Gastroesophageal reflux disease is associated with enteric hormone abnormalities

Castroesophageal Reflux Disease Is Associated With Enteric Hormone Abnormalities Galen Perdikis, MD, Paul Wilson, FRcsnd, Ronald A. Hinder, MD, PhD, Elizabeth J. Redmond, FRCS, Gerold J. Wetscher, MD, Shuji Saeki, MD, Thomas E. Adrian, PhD, MRCPath, Omaha, Nebraska

Rasal and postprandial levels of the foregut hormones gastrin, cholecystokinin (UK), motilin, and pancreatic polypeptide, and the distal gut hormones neurotensin and peptide YY were measured in 20 patients with gastroesophageal reflux disease (CERD) . GERD was defined by abnormal esophageal’ exposure to pH less than 4. Ten CERD patients had decreased lower esophageal sphincter (LES) pressure (mean: 4.5 mm Hg, range: 0.8 to 6.8 mm Hg), and 10 patients had normal LES pressures (mean: 14.1 mm Hg, range: 9.7 to 22.4 mm Hg) . Eight age-matched healthy subjects were also studied. Rasal levels of peptide YY were moderately decreased in GERD patients compared with controls irrespective of LES pressure. In patients with ahnormal LES pressure, hasal levels of motilin and the postprandial response of CCK were significantly decreased compared with controls; and basal levels of neurotensin and the postprandial respouse of gastrin were significantly increased compared with controls. Pancreatic polypeptide levels were similar in all groups. These gut hormone changes, which are more marked in patients with poor LES pressure, may reflect primary or secondary abnormalities in GERD.

he pathogenesis of gastroesophageal reflux is multiT factorial ,2]. Most patients with gastroesophageal reflux disease (GERD) are found to have an incompetent [I

lower esophageal sphincter (LES) with a combination of poor sphincter pressure, short intra-abdominal length, and short total sphincter length [3]; however, some patients with GERD have normal sphincter pressures. There is increasing evidence that GERD may be part of a more generalized foregut disorder. Gastric emptying has been shown on average to be slower in patients with GERD [4,5]. Duodenogastric reflux has been implicated in alkaline GERD and has been shown to be associated with altered gastric emptying, altered antroducdenal motility, and associated hormonal changes [6-101. Although esophagitis can impair esophageal motility, there is evidence that part of the impairment is a primary disorder, which may reflect a more generalized foregut motility disorder in these patients [II]. Gastrointestinal hormones have various effects on foregut motility. Furthermore, motor abnormalities are associated with changes in hormonal profiles. For example, low levels of motilin are seen in patients with idiopathic delayed gastric emptying [ZZ]; elevated peptide YY (PYY), neurotensin, and enteroglucagon levels accompany conditions associated with rapid intestinal transit and the postgastrectomy dumping syndrome [13-14; cholecystokinin (CCK) levels are ‘increased following gastrectomy [I7]; and alteredlevels of a number of hormones are seen in patients with primary duodenogastric reflux [6]. Several enteric hormones influence LES pressure. Motilin increases LES pressure [ 18-211, whereas neurotensin relaxes the sphincter [22,23]. CCK and gastrin, which were initially thought to be important in maintaining LES pressure, appear only to have significant effects at pharmacologic doses [24-271. Since GERD may be part of a more generalized motility disorder, we investigated the association of the disease with changes in circulating gastrointestinal hormones known to have motor effects on the foregut. PATIENTS AND METHODS Patient groups: Informed

From the Departments of Surgery (GP, PW, RAH, EJR, GJW, SS) and Biomedical Sciences (TEA). Creiahton Universitv School of Meditine, Omaha, Nebraska. Requests for reprints should be addressed to Thomas E. Adrian, PhD, MRCPath, Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68 178. Presented at the 34th Annual Meeting of The Society for Surgery of the Alimentary Tract, Boston, Massachusetts, May 17-19, 1993. I,

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written consent was ob tained from all subjects. The study was approved by the Institutional Review Board at Creighton University. The basal and postprandial plasma concentrations of the enteric hormones gastrin, CCK, motilin, pancreatic polypeptide (PP), neurotensin, and PYY were measured in the following groups of patients: 1) Normal controls: Eight healthy volunteers had a mean age of 54.6 years and a range of 46 to 66 years. There were four men and four women. 2) Gastroesophageal reflux patients: Twen-

