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• W4317528037 abstract "Severe Raynaud’s phenomenon developed in a 5-year-old girl with chronic hepatitis C infection at the fifth month of interferon therapy in the absence of cryoglobulinemia and other conditions commonly associated with secondary Raynaud’s phenomenon. Although interferon therapy was promptly discontinued, Raynaud’s phenomenon persisted for 4 months with appearance of necrotic-ulcerous lesions at the tips of fingers. A spectrum of extrahepatic manifestations associated with chronic hepatitis C has been reported in adults. 1, 2 The specific viral and host features that predispose patients to extrahepatic disease have not been elucidated. 1 The wide geographic variation in the prevalence of many extrahepatic manifestations suggests genetic or environmental influences. 2 A high prevalence of genotype 2 infection has been reported in many patients with various extrahepatic manifestation of disease. 2 Cryoglobulinemia is the most frequent and well-known extrahepatic manifestation of hepatitis C virus (HCV) disease, occurring in 11 to 56% of HCV-infected patients. 3–5 Raynaud’s phenomenon occurs in 20 to 50% of adult patients with HCV infection and cryoglobulinemia. 6 More than 50% of HCV-infected patients with clinical features of cryoglobulinemia respond to interferon (IFN) therapy with reduction of circulating HCV-RNA and serum cryoglobulin as well as improvement in clinical features of disease. 7, 8 Raynaud’s phenomenon has been previously described as a side effect in patients treated with IFN. 9 In some of these patients, IFN withdrawal was followed by disappearance of Raynaud’s phenomenon. 8, 9 Raynaud’s phenomenon is rare in childhood and occurs in 33% as a primary phenomenon and in 52% in association with connective tissue disease. 10 Here we describe the case of a girl with chronic hepatitis C infection who experienced severe Raynaud’s phenomenon during IFN-alpha therapy. Case report. The patient was a 5-year-old girl with histologically proven chronic hepatitis C infection acquired by the vertical route from her HCV-infected mother. Mother and child were infected by genotype 2, subtypes 2a-2c, determined by reverse hybridization with a probe hybridization assay (InnoLiPA HCV; Innogenetics, Ghent, Belgium). The patient looked well with no physical signs of liver disease. Growth and development were normal. Serum aminotransferases were increased (aspartate aminotransferase 97 IU/l, alanine aminotransferase 279 IU/l; normal values <40 IU/l). Other liver function tests were normal. Antibodies to HCV, tested by a third generation recombinant immunoblot assay (Ortho Diagnostic System, Raritan, NJ), were present in serum. Serum HCV RNA, quantified by a polymerase chain reaction assay with a sensitivity of 100 copies/ml (National Genetics Institute, Los Angeles, CA), was 4700 copies/ml. Liver biopsy performed at the age of 4 years showed minimal chronic hepatitis, with lobular activity. Ishak score grading was 6, staging 2. 11 There were no clinical and/or laboratory signs of autoimmunity, including cryoglobulinemia. Principal causes of hypertransaminasemia other than HCV infection, such as hepatitis B virus, HIV, cytomegalovirus, Epstein-Barr virus, autoimmune hepatitis, biliary tract disorders, celiac disease, obesity-related liver disease, primary liver metabolic disorders such as Wilson’s disease and alpha-1-antitrypsin deficiency were absent. No clinical and/or laboratory evidence of other more common inborn errors of metabolism associated with hypertransaminasemia, such as galactosemia, hereditary fructose intolerance, glycogen storage disease, ornithine carbamyltransferase deficiency and hemochromatosis, was present. At the age of 5 years, the patient was treated with interferon-alpha-2a in a dosage of 5 million units/m2 of body surface intramuscularly three times a week. IFN treatment was planned for 6 months. During the fourth month of IFN treatment, the patient showed biochemical and virologic remission which persisted for the following 30 months of observation. At the fifth month of therapy, the patient developed Raynaud’s phenomenon, involving the tips of fingers and toes, accompanied by severe pain. Fingers were more severely involved than toes and thumbs. Although IFN therapy was promptly discontinued, Raynaud’s phenomenon persisted and necrotic-ulcerous lesions appeared at the tips of the fingers but not the thumbs. Necrotic-ulcerous lesions did not occur in the toes. By Doppler sonography the peak systolic velocity and the end diastolic velocity were lower than normal in the proper palmar digital artery and the deep radial arch. Nail-fold capillary microscopy showed large confluent avascular areas and enlarged capillary loops at the fingertips of both hands, with the exception of the thumbs. When Raynaud’s phenomenon appeared, nifedipine was administrated (1 