Hereditary Hemochromatosis: Early Detection of a Common Yet Elusive Disease

Although widely regarded as a rare disorder, hereditary hemochromatosis is the most common genetic disease in Caucasians. In certain populations of northern European descent, 1 of every 200 persons is homozygous for the causative mutation.¹

Hereditary hemochromatosis is also the most common cause of primary iron overload. Persons with this disease are predisposed to absorb excess iron from the GI tract; the excess iron deposits in the parenchyma of organs and produces such clinical manifestations as diabetes, cirrhosis, and heart failure. (In secondary iron overload, excess iron results from cirrhosis, sideroblastic anemias that cause ineffective erythropoiesis, multiple transfusions, or other exogenous sources.)

The diagnosis is frequently overlooked because:

• Affected patients may have no obvious symptoms.
• The clinical manifestations are protean; they include osteoarthritis (OA) and diabetes.
• Hereditary hemochromatosis is often not considered in the differential diagnosis because of its perceived rarity.

Early diagnosis is crucial—before irreversible tissue damage occurs. Here, I highlight the symptoms, laboratory results, and biopsy findings that suggest hereditary hemochromatosis, even in its early stages. I also outline a treatment approach and explore the pros and cons of screening.

PREVALENCE
In North America, it has been estimated that a physician will see a patient with hereditary hemochromatosis approximately every 3 weeks.² This estimate may be conservative.

In population studies, the prevalence of hereditary hemochromatosis is surprisingly high. Of 16,031 asymptomatic patients from 22 ambulatory practices in Rochester, NY, who were screened with iron studies, 25 had biopsy-proven hereditary hemochromatosis. Another 22 patients met clinical criteria for the disease but declined biopsy.³ The prevalence was 4.5 per 1000 patients, which is consistent with the known frequency of the hereditary hemochromatosis mutation. Routine screening of the general population for hereditary hemochromatosis is controversial (Box).

How does the prevalence of hereditary hemochromatosis compare with that of a relatively common entity such as iron deficiency anemia? In a West German study, 3027 outpatients and 3012 employees of industrial companies were screened for both conditions. ⁴ All participants were asymptomatic. Among the outpatients, 1.6% of the men had hemochromatosis, and only 1.5% had iron deficiency anemia. In the employee group, 1% of the men had hemochromatosis, and only 0.3% had iron deficiency anemia. Among the women, iron deficiency was more common than iron overload; however, 1.9% of the female outpatients and 1.1% of the female employees had hemochromatosis.

These 2 studies included only asymptomatic patients. Population studies in patients with disorders that might be related to iron overload reveal an even greater prevalence of hereditary hemochromatosis. For example, the prevalence may be as high as 5% in patients with peripheral arthritis, 6% in those with chronic liver disease or cirrhosis, and 15% in those with hepatocellular carcinoma.⁵

When persons with 2 or more disorders that may be related to iron excess are screened, the prevalence of hereditary hemochromatosis skyrockets. Persons with both liver disease and diabetes are 43 times more likely to have hereditary hemochromatosis than are those with neither disease. Patients who have diabetes and liver neoplasia are 83 times more likely to have hereditary hemochromatosis.⁶

GENETIC BASIS
During the past decade, the candidate gene for hemochromatosis was identified. The gene is found on chromosome 6 and encodes a major histocompatability complex class I–like protein that, like a typical HLA molecule, spans cell membranes. Because of this similarity, the gene was initially named HLA-H, but was later renamed HFE.⁷ Although the HFE protein is found in many human cells, it is most abundant in the duodenum—which suggests a prominent role in the absorption of iron. The mechanism by which HFE regulates iron absorption is not fully understood. Studies with monoclonal antibodies have also confirmed the presence of the protein in crypt cells, where it is associated with the transferrin receptor.⁸

Major mutation. Two missense mutations of the HFE gene play an important role in hereditary hemochromatosis. The major HFE mutation, C282Y, results in a cysteine( to tyrosine change at amino acid 282. Depending on the population studied, between 69% and 100% of patients with hemochromatosis exhibit this major mutation on both chromosomes in a pair—that is, are homozygotes.^7,9-11 This is a significant percentage; of Caucasian patients who have cystic fibrosis, for example, only 70% exhibit the most common mutation associated with that disease (CFTR, or delta 508 mutation). It is estimated that 1 in 385 Americans is homozygous for the major mutation associated with hereditary hemochromatosis (C282Y).¹²

