Fat maldigestion with steatorrhoea is the main problem in the management of exocrine pancreatic insufficiency (EPI).1 When uncoated pancreatic enzyme extracts are used for therapy, inhibition of gastric acid secretion is frequently needed to avoid acid mediated lipase inactivation.2,3,4 Modern pancreatic enzyme preparations in the form of enteric coated mini‐microspheres were developed to avoid this problem but fat maldigestion still persists in a relevant proportion of patients with this therapy. Patients with EPI frequently have low pancreatic bicarbonate secretion which may become insufficient to neutralise the acidity of the chyme emptied from the stomach.5 Bile acids precipitate at acidic pH, and lipase is only released from coated spheres once the pH is higher than 5.0, which occurs in distal segments of the gut in some EPI patients.6,7
We hypothesise that potent inhibition of gastric acid secretion, by avoiding bile acid precipitation and allowing lipase release within the proximal gut, may improve the therapeutic efficacy of enteric coated pancreatic enzymes for EPI. To test this hypothesis, a prospective, consecutive, open, comparative study was carried out.
According to previous sample size calculation, 21 consecutive patients (age range 36–76 years, 16 males) newly diagnosed with fat maldigestion secondary to severe alcohol related chronic pancreatitis, were included. Severe chronic pancreatitis was confirmed by magnetic resonance pancreatography and endoscopic ultrasound. All patients had steatorrhoea with a daily fat excretion of 19.2 (10.3) g.
Patients were treated with oral pancreatic enzyme supplements in the form of capsules containing enteric coated mini‐microspheres (Creon 10 000; Solvay Pharmaceuticals, Hannover, Germany) for three months. Four capsules were administered together with each of the three main daily meals (40 000 Eur Ph U lipase per meal), according to previously described protocols.8 Esomeprazole 40 mg (Nexium; AstraZeneca, Sweden) was then added as a single daily dose before breakfast for a further 14 days. The study was conducted in accordance with the current guidelines of good clinical practice.
Fat digestion was evaluated on the day before starting pancreatic enzyme therapy (basal), on the last day of the three month period of pancreatic enzyme monotherapy, and on the last day of the 14 day period of combined enzyme‐proton pump inhibitor (PPI) therapy by means of a previously optimised, standardised, and validated 13C‐mixed triglyceride (13C‐MTG) breath test.8,9,10 Except for the basal test, four capsules of pancreatic enzymes were taken together with the test meal. In addition, esomeprazole 40 mg was given orally 30 minutes before the test meal on the last study day. Breath samples were collected at 15 minute intervals for six hours and the global cumulative recovery rate of 13CO2 (13CO2‐CRR) was considered the result of the test. Based on previous studies, a 13CO2‐CRR higher than 58% was considered normal.8,9
Basal 13CO2‐CRR was 22.6% (95% confidence interval (CI) 0–55.5%). Therapy with oral pancreatic enzymes increased 13CO2‐CRR to 61.0% (95% CI 37.9–100%) (p<0.001 compared with basal). Addition of esomeprazole 40 mg daily to pancreatic enzyme substitution therapy further increased 13CO2‐CRR to 69.4% (95% CI 47.4–100%) (NS compared with enzyme monotherapy) (fig 1).
Figure 1 Results of the 13C mixed triglyceride breath test before (basal) and during therapy with exogenous pancreatic enzymes alone and associated with esomeprazole (PPI). The lower limit of normal of the test is shown as a broken horizontal line. Individual data for patients with an adequate response to enzyme monotherapy and those with an incomplete response to this therapy are shown. Bars represent 95% confidence interval.
In 57% of patients, fat digestion normalised (normal 13C‐MTG breath test result) with pancreatic enzyme substitution therapy. In this group of patients, association of esomeprazole did not further improve fat digestion (fig 1). In the 43% of patients with persisting fat maldigestion despite pancreatic enzyme therapy, addition of esomeprazole led to an absolute improvement in fat digestion of 14.3% (95% CI 3.4–47.6%) (fig 1); 67% (29% of total) normalised fat digestion. Fat maldigestion persisted in 14% of patients despite combined therapy with esomeprazole and pancreatic enzyme supplements.
The present study demonstrates the existence of two different populations of patients with EPI regarding response to enteric coated enzyme substitution therapy. More than half of patients respond properly to this therapy and fat digestion is normalised. This may be explained by preserved pancreatic bicarbonate secretion and/or reduced gastric acid secretion. On the other hand, less than half of patients show an insufficient response to enteric coated enzyme therapy, the efficacy of which improves significantly with the addition of a potent inhibitor of gastric acid secretion. These patients most probably have normal or increased gastric acid secretion together with insufficient secretion of pancreatic bicarbonate to neutralise the acidic pH of chyme.
In conclusion, addition of a PPI leads to a significant improvement and even normalisation of fat digestion in patients with EPI and an incomplete response to enzyme substitution therapy. However, patients with an adequate response to enzyme substitution therapy do not profit from additional PPI.
Acknowledgement
This study was supported by a grant from the Health Institute Carlos III, Spanish Ministry of Health, reference No G03/156.
Footnotes
Conflict of interest: None declared.
References
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