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• W2316686875 abstract "Hereditary hemochromatosis (HH) is an autosomal recessive metabolic disorder characterized by prolonged increased iron absorption. It is the most common metabolic disorder in the white population, and the majority of patients are homozygous for the C282Y mutation in HFE gene on the short arm of chromosome 6 (1). HH is rare in Japanese individuals (2,3) and usually remains undetected in childhood (4). We encountered two Japanese boys tentatively diagnosed with chronic asymptomatic hepatitis who were later recognized to have HH. CASE REPORT 1 A 13-year-old Japanese boy was referred to pediatric gastroenterology of our hospital for assessment for chronic liver disease. He weighed 3,120 g at birth, after a full-term, uncomplicated pregnancy, labor, and delivery. The history was benign except for atopic dermatitis in his infancy. He had no history of excessive iron ingestion, alcohol consumption, anemia, blood loss, or transfusions. His mother was healthy, but his father suffered from hepatic dysfunction and arrhythmia. One of his brothers had epilepsy, and another brother, a 17-year-old, had been diagnosed as having elevated serum aminotransferases since the age of 12. The patient was asymptomatic. Physical examination showed that he was 160 cm in height (−0.1 standard deviation) and weighed 52 kg (+0.1 standard deviation). His skin had no bronze pigmentation, and his liver and spleen were not palpable. No abnormalities were found during any other physical examinations. Laboratory evaluation revealed a hemoglobin level of 14.6 g/dL and hematocrit of 46.6%. Leukocyte count, erythrocyte indices, platelet count, urinalysis, renal function, serum electrolytes, and urate were all normal. However, serum levels of liver enzymes were found to be elevated. Serum markers of the hepatitis virus B and C were negative and serum gamma-globulin, copper, and ceruloplasmin values were normal. Amino acid quantitation of the blood was normal and negative for antinuclear antibodies. Roentgenograms of the chest and abdomen showed no abnormality and no anatomic abnormality was detected on abdominal ultrasonography. Plain abdominal computed tomography (CT) scanning revealed markedly increased hepatic CT density (83 Hounsfield Units), but the spleen appeared normal. Based on iron study, iron overload was confirmed (Table 1). Histologic findings of a needle biopsy of the liver revealed diffuse deposition of iron-containing granules in hepatic parenchymal cells [grade 3, according to the scale devised by Scheuer et al. (5)] and mild fibrosis. From these data, a diagnosis of HH was established. Electrocardiogram and thallium myocardial scintigraphy detected no myocardial complications. No endocrine abnormalities (e.g., urinary 17-ketosteroids, 17-hydroxycorticosteroids or serum cortisol levels) were present.TABLE 1: Laboratory findings of the two sibling patients and their familyClinical diabetes was not present, and fasting serum glucose level was 97 mg/dL. The patient was started on phlebotomy treatment: 400 mL blood was taken once a week. The treatment was well tolerated and serum levels of ferritin, aminotransferases, and transferrin saturation improved gradually (Fig. 1, upper panel). The patient is currently still asymptomatic. Mutations of the HFE gene (C282Y and H63D) (1) were investigated according to the methods previously reported (3,6); however, these mutations were not detected.FIG. 1.: Iron study and ALT with the dose of iron removed in patient 1 (upper) and patient 2 (lower). SF, serum ferritin; ALT, alanine aminotransferase; TS, transferrin saturation.The patient's parents and two of his three brothers were screened for the disease. Currently, his parents and one of his brothers show no evidence of iron overload. CASE REPORT 2 One sibling of patient 1, a 17-year-old boy, had elevated serum levels of aminotransferases, ferritin, and transferrin saturation (Table 1). He was also asymptomatic. He refused to undergo a liver biopsy, but iron study findings and his medical history were consistent with HH and phlebotomies were started. After a total of 22 L of blood had been drawn, biochemical abnormalities normalized (Fig. 1, lower panel). He is now well but refused to be assessed for the HFE gene mutation. DISCUSSION Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism characterized by inappropriately increased dietary iron absorption. This results in progressive iron deposition in the parenchymal cells of the liver, heart, and endocrine organs. Although the genetic defect is present at birth, HH is rarely recognized in childhood (4,7). After a typically long asymptomatic period, the majority of symptoms develop between the ages of 40 and 60 years. HH is often detected by chance during management of incidental illnesses. The predominant diagnostic feature is liver damage, evidenced by hepatomegaly, abnormal liver function tests, or increased hepatic density on abdominal CT scanning (8). In patient 1, liver CT findings alerted us to the possibility that excess iron was causing liver damage. In patient 2, although a liver biopsy was not obtained, the evidence from affected sibling in conjunction with biochemical markers indicated HH. Moreover, the fact that more than 22 L of blood had to be taken to normalize iron status confirmed this diagnosis (9). These siblings are the youngest to be diagnosed with HH in Japan. The aminotransferase levels of the siblings have gradually decreased as phlebotomies have continued, indicating iron hepatotoxicity. Previous research has suggested that screening for hemochromatosis should be undertaken in younger patients presenting with unexplained cardiomyopathy, hypogonadism, amenorrhea, diabetes mellitus, or a protracted course of acute hepatitis (7,10). The findings reported herein indicate that liver enzyme abnormality of unknown etiology should also be included in this list of disorders. Kaikov et al. (4) reported that 11 of 16 children with symptomatic HH died within 2 years of diagnosis, whereas 29 other children diagnosed in the asymptomatic stage recovered completely. Therefore, diagnosis in the asymptomatic stage is critical and prophylactic phlebotomy must be performed because potential organ damage cannot be reliably predicted (11). In the two patients discussed herein, phlebotomies were harmless and effective, as previously reported (4,12). Physicians caring for children must learn to recognize this potentially treatable disorder. In Japan, HH is very rare and most reported cases are not familial but sporadic. The present report is the seventh description of HH that has been diagnosed in more than one family member (2) and the first study in which sibling patients with HH underwent both HLA and candidate gene mutation (1) evaluations. In Japanese patients with HH, no specific HLA pattern has been reported (2). Hattori et al. (13) reported that none of six unrelated Japanese patients with HH had the C282Y mutation. Furthermore, the two patients reported here did not possess the HLA types commonly seen in white patients, and the candidate gene mutations (C282Y and H63D) were not detected in patient 1. These findings indicate that Japanese HH patients should be distinguished from white HH patients (14) and may suggest the existence of other mutations. Recently, two additional types of non–HFE-associated hemochromatosis have been identified. The first juvenile hemochromatosis, is associated with chromosome 1q and results in severe iron deposition by the age of 30 (15). Because of their very high iron load, the two siblings discussed in the present study could have suffered juvenile hemochromatosis during their presymptomatic state. The other new type of hemochromatosis results from a homozygous nonsense mutation in the gene encoding transferrin receptor-2 (TFR-2) on 7q22 (16). To better understand the pathophysiology of Japanese hemochromatosis, further investigation appears necessary. Acknowledgments: The authors thank Dr. Tetsuro Sohda, First Department of Internal Medicine, Fukuoka University, for HFE gene analysis." @default.
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• W2316686875 title "Hereditary Hemochromatosis Not Associated with Common HFE Gene Mutation in Japanese Siblings" @default.
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