Hemochromatosis and Autoimmune Conditions

[Gimpy]

Psyche, one of the papers I read - of the bunch I've been uploading to my brain - mentioned something about Raynaud's syndrome being related. Can you find anything on that for Lisa Guliani.

I swear, I think everybody who is fit enough ought to go and donate a pint of blood just to see how it makes them feel in the days after. And ask for regular ferritin checks if they can do so.

I'll be decanting a pint asap.

Yeah, I'm not allowed to give blood. Had to laugh over that one. These papers are turning lights on in my head, but I'm not sure how to approach my GP on it. I just had a raft of blood work done but it was all metabolic, I'll look again for the iron levels.

I've had nasty reactions to taking Lactoferrin, bad reactions to taking too much LV C, and with the bleeding problems going on right now this is all making sense of a kind, but I'm struggling with it.

Time seems to be a factor in all the remedies and processes we find. I admit to being pooped with waiting.

 

[Horseofadifferentcolor]

I've also read that there are several skin conditions associated with hemochromatosis, including psoriasis, and possibly hydradenitis suppurativa. So, it might be worth exploring some more, and donating blood in the meantime.

That is an interesting line of inquiry. It seems iron chelators are used to rejuvenate the skin because of iron's role on damaging/oxidizing the skin:

J Cosmet Dermatol. 2006 Sep;5(3):210-7.
Iron chelators may help prevent photoaging.
Kitazawa M, Iwasaki K, Sakamoto K.


AminoScience Laboratories, Ajinomoto Co., Inc., Kawasaki, Japan.

Abstract




Ok, I might be way off on this but this thought about sunlight crossed my mind yesterday. Since her levels of vit. D is low and her symtoms got worse with the vit. C supplements, I was thinking that the two might be related with sun exposure.
I had tried taking vit. C a while back and just had gurgle tummy so I figured I did not need it. Now that the oak is growing in my alergies have kicked in so the past few days I have been taking Vit C and my runny nose has been greatly helped and I do not get gurgle tummy. So, I am wondering if I am able to use the vit C becuase I have had alot of sunlight the past few weeks. In nature vit.C producing plants grow when lots of sunlight and warmth are present. So, my point being that mabey sun has a direct effect on how and what vit. are needed and used in the body.
Has she been getting any sunshine? Just a thought. I could be way off
Also about the vit. C here is this from Sott on GMO Now brand vit. C

http://www.sott.net/article/259325-Warning-Major-supplements-openly-contain-GMO-vitamin-sources





For years, cosmetic ingredients for anti-aging treatments have attracted consumers. Skin aging is accelerated by reactive oxygen species (ROS), generated by exposure to solar ultraviolet radiation (UVR), in a process known as photoaging. Because cutaneous iron catalyses ROS generation, it is thought to play a key role in photoaging. Iron is essential to almost all forms of life. However, excess iron is potentially toxic as its catalytic activity induces the generation of ROS. Iron-catalysed ROS generation is involved in numerous pathological conditions, including cutaneous damage. When skin is directly exposed to UVR, cutaneous intracellular catalytic iron levels increase because of the release of iron from iron-binding proteins such as ferritin. Consequently, the subsequent ROS generation may overwhelm cutaneous defense systems such as the cellular iron sequestration and ROS scavenging capacity. The harmful role of excess cutaneous iron implies that there may be a potential for topical iron chelator treatments. We now consider cutaneous photodamage skin photoaging as the result of iron-catalysed ROS generation and discuss preventative strategies based on iron chelators.

This seems to connect ferritin and sun exposure skin damage seen in so many autoimmune diseases, being lupus and its related diseases the classic one!

 

[Gaby]

More clues.

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

_http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096807/

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. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON− status was determined in a cohort of 63 healthy older individuals. 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.

INTRODUCTION

Iron is essential for cell function, however, elevated tissue iron can promote tissue-oxidative damage to which the brain is especially vulnerable (Halliwell and Gutteridge, 1985; Kell, 2009; Zecca et al, 2004). Abnormally high brain iron levels are observed in age-related degenerative diseases such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease (PD) (Bartzokis et al, 2007a; Kell, 2009). Brain iron levels increase with age (Bartzokis et al, 2007c; Hallgren and Sourander, 1958) and recent studies reveal elevated levels even in preclinical stages of AD (Lavados et al, 2008; Smith et al, 2010), suggesting an accelerated trajectory of brain iron accumulation may be occurring during the transition from healthy aging into preclinical stages and eventually dementia (Bartzokis, 2009).

Age-related dementing disorders such as AD are characterized by progressive memory deficits that begin developing years before the diagnosis can be made (Amieva et al, 2008; den Heijer et al, 2006). The hippocampus (Hip) is a key region in memory function that is severely affected in aging and dementing disorders such as AD (Braak and Braak, 1991; Squire and Zola-Morgan, 1991). Hippocampal iron levels increase with age in healthy individuals (Bartzokis et al, 2007a) and postmortem studies have shown that hippocampal iron is increased in AD beyond levels of non-demented controls (Bouras et al, 1997; Deibel et al, 1996; Pankhurst et al, 2008; Smith et al, 1997).

Magnetic resonance imaging (MRI) can be used to indirectly assess relationships between cognition and brain iron in living individuals. Several methods of varying sensitivity and specificity have been published (reviewed in Haacke et al, 2005; Pfefferbaum et al, 2009). MRI can measure brain iron levels through the effect of iron on transverse relaxation rates (R2) (Bartzokis et al, 1993; Bartzokis et al, 1994; Vymazal et al., 1996a; Yao et al, 2009). The bulk of brain iron is stored in ferritin molecules (Floyd and Carney, 1993; Morris et al, 1992) and an in vivo MRI method called field-dependent relaxation rate (R2) increase (FDRI) can measure their iron content (Bartzokis et al, 1993; Bartzokis et al, 1994). Briefly, FDRI is the difference in measures of brain R2 obtained with two different field-strength MRI instruments. The FDRI is specifically associated with the total iron contained in ferritin molecules (Bartzokis et al, 1993; Vymazal et al, 1996a) and has been shown to be independent of the amount of iron loading (number of iron atoms per molecule of ferritin) (Vymazal et al, 1996b) and to increase linearly with field-strength (Bartzokis et al, 1993; Gossuin et al, 2004; Vymazal et al, 1996a; Vymazal et al, 1995a; Vymazal et al, 1996b; Yao et al, 2009). In vivo FDRI data has been validated by demonstrating very high correlations with published postmortem data on adult human brain iron distribution as well as replicating the striking age-related increases in iron levels in basal ganglia regions documented in postmortem studies (Bartzokis et al, 2007c; Hallgren and Sourander, 1958; Klintworth, 1973). Thus, FDRI measures the iron contained in ferric oxyhydroxide particles that form the mineral core of ferritin molecules. In human tissue, ferritin and its breakdown product (hemosiderin) are the only known physiologic sources of such particles (Bartzokis et al, 1993; Bulte et al, 1997; Vymazal et al, 1996a; Vymazal et al, 1995b). The FDRI measure will therefore be referred herein as ferritin iron (Bartzokis et al, 1999; Bartzokis et al, 2000).

Recently, Ding et al (2009) used a phase-shift imaging MRI technique that, amongst other things, is affected by tissue iron, and reported that increased iron in the Hip of subjects with AD may be related to worse cognitive performance and duration of illness. Whether age-related increases in hippocampal iron levels in healthy individuals may represent a trajectory of increasing risk of cognitive decline into AD (Bartzokis, 2009) and are associated with decreased memory performance have yet to be assessed. Herein we present the first study that examines associations between ferritin iron levels in the Hip as well as basal ganglia and white matter regions on memory and processing speed of healthy older individuals.

We, recently, observed higher ferritin iron in men than women (Bartzokis et al, 2007c) and suggested that the increased levels may contribute to the risk of developing neurodegenerative diseases at earlier ages in men (Bartzokis et al, 2007a; Bartzokis et al, 2004; Raber et al, 2004). We also observed that gene variants involved in iron metabolism (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2) variants) are associated with higher brain iron levels in healthy older men (Bartzokis et al, 2010). These two gene variants are highly prevalent (affecting approximately 50% of the population), and some studies have shown an association of these variants with higher risk of developing AD (Connor and Lee, 2006; Lehmann et al, 2010; Sampietro et al, 2001; Moalem et al, 2000). We therefore examined memory function in the context of gender and the presence (IRON+) or absence (IRON−) of these iron gene variants.

