the normal total body iron content of 34 g is the result of a tight balance between iron absorbed from the gastrointestinal tract and iron lost in stool , sweat and via shed skin cells .
if the iron supply or gastrointestinal tract absorption of dietary iron exceeds the amount needed , there is no mechanism to eliminate the excessive iron .
this state of presence of iron in excess of what is needed is called iron overload .
iron overload diseases are frequently associated with hereditary defects or secondary disturbances of iron metabolism that result from excessive blood transfusions , iron supplementation or iron injections .
hereditary hemochromatosis , which is characterized by a genetic predisposition to absorb excess iron from the diet , is the most frequent form of genetic iron overload .
iron overload , irrespective of the underlying etiology , has varying manifestations , depending on the organs affected by the excessive iron deposit .
it may present as fatigue , skin color changes , abdominal pain , joint pain , irregular menstruation , infertility , impotence , irregular heart rhythm , heart failure , new - onset diabetes or difficulty controlling established diabetes and elevation in liver enzymes .
hemochromatosis , the most common genetic iron overload disorder , may also lead to the development of life - threatening complications like cirrhosis and hepatocellular carcinoma .
manifestations of iron overload in hemochromatosis are related to mutations of the hfe gene , but not all patients with an inherited hemochromatosis - like phenotype carry pathogenic mutations in the hfe gene .
several other genetic mutations involving the hemojuvelin , the hepcidin , the transferrin receptor 2 and the ferroportin gene have been discovered and known to cause manifestations similar to classic hereditary hemochromatosis . the hemojuvelin and hepcidin genes are implicated in causing juvenile hemochromatosis , transferrin receptor 2 gene mutation causes type 3 hemochromatosis , and ferroportin gene mutation leads to ferroportin disease .
these diseases were traditionally classified under non - hfe hemochromatosis , but recently the identification of new iron genes has made it possible to distinctly identify these disorders .
he had been well until 1 week prior to presentation , when he started feeling short of breath initially on exertion , but later at rest .
he was anxious and tremulous . since the onset of symptoms his exercise tolerance had declined from a baseline of more than ten blocks to two blocks .
he reported no fever , chest pain , dizziness , syncope , rash or weight loss .
medications at the time of presentation included aspirin 81 mg daily , hydrochlorothiazide 12.5 mg daily , diltiazem 30 mg three times a day , losartan 25 mg daily as well as fenofibrate and subcutaneous insulin ( 70/30 ) 40 units twice a day .
he reported active tobacco use with a five pack year history of smoking , drank three beers daily and had occasionally snorted cocaine , but stopped 2 years earlier .
he had been born in us , had studied until 11th grade and had worked in a food store , but was currently unemployed .
he was living in an apartment with his wife and was sexually active in a monogamous relationship .
his mother and sister have diabetes mellitus and his father had died of an unknown cancer . on examination , he was afebrile .
his pulse rate was 100 beats per minute , blood pressure 142/84 mm hg , respiratory rate 18 breaths per minute with oxygen saturation 94% on room air that improved to 100% on 2 liters of oxygen through a nasal cannula , and his body mass index was 28.8 .
the abdomen was non - distended , soft and non - tender ; the liver was palpable 5 cm below the right costal margin and bowel sounds were normal .
he was alert and fully oriented , with motor strength and sensation normal in all extremities .
hematocrit was 41.2% , white blood cell count 6.4  10/l and platelet count 245  10/l .
the basic metabolic panel including serum sodium , serum potassium , blood urea nitrogen and serum creatinine was normal .
the results of liver function tests , iron studies and tests to evaluate other etiologies of elevated transaminases are given in table 1 .
the blood level of probnp was elevated to 1,002 pg / ml and hemoglobin a1c was 7.8% .
the patient was admitted to hospital with an initial impression of systolic congestive heart failure .
high levels of serum ferritin in conjunction with the clinical findings of heart failure , hepatomegaly and diabetes mellitus suggested an iron overload state .
we expected the transferrin saturation to be > 45% , as seen in hereditary hemochromatosis , the most commonly identified genetic iron overload disorder .
dna mutation analysis showed that the patient was heterozygous for c282y mutation and negative for h63d mutation .
in a 55-year - old man with features of iron overload  elevated ferritin , diabetes mellitus , enlarged liver , elevated liver enzymes and heart failure  diseases under the following two categories   need consideration : ( 1 ) type 1 hemochromatosis  hfe hemochromatosis .
