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Hereditary Hemochromatosis

Our HHC Science Library is laid out similar to the other libraries on this web site. We do not present a lengthy narrative on each body system affected by HHC, but rather will briefly summarize or quote the most relevant take-home points and/or research conclusions from each study. Article titles are linked to abstracts archived at the U.S. National Library of Science. Many articles also have "Full free text" PDF links. Our Iron Science Library pages include:



Health-e-Iron Note: our newest article on managing hereditary hemochromatosis is directly below; it's an important one from our colleagues in Australia!

Management of human factors engineering-associated hemochromatosis: A 2015 update Free full text 

This review focuses on the management of iron metabolism and iron overload experienced in the hereditary condition, human factors engineering (HFE)-associated hemochromatosis. Hemochromatosis refers to a group of genetic diseases that result in iron overload; the major one globally is HFE-associated hemochromatosis. The evolution in understanding of the most common form of hereditary hemochromatosis, being the substation of cysteine to a tyrosine at position 282 in the HFE gene, has been extensively studied Novel mutations in both HFE and non-HFE genes have been indicated in this disease which hold significance in its application for the Asia-Pacific region. In conditions with iron overload, the storage of excess iron in various body tissues leads to complications and toxic damage. The most common presenting complaint for this disease is malaiselethargy and other non-specific symptoms. In order to diagnose hereditary hemochromatosis, there are biochemical, imaging and genetic testing options. Currently, cascade screening of affected families is preferred over population-level screening. The mainstay of treatment is venesection and the appropriate approach to treatment has been consolidated over the years. Recently, the indications for venesection therapy of hemochromatosis have been challenged and are the subject of ongoing research.


This is the practice guideline approved by the American Association for the Study of Liver Diseases (AASLD). It represents the position of the association. The full text contains the compete guideline, which provides a good overview of hereditary hemochromatosis (HHC) as well as other genetic and acquired iron overload conditions. The guideline provides 16 AASLD recommendations relative to the diagnosis and treatment of HHC. [Health-e-iron note: This report, and several other reports on this page, are centered on HHC and the liver and/or heart, which are the the organs typically most affected by iron overload in HHC. Other papers on this page cover other conditions, diseases and tissue sites that are also implicated in the damage processes associated with the most common HHC gene mutations or variants. These include several common cancer types and neurodegenerative diseases. The gene associated with hereditary iron overload is the HFE gene and the two most common gene variants are generally referred to as C282Y and H63D. Figure 3 and Table 5 from the Guideline are reproduced below]


 Fig. 3. An algorithm can provide some further direction regarding testing and treatment for HH. The algorithm is modified from the version used in the previous AASLD guidelines.

 

 

Increased Risk of Death from Iron Overload Among 422 Treated Probands with HFE Hemochromatosis and Serum Levels of Ferritin Above 1000 mg/L at Diagnosis (2) Free full text

The investigators in this 2012 reported study reviewed mortality statistics of 422 individuals who were measured with a ferritin of 1000 ng/mL or above when they were first diagnosed with HHC. "We compared serum levels of ferritin at diagnosis and other conditions with the rate of iron overload-associated death using data from 2 cohorts of probands with hemochromatosis who were homozygous for HFE C282Y (an Alabama cohort, n = 294, 63.9% men and an Ontario cohort, n = 128, 68.8% men)." "We defined iron overload-associated causes of death as cirrhosis (including hepatic failure and primary liver cancer) caused by iron deposition and cardiomyopathy caused by myocardial siderosis. All probands received phlebotomy and other appropriate therapy." "The mean survival times after diagnosis were 13.2 ± 7.3 y and 12.5 ± 8.3 y in Alabama and Ontario probands, respectively. Serum levels of ferritin greater than 1000 μg/L at diagnosis were observed in 30.1% and 47.7% of Alabama and Ontario probands, respectively." "Of probands with serum levels of ferritin greater than 1000 μg/L at diagnosis, 17.9% of those from Alabama and 14.8% of those from Ontario died of iron overload. Among probands with serum levels of ferritin greater than 1000 μg/L, the relative risk of iron overload-associated death was 5.4 for the Alabama group ... and 4.9 for the Ontario group..." The investigators concluded, "In hemochromatosis probands homozygous for HFE C282Y, serum levels of ferritin greater than 1000 μg/L at diagnosis were positively associated with male sex and cirrhosis. Even with treatment, the relative risk of death from iron overload was 5-fold greater in probands with serum levels of ferritin greater than 1000 μg/L."

 

Screening for hemochromatosis in asymptomatic subjects with or without a family history (3) Free full text

This 2006 Australian study provided the following background; "Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history." "We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks." "Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2-4) in 18.4% and 5.4%; and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic." The researchers concluded, "Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal." [Health-e-Iron note: the full paper contains several tables and figures that will help identify iron levels that are predictive of liver damage (fibrosis or cirrhosis) based on serum iron measurements (SF and TS%). Figure 4 (pg. 300) illustrates that significant liver fibrosis can be reversed by phlebotomy in cases that are diagnosed early (i.e. before cirrhosis occurs). The study directly below provides a good example of the benefits of being diagnosed before ferritin reaches 1000 ng/mL. Figure 3 and Table 5 from the Guideline are reproduced below. Table 3 and Figure 4 from this study are reproduced below]

Figure 4. Reduction in fibrosis following phlebotomy therapy. Twenty-five subjects underwent a second liver biopsy after phlebotomy. Five subjects were excluded from analysis owing to significant alcohol intake (60 g/d). In the remaining 20 subjects, the fibrosis score improved significantly following removal of iron by phlebotomy except where cirrhosis was present.


