2010-04-12 17:49:55 UTC

First-Line PPI Therapy Masks Underlying Conditions

April 12, 2010

Kenneth E.L. McColl, MD, FRCP, FMedSci, FRSE

Kenneth E.L. McColl, MD, FRCP, FMedSci, FRSE

Professor of Gastroenterology, Cardiovascular and Medical Sciences, University of Glasgow, U.K.  


The proposition is that proton pump inhibitors (PPIs) should be prescribed as first-line therapy to patients with uninvestigated upper GI symptoms, whether predominantly retrosternal or epigastric in location. This practice is being increasingly widely employed, but is not without its potential disadvantages and pitfalls.

Firstly, we must always consider the possibility of upper GI symptoms being due to underlying malignancy. Patients should be asked about sinister symptoms, including dysphagia, weight loss, persistent vomiting or a strong family history of upper GI cancer. If any are present, then urgent endoscopy should be organized and undertaken before commencing PPI therapy. Even malignant ulcers may heal with PPIs, masking underlying malignancy and making it more difficult to detect at an early curable stage.

Secondly, though PPIs are highly effective at controlling acid-related diseases, they do not cure the underlying condition or improve its natural history. Indeed, the opportunity to address the root cause of the patient’s symptoms may be lost by the too early introduction of PPI therapy. This applies to both of the underlying upper GI disorders with symptoms responsive to PPI therapy, namely peptic ulcer disease and GERD.

Ulceration of the stomach or duodenum typically presents with upper GI symptoms. Though PPI therapy will produce healing of the ulcer and improvement of symptoms, it will not cure the underlying ulcer diathesis, and both the ulcer and symptoms will almost certainly recur when the PPI therapy is stopped or interrupted. In patients not taking NSAIDs, the most common cause of peptic ulcer disease is Helicobacter pylori (H. pylori) infection. Eradicating the infection will produce long-term cure of the ulcer disease and its associated symptoms. Commencing a patient with underlying peptic ulcer disease on PPI therapy at their initial presentation with upper GI symptoms and before any investigations are performed carries a risk of treating an eminently curable condition with long-term, unnecessary medication. Considering underlying H. pylori-related ulcer disease is particularly important in populations which have a substantial prevalence of H. pylori infection and in individuals with risk factors for ulcer disease such as male gender, smokers and family history.

There can be medico-legal implications of commencing a patient on empiric PPI therapy for epigastric pain if they subsequently present with an ulcer complication such as bleeding or perforation, and with possible fatal outcome. It may be reasonably argued that such an outcome could and would have been avoided if more consideration had been given to identify the nature of the underlying symptoms and appropriately treating the ulcer with H. pylori eradication therapy. I have personally been asked to provide expert legal evidence in several such cases.

The intention in first-line empiric PPI therapy for upper GI symptoms is often to determine whether the symptoms respond to such therapy and to later discontinue the therapy and perform more definitive investigations if the symptoms recur. However, in practice, once a patient is commenced on PPI therapy and enjoys the symptomatic benefit, they may well be reluctant to have further investigations or may simply be lost to appropriate follow-up. In addition, it is difficult to reliably determine a patient’s H. pylori status during or shortly after PPI therapy1 due to the medication suppressing H. pylori urease activity and also the density of H. pylori colonization. In addition, PPI therapy may mask ulcer disease. In such situations, I would suggest that first-line empiric PPI therapy is inappropriate and non-invasive H. pylori testing and treatment, or endoscopy, should be employed. In addition, if acid suppressive medication is considered necessary in first presentation, then antacids and H2 receptor antagonists are more appropriate, as they are quicker in relieving symptoms than PPIs.

The other underlying disorder in which PPI therapy produces symptomatic relief is GERD. However, again, one must consider the fact that early prescribing of PPI therapy may miss the opportunity to address and modify the underlying disease process. There is increasing evidence that central obesity is important in the etiology of GERD and its complications. Though the effect of weight reduction has not been adequately studied to date, it would seem appropriate to advise patients about the strong association and encourage them to take appropriate measures. Various dietary habits are also associated with GERD symptoms, including high fat intake, ingestion of large meals late in the evening and smoking; these lifestyle factors should also be addressed. Lifestyle therapy should be first-line therapy rather than PPI therapy.