( 2 ) type 2 hemochromatosis  juvenile hemochromatosis : ( a ) type 2a  mutation in hemojuvelin gene ; ( b ) type 2b  mutation in hepcidin gene . ( 3 ) type 3 hemochromatosis 
ferroportin disease : ( a ) type 4a  with low transferrin saturation ; ( b ) type 4b  with high transferrin saturation .
( 1 ) iatrogenic : ( a ) multiple blood transfusions ; ( b ) parenteral iron therapy ; ( c ) oral iron therapy . ( 2 )
chronic liver disease : ( a ) alcoholic liver disease ; ( b ) hepatitis b and c ; ( c ) porphyria cutanea tarda .
( 3 ) anemias : ( a ) thalassemia major ; ( b ) chronic hemolytic anemia ; ( c ) pyruvate kinase deficiency . ( 4 ) others : ( a ) dysmetabolic hyperferritinemia .
juvenile hemochromatosis : ( a ) type 2a  mutation in hemojuvelin gene ; ( b ) type 2b  mutation in hepcidin gene .
ferroportin disease : ( a ) type 4a  with low transferrin saturation ; ( b ) type 4b  with high transferrin saturation .
( 1 ) iatrogenic : ( a ) multiple blood transfusions ; ( b ) parenteral iron therapy ; ( c ) oral iron therapy . ( 2 ) chronic liver disease : ( a ) alcoholic liver disease ; ( b ) hepatitis b and c ; ( c ) porphyria cutanea tarda . ( 3 ) anemias : ( a ) thalassemia major ; ( b ) chronic hemolytic anemia ; ( c ) pyruvate kinase deficiency . ( 4 ) others : ( a ) dysmetabolic hyperferritinemia .
iron overload can manifest as fatigue , joint pain , liver disease , heart disease , hypogonadism , diabetes mellitus and skin pigmentation ( bronze skin ) .
features of iron overload with an abnormal gene point towards a differential diagnosis that includes hemochromatosis type 1 ( hfe ) , hemochromatosis type 2 , hemochromatosis type 3 , hemochromatosis type 4 , atransferrinemia and aceruloplasminemia .
it is an autosomal recessive disorder due to two mutant alleles , usually c282y , of the hfe gene and is characterized by tissue iron overload with potential for organ disease [ 2 , 4 ] . in a patient with signs of tissue iron overload with increased plasma iron content , as evidenced by hyperferritinemia and increased transferrin saturation , genetic testing for c282y mutation of the hfe gene should be performed for diagnosis of hfe hemochromatosis .
approximately 8590% of patients with inherited forms of iron overload are homozygous for c282y mutation in hfe .
a very small proportion of patients are compound heterozygotes , and either have one allele with c282y mutation and the other allele with h63d mutation ( c282y / h63d ) , or one allele with c282y mutation and the other allele with s65c mutation ( c282y / s65c ) .
the remaining 1015% of patients with inherited forms of iron overload without pathogenic mutations in the hfe gene come under the definition of non - hfe hemochromatosis .
ferroportin disease was first described in 1999 as an autosomal dominant disorder with similar features as those of hfe hemochromatosis .
clinically , the disease is usually limited to liver disease and mild anemia , however the full spectrum of clinical symptoms typical of hemochromatosis is seen in some patients .
it is caused by mutation in the slc40a1 gene , which codes for ferroportin protein .
ferroportin protein is expressed in enterocytes , macrophages , kupffer cells , placental cells and hepatocytes , where it plays the role of an iron exporter .
ferroportin protein helps in release of both dietary iron from enterocytes as well as iron released by damaged or senescent red blood cells into the circulation ( fig .
