I built this compendium of information attempting to remember what might be good about having genetic hemochromatosis along with what was definitely bad. Some of this did not copy in well at all, but the links work to the original source of anything that is hard to read.
Good:
TB and Typhoid: The hemochromatosis C282Y mutation is present in up to 12.5% of people in populations of northern and central European origin. The prevalence of this mutation suggests that it may confer some type of epidemiologic advantage. One hypothesis has proposed that female heterozygotes have enhanced dietary iron absorption during their reproductive years, but evidence in support of this concept is not available. A second hypothesis is based on the observation that macrophages in iron-loaded C282Y homozygotes are very low in iron. These persons would be predicted to have increased resistance to pathogens that require iron for growth in macrophages. Notable examples of such pathogens are S. typhi and M. tuberculosis, the bacteria that cause typhoid fever and tuberculosis. Several cellular models that provide evidence for the low-iron macrophage hypothesis have recently been described.
http://muse.jhu.edu/login?auth=0&&url=/journals/perspectives_in_biology_and_medicine/v051/51.1weinberg.html
Salmonella: Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis.
http://bloodjournal.hematologylibrary.org/content/114/17/3642.long
Arteriosclerosis:
Low hepcidin expression is a mutational effect of hemochromatosis and a feature of systemic iron deficiency that may protect against iron-mediated atherogenesis in both conditions. What is known at present about disease patterns in genetic iron overload is compatible with the hypothesis that iron depletion protects against cardiovascular disease. Hereditary hemochromatosis may represent a special case of selective cellular iron depletion that inhibits atherogenesis.
http://circgenetics.ahajournals.org/content/2/6/652.full
Parkinson’s:
Iron homeostasis is altered in Parkinson’s disease (PD) hereditary haemochromatosis
possession of the 282Tyr allele may offer some protection against the development of PD (Buchanan et al. 2002).
Bad:
Osteoarthritis: This is the first report to show an increased risk of OA among individuals who are heterozygous for the C282Y HFE mutation. The increase in this mutation in patients older than 65 suggests that this is associated with a late onset subset of OA.
http://www.ncbi.nlm.nih.gov/pubmed/12508400
Natural history, diagnosis and management of subclinical thyroid dysfunctionB Biondi - Best Practice & Research Clinical Endocrinology & …, 2012
... [1], [2] and [8] Transient or persistent increases in serum TSH may occur after subacute,
post-partum or painless thyroiditis and after an infiltrative disease (Riedel's thyroiditis, amyloidosis,
hemochromatosis and cystinosis) or infectious disorder of the thyroid gland. [1], [2] and [8]. ...
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039363
Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to InflammationLittle is known about the frequency of pulmonary infections in HH patients. Because neutrophils are an important first line of defense against bacterial pathogens, our results in a murine disease model suggest that HH may be associated with increased susceptibility to bacterial infections of the respiratory system. Further, we speculate that Hfe may be implicated in bacterial host defense, as well as acute and chronic neutrophilic inflammatory processes of the lung in subjects without HH, and may thus serve as a novel target for anti-infective and anti-inflammatory therapies for common lung diseases including pneumonia, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and cystic fibrosis.
http://scholar.google.com/scholar_url?hl=en&q=http://dx.plos.org/10.1371/journal.pone.0039363&sa=X&scisig=AAGBfm01lxn3zTljcaiCl8hOl0Q9MrXIDg&oi=scholaralrt
http://www.sciencedirect.com/science/article/pii/S0304394005004519
Ristic et al. (2005) found that HFE polymorphisms do not contribute to the susceptibility
to multiple sclerosis (MS) but MS patients carrying the mutant C282Y allele exhibited earlier
onset of disease symptom relative to other genotypes.
