NATAP: Hep C, cryoglobulinemia

[Guest guest]

NATAP - http://www.natap.org

American Journal of Gastroenterology

Volume 96 Issue 8 Page 2489 - August 2001

doi:10.1111/j.1572-0241.2001.04059.x

Hepatitis C, cryoglobulinemia, and cutaneous vasculitis associated with unusual and serious manifestations

Méndez, M.D. a , Kia Saeian, M.D. a , K. Rajender Reddy, M.D. a * , Zobair M. Younossi, M.D. c , Francisco Kerdel, M.D. b , Salvatore Badalamenti, M.D. a , Lennox J. Jeffers, M.D. a , Eugene R. Schiff, M.D. a

Hepatitis C viral infection is currently the leading cause of chronic hepatitis and cirrhosis. It also is a major predisposing factor for the development of hepatocellular carcinoma. It is estimated that approximately 12% of patients with hepatitis C infection have nonhepatic manifestations that are protean in nature. In this report, we describe six unusual cases of nonhepatic manifestations: abdominal vasculitis in two, peripheral neuropathy in two, and one patient each with central nervous system vasculitis and necrotizing cutaneous vasculitis. All patients had cutaneous vasculitis and cryoglobulinemia. None of our patients had cirrhosis, yet three of the six patients died. Because of the severe manifestations, aggressive therapy was instituted with interferon, immunosuppressive medications, i.v. immunoglobulin, and plasmapheresis. Our report underscores the importance of recognizing nonhepatic manifestations in patients with hepatitis C infection that may be associated with high morbidity and mortality.

Introduction

Nearly 3.9 million Americans are infected with the hepatitis C virus (HCV), but only 2530% are sufficiently symptomatic to be brought to medical attention (1). Approximately 85% of acute infections eventually evolve to chronic infections and are thus at risk for development of a wide spectrum of consequences, ranging from asymptomatic and mild disease to cirrhosis and hepatocellular carcinoma (2). Further, HCV has been associated with a wide array of extrahepatic manifestations (24), the most common and well-recognized being mixed cryoglobulinemia (58), glomerulonephritis (912), and porphyria cutanea tarda (1315).

Among patients with chronic hepatitis C infection, a third have serological evidence of cryoglobulinemia, but the clinical syndrome of essential mixed cryoglobulinemia (EMC) only occurs in 12% (2, 16). As a systemic illness, cryoglubulinemia may present with purpura, arthralgia, peripheral neuropathy, glomerulonephritis, and any of the protean manifestations of vasculitis. Historically, it has been classified into three distinct types. Type I cryoglobulinemia is associated with immunological malignancies and consists of monoclonal immunoglobulins. Types II and III cryoglobulinemia are polyclonal and thus are called mixed cryoglobulinemias. Type II cryoglobulinemia consists of polyclonal IgG and monoclonal IgM rheumatoid factors, whereas type III consists of polyclonal IgG and IgM rheumatoid factors (17, 18). Although some of the mixed cryoglobulinemias are secondary, those without any clear underlying etiology have been classified as EMC. Recent studies have reported that 8096% of patients with mixed cryoglobulinemia have positive HCV antibodies and detectable HCV RNA (57).

Herein we report six cases of chronic HCV, cryoglobulinemia, and cutaneous vasculitis that had unusual and infrequently encountered extrahepatic manifestations. Two patients each had abdominal vasculitis and peripheral neuropathy, and one patient each had central nervous system (CNS) vasculitis and necrotizing cutaneous vasculitis.

Case 1

A 36-yr-old patient with HCV infection and histology evidence of mild chronic hepatitis presented with bilateral lower extremity rash associated with arthralgias (Table 1). Hepatitis B serology was negative. Treatment with interferon (3 million U s.c.) three times a week for 6 months yielded no response. Subsequently, intractable nausea, vomiting, and acute abdominal pain necessitated hospitalization, at which time an exploratory laparotomy revealed small bowel infarction. He underwent bowel resection. Pathology demonstrated necrotizing vasculitis affecting small vessels (Fig. 1). Treatment with plasmapheresis and pulse i.v. corticosteroids resulted in temporary improvement. One week later he developed abdominal distention, at which time repeat exploratory laparotomy revealed fascial dehiscence and ascites. An intraoperative liver biopsy noted chronic portal triaditis with the presence of fibrin thrombi in the small portal vessels (Fig. 2). The serum bilirubin was 34.3 mg/dl; albumin, 2.5 g/dl; creatinine, 1.0 mg/dl; and PT, 14.1 s. Polyarteritis nodosa was diagnosed and i.v. cyclophosphamide was started. Despite treatment, severe ischemic colitis evolved, complicated by multiple intra-abdominal abscesses. Subsequently, sepsis and acute renal and liver failure ensued and the patient died.