The increasing readiness to prescribe PPIs on first presentation with GI symptoms means that an increasing proportion of patients taking PPI therapy are receiving them unnecessarily.2 Approximately 50 percent of upper GI symptoms are of the functional subtype and do not respond to acid inhibition. This would not be a problem if one could determine reliably whether PPI therapy was actually benefiting the patient’s symptoms. However, it is surprisingly difficult to determine whether a patient’s symptoms are acid-related by assessing their response to PPI therapy.3 The PPI test has poor sensitivity and specificity. The main way patients often decide whether PPIs are actually helping them or not is by seeing whether their symptoms return when they stop the therapy. However, stopping PPI therapy is associated with rebound acid hypersecretion, and it has now been clearly shown that this results in rebound symptoms, even in healthy volunteers who have never previously experienced upper GI symptoms.4,5 This means that patients commenced on PPI therapy may think they need long-term treatment and remain on such therapy even though there was no original indication for it.

For the reasons discussed above, it is likely that early empiric PPI therapy may result in many patients receiving long-term, unnecessary PPI therapy. Such treatment may be unnecessary either due to missing ways of curing the disease by either H. pylori eradication therapy or modifications of lifestyle, or due to the treatment itself inducing symptoms in a patient whose symptoms were originally unrelated to acid.

Apart from the cost and inconvenience of long-term unnecessary therapy, there are increasing concerns about side effects associated with such treatment. The problem of rebound acid hypersecretion has already been discussed. Elevation of intra-gastric pH also makes patients more susceptible to enteric infection and possibly chest infections.6 There is some concern about the possible association with osteoporosis, and of course, some of the PPIs may interact with other medication, e.g., by reducing the efficacy of clopidrogel.6, 7 As with most drugs, the list of side effects is increasing with longer and wider use of the medication.

We live in the age of economic analysis, modeling and guidelines. A number of international guidelines have encouraged early empiric PPI therapy for upper GI symptoms. The evidence used for such advice comes from comparing large groups treated with empiric PPI therapy versus other management strategies. However, though the mean outcome for one group may be superior with one treatment, this does not mean that it is the more appropriate treatment for each individual in the group. The increased use of guidelines has encouraged treating everyone the same — a “one size fits all” mentality. There is still a need to consider what is likely to be the best management for the individual consulting you, and to recognize that it may be different from the latest guideline. It is also important to recognize that guidelines are often based on short-term outcome and may not be relevant in the longer term. One-year outcome is of little relevance in the management of chronic disorders such as peptic ulcer or GERD.

We must resist the increasing trend of reflex prescribing of PPI therapy to patients presenting with uninvestigated upper GI symptoms. We need to return to more rational and thoughtful management. It is important to determine the best management for each individual patient considering both short-term and long-term consequences.


  1. Chey W D, Woods M, Scheiman J M, Nostrant T T, DelValle J. Lansoprazole and ranitidine affect the accuracy of the 14C-urea breath test by a pH-dependent mechanism. Am J Gastroenterol 1997; 92: No. 3: 446-450.
  2. Raghunath A S, O’Morain C, McLoughlin R C. Review article: the long-term use of proton pump inhibitors. Aliment Pharmacol Ther 2005; 22(suppl. 1): 55-63.
  3. Gaisorowska A, Fass R. The proton pump inhibitor (PPI) test in GERD – Does it still have a role? J Clin Gastroenterol 2008; 42: 8: 867-874.
  4. Gillen D, Wirz A A, Ardill J E, McColl K E L. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999; 116: 239-247.
  5. Reimer C, Songergaard B, Hilsted L, Bytzer P. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137: 80-87.
  6. Dial M S. Proton pump inhibitor use and enteric infections. Am J Gastroenterol 2009; 104: S10-S16.
  7. Laine L. Proton pump inhibitors and bone fractures? Am J Gastroenterol 2009; 104: S21-S26.

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