1. Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment
Antonello Pietrangelo 
Gastroenterology 
Volume 139, Issue 2, Pages e2 (August 2010)
DOI: /j.gastro
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2. Figure 1
The common genetic basis and phenotypic continuum of hemochromatosis. The basic features of hereditary hemochromatosis can be produced by pathogenic mutations of a number of iron metabolism genes (HJV, HAMP, TfR2, FPN, and HFE). Depending on the gene involved and its role in hepcidin biology, the hemochromatosis phenotype varies. If the altered gene plays a dominant role in hepcidin synthesis (eg, HAMP itself or HJV), circulatory iron overload occurs rapidly and reaches high levels. In these cases, the clinical presentation will invariably be dramatic, with early onset (first to second decade) of full-blown organ disease (particularly affecting the heart and endocrine glands). If the hemochromatosis gene is less critical to this process (eg, HFE), a milder late-onset phenotype will arise. This continuum also includes ”intermediate phenotypes” (eg, those caused by pathogenic mutations of TfR2 or by rare combinations of mutations).
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3. Figure 2
Hepcidin-FPN axis regulation of iron metabolism. (A) Hepcidin is secreted by the liver in response to excess iron or inflammation; it binds to the extracellular region of FPN, between transmembrane domains 7 and 8, likely at or nearby C326. (The N-terminus of the hormone seems to be critical for this interaction.) Binding causes Jak2-mediated tyrosine phosphorylation at residues 302 and 303 in the cytosolic loop of FPN. Fpn is then internalized, dephosphorylated, ubiquitinated, and ultimately degraded in the late endosome/lysosome compartment. (B) The hepcidin iron-sensing machinery. The iron content of the blood, reflected by transferrin-bound and not transferrin-bound iron (the latter appearing during iron overload), is monitored by the hepatocytes. Within normal levels, the sensing process probably involves the local iron-induced production of BMPs such as BMP6 and the subsequent assembly of a membrane-associated hetero-tetrameric signaling complex, composed of 2 type I and 2 type II serine threonine kinase receptors. BMP ligands interact with a limited number of receptors, all of which activate a common signal transduction cascade at the intracellular level. The process involves the phosphorylation of intracellular receptor-activated Smad1, Smad5, and Smad8, which interact with Smad4 in the cytoplasm. The resulting complex then translocates to the nucleus, where it activates transcription of the hepcidin gene (see text for details). Neogenin, a membrane receptor for RGM, has been proposed to stabilize HJV and participate in HJV shedding, but its role is still controversial. The soluble form of HJV (sHJV), whose release (HJV shedding) is inhibited by increasing extracellular concentrations of iron, is believed to compete for BMP binding with its membrane-anchored counterpart (either by sequestering free ligands or by displacing HJV from its BMP-R binding site), thereby providing iron-sensitive modulation of hepcidin expression. Iron may also stimulate the expression of other mediators and modulators, such as SMAD7, which seems to attenuate the signal for hepcidin activation. Normal HFE definitely interacts with TfR1 and probably also with TfR2. Together, these 3 proteins might constitute a functional sensing unit responsible for conveying the iron signal to hepcidin. It is currently unclear whether this sensing unit responds directly to serum iron (diferric transferrin) or works in tandem with the BMP/HJV/SMAD system, or if it cooperates with the latter and forms a unique multi-protein sensing complex (see text for details). Recent studies indicate that the presence of HFE is necessary for efficient BMP/SMAD signaling responses to iron, suggesting that it may help sensitize the hepatocytes to low levels of BMPs. A similar activity is likely played also by TfR2.
