Diagnosis of Hemochromatosis

Iron overload disease occurs in two general forms, primary and secondary (Table 1). Primary iron overload stems from an inherent defect in iron regulation that results in continuous overabsorption of iron from the gastrointestinal tract. The exact biological mechanism for this overabsorption is not understood. In some cases, iron accumulates in the parenchyma of various organs, particularly the liver, pancreas, and heart, eventually causing organ damage and the characteristic signs and symptoms of iron overload [1]. Table 1. Categories of Iron Overload Hemochromatosis is the most common type of primary iron overload disease, but it remains under-diagnosed because of the lack of awareness of it, its long latency period, and its nonspecific symptoms [2, 3]. Recently, increased emphasis has been placed on early detection, shifting the case definition and diagnosis to earlier stages of the disease. This has led to various views on the best diagnostic methods and the essential components of the diagnostic evaluation. In the next few years, these issues should become clearer as we gain insight into the natural history and expression of hemochromatosis. In this article, we update the description of hemochromatosis and the tests used to diagnose it. Background Hemochromatosis was first recognized more than a century ago as a condition with a triad of symptoms-diabetes, skin bronzing, and cirrhosis-associated with hepatic iron overload [1]. The condition was first called hemochromatosis in 1889 [4], and it was first proposed as an inherited disorder in 1935 [5]. Its inheritability remained controversial for four decades [6], until Simon and colleagues [7] demonstrated the close association between HLA-linked hemochromatosis and HLA-A3 and established that the responsible gene was tightly linked to the HLA-A locus on the short arm of chromosome 6. In recent years, a candidate gene for HLA-linked hemochromatosis, HFE, has been cloned, and a single G-to-A mutation resulting in a cysteine-to-tyrosine substitution (C282Y) has been identified in 60% to 100% of study patients with hereditary hemochromatosis [8-11]. A second mutation, H63D, was linked to an additional 1% to 10% of cases in one series [11], but no large population-based studies have been done to definitively establish the prevalence of this mutation in the general population. Cases of and families with hemochromatosis not associated with either the C282Y or the H63D mutation (non-HFE-associated hemochromatosis) have been reported from studies of European populations, and the genetic basis for these cases is being studied [10, 11]. Historically, hemochromatosis was a clinical and pathologic diagnosis. Diagnosis relied on the classic features of cirrhosis: pigmentation, diabetes, and arthralgia. As a result, hemochromatosis was described as rare, with an estimated frequency of 1 case in 20 000 hospital admissions in the United States [12]. However, autopsy studies [13, 14] found a much higher frequency: 1 to 2 cases per 1000 persons. More recently, population-based screening studies in several western countries [15-18] have established the prevalence of hemochromatosis as approximately 1 case per 300 persons. With the advent of genetic testing, earlier diagnosis is possible. In addition, some long-standing cases of hemochromatosis have been reviewed and found to be due to the heterozygous form of the C282Y mutation [11, 19]. To date, it seems that in case series of patients with hemochromatosis, 0.5% to 14% of patients have actually been heterozygous [11]. Expression and Natural History The natural history of hemochromatosis begins with a genetic potential (Table 2). This condition expresses itself as a tendency to overabsorb iron from the gastrointestinal tract. At least 50% of male and 25% of female persons homozygous for hemochromatosis are likely to develop potentially life-threatening complications of the disease [1, 18, 19], especially in countries with high dietary intake of iron [19-24]. Table 2. Progression of Hemochromatosis throughout the Lifespan: Pathogenesis and Diagnosis* The first phenotypic expression of disease is an elevation in serum transferrin saturation, which represents the transport of excess iron from the intestine and occurs before significant iron loading (Table 2). As iron accumulates in tissue, the serum ferritin concentration increases in direct linear relation to total-body iron stores [1, 24]. Patients usually begin to have symptoms between age 30 and 50 years. This natural history varies; symptoms occur much earlier in some patients. Early symptoms and signs of hemochromatosis include severe fatigue, impotence, arthralgia, arthritis, and an elevated concentration of liver enzymes [1]. Later, patients may experience skin bronzing; arthropathy; cardiomyopathy; and endocrine disorders, including diabetes and hypogonadism [1, 21-26]. Once the hepatic iron concentration reaches 400 mol per g dry weight, cirrhosis is