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1.
FASEB J ; 37(11): e23245, 2023 11.
Article in English | MEDLINE | ID: mdl-37874260

ABSTRACT

Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.


Subject(s)
Hemochromatosis , Iron Overload , Osteoporosis , Animals , Mice , Iron/metabolism , Hepcidins/genetics , Hepcidins/metabolism , Hemochromatosis/genetics , Alkaline Phosphatase/metabolism , Hemochromatosis Protein/genetics , Histocompatibility Antigens Class I/genetics , Iron Overload/complications , Iron Overload/genetics , Iron Overload/metabolism , Liver/metabolism , Osteoporosis/genetics , Collagen/metabolism , Mice, Knockout
2.
JAMA Netw Open ; 6(10): e2338995, 2023 10 02.
Article in English | MEDLINE | ID: mdl-37870835

ABSTRACT

Importance: HFE gene-associated hereditary hemochromatosis type 1 (HH1) is underdiagnosed, resulting in missed opportunities for preventing morbidity and mortality. Objective: To assess whether screening for p.Cys282Tyr homozygosity is associated with recognition and management of asymptomatic iron overload. Design, Setting, and Participants: This cross-sectional study obtained data from the Geisinger MyCode Community Health Initiative, a biobank of biological samples and linked electronic health record data from a rural, integrated health care system. Participants included those who received a p.Cys282Tyr homozygous result via genomic screening (MyCode identified), had previously diagnosed HH1 (clinically identified), and those negative for p.Cys282Tyr homozygosity between 2017 and 2018. Data were analyzed from April 2020 to August 2023. Exposure: Disclosure of a p.Cys282Tyr homozygous result. Main Outcomes and Measures: Postdisclosure management and HFE-associated phenotypes in MyCode-identified participants were analyzed. Rates of HFE-associated phenotypes in MyCode-identified participants were compared with those of clinically identified participants. Relevant laboratory values and rates of laboratory iron overload among participants negative for p.Cys282Tyr homozygosity were compared with those of MyCode-identified participants. Results: A total of 86 601 participants had available exome sequences at the time of analysis, of whom 52 994 (61.4%) were assigned female at birth, and the median (IQR) age was 62.0 (47.0-73.0) years. HFE p.Cys282Tyr homozygosity was disclosed to 201 participants, of whom 57 (28.4%) had a prior clinical HH1 diagnosis, leaving 144 participants who learned of their status through screening. There were 86 300 individuals negative for p.Cys282Tyr homozygosity. After result disclosure, among MyCode-identified participants, 99 (68.8%) had a recommended laboratory test and 36 (69.2%) with laboratory or liver biopsy evidence of iron overload began phlebotomy or chelation. Fifty-three (36.8%) had iron overload; rates of laboratory iron overload were higher in MyCode-identified participants than participants negative for p.Cys282Tyr homozygosity (females: 34.1% vs 2.1%, P < .001; males: 39.0% vs 2.9%, P < .001). Iron overload (females: 34.1% vs 79.3%, P < .001; males: 40.7% vs 67.9%, P = .02) and some liver-associated phenotypes were observed at lower frequencies in MyCode-identified participants compared with clinically identified individuals. Conclusions and Relevance: Results of this cross-sectional study showed the ability of genomic screening to identify undiagnosed iron overload and encourage relevant management, suggesting the potential benefit of population screening for HFE p.Cys282Tyr homozygosity. Further studies are needed to examine the implications of genomic screening for health outcomes and cost-effectiveness.


Subject(s)
Hemochromatosis , Iron Overload , Male , Infant, Newborn , Humans , Female , Middle Aged , Aged , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Hemochromatosis/therapy , Cross-Sectional Studies , Hemochromatosis Protein/genetics , Iron Overload/diagnosis , Iron Overload/genetics , Iron Overload/complications , Genetic Testing
3.
J Biol Chem ; 298(12): 102667, 2022 12.
Article in English | MEDLINE | ID: mdl-36334631