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ty patients with symptoms of gastroesophageal reflux and abnormal esophageal exposure to pH less than 4 on 24hour pH monitoring (DeMeester score greater than 14.7) had a mean age of 52.9 years and a range of 28 to 77 years. There were 13 men and 7 women. Ten patients had abnormally low LES pressures (mean: 4.5 mm Hg, range: 0.8 to 6.8 mm Hg [mean age: 58.9 years, range: 36 to 77 years; 6 men and 4 women]). The other 10 patients had normal LES pressures (mean: 14.1 mm Hg, range: 9.7 to 22.4 mm Hg [mean age: 47.6 years, range: 28 to 73 years; 7 men and 3 women]). Esophagealmanometry: Stationary manometry was performed utilizing a live channel catheter and a lowcompliance, pneumohydraulic capillary infusion system (Amdorfer Medical Specialties, Greendale, WI) [3]. The LES pressure was measured in each channel as the difference between the gastric baseline and the pressure at the respiratory inversion point during the middle of the respiratory cycle. Data were recorded using a polygraph (Synectics, Irving, TX), which transferred the data to a IBM personal computer. The data were analyzed with the help of a commercially available software program (Polygram, Gastrosoft, Irving, TX). The mean of the pressures obtained from all five channels was recorded as the LES pressure. Blood collection:After the patients fasted overnight, blood specimens were drawn from an antecubital vein via an indwelling venous cannula. Three basal samples were obtained at 15minute intervals. The subjects then ingested a standardized meal consisting of two hard-boiled eggs, two slices of toast, 10 g of butter, 10 g of marmalade, and 200 mL of fresh orange juice. This standardized meal contained 22 g of fat, 66 g of carbohydrate, and 18 g of protein, for a total of 530 calories. Further blood samples were drawn following the meal at 15,30,60,120, and 180 minutes. Blood samples were collected in chilled tubes containing ethylene diamine tetraacetic acid (2 mg/mL) and aprotinin (400 KIU/mL, Sigma Chemical Co., St. Louis, MO). Samples were centrifuged at 3,000 rpm for 10 minutes. The plasma was decanted and stored at -80°C prior to radioimmunoassay. Radioimmunoassay technique: Plasma concentrations of gastrin, CCK, motilin, PP, neurotensin, and PYY were measured using specific and sensitive radioimmunoassays that have been previously described in detail [6,28,29]. Statisticalanalysis: Data are expressed as the mean f SEM. The mean basal level, the incremental integrated response (IIRtsc), and the total integrated response (TIRrsc) (Figure 1) for each hormone were compared between groups. The IIRtsc and TIRtss were calculated utilizing the trapezoidal method. Comparisons between normal controls and GERD patients were made using the Mann-Whitney test for non-parametric data. When comparing normal controls, GERD patients with normal LES pressures, and GERD patients with low LES pressures, the Kruskal-Wallis test for non-parametric data was used to take into account the multiple comparisons made. Correlations between LES pressure and hormone levels were made utilizing linear regression analysis. Dif-

pmol/l

,oo

80-

1

6040Total Integrated Response 20-

01-30

0

30

60

90

120

150 180

Minutes

40

20

i

I

Incremental Integrated Response

1 -1 -30

0

30

60

90

120 150 180

Minutes Flguo1.lkesegephsillustratehcwthspcsQwWalrwpcnses of gastrcintestinalhumcneswerecalcuiated.Thetctalyltegrated respcnseisderlvedfrcmlhetctalareaunderthecuwe.Ths incrementalinteg’atedrespcnseisderivedfrcmtheareaunder the cuve abcve basal levels.

ferences were regarded as significant if the two-tailed p value was <0.05.

RESULTS The basal plasma levels, IIRtm, and TIRtso for each hormone are shown in TablesI and II. F@re 2 graphically illustrates the release pattern for each hormone. The results of linear regression analysis are shown in Table III. Castrim Fasting levels, the IIRtsO, and the TIRtso for plasma gastrin were found to be similar between GERD patients as a whole group and the patients in the healthy control group. However, GERD patients with low LES pressure had a significantly increased IIRtsa compared with GERD patients with normal LES pressure (p = 0.03). CCK: The fasting plasma CCK concentrations were not different in GERD patients compared with controls. However, the postprandial response as measured by the IIRtsO was significantly decreased in GERD patients compared with controls (p = 0.02). GERD patients with low LES pressure had a significantly decreased IIRlss and TIRiso compared with controls (p = 0.01 and p = 0.04, respectively), but the postprandial CCK response in

