IgG subclass levels in referred hemochromatosis probands with HFE p.C282Y/p.C282Y.

BACKGROUND: IgG subclass levels in hemochromatosis are incompletely characterized. METHODS: We characterized IgG subclass levels of referred hemochromatosis probands with HFE p.C282Y/p.C282Y (rs1800562) and human leukocyte antigen (HLA)-A and -B typing/haplotyping and compared them with IgG subclass levels of eight published cohorts of adults unselected for hemochromatosis. RESULTS: There were 157 probands (82 men, 75 women; mean age 49±13 y). Median serum ferritin, mean body mass index (BMI), median IgG4, and median phlebotomy units to achieve iron depletion were significantly higher in men. Diabetes, cirrhosis, and HLA-A*03,-B*44, -A*03,B*07, and -A*01,B*08 prevalences and median absolute lymphocyte counts in men and women did not differ significantly. Mean IgG subclass levels [95% confidence interval] were: IgG1 5.31 g/L [3.04, 9.89]; IgG2 3.56 g/L [1.29, 5.75]; IgG3 0.61 g/L [0.17, 1.40]; and IgG4 0.26 g/L [<0.01, 1.25]. Relative IgG subclasses were 54.5%, 36.6%, 6.3%, and 2.7%, respectively. Median IgG4 was higher in men than women (0.34 g/L [0.01, 1.33] vs. 0.19 g/L [<0.01, 0.75], respectively; p = 0.0006). A correlation matrix with Bonferroni correction revealed the following positive correlations: IgG1 vs. IgG3 (p<0.01); IgG2 vs. IgG3 (p<0.05); and IgG2 vs. IgG4 (p<0.05). There was also a positive correlation of IgG4 vs. male sex (p<0.01). Mean IgG1 was lower and mean IgG2 was higher in probands than seven of eight published adult cohorts unselected for hemochromatosis diagnoses. CONCLUSIONS: Mean IgG subclass levels of hemochromatosis probands were 5.31, 3.56, 0.61, and 0.26 g/L, respectively. Median IgG4 was higher in men than women. There were positive associations of IgG subclass levels. Mean IgG1 may be lower and mean IgG2 may be higher in hemochromatosis probands than adults unselected for hemochromatosis.

Height of non-Hispanic white adults with homeostatic iron regulator HFE genotypes p.C282Y/p.C282Y and wt/wt.

BACKGROUND: We sought to evaluate height in white adults with hemochromatosis. METHODS: We analyzed the height of (1) post-screening examination participants with HFE p.C282Y/p.C282Y (rs1800562) and wt/wt (absence of p.C282Y and p.H63D (rs1799945)) and (2) referred hemochromatosis probands with p.C282Y/p.C282Y. RESULTS: There were 762 participants (270 p.C282Y/p.C282Y, 492 wt/wt; 343 men, 419 women) and 180 probands (104 men, 76 women). Median height of male participants with p.C282Y/p.C282Y or wt/wt was 177.8 cm. Median height of female participants was greater in those with p.C282Y/p.C282Y than wt/wt (165.1 cm vs 162.6 cm, respectively; p = 0.0298). Median height of p.C282Y/p.C282Y participants and probands was the same (men 177.8 cm; women 165.1 cm). Regressions on height of male and female participants revealed no associations with HFE genotype and inverse and positive associations with age and weight, respectively. Height of female participants was positively and inversely associated with transferrin saturation and serum ferritin, respectively. Regressions on height of male and female probands revealed positive associations with weight. CONCLUSIONS: The height of men with HFE p.C282Y/p.C282Y and wt/wt does not differ significantly. The height of female participants was greater in those with p.C282Y/p.C282Y than wt/wt. We found no independent association of HFE genotype with the height of men or women.

Quantifying microcyte and macrocyte percentages in archived red blood cell volume histogram images.

INTRODUCTION: We sought to quantify percentages of microcytes and macrocytes in archived automated hematology analyzer (AHA) red blood cell (RBC) volume histogram images. METHODS: In preliminary studies, we demonstrated that an on-line application of Gauss' area formula (SketchAndCalc™) measured percentage areas of 20 segments under a computer-generated normal distribution curve (-3.0 standard deviations [SD] to +3.0 SD) with accuracy and precision (Pearson's correlation of measured areas with corresponding theoretical areas r [20] = 0.9962 [p < 0.0001]). Thus, we used SketchAndCalc™ to quantify percentages of microcytes (50-80 fL) and macrocytes (110-200 fL) in archived AHA histogram images in women with previously untreated iron-deficiency anemia (IDA) and previously untreated hemochromatosis. RESULTS: Median microcyte percentages in 13 women with IDA and 13 women with hemochromatosis were 63.6% (range 13.5-76.8) and 6.7% (range 3.4-24.8), respectively (p < 0.0001). Mean macrocyte percentages in women with IDA and hemochromatosis were 8.8% ± 6.1 SD and 33.8% ± 11.7 SD, respectively (p < 0.0001). Spearman's correlations of microcyte percentages with macrocyte percentages, mean corpuscular volume, and mean corpuscular hemoglobin in 26 women were rs [26] = -0.9485, rs [26] = -0.9641, and rs [26] = -0.9036, respectively (each p < 0.0001). CONCLUSIONS: This method of quantifying microcyte and macrocyte percentages could enable other studies of RBC volume subpopulations in archived AHA histogram images.

