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Crohn’s disease involving the gallbladder
AJG – February, 2003
Letters to the Editor
509
Figure 2. Number of bowel movements per day (solid line) and jet lag values established using the Columbia Jet Lag Scale questionnaire (dotted line) before, during, and after the trip. Statistical correlation was only obtained for the first day after the trip (*). Values are means and SDs.
Graciela Salis Gastroenterology Department Hospital Profesor Alejandro Posadas Buenos Aires, Argentina
REFERENCES 1. DuPont HL, Ericsson CD. Prevention and treatment of traveler’s diarrhea. N Engl J Med 1993;328:1821–7. 2. Wood JD, Alpers DH, Andrews PLR. Fundamentals of neurogastroenterology. Gut 1999;45(suppl II):II6 –II16. 3. Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol 1994;19:28 –30. 4. Spitzer RL, Terman M, Williams JB, et al. Jet lag: Clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Am J Psych 1999;9:1392–6. 5. Metcalf AM, Phillips SF, Zinsmeister AR, et al. Simplified assessment of segmental colonic transit. Gastroenterology 1987;92:40 –7. 6. Grupo Espan˜ ol Para el Estudio de la Motilidad Digestiva. Medida del tiempo de tra´ nsito colo´ nico (total y segmentario) con marcadores radiopacos. Valores de referencia nacional obtenidos en 192 sujetos sanos. Gastroenterol Hepatol 1998;21: 71–5.
Reprint requests and correspondence: Fermı´n Mearin, Institute of Functional and Motor Digestive Disorders, Centro Me´ dico Teknon, Vilana 12, 08022 Barcelona, Spain. Received Oct. 24, 2001; accepted Sep. 19, 2002.
Crohn’s Disease Involving the Gallbladder: Case Report and Review of the Literature TO THE EDITOR: Crohn’s disease is known to involve the gastrointestinal tract from the oral cavity to the anus. Extraintestinal involvement has also been described, including the hepatobiliary system. We present a case report and review of the literature of acute cholecystitis caused by Crohn’s disease of the gallbladder. A 64-yr-old man presented to the Audie L. Murphy Memorial Veterans Hospital in San Antonio, TX, with complaints of abdominal pain, anorexia, and nausea occurring for approximately 1 wk. The pain was localized to the right upper quadrant and made worse by food ingestion. He denied fevers, chills, melena, hematochezia, scleral icterus, or dark colored urine. His past medical history included Crohn’s disease, which had been diagnosed 5 yr before presentation after being admitted to an outside institution with a clinical picture compatible with a small bowel obstruction. Laparotomy had revealed transmural inflammation involving the distal ileum requiring resection of 20 cm of ileum with 30 cm of colon and an ileotransverse anastomosis. The diagnosis of Crohn’s disease was confirmed by pathological examination of the submitted specimen. The patient recovered uneventfully and remained asymptomatic without medications until the time of admission to our hospital years later. At the time of admission, the patient’s vital signs were: temperature 100.8 F, blood pressure 119/78 mm Hg, and pulse 92 beats/min. Physical examination revealed a man in
510
Letters to the Editor
mild discomfort, with pain to palpation to the right upper quadrant with guarding but no rebound. Murphy’s sign was negative. Pertinent laboratory data included a white blood cell count of 8.9 (⫻103/L), hematocrit of 25% and albumin of 2.0 g/dl. Values of total bilirubin, transaminases, ALP, amylase, and lipase were within the normal range. An abdominal sonogram showed a somewhat dilated gallbladder with a thickened wall and pericholecystic fluid. Discrete hyperechoic areas filled the gallbladder, without distinct acoustic shadows. The intra- and extrahepatic bile ducts appeared normal. The findings