Abstract
Introduction
Over the past decade, obesity has become epidemic, and the number of cholecystectomies as well as the percentage with acalculous cholecystitis have increased. We have recently reported that congenitally obese mice and lean mice fed a high fat diet have increased gallbladder wall lipids and poor gallbladder emptying. Therefore, we tested the hypothesis that compared to patients with a normal gallbladder, patients with both acalculous and calculous cholecystitis would have increased gallbladder wall fat.
Methods
Sixteen patients who underwent cholecystectomy for acalculous cholecystitis were identified. Sixteen nondiseased controls who underwent incidental cholecystectomy during surgery for liver or pancreatic disease and 16 diseased controls whose gallbladder was removed for chronic calculous cholecystitis were chosen to match the acalculous patients for gender and Body Mass Index. Pathology specimens were reviewed in a blinded fashion for gallbladder wall fat, thickness, and inflammation.
Results
Acalculous cholecystitis patients were younger (p < 0.01) than nondiseased or diseased controls. Gallbladder wall fat was significantly increased (p < 0.02) in the acalculous and calculous cholecystitis patients compared to the nondiseased controls. Gallbladder wall thickness (p < 0.02) and inflammatory score (p < 0.01) were highest in the calculous cholecystitis patients.
Conclusions
These data suggest that compared to nondiseased controls, (1) patients with acalculous cholecystitis are younger and have increased gallbladder fat and (2) patients with calculous cholecystitis have increased gallbladder fat and inflammation. We conclude that increased gallbladder fat may lead to poor gallbladder emptying and biliary symptoms. Thus, cholecystosteatosis may explain, in part, the increased need for cholecystectomy and the higher percentage of these patients with acalculous cholecystitis.
Similar content being viewed by others
References
Steiner C, Bass EB, Talamini MA, Pitt HA, Steinberg EP. Laparoscopic cholecystectomy in Maryland: trends in surgical rates and operative mortality. N Engl J Med 1994;330:403–408.
Escare JJ, Chen W, Swartz JS. Falling cholecystectomy thresholds since the introduction of laparoscopic cholecystectomy. JAMA 1995;273:1581–1585.
Cohen MM, Young W, Theriault ME, Hernandez R. Has laparoscopic cholecystectomy changed patterns of practice and patient outcome in Ontario? Can Med Assoc J 1996;154:491–500.
Lam CM, Murray FE, Cuschieri A. Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy in Scotland. Gut 1996;38:1581–1585.
Marshal D, Clark E, Hailey D. The impact of laparoscopic cholecystectomy in Canada and Australia. Health Policy 1994;26:221–230.
Graves EJ, Owings MF, 1995 Summary: National Hospital Discharge Survey. Advance data from vital and health statistics; no.291. National Center of Health Statistics 1997.
Mokad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;289:76–79.
Centers for Disease Control and Prevention. National diabetes fact sheet: General information and national estimates on diabetes in the United States, 2003. Atlanta, GA, 2003.
Joahanning JM, Gruenberg JC. The changing face of cholecystectomy. Am Surg 1998;64:643–647.
Patel NA, Lamb JJ, Hogle NJ, Fowler DL. Therapeutic efficacy of laparoscopic cholecystectomy in the treatment of biliary dyskinesia. Am J Surg 2004;187:209–212.
Corazziari E, Shaffer EA, Hogan WJ, Sherman S, Toouli J. Functional disorders of the biliary tract and pancreas. Gut 1999;45(Suppl II):II48–II54.
Bingener J, Richards ML, Schwesinger H, Sirinek KR. Laparoscopic cholecystectomy for biliary dyskinesia. Surg Endosc 2004;18:802–806.
Majeski J. Gallbladder ejection fraction: an accurate evaluation of symptomatic acalculous gallbladder disease. Int Surg 2003;88:95–99.
Kline LW, Karpinski E. Progesterone inhibits gallbladder motility through multiple signaling pathways. Steroids 2005;70:673–679.
