Human MutationVolume 15, Issue 4 p. 389-389 Mutation and Polymorphism Report A novel polymorphism (219G>A) in the transferrin receptor gene † Mirella Meregalli, Mirella Meregalli University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorNoemi Corbetta, Noemi Corbetta University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorAndrea Pellagatti, Andrea Pellagatti University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorFranco Martinez di Montemuros, Franco Martinez di Montemuros University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorDario Tavazzi, Dario Tavazzi University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorSilvia Fargion, Silvia Fargion University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorMaurizio Sampietro, Maurizio Sampietro University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this author Mirella Meregalli, Mirella Meregalli University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorNoemi Corbetta, Noemi Corbetta University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorAndrea Pellagatti, Andrea Pellagatti University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorFranco Martinez di Montemuros, Franco Martinez di Montemuros University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorDario Tavazzi, Dario Tavazzi University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorSilvia Fargion, Silvia Fargion University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this authorMaurizio Sampietro, Maurizio Sampietro University of Milan, Department of Internal Medicine - IRCCS Ospedale MaggioreSearch for more papers by this author First published: 22 March 2000 https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<389::AID-HUMU28>3.0.CO;2-HCitations: 2 † Communicated by: Mark H. Paalman ‡ Online Citation: Human Mutation, Mutation and Polymorphism Report #101 (1999) Online http://journals.wiley.com/1059-7794/pdf/mutation/mpr101.pdf § Acknowledgments: This work was supported by MURST (ex 40%) and by intramural research funding at IRRCS Ospedale Maggiore. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume15, Issue4April 2000Pages 389-389 RelatedInformation

Sporadic porphyria cutanea tarda (PCT) is caused by a reduced activity of uroporphyrinogen decarboxylase (URO-D) in the liver. Mild to moderate iron overload is common in PCT, as iron is one of the factors which trigger the clinical manifestations of the disease through the inactivation of URO-D. A role for genetic hemochromatosis in the development of iron overload in sporadic PCT has been hypothesized in the past. The aim of this work was to investigate whether mutations of HFE, which is a candidate gene for hemochromatosis, play the role of genetic susceptibility factors for PCT in Italian patients, who have a high prevalence of acquired triggering factors, such as hepatitis C virus (HCV) chronic infection and alcohol. We determined HFE genotypes of 68 male patients with PCT. Our data do not confirm an association of PCT with the Cys282Tyr HFE mutation, strongly associated with hemochromatosis in Northern European countries. A second mutation of HFE, His63Asp, however, had a significantly increased frequency as it was present in half of the patients. Surprisingly, the presence of the His63Asp mutation was not related to the iron status of patients, suggesting that a subtle abnormality of iron metabolism induced by this mutation could escape detection by the standard parameters of iron status. In PCT patients with liver disease, the presence of the mutation could contribute to the inactivation of URO-D, either directly or through a synergistic action with other factors that cause liver damage.

BACKGROUND AND AIMS:At least 10% of post-transfusion and community-acquired hepatitis cases are not accounted for by the A to E viruses. Hepatitis G virus (HGV), a novel agent belonging to the Flaviviridae and distantly related to HCV has recently been identified. The epidemiology and clinical significance of this infection in the geriatric setting is still little known. Aim of the investigation was to assess the prevalence and clinical significance of HGV infection in the geriatric setting.PATIENTS:105 unselected consecutive patients (mean age 73.4 years).METHODS:HGV-RNA was detected by a single-tube reverse-transcription heminested polymerase chain reaction with primers from the 5' untranslated region of the virus. Anti-HGV antibodies were detected with a commercial anti-E2 immunometric assay.RESULTS:3/105 patients (2.9%) were viraemic, without a history or clinical evidence of hepatitis. Anti-HGV antibodies were detected in 25 patients (23.8%), 40% of whom had associated anti-HCV antibodies. The presence of HGV-RNA and anti-HGV antibodies was mutually exclusive.CONCLUSIONS:HGV infection is highly prevalent in our population and the cumulative risk of exposure is proportional to age. In most cases, HGV infection is self-limiting and clinically irrelevant. Immunity against E2 or other associated uncharacterized viral epitopes appears to be protective.

