Proton Pump Inhibitor Induced Hypomagnesemia

(a) Relevancy
At least 2 million people in the Dutch population make use of gastric acid
blockers (PPI's) on a regular basis. PPIs are the first line treatment drug for
gastric acid related diseases in human. These diseases include dyspepsia,
inflammatory processes in esophagus, stomach and duodenum, and chronic diseases
like Morbus Cron and others.

(b) Mode of action of PPI's
PPIs are potent and specific inhibitors of the gastric H-K-ATPase which is
centrally involved in gastric acid production. All known PPIs (a group of
related molecules) form inhibitory complexes with the H-K-ATPase. This complex
formation results in the restriction proton secretion into the lumen of the
stomach and a concomitant raise in pH. This change in pH is the desired effect
that supports the treatment of priorly mentioned diseases.
The use of PPI's is considered to be safe. PPI's have a low toxicity and the
rate and severeness of adverse reactions in general is low. These facts
contributed to the release of PPI's for retail marketing without need for
prescription by the physician.

(c) Subject
However, this study investigates on a rather rare but in some cases severe
adverse effect of PPI usage. In the literature several cases (± 30) of PPI
induced hypomagnesemia are discribed. In these cases there was a causative link
between the hypomagnesmic status of the patient and the intake of PPIs. These
patients more or less show common symptoms of a severe ion imbalance. The
hypomagnesemia is often accompanied by hypocalcemia and hypokalemia. The
combination of these is responsible for the symptoms seen in affected persons,
like severe arrythemia of the heart and other neuromuscular pathies.

(d) Causes
The exact molecular and physiological causes of PPI induced hypomagnesemia
still are not known. However, it can be assumed that this type of
hypomagnesamia develops due to malabsorbtion of magnesium in the intestinal
tract. This assumption is supported by the fact, that in the case reports the
affected individuals do not show any renal leakage of magnesium.

The knowledge on PPI induced hypomagnesemia is restricted. For that reason,
this study has two key objectives which investigate on the frequency and the
causes of PPI induced hypomagnesemia:

1. The investigation of the prevalence of PPI induced hypomagnesemia.
- This is an important factor for the estimation of the clinical relevance of
this deviation.

2. A genetical screening of patients with PPI induced hypomagnesemia.
- This is important part to facilitate the generation of new knowledge on the
aetiology of the deviation and for gaining insight in possibly unknown
regulatory mechanisms of the magnesium homeostasis.

This study is of exploratory character and can be divided into two steps (a+b):

(a) Selection of participants
All potential participants is are recruited from regular visitors of the
departments internal medicine UMC St Radboud and the CWZ (Canisius
Wilhelmina-Ziekenhuis) Nijmegen. The participants with dyspepsia and PPI use
are the target group for this selection, because of having a restricted amount
of comorbidity. This is important to rule out disease parameters that might
interfere with serum magnesium.

(b) Measurements
Selected participants that signed the informed consent agreement will undergo a
bimodal blood screening with a single vena puncture. Two different blood
samples will be collected.
1. One sample clot-blood or heparin-blood of approximately 5 ml volume.
- This sample is used to determine the serum magnesium concentration (and
eventually also serum calcium). This analysis is performed to identify
hypomagnesemic individuals and give an indication for the prevalence within the
complete study population.
2. One sample EDTA blood of approximately 10 ml volume.
- This sample is intended for the whole genome SNP array. This is performed to
identify a possible genetic variation that may make individuals prone to the
development of PPI induced hypomagnesemia.

(c) Usage of proton pump inhibitors
At patient visit the following information will be collect over the patient's
useage op the PPI's:
- The name and the doage of the durg.
- The frequency of PPI intake.
- The total period/history of PPI use.

The cumulative risk or burden that the participants undergo is low.

(a) Aim is it to work within a regular blood-withdrawal to prevent unnecessary
vena puntures.
(b) However the participant admits an vena puncture for only for the benefit of
the study if the participant would not undergo an otherwise indicated puncture.
De risk of a single vena puncture and the withdrawal of a small amount of blood
(approximately 15 ml) can be reasonably considered to be very small. There is a
5% chance of a fully reversible haematome resulting from the vena puncture.
(c) All blood sampling is performed in clinical context by professionally
trained and experienced personnel from the daily practice.
(d) This study has the chance to gain new scientific knowledge on a possibly
relevant subject within the healthcare of human. Considering the minimal burden
for the participant it can be reasonably argued that this study in this sense
is justified.