Extrahepatic Manifestations Of Chronic Hepatitis Research Articles

Plasmapheresis in cryoglobulinemic neuropathy: a clinical study

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. The clinical expression of cryoglobulinemia varies from an indolent course to the development of systemic vasculitis. The renal manifestations may range from isolated proteinuria to overt nephritic or nephrotic syndrome with variable progression towards chronic renal insufficiency. Plasmapheresis appears to be a useful adjunct to conventional therapy in the treatment of anti-GBM nephritis, severe dialysis-dependent forms of pauciimmune RPGN, cryoglobulinemia, and HUS-TTR Therapy with plasmapheresis produced a marked decrease in cryoglobulin levels and a subsequent relevant clinical improvement of cutaneous lesions and renal function. In cryoglobulinemia, plasmapheresis can be used as effective further therapy to minimize cutaneous, renal and/or neurologic involvement.

Oral Lichen Planus and Chronic Hepatitis C

Our aim was to study the possible association between oral lichen planus and chronic hepatitis C in patients from the state of Minas Gerais, Brazil. Two groups of patients were studied: group 1, 50 patients with oral lichen planus evaluated for the presence of chronic hepatitis C; and group 2, 215 patients with chronic hepatitis C examined for evidence of oral lichen planus. Diagnosis of oral lichen planus in both groups was based on clinical and histologic findings. One case of chronic hepatitis C was diagnosed in group 1 (2.0%), which was not considered statistically significant (P = .464). In group 2, the prevalence of oral lichen planus was 2.3% (5 cases), which showed statistical significance (P = .002). Although our results suggest oral lichen planus as an extrahepatic manifestation of chronic hepatitis C in the studied population, the association between these two entities should be further investigated.

Extrahepatic manifestations of HCV infection: A brief review and update

Hepatitis C affects approximately 3% of the population worldwide and extrahepatic manifestations may occur in nearly 40% of all patients. Recent efforts have focused on incidence, prevalence, clinical significance, mechanism of disease, and the role of antiviral therapy in treatment. Cryoglobulinemia, cryoglobulinemic vasculitis, membranoproliferative glomerulonephritis, and lymphoproliferative disorders have a well-established link to hepatitis C, and many other endocrine, autoimmune, and dermatologic associations may exist. This article reviews the recent literature detailing the extrahepatic manifestations of chronic hepatitis C.

Extrahepatic Manifestations of Hepatitis C

Hepatitis C affects approximately 170 million people worldwide. Extrahepatic manifestations of chronic hepatitis C infection are clinically evident in nearly 40% of patients. Much research has been done over the last decade to better understand their incidence, clinical presentation, mechanism of disease, and the role of antiviral therapy in their treatment. Of the commonly reported manifestations, cryoglobulinemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda remain the best understood manifestations. More recently, the association of insulin resistance and diabetes mellitus with chronic hepatitis C has been demonstrated. This paper serves to review the growing body of literature detailing the extrahepatic manifestations of chronic hepatitis C.

Extrahepatic manifestations in transgenic mice of osteopontin in hepatocytes—A clue to advent of pathological state in various organs of chronic hepatitis C patients

Osteopontin is a cytokine essential for initiation of Th1 immune reaction. We established transgenic mice expressing osteopontin in hepatocyte, in which liver necrosis with lymphocyte infiltration developed gradually from 12 weeks of age with up-regulated osteopontin levels in the circulation, suggesting that extrahepatic manifestations might also occur as a result of excessive Th1 immune reaction. We examined histological and immunohistochemical features of various organs in these mice. Splenomegaly and enlargement of lymph nodes around the liver and intestine became apparent with marked infiltration of small lymphocytes in the transgenic mice later than 24 weeks of age. Immunostaining revealed that lymphocytes in the spleen and lymph nodes were positive for either CD3 or CD20, suggesting that the infiltrating lymphocytes were both B and T cells. Similar lymphocyte infiltration was found in the lung, kidney and submandibular gland. Alveolar septa became hypertrophic with lymphocyte infiltration, and the lung showed the appearance of interstitial pneumonia. These lesions are similar to extrahepatic manifestations in chronic hepatitis C patients, suggesting that augmented Th1 immune reaction to hepatitis C virus (HCV) proteins or the proteins with molecular mimicry of HCV may be a contributing factor for the formation of the pathological state not only in the liver but also in various organs under chronic infection of hepatitis C virus.