Tierney S, Qian Z, Burrow C, Lipsett PA, Pitt HA, Lillemoe KD. Estrogen inhibits sphincter of Oddi motility. J Surg Res 1994;57:69–73.
Tierney S, Qian Z, Yung B, Lipsett PA, Pitt HA, Sostre S, Lillemoe KD. Gender influences sphincter of Oddi response to cholecystokinin in the prairie dog. Am J Physiol 1995;269:G476–G480.
Goldblatt MI, Swartz-Basile DA, Al-Azzawi HA, Tran KQ, Nakeeb A, Pitt HA. Nonalcoholic fatty gallbladder disease: the influence of diet. J Gastrointest Surg 2006;10:193–201.
Ponsky TA, Sagun RD, Brody F. Surgical therapy for biliary dyskinesia: a meta-analysis and review of the literature. J Laparoendosc Adv Surg Tech A 2005;15:439–442.
Corazziari E, Shaffer EA, Hogan WJ, Sherman S, Toouli J. Functional disorders of the biliary tract and pancreas. In Drossman DA, Corazziari E, Talley NJ, Thompson WG, Whitehead WE, eds. Rome II: The Functional Gastrointestinal Disorders, 2nd ed. McLean, VA: Degnon Associates, 2000, pp 433–482.
Zech ER, Simmons LB, Kendrick RR, Soballe PW, Olcese JAM, Goff WB II, Lawrence DP, DeWeese RA. Cholecystokinin enhanced hepatobiliary scanning with ejection fraction calculation as an indicator of disease of the gallbladder. Surg Gynecol Obstet 1991;172:21–24.
Ozden N, DiBaise JK. Gallbladder ejection fraction and symptom outcome in patients with acalculous biliary-like pain. Dig Dis Sci 2003;48:890–897.
Poynter MT, Saba AK, Evans RA, Johnson WM, Hasl DM. Chronic acalculous biliary disease: cholecystokinin cholescintigraphy is useful in formulating treatment strategy and predicting success after cholecystectomy. Am Surg 2002;68:382–384.
Nakeeb A, Comuzzie AG, Al-Azzawi H, Sonnenberg GE, Kissebah AH, Pitt HA. Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg 2006;10(7):940–949.
GREPCO (The Rome Group for Epidemiology and Prevention of Cholelithiasis). The epidemiology of gallstone disease in Rome, Italy. I. Prevalence data in men. Hepatology 1988;8:904–906.
GREPCO (The Rome Group for Epidemiology and Prevention of Cholelithiasis). Prevalence of gallstone disease in an Italian adult female population. Am J Epidemiol 1984;119:796–805.
Yap L, Wycherly AG, Morphett AD, Toouli J. Acalculous biliary pain: cholecystectomy alleviates symptoms in patients with abnormal cholescintigraphy. Gastroenterology 1991;101:786–793.
Amaral J, Xiao Z, Chen Q, Yu P, Biancani P, Behar J. Gallbladder muscle dysfunction in patients with chronic acalculous disease. Gastroenterology 2001;120:506–511.
Goldblatt MI, Swartz-Basile DA, Svatek CL, Nakeeb A, Pitt HA. Decreased gallbladder response in leptin-deficient obese mice. J Gastrointest Surg 2002;6:438–444.
Tran KQ, Swartz-Basile DA, Nakeeb A, Pitt HA. Gallbladder motility in Agouti-Yellow and leptin-resistant obese mice. J Surg Res 2003;113:56–61.
Graewin SJ, Kiely JM, Svatek CL, Pitt HA. CNTF restores gallbladders contractility in leptin-resistant obese diabetic mice. J Surg Res 2006;130:146–51.
Tran KQ, Goldblatt MI, Swartz-Basile DA, Svatek CL, Nakeeb A, Pitt HA. Diabetes and hyperlipidemia correlate with gallbladder contractility in leptin-related murine obesity. J Gastrointest Surg 2003;7:857–863.
