hemochromatosis is a hereditary or secondary disorder resulting from iron - overload and iron - impregnation in the organs , leading to organ damage .
hereditary hemochromatosis is an autosomal recessive disease common in caucasians and caused by a gene mutation related to iron absorption in the bowels .
some case reports from korea suggest that end - stage renal disease patients with hemodialysis or patients with aplastic anemia had secondary hemochromatosis caused by repeated transfusions .
unlike hereditary hemochromatosis where iron is impregnated in parenchymal cells , repeated transfusion induced - iron - overload mainly impregnates iron into reticuloendothelial cells which has been considered to be less harmful organ failure than parenchymal iron accumulation .
the authors report a case of a patient with aplastic anemia who received a total of approximately 1,400 units of red blood cells ( rbcs ) over 15 years .
she was admitted for asymptomatic hypocalcaemia and diagnosed with secondary hemochromatosis accompanied by hypoparathyroidism , hypothyroidism , hepatic dysfunction , and cardiac dysfunction . to the best of the author 's knowledge ,
fifteen years ago she was diagnosed with aplastic anemia , treated with antilymphocyte globulin and antithymocyte globulin , and had routine transfusions of rbcs of 2 units per week ( about 1,400 units over 15 years ) . in addition , starting 10 years ago , selective iron - chelating agent ( deferasirox 1,500 mg / day ) was administered due to increased serum ferritin levels .
continued hypocalcaemia was detected in blood tests at regular follow - up visits and the patient visited the endocrinologic department as an outpatient for additional examinations and treatment .
she had a blood pressure of 120/80 mm hg , pulse rate of 78 beats per minute , temperature of 36.8 , and a respiratory rate of 20 breaths per minute .
chest examination showed that breathing was clear , heartbeat was regular and no unusual sounds were detected .
her abdomen was flat and soft with no unusual sounds , and the liver and spleen were not palpated .
neurological tests showed no local neurological symptoms , chvostek sign or trousseau sign . in the laboratory findings ,
peripheral blood test indicated a white blood cell count of 700/mm ( neutrophil 150 ) , hemoglobin level of 8.0 g / dl , and platelet count of 37,000/mm .
a serum biochemical test reported blood urea nitrogen levels of 10.1 mg / dl , serum creatinine of 0.7 mg / dl , albumin levels of 3.9 g / dl , aspartate aminotransferase levels of 53 iu / l , alanine aminotransferase levels of 60
iu / l , alkaline phosphatase of 94 iu / l , and total bilirubin of 0.5 mg / dl . in a serum electrolyte test ,
however , total calcium was 6.7 meq / dl ( albumin corrected calcium 6.78 meq / dl ; normal range , 8.4 to 10.2 ) , and ionized calcium was 1.78
serum ferritin levels were 27,583.03 ng / ml ( normal range , 4.63 to 274.6 ) , iron levels were 291 g / dl ( normal range , 65 to 157 ) , and total iron binding capacity was 389 g / dl ( normal range , 256 to 426 ) which showed an increase .
the transferrin saturation level was high to 74.8% ( normal range , 22% to 46% ) .
she was diagnosed with hypocalcaemia induced by hypoparathyroidism based on test results showing intact parathyroid hormone ( ipth ) levels of 31 pg / ml ( normal range , 9 to 55 ) , 25(oh)vitd of 7.03 ng / ml ( normal range , 4.8 to 52.8 ) , and 1,25(oh)2vitd levels of 36.2 pg / ml ( normal range , 25.1 to 66.1 ) . although 1,000 mg of calcium carbonate and 0.5 g of alfacalcidol were given twice a day , hypocalcaemia continued with increased levels of 24 hours urine calcium ( 700 mg / day ) and 24 hours urine creatinine ( 0.99 g / day ) ; thiazide 12.5 mg was also administered to maintain the total calcium at 7.5 to 8.0 meq / dl and ionized calcium at 1.9 to 2.2
tests were performed to determine if the hemochromatosis had spread to other organs ; chest x - rays showed no signs of cardiomegaly , but computed tomography ( ct ) before contrast enhancement showed thyroid ( hounsfield unit 157.0 ) and liver ( hounsfield unit 136.0 ) , as well as a increased signal intensity associated with the cardiac muscle and enlarged inferior vena cava and hepatic veins ( fig .
