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Hemochromatosis is a disorder characterized by excessive iron accumulation in body tissues that leads to the dysfunction of various organs. Normally, iron absorption is tightly regulated, but in hemochromatosis, the body absorbs too much iron, which it cannot excrete. Hereditary hemochromatosis, the most common form, is an autosomal recessive disorder predominantly found in individuals of European descent. The disorder is caused by mutations in HFE, resulting in increased iron absorption. Excess iron is deposited in organs, including the liver, pancreas, heart, and skin, often leading to conditions such as liver disease, diabetes, heart failure, and skin discoloration, known as "bronze diabetes." The types of hereditary hemochromatosis vary based on genetic mutations. Type 1 is the most common, while types 2, 3, and 4 are rarer variants. Secondary hemochromatosis can occur due to frequent blood transfusions or certain hematological disorders. The symptoms of hemochromatosis typically appear in adulthood and may include fatigue, joint pain, and skin darkening, among others. Diagnosis is made through blood tests measuring iron levels and genetic testing. Treatment of hemochromatosis primarily involves regular phlebotomy to remove excess iron from the body, and early detection can prevent severe organ damage. Objectives: Identify the clinical features of hemochromatosis. Determine the appropriate evaluation for a patient with suspected hemochromatosis. Compare the management options available for hemochromatosis. Apply interprofessional team strategies to improve care coordination and outcomes in patients affected by hemochromatosis. Access free multiple choice questions on this topic.

Primary hemochromatosis is an autosomal recessive disorder, particularly among those of northern European descent, that disrupts the body’s ability to regulate iron absorption, leading to systemic iron overload. Despite the high prevalence of the gene mutation, the condition often shows variable clinical expression with low penetrance. Excess iron accumulates in critical organs, including the liver, pancreas, heart, joints, skin, and pituitary gland, leading to cellular dysfunction. The condition is typically diagnosed in middle age; women are often diagnosed later in life due to the iron loss associated with menstruation. Symptoms are generally nonspecific, and many cases are discovered through elevated transaminase, ferritin, and transferrin saturation levels. While primary hemochromatosis is hereditary, secondary hemochromatosis can develop from disorders in erythropoiesis or as a result of treatments involving blood transfusions, such as in thalassemia, sickle cell anemia, and hereditary spherocytosis. These secondary conditions lead to iron accumulation from damaged red blood cells, further complicating iron regulation. Phlebotomy is the primary treatment, reducing iron levels and improving organ function. In severe cases, particularly when liver damage is extensive, liver transplantation may be necessary. Relatives of individuals with hereditary hemochromatosis are advised to undergo genetic testing to assess their risk.

Retained iron is primarily deposited in the parenchymal cells in hereditary hemochromatosis, whereas transfusional hemochromatosis predominately results in iron deposition in the reticuloendothelial cells. The excess iron is deposited in the cells as hemosiderin, eventually leading to cell death and replacement of these cells by a fibrous deposition that causes destruction or impairment of organ function. Hereditary hemochromatosis is traditionally classified into 4 classes or types with some additional subtypes. Type 1 hereditary hemochromatosis occurs in patients who are typically homozygous for loss-of-function mutations in HFE. These mutations cause increased iron absorption despite an average dietary iron intake. While more than 100 HFE mutations can cause Type 1 hereditary hemochromatosis, the most common mutation is the p.Cys282Tyr or C282Y variant; the second most common mutation is the p.His63Asp or H63D mutation.[1] HFE is present on the short arm of chromosome 6 (6p21.3). The resultant anomaly is a decreased hepcidin production or a state of hepcidin resistance.[2] This is considered the classic form of hereditary hemochromatosis, is inherited in an autosomal recessive fashion, and disproportionately affects males.[3][4] Type 2 hereditary hemochromatosis is also inherited in an autosomal recessive fashion without a predilection for either sex. Historically, this disease was referred to as "juvenile" hemochromatosis, and the typical age of onset is in adolescence or early adulthood (15 to 20 years). Type 2 hereditary hemochromatosis has 2 subtypes, 2a and 2b. Type 2a is due to a mutation in the gene initially referred to as hemojuvelin but now known as HFE2. Type 2b is due to mutations in the hepcidin antimicrobial peptide (HAMP) gene on chromosome 19. Type 3 hereditary hemochromatosis, also inherited in an autosomal recessive fashion, has a typical age of onset of 30 to 40 years. This type is due to mutations in the transferrin-receptor gene (TFR2) on chromosome 7.[5]

