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1.  Comparisons of CVID and IgGSD: Referring Physicians, Autoimmune Conditions, Pneumovax Reactivity, Immunoglobulin Levels, Blood Lymphocyte Subsets, and HLA-A and -B Typing in 432 Adult Index Patients 
Journal of Immunology Research  2014;2014:542706.
Common variable immunodeficiency (CVID) and immunoglobulin (Ig) G subclass deficiency (IgGSD) are heterogeneous disorders characterized by respiratory tract infections, selective Ig isotype deficiencies, and impaired antibody responses to polysaccharide antigens. Using univariable analyses, we compared observations in 34 CVID and 398 IgGSD adult index patients (81.9% women) referred to a hematology/oncology practice. Similarities included specialties of referring physicians, mean ages, proportions of women, reactivity to Pneumovax, median serum IgG3 and IgG4 levels, median blood CD56+/CD16+ lymphocyte levels, positivity for HLA-A and -B types, and frequencies of selected HLA-A, -B haplotypes. Dissimilarities included greater prevalence of autoimmune conditions, lower median IgG, IgA, and IgM, and lower median CD19+, CD3+/CD4+, and CD3+/CD8+ blood lymphocytes in CVID patients. Prevalence of Sjögren's syndrome and hypothyroidism was significantly greater in CVID patients. Combined subnormal IgG1/IgG3 occurred in 59% and 29% of CVID and IgGSD patients, respectively. Isolated subnormal IgG3 occurred in 121 IgGSD patients (88% women). Logistic regression on CVID (versus IgGSD) revealed a significant positive association with autoimmune conditions and significant negative associations with IgG1, IgG3, and IgA and CD56+/CD16+ lymphocyte levels, but the odds ratio was increased for autoimmune conditions alone (6.9 (95% CI 1.3, 35.5)).
doi:10.1155/2014/542706
PMCID: PMC4180398  PMID: 25295286
2.  Serum immunoglobulins in 28 adults with autoimmune sensorineural hearing loss: increased prevalence of subnormal immunoglobulin G1 and immunoglobulin G3 
BMC Immunology  2014;15(1):43.
Background
Our informal observations suggested that some patients with acute sensorineural hearing loss (ASNHL) have subnormal serum immunoglobulin (Ig) levels. We evaluated 28 consecutive adults (18 men, 10 women) at ASNHL diagnosis using: antibodies to 68 kD protein, 30 kD protein, and type II collagen; and serum total IgG, IgG subclasses, total IgA, and IgM. Reference ranges for Ig levels were mean ± 2 SD. We compared prevalences of subnormal IgG subclasses to those in 275 healthy European adults in previous reports. We also reviewed charts of consecutive adult index patients with primary Ig deficiency (35 common variable immunodeficiency, 406 IgG subclass deficiency) to identify other patients with probable ASHNL.
Results
Mean age was 53 ± 10 (SD) y. Six patients (21.4%) had other autoimmunity manifestations. Antibodies to 68 kD protein, 30 kD protein, and type II collagen were detected in 21.4% (6/28), 21.1% (4/19) and 18.8% (3/16), respectively. Three patients (10.7%) had subnormal IgG1, six (21.4%) had subnormal IgG3, and four (14.3%) had subnormal IgG1 and IgG3. Some had subnormal IgG2, IgG4, IgA, and IgM (n = 1, 2, 3, and 1, respectively). Prevalences of subnormal IgG1 or IgG3 were greater in ASNHL patients (25.0% and 35.7%) than 275 controls (2.1% and 3.3%), respectively (p < 0.0001, each comparison). Relative risks of subnormal IgG1 and IgG3 in ASNHL were 11.5 [95% CI: 4.1, 31.7] and 10.9 [4.8, 25.6], respectively. Hearing improved after initial therapy in 17 patients (60.7%). Multiple regressions on Ig levels revealed no significant associations with other available variables. Logistic regressions on initial therapy response revealed a positive association with men (p = 0.0392) and a negative association with IgA (p = 0.0274). Our estimated prevalence of probable ASNHL in 35 patients with common variable immunodeficiency during a follow-up interval of 8 ± 4 y was 0% [95% CI: 0, 12.3]). Prevalence of probable ASNHL in 406 patients with IgG subclass deficiency during the same interval was 0.74% [0.19, 2.33].
