Fluid Secretion in the Duodenum and Intestinal Handling of Water and Electrolytes in Zollinger-Ellison Syndrome JEAN-CLAUDE RAMBAUD, MD, ROBERT MODIGLIANI, MD, PHILIPPE EMONTS, MD, CLAUDE MATUCHANSKY, MD, NICOLE VIDON, MAITRE DE R E C H E R C H E , HARVEY BESTERMAN, MD, and JEAN-JACQUES BERNIER, MD
The stow marker perfusion technique was used in five patients with the Zollinger-Ellison syndrome in order to determine the basal and postcibal flow rates o f fluids passing the duodenojejunal junction and distal ileum, and the composition of those fluids. Fecal water and electrolyte excretions were also measured. The 24-hr outputs at the ligament of Treitz were markedly increased, while fecal losses were normal or only slightly increased. Thus, the overall intestinal reabsorption of water was 96%. Fasting rates of fluid and electrolyte flow at the ligament of Treitz were also measured during a basal period, followed by a period of continuous gastric aspiration. Removal of gastric secretion had the following effects on the fluid passing through the duodenum: (1) dramatic decrease in flow rate; (2) an increase in osmolaIity, from hypotonicity to isotonicity; (3) rise of pH, from acid to alkaline values; (4) a decrease of Pco2, from high to normal values. No increase in fasting plasma levels of immunoreactive secretin and motilin was observed in Zollinger-Ellison syndrome, whereas normal subjects respond to acid in the duodenum by a marked rise in the circulating levels of these hormones. These facts suggest that, in Zollinger-Ellison syndrome: (1) the ability of the small bowel and colon to reabsorb water and electrolytes is normal; (2) duodenal dissipation of hydrogen ions is mainly due to intraluminal neutralization by bicarbonate; and (3) stimulation o f water and electrolyte secretion by the pancreas is inadequate.
After peptic ulcer, diarrhea is the second most prominant symptom of the Zollinger-Ellison syndrome (ZES) (1, 2). Although the pathophysiology of the s t e a t o r r h e a that is also f r e q u e n t l y found in ZES (3, 4) has been well studied (5-7), the mechanisms of the increased fecal water and electrolyte losses are incompletely known. From the Research Unit on Pathophysiology of Digestion (INSERM U 54) Hrpital Saint Lazare, Paris, France, and Royal Postgraduate Medical School. Hammersmith Hospital, London. England. This paper was presented in abstract form at the annual meeting of the ]British Society of Gastroenterology, Oxford, England, October. 1975. Address for reprint requests: Prof. J.C. Rambaud. Hrpital Saint-Lazare~ 107 Bis, rue du Fg St Denis, 75475 Paris Crdex 10.
Numerous clinical and experimental data strongly suggest that gastric acid hypersecretion plays a major role in the pathogenesis of diarrhea (3, 4, 8). High fasting and postprandial flow rates of fluid have been observed in the proximal jejunum of a few patients (8-10). Studies in normal subjects and ZES patients have suggested that several factors could lead to water and electrolyte malabsorption in the proximal small intestine (3, 4): however, no data are available on rates of fluid absorption from the small and large intestines in ZES. It has also been suggested that neutralization of acid by intraluminal bicarbonate is the main mechanism for dissipation of hydrogen ions in the duodenum (8-10). The aims of the present studies were to assess in
Digestive Diseases, Vol. 23, No. 12 (December 1978)
0002-9211/78/1200-1089505 00/1 9 1978DlgesttveDiseaseSystems,Inc.
1089
RAMBAUD ET AL Z E S : (1) n e t w a t e r a n d e l e c t r o l y t e m o v e m e n t s in the small a n d large i n t e s t i n e s ; (2) the r e s p e c t i v e c o n t r i b u t i o n s o f the gastric acid a n d d u o d e n a l - b i l i a r y - p a n c r e a t i c (DBP) a l k a l i n e s e c r e t i o n s to the fluid e n t e r i n g the j e j u n u m ; a n d (3) the m e c h a n i s m o f h y d r o g e n i o n d i s s i p a t i o n in the d u o d e n u m . M A T E R I A L S AND M E T H O D S
Subjects Five patients with ZES and a history of diarrhea were studied, before any surgical procedure was performed. The main clinical, laboratory and pathological findings are summarized in Table 1. All patients were in partial or total remission of diarrhea at the time of perfusion studies; none was receiving cimetidine or other medical treatment. Control subjects were five healthy male students, 20-29 years old. All subjects gave informed consent.
