Curr Diab Rep (2014) 14:488 DOI 10.1007/s11892-014-0488-y
DIABETES AND OTHER DISEASES-EMERGING ASSOCIATIONS (JJ NOLAN, SECTION EDITOR)
Diabetes and Hemochromatosis T. Creighton Mitchell & Donald A. McClain
Published online: 30 March 2014 # Springer Science+Business Media New York 2014
Abstract The common form of hereditary hemochromatosis is an autosomal recessive disorder most prevalent in Caucasians that results in excessive iron storage. The clinical manifestations of hemochromatosis are protean. HFE genotype, which determines the degree of iron overload and duration of disease have profound effects on disease expression. The prevalence of diabetes in this population has likely been underestimated because of studies that include a broad range of ethnicities and associating diabetes with allele frequency in spite of the decreased risk of diabetes in heterozygotes compared with homozygotes. Loss of insulin secretory capacity is likely the primary defect contributing to development of diabetes with insulin resistance playing a secondary role. Phlebotomy can ameliorate the defects in insulin secretion if initiated early. Screening a select population of individuals with type 2 diabetes may identify patients with hemochromatosis early and substantially impact individual clinical outcomes. Keywords Hemochromatosis . Diabetes . Iron overload . Glucose metabolism . Prevalence . Insulin secretion
Introduction Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron storage affecting 0.3 %–0.5 % of Caucasians of northern European descent [1••]. Two missense mutations in the HFE gene account for the majority of cases of HH: C282Y and H63D [1••, 2]. In the absence of HFE function, hepcidin, a protein required for regulation of iron entry into the circulation, is reduced and This article is part of the Topical Collection on Diabetes and Other Diseases-Emerging Associations T. Creighton Mitchell : D. A. McClain (*) Department of Medicine, Division of Endocrinology, University of Utah, 15 North 2030 East, Salt Lake City, UT 84108, USA e-mail: [email protected]
iron levels are inappropriately high [3]. Because there is no means of secreting iron in a regulated fashion, excess iron accumulates intracellularly in most tissues. As iron accumulates in parenchymal cells, the classic clinical manifestations of cirrhosis, diabetes, and hyperpigmentation ensue. The mechanisms by which iron overload in hemochromatosis causes diabetes have been controversial but recent studies have added significantly to our knowledge of this common genetic disorder. This review will consider the evidence for altered insulin secretion, insulin action, and other factors such as oxidant stress in the pathogenesis of diabetes in HH.
Iron Homeostasis Iron homeostasis has been extensively reviewed, for example [4] but will be briefly outlined herein (Fig. 1). Iron is an indispensable element involved in fuel oxidation and electron transport; however, excess iron may result in oxidative damage and thus, the uptake and fate of iron are carefully regulated. Total body iron content is approximately 3–5 g with the majority contained in hemoglobin and myoglobin. Iron (20– 25 mg/day) is recycled through the erythroid pool by macrophages as senescent erythrocytes are endocytosed. Excess iron (1000 mg) is stored in the liver, sequestered in ferritin. Because no regulated mechanism for iron excretion exists for most tissues, entry of iron from the intestines is strictly governed. Free ferric iron (Fe3+) is reduced and enters the duodenal enterocytes through the divalent metal transporter 1 (DMT1). Dietary heme is directly absorbed and heme oxygenase releases the iron. Iron uptake from the enterocyte into plasma occurs through ferroportin (FPN), the sole export channel of inorganic iron in mammals. Iron is then re-oxidized to Fe3+ by hephaestin, bound by transferrin, and circulated throughout the body. Ferroportin is regulated by secretion of hepcidin from the hepatocyte. Binding of hepcidin to ferroportin results in internalization and degradation of this iron export protein.
