Hereditary Hemochromatosis – Classification

ClassificationGenes involvedInheritanceProtein functionClinical manifestations
Type 1A HH (homozygote)Mutations in HFE: C282YARInvolved in hepcidin synthesis via
BMP6, interaction with TFR1.
Arthropathy, skin pigmentation, liver
damage, diabetes mellitus,
endocrine dysfunction,
cardiomyopathy, hypogonadism.
Type 1B HH (compound
heterozygote)
Mutations in HFE:
C282Y
H63D
ARInvolved in hepcidin synthesis via
BMP6, interaction with TFR1.
Arthropathy, skin pigmentation, liver
damage, diabetes mellitus,
endocrine dysfunction,
cardiomyopathy, hypogonadism.
Type 1C HHMutations in HFE:
S65C
ARPossible elevations in serum iron/
ferritin, no evidence of tissue iron
deposition.
Type 2A juvenile HHHJV (hemojuvelin)ARInvolved in hepcidin synthesis, BMP
co-receptor.
Earlier onset, ,30 years old,
hypogonadism and cardiomyopathy
are prevalent.
Type 2B juvenile HHHAMP (hepcidin) ARDownregulation of iron efflux from
erythrocytes.
Earlier onset, ,30 years old,
hypogonadism and cardiomyopathy
are prevalent.
Type 3 HHTFR2 (transferrin receptor 2)ARInvolved in hepcidin synthesis,
interaction with transferrin.
Arthropathy, skin pigmentation, liver
damage, diabetes mellitus,
endocrine dysfunction,
cardiomyopathy, hypogonadism.
Type 4A HH (FPN disease)SLC40A1 (FPN)ADDuodenal iron export.Iron deposition in the spleen is very
common, lower tolerance to
phlebotomies and may have anemia.
Type 4B HH (nonclassical
FPN disease)
SLC40A1 (FPN)ADResistance to hepcidin.Fatigue, joint pain.
AD, automosomal dominant; AR, autosomal recessive; FPN, ferroportin; HAMP, hepatic antimicrobial protein; HH, hereditary hemochromatosis. From Am J Gastroenterol 2019;114:1202–1218.