We hypothesized that even in healthy individuals, age-related increases in ferritin iron levels in the Hip, which is damaged early and severely in dementia-causing diseases such as AD and DLB (Braak et al, 1996; Kotzbauer et al, 2001), will negatively impact memory function (Bartzokis et al, 2007a; Bartzokis et al, 2007c; Bartzokis et al, 2004). Based on data that men may develop neurodegenerative diseases at younger ages (Barker et al, 2002; Friedman, 1994; Miech et al, 2002; Pantelatos and Fornadi, 1993; Raber et al, 2004) (reviewed in Bartzokis et al, 2004), we also hypothesized that healthy older men may be at increased risk for such iron-associated declines in memory function compared to women (Bartzokis et al, 2007c; Bartzokis et al, 2004). In exploratory analyses we also examined the effects of gender and iron gene variants (HFE H63D and TfC2) in basal ganglia and white matter regions on working memory/attention and processing speed functions.

[...]

DISCUSSION

This is the first demonstration that in healthy older men, declarative memory function may be adversely affected by increased Hip ferritin iron. A male-specific association is in line with our previously observed higher brain iron levels in men compared to women across the lifespan (Bartzokis et al, 2007c) and increased iron levels in male carriers of highly prevalent allelic variants of genes (HFE H63D and/or TfC2) that encode proteins involved in iron metabolism (Bartzokis et al, 2010). These observations are consistent with the proposition that a portion of the suggested earlier age at onset in men of neurodegenerative diseases such as AD, PD, and DLB (Barker et al, 2002; Raber et al, 2004) may be accounted for, at least in part, by their higher brain ferritin iron (Bartzokis et al, 2004) (reviewed in Bartzokis et al, 2007c). In women, the iron–memory association was significantly different from the one observed in men. The association could be substantially modified in women because of the gender-specific pattern of iron requirements such as those produced by menstruation and/or metabolism (see below) (Coppus et al, 2009; Whitfield et al, 2003) (reviewed in Bartzokis et al, 2007c).

Animal data suggest that during early postnatal development, increases in Hip ferritin iron are necessary for normal cognitive function and memory (Carlson et al, 2009; Georgieff, 2008; Schmidt et al, 2007; Shoham and Youdim, 2002; Siddappa et al, 2004) and that early deficits can have long-lasting detrimental effects on cognition even when corrected through supplementation (Schmidt et al, 2007). Differentiating oligodendrocytes have very high iron requirements and may have a critical role in brain iron uptake (reviewed in Bartzokis et al, 2007a; Bartzokis et al, 2007b). This may be especially important in the hippocampus where 50% of oligodendrocytes are juxtaposed directly on blood vessels and may thus be in a position to acquire iron directly from the vasculature (Vinet et al, 2010). On the other hand, iron overload may also cause cognitive deficits (Maaroufi et al, 2009) and increased neonatal iron intake as well as overexpression of ferritin may be associated with increased risk of neurodegenerative disease in late life (Carlson et al, 2008; Kaur et al, 2006a; Kaur et al, 2006b). It is thus becoming evident that regulating the processes underlying brain iron accumulation trajectories has important consequences throughout the lifespan. Furthermore, many neurodegenerative diseases are associated with dysregulated iron metabolism (Bartzokis, 2009; Kell, 2009; Roth et al, 2010; Zecca et al, 2004). Such dysregulations are often manifested as increases in tissue iron that go beyond those observed in healthy individuals (reviewed in Bartzokis et al, 2007c; Kell, 2009; Zecca et al, 2004). One mechanism leading to such iron increases could result from abnormal intracellular and extracellular protein deposits (proteinopathies) triggering inappropriate iron accumulation in multiple disorders (Singh et al, 2009; Smith et al, 1997) (reviewed in Bartzokis, 2009; Bartzokis et al, 2007a).

Iron regulation in neurons seems to be strongly dependent on the ferroxidase activity of amyloid precursor protein (APP) that is responsible for removing excess iron (Duce et al, 2010) and may thus mitigate intracellular iron-catalyzed oxidative damage (Halliwell and Gutteridge, 1988). The iron-management function of APP is also supported by the observation that APP transcription is controlled, at least in part, by the same iron-sensing mechanism that controls transcription of two canonical iron metabolism proteins: ferritin and transferrin (Cahill et al, 2008). Neurons may be especially susceptible to excess iron because of the disproportionately long processes (axons) connecting neuron body to synapses, and APP is well suited for its iron management function because of its presence throughout the neuron. The other well-known function of APP is to adhere the ‘cargo' (eg, vesicles) to the ‘motors' powering the fast axonal transport (FAT) that moves supplies from the neuron body to axons and synapses, and back. The two-way FAT traffic thus automatically provides the ferroxidase function of APP throughout, and especially near mitochondria that amass all along the axon at the nodes of Ranvier as well as at distant synapses. Removal of iron liberated from any source, such as damaged iron-rich mitochondria being transported back to the neuronal body for degradation, would be crucial throughout the FAT transport system (reviewed in Bartzokis, 2009).

The Hip region has been shown to have elevated iron levels in AD (Deibel et al, 1996; Good et al, 1992; Smith et al, 1997; Thompson et al, 1988) (Bartzokis et al, unpublished data), and is affected early and severely in age-related proteinopathies such as AD and DLB (Braak et al, 1996; Kotzbauer et al, 2001) that cause the vast majority (over 70%) of dementia (Barker et al, 2002; Fratiglioni et al, 2000; Lobo et al, 2000). The observation that increased hippocampal iron is associated with poorer memory function even in healthy older individuals supports the suggestion that the ‘normal' trajectory of age-related increases in brain ferritin iron may represent an underlying risk factor for age-related degenerative brain diseases (Chen et al, 2009) (reviewed in Bartzokis, 2009). Age-related accumulations of brain iron in structures such as basal ganglia and Hip of healthy individuals (Bartzokis et al, 2007c; Hallgren and Sourander, 1958) may be conceptualized as ‘normal' trajectories toward brain iron overload of vulnerable regions (Bartzokis, 2009) that may be modified by gender and genetic differences (Bartzokis et al, 2010; Bartzokis et al, 2007c). These differences may modify trajectories of iron accumulation from normal age-related memory declines (Figures 2 and ​and3)3) into preclinical stages of degeneration and eventually dementias (Bartzokis, 2009; Lavados et al, 2008; Smith et al, 1997; Smith et al, 2010).

As reviewed above, however, both iron deficiency and brain iron excess can have deleterious consequences on cognition. In old age, adequate iron levels are essential for the continual process of myelin repair/replacement, a key process in maintaining cognitive functions (reviewed in Bartzokis, 2009). Thus the opposite association we observed in men compared to that in women in the Hip–memory correlations are not entirely unexpected given known gender differences in iron status. Women begin their postmenopausal years in a state of relative peripheral iron deficiency compared with men and their iron levels increase for the first 15–20 years after menopause without fully ‘catching up' to those in men (Whitfield et al, 2003). As the peripheral iron levels can influence brain iron accumulation (Bartzokis et al, 2007c; House et al, 2010; Li et al, 2010), these peripheral effects could manifest in the brain. Thus, as the two genders approach older ages, it is possible that the already higher levels of iron observed in men push them into a toxic range earlier as they enter older ages, whereas women, who start with considerably lower iron levels, may initially experience a cognitive benefit from increasing postmenopausal iron levels.

The basal ganglia accumulate markedly more iron with age than most other brain structures (Bartzokis et al, 2007c; Hallgren and Sourander, 1958) and may thus require additional protection from iron-associated toxicity. Further analyses revealed an unexpected modifying effect of prevalent iron metabolism gene variants on the association between basal ganglia ferritin iron and working memory function (Figure 3). This observation is consistent with the direct involvement of the basal ganglia in working memory networks (Battig et al, 1960; Chorover and Gross, 1963) (reviewed in Constantinidis and Procyk, 2004; Simpson et al, 2010). Striatofrontal networks interconnect specific areas of the prefrontal cortex to subregions of the basal ganglia, forming loops that are intricately involved in higher cognitive functions including working memory (Alexander et al, 1986; Battig et al, 1960; Chorover and Gross, 1963; Landau et al, 2009; Lewis et al, 2004). In iron gene noncarriers (IRON− group), higher brain iron in the basal ganglia was again significantly associated with worse verbal working memory. A different (opposite, albeit nonstatistically significant) relationship was seen in the gene carrier (IRON+) group. These genes have been associated with brain iron uptake as well as complex interactions between basal ganglia ferritin iron levels, metabolic processes, and cognitive functions (Burdo et al, 2004; Lee et al, 2007; Li et al, 2010; Ma et al, 2008; Mitchell et al, 2009). The presence of these genes seems to mitigate the detrimental effect of basal ganglia iron accumulation on working memory function observed in the IRON− group and this may help explain, at least in part, the very high prevalence of these genes in the population.

