Continuing Education Activity

Hemochromatosis is a disorder that causes excess iron deposition and, in turn, multiple organ dysfunction. Organs affected by hemochromatosis include the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. This activity reviews the evaluation and management of hemochromatosis and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the epidemiology of hemochromatosis.
• Describe the evaluation of hemochromatosis.
• List the management options available for hemochromatosis.
• Identify interprofessional team strategies for improving care, coordination, and communication to enhance outcomes for patients affected by hemochromatosis.

Introduction

Hemochromatosis is a disorder associated with deposits of excess iron that causes multiple organ dysfunction. Normally, iron absorption is tightly regulated because the body is incapable of excreting excess iron. Hemochromatosis occurs when there are high pathologic levels of iron accumulation in the body. Hemochromatosis has been called “bronze diabetes” due to the discoloration of the skin and associated disease of the pancreas. Hereditary hemochromatosis is the most common autosomal recessive disorder in whites. Secondary hemochromatosis occurs because of erythropoiesis disorders and treatment of the diseases with blood transfusions. After the damage of transfused red blood cells by macrophages, iron freed from heme is accumulated in the body. Secondary hemochromatosis is mainly caused by thalassemia, sickle cell anemia, hereditary spherocytosis, X-linked sideroblastic anemia, and pyruvate kinase deficiency.

Etiology

Retained iron is primarily deposited in the parenchymal cells in hereditary hemochromatosis, whereas in the case of transfusional hemochromatosis, it is primarily deposited in the reticuloendothelial cells. The excess iron is deposited in the cells as hemosiderin. This eventually leads to cell death and replacement of these cells by a fibrous deposition that causes destruction or impairment of organ function. Hereditary hemochromatosis occurs in homozygotes with a mutation of the hemochromatosis gene (HFE) protein. A mutation in the HFE gene causes increased absorption of iron despite a normal dietary iron intake. C282Y and H63D are the most common mutations of the HFE gene.[1] HFE gene is present on the short arm of chromosome 6 (6p21.3).

Different types of hereditary hemochromatosis are:

1. Type 1 (HFE-related): It is the classic form of hereditary hemochromatosis that is inherited in an autosomal recessive fashion with worldwide prevalence.[2][3]
2. Type 2a (mutations of hemojuvelin gene) and type 2b (mutations of the hepcidin gene): Autosomal recessive disorder that is seen both in whites and non-whites. Its onset is usually at 15-20 years.
3. Type 3 (mutations of transferrin receptor-2 gene): Autosomal recessive disorder that is seen both in whites and non-whites. Its onset is at 30-40 years.[4]
4. Type 4 (mutations of the ferroportin gene): Autosomal dominant disease that is seen both in whites and non-whites. Its onset is at 10-80 years.

Epidemiology

Hereditary hemochromatosis is the most common autosomal recessive disorder in whites, with a prevalence of 1 in 300 to 500 individuals.[5] Hereditary hemochromatosis type 2, 3, and 4 are seen worldwide but type 1 is mostly seen in people of northern European descent.[6] The prevalence of hemochromatosis is the same in Europe, Australia, and other Western countries with excess in people of Celtic origin. It is less prevalent in patients of African descent. The white population has a six times higher risk of developing the disease than blacks.

In hemochromatosis, men are affected around 2-3 times as often as 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. In men, the disease usually becomes apparent in the fifth decade; however, in women, it presents in the sixth decade often. In contrast, juvenile hemochromatosis may appear in persons aged 10-30 years.

Pathophysiology

Organs affected by hemochromatosis include the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. Excessive alcohol intake and viral hepatitis accelerate the pathology associated with hemochromatosis, especially with respect to the liver and pancreatic toxicity.

• Cirrhosis is present in 70% of patients with hemochromatosis. In these patients, there is a marked increased incidence of hepatocellular carcinoma, which is a significant cause of death.

• Diabetes is the primary manifestation of pancreatic iron deposition. The incidence of diabetes is approximately 50% in symptomatic patients, and the risk is increased in heterozygotes for hereditary hemochromatosis.

• Arthropathy manifests as joint pain without joint destruction. Although the presentation is identical to that of degenerative joint diseases, calcium pyrophosphate crystals can be found in the synovial fluid. It can still progress after the normalization of iron stores.

• Cardiac symptoms result from iron deposition in the cardiac muscle fibers and cells of the conduction system. Electrocardiac abnormalities can be present before true cardiac dysfunction occurs. Symptoms are due to congestive heart failure as a result of dilated cardiomyopathy and cardiac arrhythmias. Left ventricular failure can sometimes be reversed with the removal of iron stores.

• Hypogonadism, with resultant impotence, is due to iron-induced hypothalamic or pituitary failure, resulting in impairment of gonadotropin hormone release.