488, Page 2 of 10
Curr Diab Rep (2014) 14:488
Fig. 1 Overview of iron trafficking. Intestinal free ferric (Fe3+) iron is reduced to Fe2+ by duodenal cytochrome b (DCTB) and enters the cell through the divalent metal-ion transporter 1 (DMT1) and possibly other carriers. Dietary heme is directly absorbed and iron is released by heme oxygenase (Hmox). Iron exits the enterocyte through the iron export channel ferroportin (FPN). After oxidization by hephaestin (HEPH) iron binds to transferrin (Tf) in the bloodstream that binds to transferrin receptors (TfR)-1 and -2 on the surface of target cells. In most cells, after endocytosis of TfR1 and acidification of the endosome, iron is released, reduced by STEAP (6 transmembrane epithelial antigen of the prostate), and enters the cytosol through DMT1 where it is used (eg, for heme or
iron-sulfur cluster synthesis in the mitochondrion) or, if in excess, sequestered by ferritin. Ferritin secreted into the blood serves as a marker for tissue iron stores. In the liver, Tf binds TfR 2 and the protein HFE. In concert with signaling via hemojuvelin (HJV), bone morphogenic proteins (BMP) and the SMAD (human ortholog of Drosophila Mothers against decapentaplegic) signal transduction pathway, production of hepcidin (HAMP) is signaled. Hepcidin induces internalization and degradation of FPN, thus, completing a negative feedback regulatory loop. With permission from: Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17:329–41. [60]
Ferroportin is not only found on enterocytes but also macrophages and its inactivation results in intracellular iron retention. Stimulation of hepcidin production occurs via a poorly understood process involving the interaction of transferrinbound iron with hepatocyte transferrin receptors and HFE. This signaling process also requires hemojuvelin, bone morphogenetic protein 6, and the signal transduction pathway involving transcriptional regulation by the human homologs of the Drosophila protein Mothers against decapentaplegic, or SMAD. Rarer mutations in many components of this pathway (transferrin receptor 2, hepcidin, hemojuvelin, and ferroportin) result in iron overload in humans (Table 1). In most cases, these mutations result in more severe iron overload and earlier presentation than is found with HFE mutations, the exception being ferroportin disease that is similar to HFE hemochromatosis.
Clinical Expression of Hemochromatosis The clinical expression of HH varies based on the underlying genotype; furthermore, the classic manifestations are diagnosed less frequently as patients are diagnosed earlier [5]. Dilated cardiomyopathy and hypogonadotropic hypogonadism are generally seen in individuals with much greater degrees of iron overload than, for example, hepatic involvement. In HFE-related HH, a spectrum of risk for iron overload has been observed with C282Y homozygotes having the highest risk followed by C282Y/H63D, C282Y/wt, H63D/H63D, and H63D/wt in descending order (Table 2) [6]. Similarly, clinical manifestations are seen most commonly in C282Y homozygotes, followed by C282Y/ H63D, and less commonly in H63D homozygotes. Widely varying estimates of the clinical penetrance of HH exist, and
Curr Diab Rep (2014) 14:488
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Table 1 Genetic forms of hereditary hemochromatosis Gene
Gene function
Inheritance and phenotype
HFE
Receptor involved in hepatic iron sensing and stimulation of hepcidin secretion. TFR2 Transferrin receptor 2, interacts with HFE and other hepatic receptors to sense iron. HAMP Hepcidin, the peptide secreted by the liver in response to HFE and inflammatory signaling that down regulated iron channels, limiting iron uptake from the gut. SLC40A1 Ferroportin, the export channel that releases iron into the circulation from cells such as gut epithelia and macrophages. HFE2 Hemojuvelin, a co-receptor for bone morphogenetic proteins that regulate hepcidin levels.
this is likely a result of disparate methods of defining clinical disease. In a cross-sectional study using data collected from the Kaiser-Permanente health system, Beutler et al identified 152 C282Y homozygotes (although 30 % of these were excluded from the final analysis) and 626 compound heterozygotes [7]. No difference in self-reported symptoms was found among those with HFE mutations compared with controls with the exception of homozygotes reporting a greater history of liver disorders. Aspartate aminotransferase levels were also 2.1 times more likely to be elevated in homozygotes compared with controls. The authors concluded that clinical hemochromatosis occurs in less than 1 % of homozygotes. In contrast, 2 large prospective studies in which severity of disease was assessed by objective criteria including liver biopsy, a much higher frequency of morbidity was observed. In the first, a clinically unselected cohort, in which relatives of patients with HH who were tested and found to be homozygous for HFE mutations, the prevalence of at least 1 diseaserelated condition was 38 % in males and 10 % in females [8]. In a second study of 203 C282Y homozygotes, iron-overload related disease was found in 28.4 % of men and 1.7 % of women [9]. Additional factors other than genotype contribute to the clinical expression of HH. There is evidence that BMI may play a role in phenotypic expression [10]. Serum ferritin varies more than 10-fold in normal, healthy humans, reflecting at
Recessive, variable penetrance, generally after the 5th decade Recessive, symptoms generally appearing in the 3rd or 4th decades Recessive, presentation in 2nd or 3rd decade, often with amenorrhea in females and sexual dysfunction or delayed puberty in males. Dominant, onset and clinical picture similar to HFE. Recessive, presentation in 2nd or 3rd decade, often with amenorrhea in females and sexual dysfunction or delayed puberty in males.