ABSTRACT

The HFE (Homeostatic Fe regulator) gene is commonly mutated in hereditary hemochromatosis. Blood of (HFE)(-/-) mice and of humans with hemochromatosis contains toxic nontransferrin-bound iron (NTBI) which accumulates in organs. However, the chemical composition of NTBI is uncertain. To investigate, HFE(-/-) mice were fed iron-deficient diets supplemented with increasing amounts of iron, with the expectation that NTBI levels would increase. Blood plasma was filtered to obtain retentate and flow-through solution fractions. Liquid chromatography detected by inductively coupled plasma mass spectrometry of flow-through solutions exhibited low-molecular-mass iron peaks that did not increase intensity with increasing dietary iron. Retentates yielded peaks due to transferrin (TFN) and ferritin, but much iron in these samples adsorbed onto the column. Retentates treated with the chelator deferoxamine (DFO) yielded a peak that comigrated with the Fe-DFO complex and originated from iron that adhered to the column in the absence of DFO. Additionally, plasma from younger and older 57Fe-enriched HFE mice were separately pooled and concentrated by ultrafiltration. After removing contributions from contaminating blood and TFN, Mössbauer spectra were dominated by features due to magnetically interacting FeIII aggregates, with greater intensity in the spectrum from the older mice. Similar features were generated by adding 57FeIII to "pseudo plasma". Aggregation was unaffected by albumin or citrate at physiological concentrations, but DFO or high citrate concentrations converted aggregated FeIII into high-spin FeIII complexes. FeIII aggregates were retained by the cutoff membrane and adhered to the column, similar to the behavior of NTBI. A model is proposed in which FeII entering blood is oxidized, and if apo-TFN is unavailable, the resulting FeIII ions coalesce into FeIII aggregates, a.k.a. NTBI.


Subject(s)
Hemochromatosis , Iron , Humans , Mice , Animals , Iron/metabolism , Hemochromatosis/genetics , Transferrin , Ferritins , Plasma
4.
Eur J Nutr ; 61(6): 2967-2977, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35320401

ABSTRACT

OBJECTIVES: We developed a natural polyphenol supplement that strongly chelates iron in vitro and assessed its effect on non-heme iron absorption in patients with hereditary hemochromatosis (HH). METHODS: We performed in vitro iron digestion experiments to determine iron precipitation by 12 polyphenol-rich dietary sources, and formulated a polyphenol supplement (PPS) containing black tea powder, cocoa powder and grape juice extract. In a multi-center, single-blind, placebo-controlled cross-over study, we assessed the effect of the PPS on iron absorption from an extrinsically labelled test meal and test drink in patients (n = 14) with HH homozygous for the p.C282Y variant in the HFE gene. We measured fractional iron absorption (FIA) as stable iron isotope incorporation into erythrocytes. RESULTS: Black tea powder, cocoa powder and grape juice extract most effectively precipitated iron in vitro. A PPS mixture of these three extracts precipitated ~ 80% of iron when 2 g was added to a 500 g iron solution containing 20 µg Fe/g. In the iron absorption study, the PPS reduced FIA by ~ 40%: FIA from the meal consumed with the PPS was lower (3.01% (1.60, 5.64)) than with placebo (5.21% (3.92, 6.92)) (p = 0.026)), and FIA from the test drink with the PPS was lower (10.3% (7.29 14.6)) than with placebo (16.9% (12.8 22.2)) (p = 0.002). CONCLUSION: Our results indicate that when taken with meals, this natural PPS can decrease dietary iron absorption, and might thereby reduce body iron accumulation and the frequency of phlebotomy in patients with HH. TRIAL REGISTRY: clinicaltrials.gov (registration date: 9.6.2019, NCT03990181).


Subject(s)
Hemochromatosis , Adult , Cross-Over Studies , Hemochromatosis/drug therapy , Hemochromatosis/genetics , Hemochromatosis/metabolism , Hemochromatosis Protein , Histocompatibility Antigens Class I/genetics , Humans , Iron , Iron, Dietary , Polyphenols/pharmacology , Powders , Single-Blind Method , Tea
5.
Genes (Basel) ; 12(9)2021 08 25.
Article in English | MEDLINE | ID: mdl-34573286

ABSTRACT

Type 1 hereditary hemochromatosis (HH) is an autosomal, recessive genetic entity with systemic iron overload. Iron homeostasis disorders develop as a result of HFE gene mutations, which are associated with hepcidin arthropathy or osteoporosis and may cause permanent disability in HH patients despite a properly conducted treatment with phlebotomies. In this study, selected parameters of calcium and phosphate metabolism were analyzed in combination with the assessment of bone mineral density (BMD) disorders in patients from northern Poland with clinically overt HFE-HH. BMD was determined by a dual-energy X-ray absorptiometry (DXA) test with the use of the trabecular bone score (TBS) function. The study included 29 HH patients (mean age = 53.14 years) who were compared with 20 healthy volunteers. A significantly lower TBS parameter and serum 25-OH-D3 concentration, a higher concentration of intact parathormone and more a frequent occurrence of joint pain were found in HH patients compared with the control group. In HH patients, the diagnosis of liver cirrhosis was associated with lower serum 25-OH-D3 and osteocalcin concentrations. In HH, DXA with the TBS option is a valuable tool in the early assessment of the bone microarchitecture and fracture risk. A supplementation of vitamin D, monitoring its concentration, should be considered especially in HH patients with liver damage and liver cirrhosis.


