin. Hypocomplementaemia and deposition of IgM and C3 in the vascular lesion and glomeruli suggested that immune complex disease played a role in the pathogenesis of extrahepatic manifestations independent of cryoglobulin. Although HCVwas successfully eliminated by treatment with interferon a, she died of cryptococcal infection. (Internal Medicine 42: , 2003) Key words: cryptococcus, immune complex disease, extrahepatic manifestations, interferon a, opportunistic infection Introduction Various clinical and biological extrahepatic manifestations are reported in 38 to 74%of patients with chronic hepatitis C virus (HCV) infection. Among them, cryoglobulin is a crucial biological manifestation which is present in % of HCV-positive patients (1-3). Not all cryoglobulinpositive patients are symptomatic but cryoglobulin-positive patients tend to have severe immunological abnormalities (3). Recently, different types of vasculitis, i.e. small vessel vasculitis (such as cryoglobulinemia) and larger vessel disease [such as polyarteritis nodosa (PN)] are thought to be associated with HCV,and cryoglobulin is often found in most of the patients with these severe types of vasculitis (4-7). Therefore the presence of cryoglobulin can be one of the important indicators of severe extrahepatic manifestations including some type of vasculitis that sometimes determine the prognosis of patients (4, 7). Here, we report a patient with chronic HCVinfection, who had sensorimotor neuropathy, leukocytoclastic vasculitis, and membranoproliferative glomerulonephritis. As the prevalence of extrahepatic manifestations is lower in Japan than in other Western countries (8) and she was constantly negative for cryoglobulin, it was difficult to diagnose that her extrahepatic manifestations were ascribed to HCV. Interferon a successfully eliminated HCVin this patient but she died of cryptococcal infection. Wediscuss the renal involvement and vasculitis independent of cryoglobulin and opportunistic infection in the context of HCV. Case Report A 64-year-old womandeveloped low-grade fever, weakness, purpura and livedo reticularis, in addition to dysesthesia of her lower extremities in December Her past history included blood transfusion at surgery for gastric ulcer when she was 33. She had no history of excess alcohol consumption or intravenous drug abuse. She had erythema nodosumon her legs intermittently for 8 years. Liver dysfunction, positive rheumatoid factor, hypergammaglobulinemia, and HCV-antibody (HCV-Ab) positivity were detected in May The serotype of HCVwas group II. Cryoglobulin was negative. The ultrasonographic findings for the liver were consistent with chronic hepatitis. A skin biopsy performed in October 1996 from the purpuric lesion revealed prominent inflammation around the capillar- From the Division of Rheumatology, ^Division of Dermatology and **Division of Internal Medicine, Tokyo Metropolitan Ohtsuka Hospital, Tokyo Received for publication July 19, 2002; Accepted for publication June 6, 2003 Reprint requests should be addressed to Dr. Ayako Nakajima, Institute of Rheumatology, Tokyo Women's Medical University, Kawada-cho, Shinjuku-ku, Tokyo

2 Extrahepatic Manifestations of HCVInfection ies of the dermis, indicating leukocytoclastic vasculitis (Fig. 1). She had no fever, photosensitivity, symptoms of sicca, Raynaud's phenomenon, nephritis, or ischemic abdominal pain. HCVmRNAlevel was under 0.50 MEQ/ml as measured by the branched HCV DNA (bdna) probe method [<0.50 MEQ/ml] and 34.0 Kcopy/ml as measured by the reverse transcription-polymerase chain reaction (RT-PCR) method [<1.0 Kcopy/ml]. The patient refused treatment with interferon a. Administration of 20 mg per day of prednisolone and concomitant glycyrrhizin normalized aminotransferase levels and improved her purpura and dysesthesia to some extent. Prednisolone was tapered to 15 mgper day and was continued at that dose (Fig. 2). The palpable purpura and livedo reticularis increased in severity and spread to her upper arms, bilateral thighs, and abdomen, and she was admitted to our hospital on April 28, Physical examination revealed a temperature of 37.6 C and a blood pressure of 190/110 mmhg.she was anemic and anicteric. Her liver was enlarged but there was no ascites or splenomegaly. Pitting edema was detected on her lower extremities. She had herpes zoster eruptions on her right back and chest at the 6th thoracic vertebra level. Skin ulcers were present on the