Platelet counts in HFE p.C282Y/p.C282Y and wt/wt post-screening clinical evaluation participants.

Our aim was to document the effects of genotype HFE p.C282Y/p.C282Y and hemochromatosis-associated laboratory and clinical manifestations on platelet counts (PC). We compiled genotype (p.C282Y/p.C282Y or HFE wt/wt (absence of p.C282Y and p.H63D (rs1799945)), age, sex, body mass index, presence/absence of chronic fatigue, swelling/tenderness of second/third metacarpophalangeal joints, and hyperpigmentation, transferrin saturation (TS), serum ferritin (SF), hemoglobin levels, absolute neutrophil, lymphocyte, and monocyte counts, C-reactive protein levels, and PC of non-Hispanic white participants in a hemochromatosis and iron overload post-screening clinical examination. There were 171 men and 254 women (141 p.C282Y/p.C282Y, 284 wt/wt) of median age 53 y. Median TS and SF were higher in p.C282Y/p.C282Y than wt/wt participants grouped by sex (p < .0001, all comparisons). Median PC by genotype was lower in men than women (p < .0001, both comparisons). Regression on PC using 14 independent variables identified these significant positive associations: absolute neutrophil, lymphocyte, and monocyte counts and C-reactive protein levels and these significant inverse associations: age, TS, and hemoglobin levels. We conclude that PC is significantly associated with absolute neutrophil, lymphocyte, and monocyte counts, and C-reactive protein (positive) and age, TS, and hemoglobin (inverse), after adjustment for other variables. HFE genotypes we studied were not significantly associated with PC.

What is the context? Hemochromatosis is typically associated with inheritance of two copies of p.C282Y, a common mutation of the HFE gene on chromosome 6p that regulates iron absorption.Platelet counts, age, and serum levels of liver enzymes have been used to estimate risks of cirrhosis in adults with hemochromatosis.Lower platelet counts in Europeans are significantly associated with a mutation in CARMIL1, a gene on chromosome 6p close to HFE.Clinical and laboratory associations of normal platelet counts in adults with HFE p.C282Y/p/C282Y and wt/wt uncomplicated by cirrhosis are unreported.What is new? We studied normal platelet counts in 425 white adults who participated in a primary care-based hemochromatosis screening program. These participants did not have cirrhosis or other conditions that often influence platelet counts.Our analyses of 14 variables identified these significant positive associations with platelet counts, after adjustment for other variables: absolute neutrophil, lymphocyte, and monocyte counts and C-reactive protein levels; and these significant inverse associations: age, TS, and hemoglobin levels.What is the impact? Laboratory and clinical factors significantly associated with platelet counts in adults with HFE p.C282/p.C282Y or wt/wt are similar to those in persons unselected for HFE genotypes or hemochromatosis.It is unlikely that genes that influence platelet counts are closely linked to HFE on chromosome 6p.Adults with hemochromatosis and HFE p.C282/p.C282Y who have abnormal platelet counts should be evaluated for cirrhosis or non-iron platelet disorders.

Non-alcoholic fatty liver disease in hemochromatosis probands with iron overload and HFE p.C282Y/p.C282Y.

