bias in the reporting of cancer risk of Barrett’s esophagus?Gastroenterology 2000;119:333–8.

6. Eckardt VF, Kanzler G, Benhard G. Life expectancy andcancer risk in patients with Barrett’s esophagus: A prospectivecontrolled investigation. Am J Med 2001;111:33–7.

7. Buttar NS, Wang KK, Sebo TJ, et al. Extent of high-gradedysplasia in Barrett’s esophagus correlates with risk of ade-nocarcinoma. Gastroenterology 2001;120:1630–9.

8. Nigro JJ, Haen JA, DeMeester TR, et al. Occult esophagealadenocarcinoma. Extent of disease and implications for effec-tive therapy. Ann Surg 1999;230:433–40.

9. Reid B, Levine D, Longton G, et al. Predictors of progressionto cancer in Barrett’s esophagus: Baseline histology and flowcytometry identify low and high risk patient subsets. Am JGastroenterol 2000;95:1669–76.

10. Reid B, Prevo L, Galipeau P, et al. Predictors of progressionin Barrett’s esophagus II: Baseline 17p (p53) loss of heterozy-gosity identifies a patient subset at increased risk for neoplasticprogression. Am J Gastroenterol 2001;96:2839–48.

11. Bani-Hani K, Martin IG, Hardie LJ, et al. Prospective study ofcyclin D1 overexpression in Barrett’s esophagus: Associationwith increased risk of adenocarcinoma. J Natl Cancer Inst2000;29:1316–21.

Reprint requests and correspondence: Richard E. Sampliner,M.D., Southern Arizona VA Health Care System, Department ofGastroenterology (111G-1), 3601 South 6th Avenue, Tuscon, AZ85723.

Received May 19, 2003; accepted June 5, 2003.

Therapy for Gastroesophageal RefluxDisease: More Is Not NecessarilyBetterGastroesophageal reflux disease (GERD) is a condition ofsignificant importance because it is exceedingly common,with 27 million Americans reporting symptoms occurringweekly and 13 million reporting symptoms daily (1). Anti-secretory therapy with proton pump inhibitors (PPIs) ismore effective than H2-receptor antagonist (H2RA) therapyfor both erosive and nonerosive disease (2, 3). However,most patients with GERD need long-term maintenancetreatment, which is expensive. Studies in patients with ero-sive esophagitis reveal that once-daily maintenance PPItherapy is effective in maintaining remission in most pa-tients (4), but some require higher-dose therapy. The pro-portion of patients with lesser degrees of GERD (i.e., non-erosive disease) requiring twice-daily therapy has not beenwell defined because population-based studies (5, 6) thatrecruit patients on the basis of symptoms alone generally donot include endoscopic assessment. Because maintenancePPI therapy is both safe and effective, initial therapy withoral PPIs is now generally accepted as the diagnostic (andtherapeutic) strategy of choice in young patients withouttrigger symptoms (i.e., without bleeding, anemia, dyspha-gia, or weight loss) (7, 8), and dose escalation in patientswith persistent foregut symptoms is commonly used inclinical practice to limit endoscopic resource utilization.

In this issue of the Journal, Inadomi et al. (from the VAAnn Arbor Healthcare System) report prospectively reduc-ing maintenance antisecretory therapy doses in 117 patientswith reflux-related symptoms (primarily heartburn and re-gurgitation) who were asymptomatic on twice-daily PPItherapy, under carefully controlled conditions (5). Aboutthree fourths of the study cohort (84/117 patients) hadpreviously been endoscoped, and only four patients (3%)had ever undergone ambulatory pH monitoring. Forty-sevenpatients were started on twice-daily therapy initially,whereas 70 had previously undergone a dose increase, pre-sumably for poor symptom control. The authors found that93 patients (79.5%) were over-treated: they remained symp-tom free 6 months after stepping down to once-daily ther-apy, and this includes 16 patients who had previously failedprior attempted dose reduction under less stringently con-trolled circumstances. In addition, logistic regression anal-ysis revealed that patients exposed to twice-daily PPI ther-apy for longer periods of time were less likely tosuccessfully reduce their maintenance therapy to once-dailydrug. The authors explain that the current study was anextension of their previously published work in a similarstudy population examining the utility of drug class reduc-tion (i.e., from maintenance PPI therapy to H2RA therapy)(6). The results of their initial study also demonstrated thata significant proportion of patients with reflux-like symp-toms were over-treated.

