Assessment and management of iron overload in β‐thalassaemia major patients during the 21st century: a real‐life experience from the Italian Webthal project

We conducted a cross‐sectional study on 924 β‐thalassaemia major patients (mean age 30·1 years) treated at nine Italian centres using the webthal software, to evaluate real‐life application of iron overload assessment and management standards. Serum ferritin <2500 ng/ml was a risk factor for never having liver iron concentration (LIC) measurement, while absence of cardiac disease and siderosis were risk factors for a delay in LIC measurement >2 years. Patients who never had a cardiac MRI (CMR) T2* measurement were <18 years, had iron intake ≤0·4 mg/kg per day, or a serum ferritin <2500 ng/ml. A history of normal CMR T2* was the main risk factor for a delay in subsequent assessment of >2 years. Deferoxamine (22·8%) was more commonly used in patients with Hepatitis C Virus or high serum creatinine. Deferiprone (20·6%) was less commonly prescribed in patients with elevated alanine aminotransferase; while a deferoxamine + deferiprone combination (17·9%) was more commonly used in patients with serum ferritin >2500 ng/ml or CMR T2* <20 ms. Deferasirox (38·3%) was more commonly prescribed in patients <18 years, but less commonly used in those with heart disease or high iron intake. These observations largely echoed guidelines at the time, although some practices are expected to change in light of evolving evidence.     

Glucose abnormalities in non‐alcoholic fatty liver disease and chronic hepatitis C virus infection: the role of iron overload

Non‐alcoholic fatty liver disease (NAFLD) and chronic hepatitis C virus (HCV) infection are major causes of liver disease frequently described in outpatient patients with glucose abnormalities. Hyperferritinemia, which suggests that iron overload plays a decisive role in the pathophysiology of insulin resistance and hyperglycemia, is a common finding in both disorders. However, the role of the hepatic iron deposition differs from one to the other. In NAFLD, a moderate liver iron accumulation has been observed and molecular mechanisms, including the downregulation of the liver iron exporter ferroportin‐1, have been described. Iron overload will enhance intrahepatic oxidative stress that promotes hepatic fibrosis, interfere with insulin signalling at various levels and may hamper hepatic insulin extraction. Therefore, liver fibrosis, hyperglycemia and hyperinsulinemia will lead to increased levels of insulin resistance and the development of glucose abnormalities. Furthermore, iron depletion by phlebotomy removes liver iron content and reduces serum glucose and insulin resistance in NAFLD patients. Therefore, it seems that iron overload participates in those glucose abnormalities associated with NAFLD. Concerning chronic HCV infection, it has been classically assumed that iron overload contributes to insulin resistance associated with virus infection. However, recent evidence argues against the presence of iron overload in these patients and points to inflammation associated with diabetes as the main contributor to the elevated ferritin levels. Therefore, glucose abnormalities, and specially type 2 diabetes, should be taken into account when evaluating serum ferritin levels in patients with HCV infection. Copyright © 2009 John Wiley & Sons, Ltd.     

Increased iron stores prolong the QT interval – a general population study including 20 261 individuals and meta‐analysis of thalassaemia major

The prolongation of cardiac repolarization (QT interval) has been investigated in studies of patients with secondary iron overload. However, no previous population‐based study examining the effect of increased iron stores on QT interval prolongation has previously been undertaken. We tested the hypothesis that increased iron stores and haemochromatosis genotype (genetically increased iron stores) are associated with prolongation of the QT interval. We included 20 261 individuals from the Danish General Suburban Population Study and examined differences in QT interval according to ferritin concentration, transferrin saturation, iron concentration, transferrin concentration and haemochromatosis genotype (C282Y/C282Y). Furthermore, we performed a meta‐analysis of case‐control studies on thalassaemia major patients and QT interval. Age‐ and C‐reactive protein‐adjusted mean corrected QT (QTc) intervals for ferritin concentration ≥99% vs. ≥25–<50% percentile were 418·9 ms vs. 412·7 ms in men (P < 0·001) and 422·4 ms vs. 419·1 ms in women (P = 0·78). Corresponding values for transferrin saturation were 417·6 ms vs. 412·6 ms in men (P = 0·02) and 421·5 ms vs. 419·4 ms in women (P = 0·86). The associations were not explained by inflammation and haemochromatosis genotype was not associated with QT interval length. In conclusion, increased iron stores, independent of haemochromatosis genotype and inflammation, are associated with prolongation of the QTc interval in men. This is a novel finding. In addition, the meta‐analysis showed prolonged QT interval in thalassaemia major patients compared to healthy controls.     