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TABLE

I

Hormone Levels in Healthy Controls and Patients With Gastroesophageal RefluX DISSSSS (GERD) Group

Hormone

Mean Fasting

Mean IlRtso

Mean TlR~so

17.9 -c 2.9 20.9 r 4.2

2,141 + 616 4,211 + 1,288

5,358 +- 989 7,973 * 1,846

Gastrin

z%‘”

Cholecystokinin

Controls GERD

Motilin

%tbo’s

70.5 t 20.9 32.8 2 5.4

Pancreatic polypeptide

%Ys

24.2 & 3.1 23.2 + 5.3

Neurotensin

&%‘”

6.0 IT 2.0 9.9 2 2.0

777 + 212 747 r 156

1,859 + 434 2,537 +- 437

Peptide W

Controls GERD

13.9 f 1.1 9.0 2 1.1*

412 + 200 708 + 150

2,910 + 164 2,328 t 311

II&so = incremental

integrated

response;

TlRwo = total integrated

1.6 + 0.2 2.0 2 0.18

750 ? 88 482 + 87* -929 -468

1,040 + 70 838 r 79

* 1,970 + 358

11,760 + 2,329 12,271 f 5,254

8,437 ? 1,871 10,780 ? 2,076

12,802 +- 2,129 14,965 2 2,762

response.

*p <0.05.

TABLE

II

Hormones in Gastroesophageal Reflux Disease (GERD) Patients With Normal Lower Esophageal Sphincter (LES) Pressure and GERD Patients Wlth Low LES Pressure Compared With Healthy Controls Hormone

Mean Fasting

Mean TlRlso

2,141 2 616 1,219 2 145 7,204 + 2,235t

5,358 r 989 4,280 +- 713 11,686 t 3,289

750 I? 88 595 + 152 369 + 76*

1,040 -c 70 948 2 130 729 -’ 84*

Controls Normal LES Low LES

17.9 f 2.9 16.9 t 3.5 24.9 2 7.7

Cholecystokinin

Controls Normal LES Low LES

1.6 f 0.2 1.9 2 0.3 2.0 + 0.2

Motilin

Controls Normal LES Low LES

70.5 + 20.9 37.1 + 8.2 28.4 f 7.1 l

Pancreatic polypeptide

Controls Normal LES LOW LES

24.2 + 3.1 24.3 -+ 8.8 22.2 + 6.7

Neurotensin

Controls Normal LES Low LES

6.0 k 2.0 6.2 r 1 .O 13.7 2 3.7*t

777 -c 212 914 2 236 580 + 202

1,856 + 432 2,036 + 356 3,038 + 791

Peptide W

Controls Normal LES Low LES

13.9 t 1.1 9.1 + 1.2* 8.9 c 1.9’

412 t 200 756 + 205 658 ? 227

2,910 2 164 2,396 + 333 2,260 -t 544

are defined

-CO.05 compared

fp ~0.05 compared

* 1,970 2 445 t 584

11,760 of: 2,328 6,160 + 1,238 4,563 + 973*

8,437 2 1,871 9,274 r 2,364 12,287 + 3,479

12,802 f 2,129 13,648 2 3,442 16,283 f 4,472

-929 -438 -499

as shown In Table I.

with controls. with GERD patients with normal LES pressure.

GERD patients with normal LE!S pressure was not altered. Motiiin: The fasting plasma motilin levels and TIRisc were lower in GERD patients compared with controls, however, these differences just failed to reach statistical significance (p = 0.06 for both comparisons). The IIRis for motilin was similar for both patient groups. GERD patients with poor LES pressure had significantly lower fasting plasma motilin levels (p = 0.04). Patients with normal LES pressure tended to have lower motilin levels compared with normal controls, but this difference did not reach statistical signilicance (p = 0.07). The TIRisa for motilin was significantly lower in GERD patients with poor LES pressure (p = 0.01) and was also low in 188