Animal models support the suggestion that iron overload is associated with memory decline (Maaroufi et al, 2009), and treatment with iron chelators have been reported to result in improved memory even in healthy aged rodents (de Lima et al, 2007). Human studies have also suggested that chelation treatment may be helpful in degenerative brain diseases (reviewed in Kell, 2009). The mechanism of iron toxicity is likely related to promotion of damaging free-radical reactions and associated inflammation (Smith et al, 1997) (reviewed in Kell, 2009). It is thus not surprising that invertebrate data (Drosophila) suggest that age-related iron accumulation is proportional to the rate of aging (Massie et al, 1985) and inhibition of iron absorption prolongs lifespan (Massie et al, 1993). Similarly, human gender differences in longevity have been proposed to relate to reproduction-related iron losses in women (Sullivan, 1989) and life-extending effects of calorie restriction have been associated with reduced dietary iron uptake and lowered iron deposits in tissue (Cook and Yu, 1998; Kastman et al, 2010; Valle et al, 2008; Xu et al, 2008).[...]

 

[Gaby]

This one is interesting because it links it at the genetic level with gluten intolerance and so many autoimmune diseases. See my comments below:

HFE Gene Variants Affect Iron in the Brain

First published February 23, 2011, doi: 10.3945/​jn.110.130351 J. Nutr. April 1, 2011 vol. 141 no. 4 729S-739S

_http://jn.nutrition.org/content/141/4/729S.long

Abstract

Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant 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. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss 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. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

Introduction

Iron plays a significant role in many biological functions essential for life. The citric acid cycle and electron transport chain of mitochondria contain several iron-dependent enzymes and complexes such as cytochromes, succinate dehydrogenase, NADH-dehydrogenase, and aconitase. The activity of ribonucleotide reductase, which catalyzes the essential step of DNA synthesis, is dependent on iron (1). Iron is also an indispensable component for neurotransmitter synthesis and myelinogenesis (1, 2). Iron deficiency affects the composition and the amount of myelin in white matter by altering the proliferation and differentiation of oligodendrocytes. In addition to brain morphology, iron deficiency also causes an alteration in dopamine and norepinephrine metabolism, which affects neurochemistry and may delay central nervous system (CNS)4 development (3).

Though iron is an essential cofactor for many proteins in the CNS, free or unbound iron can serve as a pro-oxidant. Ferrous iron (Fe2+) catalyzes the conversion of reactive oxygen species (ROS) to highly reactive hydroxyl radical (•OH) via Fenton reaction, while ferric iron (Fe3+) can react with superoxide (O2•-) and generates Fe2+, leading to •OH formation via the Heber-Weiss reaction. Excess iron can cause protein peroxidation, lipid peroxidation, and DNA oxidation, which eventually can lead to cellular and neuronal damage or death (4, 5). Therefore, iron content in the body and in the CNS is strictly regulated via expression of several proteins (6, 7).

One iron regulatory protein that is receiving increased attention in neuroscience is the HFE protein. Mutations in the HFE gene are commonly associated with the iron overload genetic disorder hereditary hemochromatosis (HH) (8, 9). Because of their association with iron accumulation, the HFE gene mutations are being investigated as genetic risks for neurodegenerative disorders (4, 7, 9–11). In this review, we will discuss iron physiology in the brain in relation to HFE structure and function and describe the relationship between HFE gene variants and 4 neurodegenerative disorders: amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and ischemic stroke.

Iron in the brain

The iron concentration in the brain is second to the liver among the organs in the body (12). Iron is distributed heterogeneously throughout the brain, with the highest concentration found in the globus pallidus, followed by the red nucleus, substantia nigra, putamen, and the dentate nucleus of the cerebellum (12, 13). In the cortical fields, the highest iron concentration was found in the motor cortex, followed by the occipital cortex, sensory cortex, and parietal cortex (12). Brain iron content increases with advancing age (2, 12, 14) and iron content rapidly increases in all brain regions except medulla oblongata during the first 2 decades of life (12). It is noteworthy that functionally, the regions of the brain that have the highest iron content are all involved in motor functions. In addition to its high iron content, the brain generates a large amount of ROS as a consequence of its high oxygen consumption (20% of the body’s total resting oxygen consumption) to meet its high metabolic rate (1, 4). Moreover, it is rich in lipids with unsaturated fatty acid and has only a moderate amount of antioxidant enzymes (5). Therefore, the brain is more vulnerable to iron- and ROS-induced toxicity.

Because both iron overload and iron deficiency cause neuronal dysfunction, the brain expresses several iron management proteins, which are involved in the uptake, export, storage, and utilization of iron (11), to regulate its iron content. The proteins involved in the brain iron homeostasis system include HFE (9), ferritin, transferrin (Tf), transferrin receptor (TfR) (15), iron regulatory protein, divalent metal transporter 1, and cerruloplasmin (4, 7, 10, 16, 17). The expression of these iron management proteins can be altered in accordance with iron availability in an attempt to maintain the iron content in the brain. For example, iron deficiency results in decreased expression of iron storage protein, ferritin, and increased expression of iron transport protein, TfR (18). The end result would be to reduce iron storage and at the same time increase iron uptake during iron deficiency. When iron is in excess, ferritin expression would be increased, while TfR expression would be decreased, resulting in limiting iron uptake and increasing iron storage (6, 10).

Traditionally, the brain was thought to be protected from iron overload by the blood brain barrier (BBB), which separates and restricts the exchange of iron and iron management proteins between the brain tissue and the blood. Thus, a paradigm became established that the brain was protected from iron-related genetic disorders such as HH. This traditional notion came from the histochemical stains for iron in late 1930s and 1940s (19, 20). However, these studies did report that besides circumventricular regions, where the BBB is absent, the deposition of iron was observed in other brain regions, including the cerebral cortex, hypothalamus, lentiform nucleus, and the dentate nucleus that are behind the BBB (19, 20). More recently, MRI studies have reported an iron accumulation in the basal ganglia of patients with HH (21–23) as well as in the substantia nigra, the red nucleus (21), and the dentate nucleus (21, 23). However, the notion that the brain is protected from iron overload in HH somehow became established in neuroscience despite evidence to the contrary. Iron overload observed in HH is primarily caused by mutations in the HFE gene (8). The HFE protein resides on the brain microvasculature and choroid plexus where it can affect iron uptake by the brain (24); therefore, it should not be surprising that HFE mutations are associated with increased brain iron and have recently been proposed to be the genetic modifiers for risk of developing neurodegenerative disorders (7, 9, 25).

The HFE gene

Simon et al. (26) first demonstrated in the late 1970s that the gene responsible for HH is closely linked to the human leukocyte antigen (HLA) locus on a short arm of chromosome 6. Twenty years later, this gene was identified and termed as HLA-H gene by Feder et al. (27). The HLA-H gene, now renamed as the HFE gene, is comprised of 7 exons and is expressed widely or at low level in most tissues, including brain.

I think this is a key concept. There is a genetic predisposition where HLA-DQ genes located on chromosome 6 makes you vulnerable to gluten intolerance. HLA stands for the human leukocyte antigen (HLA) system which is also known as the major histocompatibility complex (MHC). The important thing to know about this system is that it contains a large number of genes related to immune system function in humans.

We now understand that it is really the epigenetic factors, the ones that are beyond the control of the gene, that are determining how DNA will be interpreted, translated and expressed. It is the epigenetic factors –regulatory proteins and post-translational modifications – the ones that are determining which genes will turn on and which ones will shut-off. And it is the diet and our environment along with its tons of pollutants the ones influencing the epigenetic factors. That is, our food sources and our environmental exposure affect our DNA and its expression.

