Hemochromatosis pathophysiology: Difference between revisions
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{{CMG}} | {{CMG}} | ||
==Overview== | ==Overview== | ||
== Pathophysiology == | |||
[[Image:Iron metabolism svg.png|thumb|left|400px|The normal distribution of body iron stores]] | |||
Since the regulation of [[iron]] metabolism is still poorly understood, a clear model of how hemochromatosis operates is still not available as of May, 2007. For example, [[HFE]] is only part of the story, since many patients with mutated [[HFE]] do not manifest clinical iron overload, and some patients with iron overload have a normal [[HFE]] [[genotype]]. | |||
In general, people with abnormal iron regulatory genes do not reduce their absorption of [[iron]] in response to increased [[iron]] levels in the body. Thus the [[iron]] stores of the body increase. As they increase the iron which is initially stored as [[ferritin]] is deposited in organs as [[haemosiderin]] and this is [[toxic]] to [[biological tissue|tissue]], probably at least partially by inducing [[oxidative stress]].<ref name=Shizukuda_2007>{{cite journal |author=Shizukuda Y, Bolan C, Nguyen T, Botello G, Tripodi D, Yau Y, Waclawiw M, Leitman S, Rosing D |title=Oxidative stress in asymptomatic subjects with hereditary hemochromatosis |journal=Am J Hematol |volume=82 |issue=3 |pages=249-50 |year=2007 |pmid=16955456}}</ref>. | |||
Iron is a [[pro-oxidant]]. Thus, hemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as [[Wilson's disease]], chronic [[manganese poisoning]], and hyperuricemic syndrome in Dalmatian dogs. The latter also experience "bronzing". | |||
=== Intestinal crypt enterocytes and iron overload=== | |||
The sensor pathway inside the [[small bowel]] [[enterocyte]] can be disrupted due to genetic errors in the [[iron]] regulatory apparatus. The [[enterocyte]] in the small bowel crypt must somehow sense the amount of circulating [[iron]]. Depending on this information, the [[enterocyte cell]] can regulate the quantity of [[iron]] [[Receptor (biochemistry)|receptors]] and channel proteins. If there is little [[iron]], the [[enterocyte cell]] will express many of these proteins. If there is a lot, the cell will turn off the expression of iron transporters. | |||
In haemochromatosis, the [[enterocyte]] is somehow constantly fooled into thinking there is [[iron]] depletion. As a consequence, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption. Details of how this process exactly works in health and disease are still being discovered as of May, 2007. | |||
These iron transport proteins are named [[DMT-1]] (divalent metal transporter), for the luminal side of the cell, and [[ferroportin]], the only known cellular iron exporter, for the basal side of the cell. | |||
===Hepcidin-ferroportin axis and iron overload=== | |||
Recently, a new unifying theory for the pathogenesis of hereditary hemochromatosis has been proposed that focuses on the [[hepcidin]]-ferroportin regulatory axis. Inappropriately low levels of [[hepcidin]], the iron regulatory hormone, can account for the clinical [[phenotype]] of iron overload. In this theory, low levels of circulating [[hepcidin]] result in higher levels of [[ferroportin]] expression in [[intestinal]] [[enterocytes]] and reticuloendothelial macrophages. As a result, this causes iron accumulation. [[HFE]], [[hemojuvelin]], BMP's and TFR2 are implicated in regulating [[hepcidin]] expression. | |||
==References== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
{{WH}} | {{WH}} | ||
{{WS}} | {{WS}} | ||
Revision as of 12:08, 29 August 2012
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Since the regulation of iron metabolism is still poorly understood, a clear model of how hemochromatosis operates is still not available as of May, 2007. For example, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype.
In general, people with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body. Thus the iron stores of the body increase. As they increase the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.[1].
Iron is a pro-oxidant. Thus, hemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricemic syndrome in Dalmatian dogs. The latter also experience "bronzing".
Intestinal crypt enterocytes and iron overload
The sensor pathway inside the small bowel enterocyte can be disrupted due to genetic errors in the iron regulatory apparatus. The enterocyte in the small bowel crypt must somehow sense the amount of circulating iron. Depending on this information, the enterocyte cell can regulate the quantity of iron receptors and channel proteins. If there is little iron, the enterocyte cell will express many of these proteins. If there is a lot, the cell will turn off the expression of iron transporters.
In haemochromatosis, the enterocyte is somehow constantly fooled into thinking there is iron depletion. As a consequence, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption. Details of how this process exactly works in health and disease are still being discovered as of May, 2007.
These iron transport proteins are named DMT-1 (divalent metal transporter), for the luminal side of the cell, and ferroportin, the only known cellular iron exporter, for the basal side of the cell.
Hepcidin-ferroportin axis and iron overload
Recently, a new unifying theory for the pathogenesis of hereditary hemochromatosis has been proposed that focuses on the hepcidin-ferroportin regulatory axis. Inappropriately low levels of hepcidin, the iron regulatory hormone, can account for the clinical phenotype of iron overload. In this theory, low levels of circulating hepcidin result in higher levels of ferroportin expression in intestinal enterocytes and reticuloendothelial macrophages. As a result, this causes iron accumulation. HFE, hemojuvelin, BMP's and TFR2 are implicated in regulating hepcidin expression.