lateral sides of both ankles. Dysesthesia, Figure 1. Leukocytoclastic vasculitis in a small vessel, including polymorphonuclear neutrophils and exhibiting leukocytoclasis (periodic acid-schiff stain, x40) Dec å // May // Oct // Apr May Jun Jul Aug 15mg Prednisolone 20 mg { - Glycyrrhizin ggg InterferOn * V///fr//////////2 6X106 u/day 3 days/week Aciclovir ^ [s\\va\\\\nj Fluconazole INSS^CvSS^ Skin biopsy Admission Liver biopsy 1 \ \ ^^ Herpes zoster /ffffth Cryptococcus infection j(\[ \ itlthm Livedo/dysesthesia HCV DNA probe (MEQ/ml) < > 40 <0.5 RT-PCR (Kcopy/ml) < 1.0 < 1.0 AST (IU//) ALT (IU//) BUN (mg/dl) Cre (mg/dl) U-prot (-) (-) (-) (2+) (2+) (2+) (1+) (-) (2+) Figure 2. Clinical course of 67 y.o. woman with HCVinfection

3 C Nakajima et al Table 1. Laboratory Data on Admission Urinalysis Blood Chemistry Immunological data Protein (2+), 1.2 g/day TP 4.8 g/dl CRP 2.3 mg/dl Sugar (-) Alb 2. 1 g/dl IgG 1,652 mg/dl Red blood cell 7-10/HPF y-glob 25.7% IgA 309 mg/dl Cast hyaline 0-1/HPF BUN mg/dl IgM 332 mg/dl Cr 0.9 mg/dl C3 30 mg/dl ESR 1 1 mm/h T-Bil 1.7 mg/dl C4 1 mg/dl BC D-Bil 0.6mg/dl CH U/ml WBC 8,400/pl AST 59 IU/Z IC (C3d) 16.4 ng/ml St 2% ALT 49 IU// RA >600 IU/ml Seg 69% y-gtp 1 05 IU// ANA (-) Lymph 21% LDH 253 IU// Anti-MPO ANCA Ab (-) Mono 8% Anti-smooth muscle Ab (-) RBC 289x 1 04/jli1 Coagulation Anti-HBV Ag (-) Hb 9.0 g/dl PT >100% Anti-HBV Ab (-) MCV 93 fl APTT 22 sec Anti-HCV Ab (+) MCH pg Fibrinogen 152 mg/dl cryoglobulin (-) MCHC 33.5% Pit 19.2xlOV hypesthesia, tendon hyporeflexia, and muscle weakness were etected in both the upper and lower distal extremities. Laboratory data on admission are summarized in Table 1. On urinalysis, 1.2 g/day of proteinuria and microhematuria were detected with hyaline casts and epithelial casts. She had hypoalbuminemia with hypergammaglobulinemia and mild liver dysfunction (aspartate aminotransferase (AST): 59 TU/l, alanine aminotransferase (ALT): 49 IU//). Tests for hepatitis B virus antigen and antibody were negative, and anti-nuclear antibody, antineutrophil cytoplasmic myeloperoxidase antibody (MPO-ANCA), and other antibodies associated with liver or collagen diseases were negative (Table 1). Cryoglobulin was negative. C3, C4, and CH50 were all reduced, to 30 mg/dl, 1 mg/dl, and 13 U/ml, respectively, and immune complexes (anti-c3d antibody method) were elevated to 16.4 jug/ml [<9.2 ixg/ml]. Electromyography revealed reduction of both sensory and motor neuron conduction velocities in the distal extremities, supporting the presence of sensorimotor neuritis. Other serious systemic conditions such as infectious diseases, collagen diseases including systemic lupus erythematosus, Henoch-Schonlein purpura, and malignancies ncluding lymphoproliferative disorders were excluded. Administration of aciclovir ameliorated her herpes zoster eruption and fever. CRP subsequently became negative. Amlodipine besilate was commenced for her hypertension. A liver biopsy specimen obtained on May 27 showed chronic active hepatitis with prominent ballooning of hepatocytes and scattered free acidphilic bodies. The level of HCV mrna increased to over 40 MEQ/ml as determined by bdna probe method and 730 Kcopy/ml as determined by the HCV RNA RT-PCR method. Aggravation of renal function was also detected (Fig. 2), but no other causes of renal injury such as infection, malignancies, or other collagen diseases were detected. Interferon a was administered and ameliorated her purpura, liver dysfunction, and proteinuria. Serum creatinine decreased from 1.4 mg/dl to 0.7 mg/dl. The level of HCV decreased to below the limit of detection. However, she developed fever and several widespread regions of subcutaneous induration with tenderness on her right thigh. Yellowish pus was aspirated on July 22 and Cryptococcus Neoformans was determined by PAS and Grocott stain. Fluconazole and antibiotics were administered followed by extensive debridement. Massive pleural effusion and cavity formation emerged with scattered nodular lesions in her right middle lung. Sensorimotor neuropathy persisted and renal dysfunction was aggravated. She died of cryptococcal infection on August 18, Postmortem examination of the kidneys revealed double countour of the thickened loop, proliferation of mesangium and mesangial cells (Fig. 3). Deposition of C3 and IgM was detected in most of the glomeruli exhibiting lobular accentuation with granular peripheral capillaries and mesangial deposits supporting the