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Spinal Cord Injury Is a Risk Factor for Gallstone Disease
GASTROENTEROLOGY 1987;92:966-8
Spinal Cord Injury Is a Risk Factor for Gallstone Disease MICHAEL D. APSTEIN and KAREN DALECKI-CHIPPERFIELD
Medical Services of the Brockton/West Roxbury Veterans Administration Medical Center and the Brigham and Women's Hospital, the Department of Medicine, Harvard Medical School, and the Harvard Digestive Disease Center, Boston, Massachusetts
The purpose of this study was to determine the prevalence of gallstone disease among patients with a spinal cord injury. We identified ali patients with a spinal cord injury of greater than 2 weeks' duration who died and underwent an autopsy between 1975 and 19$5. These 38 patients with spinal cord injury were age-, sex-, and race-matched with 38 patients without spinal cord injury who underwent an autopsy during the same period. Gallstone disease was significantly more prevalent in patients with spinal cord injury (11 of 38 or 29%) compared to the control population (4 of 38 or 11%) (p < 0.05; odds ratio of 3.46 with 95% confidence interval of 1.08-11.24). A significant difference in age or level or duration of spinal cord injury was not found between patients with spinai cord injury who had gallstone disease and those who did not. Possible explanations for this threefold increase in risk of gallstone disease among patients with spinal cord injury include abnormal gallbladder motility resulting in stasis, decreased intestinal transit leading to an abnormal enterohepatic circulation, and metabolic changes leading to abnormal biliary lipid secretion. Patients with spinal cord injury have disorders of gastric, duodenal, and colonic motility (1,2). As the gallbladder receives sympathetic innervation from T-7 through T-10 (3), patients with a spinal cord injury above this level could also have decreased gallbladder motility. Decreased gallbladder motility as a result of a variety of disorders is associated with gallstone formation (4). Therefore, patients with spinal cord injury might be at increased risk for diwelReceived June 17, 1986. Accepted September 25, 1986. Address requests for reprints to: Michael D. Apstein, M.D., Chief, Gastroenterology Section, Veterans Administration Medical Center, 1400 VFW Parkway, West Roxbury, Massachusetts 02132. This work was supported by the Veterans Administratioh. © 1987 by the American Gastroenterological Association 0016-5085/87/$3.50
oping gallstones. The purpose of this study was to determine if spinal cord injury is a risk factor for gallstones. We found that gallstones were three tiines more common in patients with spinal cord injury at autopsy than in fm age-, sex-, and race-matched non-spinal cord injury control population.
Methods Subjects Studied We reviewed the original autopsy reports of all patients with a spinal cord injury of greater than 2 weeks' duration who died between 1975 and 1985 at the West Roxbury Veterans Administration Medical Center. There were 38 such patients whose gallbladder and bile ducts were examined and the results recorded. To obtain a control group, we matched each of the 38 patients with spinal cord injury with the next patient without spinal cord injury to undergo an autopsy who was the same sex and race and was within 2 yr of age of the patient with spinal cord injury. We reviewed the autopsy reports of these patients to determine the prevalence of gallstone disease. As the presence of gallstones is the indication for >95% of all cholecystectomies done in this hospital, we assumed that all patients, spinal cord injury or control, who had undergone a cholecystectomy had gallstones.
Statistical Analysis The group of patients with spinal cord injury and matched control!> were compared using the X 2 test for paired samples. Odds ratio imd 95% confidence intervals were calculated by standard methods (5). Characteristics of the patients with spinal cord injury and gallstones and those without gallstones were compared using the X 2 test or Student's t-test for unpaired observations. Values <0.05 were considered significant.