Case 2

A 52-yr-old woman with chronic hepatitis C developed an intermittent rash over her abdomen, more prominent on the lower extremities, followed by recurrent episodes of epigastric abdominal pain. Multiple studies ruled out peptic ulcer disease. An upper GI and small bowel series demonstrated thickened mucosal folds in the entire duodenum and proximal jejunum. A presumptive diagnosis of intestinal vasculitis was made, and the patient was treated with corticosteroid therapy. Interferon treatment, on two occasions, led to poor tolerability and therefore was discontinued. She has remained free of pain as long as she is maintained on at least 10 mg of prednisone a day. She also did develop one episode of pancreatitis with no evidence of gallstones.

Case 3

In February, 1993, a 33-yr-old man developed bilateral lower extremity purpura, left leg numbness, and loss of sensation on the superior aspect of the left foot. At that time, serum cryoglobulins were negative, electromyography revealed moderately severe demyelinating axonal neuropathy, and a skin biopsy was consistent with leukocytoclastic vasculitis. A diagnosis of inflammatory neuropathy and vasculitis was made. He was treated with prednisone (60 mg/day), with partial response. Mild symptoms persisted for 1 yr, after which anti-HCV was detected and HCV infection was confirmed by serum polymerase chain reaction. Cryoglobulins were now positive, but treatment with corticosteroids and interferon yielded no benefit. Recurrent episodes of paresthesia and lower extremity purpura persisted despite continued treatment. In 1997, the purpura progressed to ulcerations and multiple open lesions on the left calf, accompanied by a 12-lb weight loss and weakness of the right hand. In January, 1998 he developed arthritis, purpura of the left fourth and fifth digits, and diffuse red s.c. nodules. Despite aggressive medical therapy and five sessions of plasmapheresis, the disease progressed unremittingly and the patient died from cardiac arrest.

Case 4

In 1980, a 30-yr-old man was evaluated for a migratory arthritis, diagnosed as rheumatoid arthritis, and treated with gold injections for 6 months with no improvement. Cortisone injections at 3-month intervals finally relieved his symptoms. In 1997 he developed intense right shoulder pain with paresthesia and muscle wasting. Hepatitis C infection was diagnosed. Electromyographic evaluation showed brachial plexitis. Oral corticosteroid therapy was initiated. Four days later he developed an erythematous vasculitic rash on both lower extremities and the left arm. The pain now extended to the left shoulder. On examination, he had atrophy and weakness of the right shoulder. Corticosteroids were discontinued and treatment with plasmapheresis, i.v. immunoglobulin, and interferon (3 million U three times a week) was started. He improved clinically and is now on interferon treatment and doing well.

Case 5

A 38-yr-old man with chronic hepatitis C was initially treated with interferon (3 million U s.c. three times a week), resulting in an initial virological and biochemical response. He had a relapse and was retreated with a higher dose of interferon (5 million U s.c. three times a week) for 11 months. Despite normalization of his transaminases, viremia persisted. Shortly thereafter, he developed pancytopenia and had unintentional weight loss. He also reported lightheadedness, tremulousness, and blurred vision. Hematological evaluation led to a bone marrow biopsy, which yielded a diagnosis of hairy cell leukemia. He was given chemotherapy, which resolved the pancytopenia and weight loss, but the lightheadedness, tremulousness, and blurred vision persisted. All of these symptoms had predated the diagnosis as well as treatment of hairy cell leukemia. Extensive workup was done that included magnetic resonance imaging of the posterior fossa of the cranium, electronystagmography, antineutrophil perinuclear antibody, antineutrophil cytoplasmic antibody, anti-smooth muscle antibody, antimitochondrial antibody, anti- anti-body, and antiribonucleoprotein, which were negative. A clinical diagnosis of CNS vasculitis was made, and he was treated with prednisone for a period of 3 months with resolution of his symptoms. Subsequently he was switched to interferon- (5 mU three times a week) and ribavirin (100 mg/day) and remains asymptomatic, with negative cryoglobulins.