Conclusions
Serum levels of IgG1 or IgG3 were subnormal in 46.4% of 28 patients with ASNHL. Among adults who present with primary Ig deficiency, some may have or later develop ASNHL.
doi:10.1186/s12865-014-0043-2
PMCID: PMC4210578  PMID: 25339459
For indexing; Autoimmune sensorineural hearing loss; Common variable immunodeficiency (CVID); IgG; IgG subclass deficiency (IgGSD); IgG1; IgG3
3.  A comparison between whites and blacks with severe, multi-organ iron overload identified in 16,152 autopsies 
Background & Aims
Little is known about differences in the prevalence of severe iron overload at death in whites and blacks. We evaluated data and samples from 16,152 autopsies (8,484 whites, 7,668 blacks) performed at a single university hospital.
Methods
Cases of severe, multi-organ iron overload were identified by review of autopsy protocols and Perls-stained tissue specimens, analysis of hepatocyte and Kupffer cell iron levels, and measurement of liver tissue iron concentrations.
Results
We analyzed autopsy data from 10,345 adults (age ≥ 21 y), 1,337 children (1–20 y), and 4,470 infants (<1y). Iron overload without reports of excessive exogenous iron was observed in 18 adults; the prevalence in whites and blacks was 0.0019 and 0.0015, respectively (p = 0.6494). Twenty-nine adults and 2 children had iron overload with reports of excessive exogenous iron. In adults, the prevalences of iron overload with reports of excessive exogenous iron in whites and blacks were 0.0040 and 0.0013, respectively (p = 0.0107). Among adults, the prevalence of cirrhosis was 6-fold greater in those with iron overload. In adults with severe iron overload, 67% without reports of excessive exogenous iron and 14% with reports of excessive exogenous iron died of hepatic failure or cardiomyopathy due to siderosis. The overall prevalence of deaths due to severe iron overload in whites and blacks was 0.0021 and 0.0009, respectively (p = 0.0842).
Conclusions
The prevalence of severe iron overload without reports of excessive exogenous iron did not differ significantly between whites and blacks. The prevalence of iron overload with reports of excessive exogenous iron was greater in whites. Hepatic failure and cardiomyopathy were common causes of death in severe iron overload cases.
doi:10.1016/j.cgh.2009.03.016
PMCID: PMC3931257  PMID: 19306945
African Americans; hemochromatosis; cirrhosis
4.  HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 μg/L 
BACKGROUND:
Many patients referred for an elevated serum ferritin level <1000 μg/L are advised that they likely have iron overload and hemochromatosis.
AIMS:
To determine the prevalence of HFE mutations in the hemochromatosis gene for 11 serum ferritin concentration intervals from 200 μg/L to 1000 μg/L in Caucasian participants in a primary care, population-based study.
METHODS:
The Hemochromatosis and Iron Overload Screening study screened 99,711 participants for serum ferritin levels, transferrin saturation and genetic testing for the C282Y and H63D mutations of the HFE gene. This analysis was confined to 17,160 male and 27,465 female Caucasian participants because the HFE C282Y mutation is rare in other races. Post-test likelihood was calculated for prediction of C282Y homozygosity from a ferritin interval. A subgroup analysis was performed in participants with both an elevated serum ferritin level and transferrin saturation.
RESULTS:
There were 3359 male and 2416 female participants with an elevated serum ferritin level (200 μg/L to 1000 μg/L for women, 300 μg/L to 1000 μg/L for men). There were 69 male (2.1%) and 87 female (3.6%) C282Y homozygotes, and the probability of being a homozygote increased as the ferritin level increased. Post-test likelihood values were 0.3% to 16% in men and 0.3% to 30.4% in women.
CONCLUSIONS:
Iron loading HFE mutations are unlikely to be the most common cause of an elevated serum ferritin level in patients with mild hyperferritinemia. Patients should be advised that there are many causes of an elevated serum ferritin level including iron overload.
PMCID: PMC3956024  PMID: 23862168
Ferritin; Haemochromatosis; Hemochromatosis; Iron overload
5.  Characteristics of participants with self-reported hemochromatosis or iron overload at HEIRS Study initial screening 
American journal of hematology  2008;83(2):126-132.
There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25–29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.
doi:10.1002/ajh.21053
PMCID: PMC3773364  PMID: 17726683
6.  Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African-Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study 
Blood cells, molecules & diseases  2007;38(3):247-252.