HFE Cys282Tyr homozygotes with serum ferritin concentrations below 1000 microg/L are at low risk of hemochromatosi(4) Free full text

This study undertaken in Australia reported, "We assessed HFE mutations in a prospective cohort of 31,192 participants of northern European descent, aged 40–69 years. An HFE-stratified random sample of 1,438 participants including all C282Y homozygotes with iron studies 12 years apart were examined by physicians blinded to HFE genotype. All previously undiagnosed C282Y homozygotes (35 male, 67 female) and all HFE wild-types (131 male, 160 female) with baseline and follow-up SF concentrations <1000 μg/L were assessed for HH-associated signs and symptoms including abnormal second/third metacarpophalangeal joints (MCP 2/3), raised liver enzymes, hepatomegaly, and self-reported liver disease, fatigue, diabetes mellitus, and use of arthritis medication. The prevalence of HH-associated signs and symptoms was similar for C282Y homozygotes and HFE wild-types for both normal and moderately elevated SF concentrations. The maximum prevalence difference between HFE genotype groups with moderately elevated SF was 11% (MCP 2/3 ... and for normal SF was 6% (arthritis medicine use, ....)" The researchers concluded, "Previously undiagnosed C282Y homozygotes with SF concentrations that remain below 1000 microg/L are at low risk of developing HH-associated signs and symptoms at an age when disease would be expected to have developed. These observations have implications for the management of C282Y homozygotes." [Health-e-Iron note: this investigation described the benefits of an early diagnosis of HHC. Importantly however, the scope of the investigation was limited to "classical" HHC-associated signs and symptoms and included only 35 C282Y homozygous males. There is no way of telling, based on the data developed in this study, whether C282Y homozygotes with ferritin below 1000 ng/mL are protected from other iron overload conditions (e.g. cancers or neurodegenerative diseases) described below on this page and in others areas on this web site."]

 

Impact of hemochromatosis gene (HFE) mutations on epithelial ovarian cancer risk and prognosis  (5) Free full text

This 2011 research was performed in Canada. The researchers reported, "In this study, we evaluated the frequency of the H63D and C282Y mutations in a cohort of 677 consecutive cases of woman with gynecological pathologies. Cases included 80 women with tumor-free pathologies normal ovary (NOV), 124 with benign ovarian tumors (BOV), 96 with epithelial ovarian cancer (EOC) tumors of low malignant potential (LPM), 264 with invasive tumors of the ovary (TOV) and 113 with endometrial cancer." "We found that the C282Y allele frequency in EOC patients was higher than that in the control NOV group (5.8% vs.1.3%, p < 0.001) and was associated with an increased risk of ovarian cancer (OR(odds ratio) = 4.88; ..." "EOC (epithelial ovarian cancer) patients with at least one C282Y allele had a decreased overall survival compared to those with no C282Y allele (p = 0.001). These results indicate that the C282Y mutation may increase the risk of developing ovarian cancer and may be further associated with poor outcomes." [Health-e-Iron note: There are approximately 10 million adult females in the U.S. with at least one C282Y allele. Iron Disorders Institute estimates that fewer than 5% of  potentially or currently affected adult females are aware of the HFE genetic status.]


Hemochromatosis and ovarian cancer (6) Free full text

This is a commentary on the research summarized directly above from the Prince Henry's Institute of Medicine in Australia. The "Executive summary" points (as listed at the end of the full text article) are as follows:

1) It is hypothesized that increased iron uptake associated with the iron storage disease hemochromatosis is also associated with a higher incidence of ovarian cancer.

2) The frequency of two mutations (C282Y, H63D) in heterozygous carriers of the hemochromatosis gene was assessed in 677 women consisting of 80 controls, 124 benign, 96 with low metastatic potential and 264 women with invasive ovarian tumors.

3) The proportion of women with a single allele of the C282Y mutation was significantly elevated in women with benign tumors and ovarian cancers (8–9%) compared with the control group (2.5%). This was reflected in a 4.9-fold increase in risk of developing ovarian cancer. No differences were observed with the H63D mutation.

4) Survival rates for women with high-grade serous ovarian cancer with the heterozygous C282Y mutation were halved from 39 to19 months.

5) While elevated iron uptake may be considered as an ovarian carcinogen, other hypotheses related to the roles of the hemochromatosis protein in immunity and reproductive status are also possible to explain these observations.

Health-e-Iron note: See additional research on ovarian cancer on our Iron-Cancer page articles 28-30


Risk of cancer by transferrin saturation levels and haemochromatosis genotype: population-based study and meta-analysis (7) Free full text

[This study also appears in our IRON-Cancer Library] In 2011 this research team from Denmark reported the following, "Increased iron overload, whether or not owing to the presence of the haemochromatosis genotype C282Y/C282Y, may be associated with an increased risk of cancer. The aim of this study was to test the hypothesis that elevated transferrin saturation levels (as a proxy for iron overload) and haemochromatosis genotype C282Y/C282Y are associated with an increased risk of cancer." The results were: "In women, transferrin saturation above 60% versus below 50% was associated with a hazard ratio of 3.6 ... for any cancer; risk of liver cancer was increased in both women and men. In women, the corresponding absolute 10-year risk of any cancer was 34% and 30% in smokers and nonsmokers, respectively. In men, haemochromatosis genotype C282Y/C282Y versus wild type/wild type was associated with a hazard ratio of 3.7... for any cancer, with a similar trend in women. In men, the corresponding absolute 10-year risk of cancer was 39% and 27% in smokers and nonsmokers, respectively." The researchers concluded, "We have demonstrated that elevated transferrin saturation levels in women and haemochromatosis genotype C282Y/C282Y in men are associated with increased risk of cancer. Thus, our results support the implementation of cancer screening programmes in patients with iron overload or with C282Y/C282Y." [Health-e-Iron note; Figures 1 and 2 from this study appear below. An important finding from this study was that the increased risk of cancer in those with transferrin saturation above 50% was greater than the risk of smoking among individuals having transferrin saturation below 50%. Smoking alone increased the risk of cancer significantly less than the risk of transferrin saturation above 50%. Smoking increased cancer risk by similar degrees across all levels of transferrin saturation]

Fig. 1 Absolute 10-year risk of any cancer by transferrin saturation levels and haemochromatosis genotype C282Y⁄C282Y. Based on 8,763 individuals from the Copenhagen City Heart Study followed for 15 years, during which time 1,417 developed cancer.