Lamivudine for the Treatment of Membranous Glomerulopathy Secondary to Chronic Hepatitis B Infection

Membranous glomerulopathy is a well-recognized extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. The authors report two cases of HBV-related nephrotic syndrome treated with lamivudine. A 46-year-old Chinese man had a hepatitis B e antigen seroconversion along with improvement in his nephrotic syndrome after lamivudine therapy. Two years after treatment was discontinued, a reactivation of HBV was successfully treated again with lamivudine. A 44-year-old Chinese woman, who was intolerant of interferon, was treated with lamivudine for 15 months without a virological response. However, two years after completing lamivudine, her nephrotic syndrome resolved. Implications for the treatment of HBV-related glomerulopathy and a review of the literature are presented.

New onset diabetes mellitus after liver transplantation: the critical role of hepatitis C infection.

Epidemiological studies suggest diabetes mellitus (DM) may be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Since diabetes and HCV are common in liver transplant recipients, we sought to examine the unique contribution of HCV infection to risk of de novo diabetes posttransplantation. Using a cohort of 555 liver transplant recipients (median age 49 years, 54% males, 82% Caucasian) without preexisting diabetes from 3 U.S. centers enrolled between 1990 and 1994 and followed for a median duration of 5 years, we determined the incidence of de novo diabetes and the independent predictors of the development of diabetes. De novo diabetes was defined by the use of antidiabetic medications. De novo diabetes developed in 209/555 (37.7%) patients of whom 157 (28.3%) had transient-DM (T-DM) and 52 (9.4%) had persistent-DM (P-DM). Among HCV-infected transplant recipients, de novo T-DM and P-DM developed in 26% and 14%, respectively. HCV was predictive of P-DM (P =.02) but not T-DM. Older age (P =.03) and tacrolimus use (P =.02) were also independent predictors of P-DM. In conclusion, de novo diabetes is common in transplant recipients, but is typically transient in nature. However, among those developing de novo persistent diabetes, HCV is one of the most important risk factors. This adds further support to the epidemiological data linking HCV and diabetes.

Extrahepatic manifestations of chronic hepatitis C

AbstractChronic hepatitis C virus (HCV) infection is associated with several extrahepatic disorders. Although the exact pathogenesis of these conditions is not fully understood, several studies have provided insight into the role of HCV in their development. This review discusses the different conditions that have been associated with HCV infection. Among the most commonly reported are cryoglobulinemia, membranoproliferative glomerulonephritis, leukocytoclastic vasculitis, Sjogren's syndrome, lichen planus and porphyria cutanea tarda. In some patients, these disorders are the first sign of HCV infection.

Sialadenitis in patients with chronic hepatitis C is not directly related to hepatitis C virus

Sjogren's syndrome has been suspected to be an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. To evaluate the association of sialadenitis with HCV infection, serum levels of salivary amylase (s-isoamylase) and antibodies to Ro (SS-A) and La (SS-B) were analyzed in 114 patients with chronic hepatitis C. Serum s-isoamylase levels were monitored before and after HCV was eradicated by interferon therapy. Immunohistochemistry and Western blotting using anti-HCV antibodies, and in situ hybridization of HCV-RNA were performed in the salivary gland. Serum s-isoamylase levels were elevated in patients with chronic hepatitis C ( P<0.0001). The s-isoamylase remained high even after HCV was eradicated. The in situ hybridization did not show the presence of HCV-RNA in the salivary gland from patients with chronic hepatitis C. A protein reacting with anti-HCV-E2 antibodies was found in the cytosol fraction of normal salivary gland from HCV-negative cases. Latent sialadenitis is frequently observed in chronic hepatitis C, which is not directly related to HCV per se. The presence of a common epitope between antigenic protein in the salivary gland and the HCV-derived protein may be a possible pathogenetic mechanisms such as molecular mimicry.

Hyperlipasemia associated with hepatitis C virus.

