Since iron accumulation is slow, HFE-hemochromatosis has late onset, usually in the 4th to 5th decades of life in males and after menopause in females. The clinical expression is low; the disease penetrance estimated in a large prospective Australian study was 28.4% in men and 1.2% in women. Symptomless patients come to medical attention because of increased liver transaminases, abnormalities of iron tests, or both. Other patients may complain of vague symptoms such as fatigue and abdominal pain due to liver enlargement. Progressive iron accumulation may cause liver fibrosis/cirrhosis, diabetes and related complications, heart failure and arrhythmias, symptoms of gonadal insufficiency such as decreased libido and impotence, and rarely other endocrine complications (see Fig. 1). Hepatocellular carcinoma is an important cause of death in cirrhotic patients, even after iron depletion. Arthritis due to chondrocalcinosis with pyro phosphate deposition typically affects the second and third metacarpal-phalangeal joints but may also involve large joints such as hip and knee, requiring replacement prosthesis in severe cases. Skin pigmentation results from excess melanin deposition. In C282Y/H63D compound heterozygotes, in the absence of contributory factors (alcohol, chronic hepatitis) iron accumulation is rare, when present is mild and liver fibrosis is exceptional. Individuals heterozygous for C282Y or H63D are not at risk of iron overload.
Fig2. CLINICAL COMPLICATIONS OF IRON OVERLOAD. The most important complications that may occur in all types of iron overload are indicated. Liver disorders, chronic fatigue, and arthropathy are more frequent in classic hemochromatosis. Cardiac disease and hypopituitarism are more frequent in juvenile hemochromatosis and in beta-thalassemia patients under chronic blood transfusions.
Acquired and genetic factors may modify the course of the HFE disease. Menses and pregnancies explain the delayed onset of the dis ease in C282Y homozygous women and blood donations may delay the diagnosis in regular blood donors. Dietary habits like abundant meat consumption and excess alcohol intake may favor iron absorption; alcohol also contributes independently to liver damage. Besides environmental factors, genetic modifiers such as SNPs of iron regulating or other genes may influence the degree of iron overload and its complications, usually with a small effect.
Clinical manifestations in non-HFE hemochromatosis are very simi lar to HFE disease but have earlier onset because hepcidin deficiency is more severe. In juvenile types the most common complications, cardio myopathy and hypogonadism, affect both genders equally and may occur as early as in the second or third decade of life, mimicking complications encountered in transfused thalassemia patients with severe iron loading. Growth and sexual maturation are delayed; secondary amenorrhea may occur in females a few years after menarche. Heart failure refractory to treatment, ventricular arrhythmias, or both may be life threatening in untreated patients. The phenotype of TFR2 hemochromatosis is variable, usually less severe than juvenile hemochromatosis although the disease onset may be early as well. Genetic and acquired modifiers have minor or no role in severe non-HFE disorders. Ferroportin disease is usually asymptomatic, in the presence of high ferritin and liver iron concentration (LIC) due to macrophage iron accumulation.
Patterns of iron deposition in non-transfusion-dependent iron-loading anemias are similar to hemochromatosis with overload of hepatocytes in adult life and iron-poor macrophages. Liver fibrosis may occur while cardiac disease is unusual. Transfusion-dependent patients show a mixed pattern (hepatocytes and macrophages) of liver iron deposition. The clinical phenotype is related to the intensity of the transfusion regimen and the individual compliance to iron chelation therapy. The phenotype is similar to that described for juvenile hemochromatosis with hypogonadism and cardiac involvement manifesting as heart failure and arrhythmias, the latter being the major causes of death in untreated or inadequately chelated patients.
Osteoporosis is frequent in all types of severe iron loading and may predispose to bone pain and fractures. All iron-loaded patients have increased susceptibility to infections by rare siderophilic pathogens such as Vibrio vulnificus and Yersinia enterocolitica. The latter gram-negative bacteria cause a self-limited infection in normal subjects, while they may cause severe, systemic, in some cases fatal infections in iron-loaded patients, since NTBI favors their rapid growth.
Atransferrinemia and DMT1 mutations lead to atypical microcytic anemia with iron overload of variable intensity. In aceruloplasminemia a late-onset clinical triad of diabetes, neurodegeneration (manifesting as dementia, dysarthria, dystonia), and retinal degeneration, often accompanied by iron overload and microcytic anemia, may suggest the diagnosis.