High frequency of heterozygosity for the C282Y mutation in patients with alcoholic
cirrhosis plus hepatocellular carcinoma suggests the presence of this mutation could be associated with an increased risk of developing hepatocellular carcinoma (Lauret et al. 2002). HH patients with HCV present with advanced fibrosis/cirrhosis at a younger age and at a lower hepatic iron concentration compared to HH patients without HCV (Diwakaran et al. 2002). The
association between hepatocellular carcinoma and HFE homozygosity is well documented, but
recently HFE hetero- and homozygosity has also been linked to non-hepatocellular malignancies, including female breast cancer. Syrjakoski et al. 2005 showed that C282Y and H63D mutations could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility but carriers of both BRCA2 9346(-2)→G and an HFE mutation is at an increased risk at the population level in Finland. According to Abraham et al. ( 2 0 0 5 ) v a r i a n t s o f t h e h emo c h r oma t o s i s -transferrin receptor system have no direct effect
on the incidence of breast cancer in Germany.
Blood donation is simultaneously associated with increased insulin sensitivity and decreased iron stores. Stored iron seems to impact negatively on insulin action even inhealthy people, and not just in classic pathologic c o n d i t i o n s a s s o c i a t e d wi t h i r o n o v e r l o a d
( h e m o c h r o m a t o s i s a n d h e m o s i d e r o s i s ) (Fernandez-Real 2005). Early diagnosis and treatment by phlebotomy can improve blood glucose control in the early stages of the disease. If diagnosis occurs later, when the patient already needs insulin therapy, diabetes will not be improved by phlebotomy (Thielen et al. 2005).
Candore et al. (2003) reported negative association between the HFE mutations and ageing in Alzheimer disease patients from North Italy. While Pulliam et al. (2003) reported strong association of HFE mutation with neurodegeration and oxidative stress in Alzheimer disease and correlation with APOE.
Haba-Rubio et al. (2005) suggests that local brain iron deficiency may occur in patients with
haemochromatosis this shows a role for brain iron metabolism in the pathophysiology of
restless legs syndrome (RLS).
The list of infectious disease agents whose virulence is enhanced by iron continues to increase (Table 1).5
These pathogens include bacteria (Gram-negative and Gram-positive), fungi, and viruses.
Table 1. Organisms whose growth in body fluids, cells, tissues, and intact vertebrate hosts is known to be stimulated by excess iron
FungiCandida, Cryptococcus, Histoplasma, Paracoccidioides, Rhizopus, Trichosporon, Aspergillus, PneumocystisProtozoaEntamoeba, Leishmania, Naegleria, Plasmodium, Toxoplasma, TrypanosomaGram-positive and acid-fast bacteriaBacillus, clostridia, corynebacteria, Erysipelothrix, Listeria, mycobacteria, staphylococci, streptococci, GemellaGram-negative bacteriaAcinetobacter, Aeromonas, Alcaligenes, Capnocytophaga, Campylobacter, Chlamydia, Ehrlichia, Enterobacter, Escherichia, Klebsiella, Legionella, Moraxella, Neisseria, Pasteurella, Proteus, Pseudomonas, Plesiomonas, Shigella, Vibrio, YersiniaVirusesHepatitis B and C, cytomegalovirus, parvovirus, HIV
Modified, with permission, from Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis 1999;5:346–52.
http://www.sciencedirect.com/science/article/pii/S1201971207000811
Hemochromatosis and infectionsA review of medical literature on Medline for the period January 1940 to January 2007, confirms McClatchie et al. as being some of the first authors to describe the association of sudden release of ferritin, previously shown to be a vasodepressor substance,34 into the circulation and shock in a patient with hemochromatosis.35 Jones suggested a possible link between infection and shock in hemochromatosis as one patient was found to have E. coli bacteremia.36 Since that time there have been numerous reports of patients with hemochromatosis having increased susceptibility to infections.
