Hemochromatosis

Article Author:
Joann Porter
Article Editor:
Prashanth Rawla
Updated:
1/28/2019 11:17:59 AM
PubMed Link:
Hemochromatosis

Introduction

Hemochromatosis is a disorder associated with deposits of an excess of iron that causes multiple organ dysfunctions. 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 Caucasians.

Etiology

Retained iron is primarily deposited in the parenchymal cells in hereditary hemochromatosis, whereas with 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 and/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.

Different types of Hereditary Hemochromatosis are:

1) Type 1 (HFE-related): It is the classic form of hereditary hemochromatosis. Autosomal recessive disorder. Worldwide prevalence.[2][3]

2) Type 2a (mutations of hemojuvelin gene) and Type 2b (mutations of the hepcidin gene): Autosomal recessive disorder. Seen in Caucasian or non-Caucasians. Onset at 15-20 years.

3) Type 3 (mutations of transferrin receptor 2 gene): Autosomal recessive disorder. Seen in Caucasian or non-Caucasians. Onset at 30-40 years.[4]

4) Type 4 (mutations of the ferroportin gene): Autosomal dominant disease. Seen in Caucasian or non-Caucasians. Onset at 10-80 years.

Epidemiology

Hereditary hemochromatosis is the most common autosomal recessive disorder in Caucasians with a prevalence of 1 in 300 to 500 individuals.[5] Type 2, 3 and 4 hereditary hemochromatosis is seen worldwide but Type 1 form is mostly seen in people of northern European descent.[6] Hemochromatosis is an autosomal recessive disorder with almost equal numbers of male and female homozygotes. Women with hemochromatosis become symptomatic later in life than men due to the blood loss and consequent iron excretion associated with menstruation.

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 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 major 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 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 a dilated cardiomyopathy and cardiac arrhythmias. Left ventricular failure has sometimes been reversed with removal of iron stores.
  • Hypogonadism, with resultant impotence, is due to iron-induced hypothalamic and/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 normal levels.

Iron overload of macrophages can cause impaired phagocytosis and lead to decreased immunity, resulting in 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, and (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.[0] 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 transferrin receptor. 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.[0][0][0] 

Causes of secondary hemochromatosis include erythropoietic hemochromatosis, a condition that results from 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 most affected. 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.[0]

Early manifestations include arthralgias, fatigue, and lethargy.

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

  • Discoloration of the skin (diffuse hyperpigmentation) can be seen.
  • Arthropathy: Occurs due to iron accumulation in tissues of the joint. Can present with arthritis, chondrocalcinosis, joint swelling commonly involving metacarpophalangeal joints, Proximal interphalangeal joints, knees, wrists, hip, back, neck, feet.
  • Liver involvement: can present with abdominal pain, hepatomegaly, Cirrhosis, Portal hypertension, Ascites, Splenomegaly, and Hepatocellular carcinoma can also be seen in up to 30% of patients.
  • Cardiac involvement: Can lead to dilated cardiomyopathy, arrhythmias, and cardiac failure.
  • Endocrine dysfunction: 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]

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 to test for iron overload in these patients. The ferritin specificity can be affected by inflammatory conditions. If the ferritin level is above 200 mcg/L in women or 300 mcg/L in men, or a transferrin saturation 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]

MRI of the liver is a non-invasive way to measure liver iron content.[15] Liver biopsy is the test which is most sensitive and specific for measuring liver iron content and can also assess liver damage. 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 should be done to check for cardiomyopathy, hormone levels to evaluate hypogonadism, bone densitometry to evaluate for osteoporosis.[18][19]

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. [0]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] Alcohol should be strictly prohibited with 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 employed 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]

Differential Diagnosis

Iron overload from chronic transfusion 

Hepatitis B and C

Nonalcoholic fatty liver disease (NAFLD)

Excessive iron supplementation

Dysmetabolic hyperferritinemia

Hereditary aceruloplasminemia

Prognosis

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

Consultations

Gastroenterology and Hepatology

Endocrinology

End-stage liver disease patients should be referred to a liver transplant center

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 a multidisciplinary effort from health care providers including the patient's primary care physicians, 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 with this condition because it can accelerate liver and pancreatic toxicity. Genetic counseling may be required in some patients.


References

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