Table 2.

Primary Iron Overload Disorders in the Differential Diagnosis of HFE-Related Hemochromatosis

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/HFE HCDistinguishing from HFE HC
BMP6
HAMP
HFE
HJV
TFR2 		Digenic HC
(caused by the presence of monoallelic or biallelic HC-related alleles in two HC-related genes)		Digenic
  • Adults affected
  • Iron accumulation in parenchymal cells
  • ↑ TS & serum ferritin
  • Arthralgias in some persons
Iron overload may be more severe in persons w/HFE HC who are also heterozygous for pathogenic alleles of BMP6, HAMP, HJV, or TFR2.
BMP6 BMP6-related iron overload (OMIM 112266)AD
  • Adults affected
  • ↑ TS & serum ferritin
  • Arthralgias in some persons
  • Iron overload typically milder than in HFE HC
  • Iron deposition in hepatocytes & Kupffer cells
  • Serum hepcidin levels normal or slightly ↑
CP Aceruloplasminemia ARProgressive iron deposition in liver & pancreas causes cirrhosis & diabetes.
  • Heavy iron deposition in brain accounts for neurologic dysfunction in adults.
  • Iron deposition in retina is distinctive.
  • Mild iron deficiency anemia by early adulthood; TS is low.
  • Rare; may be more common among Japanese.
HAMP
HJV 		Juvenile hemochromatosis AR
  • Iron accumulation in parenchymal cells
  • Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
  • Earlier onset
  • More severe clinical manifestations
  • Hepatocellular cancer not reported (possibly due to short life span)
SLC40A1 SLC40A1-related hemochromatosis assoc w/gain-of-function alleles 1 (OMIM 606069)AD
  • ↑ TS & serum ferritin
  • Iron deposition in hepatocytes
Iron & serum ferritin phenotypes are similar to those of HFE HC.
TFR2 TFR2-related hemochromatosis AR
  • Iron accumulation in parenchymal cells
  • Cirrhosis, hypogonadotropic hypogonadism, arthropathy, osteoporosis, & diabetes common
  • Earlier onset
  • Progression similar to juvenile hemochromatosis

AD = autosomal dominant; AR = autosomal recessive; HC = hemochromatosis; HFE HC = HFE-related hemochromatosis; MOI = mode of inheritance; TS = transferrin saturation

1.

The phenotype associated with loss-of-function SLC40A1 pathogenic alleles (i.e., the "classic" subtype) is distinct from HFE HC and is associated with anemia, elevated serum ferritin, normal or low TS, reticuloendothelial cell iron deposition, low tolerance to phlebotomy therapy, and a late age of onset. Many persons with loss-of-function SLC40A1 pathogenic alleles have little or no liver injury.

From: HFE-Related Hemochromatosis

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