Although some things might be "set on stone", there are several other things we can do to be functional.

So back to the paper I was quoting above:

Two common polymorphisms in the HFE gene associated with HH

A G-to-A transition at nucleotide 845 changes cysteine to tyrosine at amino acid 282 (C282Y) and a C-to-G transition at nucleotide 187 results in a histidine to aspartic acid substitution at amino acid 63, i.e., H63D (27). Eighty-five to 90% of HH patients are homozygous for the C282Y variant and 5% of patients are compound heterozygous for the C282Y and H63D variants (27–29). HH is an autosomal recessive disorder characterized by an excessive absorption of dietary iron leading to abnormal iron accumulation, with secondary tissue damage in various organs such as liver, pancreas, and heart. The clinical consequences of HH include cirrhosis, hepathomegaly, diabetes mellitus, and cardiomyopathy (30, 31). HH is the most common inherited disorder in individuals of Northern European descent (1 in every 200–400 individuals), with even higher prevalence in Ireland (1:100) (28). Although the C282Y HFE variant is more commonly associated with HH, the H63D HFE variant (8.1%) is more frequently present in the general population than the C282Y variant (1.9%). Similar to the distribution of HH, the C282Y HFE variant is more abundantly present in those of Northern European descent. The H63D HFE variant has a more general and broader distribution with a higher frequency in Europe (14.9%) and moderate frequency in Asia, Africa, Middle East, and America (28, 32). The product of the HFE gene is a 343 residue type 1 transmembrane glycoprotein named HFE (27, 33, 34).

The structure of HFE protein

The HFE protein is a member of the major histocompatibility complex class-1 (MHC-1)-like family. Like other MHC class-I like molecules, a single polypeptide HFE protein contains a transmembrane region, short cytoplasmic tail, and 3 extracellular domains (α1, α2, and α3) (27, 34). Two peptide-binding domains (α1 and α2) consist of 8 antiparallel β strands and 2 antiparallel α helices, and are positioned on the top of an immunoglobulin-like domain (α3) (34). The HFE protein contains 4 cysteine residues forming a disulphide bridge in α2 and α3 domains (27), which is 1 of the important conserved features of the MHC class-I family required for noncovalent interacting with β2 microglobulin (35) and for a transport from the endoplasmic reticulum to the cell surface (36, 37). However, the peptide binding groove in the HFE protein is narrower by the translation of α1 helix toward α2 helix and the HFE protein has only 2 of 4 tyrosine residues in the peptide-binding region, which are important for peptide binding. Therefore, unlike other MHC-1 proteins, the HFE protein does not function as an antigen-presenting molecule (27, 33).

Function of HFE protein

The major function of the HFE protein is to regulate iron homeostasis. The HFE protein interacts with β2 microglobulin in the endoplasmic reticulum and is transported to the plasma membrane (37, 38) where the HFE protein forms a stable complex with the TfR (39). The binding of the HFE protein to the TfR is pH dependent, with a tight interaction at pH 7.5 but very weak or no binding at acidic pH (33, 40). The HFE-TfR interaction lowers the affinity of the TfR for holotransferrin, i.e. Fe-Tf (39). Lebrón et al. (41) later reported that HFE bound to TfR at or near the Fe-Tf binding site where it could competitively inhibit Tf binding to the TfR. In the absence of the HFE, TfR homodimers bind 2 Fe-Tf molecules, while HFE-bound TfR binds only 1 Fe-Tf molecule by forming a ternary complex consisting of 1 HFE, 2 TfR polypeptide chains, and 1 Fe-Tf (33, 41). Therefore, the HFE protein functions in the regulation of iron homeostasis by binding to the TfR and reducing the transport of Fe-Tf molecules.

The cysteine residue in α3 domain that is altered in the C282Y HFE variant is one of the conserved residues important for forming disulphide linkages and interacting with β2-microgloblulin for cell surface expression (27, 37, 38). Therefore, the C282Y HFE variant is located primarily intercellular (37, 38) and does not bind to the TfR to limit transferrin-mediated iron uptake (39). The functional consequence of the H63D HFE variant was first reported by Feder et al. (39). Similar to the wild-type HFE protein, the H63D HFE interacts with β2-microglobulin and is transported to the plasma membrane (37, 38); however, the interaction of the H63D HFE with the TfR does not limit transferrin-mediated iron uptake (39). Because the H63D mutation is present in the α1 domain of the peptide-binding region (27, 41), the functional consequence of this variant is reduction of the affinity of the H63D protein for TfR. Thus, both C282Y and H63D HFE are associated with an increased iron accumulation compared with expression of the wild-type HFE.

In addition to its important role in iron homeostasis, the HFE protein affects a range of cellular functions, including innate immunity (42, 43). Lee et al. (44) developed stable human neuroblastoma cell lines (SH-SY5Y) carrying the wild-type, C282Y, or H63D HFE and demonstrated that HFE mutations were associated with iron accumulation and increased oxidative stress. Neuroblastoma cells carrying HFE mutations, in particular the H63D HFE, also increase intracellular calcium levels, have greater glutamate secretion and reduced uptake (45), and increase production of monocyte chemoattractant protein-1, i.e. MCP-1 (46). Each of the above mechanisms, including oxidative stress and iron accumulation, has been considered as an underlying mechanism contributing to the pathogenesis of neurodegenerative disorders (2, 4, 5, 10, 47).

HFE and neurodegenerative disorders

In order for the HFE protein to affect brain iron accumulation, it should be found in the brain. Indeed the HFE protein is expressed in choroid plexus epithelial cells, endothelial cells of the microvasculature, and ependymal cells lining the ventricle in the brain along with TfR, where it can influence iron uptake into the brain (24, 48). Nevertheless, the relationship between HFE mutations and CNS diseases has not received much attention until recently. Because brain iron concentration increases with age (2, 12) and HFE gene mutations are associated with excess iron accumulation (49–51) in different organs, it is logical that individuals who carry a HFE variant are at higher risk for brain iron accumulation and the accompanying neurological sequelae (31). A recent study of Bartozokis et al. (52) demonstrated that the presence of the H63D HFE gene variant and/or C2 allele of transferrin gene was associated with increased brain ferritin iron in older men compared with noncarriers. Given the presence and location of the HFE protein at the interface between the brain and the vasculature and the cerebrospinal fluid (CSF) where it can influence brain iron uptake (24, 48), it is not a surprise that the mutant forms of HFE could contribute to iron overload in neurodegenerative disorders (4, 10, 17, 53–56). Thus, it was a logical quest to examine HFE genotypes and how they influence the course of neurodegenerative disorders.

I haven't read the rest of the paper, but it is available at the link above. It then describes HFE protein and Alzheimer's disease, Parkinson's disease, and ischemic stroke.

 

[Gaby]

_http://www.ncbi.nlm.nih.gov/pubmed/?term=RNA+modifications+by+oxidation%3A+a+novel+disease+mechanism%3F

Free Radic Biol Med. 2012 Apr 15;52(8):1353-61. doi: 10.1016/j.freeradbiomed.2012.01.009.

Epub 2012 Jan 28.

RNA modifications by oxidation: a novel disease mechanism?

Poulsen HE, Specht E, Broedbaek K, Henriksen T, Ellervik C, Mandrup-Poulsen T, Tonnesen M, Nielsen PE, Andersen HU, Weimann A.