Type 2 hereditary hemochromatosis is also inherited in an autosomal recessive fashion without a predilection for either sex. Historically, this disease was referred to as "juvenile" hemochromatosis, and the typical age of onset is in adolescence or early adulthood (15 to 20 years). Type 2 hereditary hemochromatosis has 2 subtypes, 2a and 2b. Type 2a is due to a mutation in the gene initially referred to as hemojuvelin but now known as HFE2. Type 2b is due to mutations in the hepcidin antimicrobial peptide (HAMP) gene on chromosome 19. Type 3 hereditary hemochromatosis, also inherited in an autosomal recessive fashion, has a typical age of onset of 30 to 40 years. This type is due to mutations in the transferrin-receptor gene (TFR2) on chromosome 7.[5] Type 4 hereditary hemochromatosis is the only known type to be inherited in an autosomal dominant fashion. Historically, this subtype was known as ferroportin disease, as the relevant mutations occur in the ferroportin transport protein known as ferroportin/solute carrier family 40 member 1, encoded by SCL40A1 on chromosome 2. The age of onset of type 4 hemochromatosis is highly variable and may be as early as 10 years or as late as 80 years.[2]

Hereditary hemochromatosis is the most common autosomal recessive disorder in White populations, with a prevalence of 1 in 300 to 500 individuals.[6] Hereditary hemochromatosis types 2, 3, and 4 are seen worldwide, but type 1 is primarily seen in people of northern European descent.[7] The prevalence of hemochromatosis is the same in Europe, Australia, and other Western countries, with excess in people of Celtic or Scandinavian origin. Hemochromatosis is less prevalent in patients of African descent. White individuals have a 6 times higher risk of developing the disease than Black individuals. In hemochromatosis, men are affected 2 to 3 times more often than women. The estimated ratio between men and women is 1.8:1 to 3:1. Women with hemochromatosis become symptomatic later in life than men due to the blood loss and consequent iron excretion associated with menstruation. The disease usually becomes apparent in men in the fifth decade; in women, it often presents in the sixth decade. In contrast, juvenile hemochromatosis may appear in persons aged 10 to 30. Analyses of a p.C282Y homozygous genotypic subset have revealed the greatest morbidity is in those patients older than 60.[8] The main risk factors for hemochromatosis include:[9] C28Y homozygosity (most significant risk factor) Positive family history Northern European heritage Male sex [9]

Hemochromatosis affects the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. Excessive alcohol consumption and viral hepatitis worsen liver and pancreatic toxicity. Micronodular cirrhosis occurs in 70% of patients with unmanaged hemochromatosis, significantly increasing the risk of hepatocellular carcinoma, a leading cause of death. Pancreatic iron deposition primarily manifests as diabetes, affecting about 50% of homozygous individuals; the risk of developing diabetes is elevated in heterozygotes. Arthropathy causes joint pain without destruction, resembling degenerative joint disease but with calcium pyrophosphate crystals in the synovial fluid. Cardiac symptoms stem from iron accumulation, leading to heart failure and arrhythmias. Iron overload also causes hypogonadism and skin hyperpigmentation. Iron overload in macrophages impairs phagocytosis, leading to decreased immunity and an increased risk of infections from organisms like Aeromonas, Listeria, Yersinia enterocolitica, and Vibrio vulnificus.[10][11][12][13] Patients with hemochromatosis should avoid handling or consuming raw shellfish due to a heightened risk of sepsis from V vulnificus. Excess iron deposits in the thyroid gland can cause hypothyroidism, with men experiencing an 80-fold greater risk than normal. While iron deposition in the adrenal and parathyroid glands rarely results in clinical symptoms, iron overload in hemochromatosis can occur due to massive oral intake, increased absorption with normal intake, or excessive red blood cell production or transfusion. Hereditary Hemochromatosis HFE mutations cause increased iron absorption despite normal dietary iron intake. HFE regulates the production of hepcidin, the protein product of HAMP, which is a circulating peptide hormone.[14] Hepcidin, made predominately in the liver, inhibits dietary iron absorption in the duodenum and its release by splenic macrophages. HFE-related mutations are responsible for 90% of the cases of hereditary hemochromatosis in people of Northern European descent. Heterozygotes may have abnormalities in clinical markers of iron metabolism but do acquire iron overload. Heterozygotes do have an increased risk of diabetes over the general population due to unknown mechanisms.[15][16] Secondary Hemochromatosis