Results The prevalence of gallstone disease was significantly greater in patients with spinal cord injury. Eleven of 38 (29%) of the patients with spinal cord
April 1987
GALLSTONES AND SPINAL CORD INJURY 967
Table 1. Prevalence of Known Risk Factors for Gallstone Disease Patients with spinal cord injury (n = 38)
Age-, sex-, and race-matched controls (n = 38)
3
6 1
Cirrhosis Ileal disease Vagotomy
o 1
o
injury had gallstone disease at autopsy compared with 4 of 38 (11%) age-, sex-, and race-matched patients without spinal cord injury (p < 0.05; odds ratio of 3.46 with 95% confidence interval of 1.08-11.24). None of the 11 patients with spinal cord injury and gallstone disease had had a cholecystectomy, compared to 2 of 4 control patients. Description of the gallstones was made infrequently. It was not possible to determine the prevalence of cholesterol or pigment gallstones. The mean age of the patients with spinal cord injury was 57 yr (range 21-87 yr) compared to 59 yr (range 24-87 yr) for the controls. All patients in both groups were men. Blacks comprised 11% of each group. The frequency of cirrhosis, ileal disease, and previous vagotomy was similar in each group (Table 1). Periampullary diverticula were not described in any of the 76 subjects. As shown in Table 2, a significant difference was not found between patients with spinal cord injury and gallstone disease and those without gallstone disease with regard to age or level or duration of spinal cord injury.
Discussion This autopsy study indicates that gallstone disease is significantly more common (29% vs 11 %) in patients with spinal cord injury than in age-, sex-, and race-matched patients without spinal cord injury. Autopsy studies are not necessarily representative of a given population because they examine only a selected segment of the population. However, we compared two groups of patients, all of whom underwent an autopsy. Whatever distortion was introduced by patient selection should be similar in each group. It is reassuring that the prevalence rate in our control group (11%) is similar to other published prevalence rates for gallstone disease in similarly aged men (6,7). We have controlled for three important risk factors for gallstone disease: sex, race, and age (4). The prevalence of cirrhosis, ileal disease, vagotomy, and periampullary diverticula, other known risk factors for gallstone disease (4), was similar in the two groups. We did not control for obesity, another
Table 2. Comparison of Patients With Spinal Cord Injury With and Without Gallstone Disease
Age (yr) Mean ± SD Range SCI above T-10 level SCI below T-10 level Duration of injury <1 yr >1 yr
With gallstones 11/38 (29%)
Without gallstones 27/38 (71%)
61 ± 14 40-87 9/33 (27%) 2/5 (40%)
56 ± 17 21-83 24/33 (73%) 3/5 (60%)
4/12 (33%) 7/26 (27%)
8/12 (67%) 19/26 (73%)
SCI, spinal cord injury. No significant difference was found between the patients with spinal cord injury with gallstone disease compared to those without gallstone disease with respect to age or level or duration of spinal cord injury.
significant risk factor (4), but think it is unlikely that our results can be explained by the patients with spinal cord injury being more obese than the controls. In fact, the body weight of patients with spinal cord injury is usually normal or less than normal. A possible explanation for the increased prevalence of gallstone disease in patients with spinal cord injury is decreased gallbladder motility causing gallbladder stasis, a known risk factor for gallstone disease (4,8-11). Patients with spinal cord injury have disorders of gastroduodenal and colonic motility probably because of abnormal sympathetic input (1,2). The gallbladder receives innervation from parasympathetic (vagus) and sympathetic nerves (3). Although vagotomy is associated with an increased risk of gallstone disease (12,13)' patients with spinal cord injury have intact vagi nerves. However, the sympathetic fibers originate from the thoracic spinal segments 7 through 10, reaching the gallbladder via the splanchnic nerves (3). Their precise role in gallbladder motility is not known, but is likely to be important. If decreased gallbladder motility mediated by sympathetic nerves alone were responsible, patients with spinal cord injury below T-l0 should not be at increased risk for gallstone disease. We had too few patients with a spinal cord injury below T-l0 to test this hypothesis. One might expect a correlation between duration of injury and prevalence of gallstone disease if stasis were the cause. However, patients who have gallbladder stasis during fasting for periods as short as 7-10 days have a 15%-35% chance of sludge formation (14). Perhaps only a relatively short period of stasis puts patients with spinal cord injury at risk for gallstone formation. Increasing the duration of gallbladder dysmotility may not increase the risk further. An alternative explanation for the increased risk of
968
APSTEIN AND DALECKI-CHIPPERFIELD
gallstones in patients with spinal cord injury may be an alteration in intestinal motility. The gastroduodenal and colonic motility disorder seen in patients with spinal cord injury may slow intestinal transit (1,2), altering bile acid pool size and biliary lipid secretion (15,16). Pharmacologically induced constipation and slowed intestinal transit has been associated with increasing cholesterol saturation of bile (16). Profound dietary and metabolic changes that occur after spinal cord injury could also playa role. Weight loss and muscle atrophy accompanied by protein and fat mobilization occurs soon after spinal cord injury. Obese individuals can acutely increase biliary cholesterol saturation during weight loss (17). Whether the same is true for patients with more normal body weight is not known. Additionally, the reduced food intake during the first several weeks after injury may put patients at risk for development of biliary sludge and subsequent gallstone formation (14).