Various infections caused by organisms including Vibrio vulnificus, [8] and [37] non-01 Vibrio cholerae,38E. coli, [36], [39] and [40]Yersinia enterocolitica [13], [41], [42] and [43] and pseudotuberculosis,44L. monocytogenes,[45] and [46]P. shigelloides,47G. haemolysans,48 cytomegalovirus,49 hepatitis B,50 C,51 and G virus,52 and HIV53 have been reported in association with hemochromatosis. Fungi including A. fumigatus54 and Rhizopus species [23] and [55] have also been described (Table 2). There is an article in German that describes parvovirus in association with hemochromatosis.56
Table 2. Various organisms and associated clinical diagnoses in patients with hemochromatosis
OrganismClinical scenario/infection [reference]Course/outcomePlesiomonas shigelloidesSepticemia [47]Twelve weeks of ofloxacin therapy instituted due to intolerance to other antimicrobialsGemella haemolysansEndocarditis [48]Two weeks of penicillin G/tobramycin with sterilization of blood culturesEscherichia coliSeptic shock [ [36], [39] and [40]]Death after 24 hours of onset, despite inotropic supportMeningitis [40]Meningitis responded to a 3 week/5 day course of IV/IT moxalactam and gentamicin, respectivelyListeria monocytogenesMeningitis/endocarditis and pericarditis [45]DeathVibrio vulnificusFever, emesis diarrhea with shock. There was history of ingestion of raw oysters [37]Death 7 hours after admission, despite aggressive medical supportNon-O1 Vibrio cholerae (NOVC)Painful edema/erythema left leg with bacteremia [38]Forty-five day therapy with oral doxycycline until resolution of cellulitisYersinia pseudotuberculosisBacteremia with aldosterone deficiency [44]Multiple antimicrobials including erythromycinYersinia enterocoliticaSeptic yersinosis [14]Oral ciprofloxacin 750 mg bid for 6 monthsLiver abscess [ [13], [41] and [43]]Oral ciprofloxacin 500 mg every 8 hours for 23 daysPeritonitis [42]Oral doxycycline 400 mg every day for 8 weeksSkin infection [43]Oral trimethoprim–sulfamethoxazole for 2 weeks after initial 9-day course of IV chloramphenicol in case 1. Oral doxycycline for 7 weeks in case 2. Oral trimethoprim–sulfamethoxazole for 6 weeksMucor species, includingPeriorbital cellulitis [23]Patient in case with ‘Mucor spp’ underwent right orbital exenteration. On postoperative day 5, patient expired after a hemorrhagic strokeCunninghamella bertholletiaeRhinocerebral mucormycosis [55]Patient diedAspergillus fumigatusPeritonitis in patient who underwent orthotopic liver transplant [54]Death secondary to liver failureHepatitis B, C and GHBV carrier [50]Severity of chronic hepatitis is linked with degree of iron deposition. Patients with chronic HBV and HCV have greater prevalence of C282Y and C2824 hemochromatosis gene mutations, respectively.Chronic HCV [51]High prevalence of hepatitis G found virus in hemochromatosisCryptogenic hepatitis [52]Cytomegalovirus (CMV)Intrauterine CMV infection; inclusions in hepatocytes, biliary epithelial cells, renal tubular epithelium. Concomitant intracellular iron seen in viscera [49]1500 g cyanotic neonate died 1.5 hours after birthParvovirusRefractory anemia [56]69-year-old woman with hemochromatosis and myelodysplastic syndrome
http://www.sciencedirect.com/science/article/pii/S1201971207000811
Interesting:
Occult celiac disease (CD) may compensate for increased divalent metal ion transporter 1
(DMT1) expression in a specific subset of individuals with homozygous C282Y mutations
in the HFE gene, thus contributing to the low penetrance of HH (Geier et al. 2005).
http://www.ncbi.nlm.nih.gov/pubmed/22720276
Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation.
RESULTS:No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.
CONCLUSION:These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.
