Hemochromatosis: The Silent Iron Overload
By: Maryam Baig
Hemochromatosis is described as a genetically induced iron overload produced by a decrease in the concentration of the iron-regulating hormone hepcidin or a decrease in hepcidin-ferroportin binding. Hepcidin controls the activity of ferroportin, the sole cellular iron exporter that has been described. If left untreated, this excess iron accumulates in various organs, including the liver, heart, and pancreas, causing severe health complications. Despite its frequency, hemochromatosis is commonly misdiagnosed or left untreated, earning the label "silent" disease.
Classic HH (hereditary haemochromatosis) type 1, which is common in Caucasians (people with European history), is caused by bi-allelic mutations of HFE (hereditary hemochromatosis gene). Severe types of HH are caused by either bi-allelic mutations of HFE2 that encode hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encode transferrin receptor 2 (Kawabata, 2017). Hemochromatosis is primarily caused by genetic abnormalities that impair the body's capacity to control iron absorption. Mutations in the HFE gene cause the most frequent kind of hereditary hemochromatosis. These mutations alter the HFE protein's normal activity, resulting in increased iron absorption from the food. Hemochromatosis has an autosomal recessive inheritance pattern, which means that an individual must inherit two copies of the defective gene (one from each parent) to develop the disorder. The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. This study aimed to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP, and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 patients with non-HFE HH was extracted from 53 publications and compared with data from 984 patients with HFE-p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE (a set of iron overload illnesses that are not caused by mutations in the HFE gene, which codes for a protein found on cell surfaces) forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP (Hepcidin Antimicrobial Peptide) HH are phenotypically and clinically very similar and have the most severe presentation (Powell, 2018).
The term "non-HFE hemochromatosis" (non-HFE HC) refers to several phenotypically similar but genetically distinct forms of hereditary hemochromatosis affecting individuals without pathogenic mutations of HFE. The involved genes are since strict, transferrin receptor 2 (TfR2), hemojuvelin (HJV), which provides instructions for making a protein called hemojuvelin, and hepcidin (HAMP). Non-HFE HC shares common pathogenic and clinical features with HFE HC. However, depending on the role of the affected gene in iron trafficking, the clinical onset may be earlier, and phenotypic expressivity more severe than classic HC (Pietranglo, 2005).
Figure 1. Diagnostic chart for genetically driven iron excess (National Library Of Medicine, 2018).
A better understanding of the symptoms of hemochromatosis would be significant in improving the diagnosis of the disease. One of hemochromatosis's problems is its wide range of symptoms, which are frequently nonspecific. When symptoms develop, chronic fatigue is prominent. In addition, joint pain is frequent and is caused by acute or chronic monoarthritis, oligoarthritis, or polyarthritis; arthritis in the second and third metacarpophalangeal joints and the ankles is particularly suggestive of hemochromatosis. Spontaneous fractures (particularly of the vertebrae) can occur owing to early-onset osteoporosis. Dermatological signs are primarily melanoderma (darkening of the skin) but can also include skin dryness and nail changes, such as white nails, flat nails, and koilonychia (that is, abnormally thin nails that curve inwards, also called ‘spoon’ nails) (McLaren, 2021).
Hemochromatosis is now a well-defined syndrome characterised by normal iron-driven erythropoiesis and the toxic accumulation of iron in parenchymal cells of liver, heart, and endocrine glands. According to Figure 1, It can be caused by mutations that affect any of the proteins that limit the entry of iron into the blood. In mice, deletion of the iron hormone hepcidin and any of 8 genes that regulate its biology, including Hfe, transferrin receptor 2 (Tfr2), and hemojuvelin (HJV),which all sense the accumulation of iron that hepcidin corrects,or ferroportin (Fpn), the cellular iron exporter down-regulated by hepcidin, cause iron overload but not organ disease. In humans, loss of TfR2, HJV, and hepcidin itself or FPN mutations result in full-blown hemochromatosis (Piatrangelo, 2010). The US Centers for Disease Control and Prevention (CDC) quote the U.S. Preventive Services Task Force
recommending against routine genetic screening for hereditary hemochromatosis in the asymptomatic general population, but state that individuals with a family member, especially a sibling, who is known to have hereditary hemochromatosis should be counselled regarding genetic testing (Basel, 2022).
Figure 2. Clinical Expression of the Hemochromatosis Gene - A Population-Based Analysis (The New England Journal Of Medicine, 1999).
