Hepatitis: Gordeuk VR

Aliyu ZY, Kato GJ, Taylor J, Babadoko A, Mamman AI, Gordeuk VR, Gladwin MT. · Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1662, USA. · Am J Hematol. · Pubmed #17910044 No free full text.

Abstract: Secondary pulmonary hypertension (PAH) has been shown to have a prevalence of 30% in patients with sickle cell disease (SCD) with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of SCD is highest in sub-Saharan Africa, especially in Nigeria (West Africa), where approximately 6 million people are afflicted. The true global incidence, prevalence, and burden of SCD and its associated end organ complications however remain unknown. Chronic hemolysis represents a prominent mechanistic pathway in the pathogenesis of SCD-associated pulmonary hypertension via a nitric oxide (NO) scavenging and abrogation of NO salutatory effects on vascular function, including smooth muscle relaxation, downregulation of endothelial adhesion molecules and inhibition of platelet activation. Many known infectious risk factors for PAH are also hyperendemic in Africa, including Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), chronic hepatitis B and C, and possibly malaria. Interactions between these infectious complications and SCD-related hemolysis could yield an even higher prevalence of pulmonary hypertension and compound the existing global health systems challenges in managing SCD. Indeed, our preliminary analysis of African immigrants currently in the United States suggests that pulmonary hypertension represents a significant complication of SCD in the African subcontinent. There is clearly a need to include Africa and other parts of the world with high SCD prevalence in future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide.

Gordeuk VR, Diaz SF, Onojobi GO, Kasvosve I, Debebe Z, Edossa A, Pantin JM, Xiong S, Nekhai S, Nouraie M, Tsukamoto H, Taylor RE. · College of Medicine, Howard University, Washington, DC 20060, USA. · Alcohol Clin Exp Res. · Pubmed #18782341 No free full text.

Abstract: BACKGROUND: Alcohol consumption is associated with increased iron stores. In sub-Saharan Africa, high dietary ionic iron and the ferroportin Q248H allele have also been implicated in iron accumulation. We examined the associations of ferroportin Q248H, alcohol and dietary iron with serum ferritin, aspartate aminotransaminase (AST) and alanine aminotransaminase (ALT) concentrations in African-Americans. METHODS: Inner-city African-Americans (103 men, 40 women) were recruited from the community according to reported ingestion of >4 alcoholic drinks/d or <2/wk. Typical daily heme iron, nonheme iron and alcohol were estimated using University of Hawaii's multiethnic dietary questionnaire. Based on dietary questionnaire estimates we established categories of < versus > or =56 g alcohol/d, equivalent to 4 alcoholic drinks/d assuming 14 g alcohol per drink. RESULTS: Among 143 participants, 77% drank <56 g alcohol/d and 23%> or =56 g/d as estimated by the questionnaire. The prevalence of ferroportin Q248H was 23.3% with alcohol >56 g/d versus 7.5% with lower amounts (p = 0.014). Among subjects with no history of HIV disease, serum ferritin concentration had positive relationships with male gender (p = 0.041), alcohol consumption (p = 0.021) and ALT concentration (p = 0.0001) but not with dietary iron intake or ferroportin Q248H. Serum AST and ALT concentrations had significant positive associations with male gender and hepatitis C seropositivity but not with alcohol or dietary iron intake or ferroportin Q248H. CONCLUSIONS: Our findings suggest a higher prevalence of ferroportin Q248H with greater alcohol consumption, and this higher prevalence raises the possibility that the allele might ameliorate the toxicity of alcohol. Our results suggest that alcohol but not dietary iron contributes to higher body iron stores in African-Americans. Studies with larger numbers of participants are needed to further clarify the relationship of ferroportin Q248H with the toxicity of alcohol consumption.

Adams PC, Passmore L, Chakrabarti S, Reboussin DM, Acton RT, Barton JC, McLaren GD, Eckfeldt JH, Dawkins FW, Gordeuk VR, Harris EL, Leiendecker-Foster C, Gossman E, Sholinsky P, Anonymous00397. · Department of Medicine, University Hospital, 339 Windermere Road, London, Ontario, Canada N6A 5A5. · Clin Gastroenterol Hepatol. · Pubmed #16797244 No free full text.