were suggestive of cholecystitis, although the presence of gallstones could not be conclusively determined. The patient was admitted to the surgical service and was initially treated conservatively with bowel rest and i.v. fluids. After 48 h, the patient continued to have low-grade fevers and right upper quadrant abdominal tenderness, so he was taken for a laparoscopic cholecystectomy. The operation was complicated by an enterotomy involving the proximal duodenum, prompting conversion to an open approach and performance of a pyloric exclusion, cholecystectomy, and loop gastrojejunostomy. During inspection and closure of the duodenotomy, no mention was made regarding mucosal abnormalities consistent with inflammatory bowel disease. The gallbladder was grossly unremarkable. The serosal surface was smooth without adhesions or exudate. The mucosa was dark and velvety without any distinct lesions. No calculi were present. Microscopically, the mucosa showed areas of acute and chronic cholecystitis intermixed with areas of relatively unaffected mucosa. The areas of acute cholecystitis were manifested by infiltration of neutrophils into the mucosal epithelial with occasional ulcer formation. Rokitansky-Aschoff sinuses were also present. Within the lamina propria were numerous well-formed granulomas composed of epithelioid histiocytes. Silver and acid fast stains failed to reveal any organisms within the granulomas, and no polarizable material could be identified. The muscle layers of the submucosa were hypertrophied, and the lymphatic channels were dilated. Numerous foci of acute serositis were also present. These changes were believed to be consistent with Crohn’s disease involving the gallbladder (Fig. 1 and 2). Six months after discharge from the hospital, the patient was referred to the gastroenterology service for evaluation of a normocytic anemia and intermittent diarrhea. The patient reported intermittent episodes of four to six loose bowel movements per day. The episodes lasted weeks at a time and had been present since his initial surgery nearly 6 yr previously. Further laboratories included: iron of 17 mcg/dl, iron saturation of 4%, and vitamin B12 level of 103 pg/ml (normal 247–911 pg/ml). An endoscopy revealed normal-appearing mucosa throughout the stomach and both limbs of the gastrojejunostomy, which was confirmed histologically. A colonoscopy revealed normal-appearing mucosa throughout the colon and into the area of the ileotrans-
AJG – Vol. 98, No. 2, 2003
Figure 1. Granulomas with overlying ulceration (hematoxylin and eosin, original magnification ⫻100).
verse anastomosis. However, the neoterminal ileum had a moderate number of aphtous ulcerations and friable mucosa. The patient was then started on 6-mercaptopurine, along with iron and vitamin B12 supplementation. Multiple hepatobiliary complications have been described in patients with Crohn’s disease, including hepatitis, cholangitis, steatosis, and amyloidosis (1). Gallbladder involvement has been frequently reported in such patients. The incidence of gallstones has been reported to be 2-fold greater than in the general population (2), this being especially likely when the ileum is involved or after its resection. Additionally, acalculous cholecystitis has been described in severely ill patients (3). Many cholecystectomies are performed in patients with Crohn’s disease who develop symptomatic calculous gallbladder disease. However, a MEDLINE search of the literature provided only two cases (4, 5), before the one herein described, of acute cholecystitis and histopathological evidence of active Crohn’s disease of the gallbladder. A third
Figure 2. Granuloma with epithelioid histiocytes (hematoxylin and eosin, original magnification ⫻200).