BACKGROUND: The aim of this study was to identify characteristics of non-alcoholic fatty liver disease (NAFLD) in adults with HFE p.C282Y/p.C282Y. METHODS: We retrospectively studied non-Hispanic white hemochromatosis probands with iron overload (serum ferritin (SF) > 300 µg/L (M), > 200 µg/L (F)) and p.C282Y/p.C282Y at non-screening diagnosis who did not report alcohol consumption > 14 g/d, have cirrhosis or other non-NAFLD liver disorders, use steatogenic medication, or have diagnoses of heritable disorders that increase NAFLD risk. We identified NAFLD-associated characteristics using univariate and multivariable analyses. RESULTS: There were 66 probands (31 men, 35 women), mean age 49 ± 14 (SD) y, of whom 16 (24.2%) had NAFLD. The following characteristics were higher in probands with NAFLD: median SF (1118 µg/L (range 259, 2663) vs. 567 µg/L (247, 2385); p = 0.0192); prevalence of elevated ALT/AST (alanine/aspartate aminotransferase) (43.8% vs. 10.0%; p = 0.0056); and prevalence of type 2 diabetes (T2DM) (31.3% vs. 10.0%; p = 0.0427). Mean age, sex, and prevalences of human leukocyte antigen-A*03 positivity, body mass index ≥ 30.0 kg/m2, hyperlipidemia, hypertension, and metabolic syndrome in probands with/without NAFLD did not differ significantly. Logistic regression on NAFLD using variables SF, elevated ALT/AST, and T2DM revealed: SF (p = 0.0318; odds ratio 1.0-1.0) and T2DM (p = 0.0342; 1.1-22.3). Median iron removed to achieve iron depletion (QFe) in probands with/without NAFLD did not differ significantly (3.6 g (1.4-7.2 g) vs. 2.8 g (0.7-11.0 g), respectively; p = 0.6862). CONCLUSIONS: NAFLD in hemochromatosis probands with p.C282Y/p.C282Y is associated with higher median SF and greater T2DM prevalence, after adjustment for other factors. NAFLD does not influence QFe significantly.

Iron overload phenotypes and HFE genotypes in white hemochromatosis and iron overload screening study participants without HFE p.C282Y/p.C282Y.

BACKGROUND: Screening program participants with iron overload (IO) phenotypes without HFE p.C282Y/p.C282Y are incompletely characterized. METHODS: We studied white participants who had IO phenotypes without p.C282Y/p.C282Y in post-screening clinical examinations (CE). We defined IO phenotypes as a) elevated serum ferritin (SF) and transferrin saturation (TS) at screening and CE, and b) absence of IO treatment, anemia, transfusion >10 units, alcohol intake >30 g/d, hepatitis B or C, and pregnancy. We defined IO-related disease as elevated alanine or aspartate aminotransferase (ALT/AST) or swelling/tenderness of 2nd/3rd metacarpophalangeal (MCP) joints. All participants had HFE p.C282Y and p.H63D genotyping. RESULTS: There were 32 men and 26 women (mean age 54±16 y). Median food/supplemental iron intakes were 14.3/0.0 mg/d. Relative risks of HFE genotypes were 12.9 (p.C282Y/p.H63D), 3.0 (p.H63D/p.H63D), 1.9 (p.C282Y/wt), 0.9 (p.H63D/wt), and 0.5 (wt/wt) compared to 42,640 white screening participants without IO phenotypes or p.C282Y/p.C282Y. Regression on SF revealed positive associations: MCV (p = 0.0006; ß coefficient = 0.4531); swelling/tenderness of MCP joints (p = 0.0033; ß = 0.3455); and p.H63D/wt (p = 0.0015; ß = 0.4146). IO-related disease (18 elevated ALT/AST, one swelling/tenderness of MCP joints) occurred in 19 participants (7 men, 12 women). Median MCV was higher in participants with IO-related disease (97 fL vs. 94 fL; p = 0.0007). Logistic regression on IO-related disease revealed a significant association with diabetes (p = 0.0416; odds ratio 18.9 (95% confidence interval 1.0, 341.1)). CONCLUSIONS: In the present 58 screening program participants who had IO phenotypes without HFE p.C282Y/p.C282Y, relative risks of HFE genotypes p.C282Y/p.H63D, p.H63D/p.H63D, and p.C282Y/wt were significantly higher than in 42,640 white screening participants with neither IO phenotypes nor p.C282Y/p.C282Y. SF was significantly associated with MCV, swelling/tenderness of 2nd/3rd MCP joints, and p.H63D/wt. IO-related disease was significantly associated with MCV and diabetes.

HLA-A*03, the hemochromatosis ancestral haplotype, and phenotypes of referred hemochromatosis probands with HFE p.C282Y homozygosity.

