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Hereditary Hemochromatosis: Preventing Chronic Effects of this Underdiagnosed Disorder

Hereditary hemochromatosis, once thought to be rare is the most common genetic disorder in the United States. Nonetheless, the condition often goes undetected and untreated until its severe effects have become apparent. What clues can lead you to the diagnosis, and how can you spot them in your patients, before significant morbidity has occurred? In this article, Drs McDonnell and Witte discuss the diagnosis and management of this underrecognized problem as well as the various issues involved in screening. An illustrative case of hemochromatosis is also included.

A 47 year-old, white, male presented with complaints of fatigue and nonspecific musculoskeletal aches and pains. History taking and physical examination offered no clues to the cause of his symptoms. Laboratory testing showed a normal complete blood count and normal glucose and Thyrotropin levels, but his alanine aminotransferase (ALT) was 50% above the normal.

The elevated ALT level had also been detected during a routine evaluation several months earlier and warranted further evaluation. ¹ The patient had no high-risk social behaviors and was a regular blood donor. Laboratory testing showed a serum iron level of 147 痢/dL, total iron binding capacity 225 痢/dL, and transferrin saturation of 65%. A second transferrin saturation test, performed after fasting and exclusion of dietary iron and vitamin C supplements for at least 24 hours, revealed a saturation of 76%. Additional testing showed the following values: serum iron 168 痢/dL, total iron binding capacity, 220 痢/dL; and serum 550 痢/L (normal, 20 to 400 痢/L). Sedimentation rate was normal. The results were strongly suggestive of hemochromatosis.²

The patient was referred to a specialist in iron overload disease, who recommended a liver biopsy because of the patient’s age, abnormal liver enzyme levels, and elevated serum ferritin concentration. Histologic examination revealed Perls’ stain grade 2 iron, primarily in hepatic parenchymal cells, and minimal inflammation. The hepatic iron index (hepatic iron concentration [mol/g dry weight] divided by patient’s age [years] was 2.1. An index of 1.9 or higher is used to differentiate hemochromatosis from other liver diseases.

The patient received weekly phlebotomy with hemoglobin monitoring before each session. After 26 weeks, a total of 24 U had been removed, his serum ferritin level was 50 痢/L, and his hemoglobin level was 13 g/dL. The patient reported marked improvement in fatigue, libido, and joint pains. He continues to receive maintenance phlebotomy therapy based on serum ferritin values.

Iron overload is classified as primary or secondary, depending on the underlying mechanism. Primary iron overload results from abnormally increased absorption of dietary iron in the small intestine. Secondary overload results mainly from iron accumulated as a consequence of ineffective erythropoiesis, multiple blood transfusions or prolonged, excessive intake of dietary iron.¹

Hereditary hemochromatosis is a type of primary iron overload. The excess iron that is absorbed is deposited in the parenchymal cells of the liver, heart, joints, pancreas, and other endocrine organs causing inflammation and subsequent fibrosis and destruction, which results in organ failure and ultimately, chronic diseases. ^1,2

Hereditary hemochromatosis is an autosomal recessive disorder previously considered to be rare. The classic diagnosis was clinical, based on the presence of bronze diabetes with cirrhosis. Recent estimates place the prevalence of the homozygous genotype at 1 in 250 persons, and about 1 in nine is a carrier, making hereditary hemochromatosis the most common known genetic disorder in the United States. ^{1, 3} The condition is under diagnosed among whites. In addition, because it most often affects white men of northern European descent, the disease may not be considered in other populations or ethnic groups (eg, African Americans, Hispanics) even when symptoms and clinical findings are consistent with the diagnosis.^{1, 4-6}

The body has no mechanism for excreting iron absorbed from the diet except through incidental losses. Thus, the level of body iron can be regulated only through absorption of iron from food. The amount of iron absorbed from the diet is influenced by the following factors: the amount of iron stores in the body, the rate and effectiveness of erythropoiesis (functional iron), the amount and chemical form of iron in the diet, and the presence of absorption enhancers and inhibitors in the diet. Persons with normal hemoglobin levels and iron stores (as reflected by serum ferritin values) absorb just enough to meet their daily needs and to balance losses (1 mg per day).⁷ In contrast, persons with hemochromatosis continue to absorb high amounts of dietary iron even when their body already has enough or too much iron.

