Aliment. Pkarmacol. Ther. (1992) 6, 399-406.
`
`Review article : metabolic consequences of long-
`term inhibition of acid secretion by omeprazole
`
`H. K O O P
`Division of Gastroenterology and Metabolism, Deparfmenf of Medicine, Philipps-
`University, Marburg, Germany
`
`Accepted for publication 20 March 1992
`
`SUMMARY
`Metabolic sequelae of profound and long-lasting inhibition of gastric
`acid secretion by omeprazole have largely been neglected. Data from
`long-term studies suggest that vitamin B,, stores decrease slightly
`over several years, although this was not clinically relevant within
`the first 4 years of therapy. Additionally, it cannot be completely
`ruled out that patients with an increased iron demand may develop
`iron deficiency, but data available at present do not provide. any
`evidence that iron malabsorption is to be expected under normal
`conditions. Protein homeostasis and calcium metabolism seem to be
`unaffected by long-term omeprazole therapy. Based upon present
`experience, serum cobalamin concentration should be monitored in
`patients undergoing omeprazole therapy for several years.
`
`INTRODUCTION
`The proton pump inhibitor omeprazole is generally established as an effective
`and safe drug for primary short-term therapy of acid peptic diseases.' Increasing
`interest is focused on possible side-effects of this compound during prolonged
`treatment, which is mandatory particularly in patients with reflux oesophagitis.'
`
`~~
`
`~
`
`~
`
`~~
`
`Correspondence to : Professor Dr Herbert Koop, Department of Medicine, Philipps-University,
`Baldingerstrasse, D-W-3550 Marburg, Germany.
`399
`
`25 2
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`400 H.KOOP
`During long-term administration omeprazole has been shown to prevent relapses
`effectively even in severe ulcer disease and reflux oe~ophagitis.'-~ While the risk of
`omeprazole to induce hypergastrinaemia and consequently lead to development of
`carcinoids has been extensively studied (for review see Refs 6,7), the metabolic
`sequelae of profound and long-lasting acid inhibition have raised little attention so
`far. This review focuses on this safety aspect of continuing proton pump inhibition
`and provides additional insight into the physiological role of gastric acid in the
`absorption process of protein, vitamin B,, and some minerals.
`
`PROTEIN A B S O R P T I O N
`Digestion of protein starts in the stomach by the protease pepsin. Omeprazole in
`general does not influence pepsin secretion.'-'' Only in the complete absence of
`acid, pepsin concentrations in gastric juice may be decreased.' This may be due to
`either lack of direct topical stimulation of chief cells by hydrochloric acid" or
`caused by degradation of pepsin at neutral pH." Independent of changes in pepsin
`secretion, the enzymatic activity of pepsin which has its pH optimum at pH 1.812f13
`declines with increasing pH to less than 5 % at pH 5.
`There is little information available whether omeprazole has any effect on the
`process of protein digestion and absorption. Omeprazole induces profound and
`long-lasting inhibition of parietal cell function. Although it usually does not induce
`achlorhydria at doses of 20-40 mg daily,'*! I5 complete suppression of acid secretion
`
`4
`
`n - 3 0
`
`30
`
`\
`0
`
`3
`
`
`
`30
`
`29
`
`28
`
`18
`
`12
`
`II
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`42
`
`48
`
`0
`
`=
`
`Months of omeprazole therapy
`
`a Serum calcium
`
`Serum protein
`Figure 1. Effect of prolonged omeprazole therapy on serum concentrations of total protein and
`calcium. Measurements were performed in 30 patients prior to and during orneprazole treatment of
`varying duration (12-48 months). Medians are given. The dotted line indicates the lower limit of
`normal.
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`METABOLIC CONSEQUENCES OF ACID SECRETION 401
`might occur in some individuals. The question has been raised whether this decrease
`in intragastric acidity leads to a clinically relevant decrease of peptic activity."
`We have performed serial determinations of total protein concentration in
`serum before and during prolonged omeprazole therapy (Fig. I). Though plasma
`proteins consist of numerous different components, many of which are largely
`independent of protein intake, the major constituent of plasma proteins is albumin
`which accounts for almost two-thirds of total protein concentration. Adequate
`protein absorption is the major prerequisite in order to maintain a constant serum
`albumin level-apart
`from undisturbed hepatic albumin synthesis and in the
`absence of renal or intestinal albumin losses. In cases of protein malabsorption,
`hypoproteinaemia will develop. Results from measurements of serum protein con-
`centration during long-term omeprazole administration did not reveal any changes
`even after therapy for several years. Since hypoproteinaemia is not a common
`feature in chronic atrophic gastritis (pernicious anaemia) either, intestinal proteo-
`lytic activity deriving from the exocrine pancreas must compensate for any decrease
`of gastric proteolysis. Thus, protein malabsorption is very unlikely to occur even
`during long-term treatment with proton pump inhibitors.