Mean IlRtsa

Gastrin

Abbreviations

lp

Group

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GERD patients with normal LES pressure compared with normal controls, although this failed to reach significance (p = 0.07). There were no differences noted when comparing the IIRis between all groups. Fasting motilin levels were shown tobe significantly correlated with LES pressure on regression analysis (p = 0.02). PP: There were no differences in fasting plasma levels, IIRis and TIRisO for PP when comparing GERD patients with controls. Similarly, when the GERD patients were split into two groups according to LES pressure and compared with normal controls, no differences were noted. Neurotensin: The fasting plasma concentrations, IIRis& and TIRlsO of neurotensin were similar between

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Plasma GASTRIN (pmol/l)

1001

Plasma CCK (pmol/l)

I

81

Gerd - N. Sphincter -30

0

30

60

90

120

150

180

-30

0

30

60

Minutes Plasma MOTILIN (pmol/l)

100 80

90

120

180

160

Minutes ,40 Plasma PP (pmol/l)

1

i

60

80 60

40

40

1

20

QERD

- Abn. Sphincter

0’

0 -30

0

30

60

90

120

IS0

180

1

-30

0

30

60

Minutes

QO

120

150

180

Minutes

Plasma NEUROTENSIN (pmol/l)

Plasma PYY (pmol/l)

25 -*

Normal8

I

20-

I

15lo-

8

5-

0’

0

1

-30

0

30

60

90

120

150

180

-30

0

Minutes Flgura2. sphincter

30

60

90

120

180

180

Minutes

Effect of a standardized test mealcmplasmagastrointestinal h~rnonesin goups pressure and in aQe-matched healthy controls.

of GERD patients

with abnormal

and normal

1

controls and GERD patients. However,when the GERD controls, GERD patients with low LETSpressure+or patients were split into two groups according to LES GERD patients with normal LES pressure. PYY: The fasting plasma concentrations of PYY pressure, patients with low LES pressure were found to have signScantly higher fasting plasma concentrations were significantly lower in GERD patients compared compared with controls (p = 0.03) and patients with with normal controls (p = 0.01); however,when comparnormal LES pressure (p = 0.01). GERD patients with ing the I&so and TIRlso for PW, there were no differnormal LES pressure and healthy controls had similar ences between GERD patients and controls. Patient basal neuroteti concentratins. The= were no differ- groups 6th both low LES pressure and normal LES ences in the IIR,so and TIRls0 of neurotensin between pressure had fasting PYY plasma concentrations signifiTHE AMERICAN

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TABLE III Fasting Hormone Levels Versus Lower Esophageal Sphincter Pressure Hormone

Correlation Coefficient

Significance

Gastrin Cholecystokinin Motilin Pancreatic polypeptide Neurotensin Peptide W

-0.14 0.19 0.5 0.09 -0.4 -0.01

K p = 0.02 NS p = 0.07 NS

I

NS = not significant.

cantly lower than controls (p = 0.05 and p = 0.01, respectively).

els are positively correlated with LES pressure; the lower the LES pressure, the lower the basal plasma motilin level. The altered TIRisa for motilin seen in patients with low LES pressure is a reflection of low basal motilin levels and not of an altered postprandial response, since excursions in motilin concentration following a meal are normally small [28]. Neurotensin is an ileal hormone that is released in response to fat and carbohydrates. Neurotensin slows gastric emptying, inhibits gastric secretion, converts the fasting motility pattern to a fed pattern, and stimulates pancreatic secretion [ 19,351. Circulating neurotensin levels are increased in malabsorptive states and with rapid gastric emptying associated with the dumping syndrome [Z&16,36]. Concentrations of neurotensin that reduce LES pressure are within the range seen after the ingestion of a fatty meal [22,23]. This suggests that neurotensin may be physiologically important in the control of LES function. The elevated plasma neurotensin concentrations in the fasting state may contribute to the poor LES pressure in GERD patients. The elevated plasma neurotensin levels in patients with poor LES pressure may also contribute to delayed gastric emptying in GERD patients. Delayed gastric emptying may account for the obtunded postprandial CCK response seen in GERD patients, particularly those with low LES pressure. Delayed gastric emptying and partial inhibition of gastric acid secretion by neurotensin would result in prolonged alkalinization of the stomach. This may explain the increased postprandial gastrin response noted in this group. In conclusion, GERD patients have an altered hormonal profile that may be primary or adaptive. The hormonal abnormalities are more marked in patients with poor LES pressure. Fasting plasma PYY concentrations are low, irrespective of LFS pressure; however, fasting plasma motilin and neurotensin concentrations are significantly altered only in patients with low LES pressure. It is tempting to speculate that the changes in neurotensin and motilin may contribute to low LES pressure. The obtunded postprandial CCK response and an increased postprandial gastrin response in GERD patients with low LES pressure are likely to be secondary phenomena. It is evident from this study that GERD is associated with significant hormonal changes, which suggests that it is part of a more generalized foregut motility disorder.