In summary, spinal cord injury appears to be a risk factor for gallstone disease. Additional prospective studies are needed to confirm this association. Possible explanations for the increased risk of gallstone disease in patients with spinal cord injury include decreased gallbladder motility leading to gallbladder stasis, decreased intestinal transit leading to an alteration in the enterohepatic circulation, and metabolic changes leading to abnormal biliary lipid secretion.
References 1. Fealey RD, Szurszewski JR, Merritt JL. DiMangno EP. Effect of traumatic spinal cord transection on human upper gastrointestinal motility and gastric emptying. Gastroenterology 1984;87:69-75. 2. Glick ME. Meshkinpour H. Haldeman S, Hoehler F. Downey N. Bradley WE. Colonic dysfunction in patients with thoracic spinal cord injury. Gastroenterology 1984;86:287-94.
GASTROENTEROLOGY Vol. 92. No.4
3. Hogan WI. Dodds WI. Geenen JE. The biliary tract. In: Christensen J. Wingate DL. eds. A guide to gastrointestinal motility. Boston: Wright PSG. 1983:157-97. 4. Apstein MD. Carey MC. Gallstone disease. In: Branch WT Jr. ed. Office practice of medicine. 2nd ed. Philadelphia: Saunders. 1987 (in press). 5. Fleiss JL. Confidence intervals for the odds ratio in casecontrol studies: the state of the art. J Chronic Dis 1979; 32:69-77. 6. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease. Observations in the Framingham study. J Chronic Dis 1966;19:273-92. 7. Newman HF. Northup JD. Collective review: the autopsy incidence of gallstones. Int Abst Surg 1959;109:1-13. 8. Messing B, Bories C, Kurstlinger F, Bernier JJ. Does total parenteral nutrition induce gallbladder sludge formation and lithiasis. Gastroenterology 1983;84:1012-9. 9. Pitt HA. King W III. Mann LL. et al. Increased risk of cholelithiasis with prolonged parenteral nutrition. Am J Surg 1983;145:106-12. 10. Roslyn Berquist WE, Pitt HA, et al. Increased risk of gallstones in children on total parenteral nutrition. Pediatrics 1983;71:784-9. 11. Roslyn n, Pitt HA. Mann LL. Ament ME, DenBesten L. Gallbladder disease in patients on long-term parenteral nutrition. Gastroenterology 1983;84:148-54. 12. Csences A, Larach I. Godoy M. Incidence of gallstones development after selective hepatic vagotomy. Acta Chir Scand 1978;144:289-91. 13. Sapala MA. Sapala JA. Resto Soto AD, Bouwman DL. Cholelithiasis following subtotal gastric resection with truncal vagotomy. Surg Gynecol Obstet 1979;148:36-8. 14. Bolondi L, Gaiani S. Tesia S. Labo G. Gallbladder sludge formation during prolonged fasting after gastrointestinal tract surgery. Gut 1985;26:734-8. 15. Duane WC. Hanson KC. Role of gallbladder emptying and small bowel transit in regulation of bile acid pool size in man. J Lab Clin Med 1978;92:858-72. 16. Marcus SN. Heaton KW. Intestinal transit, deoxycholic acid and the cholesterol saturation of bile-three inter-related factors. Gut 1986;27:550-8. 17. Bennion LI. Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 1975; 56:996-1011.
n.