presence of membranoproliferative glomerulonephritis (MPGN). Vasculitis with fibrinoid formation was detected in the small vessels in both lower extremities and in the retroperitomeum. Deposition of IgM was detected in the vessel walls in the dermis. Cryptococcus was also detected in kidneys, thyroid, and lymph nodes with granuloma Discussion In this article we describe a patient with various extrahepatic manifestations in chronic HCV infection. She presented purpura and livedo reticularis due to leukocytoclastic vasculitis, sensorimotor neuropathy, and MPGN accompanied by the presence of immune complexes and hypocomplementemia but lacked cryoglobulin. She had no 1 044

4 Extrahepatic Manifestations of HCV Infection Figure 3. Postmortem examination of the kidney. Double countour of the thickened loop and proliferation of mesangium and mesangial cells were detected (periodic acid-silver methenamine stain, xl60). signs of collagen diseases such as systemic lupus erythematosus or rheumatoid arthritis, Henoch-Schonlein purpura, streptococcal infection, or malignancies those are attributable to systemic vasculitis. Vasculitis related to HCV, such as cryoglobulinemic-type vasculitis or PN-type vasculitis, were supposed to be considered. Based on the size and pathological findings of the affected vessels and the glomerular involvement, PN-type vasculitis was excluded in this patient. From the presence of palpable purpura and livedo reticularis with neurological symptoms, it was necessary to differentiate another type of vasculitis, i.e. microscopic polyangiitis (MPA)-type vasculitis. As MPA is usually accompanied by crescent formation in glomeruli as 'pauci-immune' disease, MPA-type angiitis was also excluded based on the pathological findings and the negativity for MPO-ANCA. Cryoglobulinemic-type vasculitis is the most probable from the size and pathological findings of affected vessels and the presence of MPGN with immune deposition. Therefore, we inferred that immune complex disease played a major role in the extrahepatic manifestations in this patient irrespective of cryoglobulin. MPGNand leukocytoclastic vasculitis in chronic HCV infection in the absence of cryoglobulin is discussed as follows. For renal manifestations, glomerular injury may result from deposition of circulating immune complexes containing HCV antibodies (IgG or IgM), HCV antigens, and complement (mainly C3) within the subendothelium and mesangium. Cryoglobulin is reported to be absent in one-third of the patients with MPGN associated with HCV infection, and formation and deposition of immune complexes can be equally observed in these patients (9-ll). Direct effects of HCV infection on renal tissue by induction of renal cell transformation, cytokine production, and adhesion molecule expression can also be inferred. For skin manifestations, the HCV viron can be found in cutaneous vasculitic lesions in association with IgM and IgG in some vessel walls, ductal epithelium, and vascular endothelium in inflamed skin (12), and these pathological findings of the region may indicate vasculitis probably derived from immune complex disease (1 1, 13). Cryoglobulin is also absent in about one-third of the patients with leukocytoclastic vasculitis in HCV infection, and no pathological difference is suggested irrespective of cryoglobulin (13-15). Therefore, it is probable that immune complex disease plays a role in the pathogenesis of vasculitis independent of cryoglobulin in HCV infection. Based on these supposed pathomechanisms and the pathological autopsy findings, we inferred that various extrahepatic manifestations were introduced in the context of HCV infection ndependent of cryoglobulin in the present case. The reason for the occurrence of opportunistic infection in this patient is not yet elucidated. Opportunistic infections are rarely reported in patients with primary chronic HCV infection (16) without organ transplantation or human immune deficiency virus (HIV) infection. Moreover, opportunistic infection is not usually induced by treatment with interferon a for HCV infection (17-19). We attempted to determine why our patient was susceptible to opportunistic infection. She was not very old (67 years old) and did not consume alcohol. She had no malignancy or other collagen diseases. She had been treated with up to 20 mg per day of prednisolone for about 6 months, but this amount of prednisolone does not usually cause opportunistic infection. We