When total body iron exceeds storage capacity (five to 10 times the normal quantity), tissue and organ damage begins. ¹ At this stage, iron overload has occurred. This condition, if left untreated, can result in arthritis, cirrhosis, diabetes, heart disease, psychological and sexual dysfunction, and premature death.¹

The clinical manifestations of hereditary hemochromatosis usually do not appear until a person reaches 40 to 60 years of age, when sufficient iron has accumulated to cause organ damage. Yet some persons have clinical manifestations by age 20, and others who are homozygous for the disease may never have clinical signs.² About 50% of men and 13% to 20% of women with untreated hereditary hemochromatosis will have clinical manifestations of iron overload by the age of 40.^{1, 8-9} After age 40, an estimated 67% to 94% of men and 41% of women with hereditary hemochromatosis eventually show signs and symptoms of the disease.⁹

The development of the clinical manifestations of iron overload may be influenced by genetic and environmental factors including menstruation, diet, and blood donation.¹ Use of alcohol and other hepatotoxic drugs lowers the ability of the liver to safely store iron and may accelerate the development of the hepatic sequelae of iron overload.²

A common early sign of progressive iron overload is asymptomatic elevation of liver enzyme levels, particularly alanine aminotransferase and aspartate aminotransferase, which later may be accompanied by recurrent right-sided abdominal pain and hepatomegaly. Arthropathy is also common, and occasionally acute episodes of inflammatory arthritis occur, at least some of which are caused by deposits of calcium pyrophosphate dihydrate.² Other early signs and symptoms include impotence, amenorrhea, irritability, depression, and fatigue.² Because these clinical conditions are not specific to iron overload, the disorder may not be considered in differential diagnosis. Consequently, the underlying cause is not recognized and treated and organ damage progresses.

Liver disease which is present in 30 to 94% of patients with iron overload is the most common complication of hemochromatosis, and cirrhosis is the most common severe sequelae.^{1, 10} An autopsy study of patients with cirrhosis showed hemochromatosis as the underlying cause in 7.5% of the deaths.¹¹ Once cirrhosis is present, risk of liver neoplasm is increased 200 fold in patients with hemochromatosis compared with persons without the disorder, and liver neoplasms account for nearly one third of all deaths among affected patients.^{1, 11, 12} Therefore, it is essential that hemochromatosis be considered in the evaluation of any liver abnormality. Other damage to tissues and organs includes gray or bronze skin pigmentation, diabetes mellitus, hypopituitarism, hypogonadism, cardiomyopathy, joint deformity (as arthritis progresses), chronic abdominal pain, and severe fatigue.¹

The degree of iron overload at the time of diagnosis of hereditary hemochromatosis has prognostic implications.^{1, 12} Patients with no evidence of tissue or organ damage have subclinical disease. With proper management, their long-term prognosis, including life expectancy, should not differ from that of healthy persons.¹³ The prognosis for persons with significant hepatic fibrosis, diabetes, or cardiomyopathy due to iron overload is poorer.

Early diagnosis of hereditary hemochromatosis based on abnormal laboratory values allows prevention and early treatment of clinical manifestations. The presence of several clinical signs of iron overload (e.g., cirrhosis, diabetes and hyperpigmentation of the skin) should not be a requirement for diagnosis, because these signs indicate late-stage disease. The diagnosis should be broadened to include manifestations of abnormal iron metabolism, such as persistent elevation in transferrin saturation and evidence of increased body iron load regardless of clinical complications. Increasingly, the diagnosis is being made in patients with abnormal laboratory values.¹⁰ The most common tests used in assessing a patient iron status and for iron-overload are described in table 1.

Table 1: Common tests used in assessment of iron status and detection of iron overload