COMMENTS Gastroesophageal reflux results from changes in foregut physiology. Poor LES pressure, impaired esophageal body function, and gastric factors such as acid hypersecretion, delayed gastric emptying, and duodenogastric reflux have been reported in GERD. The gastroesophageal region is subject to a complex neurohumoral control system [30], which, although reasonably well elucidated, has not been adequately studied in patients with GERD. This study demonstrates significant abnormalities in gastrointestinal hormones in patients with GERD. GERD patients, irrespective of LES pressure, show moderately decreased fasting PYY plasma concentrations, and their postprandial CCK response is significantly obtunded. PYY is a distal gut hormone that inhibits gastric emptying, small bowel transit, the interdigestive migrating complex, and gastric secretion [29,31] and is increased in conditions associated with rapid nutrient transport such as the postgastrectomy dumping syndrome or after small bowel resection [13,32]. CCK is released in response to fat and protein digestion products in the proximal small intestine. In addition to contracting the gallbladder, CCK stimulates pancreatic enzyme secretion and inhibits gastric emptying [19]. When GERD patients are subgrouped according to LES pressure, those with poor LES pressure had significantly greater hormonal abnormalities. In GERD patients with low LES pressure, fasting plasma motilin concentrations were greatly decreased, and fasting plasma neurotensin concentrations were substantially elevated. Another condition associated with low motilin concentrations is postoperative ileus [19]. Motilin is intimately associated with the development of phase III fronts in the interdigestive migrating motor complex and may be important in its overall control [12,32]. Motilin has also been shown to increase LES pressure at plasma levels that are within the physiologic range [Z&20,21]. During fasting, LES contractions have been shown to correlate with both increased motilin levels and phase III of the migrating motor complex [22,34]. The present study shows that fasting plasma motilin concentrations are low in all GERD patients, but particularly the subgroup with poor LES pressure. Furthermore, motilin lev-

1. Dodds WJ. The pathogenesis of gastroesophageal reflex disease. Am J Radio1 1988; 151: 49-56. 2. Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser R, Pate1 GK. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982; 307: 1547-9. 3. Zaninotto G, DeMeester TR, Schwizer W, Johannsson KE, Cheng SC. The lower esophageal sphincter in health and disease. Am J Surg 1988; 155: 104-10. 4. Schwizer W, Hinder RA, DeMeester TR. Does delayed gastric emptying contribute to gastroesophageal reflux disease.? Am J Surg 1989; 157: 74-81. 5. Maddem GJ, Chatterton BE, Collins PJ, Horowitz M, Shearman DJC, Jan&son GG. Solid and liquid gastric emptying in

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HORMONES IN GASTROESOPHAGEAL REFLUX