AJG – February, 2003
Letters to the Editor
case of extensive Crohn’s disease involving the liver, pancreas, and gallbladder has also been reported in the French literature; however, details on this patient’s clinical details are lacking (6). The predominant clinical picture common in all three cases was that of upper gastrointestinal symptoms, with abdominal pain more often localized to the right upper quadrant in an ill-appearing patient, prompting investigations or interventions for biliary disease. Small bowel involvement was concomitantly identified in all cases. Furthermore, the pathological findings in the gallbladder were similar to those seen in the bowel such as transmural inflammation, granulomatous change, and lymphatic channel dilation. We can only speculate if the initiation of conventional induction therapy for Crohn’s disease would have changed the clinical course of these patients. The answer is not likely to be evidence based, given the rarity of this clinical presentation. In conclusion, we herein describe the third reported case of acute cholecystitis caused by Crohn’s disease of the gallbladder. Carlos A. Rettally, M.D. Hector H. Trevin˜ o, M.D. Kim Molina, M.D. Department of Gastroenterology and Nutrition and Department of Pathology University of Texas Health Science Center at San Antonio San Antonio, Texas Sunanda V. Kane, M.D. Department of Medicine Division of Gastroenterology University of Chicago Chicago, Illinois
REFERENCES 1. Christophi C, Hughes ER. Hepatobiliary disorders in inflammatory bowel disease. Surg Gynecol Obstet 1985;160:187–93. 2. Lapidus A, Bangstad M, Astrom M, et al. The prevalence of gallstone disease in a defined cohort of patients with Crohn’s disease. Am J Gastroenterol 1999;94:1261–6. 3. Hyams JS, Baker E, Schwartz AN, et al. Acalculous cholecystitis in Crohn’s disease. J Adolesc Health Care 1989;10:151–4. 4. McClure J, Banerjee SS, Schofield PS. Crohn’s disease of the gallbladder. J Clin Pathol 1984;37:516 –8. 5. Post AB, van Stolk R, Broughan TA, et al. Crohn’s disease of the gallbladder. J Clin Gastroenterol 1993;16:139 –42. 6. Bouteloup C, Guedon C, Francois A, et al. Gallbladder involvement in Crohn disease. Gastroenterol Clin Biol 1997;21:153–5. Reprint requests and correspondence: Carlos A. Rettally, M.D., Department of Gastroenterology and Nutrition, MC 7878, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Received Sep. 17, 2002; accepted Sep. 25, 2002.
511
Granulocytapheresis for Crohn’s Disease: A Report on Seven Refractory Patients TO THE EDITOR: Active Crohn’s disease (CD) is often associated with elevated and activated monocytes/macrophages and granulocytes (1–3), which are major sources of inflammatory cytokines (4), and therefore, are likely to have a prominent role in the initiation and perpetuation of CD. Further, a recent study found an association between fecal calprotectin (a neutrophil protein), intestinal inflammation, and inflammatory bowel disease relapse (5). Accordingly, application of granulocyte and monocyte/macrophage adsorptive apheresis (GCAP) to reduce the level of activated peripheral blood leukocytes in patients with ulcerative colitis was associated with a significant clinical efficacy, suppression of proinflammatory cytokine produced by peripheral blood leukocytes, and downregulation of L selectin expression on leukocytes (6). These actions should reduce leukocyte infiltration of the mucosa, inflammation, and promote remission in patients with active CD. With these findings in mind, we applied GCAP therapy to seven patients with active CD unresponsive to conventional medications (CM). Our patients were two men and five women (mean age 32 yr, range 24 – 64 yr) and a previous diagnosis of CD. All patients agreed to receive GCAP therapy and signed the informed consent forms after they were told of the purpose and the nature of the procedures involved. They were selected for GCAP therapy on the basis that CM alone had failed to induce remission or improve the disease, as shown in Figure 1. GCAP was done according to a study in patients with ulcerative colitis (6). The apheresis column (Adacolumn) was obtained from Japan Immunoresearch Laboratories (Takasaki, Japan). Adacolumn contains adsorptive carriers that remove about 67% of granulocytes, 55% of monocytes/ macrophages, and a small fraction of lymphocytes from the blood in the column (7). Each patient received five or six GCAP sessions, one session/wk for 5 or 6 consecutive wk. Perfusion rate was 30 ml/min, duration 60 min. No new CM was given during GCAP, but patients were not required to discontinue CM, which they were receiving before GCAP (see Fig. 1). The Crohn’s Disease Activity Index (CDA) scores for all seven patients at recruitment, at the entry to GCAP, and at the conclusion of GCAP therapy are presented in Figure 1. During the initial course of CM, no marked decrease in CDAI scores was noted. In contrast, during GCAP therapy, the CDAI scores decreased dramatically in five of seven patients. The group CDAI score fell from 244.7 ⫾ 50.4 at entry to GCAP to 103.4 ⫾ 8.4 (p ⬍ 0.01) after GCAP therapy. In the five patients who achieved remission, the CDAI score fell from a baseline value of 285.4 ⫾ 62.0 to 94.4 ⫾ 3.7 (p ⬍ 0.01). GCAP responders were younger with relatively short disease history and had colitis as the main
Letters to the Editor
509
Figure 2. Number of bowel movements per day (solid line) and jet lag values established using the Columbia Jet Lag Scale questionnaire (dotted line) before, during, and after the trip. Statistical correlation was only obtained for the first day after the trip (*). Values are means and SDs.
