Hemochromatosis

Etiology

Retained iron is primarily deposited in the parenchymal cells in hereditary hemochromatosis, whereas transfusional hemochromatosis predominantly results in iron deposition in the reticuloendothelial cells. Excess iron is deposited in cells as hemosiderin, eventually leading to cell death and replacement with fibrous deposits that cause destruction or impairment of organ function. Hereditary hemochromatosis is traditionally classified into 4 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 (C282Y) variant; the second most common is the p.His63Asp (H63D) variant.[1] HFE is present on the short arm of chromosome 6 (6p21.3). The resulting anomaly is decreased hepcidin production or 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/protein initially referred to as HFE2a but presently as hemojuvelin (HJV).[5][6] Type 2b is due to mutations in the hepcidin antimicrobial peptide (HAMP) gene on chromosome 19. Hemojuvelin is akin to an iron "sensor" controlling hepcidin production in response to dietary iron and is produced by the liver. Hemojuvelin is a glycosylphosphatidylinositol-anchored protein that induces hepcidin production (via ALK2 and ALK3 receptors) from a coproductive action with bone-morphogenetic protein, which itself is affected by the inhibitory action of erythroferrone (ERFE).[7] ERFE, in turn, is controlled by erythropoietin (EPO). The HJV mutation causes an elevation in serum iron levels that selectively deposits in cardiac tissue.[8] This is due to the high concentration of L-type calcium channels in the cardiac tissue. The results of this deposition are a cardiac myopathy and other sequelae most characteristic of this youth-oriented disease. 

Type 3 hereditary hemochromatosis, also inherited in an autosomal recessive fashion, typically presents at 30 to 40 years of age. This type is due to mutations in the transferrin-receptor gene (TFR2) on chromosome 7.[9] 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]

Epidemiology

Hereditary hemochromatosis is the most common autosomal recessive disorder in white populations, with a prevalence of 1 in 300 to 500 individuals.[10] Hereditary hemochromatosis types 2, 3, and 4 are seen worldwide, but type 1 is primarily seen in people of northern European descent.[11] The prevalence of hemochromatosis is the same in Europe, Australia, and other Western countries, with an excess in people of Celtic or Scandinavian origin. Hemochromatosis is less prevalent in patients of African descent. Incidentally, it has been noted that patients from Colombia have a lower prevalence of C282Y and a higher penetrance of H63D compared with Europeans.[8] 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 that the greatest morbidity is in those patients older than 60.[12] The main risk factors for hemochromatosis include:

• C28Y homozygosity (most significant risk factor)
• Positive family history
• Northern European heritage
• Male sex [13]

Pathophysiology

Hemochromatosis affects the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary gland. Excessive alcohol consumption and viral hepatitis worsen the liver and pancreatic toxicity. Alcohol consumption alone decreases hepcidin and increases the risk of hepatic fibrosis/cirrhosis.[14] 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. The H63D variant, which manifests a modicum of symptoms, becomes highly problematic in the face of chronic alcohol abuse.[15]

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 caused by organisms, eg, Aeromonas, Listeria, Yersinia enterocolitica, and Vibrio vulnificus.[16][17][18][19] 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 women. 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.[20] Hepcidin, made predominantly 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.[21][22]

Secondary Hemochromatosis

Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition resulting from excessive iron absorption due to increased red blood cell production. This often occurs due to an underlying disease of the red blood cells that makes them more fragile and, therefore, shorter-lived. When the cells are destroyed, their iron is deposited in the body tissues. The same mechanism is at work in patients who receive multiple, usually chronic, red blood cell transfusions.

Other less common conditions, eg, 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.[23]

History and Physical

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.[24]

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: Examining the lateral aspects of the nails may reveal finger-prick marks indicating diabetes, and an abdominal examination may suggest lipodystrophy as a clue to insulin administration.