Test	Description	Normal Values	Value Indicating Overload	Notes
Transferrin Saturation	Most sensitive test for detecting hemochromatosis. Iron is transported in the body by the protein transferrin. Saturation (the extent to which transferrin has vacant iron-binding sites) is calculated by dividing serum iron concentration by total iron binding capacity. High saturation indicates high level of body iron.	>15-40%	>60% in men; 50% in women	A fasting test eliminates short-term effects of diet on saturation. Infection and inflammation can depress saturation. Compared with normal population heterozygotes for hereditary hemochromatosis have elevated levels but not as high as those in homozygotes. Saturation <15%: indicates iron deficiency
Serum Ferritin Concentration	Ferritin is an intracellular iron storage protein. Its concentration in serum indicates the level of iron stored in the body (concentration 1 痢/L = 10 mg of stored iron).	20 to 400 痢/L in men; 20 to 200 痢/L in women of childbearing age; 20 to 300 痢/L in postmenopausal women	> 400 痢/L in men; >200 痢/L in women of childbearing age and > 300 痢/L in Post-menopausal women	A high concentration may also indicate infection or inflammation, especially liver disease. Level of <20 痢/L indicates iron deficiency; <12 痢/L indicates iron depletion
Hemoglobin	Hemoglobin content in circulating red blood cells.	13.6 mg/L in men; 12 mg/L in women:	Normal or low	High level does not occur with iron overload. Iron deficiency may occur due to anemia from chronic inflammation and illness
Quantitative Phlebotomy	Removal of blood until iron deficiency develops. The amount of blood removed indicates total body iron load	Variable, usually >2 to 3 U in 2 wk result in drop in hemoglobin	About 10 U whole blood	Also used to treat iron overload.
Liver Biopsy	The amount of iron in the liver (hepatic iron concentration) is measured by atomic absorption spectrophotometry of hepatic parenchymal cells or extimated histologically with perls’ stain.	Hepatic iron concentration <80 mol/g dry weight	Hepatic iron concentration >80 mol/g dry weight	Biopsy used to evaluate prognosis on the basis of extent of iron infiltration into tissues (fibrosis and cirrhosis).
	Hepatic iron index equals the hepatic iron concentration divdided by the patients age.	Hepatic iron index <1.1	Hepatic iron index > 1.9	Used to differentiate hemochromatosis from other liver diseases. Liver iron levels are affected by age, menstruation, blood donation, and pathologic blood losses.
	Perls’ staining using a gradeing system to describe the amount of parenchymal iron on a scale from 0-4	Perls’ stain grade 0-1 stainable hepatic parenchymal iron	Grade 3-4 stainable liver iron	Young homozygotes will have normal or near- normal stainable iron

Patients with persistent elevation of transferrin saturation have phenotypic evidence of hemochromatosis. Further evaluation is necessary to determine whether such patients have iron overload and associated organ damage. An elevated serum ferritin concentration not related to an acute-phase response is correlated with excess iron stores and is more predictive of organ damage than an elevated transferrin saturation. The presence and amount of iron may be confirmed by quantitative phlebotomy or liver biopsy.

Quantitative phlebotomy is the removal of a unit (500 mL) of whole blood (200-250 mg of iron) once or twice weekly until iron deficiency develops (as reflected by hemoglobin and serum ferritin levels). The total amount of blood that must be removed to produce iron deficiency provides an estimate of total body iron load and thus, an estimate of excess body iron. The amount of blood needed to confirm iron overload is controversial; most diagnosticians require at least ten units or 3-5 g.²

Liver biopsy has long been considered the "gold standard" for the diagnosis of hemochromatosis, because it can detect fibrosis and cirrhosis. Many specialists prefer liver biopsy over phlebotomy, particularly when clinical or laboratory evidence of hepatic involvement is present. In patients less than 40 years of age who have a serum ferritin concentration of less than 750 ng/mL and normal liver enzyme levels, phlebotomy therapy can be started without biopsy. In all other cases, biopsy remains essential for diagnosis and optimal management. The amount of iron can be measured chemically or estimated histologically with Perls’ stain.¹

A recently discovered genetic mutation, the HFE gene, is associated with a large number of cases of severe hereditary hemochromatosis ¹³ However, other genes may be involved, and hemochromatosis can develop in a person who is "normal" or heterozygous for the HFE gene. A "positive" gene test does appear to indicate increased risk. Thus, homozygous patients who have normal iron measures should undergo monitoring for serum ferritin every 2 years to detect iron loading.

Iron overload is treated with successive phlebotomies in both patients with and those without clinical manifestations. The approach has two phases:

Once the diagnosis is made, patients need information and support. Patient advocacy groups such as the Iron Overload Diseases Association^* can assist in providing information. All patients should be advised that their first-degree relatives should undergo screening for hemochromatosis. A genetics counselor may helpful to patients who are trying to understand the disease.