patients with gastro-cesophageal reflux. Br J Surg 1985; 72: 344-7. 6. Wilson P, Welch NT, Hinder RA, et al. Abnormal plasma gut hormones in pathologic duodenogastric reflux and their response to surgery. Am J Surg 1993; 165: 169-77. 7. Rees WDW, Go VLW, Malagelada JR. Simultaneous measurement of antroduodenal motility, gastric emptying and duodenogastric reflux in man. Gut 1979; 20: 963-70. 8. Keane FB, Diigno EP, Malagelada JR. Duodenogastric reflux in humans: its relationship to fasting antroduodenal motility and gastric, pancreatic and biliary secretion. Gastroenterology 1981; 81: 726-31. 9. Attwood SEA, DeMeester TR, Bremner CG, Barlow AP, Hinder RA. Alkaline gastroesophageal reflux: implications in the development of complications in Barrett’s columnar-lined lower esophagus. Surgery 1989; 106: 764-70. 10. Gowen GF. Spontaneous enterogastric reflux gastritis and esophagi&. Ann Surg 1985; 201: 170-5. 11. Eriksen CA, Sadek SA, Cranford C, Sutton D, Kennedy N, Cuschieri A. Reflux oesophagitis and oesophageal transit: evidence for a primary oesophageal motor disorder. Gut 1988; 29: 448-52. 12. Labo G, Bortolotti P, Vezzadini G, Bonora G, Bersani G. Interdigestive gastroduodenal motility and serum motilin levels in patients with idiopathic delay in gastric emptying. Gastroenterology 1986; 90: 20-6. 13. Adrian TE, Long RG, Fuessl HS, Bloom SR. Plasma peptide YY (PYY) in the dumping syndrome. Dig Dis Sci 1985; 89: 1145-8. 14. Besterman HS, Adrian TE, Mallinson CN, et al. Gut hormone release after intestinal resection. Gut 1982; 23: 854-61. 15. Preston DM, Adrian TE, Christofides ND, Lennard-Jones JE, Bloom SR. Positive correlation between symptoms and circulating motilin, pancreatic polypeptide and gastrin levels in functional bowel disease. Gut 1985; 26: 1059-64. 16. Blackburn AM, Christofides ND, Ghatei MA, et al. Elevation of plasma neurotensin in the dumping syndrome. Clin Sci 1980; 59: 237-43. 17. Hopman WPM, Jansen JBMJ, Lamers CHHW. Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy. Ann Surg 1984; 199: 276-80. 18. Meissner AJ, Bowes KL, Zwick R, Daniel EE. Effect of motilin on the lower oesophageal sphincter. Gut 1976; 17: 925-32. 19. Green DW, Gomez G, Greeley GH Jr. Gastrointestinal peptides. Gastroenterol Clin North Am 1989; 18: 695-733. 20. Domschke W, Lux G, Mitznegg P, et al. Relationship of plasma motilin response to lower esophageal pressure in man. &and J Gastroenterol 1976; 11 (Suppl 39): 81-4. 2 1. Holloway RH, Blank E, Takahashi I, Dodds WJ, Layman RD. Motilin: a mechanism incorporating the opossum lower esophageal sphincter into the migrating motor complex. Gastroenterology 1985; 89: 507-15. 22. Theodorsson-Norheim E, Thor K, Rose11S. Relation between lower esophageal sphincter (LES) pressure and the plasma concentration of neurotensin during intravenous infusion of neurotensin( l13) and (Gln4)neurotensin( 1- 13) in man. Acta Physiol &and 1983; (Suppl) 515: 29-35. 23. Thor K, Rokaeus A. Studies on the mechanisms by which (Gln4)-neurotensin reduces lower esophageal sphincter (LES) pressure in man. Acta Physiol Stand 1983; 118: 373-7. 24. Henderson JM, Lidgard G, Osborne DH, Carter DC, Heading RC. Lower oesophageal sphincter response to gastrin-pharmacological or physiological? Gut 1978; 19: 99-102. 25. Wright LF, Slaughter RL, Gibson RG, Hirschowitz BI. Correlation of lower esophageal sphincter pressure and serum gastrin level in man. Dig Dis 1975; 20: 603-6. 26. Brazer SR, Borislow DS, Liddle RA. Cholecystokinin is not a major hormonal regulator of lower esophageal sphincter pressure.

Gastroenterology 1990; 99: 641-5. 27. Behar J, Biincani P. Effect of cholecystokinin-octapeptide on lower esophageal sphincter. Gastroenterology 1977; 73: 57-61. 28. Bloom SR, Long RG, editors. Radioimmunoassay of gut regulatory peptides. Philadelphia: WB Saunders, 1982. 29. Adrian TE, Ferri G-L, Bacarese-Hamilton AJ, Fuessl HS, Polak JM, Bloom SR. Human distribution and release of a putative new gut hormone peptide YY. Gastroenterology 1985; 89: 1070-7. 30. Thompson JC. Humoral control of gut function. Am J Surg 1991; 161: 6-18. 31. Adrian TE, Savage AP, Sagol GR, et al. Effect of PYY on gastric, pancreatic and biliary functions in humans. Gastroenterology 1985; 89: 484-99. 32. Adrian TE, Savage AP, Fuessl HS, Wolfe K, Besterman HS, Bloom SR. Release of peptide YY (PYY) after resection of small bowel, colon or pancreas in man. Surgery 1987; 101: 715-9. 33. Tamalea M, Sarr M, VanLier Ribbink J. Gastrointestinal motor patterns: motilin as a coordinating factor. J Surg Res 1989; 147: 325-31. 34. Itoh Z, Aizawa I, Honda R, Hiwatashi K, Couch E. Control of lower esophageal sphincter contractile activity by motilin in conscious dogs. Dig Dis 1978; 23: 341-5. 35. Keinki 0, Wulschke S, Ehrlein HJ. Neurotensin slows gastric emptying by a transient inhibition of gastric and a prolonged inhibition of duodenal motility. Digestion 1986; 34: 28 1-8. 36. Sirinek KR, G’Dorisio TM, Howe B, McFee AJ. Neurotensin, vasoactive intestinal peptide, and Roux-en-Y gastrojejunostomy. Their role in the dumping syndrome. Arch Surg 1985; 120: 605-9.