BACKGROUND: Human leukocyte antigen (HLA)-A*03, hemochromatosis ancestral haplotype marker, was associated with greater iron overload in hemochromatosis cohorts reported before discovery of the HFE gene. We sought to learn whether an A*03-linked locus influences phenotypes in referred HFE p.C282Y homozygotes. METHODS: We tabulated these phenotypes in probands with p.C282Y homozygosity: age, transferrin saturation (TS), serum ferritin (SF), conditions related to iron overload, fibrosis-four variables (FIB-4) index and aspartate aminotransferase-to-platelet ratio index (APRI) predictors of severe hepatic fibrosis, and iron removed to achieve depletion (QFe/age). We analyzed phenotypes of men and women separately across three A*03 subgroups. RESULTS: There were 104 men (57.8%) and 76 women (42.2%). Mean age (SD) was 49 ± 13 y. Mean TS was 79 ± 17%. Median SF (range) was 715 µg/L (28, 6103). Related conditions included: hemochromatosis arthropathy (21.7%); type 2 diabetes (18.9%); hypogonadotropic hypogonadism (5.8% of men); cardiomyopathy (0%); and cirrhosis (10.0%). Median QFe/age was 61 mg/y (0, 714). A*03 homozygosity, heterozygosity, and no A*03 occurred in 37 (20.6%), 104 (57.8%), and 39 probands (21.7%), respectively. In men, mean TS and median SF were significantly higher in A*03 homozygotes than heterozygotes but not A*03-negative probands. In men, median APRI was significantly lower in A*03 heterozygotes than homozygotes and A*03-negative probands. No other phenotypes, including QFe/age, differed significantly across A*03 subgroups in either men or women. CONCLUSIONS: Our results suggest that an A*03-linked locus does not influence phenotypes in referred HFE p.C282Y homozygotes. It is unlikely that heritable factors that modify phenotypes of p.C282Y homozygotes are linked to the hemochromatosis ancestral haplotype.

Hydroxychloroquine Therapy and Serum Immunoglobulin Levels in Women with IgG Subclass Deficiency and Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis: A Retrospective Study.

Hydroxychloroquine (HCQ) therapy decreased immunoglobulin (Ig) levels in patients with Sjögren syndrome (SS) and rheumatoid arthritis (RA) in previous studies. We found no report of Ig levels of women with IgG subclass deficiency (IgGSD) and systemic lupus erythematosus (SLE), SS, or RA treated with HCQ. We retrospectively evaluated IgG, IgG subclass, IgA, and IgM levels and other characteristics of women at IgGSD diagnosis who did and did not take HCQ for SLE, SS, or RA. There were 132 women (48 subnormal IgG1 only, 49 combined subnormal IgG1/IgG3, and 35 subnormal IgG3 only). Mean age was 49 ± 13 years. Twenty-two women with SLE, SS, RA, or combination thereof reported HCQ ≥ 200 mg/day ≥ 6 months. In each IgGSD subtype, median Ig levels of women who took HCQ were not significantly lower than those of women who did not take HCQ. Women with combined subnormal IgG1/IgG3 who took HCQ had greater median IgG2 than women who did not take HCQ (4.89 g/L (range 4.43, 4.94) vs. 2.57 g/L (1.21, 6.44), respectively; p = 0.0123). Regressions on IgG1, IgG2, and IgG3 revealed positive associations with HCQ therapy (p = 0.0043, 0.0037, and 0.0139, respectively). There were no significant Ig associations with age, SLE, SS, or RA as independent variables. HCQ therapy of SLE, SS, or RA in women with IgGSD was not associated with significantly lower IgG, IgG subclass, IgA, or IgM levels. IgG1, IgG2, and IgG3 were positively associated with HCQ therapy, after adjustment for other variables.

Abdominal pain and cirrhosis at diagnosis of hemochromatosis: Analysis of 219 referred probands with HFE p.C282Y homozygosity and a literature review.

BACKGROUND: In hemochromatosis, causes of abdominal pain and its associations with cirrhosis are poorly understood. METHODS: We retrospectively compared characteristics of referred hemochromatosis probands with HFE p.C282Y homozygosity with/without biopsy-proven cirrhosis: sex, age, diabetes, heavy alcohol consumption, abdominal pain/tenderness, hepatomegaly, splenomegaly, non-alcoholic fatty liver disease, chronic viral hepatitis, ascites, transferrin saturation (TS), serum ferritin (SF), and iron removed by phlebotomy (QFe). We performed logistic regression on cirrhosis using characteristics identified in univariate comparisons. We performed computerized and manual searches to identify hemochromatosis case series and compiled prevalence data on cirrhosis and abdominal pain and causes of abdominal pain. RESULTS: Of 219 probands, 57.1% were men. Mean age was 48±13 y. In 22 probands with cirrhosis, proportions of men, mean age, prevalences of heavy alcohol consumption, abdominal pain, abdominal tenderness, hepatomegaly, splenomegaly, and chronic viral hepatitis, and median TS, SF, and QFe were significantly greater than in probands without cirrhosis. Regression analysis revealed three associations with cirrhosis: abdominal pain (p = 0.0292; odds ratio 9.8 (95% CI: 1.2, 76.9)); chronic viral hepatitis (p = 0.0153; 11.5 (95% CI: 1.6, 83.3)); and QFe (p = 0.0009; 1.2 (95% CI: 1.1, 1.3)). Of eight probands with abdominal pain, five had cirrhosis and four had diabetes. One proband each with abdominal pain had heavy alcohol consumption, chronic viral hepatitis B, hepatic sarcoidosis, hepatocellular carcinoma, and chronic cholecystitis, cholelithiasis, and sigmoid diverticulitis. Abdominal pain was alleviated after phlebotomy alone in four probands. In 12 previous reports (1935-2011), there was a negative correlation of cirrhosis prevalence and publication year (p = 0.0033). In 11 previous reports (1935-1996), a positive association of abdominal pain prevalence and publication year was not significant (p = 0.0802). CONCLUSIONS: Abdominal pain, chronic viral hepatitis, and QFe are significantly associated with cirrhosis in referred hemochromatosis probands with HFE p.C282Y homozygosity. Iron-related and non-iron-related factors contribute to the occurrence of abdominal pain.