Spinal Cord Injury Is a Risk Factor for Gallstone Disease MICHAEL D. APSTEIN and KAREN DALECKI-CHIPPERFIELD
Medical Services of the Brockton/West Roxbury Veterans Administration Medical Center and the Brigham and Women's Hospital, the Department of Medicine, Harvard Medical School, and the Harvard Digestive Disease Center, Boston, Massachusetts
The purpose of this study was to determine the prevalence of gallstone disease among patients with a spinal cord injury. We identified ali patients with a spinal cord injury of greater than 2 weeks' duration who died and underwent an autopsy between 1975 and 19$5. These 38 patients with spinal cord injury were age-, sex-, and race-matched with 38 patients without spinal cord injury who underwent an autopsy during the same period. Gallstone disease was significantly more prevalent in patients with spinal cord injury (11 of 38 or 29%) compared to the control population (4 of 38 or 11%) (p < 0.05; odds ratio of 3.46 with 95% confidence interval of 1.08-11.24). A significant difference in age or level or duration of spinal cord injury was not found between patients with spinai cord injury who had gallstone disease and those who did not. Possible explanations for this threefold increase in risk of gallstone disease among patients with spinal cord injury include abnormal gallbladder motility resulting in stasis, decreased intestinal transit leading to an abnormal enterohepatic circulation, and metabolic changes leading to abnormal biliary lipid secretion. Patients with spinal cord injury have disorders of gastric, duodenal, and colonic motility (1,2). As the gallbladder receives sympathetic innervation from T-7 through T-10 (3), patients with a spinal cord injury above this level could also have decreased gallbladder motility. Decreased gallbladder motility as a result of a variety of disorders is associated with gallstone formation (4). Therefore, patients with spinal cord injury might be at increased risk for diwelReceived June 17, 1986. Accepted September 25, 1986. Address requests for reprints to: Michael D. Apstein, M.D., Chief, Gastroenterology Section, Veterans Administration Medical Center, 1400 VFW Parkway, West Roxbury, Massachusetts 02132. This work was supported by the Veterans Administratioh. © 1987 by the American Gastroenterological Association 0016-5085/87/$3.50
oping gallstones. The purpose of this study was to determine if spinal cord injury is a risk factor for gallstones. We found that gallstones were three tiines more common in patients with spinal cord injury at autopsy than in fm age-, sex-, and race-matched non-spinal cord injury control population.
Methods Subjects Studied We reviewed the original autopsy reports of all patients with a spinal cord injury of greater than 2 weeks' duration who died between 1975 and 1985 at the West Roxbury Veterans Administration Medical Center. There were 38 such patients whose gallbladder and bile ducts were examined and the results recorded. To obtain a control group, we matched each of the 38 patients with spinal cord injury with the next patient without spinal cord injury to undergo an autopsy who was the same sex and race and was within 2 yr of age of the patient with spinal cord injury. We reviewed the autopsy reports of these patients to determine the prevalence of gallstone disease. As the presence of gallstones is the indication for >95% of all cholecystectomies done in this hospital, we assumed that all patients, spinal cord injury or control, who had undergone a cholecystectomy had gallstones.
Statistical Analysis The group of patients with spinal cord injury and matched control!> were compared using the X 2 test for paired samples. Odds ratio imd 95% confidence intervals were calculated by standard methods (5). Characteristics of the patients with spinal cord injury and gallstones and those without gallstones were compared using the X 2 test or Student's t-test for unpaired observations. Values <0.05 were considered significant.