Phillips J, Tran KQ, Goldblatt MI, Swartz-Basile DA, Nakeeb A, Pitt HA. Leptin ameliorates the gallbladder’s response to neurotransmitters in congenitally obese mice. Gastroenterology 2002;123:9.
Alam SQ, Ren YF, Alam BS. Effect of cholesterol feeding on membrane fluidity, (Na-K) ATPase, adenylate cyclase, [3H]-ouabain- and [3H]-dihydroalprenolol-binding in rat submandibular salivary glands. J Dent Res 1987;66:605–607.
Gleason MM, Medow MS, Tulenko TN. Excess membrane cholesterol alters calcium movements, cytosolic calcium levels, and membrane fluidity in arterial smooth muscle cells. Circ Res 1991;69:216–227.
Yu P, Chen Q, Biancani P, Behar J. Membrane cholesterol alters gallbladder muscle contractility in prairie dogs. Am J Physiol 1996;271:G56–G61.
Chen Q, Amaral J, Biancani P, Behar J. Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity. Gastroenterology 1999;116:678–685.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–432.
Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–1271.
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–2556.
Louise H, Johannes BP. Fat as an endocrine organ: relationship to the metabolic syndrome. Am J Med Sci 2005;330:280–289.
Traythurn P, Wood IS. Signalling role of adipose tissue: adipokines and inflammation in obesity. Biochem Soc Trans 2005;33:1078–1081, 2005.
Critiana EJ, Elvire H, Chritoph AM. Adipose tissue: a regulator of inflammation. Best Pract Res Clin Endocrinol Metab 2005;19:547–556.
Bullo M, Garcia-Lorda P, Megias I, et al. Systemic inflammation, adipose tissue tumor necrosis factor, and leptin expression. Obes Res 2003;11:525–531.
Hui-Yuen JS, Duong TT, Yeung RS. TNF-{alpha} is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease. J Immunol 2006;176:6294–6301.
Van Deventer SJ. Tumor necrosis factor and Crohn’s disease. Gut 1997;40:443–448.
Rege RV. Inflammatory cytokines alter human gallbladder epithelial cell absorption/secretion. J Gastrointest Surg 2000;4:185–192.
Gilloteaux J, Tomasello LM, Elgison DA. Lipid deposits and lipo-mucosomes in human cholecystitis and epithelial metaplasia in chronic cholecystitis. Ultrastruct Pathol 2003;27:313–321.
Gilloteaux J, Miller D, Morrison RL. Intracellular liposomes and cholesterol deposits in chronic cholecystitis and biliary sludge. Ultrastruct Pathol 2004;28:123–136.
Doty JE, Pitt HA, Kuchenbecker SL, DenBesten L. Impaired gallbladder emptying before gallstone formation in the prairie dog. Gastroenterology 1983;85:168–174.
Conter RL, Roslyn JJ, Porter-Fink V, DenBesten L. Gallbladder absorption increases during early cholesterol gallstone formation. Am J Surg 1986;151:184–191.
McGavock JM, Victor RG, Unger RH, Szczepaniank LS. Adiposity of the heart, revisited. Ann Intern Med 2006;144:517–524.
Schaffer JE. Lipotoxicity: when tissues overeat. Curr Opin Lipidol 2003;14:281–287.
Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg 2002;12:49–51.
Sabir N, Sermez Y, Kazil S, Zencir M. Correlation of abdominal fat accumulation and liver steatosis: importance of ultrasonographic and anthropometric measurements. Eur J Ultrasound 2001;14:121–128.
Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzettoet M. Nonalcoholic fatty liver, steatohepatitis and the metabolic syndrome. Hepatology 2003;37:917–923.
Acknowledgement
This work is supported by NIH grant R-01 DK44279.