Chromosome 6p SNP microhaplotypes and IgG3 levels in hemochromatosis probands with HFE p.C282Y homozygosity.

Subnormal IgG1 or IgG3 levels occurred in 30% of hemochromatosis probands with HFE p.C282Y homozygosity and were concordant in HLA-identical siblings. We sought to identify factors associated with IgG subclasses in Alabama probands with p.C282Y homozygosity evaluated for 500 kb microhaplotypes AAT and GGG defined by SNPs in chromosome 6p genes PGBD1, ZNF193, and ZNF165. In regressions on IgG subclasses, we used: age; sex; GGG (dichotomous); iron removed to achieve depletion; CD8+ T-lymphocytes; and other IgG subclasses. Among 49 probands, AAT and GGG occurred in 95.9% and 16.3%, respectively. Thirteen probands (26.5%) had subnormal IgG1; 11 probands (22.4%) had subnormal IgG3. Mean IgG3 was higher in probands with than without GGG (75 mg/dL [95% confidence interval 63, 89] vs. 58 mg/dL [49, 71], respectively; p = 0.0321). Regression on IgG3 revealed: GGG positivity (p = 0.0106); and IgG1 (p = 0.0015). In a replication cohort of 22 Portugal probands with p.C282Y homozygosity, mean IgG3 was higher in probands with than without GGG (46 ±â€¯16 vs. 31 ±â€¯12 mg/dL, respectively; p = 0.0410). We conclude that mean IgG3 levels are higher in hemochromatosis probands with p.C282Y homozygosity with chromosome 6p microhaplotype GGG than in probands homozygous for microhaplotype AAT.

Pneumococcal vaccination responses in adults with subnormal IgG subclass concentrations.

BACKGROUND: We sought to compare Pneumovax®23 responses in adults with subnormal IgG subclass concentrations. We studied adults with normal total IgG, frequent/severe respiratory infection, and subnormal IgG1, IgG3, or IgG1 + IgG3 before and after Pneumovax®23. We defined response as serotype-specific IgG > 1.3 µg/mL and aggregate response as IgG > 1.3 µg/mL for ≥70% of all serotypes tested. We compared patients with and without serotype-specific responses and performed logistic regression on aggregate responses using: age; male sex; body mass index; autoimmune condition(s); atopy; other allergies; subnormal IgGSc immunophenotypes; IgA; and IgM. RESULTS: There were 59 patients (mean age 44 ± 13 (SD) years; 83.1% women). Median days between pre- and post-Pneumovax®23 testing was 33 (range 19-158). The median post-vaccination summated concentration of serotype-specific IgG was higher in patients with subnormal IgG1 than subnormal IgG3 (responders and non-responders). All subnormal IgG1 + IgG3 non-responders responded to serotypes 8, 9 and 26, unlike other non-responders. Subnormal IgG3 responders had lower responses to serotypes 1, 4, 12, 23, 26, and 51. Subnormal IgG3 non-responders had higher responses to serotypes 1, 3, 8, 9, 12, 14, 19, 51, and 56. Response rates decreased with increasing age. Aggregate responders were: subnormal IgG1, 54%; IgG3, 46%; and IgG1 + IgG3, 46%. Regression on aggregate response revealed lower response with male sex (odds ratio 0.09 [95% CI 0.01, 0.77]) and atopy (0.17 [0.03, 0.83]). CONCLUSIONS: Serotype-specific IgG responses to Pneumovax®23 were greater in patients with subnormal IgG1 than subnormal IgG3. Male sex and atopy were associated with lower aggregate responses.