mg/kg/day for 1 month), with no improvement. Therefore nifedipine was discontinued and replaced with atenolol (1 mg/kg/day) and flunarizine (0.1 mg/kg/day) for the following 30 months. Mild, progressive and persistent improvement was observed so that 6 months after introducing atenolol and flunarizine ulcerous-necrotic lesions disappeared and skin integrity was restored. The extremities of the fingers were cyanotic for the following months of observation. At the 30th month from the onset of Raynaud’s phenomenon, small scars were present at the tips of the second and fourth finger of the right hand. Doppler sonography performed after 12 and 30 months did not show any abnormality. Nail-fold capillary microscopy remained unchanged during follow-up. During the entire period of observation the patient showed neither clinical nor laboratory signs of connective tissue disease. Blood pressure remained normal. Erythrocyte sedimentation rate was normal. Antinuclear, anti-smooth muscle, anti-liver kidney microsomal type 1, anti-thyroperoxidase, anti-thyroglobulin antibodies, rheumatoid factor, anti-double stranded DNA, anti-ribonucleoprotein, cryoglobulins, cold agglutinins and immune complexes were persistently negative. Cryoglobulins were measured by immunoblotting at 37°C as previously described and considered positive when their values reached 0.05 g/l at least on two determinations. 12 Serum immunoglobulins and complement components C3 and C4 were normal. Renal function tests, thyroid hormone profile and creatine kinase were normal. The study of the HLA system, performed by a standard complement-dependent microlymphocytotoxicity assay, showed the following phenotype: A1-A3; B49-B51; BW4; CW 7; DR1-DR7; DQ2-DQ5. Discussion. This is the first reported case of Raynaud’s phenomenon in a pediatric patient with chronic hepatitis C infection during IFN therapy. In our patient Raynaud’s phenomenon was not associated with cryoglobulinemia or with clinical and laboratory signs of autoimmunity during the entire period of observation. Because extrahepatic manifestations of HCV infection usually occur when active viral replication is present and considering that Raynaud’s phenomenon in our patient appeared 1 month after achievement of virologic and biochemical response to IFN therapy, Raynaud’s phenomenon seemed to be an IFN-related side effect rather than an extrahepatic manifestation of hepatitis C disease. 2 As previously reported in some adult patients, 8, 9 however, Raynaud’s phenomenon persisted in our patient despite the prompt suspension of IFN therapy. In contrast to the typical behavior of IFN-related side effects, Raynaud’s phenomenon worsened notably during the first 4 months after IFN discontinuation. Alternatively in this patient Raynaud’s phenomenon could have been the first clinical sign of a silent collagen disease, but during the entire period of observation none of the most frequent conditions associated with secondary Raynaud’s phenomenon, such as systemic sclerosis, systemic lupus erythematosus and rheumatoid arthritis, were found. 2 The analysis of HLA haplotype did not give further information in this regard. The hypothesis of primary Raynaud’s phenomenon was supported by the absence of clinical and laboratory features of autoimmune diseases and by the absence of antinuclear antibody. 10 In contrast to this hypothesis, the patient had abnormal nail-fold capillary pattern and pitting scars, which are more common in secondary Raynaud’s phenomenon. 10 Regarding the improvement of Raynaud’s phenomenon observed in the studied patient after the fourth month of vasodilatatory therapy, it is difficult to establish whether or not improvement was related to this therapy. In fact during the first months of vasodilatatory therapy our patient did not have a favorable response. Although no defined guideline for treatment of Raynaud’s phenomenon in children is available, vasodilatatory drugs are currently used because they may have a favorable effect on the contractility of the arterioles that supply blood to the fingers and toes. 13 In fact these drugs decrease the frequency and severity of attacks in about two-thirds of patients who have primary and secondary Raynaud’s phenomenon and can help heal skin ulcers on the fingers or toes. 13 In previous studies iloprost has been effective in severe cases of Raynaud’s phenomenon in preventing amputation, 14 but it was not used in our patient because the risk of amputation was not considered high. Our experience draws attention to the possible occurrence of this phenomenon in children and to the difficulties of its management and its impact on health-related quality of life. 15" @default.
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• W4317528037 title "Severe Raynaud’s phenomenon with chronic hepatitis C disease treated with interferon" @default.
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