Methods General Procedure. The subjects were intubated with a 6-lumen tube (Figure 1). The composition and flow rate of fluid were determined at the ligament of Treitz, in the proximal jejunum, and in the terminal ileum, according to the slow marker perfusion technique (11). Tube 1 was used to perfuse (at point P) a nonabsorbable marker, polyethylene glycol 4000 (PEG) at a high concentration (50 g/liter). The marker was diluted in saline to a final osmolality of 300 mOsm/kg and infused at a constant slow rate (0.5 ml/min in studies at the ligament of Treitz and in proximal jejunum, and 0.25 ml/min in the distal ileum).
15cm
5
30cm
35cm
_4 ~ ~ # / # / # / # / / / / / # ~ _ ~
J. I
]
Fig 1. Schematic drawing of the 6-lumen tube allowing measurement of intraintestinal fluid flow rate and electrolyte composition. Tube 1 was used to peffuse the nonabsorbable marker. Intestinal fluid was recovered with tubes 2 (studies at the ligament of Treitz) or 4 (studies in proximal jejunum and distal ileum). Tubes 3 and 5 allowed an air inlet in order to prevent intestinal collapse. The mercury bag tracting the whole tube assembly could be inflated with air (in order to hasten tube progression in the small bowel).
Tube 2 ended at point T, 15 cm below the perfusion point P and tube 4 ended at point J-I, 45 cm distal to the perfusion point. These were used for collecting intestinal fluid at the ligament of Treitz or from the jejunum and ileum, respectively. Fluid was aspirated continuously with a Technicon peristaltic pump; air inlets through tubes 3 and 5 prevented intestinal collapse and facilitated recovery of fluid. After a 4-hr equilibration period, successive 30-min samples were obtained. A mercury bag completed the tube assembly; it could be inflated with air through tube 6. Experimental Design. Movements of water and electrolytes through the small bowel and colon were evaluated over a 24-hr period from the output of water and electrolytes (1) near the ligament of Treitz, (2) near the ileocecal junction, and (3) in stools.
TABLE 1. FEATURESOF FIVE PATIENTSWITHZOLLINGER-ELLISONSYNDROME Coarse DuoPeptic denal Ulcer Duodenal Fecal and jejunal and~or jejunal Pre- PresPaAge Perma- Interfat folds tients Sex (years) nent mittent (g/24 hr) at x-rays biopsies vious ent Diarrhea
LR
M
44
+
38.4
+
TC
F
54
+
25
+
IF$
+
MY
F
40
6
+
SVAw
MP +
M
50
+
CM
M
42
+
+ +
+ 9.4
+
IF$
Fasting Basal gastric plasma Positive acid output gastrin seeretin Pathological (mEq/hr)* (pg/ml)* test? findings
18.7
210
+
Islet cell carcinoma
-
29.0
200
+
Islet cell hyperplasia
?
+
31.2
800
-
-
34.0
300
-
+
23.4
300
+ +
Islet cell adenoma Islet cell adenoma Islet cell adenoma
*Highest values found during the course of the disease (normal gastrin level < 50 pg/ml). ?Secretin (GIH; 3 CU/kg infused intravenouslyduring 1 hr) induced in each of the four patients tested a statistically significant increase in plasma gastrin levels compared to the preceding 1-hr basal period. ~Inflammatory changes. w villous atrophy.
