M. Roest, Y.T. van der Schouw, J J.M. Marx
Hereditary hemochromatosis (HH) is the most common autosomal recessive disorder, with prevalences ranging from 1:200 to 1:400 in populations of European origin. HH patients have a disturbed absorption of iron by intestinal mucosal cells and excessive iron deposition in parenchymal cells of the liver and other organs. Clinical symptoms include damage and impaired function of the liver, pancreas, heart, and the pituitary. HH can be diagnosed by a combined measurement of ferritin and transferrin iron saturation. If not treated, some HH patients may die from liver cirrhosis, liver cancer, or cardiomyopathy. The major symptoms of HH are arthralgia, fatigue, and abdominal pain. Phlebotomy has proved to be a successful treatment to reduce the risk of early mortality and to prevent clinical symptoms.
The mutation coding for the most common variant of HH is a G to A mutation, located at position 845 of the HFE-gene on the short arm of chromosome 6. This mutation is responsible for a cysteine to tyrosine transition at position 260 of the protein (formerly described as HFE Cys282Tyr). Both the HFE-gene and the Cys260Tyr mutation were for the first time described in August 1996 by Feder and colleagues. More than 83 percent of HH patients are homozygous for this mutation, meaning that the HFE-gene in both chromosomes 6 contains the Cys260Tyr mutation.
Normal HFE (wildtype) is a HLA class 2 protein that is involved in the modulation of iron uptake in the small intestine. How HFE regulates iron homeostasis is not yet fully understood, but HFE is only active when bound to 2-microglobulin (2m) as shown in 2m knockout mice, which develop similar symptoms as HH patients (Santos et al, 1996). Furthermore, HFE is involved in modulation of iron homeostasis via the transferrin receptor. The mechanism of HFE Cys260Tyr leading to HH remains to be established. It has been suggested that HFE is needed to express the transferrin receptor on the basolateral membrane in the crypts of Lieberkühn in the small intestine, which enhances iron uptake needed for cell proliferation (Waheed et al, 1999). Impairment of this function caused by HFE-gene mutations could provide a paradoxical signal in crypt enterocytes that programs the differentiating enterocytes to absorb more dietary iron when they mature into villus enterocytes.
Subjects are called HH carriers when only one chromosome 6 contains a Cys260Tyr mutation in the HFE-gene while the other chromosome 6 contains the wildtype HFE-gene. The prevalence of HH carriers is 7 to 10 percent in populations with European origin. HH carriers do not develop clinical symptoms of HH but express slightly higher levels of serum iron, serum ferritin, and transferrin saturation in comparison to non-HH carriers, indicating that HH carriers are exposed to moderately excessive iron throughout their entire life. HH carriership is therefore a unique opportunity to study genetically determined increased iron exposure in large population studies. Unlike plasma markers, genes have the advantage to be fixed at the conception and do not change until death; genetic markers are therefore not subject to confounding by disturbing variables.
At present, two large population studies on the relationship between HH carriership and cardiovascular disease have been published. In a Dutch cohort study of 12,239 postmenopausal women who were followed on cardiovascular mortality for up to 18 years (182,976 follow up years), it was found that HH carriers had a 1.6-fold (95 percent CI: 1.1-2.4) increased risk to die from any kind of cardiovascular disease (Roest et al, 1999). More specificly, the HH polymorphism is predictive of a 1.5-fold (95 percent CI: 0.9-2.5) increased risk to die from myocardial infarction, a 2.4-fold (95 percent CI: 1.3-3.5) increased risk to die from cerebrovascular diseasea and a 1.2-fold (95 percent CI: 0.7-2.3) increased risk to die from any other form of cardiovascular disease (Table 1). The population attributable risks of HH heterozygosity for mortality by myocardial infarction, cerebrovascular mortality, and mortality by any other form of cardiovascular mortality were 3.3, 8.8, and 1.4 percent, respectively. This means that 3.3 percent of mortality by myocardial infarction in the entire population was attributable to the HH mutation, while even 8.8 percent of the cerebrovascular mortality in the entire population was attributable to the HH mutation. The second cohort study comprised 1150 Finnish men who have been followed for up to 12.8 years on incidence of myocardial infarction. HH carriers had a 2.3-fold (95 percent CI: 1.1-4.8) higher risk to get an acute myocardial infarction than wildtypes (Tuomainen et al, 1999).
Incidence Rates (Per 1000 Person Years), Rate Ratios, and Population Attributable Risks (PAR) for Mortality by Myocardial Infarction, Cerebrovascular Accidents, and Other Forms of Cardiovascular Disease According to HH Genotype
The pathophysiology of cardiovascular disease is influenced by multiple interacting factors. This was also found in the Dutch cohort study, in which the relationship between HH carriership and cardiovascular mortality was stronger when women were also exposed to other cardiovascular risk factors (Roest et al, 1999). The relationship between HH genotype and cardiovascular mortality was strongest expressed in women who were smoking and hypertensive. Risk profiles of HH carriership (yes/no), hypertension (yes/no), and smoking (yes/no), in relation to cardiovascular mortality, were compared as demonstrated in Table 2 and Figure 1. Smoking, hypertension, and the HH mutation are all moderate risk factors for cardiovascular mortality with a single relative risk of lower than 2. However, a strongly increased cardiovascular mortality risk was observed when all three risk factors were present: women who were smoking, hypertensive, and HH carriers have a 21-fold (95 percent CI: 9.16-47.48) higher risk of cardiovascular mortality during follow-up than women who were nonsmokers, not hypertensive, and HH wildtype. HH carriership plays an important role in this statistical interaction, because women who were smokers and hypertensive but not HH carriers had a 2.1-fold (95 percent CI: 1.4-3.2) increased risk of cardiovascular mortality in comparison to women who were nonsmokers, not hypertensive, and HH wildtype. In subjects with normal blood pressure who did not smoke, HH carriership appeared to play a minor role in the cardiovascular mortality risk; the relative risk was 1.2 (95 percent CI: 0.5-2.6).