least in part a high variation in iron intake. Thus, even in the presence of the HH genotype, if dietary iron is low there will be less tissue iron accumulation. Not unexpectedly, therefore, serum ferritin is one of the strongest predictors of hemochromatosis symptoms and cirrhosis. C282Y homozygotes with serum ferritin greater than 1000 μg/L have a higher risk of HH related symptoms and liver disease [9]. In a prospective study of 203 C282Y homozygotes, 37 % of men and 3 % of women had a serum ferritin greater than 1000 μg/L at diagnosis [11]. For individuals with serum ferritin 300–1000 μg/L, the probability of developing serum ferritin greater than 1000 μg/L was as high as 35 % while individuals with normal ferritin at presentation had less than a 15 % probability of developing a serum ferritin >1000 μg/L. Long-term survival from hemochromatosis is dependent on the degree and duration of iron overload [12].
HFE Mutations and Diabetes There has been controversy about the prevalence of diabetes in HH. Prior to the advent of genetic testing, there was clear selection bias for individuals with “bronze diabetes,” but even after the discovery of the HFE mutations, studies have yielded dramatically differing results. Large epidemiologic studies have examined the prevalence of diabetes in those with HFE
Table 2 Biochemical and clinical phenotype of HFE genotypes C282Y/C282Y (C282Y homozygote)
C282Y/H63D (compound heterozygote)
C282Y/WT (C282Y heterozygote)
H63D/H63D (H63D homozygote)
H63D/WT (H63D heterozygote)
Serum iron indices a
Very elevated Yes
Upper end of normal range No
Slightly to moderately elevated Yes (less than C282Y/ C282Y)
Normal
Clinically significant iron overloada,b
Moderately elevated Yes
No
a
Host factors (eg, menses, blood loss, alcohol intake, nonalcoholic fatty liver disease, and viral hepatitis) alter biochemical and clinical phenotype
b
As determined by elevated hepatic iron index or other measures of excess iron based on liver biopsy and mobilizable iron by quantitative phlebotomy
488, Page 4 of 10
mutations and the prevalence of HFE mutations in individuals with diabetes (Table 3). In the Kaiser-Permanente health system, Beutler et al did not observe an increased prevalence of diabetes in individuals with HFE mutations compared with a control population [7]. As discussed above, however, exclusion of a percentage of those with known hemochromatosis and inclusion of Hispanic individuals (an ethnic group with nearly double the prevalence of type 2 diabetes compared with whites [13]) in the control population likely affected the analysis. Other large epidemiologic studies that have evaluated the prevalence of HFE mutations in individuals with and without diabetes yield surprisingly discordant results. Acton et al found no difference in the frequency of HFE genotypes at known mutation sites in individuals with and without selfreported diabetes when stratified by ethnicity [14]. Although there was no difference in ferritin concentration among male carriers of all HFE genotypes with and without self-reported diabetes, women with any HFE genotype (other than C282Y/ C282Y and C282Y/H63D) and diabetes had significantly elevated ferritin concentrations. Women with diabetes and C282Y/C282Y had lower mean serum ferritin concentrations compared with women with the same haplotype but no diabetes. Ferritin concentration was similar in HFE C282Y/ H63D women with or without diabetes. These findings are in conflict with a large body of evidence showing that C282Y homozygotes have the highest ferritin concentrations and the greatest risk for iron overload-related disease [15]. This is not an effect of previous treatment, because individuals who received phlebotomy were excluded from the study. While appropriate, this exclusion criterion may have selected for individuals with a milder disease phenotype. Despite a lack of association between genotype and diabetes, an association between ferritin level and diabetes was observed in this population with an OR of 1.24 (CI 1.2–1.3) [14]. A positive association between diabetes risk and HFE mutations has been observed in several studies. The greatest risk of developing diabetes in individuals with HFE mutations has been reported in a Polish population. Moczulski et al found an OR of 5.3 (CI 1.6–17.3) for C282Y homozygosity or heterozygosity in 563 patients with type 2 diabetes