A pilot study of recombinant interferon beta‐1a for the treatment of chronic hepatitis C

Abstract: Aims: Interferon alpha monotherapy induces a sustained response in less than 20% of patients treated for chronic hepatitis C. Interferon beta represents a potential therapeutic alternative for the treatment of chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and tolerance of recombinant interferon beta‐1a administered subcutaneously. Methods: Twenty‐one drug‐naive patients with chronic hepatitis C were treated with recombinant interferon beta‐1a administered, subcutaneously, for 24 weeks using two different regimens: 9 MU, three times per week (n=11) and 12 MU, three times per week (n=10). Results: At the end of the treatment period, nine (43%) patients had a biochemical and virological response (i.e. normal ALT and absence of hepatitis C virus RNA by PCR). Four of these patients were in the 9 MU group and five in the 12 MU group. A biochemical and virological sustained response occurred in four (19%) patients, all in the 9 MU dose group. The 4 patients with a sustained response maintained their response during a follow‐up period of 33 to 58 months. Side effects were mild and 19 (90%) patients completed the treatment period. Conclusions: The results of this pilot study indicate that interferon beta‐1a administered subcutaneously is an effective therapy for some patients with chronic hepatitis C, and suggest that interferon beta‐1a deserves further evaluations in larger trials especially in combination with ribavirin.     

Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: a meta‐analysis

Background: The association between occult hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) remains controversial. Aims: We conducted a meta‐analysis of prospective studies and retrospective studies to examine whether occult HBV infection increases the risk of HCC. Methods: Two independent reviewers searched databases for eligible studies published in English or Chinese dated from 1966 to 6 April 2010. The odds ratios or the relative risks (RRs) of each study were considered respectively. Results: We identified 16 eligible studies. A significantly increased risk of HCC was found in subjects with occult HBV infection in comparison with non‐infected controls in both retrospective [OR_unadjusted=6.08, 95% confidence interval (CI)=3.45–10.72] and prospective studies (RR_adjusted=2.86, 95% CI=1.59–4.13), and occult HBV increased the risk for HCC in both hepatitis C virus (HCV)‐infected populations (summary RR=2.83, 95% CI=1.56–4.10) and in non‐infected populations (OR_unadjusted=10.65, 95% CI=5.94–19.08). A higher prevalence of occult HBV was observed in individuals who were positive for anti‐HBs and anti‐HBc (OR_unadjusted=1.81, 95% CI=1.06, 3.09). Conclusion: Our findings suggest that occult HBV infection was associated with an increased risk of HCC. Occult HBV may serve as a cofactor in the development of HCV‐related HCC, and it may also play a direct role in promoting Non‐B and Non‐C HCC growth. Suggestive evidence indicates that individuals with a concomitant presence of anti‐HBs and anti‐HBc had an increased risk of occult HBV infection. However, further studies are needed to clarify these observations.     

Syndecan 1 (CD138) serum levels: a novel biomarker in predicting liver fibrosis stage in patients with hepatitis C

Background and Aims: Syndecan 1 (CD 138) is a cell surface proteoglycan shed by cells in several pathological conditions, including wound healing. The aim of this study was to test whether CD138 could serve as a non‐invasive marker for detection of liver fibrosis and thereby reduce the need for liver biopsy. Patients and Methods: An estimation set of 134 patients and a validation set of 67 patients with chronic hepatitis C were studied. There were 80 normal healthy volunteers. Patients were staged according to liver biopsies (Metavir fibrosis staging, stage F0, n=35; F1, n=40; F2, n=37, F3, n=39; F4, n=51). Serum CD138 levels were retrospectively measured by enzyme‐linked immunoabsorbent assay the same day of the liver biopsy. The primary endpoints were the diagnostic values of CD138 for F2–F4, F3–F4 and F4. Results: Respective areas under receiver operating characteristic curve of CD138 for F2–F4, F3–F4 and F4 diagnosis were 0.82, 0.76 and 0.81. CD138 had a positive predictive value of 82% for F2–F4 diagnosis and a high negative predictive value (86%) and specificity (84%) for exclusion of F4. Conclusion: CD138 is a new simple non‐invasive marker for predicting liver fibrosis in patients with chronic hepatitis C. The relevance of this marker in combination with other fibrosis markers should be explored.     