Prevalence and characteristics of anti-HCV positivity and chronic hepatitis C virus infection in HFE p.C282Y homozygotes.

INTRODUCTION AND AIM: Observations of hepatitis C virus (HCV) infection in adults with hemochromatosis are limited. MATERIALS AND METHODS: We determined associations of serum ferritin (SF) with anti-HCV in non-Hispanic white North American adults in a post-screening examination. Cases included p.C282Y homozygotes (regardless of screening transferrin saturation (TS) and SF) and participants (regardless of HFE genotype) with high screening TS/SF. Controls included participants without p.C282Y or p.H63D who had normal screening TS/SF. Participants with elevated alanine aminotransferase underwent anti-HCV testing. We determined prevalence of chronic HCV infection in consecutive Alabama and Ontario referred adults with HFE p.C282Y homozygosity. RESULTS: In post-screening participants, anti-HCV prevalence was 0.3% [95% CI: 0.02, 2.2] in 294 p.C282Y homozygotes, 9.5% [7.2, 12.3] in 560 Cases without p.C282Y homozygosity, and 0.7% [0.2, 2.3] in 403 Controls. Anti-HCV was detected in 7.2% of 745 participants with and 0.8% of 512 participants without elevated SF (odds ratio 9.9 [3.6, 27.6]; p<0.0001). Chronic HCV infection prevalence in 961 referred patients was 1.0% (10/961) [95% confidence interval (CI): 0.5, 2.0]. Ten patients with chronic HCV infection had median age 45y (range 29-67) and median SF 1163µg/L (range 303-2001). Five of eight (62.5%) patients had biopsy-proven cirrhosis. CONCLUSIONS: Odds ratio of anti-HCV was increased in post-screening participants with elevated SF. Prevalence of anti-HCV in post-screening participants with HFE p.C282Y homozygosity and chronic HCV infection in referred adults with HFE p.C282Y homozygosity in North America is similar to that of Control participants with HFE wt/wt and normal screening TS/SF.

Pagophagia in men with iron-deficiency anemia.

Few case series of pagophagia and iron deficiency include men. We performed a retrospective study of non-Hispanic white men with iron-deficiency anemia whose anemia and pagophagia, thrombocytosis, and thrombocytopenia (if present) resolved after iron replacement. Iron-deficiency anemia was defined as transferrin saturation (TS) <15%, serum ferritin (SF) <30 µg/L, and hemoglobin (Hb) <13.0 g/dL. We excluded men with: anemia, thrombocytosis, or thrombocytopenia due to non-iron-deficiency causes; malignancy; chronic inflammatory conditions; hemochromatosis; or creatinine >1.1 mg/dL. We computed univariate and multivariable pagophagia associations with: age; gastrointestinal bleeding; TS; SF; Hb; red blood cell (RBC) count; mean corpuscular volume (MCV); RBC distribution width (RDW); and platelet count. Median age of 41 men was 54 y (range 18-81). Fourteen men (34.1%) had pagophagia. Thirty-six men (87.8%) had gastrointestinal bleeding. Mean Hb was 9.4 ±â€¯2.2 g/dL. Six men (14.6%) had thrombocytosis; two (4.9%) had thrombocytopenia. Logistic regression on pagophagia revealed: age (p = 0.0158; odds ratio 0.92 [95% confidence interval: 0.85, 0.99]) and platelet count (p = 0.0187; 0.98 [0.97, 1.00]) (41.4% of pagophagia occurrence; ANOVA p = 0.0053). We conclude that pagophagia occurred in 34% of men with iron-deficiency anemia and was negatively associated with age and platelet count, after adjustment for other variables.

Clinical and Laboratory Associations with Persistent Hyperferritinemia in 373 Black Hemochromatosis and Iron Overload Screening Study Participants.