Subject(s)
Arthralgia/epidemiology , Cancellous Bone/diagnostic imaging , Hemochromatosis/congenital , Osteoporosis/diagnosis , Osteoporotic Fractures/epidemiology , Absorptiometry, Photon/statistics & numerical data , Adult , Aged , Arthralgia/genetics , Bone Density/genetics , Case-Control Studies , Female , Healthy Volunteers , Hemochromatosis/blood , Hemochromatosis/genetics , Hemochromatosis Protein/genetics , Humans , Male , Middle Aged , Mutation , Osteoporosis/genetics , Osteoporotic Fractures/genetics , Poland/epidemiology , Risk Assessment/methods , Risk Assessment/statistics & numerical data
6.
Clin Res Hepatol Gastroenterol ; 45(2): 101658, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33676066

ABSTRACT

INTRODUCTION AND OBJECTIVES: The goal of this study was to assess lifestyle habits and physician counseling of patients with hereditary hemochromatosis (HH), and determine the prevalence of direct-to-consumer (DTC) genetic testing. MATERIALS AND METHODS: A 52-question survey was created to collect information on lifestyle habits and physician counseling among patients with HH, and the use of DTC genetic testing of patients referred to a clinic for evaluation of HH. A multivariate logistic regression model was applied to identify predictors of DTC genetic testing use. RESULTS: The survey was e-mailed to 379 patients, of which 101 responded (26.6%). Among patients with HH, 37% reported alcohol use more than once weekly and 50% reported red meat consumption. The use of a vitamin C supplement was reported by 38.9% of participants. Among patients with living children and siblings, physicians failed to recommend HH screening 15.3% and 21.2% of the time respectively. Thirty-one patients reported DTC genetic testing, of which 46.7% (14/31) reported their DTC genetic test screened for HH. Six (19%) of those patients were prompted to see a specialist in HH based on the results. CONCLUSIONS: Among patients with HH, lifestyle habits that may impact iron stores are common, but not all receive appropriate counseling. Direct-to-consumer genetic testing is common, and physicians should be aware of its limitations when patients seek further evaluation for HH based on their test results.


Subject(s)
Hemochromatosis , Physicians , Child , Counseling , Genetic Testing , Habits , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Hemochromatosis Protein , Humans , Life Style
7.
Clin Res Hepatol Gastroenterol ; 45(6): 101624, 2021 11.
Article in English | MEDLINE | ID: mdl-33676282

ABSTRACT

AIM: Hereditary hemochromatosis (HH) is a group of inherited disorders that causes a slow and progressive iron deposition in diverse organs, particularly in the liver. Iron overload induces oxidative stress and tissue damage. Coenzyme Q10 (CoQ10) is a cofactor in the electron-transport chain of the mitochondria, but it is also a potent endogenous antioxidant. CoQ10 interest has recently grown since various studies show that CoQ10 supplementation may provide protective and safe benefits in mitochondrial diseases and oxidative stress disorders. In the present study we sought to determine CoQ10 plasma level in patients recently diagnosed with HH and to correlate it with biochemical, genetic, and histological features of the disease. METHODS: Plasma levels of CoQ10, iron, ferritin, transferrin and vitamins (A, C and E), liver tests (transaminases, alkaline phosphatase and bilirubin), and histology, as well as three HFE gene mutations (H63D, S654C and C282Y), were assessed in thirty-eight patients (32 males, 6 females) newly diagnosed with HH without treatment and in twenty-five age-matched normolipidemic healthy subjects with no HFE gene mutations (22 males, 3 females) and without clinical or biochemical signs of iron overload or liver diseases. RESULTS: Patients with HH showed a significant decrease in CoQ10 levels respect to control subjects (0.31 ±â€¯0.03 µM vs 0.70 ±â€¯0.06 µM, p < 0.001, respectively) independently of the genetic mutation, cirrhosis, transferrin saturation, ferritin level or markers of hepatic dysfunction. Although a decreasing trend in CoQ10 levels was observed in patients with elevated iron levels, no correlation was found between both parameters in patients with HH. Vitamins C and A levels showed no changes in HH patients. Vitamin E was significantly decreased in HH patients (21.1 ±â€¯1.3 µM vs 29.9 ±â€¯2.5 µM, p < 0.001, respectively), but no correlation was observed with CoQ10 levels. CONCLUSION: The decrease in CoQ10 levels found in HH patients suggests that CoQ10 supplementation could be a safe intervention strategy complementary to the traditional therapy to ameliorate oxidative stress and further tissue damage induced by iron overload.