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4. Figure 3
Hepcidin deficiencies are the central pathogenic factor in hemochromatosis. (A) In healthy subjects, hepcidin secreted by the liver regulates iron release from macrophages and duodenal enterocytes by interacting with the FPN expressed on their surfaces. HFE, TfR2, and HJV are all required to adjust hepcidin expression to current iron needs. Loss of any one of these hepcidin regulators leads to unrestricted flow of iron into the plasma iron pool. Some of the iron will be taken up by the bone marrow for erythropoiesis or by skeletal muscle for incorporation in myoglobin; some will be stored in the hepatocytes in the form of ferritin. The rest remains in circulation because, other than menstruation, the body has no effective way of eliminating iron. From the blood, the excess iron spills over into parenchymal tissues, where it causes oxidative damage to key cell structures. The characteristics of the circulatory iron loading depend on which hepcidin regulator is lost. The buildup can be (B) mild-moderate and gradual in the absence of HFE or (C) massive and rapid, as it is when HJV is lost, and this results in milder (HFE associated) or more severe forms of hemochromatosis (HJV or HAMP associated). Loss of TfR2 probably causes an intermediate level of hepcidin deficiency that produces an adult-onset iron-loading syndrome that appears somewhat earlier than HFE-related hemochromatosis and is somewhat more severe. (D) Classic hemochromatosis can also be associated with rare mutations in FPN that render the iron exporter unresponsive to hepcidin. Although hepcidin is appropriately synthesized and released in response to rising plasma levels of iron, the mutant FPN continues to release dietary iron into the plasma. Modified with permission from Pietrangelo A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 2004;350:2383–2397.
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5. Figure 4
Algorithm for the diagnosis and management of hemochromatosis. In patients with symptoms or signs suggestive of hemochromatosis, serum iron parameters should be evaluated. If any of the symptoms are related to hemochromatosis, the TS and serum ferritin level will both be increased. Findings of this type in white subjects are an indication for HFE gene testing. If the patient is a C282Y homozygote, the diagnosis of HFE-related hemochromatosis is confirmed. In the presence of any other genotype, comorbidities (eg, obesity, chronic alcohol consumption) have to be considered first. Factors of this type are almost always also responsible for altered iron parameters in nonwhite patients, who rarely have HFE-related hemochromatosis. In the absence of these comorbidities, or if the iron abnormalities persist after these conditions have been effectively treated, tissue iron overload must be confirmed, ideally by liver biopsy, before considering non–HFE-related forms of hemochromatosis. Parenchymal iron overload in the absence of hematologic disorders or advanced cirrhosis is typical of TfR2-related hemochromatosis or rarer forms of HFE-related hemochromatosis. In symptomatic patients with combined heterozygosity for C282Y/H63D or H63D homozygosity, the actual pathogenic factors are usually unrecognized comorbidities. In the absence of these, they can present with increased iron measures and modest periportal hepatic iron overload, which can be reversed by phlebotomy. In symptomatic patients with abnormal TS and normal serum ferritin level, hemochromatosis can be excluded because the symptoms of hemochromatosis organ disease are invariably accompanied by an increased serum ferritin level. In symptomatic patients with increased serum ferritin levels and a normal TS, the workup should focus on other common causes of hyperferritinemia. If they are not found, or if the hyperferritinemia persists after treatment, the next step depends on whether or not the liver iron content is increased on magnetic resonance imaging or liver biopsy. If so, hereditary non–HFE-related iron overload such as FPN disease can be considered (see text for details).
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6. Supplementary Figure 1
Liver histology in patients with hemochromatosis. Perls' Prussian blue stain for iron. (A) HFE-related hemochromatosis is characterized by purely parenchymal iron overload that is heaviest in the periportal areas and less intense in the centrolobular areas. (B) TfR2-related hemochromatosis. The histopathologic picture is identical to HFE-related hemochromatosis with iron accumulation in periportal parenchymal cells. (C) HJV-related juvenile-onset hemochromatosis: massive pan-lobular parenchymal iron overload. (D) Classic ferroportin disease. Unlike the previous 3 cases, this liver displays iron overload that predominantly affects the Kupffer cells (arrows).
Gastroenterology  , e2DOI: ( /j.gastro )
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