BACKGROUND: 373 black participants had elevated screening and post-screening serum ferritin (SF) (> 300 µg/L men; > 200 µg/L women). MATERIAL AND METHODS: We retrospectively studied SF and post-screening age; sex; body mass index; transferrin saturation (TS); ALT; AST; GGT; elevated C-reactive protein; ß-thalassemia; neutrophils; lymphocytes; monocytes; platelets; metacarpophalangeal joint hypertrophy; hepatomegaly; splenomegaly; diabetes; HFE H63D positivity; iron/alcohol intakes; and blood/erythrocyte transfusion units. Liver disease was defined as elevated ALT or AST. We computed correlations of SF and TS with: age; body mass index; ALT; AST; GGT; C-reactive protein; blood cell counts; and iron/alcohol. We compared participants with SF > 1,000 and ≤ 1,000 µg/L and performed regressions on SF. RESULTS: There were 237 men (63.5%). Mean age was 55 ± 13 (SD) y. 143 participants had liver disease (62 hepatitis B or C). There were significant correlations of SF: TS, ALT, AST, GGT, and monocytes (positive); and SF and TS with platelets (negative). 22 participants with SF > 1,000 µg/L had significantly higher median TS, ALT, and AST, and prevalences of anemia and transfusion > 10 units; and lower median platelets. Regression on SF revealed significant associations: TS; male sex; age; GGT; transfusion units (positive); and splenomegaly (negative) (p < 0.0001, 0.0016, 0.0281, 0.0025, 0.0001, and 0.0096, respectively). Five men with SF > 1,000 µg/L and elevated TS had presumed primary iron overload (hemochromatosis). Four participants had transfusion iron overload. CONCLUSION: Persistent hyperferritinemia in 373 black adults was associated with male sex, age, TS, GGT, and transfusion. 2.4% had primary iron overload (hemochromatosis) or transfusion iron overload.

White blood cells and subtypes in HFE p.C282Y and wild-type homozygotes in the Hemochromatosis and Iron Overload Screening Study.

The major histocompatibility complex is linked to white blood cell (WBC) and lymphocyte counts in subjects unselected for HFE genotypes. We compared age, sex, body mass index, total WBC and subtypes (neutrophils, lymphocytes, monocytes, eosinophils, basophils) (Beckman Coulter® Gen-S), transferrin saturation, and serum ferritin of HFE p.C282Y and wild-type (p.C282Y, p.H63D negative) homozygotes without acquired conditions that influence WBC counts. We performed regressions on WBC and subtypes. There were 161 p.C282Y homozygotes (45.3% men) and 221 wild-type homozygotes (40.3% men). Mean WBC of men and women and between HFE genotypes were similar. Mean lymphocytes were higher in male p.C282Y homozygotes: 1.6×109/L [95% confidence interval: 1.5,1.7] vs. 1.4 [1.3,1.5], p=0.0002. Mean lymphocytes and basophils were higher in female p.C282Y homozygotes: 1.6 [1.5,1.7] vs. 1.4 [1.3,1.5], p=0.0002; and 0.065 [0.059,0.071] vs. 0.052 [0.051,0.054], p=0.0001, respectively. Transferrin saturation was associated with neutrophils (negative; p=0.0163). Age was associated with lymphocytes (negative; p=0.0003) and monocytes (positive; p<0.0001). Regressions on lymphocytes and basophils revealed positive associations with p.C282Y homozygosity (p=0.0043 and 0.0003, respectively). There were significant positive associations of neutrophils, lymphocytes, monocytes, and eosinophils. We conclude that HFE p.C282Y homozygosity is significantly associated with lymphocyte and basophil counts.

Selective Subnormal IgG1 in 54 Adult Index Patients with Frequent or Severe Bacterial Respiratory Tract Infections.

We characterized 54 adult index patients with reports of frequent or severe bacterial respiratory tract infections at diagnosis of selective subnormal IgG1. Mean age was 50 ± 13 (SD) y; 87.0% were women. Associated disorders included the following: autoimmune conditions 50.0%; hypothyroidism 24.1%; atopy 38.9%; and other allergy 31.5%. In 35.5%, proportions of protective S. pneumoniae serotype-specific IgG levels did not increase after polyvalent pneumococcal polysaccharide vaccination (PPPV). Blood lymphocyte subset levels were within reference limits in most patients. Regressions on IgG1 and IgG3 revealed no significant association with age, sex, autoimmune conditions, hypothyroidism, atopy, other allergy, corticosteroid therapy, or lymphocyte subsets. Regression on IgG2 revealed significant associations with PPPV response (negative) and CD19+ lymphocytes (positive). Regression on IgG4 revealed significant positive associations with episodic corticosteroid use and IgA. Regression on IgA revealed positive associations with IgG2 and IgG4. Regression on IgM revealed negative associations with CD56+/CD16+ lymphocytes. Regressions on categories of infection revealed a negative association of urinary tract infections and IgG1. HLA-A(⁎)03, HLA-B(⁎)55 and HLA-A(⁎)24, HLA-B(⁎)35 haplotype frequencies were greater in 38 patients than 751 controls. We conclude that nonprotective S. pneumoniae IgG levels and atopy contribute to increased susceptibility to respiratory tract infections in patients with selective subnormal IgG1.

Pica for Uncooked Basmati Rice in Two Women with Iron Deficiency and a Review of Ryzophagia.