Minor mutation. Another significant mutation, the “minor mutation,” or H63D, also has a role in some patients. Between 4% and 7% of patients with hereditary hemochromatosis are compound heterozygotes (persons who exhibit both C282Y and H63D mutations).^7,11,13 Nearly 1 in 50 Americans may be a compound heterozygote. ¹² “Simple” heterozygotes (patients who have either the C282Y or H63D mutation but not both) may account for 3% to 4% of cases of hereditary hemochromatosis; these patients may have other HFE mutations as well.^13,14 However, iron overload rarely develops in simple heterozygotes unless they have another concurrent liver disease.

Although the HFE gene plays an important role in hemochromatosis, this role is still not clearly understood or well-defined. Up to 7% of patients with hereditary hemochromatosis exhibit neither the major nor the minor HFE mutation.^9,13,15 Moreover, some patients who are homozygous for the major mutation or who are compound heterozygotes have no clinical or biochemical evidence of iron overload. Thus, environmental or other genetic influences also appear to have a role in the disease.¹

CLINICAL MANIFESTATIONS
Most patients with hereditary hemochromatosis do not present with the classic finding of “bronze diabetes,” which is a late manifestation of the disease; many have nonspecific symptoms. The 3 most common complaints are fatigue, arthralgia, and libido loss.¹⁶ Symptoms are often attributed to other diseases or to functional entities and are usually present for an average of 10 years before a diagnosis is made.

GI system. Hereditary hemochromatosis commonly involves the GI system; the liver is most frequently affected. Excess iron deposits, in the form of ferritin and hemosiderin, cause hepatomegaly and ultimately lead to fibrosis and cirrhosis. Patients may present with abdominal pain, particularly in the right upper quadrant. Aminotransferase levels are typically elevated. However, only 60% of patients with hereditary hemochromatosis have abnormal liver function test results at the time of diagnosis,¹⁷ so normal results cannot reliably exclude the disease. Ultimately, cirrhosis and its attendant problems, such as varices and ascites, develop in untreated patients. Hepatocellular carcinoma is one of the most serious complications of hemochromatosis and is a frequent cause of death.

Musculoskeletal system. More than 50% of patients with hereditary hemochromatosis have musculoskeletal complaints; arthralgia is the most common of these symptoms. The arthritis of hereditary hemochromatosis results from calcium pyrophosphate deposition in the joints. The joints most frequently involved are the wrists, distal interphalangeals, and metacarpals (particularly the second and third); however, it is not un- usual to see knee, hip, or even shoulder arthritis.

Radiographic findings are similar to those of OA—joint-space narrowing, subchondral cysts, and sclerosis. Sometimes distinctive hook-like or beak-like osteophytes are seen on the radial aspects of the metacarpal heads. Despite the fact that the radiographic findings mimic those of classic OA, osteoarthritic changes in the metacarpals and wrist joints are rarely seen. Thus, OA in unusual sites, such as the wrist, elbow, or ankle, is a clue to hereditary hemochromatosis—especially when there is no history of trauma to these joints.

Another clue that suggests hereditary hemochromatosis is OA in large non–weight-bearing joints—particularly the shoulder—when there is no history of trauma. Patients in whom arthritis develops before age 50 years, especially those who require early joint replacement, may also have underlying hereditary hemochromatosis.

Finally, hereditary hemochromatosis should be included in the differential diagnosis of unexplained chondrocalcinosis.

Cardiovascular system. Cardiac manifestations occur in about 15% of affected patients. Bradyarrhythmias are common; of patients who have these arrhythmias, up to 2% have underlying hereditary hemochromatosis.¹⁸ Diastolic dysfunction with restriction occurs early in the disease; systolic dysfunction with dilated cardiomyopathy occurs later.¹⁹

Up to 5% of patients referred to The Johns Hopkins Hospital for “idio- pathic” cardiomyopathy had previously undiagnosed infiltrative diseases of the heart, including hereditary hemochromatosis.²⁰ Consider routinely testing patients with heart failure for hereditary hemochromatosis once you have excluded ischemia and other obvious causes. Congestive heart failure (CHF) is a common cause of death in patients who have hereditary hemochromatosis.