1 ) . expression of ferroportin , a transmembrane receptor protein , is regulated by its ligand , hepcidin .
hepcidin , a negative regulator of iron absorption , binds to ferroportin transmembrane protein during states of excess iron or inflammation .
the amount of iron released into the circulation by enterocytes and macrophages is reduced as a result . on the other hand , during states of iron deficiency , there is a decline in the expression of hepcidin , and hence excess iron is released into the circulation .
the mutation of ferroportin protein as in the case of ferroportin disease makes it resistant to hepcidin , hence removing the negative regulation and leading to excess iron release into the circulation . in our patient ,
normal transferrin saturation along with heterozygosity for c282y mutation made the diagnosis of hemochromatosis unlikely .
a(hypo)transferrinemia is an extremely rare autosomal recessive disorder of iron overload characterized by severe microcytic anemia , which was not present in this patient .
the possibility of ferroportin disease should only be entertained once the more common secondary causes of hyperferritinemia are excluded .
secondary or acquired iron overload state , in the absence of an abnormal gene , suggests disorders such as chronic hemolytic anemias , dysmetabolic hyperferritinemia , chronic liver disease due to alcohol , hepatitis b or c , porphyria cutanea tarda and iatrogenic iron overload conditions . in the absence of hepatitis c antibody or hepatitis b surface antigen in our patient , viral hepatitis b or c was very unlikely to be the cause .
our patient did not report any history of iron therapy , excluding iatrogenic overload . in the presence of normal hemoglobin and hematocrit , chronic hemolytic anemia was also unlikely to be the cause .
alcoholic liver disease was also unlikely to be the cause , as it is associated with elevated transferrin saturation .
chronic alcohol use leads to downregulation of hepcidin , which alters the iron hemostasis , causing iron excess .
dysmetabolic hyperferritinemia , also known as insulin resistance associated with iron overload , is a much more common disorder than recognized clinically by physicians .
it is characterized by the presence of elevated serum ferritin , but normal transferrin saturation in an individual with features of metabolic syndrome . in our overweight patient , who had other features of metabolic syndrome including diabetes mellitus , hypertension and hyperlipidemia
, this diagnosis seems most likely , especially in the absence of genetic mutation for hfe hemochromatosis and exclusion of other secondary causes of iron overload ( fig .
in a patient with signs and symptoms of tissue iron overload and high serum ferritin levels , low or normal transferrin saturation should alert the physician to other  primary as well as secondary  causes of iron overload besides hemochromatosis .
other primary iron overload conditions with normal transferrin saturation include ferroportin disease type a and aceruloplasminemia .
dysmetabolic hyperferritinemia , being more prevalent especially in the presence of metabolic syndrome , should be considered as the most likely disorder in such scenarios of high ferritin with normal transferrin saturation .
 disturbances in iron metabolism can be genetic or acquired and accordingly manifest as primary or secondary iron overload state 
 . organ damage may result from iron overload and manifest clinically as cirrhosis , diabetes mellitus , arthritis , endocrine abnormalities and cardiomyopathy . 
 hemochromatosis inherited as an autosomal recessive disorder is the most common genetic iron overload disorder . 
 expert societies recommend screening of asymptomatic and symptomatic individuals with hemochromatosis by obtaining transferrin saturation ( calculated as serum iron / total iron binding capacity  100 ) . 
 further testing for the hemochromatosis gene is recommended if transferrin saturation is > 45% with or without hyperferritinemia . 
 however , management of individuals with low or normal transferrin saturation is not clear . in patients with features of iron overload and high serum ferritin levels , low or normal transferrin saturation should alert the physician to other  primary as well as secondary  causes of iron overload besides hemochromatosis . 
 we present here a possible approach to patients with hyperferritinemia but normal transferrin saturation . 
Introduction
Case Presentation
Differential Diagnosis
Genetic Iron Overload
Acquired Iron Overload
Discussion
Conclusion
Disclosure Statement