did not examine for HIV infection, but she did not have drug addiction or extramarital sex. Her white blood cell count and CD4+ lymphocyte count and serum level of immunoglobulin were all normal. But her complement levels were consistently extremely low at least during these two years. Moreover some unpleasing and undetectable modification might have affected her immune system for more than 10 years while she had erythema nodosum attributable to HCV, since HCV is oth hepatotrophic and lymphotrophic. HCV was successfully eliminated and renal function was once improved by interferon a but concurrent intractable infection probably caused multiple organ failure including renal impairment. The possibility that interferon a precipitated other autoimmune diseases and exacerbated renal impairment may be excluded in this patient (20, 21), because overall serious side effects of interferon a were few and her clinical course was not so severe and the autopsy findings did not present severe angiitis. For future benefit, the notion that several extrahepatic manifestations can occur in HCV infection irrespective of cryoglobulin should be noted. Earlier introduction of interferon a and subsequent intensive immunosuppressive therapies including high-dose glucocorticoid, plasmapheresis, or immunosuppressive agents will likely achieve a better prognosis (4, 7, 10, 20). References 1) Lunel F, Musset L, Cacoub P, et al. Cryoglobulinemia in chronic liver 1045

5 Nakajima et al diseases: role of hepatitis C virus and liver damage. Gastroenterol 106: , 1994 (Published erratum in Gastroenterol 108: 620, 1995). 2) Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. Medicine (Baltimore) 79: 47-56, ) Cicardi M, Cesana B, Del Ninno E, et al. Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C. J Viral Hepat 7: , ) Roithinger FX, Allinger S, Kirchgatterer A, et al. A lethal course of chronic sponsive hepatitis C, glomerulonephritis, to interferon treatment. and pulmonary AmJ Gastroenterol vasculitis unre- 90: , ) Quigg RJ, Brathwaite M, Gardner DF, Gretch DR, Ruddy S. Successful cyclophosphamidetreatment of cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Am J Kidney Dis 25: , ) Cacoub P, Maisonobe T, Thibault V, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol 28: , ) Mendez P, Saeian K, Reddy KR, et al. Hepatitis C, cryoglobulinemia, and cutaneous vasculitis associated with unusual and serious manifestations. AmJ Gastroenterol 96: , ) Tanaka K, Aiyama T, Imai J, Morishita Y, Fukatsu T, Kakumu S. Serum cryoglobulin and chronic hepatitis C virus disease among Japanese patients. Am J Gastroenterol 90: , ) Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated J Med 328: , with hepatitis C virus infection. N Engl 10) Komatsuda A, Imai H, Wakui H, et al. Clinicopathological analysis and therapy in hepatitis C virus-associated nephropathy. Intern Med 35: , ) Willson RA. Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol 92: 4-17, ) Agnello V, Abel G. Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis Rheum 40: , ) Manna R, Todaro L, Latteri M, et al. Leucocytoclastic vasculitis associated with hepatitis C virus antibodies. Br J Rheumatol 36: , ) Karlsberg PL, Lee WM, Casey DL, Cockerell CJ, Cruz PD Jr. Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia. Arch Dermatol 131: , ) Gungor E, Cirit A, Alii N, Karakayali G, Gur G, Artiiz F. Prevalence of hepatitis C virus antibodies and cryoglobulinemia in patients with leukocytoclastic vasculitis. Dermatology 198: 26-28, ) Flagg SD, Chang YJ, Masuell CP, Natarajan S, Hermann G, Mendelson MH.Myositis resulting from disseminated cryptococcosis in a patient with hepatitis C cirrhosis. Clin Infect Dis 32: , ) Ferri C, Marzo E, Longombardo G, et al. Interferon-oc in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 81: , ) Misiani R, Bellavita P, Fenili D, et al. Interferon al fa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330: , ) Naarendorp M, Kallemuchikkal U, Nuovo GJ, Gorevic PD. Longterm efficacy of interferon-a for extrahepatic disease associated with hepatitis C virus infection. J Rheumatol 28: , ) Gordon ACH, Edgar JDM, Finch RG. Acute exacerbation of vasculitis during interferon-a therapy for hepatitis C-associated cryoglobulinaemia. J Infect 36: , ) Boonyapisit K, Katirji B. Severe excerbation of hepatitis C-associated vasculitic neuropathy following treatment with interferon alpha: a case report and literature review. Muscle Nerve 25: ,