The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥300 μg/L in men and ≥200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P = 0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P = 0.047); corresponding differences were not observed among women. This appeared to be unrelated to self-reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P = 0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF.
doi:10.1016/j.bcmd.2006.12.002
PMCID: PMC3727273  PMID: 17276706
genetics; mutation; transferrin saturation
7.  Effects of Highly Conserved Major Histocompatibility Complex (MHC) Extended Haplotypes on Iron and Low CD8+ T Lymphocyte Phenotypes in HFE C282Y Homozygous Hemochromatosis Patients from Three Geographically Distant Areas 
PLoS ONE  2013;8(11):e79990.
Hereditary Hemochromatosis (HH) is a recessively inherited disorder of iron overload occurring commonly in subjects homozygous for the C282Y mutation in HFE gene localized on chromosome 6p21.3 in linkage disequilibrium with the human leukocyte antigen (HLA)-A locus. Although its genetic homogeneity, the phenotypic expression is variable suggesting the presence of modifying factors. One such genetic factor, a SNP microhaplotype named A-A-T, was recently found to be associated with a more severe phenotype and also with low CD8+T-lymphocyte numbers. The present study aimed to test whether the predictive value of the A-A-T microhaplotype remained in other population settings. In this study of 304 HH patients from 3 geographically distant populations (Porto, Portugal 65; Alabama, USA 57; Nord-Trøndelag, Norway 182), the extended haplotypes involving A-A-T were studied in 608 chromosomes and the CD8+ T-lymphocyte numbers were determined in all subjects. Patients from Porto had a more severe phenotype than those from other settings. Patients with A-A-T seemed on average to have greater iron stores (p = 0.021), but significant differences were not confirmed in the 3 separate populations. Low CD8+ T-lymphocytes were associated with HLA-A*03-A-A-T in Porto and Alabama patients but not in the greater series from Nord-Trøndelag. Although A-A-T may signal a more severe iron phenotype, this study was unable to prove such an association in all population settings, precluding its use as a universal predictive marker of iron overload in HH. Interestingly, the association between A-A-T and CD8+ T-lymphocytes, which was confirmed in Porto and Alabama patients, was not observed in Nord-Trøndelag patients, showing that common HLA haplotypes like A*01–B*08 or A*03–B*07 segregating with HFE/C282Y in the three populations may carry different messages. These findings further strengthen the relevance of HH as a good disease model to search for novel candidate loci associated with the genetic transmission of CD8+ T-lymphocyte numbers.
doi:10.1371/journal.pone.0079990
PMCID: PMC3839968  PMID: 24282517
8.  Tumor necrosis factor-alpha promoter variants and iron phenotypes in 785 Hemochromatosis and Iron Overload Screening (HEIRS) Study participants 
Blood cells, molecules & diseases  2010;44(4):10.1016/j.bcmd.2010.01.007.
We sought to determine if TNF promoter variants could explain iron phenotype heterogeneity in adults with previous HFE genotyping. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened the TNF promoter region in each participant. We performed multiple regression analyses in C282Y homozygotes using age, sex, HEIRS Study Field Center, and positivity for TNF −308G→A and −238G→A to determine if these attributes predicted ln TS or ln SF. DHPLC analyses were successful in 99.3% of 791 participants and detected 9 different variants; TNF −308G→A and −238G→A were the most prevalent. Most subjects positive for variants were heterozygous. The phenotype frequencies of each variant did not differ significantly (p <0.05) across subgroups of C282Y homozygotes, or across white, black, Hispanic, and Asian non-C282Y homozygotes subgrouped as high TS/SF phenotypes and controls. TNF −308G→A positivity was a significant predictor of initial screening ln TS but not ln SF; TNF −238G→A predicted neither ln TS nor ln SF. We conclude that TNF promoter variants have little, if any, effect on initial screening SF values in adults with or without C282Y homozygosity. We cannot exclude a possible association of homozygosity for TNF promoter variants on TS and SF values.
doi:10.1016/j.bcmd.2010.01.007
PMCID: PMC3836206  PMID: 20178892
iron; iron overload; hemochromatosis; phenotype; tumor necrosis factor
9.  Heritability of Serum Iron Measures in the Hemochromatosis and Iron Overload Screening (HEIRS) Family Study 
American journal of hematology  2010;85(2):10.1002/ajh.21585.
Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation.
doi:10.1002/ajh.21585
PMCID: PMC3816512  PMID: 20095037
HFE; familial aggregation; transferrin saturation; serum ferritin concentration
10.  Predictors of shingles reports at diagnosis of common variable immunodeficiency and selective immunoglobulin G subclass deficiency in 212 Alabama adults 
Infectious Disease Reports  2012;4(2):e34.
We sought to determine predictors of shingles reports in adults with common variable immunodeficiency or immunoglobulin (Ig) G subclass deficiency (CVID/IgGSD). We tabulated observations at diagnosis of CVID/IgGSD in 212 white adult index patients (165 women, 47 men) who responded to a question about having had shingles. None had been vaccinated for herpes zoster. We analyzed age, sex, and shingles reports; blood levels of CD19+, CD4+, CD8+, and CD56+ mononuclear cells; serum levels of IgG subclasses, IgA, and IgM; and positivity for human leukocyte antigen (HLA)-A and -B haplotypes. Cell counts and immunoglobulin levels were normalized with loge (ln) transformation for analyses. Thirty-one patients (14.6%) reported shingles; 11 reported recurrent or disseminated shingles. Patients with shingles reports had greater mean age at diagnosis of CVID/IgGSD [54±13 (standard deviation) years vs. 47±12 years; P=0.0130] and a greater prevalence of HLA-A*01, B*08 positivity (35.5% vs. 17.7%; P=0.0227). In a 13-factor logistic regression model, there was a positive association of age with shingles reports [P=0.0151; odds ratio (1.05, 95% confidence interval 1.01, 1.08)]. HLA-A*01, B*08 positivity was also positively associated with shingles reports [P=0.0480; odds ratio 2.61 (1.00, 6.81)]. During a mean followup interval of 7.5 years after CVID/IgGSD diagnosis, the prevalence of recurrent shingles was almost five-fold greater in patients with previous shingles reports. In conclusion, in white adults at CVID/IgGSD diagnosis, age at diagnosis and positivity for HLA-A*01, B*08 have significant positive associations with reports of previous shingles.
doi:10.4081/idr.2012.e34
PMCID: PMC3892630  PMID: 24470948
herpes zoster; human leukocyte antigen; hypogammaglobulinemia; immune deficiency.
11.  Bivariate mixture modeling of transferrin saturation and serum ferritin concentration in Asians, African Americans, Hispanics, and whites in the Hemochromatosis and Iron Overload Screening (HEIRS) Study 
Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43–82 μg/L for women, 165–242 μg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 μg/L for women (<47 μg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9–47.5 for women, 60.6–3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4–1.8 for women, 1.2–1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement.
doi:10.1016/j.trsl.2007.10.002
PMCID: PMC3785302  PMID: 18201677
12.  Accuracy of Family History of Hemochromatosis or Iron Overload: The Hemochromatosis and Iron Overload Screening Study 
Background & Aims
The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload.
Methods
A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload.
Results
The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41–28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53–38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload.
Conclusions
Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis.
doi:10.1016/j.cgh.2008.04.003
PMCID: PMC3779058  PMID: 18585964
13.  Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population 
American journal of hematology  2008;83(8):618-626.
How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores.
doi:10.1002/ajh.21179
PMCID: PMC3773165  PMID: 18429050
14.  Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the HEIRS Study 
Hepatology (Baltimore, Md.)  2012;55(6):1722-1726.
Background
Hemochromatosis is considered by many to be an uncommon disorder, although the prevalence of HFE C282Y homozygosity is relatively high in Caucasians. Liver disease is one of the most consistent findings in advanced iron overload due to hemochromatosis. Liver clinics are often thought to be ideal venues for diagnosis of hemochromatosis, but diagnosis rates are often low.
Methods
The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 99, 711 primary care participants in North America for iron overload using serum ferritin and transferrin saturation measurements and HFE genotyping. In this HEIRS substudy, serum hepatic transaminases activities (ALT, AST) were compared between 162 C282Y homozygotes and 1,367 non-homozygotes with a serum ferritin > 300 μg/L in men and > 200 μg/L in women and transferrin saturation > 45 % in women and 50 % in men. The probability of being a C282Y homozygote was determined for AST and ALT ranges.
Results
Mean ALT and AST activities were significantly lower in C282Y homozygotes than non-homozygotes. The probability of being a C282Y homozygote increased as the ALT and AST activities decreased.