Endocrine system. Endocrine problems are also common in patients with hereditary hemochromatosis. These include decreased libido (one of the most common complaints), erectile dysfunction, testicular atrophy, amenorrhea, sterility, and even osteoporosis secondary to gonadal failure. Such problems are most likely the result of hypogonadotrophic hypogonadism caused by iron deposition in the pituitary gland; patients have low or normal follicle-stimulating hormone and luteinizing hormone levels with low sex hormone levels.

Diabetes mellitus occurs in up to 50% of symptomatic patients with hereditary hemochromatosis.¹⁷ Hyperglycemia results from iron deposition in pancreatic parenchyma and seems to be selective for the pancreatic beta cell.

Other endocrine problems include hypoparathyroidism and adrenal insufficiency secondary to infiltrative disease. Hypothyroidism can also occur; iron deposits cause gland fibrosis.

Figure 1

Skin. The classic dermatologic presentation—hyperpigmentation—is seen late in the course of hereditary hemochromatosis (Figure 1). Hemosiderin deposition and direct iron stimulation of melanocytes result in darkening of the skin.²¹ Although the classic description of this phenomenon is bronzing, in early stages it resembles tanning.

Nervous system. Neuropsychiatric symptoms can also occur; depression is the most common. In patients with advanced hereditary hemochromatosis, a dementia-like illness and peripheral neuropathy have been seen.

Immune system. Affected patients are more susceptible to severe Vibrio, Yersinia, and Listeria infections. ²² The increased susceptibility probably results from the increased availability of iron for the bacteria’s metabolism.

DIAGNOSTIC TESTS
Transferrin saturation. The first phenotypic expression of the disease is an elevated transferrin saturation (TS). (To calculate TS, divide the serum iron level by the total iron-binding capacity.) An elevated TS correlates with increased GI iron absorption. A common misconception is that measurement of ferritin or serum iron is the most appropriate screening test for hereditary hemochromatosis. However, ferritin levels rise only after parenchymal cells are overloaded. Asymptomatic patients or those with arthralgia or other early symptoms may have normal serum ferritin levels.

Figure

I consider any TS greater than 45% as indicative of hereditary hemochromatosis. Different authorities use different cutoffs. The problem with using higher cutoffs is that you may miss disease; using lower cutoffs results in more false-positive readings.²³

A random blood sample may be used for the initial TS; however, if this percentage is high, obtain a second TS level after fasting. Iron levels are highest after meals; thus, a postprandial TS level may be falsely elevated. If the second (fasting) TS is elevated, measure the serum ferritin level and test for the HFE mutation (Algorithm).

Serum ferritin. Ferritin levels greater than 300 μg/L (200 μg/L for premenopausal women) are suspect. However, ferritin is an acute phase reactant and may be elevated because of an unrelated systemic inflammatory process. Ferritin concentration is also increased in other liver diseases, such as chronic viral hepatitis, alcohol(ic liver disease, and nonalcoholic steatohepatitis. Genetic testing may help clarify the source of iron overload.

HFE mutations. Biochemical evidence of iron overload along with C282Y homozygosity confirms the diagnosis of hereditary hemochromatosis. If a homozygous patient has a normal serum ferritin level but an elevated fasting TS, two explanations are possible. The patient may have a frustrated (clinically nonpenetrant) form of hereditary hemochromatosis, and clinical manifestations of the disease may never develop. Alternatively, the patient may be in an early stage of the disease, in which case periodic ferritin monitoring is required. Once the ferritin level reaches a critical threshold (300 μg/L, or 200 μg/L for premenopausal women), treatment can be started. Because it is impossible to distinguish between these 2 forms of the disease, ferritin levels must be monitored indefinitely.