 

 Fig. 2 Meta-analysis of prospective studies of risk of any cancer (transferrin saturation ≤60% vs. reference group). The reference groups varied slightly across studies (≥30% to <60%) (see Supplementary Table S3). Horizontal lines indicate confidence intervals, and filled circles show the risk estimates.

 

Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy (8) Free full text

Also from Denmark, in 2010 this research team "hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH)." The researchers analyzed data from nearly 50,000 individuals. They found that "Adjusted hazard ratios for transferrin saturation ≥80% + C282Y⁄C282Y genotype compared to transferrin saturation <50% + wild type ⁄ wild type genotype was 2.3... overall ... and 3.1 ... in men ...; results were still significant after correction for multiple comparisons. Results in women were not significant." The researchers concluded, "We found that haemochromatosis genotype C282Y/C282Y and extremely elevated transferrin saturation either separately or combined were associated with increased risk of anti hypertensive medication use. Therefore, testing for haemochromatosis genotype C282Y/C282Y and extreme transferrin saturation could be considered in patients with essential hypertension." [Health-e-Iron note: Figure 1 and 2 from this study appear below]

Fig.1 Cumulative incidence of antihypertensive medication use. C282Yhaemochromatosis genotype (a), iron overload(b) or the combination of genotype and iron overload(c) in the Copenhagen General Population Study (CGPS) in men.TS, transferrin saturation.

Fig.2  Absolute 10-year risk of antihypertensive medication use. Risk is stratified by haemochromatosis genotype, iron overload (TS, transferrin saturation) or the combination of genotype and iron overload according to gender.

 

Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women (9) Free full text

In a study from the Netherlands reported in 1999 the researchers noted that "Heterozygosity for HH is associated with moderately increased iron levels and could be a risk factor for cardiovascular death." "We studied the relation between HH heterozygosity and cardiovascular death in a cohort study among 12,239 women 51 to 69 years of age residing in Utrecht, the Netherlands. Women were followed for 16 to 18 years (182,976 follow-up years). The allele prevalence of the HH gene in the reference group was 4.0 (95% CI 2.9 to 5.4). The mortality rate ratios for HH heterozygotes compared with wild types was 1.5 (95% CI 0.9 to 2.5) for myocardial infarction (n=242), 2.4 (95% CI 1.3 to 3. 5) for cerebrovascular disease (n=118), and 1.6 (95% CI 1.1 to 2.4) for total cardiovascular disease (n=530). The population-attributable risks of HH heterozygosity for myocardial infarction and cerebrovascular and total cardiovascular death were 3. 3%, 8.8%, and 4.0%, respectively." "In addition, we found evidence for effect modification by hypertension and smoking." The researchers concluded, "We found important evidence that inherited variation in iron metabolism is involved in cardiovascular death in postmenopausal women, especially in women already carrying classic risk factors." [Health-e-iron note: The researchers n this study analyzed mortality data from female C282Y heterozygotes compared to women not having a C282Y gene variant. C282Y heterozygotes carry a single mutation that was inherited from one of their parents. In the U.S there are approximately 10 million adult females who have inherited a single C282Y mutation. Iron Disorders Institute estimates that fewer than 5% of potentially or currently affected adult females are aware of the HFE genetic status.]

 

Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer (10) Free full text

This 2004 study was undertaken in the Tennessee. The researchers noted and hypothesized, "Individuals with the major hemochromatosis (HFE) allele C282Y and iron overload develop hepatocellular and some extrahepatic malignancies at increased rates. No association has been previously reported between the C282Y allele and breast cancer. We hypothesized that due to the pro-oxidant properties of iron, altered iron metabolism in C282Y carriers may promote breast carcinogenesis. Because 1 in 10 Caucasians of Northern European ancestry carries this allele, any impact it may have on breast cancer burden is potentially great." "We determined C282Y genotypes in 168 patients who underwent high-dose chemotherapy and blood cell transplantation for cancer: 41 with breast cancer and 127 with predominantly hematological cancers (transplant cohort)." "The frequency of at least one C282Y allele in breast cancers was higher (36.6%, 5 homozygotes/10 heterozygotes) than frequencies in Tennessee (12.7%, P < 0.001), the general population (12.4%, P < 0.001), and similarly selected nonbreast cancers (17.0%, P = 0.008)." "These results were supported by the finding in a nontransplant cohort of a higher frequency of C282Y mutations in Caucasian (18.4%, P = 0.039) and African-American (8.5%, P = 0.005) women with breast cancer than race-specific national frequency estimates." The researchers concluded, "A high prevalence of C282Y alleles in women with breast cancer with and without poor risk features suggests that altered iron metabolism in C282Y carriers may promote the development of breast cancer and/or more aggressive forms of the disease." [Health-e-Iron note: Table 3 from this study appears below]


The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation (11) Free full text

This 2005 study is also from Tennessee. The researchers stated, "Hepatic veno-occlusive disease (HVOD) is a serious complication of hematopoietic stem cell transplantation (HSCT). Since the liver is a major site of iron deposition in HFE-associated hemochromatosis, and iron has oxidative toxicity, we hypothesized that HFE genotype might influence the risk of HVOD after myeloablative HSCT." "We determined HFE genotypes in 166 HSCT recipients who were evaluated prospectively for HVOD. We also tested whether a common variant of the rate-limiting urea cycle enzyme, carbamyl-phosphate synthetase (CPS), previously observed to protect against HVOD in this cohort, modified the effect of HFE genotype."  "Risk of HVOD was significantly higher in carriers of at least one C282Y allele (RR=3.7,... and increased progressively with C282Y allelic dose (RR=1.7... in heterozygotes; RR=8.6, ... in homozygotes." "The researchers concluded "that HFE C282Y is a risk factor for HVOD and that CPS polymorphisms may counteract its adverse effects. Knowledge of these genotypes and monitoring of iron stores may facilitate risk-stratification and testing of strategies to prevent HVOD, such as iron chelation and pharmacologic support of the urea cycle."