Graciela Salis Gastroenterology Department Hospital Profesor Alejandro Posadas Buenos Aires, Argentina
REFERENCES 1. DuPont HL, Ericsson CD. Prevention and treatment of traveler’s diarrhea. N Engl J Med 1993;328:1821–7. 2. Wood JD, Alpers DH, Andrews PLR. Fundamentals of neurogastroenterology. Gut 1999;45(suppl II):II6 –II16. 3. Heaton KW, O’Donnell LJ. An office guide to whole-gut transit time. Patients’ recollection of their stool form. J Clin Gastroenterol 1994;19:28 –30. 4. Spitzer RL, Terman M, Williams JB, et al. Jet lag: Clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized, double-blind trial. Am J Psych 1999;9:1392–6. 5. Metcalf AM, Phillips SF, Zinsmeister AR, et al. Simplified assessment of segmental colonic transit. Gastroenterology 1987;92:40 –7. 6. Grupo Espan˜ ol Para el Estudio de la Motilidad Digestiva. Medida del tiempo de tra´ nsito colo´ nico (total y segmentario) con marcadores radiopacos. Valores de referencia nacional obtenidos en 192 sujetos sanos. Gastroenterol Hepatol 1998;21: 71–5.
Reprint requests and correspondence: Fermı´n Mearin, Institute of Functional and Motor Digestive Disorders, Centro Me´ dico Teknon, Vilana 12, 08022 Barcelona, Spain. Received Oct. 24, 2001; accepted Sep. 19, 2002.
Crohn’s Disease Involving the Gallbladder: Case Report and Review of the Literature TO THE EDITOR: Crohn’s disease is known to involve the gastrointestinal tract from the oral cavity to the anus. Extraintestinal involvement has also been described, including the hepatobiliary system. We present a case report and review of the literature of acute cholecystitis caused by Crohn’s disease of the gallbladder. A 64-yr-old man presented to the Audie L. Murphy Memorial Veterans Hospital in San Antonio, TX, with complaints of abdominal pain, anorexia, and nausea occurring for approximately 1 wk. The pain was localized to the right upper quadrant and made worse by food ingestion. He denied fevers, chills, melena, hematochezia, scleral icterus, or dark colored urine. His past medical history included Crohn’s disease, which had been diagnosed 5 yr before presentation after being admitted to an outside institution with a clinical picture compatible with a small bowel obstruction. Laparotomy had revealed transmural inflammation involving the distal ileum requiring resection of 20 cm of ileum with 30 cm of colon and an ileotransverse anastomosis. The diagnosis of Crohn’s disease was confirmed by pathological examination of the submitted specimen. The patient recovered uneventfully and remained asymptomatic without medications until the time of admission to our hospital years later. At the time of admission, the patient’s vital signs were: temperature 100.8 F, blood pressure 119/78 mm Hg, and pulse 92 beats/min. Physical examination revealed a man in
510
Letters to the Editor
mild discomfort, with pain to palpation to the right upper quadrant with guarding but no rebound. Murphy’s sign was negative. Pertinent laboratory data included a white blood cell count of 8.9 (⫻103/L), hematocrit of 25% and albumin of 2.0 g/dl. Values of total bilirubin, transaminases, ALP, amylase, and lipase were within the normal range. An abdominal sonogram showed a somewhat dilated gallbladder with a thickened wall and pericholecystic fluid. Discrete hyperechoic areas filled the gallbladder, without distinct acoustic shadows. The intra- and extrahepatic bile ducts appeared normal. The findings were suggestive of cholecystitis, although the presence of gallstones could not be conclusively determined. The patient was admitted to the surgical service and was