HFE mutations cause increased iron absorption despite normal dietary iron intake. HFE regulates the production of hepcidin, the protein product of HAMP, which is a circulating peptide hormone.[14] Hepcidin, made predominately in the liver, inhibits dietary iron absorption in the duodenum and its release by splenic macrophages. HFE-related mutations are responsible for 90% of the cases of hereditary hemochromatosis in people of Northern European descent. Heterozygotes may have abnormalities in clinical markers of iron metabolism but do acquire iron overload. Heterozygotes do have an increased risk of diabetes over the general population due to unknown mechanisms.[15][16] Secondary Hemochromatosis Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition that results from excess iron absorption because the patient is producing excessive amounts of red blood cells. This often occurs due to an underlying disease of the red blood cells that causes them to be more fragile and, therefore, to have a shortened lifespan. When the cells are destroyed, their iron is deposited in the body tissues. The same mechanism is in effect in patients who receive multiple, usually chronic, transfusions of red blood cells. Other less common conditions, such as porphyria cutanea tarda, can cause iron overload. Erythropoietic hemochromatosis follows the prevalence of the underlying disease and is found in a broader range of ethnicities than the hereditary form of the disorder. Furthermore, excessive iron consumption can also cause hemochromatosis. Historically, this has resulted from drinking beer prepared in steel drums. Accidental and intentional overdoses of iron can result from the consumption of some over-the-counter dietary supplements.[17]

Clinical signs of hemochromatosis are dictated by the organ system most severely affected. Patients are usually asymptomatic until adulthood, and often, a diagnosis will not be made until multiple systems are affected. Almost all patients complain of severe fatigue. Other early manifestations include arthralgias and lethargy. Patients are typically symptomatic for up to 10 years before diagnosis. A high index of suspicion, combined with a thorough family history, is required to diagnose hemochromatosis. Women with hemochromatosis become symptomatic later in life than men due to the blood loss and consequent iron excretion associated with menstruation.[18] The following late manifestations occur when iron is deposited progressively in various tissues: Koilonychia: Koilonychia affects the thumb and index finger, and it has been observed in 50% of patients. However, in 25% of patients, all nails are affected. Secondary diabetes: Looking at the lateral aspects of the nails during the examination may reveal finger prick marks indicating diabetes, and an abdominal examination may be suggestive of lipodystrophy as a clue towards insulin administration. Diffuse hyperpigmentation: Skin discoloration is seen in more than 90% of patients with hemochromatosis and is one of the earliest manifestations of the disease. Although it may be mild, hyperpigmentation is more evident in sun-exposed areas of the skin. Other cutaneous manifestations may involve ichthyosiform changes and skin atrophy on the anterior aspects of the legs. Arthropathy: This occurs due to calcium pyrophosphate crystal deposition in the joints. Arthropathy can present with arthritis, chondrocalcinosis, and joint swelling, commonly involving metacarpophalangeal and proximal interphalangeal joints. Other commonly affected areas include knees, wrists, hip, back, neck, and feet.

Arthropathy: This occurs due to calcium pyrophosphate crystal deposition in the joints. Arthropathy can present with arthritis, chondrocalcinosis, and joint swelling, commonly involving metacarpophalangeal and proximal interphalangeal joints. Other commonly affected areas include knees, wrists, hip, back, neck, and feet. Liver involvement: Jaundice may or may not be present; liver dysfunction is encountered in 75% of patients. Jaundice is usually absent earlier in the course of the illness. Liver disease can present with abdominal pain, hepatomegaly, cirrhosis, portal hypertension, ascites, and splenomegaly. While cirrhosis only occurs in 10% to 15% of patients, the risk of hepatocellular carcinoma increases in patients with coexisting hemochromatosis and cirrhosis. The risk of hepatocellular carcinoma may amount to 30% of patients. A hepatic bruit may indicate hepatocellular carcinoma, and hepatic hum may suggest portal hypertension in such patients. Cardiac involvement: This can lead to restrictive or dilated cardiomyopathy, arrhythmias, and cardiac failure. Clinicians should listen for the third and fourth heart sounds in suspected cases. Endocrine dysfunction: This can lead to diabetes, pituitary hypogonadism, manifested by decreased libido and impotence in men and amenorrhea in women, hypopituitarism, thyroid dysfunction, adrenal dysfunction, parathyroid defects, and osteoporosis.[19] Gynecomastia and decreased body hair can be secondary to both chronic liver disease and hypogonadism. Partial loss of body hair is seen in 60% of patients, and complete hair loss is seen in 12% of patients. The pubic region is the most commonly involved area. Cancers: When compared with the general population, the risk of hepatocellular carcinoma is increased by 20-fold in patients with hemochromatosis. Infections: Patients with iron overload are at increased risk of infection from Yersinia enterocolitica, Listeria monocytogenes, and V vulnificus. Cranial nervous system: Hereditary hemochromatosis has been thought to lead to Parkinson disease, chorea, and tremors through its iron deposition in the basal ganglia, dentate, red nuclei, and the substantia nigra.[13]