Conclusions
Patients with hyperferritinemia are more likely to be C282Y homozygotes if they have normal liver transaminase activities. This paradox could explain the low yields of hemochromatosis screening reported by some liver clinics.
doi:10.1002/hep.25538
PMCID: PMC3355194  PMID: 22183642
15.  Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation 
BACKGROUND:
HFEC282Y homozygotes have an increased risk for developing increased iron stores and related disorders. It is controversial whether dietary iron restrictions should be recommended to such individuals.
OBJECTIVE:
To determine whether dietary iron content influences iron stores in HFEC282Y homozygotes as assessed by serum ferritin concentration.
DESIGN:
Serum ferritin concentration was measured and a dietary iron questionnaire was completed as part of the evaluation of 213 HFEC282Y homozygotes who were identified through screening of >100,000 primary care patients at five HEmochromatosis and IRon Overload Screening (HEIRS) Study Field Centers in the United States and Canada.
RESULTS:
No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.
CONCLUSION:
These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.
PMCID: PMC3378281  PMID: 22720276
Haemochromatosis; Hemochromatosis; Iron overload; Iron supplementation
16.  Common TMPRSS6 mutations and iron, erythrocyte, and pica phenotypes in 48 women with iron deficiency or depletion 
Blood cells, molecules & diseases  2012;48(2):124-127.
Background
TMPRSS6 A736V is associated with lower transferrin saturation (TS), hemoglobin (Hb), and mean corpuscular volume (MCV) levels in general adult populations. We sought to identify relationships of TMPRSS6 K253E, A736V, and Y739Y to iron, erythrocyte, and pica phenotypes in women with iron deficiency or depletion.
Methods
We tabulated observations on 48 outpatient non-pregnant women who had iron deficiency (serum ferritin (SF) <14 pmol/L and TS <10%) or iron depletion (SF<112 pmol/L). We performed direct sequencing of TMPRSS6 exons 7 and 17 in each patient. We used age, TS, SF, Hb, MCV, pica, and TMPRSS6 allele positivity (dichotomous) or mutation genotypes (trichotomous) as variables for analyses.
Results
Forty-six women were white; two were black. 58.3% had iron deficiency. 45.8% had pica (pagophagia, each case). Allele frequencies were 41.7% (K253E), 36.5% (A736V), and 39.6% (Y739Y). K253E frequency was greater in women with TS ≥10% (p = 0.0001). Y739Y was more frequent in women with TS <10% (p = 0.0135). Mean TS was also lower in women positive for Y739Y (6 ± 4% vs. 13 ± 16%, respectively; p = 0.0021). In multiple regressions, neither K253E, A736V, nor Y739Y genotypes were significantly associated with other variables.
Conclusions
TMPRSS6 K253E frequency was greater in women with TS ≥10%. Frequency of Y739 was greater in women with TS <10%. Mean TS was lower in women with Y739Y. We observed no other significant relationship of TMPRSS6 K253E, A736V, or Y739Y with iron, erythrocyte, or pica phenotypes.
doi:10.1016/j.bcmd.2011.12.003
PMCID: PMC3271795  PMID: 22265928
hemoglobin; iron absorption; matriptase-2; mean corpuscular volume; pagophagia; pica
17.  Thyroid-Stimulating Hormone and Free Thyroxine Levels in Persons with HFE C282Y Homozygosity, a Common Hemochromatosis Genotype: The HEIRS Study 
Thyroid  2008;18(8):831-838.
Background
Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care–based Hemochromatosis and Iron Overload Screening (HEIRS) Study.
Methods
We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU/L and free T4 <0.70 ng/dL, and hyperthyroidism as having TSH <0.400 mIU/L and free T4 >1.85 ng/dL. Multivariate analyses were performed using age, sex, Field Center, log10 serum ferritin (SF), HFE genotype, log10 TSH, and log10 free T4.
Results
Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log10 SF with log10 free T4 were positive (p = 0.2368, C282Y homozygotes; p = 0.0492, controls). Independent predictors of log10 free T4 were log10 TSH (negative association) and age (positive association); positive predictors of log10 SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly.
Conclusions
Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.
doi:10.1089/thy.2008.0091
PMCID: PMC2857452  PMID: 18651828
18.  Dupuytren’s Contracture in Alabama HFE Hemochromatosis Probands 
Background
Dupuytren’s contracture (DC) and HFE hemochromatosis occur in some of the same at-risk populations and present with similar comorbid conditions.