This study has at least two findings of potential impor-tance that should be examined in more detail. First, manypatients with heartburn and regurgitation might be receivinghigher doses of maintenance therapy than they actuallyneed—a finding with potentially significant economic im-plications. Taken at face value, the data from this (5) and thesame group’s prior study (6) suggest that GERD is easilymanaged in many patients without the need for high-dose,potent antisecretory therapy (i.e., PPIs). On the other hand,maintenance-of-remission studies in patients with erosiveesophagitis reveal that maintenance and healing doses forpatients with erosive disease do not differ significantly (4,9), and PPIs invariably outperform H2RAs for both healingand maintenance (2, 3, 9). Moreover, another population-based, randomized, double-blind, switchover study de-signed to compare step-down (i.e., PPI to H2RA), step-up(i.e., H2RA to PPI), and step-in (i.e., PPI to PPI) strategiesfor maintenance therapy in heartburn patients presenting toprimary care physicians identified step-in therapy as thepreferred management strategy (10).

How does one explain the apparently discrepant resultsfrom these studies? The simple answer might be that erosiveand nonerosive reflux diseases are two different conditionswith different therapeutic requirements. In support of thisargument, we know that the vast majority of heartburnpatients have normal upper endoscopic findings (3, 11); thissuggests that population-based, nonendoscopic study popu-lations contain primarily nonerosive patients. Moreover, it isalso well known that patients with erosive disease have

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more profound disruption of the gastroesophageal barrierwith longer esophageal acid exposure times than do theircounterparts with nonerosive disease (12). An alternativeand not mutually exclusive explanation is that population-based reflux trials are often contaminated by patients withother foregut syndromes (e.g., functional dyspepsia or pep-tic ulcer disease) that respond well to intermittent therapywith less potent antisecretory regimens. It should be pointedout that only four patients in the current study (5) hadpreviously undergone 24-h pH-metry (arguably the bestgold standard for diagnosing reflux disease), only threefourths had undergone endoscopy, and the results of thesestudies were not provided in the article. Although we like toteach that dyspepsia and reflux are easily distinguished onclinical grounds (i.e., the former is characterized by inter-mittent episodes of epigastric pain that wax and wane andusually, but not always, occur after meals, whereas the latteris characterized by a predictable retrosternal burning sensa-tion that rises up into the chest after inciting meals), thisdistinction might not always be made easily in clinicalpractice, and inaccurate categorization and/or overlap syn-dromes might occur frequently (13). Finally, it is also im-portant to note that many of the patients in the current study(5) were started on double-dose PPI therapy without priordocumentation of failure on lower-dose therapy, whereasothers were previously stepped up to twice-daily therapy forongoing symptoms without prior 24-h pH-metric documen-tation of therapeutic failure at the initial dose. Because theplacebo response rate for non-GERD foregut disease statesmight be as high as 80% (14), one cannot be sure that theresponse to high-dose therapy (whether preceded by failureto respond to a lower dose or not) was a consequence of thetherapy itself. Thus, although I agree with the general con-clusions in the current study (5), I believe it important topoint out that these data refer to a population-based study ofreflux-like symptom patients, most of whom are likely ero-sion free, many of whom were empirically over-treated tostart with, and at least some of whom might not have hadtrue GERD. These comments notwithstanding, I fully sup-port the authors contention that over-treatment of patientswith foregut symptoms is unnecessarily expensive.

The second finding of potential importance in the currentstudy is that PPI dependence increases with increasing du-ration of therapy (5). This finding has potentially profoundpathophysiological implications. The presumed mechanismby which this develops is that prolonged and profoundinhibition of gastric acid secretion interferes with the normalfeedback control of gastric acid production leading to G-cellhyperplasia, hypergastrinemia (15), enterochromaffin-like(ECL)-cell hyperplasia, and excessive histamine stimulationof parietal cells. These effects in combination lead to anincrease in the parietal cell mass and the potential forrebound hypersecretion on drug withdrawal. However, tol-erance does not develop during maintenance therapy (4)because PPIs concentrate in the secretory canaliculus and

are delivered to their active site at concentrations sufficientto maintain efficacy.