Liver biopsy. Results help you rule out other causes of liver disease. Also, in the absence of known causes of secondary iron overload, the diagnosis of hereditary hemochromatosis is confirmed when at least one of the following criteria is met:

• Hepatic iron concentration of more than 71 μmol/g.
• Hepatic iron index (HII) of 1.9 or greater. The HII is calculated by dividing the hepatic iron concentration (expressed in μmol/g) by the patient’s age in years. The 1.9 cutoff helps distinguish alcohol-related and other types of liver disease from hereditary hemochromatosis.²⁴

The HII is not a perfect indicator; if a patient with hereditary hemochromatosis loses iron because of GI bleeding, the value may drop below 1.9. However, genetic testing has made it possible to diagnose this condition in patients whose index is between 1.5 and 1.9 (for example, by differentiating between heterozygotes and homozygotes who had donated blood).

Figure 2

Figure 3

The location of hepatic iron on light microscopy also aids in the diagnosis of hereditary hemochromatosis. When iron overload results from a secondary cause, iron tends to accumulate in macrophages or Kupffer cells, and thus appears in the liver sinusoids (Figure 2). If a patient demonstrates iron accumulation of this type, it is probably not necessary to quantitate the hepatic iron concentration and calculate the HII. The excess iron that results from hereditary hemochromatosis accumulates mostly in the periportal hepatocytes and generally spares the sinusoids (Figure 3).

A genetic test for C282Y homozygosity may obviate the need for liver biopsy in patients whose TS and ferritin levels are consistent with the diagnosis. If the patient has normal liver function tests, normal liver size, a serum ferritin level less than 1000 μg/L—and is homozygous—cirrhosis is extremely unlikely.²⁵ Heterozygotes are at lower risk for iron overload than homozygotes; in fact, liver disease caused solely by hereditary hemochromatosis is rare in heterozygotes. ²⁶ Investigate concomitant causes of liver disease—such as hepatitis C—in heterozygous patients.

Liver biopsy can be used prognostically as well as diagnostically. If cirrhosis is found, aggressive screening for hepatocellular carcinoma is warranted.

TREATMENT
Phlebotomy. The most widely used treatment is therapeutic phlebotomy, which is safer, more effective, and less expensive than chelation. The latter is used only in patients who cannot tolerate or who refuse blood draws. Although many problems related to hereditary hemochromatosis can be reversed by phlebotomy, several are irreversible (Table).

Initiate phlebotomy when the serum ferritin level is greater than 300 μg/L (200 μg/L for premenopausal women). Do not delay treatment until symptoms develop, because symptoms correlate with organ damage. Draw 1 unit of blood per week until mild hypoferritinemia occurs (approximately 10 μg/L to 20 μg/L). Patients with a high body mass index may tolerate having up to 2 units drawn weekly, while frail or elderly patients may tolerate the drawing of only half a unit per week. Continue phlebotomy for the patient’s lifetime, with a ferritin goal of less than 50 μg/L.²⁷ After the target level has been achieved, phlebotomies may be needed only 2 to 6 times per year.²¹

Dietary restrictions and other measures. Adherence to dietary guidelines is important. Patients with hereditary hemochromatosis need to limit their intake of red meat because it is one of the richest sources of bioavailable iron. Although avoiding iron supplements seems obvious, remind patients that most multivitamins contain at least some iron. Vitamin C supplements must also be limited because ascorbic acid( increases intestinal iron absorption. Abstaining from alcohol is crucial for those with hepatic disease. Have patients avoid shellfish, or at least cook it thoroughly; several fatal cases of Vibrio vulnificus infection have been reported in patients with hereditary hemochromatosis who ate contaminated seafood.²²

Finally, vaccinate all patients with hereditary hemochromatosis against hepatitis A and B if they are not already immune.

Expected outcomes. Decreasing and maintaining iron stores at nearly normal levels through phlebotomy significantly improves the life expectancy of patients with hereditary hemochromatosis. With therapy, 5-year survival increases from roughly 30% to nearly 90%. Furthermore, life expectancy is normal if patients begin treatment before the development of cirrhosis or cardiomyopathy. ²⁸ In untreated patients, CHF and hepatocellular carcinoma are the most frequent causes of death.