FIGURE 1: Cardiovascular mortality (incidence/1000 years) according to HH
genotype, blood pressure, and smoking.
Cardiovascular mortality, mortality from myocardial infarction, cerebrovascular mortality, and all other forms of cardiovascular mortality in subgroups: HH carrier/not HH carrier by nonhypertensives and nonsmoker (left columns); either hypertensive or smoker (center columns); and both hypertensive and smoker (right columns). Smoking was defined as reported to be current smoker in the baseline questionnaire. Hypertension was defined as (diastolic pressure >95 and/or systolic pressure >160).
The findings that HH is associated with an increased risk of cardiovascular mortality is direct evidence for the hypothesis that iron is involved in cardiovascular disease (Sullivan, 1999). Until recently, this hypothesis was based on observations that premenopausal women have a much lower risk of developing cardiovascular disease than postmenopausal women or men. A plausible explanation for this difference is that the reduced risk of cardiovascular disease in premenopausal women is a consequence of monthly iron loss during menstruation. Alternatively, premenopausal women have high estrogen levels that may protect against cardiovascular disease; however, to date, there is only one clinical trial on estrogen replacement therapy and cardiovascular disease incidents (Hulley et al, 1998). The negative findings of this trial provide strong evidence against the hypothesis that estrogens are the explanation that premenopausal women are protected against cardiovascular disease. The theory that regular blood loss and, hence, iron reduction protect against cardiovascular disease is confirmed in blood donors who have a lower risk of myocardial infarction than nondonors (Salonen et al, 1998). Further indications that iron is involved in cardiovascular disease are the findings that (1) excessive iron intake via red meat is associated with an increased risk of cardiovascular disease; (2) the transferrin receptor ferritin ratio is associated with a reduced risk of cardiovascular disease; and (3) plasma ferritin levels, serum iron levels, or total iron binding capacity (TIBC) may be associated with increased risk of cardiovascular disease.
The expected mechanism of HH and iron being involved in cardiovascular disease is a multistep process as shown in Figure 2. The relationship between the HH mutation and moderately increased iron stores (step 1) is established in several clinical and epidemiologic studies. HH carriership might lead to moderately increased deposition of iron in sensitive cells and generation of catalytically active, labile forms of iron. Iron is a major pro-oxidant that is involved in the hydroxyl radical formation (OH•, step 2) via the Haber-Weiss reaction (Fig. 3). Excessive and labile iron may lead to increased hydroxyl radical formation and, hence, local tissue damage or other detrimental processes. Population studies have shown that pro-oxidative state is predictive of an increased risk of cardiovascular disease (step 3). The pathway of oxygen radical formation leading to cardiovascular disease remains to be elucidated. The recent findings that the HH mutation is directly predictive of an increased risk of cardiovascular morbidity and mortality (steps 1 + 2 + 3) completes the causal chain.
FIGURE 2: HH and iron in cardiovascular disease.
FIGURE 3: Haber-Weiss reaction.
To date it is not clear through what mechanism HH and iron depletion lead to cardiovascular morbidity and mortality, but several plausible hypotheses are proposed. The most extensively studied mechanism of oxygen radicals involved in atherosclerosis is oxidation of LDL in endothelial cells, smooth muscle cells, lymphocytes, or macrophages. Unlike normal LDL, oxidized LDL is recognized by the scavenger receptors on tissue macrophages followed by phagocytosis and accumulation of lipids in these cells that become foam cells, the characteristic cells of the fatty streak in early atherosclerosis. Moreover, oxidized LDL has cytotoxic capacity that induces changes in endothelial cells with loss of endothelial integrity, which could facilitate further accumulation of both circulating monocytes and LDL and thus promote further progression of the atherosclerotic lesion. However, HH is not associated with intima media thickness and atherosclerosis is not recognized as one of the major clinical symptoms of HH. Alternatively, iron may be involved in nonatherogenic processes in the late onset of cardiovascular disease. A plausible mechanism is that iron-induced oxygen radicals can damage the fibrous cap of the atherosclerotic plaque leading to its destabilization, and, hence, increased risk of plaque rupture and ischemic infarction. Furthermore, iron may increase the infarction size, because iron-mediated free radicals are generated after restoration of blood flow to ischemic myocardium, causing so-called reperfusion injury.
The discovery of the HH mutation was an important step forward in the research to the role of iron in cardiovascular disease. The HH mutation was a unique opportunity to study inherited lifelong exposure to moderately elevated iron in relation to cardiovascular morbidity and mortality in large prospective studies. The findings of those studies provided direct evidence that iron is involved in cardiovascular disease etiology. The HH mutation is a human genetic model of disturbed iron metabolism, which facilitates research to the mechanism of HH and iron involved in cardiovascular disease. We expect that in the near future, the mechanism of disturbed iron metabolism leading to cardiovascular disease in human will be better understood.
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