Methods
We estimated DC prevalence in two cohorts of white Alabama hemochromatosis probands (294 C282Y homozygotes, 67 C282Y/H63D compound heterozygotes) in a retrospective study. We performed logistic regressions on DC using the following independent variables: age, body mass index, heavy ethanol consumption, serum ferritin, elevated serum AST/ALT, non-alcoholic fatty liver disease, viral hepatitis, cirrhosis, and diabetes.
Results
One man and two women with C282Y homozygosity had DC (prevalence 1.02%; 95% CI 0.35%–2.96%). A man with C282Y/H63D had DC (prevalence 1.49%; 95% CI 0.26%–7.98%). DC occurred as an autosomal dominant trait in his kinship. In regression analyses, no single variable predicted DC. We observed no new DC cases after the diagnosis of hemochromatosis (mean follow-up 12.9 ± 7.5 years (1 SD), and 9.0 ± 5.1 years, respectively).
Conclusions
Our prevalence estimates of DC in white Alabama hemochromatosis probands are similar to those found in the white US population cohorts. DC risk was unrelated to the variables we studied.
doi:10.4137/CMAMD.S9935
PMCID: PMC3431974  PMID: 22952417
Dupuytren’s contracture; epidemiology; hemochromatosis; iron overload; prevalence
19.  SLC40A1 Q248H allele frequencies and Q248H-associated risk of non-HFE iron overload in persons of sub-Saharan African descent 
Blood cells, molecules & diseases  2007;39(2):206-211.
The ferroportin polymorphism SLC40A1 Q248H (exon 6, cDNA 744G→T; Gln248His) occurs in persons of sub-Saharan African descent with and without iron overload, and is associated with elevated serum ferritin concentrations (SF). However, the risk of iron overload associated with Q248H has not been defined. We tabulated previously reported Q248H allele frequency estimates in African Americans and Native Africans, and computed the risk of iron overload associated with Q248H in subjects who lacked HFE C282Y. The aggregate Q248H allele frequency in 1,038 African Americans in two cohorts from Alabama and one cohort each from Washington, D.C. and California was 0.0525 (95% CI: 0.0451, 0.0652); there was no significant difference in frequencies across these cohorts. The aggregate frequency in 259 Natives from southeast Africa in two cohorts was 0.0946 (95% CI: 0.0694, 0.1198); the difference between the frequencies of these cohorts was not significant. The aggregate Q248H frequencies in African Americans and Native Africans differed significantly (0.0525 vs. 0.0946, respectively; p = 0.0021). There were reports of 24 unrelated African Americans and 15 unrelated Native Africans without HFE C282Y who had iron overload. In African Americans, the odds ratio (OR) of Q248H-associated risk of iron overload using 610 C282Y-negative control subjects unselected for SF was 1.57 (95% CI: 0.52, 4.72; p = 0.29). In Native Africans, the OR using 208 control subjects unselected for SF was 1.05 (95% CI: 0.28, 3.90; p = 0.58). We conclude that the frequency of SLC40A1 Q248H is significantly lower in African Americans than in Native Africans. Although OR estimates of iron overload in African Americans and Native Africans with Q248H were greater than unity, the increased OR were not statistically significant.
doi:10.1016/j.bcmd.2007.03.008
PMCID: PMC1986732  PMID: 17490902
ferroportin; genetics; hemojuvelin A310G; mutation
20.  Pica associated with iron deficiency or depletion: clinical and laboratory correlates in 262 non-pregnant adult outpatients 
BMC Blood Disorders  2010;10:9.
Background
There are many descriptions of the association of pica with iron deficiency in adults, but there are few reports in which observations available at diagnosis of iron deficiency were analyzed using multivariable techniques to identify significant predictors of pica. We sought to identify clinical and laboratory correlates of pica in adults with iron deficiency or depletion using univariable and stepwise forward logistic regression analyses.
Methods
We reviewed charts of 262 non-pregnant adult outpatients (ages ≥18 y) who required treatment with intravenous iron dextran. We tabulated their sex, age, race/ethnicity, body mass index, symptoms and causes of iron deficiency or depletion, serum iron and complete blood count measures, and other conditions at diagnosis before intravenous iron dextran was administered. We excluded patients with serum creatinine >133 μmol/L or disorders that could affect erythrocyte or iron measures. Iron deficiency was defined as both SF <45 pmol/L and TS <10%. Iron depletion was defined as serum ferritin (SF) <112 pmol/L. We performed univariable comparisons and stepwise forward logistic regression analyses to identify significant correlates of pica.