Serum miR‐122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR‐122 in HCV‐infected subjects

Circulating microRNAs (miRNA) have been intensely investigated as biomarkers in disease and therapy. Several studies have identified miR‐122 as an important regulator of HCV replication. The effect of new therapies that directly target the HCV replication life cycle on circulating microRNA levels has not been elucidated. We performed expression profiling of circulating miRNA in serum in subjects treated with HCV direct‐acting antiviral agents (DAAs). Serum miRNA levels were evaluated from two studies in HCV GT1‐infected treatment‐naïve subjects and prior nonresponders to pegylated interferon (pegIFN) and ribavirin (RBV) who received paritaprevir/ritonavir + dasabuvir + RBV for 12 weeks, and in treatment‐naïve genotype (GT)1‐3‐infected subjects who received paritaprevir/ritonavir + ombitasvir ± RBV for 12 weeks. Over 100 different miRNA species were detected in serum. Of these, levels of miR‐122 showed the most consistent change in response to treatment across all HCV genotypes. In all subjects, miR‐122 showed an average four‐fold reduction between baseline and week 2, and remained below baseline through post‐treatment week 12 in subjects who achieved sustained virological response. In contrast, in subjects who did not achieve SVR, miR‐122 levels began to return to baseline levels after the second week of treatment. The change in miR‐122 levels was similar across genotypes, and was comparable with or without RBV. This is the first report comparing expression levels of circulating miRNA in HCV GT1‐3 subjects treated with IFN‐free combinations of DAAs. The results suggest that serum levels of miR‐122 are reduced following treatment in subjects who achieve SVR, and correlate with HCV RNA levels across genotypes.     

Hepatitis C virus infection and risk of multiple myeloma: Evidence from a meta‐analysis based on 17 case‐control studies

Hepatitis C virus (HCV) infection is a leading cause of chronic liver damage and is associated with other diseases. Some studies reported that patients with HCV have a significantly increased risk of multiple myeloma while others do not report an association. We aimed to clarify the association between HCV and multiple myeloma and analyse the factors that affect the controversial conclusions through a meta‐analysis. We conducted a systematic literature search of HCV and myeloma in the databases of PubMed/MEDLINE, Cochrane Library, EMBASE, Wanfang and China National Knowledge Infrastructure (CNKI) from inception to September 2016. Outcomes were expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). A positive correlation between HCV infection and risk of developing multiple myeloma was revealed (OR=2.67, 95% CI=1.35‐5.26, P=.005) based on meta‐analysis of 17 case‐control observational studies. When the data were stratified by source of control, significant associations were observed in hospital‐based studies, but not population‐based studies. Further subgroup analyses showed increased risk of multiple myeloma in HCV patients when studies were conducted in high HCV prevalent countries, but not in low or moderate HCV prevalent countries. In addition, similar positive association was detected in studies performed in the East Asia and in intermediate‐quality studies. In summary, the association of HCV infection with increased risk of multiple myeloma depended on several factors, including study design, quality and environmental HCV prevalence. Further large‐scale, well‐designed studies are needed to validate the role of HCV in the aetiology of multiple myeloma.     

Rare occurrence of occult hepatitis C virus in apparently uninfected injecting drug users: a two‐centre,masked, case–control study

Occult hepatitis C virus (HCV) is a phenomenon where serum HCV RNA is not detected by sensitive commercial assays, but viral RNA is detected by ultrasensitive techniques. Occult HCV infection has not previously been studied in highly exposed, but apparently uninfected (EU) individuals. Two studies examining occult infection in EU subjects were undertaken – an initial two‐centre, masked, case–control study based on cross‐sectional samples (n = 35 subjects) and a single‐centre confirmatory study based on longitudinal samples (n = 32 subjects). Plasma and peripheral blood mononuclear cells were tested for HCV RNA using an ultrasensitive nested polymerase chain reaction assays. Two EU subjects in the first study (10%) and one in the second study (3%) were found to have consistently detectable HCV RNA. Occult HCV infection occurs in high‐risk, apparently uninfected subjects.     