Laboratory Studies Evaluation of hemochromatosis begins with serum transferrin saturation or serum ferritin concentration testing.[20] The mainstay of diagnosis requires a transferrin saturation greater than 45% or a serum ferritin greater than 200 µg/L in females or 300 μg/L in males.[2] Transferrin saturation testing in erythropoietic hemochromatosis may not be as effective in testing for iron overload in these patients. Ferritin specificity can be affected by inflammatory conditions. Ferritin is a "phase reactive protein," and in conditions of inflammation, indicated by an increase in either the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), ferritin may appear elevated, giving a false level of concentration. Ferritin levels above 200 mcg/L in women or 300 mcg/L in men or a transferrin saturation of >40% in women or 50% in men should lead to further testing. Transaminases are usually elevated but are generally not higher than twice normal.[21] Additionally, fasting blood glucose levels need to be checked for diabetes. Glycosylated hemoglobin levels might not be reliable in patients with high red cell turnover.[22] In the United States, where the HFE mutation is prevalent, further genetic testing for the mutations C282Y and H63D should be obtained.[23] Genetic testing for these mutations will confirm the diagnosis in over 90% of cases. For a more comprehensive discussion of the evaluation of hemochromatosis, please see StatPearls' companion reference, "Laboratory Evaluation of Hereditary Hemochromatosis." Imaging Studies Echocardiography can be used to identify and evaluate the severity of cardiomyopathy in patients with hemochromatosis. A chest radiograph may indicate cardiomegaly and increased pulmonary vascular markings, but is not diagnostic of cardiac disease. Magnetic resonance imaging (MRI) of the liver is a noninvasive way to measure liver iron content.[24] The contrast of hepatic iron excess with the relative paucity of splenic iron is highly suggestive of hepcidin deficiency.[25] Additional Testing

Echocardiography can be used to identify and evaluate the severity of cardiomyopathy in patients with hemochromatosis. A chest radiograph may indicate cardiomegaly and increased pulmonary vascular markings, but is not diagnostic of cardiac disease. Magnetic resonance imaging (MRI) of the liver is a noninvasive way to measure liver iron content.[24] The contrast of hepatic iron excess with the relative paucity of splenic iron is highly suggestive of hepcidin deficiency.[25] Additional Testing Liver biopsy is the most sensitive and specific test for measuring liver iron content and can also assess liver damage. On histopathological analysis with Perls Prussian blue staining, there is a classic pattern in which iron deposits are primarily in hepatocytes and biliary epithelial cells, with slight involvement of Kupffer cells. A liver biopsy is indicated in the following situations: Elevated liver enzymes in a diagnosed case of hemochromatosis Serum ferritin levels greater than 1000 mcg/L Additional tests that need to be conducted in patients with high ferritin levels are echocardiogram for cardiomyopathy, hormone levels to evaluate hypogonadism, and bone densitometry to evaluate for osteoporosis.[26][27] All relatives of patients with hemochromatosis should be offered genetic testing.