Subject(s)
Ataxia , Hemochromatosis , Mitochondrial Diseases , Muscle Weakness , Ubiquinone/deficiency , Ataxia/epidemiology , Case-Control Studies , Female , Hemochromatosis/blood , Hemochromatosis/epidemiology , Hemochromatosis/genetics , Humans , Male , Mitochondrial Diseases/epidemiology , Muscle Weakness/epidemiology , Ubiquinone/analogs & derivatives , Ubiquinone/blood
8.
Eur J Gastroenterol Hepatol ; 33(10): 1327-1331, 2021 10 01.
Article in English | MEDLINE | ID: mdl-32769410

ABSTRACT

BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) may reduce iron absorption and serum ferritin levels in patients with homeostatic iron regulator (HFE)-related hemochromatosis, reducing the need for frequent phlebotomies. Our study aimed to perform for the first time a meta-analysis of existing observational and randomized controlled studies to ascertain the overall effect of PPI use in patients with HFE-related hemochromatosis. METHODS: Studies in adults reporting the outcomes of PPIs use in hereditary hemochromatosis patients from Medline, Embase, Scopus and Google Scholar databases from inception to December 2019 were systematically searched. The study outcomes were the serum ferritin levels and annual requirement for phlebotomies. Pooled mean difference, and 95% confidence intervals (CIs) were obtained by the random-effects model. Forrest plots were constructed to show the summary pooled estimate. Heterogeneity was assessed by using I2 measure of inconsistency. RESULTS: Following an initial search of 202 manuscripts, a total of three studies involving 68 patients with hemochromatosis (34 in the PPIs group and 34 in the placebo or non-PPI group) were included. A minimum duration of PPI use was 1 year. Patients who received PPIs therapy did not have a statistically significant lower serum ferritin levels (mean difference: -18.86, 95% CI: -60.44, 22.72, P = 0.37, I2 = 88%) but required significantly less sessions of phlebotomies annually (mean difference: -3.10, 95% CI: -4.46, -3.08, P < 0.00001, I2 = 93%). No publication bias was found on Egger (P = 0.94) or Begg (P = 0.98) tests. CONCLUSION: PPIs can be used as an adjuvant therapy to reduce phlebotomy burden in patients with HFE-related hemochromatosis.


Subject(s)
Hemochromatosis , Proton Pump Inhibitors , Adult , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Hemochromatosis/therapy , Hemochromatosis Protein/genetics , Humans , Observational Studies as Topic , Phlebotomy , Proton Pump Inhibitors/therapeutic use
9.
Signal Transduct Target Ther ; 5(1): 138, 2020 07 31.
Article in English | MEDLINE | ID: mdl-32732975

ABSTRACT

Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe-/- mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-κB pathway. In C57BL/6J mice, acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe-/- mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe-/- mice. Notably, high-dose AUR (25 mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.


Subject(s)
Auranofin/pharmacology , Ferroptosis/drug effects , Hemochromatosis , Iron Overload , Signal Transduction/drug effects , Animals , Cell Line, Tumor , Female , Ferroptosis/genetics , HEK293 Cells , Hemochromatosis/drug therapy , Hemochromatosis/genetics , Hemochromatosis/metabolism , Hemochromatosis/pathology , Humans , Iron Overload/drug therapy , Iron Overload/genetics , Iron Overload/metabolism , Iron Overload/pathology , Male , Mice , Mice, Knockout , Signal Transduction/genetics
10.
FASEB J ; 33(12): 14625-14635, 2019 12.
Article in English | MEDLINE | ID: mdl-31690120