• Skin hyperpigmentation is a result of both iron and melanin deposition. It does not usually occur before the iron stores exceed five times the normal levels.

Iron overload of macrophages can cause impaired phagocytosis and lead to decreased immunity, resulting in an increased risk of infection from Listeria, Yersinia enterocolitica, and Vibrio vulnificus. Patients with hemochromatosis should not handle or eat raw shellfish due to the increased risk of sepsis from Vibrio vulnificus.

• Iron deposition in the thyroid gland causes hypothyroidism. The risk of hypothyroidism is 80 times greater than normal for men with hemochromatosis.

• Iron deposition in the adrenal and parathyroid glands rarely results in clinical manifestations.

• The iron overload that causes hemochromatosis can occur in three ways:
  1. Massive oral intake of iron
  2. Increased iron absorption with normal iron intake
  3. Excessive production or massive transfusion of red blood cells

The most common cause of hemochromatosis is an inherited autosomal recessive condition with variable penetrance. This condition is classified as primary hemochromatosis. Hereditary hemochromatosis occurs in homozygotes with a mutation of the HFE protein. A mutation in the HFE gene causes increased absorption of iron despite a normal dietary iron intake. The HFE protein regulates the production of hepcidin, the iron regulatory hormone.[7] Hepcidin is produced by the liver, and it determines how much iron is absorbed from the diet and released from storage sites in the body. The normal function of HFE appears to be the control of iron uptake by cells through its interaction with the transferrin receptors. Two mutations of the HFE gene 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.[8][9]

Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition that results from the absorption of excess iron because the patient is producing excessive amounts of red blood cells. This often occurs as a result of 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, the iron from them 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 also cause iron overload. Erythropoietic hemochromatosis follows the prevalence of the underlying disease (i.e., thalassemia, spherocytosis) and is found in a wider range of races than the hereditary form of the disorder.

Finally, excessive iron consumption also can 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.[10]

History and Physical

Clinical signs of the condition depend on the organ system that is affected the most. Patients usually are asymptomatic until adulthood, and often a diagnosis will not be made until multiple systems are affected. Symptoms are related to the organ affected, but almost all patients complain of severe fatigue. Patients are typically symptomatic for up to ten years before diagnosis. A high index of suspicion, combined with a thorough family history, is required to diagnose this condition. Women with hemochromatosis become symptomatic later in life than men due to the blood loss and consequent iron excretion associated with menstruation.[11]

Early manifestations include arthralgias, fatigue, and lethargy.

Late manifestations occur when iron starts getting deposited in the tissue progressively.

• Koilonychia: Koilonychia affecting the thumb and index finger has been observed in 50% of patients while 25% of patients tend to have it in all nails.
• Secondary diabetes: Looking at the lateral aspects of the nails during the examination may reveal finger prick marks indicating diabetes and abdominal examination may be suggestive of lipodystrophy as a clue towards insulin administration.
• Discoloration of the skin (diffuse hyperpigmentation) is seen in more than 90% of patients with idiopathic hemochromatosis and is one of the earliest manifestations of the disease. Although it may be mild, it is more evident in the 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 (pseudogout). It 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; however, liver function abnormalities are 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 10-15% of patients, the risk of hepatocellular carcinoma (HCC) increases in patients with coexisting hemochromatosis and cirrhosis. The risk of HCC 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. One must listen for the third and fourth heart sounds in suspected cases.
• Endocrine dysfunction: This can lead to diabetes mellitus, pituitary hypogonadism (as manifested by decreased libido and impotence in men and amenorrhea in women), hypopituitarism, thyroid dysfunction, adrenal dysfunction, parathyroid defects, and osteoporosis.[12] 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 liver cancer 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 Vibrio vulnificus.

Evaluation

The investigation should start with the measurement of serum transferrin saturation or serum ferritin concentration.[13] It should be noted that transferrin saturation testing in erythropoietic hemochromatosis may not be as effective in testing for iron overload in these patients. The ferritin specificity can be affected by inflammatory conditions. Ferritin level above 200 mcg/L in women or 300 mcg/L in men or transferrin saturation of more than 40% in women or 50% in men should lead to further testing. In the United States, where the HFE mutation is prevalent, further genetic testing for the mutations C282Y and H63D should be obtained.[14] Genetic testing for these mutations will confirm the diagnosis in over 90% of cases.