Extrahepatic manifestations of chronic hepatitis C virus (HCV) infection have been well described. However, hyperlipasemia and/or pancreatitis have not been reported. Following the observation that several HCV patients had elevated lipase levels, this retrospective study was conducted to assess the association between hyperlipasemia and/or pancreatitis with hepatitis C infection. Of 204 subjects who underwent evaluation for hepatitis C, 103 had lipase levels determined at baseline. The control group consisted of 41 nonHCV subjects with a variety of gastrointestinal diseases including 18 with nonalcoholic liver disease. Twenty-five percent of HCV patients had elevated lipase at baseline as compared to 10% of controls (P = 0.04; OR = 3.1; 95% CI: 1.02-9.60). Mean lipase levels were 253 +/- 72 units/liter (normal range 114-286 units/liter and 210 +/- 42 units/liter for the HCV and control groups, respectively (P = 0.002). No significant difference in amylase was found between the groups. There was a significant association between ALT (> 1.5 times the upper limit of normal) and lipase (P = 0.02; OR = 3.0; 95% CI: 1.1-7.5). Among 30 patients who received interferon-based therapy +/- ribavirin, 11 had elevated lipase at baseline. Six of these patients responded to therapy and demonstrated normalization of lipase levels. In contrast, all nonresponders with baseline hyperlipasemia continued to have high lipase levels (P = 0.17; OR = 4.0; 95% CI: 0.6-28.4). Furthermore, only 3 of 8 (37.5%) patients with normal lipase responded to treatment as compared to 6 of 10 (60%) of hyperlipasemic patients (P = 0.36; OR = 2.5; 95% CI: 0.4-16.9). In conclusion, hyperlipasemia and/or subclinical pancreatitis may represent extrahepatic manifestations of HCV infection and should not preclude treatment.

Interferon alpha and ribavirin for membranoproliferative glomerulonephritis and hepatitis C infection

Cryoglobulinemic membranoproliferative glomerulonephritis, an extrahepatic manifestation of chronic hepatitis C virus infection, often poses a therapeutic challenge (1). Although glucocorticosteroids and interferon alpha are effective in controlling the acute phase of the disease, a sustained response is unusual after discontinuation of treatment (2,3). The combination of interferon alpha and ribavirin, a nucleoside analog with broad activity against both deoxyribonucleic acid and ribonucleic acid (RNA) viruses, may improve the prognosis of hepatitis C virus infection in patients without renal disease (4,5). The few studies of this combination in patients with hepatitis C virus–associated cryoglobulinemic glomerulonephritis have had variable results (6-8). We report two additional patients who achieved a long-term response with early combination antiviral treatment.

Subclinical impairment of brain function in chronic hepatitis C infection.

Central nervous system abnormalities such as fatigue and depression occur more frequently in chronic hepatitis C virus (HCV) infection than in many other causes of chronic liver disease. The finding that fatigue is unrelated to activity of hepatitis or mode of infection could indicate an independent effect of HCV on brain function. This study tested the hypothesis of a subclinical cognitive dysfunction in HCV-infected patients. One-hundred untreated HCV-RNA positive biopsy-proven patients were investigated by P300 event-related potentials, a sensitive electrophysiologic test of cognitive processing. Health-related quality of life and fatigue were assessed using the SF-36 questionnaire and the Fatigue Impact Scale, respectively. Cognitive brain function was subclinically impaired in the cohort of HCV-infected patients as indicated by significantly prolonged P300 latencies (P=0.01 for comparison to matched healthy subjects) and reduced P300 amplitudes (P<0.001, respectively). Seventeen of the 100 HCV-infected patients had P300 latencies outside the age-adjusted normal range. Abnormal P300 characteristics were not related to the degree of histologic or biochemical activity of hepatitis, severity of fatigue or mental health impairment. This study demonstrates that patients with HCV infection showed a slight but significant neurocognitive impairment, possibly indicating a further extrahepatic manifestation of chronic hepatitis C.

Interferon-α in combination with ribavirin as initial treatment for hepatitis C virus–associated cryoglobulinemic membranoproliferative glomerulonephritis

Mixed cryoglobulinemia (MC) and glomerulonephritis are the most important extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. In HCV-infected patients with MC, renal involvement worsens the overall prognosis because of a high incidence of infection or cardiovascular disease. The relationship between MC and HCV infection has prompted the use of antiviral therapy. Two patients with chronic HCV infection, type-II MC and membranoproliferative glomerulonephritis (MPGN), presenting as nephrotic syndrome were treated with interferon (IFN)-α (3 MU 3 times per week) and ribavirin (15 mg/kg daily) for 6 months. Laboratory tests included measurement of anti-HCV antibodies, HCV RNA, and HCV genotyping, and characterization of circulating cryoglobulins. A pretreatment renal biopsy was performed, and the histopathologic lesions were scored according to the index of disease activity. Viremia and cryoglobulinemia were suppressed in both patients. However, a complete remission of proteinuria was observed in 1 patient only. The evaluation of the renal biopsy specimens revealed a mild MPGN (activity score: 5/24) in the patient with remission of proteinuria and a severe MPGN (activity score: 15/24) in the patient who maintained a nephrotic-range proteinuria. Although a fully satisfactory treatment is not yet available, we feel that a reasonable therapeutic strategy for HCV-infected patients with MC nephritis could be as follows: (1) antiviral treatment alone for patients with a low-grade kidney involvement, and (2) a short-term course of steroids and cytotoxic drugs followed by antiviral therapy for acute exacerbations and/or rapidly progressive GN. © 2001 by the National Kidney Foundation, Inc.