Good:
TB and Typhoid: The hemochromatosis C282Y mutation is present in up to 12.5% of people in populations of northern and central European origin. The prevalence of this mutation suggests that it may confer some type of epidemiologic advantage. One hypothesis has proposed that female heterozygotes have enhanced dietary iron absorption during their reproductive years, but evidence in support of this concept is not available. A second hypothesis is based on the observation that macrophages in iron-loaded C282Y homozygotes are very low in iron. These persons would be predicted to have increased resistance to pathogens that require iron for growth in macrophages. Notable examples of such pathogens are S. typhi and M. tuberculosis, the bacteria that cause typhoid fever and tuberculosis. Several cellular models that provide evidence for the low-iron macrophage hypothesis have recently been described.
http://muse.jhu.edu/login?auth=0&&url=/journals/perspectives_in_biology_and_medicine/v051/51.1weinberg.html
Salmonella: Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis.
http://bloodjournal.hematologylibrary.org/content/114/17/3642.long
Arteriosclerosis:
Low hepcidin expression is a mutational effect of hemochromatosis and a feature of systemic iron deficiency that may protect against iron-mediated atherogenesis in both conditions. What is known at present about disease patterns in genetic iron overload is compatible with the hypothesis that iron depletion protects against cardiovascular disease. Hereditary hemochromatosis may represent a special case of selective cellular iron depletion that inhibits atherogenesis.
http://circgenetics.ahajournals.org/content/2/6/652.full
Parkinson’s:
Iron homeostasis is altered in Parkinson’s disease (PD) hereditary haemochromatosis
possession of the 282Tyr allele may offer some protection against the development of PD (Buchanan et al. 2002).
Bad:
Osteoarthritis: This is the first report to show an increased risk of OA among individuals who are heterozygous for the C282Y HFE mutation. The increase in this mutation in patients older than 65 suggests that this is associated with a late onset subset of OA.
http://www.ncbi.nlm.nih.gov/pubmed/12508400
Natural history, diagnosis and management of subclinical thyroid dysfunctionB Biondi - Best Practice & Research Clinical Endocrinology & …, 2012
... [1], [2] and [8] Transient or persistent increases in serum TSH may occur after subacute,
post-partum or painless thyroiditis and after an infiltrative disease (Riedel's thyroiditis, amyloidosis,
hemochromatosis and cystinosis) or infectious disorder of the thyroid gland. [1], [2] and [8]. ...
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0039363
Hfe Deficiency Impairs Pulmonary Neutrophil Recruitment in Response to InflammationLittle is known about the frequency of pulmonary infections in HH patients. Because neutrophils are an important first line of defense against bacterial pathogens, our results in a murine disease model suggest that HH may be associated with increased susceptibility to bacterial infections of the respiratory system. Further, we speculate that Hfe may be implicated in bacterial host defense, as well as acute and chronic neutrophilic inflammatory processes of the lung in subjects without HH, and may thus serve as a novel target for anti-infective and anti-inflammatory therapies for common lung diseases including pneumonia, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and cystic fibrosis.
http://scholar.google.com/scholar_url?hl=en&q=http://dx.plos.org/10.1371/journal.pone.0039363&sa=X&scisig=AAGBfm01lxn3zTljcaiCl8hOl0Q9MrXIDg&oi=scholaralrt
http://www.sciencedirect.com/science/article/pii/S0304394005004519
Ristic et al. (2005) found that HFE polymorphisms do not contribute to the susceptibility
to multiple sclerosis (MS) but MS patients carrying the mutant C282Y allele exhibited earlier
onset of disease symptom relative to other genotypes.
