Hyperferritinemia and liver iron content determined with MRI: Reintroduction of the liver iron index.

BACKGROUND: Hyperferritinemia is found in around 12 % of the general population. Analyzing the cause can be difficult. In case of doubt about the presence of major iron overload most guidelines advice to perform a MRI as a reliable non-invasive marker to measure liver iron concentration (LIC). In general, a LIC of ≥ 36 µmol/g dw is considered the be elevated however in hyperferritinemia associated with, for example, obesity or alcohol (over)consumption the LIC can be ≥ 36 µmol/g dw in abscence of major iron overload. So, unfortunately a clear cut-off value to differentiate iron overload from normal iron content is lacking. Previously the liver iron index (LII) (LIC measured in liver biopsy (LIC-b)/age (years)), was introduced to differentiate between patients with major (LII ≥ 2) and minor or no iron overload (LII < 2). Based on the good correlation between the LIC-b and LIC determined with MRI (LIC-MRI), our goal was to investigate whether a LII_MRI ≥ 2 is a good indicator of major iron overload, reflected by a significantly higher amount of iron needed to be mobilized to reach iron depletion. METHODS: We compared the amount of mobilized iron to reach depletion and inflammation-related characteristics in two groups: LII-MRI ≥ 2 versus LII-MRI <2 in 92 hyperferritinemia patients who underwent HFE genotyping and MRI-LIC determination. RESULTS: Significantly more iron needed to be mobilized to reach iron depletion in the LII ≥ 2 group (mean 4741, SD ± 4135 mg) versus the LII-MRI <2 group (mean 1340, SD ± 533 mg), P < 0.001. Furthermore, hyperferritinemia in LII-MRI < 2 patients was more often related to components of the metabolic syndrome while hyperferritinemia in LII-MRI ≥ 2 patients was more often related to HFE mutations. ROC curve analysis showed good performance of LII =2 as cut-off value. However the calculations showed that the optimal cut-off for the LII = 3.4. CONCLUSION: The LII-MRI with a cut-off value of 2 is an effective method to differentiate major from minor iron overload in patients with hyperferritinemia. But the LII-MRI = 3.4 seems a more promising diagnostic test for major iron overload.

Inflammation can increase hepcidin in HFE-hereditary hemochromatosis.

We present a p.C282Y homozygous patient with high hepcidin levels and normal iron parameters during systemic inflammation. This suggests that in the absence of a proper functioning HFE, resulting in blockage of the BMP/SMAD pathway, the innate low hepcidin concentration can be upregulated by inflammation, probably via the JAK/STAT3 pathway.

Absorption of nonheme iron during gastric acid suppression in patients with hereditary hemochromatosis and healthy controls.

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton-pump inhibitors (PPIs) can reduce the number of phlebotomies in patients with HH. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. In 10 p.cysteine282tyrosine (p.C282Y) homozygous HH patients with normalized iron stores and 10 healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron [ferric iron (Fe3+)] polymaltose and hourly for 4 h afterward. This was repeated after 7 days of treatment with pantoprazole 40 mg once daily. Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the patients with HH, whereas no changes were observed in the HCs. Hepcidin concentrations were lower in the patients with HH compared with the HCs both before and during PPI use. In both groups, hepcidin levels did not significantly decrease during the treatment. Seven-day PPI use significantly reduces iron absorption in patients with HH but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size.NEW & NOTEWORTHY This study confirms that lowering gastric acidity by proton pump inhibitors results in a reduction in iron absorption in patients with hemochromatosis and not in healthy control subjects. The presupposition that a decrease in hepcidin concentration in healthy control subjects in response to lowering gastric acidity can explain the difference in iron absorption between these groups could not be confirmed probably because of a small sample size.

Hyperferritinemia in Nonalcoholic Fatty Liver Disease: Iron Accumulation or Inflammation?

Hyperferritinemia, observed in inflammation, iron overload as well as in combination of both, is found in ∼30% of nonalcoholic fatty liver disease (NAFLD) patients. The authors summarized the evidence regarding the potential cause of hyperferritinemia in NAFLD, as this may affect the indicated therapy. A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, and the Cochrane library. In the majority of NAFLD patients, hyperferritinemia is due to inflammation without hepatic iron overload. In a smaller group, a dysmetabolic iron overload syndrome (DIOS) is found, showing hyperferritinemia in combination with mild iron accumulation in the reticuloendothelial cells. The smallest group consists of NAFLD patients with hemochromatosis. Phlebotomy is only effective with hepatocellular iron overload and should not be the treatment when hyperferritinemia is related to inflammation, whether or not combined with DIOS. Treatment with lifestyle changes is to date probably the more effective way until new medication is becoming available.

The modified iron avidity index: a promising phenotypic predictor in HFE-related haemochromatosis.

OBJECTIVE: Phenotypes of the HFE-related haemochromatosis vary considerably, making it hard to predict the course of iron accumulation. The aim of this retrospective study was to determine if the Iron Avidity Index (IAI) is a good phenotypic predictor of the number of phlebotomies needed per year during maintenance treatment (NPDMT) in patients with homozygous p.C282Y hereditary haemochromatosis (HH). METHODS: Patients with HH homozygous for p.C282Y, on maintenance treatment for at least 1 year were included. The IAI (ferritin level at diagnosis/age at diagnosis) was calculated. RESULTS: Ninety-five patients were included in the analysis. Linear regression analysis showed the confounding effect of sex on the relationship between IAI and NPDMT. A modified IAI, adjusted for sex, was calculated. As proton pump inhibitor (PPI) use was independently associated with NPDMT, the group was split in PPI- and non-PPI-users. A positive correlation between the modified IAI and the NPDMT was shown in both groups (PPI r = 0.367, P = 0.023; non-PPI r = 0.453, P < 0.001). An ROC was computed to measure the accuracy of the modified IAI to predict who needed 0-2 vs. ≥3 maintenance treatments per year. The AUROC in the PPI and non-PPI group were respectively 0.576 (0.368-0.784) and 0.752 (0.606-0.899). CONCLUSION: The modified IAI is a fairly good predictor in non-PPI-using homozygous C282Y HH patients, to differentiate who needs ≥3 maintenance phlebotomies per year. Therefore, this index might help to select patients that benefit from an alternative less frequent therapy, e.g. erythrocytapheresis.