common and the risk for hepatocellular carcinoma and death are markedly increased [26]. However, this threshold may be lower if cofactors, such as ethanol intake and chronic hepatitis, are present [1]. Although persons who are heterozygous for hemochromatosis sometimes have phenotypic expression, they do not generally develop overt clinical disease [1]. Of persons detected through family screening who are established as heterozygous for hemochromatosis (for example, by HLA typing), approximately 25% have mild biochemical abnormalities and increased body iron stores (as assessed by liver biopsy or quantitative phlebotomy) but do not develop clinical disease from progressive iron loading or the consequent organ damage [1, 18, 27, 28]. If a patient is heterozygous for the C282Y mutation and has a coexisting condition (such as hepatitis, alcoholism, or porphyria cutanea tarda) that increases hepatic iron stores, however, symptoms of organ damage may appear [19, 25]. Thus, consideration of coexisting conditions is important for heterozygous as well as homozygous patients. The expression of hemochromatosis is affected by environmental factors. The use of supplementary iron and vitamin C (which increases iron absorption) may lead to earlier phenotypic expression. On the other hand, blood donation, physiologic blood loss (through menstruation and pregnancy), and pathologic blood loss (for example, through peptic ulceration or inflammatory bowel disease) may delay phenotypic expression and decrease the amount of iron stored in the liver. The belief that premenopausal women cannot develop symptomatic or even life-threatening hemochromatosis is a misconception [29-31]. Diagnosis The basis for the early diagnosis of hemochromatosis has shifted from clinical symptoms to biochemical tests. This shift has spared patients the sequelae of protracted iron overload and chronic disease, although it has also spawned differences of opinion about the role and necessity of certain diagnostic tests, particularly liver biopsy. As more information about the disease is gathered, the case definition for hemochromatosis is likely to continue to evolve in this rapidly changing field. Clinical Features Hemochromatosis has many clinical presentations, and heightened awareness on the part of the physician is required for early diagnosis [1]. Fatigue and arthralgia are the most common symptoms prompting a visit to a physician. Patients may also present with hepatomegaly, diabetes mellitus, arthritis, heart failure, increased skin pigmentation, or abdominal pain, any of which might lead to referral to a specialist. The prevalence of hemochromatosis in patients attending diabetes and rheumatology clinics is greater than that expected in the general population [25, 32, 33]. Another mode of presentation may be cardiomyopathy, particularly in younger patients [1, 2]. Patients may present with congestive heart failure or arrhythmia. Occasionally, no clinical symptoms are seen even when hemochromatosis is advanced and cirrhosis is present [24]. Biochemical Tests Indicating Phenotypic Expression Biochemical measures of iron status are used to screen for hemochromatosis (Table 2); tests for transferrin saturation (serum iron concentration divided by total iron-binding capacity, multiplied by 100) and serum ferritin level are recommended. A persistently elevated transferrin saturation in the absence of other causes of iron overload strongly suggests hemochromatosis. A fasting transferrin saturation of 45% or more is typically used as the screening threshold because it identifies 98% of affected persons while producing relatively few false-positive results [34]. An alternative screening strategy may use the test for unsaturated iron-binding capacity, which is inexpensive and may be best used in population screening. However, this test has yet to be thoroughly evaluated. The follow-up evaluation also includes physical examination, estimation of the serum ferritin level, complete blood count, and liver function tests. A high transferrin saturation is the earliest phenotypic evidence of hemochromatosis. If a patient has a transferrin saturation of more than 45% but less than 55% on a repeated test and the elevation has no other evident cause, such as inflammatory liver disease, hemochromatosis may be present. If the serum ferritin level is normal, the patient should have repeated tests after 2 years to identify any change. The patient may be either homozygous or heterozygous for hemochromatosis. We do not have enough information to know the usual course of disease detected at this stage. If the transferrin saturation is 55% or more on a repeated test, the first step is to check for the presence of increased body iron stores. Patients who have an elevated transferrin saturation on repeated tests but have a normal serum ferritin level may be classified as having nonexpressed hemochromatosis. These patients warrant annual or biennial assessment to watch for increases in ir