High frequency of heterozygosity for the C282Y mutation in patients with alcoholic
cirrhosis plus hepatocellular carcinoma suggests the presence of this mutation could be associated with an increased risk of developing hepatocellular carcinoma (Lauret et al. 2002). HH patients with HCV present with advanced fibrosis/cirrhosis at a younger age and at a lower hepatic iron concentration compared to HH patients without HCV (Diwakaran et al. 2002). The
association between hepatocellular carcinoma and HFE homozygosity is well documented, but
recently HFE hetero- and homozygosity has also been linked to non-hepatocellular malignancies, including female breast cancer. Syrjakoski et al. 2005 showed that C282Y and H63D mutations could contribute to male breast cancer (MBC) and prostate cancer (PC) susceptibility but carriers of both BRCA2 9346(-2)→G and an HFE mutation is at an increased risk at the population level in Finland. According to Abraham et al. ( 2 0 0 5 ) v a r i a n t s o f t h e h emo c h r oma t o s i s -transferrin receptor system have no direct effect
on the incidence of breast cancer in Germany.
Blood donation is simultaneously associated with increased insulin sensitivity and decreased iron stores. Stored iron seems to impact negatively on insulin action even inhealthy people, and not just in classic pathologic c o n d i t i o n s a s s o c i a t e d wi t h i r o n o v e r l o a d
( h e m o c h r o m a t o s i s a n d h e m o s i d e r o s i s ) (Fernandez-Real 2005). Early diagnosis and treatment by phlebotomy can improve blood glucose control in the early stages of the disease. If diagnosis occurs later, when the patient already needs insulin therapy, diabetes will not be improved by phlebotomy (Thielen et al. 2005).
Candore et al. (2003) reported negative association between the HFE mutations and ageing in Alzheimer disease patients from North Italy. While Pulliam et al. (2003) reported strong association of HFE mutation with neurodegeration and oxidative stress in Alzheimer disease and correlation with APOE.
Haba-Rubio et al. (2005) suggests that local brain iron deficiency may occur in patients with
haemochromatosis this shows a role for brain iron metabolism in the pathophysiology of
restless legs syndrome (RLS).
The list of infectious disease agents whose virulence is enhanced by iron continues to increase (Table 1).5
These pathogens include bacteria (Gram-negative and Gram-positive), fungi, and viruses.
Table 1. Organisms whose growth in body fluids, cells, tissues, and intact vertebrate hosts is known to be stimulated by excess iron
FungiCandida, Cryptococcus, Histoplasma, Paracoccidioides, Rhizopus, Trichosporon, Aspergillus, PneumocystisProtozoaEntamoeba, Leishmania, Naegleria, Plasmodium, Toxoplasma, TrypanosomaGram-positive and acid-fast bacteriaBacillus, clostridia, corynebacteria, Erysipelothrix, Listeria, mycobacteria, staphylococci, streptococci, GemellaGram-negative bacteriaAcinetobacter, Aeromonas, Alcaligenes, Capnocytophaga, Campylobacter, Chlamydia, Ehrlichia, Enterobacter, Escherichia, Klebsiella, Legionella, Moraxella, Neisseria, Pasteurella, Proteus, Pseudomonas, Plesiomonas, Shigella, Vibrio, YersiniaVirusesHepatitis B and C, cytomegalovirus, parvovirus, HIV
Modified, with permission, from Weinberg ED. Iron loading and disease surveillance. Emerg Infect Dis 1999;5:346–52.
http://www.sciencedirect.com/science/article/pii/S1201971207000811
Hemochromatosis and infectionsA review of medical literature on Medline for the period January 1940 to January 2007, confirms McClatchie et al. as being some of the first authors to describe the association of sudden release of ferritin, previously shown to be a vasodepressor substance,34 into the circulation and shock in a patient with hemochromatosis.35 Jones suggested a possible link between infection and shock in hemochromatosis as one patient was found to have E. coli bacteremia.36 Since that time there have been numerous reports of patients with hemochromatosis having increased susceptibility to infections.
