Disease progression and liver cancer in the ferroportin disease

Ferroportin‐associated iron overload (also known as the ferroportin disease) was clinically recognised in 1999,¹ and linked in 2001 to the A77D mutation of ferroportin (FPN).² Owing to the mild clinical expressivity reported in the literature, doubts have been raised on the penetrance of the genetic defect and the rationale for iron‐removal therapy.³ However, so far, no prospective data have been collected pertaining to this disorder.

We have had the opportunity to study six members of a pedigree carrying the A77D mutation of FPN for 11–24 years in whom the disease was first described.¹,²

The proband (subject V₁₃, table 1) was diagnosed at the age 59 years. After being on weekly phlebotomy for 2 years, he was on a maintenance programme for 18 years (one phlebotomy every 3 months). At the age of 79 years, he refused to continue on phlebotomy. In 2006, at the age of 83 years, hepatic ultrasound (US) examination of the proband identified two hyperechoic nodules in the liver; contrast‐enhanced MRI scan confirmed the US examination findings and a US‐guided liver biopsy documented a well‐differentiated hepatocellular carcinoma (fig 1A), as shown by antihepatocyte antibody stain (not shown here), in the absence of cirrhosis. Strong p53‐positive stain was also detected in the tumour specimen by using a specific antibody (fig 1B). The level of serum α fetoprotein was 5.0 ng/ml (normal value <10 ng/ml). The patient reported no alcohol intake for the past two decades. No antibodies against hepatitis C virus and hepatitis B virus (HBV) were found. However, HBV sequences corresponding to all the four different viral genomic regions tested were detected by nested PCR in the tumour biopsy specimen. In addition, HBV DNA was also found in the liver specimens collected at the age 59 and 79 years. The patient's liver nodules were treated by chemoembolisation.

Table 1 Biochemical and clinical data of the subjects with ferroportin‐related iron overload.

No	Subjects	Age at diagnosis (years)*	Years on phlebotomy	Serum ferritin level at present, (μg/l)	Liver iron concentration at present, (μmol/g)	Liver fibrosis at diagnosis	Liver fibrosis at present
1	V13	59	20	690	55	F1	F2
2	VI25	34	15	650	35	F0	F0
3	VI26	20	11	670	35	F0	F0
4	VI30	37	12	410	28	F0	F0
5	VI33	39	11	827	75	F0	F3
6	VI36	34	15	750	65	F0	F2

Patient numbering is the same as that used in the original publication¹.

*All patients were male.

Figure 1 Histological and imaging data from affected family members. (A,B) Specimens from the proband's tumour. (A) A well‐differentiated hepatocellular carcinoma, intratumour fibrous tissue entrapping iron‐laden non‐parenchymal cells and necrosis areas . (B) In the nodule, most cells stain positive for p53 antibody (brown nuclei). Sirius red stain show various degrees of fibrosis in (C) subject VI₃₆ and (D) subject VI₃₃. (E,F) MRI scans. T2‐weighted gradient‐echo sequences were used to detect iron accumulation. Owing to residual iron accumulation, significant decrease in MRI signal is still appreciable in the spleen and the spine of a patient who showed low compliance to therapy (E; subject V₃₃; and also, although to a lesser extent, in a well‐treated subject with normal liver iron content (F; subject V₃₀).

All the proband's relatives, underwent regular phlebotomy, except for two who showed low adherence and, after reaching iron depletion, underwent phlebotomy occasionally, usually once a year (subject VI₃₃ and VI₃₆; table 1). Both patients presented signs of the progression of fibrosis as compared with the first assessment reported in 1999¹ (fig 1C,D), with appreciable increase in portal blood flow in subject VI₃₃ at colour Doppler US examination (velocity 17 cm/s), and liver iron content more than twofold the normal value.

In conclusion, the ferroportin disease may progress if not properly treated, and complicate with liver cancer even without cirrhosis, in the presence of cocarcinogenic factors, such as occult HBV infection. The hallmark of the classic FPN disease is marked iron accumulation in Kupffer cells.⁴ Kupffer cells are vital in producing fibrogenic mediators,⁵ in immunological tumour surveillance and disposal of transformed hepatocytes.⁶,⁷ Selective and massive iron overload might impair these activities and favour fibrogenesis and carcinogenesis. Macrophage iron overload is very resistant to iron withdrawal in this disorder, even in patients who are apparently well treated (fig 1E,F). As for the development of liver cancer in the proband, we speculate that adequate phlebotomy “controlled” the oncogenic potential of HBV (which was present in the patient's liver since his first hospital admission at the age of 59 years). However, once the 20‐year‐long treatment was discontinued, the underlying hepatitis B infection could express its cofactorial oncogenic activity and contribute, with the rising iron burden, to the development of neoplastic nodules. In this vein, iron‐dependent loss in p53 growth‐suppressor activity, also implicated in liver carcinogenesis in classic haemochromatosis,⁸ may have had a role and facilitated the HBV oncogenic potential.⁹ Our results prompt for a thorough lifelong maintenance therapy and regular screening for liver cancer in the patients with ferroportin disease.