Case 6

In 1988, a 35-yr-old man developed asymptomatic hematuria, proteinuria, thrombocytopenia, and hemolytic anemia. Renal biopsy was normal, and a presumptive diagnosis of Evan's syndrome was made. The patient was treated with prednisone and splenectomy with adequate response. In 1989 he developed necrotic fingers and toes. Skin biopsy revealed homogenous staining of dermal vessels in the upper dermis with immunoperoxidase staining antiserum specific for IgG and light chains. Although serum cryoglobulins were negative at that time, a diagnosis of cryoglobulinemia was made based on the skin biopsy; the patient was treated with plasmapheresis and corticosteroids.

Subsequently he was diagnosed with HCV, and interferon (3 million U three times a week) was added to the treatment regimen. Although his necrotizing vasculitis responded, he continued to have elevated aminotransferases and hepatitis C viremia. In 1996 he developed vasculitic lesions on his penis (Fig. 3), posterior left thigh, and lower abdomen. A hypercoagulable screen (protein C and S, antithrombin III, lupus anticoagulant) was negative, but serum cryoglobulins were now positive. Repeat skin biopsy of the left thigh revealed leukocytoclastic vasculitis. Despite treatment with i.v. corticosteroids, i.v. immunoglobulin, azathioprine, and plasmapheresis, the patient died of a myocardial infarction.

Discussion

We have described six patients with chronic hepatitis C and cryoglobulinemia, each presenting with an extrahepatic manifestation associated with cutaneous leukocytoclastic vasculitis. Patients 1 and 2 developed intestinal vasculitis, with a severe necrotizing vasculitis in one patient that was associated with morbidity and mortality. Hitherto, there had been only an occasional report on hepatitis C, cryoglobulinemia, and severe GI necrotizing vasculitis (19). Second, our patient had eventual liver failure, although initial liver histology revealed chronic hepatitis without cirrhosis. Fibrin thrombi were noted in the vessels of the portal triads that presumably led to ischemic necrosis of the liver. Such an occurrence is likely to be rare and has not been described in association with hepatitis C infection, although polyarteritis nodosa that may cause a necrotizing vasculitis has been associated with a high prevalence of anti-HCV as determined by recombinant immunoblot assay and has varied between 5% and 12% (2022).

Two other patients (3 and 4) developed peripheral neuropathy documented by electromyography with an evaluation negative for other potential etiologies. There have been sporadic reports on peripheral neuropathy in association with hepatitis C (23, 24). The detection of anti-HCV and HCV RNA in cerebrospinal fluid lends credence to a direct viral mechanism in the pathogenesis of the neuropathy (23). However, large series on the role of HCV in peripheral neuropathy are lacking. An evaluation of eight nerve biopsy samples from patients with EMC and peripheral neuropathy failed to demonstrate HCV RNA by immunohistochemistry, though seven of these had histological evidence of vasculitis (25). One of our two patients with peripheral neuropathy responded well to therapy, a response rate that seems comparable to what is reported in the sparse literature that is available (24).

One of our patients (case 5) had CNS vasculitis and hairy cell leukemia. The association between hairy cell leukemia and HCV in our patient may be fortuitous rather than a true one. However, hematological extrahepatic manifestations have been reported in association with HCV, and these include non-Hodgkin's B-cell lymphoma, thrombocytopenia, and aplastic anemia (2631). The histological and immunogenotyping features of portal lymphoid aggregates in type II and III cryoglobulinemia have corresponded to a low grade malignant B-cell non-Hodgkin's lymphoma (32). However, a true cause and effect relationship between lymphoma and HCV has not been convincingly demonstrated. Conflicting data have been presented on the presence and absence of the minus strand, replicative form of HCV RNA in peripheral blood mononuclear cells (32). Further, immunohistochemical studies for HCV antigens or in situ polymerase chain reaction detection of HCV RNA in lymphoma tissue are lacking.

The relationship between HCV and the cutaneous manifestation of vasculitis has been most convincingly demonstrated using immunohistochemical and in situ hybridization techniques (33). Utilizing murine monoclonal antibodies developed against C22-3, C33-C, C100-3 epitopes of HCV, immunoreactive deposits have been observed in 40% of anti-HCV patients with type II cryoglobulinemia (18, 25). Similarly, in situ hybridization has detected HCV RNA in a significant number of HCV-infected and cryoglobulinemic patients with cutaneous vasculitis. Other cutaneous manifestations have been reported in association with HCV, and these include lichen planus, erythema multiforme, erythema nodosum, and porphyria cutanea tarda (1315, 3437). Cutaneous necrotizing vasculitis as observed in one of our patients has been described in association with cryoglobulinemia, although specific reports in association with hepatitis C have been sporadic. Further, the same patient also had a dramatic manifestation of penile necrosis.