initially treated conservatively with bowel rest and i.v. fluids. After 48 h, the patient continued to have low-grade fevers and right upper quadrant abdominal tenderness, so he was taken for a laparoscopic cholecystectomy. The operation was complicated by an enterotomy involving the proximal duodenum, prompting conversion to an open approach and performance of a pyloric exclusion, cholecystectomy, and loop gastrojejunostomy. During inspection and closure of the duodenotomy, no mention was made regarding mucosal abnormalities consistent with inflammatory bowel disease. The gallbladder was grossly unremarkable. The serosal surface was smooth without adhesions or exudate. The mucosa was dark and velvety without any distinct lesions. No calculi were present. Microscopically, the mucosa showed areas of acute and chronic cholecystitis intermixed with areas of relatively unaffected mucosa. The areas of acute cholecystitis were manifested by infiltration of neutrophils into the mucosal epithelial with occasional ulcer formation. Rokitansky-Aschoff sinuses were also present. Within the lamina propria were numerous well-formed granulomas composed of epithelioid histiocytes. Silver and acid fast stains failed to reveal any organisms within the granulomas, and no polarizable material could be identified. The muscle layers of the submucosa were hypertrophied, and the lymphatic channels were dilated. Numerous foci of acute serositis were also present. These changes were believed to be consistent with Crohn’s disease involving the gallbladder (Fig. 1 and 2). Six months after discharge from the hospital, the patient was referred to the gastroenterology service for evaluation of a normocytic anemia and intermittent diarrhea. The patient reported intermittent episodes of four to six loose bowel movements per day. The episodes lasted weeks at a time and had been present since his initial surgery nearly 6 yr previously. Further laboratories included: iron of 17 mcg/dl, iron saturation of 4%, and vitamin B12 level of 103 pg/ml (normal 247–911 pg/ml). An endoscopy revealed normal-appearing mucosa throughout the stomach and both limbs of the gastrojejunostomy, which was confirmed histologically. A colonoscopy revealed normal-appearing mucosa throughout the colon and into the area of the ileotrans-
AJG – Vol. 98, No. 2, 2003
Figure 1. Granulomas with overlying ulceration (hematoxylin and eosin, original magnification ⫻100).
verse anastomosis. However, the neoterminal ileum had a moderate number of aphtous ulcerations and friable mucosa. The patient was then started on 6-mercaptopurine, along with iron and vitamin B12 supplementation. Multiple hepatobiliary complications have been described in patients with Crohn’s disease, including hepatitis, cholangitis, steatosis, and amyloidosis (1). Gallbladder involvement has been frequently reported in such patients. The incidence of gallstones has been reported to be 2-fold greater than in the general population (2), this being especially likely when the ileum is involved or after its resection. Additionally, acalculous cholecystitis has been described in severely ill patients (3). Many cholecystectomies are performed in patients with Crohn’s disease who develop symptomatic calculous gallbladder disease. However, a MEDLINE search of the literature provided only two cases (4, 5), before the one herein described, of acute cholecystitis and histopathological evidence of active Crohn’s disease of the gallbladder. A third
Figure 2. Granuloma with epithelioid histiocytes (hematoxylin and eosin, original magnification ⫻200).