Reports of pica for uncooked rice (ryzophagia) in adults who reside in European and derivative countries are uncommon. We evaluated and treated two nonpregnant women with pica for uncooked basmati rice. Both women reported fatigue, abdominal discomfort after consuming large quantities of uncooked basmati rice, and hair loss. One woman was from India and the other was from Pakistan. Both women were vegetarians. Basmati was the local rice in their native countries and their usual rice in the USA. Both women had tooth damage due to eating uncooked rice and iron deficiency with microcytic anemia attributed to menorrhagia and multiparity. Ryzophagia and other manifestations (except tooth damage) resolved after iron dextran therapy. We review and discuss other reports of ryzophagia associated with iron deficiency, pregnancy, race/ethnicity, geographic origin, and local traditions. We conclude that adults with ryzophagia in European and derivative countries are likely to be non-Europeans.

Risk Factors for Insulin Resistance, Metabolic Syndrome, and Diabetes in 248 HFE C282Y Homozygotes Identified by Population Screening in the HEIRS Study.

BACKGROUND: We sought to identify risk factors for insulin resistance, metabolic syndrome (MetS), and diabetes mellitus in 248 non-Hispanic white HFE C282Y homozygotes identified by population screening. METHODS: We analyzed observations obtained prospectively in a postscreening examination: age; sex; body mass index (BMI); systolic/diastolic blood pressure; metacarpophalangeal (MP) joint hypertrophy; hepatomegaly; complete blood counts; alanine/aspartate aminotransferase levels; elevated C-reactive protein (>0.5 mg/dL); transferrin saturation; serum ferritin; homeostasis model assessment-insulin resistance (HOMA-IR); and MetS. RESULTS: Twenty-six participants (10.5%) had diabetes diagnoses. A significant trend across HOMA-IR quartiles was observed only for blood neutrophils. Logistic regression on HOMA-IR fourth quartile revealed positive associations: age (P = 0.0002); male sex (P = 0.0022); and BMI (P < 0.0001). HOMA-IR fourth quartile predicted MetS (P < 0.0001). Logistic regression on diabetes revealed positive associations: age (P = 0.0012); male sex (P = 0.0068); MP joint hypertrophy (P = 0.0167); neutrophils (P = 0.0342); and MetS (P = 0.0298). Serum ferritin did not predict HOMA-IR fourth quartile, MetS, or diabetes. CONCLUSIONS: In screening C282Y homozygotes, age, male sex, and BMI predicted HOMA-IR fourth quartile. HOMA-IR fourth quartile alone predicted MetS. Diabetes was associated with greater age, male sex, MP joint hypertrophy, greater blood neutrophil counts, and MetS.

Undiagnosed diabetes and impaired fasting glucose in HFE C282Y homozygotes and HFE wild-type controls in the HEIRS Study.

OBJECTIVE: To determine prevalences and predictors of undiagnosed diabetes mellitus (UDM) and impaired fasting glucose (IFG) in non-Hispanic whites with HFE p.C282Y homozygosity and controls without common HFE mutations identified in population screening. RESEARCH DESIGN AND METHODS: We analyzed these observations in a postscreening examination: age; sex; body mass index; systolic/diastolic blood pressure; metacarpophalangeal joint hypertrophy; hepatomegaly; blood neutrophils; alanine and aspartate aminotransferase; elevated C reactive protein; transferrin saturation; serum ferritin; and Field Center. RESULTS: There were 223 p.C282Y homozygotes and 449 controls without diagnosed diabetes (43.9% men). Mean age of p.C282Y homozygotes was 52±13 years (controls 57±14 years; p<0.0001). Mean transferrin saturation in p.C282Y homozygotes was 67±26% (controls 34±14%; p<0.0001). Mean serum ferritin in p.C282Y homozygotes was 607 pmol/L (95% CI 497 to 517; controls 274 pmol/L (247 to 301); p<0.0001). Overall prevalences of UDM (4.0% vs 4.2%) and IFG (23.8% vs 25.6%) did not differ significantly between p.C282Y homozygotes and wt/wt controls, respectively. In logistic regressions, male sex, body mass index, and alanine aminotransferase were significantly associated with UDM. ORs were 2.7 (1.2 to 2.8); 1.0 (1.0 to 1.1); and 1.0 (1.0 to 1.0), respectively. Age, male sex, and body mass index were significantly associated with IFG. ORs were 1.0 (1.0 to 1.1); 2.8 (1.9 to 4.2); and 1.0 (1.0 to 1.1), respectively. CONCLUSIONS: Prevalences of UDM and IFG were similar in p.C282Y homozygotes and controls in a postpopulation screening examination. Male sex was the strongest predictor of UDM and IFG.