 

HFE C282Y homozygotes are at increased risk of breast and colorectal cancer (12) Free full text

This 2010 research was generated in Australia. The researcher analyzed cancer registries following a 14-year period of individuals born in Australia, New Zealand, the United Kingdom, or Ireland, who had been genotyped for HFE C282Y. "Compared to those with no C282Y variant, C282Y homozygotes were at increased risk of colorectal cancer (HR = 2.28; ... and female C282Y homozygotes were at increased risk of developing breast cancer (HR = 2.39; .., but male C282Y homozygotes were not at increased risk for prostate cancer ... C282Y/H63D compound heterozygotes were not at increased risk for colorectal cancer .., breast cancer .., or prostate cancer ..." The researchers concluded, "HFE C282Y homozygotes have twice the risk of colorectal and breast cancer compared with those individuals without the C282Y variant."


Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer (13) Free full text

This 2003 reported study was led by researchers from the University of North Carolina, Chapel Hill. The researchers "...assessed the risk of colon cancer among individuals with and without HFE gene mutations." In this case-control study in North Carolina, "1,308 subjects participated (475 case patients, 833 control subjects). The allele frequencies of the H63D and C282Y mutations were greater among case patients (0.11 and 0.046, respectively) than among control subjects ..." "When we controlled for age, race, sex, red meat consumption, NSAID use, and total iron intake, subjects with any HFE gene mutation were more likely to have colon cancer than subjects with no HFE gene mutations (adjusted odds ratio [OR (odds ratio)] = 1.40, ... The magnitude of the effect was similar for both the H63D (adjusted OR = 1.44, 95% ... and C282Y mutations (adjusted OR = 1.39,...  "Among those with HFE mutations, cancer risk increased with increasing age and total iron intake." The researchers concluded, "HFE gene mutations are associated with an increased risk of colon cancer. Cancer risk is greatest in mutation carriers who are older or consume high quantities of iron."

 

Re: Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer (14) Free full text

This 2003 article is a letter from Dr. JL Sullivan in response to the research described directly above. The full text of this letter is followed by a response from Dr. N. Shaheen, the lead investigator of the above study. This research study was enrolled patients soon after the discovery of the HFE gene mutations, C282Y and H63D. In retrospect, significant additional research has been reported over the last decade that supports many of Dr. Sullivan's comments. [Health-e-Iron note: we have highlighted a section of Dr. Sullivan's letter to emphasize matters that are very relevant today]

 

Hereditary hemochromatosis genotypes and risk of ischemic stroke (15)

In this 2007 study from Denmark the researchers, "tested the hypothesis that the HFE genotypes H63D/H63D, H63D/wild type, C282Y/H63D, C282Y/C282Y, and C282Y/wild type are risk factors for symptomatic carotid atherosclerosis, ischemic cerebrovascular disease (ICVD), and ischemic stroke." "We performed an age- and gender-matched case-control study of 701 cases with symptomatic carotid atherosclerosis vs 2,777 controls, and a prospective study of 9,178 individuals from the Danish general population followed for 24 years, during which 504 developed ICVD, of whom 393 had ischemic stroke." "Genotype was not consistently associated with symptomatic carotid atherosclerosis. The cumulative incidences of ICVD and ischemic stroke by age were increased for H63D/H63D vs wild type/wild type ... H63D/H63D vs wild type/wild type had an age- and multifactorially adjusted hazard ratio of 2.0 ... and 2.1 ... for ICVD and of 2.4 ... and 2.8 ... for ischemic stroke; these remained significant after correction for multiple comparisons. Other hereditary hemochromatosis genotypes were not associated with ICVD or ischemic stroke." The researchers concluded, "Hereditary hemochromatosis H63D homozygosity predicts a two- to threefold risk of ICVD and ischemic stroke."

 

HFE Genotype, Parenchymal Iron Accumulation, and Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease (16)

In this 2009 reported study the investigators "studied clinical, histologic (liver biopsy samples for hepatocellular iron accumulation), serologic (iron and enzyme levels), and genetic (HFE genotype) data from 587 patients from Italy with NAFLD and 184 control subjects." "Iron accumulation predominantly in hepatocyes was associated with a 1.7-fold higher risk of a fibrosis stage greater than 1 (95% confidence interval [CI]: 1.2–2.3), compared with the absence of siderosis (after adjustment for age, body mass index, glucose tolerance status, and alanine aminotransferase level). Nonparenchymal/mixed siderosis was not associated with moderate/severe fibrosis (odds ratio, 0.72; 95% CI: 0.50–1.01). Hepatocellular siderosis was more prevalent in patients with HFE mutations than in those without; approximately one third of patients with HFE mutations had parenchymal iron accumulation (range, 29.8%–35.7%, depending on HFE genotype). Predominantly hepatocellular iron accumulation occurred in 52.7% of cases of patients with HFE mutations. There was no significant association between either the presence of HFE mutations or specific HFE genotypes and the severity of liver fibrosis. The investigators concluded, "Iron deposition predominantly in hepatocyes is associated with more severe liver damage in patients with NAFLD. However, HFE mutations cannot be used to identify patients with hepatocellular iron accumulation."

