Slow-transit constipation

Slow-Transit Constipation Solitary Symptom of a Systemic Gastrointestinal Disease

Donato F. Altomare, M.D.,* Piero Portincasa, M.D., Ph.D.,t Marcella Rinaldi, M.D.,* Agostino Di Ciaula, M.D.,~- Elisabetta Martinelli, M.D.,* Annacinzia Amoruso, M.D.,t Giuseppe Palasciano, M.D.,I-Vincenzo Memeo, M.D.*

From the *tst#uto di Clinica Chirurgica, tCattedra di Semeiotica Medica, Dipartimento di Medicina Interna e del Lavoro (DiMIL)~ *Cattedra di Gastroenterologia University of Bar/Medical School, Bari, Italy

INTRODUCTION: Autonomic neuropathy is thought to play a role in the pathogenesis of slow-transit constipation, but other gastrointestinal organs may also be involved, even if they are symptom-free. We investigated whether motility in gastrointestinal organs other than the colon was impaired in patients with slow-transit constipation and whether the autonomic nervous system was involved. METHODS: Twen- ty-one consecutive patients (18 females; median age, 46 years) with severe chronic constipation (--<2 defecations/ week and delayed colonic transit time) were studied. Auto- nomic neuropathy function was tested with esophageal manometry, gastric and gallbladder emptying (fasting and postprandial motility) by ultrasonography, orocecal transit time (Ha-breath test), colonic transit time (radiopaque markers), and anorectal volumetric manometry. The integrity of the autonomic nervous system was assessed by a quantita- tive sweat-spot test for preganglionic and postganglionic fibers, tilt-table test, and Valsalva electrocardiogram R-R ratio. RESULTS: Esophageal manometry showed gastro- esophageal reflux or absence of peristalsis in five of the seven patients examined. Gallbladder dysmotility (i.e., increased fasting, postprandial residual volume, or both) was observed in 6 of 14 (43 percent) patiems. Gastric emptying was decreased in 13 of 17 (76 percent) patients. Orocecal transit, time was delayed in 18 of 20 (90 percent) patients; median transit time was 160 (range, 90-200) minutes. Me- dian colonic transit time Was 97 (range, 64-140) hours. Anorectal function showed abnormal rectoanal inhibitory reflex and decreased rectal sensitivity in 11 of 19 (58 percent) patients. Signs of autonomic neuropathy of the sympathetic cholinergic system were found in 14 of 18 (78 percent) patients. Only one of nhae patients had vagal abnormalities detected with the Valsalva test and four of five patients with a history of orthostatic hypotension had a positive tilt-table test. CONCLUSIONS: Slow-transit constipation may be associated with impaired function of other gastrointestinal organs. More than 70 percent of patients with slow-transit constipation present some degree of autonomic neuropathy. Severe constipation may be the main complaint in patients with a systemic disease involving several organs and possibly involving the autonomic nervous system. This should be considered in the management of such cases. [Key words: Constipation; Colonic inertia; Autonomic neuropathy; Gastrointestinal motility; Stomach; Gallbladder motility]

Altomare DF, Portincasa P, Rinaldi M, Di Ciaula A, Martinelli E, Amoruso A, Palasciano G, Memeo V. Slow-transit consti-

Presented in part at the International Symposium on Gastrointesti- nal Motility, Copenhagen, Denmark, June 5 to 8, 1996. Address requests to Dr. Altomare: Istituto di Clinica Chirurgica, University of Bari, Policlinico-70124, Bari, Italy.

231

pation: solitary symptom of a systemic gastrointestinal disease. Dis Colon Rectum 1999;42:231-240.

C hronic idiopathic coI~stipation caused by slow

transit (STC) is one of the most c o m m o n forms

of const ipat ion in Western countries. The cause of this

complaint is still uncertain, and m a n y theories have

been proposed , including insufficient intake of di-

etary fiber, a h o r m o n e disorder 1 (STC is almost exclu-

sively a female complaint) , and various degrees o f

intestinal neuronal agenesis. 2 However , the frequent

observat ions in these patients of other dis turbances

involving the s tomach 3 or anorectal funct ion and the

bladder 4 or b lood pressure control 5 suggest that STC

could be the mos t apparen t manifestat ion o f an oth-

erwise asymptomat ic idiopathic au tonomic neuropa-

thy (AN) involving the functional control of other

hol low organs. Functional disorders o f the au tonomic

nervous system are usually characterized by wide-

spread abnormalit ies involving the cardiovascular,

urinary, sexual, and digestive systems, one o f the

most f requent symptoms being constipation.