DISCUSSION Bernard Langer (Toronto, Ontario, Canada): You

have stated that reflux disease is related to pie-existing hormonal abnormalities. Is it possible that the hormonal abnormalities are related to the reflux disease? Have you studied any patients who have had surgical repairs that corrected their problem? Galen Perdikis: We have not studied any patients after surgery or after medical therapy. It is difficult to say what comes first-whether the hormone abnormality initiates the disease or the disease initiates the hormone changes. We should regard gastroesophageal reflux disease (GERD) as part of a foregut motility disorder and not just as an isolated lower esophageal sphincter (LES) phenomenon. From the results of this study, it seems possible that abnormalities in the neurohumoral control of the LES are part of the primary event in these patients. LawrenceW. Way (San Francisco, CA): What is the evidence that you are dealing with a generalized foregut motility disorder? Galen Perdikis: Many enteric hormones have been shown to be abnormal in various foregut motility disorders, such as the postgastrectomy dumping syndrome and others. Hormones such as motilin have very marked effects on normal foregut physiology. The numerous hormone changes seen in patients with GERD suggest that the disease is part of a more generalized motility disorder. LawrenceWay: You should be cautious in extrapolating from your observations to your conclusions. Galen Perdikis: Abnormal motilin levels in reflux

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patients are very interesting. We are presently studying antroduodenal motility in patients with GERD, because there is evidence to suggest that motilin recruits antral, gastric, and lower esophageal function, and we are hoping to show some relationship between antroduodenal motility, LES characteristics, and motilin, viewing gastroesophageal reflux as part of a generalized motility disorder. Ronald A. Hinder: We have also found abnormalities in gastric emptying and a higher incidence of gallstones in patients with GERD, suggesting gallbladder dysfunction. These suggest an associated antroduodenal and biliary motility disorder in these patients. Sean J. Mulvihill(San Francisco, CA): The concepts of regulation of gut motility are changing. There is very little evidence that there are important endocrine effects on the LES; instead, the regulation seems to be due to the enteric nervous system. Do you have any evidence that these endocrine factors alter LES pressure? Do abnormalities in the release of gut hormones actually influence LES tone? Galen Perdikis: When the dynamics of the LES are studied, neural, humeral, and myogenic factors are found to play a role. Direct evidence of any neural input in this study is obviously lacking, since we only studied the humeral effects in GERD. We have shown that motilin is deficient in gastroesophageal disease. Another report, presented this afternoon, demonstrates that when erythromycin, which acts via motilin’s pathways, is given to

patients with GERD, there is a significant increase in LES pressure. Together, these studies provide good evidence for motilin’s importance in the regulation of LES pressure. Bruce D. Schirmer(Charlottesville, VA): You must be cautious about interpreting systemic levels of a hormone as accurately reflecting its local action. Have you done any specific test to show us that motilin was acting on the esophagus itself rather than just seeing the systemic change in the hormone level? Why do you think there was no change in the postprandial motilin level? Motilin and neurotensin originate in different areas of the gastrointestinal tract, motilin being more the foregut and neurotensin more of a hindgut hormone. Which of these do you think is really the most important? Galen Perdikis: It is known that motilin does not increase postprandially, or, if it does, the increase is very small. Therefore, there should not be any change in motilin’s postprandial response. Motilin, when compared with neurotensin, has been shown to have many effects on foregut physiology; therefore, we should concentrate our attention on motilin. Bernard Langer:Can you comment on what medications the patients in your study group were on, and whether their medications might have any effect on gut hormone levels? Calen Perdikk Patients are taken off all medication for a period of at least 5 days prior to any studies.

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THE AMERICAN

JOURNAL

OF SURGERY

VOLUME

JANUARY

1994