Laboratory of Clinical Pharmacology Q7642, Rigshospitalet, DK-2100 Copenhagen, Denmark. hepo@rh.dk

Abstract

The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. {which are viral-like BTW} Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed into RNA, and this RNA has been found to encompass various classes of novel regulatory RNAs, including, e.g., microRNAs. It is well known that DNA is constantly oxidized and repaired by complex genome maintenance mechanisms. Analogously, RNA also undergoes significant oxidation, and there are now convincing data suggesting that oxidation, and the consequent loss of integrity of RNA, is a mechanism for disease development. Oxidized RNA is found in a large variety of diseases, and interest has been especially devoted to degenerative brain diseases such as Alzheimer disease, in which up to 50-70% of specific mRNA molecules are reported oxidized, whereas other RNA molecules show virtually no oxidation. The iron-storage disease hemochromatosis exhibits the most prominent general increase in RNA oxidation ever observed. Oxidation of RNA primarily leads to strand breaks and to oxidative base modifications. Oxidized mRNA is recognized by the ribosomes, but the oxidation results in ribosomal stalling and dysfunction, followed by decreased levels of functional protein as well as the production of truncated proteins that do not undergo proper folding and may result in protein aggregation within the cell. Ribosomal dysfunction may also signal apoptosis by p53-independent pathways. There are very few reports on interventions that reduce RNA oxidation, one interesting observation being a reduction in RNA oxidation by ingestion of raw olive oil. High urinary excretion of 8-oxo-guanosine, a biomarker for RNA oxidation, is highly predictive of death in newly diagnosed type 2 diabetics; this demonstrates the clinical relevance of RNA oxidation. Taken collectively the available data suggest that RNA oxidation is a contributing factor in several diseases such as diabetes, hemochromatosis, heart failure, and β-cell destruction. The mechanism involves free iron and hydrogen peroxide from mitochondrial dysfunction that together lead to RNA oxidation that in turn gives rise to truncated proteins that may cause aggregation. Thus RNA oxidation may well be an important novel contributing mechanism for several diseases.

So stabilizing our viral-like genes with the keto diet is very important, or so it seems to me.

 

[WIN 52]

Ok, I might be way off on this but this thought about sunlight crossed my mind yesterday. Since her levels of vit. D is low and her symtoms got worse with the vit. C supplements, I was thinking that the two might be related with sun exposure.
I had tried taking vit. C a while back and just had gurgle tummy so I figured I did not need it. Now that the oak is growing in my alergies have kicked in so the past few days I have been taking Vit C and my runny nose has been greatly helped and I do not get gurgle tummy. So, I am wondering if I am able to use the vit C becuase I have had alot of sunlight the past few weeks. In nature vit.C producing plants grow when lots of sunlight and warmth are present. So, my point being that mabey sun has a direct effect on how and what vit. are needed and used in the body.
Has she been getting any sunshine? Just a thought. I could be way off
Also about the vit. C here is this from Sott on GMO Now brand vit. C

I found this interesting.
The vitC, started this fall made a great improvement on the itchy legs. I started vitD with that because of the winter months ahead.

I did have a great deal of distress last summer going full keto, after doing so well with reduced carbs since 2009.
I had quit all supplements thinking this was the cause.
I went back on my stroke medication, not knowing where to turn.

Now with C, D, Mag, Krill Oil and as of yesterday C0Q10 things have improved.
Getting back to where I was a year ago.
Adding supplements back in one or two at a time to see if I could detect improvement.
As of two weeks ago I have dropped the statin drugs with BP slightly high but not bad for me.
This morning after starting the C0Q10 I felt like not taking the other drugs including asperin, so I didn't.
So far BP is good...no spikes

With my health being so poor for so many years, it may take time to correct things. I think the job will last the rest of my life

 

[Regulattor]

I've checked my serum Fe and Ferritin levels today.

Fe 19,2 µmol/L (ref: 11-32)
Ferritin 174,7 ng/mL (ref: males 23,9 - 336,2)

Both are looking good. However, since I'm still having troubles with KD I'm going to give a blood donation and report back.

 

[Laura]

I've checked my serum Fe and Ferritin levels today.

Fe 19,2 µmol/L (ref: 11-32)
Ferritin 174,7 ng/mL (ref: males 23,9 - 336,2)

Both are looking good. However, since I'm still having troubles with KD I'm going to give a blood donation and report back.

Yeah. If the ideal ferritin level is around 25-50, you are a bit high. How old are you? If you are still young, maybe it means you have gradual accumulation going on.

Two of our crew gave today and another few will go on Tuesday, I think.

 

[Gawan]

My last Ferritin level from 2009 was about 99 ng/ml and 2010: 173.3 ng/ml. And today I called the blood donation institute and they told me that I'm not allowed doing it that way, so blood letting seems to be the way to go.

 

[Gaby]

Some gene mapping. It also basically says that if your genetic testing comes back negative, it doesn't mean you are not a carrier of one of the gene mutations.

HFE Gene and Hereditary Hemochromatosis: A HuGE Review

http://aje.oxfordjournals.org/content/154/3/193.long

Abstract

Hereditary hemochromatosis (HHC) is an autosomal recessive disorder of iron metabolism characterized by increased iron absorption and deposition in the liver, pancreas, heart, joints, and pituitary gland. Without treatment, death may occur from cirrhosis, primary liver cancer, diabetes, or cardiomyopathy. In 1996, HFE, the gene for HHC, was mapped on the short arm of chromosome 6 (6p21.3). Two of the 37 allelic variants of HFE described to date (C282Y and H63D) are significantly correlated with HHC. Homozygosity for the C282Y mutation was found in 52–100% of previous studies on clinically diagnosed probands. In this review, 5% of HHC probands were found to be compound heterozygotes (C282Y/H63D), and 1.5% were homozygous for the H63D mutation; 3.6% were C282Y heterozygotes, and 5.2% were H63D heterozygotes. In 7% of cases, C282Y and H63D mutations were not present. In the general population, the frequency of the C282Y/C282Y genotype is 0.4%. C282Y heterozygosity ranges from 9.2% in Europeans to nil in Asian, Indian subcontinent, African/Middle Eastern, and Australasian populations. The H63D carrier frequency is 22% in European populations. Accurate data on the penetrance of the different HFE genotypes are not available. Extrapolating from limited clinical observations in screening studies, an estimated 40–70% of persons with the C282Y homozygous genotype will develop clinical evidence of iron overload. A smaller proportion will die from complications of iron overload. To date, population screening for HHC is not recommended because of uncertainties about optimal screening strategies, optimal care for susceptible persons, laboratory standardization, and the potential for stigmatization or discrimination.

[...]

In 1996, Feder et al. (4) identified a 250-kilobase region located more than three megabases telomeric from the major histocompatibility complex on chromosome 6 that was identical by descent in 85 percent of HHC patients. In this region, they identified a gene related to the major histocompatibility complex class I family that they called HLA-H, but it was subsequently named HFE (5). Feder et al. (4) described two missense mutations of this gene (C282Y and H63D) that accounted for 88 percent of the 178 HHC probands in their study. The HFE gene is located at 6p21.3, approximately 4.6 megabases telomeric from HLA-A, and covers approximately 10 kilobases (6). [...]

POPULATION FREQUENCIES

[...]

{It is worth seeing it through the tables which are here:

HFE genotype frequencies in clinically diagnosed probands
http://aje.oxfordjournals.org/content/154/3/193/T1.expansion.html

HFE genotype frequencies in the general population
http://aje.oxfordjournals.org/content/154/3/193/T2.expansion.html}

In table 1, the frequency of the HFE genotypes in clinically diagnosed probands is reported by geographic location. Except for two studies (14, 20), case definitions of HHC included diagnostic evidence of iron overload by liver biopsy or quantitative phlebotomy. In European countries, the estimated prevalence of homozygosity for the C282Y mutation in 2,229 HHC probands ranged from 52 percent (21) to 96 percent (22). In North America, C282Y homozygosity was present in 81 percent of 588 probands (range, 67–95 percent). Worldwide, among 2,929 probands, 6.9 percent (95 percent confidence interval (CI): 6.0, 7.9) were homozygous for the wild allele. This finding suggests that a nongenetic influence; additional HFE mutations; genetic redundancy, which is known to occur in the HLA system (23); or variation in additional genes affecting iron metabolism, as a recent twin study has suggested (24), may also cause iron overload. Heterozygosity for the H63D mutation and compound heterozygosity each accounted for 6 percent of European cases and 4 percent of North American cases. Globally, 3.6 percent (95 percent CI: 2.9, 4.3) of proband patients had the C282Y/wild genotype, and 1.5 percent (95 percent CI: 1.1, 2.1) had the H63D/H63D genotype.

The estimated frequency of the HFE genotype in the general population is shown in table 2; 27 studies were evaluated. A total of 6,203 samples from European countries revealed, on average, a C282Y homozygous and heterozygous prevalence of 0.4 and 9.2 percent, respectively. However, C282Y homozygosity has not been reported in the general population of southern or eastern Europe. The frequency of C282Y heterozygosity is 1–3 percent in southern and eastern Europe and as high as 24.8 percent in Ireland. In North America (3,752 samples), these percentages were 0.5 (C282Y homozygous) and 9.0 percent (C282Y heterozygous). In the Asian, Indian subcontinent, Africans/Middle Eastern, and Australasian populations, C282Y homozygotes were not found, and the frequency of C282Y heterozygosity was very low (range, 0–0.5 percent). C282Y/H63D compound and H63D homozygosity were each found in 2 percent of the European general population and in 2.5 and 2.1 percent of the Americas populations, respectively. The carrier frequency of the H63D mutation was 22 percent in Europe and 23 percent in North America.