Results The prevalence of gallstone disease was significantly greater in patients with spinal cord injury. Eleven of 38 (29%) of the patients with spinal cord
April 1987
GALLSTONES AND SPINAL CORD INJURY 967
Table 1. Prevalence of Known Risk Factors for Gallstone Disease Patients with spinal cord injury (n = 38)
Age-, sex-, and race-matched controls (n = 38)
3
6 1
Cirrhosis Ileal disease Vagotomy
o 1
o
injury had gallstone disease at autopsy compared with 4 of 38 (11%) age-, sex-, and race-matched patients without spinal cord injury (p < 0.05; odds ratio of 3.46 with 95% confidence interval of 1.08-11.24). None of the 11 patients with spinal cord injury and gallstone disease had had a cholecystectomy, compared to 2 of 4 control patients. Description of the gallstones was made infrequently. It was not possible to determine the prevalence of cholesterol or pigment gallstones. The mean age of the patients with spinal cord injury was 57 yr (range 21-87 yr) compared to 59 yr (range 24-87 yr) for the controls. All patients in both groups were men. Blacks comprised 11% of each group. The frequency of cirrhosis, ileal disease, and previous vagotomy was similar in each group (Table 1). Periampullary diverticula were not described in any of the 76 subjects. As shown in Table 2, a significant difference was not found between patients with spinal cord injury and gallstone disease and those without gallstone disease with regard to age or level or duration of spinal cord injury.
Discussion This autopsy study indicates that gallstone disease is significantly more common (29% vs 11 %) in patients with spinal cord injury than in age-, sex-, and race-matched patients without spinal cord injury. Autopsy studies are not necessarily representative of a given population because they examine only a selected segment of the population. However, we compared two groups of patients, all of whom underwent an autopsy. Whatever distortion was introduced by patient selection should be similar in each group. It is reassuring that the prevalence rate in our control group (11%) is similar to other published prevalence rates for gallstone disease in similarly aged men (6,7). We have controlled for three important risk factors for gallstone disease: sex, race, and age (4). The prevalence of cirrhosis, ileal disease, vagotomy, and periampullary diverticula, other known risk factors for gallstone disease (4), was similar in the two groups. We did not control for obesity, another
Table 2. Comparison of Patients With Spinal Cord Injury With and Without Gallstone Disease
Age (yr) Mean ± SD Range SCI above T-10 level SCI below T-10 level Duration of injury <1 yr >1 yr
With gallstones 11/38 (29%)
Without gallstones 27/38 (71%)
61 ± 14 40-87 9/33 (27%) 2/5 (40%)
56 ± 17 21-83 24/33 (73%) 3/5 (60%)
4/12 (33%) 7/26 (27%)
8/12 (67%) 19/26 (73%)
SCI, spinal cord injury. No significant difference was found between the patients with spinal cord injury with gallstone disease compared to those without gallstone disease with respect to age or level or duration of spinal cord injury.
significant risk factor (4), but think it is unlikely that our results can be explained by the patients with spinal cord injury being more obese than the controls. In fact, the body weight of patients with spinal cord injury is usually normal or less than normal. A possible explanation for the increased prevalence of gallstone disease in patients with spinal cord injury is decreased gallbladder motility causing gallbladder stasis, a known risk factor for gallstone disease (4,8-11). Patients with spinal cord injury have disorders of gastroduodenal and colonic motility probably because of abnormal sympathetic input (1,2). The gallbladder receives innervation from parasympathetic (vagus) and sympathetic nerves (3). Although vagotomy is associated with an increased risk of gallstone disease (12,13)' patients with spinal cord injury have intact vagi nerves. However, the sympathetic fibers originate from the thoracic spinal segments 7 through 10, reaching the gallbladder via the splanchnic nerves (3). Their precise role in gallbladder motility is not known, but is likely to be important. If decreased gallbladder motility mediated by sympathetic nerves alone were responsible, patients with spinal cord injury below T-l0 should not be at increased risk for gallstone disease. We had too few patients with a spinal cord injury below T-l0 to test this hypothesis. One might expect a correlation between duration of injury and prevalence of gallstone disease if stasis were the cause. However, patients who have gallbladder stasis during fasting for periods as short as 7-10 days have a 15%-35% chance of sludge formation (14). Perhaps only a relatively short period of stasis puts patients with spinal cord injury at risk for gallstone formation. Increasing the duration of gallbladder dysmotility may not increase the risk further. An alternative explanation for the increased risk of
968
APSTEIN AND DALECKI-CHIPPERFIELD
gallstones in patients with spinal cord injury may be an alteration in intestinal motility. The gastroduodenal and colonic motility disorder seen in patients with spinal cord injury may slow intestinal transit (1,2), altering bile acid pool size and biliary lipid secretion (15,16). Pharmacologically induced constipation and slowed intestinal transit has been associated with increasing cholesterol saturation of bile (16). Profound dietary and metabolic changes that occur after spinal cord injury could also playa role. Weight loss and muscle atrophy accompanied by protein and fat mobilization occurs soon after spinal cord injury. Obese individuals can acutely increase biliary cholesterol saturation during weight loss (17). Whether the same is true for patients with more normal body weight is not known. Additionally, the reduced food intake during the first several weeks after injury may put patients at risk for development of biliary sludge and subsequent gallstone formation (14).