1 ) . the t2-weighted magnetic resonance imaging ( mri ) of the abdomen revealed a dark signal intensity in the liver , spleen , bone marrow , and pancreas , leading to the secondary diagnosis of hemochromatosis ( fig .
organs showing signs of iron impregnation were tested for function ; the thyroid function test showed elevated levels of thyroid stimulating hormone ( tsh , 17.18 iu / ml ; normal range , 0.4 to 4.8 ) with free thyroxine levels of 1.28 ng / dl ( normal range , 0.8 to 1.71 ) , and triiodothyronine levels of 1.43 ng / ml ( normal range , 0.6 to 1.6 ) . thyroid peroxidase antibody and thyroglobulin antibody were both negative which resulted in apparent hypothyroidism caused by hemochromatosis .
the patient was receiving low - dose of thyroid hormone ( levothyroxine 50 g / day ) , but her tsh levels were still over 10 iu / ml at follow - up .
the most recent test result showed tsh levels of 8.12 iu / ml , and the dose of thyroid hormone was increased to 150 g / day for follow - up observation .
echocardiography revealed dilated left ventricular chamber size ( left ventricular end diastolic diameter 54 mm ) with global hypokinesia , and a moderate to severe left ventricular systolic dysfunction ( ejection fraction 23% ) , which suggests congestive heart failure with dilated cardiomyopathy and restrictive diastolic dysfunction induced by hemochromatosis .
the patient is medicated with digoxin 0.1875 mg , candesartan 8 mg , bisoprolol 2.5 mg , and spiractone 25 mg without any significant symptoms and is on follow - up observation as an outpatient .
with this patient , secondary hemochromatosis occurred , induced by iron over - absorption due to repeated transfusion for aplastic anemia . while on follow - up observation , she was diagnosed with hypocalcaemia caused by hypoparathyroidism , subclinical hypothyroidism , hepatic failure , and cardiac dysfunction .
excessive iron absorption is known to cause various organ failures due to iron accumulation of the multiple organs , but it is rare to find clinically severe organ failure cases that involve secondary hemochromatosis induced by transfusion .
hemochromatosis is a genetic or secondary disorder caused by damaged cells and organ failure after iron overload within the parenchyma of the organ .
patients with symptoms and signs such as increased levels of iron concentration in the blood , iron - binding capacity , and serum ferritin concentration , hepatomegaly , pigmented skin , diabetes mellitus , heart disease , arthritis , and lower urinary tract symptoms can be diagnosed if the patient has a secondary cause that induces iron overload or if iron impregnation is confirmed by tissue biopsy - with hfe genetic mutation .
normally the human body maintains iron levels at 3 to 4 g. one milligram of iron for males and 1.5 mg for menstruating females are lost every day , but equal amounts of iron are absorbed by intestinal mucosa .
however , in the case of hemochromatosis , 4 mg of iron are absorbed per day , which increases iron levels in the blood , leading to increased blood ferritin levels and iron - impregnation of the organs .
hereditary hemochromatosis was transmitted as an autosomal recessive trait associated with the hla - a locus on the short arm of chromosome 6 .
secondary factors include over - absorption of iron due to inadequate production of rbcs in cases of mediterranean anemia and sideroblastic anaemia .
when 1 unit of rbc is transfused it contains 200 to 250 mg of iron . if rbc production is inadequate because of bone marrow failure such as aplastic anemia , infused iron can not be used to produce rbcs and instead is captured by macrophages .
when this iron - capturing behavior of macrophages reaches its limit , overloaded iron is impregnated into multiple organs such as the liver , heart , spleen , pancreas , and bone marrow , which results in multiple organ failures . in the early stages of hemochromatosis , fatigue or weakness can be accompanied by arthritis or skin pigmentation . increased levels of iron impregnation in organs such as
the liver , heart , pancreas , thyroid , parathyroid , and pituitary gland can cause functional failures .
one of the organs commonly impregnated is the liver , and impregnation of iron in the parenchyma of the liver can cause hepatomegaly , which is associated with increased levels of hepatic enzyme and can cause of liver cirrhosis and hepatocellular carcinoma .
hepatocellular carcinoma , cardiomyopathy , conduction disturbance , and congestive heart failure can increase mortality in patients with hemochromatosis .
regular check - ups with follow - up visits are necessary to prevent these issues .
diabetes mellitus is the most common disease associated with endocrine system abnormalities , and is due to reduced insulin resistance and secretion induced by siderosis in liver and pancreas -cells .
gonadotropin deficiency commonly includes the entire pituitary hormone , resulting in impotency , menstrual irregularities , and decreased libido .
