Proton pump inhibitors in the prevention of iron reaccumulation in patients with hereditary hemochromatosis

Hereditary Hemochromatosis (HH) is a genetic disorder of iron metabolism,
resulting in excessive iron overload causing damage of different important
organs like heart, liver, pancreas and joints. Complications and symptoms can
regress by intensive treatment reducing the iron overload stores(Adams et al,
Pietrangelo et al, van der Plas et al).
Different genes have been identified playing a role in the pathofysiology of
iron overload. A clinically important HFE gene mutation is the C282Y, located
on chromosome 6. The homozygous mutation is found in 1 out of 200-400 people in
the Netherlands with a variable penetrance for clinical HH of 10%, estimating
that about 4.000 * 8.000 individuals in the Netherlands are at risk and require
therapy (Swinkels et al, Jacobs et al).
Phlebotomy is currently the standard therapy which consists of removal of 500
ml whole blood weekly, representing a loss of 250 mg iron. In naive patients
between 20 to 100 phlebotomies are required to reduce the serum ferritine
levels to 50 *g/L. Thereafter, a lifelong maintenance therapy of 3 to 6
phlebotomies yearly is needed.
For absorption, dietary iron ( 70%) is reduced by gastric acid form the ferric
(Fe3+) to the ferrous form (Fe2+). Recently, in an observational open study,
Hutchinson et al. found that HH patients treated with proton pump inhibitors
(PPI) needed fewer phlebotomies, resulting in a drop of 2.5 (SEM 0.25) to 0.5
(SEM 0.25) liter per year (Hutchinson et al).
Since PPI therapy is very common, we foresee within short notice an expansion
of PPI prescription in HH patients. Thus, structured evaluation of efficacy,
costs and patients compliance, acceptance and therapy preference is now
mandatory.
Research question: The primary objective is to determine the effectiveness and
cost effectiveness of PPI*s compared to standard phlebotomy therapy in the
prevention of iron overload in HH patients.

The effectiveness an cost effectiveness of PPIs compared to standard phlebotomy
therapy in the prevention of iron overload in patients with hereditary
hemochromatosis.

Multi-center trial in two hospitals in the South of Limburg (Atrium medical
Center, Maastricht university medical center) and hospital in Belgium
(University Hospital Gasthuisberg). The study will be conducted in randomised
double blind manner. The follow up will be one year.

patients are randomized either for the group receiving a PPI or a placebo.
Every 2 month the ferritin level is measured and decided if the patient need a
phlebotomy (Ferritin >50 µg/L).

The patient should take on tablet a day (placebo/PPI). Two times a year an
outpatient clinic visit is planned, which is normal for the patient. Every two
months a blood sample is taken. When the ferritin is > 100 ug/l a phlebotomy is
planned. We asked the patient to fill in questionnaires every two months
(BASDAI/ SF-36/EQ-5D). At inclusion the patient will be physical examined.

Side effects of PPIs are rare. The most often mentioned (1-10%) are pain in
upper abdomen, diarrhoea, constipation, flatulence and headache. Data of long
term complications are sparse. Elevation of hormone Gastrin is found and can
lead to expansion of enterochromafinlike cells (ECL)7-14 without risk of
carcinoma 15. In small studies bacterial overgrowth has been observed as a
consequence of strong acid suppression 16-18. The patients have a slight
elevated change of bacterial gastrointestinal infections 19 and pneumonia 20.