Assuming that the proband studies are correct in indicating that 78 percent of affected persons are homozygous for C282Y, the estimated prevalence of HHC ranges from 51 to 64 per 10,000 persons. In population-based intervention trials, the estimated prevalence of homozygosity based on phenotype, defined as biochemical evidence of iron overload, is 50 per 10,000 (25). In primary care settings among Whites, the estimated prevalence of clinically proven or biopsy-proven HHC is 54 per 10,000 (26). A higher prevalence (80/10,000) was obtained in one study when elevated transferrin saturation alone was used for a case definition (27). This finding may simply reflect the fact that a significant proportion of unaffected or heterozygous persons have transferrin saturation levels above the cutoff, especially when thresholds of 50 percent are used (25).

[...]

Phenotypic expression of HHC, which is variable, appears to depend on a complex interplay of the severity of the genetic defect, age, sex, and such environmental influences as dietary iron, the extent of iron losses from other processes, and the presence of other diseases or toxins (e.g., alcohol) (32). The rate of iron accumulation and the frequency and severity of clinical symptoms vary markedly; early complaints may include fatigue, weakness, joint pain, palpitations, and abdominal pain (33). Because these symptoms are relatively nonspecific, HHC often is not diagnosed at this stage. The disease can ultimately lead to hyperpigmentation of the skin, arthritis, cirrhosis, diabetes mellitus, chronic abdominal pain, severe fatigue, hypopituitarism, hypogonadism, cardiomyopathy, primary liver cancer, or an increased risk of certain bacterial infections (34). Most of these advanced complications are also common primary disorders, and iron overload can be missed at this stage unless looked for specifically.

The liver is usually the first organ to be affected, and hepatomegaly is one of the most frequent findings at clinical presentation (35). In one study, noncirrhotic probands at clinical presentation reported weakness, lethargy, and loss of libido more frequently than probands with cirrhosis, but symptoms of abdominal pain were markedly more frequent in the cirrhotic patients (34). The proportion of patients with cirrhosis at clinical presentation has varied from 22 to 60 percent (34, 36, 37).

Primary hepatocellular carcinoma is 200 times more common in HHC patients (34), but it rarely occurs without cirrhosis. Hepatocellular carcinoma has been reported to account for 30–45 percent of deaths among the HHC patients seen in referral centers (38, 39). In patients with this kind of cancer, the prevalence of HHC ranges from 11 to 15 percent (40).

Diabetes mellitus is the major endocrine disorder associated with HHC. The mechanisms responsible are still obscure, but iron deposition that damages the pancreatic beta cells and insulin resistance (38) have been postulated. Hypogonadism also occurs and is caused primarily by a gonadotropin deficiency resulting from iron deposition at the pituitary or hypothalamic levels. Other endocrine disorders involving an effect of HHC on the thyroid, parathyroid, or adrenal glands are rarely seen.

Cardiac manifestations include cardiomyopathy and arrhythmias. Congestive heart failure has been observed in 2–35 percent and arrhythmias are present in 7–36 percent of HHC patients (41).

Increases in melanin (42) lead to hyperpigmentation in 27–85 percent of patients (41). Loss of body hair, atrophy of the skin, and koilonychia (dystrophy of the fingernails) may also occur.

Arthropathies are found in 40–75 percent of patients (38). These diseases may affect the second and third metacarpals (43), wrist, shoulder, knees, or feet.

Symptoms of HHC usually appear between ages 40 and 60 years, with the onset normally later in women (44). This difference may relate to their loss of iron with menstruation, pregnancy, and lactation and to their lower iron intake relative to their iron needs (45). Men are more likely to develop clinical disease. Presenting signs and symptoms of HHC also vary by sex, with women more likely to present with fatigue, arthralgia, and pigmentation changes and men presenting more often with symptoms of liver disease (37).

Symptoms and disease complications increase with age; in one study, 73 percent of men and 44 percent of women HHC homozygotes over age 40 years had at least one clinical finding consistent with HHC (25). A smaller proportion, not yet well defined, is likely to develop potentially life-threatening complications (21, 46⇔–48).

Treatment

Periodic phlebotomy or venesection to remove iron is a safe, inexpensive, and effective treatment for HHC. Venesection is usually initiated when serum ferritin concentrations indicate excess accumulation of iron stores. For example, the College of American Pathologists recommends initiation of venesection when serum ferritin levels reach 300 μg/liter in men and 200 μg/liter in women (41); however, the appropriate cutoff for women may vary with their reproductive status (49). To our knowledge, there have been no controlled trials of phlebotomy treatment, but observational studies in referral centers suggest that iron removal markedly increases survival (34, 38, 50, 51). Dietary management includes avoidance of iron supplements, excess vitamin C, and uncooked seafood, which is known to increase the risk of Vibrio vulnificus and Salmonella enteritidis infections in HHC patients (49).

If treated early in the course of the illness, complications improve in some patients after iron depletion. In patients with established iron overload, liver function, weakness and lethargy (or fatigue), right upper-quadrant abdominal pain, abnormal skin pigmentation, and cardiomyopathy usually improve, but hypogonadotropic hypogonadism does not (49). Response to treatment for patients with arthralgias is highly variable. Removal of excess iron does not reverse diabetes but can reduce insulin requirements (34, 50). Chelation therapy, which increases iron excretion, is less efficient and more expensive than phlebotomy. In general, management of HHC complications including liver failure, cardiac failure, and diabetes differs little from conventional management of these diseases.

[...]

INTERACTIONS

Clinical expression of HHC is influenced by a variety of factors, both genetic and environmental. In HFE knockout mice, mutations of other genes involved in iron metabolism, such as beta2-microglobulin, transferrin receptor, and DTM1 (transmembrane iron import molecule), strongly modify the amount of iron in the liver (55), suggesting that modifier genes may influence the course of HHC in humans. There is also evidence that sex plays a primary role in the clinical manifestation of HHC. Family studies based on HLA linkage report an equal frequency of affected brothers and sisters, as expected for an autosomal recessive disorder, but the proportion of females among probands diagnosed on the basis of clinical symptoms is 11–35 percent lower than in males (33, 34, 39). Furthermore, in a large screening trial, the prevalence of iron overload, as determined by liver biopsy or phlebotomy, was twice as frequent in males as females (47). This sex difference has been attributed to the lower degree of iron overload in women because of menstruation, pregnancy, and lactation.

The environment has also been reported to modify the expressivity, or penetrance, of HHC genotypes. Possible positive (beneficial) modifiers of disease phenotype include pregnancy and menstruation in females and chronic blood loss (gastrointestinal bleeding, regular hematuria, helminthic or other parasitic infections) and regular blood donation in both men and females. Detrimental factors include alcohol abuse, excessive iron intake, or other modifiers that increase iron stores (e.g., vitamin C). Tannates, phytates, oxalates, calcium, and phosphates also modify HHC because they are known to bind iron and inhibit iron absorption (49).

Chronic viral hepatitis B and C, and metals such as zinc and cobalt, may also influence expression of HHC (49, 56). Iron modulates the course of hepatitis B (57), and iron reduction has been shown to decrease the severity of chronic hepatitis C while increasing the likelihood of response to antiviral therapy. Hepatitis C virus infection and HFE mutations have also been identified as risk factors for porphyria cutanea tarda (57).

Conte et al. (58), who studied 894 diabetic patients from northern Italy, calculated an odds ratio of 6.3 for HHC and a 1.34 percent prevalence of HHC in type II patients. The authors suggested that screening diabetic patients for HHC might be beneficial (58). However, Frayling et al. found a type II C282Y homozygosity prevalence of 0.42 percent, similar to that in an age-matched normoglycemic control group (59). Larger, population-based studies are needed to reach definitive conclusions.

Iron overload can be a complication of certain disorders characterized by increased erythropoietic activity. Studies evaluating the impact of HHC on hereditary spherocytosis and acquired anemia have been inconsistent (60).