Abstract: BACKGROUND AND AIMS: The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101,168 primary care participants for iron overload with serum transferrin saturation (TS), ferritin, and C282Y and H63D mutations of the HFE gene. METHODS: All C282Y homozygotes and participants with an increased TS (>45% women, >50% men) and serum ferritin level (> 200 microg/L women, >300 microg/L men) were recalled for a clinical history and physical examination, and blood tests including alanine transaminase (ALT) and aspartate transaminase levels. Hepatitis B surface antigen and anti-hepatitis C virus were measured if the ALT level was increased (>31 IU/L in women, >40 IU/L in men). RESULTS: In the group of participants selected to return for clinical examination because of increased TS and ferritin levels, ALT increases and anti-hepatitis C virus were found in 95 of 284 (33%) African Americans, 50 of 466 (11%) Asian and Pacific Islanders, 21 of 120 (18%) Hispanics, and 40 of 477 (8.4%) Caucasians. ALT increases and hepatitis B surface antigen were detected in 24 of 466 (5%) Asian and Pacific Islanders, 10 of 284 (3.5%) African Americans, 3 of 120 (2.5%) Hispanics, and 2 of 477 (.42%) Caucasians. Of 86 liver biopsy specimens obtained for clinical purposes, 53 were reviewed by a single study pathologist. Liver fibrosis (stage 3 or 4) was present in 2 of 11 (18.2%) C282Y homozygotes that underwent central review and 2 of 302 (.66%) C282Y homozygotes attending the clinical examination. CONCLUSIONS: Screening for iron overload with ferritin and TS detects persons with viral hepatitis and other types of liver disease. A minimum of .66% C282Y homozygotes have liver fibrosis.

McLaren CE, Li KT, Gordeuk VR, Hasselblad V, McLaren GD. · Division of Epidemiology, University of California, Irvine, College of Medicine, Irvine, CA 92697-7550, USA. · Blood. · Pubmed #11588029 links to  free full text

Abstract: In previous analyses of transferrin saturation data in African Americans and Caucasians from the second National Health and Nutrition Examination Survey (NHANES II), subpopulations were found consistent with population genetics for common loci that influence iron metabolism. The goal of this new study was to determine if these transferrin saturation subpopulations have different levels of iron stores. Statistical mixture modeling was applied to transferrin saturation data for African Americans and Caucasians from the third National Health and Nutrition Examination Survey (NHANES III), and then the mean serum ferritin concentrations were determined for the transferrin saturation subpopulations that were identified. After adjustment for diurnal variation, 3 subpopulations of transferrin saturation were identified in each racial group. Satisfying Hardy-Weinberg conditions for major locus effects, in both racial groups the sum of the square roots of the proportion with the lowest mean transferrin saturation and the proportion with the highest mean transferrin saturation was approximately 1. When weighted to reflect the US adult population as a whole, these subpopulations of increasing transferrin saturations had progressively increasing mean age-adjusted serum ferritin concentration values in each ethnic grouping as stratified by sex (trend test, P <.002 for all). These results are consistent with the concept that population transferrin saturation subpopulations reflect different levels of storage iron.

Weiss G, Umlauft F, Urbanek M, Herold M, Lovevsky M, Offner F, Gordeuk VR. · Department of Internal Medicine, University Hospital, Anichstr. 35, A-6020 Innsbruck, Austria. · J Infect Dis. · Pubmed #10515803 No free full text.

Abstract: We studied the associations of macrophage activity, T-helper cell types 1 and 2 (Th-1/Th-2) responses, and iron status in 55 patients with hepatitis C virus (HCV)-related liver disease and 28 control patients with noninfectious liver disease. Serum concentrations of soluble tumor necrosis factor receptor type II (sTNFrec 75), a macrophage activation marker, were higher in cirrhotic than in noncirrhotic patients (P<.001) regardless of their HCV status, whereas levels of neopterin, interleukin (IL)-4 and IL-10 did not differ significantly. In HCV-positive patients, sTNFrec 75 levels and transferrin saturation (TfS) correlated positively with levels of aspartate transaminase (P<.001 for sTNFrec 75 and P=.028 for TfS) and alanine transaminase (P=.003 for sTNFrec 75 and P=.039 for TfS). Increased TfS correlated significantly with both advanced liver disease and a predominant Th-2 pattern in HCV patients. Our data suggest that an association exists between macrophage activation and hepatic dysfunction, and that iron status may affect the clinical course of HCV infection by modulating Th-1/Th-2 responses in vivo.