In this s tudy we analyzed the funct ion of the entire

gastrointestinal tract and the gallbladder in a series o f

patients with severe, chronic, slow-transit constipa-

tion with the aim of detect ing any associated asymp-

tomatic gastrointestinal abnormalities. The functional

integrity o f the au tonomic nervous system was also

tested to elucidate its role in the pa thogenes is o f this

c o m m o n complaint.

PATIENTS AND METHODS Informed consent was obta ined from all subjects,

and the research protocol was a p p r o v e d by the ethics

commit tee of Bari University Medical School. More

than 79 patients were referred to our tertiary Center of

Gastrointestinal PathophysiologT f rom general practi-

tioners or other hospitals be tween May 1995 and

September 1996. Of these, 21 patients (18 female)

with a median age o f 46 (range, 17-76) years and

232 ALTOMARE ETAL Dis Colon Rectum, February 1999

severe chronic constipation caused by slow transit entered the study.

The inclusion criteria were

1. Number of spontaneous defecations - -2/week 2. More than two years of unsuccessful treatment

of constipation with dietary fiber supplements and oral laxatives

3. Total colonic transit time ->64 hours.

The exclusion criteria were

1. Organic colonic disease shown by colonoscopy, barium enema, or both

2. Previous abdominal surgery (except for two patients who underwent laparoscopic cholecystec- tomy)

3. Diabetes or other systemic metabolic disease 4. History of peptic ulcer.

Three patients complained of upper gastrointestinal-tract symptoms such as dyspepsia or gastroesoph- ageal reflux. None had gallstones, as confirmed by ultrasound. Sixteen patients had a radiologic finding of dolichocolon and melanosis coli was diagnosed in four patients at endoscopy.

Esophageal Function

All medication was withdrawn two days before the study. After an overnight fast the patient was placed in

the semirecumbent position. Esophageal function was evaluated with both stationary and pull-through manometry with use of a microtip probe (Gaeltec, Isle of Skye, Scotland) 3 mm in diameter with three mi- crotransducers 5 cm apart, inserted through the nose. The probe was connected to a computer (Griffon, Albyn Medical, Dingwall, Scotland) with dedicated software for computer analysis (Phoenix, Dingwall, Scotland). Function was considered to be impaired if any abnormality of the motility pattern was recorded (i .e. , synchronous contractions, low pressure in the lower esophageal sphincter, or absent or abnormal peristaltic waves).

Gallbladder and Gastric Motility

Motility of the gallbladder and the antrum were

studied simultaneously with a scanner (Ansaldo-Hita- chi Model AU-450, Genova, Italy) with a 3.5-MHz transducer. Sagittal and transverse images of the gallbladder were obtained, and gallbladder volume was measured from these still images, assum.ing an ellip- soid shape of the organ.< 7 The following markers of gallbladder motility were measured: 1) fasting vol-

ume, i.e., the mean of three measurements taken 15, 5, and 0 minutes before a meal; 2) postprandial volumes at 5-minute intervals up to 45 minutes and then at 15-minute intervals up to 120 minutes; 3) residual

volume, i.e., the minimum volume measured at any

time postprandially; 4) postprandial ejection volume,

determined by calculating the difference between

fasting and residual volume; 5) integrated gallbladder emptying, i.e., the area under emptying-time curves

(AUC) after subtraction of basal volumes, expressed

as a percentage of fasting volume divided by 120

minutes; and 6) half-emptying time ( T 1 / 2 ) , the time in minutes taken for the gallbladder volume to decrease

by 50 percent7 Gallbladder volume was expressed in

milliliters and as a percentage of fasting (basal) vol-

ume. Gallbladder emptying curves were obtained by

plotting gallbladder volume vs. time.

Gastric emptying was assessed by monitoring changes in the antral area with use of ultrasound, s, 9

With the subject sitting in a chair and leaning slightly

backward, the sonographic probe was positioned

longitudinally at the epigastrium to measure the pre-

spinal antral area at the level of the antrum-body

connection in a single section. The superior mesen-

teric vein and the aorta were used as reference mark-

ers. Both the sitting position and the small volume of

liquid meal (i .e. , <300 ml) are safe factors against

artifacts caused by floating or redistribution of gastric

contents in the corpus and fundus. The following

markers of gastric motility were measured: 1) basal

antral area, the mean of two measurements taken five

and zero minutes before the meal; 2) maximum post-

prandial area, measured after maximum widening of

the antrum had occurred, usually within two minutes after the meal; 3) minimum postprandial antral area,

the smallest area measured at any time postprandiaUy;