ABSTRACT

Ferroportin 1 (FPN1) is a major facilitator superfamily transporter that is essential for proper maintenance of human iron homeostasis at the systemic and cellular level. FPN1 dysfunction leads to the progressive accumulation of iron in reticuloendothelial cells, causing hemochromatosis type 4A (or ferroportin disease), an autosomal dominant disorder that displays large phenotypic heterogeneity. Although crystal structures have unveiled the outward- and inward-facing conformations of the bacterial homolog Bdellovibrio bacteriovorus Fpn (or Bd2019) and calcium has recently been identified as an essential cofactor, our molecular understanding of the iron transport mechanism remains incomplete. Here, we used a combination of molecular modeling, molecular dynamics simulations, and Ala site-directed mutagenesis, followed by complementary in vitro functional analyses, to explore the structural architecture of the human FPN1 intracellular gate. We reveal an interdomain network that involves 5 key amino acids and is likely very important for stability of the iron exporter facing the extracellular milieu. We also identify inter- and intradomain interactions that rely on the 2 Asp84 and Asn174 critical residues and do not exist in the bacterial homolog. These interactions are thought to play an important role in the modulation of conformational changes during the transport cycle. We interpret these results in the context of hemochromatosis type 4A, reinforcing the idea that different categories of loss-of-function mutations exist. Our findings provide an unprecedented view of the human FPN1 outward-facing structure and the particular function of the so-called "gating residues" in the mechanism of iron export.-Guellec, J., Elbahnsi, A., Le Tertre, M., Uguen, K., Gourlaouen, I., Férec, C., Ka, C., Callebaut, I., Le Gac, G. Molecular model of the ferroportin intracellular gate and implications for the human iron transport cycle and hemochromatosis type 4A.


Subject(s)
Cation Transport Proteins/deficiency , Hemochromatosis/genetics , Molecular Dynamics Simulation , Mutation , Cation Transport Proteins/chemistry , Cation Transport Proteins/genetics , Cation Transport Proteins/metabolism , HEK293 Cells , Humans , Iron/metabolism , Protein Domains
11.
Med Hypotheses ; 122: 134-138, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30593397

ABSTRACT

Cystic fibrosis, hereditary hemochromatosis and palmar fibromatosis are often described as "Celtic", based on their contemporary prevalence. The former two are among genetically defined disorders that seem to provide survival advantages to heterozygote individuals, while severe health problems happen in homozygote mutation carriers. Although palmar fibromatosis has no defined mutations, its prevalence has been linked to the prevalence of Y-Chromosome Haplogroup I that expanded after the Last Ice Age, thus making th distribution of all three "Celtic" diseases dependent on the global climate from 40 to 8 Kya. During the Last Ice Age, the global climate was dry and dark due to dust-laden atmosphere (20-25 times more than today). It has been postulated that skin pigmentation was related to insolation, UV protection and skin synthesis of vitamin D, so when our ancestors moved to Eurasia, individuals with pale skin became advantageous. Deficiency of vitamin D has several health consequences and some of them have been proposed by other authors as important for the spreading of cystic fibrosis mutations: rickets/osteomalacia; susceptibility to diarrheal diseases and tuberculosis and salt induced arterial hypertension. The here proposed link is between vitamin D deficiency and the anaemia of chronic disease that might have facilitated spreading of the hemochromatosis mutation. It seems plausible that the risk of health problems in the offspring of close relatives might have resulted in social taboos of consanguinity in Eurasian protosocieties. Ancient steam bath rituals seem linked to lower incidences of cystic fibrosis in several European populations, thus suggesting health protection in an arid, dusty climate of the last glaciation, that made CFTR mutations in heterozygote carriers less advantageous.


Subject(s)
Climate , Cystic Fibrosis/epidemiology , Dupuytren Contracture/epidemiology , Dust , Hemochromatosis/epidemiology , Human Migration/history , Anemia , Consanguinity , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Dupuytren Contracture/genetics , Europe , Hemochromatosis/genetics , Heterozygote , History, Ancient , Homozygote , Humans , Mutation , Risk , Vitamin D Deficiency
12.
Ann Hepatol ; 17(5): 871-879, 2018 Aug 24.
Article in English | MEDLINE | ID: mdl-30145563