In summary, spinal cord injury appears to be a risk factor for gallstone disease. Additional prospective studies are needed to confirm this association. Possible explanations for the increased risk of gallstone disease in patients with spinal cord injury include decreased gallbladder motility leading to gallbladder stasis, decreased intestinal transit leading to an alteration in the enterohepatic circulation, and metabolic changes leading to abnormal biliary lipid secretion.
References 1. Fealey RD, Szurszewski JR, Merritt JL. DiMangno EP. Effect of traumatic spinal cord transection on human upper gastrointestinal motility and gastric emptying. Gastroenterology 1984;87:69-75. 2. Glick ME. Meshkinpour H. Haldeman S, Hoehler F. Downey N. Bradley WE. Colonic dysfunction in patients with thoracic spinal cord injury. Gastroenterology 1984;86:287-94.
GASTROENTEROLOGY Vol. 92. No.4
3. Hogan WI. Dodds WI. Geenen JE. The biliary tract. In: Christensen J. Wingate DL. eds. A guide to gastrointestinal motility. Boston: Wright PSG. 1983:157-97. 4. Apstein MD. Carey MC. Gallstone disease. In: Branch WT Jr. ed. Office practice of medicine. 2nd ed. Philadelphia: Saunders. 1987 (in press). 5. Fleiss JL. Confidence intervals for the odds ratio in casecontrol studies: the state of the art. J Chronic Dis 1979; 32:69-77. 6. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease. Observations in the Framingham study. J Chronic Dis 1966;19:273-92. 7. Newman HF. Northup JD. Collective review: the autopsy incidence of gallstones. Int Abst Surg 1959;109:1-13. 8. Messing B, Bories C, Kurstlinger F, Bernier JJ. Does total parenteral nutrition induce gallbladder sludge formation and lithiasis. Gastroenterology 1983;84:1012-9. 9. Pitt HA. King W III. Mann LL. et al. Increased risk of cholelithiasis with prolonged parenteral nutrition. Am J Surg 1983;145:106-12. 10. Roslyn Berquist WE, Pitt HA, et al. Increased risk of gallstones in children on total parenteral nutrition. Pediatrics 1983;71:784-9. 11. Roslyn n, Pitt HA. Mann LL. Ament ME, DenBesten L. Gallbladder disease in patients on long-term parenteral nutrition. Gastroenterology 1983;84:148-54. 12. Csences A, Larach I. Godoy M. Incidence of gallstones development after selective hepatic vagotomy. Acta Chir Scand 1978;144:289-91. 13. Sapala MA. Sapala JA. Resto Soto AD, Bouwman DL. Cholelithiasis following subtotal gastric resection with truncal vagotomy. Surg Gynecol Obstet 1979;148:36-8. 14. Bolondi L, Gaiani S. Tesia S. Labo G. Gallbladder sludge formation during prolonged fasting after gastrointestinal tract surgery. Gut 1985;26:734-8. 15. Duane WC. Hanson KC. Role of gallbladder emptying and small bowel transit in regulation of bile acid pool size in man. J Lab Clin Med 1978;92:858-72. 16. Marcus SN. Heaton KW. Intestinal transit, deoxycholic acid and the cholesterol saturation of bile-three inter-related factors. Gut 1986;27:550-8. 17. Bennion LI. Grundy SM. Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 1975; 56:996-1011.
n.