To the Editor: Few studies have examined seroprevalence rates of hepatitis C virus (HCV) infection in the general population and in older people in particular. A detailed analysis of HCV markers in the geriatric population would not only add to the epidemiology of HCV but would also contribute to the description of the natural history of this infection. To assess the frequency and clinical significance of HCV markers in a population of older individuals, we screened 500 unselected, consecutive outpatients (176 men, 324 women, age range 60–98, median age 71) admitted to a geriatric day-hospital for HCVAb (EIAII/III Ortho Diagnostic Systems, Raritan, NJ). The main diagnosis at admission for all patients is reported in Table 1. Patients testing HCVAb positive underwent a virological evaluation that included recombinant immunoblot assay (RIBA 3.0, Ortho Diagnostic Systems, Raritan, NJ), detection of viremia by HCV-RNA,1 characterization of viral genotype,2 and serotype.3 Sixty-two patients (12.4%) tested HCVAb positive, a prevalence much higher than the 1.7% found in blood donors from the same area.4 Forty-six patients were available for further analysis; 16 were dropped from the study for poor compliance or supervening pathological conditions unrelated to HCV infection. HCV-RNA was present in 23 of 46 (50%) patients. RIBA was positive in 34 of 46 patients (73.9%); an indeterminate RIBA present in 12 patients was caused by reactivity to the single antigen, c22.3. Antibody profiles were related to viral replication. A broader RIBA pattern with a positive reaction to three to four antigens was more frequent in viremic than in nonviremic patients (73.9% vs 26.1%, P =.002); reactivity against the isolated core antigen, c22.3, was predominant in nonviremic patients (47.8% vs 4.3% of viremic patients, P =.001). An isolated reactivity to c22.3 is conventionally considered an indeterminate result; there is evidence, however, that isolated reactivity to c22.3 could reflect a specific reaction to HCV infection,5-7 and in three of our patients, the association of c22.3 reactivity with antibodies against type-specific antigens confirmed a genuine response to HCV. HCV genotype 1b was found in 10 of 23 (43.5%) viremic patients, genotype 2 in 12 of 23 (52.2%), and genotype 4 in 1/23 (4.3%). The low prevalence of HCVlb in geriatric patients is likely the effect of selection, indirectly confirming the lesser pathogenic potential of HCV type 2.8, 9 At serotype analysis, 23 of 46 sera (50%) were not reactive, and seven (15.2%) were nonspecifically reactive. Among patients in whom serotype could be identified, seven (43.7%) had serotype 1, and nine (56.3%) had serotype 2. Serotype could be characterized in only three nonviremic RIBA-indeterminate patients, with type 2 identified in each of them. Of the patients studied, 69.6% did not have a clinically significant hepatitis and were previously unaware of liver disease or HCV infection. Data from these patients are summarized in Table 2. They had a low prevalence of viremia, 40% versus 70% in Italian nongeriatric clinically silent HCVAb positive subjects,9 with genotype 2 prevailing among viremic patients. None of them had abnormal liver enzymes on three controls 3 months apart. Mild abnormalities of ultrasound liver scan (minimal dishomonegeneity and/or steatosis) were found in half of the patients, but none had signs of portal hypertension or nodular regeneration of the liver. Mild sonographic abnormalities were significantly more frequent in viremic patients (P =.029). The analysis of risk factors indicated that the infection had been mostly community acquired. Transfusion was reported in 19.6% of patients positive for HCVAb, not significantly different from 14.0% of patients negative for HCVAb. HBcAb positivity, a surrogate evidence of past parenteral exposure, was found in 58.7% of patients positive for HCVAb compared with 32.4% of 398 individuals negative for HCVAb (P <.001). Patients testing HCVAb positive had undergone more surgical procedures (2.72 ± 1.34 vs 2.11 ± 1.30, P =.006), and history of delivery was more frequent in HCVAb positive women (90.9% vs 74.7%, P =.047). The increased frequency of surgery and deliveries among patients who were HCVAb positive suggests a possible role for nosocomial infections. Hepatitis C virus infection is thought to persist in a large proportion of infected cases,10-12 but in the setting of community-acquired infection, the asymptomatic course of acute infection and the long subclinical evolution of chronic hepatitis make it difficult to assess the proportion of primary infections evolving to chronicity and causing liver disease. Our study indicates that the prevalence of HCV infection in the general Italian population may be significantly higher than previously realized, with higher rates found in older people. In community-acquired infections, the recovery or long-term disease-free survival could be more common than presently thought.

The risk of polytransfused patients for hepatitis C virus (HCV) infection is likely to extend to another recently identified member of the Flaviviridae, hepatitis G virus (HGV). We investigated the prevalence of HGV in 40 adult Italian patients with transfusion‐dependent thalassaemia and evaluated the clinical significance of HGV infection. HGV‐RNA was detected in 9/40 patients (22.5%). HGV infection was significantly associated with HCV viraemia (P =0.0012), with all patients positive for HGV being also viraemic for HCV. Overall, the clinical picture of patients with HCV/HGV co‐infection was not different from that of patients with isolated HCV. However, patients co‐infected with both viruses had lower values of alanine‐transferase (P =0035) and a lower titre of HCV viraemia (P =0042) in the absence of other evident factors which could influence the clinical expression of HCV infection. In conclusion, HGV is highly prevalent among Italian polytransfused patients. No evidence of a clinically significant pathogenic role for HGV in liver disease could be found in these patients. In a subset of cases a possible interference of HGV with HCV infection was observed.