ABSTRACT

INTRODUCTION AND AIM: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. MATERIAL AND METHODS: We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. RESULTS: Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metacarpophalangeal joints, mean serum ferritin, elevated alanine aminotransferase, elevated aspartate aminotransferase, and mean iron removed; and significantly fewer mean blood pints/units donated. GNPAT p.D519G positivity was detected in 82 of 188 participants (43.6%). In a multivariable model for cirrhosis, there were four significant positive associations: age (10-y intervals) (odds ratio 2.2 [95% confidence interval 1.5, 3.3]); diabetes (3.3; [1.1, 9.7]); alcohol intake (14 g alcohol drinks/d) (1.5 [1.2, 1.8]); and iron removed, g (1.3 [1.2, 1.4]). There was no statistical evidence of two-way interactions between these variables. CONCLUSION: In conclusion, cirrhosis in HFE p.C282Y homozygotes is significantly associated with age, diabetes, daily alcohol intake, and iron removed by phlebotomy, taking into account the effect of other variables.


Subject(s)
Hemochromatosis Protein/genetics , Hemochromatosis/genetics , Homozygote , Liver Cirrhosis/genetics , Mutation , Acyltransferases/genetics , Adult , Age Factors , Alcohol Drinking/adverse effects , Alcohol Drinking/epidemiology , Australia/epidemiology , Comorbidity , Cross-Sectional Studies , Diabetes Mellitus/epidemiology , Female , Genetic Predisposition to Disease , Hemochromatosis/diagnosis , Hemochromatosis/epidemiology , Hemochromatosis/therapy , Humans , Liver Cirrhosis/epidemiology , Liver Cirrhosis/pathology , Male , Middle Aged , Phenotype , Phlebotomy , Polymorphism, Single Nucleotide , Prevalence , Risk Assessment , Risk Factors , United States/epidemiology
13.
Hepatol Int ; 12(2): 83-86, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29589198

ABSTRACT

Although guidelines are available for hereditary hemochromatosis, a high percentage of the recommendations within them are not shared between the different guidelines. Our main aim is to provide an objective, simple, brief, and practical set of recommendations about therapeutic aspects of HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype, based on the published scientific studies and guidelines, in a form that is reasonably comprehensible to patients and people without medical training. This final version was approved at the Hemochromatosis International meeting on 12th May 2017 in Los Angeles.


Subject(s)
Hemochromatosis , Female , Humans , Male , Chelation Therapy/methods , Diet , Hemochromatosis/genetics , Hemochromatosis/therapy , Hemochromatosis Protein/genetics , Homozygote , Phlebotomy/methods
14.
J Med Case Rep ; 12(1): 18, 2018 Jan 26.
Article in English | MEDLINE | ID: mdl-29373985

ABSTRACT

BACKGROUND: Juvenile hemochromatosis is the most severe form of iron overloading phenotype. Although rare, it should be suspected in patients who present with hypogonadotropic hypogonadism, diabetes mellitus, or cardiomyopathy without a clear cause. CASE PRESENTATION: A young Serbian male presenting with end-stage heart failure was referred for extracorporeal membrane oxygenation. An endomyocardial biopsy revealed cytoplasmic iron deposits in myocytes. His condition was stabilized with biventricular assist devices and he was listed for heart transplantation. Iron chelation therapy was commenced and resulted in rapid removal of iron burden. Serial outpatient echocardiograms demonstrated myocardial recovery such that a successful biventricular assist device explant occurred 131 days after initial implant. Targeted gene sequencing revealed a loss-of-function mutation within the HJV gene, which is consistent with juvenile hemochromatosis. CONCLUSIONS: This rare case of a patient with juvenile hemochromatosis associated with a HJV mutation provides histologic evidence documenting the reversal of associated end-stage heart failure, requiring emergent mechanical circulatory support, with iron chelation therapy.


Subject(s)
Chelation Therapy , Deferoxamine/therapeutic use , Heart Failure/diagnostic imaging , Heart Failure/therapy , Hemochromatosis/therapy , Iron Chelating Agents/therapeutic use , Adult , Biopsy , Echocardiography , Ferritins/blood , Heart Failure/etiology , Heart Ventricles/pathology , Hemochromatosis/complications , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Hemochromatosis Protein , Humans , Liver/pathology , Loss of Function Mutation , Male , Tomography, X-Ray Computed
15.
Free Radic Biol Med ; 115: 127-135, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29157668