4) integrated antral emptying, the area under empty-

ing-time curves after subtraction of basal values, and

expressed as a percentage of the basal antral area

multiplied by 120 minutes-I; and 5) half-emptying

time, the time taken for the maximum antral area to

decrease by 50 percent (T1/2, minutes), calculated by

linear regression analysis from the linear part of the

antral emptying curve. This index closely correlates

with scintigraphic half-emptying time. 1° Antral area

was expressed in square centimeters and, postpran-

dially, as a percentage of maximum areas after sub-

tracting basal areas: s 100 × (A - a)/(Am~ x - a), where A = postprandial area at any given time; a = basal

area, Am~ x = maximum postprandial area, all in

Vol. 42, No. 2 CONSTIPATION AS GASTROINTESTINAL SYMPTOM 233

square centimeters. Antral emptying curves were ob-

tained by plotting antral areas vs. time. Ultrasonographic studies were performed be tween

8:00 a.m. and 11:30 a.m. after an overnight fast (of

both food and drink) of 10 to 12 hours. The liquid test meal (11 g of fat, 120 kcaD was emulsified in 200 ml

of tap water and drunk at room temperature during

one minute. In healthy subjects this meal induced a decrease of more than 50 percent in fasting gallblad-

der volume. 7 Caffeine and smoking were not allowed

on the day of the test.

Gallbladder and antral emptying were also assessed

in 16 healthy volunteers with no gastrointestinal com-

plaint and with normal abdominal ultrasound. This group was matched with the patients for age, gender,

and body size.

Gallbladder and antral emptying were considered

defective when at least one of the measurements was

above the 90th percentile of healthy controls as reported in previous studies by our group 7, 9 (Table 1).

Orocecal Transit Time

Orocecal transit time was measured with use of the breath hydrogen technique. 11 Patients had three days

of preparation (special diet, no antibiotics, no smok-

ing, and no prokinetics). A cleansing enema was per-

formed the day before the study to prevent the effect

of colonic distention on small-bowel function. The

fasting patients ingested 10 g of lactulose, and expi-

ratory breath samples were collected in a 20-ml plastic

syringe 30 minutes and immediately before the test

meal and every 10 minutes thereafter, until a late peak of breath hydrogen occurred (documented by an in-

Table 1. Limits of Normal Values for Gallbladder and Antral

Emptying After Standard Liquid Meal from 16 Healthy Subjects (90th Percentile)

Normal Value

Gallbladder Fasting volume (ml) <45.7 Residual volume (ml) <12 Residual volume (% of fasting volume) <45.4 Half-emptying time (min) <26 AUCo_12o (% 120 min -1) >6,442

Antrum Min postprandial area (cm 2) <9.1 Min postprandial area (%) <36 Half-emptying time (min) <40 AUCo_12o (% 120 min -1) >6,871

AUC = area under volume-time curves.

crease of 10 p p m above baseline on two consecutive

occasions or else for a total of 200 minutes from the

ingestion of the meaD. Breath samples were analyzed immediately with use of a precalibrated, hydrogen-

sensitive electrochemical device (Microlyzer Model 12, Quintron, Milwaukee, WI). Mean orocecal transit

time observed in 50 healthy matched subjects (12

males; mean age, 42; range, 20-69 years) was 75.2 -+

12.8 minutes, with a 95 percent confidence interval

(CI) of 71.6-78.8 minutes). Transit times longer than 100 minutes (mean + 2 standard deviations (SD))

were therefore considered abnormal.

Colonic Transit Time

Total colonic transit time was assessed with use of radiopaque markers, 12 with three consecutive adminis-

trations of a capsule containing 20 small radiopaque

markers on Days 1, 2 and 3 and an abdominal x-ray on

Days 4 and 7 taken at the same time as the capsule

administration on the previous days. The simplified cal-

culation method proposed by Metcalf e t al. 13 was used.

During the test week oral laxatives or cleansing enemas

were withdrawn. Delayed colonic transit was defined as

a total colonic transit time longer than 64 hours, which is the mean _+ 2 SD of colonic transit time in a healthy

control group studied by Chaussade. 12

Anorectal Function

Anorectal function was studied by anorectal volu-

metric manometry and dynamic videoproctography.