LABORATORY TESTS

Transferrin saturation and serum ferritin

The most widely used biochemical markers of body iron status are transferrin saturation percentage (transferrin saturation = serum iron/total iron binding capacity × 100) and serum ferritin values. Transferrin saturation is usually elevated before symptoms occur or other studies indicate iron overload. The cutoff transferrin saturation values recommended for screening have varied from 45 to 70 percent (26, 41, 61, 62). If transferrin saturation is above the threshold and no other explanations exist for iron overload (e.g., chronic anemias, liver diseases due to alcohol consumption or viral infection), the test should be repeated after an overnight fast (41). Subjects should avoid iron and vitamin C supplements for at least 24 hours before testing. Simultaneously, tests of liver function and a complete blood count should be performed. A second elevated transferrin saturation level indicates that the person may have HHC. If serum ferritin levels are also elevated, then additional diagnostic testing (quantitative phlebotomy or liver biopsy) is recommended to confirm the presence of iron overload (17). In persons identified by this screening and diagnostic process as having iron overload related to HHC, the probability of developing clinical complications is uncertain. Family and screening trials suggest that 50–70 percent of males and 40–50 percent of females will develop symptoms or complications of HHC (25, 63), but most complications recorded in such studies were common and nonspecific clinical manifestations such as joint pain and diabetes. In the absence of control groups, the proportion of complications attributable to HHC is difficult to determine; as a result, the probability of developing clinical complications may be considerably lower.

The analytical validity of the transferrin saturation test can be evaluated by its sensitivity, specificity, and predictive value for the genotype, which depend in turn on the characteristics of the test and the underlying gene frequency. Using data from family studies and screening trials, Bradley et al. (25) found that screening at a transferrin saturation cutoff value of 50 percent would identify approximately 94 percent of homozygote men and 82 percent of homozygote women and that the results for approximately 6 percent of men and 3 percent of women would be false positive. Assuming an HHC genotype prevalence of 50 in 10,000, the odds of being affected given a positive result would be about 1:12 for males and 1:8 for females, corresponding to a positive predictive value of 8 and 11 percent, respectively. Positive predictive values using HLA typing as the standard increase when an initial elevated transferrin saturation finding is followed by a fasting transferrin saturation that is higher than the first one (64).

The lack of a standard case definition makes it difficult to assess the clinical validity of the transferrin saturation test. In a large, population-based screening study, the sensitivity of a single elevated transferrin saturation for HHC (defined as the presence of iron overload with serum ferritin ≥95th percentile and mobilizable iron >99th percentile) was 100 percent, with a specificity of 97 percent and a positive predictive value of 8 percent (27). The positive predictive value rises with increasing prevalence of HHC. In a screening study of patients with liver disease, who presumably are more likely to have HHC, the positive predictive value of a single elevated transferrin saturation test was 41 percent (65). In patients with diabetes, the positive predictive value of repeated elevated transferrin saturation tests ranged from 63 to 83 percent when HHC was defined as increased liver iron stores (58, 66, 67).

Ferritin is an intracellular iron storage protein, and serum ferritin concentration significantly correlates with body iron stores (1 ng/ml = 10 mg of stored iron) (68). Serum ferritin values, but not transferrin saturation values, are associated with clinical signs of HHC, and serum ferritin is higher for those with clinical manifestations (25). Serum ferritin has been used as a second screening test in many trials, and it can be very effective in reducing the number of false positives (47), if cutoffs appropriate for age and sex are used. However, elevation of the serum ferritin concentration in HHC must be differentiated from other liver disorders such as alcoholic liver disease, chronic viral hepatitis, and nonalcoholic steatohepatitis. Serum ferritin is also an acute-phase reactant, and levels can be elevated during infection or chronic inflammation or when the subject has a histiocytic neoplasm (41).

HFE gene mutation analysis

Methodologies used for identifying the C282Y and H63D allelic variants of the HFE gene should be sensitive and specific; however, data on technical performance are pending. The accuracy of the mutation analysis in predicting the HHC phenotype is uncertain because of genetic heterogeneity, reduced penetrance, and the lack of a standardized HHC case definition. Because C282Y and H63D account for most, but not all clinically diagnosed cases of HHC in Whites (table 1), it is plausible that other mutations or other genes yet to be identified (30, 31) may also cause HHC. In addition, even in persons with detectable mutations, the penetrance of the HFE genotype is not complete. In the general population, the C282Y/H63D and H63D/H63D genotypes occur more frequently than the C282Y/C282Y genotype (table 2), but, among clinically diagnosed probands, C282Y/H63D and H63D/H63D account for only a small proportion of cases, suggesting low penetrance of the H63D allele (table 1). Studies on the HFE protein showing a lower loss of protein function with the H63D mutation corroborate this observation (7, 41). Reduced penetrance is likely for the C282Y/C282Y genotype, as indicated by case reports of elderly persons with this genotype and no evidence of significant disease (69, 70). That death from HHC complications does not lead to underrepresentation of this genotype in the elderly is suggested by a study of 600 patients over age 70 years that reported a prevalence of C2828Y homozygosity of 1 in 150 (71). Taken as a whole, the data indicate that mutation analysis alone cannot provide a simple positive or negative screening test for HHC.

[...]

APPENDIX TABLE 1.

Internet sites pertaining to the HFE gene and hereditary hemochromatosis
http://aje.oxfordjournals.org/content/154/3/193/T3.expansion.html

 

[Regulattor]

I've checked my serum Fe and Ferritin levels today.

Fe 19,2 µmol/L (ref: 11-32)
Ferritin 174,7 ng/mL (ref: males 23,9 - 336,2)

Both are looking good. However, since I'm still having troubles with KD I'm going to give a blood donation and report back.

Yeah. If the ideal ferritin level is around 25-50, you are a bit high. How old are you? If you are still young, maybe it means you have gradual accumulation going on.

Two of our crew gave today and another few will go on Tuesday, I think.

I'm 40 y.o. so I'm not so young anymore but I also think if 25-50 is recommended that I'll try to lower my current ferritin and see how it goes.

 

[Voyageur]

This has been an interesting thread, much to learn and hope resolve can be found for those needing help.

I've been trying to give blood, thinking before about iron buildup after reading and there are no clinics within 300 km. who take blood. Have been reading in various articles alongside this about bacteria trying to sequester iron and the bodily fight to withhold it from bacteria. So problems arise when bacteria can absorb iron and grow, and as such, many people end up fighting infections.

Was wondering about this as a means to rid the body of iron also; is there a bacteria that is safe? There is something called super-Shewanella, which is not used in humans, yet seems to sequester iron, cobalt etc., and is being experimented with on energy toxins. So this is briefly divergent, yet related and possibly a future factor to consider - however don't know how.

_http://www.eurekalert.org/features/doe/2002-07/dnnl-s073102.php

Shewanella:

It can convert soluble metals and compounds, like uranium, into insoluble forms. It can live aerobically, in the presence of oxygen, or anaerobically, without oxygen. It can grow naturally almost anywhere and does not cause disease in humans, animals or other organisms.
[...]
Similar to a human breathing in oxygen and exhaling carbon dioxide, Shewanella has the ability to "inhale" certain metals as electron acceptors and "exhale" them in an altered state. For example, it can change oxidized uranium, which is water soluble, into reduced uranium, which is insoluble.
[...]
Iron, the principal electron acceptor for Shewanella and other metal-reducing bacteria thriving in environments lacking oxygen, is the fourth most abundant element on earth. Before bacteria and plants produced oxygen via photosynthesis, iron was likely the most abundant electron acceptor on prehistoric earth. Hence, metal-reducing organisms, like Shewanella, were likely to have developed before other respiratory organisms.

Makes me think down the road, which is not helpful here, if safe bacteria such as this, one day could help rid the body of metals such as iron (and other heavy metals) and extricate them from the body in measured quantities and as needed.

Coming back to what is known, in reading what was posted above, thought the relationship with MS was interesting and had never considered that before, amongst other diseases, so thank you for starting this thread.

 

[Gaby]

Read a few papers today and some have very important concepts. So I'll leave the abstracts and/or some quotes, the full texts are available on the link.