ABSTRACT

Iron promotes formation of hydroxyl radicals by the Fenton reaction, subsequently leading to potential oxidatively generated damage of nucleic acids. Oxidatively generated damage to RNA, measured as 8-oxo-7,8-dihydroguanosine (8-oxoGuo) in urine, is increased in patients with genetic iron overload, which have led us to test the hypothesis that high iron status, assessed by iron biomarkers and genetic disposition, increases urinary excretion of 8-oxoGuo. In a general Danish population study we used a Mendelian randomization design with HFE genotypes as a proxy for iron status and supplemented with ex vivo experiments in mice muscle tissue exposed to iron(II) sulfate to attempt to clarify this hypothesis. The biomarkers ferritin, transferrin, and transferrin saturation (TS) were associated with 8-oxoGuo (in linear univariable and multivariable regression analyses: P < 0.001). Mendelian randomization indicated a causal pathway between genetically elevated iron biomarkers (assessed by ferritin and TS) and high levels of 8-oxoGuo. The ex vivo experiments showed a monotonically increase in 8-oxoGuo with increased iron concentration (ANOVA: P = 0.0008) that was prevented with iron chelation (P = 0.01). Our results indicate a causal relationship between iron biomarkers and 8-oxoGuo. Furthermore, the ex vivo experiment shows a mechanistic link between iron and 8-oxoGuo formation. Both iron overload and the biomarker 8-oxoGuo have been linked to e.g. diabetes, which merits future studies to investigate if iron induced 8-oxoGuo is involved in disease development.


Subject(s)
Biomarkers/urine , Diabetes Mellitus/metabolism , Genotype , Guanosine/analogs & derivatives , Hemochromatosis Protein/genetics , Hemochromatosis/metabolism , Iron Overload/metabolism , Iron/metabolism , Adult , Aged , Animals , Cross-Sectional Studies , Denmark , Diabetes Mellitus/genetics , Female , Guanosine/urine , Hemochromatosis/genetics , Humans , Iron Overload/genetics , Male , Mice , Mice, Inbred C57BL , Middle Aged , Oxidation-Reduction , Polymorphism, Single Nucleotide , RNA/metabolism
16.
Presse Med ; 46(12 Pt 2): e288-e295, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29158016

ABSTRACT

The term hemochromatosis (HC) corresponds to several diseases characterized by systemic iron overload of genetic origin and affecting both the quality of life and life expectancy. Major improvement in the knowledge of iron metabolism permits to divide these diseases into two main pathophysiological categories. For most HC forms (types 1, 2, 3 and 4B HC) iron overload is related to cellular hepcidin deprivation which causes an increase of plasma iron concentration and the appearance of plasma non-transferrin bound iron. In contrast, iron excess in type 4A ferroportin disease is related to decreased cellular iron export. Whatever the HC type, the diagnosis rests on a non-invasive strategy, combining clinical, biological and imaging data. The mainstay of the treatment remains venesection therapy with the perspective of hepcidin supplementation for hepcidin deprivation-related HC. Prevention of HC is critical at the family level and, for type 1 HC, remains a major goal, although still debated, at the population level.


Subject(s)
Hemochromatosis/genetics , Hemochromatosis/diagnosis , Hemochromatosis/physiopathology , Hemochromatosis/therapy , Hepcidins/physiology , Humans , Iron/metabolism
17.
Drug Discov Ther ; 10(3): 177-80, 2016.
Article in English | MEDLINE | ID: mdl-27301711

ABSTRACT

Non-arteritic posterior ischemic optic neuropathy (NA-PION) is a disorder involving reduced blood flow to the retrobulbar portion of the optic nerve. This disorder usually develops acutely, and research has suggested that high-dose steroid therapy soon after the onset of visual loss can result in significant visual improvement. This treatment, however, is not universally successful. The addition of a potent vasodilator could help to restore ocular blood flow. This case report describes the use of prostaglandin E1 (PGE1), a powerful vasodilator of the microcirculation, to treat three separate episodes of NA-PION over five years in the same patient. A 68-year-old white male was first seen in June 2009 with NA-PION in the left eye, and the condition was treated with steroids and PGE1. The patient had a subsequent episode in July 2010 that was treated with steroids and PGE1 and another in May 2014 that was treated with PGE1 alone. Visual acuity improved from 4/10 to 11/10 in 2009, from 4/10 to 11/10 in 2010, and from 5/10 to 10/10 in 2014. No complications due to the use of PGE1 were noted. PGE1 should be considered as a treatment for NA-PION to immediately restore blood flow and potentially improve vision.