Results
There were 230 women (184 white, 46 black; ages 19-91 y) and 32 men (31 white, 1 black; ages 24-81 y). 118 patients (45.0%) reported pica; of these, 87.3% reported ice pica (pagophagia). In univariable analyses, patients with pica had lower mean age, black race/ethnicity, and higher prevalences of cardiopulmonary and epithelial manifestations. The prevalence of iron deficiency, with or without anemia, did not differ significantly between patients with and without pica reports. Mean hemoglobin and mean corpuscular volume (MCV) were lower and mean red blood cell distribution width (RDW) and platelet count were higher in patients with pica. Thrombocytosis occurred only in women and was more prevalent in those with pica (20.4% vs. 8.3%; p = 0.0050). Mean total iron-binding capacity was higher and mean serum ferritin was lower in patients with pica. Nineteen patients developed a second episode of iron deficiency or depletion; concordance of recurrent pica (or absence of pica) was 95%. Predictors of pica in logistic regression analyses were age and MCV (negative associations; p = 0.0250 and 0.0018, respectively) and RDW and platelet count (positive associations; p = 0.0009 and 0.02215, respectively); the odds ratios of these predictors were low.
Conclusions
In non-pregnant adult patients with iron deficiency or depletion, lower age is a significant predictor of pica. Patients with pica have lower MCV, higher RDW, and higher platelet counts than patients without pica.
doi:10.1186/1471-2326-10-9
PMCID: PMC3022645  PMID: 21176208
21.  Potential Nonresponse Bias in a Clinical Examination After Initial Screening Using Iron Phenotyping and HFE Genotyping in the Hemochromatosis and Iron Overload Screening Study 
Background: Little is known about the factors affecting participation in clinical assessments after HEmochromatosis and IRon Overload Screening. Methods: Initial screening of 101,168 primary care patients in the HEmochromatosis and IRon Overload Screening study was performed using serum iron measures and hemochromatosis gene (HFE) genotyping. Using iron phenotypes and HFE genotypes, we identified 2256 cases and 1232 controls eligible to participate in a clinical examination. To assess the potential for nonresponse bias, we compared the sociodemographic, health status, and attitudinal characteristics of participants and nonparticipants using adjusted odds ratios (ORs) and 95% confidence interval (CI). Results: Overall participation was 74% in cases and 52% in controls; in both groups, participation was highest at a health maintenance organization and lowest among those under 45 years of age (cases: OR = 0.68; 95% CI 0.53, 0.87; controls: OR = 0.59; 95% CI 0.44, 0.78). In controls only, participation was also lower among those over 65 years of age than the reference group aged 46–64 (OR = 0.64; 95% CI 0.47, 0.88). Among cases, participation was higher in HFE C282Y homozygotes (OR = 3.98; 95% CI 2.60, 6.09), H63D homozygotes (OR = 2.79; 95% CI 1.23, 6.32), and C282Y/H63D compound heterozygotes (OR = 1.82; 95% CI 1.03, 3.22) than in other genotypes, and lower among non-Caucasians and those who preferred a non-English language than in Caucasians and those who preferred English (p < 0.0001). Conclusions: Subjects with greatest risk to have iron overload (C282Y homozygotes; cases ≥45 years; Caucasians) were more likely to participate in a postscreening clinical examination than other subjects. We detected no evidence of strong selection bias.
doi:10.1089/gtmb.2009.0003
PMCID: PMC2935839  PMID: 19860558
22.  Screening for iron overload: Lessons from the HEmochromatosis and IRon Overload Screening (HEIRS) Study 
BACKGROUND:
The HEmochromatosis and IRon Overload Screening (HEIRS) Study provided data on a racially, ethnically and geographically diverse cohort of participants in North America screened from primary care populations.
METHODS:
A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations, and measuring serum ferritin concentration and transferrin saturation. In the present review, lessons from the HEIRS Study are highlighted in the context of the principles of screening for a medical disease as previously outlined by the World Health Organization.
RESULTS:
Genetic testing is well accepted, with minimal risk of discrimination. Transferrin saturation has high biological variability and relatively low sensitivity to detect HFE C282Y homozygotes, which limits its role as a screening test. Symptoms attributable to HFE C282Y homozygosity are no more common in individuals identified by population screening than in control subjects.