Physicians are generally comfortable prescribing high-dose PPI maintenance regimens for patients with GERDbecause they know the therapy works, and they believe it tobe safe as well. Long-term studies in patients with bothGERD (4) and Zollinger-Ellison Syndrome (16), have dem-onstrated virtually no risks for such an approach, and tachy-phylaxis is not felt to be a concern either. On the other hand,there are now a number of studies suggesting that prolongedand profound acid suppression predisposes to PPI-depen-dence and rebound gastric acid hypersecretion on with-drawal (17–19). For example, abrupt withdrawal of therapyin 14 patients with erosive reflux disease maintained on20–60 mg of omeprazole daily for up to 6 months led torecurrent reflux symptoms in 50% within 24 h and in 100%at 10 days, by which time erosive disease had recurred in allpatients and drug-induced hypergastrinemia resolved (17).A second study demonstrated significant increases in ECL-cell mass and acid secretory parameters after withdrawal ofPPI therapy in nine patients treated with 40 mg of omepra-zole daily for 90 days (18). A third study demonstrated thatwithdrawal of oral PPI therapy in patients with a history oferosive esophagitis leads to partial recovery of acid secre-tory capabilities within 24 h and complete loss of efficacywithin 7 days, in comparison with effective maintenance ofacid secretory inhibition in patients whose oral therapy isswitched for i.v. therapy at the same dose (19). An addi-tional study in patients with Barrett’s esophagus who re-ceived high-dose PPI therapy for prolonged periods devel-oped significant gastric acid hypersecretion on withdrawalin association with documented increases in oxyntic muco-sal thickness on gastric biopsy (Weinstein WM, personalcommunication, 1999). Finally, the current study (5)showed an inverse association between the likelihood ofsuccessful dose reduction and the duration of high-dose PPItherapy.

Taken together, the above studies suggest that it might beimportant to use the lowest effective dose of PPI therapy forpatients with reflux symptoms and that this dose should besought early in the treatment process. There is, in fact,precedent for every-other-day PPI therapy in patients withdocumented GERD (20). Furthermore, abrupt withdrawal oforal maintenance PPI therapy in hospitalized patients whocannot take oral agents might predispose to recurrent symp-toms and possibly complications; this supports switching toan i.v. PPI dosage form to prevent rebound gastric acidhypersecretion in this population (19). Finally, in the eventthat one desires to withdraw maintenance PPI therapy in agiven individual (e.g., after a failed empiric trial of twice-daily PPI therapy for presumed supraesophageal GERD), itmight be important to wean therapy slowly over a number ofmonths rather than stopping therapy abruptly, to avoid therisk of inducing acid-peptic disease. The rate at which towean therapy can only be guessed from studies in patientswith Zollinger-Ellison Syndrome (21), in whom acid secre-

1914 Editorials AJG – Vol. 98, No. 9, 2003

tory parameters stabilized within 3–6 months, because thereare no data evaluating reversal in patients treated previouslywith PPIs.

David C. Metz, M.D.Division of Gastroenterology

University of Pennsylvania Health SystemPhiladelphia, Pennsylvania

REFERENCES

1. The Gallup Organization. Survey on heartburn across Amer-ica, 1998. Princeton, NJ: The Gallup Organization, 1998.

2. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed ofhealing and symptom relief in grade II to IV gastroesophagealreflux disease: A meta-analysis. Gastroenterology 1997;112:1798–810.

3. Richter JE, Campbell DR, Kahrilas PJ, et al. Lansoprazolecompared with ranitidine for the treatment of nonerosive gas-troesophageal reflux disease. Arch Intern Med2000;160:1803–9.

4. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term ome-prazole treatment in resistant gastroesophageal reflux disease:Efficacy, safety, and influence on gastric mucosa. Gastroen-terology 2000;118:661–9.

5. Inadomi JM, McIntyre L, Bernard L. Step-down from multi-ple- to single-dose proton pump inhibitors (PPIs): A prospec-tive study of patients with heartburn or acid regurgitationcompletely relieved with PPIs. Am J Gastroenterol 2003;98:1940–1944.

6. Inadomi JM, Jamal R, Murata GH, et al. Step-down manage-ment of gastroesophageal reflux disease. Gastroenterology2001;121:1095–100.

7. Fass R, Ofman JJ, Sampliner RE, et al. The omeprazole test isas sensitive as 24-h oesophageal pH monitoring in diagnosinggastro-oesophageal reflux disease in symptomatic patientswith erosive oesophagitis. Aliment Pharmacol Ther 2000;14:389–96.

8. Johnsson F, Weywadt L, Solhaug JH, et al. One-week ome-prazole treatment in the diagnosis of gastro-oesophageal refluxdisease. Scand J Gastroenterol 1998;33:15–20.

