INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. It is the most common inherited liver disease in whites and the most common autosomal recessive genetic disorder.

Pathophysiology: Hereditary hemochromatosis is an adult-onset disorder characterized by inappropriately high iron absorption resulting in progressive iron overload. The organs involved are the liver, heart, pancreas, pituitary, joints, and skin.

Adults preserve a constant level of body iron by efficient conservation, maintaining rigorous control over absorption to balance losses. An adult man loses approximately 1 mg of iron daily, mostly in desquamated epithelium and secretions from the gut and skin. During the childbearing years, healthy women lose an average of an additional milligram of iron daily from menstrual bleeding (40 mL blood loss) and approximately 500 mg with each pregnancy. In addition, normal daily fecal loss of approximately 0.7 mL of blood (0.3 mg of iron) occurs. Only a small quantity of iron is excreted in urine (<0.1 mg/d).

In healthy adults, losses are balanced by absorption of sufficient dietary iron (1-2 mg) to maintain a relatively constant amount of body iron throughout life. Although excretion is quantitatively as important as absorption in the maintenance of iron balance, absorption usually plays the more active regulatory role. In hereditary hemochromatosis, dysregulation of intestinal iron absorption occurs, wherein iron continues to be efficiently absorbed even in the face of substantial elevation of body iron stores.

The gene responsible for the disease is called HFE and is located on chromosome 6. It is mutated in the vast majority of individuals with hereditary hemochromatosis. HFE interacts with the transferrin receptor and causes a clear decrease in the affinity with which the receptor binds transferrin. This interaction also may modulate cellular iron uptake and decrease ferritin levels. When a mutant or nonfunctional variant of the HFE gene is present, ferritin levels are not under influence of a normal and functional HFE gene, which leads to enhanced accumulation of iron in peripheral tissues.

Findings suggestive of increased iron transport at the basolateral membrane of enterocytes in hemochromatosis have emerged from numerous studies of HFE-related hemochromatosis in humans and in mice.

Hepcidin, a human antimicrobial peptide synthesized in the liver, plays a key role in the down-regulation of iron release by enterocytes and macrophages. The absence of this new peptide is associated with severe early-onset iron-loading phenotype. It is also inappropriately low in adult-onset HFE-related disease.

Excess iron is hazardous because it produces free radical formation. The presence of free iron in biological systems can lead to the rapid formation of damaging reactive oxygen metabolites such as the hydroxyl radical and the superoxide radical. These can produce DNA cleavage, impaired protein synthesis, and impairment of cell integrity and cell proliferation, leading to cell injury and fibrosis.

Frequency:

• In the US: Prevalence is approximately 1 case in 300 persons. Most are of northern European origin. The carrier state is estimated to be approximately 10%.

• Internationally: It has the same prevalence in Europe, Australia, and other Western countries, the highest prevalence being noted in people of Celtic origin. It is less common among Africans.

Mortality/Morbidity: Hemochromatosis results in liver cirrhosis, heart failure, diabetes mellitus, impotence, and arthritis. If untreated, it may lead to death from cirrhosis, diabetes, malignant hepatoma, or cardiac disease.

• Mortality is estimated to be 1.7 cases per 10,000 deaths. This number increases to 3.2 cases per 10,000 deaths in autopsy series.

• The death rate associated with hemochromatosis increased from 0.5 persons per million population in 1968 to 0.9 persons per million population in 1992 due to improved recognition of the disease.

• Mortality is higher in infants and adults older than 50 years. Also, mortality is higher in men and in whites than in women, African Americans, and other groups.

Race:

• Prevalence in whites is 6 times higher than in African Americans.

• Recently, it has become prevalent in the Hispanic population. The frequency is much lower among Hispanic persons (0.27 in 1000), Asian Americans (<0.001 per 1000), Pacific Islanders (0.12 per 1000), and black persons (0.14 per 1000)

• The Celtic population is affected most frequently.

Sex:

• Men are affected more often than women, with an estimated ratio of 1.8:1.

Age:

• The disease usually becomes apparent after age 40 years in men and after age 50 years in women.

• Median age in women is 66 years.

• Median age in men is 51 years.

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• Symptoms usually begin between age 30 years and age 50 years, but they may occur much earlier. Clinical manifestations include the following:

• Liver disease

• Skin pigmentation

• Diabetes mellitus

• Arthropathy

• Impotence in males

• Cardiac enlargement, with or without heart failure or conduction defects

• Early symptoms include the following:

• Severe fatigue (74%)

• Impotence (45%)

• Arthralgia (44%)

• Later, patients may experience the following symptoms:

• Skin bronzing or hyperpigmentation (70%): This reflects a combination of iron deposition and melanin. The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation occurs late in the disease, when total iron body content is 20 grams (ie, >5-times normal).

• Diabetes mellitus (48%): This is due to progressive iron accumulation in the pancreas. The defect appears to be relatively selective for the pancreatic beta cells. Most patients with hemochromatotic diabetes have other signs of hemochromatosis such as liver disease or skin pigmentation.

• Cirrhosis: This is one of the most common disease manifestations of the tissue damage caused by hemochromatosis, and it may progress to liver cancer years later (risk >200-fold). It also is the most common cause of death in patients with hereditary hemochromatosis.
  • It is due to progressive iron deposition in the liver parenchyma.