compared with 196 controls [16]. The OR for H63D mutations was 1.5 (CI 1–2.1) in this same population. In a crosssectional study of a Canadian population of European origin, 21.9 % of participants with type 2 diabetes and 11.7 % of participants with type 1 diabetes had at least 1 copy of the C282Y mutation [17]. A carrier frequency of 6.9 % for the C282Y mutation was observed in a prospective Finnish cohort study [18]. During 4 years of follow-up, 11 % of individuals with C282Y mutation and 5 % of individuals without C282Y mutation developed diabetes. Carriers of the C282Y mutation had an OR of 3.51 (CI 1.02–12.08) for developing diabetes compared with noncarriers; this is greater than the OR for
Curr Diab Rep (2014) 14:488
BMI and diabetes found in this population. In a retrospective, case-controlled study in a Danish population of individuals who developed diabetes after 30 years of age, Ellervik et al noted an OR of 4.6 (CI 2.0–10.1) for diabetes and C282Y homozygosity [19]. A relationship between compound heterozygosity or H63D homozygosity and diabetes was not seen. Much as the individual studies show conflicting results, meta-analyses also provide differing degrees of association between HFE mutations and diabetes. In a meta-analysis of 11 studies, including those with the greatest odds ratios by Moczulski et al and Kwan et al discussed above, Halsall et al did not find evidence of increased C282Y allele frequency in patients with type 2 diabetes compared with a control population without diabetes (OR 1.085, CI 0.911–1.292) [20]. Rong et al also observed no increased risk for individuals carrying a C282Y allele compared with those without HFE mutations in a more extensive meta-analysis including 23 studies [21]. On the other hand, individuals carrying an H63D mutation did have an increased OR for type 2 diabetes. In a meta-analysis by Qi et al an association with diabetes and H63D mutation was also observed: carriers of H63D and compound heterozygotes were both found to have increased OR for type 2 diabetes [1.11 (CI 1.0– 1.25) and 1.6 (CI 0.99–2.60), respectively], compared with individuals without HFE mutations [22]. As in the other 2 meta-analyses, increased risk of diabetes was not found in patients with C282Y mutations. However, these studies examined the relation of diabetes to allele frequency, and because there is very modest if any iron overload in heterozygotes, these studies are likely to have underestimated diabetes risk for homozygous patients. In 2 recent cross-sectional studies, the prevalence of diabetes in HH was found to be 13 %–23 % and impaired glucose tolerance (IGT) 15 %–30 % [23•, 24]. In the former series, 13 % and 15 % of individuals with HH were found to have diabetes and IGT, respectively, after undergoing detailed assessment of glucose metabolism. In the latter study of adults over the age of 40, the prevalence of diabetes and IGT was higher when assessed with both oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) [24]. Importantly, this study included a chart review of over 300 homozygotes ascertained largely by transferrin saturation and, hence, not clinically biased by pre-existing presence of a medical condition like diabetes. There are likely numerous reasons for the varying results of the studies described above. Not all HFE genotypes lead to significant iron overload, and this likely weakens any relationship observed in studies including all HFE mutations and the risk of diabetes. Likewise, the development of diabetes is age-related, so inclusion of younger adults without diabetes will yield a lower prevalence even though those same
Caucasian
Caucasian
Caucasian, Hispanic, Black, Asian, Other
Caucasian, Native Am, Hispanic, Black, P Islander, Asian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
O’sullivan, 2008 [26]
Salonen, 2000 [18]
Beutler, 2002 [7]
Adams, 2005 [25]
Allen, 2008 [9]
Hatunic, 2010 [23•]
Kwan, 1998 [17]
Moczulski, 2001 [16]
Ellervik, 2001 [19]
Halsall, 2003 [20]
512
716 508
9174
196
103
105§ 563
20
361
99,711
22,347
473
NA
Controls/ participants
53
1290
6997‡
718 [in analysis of diabetes]
35
237
Cases
Cases are type 2 diabetics and controls are type 1 diabetics
Individuals with at least 1 C282Y allele
Includes all forms of C282Y heterozygotes
*Includes C282Y homozygotes and heterozygotes
§
‡
†
NA not applicable
Ethnic origin
Author, year (reference no.)