Radiography can be utilized in diagnosing organ involvement, such as echocardiography to preclude cardiomyopathy. A chest radiograph may indicate cardiomegaly and increased pulmonary vascular markings. MRI of the liver is a non-invasive way to measure liver iron content.[15]

Liver biopsy is the test that is most sensitive and specific 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 primarily in hepatocytes and biliary epithelial cells, with slight involvement of Kupffer cells. A liver biopsy is indicated in the following situations:

1. Elevated liver enzymes in a diagnosed case of hemochromatosis
2. Serum ferritin levels more than 1000 mcg/L

Liver enzymes are usually elevated, with most patients having elevated aminotransferase levels, but the liver enzymes are usually not higher than twice the normal levels.[16]

Fasting blood glucose levels need to be checked for diabetes. Glycosylated hemoglobin levels might not be reliable in patients with high red cell turnover.[17] Other tests that need to be done in patients with high ferritin levels are echocardiogram for cardiomyopathy, hormone levels to evaluate hypogonadism, and bone densitometry to evaluate for osteoporosis.[18][19]

First-degree relatives of patients with hemochromatosis should undergo screening with genetic testing.

Treatment / Management

The conventional therapy for primary hemochromatosis is phlebotomy. By drawing off red blood cells, the major mobilizer of iron in the body, iron toxicity, can be minimized.[20] 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 (typically 3-4 times a year) is required. The objective is to obtain a ferritin level of less than 50 mcg/L.[21][22] Iron removal through phlebotomy improves insulin sensitivity, skin pigmentation, and fatigue; however, cirrhosis, hypogonadism, and arthropathy remain unchanged.

Alcohol should be strictly prohibited in this condition because it can accelerate liver and pancreatic toxicity. Preexisting end-organ damage is rarely reversed by phlebotomy. Treatment for associated end-organ dysfunction, such as insulin for pancreatic dysfunction, is indicated. If hemochromatosis is detected early, treatment prevents end-organ dysfunction, and there is little mortality or morbidity associated with it. However, patients rarely live more than two years after the diagnosis if severe end-organ damage has occurred.

Although chelation is not as effective in hereditary hemochromatosis, it is of more benefit in erythropoietic hemochromatosis, where phlebotomy is not typically an option.[23] Deferoxamine is an intravenous iron-chelating agent. Deferiprone and deferasirox are oral iron chelators. They are all equivalent in efficacy in mobilization and excretion of iron.[24]

Erythropoietin, in combination with phlebotomy, 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. Studies have shown that when compared to non-hemochromatosis causes, patients with iron overload disorders who undergo liver transplantation have lower survival rates.[25]

Since HCC accounts for around 30% of mortality in hemochromatosis, all patients with hemochromatosis would undergo surveillance, with six-monthly ultrasound and alpha-fetoprotein levels.

Differential Diagnosis

On account of the involvement of multiple organ systems in hemochromatosis, the differential diagnoses are also broad.

• Iron overload from chronic transfusion 
• Hepatitis B and C
• Nonalcoholic fatty liver disease (NAFLD)
• Excessive iron supplementation
• Dysmetabolic hyperferritinemia
• Hereditary aceruloplasminemia
• Alcoholic liver disease
• Porphyria cutanea tarda
• Marrow hyperplasia
• Hemolytic anemia
• Biliary cirrhosis

Prognosis

If left untreated, it can lead to progressive damage of the liver and lead to cirrhosis, hepatocellular carcinoma and other complications associated with iron overload in the tissues and organs.[26] With advances in diagnosis and management of this condition, the prognosis has improved in the last few decades. 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.

Complications

Patients are more likely to develop cirrhosis in the presence of additional factors like alcoholism or hepatitis. Other complications seen are:

• Hepatocellular carcinoma
• Diabetes mellitus
• Congestive heart failure
• Hypogonadism
• Osteoporosis
• Patients with iron overload are at increased risk of infection from Yersinia enterocolitica, Listeria monocytogenes, and Vibrio vulnificus.[27]

Consultations

Owing to multiple organ system pathologies, involvement of various specialties may be required in the management of patients with hemochromatosis. These consultations include the following:

1. Gastroenterology and hepatology
2. Endocrinology
3. End-stage liver disease patients should be referred to a liver transplant center
4. Cardiology
5. Rheumatology
6. Dermatology

Deterrence and Patient Education

Patients should be educated that regular treatment with phlebotomy and chelating agents can prevent most of the complications associated with hemochromatosis. Avoidance of alcohol should be emphasized. Patients should also avoid supplements that contain iron or vitamin C. There are no special diet recommendations for patients with hemochromatosis.

Enhancing Healthcare Team Outcomes

Management of hemochromatosis needs an interprofessional effort from health care providers, including the patient's primary care providers, gastroenterologists, and hepatologists. Patients should be referred to consultants for managing complications like endocrinologists, orthopedics, and cardiologists if complications arise from progressive iron overload. Nurses should educate patients that alcohol should be strictly prohibited in this condition because it can accelerate liver and pancreatic toxicity. Genetic counseling may be required in some patients.