Author information
Authors and Affiliations
Corresponding author
Additional information
Discussion
Dr. Bingener-Casey (San Antonio, TX): Thank you very much for the opportunity to review this interesting paper ahead of time. Against the backdrop of rising obesity and cholecystectomy rates, your group examined whether fatin the gallbladder wall of diseased gallbladders versus normal gallbladders would be increased. In the manuscript you do not describe how you actually measured the fat content in the gallbladder wall, if you used histomorphometry or if you used Sudan red or any biochemical method. It would be interesting to know forothers to confirm your findings. You also showed that only thechronic cholecystitis group had an increase in inflammatory cells. So my question is, is it truly steatocholecystitis that you saw inthe patients with acalculous cholecystitis or biliary dyskinesia? And then, did the symptoms of the patients with biliary dyskinesia resolve? Is there a correlation between the amount of fat content you saw in the ejection fraction which would support your hypothesis? Is the fat content in the gallbladder wall of patients with biliary dyskinesia different than it was before the introduction of laparoscopic cholecystectomy? Do you have any historical control? And how do you plan to correct for confounderssuch as a changed risk-benefit ratio of laparoscopic versus open cholecystectomy if you are trying to explain the increased rates of cholecystectomy for both biliary dyskinesia and acalculous cholecystitis with increased fat in the gallbladder wall?
Dr. Al-Azzawi: With respect to your first question, we measured the thickness of the fat and the full wall thickness in millimeters in H&E stained gallbladder sections. From these two values, we calculated the percentage of gallbladder fat in the wall.
With respect to your second question regarding inflammatory cells, they were only increased in the gallstone patients. However, we believe that cytokines are increased in the chronic acalculous cholecystitis patients. We have data demonstrating increased gallbladder wall fat and cytokines in animals fed a high fat diet. These animals have decreased gallbladder emptying in the absence of gallstones. We are prospectively collecting human gallbladders for fat and cytokine analysis, but this study has not been completed.
With respect to clinical outcomes, the number of patients whose gallbladders were examined histologically was small. In our experience, however, patients who have typical biliary symptoms, a very low ejection fraction and no gallstones generally get a good clinical response from cholecystectomy.
All of our patients with chronic acalculous cholecystitis had very low ejection fractions and most had elevated gallbladder fat. Therefore, no obvious correlation was found.
With respect to your questions of gallbladder fat content with open versus laparoscopic cholecystectomy, we have no data. However, the percentage of patients with chronic acalculous cholecystitis coming to cholecystectomy clearly has increased in recent years.
Dr. H. Kaufman (Los Angeles, CA): Very nicely presented. Your BMI in the symptomatic group with a mean BMI less than 30 doesn't really seem to fit the demographic of someone with chronic cholecystitis. Can you speak to the BMI range? Also, have you looked at patients with larger BMIs to see if there is an increase in gallbladder wall fat as BMI increases?
Dr. Al-Azzawi: The BMI of the patients ranged from 15 to 56, but the mean in each group was less than 30. Initially, we matched the groups for gender and BMI and found differences in gallbladder fat but not in metabolic syndrome parameters. We thought that controlling for patient BMI was important in demonstrating differences in gallbladder wall fat.
Dr. R. Prinz (Chicago, IL): I just wanted to ask you about your control group. It seems that these were patients undergoing operations for tumors in the liver and pancreas. If that is correct, does that malignancyhave an effect here on the amount of fat you are going to find in the control patients, since many of these will either have lost weight or certainly have had anorexia near the time their gallbladder is removed? So I would like your comments on that.
Dr. Al-Azzawi: Only six of our 16 control patients had adenocarcinomas. Four had non invasive intraductal papillary mucinous neoplasms of the pancreas, two had hepatic adenomas, two had neuroendocrine tumors, and two had benign pancreatobiliary problems. Again, these control patients were matched with the acalculous and calculous cholecystitis patients for BMI.
Rights and permissions
About this article
Cite this article
Al-Azzawi, H.H., Nakeeb, A., Saxena, R. et al. Cholecystosteatosis: an Explanation for Increased Cholecystectomy Rates. J Gastrointest Surg 11, 835–843 (2007). https://doi.org/10.1007/s11605-007-0169-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11605-007-0169-0