Chronic hepatitis C virus infection is associated with increased risk of preterm birth: a meta‐analysis of observational studies

Although several epidemiological studies reported that maternal chronic hepatitis C virus (HCV) infection had significantly increased risk of undergoing adverse obstetrical and perinatal outcomes, studies on the relationship between HCV infection and risk of preterm birth (PTB) have yielded inconclusive and inconsistent results. Therefore, we conducted a meta‐analysis to investigate the association between HCV infection and PTB. The electronic database was searched until 1 September 2014. Relevant studies reporting the association between HCV infection and the risk of PTB were included for further evaluation. Statistical analysis was performed using revmen 5.3 and stata 10.0. Nine studies involving 4186698 participants and 5218 HCV infection cases were included. A significant association between HCV infection and PTB was observed (odds ratio = 1.62, 95% CI 1.48–1.76, P < 0.001, fixed‐effects model). Stratification according to maternal smoking/alcohol abuse, maternal drug abuse or coinfected with HBV and/or HIV matched groups still demonstrated that women with HCV infection had a high risk for PTB. Findings from our meta‐analysis suggested that maternal HCV infection was significantly associated with an increased risk of PTB. In the future, pathophysiological studies are warranted to ascertain the causality and explore the possible biological mechanisms involved.     

Utilization of increased risk for transmission of infectious disease donor organs in solid organ transplantation: Retrospective analysis of disease transmission and safety

The inadequate supply of transplantable organs necessitates new approaches to organ availability. Serologies and nucleic acid testing (NAT) for hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) are used in microbiologic screening of potential organ donors. Organs from donors considered at “high risk” (Centers for Disease Control and Prevention, CDC 1994) or “increased risk” (U.S. Public Health Service, PHS 2013) for transmission of viral infection to recipients may provide an expanded source of organs for transplantation. We review a single‐center experience with 257 adult organ recipients of organs from donors meeting either CDC 1994 or PHS 2013 risk criteria between 2011 and 2016. Tracking these transplants required modification of the Transplant Center electronic database to identify all recipients of increased‐risk donor (IRD) organs, documentation of informed consent, and microbiologic testing data. No transmissions of HIV, HBV, or HCV were identified by NAT or clinically. Nine patients developed positive serologic assays for one of the tested viruses; all recipients were retested and remain negative by NAT. Notably, post‐transplant HBV core serologies reverted to negative on re‐testing; these positive serologies are likely false positives caused by receipt of blood products. Use of IRD organs can be performed safely with appropriate informed consent and rigorous pre‐ and post‐transplant microbiological testing.     

Clarification of interspousal hepatitis C virus infection in acute hepatitis C patients by molecular evolutionary analyses: Consideration on sexual and non‐sexual transmission between spouses

Aim: Previous studies evaluating the possibilities of interspousal sexual transmission of hepatitis C virus (HCV) have yielded many conflicting results. The aim of this study was to clarify the source of HCV infection in acute hepatitis C patients using phylogenetic analyses of nucleotide sequences of HCV E1 region. Methods: Four acute hepatitis C patients were hospitalized in 2002–2007. The diagnosis was based on medical records, laboratory tests including HCV markers, and ultrasonographic examination of the liver. In each spouse of four patients, serum HCV antibody was assayed. In the subjects whose serum HCV antibody was positive, additional tests on HCV viral load and genotype were carried out. Then phylogenetic analyses of nucleotide sequences of partial HCV E1 region (440 nucleotides) of the patients and their spouses were performed. Results: Hepatitis C virus antibody changed from negative to positive in the course of hospitalization and HCV RNA could be detected in every patient. Therefore they were diagnosed as acute hepatitis caused by HCV infection. In every spouse of four patients, HCV antibody and HCV RNA were positive. Three of four couples had the identical genotype and homogeneity of nucleotide sequences of HCV E1 region in three couples ranged from 97.9% to 100%. The results of phylogenic analyses suggested that interspousal HCV infection occurred in the three couples. Conclusion: In conclusion, interspousal infection might be one of the important sources of acute HCV infection in Japan. The usefulness of phylogenetic analysis of nucleotide sequences of HCV E1 region for clarifying interspousal HCV infection was validated.