The conventional therapy for primary hemochromatosis is phlebotomy. By removing circulating erythrocytes, the major mobilizer of iron in the body, iron toxicity can be minimized.[28] Patients may require 50 to 100 phlebotomies of 500 mL each to reduce iron levels to normal. Phlebotomy is usually performed once or twice a week. Once iron levels have normalized, lifelong but less frequent phlebotomy is required, typically 3 to 4 times a year. The objective is to obtain a ferritin level of less than 50 µg/L.[29][30] Iron removal through phlebotomy improves insulin sensitivity, skin pigmentation, and fatigue; cirrhosis, hypogonadism, and arthropathy remain unchanged. Erythrocytapheresis has been suggested as an alternative to phlebotomy as it operates more rapidly.[9] Erythrocytapheresis has been shown to improve cognition, fatigue, and the ferritin level quickly.[31] Alcohol should be strictly prohibited in this condition due to its potential to accelerate liver and pancreatic toxicity. Phlebotomy rarely reverses preexisting end-organ damage. Treatment for associated dysfunction, such as insulin for pancreatic dysfunction, remains essential. Early detection of hemochromatosis allows for treatment that can prevent end-organ dysfunction, resulting in minimal mortality or morbidity. However, severe end-organ damage often leads to a life expectancy of less than two years following diagnosis. Although chelation is not as effective in hereditary hemochromatosis, it is of more benefit in erythropoietic hemochromatosis, where phlebotomy is not typically an option.[32] Deferoxamine is an intravenous iron-chelating agent. Deferiprone and deferasirox are oral iron chelators. Deferoxamine, deferiprone, and deferasirox are all equivalent in efficacy in the mobilization and excretion of iron.[33] In combination with phlebotomy, erythropoietin is sometimes administered to maintain the hemoglobin concentration while forcing iron mobilization.

Although chelation is not as effective in hereditary hemochromatosis, it is of more benefit in erythropoietic hemochromatosis, where phlebotomy is not typically an option.[32] Deferoxamine is an intravenous iron-chelating agent. Deferiprone and deferasirox are oral iron chelators. Deferoxamine, deferiprone, and deferasirox are all equivalent in efficacy in the mobilization and excretion of iron.[33] In combination with phlebotomy, erythropoietin is sometimes administered to maintain the hemoglobin concentration while forcing iron mobilization. Patients who have end-stage liver disease may be candidates for liver transplantation. Initial studies have shown that compared to patients with non-hemochromatosis causes, patients with iron overload disorders who undergo liver transplantation have lower survival rates.[34][35] However, the reduced survival rates were noted to be due to cardiac complications and infections. Data accumulated over recent years showed an increase in posthepatic transplant survival with hepatocellular carcinoma.[9] A 1-year posttransplant survival of approximately 89% and a 5-year survival of about 78% were noted. Since hepatocellular carcinoma accounts for around 30% of mortality in patients with hemochromatosis, all patients should undergo surveillance with ultrasounds and alpha-fetoprotein levels every 6 months.

Due to the involvement of multiple organ systems, several differential diagnoses must also be considered when evaluating patients with clinical features of hemochromatosis, including: Iron overload from chronic transfusion Hepatitis B and C Metabolic dysfunction associated steatotic liver disease (MASLD; formerly nonalcoholic fatty liver disease or NAFLD) Excessive iron supplementation Dysmetabolic hyperferritinemia Hereditary aceruloplasminemia Alcoholic liver disease Porphyria cutanea tarda Marrow hyperplasia Hemolytic anemia Biliary cirrhosis

If left untreated, hemochromatosis can lead to progressive liver damage and cirrhosis, hepatocellular carcinoma, and other complications associated with iron overload in the tissues and organs.[36] The prognosis has improved in the last few decades with advances in diagnosis and management of this condition. Hepatic fibrosis or cirrhosis is the main prognostic indicator at the time of diagnosis. Early diagnosis and regular treatment with phlebotomy can decrease most of the complications associated with hemochromatosis.

Patients are more likely to develop cirrhosis in the presence of additional factors like alcohol use disorder or hepatitis. Other complications of hemochromatosis include: Hepatocellular carcinoma Diabetes mellitus Heart failure Hypogonadism Osteoporosis

Owing to multiple organ system pathologies, the involvement of various specialties may be required in the management of patients with hemochromatosis, including: Gastroenterology and hepatology Endocrinology Cardiology Rheumatology Dermatology

Patients should be educated that regular treatment with phlebotomy and chelating agents can prevent most hemochromatosis complications. Alcohol should be avoided. Patients should also avoid supplements that contain iron or vitamin C, which promotes iron absorption. There are no special diet recommendations for patients with hemochromatosis. Patients should avoid eating raw or undercooked shellfish. This is because of the risk of bacterial infections, especially those caused by Vibrio vulnificus, which thrives in iron-rich environments.

Management of hemochromatosis requires an interprofessional effort from healthcare clinicians, including the patient's primary care clinicians, gastroenterologists, and hepatologists. If complications arise from progressive iron overload, patients should be referred to consultants for managing complications, such as endocrinologists, orthopedics, and cardiologists. Nurses should educate patients that alcohol should be strictly prohibited in this condition because it can accelerate liver and pancreatic toxicity. Genetic counseling for family members is advocated for those patients with the hereditary form.