Enhanced ferritin/iron ratio in psoriasis

_http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401697/

Psoriasis is a chronic and recurrent skin disorder characterized by marked inflammatory changes in the epidermis and dermis1. The pathogenesis of this complex, multifactorial disease is incompletely understood. The genetic susceptibility and involvement of the innate immune system in psoriasis have been reported2,3. The involvement of proinflammatory cytokines, such as interleukins (ILs), tumour necrosis factor (TNF), and interferon-γ (IFN-γ), has been identified in psoriasis4,5. The worsening of psoriasis has been linked with oxidative stress1. Disorders in the antioxidant defense mechanisms are known to be involved in the pathogenesis of psoriasis6,7. The Psoriasis Area Severity Index (PASI)8 is a useful tool in monitoring the response of psoriasis to any therapeutic regimen. Besides the use of clinical measures like PASI, attempts have been made to establish markers for psoriasis at both tissue9 and serum levels10,11.

There is some evidence regarding the roles of various metals and metal binding proteins in psoriasis and possibilities of evaluating these as potential markers of the disease would provide better targets for effective control of the disease. The involvement of trace metals12–14 and altered trace metal homeostasis15 in psoriasis has been reported. However, very limited studies have focused on the involvement of metal binding proteins in psoriasis1,16–18. The metalloproteins are known to ameliorate the deleterious effects of the reactive oxygen species (ROS) by binding to the redox active metals like copper (Cu) and iron (Fe), thus minimizing their capacity to catalyze ROS production via the Fenton reaction19. Ferritin is an iron storage protein, the levels of which is known to increase as a result of oxidative stress20 and inflammation21. The role of ferritin in patients with rosacea22 and alopecia23 has been reported. The present study was undertaken to investigate the role of ferritin and iron in psoriasis.

Ferritin in Adult-Onset Still's Disease: Just a Useful Innocent Bystander?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321299/

Abstract

Background. Adult-Onset Still's Disease (AOSD) is an immune-mediated systemic disease with quotidian-spiking fever, rash, and inflammatory arthritis. Hyperferritinemia is a prominent feature, often used for screening. Methods. The key terms “ferritin” and “hyperferritinemia” were used to search PubMed and Medline and were cross-referenced with “Still's Disease.” Results. Hyperferritinemia, although nonspecific, is particularly prevalent in AOSD. While most clinicians associate ferritin with iron metabolism, this is mostly true for the H isoform and not for the L isoform that tends to increase dramatically in hyperferritenemia. In these situations, hyperferritinemia is not associated with iron metabolism and may even mask an underlying iron deficiency. We review, in systematic fashion, the current basic science and clinical literature regarding the regulation of ferritin and its use in the diagnosis and management of AOSD. Conclusion. Serum hyperferritinemia in AOSD has been described for 2 decades, although its mechanism has not yet been completely elucidated. Regulation by proinflammatory cytokines such as interleukin (IL)-1b, IL-6, IL-18, MCSF, and INF-α provides a link to the disease pathogenesis and may explain rapid resolution of hyperferritinemia after targeted treatment and inhibition of key cytokines.

Isr Med Assoc J. 2008 Jan;10(1):83-4.

Hyperferritinemia in autoimmunity.

Zandman-Goddard G, Shoenfeld Y.
_http://www.ima.org.il/IMAJ/ViewArticle.aspx?year=2008&month=01&page=83

Abstract

Controlling iron/oxygen chemistry in biology depends on multiple genes, regulatory messenger RNA structures, signaling pathways and protein catalysts. Ferritin synthesis is regulated by cytokines (tumor necrosis factor-alpha and interleukin-1alpha) at various levels (transcriptional, post-transcriptional, translational) during development, cellular differentiation, proliferation and inflammation. The cellular response by cytokines to infection stimulates the expression of ferritin genes. The immunological actions of ferritin include binding to T lymphocytes, suppression of the delayed-type hypersensitivity, suppression of antibody production by B lymphocytes, and decreased phagocytosis of granulocytes. Thyroid hormone, insulin and insulin growth factor-1 are involved in the regulation of ferritin at the mRNA level. Ferritin and iron homeostasis are implicated in the pathogenesis of many disorders, including diseases involved in iron acquisition, transport and storage (primary hemochromatosis) as well as in atherosclerosis, Parkinson's disease, Alzheimer disease, and restless leg syndrome. Mutations in the ferritin gene cause the hereditary hyperferritinemia-cataract syndrome and neuroferritinopathy. Hyperferritinemia is associated with inflammation, infections and malignancies, and in systemic lupus erythematosus correlates with disease activity. Some evidence points to the importance of hyperferritinemia in dermatomyositis and multiple sclerosis, but further mechanistic investigations are warranted.

 

[Gaby]

This one is a very interesting article. He basically says that a poorly liganded iron is what makes taking vitamin C dangerous. Also, that melatonin chelates iron from the body. He makes the link with several diseases, viral and bacterial infections, heavy metals and other toxins. Anyhow, I haven't read it fully yet, but here is the link and some concepts:

Arch Toxicol. 2010 November; 84(11): 825–889.

Published online 2010 August 17. doi: 10.1007/s00204-010-0577-x

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples


Douglas B. Kell

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988997/

Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

Nearly half of all enzymes are metalloproteins (Waldron
et al. 2009), and iron is also of considerable importance in
biology as a component of all kinds of metalloproteins
(Andreini et al. 2008, 2009) from haemoglobin to cytochromes,
as well as in the directed evolution of novel enzyme
activitie

Doxycycline, at low doses, inhibits Matrix metalloproteins activity. It has been used in arthritis.

A key point
here is that despite the widespread and uncritical use of the
term ROS to describe any ‘Reactive Oxygen Species’, most
such as superoxide and peroxide are not terribly reactive, in
contrast to the hydroxyl radical (and peroxynitrite) which is,
and unliganded iron is required for hydroxyl radical
production in the Fenton reaction. Hence the focus on
unliganded iron rather than the more nebulous ROSs, albeit
that (su)peroxide is necessarily involved.

Since iron cannot be transmuted
into any other substance, the only way to stop the
damaging activity of free or partially liganded ‘iron’ is
to ensure that all of its six possible liganding sites are
satisfied, whether by endogenous chelators or those
added from the diet or as pharmaceuticals. Put another
way, it is not simply enough to know that ‘iron’ is present
at an adequate level but that it is available in a suitably
liganded form. Anaemia can be caused by poor liganding
as well as by an actual shortage of ‘iron’ itself. Note too
that partial chelation in the presence of an antioxidant
agent such as ascorbate (vitamin C) can in fact make
ascorbate (or other reducing agent) act as a pro-oxidant and
thus actually promote the production of OH• radicals in the
presence of inappropriately or inadequately liganded Fe(II)

The natural iron-chelating antioxidant melatonin has been found to be particularly effective in preventing septic shock

For phlebotomy, he says:

Phlebotomy

In addition, as follows implicitly from Sullivan’s ‘iron hypothesis’ (Sullivan 1981, 2001, 2003, 2004) (and see Kell 2009a), one way to decrease the amount of iron in the body is to remove it by blood-letting or phlebotomy. While phlebotomy is a very traditional nostrum, often assumed or considered to have rather dubious or at best modest scientific support, there is in fact increasing literature implying its benefits in a variety of conditions (e.g. Aigner et al. 2008; Beutler 2007; Broedbaek et al. 2009; Brudevold et al. 2008; Busca et al. 2010; DePalma et al. 2007, 2010; Dereure et al. 2008; Desai et al. 2008; Dwyer et al. 2009; Equitani et al. 2008; Facchini et al. 2002; Fargion et al. 2002; Fernández-Real et al. 2002; Fujita et al. 2009; Fujita and Takei 2007; Hayashi et al. 2006; Hayashi and Yano 2002; Heathcote 2004; Horwitz and Rosenthal 1999; Hua et al. 2001; Kaito 2007; Kaito et al. 2006; Kato et al. 2001, 2007; Kom et al. 2006; Rajpathak et al. 2009; Sullivan 2009; Sumida et al. 2009; Tanaka et al. 2007, 2009; Toyokuni 2009b; Zacharski et al. 2008). Plausibly such benefits are due to its role in decreasing iron stores.

 

[LQB]

Arch Toxicol. 2010 November; 84(11): 825–889.

Published online 2010 August 17. doi: 10.1007/s00204-010-0577-x

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

That looks to be an excellent paper Psyche! It's 65 pages - 23 text, and the rest is references. Should be a good read.