Anal volumetric manometry was performed with use

of a three-microtip probe with a diameter of 4 mm,

inserted through the anus after bowel preparat ion and

connected to the same computer system used for esophageal manometry. The rectoanal inhibitory re-

flex (RIAR) was elicited by step inflation of a low-

compliance latex balloon placed in the rectal ampulla,

and rectal compliance was determined after continu-

ous filling (50 ml/minute) of the rectal balloon with warm tap water to test its proprioceptive sensitivity to

distention. The features of the anorectal reflex and the

compliance values were compared with those of 15

age-matched controls (10 males; mean age, 56 years)

without anorectal or bowel dysfunction. No difference was noted between males and females among

controls. A resting pressure --<30 mmHg, a RIAR requiring

more than 80 ml of air, and a minimum balloon

volume greater than 100 ml and 250 ml to elicit rectal

sensation or defecatory stimulus, respectively, were

234 ALTOMARE E T A L Dis Colon Rectum, February 1999

considered abnormal. Dynamic videoproctography was performed in patients complaining of difficult evacuation in association with slow colonic transit to evaluate outlet obstruction. The test was performed by video recording of the defecation of an enema containing boiled porridge and barium sulfate at 37oc 14

A u t o n o m i c N e u r o p a t h y

The integrity of the autonomic nervous system was assessed by the sweat-spot test (SST) and the tilt-table test for sympathetic function, and the Valsalva R-R ratio for parasympathetic function. The SST ~5 investigates the presence of subclinical autonomic neuropathy involving cholinergic sympathetic fibers by ana- lyzing sweat abnormalities. The skin of the dorsum of the foot is coated with iodine and a fine emulsion of starch in arachis oil. Sweat is stimulated either by an intradermal injection of ace@choline (ace@choline SST), or a standardized thermal stimulus that includes preganglionic fibers (thermal SST). ~6 A colorimetric reaction between starch and iodine is triggered by the sweat from stimulated glands, so that each pore is seen as a small black dot. The number and distribution of these dots is counted on a magnified photo- graph with use of a grid. A normal SST is expressed by a score ->12 and/or <8 percent of abnormal subareas (each square of the grid having less than 6 dots) as determined by Ryder et al. ~5 and confirmed by our group 17 in 21 healthy matched controls. Only patients

with both indexes (SST score and percent of abnormal subareas) outside normal limits were considered to have a degree of autonomic neuropathy.

The tilt-table test investigates adrenergic function after inducing orthostatic hypotension. Blood pressure is measured three times before and after a change of position from supine to orthostatic with use of a tilt table. A rapid and persisting fall in systolic and diastolic blood pressure ->30 mmHg with or without an unchanged heart rate indicate an impaired adrenergic response to stimulated baroceptors. ~s

The Valsalva R-R ratio test was used to assess vagal function by recording the heart rate changes on an electrocardiogram. The ratio in millimeters between the longest R-R interval after and the shortest R-R interval during Vatsalva's maneuver should be ->1.2.

Statistical Analysis Results are expressed as mean _+ standard error

unless otherwise specified. Differences between

groups were tested for statistical significance with use of the unpaired Student's t-test. When data were not normally distributed, they were analyzed with the Mann-Whitney rank-sum test. The analysis of variance was used when comparing several groups; when a significant difference was detected, results were compared further for contrasts by Fisher's least significant difference test. Comparison of observed frequencies among groups was performed with the chi-squared test. Linear regression analysis was performed by the least squares method. Multiple regression analysis was used to identify the best predictors for some dependent variables. A two-tailed probability (P) of less than 0.05 was considered statistically significant. 19

RESULTS Median duration of constipation was 16 (range,

3-50) years; 11 patients had symptoms lasting longer than 20 years. Eight had been constipated since childhood. The number of spontaneous defecations

ranged between one every 4 days to one every 30 days, with a mean of one every 7 days.

Three of these patients underwent total colectomy because of the severity and unresponsiveness of their

symptoms. They were followed up for a mean period of 25 months. Although their quality of life is slighltly better than before the operation they still need to take oral laxatives regularly and sometimes an enema to defecate. Furthermore, they still complain of abdominal bloating, nausea, and sometimes vomiting.

The other patients were treated for at least three months with a high-fiber diet (50 g/day), 2 liters of mineral water, and cisapride 30 mg three times per day. Only five (28 percent) patients had a temporary symptomatic improvement that lasted for three to six months after treatment. After this period the same

abdominal symptoms returned.

Esophagus Esophageal manometry was performed in seven

patients. Two patients had symptoms of esophageal reflux, and one patient had symptoms of dysphagia. Five patients showed gross manometric abnormalities, including complete absence of peristalsis (1 pa-

tient), uncoordinated propulsive activity caused by synchronous contractions (1 patient), nutcracker esophagus (1 patient), and uncoordinated activity of the lower esophageal sphincter causing gastroesoph- ageal reflux (2 patients).