Table 3 Prevalence of HFE mutations and diabetes in select populations
0.11 0.027 0.014 0.012 0.000039
Native Am Hispanic Black P Islander Asian
1.4 in controls 1.1 in diabetics 0.6 in controls 1.8 in diabetics
0.25 in controls
0.4 in diabetics
1.5 in controls 7.6 in diabetics*
11.7 in T1DM
†
0.95 in T2DM
NA
2.4
0.096 0.0055
0.071
0.33
0.77
2.0
1.5
6.7†
NA
C282Y/H63D
1.26 in diabetics 0.8 in controls
0 in T1DM
NA
0.7
0.44
Caucasian
0.4
0.2
NA
C282Y/C282Y
Prevalence of HFE mutations (%)
11.7 in diabetics
9.4 in diabetics 9.4 in controls
9.2 in controls
20.9 in T2DM†
NA
11.1
2.0 0.12
2.3
2.9
5.7
10
NA
C282Y/wt
NA
NA
NA
Diabetes 13 % IGT 15 %
C282Y/H63D 2.5 %
-ferritin≥1000 ug/L 3 % -ferritin
DIABETES AND OTHER DISEASES-EMERGING ASSOCIATIONS (JJ NOLAN, SECTION EDITOR)
Diabetes and Hemochromatosis T. Creighton Mitchell & Donald A. McClain
Published online: 30 March 2014 # Springer Science+Business Media New York 2014
Abstract The common form of hereditary hemochromatosis is an autosomal recessive disorder most prevalent in Caucasians that results in excessive iron storage. The clinical manifestations of hemochromatosis are protean. HFE genotype, which determines the degree of iron overload and duration of disease have profound effects on disease expression. The prevalence of diabetes in this population has likely been underestimated because of studies that include a broad range of ethnicities and associating diabetes with allele frequency in spite of the decreased risk of diabetes in heterozygotes compared with homozygotes. Loss of insulin secretory capacity is likely the primary defect contributing to development of diabetes with insulin resistance playing a secondary role. Phlebotomy can ameliorate the defects in insulin secretion if initiated early. Screening a select population of individuals with type 2 diabetes may identify patients with hemochromatosis early and substantially impact individual clinical outcomes. Keywords Hemochromatosis . Diabetes . Iron overload . Glucose metabolism . Prevalence . Insulin secretion
Introduction Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by excessive iron storage affecting 0.3 %–0.5 % of Caucasians of northern European descent [1••]. Two missense mutations in the HFE gene account for the majority of cases of HH: C282Y and H63D [1••, 2]. In the absence of HFE function, hepcidin, a protein required for regulation of iron entry into the circulation, is reduced and This article is part of the Topical Collection on Diabetes and Other Diseases-Emerging Associations T. Creighton Mitchell : D. A. McClain (*) Department of Medicine, Division of Endocrinology, University of Utah, 15 North 2030 East, Salt Lake City, UT 84108, USA e-mail: [email protected]
iron levels are inappropriately high [3]. Because there is no means of secreting iron in a regulated fashion, excess iron accumulates intracellularly in most tissues. As iron accumulates in parenchymal cells, the classic clinical manifestations of cirrhosis, diabetes, and hyperpigmentation ensue. The mechanisms by which iron overload in hemochromatosis causes diabetes have been controversial but recent studies have added significantly to our knowledge of this common genetic disorder. This review will consider the evidence for altered insulin secretion, insulin action, and other factors such as oxidant stress in the pathogenesis of diabetes in HH.
Iron Homeostasis Iron homeostasis has been extensively reviewed, for example [4] but will be briefly outlined herein (Fig. 1). Iron is an indispensable element involved in fuel oxidation and electron transport; however, excess iron may result in oxidative damage and thus, the uptake and fate of iron are carefully regulated. Total body iron content is approximately 3–5 g with the majority contained in hemoglobin and myoglobin. Iron (20– 25 mg/day) is recycled through the erythroid pool by macrophages as senescent erythrocytes are endocytosed. Excess iron (1000 mg) is stored in the liver, sequestered in ferritin. Because no regulated mechanism for iron excretion exists for most tissues, entry of iron from the intestines is strictly governed. Free ferric iron (Fe3+) is reduced and enters the duodenal enterocytes through the divalent metal transporter 1 (DMT1). Dietary heme is directly absorbed and heme oxygenase releases the iron. Iron uptake from the enterocyte into plasma occurs through ferroportin (FPN), the sole export channel of inorganic iron in mammals. Iron is then re-oxidized to Fe3+ by hephaestin, bound by transferrin, and circulated throughout the body. Ferroportin is regulated by secretion of hepcidin from the hepatocyte. Binding of hepcidin to ferroportin results in internalization and degradation of this iron export protein.