  • Reversibility with iron removal has been reported even with development of varices, but this is more likely early in the course of liver disease.

  • All patients with cirrhosis should undergo diagnostic endoscopy to document the presence of varices and to determine their risk of variceal hemorrhage. Patients at risk for variceal hemorrhage should be considered for primary prophylaxis with propranolol or nadolol.

  • Hepatocellular carcinoma is one of the most serious complications of hemochromatosis.

  • Most hepatologists recommend periodic screening with serum alpha-fetoprotein (AFP) every 6 months in patients with cirrhosis.

  • The most cost-effective imaging test used to supplement serum AFP screening is ultrasound. The sensitivity is approximately 80% when serum AFP and ultrasound are combined for the screening of hepatocellular carcinoma.

  • Liver transplant may be used to treat patients with hepatocellular carcinoma, but careful patient selection is advised. Particularly, these patients should have a single tumor of 5 cm or smaller in diameter. If multiple tumors are present, the acceptable number is 3 or less, smaller than 3 cm. The 4-year survival rate can be approximately 90% if these criteria are respected.

• Other symptoms may include the following:

• Fatigue and arthralgia are the most common symptoms prompting a visit to a physician.

• Most patients are asymptomatic (75%) and are diagnosed when elevated serum iron levels are noted on a routine a chemistry screening panel or when screening is performed because a relative is diagnosed with hemochromatosis.

• Cardiomyopathy is another mode of presentation, particularly in younger patients. These patients may present with congestive heart failure or arrhythmias.

• Dilated cardiomyopathy is characterized by the development of heart failure and conduction disturbances such as sick sinus syndrome. In the past, cardiac disease was the presenting manifestation in as many as 15% of patients; therefore, the absence of other manifestations of hemochromatosis should not preclude the diagnosis.

• Hypogonadism is the most common endocrine abnormality causing decreased libido and impotence in men. It usually is due to pituitary involvement by iron deposition. Primary hypogonadism, presumably due to testicular iron deposition, also can occur but is much less common.

• Amenorrhea can occur in women but is less frequent than hypogonadism in men.

• Arthropathy is due to iron accumulation in joint tissues. It is associated with characteristic radiologic findings, ie, squared-off bone ends and hooklike osteophytes in the metacarpophalangeal (MCP) joints, particularly in the second and third MCP joints. Symptoms usually do not respond to iron removal.

• Hypothyroidism may occur rarely.

Physical:

• The most common signs at the time of presentation are hepatomegaly (13%), skin pigmentation, and arthritis.

• Liver function abnormalities occur in 35-75% of patients.

• Cirrhosis occurs in 13%, usually late in the disease.

• Other findings upon examination include the following:

• Right upper quadrant tenderness with hepatomegaly or splenomegaly if cirrhosis present

• Signs of fluid overload with congestive heart failure

• Sick sinus syndrome with conduction abnormalities

• Patients may have susceptibility to certain bacterial infections such as Yersinia enterocolitica liver abscess, Yersinia pseudotuberculosis sepsis, Vibrio vulnificus sepsis, and Listeria monocytogenes meningitis.

• The most commonly affected joints include the following:

• MCP joints

• Proximal interphalangeal joints

• Knees

• Feet

• Wrists

• Back

• Neck

• Chondrocalcinosis, which involves the knees and wrists, may occur and may be asymptomatic.

Causes:

• Hereditary hemochromatosis is a genetic disorder inherited as an autosomal recessive trait.

• The gene is tightly linked to the human leukocyte antigen (HLA)-A region on the short arm of chromosome 6.

• HGE, a specific gene for hemochromatosis, has been identified.

• Homozygosity for a missense mutation, with substitution of a cysteine residue for a tyrosine residue at amino acid position 282 (C282Y) of HFE is found in 70-100% of clinically diagnosed patients.

• A second missense mutation, with substitution of histidine for aspartate at amino acid 63 (H63D), also has been identified. The clinical effects of this mutation appear to be limited.

• C282Y homozygotes and, possibly, C282Y/H63D compound heterozygotes, appear to be at risk for clinical iron overload. The clinical significance of other rarer forms of compound heterozygosity, such as heterozygosity for C282Y and a mutation in which cysteine replaces serine at position 65 (S65C) or heterozygosity for H63D and S65C, is still controversial.

• The precise mechanism by which mutations in the HFE gene lead to iron overload is unknown.

• The outcome is increased intestinal iron absorption and predominantly hepatocellular accumulation of hepatic iron.

• Although relatively few cases have been described to date, the iron-overload phenotype associated with mutations in the gene encoding transferrin receptor 2 (TfR2) appears to be very similar to that of classic HFE-related hemochromatosis.

• Rare cases of juvenile hereditary hemochromatosis have recently been linked to a homozygous mutation in the HAMP gene, which encodes hepcidin, a peptide that plays a key role in human iron metabolism. However, most juvenile-onset cases have been mapped to chromosome 1q, where the gene that produces hemojuvelin, HJV (originally called HFE2), has been identified.

• Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Recent studies suggest that TfR2 is a modulator of hepcidin production in response to iron; hepcidin was low or undetectable in most cases of patients homozygous for TfR2 mutation.