 

The influence of iron status and genetic polymorphisms in the HFE gene on the risk for postoperative complications after bariatric surgery: a prospective cohort study in 1,064 patients (16) Free full text

In this 2001 reported study from Pennsylvania, the researchers "...analyzed 1,064 extremely obese Caucasian individuals who underwent open and laparoscopic Roux-n-Y gastric bypass surgery at the Geisinger Clinic. Serum iron, ferritin, transferrin, and iron binding capacity were measured pre-operatively. All patients had intra-operative liver biopsies and were genotyped for the C282Y and H63D mutations in the HFE gene. Associations between surgical complications and serum iron measures, HFE gene status, and liver iron histology were determined." "We found that increased serum iron and transferrin saturation were present in patients with any post-operative complication, and that increased serum ferritin was also increased in patients with major complications. Increased serum transferrin saturation was also associated with wound complications in open RYGB, and transferrin saturation and ferritin with prolonged lengths of stay. The presence of 2 or more HFE mutations was associated with overall complications as well as wound complications in open RYGB. No differences were found in complication rates between those with stainable liver iron and those without." The researches concluded, "Serum iron status and HFE genotype may be associated with complications following RYGB surgery in the extremely obese."

 

Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis (17) Free full text

This 2010 study was undertaken to "To clarify the relationship between C282Y and H63D mutations and HCC, a meta-analysis including nine studies (1,102 HCC cases and 3,766 controls, mainly came from European populations) was performed." "Meta-analysis of nine studies showed that allele of C282Y was associated with HCC risk: RE OR reached 1.50.... Subgroup analysis of seven studies also showed Y allele was associated with HCC risk in healthy populations: RE OR reached 1.61 .... We further did subgroup analysis in alcoholic liver cirrhosis (LC) patients of four studies (224 cases and 380 controls) and found that both the dominant model and Y allele of C282Y were associated with HCC risk (FE OR reached 4.06, ... and 3.41..., respectively). "[Health-e-Iron note: Figure 1 from this study appears below]


Ferritin concentrations in synovial fluid are higher in osteoarthritis patients with HFE gene mutations (C282Y or H63D) (18)

This was a 2010 study reported in Australia. The investigators established this hypothesis: "In view of the clinical similarities between polyarticular osteoarthritis (POA) with metacarpophalangeal (MCP) joint involvement and the arthropathy that occurs in hereditary haemochromatosis (HH), it was hypothesized that osteochondral damage in both disorders may be due to localized iron overload. Accordingly, it was predicted that the concentration of ferritin in synovial fluid (SF) would be higher in OA patients with HFE gene mutations than in HFE wild-type (wt) OA patients. The aim of this study was to test this proposition." "Sequential patients with physician-diagnosed OA and, for comparison, diverse inflammatory diseases of the joints, who required diagnostic or therapeutic arthrocentesis, were studied. Participants underwent HFE genotyping. SF samples were assayed for ferritin and also for selected cytokines and matrix metalloproteinases (MMPs)." "Seventy-three patients with diverse rheumatic disorders were recruited. Of the 29 patients who had knee OA, 15 were wt (wild type) and 14 were heterozygous for HFE mutations (C282Y or H63D). Mean SF ferritin concentrations in the wt and heterozygous OA groups were 273 and 655 ng/mL, respectively ..." The researchers concluded, "A predicted difference in SF ferritin concentrations in patients with knee OA was confirmed. Concentrations of ferritin in the SF were found to be two- to threefold higher in knee OA patients with HFE gene mutations compared to wt patients. This finding is consistent with the possibility that, in OA patients with HFE gene mutations, localized iron overload may contribute either directly or indirectly to osteochondral damage, possibly in a similar way to that which occurs in the arthropathy that complicates HH."

 

HFE C282Y Homozygosity Is Associated with an Increased Risk of Total Hip Replacement for Osteoarthritis (19)

This 2011 study was also from Australia. The researchers "examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study." "Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, ... and bilateral total hip replacement (OR 5.86... for osteoarthritis, adjusting for age, sex, body mass index, and educational level." "C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement."

 

Hereditary hemochromatosis as a risk factor for joint replacement surgery  (20)

This study in Germany was reported in 2010. The prevalence of joint replacement surgery in hip, knee, and ankle joints because of secondary osteoarthritis was assessed in199 individuals with hereditary hemochromatosis. "Data were compared with 917 healthy subjects from the population-based Bruneck study." "A total of 32 of 199 individuals with hemochromatosis received joint replacement surgery with a total number of 52 joints replaced. Compared with expected rates in healthy individuals, patients with hemochromatosis had a significantly higher risk for joint replacement surgery (odds ratio 9.0; confidence interval, 4.6-17.4). Joint replacement occurred significantly earlier in life in patients with hemochromatosis; 21.9% of the patients with hemochromatosis and 1.7% of healthy individuals required joint replacement before the age of 50 years (P=.0027). Moreover, patients with hemochromatosis were more likely to require multiple joint replacements (8.5%) than the control group (expected rate 0.3%; P=.0001)." The researchers concluded, "Hemochromatosis is a risk factor for joint replacement surgery because of severe secondary osteoarthritis."