CONCLUSIONS:
Generalized population screening in a primary care population as performed in the HEIRS Study is not recommended. There may be a role for focused screening in Caucasian men, with some debate regarding genotyping followed by phenotyping, or phenotyping followed by genotyping.
PMCID: PMC2777090  PMID: 19893773
Haemochromatosis; Hemochromatosis; HFE; Iron overload
23.  Differences in Hepatic Phenotype Between Hemochromatosis Patients with HFE C282Y Homozygosity and Other HFE Genotypes 
Objective
There are limited data comparing hepatic phenotype among hemochromatosis patients with different HFE genotypes. The goal of this study was to compare hepatic histopathologic features and hepatic iron concentration (HIC) among patients with phenotypic hemochromatosis and different HFE genotypes.
Methods
We studied 182 U.S. patients with phenotypic hemochromatosis. Degree of hepatic fibrosis, pattern of iron deposition, presence of steatosis or necroinflammation, and HIC were compared among different HFE genotypes.
Results
C282Y/H63D compound heterozygotes and patients with HFE genotypes other than C282Y/C282Y were more likely to have stainable Kupffer cell iron (31.1% vs 9.5%; p=0.02), portal or lobular inflammation (28.9% vs 15.6%; p=0.03) and steatosis (33.3% vs 10.2%; p<0.01) on liver biopsy than C282Y homozygotes. Mean log10 HIC (p<0.05) and log10 ferritin (p<0.05) were higher among C282Y homozygotes than in patients with other HFE genotypes. In a logistic regression analysis using age, gender, HFE genotype, log10 ferritin, and log10 HIC as independent variables, log10 SF (p = 0.0008), male sex (p = 0.0086), and log10 HIC (p=0.047), but not HFE genotype (p = 0.0554) were independently associated with presence or absence of advanced hepatic fibrosis.
Conclusions
C282Y/H63D compound heterozygotes and other non-C282Y homozygotes who express the hepatic hemochromatosis phenotype frequently have evidence of steatosis or chronic hepatitis and lower body iron stores than C282Y homozygotes. These data suggest that presence of concomitant liver disease may explain expression of the hemochromatosis phenotype among non-C282Y homozygotes. Increased age, HIC and ferritin are associated with advanced hepatic fibrosis, regardless of HFE genotype.
doi:10.1097/MCG.0b013e3181919a33
PMCID: PMC2700181  PMID: 19359997
24.  Heme carrier protein 1 (HCP1) genetic variants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study participants 
Blood cells, molecules & diseases  2009;42(2):150-154.
Heme carrier protein 1 (HCP1) has been identified as a possible heme carrier by in vitro analysis. To determine the association of mutations within the HCP1 gene with iron phenotypes, we examined the entire coding region of the HCP1 gene in 788 US and Canadian participants selected from the Hemochromatosis and Iron Overload Screening (HEIRS) Study using denaturing high-performance liquid chromatography. We sequenced the exon and flanking intronic regions if variants were detected. We tested 298 non-C282Y homozygotes from four racial/ethnic backgrounds (White, Black, Asian, and Hispanic) selected because they had high serum ferritin (SF) and transferrin saturations (TS). As controls, we chose 300 other random participants of the same racial/ethnic backgrounds from the same geographic locations. From the 333 HEIRS Study C282Y homozygotes, we selected 75 based on high SF and TS, 75 based on low SF and TS; 75 were selected randomly as controls. Thirty-five of the randomly selected C282Y homozygotes were also included in the high and the low SF and TS groups due to numerical limitations. We identified eight different HCP1 genetic variants; each occurred in a heterozygous state. Except one, each was found in a single HEIRS Study participant. Thus, HCP1 variants are infrequent in the populations that we tested. Five HEIRS Study participants had non-synonymous, coding region HCP1 variants. Each of these five had TS above the 84th gender- and ethnic/racial group-specific percentile (TS percentiles: 84.7, 91.3, 97.9, 99.5, and 99.9).
doi:10.1016/j.bcmd.2008.11.003
PMCID: PMC2710880  PMID: 19176287
25.  Purification and Characterization of Sideroblasts from Patients with Acquired and Hereditary Sideroblastic Anemia 
British journal of haematology  2008;143(3):446-450.
doi:10.1111/j.1365-2141.2008.07358.x
PMCID: PMC2603068  PMID: 18729851
sideroblastic anemia; iron overload; mitochondria; oxidative stress; MDS

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