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Acute pancreatitis following octreotide withdrawal
BRIEFCLINICALOBSERVATIONS ACUTE PANCREATITIS FOLLOWINGOCTREOTIDE WITHDRAWAL The long-acting somatostatin analogue octreotide (SMS 201-995, Sandostatin, Sandoz) has been reported to be effective in the treatment of acromegaly [ 11. Various side effects, mostly digestive, have been associated with its administration [l-3]. Particularly, there is increasing evidence that octreotide therapy is associated with a risk of asymptomatic gallstone development [2,3]. Only one case of symptomatic cholelithiasis has been reported [4]. In the present report, we describe a patient who developed acute pancreatitis as a complication of cholelithiasis 2 months after octreotide had been discontinued, following 1 year of treatment for an invasive mixed growth hormone (GH)/prolactin (PRL)-secreting pituitary adenoma. This 24-year-old man was first seen in July 1987. At that time, there was clinical evidence of elevated intracranial pressure and acromegaly. Computed tomographic scanning and magnetic resonance imaging (MRI) revealed a large tumor (main diameter 76 mm) arising from a vanishing sella turcica and expanding in all directions. Visual field examination disclosed a bitemporal hemianopsia. The inferior and anterior process of the tumor allowed a biopsy through a nasal speculum; histologic findings were compatible with a pituitary adenoma with positive immunostaining for GH and PRL. Random GH and PRL levels were 130 rug/L (normal value less than 5 pg/L) and 4,200 pg/L (normal value less than 20 pg/L), respectively. A urinary infection triggered the development of diabetic ketoacidosis. The result of ultrasonography of the abdomen was unremarkable. Treatment
with octreotide (100 pg subcutacystectomy with external biliary neously, three times a day) was diversion and peritoneal washing started, followed 6 weeks later by were performed. The course was a combination of octreotide uneventful. Octreotide treatment (same regimen) and bromocripwas not subsequently resumed tine (5 mg orally three times a and GH levels have since reday). Headaches and the visual mained within normal limits. field defect improved dramatiTreatment with bromocriptine cally; insulin requirements de- (2.5 mg/day) had to be resumed clined to a complete termination. in order to keep PRL levels withSix months later, GH and PRL in the normal range. Twenty levels were less than 15 pg/L and months after octreotide withdrawal, MRI showed no evidence less than 100 pg/L, respectively; MRI showed a dramatic shrinkof tumor relapse. age of the tumor. One year after Besides the dramatic tumor the start of octreotide adminisshrinkage, this case highlights tration, GH and PRL levels were the potentially hazardous effect in the normal range and MRI re- of long-term octreotide use. Invealed a complete regression of deed, the occurrence of gallstones the tumor. The excellent out]2-71, and even of symptomatic come allowed us to discontinue, cholelithiasis [4], has been previfirst, octreotide, and later on (1 ously documented in anecdotal or month) bromocriptine. prospective reports. However, The result of abdominal ultraour case is, to our knowledge, the sound examination at 6 months first report of pancreatitis in such of treatment was unremarkable. a therapeutic setting. Although Examination at 12 months (i.e., ultrasound examination was not when octreotide was discontindefinitely conclusive, it is likely ued) disclosed a slight thickening that small calculi or sludge was of the gallbladder walls with a present at the end of treatment in narrowing of its lumen, but withour patient. We would like to sugout detectable sludge or calculi. gest that the progressive restoraThree weeks after octreotide tion of gallbladder motility rewithdrawal, the patient comsulting from octreotide withplained of right upper quadrant drawal was the main event that abdominal pain. This episode re- made the small calculi migrate solved with common analgesics, into the main bile duct, eventualbut a relapse occurred twice in ly causing pancreatitis. Indeed, the next 2 weeks. Finally, a fourth acute [8] and chronic [9] inhibitoepisode, 2 months after octreory effects of octreotide upon galltide withdrawal, prompted ad- bladder motility have been demmission of the patient to the hos- onstrated. These effects may expital. He had clinical and biologic plain both the development of evidence of acute cholecystitis. asymptomatic cholelithiasis durUltrasound examination dising the course of long-term occlosed intrahepatic biliary dilatatreotide therapy and the occurtion and multiple small calculi of rence of complications (e.g., panthe gallbladder; the main bile creatitis in our case) following the duct was slightly dilated (7 mm), drug’s withdrawal. Since longA surgical procedure was per- term treatment with high doses formed. The surgeon found an of bromocriptine in prolactinoedematous pancreatic area with mas or Parkinson’s disease has diffuse small cytosteatonecrotic not been reported to result in bilpatchy lesions and an amylaseiary side effects, it is reasonable rich peritoneal effusion. Chole- to ascribe the occurrence of gall-
June
1991
The American
Journal
of Medicine
Volume
90
763
BRIEF CLINICAL
OBSERVATIONS
stones in our patient to octreotide treatment, although we cannot exclude the possibility that the combined use of the two drugs may have reinforced the effects of octreotide. In conclusion, a careful ultrasonographic search for direct (sludge or gallstones) and indirect (thickened gallbladder walls) warning features is warranted not only before and during octreotide administration but also after octreotide withdrawal. JEAN-LOUIS SADOUL, M.D. DANIEL BENCHIMOL, M.D. ANTOINE THYSS, M.D. PIERRE FREYCHET, M.D.
