The absorption of non-haem iron during suppression of gastric acid secretion

Food is the most common source for iron, in which it can be found as non-haem
or haem iron. Non-haem iron enters the enterocytes via the divalent metal
transporter 1 (DMT-1) located in the apical membrane of enterocytes. This
transporter is selective for ferrous iron (Fe2+), making a reduction step of
ferric iron (Fe3+) necessary, because dietary iron is in the ferric form.
Non-haem iron supplies at least two thirds of dietary iron requirements.
Gastric hydrochloric acid (HCl) acts to promote the optimum absorption by
reducing ferric iron (Fe3+) to the more soluble ferrous form (Fe2+).
Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism
resulting in excessive iron overload causing damage of different important
organs such as liver, heart, pancreas and joints. It has been suggested that
iron accumulation in most types of hemochromatosis is due to deficiency of
hepcidin, a central iron regulator.

A close correlation has been demonstrated between iron absorption and the
capacity of gastric juice to release food iron. At high levels of gastric pH
(>3,6), negligible amounts of non-haem iron would be released from dietary
components and reduction of ferric iron and formation of ferric chelates would
be impaired. This would have a major impact on iron absorption. In an open
observational open study, Hutchinson et al found that administration of a
proton pump inhibitor (PPI) to patients with hereditary haemochromatosis gives
a significant reduction in the maximum increase in serum iron concentration
following ingestion of a test meal, containing highly bioavailable iron.
However, long-term use of PPI has not been reported to compromise iron status
in normal subjects.
Since PPI therapy is very common, we foresee within short notice an expansion
of PPI prescription in (hemochromatosis) patients. Thus structured evaluation
of the mechanism behind reduction in increase of serum iron after an oral iron
challenge during gastric acid suppression is mandatory.
How can the difference in iron absorption between hemochromatosis patients and
healthy controls be explained? We hypothesize that due to diminished gastric
acid production the reduction step of ferric to ferrous iron will be reduced;
as a consequence the hepcidin concentration in HCs decreases, after gastric
acid suppression, to compensate for the reduced availability of ferrous iron
(Fe2+).

A nonrandomized study among hemochromatosis patients and healthy controls on
the effect of gastric acid suppression on serum iron and hepcidin
concentration. After a test dose of ferric iron, the course of the parameters
will be studied in both the hemochromatosis patients and healthy controls.

After an overnight fast serum iron and hepcidin concentration will be
determined. Healthy controls and hemochromatosis patients will then receive
iron (Fe3+) polymaltose containing 50 mg of iron, the standard advised dose of
oral liquid. Serum iron will be measured hourly for 4 hours, and hepcidin
concentrations are measured after 3 and 4 hours after ingestion of the
solution. Then all the participants will use pantoprazole 40 mg daily for a
week, after which they will have iron polymaltose again and the same parameters
are measured.

At inclusion a history of the patient will be taken and a physical examination
will be performed. Furthermore routine blood tests will be performed as
depicted in the table. Besides a bruise, no side effects of the venepuncture
are expected as patients will be sitting or lying down when undergoing
venepunction. After an overnight fast, serum iron and hepcidin concentrations
will be measured. Then the participants have to ingest iron polymaltose, after
which blood samples will be taken.
The participants will use a pantoprazole for a week, one tablet a day in the
morning. Then the oral iron challenge will be repeated in the same way as
before pantoprazole use.
Side effects of PPIs are rare. Possible side-effects (1-10%) are pain in upper
abdomen, diarrhoea, constipation, flatulence and headache. Data of long term
complications are sparse. Elevation of gastrin is found and can lead to
expansion of enterochromaffin-like cells (ECL) without risk of carcinoma. In
small studies bacterial overgrowth has been observed as a consequence of strong
acid suppression. The patients have a slightly elevated change of bacterial
gastrointestinal infection and pneumonia. Since the subjects only use the
pantoprazole for one week, no side effects are expected.
Side effects of oral iron are mainly gastro-intestinal disturbances. Since
participants will receive a small dose (50 mg) not on regular basis, little to
none side-effects are expected.