Development of multiple myeloma in a patient with chronic hepatitis C: A case report and review of the literature

An association between chronic hepatitis C virus (HCV) infection and essential mixed cryoglobulinaemia and non-Hodgkin lymphoma (NHL) has been suggested. However, a causative role of HCV in these conditions has not been established. The authors report a case of a 50 year-old woman with chronic hepatitis C (CHC) who has been followed up since 1998 due to a high viral load, genotype 1b and moderately elevated liver function tests (LFTs). Laboratory data and liver biopsy revealed moderate activity (grade: 5/18, stage: 1/6). In April 1999, one-year interferon therapy was started. HCV-RNA became negative with normalization of LFTs. However, the patient relapsed during treatment. In September 2002, the patient was admitted for chronic back pain. A CT examination demonstrated degenerative changes. In March 2003, multiple myeloma was diagnosed (IgG-kappa, bone marrow biopsy: 50% plasma cell infiltration). MRI revealed a compression fracture of the 5(th) lumbar vertebral body and an abdominal mass in the right lower quadrant, infiltrating the canalis spinalis. Treatment with vincristine, adriamycin and dexamethasone (VAD) was started and bisphosphonate was administered regularly. In January 2004, after six cycles of VAD therapy, the multiple myeloma regressed. Thalidomide, as a second line treatment of refractory multiple myeloma (MM) was initiated, and followed by peginterferon-(alpha)2b and ribavirin against the HCV infection in June. In June 2005, LFTs returned to normal, while HCV-RNA was negative, demonstrating an end of treatment response. Although a pathogenic role of HCV infection in malignant lymphoproliferative disorders has not been established, NHL and possibly MM may develop in CHC patients, supporting a role of a complex follow-up in these patients

Ombitasvir/paritaprevir/ritonavir + dasabuvir + ribavirin in HCV genotype 1 infected patients who failed previous protease inhibitor therapy

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Bocepreviralapú hármas kezelés hatékonyságának és biztonságosságának retrospektív elemzése előrehaladott fibrosisstádiumú, hepatitis C-vírus 1-es genotípussal fertőzött, korábban sikertelenül kezelt magyar betegeknél

INTRODUCTION: During 2011 and 2013, 155 Hungarian hepatitis C genotype 1 infected patients, mostly with advanced liver fibrosis, who did not respond to prior peginterferon + ribavirin dual therapy, started boceprevir based triple therapy in an early access program. AIM AND METHOD: Efficacy and safety of the therapy was retrospectively assessed based on sustained virologic responses, as well as on frequency and type of serious adverse events and of those leading to therapy discontinuation. RESULTS: In an intent-to-treat analysis 39.4% patients (61/155) reached sustained virologic response. Amongst pervious relapsers, partial responders and null-responders 59.5%, 41.4 % and 22.9% (p<0.05 compared to the other two categories) reached sustained virologic response, respectively, while amongst non-cirrhotics and cirrhotics 52.5% and 31.3% (p<0.05 compared to the non-cirrhotics) achieved sutained virologic response, respectively. Six out of the 33 most difficult to cure patients (previous null responder and cirrhotic) have reached sustained virologic response (18.2%). Frequency of early discontinuations due to insufficient virologic response was 31.1%, while due to adverse event 10.3%. Reported frequency of serious adverse event was 9.8%. These events represented anemia, diarrhoea, depression, agranulocytosis, elevated aminotransferases, generalized dermatitis and severe gingivitis with loss of teeth, prolonged QT interval on ECG, generalized oedema and severe dyspnoea, uroinfection, exacerbation of Crohn's disease, Campylobacter pylori infection and unacceptable weakness and fatigue. Eight patients received transfusion, 4 patients erythropoietin and 1 granulocyte colony stimulating factor during therapy. No death has been reported. CONCLUSIONS: With boceprevir based triple therapy, one of the bests available in 2011-2013 in Hungary, a relevant proportion of hepatitis C infected patients with advanced liver fibrosis achieved sustained viral response. In this cohort, side-effects resembled those reported in registration studies, and resulted in therapy discontinuation with consequent treatment failure in a relevant number of patients. Efficacy and tolerability of boceprevir-based triple therapy are suboptimal, particularly in the most difficult to cure patient population. Orv. Hetil., 2016, 157(34), 1366-1374

Ribavirin in the treatment of hepatitis C

The hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, with approximately 170-200 million people infected. The HCV virus is transmitted by blood and blood products and such transmission occurs primarily through drug use by injection, sex with an infected partner and occupational exposure. The severity of the disease varies widely from mild chronic hepatitis to cirrhosis and hepatocellular carcinoma (HCC). Nowadays, the reference treatment is combination therapy of pegylated interferon and ribavirin, which is an inosine monophosphate dehydrogenase inhibitor and immunomodulator. Efficacy of treatment in our clinical trials is 87% in patients infected by HCV genotypes 2 or 3, whereas in patients infected by HCV genotype I response to treatment is 66%. The current combination treatment has significant side-effects and sometimes is poorly tolerated. HCV genotypes 2 or 3 can be treated with a lower dose of ribavirin and a shorter course of therapy, 24 weeks vs 48 weeks for patients with genotype 1. There is a growing consensus that acute control of HCV infection is associated with a vigorous intrahepatic antiviral CD4+ and CD8+ T-cell response, enhanced Th1 and natural killer activity. Pretreatment genotype and response to therapy measured at weeks 12 and 24 of treatment have been identified as key determinants in decisions about continuing treatment. Elevated serum ferritin levels and hepatic iron deposition as well as hepatic steatosis and high ALT levels with chronic hepatitis C are risk factors for HCC development. Heterozygosity for the C282Y mutation in HFE contributes to iron accumulation and fibrosis progression in chronic hepatitis C. Ribavirin could cause dose-dependent reversible haemolytic anaemia, which can be managed with dose reductions or with administration of epoetin alpha at 40, 000 IU once weekly without sacrificing the optimal dosing of ribavarin. Among patients who received ribavirin alone, serum ALT levels and necroinflammatory features of liver histology were improved, whereas symptoms, HCV RNA levels and hepatic fibrosis scores were not changed significantly from baseline. For HCV-HTV co-intected patients, treatment is given when blood CD4 counts are above 350/ml and before antiretroviral (ART) treatment is needed