488, Page 2 of 10
Curr Diab Rep (2014) 14:488
Fig. 1 Overview of iron trafficking. Intestinal free ferric (Fe3+) iron is reduced to Fe2+ by duodenal cytochrome b (DCTB) and enters the cell through the divalent metal-ion transporter 1 (DMT1) and possibly other carriers. Dietary heme is directly absorbed and iron is released by heme oxygenase (Hmox). Iron exits the enterocyte through the iron export channel ferroportin (FPN). After oxidization by hephaestin (HEPH) iron binds to transferrin (Tf) in the bloodstream that binds to transferrin receptors (TfR)-1 and -2 on the surface of target cells. In most cells, after endocytosis of TfR1 and acidification of the endosome, iron is released, reduced by STEAP (6 transmembrane epithelial antigen of the prostate), and enters the cytosol through DMT1 where it is used (eg, for heme or
iron-sulfur cluster synthesis in the mitochondrion) or, if in excess, sequestered by ferritin. Ferritin secreted into the blood serves as a marker for tissue iron stores. In the liver, Tf binds TfR 2 and the protein HFE. In concert with signaling via hemojuvelin (HJV), bone morphogenic proteins (BMP) and the SMAD (human ortholog of Drosophila Mothers against decapentaplegic) signal transduction pathway, production of hepcidin (HAMP) is signaled. Hepcidin induces internalization and degradation of FPN, thus, completing a negative feedback regulatory loop. With permission from: Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17:329–41. [60]
Ferroportin is not only found on enterocytes but also macrophages and its inactivation results in intracellular iron retention. Stimulation of hepcidin production occurs via a poorly understood process involving the interaction of transferrinbound iron with hepatocyte transferrin receptors and HFE. This signaling process also requires hemojuvelin, bone morphogenetic protein 6, and the signal transduction pathway involving transcriptional regulation by the human homologs of the Drosophila protein Mothers against decapentaplegic, or SMAD. Rarer mutations in many components of this pathway (transferrin receptor 2, hepcidin, hemojuvelin, and ferroportin) result in iron overload in humans (Table 1). In most cases, these mutations result in more severe iron overload and earlier presentation than is found with HFE mutations, the exception being ferroportin disease that is similar to HFE hemochromatosis.
Clinical Expression of Hemochromatosis The clinical expression of HH varies based on the underlying genotype; furthermore, the classic manifestations are diagnosed less frequently as patients are diagnosed earlier [5]. Dilated cardiomyopathy and hypogonadotropic hypogonadism are generally seen in individuals with much greater degrees of iron overload than, for example, hepatic involvement. In HFE-related HH, a spectrum of risk for iron overload has been observed with C282Y homozygotes having the highest risk followed by C282Y/H63D, C282Y/wt, H63D/H63D, and H63D/wt in descending order (Table 2) [6]. Similarly, clinical manifestations are seen most commonly in C282Y homozygotes, followed by C282Y/ H63D, and less commonly in H63D homozygotes. Widely varying estimates of the clinical penetrance of HH exist, and
Curr Diab Rep (2014) 14:488
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Table 1 Genetic forms of hereditary hemochromatosis Gene
Gene function
Inheritance and phenotype
HFE
Receptor involved in hepatic iron sensing and stimulation of hepcidin secretion. TFR2 Transferrin receptor 2, interacts with HFE and other hepatic receptors to sense iron. HAMP Hepcidin, the peptide secreted by the liver in response to HFE and inflammatory signaling that down regulated iron channels, limiting iron uptake from the gut. SLC40A1 Ferroportin, the export channel that releases iron into the circulation from cells such as gut epithelia and macrophages. HFE2 Hemojuvelin, a co-receptor for bone morphogenetic proteins that regulate hepcidin levels.
this is likely a result of disparate methods of defining clinical disease. In a cross-sectional study using data collected from the Kaiser-Permanente health system, Beutler et al identified 152 C282Y homozygotes (although 30 % of these were excluded from the final analysis) and 626 compound heterozygotes [7]. No difference in self-reported symptoms was found among those with HFE mutations compared with controls with the exception of homozygotes reporting a greater history of liver disorders. Aspartate aminotransferase levels were also 2.1 times more likely to be elevated in homozygotes compared with controls. The authors concluded that clinical hemochromatosis occurs in less than 1 % of homozygotes. In contrast, 2 large prospective studies in which severity of disease was assessed by objective criteria including liver biopsy, a much higher frequency of morbidity was observed. In the first, a clinically unselected cohort, in which relatives of patients with HH who were tested and found to be homozygous for HFE mutations, the prevalence of at least 1 diseaserelated condition was 38 % in males and 10 % in females [8]. In a second study of 203 C282Y homozygotes, iron-overload related disease was found in 28.4 % of men and 1.7 % of women [9]. Additional factors other than genotype contribute to the clinical expression of HH. There is evidence that BMI may play a role in phenotypic expression [10]. Serum ferritin varies more than 10-fold in normal, healthy humans, reflecting at
Recessive, variable penetrance, generally after the 5th decade Recessive, symptoms generally appearing in the 3rd or 4th decades Recessive, presentation in 2nd or 3rd decade, often with amenorrhea in females and sexual dysfunction or delayed puberty in males. Dominant, onset and clinical picture similar to HFE. Recessive, presentation in 2nd or 3rd decade, often with amenorrhea in females and sexual dysfunction or delayed puberty in males.