9. Metz DC, Bochenek WJ and the Pantoprazole US StudyGroup. Pantoprazole maintenance therapy prevents relapse oferosive esophagitis. Aliment Pharmacol Ther 2003;17:155–64.

10. Howden CW, Henning JM, Huang B, et al. Management ofheartburn in a large, randomized, community-based study:Comparison of four therapeutic strategies. Am J Gastroenterol2001;96:1704–10.

11. Fass R, Fennerty MB, Vakil N. Nonerosive reflux disease—current concepts and dilemmas. Am J Gastroenterol 2001;96:303–14.

12. Jones MP, Sloan SS, Rabine JC, et al. Hiatal hernia size is thedominant determinant of esophagitis presence and severity ingastroesophageal reflux disease. Am J Gastroenterol 2001;96:1711–7.

13. Bytzer P, Talley NJ. Dyspepsia. Ann Int Med 2001;134:815–22.

14. Mearin F, Balbao A, Zarate N, et al. Placebo in functionaldyspepsia: Symptomatic, gastrointestinal motor, and gastricsensorial responses. Am J Gastroenterol 1999;94:116–25.

15. Klinkenberg-Knol EC, Festen HP, Jansen JB, et al. Long-termtreatment with omeprazole for refractory reflux esophagitis:Efficacy and safety. Ann Intern Med 1994;121:161–7.

16. Metz DC, Strader DB, Orbuch M, et al. Use of omeprazole in

Zollinger-Ellison syndrome: A prospective nine-year study ofefficacy and safety. Aliment Pharmacol Ther 1993;7:597–610.

17. Klinkenberg-Knol EC, Jansen JB, Lamers CB, et al. Tempo-rary cessation of long-term maintenance treatment with ome-prazole in patients with H2-receptor-antagonist-resistant re-flux oesophagitis. Effects on symptoms, endoscopy, serumgastrin, and gastric acid output. Scand J Gastroenterol 1990;25:1144–50.

18. Waldum HL, Arnestad JS, Brenna E, et al. Marked increase ingastric acid secretory capacity after omeprazole treatment. Gut1996;39:649–53.

19. Metz DC, Pratha V, Martin P, et al. Oral and intravenousdosage forms of pantoprazole are equivalent in their ability tosuppress gastric acid secretion in patients with gastroesopha-geal reflux disease. Am J Gastroenterol 2000;95:626–33.

20. Bieszk N, Kale-Pradhan PB. The efficacy of extended-intervaldosing of omeprazole in keeping gastroesophageal reflux dis-ease patients symptom free. Ann Pharmacother 1999;33:638–41.

21. Pisegna JR, Norton JA, Slimak GG, et al. Effects of curativegastrinoma resection on gastric secretory function and antise-cretory drug requirements in Zollinger-Ellison syndrome. Gas-troenterology 1992;102:767–78.

Reprint requests and correspondence: David C Metz, M.D.,University of Pennsylvania, HUP, Division of Gastroenterology, 3Ravdin, 3400 Spruce Street, Philadelphia, PA 19104.

Received Apr. 16, 2003; accepted Apr. 29, 2003.

Nonalcoholic Fatty Liver Disease(NAFLD)—Two Decades Later: AreWe Smarter About Its NaturalHistory?In 1980, Ludwig and colleagues described nonalcoholicsteatohepatitis (NASH) in individuals whose liver biopsiesshowed findings similar to alcoholic hepatitis in the absenceof significant alcohol intake (1). More recently, investiga-tors have included simple steatosis and steatosis with non-specific inflammation together with NASH in the expandedspectrum of conditions that constitutes nonalcoholic fattyliver disease (NAFLD) (2, 3). The prevalence of NAFLDhas been estimated to be high and is expected to increasewith the epidemic of obesity in the United States.

In many early accounts, cirrhosis was observed in up to26% of subjects with NAFLD (1, 4). Additonally, NAFLDis thought to be a key precursor of cryptogenic cirrhosis (5,6) and has also been described as leading to hepatocellularcarcinoma (7, 8). A recent study reported that only 2.6% ofevaluations for liver transplantation were for end-stage liverdisease secondary to NASH (9). However, a large number ofpatients undergoing liver transplantation for cryptogeniccirrhosis might actually have “burned-out NASH.” The nat-ural history of NAFLD has been difficult to define becausemost studies have been retrospective, lacked systematicfollow-up data, or have involved small numbers of highlyselected subjects (e.g., abnormal liver enzymes, overweightor obese).

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