Gallbladder

Seventeen patients with slow-transit constipation (3 males) and 16 healthy controls (6 males) had ultrasonographic studies. The two groups were matched for gender, age (44 2 4 and 41 + 4 years; patients and controls, respectively) and body size (23.3 -+ 1.0 and 23.3 -+ 0.8 kg/m2; patients and controls, respectively). Gallbladder motility was studied in 14 patients; 3 were excluded because of a previous laparoscopic chole- cystectomy (2 patients) or a shrunk gallbladder (1 patient; fasting volume of 4 ml, measured on two different occasions). Table 2 gives indexes of gallbladder function at ultrasonography. Although mean fasting gallbladder volume tended to be larger in patients with STC than in controls, this difference did not achieve statistical significance. Also, there was no statistically significant difference in gallbladder emptying between patients and controls with regard to residual volume (both in milliliters and percentage) and area under emptying-time curves. However, postprandial gallbladder emptying was 15 percent slower in patients than controls; overall gallbladder emptying was defective in 43 percent of patients with STC according to the cutoff values. All patients with impaired gallbladder motility also had impaired gastric

emptying.

S t o m a c h

The increase from basal to maximum postprandial antral area was similar in patients (4.1 _+ 0.4 to 14.4 + 0.8 cm2; n = 17) and controls (3.6 -+ 0.3 to 13.0 + 0.8 cm2; n = 16). However, patients had impaired gastric

emptying compared with controls, as shown by the analysis of antrat emptying curves with regard to both

Table 2. Data on Gallbladder Emptying in Patients with

Slow-Transit Constipation and Control Healthy Subjects

Constipated Controls P

No. 14 16 Male/female 2/12 6/10 NS Fasting volume (ml) 28.8 + 2.4 25 +_ 2.4 NS Residual volume (ml) 6,4 _+ 1.6 5.6 _ 1.0 NS Residual volume (%) 23.0 _+ 5.0 23.8 _ 3.5 NS AUC(%120min -1) 8177_+346 8313_+552 NS Half-emptying 26 _+ 4 17 ± 2 0.032

time (min)

NS = not significant; AUC = area under volume-time curve.

Figures are mean _+ standard error.

total and percentage of antrat area (Fig. 1) and by a significant increase in the minimum postprandial area (6.7 _+ 0.9 vs. 4.4 _+ 0.8 cm2; P < 0.05) and half- emptying time (2~/2, 45 + 4 vs. 23 -+ 2 minutes; P < 0.05). According to the cutoff values, antral emptying was delayed in 76 percent of patients.

Table 3 shows the gallbladder and stomach ultrasound transit study in healthy- controls and patients with STC. Among these, four had normal emptying, seven had impaired gastric emptying, and six had impaired gallbladder and gastric emptying.

Half-emptying time of fasting gallbladder volume was increased, particularly in those patients with

combined gallbladder and gastric delayed emptying. Furthermore, the basal antral area was significantly greater in those patients with constipation but normal

motility of gallbladder and stomach, impaired gastric emptying, and impaired gastric and gallbladder emptying (ANOVA; P < 0.05). There were no differences among the three subgroups of patients with regard to other indexes of small intestine and colon transit time and the autonomic nervous system tests.

Orocecal Transit Time

Orocecal transit time was delayed in 18 of 20 (90 percent) patients examined, with a median transit time of 160 (range, 60-200) minutes. This value was significantly longer than in controls (P < 0.001). Two patients had normal transit time (60 and 90 minutes) despite abnormal colonic, gallbladder, and gastric function. However, all other patients had an orocecal transit time longer than 140 minutes. Severity of the delay was not correlated with ages of the patients. It was significantly longer in those patients (n = 12) with less than one defecation per week than in those (n = 8) with one or two defecations per week (175.4 + 7.2 vs. 126.3 + 13.1 minutes; P < 0.002), although no correlation with colonic transit time was found.

C o l o n

All 21 patients underwent evaluation of colonic

transit time because it was included in the entry criteria. Median total colonic transit time was 97 (range, 64-140; 95 percent CI = 84-110) hours. Markers were distributed throughout the colon in all patients. Du-

ration of the colonic transit time did not correlate with

age, small-bowel transit time, or autonomic neuropa-

thy.