least in part a high variation in iron intake. Thus, even in the presence of the HH genotype, if dietary iron is low there will be less tissue iron accumulation. Not unexpectedly, therefore, serum ferritin is one of the strongest predictors of hemochromatosis symptoms and cirrhosis. C282Y homozygotes with serum ferritin greater than 1000 μg/L have a higher risk of HH related symptoms and liver disease [9]. In a prospective study of 203 C282Y homozygotes, 37 % of men and 3 % of women had a serum ferritin greater than 1000 μg/L at diagnosis [11]. For individuals with serum ferritin 300–1000 μg/L, the probability of developing serum ferritin greater than 1000 μg/L was as high as 35 % while individuals with normal ferritin at presentation had less than a 15 % probability of developing a serum ferritin >1000 μg/L. Long-term survival from hemochromatosis is dependent on the degree and duration of iron overload [12].
HFE Mutations and Diabetes There has been controversy about the prevalence of diabetes in HH. Prior to the advent of genetic testing, there was clear selection bias for individuals with “bronze diabetes,” but even after the discovery of the HFE mutations, studies have yielded dramatically differing results. Large epidemiologic studies have examined the prevalence of diabetes in those with HFE
Table 2 Biochemical and clinical phenotype of HFE genotypes C282Y/C282Y (C282Y homozygote)
C282Y/H63D (compound heterozygote)
C282Y/WT (C282Y heterozygote)
H63D/H63D (H63D homozygote)
H63D/WT (H63D heterozygote)
Serum iron indices a
Very elevated Yes
Upper end of normal range No
Slightly to moderately elevated Yes (less than C282Y/ C282Y)
Normal
Clinically significant iron overloada,b
Moderately elevated Yes
No
a
Host factors (eg, menses, blood loss, alcohol intake, nonalcoholic fatty liver disease, and viral hepatitis) alter biochemical and clinical phenotype
b
As determined by elevated hepatic iron index or other measures of excess iron based on liver biopsy and mobilizable iron by quantitative phlebotomy
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mutations and the prevalence of HFE mutations in individuals with diabetes (Table 3). In the Kaiser-Permanente health system, Beutler et al did not observe an increased prevalence of diabetes in individuals with HFE mutations compared with a control population [7]. As discussed above, however, exclusion of a percentage of those with known hemochromatosis and inclusion of Hispanic individuals (an ethnic group with nearly double the prevalence of type 2 diabetes compared with whites [13]) in the control population likely affected the analysis. Other large epidemiologic studies that have evaluated the prevalence of HFE mutations in individuals with and without diabetes yield surprisingly discordant results. Acton et al found no difference in the frequency of HFE genotypes at known mutation sites in individuals with and without selfreported diabetes when stratified by ethnicity [14]. Although there was no difference in ferritin concentration among male carriers of all HFE genotypes with and without self-reported diabetes, women with any HFE genotype (other than C282Y/ C282Y and C282Y/H63D) and diabetes had significantly elevated ferritin concentrations. Women with diabetes and C282Y/C282Y had lower mean serum ferritin concentrations compared with women with the same haplotype but no diabetes. Ferritin concentration was similar in HFE C282Y/ H63D women with or without diabetes. These findings are in conflict with a large body of evidence showing that C282Y homozygotes have the highest ferritin concentrations and the greatest risk for iron overload-related disease [15]. This is not an effect of previous treatment, because individuals who received phlebotomy were excluded from the study. While appropriate, this exclusion criterion may have selected for individuals with a milder disease phenotype. Despite a lack of association between genotype and diabetes, an association between ferritin level and diabetes was observed in this population with an OR of 1.24 (CI 1.2–1.3) [14]. A positive association between diabetes risk and HFE mutations has been observed in several studies. The greatest risk of developing diabetes in individuals with HFE mutations has been reported in a Polish population. Moczulski et al found an OR of 5.3 (CI 1.6–17.3) for C282Y homozygosity or heterozygosity in 563 patients with type 2 diabetes compared with 196 controls [16]. The OR for H63D mutations was 1.5 (CI 1–2.1) in this same population. In a crosssectional study of a Canadian population of European origin, 21.9 % of participants with type 2 diabetes and 11.7 % of participants with type 1 diabetes had at least 1 copy of the C282Y mutation [17]. A carrier frequency of 6.9 % for the C282Y mutation was observed in a prospective Finnish cohort study [18]. During 4 years of follow-up, 11 % of individuals with C282Y mutation and 5 % of individuals without C282Y mutation developed diabetes. Carriers of the C282Y mutation had an OR of 3.51 (CI 1.02–12.08) for developing diabetes compared with noncarriers; this is greater than the OR for