1090
Digestive Diseases, Vol. 23, No. 12 (December 1978)
TRANSINTESTINAL
FLUID MOVEMENTS
IN GASTRINOMAS
TABLE 2.24-HR ELECTROLYTE OUTPUTS AT THE LIGAMENT OF TREITZ, IN DISTAL ILEUM, AND IN FECES Patients LR
Water (liter 24 hr) Treitz DistaliIeum Stools Sodium (mEq/24 hr) Treitz Distal f[eum Stools Potassium (mEq/24 hr) Treitz Distal ileum Stools Hydrogen (mEq/24 hr) Treitz Distal ileum Chloride (mEq/24 hr) Treitz Distalileum Stools Bicarbonate (mEq/24 hr) Treitz Distalileum
TC
23.6 0.4 1769
MY
14.6 6.3 0.2
CM
15.6 4.5 0.1
14.6 3.8 0.4
Controls (range)
P* value
3 . 3 - 4.5 ! . 8 - 2.5 0.04- 0.04
The stow marker perfusion technique was used in five patients with the Zollinger-Ellison syndrome in order to determine the basal and postcibal flow rates o f fluids passing the duodenojejunal junction and distal ileum, and the composition of those fluids. Fecal water and electrolyte excretions were also measured. The 24-hr outputs at the ligament of Treitz were markedly increased, while fecal losses were normal or only slightly increased. Thus, the overall intestinal reabsorption of water was 96%. Fasting rates of fluid and electrolyte flow at the ligament of Treitz were also measured during a basal period, followed by a period of continuous gastric aspiration. Removal of gastric secretion had the following effects on the fluid passing through the duodenum: (1) dramatic decrease in flow rate; (2) an increase in osmolaIity, from hypotonicity to isotonicity; (3) rise of pH, from acid to alkaline values; (4) a decrease of Pco2, from high to normal values. No increase in fasting plasma levels of immunoreactive secretin and motilin was observed in Zollinger-Ellison syndrome, whereas normal subjects respond to acid in the duodenum by a marked rise in the circulating levels of these hormones. These facts suggest that, in Zollinger-Ellison syndrome: (1) the ability of the small bowel and colon to reabsorb water and electrolytes is normal; (2) duodenal dissipation of hydrogen ions is mainly due to intraluminal neutralization by bicarbonate; and (3) stimulation o f water and electrolyte secretion by the pancreas is inadequate.
After peptic ulcer, diarrhea is the second most prominant symptom of the Zollinger-Ellison syndrome (ZES) (1, 2). Although the pathophysiology of the s t e a t o r r h e a that is also f r e q u e n t l y found in ZES (3, 4) has been well studied (5-7), the mechanisms of the increased fecal water and electrolyte losses are incompletely known. From the Research Unit on Pathophysiology of Digestion (INSERM U 54) Hrpital Saint Lazare, Paris, France, and Royal Postgraduate Medical School. Hammersmith Hospital, London. England. This paper was presented in abstract form at the annual meeting of the ]British Society of Gastroenterology, Oxford, England, October. 1975. Address for reprint requests: Prof. J.C. Rambaud. Hrpital Saint-Lazare~ 107 Bis, rue du Fg St Denis, 75475 Paris Crdex 10.
Numerous clinical and experimental data strongly suggest that gastric acid hypersecretion plays a major role in the pathogenesis of diarrhea (3, 4, 8). High fasting and postprandial flow rates of fluid have been observed in the proximal jejunum of a few patients (8-10). Studies in normal subjects and ZES patients have suggested that several factors could lead to water and electrolyte malabsorption in the proximal small intestine (3, 4): however, no data are available on rates of fluid absorption from the small and large intestines in ZES. It has also been suggested that neutralization of acid by intraluminal bicarbonate is the main mechanism for dissipation of hydrogen ions in the duodenum (8-10). The aims of the present studies were to assess in
Digestive Diseases, Vol. 23, No. 12 (December 1978)
0002-9211/78/1200-1089505 00/1 9 1978DlgesttveDiseaseSystems,Inc.
1089
RAMBAUD ET AL Z E S : (1) n e t w a t e r a n d e l e c t r o l y t e m o v e m e n t s in the small a n d large i n t e s t i n e s ; (2) the r e s p e c t i v e c o n t r i b u t i o n s o f the gastric acid a n d d u o d e n a l - b i l i a r y - p a n c r e a t i c (DBP) a l k a l i n e s e c r e t i o n s to the fluid e n t e r i n g the j e j u n u m ; a n d (3) the m e c h a n i s m o f h y d r o g e n i o n d i s s i p a t i o n in the d u o d e n u m . M A T E R I A L S AND M E T H O D S
Subjects Five patients with ZES and a history of diarrhea were studied, before any surgical procedure was performed. The main clinical, laboratory and pathological findings are summarized in Table 1. All patients were in partial or total remission of diarrhea at the time of perfusion studies; none was receiving cimetidine or other medical treatment. Control subjects were five healthy male students, 20-29 years old. All subjects gave informed consent.