siderosis can also cause functional failures in the adrenal , parathyroid , and thyroid , although these issues are less common than diabetes or gonadotropin deficiency .
there are not a sufficient number of studies on the correlation between multiple organ damage and degree and period of siderosis . in 2001 , kwon et al .   reported a correlation between total volume of blood transfusion and increased serum ferritin , but there was no correlation between total volume of blood transfusions and endocrine system complications in 14 pediatric patients with repeated transfusions .
chern and lin   reported that 10.7% ( 3/28 ) of patients who received blood transfusions over an extended period acquired hypoparathyroidism , which is often accompanied by other issues such as hypogonadism and diabetes mellitus . in the case
study being presented here , the patient was diagnosed with hypoparathyroidism from hypocalcaemia without markedly increased ipth , and organ examinations confirmed iron accumulation to the thyroid , liver , and cardiac muscle .
this indicates that hemochromatosis patients with the rare complication of hypothyroidism and hypoparathyroidism need to be tested for other organ functions and treated accordingly . in the future ,
larger - scale prospective studies are necessary to determine correlations between symptoms and the volume and period of blood transfusions that accompany multiple organ failures .
hemochromatosis can be correctly diagnosed if siderosis is confirmed from a liver tissue biopsy . however , as shown in this case , for a patient with low platelet levels , even with repeated platelet transfusions , an invasive examination is difficult to perform . instead of a liver tissue biopsy ,
reported a correlation between blood ferritin levels and signal intensity of the liver in ct , and suggested that if serum ferritin levels are above 1,000 ng / ml .
however , although ct has a high specificity ( 96% ) , its sensitivity is relatively low ( 63% ) for diagnosing secondary hemochromatosis .
meanwhile , mri has both high specificity and sensitivity for diagnosing hemochromatosis and evaluating the treatment progress . in this case study , ct before contrast enhancement showed markedly elevated hounsfield units in the liver ( 136.0 ) compared to the normal range ( 61.09.0 ) , and a t2-weighted liver mri revealed darker sections of liver , spleen , and bone marrow , which also suggest hemochromatosis . in the case
presented here , hypothyroidism related to other factors was excluded since the patient had multiple functional failures of the organs caused by hemochromatosis .
the ct results included elevated hounsfield units of the thyroid ( 157 ) compared to normal range ( 118.112.2 ) , graves disease level of 69.517.6 , and hashimoto thyroiditis of 61.49.1 .
the elevated hounsfield units led to the patient 's diagnosis of siderosis - induced hypothyroidism . in terms of hypoparathyroidism , previous studies also reported hemochromatosis in the study subjects . due to difficulties with imaging and biopsy examinations ,
hypoparathyroidism induced by hemochromatosis was diagnosed although the patients presented with hypocalcemia without increased ipth .
patients with secondary hemochromatosis induced from repeated transfusions may have irreversible functional disorders with severe impacts or consequences on their daily life .
therefore , it is critical to restrict transfusions and iron chelate agents as needed , and schedule patients for regular follow - up visits . furthermore , it is necessary to establish screening examinations each period , with a larger - scale study requiring repeated transfusions to clarify the effects of the amount and period of blood transfusions on endocrine failure .
 hemochromatosis is an inherited genetic disorder of iron metabolism which can also occur as a secondary result of iron - overload . 
 it leads to organ damage such as cardiomyopathy , liver cirrhosis , hypogonadism , and diabetes . 
 this paper discusses a case of secondary hemochromatosis associated with repeated transfusions , presenting as asymptomatic hypoparathyroidism and subclinical hypothyroidism with multiple organ involvement . 
 the 29-year - old female , who had severe aplastic anemia , received multiple transfusions totaling approximately 1,400 units of red blood cells over 15 years . during her routine laboratory examination , 
 hypocalcemia was detected with decreased intact parathyroid hormone and increased thyroid stimulating hormone . 
 serum ferritin , iron , and total iron binding capacity had increased to 27,583.03 ng / ml , 291 g / dl , and 389 g / dl , respectively . 
 she had unusually bronze skin and computed tomography revealed iron deposition in the thyroid , liver , and heart . 
 multiorgan involvement as seen in this case is rare in hemochromatosis associated with secondary transfusions . to the best of the author 's knowledge , 
 this is the first case report in korea of hypoparathyroidism and subclinical hypothyroidism due to iron deposition in the parathyroid and thyroid gland . 