BACKGROUND:A strong association between sporadic porphyria cutanea tarda and chronic hepatitis C virus infection was recently described in Italy, France and Spain.AIMS:To explore whether hepatitis C virus genotype plays a role in porphyria cutanea tarda complicating chronic hepatitis C.PATIENTS:Forty-seven hepatitis C virus-positive porphyria cutanea tarda patients and a control group of 45 patients of similar age with hepatitis C virus-associated chronic liver disease.METHODS:Comparison of frequency of hepatitis C virus genotypes in the two groups and in relation to the age of patients, hepatic histopathology and with the presence of other factors potentially able to trigger porphyria cutanea tarda.RESULTS:A single genotype, hepatitis C virus 1b, was found to be present in nearly 90% of porphyria cutanea tarda-associated chronic liver disease, significantly exceeding the frequency of the same genotype in the control group (p = 0.0001). The presence of hepatitis C virus 1b was not related to the age of patients or disease severity as evaluated by hepatic histopathology.CONCLUSIONS:Hepatitis C virus-associated chronic hepatitis found in the majority of Italian patients with porphyria cutanea tarda is usually sustained by hepatitis C virus genotype 1b. This viral strain might have a direct pathogenic role in inducing porphyria cutanea tarda or could increase the susceptibility of patients of other triggering factors such as iron overload or alcohol abuse.

PURPOSE OF THE STUDY: We evaluated the presence of HCV in the peritoneal effluents of viraemic patients treated with continuous ambulatory peritoneal dialysis (CAPD) to evaluate the risk of transmitting the infection with this procedure. PROCEDURE: Fifteen of 81 CAPD patients (18.5%) had anti-HCV antibodies and eight were viraemic. At the beginning of CAPD two of the viraemic patients had ascites with a clinical picture of chronic active hepatitis and cirrhosis. Peritoneal dialysates were collected after an overnight exchange with 1.36% glucose and after a 4-h exchange with 3.86% glucose. Fluids from the overnight exchange were spun to obtain a cellular pellet and the supernatant 100-fold concentrated. RESULTS: No viral genome could be detected in unconcentrated samples and in cellular pellets, while HCV-RNA at low titre was detected in concentrated dialysates from the two patients with active liver disease. CONCLUSIONS: Our findings confirm that HCV may be present in the CAPD effluent of some patients; however, the titre of virus in the effluent was extremely low, at the limit of detection of the PCR assay. Peritoneal fluids originating from patients with HCV associated severe liver disease may be a potential source of infection.

The increased risk of hemodialysis patients for infections sustained by hepatitis viruses is likely to extend to a newly discovered parenterally transmitted virus, HGBV-C/HGV, able to cause acute and chronic hepatitis. The aim of this study was to assess the prevalence and clinical relevance of this infection in Italian hemodialysis patients. Nineteen of 100 patients (19%) on maintenance hemodialysis were viremic for HGBV-C/HGV, and all of them were infected with a HGV-like genotype. Eight of these patients were coinfected by hepatitis B or hepatitis C viruses. A clinical picture of chronic hepatitis was not appreciable in patients with isolated HGV infection and the presence of HGV did not appear to modify the clinical course of hepatitis B and hepatitis C infections.

We studied 81 patients with chronic hepatitis C to investigate the relationship between iron and alpha-interferon response. Sixty-one patients (group A) were given alpha-interferon irrespective of iron status, whereas 20 (group B) with iron overload, were iron depleted before alpha-interferon therapy. In group A, 21 patients responded to alpha-interferon and 40 were non-responders. Increased iron indices were significantly more frequent in non-responders than responders. Multivariate analysis showed that among the independent variables evaluated, only gamma-GT and liver iron concentration predicted therapy outcome. After phlebotomy treatment, serum alanine aminotransferase fell significantly both in patients of group B (196 +/- 122 IU/l vs 82 +/- 37 IU/l, p < 10(-6)) and in 12 non-responders of group A (198 +/- 89 IU/l vs 107 +/- 81 IU/l, p < 10(-6)). In 16 iron depleted patients, eight from each group, subsequent treatment with alpha-interferon produced a response in only one patient. These results suggest that increased liver iron is a negative prognostic factor for alpha-interferon response in chronic hepatitis C. Iron depletion had a beneficial effect on serum alanine aminotransferase in all the patients treated, but did not improve the response to alpha-interferon.