Curr Diab Rep (2014) 14:488
BMI and diabetes found in this population. In a retrospective, case-controlled study in a Danish population of individuals who developed diabetes after 30 years of age, Ellervik et al noted an OR of 4.6 (CI 2.0–10.1) for diabetes and C282Y homozygosity [19]. A relationship between compound heterozygosity or H63D homozygosity and diabetes was not seen. Much as the individual studies show conflicting results, meta-analyses also provide differing degrees of association between HFE mutations and diabetes. In a meta-analysis of 11 studies, including those with the greatest odds ratios by Moczulski et al and Kwan et al discussed above, Halsall et al did not find evidence of increased C282Y allele frequency in patients with type 2 diabetes compared with a control population without diabetes (OR 1.085, CI 0.911–1.292) [20]. Rong et al also observed no increased risk for individuals carrying a C282Y allele compared with those without HFE mutations in a more extensive meta-analysis including 23 studies [21]. On the other hand, individuals carrying an H63D mutation did have an increased OR for type 2 diabetes. In a meta-analysis by Qi et al an association with diabetes and H63D mutation was also observed: carriers of H63D and compound heterozygotes were both found to have increased OR for type 2 diabetes [1.11 (CI 1.0– 1.25) and 1.6 (CI 0.99–2.60), respectively], compared with individuals without HFE mutations [22]. As in the other 2 meta-analyses, increased risk of diabetes was not found in patients with C282Y mutations. However, these studies examined the relation of diabetes to allele frequency, and because there is very modest if any iron overload in heterozygotes, these studies are likely to have underestimated diabetes risk for homozygous patients. In 2 recent cross-sectional studies, the prevalence of diabetes in HH was found to be 13 %–23 % and impaired glucose tolerance (IGT) 15 %–30 % [23•, 24]. In the former series, 13 % and 15 % of individuals with HH were found to have diabetes and IGT, respectively, after undergoing detailed assessment of glucose metabolism. In the latter study of adults over the age of 40, the prevalence of diabetes and IGT was higher when assessed with both oral glucose tolerance test (OGTT) and intravenous glucose tolerance test (IVGTT) [24]. Importantly, this study included a chart review of over 300 homozygotes ascertained largely by transferrin saturation and, hence, not clinically biased by pre-existing presence of a medical condition like diabetes. There are likely numerous reasons for the varying results of the studies described above. Not all HFE genotypes lead to significant iron overload, and this likely weakens any relationship observed in studies including all HFE mutations and the risk of diabetes. Likewise, the development of diabetes is age-related, so inclusion of younger adults without diabetes will yield a lower prevalence even though those same
Caucasian
Caucasian
Caucasian, Hispanic, Black, Asian, Other
Caucasian, Native Am, Hispanic, Black, P Islander, Asian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
Caucasian
O’sullivan, 2008 [26]
Salonen, 2000 [18]
Beutler, 2002 [7]
Adams, 2005 [25]
Allen, 2008 [9]
Hatunic, 2010 [23•]
Kwan, 1998 [17]
Moczulski, 2001 [16]
Ellervik, 2001 [19]
Halsall, 2003 [20]
512
716 508
9174
196
103
105§ 563
20
361
99,711
22,347
473
NA
Controls/ participants
53
1290
6997‡
718 [in analysis of diabetes]
35
237
Cases
Cases are type 2 diabetics and controls are type 1 diabetics
Individuals with at least 1 C282Y allele
Includes all forms of C282Y heterozygotes
*Includes C282Y homozygotes and heterozygotes
§
‡
†
NA not applicable
Ethnic origin
Author, year (reference no.)
Table 3 Prevalence of HFE mutations and diabetes in select populations
0.11 0.027 0.014 0.012 0.000039
Native Am Hispanic Black P Islander Asian
1.4 in controls 1.1 in diabetics 0.6 in controls 1.8 in diabetics
0.25 in controls
0.4 in diabetics
1.5 in controls 7.6 in diabetics*
11.7 in T1DM
†
0.95 in T2DM
NA
2.4
0.096 0.0055
0.071
0.33
0.77
2.0
1.5
6.7†
NA
C282Y/H63D
1.26 in diabetics 0.8 in controls
0 in T1DM
NA
0.7
0.44
Caucasian
0.4
0.2
NA
C282Y/C282Y
Prevalence of HFE mutations (%)
11.7 in diabetics
9.4 in diabetics 9.4 in controls
9.2 in controls
20.9 in T2DM†
NA
11.1
2.0 0.12
2.3
2.9
5.7
10
NA
C282Y/wt
NA
NA
NA
Diabetes 13 % IGT 15 %
C282Y/H63D 2.5 %
-ferritin≥1000 ug/L 3 % -ferritin
