HFE gene in primary and secondary hepatic iron overload

Table 1 Nomenclature for iron overload states

Primary iron overload-hereditary haemochromatosis (HH)

HFE-associated HH

1 C282Y homozygosity

2 C282Y/H63D compound heterozygosity

3 Other mutations

Non HFE-associated HH

1 Juvenile haemochromatosis

2 TfR2-related haemochromatosis

3 Autosomal dominant haemochromatosis

Secondary iron overload-acquired

Iron-loading anaemias

1 Thalassaemia major

2 Sideroblastic anaemia

3 Chronic haemolytic anaemias

Chronic liver diseases

1 Hepatitis C

2 Alcoholic liver disease

3 Non-alcoholic steatohepatitis

4 Porphyria cutanea tarda

5 IR-HIO

6 Post-portacaval shunting

7 Transfusional and parenteral iron overload

8 Dietary iron overload

Miscellaneous

1 Iron overload in sub-Saharan Africa

2 Neonatal iron overload

3 Acaeruloplasminaemia

4 Congenital atransferritinaemia

Table 2 Studies of the relationship between chronic hepatitis C, iron and HFE mutations

Reference	Casesn	Ethnicity	HFErelationshipwith serumiron indices	HFErelationshipwith HI	HFErelationshipwith fibrosis
[70]	206	Italian	Yes	Yes	Yes
[83]	120	Mostly Swiss and Italian	No	No	No
[88]	242	Mostly Caucasian	No	No	No
[89]	164	Mostly Caucasian	No	No	No
[90]	137	Caucasian	Yes	Yes	Yes
[91]	135	Brazilian	Yes	Yes	Yes
[92]	119	Mostly Caucasian, non-Hispanic	Yes	Yes	Yes
[93]	316	Mostly White	Yes	Yes	Yes
[94]	401	Mostly German	Yes	Yes	Yes
[95]	184	White, non-Hispanic	Yes	No	No
[96]	273	NA	Yes	Yes (only H63D)	No
[97]	1051	Mostly White, non-Hispanic	Yes	Yes	No

NA: not available; HI: hepatic iron (histological and/or biochemical evidence).

Table 3 Studies of the relationship between alcoholic liver disease, iron and HFE mutations

Reference	Casesn	Ethnicity	HFErelationship withserum iron indices	HFErelationshipwith HI	HFErelationshipwith ALD
[120]	257	Caucasian	NA	No	No
[121]	254	Caucasian	No	Yes	No
[129]	179	White Hispanic	Yes (C282Y)	NA	No
[130]	61	White, non- Hispanic	NA	NA	NA

NA: not available; HI: hepatic iron; ALD: alcoholic liver disease (histological and/or biochemical evidence).

Table 4 Studies of the relationship between NAFLD-NASH, iron and HFE mutations

Reference	Casesn	Ethnicity	HFErelationshipwith serumiron indices	HFErelationshipwith HI	HFErelationshipwithfibrosis
[139]	51	Australian	Yes with transferrin saturation, no with ferritin	Yes	Yes
[142]	31	Italian	No	Yes	No
[146]	263	Italian	Yes (C282Y)	No	No
[151]	57	Caucasian	Yes	Yes	Yes
[152]	32	Mostly Caucasian	No	No	No
[153]	38	Asian	No	No	No
[154]	31	Asian Indian	No	No	No
[155]	93	Mostly Caucasian	No	Yes	No

NA: not available; HI: hepatic iron (histological and/or biochemical evidence).

Table 5 Studies of the relationship between porphyria cutanea tarda, iron and HFE mutations

Reference	Casesn	Ethnicity	HFErelationshipwith serumiron indices	HFErelationshipwith HI	HFErelationshipwithfibrosis
[163]	41	Caucasian	NA	NA	NA
[164]	108	Australian	Yes	Yes	No
[165]	70	North American	NA	NA	NA
[167]	23	Brazilian	Yes	No	Yes
[168]	36	Southern France	No	NA	NA
[170]	190	German	No	No	No
[172]	68	Italian	No	NA	NA
[174]	62	German	Yes	NA	NA

NA: not available; HI: hepatic iron (histological and/or biochemical evidence).

Table 6 Secondary iron overload: common features and differences

Common features

1 Mixed distribution of hepatic iron (parenchymal and reticuloendothelial)

2 Mild to moderate iron overload in most cases, rarely severe iron overload

3 Phlebotomy possibly improves the course of disease and response to therapy

Differences

1 C282Y: accepted role in PCT, possible cofactor in CHC and NAFLD (especially in populations of Northern European descent)

2 H63D: unclear role in NAFLD and PCT

3 No role for HFE mutations in ALD or CHB

PCT: porphyria cutanea tarda; CHC: chronic hepatitis C; NAFLD: non-alcoholic fatty liver disease; ALD: alcoholic liver disease; CHB: chronic hepatitis B; CLDs: chronic liver diseases.