Renal disease associated with cryoglobulinemia is often characterized by membranoproliferative glomerulonephritis and, less commonly, membranous glomerulonephritis (9). Renal disease occurs in 50% of cases of EMC and carries a worse prognosis. A clinically well-recognized extrahepatic manifestation of HCV is glomerulonephritis, of both membranous and membranoproliferative types (912). In contrast to cutaneous vasculitis, HCV antigens and HCV RNA have been infrequently demonstrated in glomerular lesions. None of our patients had glomerulopathy.

The relationship between hepatitis C and the extrahepatic manifestations is largely circumstantial, based on the presence of a higher prevalence of hepatitis C infection in the various conditions and presence of anti-HCV and HCV RNA in cryoprecipitates and, rarely, cerebrospinal fluid (23). A cause and effect relationship may be difficult to demonstrate because of the lack of reliable and readily available immunohistochemical staining methods for HCV.

The treatment of extrahepatic manifestations has focused on treatment of hepatitis C infection with interferon and, more recently, with interferon and ribavirin (38). Response to interferon therapy has been similar in patients with and without cryoglobulinemia. However, patients may not respond or have severe manifestations necessitating consideration of alternative therapy. Such treatment involves immunosuppressive therapy with corticosteroids and/or cyclophosphamide and plasmapheresis (39, 40).

The extrahepatic manifestations associated with hepatitis C infection need not necessarily be associated with severe liver disease. Previous studies have observed a spectrum ranging from mild chronic hepatitis to cirrhosis. There has been a higher prevalence of cirrhosis in patients with cryoglobulinemia than in patients without cryoglobulinemia (4, 5). None of our patients had cirrhosis, despite dramatic extrahepatic manifestations. Most strikingly, however, the mortality related to nonhepatic manifestations in our series was high, in that three of six died. This may represent a small numerator of patients among a large denominator of recognized and unrecognized patients with extrahepatic manifestations. Nevertheless, our experience underscores the high morbidity and mortality associated with hepatitis C infection.

References

1

.. Alter M.J.. Epidemiology of hepatitis C. Hepatology 1997;26(suppl):62S65S.

2

.. Hoofnagle J.H.. Hepatitis C: The clinical spectrum of disease. Hepatology 1997;26(suppl):15S20S.

3

.. Willson R.. Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol 1997;92:317.

4

.. Gumber S.C., Chopra S.. Hepatitis C: A multifaceted disease. Ann Intern Med 1995;123:615620.

5

.. Lunel F., Musset L., Cacoub P., et al. Cryoglobulinemia in chronic liver diseases: Role of hepatitis C virus and liver damage. Gastroenterology 1994;106:12911300.

6

.. Levey J.M., Bjornsson B., Banner B., et al. Mixed cryoglobulinemia in chronic hepatitis C infection. A clinicopathologic analysis of 10 cases and review of recent literature. Medicine 1994;73:5367.

7

.. Misiani R., Mantero G., Bellavita P., et al. GB virus-C infection in patients with type II mixed cryoglobulinemia. Ann Intern Med 1997;127:891894.

8

.. Gorevic P.D., Kassab H.J., Leso Y.. Mixed cryoglobulinemia: Clinical aspects and long term follow-up of 40 patients. Am J Med 1980;69:287308.

9

.. D'Amico G., Colosanti G., Ferrario F., et al. Renal involvement in essential mixed cryoglobulinemia. Kidney Int 1989;35:10041014.

10

.. Burstein D.M., Rodby R.A.. Membranoproliferative glomerulonephritis associated with HCV infection. J Am Soc Nephrol 1993;4:12881293.

11

.. R.J., Willson R., Yamabe H., et al. Renal manifestations of hepatitis C virus infection. Kidney Int 1994;3:12551263.

12

.. Rollino C., Roccatello D., Gianchino O., et al. Hepatitis C virus, and membranous glomerulonephritis. Nephron 1991;59:319320.

13

.. DeCastro M., J., Herrera J.F., et al. Hepatitis C virus antibodies, and liver disease in patients with porphyria cutanea tarda. Hepatology 1993;17:551557.

14

.. Hadziyannis S.J.. Nonhepatic manifestations and combined disease in HCV infection. Dig Dis Sci 1996;41(suppl):63S74S.