Strict dietary restrictions are not indicated. However, patients interested in limiting the amount of iron in their diet should be provided information on dietary sources of iron as well as inhibitors and enhancers of iron absorption. Referral to a dietician may be helpful.

Hemochromatosis may exacerbate viral hepatitis, alcoholism and other liver diseases. Alcohol may be consumed in moderation unless there is evidence of liver disease. Persons with both hepatitis C and iron overload respond poorly to treatment with interferon, possibly because iron reduces the effectiveness of the drug.¹⁴ Patients who have iron overload are also at increased risk for infection Vibrio vulnificus and Yersinia entercolitica. V. vulnificus infection is associated with eating raw shellfish, particularly oysters, and nearly 40% of infected persons die.¹⁵

Iron overload disease meets many of the criteria for population-based screening: The disorder is common; a sensitive screening test (i.e., transferrin saturation) allows detection during a long presymptomatic phase; and a safe, effective treatment is available, which can eliminate morbidity and premature mortality and reduce health care costs. ^{1, 16, 17} The transferrin saturation test can be readily included in blood chemistry tests done during routine adult physical examinations. The test also can e used to detect iron deficiency.¹⁷

Although data supporting universal screening are compelling, several important concerns exist. First, transferrin saturation is quite variable (biologically and analytically), which calls into question the predictive value of the test. Second, many physicians are unfamiliar with the diagnosis and management of hemochromatosis. Third, the extent to which iron overload contributes to the overall burden of disease in the United States remains to be determined. Fourth, patients may need protection from possible discrimination by employers and health and life insurance companies. Many social, legal, and ethical issues of genetic diseases and their testing are unresolved. Recently, an expert committee of the Centers for Disease Control and Prevention and the National Institutes of Health reached a consensus that gene testing for hemochromatosis should only be used only for research purposes and should not be applied clinically until its prognostic significance is clarified.¹⁸

The ideal age for screening is long before a person has accumulated enough iron to result in organ damage. However, young adults seldom seek medical care except for employment physical examinations, prenatal care, and treatment of acute symptoms. These settings provide good opportunities for screening. Women may need to undergo screening again after menopause, when iron excretion declines. Screening of asymptomatic persons is prudent but must be done through collaboration of the local laboratories and caregivers.

The College of American Pathologists recommends screening for iron overload with the transferrin saturation test in all persons 18 years of age or older as part of a routine medical care (e.g., during an employment physical examination, curative services, or gynecologic care).¹ Screening is also advised in all persons, regardless of age, who have one or more of the following risk factors: a family history of iron overload disease, any of the clinical manifestations of iron overload (e.g., impotence, severe fatigue, hypogonadism, amenorrhea, cardiomyopathy, diabetes mellitus, liver disease, or arthritis), and abnormalities found during a routine health examination or testing for iron deficiency (table 1). Pregnant women should not undergo an initial screening for iron overload; first-time screening should occur no sooner than 3 months postpartum, when measures of iron status have stabilized.

If the transferrin saturation is elevated (>50% for women and >60% for men), it should be repeated to enhance specificity. Before the second test, the patient should fast overnight and avoid iron or vitamin C supplements for at least 24 hours. Liver enzyme levels, serum ferritin concentration, and complete blood cell count should be assessed at that time. Physical examination for liver, heart, and endocrine disease should be performed.

When the transferrin saturation is persistently elevated and cannot be explained by the presence of other medical conditions (e.g., liver disease from another cause or secondary iron overload), a presumptive diagnosis of hereditary hemochromatosis may be made. A patient who has a persistently elevated transferrin saturation, with or without high iron stores (elevated serum ferritin level) or clinical signs of iron overload, should be referred to a physician familiar with iron overload disease for further diagnosis and management. If the transferrin saturation is not elevated on follow-up testing but the serum ferritin concentration is, evaluation for causes of inflammation is warranted.

A detailed description of screening, diagnosis, treatment, and follow-up of hereditary hemochromatosis can be found in the practice parameters developed by the College of American Pathologists.¹

Diagnosis of iron overload is often delayed until clinical manifestations have appeared and it is too late to prevent organ damage. Therefore, basic and continuing medical education about the disease is urgently needed. Physicians and their specialty groups will be important leaders for change. Further studies on the prevalence and penetrance of hereditary hemochromatosis, the capability of current laboratory tests to detect this disease and the cost-effectiveness of screening for the disease are also needed.