`
`C 0 B AL A M I N A B S 0 , R P T I 0 N
`Under normal circumstances, vitamin B,, is freed from dietary sources (predomin-
`antly apoenzymes) under the action of gastric acid whereas pepsin secretion does
`not appear to play a major r01e.I~ In the stomach cobalamin binds to salivary R
`protein; at acidic pH the affinity of cobalamin to R protein is much greater than to
`intrinsic factor predominantly (about 50 times higher at pH 2)." Cobalamin is
`transferred from R protein to intrinsic factor in the proximal small bowel after the R
`protein is degraded by pancreatic proteases."
`Complete absence of gastric acid may lead to inefficient extraction of cobalamin
`from food, despite sufficient intrinsic factor secretion and unaltered absorption of
`crystalline vitamin B,,." This observation has to be attributed to achlorhydria
`It has been demonstrated that inhibition of acid secretion by H,-receptor
`itself."#
`antagonists decreases absorption of protein-bound c ~ b a l a m i n , ~ ~ ~ ~ ~
`even though
`intrinsic factor secretion is only slightly diminished. However, any clinically rel-
`evant vitamin B,, deficiency or even megaloblastic anaemia has not been reported
`in patients on maintenance treatment with H,-receptor antagonists. This may be
`due to the usual nocturnal administration of H,-blockers which leaves acid secretion
`undisturbed over the day.
`Somewhat different conditions apply for continuous omeprazole therapy since
`acid secretion is decreased more efficiently and acid suppression persists for the
`whole 24-h period. This constant decrease in intragastric acidity resembles that
`found after vagotomy, and cobalamin deficiency is known to develop in some
`patients after vagotomy.26 Like H,-receptor antagonists, omeprazole decreases
`absorption of food-bound ~obalamin,'~ while intrinsic factor secretion is not affected
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`402 H.KOOP
`
`500 r
`
`n - 4
`
`12
`
`14
`
`16
`
`13
`
`I1
`
`I I
`
`7
`
`6
`
`12
`
`24
`36
`18
`Months of omeprazole therapy
`
`30
`
`42
`
`48
`
`*: P(O.05 vs. 12,18 and 24 months
`* *
`
`: P<0.05 vs. 24 months
`Figure 2. Effect of prolonged omeprazole therapy on serum concentrations of vitamin B,, (medians)
`in 34 patients with H,-blocker resistant peptic diseases. Measurements were carried out during
`continuous omeprazole therapy; however, data from pre-treatment values were not available. The
`numbers placed above the columns indicate the number of individual observations. The dotted line
`indicates the lower limit of normal.
`
`by the proton pump inhibitor due to its specific mode of action.8 Data from long-
`term therapy with omeprazole (Fig. 2) indicate that serum vitamin B,, concentration
`remains constant within the initial 3 years of treatment.” However, significant
`decreases of serum cobalamin level developed after more extended periods of
`therapy (Fig. 2); circulating vitamin B,, concentrations showed a subtle downward
`trend during therapy and were found to be diminished significantly after more than
`3 years of therapy. The observation that serum cobalamin remained in the normal
`range in all cases is probably due to large cobalamin stores which are able to
`maintain normal serum levels for several yearsz9 despite diminished vitamin B,,
`absorption. Data from larger populations and periods of 5-10 years duration are
`mandatory to clarify whether clinically relevant vitamin B,, malabsorption
`develops. From the practical point of view, regular determination of serum cobala-
`min concentration is recommended in patients undergoing prolonged omeprazole
`therapy.
`
`I R O N A B S O R P T I O N
`Gastric acid is an important factor for iron absorption : HC1 facilitates transformation
`of trivalent ferric iron to soluble bivalent ferrous iron3’ and prevents formation of
`insoluble iron complexes of non-haem iron ;31 such insoluble iron complexes (mak-
`ing up about 90% of dietary iron in the western world) are poorly ab~orbed.~’ O n
`the other hand, absorption of haem-iron (present predominantly in meat) is largely
`undisturbed in the absence of gastric
`Along with observations that gastric
`resection, vagotomy, and severe atrophic gastritis3’. 33-35 may lead to iron deficiency
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`METABOLIC CONSEQUENCES OF ACID SECRETION 403
`
`"
`
`6
`
`12
`
`30
`18
`24
`Months of omeprazole therapy
`Figure 3. Serum ferritin levels (medians) during long-term administration of omeprazole in 34
`patients with H,-blocker refractory peptic diseases. The numbers placed above the columns indicate
`the number of individual observations at those time intervals. The dotted line indicates the lower
`limit of normal.
`
`36
`
`42
`
`48
`
`(particularly when associated with diets containing little meat), drug-induced in-
`hibition of acid secretion may also have some impact on iron absorption.