15

.. Carpintero P., DeCastro M., -Monzon C., et al. Hepatitis C infection detected by viral RNA analysis in porphyria cutanea tarda. J Infect 1997;34:6164.

16

.. Agnello V., Chung R.T., Kaplan L.M.. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992;327:14901495.

17

.. Agnello V.. Hepatitis C virus infection and type II cryoglobulinemia: An immunological perspective. Hepatology 1997;26:13751379.

18

.. Kunkel H.G., Agnello V., Joslin F.G., et al. Cross-idiotypic specificity among monoclonal IgM proteins with anti-globulin activity. J Exp Med 1973;137:331342.

19

.. Garas G., C.A.. Hepatitis C and mixed cryoglobulinemia: A case of primary gastrointestinal necrotizing vasculitis. N Z J Med 1996;26:110111.

20

.. Cacoub P., Lunel-Fabiani F., Du L.T.. Polyarteritis nodosa and hepatitis C virus infection. Ann Intern Med 1992;116:605606.

21

.. Carson C.W., Conn D.L., Czaja A.J., et al. Frequency and significance of antibodies to hepatitis C virus in polyarteritis nodosa. J Rheumatol 1993;20:304309.

22

.. Deny P., Guillevin L., Bonacorsi S., et al. Association between hepatitis C virus and polyarteritis nodosa. Clin Exp Rheumatol 1992;10:319.

23

.. Caudai C., Maimone D., Almi P., et al. The potential role of hepatitis C virus in the pathogenesis of the neurological syndrome in chronic hepatitis C. Gut 1997;41:411412.

24

.. Ferri C., La Civita L., Cirafisi C., et al. Peripheral neuropathy in mixed cryoglobulinemia: Clinical and electrophysiologic investigations. J Rheumatol 1992;19:889895.

25

.. Agnello V.. The etiology and pathophysiology of mixed cryoglobulinemia secondary to hepatitis C virus infection. Springer Semin Immunopathol 1997;19:111129.

26

.. Moriyama K., Okamura T., Nakano S.. Hepatitis GB virus C genome in the serum of aplastic anemia patients receiving frequent blood transfusions. Br J Haematol 1997;96:864867.

27

.. Issaragrisil S., Kaufman D., Thongput A., et al. Association of seropositivity for hepatitis viruses and aplastic anemia in Thailand. Hepatology 1997;25:12551257.

28

.. McColl M.D., Singer I.O., Tait R.C., et al. The role of hepatitis C virus in the aetiology of non-Hodgkins lymphomaa regional association?. Leuk Lymphoma 1997;26:127130.

29

.. Luppi M., Longo G., Ferrari M.G., et al. Prevalence of HCV infection, and second neoplasms in marginal zone lymphomas. Br J Haematol 1997;96:873874.

30

.. Silvestri F., Barillari G., Fanin R., et al. Hepatitis C virus infection (and additional neoplasms) among marginal zone lymphomas. Br J Haematol 1997;96:427428.

31

.. De G., Gobbo M.L., De Renzo A., et al. High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy. Am J Haematol 1997;55:7782.

32

.. Monteverde A., Ballare M., Pileri S.. Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia. Springer Semin Immunopathol 1997;19:99110.

33

.. Agnello V., Abel G.. Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia. Arthritis Rheum 1997;40:20072015.

34

.. Imhof M., Popal H., Lee J.H., et al. Prevalence of hepatitis C virus antibodies and evaluation of hepatitis C genotypes in patients with lichen planus. Dermatology 1997;195:15.

35

.. Schwaber M.J., Zlotogorski A.. Dermatologic manifestations of hepatitis C infection. Int J Dermatol 1997;36:251254.

36

.. Tanei R., Ohta Y., Katsuoka K.. Lichen Planus and Sjorgen-type sicca syndrome in a patient with chronic hepatitis C. J Dermatol 1997;24:2027.

37

.. Sansonno D., Cornacchiulo V., Tacobelli A.R., et al. Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia. Hepatology 1995;21:305312.

38

.. Blanche P., Bouscary D.. Ribavirin therapy for cryoglobulinemia and thrombocytopenia associated with hepatitis C virus infection. Clin Infect Dis 1997;25:14721473.

39

.. McGovern T.W., Enzenauer R.J., Fitzpatrick J.E.. Treatment of recalcitrant leg ulcers in cryoglobulinemia type I and II with plasmapheresis. Arch Dermatol 1996;132:498500.

40

.. Misiani R., Bellavita P., Fenili D., et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330:751756.