Methods General Procedure. The subjects were intubated with a 6-lumen tube (Figure 1). The composition and flow rate of fluid were determined at the ligament of Treitz, in the proximal jejunum, and in the terminal ileum, according to the slow marker perfusion technique (11). Tube 1 was used to perfuse (at point P) a nonabsorbable marker, polyethylene glycol 4000 (PEG) at a high concentration (50 g/liter). The marker was diluted in saline to a final osmolality of 300 mOsm/kg and infused at a constant slow rate (0.5 ml/min in studies at the ligament of Treitz and in proximal jejunum, and 0.25 ml/min in the distal ileum).
15cm
5
30cm
35cm
_4 ~ ~ # / # / # / # / / / / / # ~ _ ~
J. I
]
Fig 1. Schematic drawing of the 6-lumen tube allowing measurement of intraintestinal fluid flow rate and electrolyte composition. Tube 1 was used to peffuse the nonabsorbable marker. Intestinal fluid was recovered with tubes 2 (studies at the ligament of Treitz) or 4 (studies in proximal jejunum and distal ileum). Tubes 3 and 5 allowed an air inlet in order to prevent intestinal collapse. The mercury bag tracting the whole tube assembly could be inflated with air (in order to hasten tube progression in the small bowel).
Tube 2 ended at point T, 15 cm below the perfusion point P and tube 4 ended at point J-I, 45 cm distal to the perfusion point. These were used for collecting intestinal fluid at the ligament of Treitz or from the jejunum and ileum, respectively. Fluid was aspirated continuously with a Technicon peristaltic pump; air inlets through tubes 3 and 5 prevented intestinal collapse and facilitated recovery of fluid. After a 4-hr equilibration period, successive 30-min samples were obtained. A mercury bag completed the tube assembly; it could be inflated with air through tube 6. Experimental Design. Movements of water and electrolytes through the small bowel and colon were evaluated over a 24-hr period from the output of water and electrolytes (1) near the ligament of Treitz, (2) near the ileocecal junction, and (3) in stools.
TABLE 1. FEATURESOF FIVE PATIENTSWITHZOLLINGER-ELLISONSYNDROME Coarse DuoPeptic denal Ulcer Duodenal Fecal and jejunal and~or jejunal Pre- PresPaAge Perma- Interfat folds tients Sex (years) nent mittent (g/24 hr) at x-rays biopsies vious ent Diarrhea
LR
M
44
+
38.4
+
TC
F
54
+
25
+
IF$
+
MY
F
40
6
+
SVAw
MP +
M
50
+
CM
M
42
+
+ +
+ 9.4
+
IF$
Fasting Basal gastric plasma Positive acid output gastrin seeretin Pathological (mEq/hr)* (pg/ml)* test? findings
18.7
210
+
Islet cell carcinoma
-
29.0
200
+
Islet cell hyperplasia
?
+
31.2
800
-
-
34.0
300
-
+
23.4
300
+ +
Islet cell adenoma Islet cell adenoma Islet cell adenoma
*Highest values found during the course of the disease (normal gastrin level < 50 pg/ml). ?Secretin (GIH; 3 CU/kg infused intravenouslyduring 1 hr) induced in each of the four patients tested a statistically significant increase in plasma gastrin levels compared to the preceding 1-hr basal period. ~Inflammatory changes. w villous atrophy.
1090
Digestive Diseases, Vol. 23, No. 12 (December 1978)
TRANSINTESTINAL
FLUID MOVEMENTS
IN GASTRINOMAS
TABLE 2.24-HR ELECTROLYTE OUTPUTS AT THE LIGAMENT OF TREITZ, IN DISTAL ILEUM, AND IN FECES Patients LR
Water (liter 24 hr) Treitz DistaliIeum Stools Sodium (mEq/24 hr) Treitz Distal f[eum Stools Potassium (mEq/24 hr) Treitz Distal ileum Stools Hydrogen (mEq/24 hr) Treitz Distal ileum Chloride (mEq/24 hr) Treitz Distalileum Stools Bicarbonate (mEq/24 hr) Treitz Distalileum
TC
23.6 0.4 1769
MY
14.6 6.3 0.2
CM
15.6 4.5 0.1
14.6 3.8 0.4
Controls (range)
P* value
3 . 3 - 4.5 ! . 8 - 2.5 0.04- 0.04