 

Total ankle arthroplasty in patients with hereditary hemochromatosis (21) Free full text

The researchers of this 2011-reported study from Switzerland noted, "More than half of patients with hereditary hemochromatosis (HH) have painful arthritis, often including hind foot osteoarthritis. Total ankle arthroplasty (TAA) is increasingly recommended for patients with painful ankle osteoarthritis."  "However, the pain relief and function experienced by patients continues to be debated particularly as compared with ankle fusion." "We retrospectively reviewed all 16 prospectively followed patients (21 implants) with HH who underwent ankle arthroplasty. They had an average age of 59.5 years at the time of surgery. We obtained a visual analog scale for pain, the SF-36, and the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score. Component stability was assessed using weightbearing radiographs. The minimum followup was 3.1 years (average, 5.3 years; range, 3.1-8.6 years)." The researchers concluded, "Our data suggest TAA in patients with ankle osteoarthritis secondary to HH is associated with a low risk of postoperative complications and produces pain relief and good function."

 

Musculoskeletal disease burden of hereditary hemochromatosis (22) Free full text

The objective of this 2010 study report in Germany was "To determine the prevalence, clinical picture, and disease burden of arthritis in patients with hereditary hemochromatosis." "In this cross-sectional observational study of 199 patients with hemochromatosis and iron overload, demographic and disease-specific variables, genotype, and organ involvement were recorded." "Joint pain was reported by 72.4% of the patients. Their mean ± SD age at the time of the initial joint symptoms was 45.8 ± 13.2 years. If joint pain was present, it preceded the diagnosis of hemochromatosis by a mean ± SD of 9.0 ± 10.7 years. Bony enlargement was observed in 65.8% of the patients, whereas synovitis was less common (13.6%). Joint space narrowing and osteophytes as well as chondrocalcinosis of the wrist and knee joints were frequent radiographic features of hemochromatosis. Joint replacement surgery was common, with 32 patients (16.1%) undergoing total joint replacement surgery due to severe OA. The mean ± SD age of these patients was 58.3 ± 10.4 years at time of joint replacement surgery. Female sex, metacarpophalangeal joint involvement, and the presence of chondrocalcinosis were associated with a higher risk of early joint failure (i.e., the need for joint replacement surgery)." The researchers concluded, "Arthritis is a frequent, early, and severe symptom of hemochromatosis. Disease is not confined to involvement of the metacarpophalangeal joints and often leads to severe damage requiring the replacement of joints."

 

HFE C282Y homozygosity is associated with an increased risk of total hip replacement for osteoarthritis (23) 

The investigators of this 2012-reported study undertaken in Australia "...examined the relationship between HFE gene mutations and risk of total hip and knee replacement using a prospective cohort study." "Compared with those with no C282Y mutation, C282Y homozygotes had an increased risk of single total hip replacement (HR 1.94, 95% CI 1.04-3.62) and bilateral total hip replacement (OR 5.86, 95% CI 2.36-14.57) for osteoarthritis, adjusting for age, sex, body mass index, and educational level. Only 3 C282Y homozygotes had single total knee replacement; the HR was 0.51 (95% CI 0.16-1.57). C282Y/H63D compound heterozygosity was not related to the risk of total hip or knee replacement." The investigators concluded, "HFE C282Y homozygosity was associated with an increased risk of both single and bilateral total hip replacement for osteoarthritis."

 

Increased risk of arthropathies and joint replacement surgery in patients with genetic hemochromatosis (24)

This is a 2012 report from Sweden. Investigators reported "Arthropathy is one of the few complications of GH (hereditary hemochromatosis) suggested not to be associated with the iron body stores; synovial iron deposition remains in iron-depleted patients." "...."We therefore assessed risks for arthropathy and joint replacement surgery in patients with GH, and in their first-degree relatives (FDR). Methods: We performed a population-based cohort study of 3,531 patients with GH and of 11,794 FDRs (assumed to be heterozygous for the C282Y mutation) using Swedish nationwide, population-based, health- and census registers..... "Results: Between 1997 and 2005, 406 of 3,531 patients were reported/hospitalized with any non-infectious arthropathies including osteoarthritis corresponding to a HR of 2.38(95% CI, 2.14-2.64). Patients were also at increased risk for hip (HR=2.77, 95% CI, 2.27-3.38) and knee replacemen(HR=2.14, 95% CI, 1.58-2.88) surgery. Among the 11,794 FDRs (patients excluded) we found no increased risk for any of the joint morbidities." The investigators concluded, "Patients with GH, but not their FDRs, are at increased risk for arthropathies, including the need for joint replacement surgery."

 

High Prevalence of Fibromyalgia in Patients with HFE-related Hereditary Hemochromatosis  (25)

This 2012-published was based on research done in Ireland. The researchers noted, "Subjects with HFE-related hereditary hemochromatosis (HH) may present with arthralgias, fatigue, and stiffness, yet little is known on the presence of fibromyalgia syndrome (FMS) in these subjects. We determined the prevalence of FMS in a cohort of subjects with HH and evaluated its relationship to subject demographics, disease status, and quality of life. METHODS:: In a cross-sectional study we collected data on 395 consecutive subjects diagnosed with HH who were attending a tertiary referral Hepatology outpatient clinic at Galway University Hospital, Ireland (between October 2009 and June 2010). Subjects underwent a standard assessment including history, clinical examination, and functional assessments for pain and disability. Univariate logistic regression was applied to determine risk factors independently associated with prevalent FMS in these subjects. RESULTS:: Three hundred ninety-five subjects met the inclusion criteria. Mean age was 43 years (range, 21 to 59 y) and 260 (66%) were males. One hundred seventy (43%) of the subjects were diagnosed with FMS. Among those with fibromyalgia fatigue and ≥11 tender points were present in all of the subjects, widespread pain in 150 (88%), depression in 70 (41%), and arthralgia/joint stiffness in 70 (41%). In subjects with FMS 33% reported some functional impairment (HAQ-DI>0), with 10% reporting moderate-severe functional impairment (HAQ-DI≥1.5)." The researchers concluded, "This study reveals a high prevalence of FMS (43%) among subjects with HFE-related hemochromatosis. Prospective studies are needed to better understand the risk factors for FMS in such patients."