Subject(s)
Alprostadil/adverse effects , Alprostadil/therapeutic use , Optic Neuropathy, Ischemic/chemically induced , Vasodilator Agents/adverse effects , Vasodilator Agents/therapeutic use , Aged , Hemochromatosis/complications , Hemochromatosis/genetics , Humans , Male , Microcirculation/drug effects , Optic Neuropathy, Ischemic/diagnostic imaging , Retinal Artery/drug effects , Retinal Artery Occlusion/drug therapy , Ultrasonography, Doppler, Color , Visual Acuity/drug effects
18.
Lancet ; 388(10045): 706-16, 2016 Aug 13.
Article in English | MEDLINE | ID: mdl-26975792

ABSTRACT

Haemochromatosis is now known to be an iron-storage disease with genetic heterogeneity but with a final common metabolic pathway resulting in inappropriately low production of the hormone hepcidin. This leads to increase in intestinal absorption and deposition of excessive amounts of iron in parenchymal cells which in turn results in eventual tissue damage and organ failure. A clinical enigma has been the variable clinical expression with some patients presenting with hepatic cirrhosis at a young age and others almost asymptomatic for life. Research is unravelling this puzzle by identifying environmental factors-especially alcohol consumption-and associated modifying genes that modulate phenotypic expression. A high index of suspicion is required for early diagnosis but this can lead to presymptomatic therapy and a normal life expectancy. Venesection (phlebotomy) therapy remains the mainstay of therapy, but alternative therapies are the subject of current research.


Subject(s)
Alcohol Drinking/adverse effects , Genetic Testing , Hemochromatosis , Hepcidins/deficiency , Iron/metabolism , Liver/metabolism , Mutation , Phlebotomy , Cation Transport Proteins/genetics , Disease Management , Environmental Exposure , Europe/epidemiology , Ferritins/blood , Genotype , Hemochromatosis/diagnosis , Hemochromatosis/genetics , Hemochromatosis/physiopathology , Hemochromatosis/therapy , Hemochromatosis Protein , Histocompatibility Antigens Class I/genetics , Humans , Liver/drug effects , Liver Diseases/etiology , Liver Diseases/physiopathology , Liver Diseases/therapy , Mass Screening/methods , Mass Screening/standards , Membrane Proteins/genetics , Phenotype , Polymorphism, Single Nucleotide , Receptors, Transferrin/genetics , Risk Factors , Sex Factors , Uncertainty , White People/genetics
19.
Bull Acad Natl Med ; 200(2): 309-325, 2016 Feb.
Article in English | MEDLINE | ID: mdl-29898327

ABSTRACT

Due to major advances in the understanding of iron metabolism as well as in the bioche- iuical, imaging, and genetic domains: i) The nosologicalframework of hemochromatosis (HC) encompasses not only HFE-HC, by far the most frequent HC form, but also non-HFE HC diseases which comprise essentially juvenile HC and the ferroportin disease. ii) The diagnostic approach has become totally non invasive, based on clinical, imaging and biological data. iii) The treatment remains, for most forms, based on venesections, but the innovative emerging therapeutic approach is represented by hepcidin supplementation.


Subject(s)
Hemochromatosis/diagnosis , Hemochromatosis/therapy , Cation Transport Proteins/metabolism , Hemochromatosis/classification , Hemochromatosis/genetics , Hepcidins/administration & dosage , Humans
20.
Environ Toxicol Pharmacol ; 40(3): 931-5, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26513689

ABSTRACT

Oxidative stress can be induced by increased concentrations of iron in the body and consequently can cause shortening of telomeres. Telomeres, called mitotic clocks, are non-coding fragments at the end of chromosomes. During the replication of genetic material they are shortened, playing the role of ageing biomarkers in eukaryotes. In human endothelial cells, oxidative stress causes a decrease in telomerase activity. Shortening of chromosomes in telomeric parts was found in patients with primary hemochromatosis and in patients taking supplements containing iron. Increased level of transferrin saturation is associated with the presence of shorter telomeres in the chromosomes of leukocytes. The relationship between iron status and telomere length is still not fully understood.


Subject(s)
Iron/adverse effects , Oxidative Stress , Telomere/drug effects , Endothelial Cells/cytology , Endothelial Cells/metabolism , Gene Expression Regulation/drug effects , Hemochromatosis/genetics , Humans , Telomerase/metabolism , Telomere Shortening , Transferrin/metabolism
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