• Diffuse hyperpigmentation: Skin discoloration is present in more than 90% of patients with hemochromatosis and is among 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 results from 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 the knees, wrists, hips, 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: Hemochromatosis involving cardiac tissues 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: Hemochromatosis involving the endocrine system can lead to diabetes and pituitary hypogonadism, the latter manifested by decreased libido and impotence in men and amenorrhea in women. Hypopituitarism, thyroid dysfunction, adrenal dysfunction, parathyroid defects, and osteoporosis also occur.[25] 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.[19]

Evaluation

Laboratory Studies

Evaluation of hemochromatosis begins with testing for serum transferrin saturation or serum ferritin concentration.[26] The mainstay of diagnosis is a transferrin saturation greater than 45% or a serum ferritin greater than 200 µg/L in females and 300 µg/L in males.[2] Transferrin saturation testing may be less effective for detecting iron overload in erythropoietic hemochromatosis. Ferritin specificity can be affected by inflammatory conditions. Ferritin is a "phase reactive protein," and in conditions of inflammation, indicated by increases in either the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), ferritin may appear elevated, yielding a false concentration. Ferritin levels above 200 µg/L in women or 300 µg/L in men, or a transferrin saturation greater than 40% in women or 50% in men, should prompt further testing.

Transaminases are usually elevated but are generally not higher than twice normal.[27] Additionally, fasting blood glucose levels should be checked to screen for diabetes. Glycosylated hemoglobin levels may be unreliable in patients with high red cell turnover.[28] In the United States, where the HFE mutation is prevalent, further genetic testing for the mutations C282Y and H63D should be obtained.[29] Genetic testing for these mutations will confirm the diagnosis in over 90% of cases. Please see StatPearls' companion reference, "Laboratory Evaluation of Hereditary Hemochromatosis," for a more comprehensive discussion of the evaluation of 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 method for measuring liver iron content.[30] The contrast of hepatic iron excess with the relative paucity of splenic iron is highly suggestive of hepcidin deficiency.[31]

Additional Testing

Liver biopsy is the most sensitive and specific test for measuring liver iron content and assessing liver damage. On histopathological analysis with Perls Prussian blue staining, a classic pattern in which iron deposits are primarily in hepatocytes and biliary epithelial cells, with slight involvement of Kupffer cells, is typically noted. A liver biopsy is indicated for patients with elevated liver enzymes with a diagnosed case of hemochromatosis or serum ferritin levels greater than 1000 µg/L.

Additional tests to be performed in patients with high ferritin levels include an echocardiogram to evaluate for cardiomyopathy, hormone levels to evaluate for hypogonadism, and bone densitometry to evaluate for osteoporosis.[32][33] All relatives of patients with hemochromatosis should be offered genetic testing.

Treatment / Management

The conventional therapy for primary hemochromatosis is phlebotomy. By removing circulating erythrocytes, the body's major iron mobilizers, iron toxicity can be minimized.[34] 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 achieve a ferritin level below 50 µg/L.[35][36] 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.[13] Erythrocytapheresis has been shown to quickly improve cognition, fatigue, and ferritin levels.[37]

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, eg, 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 2 years following diagnosis.

Although chelation is less effective in hereditary hemochromatosis, this treatment modality is more beneficial in erythropoietic hemochromatosis, where phlebotomy is not typically an option.[38] 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.[39] 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 nonhemochromatosis causes, patients with iron overload disorders who undergo liver transplantation have lower survival rates.[40][41] 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.[13] 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.(B2)

Differential Diagnosis

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

Prognosis

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.[42] The prognosis has improved over the last few decades, driven by advances in the 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 reduce most complications associated with hemochromatosis.

Complications

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 (HCC): Iron overload has been advocated as both a diagnostic and prognostic marker for HCC.[43]
• Diabetes mellitus: Approximately 50% of patients with hemochromatosis will have diabetes due to beta-cell damage from iron deposition.[25] This manifests as both decreased insulin and insulin resistance.
• Heart failure: Cardiac hemochromatosis is characterized by the development of a dilated cardiomyopathy.[44][45] The resulting decrease in ejection fraction, coupled with cardiac conduction defects (especially of the AV node), leads to heart failure.
• Hypogonadism: Hypogonadotropic hypogonadism occurs with iron deposition in the pituitary gland as well as the testicles.[46]
• Osteoporosis: Osteoblastic activity is inhibited in favor of osteoclastic bone resorption.[47][48] Studies have noted that about a third of hemochromatosis patients have osteoporosis, while nearly double that percentage had osteopenia. Fractures are an inevitable consequence.