 

Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men (26) Free full text

This 2010 reported research from The David Geffen School of Medicine at UCLA noted, "Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimer's disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinson's disease, where it has been reported to contribute to younger age at onset in men." "The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76." "47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI  (iron content of ferritin molecules) compared to IRON- men (p=0.013). The researchers concluded, "Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases."

 

Gender and iron genes may modify associations between brain iron and memory in healthy aging (27) 

This study was reported in 2011. The researchers reported, "Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON-) status (for HFE H63D/TfC2) modify the associations." "Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=-0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON- group (r=-0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups."

 

HFE gene variants affect iron in the brain (28) Free full text

In this 2011 review, the authors describe how one of the common hemochromatosis gene variants, H63D, (approximately 74 million people in the U.S. have at least one H63D mutation) "...is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. "This review discusses, "the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke." [Health-e-Iron note: This review, plus a number of other related papers, appears on our page: "Oxidative Stress and Neurodegeneration; Parkinson's, Alzheimer's, Huntington's, Multiple Sclerosis"]

 

HFE C282Y homozygotes have reduced LDL cholesterol: the Atherosclerosis Risk in Communities (ARIC) Study (29) Free full text

This 2008 study, lead by researchers from the University of Minnesota "examined cardiovascular disease risk factors and iron and liver biomarkers, as well as morbidity and mortality associated with the C282Y and H63D variants of HFE in the Atherosclerosis Risk in Communities (ARIC) study, which is a population-based cohort of nearly 16,000 U.S. white and black men and women who were 45-64 years old at baseline."  "Subjects were followed for an average of 15 years for death, incident coronary heart disease, stroke, and heart failure, and an average of 8 years for incident diabetes. The prevalence of C282Y homozygosity was 0.42% (45/10,800) in whites, which is similar to other North American population-based studies. C282Y homozygotes had significantly lower mean low-density lipoprotein (LDL) cholesterol and fibrinogen as well as higher mean levels of iron (ferritin, transferrin saturation) and liver biomarkers (alanine aminotransferase, Hepascore) compared with HFE wild-type subjects." "Rates of all-cause mortality, cardiovascular disease, and diabetes were similar across HFE genotypes. These prospective, population-based data indicate higher serum iron indices and possible mild liver dysfunction or disease in some C282Y homozygotes, but they provide little evidence that HFE C282Y or H63D mutations are related to all-cause mortality, cardiovascular disease, or diabetes."

 

HFE C282Y homozygosity is associated with lower total and low-density lipoprotein cholesterol: The hemochromatosis and iron overload screening study (30) Free full text

In 2009 a study very similar to the one described directly above was reported by investigators engaged in the Hemochromatosis and Iron Overload Screening study screened 101,168 participants in primary care from 5 field centers in the United States and Canada with serum ferritin, transferrin saturation, and HFE genotyping for C282Y and H63D mutations. "The proportion of subjects who reported using prescription cholesterol-lowering medications was approximately 3 times higher in HFE wild-type subjects than C282Y homozygotes among men (22% versus 7%; P=0.02) and, in women, 2 times higher (16% versus 8%; P=0.07)." "After excluding subjects taking cholesterol medications, C282Y homozygotes had significantly lower mean total and low-density lipoprotein cholesterol concentrations than wild-type subjects, with larger genotypic differences for low-density lipoprotein in men (-0.62 mmol/L; ...) than in women (-0.28 mmol/L; 95%, ...." The investigators concluded, "Total mean serum cholesterol and low-density lipoprotein levels were lower in C282Y homozygotes than in HFE wild-type participants. Further studies are required to determine whether this is related to iron overload, HFE alleles, or other factors on C282Y-positive chromosome 6p haplotypes." [Health-e-Iron note: This protective phenomena associating C282Y homozygosity with lower LDL cholesterol that was reported in this and the preceding study appears to be well supported by these and other studies. The most plausible explanation of this (we believe) is put forth in the full text letter from Dr. Jerome Sullivan (see directly below)]

 

Letter by Sullivan regarding article, "HFE C282Y homozygosity is associated with lower total and low-density lipoprotein cholesterol: the hemochromatosis and iron overload screening study" (31) Free full text

An excerpt from Dr. Sullivan's 2010 letter follows: "Protection against cardiovascular disease by iron depletion has been proposed. A frequent objection to this hypothesis has been that it is incompatible with the apparently lower prevalence of cardiovascular disease in hemochromatosis. The physiology of hepcidin suggests an explanation for the contradiction of a protective role for iron depletion, despite less cardiovascular disease in massive iron overload. Both iron deficiency and homozygosity for C282Y are characterized by very low levels of hepcidin with consequently low iron concentrations in the macrophage. It has been proposed that homozygous hemochromatosis may confer some specific protection against atherogenesis because of diminished iron load in atherosclerotic plaque macrophages. One possible contributing mechanism for such protection could involve the associated lower levels of cholesterol and low-density lipoprotein reported by Adams et al."