Mediastinal lymphadenopathy: an extrahepatic manifestation of chronic hepatitis C?

Normal and enlarged perihepatic and mediastinal lymph nodes are detectable by ultrasonography. Aim of the present study is to determine the detection rate, size, and correlation of mediastinal and perihepatic lymphadenopathy in patients with chronic hepatitis C, healthy controls, and patients with inflammatory or neoplastic mediastinal lymphadenopathy. The mediastinum and liver hilus of 89 patients with chronic hepatitis C as well as of 34 healthy volunteers and 20 patients with mediastinal lymphadenopathy of different origin with adequate sonographic visualization were screened for the number and size of lymph nodes by high resolution ultrasonography. Lymph nodes were detectable in the mediastinum of 75/89 (84%) patients with chronic hepatitis C and 22/34 (65%) healthy volunteers (total lymph node volume [LNV]: 1.0 +/- 0.8 mL versus 0.3 +/- 0.4 mL, p < 0.001). In all patients with mediastinal lymphadenopathy, the mediastinal lymph node volume was above 15 mL. In patients with chronic hepatitis C a trend could be observed, that patients with larger perihepatic lymph nodes reveal also larger mediastinal lymph nodes. High resolution ultrasonography is able to detect enlarged mediastinal lymph nodes in patients with chronic hepatitis C. Mediastinal lymphadenopathy is considered as an extrahepatic manifestation of chronic hepatitis C. In general, the mediastinal lymph node volume differs in size to patients with lymphadenopathy related to neoplasia or sarcoidosis. The mechanism of lymphadenopathy in the liver hilus and mediastinum in patients with chronic hepatitis C is yet unknown.

Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C.

To assess the prevalence of clinical and biologic extrahepatic manifestations of hepatitis C virus (HCV) infection and to identify associations between clinical and biologic manifestations. To analyze the natural history of extrahepatic manifestations of HCV infection, we reviewed only the data recorded prospectively during the first visit of 1,614 patients with chronic HCV infection, coming from a single monocenter cohort. Exclusion criteria were positivity for hepatitis B surface antigen or human immunodeficiency virus. The prevalence of dermatologic, rheumatologic, neurologic, and nephrologic manifestations; diabetes; arterial hypertension; autoantibodies; and cryoglobulins were assessed. Then, using multivariate analysis, we identified demographic, biochemical, immunologic, virologic, and liver histologic factors associated with the presence of extrahepatic manifestations. At least 1 clinical extrahepatic manifestation was observed in each of 1,202 patients (74%). Five manifestations had a prevalence >10%: arthralgia (23%), paresthesia (17%), myalgia (15%), pruritus (15%), and sicca syndrome (11%). Four biologic abnormalities had a prevalence >5%: cryoglobulins (40%), antinuclear antibodies (10%), low thyroxine level (10%), and anti-smooth muscle antibodies (7%). Only vasculitis, arterial hypertension, purpura, lichen planus, arthralgia, and low thyroxine level were associated with cryoglobulin positivity. By univariate and multivariate analyses, the most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations were age, female sex, and extensive liver fibrosis. Extrahepatic clinical manifestations are frequently observed in HCV patients and involve primarily the joints, muscles, and skin. The most frequent immunologic abnormalities include mixed cryoglobulins, antinuclear antibodies, and anti-smooth muscle antibodies. The most frequent risk factors for the presence of clinical and biologic extrahepatic manifestations are advanced age, female sex, and extensive liver fibrosis.

Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjögren's syndrome and hepatitis C in Swedish patients.