Seasonal fertility differences in synchronised dairy cows: Ultrasonic, metabolic and endocrine findings

The aim of this study was to identify relationships among seasonal differences of fertility, metabolic parameters and appearance of irregular luteal forms in high-yielding dairy cows. Holstein-Friesian cows were put on the Provsynch regimen in winter (n = 10) and in summer (n = 10). Blood sampling (starting 35 days post partum) and rectal ultrasound examinations (starting post insemination) were carried out once a week in each examination period. Metabolic [plasma nonesterified fatty acid (NEFA) and beta-hydroxybutyrate (BHB) levels, ferric reducing ability of plasma (FRAP) and serum beta-carotene] and endocrine parameters [plasma thyroxine (T4), triiodothyronine (T3), insulin-like growth factor (IGF-I) and insulin levels] were measured. In summer, two cows were excluded from the study because of metritis and none of the remaining animals became pregnant, but 6 of the 8 cows had irregular luteal forms (ILF) on their ovaries. In winter, one cow was excluded because of metritis and 6 of the 9 cows became pregnant, while 2 of the 3 open cows had irregular luteal forms. In summer the mean plasma NEFA and BHB concentrations were significantly higher, while serum carotene and plasma IGF-I concentrations were significantly lower than in winter. The high plasma NEFA concentration found in summer seemed to be in association with the lower body condition score (BCS) caused by depressed appetite. In conclusion, statistical analysis supports the hypothesis that increased plasma NEFA and BHB and decreased plasma IGF-I concentrations may result in reduced fertility in summer. These changes may be associated with the more frequent appearance of ILFs and probably have a negative effect on ovarian function and/or oocyte quality

Chronic hepatitis C virus infection associated with autonomic dysfunction

Background: Impaired autonomic function has been described in patients with chronic liver diseases from different aetiologies, and has proven to be a poor prognostic indicator. To date, it is not known how chronic hepatitis C virus (HCV) infection affects the autonomic nervous system. Aims: In the present study, we compared cardiovagal autonomic function in patients with chronic HCV infection and healthy controls and examined the relation between autonomic function and serum levels of aminotransferases, HCV RNA, cryoglobulins, albumin and glucose. Methods: Autonomic function was assessed in 45 treatment-naı¨ve patients with chronic HCV infection and in 40 healthy controls by determining spontaneous baroreflex sensitivity (BRS) and heart rate variability (HRV) indices. The R–R interval was determined by electrocardiogramrecording; continuous radial artery pressure was monitored simultaneously by applanation tonometry. Laboratory analyses and quantitative polymerase chain reaction for serum HCV RNA level were performed by standard procedures. Results: BRS and HRV time and frequency domain indices were lower in patients with HCV infection compared with healthy controls [7.1+/-3.4 vs. 11.5+/-6.5 ms/mmHg for BRS, 168.5+/-160.9 vs. 370.7+/-349.4 ms2 for low-frequency HRV (mean+/-SD); Po0.01]. Multivariate analysis showed that autonomic dysfunction in HCV-infected patients correlated with elevated alanine aminotransferase levels, but was not associated with serum HCV RNA levels and cryoglobulins. Conclusion: Our results suggest that impaired autonomic function is caused by chronic HCV infection. Further studies are needed, however, to identify the underlying mechanisms

Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease

Background/aims Diagnosis of Wilson's disease may be difficult in patients presenting with liver disease and in asymptomatic siblings. The aim of the present study was to assess the impact of genetic testing for diagnosis of the disease in a large cohort (n = 109) from Hungary. Patients/methods One hundred and nine patients with Wilson's disease were studied (65 men and 44 women; mean age at onset of symptoms: 20 9 years). Diagnosis of the disease was based on typical clinical and laboratory features (all had a Wilson's disease score of >=, 4). H1 069Q was assessed by the semi-nested polymerase chain reaction-based restriction fragment length polymorphism assay. H1 069Q heterozygotes and H1 069Q negative samples were then screened for mutations (on exons 6 to 20) by denaturating high-performance liquid chromatography and than sequenced on a genetic analyser. Results Twenty-three different mutations were found. H1 069Q was the most frequent mutation in Hungary, detected in 77 patients (71%). Fourteen further known mutations were found by sequencing. We identified eight new mis-sense mutations not described before: N6761, S693Y, Y715H, M769L, W939C, P1 273S, G1 281 D and G1 341 V. In 36/109 patients (33%) the diagnosis of Wilson's disease was established by adding mutational analysis. The Kayser-Fleischer ring was more frequent in H1 069Q homozygous patients and their mean age at the time of diagnosis was higher than in patients heterozygous or negative for H1069Q. Conclusion Eight novel mutations in addition to the 15 that are already known were found in Hungarian patients with Wilson's disease. Our results underline the importance and usefulness of genetic testing for patients presenting with liver disease and for family screening