Hemochromatosis is a common autosomal recessive condition found in the homozygous state, meaning that
if a person receives two identical copies of a dangerous gene variant, they are prone to a disorder
The disease affects 1/200-1/400 people of northern-, central-, and western-European origin. It causes increased iron storage, which may lead to liver cirrhosis, liver cancer, heart disease, arthritis, and diabetes in many but not all affected adults, with a higher frequency in males. The condition is easily treated by repeated venesections without side effects but is frequently overlooked. Population screening of adults using iron indices alone or combined with DNA testing has therefore been recommended, but a consensus conference in 1997 recommended that such screening be deferred, owing to uncertainty regarding the extent of clinical disease that may develop in individuals detected by such programs (Beutler, 2000).
The degree to which the hemochromatosis mutation affects the development of iron overload and clinical disease is unknown. Recent family studies of subjects of known genotypes with
hereditary hemochromatosis have shown that in up to 26 percent of subjects who are homozygous for the C282Y mutation, iron overload may not develop. These studies suggest that rates of expression of the disease may be variable and lower than previously believed. The scientists conducted a population-based study to determine the prevalence of the C282Y mutation, the frequency of the clinical expression of iron overload, and genotype-phenotype correlations over four years (Cullen, 1999).
Figure 3. Phenotypic classification of Hemochromatosis associated with hepcidin deficiency is proposed (National Library Of Medicine, 2018).
After the diagnosis is confirmed, the severity of hemochromatosis should be assessed by determining the amount of body iron excess and the extent of organ damage. A five-grade classification can be used for hemochromatosis related to hepcidin deficiency, which is similar to the classification initially proposed for HFE-associated hemochromatosis. According to Figure 3, this classification is based on the presence or absence of increased plasma transferrin saturation, increased plasma ferritin, affected quality of life, and signs jeopardising prognosis. For example, plasma ferritin levels >1,000 μg per litre at diagnosis have been reported to correspond to an increased risk of death in HFE-associated hemochromatosis (Brissot 2021). A total of 101,168 participants were screened by testing for HFE C282Y and H63D mutations and measuring serum ferritin concentration and transferrin saturation (Barton, 2009).
Figure 4. (Phlebotomy) The most common treatment of Hemochromatosis (Detecto, 2021).
As you can see in Figure 4, Phlebotomy is a treatment that involves drawing blood. It is a great way to remove extra iron from your blood. Individuals recline in a chair while a needle is employed to extract a modest quantity of blood, often 500 mL, from a vein in their arm. The extracted blood comprises erythrocytes that contain iron, and your body will require additional iron to replenish them. Phlebotomy is simple, inexpensive, and safe. How much blood is drawn and how often depends on your iron levels. Doctors usually start by having a pint of blood drawn once or twice a week for several months (Figure 4). Doctors will order regular blood tests to check iron and ferritin NIH external link levels (NIDDK, 2020). After excess iron has been removed, maintenance phlebotomy is essential to prevent iron from accumulating again. This is because the body continues to absorb iron even if the iron levels are normal or elevated.
Maintenance phlebotomy involves approximately every two to four months (Phatak, 2023). A typical iron study in individuals with nonhereditary hemochromatosis genotypes often results in an incorrect diagnosis of hereditary hemochromatosis and the use of inappropriate phlebotomy treatment. This error frequently occurs when there are increased iron study results due to chronic liver disorders. According to the National Library Of Medicine, 53% of the patients were incorrectly diagnosed with hereditary hemochromatosis, whereas 38% of them underwent phlebotomy.
Overall, this work demonstrates that hemochromatosis is defined as genetically driven iron overload caused by a decrease in the concentration of the iron-regulating hormone hepcidin or in hepcidin-ferroportin binding. Mutations in the HFE gene produce the most common kind of hereditary hemochromatosis. One of the challenges with hemochromatosis is that its
symptoms are sometimes ambiguous. When symptoms appear, chronic weariness is predominant. It causes excessive iron accumulation, which can lead to liver cirrhosis, liver cancer, heart disease, arthritis, and diabetes in many but not all affected adults, with males having a higher incidence. The problem can be readily cured with recurrent venesections with no adverse effects, however it is often neglected. The most frequent treatment for hemochromatosis is phlebotomy, which eliminates excess iron from the bloodstream. Typical iron study findings in people with nonhereditary hemochromatosis genotypes frequently lead to a mistaken diagnosis of hereditary hemochromatosis and inadequate phlebotomy treatment.
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