Various infections caused by organisms including Vibrio vulnificus, [8] and [37] non-01 Vibrio cholerae,38E. coli, [36], [39] and [40]Yersinia enterocolitica [13], [41], [42] and [43] and pseudotuberculosis,44L. monocytogenes,[45] and [46]P. shigelloides,47G. haemolysans,48 cytomegalovirus,49 hepatitis B,50 C,51 and G virus,52 and HIV53 have been reported in association with hemochromatosis. Fungi including A. fumigatus54 and Rhizopus species [23] and [55] have also been described (Table 2). There is an article in German that describes parvovirus in association with hemochromatosis.56
Table 2. Various organisms and associated clinical diagnoses in patients with hemochromatosis
OrganismClinical scenario/infection [reference]Course/outcomePlesiomonas shigelloidesSepticemia [47]Twelve weeks of ofloxacin therapy instituted due to intolerance to other antimicrobialsGemella haemolysansEndocarditis [48]Two weeks of penicillin G/tobramycin with sterilization of blood culturesEscherichia coliSeptic shock [ [36], [39] and [40]]Death after 24 hours of onset, despite inotropic supportMeningitis [40]Meningitis responded to a 3 week/5 day course of IV/IT moxalactam and gentamicin, respectivelyListeria monocytogenesMeningitis/endocarditis and pericarditis [45]DeathVibrio vulnificusFever, emesis diarrhea with shock. There was history of ingestion of raw oysters [37]Death 7 hours after admission, despite aggressive medical supportNon-O1 Vibrio cholerae (NOVC)Painful edema/erythema left leg with bacteremia [38]Forty-five day therapy with oral doxycycline until resolution of cellulitisYersinia pseudotuberculosisBacteremia with aldosterone deficiency [44]Multiple antimicrobials including erythromycinYersinia enterocoliticaSeptic yersinosis [14]Oral ciprofloxacin 750 mg bid for 6 monthsLiver abscess [ [13], [41] and [43]]Oral ciprofloxacin 500 mg every 8 hours for 23 daysPeritonitis [42]Oral doxycycline 400 mg every day for 8 weeksSkin infection [43]Oral trimethoprim–sulfamethoxazole for 2 weeks after initial 9-day course of IV chloramphenicol in case 1. Oral doxycycline for 7 weeks in case 2. Oral trimethoprim–sulfamethoxazole for 6 weeksMucor species, includingPeriorbital cellulitis [23]Patient in case with ‘Mucor spp’ underwent right orbital exenteration. On postoperative day 5, patient expired after a hemorrhagic strokeCunninghamella bertholletiaeRhinocerebral mucormycosis [55]Patient diedAspergillus fumigatusPeritonitis in patient who underwent orthotopic liver transplant [54]Death secondary to liver failureHepatitis B, C and GHBV carrier [50]Severity of chronic hepatitis is linked with degree of iron deposition. Patients with chronic HBV and HCV have greater prevalence of C282Y and C2824 hemochromatosis gene mutations, respectively.Chronic HCV [51]High prevalence of hepatitis G found virus in hemochromatosisCryptogenic hepatitis [52]Cytomegalovirus (CMV)Intrauterine CMV infection; inclusions in hepatocytes, biliary epithelial cells, renal tubular epithelium. Concomitant intracellular iron seen in viscera [49]1500 g cyanotic neonate died 1.5 hours after birthParvovirusRefractory anemia [56]69-year-old woman with hemochromatosis and myelodysplastic syndrome
http://www.sciencedirect.com/science/article/pii/S1201971207000811
Interesting:
Occult celiac disease (CD) may compensate for increased divalent metal ion transporter 1
(DMT1) expression in a specific subset of individuals with homozygous C282Y mutations
in the HFE gene, thus contributing to the low penetrance of HH (Geier et al. 2005).
http://www.ncbi.nlm.nih.gov/pubmed/22720276
Dietary iron intake and serum ferritin concentration in 213 patients homozygous for the HFEC282Y hemochromatosis mutation.
RESULTS:No significant relationships between serum ferritin concentration and dietary heme iron content, dietary nonheme iron content or reports of supplemental iron use were found.
CONCLUSION:These results do not support recommending dietary heme or nonheme iron restrictions for HFEC282Y homozygotes diagnosed through screening in North America.