Hemochromatosis and iron-overload screening in a racially diverse population (32) Free full text

This 2005 report was the first of several papers that were published following "The Hemochromatosis and Iron Overload Screening (HEIRS) study. (This study) was designed to evaluate the prevalence, genetic and environmental determinants, and potential clinical, personal, and societal effects of iron overload and hemochromatosis in a multicenter, multiethnic sample of 101,168 primary care adults 25 years of age or older." The ethnicities of the 99,711 participants (36.5% men), and their respective percentage of the population tested, were: White; 44.2%, Native American; .6%, Hispanic; 12.6%, Black; 27.2%, Pacific Islander: .7%,, Asian; 12.8%, Multiple/unknown; 1.9%. There were a total of 299 C282Y homozygotes (i.e. 2 copies of the C282Y mutation), of whom 227 (76%) had not previously been diagnosed with iron overload. 16.7% of the participants (n=  16,609) had serum ferritin (SF) indicative of iron overload, or above 400 ng/mL in men or 300 ng/mL in women. Of 364 participants with SF above 1,000 ng/mL, only 29 (8%) were C282Y homozygotes. 13.6% (n= 13,582) had transferrin saturation percentages above 45%. Significantly more details from this study are described in the full text. [Health-e-Iron note: although the majority of C282Y homozygotes were White, each of the other minority populations had a greater relative percentage of participants with SF above 1,000 ng/mL (see study #2 above; in that study C282Y homozygotes participants who were first diagnosed with SF above 1,000 ng/mL experienced a 5-fold increased mortality risk even when treated thereafter with appropriate therapy). When the the number of participants with SF above 1,000 (n=364) is extrapolated the the U.S. adult population, the result indicates that as many as 700,000 U.S. adults may have SF above 1,000 ng/mL (prior to a gender adjustment increase to normalize M/F distribution). The distribution of HFE genotypes in the population studied is summarized in Table 1 below]


 


African Americans at risk for increased iron stores or liver disease (33) Free full text

This paper was published in 2007. It was based on the above-described HEIRS study population. The researchers "sought to determine the prevalence of elevated measures of iron status in African Americans and whether the combination of serum ferritin concentration >200 microg/L for women or >300 microg/L for men and transferrin saturation in the highest quartile represents increased likelihood of mutation of HFE, self-reported iron overload or self-reported liver disease." Among 27,224 African Americans 25 years of age or older, "Serum ferritin concentration >200 ng/mL for women or >300 ng/mL for men occurred in 5,263 (19.3%) of African Americans, while serum ferritin concentration in this range with highest-quartile transferrin saturation (>29% women; >35% men) occurred in 1,837 (6.7%)." "...self-reported liver disease (5.18 women, 3.73 men) were greater with elevated serum ferritin concentration and highest-quartile transferrin saturation than with nonelevated serum ferritin concentration (each P <.05)." The researchers concluded, "Serum ferritin concentration >200 ng/mL for women or >300 ng/mL for men in combination with transferrin saturation >29% for women or >35% for men occurs in approximately 7% of adult African American primary care patients. Patients with this combination of iron test results should be evaluated for increased body iron stores or liver disease."

 

Serum ferritin concentrations and body iron stores in a multicenter, multiethnic primary-care population (34) Free full text

This 2008 research was another study based on data from the HEIRS study. In a follow-up evaluation, the researchers employed qualitative phlebotomy to estimate hepatic iron stores in a sample population of 122 C282Y homozygotes and 122 non-C282Y homozygotes. "The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900ng/mL at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g(rams) in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 ng/mL 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. The researchers concluded, "...serum ferritin >900 ng/mL 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 microg/L in male C282Y homozygotes is predictive of moderately increased iron stores."

 

Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first-degree relatives: a nationwide, population-based study (35) 

This 2012-reported study was undertaken in Sweden. The investigators noted, "Iron-loaded macrophages increase atherosclerosis formation. Genetic haemochromatosis (GH) is an autosomal recessive disease characterized by iron overload, for example in the myocardium, but the reticuloendothelial system is depleted of iron. In contrast to the elevated risk of cardiomyopathy in GH, the risk of ischaemic heart disease (IHD) may therefore not be increased. Little is known of these risks among heterozygotes also being first-degree relatives (FDRs), thus sharing other factors for phenotypic expression of GH." The aim of the investigation was to "To assess the risks of IHD and cardiomyopathy among haemochromatosis patients and their FDRs." "A total of 3,531 haemochromatosis patients and 11,794 FDRs were identified using nationwide, population-based health and census registers. Matched (1:10) population controls were randomly selected. Individuals with a record of IHD and cardiomyopathy during 1997-2005 were identified through linkage with the National Patient Register. Relative risks were estimated using Cox proportional hazard regression." "Of the 3,531 patients, 259 were diagnosed with IHD compared with 3,077 of the 37,369 controls [hazard ratio (HR) = 1.17; 95% CI, 1.03-1.33]. Based on 30 patients versus 115 controls, the HR for cardiomyopathy was 3.21 (95% CI, 2.15-4.81). Of 11,794 FDRs of haemochromatosis patients, 582 were registered with IHD compared with 6,197 among FDRs of controls (HR = 1.05; 95% CI, 0.97-1.15). Based on 28 FDRs of patients versus 291 FDRs of controls registered with cardiomyopathy, the HR for cardiomyopathy was 1.06 (95% CI, 0.72-1.56)." The investigators concluded, "In patients with haemochromatosis, the increased risk of cardiomyopathy is much more pronounced than that of IHD, which is barely elevated. FDRs of haemochromatosis patients are not at increased risk of cardiomyopathy or IHD."





A video slide presentation about the genetic tests for Hereditary Hemochromatosis

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A video from the Canadian Hemochromatosis Society answering the question - What is Hemochromatosis?

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An Important Video from Chris Kressor, MS, LAc - July 2013

"Iron Behaving Badly"

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VIDEO LINKS

[Health-e-Iron note: Reminder, when GGT is elevated, glutathione and most other antioxidants are insufficient!]

"Understanding Antioxidants" (2:31)

"Antioxidants vs. free radicals" (3:10)


Dr. Mercola on "Is iron helping or slowly killing you?"

Dr. Mercola on iron as "anti-antioxidant?" (8:44)


To learn more about the antioxidant protection afforded by various fruits, you can read more on this site:

 Fruitsinfo.com