AJG – February, 2003
Letters to the Editor
case of extensive Crohn’s disease involving the liver, pancreas, and gallbladder has also been reported in the French literature; however, details on this patient’s clinical details are lacking (6). The predominant clinical picture common in all three cases was that of upper gastrointestinal symptoms, with abdominal pain more often localized to the right upper quadrant in an ill-appearing patient, prompting investigations or interventions for biliary disease. Small bowel involvement was concomitantly identified in all cases. Furthermore, the pathological findings in the gallbladder were similar to those seen in the bowel such as transmural inflammation, granulomatous change, and lymphatic channel dilation. We can only speculate if the initiation of conventional induction therapy for Crohn’s disease would have changed the clinical course of these patients. The answer is not likely to be evidence based, given the rarity of this clinical presentation. In conclusion, we herein describe the third reported case of acute cholecystitis caused by Crohn’s disease of the gallbladder. Carlos A. Rettally, M.D. Hector H. Trevin˜ o, M.D. Kim Molina, M.D. Department of Gastroenterology and Nutrition and Department of Pathology University of Texas Health Science Center at San Antonio San Antonio, Texas Sunanda V. Kane, M.D. Department of Medicine Division of Gastroenterology University of Chicago Chicago, Illinois
REFERENCES 1. Christophi C, Hughes ER. Hepatobiliary disorders in inflammatory bowel disease. Surg Gynecol Obstet 1985;160:187–93. 2. Lapidus A, Bangstad M, Astrom M, et al. The prevalence of gallstone disease in a defined cohort of patients with Crohn’s disease. Am J Gastroenterol 1999;94:1261–6. 3. Hyams JS, Baker E, Schwartz AN, et al. Acalculous cholecystitis in Crohn’s disease. J Adolesc Health Care 1989;10:151–4. 4. McClure J, Banerjee SS, Schofield PS. Crohn’s disease of the gallbladder. J Clin Pathol 1984;37:516 –8. 5. Post AB, van Stolk R, Broughan TA, et al. Crohn’s disease of the gallbladder. J Clin Gastroenterol 1993;16:139 –42. 6. Bouteloup C, Guedon C, Francois A, et al. Gallbladder involvement in Crohn disease. Gastroenterol Clin Biol 1997;21:153–5. Reprint requests and correspondence: Carlos A. Rettally, M.D., Department of Gastroenterology and Nutrition, MC 7878, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Received Sep. 17, 2002; accepted Sep. 25, 2002.
511
Granulocytapheresis for Crohn’s Disease: A Report on Seven Refractory Patients TO THE EDITOR: Active Crohn’s disease (CD) is often associated with elevated and activated monocytes/macrophages and granulocytes (1–3), which are major sources of inflammatory cytokines (4), and therefore, are likely to have a prominent role in the initiation and perpetuation of CD. Further, a recent study found an association between fecal calprotectin (a neutrophil protein), intestinal inflammation, and inflammatory bowel disease relapse (5). Accordingly, application of granulocyte and monocyte/macrophage adsorptive apheresis (GCAP) to reduce the level of activated peripheral blood leukocytes in patients with ulcerative colitis was associated with a significant clinical efficacy, suppression of proinflammatory cytokine produced by peripheral blood leukocytes, and downregulation of L selectin expression on leukocytes (6). These actions should reduce leukocyte infiltration of the mucosa, inflammation, and promote remission in patients with active CD. With these findings in mind, we applied GCAP therapy to seven patients with active CD unresponsive to conventional medications (CM). Our patients were two men and five women (mean age 32 yr, range 24 – 64 yr) and a previous diagnosis of CD. All patients agreed to receive GCAP therapy and signed the informed consent forms after they were told of the purpose and the nature of the procedures involved. They were selected for GCAP therapy on the basis that CM alone had failed to induce remission or improve the disease, as shown in Figure 1. GCAP was done according to a study in patients with ulcerative colitis (6). The apheresis column (Adacolumn) was obtained from Japan Immunoresearch Laboratories (Takasaki, Japan). Adacolumn contains adsorptive carriers that remove about 67% of granulocytes, 55% of monocytes/ macrophages, and a small fraction of lymphocytes from the blood in the column (7). Each patient received five or six GCAP sessions, one session/wk for 5 or 6 consecutive wk. Perfusion rate was 30 ml/min, duration 60 min. No new CM was given during GCAP, but patients were not required to discontinue CM, which they were receiving before GCAP (see Fig. 1). The Crohn’s Disease Activity Index (CDA) scores for all seven patients at recruitment, at the entry to GCAP, and at the conclusion of GCAP therapy are presented in Figure 1. During the initial course of CM, no marked decrease in CDAI scores was noted. In contrast, during GCAP therapy, the CDAI scores decreased dramatically in five of seven patients. The group CDAI score fell from 244.7 ⫾ 50.4 at entry to GCAP to 103.4 ⫾ 8.4 (p ⬍ 0.01) after GCAP therapy. In the five patients who achieved remission, the CDAI score fell from a baseline value of 285.4 ⫾ 62.0 to 94.4 ⫾ 3.7 (p ⬍ 0.01). GCAP responders were younger with relatively short disease history and had colitis as the main