To analyse the frequency of some extrahepatic manifestations of chronic hepatitis C virus (HCV) infection in northern European patients, including a postulated association between HCV and primary Sjögren's syndrome (SS). Cohort study. Department of Medicine, Malmö University Hospital, Sweden. Twenty-one patients with HCV infection and 53 with primary SS (according to the Copenhagen criteria). Cryoglobulins were analysed in all patients, while patients with primary SS were investigated with regard to markers of HCV infection, and HCV patients with objective tests of SS (Schirmer-1 test, break-up time, van Bijsterveld score, sialometry, labial salivary gland biopsy) and antibodies against nuclear antigens, smooth muscle (SMA) and mitochondria (AMA). HCV antigens in small salivary glands from lower lip biopsies were detected by immunohistochemical analysis. Only one of the SS patients had detectable cryoprecipitates, while another was HCV-positive. None of the 21 HCV patients had cryoprecipitates. A total of 14/21 (67%) patients with HCV infection had at least one abnormal objective test suggestive of xerostomia or keratoconjunctivitis sicca, while eight (38%) had objective evidence of both eye and salivary gland involvement. HCV antigens were not detected in affected glands. Only two patients had clinical symptoms of SS, and two fulfilled the Copenhagen criteria for SS. None of the HCV-positive patients had detectable antibodies against SS-A, SS-B, RNP, Jo-1, PCNA or Scl-70, and the frequency of ANA/SMA/AMA was low. While involvement of salivary and lacrimal glands was common in Swedish patients with HCV infection, cryoglobulinaemia was not observed. The pathogenetic mechanism responsible for glandular inflammation appears to be different from that in primary SS. HCV infection does not seem to be an aetiological factor for primary SS in this population. These observations suggest that viral, genetic or possibly environmental factors may be responsible for the reported high frequencies of systemic complications associated with chronic hepatitis C infection in southern Europe.

Morbidity of chronic hepatitis C as seen in a tertiary care medical center.

We studied the morbidity of chronic hepatitis C in patients referred to a tertiary care medical facility. The medical records of 500 consecutive cases of chronic hepatitis C were examined for the following: (1) source and time of exposure, (2) signs and symptoms of liver disease, (3) degree of alcohol intake, (4) liver biopsy findings, (5) extrahepatic disease manifestations, and (6) coexisting illnesses that could have an impact on morbidity. Morbidity and histologic findings were evaluated in relation to the duration of hepatitis C. The onset of infection could be determined in 376 patients (75%). A close relationship between the length of infection and disease features was not observed. Fatigue was common at all stages of infection. Whereas cirrhosis occurred more frequently in patients with disease of long duration, 15-24% of patients had signs of advanced liver disease (ascites, encephalopathy, thrombocytopenia) within six years of exposure. Overt extrahepatic manifestations of chronic hepatitis C occurred infrequently, and depression was reported in 24% of untreated patients. In conclusion, in patients referred to a tertiary care setting, chronic hepatitis C is often associated with significant morbidity.

Subcellular localization of hepatitis C virus structural proteins in the liver of transgenic mice.

Hepatitis C virus (HCV) core and envelope proteins are suggested to be responsible for the pathogenesis of hepatic and extrahepatic manifestations in chronic hepatitis C. Moreover, the core protein is implicated in the regulation of the transcription of cellular genes including c-myc, RB and p53. Determining the subcellular localization of the core and envelope proteins is therefore necessary to elucidate their behaviors, particularly in vivo ones, regarding the interaction with transcriptional regulatory proteins or gene elements. We defined the subcellular localization of HCV envelope and core proteins which were expressed in substantial levels in the liver of transgenic mice. Subcellular fractionation by ultra-centrifugation revealed that the envelope proteins were present principally in the microsomes of the liver, while a small amount of the protein was detected also in the nuclei. Immunohistochemistry confirmed the localization of envelope proteins in the nuclei. In contrast, the core protein was detected principally in the cytoplasmic fraction, where it was closely associated with lipids. A low level of the core protein was detected also in the nuclei and microsomal fraction. These results suggest possible interaction of the HCV structural proteins with some factors in hepatocytes thereby perturbing intracellular circumstances.

Extrahepatic Manifestations of Hepatitis C Virus Infection

Letters15 August 1996Extrahepatic Manifestations of Hepatitis C Virus InfectionC. Ferri, MD, L. La Civita, MD, and A.L. Zignego, MDC. Ferri, MDUniversity of Pisa, Pisa, ItalyUniversity of Florence, Florence, ItalySearch for more papers by this author, L. La Civita, MDUniversity of Pisa, Pisa, ItalyUniversity of Florence, Florence, ItalySearch for more papers by this author, and A.L. Zignego, MDUniversity of Pisa, Pisa, ItalyUniversity of Florence, Florence, ItalySearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-125-4-199608150-00017 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Gumber and Chopra [1] recently reviewed the extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. They focused on the striking association between HCV and mixed cryoglobulinemia. This immune-complex-mediated systemic vasculitis is secondary to “benign” B-lymphocyte expansion.The HCV infection of lymphocytes [2] represents the remote event that triggers chronic B-cell proliferation. The immune system alteration may promote various disorders (mixed cryoglobulinemia, autoimmune hepatitis, porphyria cutanea tarda, membranoproliferative glomerulonephritis, and lung fibrosis. These manifestations could be the result of a variable combination of genetic and environmental factors, HCV mutants [3], and other infectious agents.Here, we point ...