`
`Slight inhibition of iron absorption by the H,-blocker ~ i m e t i d i n e ~ ~ is without
`clinical relevance. However, it has been suggested that more profound inhibition of
`
`gastric acidity induced by omeprazole may cause iron malab~orption.~~ In rat
`experiments, iron deficiency developed within a short period of time during
`omeprazole administration (given in doses to mimick the extent of acid suppression
`in humans) while the animals were maintained on a low-iron diet whereas in rats
`exposed to a normal iron-containing diet, iron absorption was affected.38 Recent
`findings in man" show that iron malabsorption might not be anticipated at least
`within the initial years of continuous omeprazole treatment (Fig. 3 ) : serum iron and
`ferritin levels (the latter of which served as a marker for iron stores) remained
`largely within the normal range up to 4 years of treatment. Slightly decreased
`serum iron Ievels were observed in very few patients, but there was no evidence
`that these changes were related to omeprazole therapy.28 Undisturbed iron homeo-
`stasis during omeprazole therapy may have two major reasons : first, omeprazole
`at doses administered in clinical practice does not induce complete achlorhydria in
`most patients ; second, dietary iron sources less dependent on low intragastric
`acidity (such as haem-iron in meat) seem to provide sufficient amounts of iron
`maintaining normal iron and ferritin levels. However, particular care should be taken
`in patients with an increased iron demand (for example, menstruating women) while
`on long-term omeprazole.
`
`CALCIUM A B S O R P T I O N
`Absorption of calcium is a complex process and dependent on a number of different
`factors such as dietary calcium content, solubility of calcium ions, dietary fibre
`content, vitamin D, etc. (for review see Ref. 39). One of these factors is thought to
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`404 H.KOOP
`be gastric acid since acidic pH seems to increase the solubility of calcium complexes :
`relatively insoluble calcium salts (for example, CaCO,) are transformed to more
`soluble CaC1,. There are conflicting reports in the literature as to whether calcium
`absorption is decreased in achlorhydria. Diminished calcium absorption has been
`demonstrated by isotope techniques, both in anima1 experiments4' and in achlor-
`hydric patient^.^' Undisturbed calcium uptake after pre-treatment with a single
`dose of 600 mg cimetidine reported by B ~ - L i n n ~ ~ may have been due-at
`least in
`part-to
`the experimental conditions : the authors employed a lavage which may
`have dissolved some calcium thus permitting calcium absorption independent of
`changes in intragastric pH.43
`Low gastric HCl secretion may be of importance for calcium uptake for another
`reason: with rising intragastric pH, calcium increasingly binds to fibre44 and other
`
`constituents of plant sources (for example, p h y t a t e ~ ) . ~ ~ , ~ ~ Such mechanisms may
`also contribute to changes in the bioavailability of calcium during prolonged proton
`pump inhibition.
`Metabolic bone disease developing in patients following gastric
`47
`supports the concept that low gastric acidity may play some role in this process.
`The exact mechanism is far from clear, but a common laboratory finding is a reduced
`serum calcium c o n c e n t r a t i ~ n . ~ ~ ~
`47f Therefore, serum calcium concentrations have
`been measured in patients before and under long-term therapy with omeprazole
`(Fig. I). The data clearly show that calcium concentrations remain constant through-
`out several years of omeprazole therapy. Though serum concentrations of calcium
`may be a somewhat insensitive parameter for changes in calcium metabolism, in
`case of putative reduction of calcium absorption some diminuation of serum calcium
`levels would have been expected as found after gastric surgery. Thus, there is no
`evidence at present that long-term inhibition of gastric acid by omeprazole has any
`deleterious effect on calcium homeostasis.
`
`CONSEQUENCES F O R CLINICAL PRACTICE
`Since omeprazole has been established as an effective and safe drug for acute
`treatment of acid-peptic diseases, increasing attention, has focused on possible side
`effects of long-term proton pump inhibition-since
`there is significant demand for
`maintenance treatment particularly in reflux oesophagitis. Possible side-effects
`which are presently under debate include alterations of vitamin homeostasis and
`diminished absorption of minerals. Data available so far suggest that cobalamin
`stores slightly decrease after several years of omeprazole treatment; whether this
`will lead to clinically relevant symptoms remains to be elucidated. Consequently,
`patients undergoing omeprazole therapy for several years should be carefully
`monitored for plasma vitamin B,, as should be those with an increased iron demand
`by determinations of serum ferritin and iron concentrations. In the immediate future,
`more data should be collected from larger series and extended periods using more
`sensitive methods to confirm or refute the low metabolic risk of prolonged proton
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`METABOLIC CONSEQUENCES OF ACID SECRETION 405
`pump inhibition. However, available experience justifies long-term omeprazole
`treatment at the present time in patients for whom alternative forms of therapy are
`not effective and/or not applicable.
`
`ACKNOWLEDGEMENT
`Investigations performed by the author were supported by the Deutsche For-
`schungsgemeinschaft, grant KO 847/1-4.
`
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