A 14 Antral area

12 10

8

6 4 2

0

B (crn2)

~ * * * constipation (n=17) 100 T ~ o5~-~-* . * /

~ ° ° - ° ~ o ~ o ~ o ~ o ~ . 50

controls (n=16) ¢

' ' ' ' ' ' ' ' ' ' . . . . . 7J5 ' ' ' ' ~ - ~ - ' ' ~ 0 0 15 30 45 60 90 105120

Antral area (% of max) O

o.-a; a ¢

(~' '1'5 . . . . . 4'5 . . . . . . . . . . . . . . . 30 60 75 90 105120

T I M E (rain) T I M E (rain)

Figure 1. Time vs. area emptying curves of the stomach in patients with slow-transit constipation and healthy controls in response to a standard liquid meal. A. Antral area as expressed in cm 2. B. Antral area as expressed in percentage of maximal antral area. Symbols indicate means and vertical lines indicate standard error of the mean. Arrows indicate the time at which the test meal was given.

A n o r e c t a l Function

Anal volumetric manometry showed abnormalities in 11 of 19 patients. Maximum anal resting tone was 77.5 + 31 vs. 89 + 29 mmHg in the control group (P = not significant), but three of them had values less than 35 mmHg (below the mean - 2 SD of the controls). Three patients showed alterations in the RIAR; it was absent in one patient, required increased volume (more than 100 ml of air) to be elicited in the second

patient, and showed an insufficient decrease in resting pressure (<20 percen0 in the third patient. Eight patients had impaired sensitivity of the rectal ampulla and required a significantly higher volume to stimu- late defecation (412 _+ 43 vs. 180 + 32 mt in controls; P < 0.01). Three patients had two abnormal findings.

Dynamic defecography showed a coexisting outlet obstruction in 7 of the 11 patients complaining of related symptoms. In five patients a rectocele was

present (associated with perineal descent in one patient and intussusception in two patients), in one patient an isolated second-degree sigmoidocele 20 was present, and in the one patient an intussusception was present.

Autonomic Nervous System

All three autonomic tests (SST, Valsalva, and tilt table) were perfbrmed in nine patients, whereas three patients had both the SST and tilt test, and six patients had only the SST. In eight patients preganglionic and postganglionic sympathetic fibers were tested with the acetylcholine and thermal SST.

The acetylcholine SST revealed the presence of autonomic neuropathy in 14 of 18 (78 percen0 pa-

tients tested, with a mean SST score of 7.46 + 3.7

(range, 0.5-14.0; 95 percent CI = 5.6-9.3). The percentage of abnormal subareas in the test ranged from 0 to 100, with a mean of 36 percent. Seven of the eight patients who had the thermal SST had a complete absence of response. These patients had a low SST score as well, whereas the remaining patient had a nonnal result in both tests.

The Valsalva R-R ratio test was positive (R-R ratio, 1.09) in only one of the nine patients tested. The mean value for this test was identical in the group with constipation and in ten healthy controls, 1.64 -+ 0.4 (range 1.1-2.5, 95 percent CI = 1.33-1.95) mm and 1.64 + 0.4 (range 1.22-2.46, 95 percent CI -- 1.27-2.0) mm, respectively.

The tilt-table test was performed in five patients who reported episodes of orthostatic hypotension. Three patients had a positive response to the test,

with a decrease in systolic blood pressure (125 -+ 12 to 93 -+ 6 mmHg) lasting more than five minutes. These three patients also had low acetylcholine SST scores. Figure 2 shows the percentage of patients with constipation with abno~nal test results at different

levels of the gastrointestinal tract, ranging from 37.5 to 100 percent.

D I S C U S S I O N

Symptoms of constipation may result from a variety of diseases, and patients with constipation can be

regarded as a heterogeneous group. Slow-transit constipation has some characteristic features, such as predominance in young females, frequent onset during childhood, unresponsiveness to bulk laxatives


Table 3. Gastrointestinal Motility and Autonomic Nervous System Function in Healthy Control Subjects and in Patients with

Slow-Transit Constipation with Normal and Defective Emptying of Stomach and Gallbladder

Control

Constipation

Normal Impaired Stomach Impaired Stomach & G B

n 16 4 7 6 Age (yr) 41 ± 4 59 + 8 36 ± 6 43 ± BMI (kg/m 2) 23.0 ± 0.8 24.4 ± 1.6 23.7 ± 1.5 23.7 ± Gallbladder

Fasting volume (ml) 25.5 ± 2.4 24.0 ± 4.8 27.9 _+ 4.8 32.6 _+ Residual volume (ml (%)) 5.6 ± 1.0 3.7 _+ 2.2 3.7 ± 2.2 10.0 ±

23.8 + 3.5 15,9 ± 6.9 13.1 _+ 6,9 34.5 _+ AUCo_~2o (% 120 min -~) 8313 _+ 552 8380 ± 509 9170 _+ 509 7379 ± T1/~ (min) 17 + 2 15 _+ 3 23 + 3 37 ±

Antrum Basal area (cm 2) Max postprandial area (cm 2) Min postprandial area (cm 2 (%))

AUCo_12o (% 120 min -1) T,/~ (min)

Small intestine Orocecal transit t ime (min)

Colon Transit t ime (hr) Defecations per week

Autonomic nervous system Sweat-Spot Test

3.6 ± 0.3 6.0 + 0.6* 3.3 ± 0.5 3.7 _+ 13.0 _+ 0.8 16,4 -+ 1.6 14.0 + 1.2 13.3 -

4.4 -+ 0.8 5.8 -+ 1.5 7.9 ± 1.2 5.7 _+ 10.8 _+ 4.5 0.2 -+ 9.0 36.8 -- 6 .9 t 19.9 _+

8980 -+ 268 10089 --- 535 7227 _+ 405t 7887 -- 23 + 2 20 ± 4 55 -± 3 t 53 ±

D

I

183.7 -+ 18.8 163 _ 12.3 123.5 _+

105.3 -+ 14.0 84.7 +- 10.6 109.3 + 0.8 ± 0.4 0.9 ± 0,3 1.3 ±

5.98 ± 2.01 9.34 -+ 4.42 6.30 _+

7 1.3

3.9 1.8 5.6 415 3*

0.5 1.4 1.4 8.1 4795 4t

13.3

11.4 0.3

1.56

AUC = area under volume-t ime curves; T1/2 = half-emptying time; BMI = body mass index. Figures are mean _ standard error of the mean. * P < 0.05 vs. all groups. t P < 0.05 vs. normal and control. $ P < 0.05 vs. normal (analysis of variance, then Scheff6 multiple comparison test).

and stool-softeners, infrequent spontaneous defecations associated with abdominal discomfort, apparent normality of the colon, and frequent association with other minor complaints related to hollow-organ dysfunction. Association of STC with gastrointestinal or urinary tract dysfunction or orthostatic hypotension and suggestions of a possible involvement of the ANS have been reported by other authors. 3, 17. 2>23 In our study the motility and function of the gastrointestinal tract in patients with STC was evaluated with use of nine independent tests. The results point to the exis- tence of multiple functional defects of several organs of the gastrointestinal tract, although the presenting complaint was severe constipation.

Esophageal manometry showed abnormal motility in approximately two of three patients, suggesting that the esophagus may be involved in patients with STC. Watier e t al . 5 found greater resting pressure in the upper esophageal sphincter, higher incidence of

spontaneous tertiary waves, and lower resting pressure with poor coordination in the low esophageal sphincter in patients with constipation caused by co- Ionic inertia than in controls. These motility disturbances were not specific to a particular esophageal disorder and occurred in patients free from esophageal symptoms. Similar dysfunction was detected in 42 percent of patients with constipation studied by Redmond e t a l . 24 Absence of distal esophageal peristalsis or hypotensive low esophageal sphicnter was reported by Camilleri and Fealey 3 in three of seven patients with various gastrointestinal disfunctions, including constipation.

The present study showed that STC was associated with significant impairment of the motility of the gallbladder and stomach. Simultaneously occurring abnormalities in gallbladder and stomach motility pat- terns were reported by our group in both patients with obesity 9 and patients with gallstones. 7 There is


% abnormal tests 100

80

60

40

20

0

.~,~o~bb~o~°'~xx~o~\ oo o~.~ ~ ' x o~" ^&~

Fi0ure 2. Pementa0e distribution of abnormal tests in the 0astrointestinal tract and autonomic nervous ws tem (AN$) in 21 patients with slow-transit constipation.

evidence that patients with gallstones have delayed gastrointestinal transit time 25, 26 and a longer cycle of the migrating motor complex, with associated disrup- tion of motilin release, iv Heaton et al. 25 reported that whole-gut transit time in females with gallstones was 20 hours longer and total stool output almost 50 percent less than in controls without gallstones. In our study abnormal gallbladder motility was frequent, occurring in up to 43 percent (6/14) of patients, exclud- ing the two patients who had previously undergone a c h o l e c y s t e c t o m y for gallstones.

The two findings of delayed intestinal transit time and hypomotile gallbladder may be linked. The increase in hepatic bile entering the proximal intestine could lead to greater exposure of bile salts to the anaerobic bacteria responsible for biotransformation of hydrophylic bile salts to more hydrophobic bile salts.2S. 29 tt is possible that the increase in these salts in the enterohepatic circulation might further impair gallbladder motility because they have been shown to have a direct effect on the gallbladder. It has been suggested recently that the biliary proportion of hydrophobic deoxycholic acid (implicated in the pathogenesis of cholesterol gallstones) is greater in patients with constipation than in healthy subjects9

Defective gallbladder emptying observed in patients with STC may also be secondary to altered

postprandial gastric emptying, because all patients with constipation with impaired gallbladder motility also had impaired gastric emptying. This may be caused by a cologastric reflex produced by colonic distention rather than by an impairment of autonomic nerves, because abnormal autonomic test results were not found to be significantly- associated with delayed gallbladder and gastric emptying.

The findings of gastric dysmotility in patients with constipation confirm previous results obtained with manometry by Camilleri and Fealey, 3 who found postprandial antral hypomotility in six of eight patients; by Bassotti et al., 2 who found motor abnormalities of stomach and small-bowel motility in 70 percent of patients with chronic idiopathic constipation; and with electrogastrography by Redmond et

al., 24 who found consistent tachygastria. Furthermore, a simultaneous impairment of gallbladder and gastric emptying was recently demonstrated by Hemingway et al. 31

We found that small-bowel transit was delayed in 90 percent of patients with constipation that we studied. This may reflect abnormal fasting and postprandial small-bowel motility, as shown by prolonged manometry in both the proximal and distal small bowel. In fact, a longer Phase II of the migrating motor complex in the duodenum and jejunum was found in females with slow-transit constipation by Kumar e t al. 32 A longer Phase II duration during sleep and occurrence of retrograde propulsion or increased tonic and phasic activity w-as demonstrated in Phase III of the migrating motor complex in the terminal ileum by Panagamuwa et al. 33 in a group of patients with constipation.

Involvement of impaired sacral parasympathetic nerves, the intrinsic enteric nervous system, or both can be hypothesized in a subset of our patients with inappropriate sphincter relaxation to rectal distention, low resting tone, and decreased rectal sensitivity. Sim- ilar findings were reported by Reynolds and col- leagues 34 in a series of patients with severe constipation and these were associated with frequent esophageal and gastric motility disturbances. Impair- ment of the motor and sensory autonomic fibers in- nervating the colon and rectum may result in constipation.

The role of impaired autonomic control of gastrointestinal motility in various motility disturbances, including colonic inertia, was recently addressed by Camilleriy although the cause remains unclear. Other authors could not fully demonstrate an auto-


nomic impairment in patients with constipation, 22,23

probably because of the lower sensitivity of the tests

or of the selective entry criteria for the detection of

AN. The SST has been shown to detect early, asymp-

tomatic forms of AN in patients with diabetes, I5 and

this was also true in a group of patients with severe

constipation. 17 The results obtained with the thermal

SST suggest a possible afferent sensory fiber impair-

ment. This was already suggested by Kamm and

Lennard-Jones 36 with use of rectal mucosal elec-

trosensory tests in idiopathic constipation, Further-

more, selective damage to the unmyelinated sensory

fibers was reported in patients with slow-transit constipation. 37

Three of our patients had positive tilt-table test

results, indicating that not only the cholinergic but

also the adrenergic sympathetic fibers could be in-

volved. The role of the sympathetic nervous system in

the modulation of gastrointestinal function and re-

flexes has recently been clarify by Iovino e t a l . 38

Although results of the Valsalva's maneuver test were

positive in only one of nine patients tested, involve-

ment of the parasympathetic pathway in this disease

cannot be excluded, because of the poor sensitivity of

this test.

In this study, with use of several routine tests of

gastrointestinal function that are easily available in

every gastrointestinal unit and well tolerated even by

patients with anxiety or depression, we have demon-

strated that in the majority of these patients asymp-

tomatic or mildly symptomatic motility disorders of

the entire gastrointestinal tract and sometimes gall-

bladder (even in gallstone-free subjects) often coexist.

The finding that more than 70 percent of patients also

show some degree of autonomic impairment sup-

ports the theory that this kind of constipation may be

caused by dysregulation of the fine mechanisms con-

trolling colonic motility as a result of impaired extrin-

sic autonomic nervous control. These considerations

could explain the persistence of gastrointestinal

symptoms even when the colon is removed, suggest-

ing the need of a complete gastrointestinal motility

workup that includes autonomic nervous system tests

in patients selected for total colectomy for constipa-

tion. Although in these patients total colectomy is

sometimes an obligatory surgical choice, they should

be informed of the possibility of the persistence of

their symptoms when autonomic impairment and mo-

tility disturbance in other gastrointestinal tract are

present.

A C K N O W L E D G M E N T S

The authors thank Mary Pragnell, B.A., for help in preparing the manuscript and Marie-Anne Pilot,

Ph.D., for her helpful comments.

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