H6pital Pasteur Nice, France
1. Lamberts SWJ. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 1988; 9: 417-36. 2. Tauber JP, BabinTH, Tauber MT, eta/. Long term effects of continuous subcutaneous infusion of the somatostatin analog octreotide in the treatment of acromegaly. J Clin Endocrinol Metab 1989; 68: 917-24. 3. Ho KY, Weissberger AJ, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analogue SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety. Ann Intern Med 1990; 112: 173-81. 4. Comi RJ. Pharmacology and use in pituitary tumors, pp 36-41. In: Gorden P, moderator. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic disease of the gut. Ann Intern Med 1989; 110: 35-50. 5. McKnight JA, McCance DR, Grothers JG. Atkinson AB. Changes in glucose tolerance and development of gallstones during high dose treatment with octreotide for acromegaly. BMJ 1989; 299: 604-5. 6. Wass JAH. Anderson JV, Besser GM, Dowling RH. Gallstones and treatment with octreotide in acromegaly. BMJ 1989; 299: 1162-3. 7. PueCBousquet C, Buscaill L, Harris AG, Ribet A, Bayard F, Tauber JP. Incidence de la microlithiase vesiculaire lors du traitement par Sandostatine (SMS) en infusion sous cutanee continue (ISCC). Ann Endocrinol 1989; 50 (46 A): 22. 6. Lembcke B. Creutzfeldt W, Schleser S, Ebert R, Shaw C, Koop I. Effect of the somatostatin analogue Sandostatin (SMS 201-995) on gastrointestinal, pancreatic and biliary function and hormone release in normal men. Digestion 1987; 36: 108-24. 9. Van Liessum PA, Hopman WPM. Pieters GFFM, et al. Postprandial gallbladder motility duringlongterm treatment with the long-acting somatostatin analog SMS 201-995 in acromegaly. J Clin Endocrinol Metab 1989; 69: 557-62. Submitted
764
August 8, 1990, and accepted form January
June
1991
The American
in revised 12, 1991
Journal
GROSSLYNEGLECTED HEMATURIA:A RARECAUSE OF IRON-DEFICIENCYANEMIA Hematuria is not generally thought of as a cause of iron-deficiency anemia. One major textbook of hematology [l] does not even include it as a potential cause, whereas idiopathic pulmonary hemosiderosis and Goodpasture’s syndrome are included. Iron-deficiency anemia not due to menstrual blood loss is most often due to gastrointestinal blood loss [l-3], undoubtedly because of its chronic, occult nature. Because occult blood loss from the urinary tract is insufficient to produce iron deficiency and because gross hematuria usually prompts a visit to a physician within several months, the development of iron-deficiency anemia due to blood loss from the urinary tract appears to be rare. We report two patients who were admitted to the Osler Medical Service of the Johns Hopkins Hospital with gross hematuria that had been neglected long enough to produce severe irondeficiency anemia. The first patient was a 48yearold homeless man with gross hematuria for 1 year. He denied hematemesis, melena, hematochezia, or a history of anemia. His stool was brown and tested negative for occult blood. Urinalysis showed reddish-colored urine with too numerous to count red blood cells (RBCs). The hemoglobin level was 23 g/L, the hematocrit was 7.1%, and the mean corpuscular volume (MCV) was 57.3 fL. Cystoscopy with biopsy revealed transitional cell carcinoma of the bladder. The second patient, a 34-yearold man with paranoid schizophrenia, was brought by his sister for evaluation of more than 4% months of gross hematuria and 2 weeks of pica. His stool was brown and tested negative for occult blood. Urinalysis revealed of Medicine
Volume
90
slightly reddish urine with too numerous to count RBCs. The hemoglobin level was 30 g/L, the hematocrit was 10.6%, and the MCV was 58.0 fL. Cystoscopy with biopsy revealed transitional cell carcinoma of the bladder. A thorough evaluation of both patients disclosed no other etiology for their anemias. Iron-deficiency anemia in this country is almost exclusively caused by blood loss from the genital tract of women and from the gastrointestinal tract of both sexes. “Unusual bleeding or discharge” is considered one of the warning signs of cancer by the American Cancer Society [4]. Most individuals appear aware of this association [5] and would promptly seek medical attention for these symptoms. Unfortunately, this assumption may not be true for patients who are impaired by socioeconomic status or mental illness. The two cases reported here illustrate that gross hematuria, if neglected, can indeed produce iron-deficiency anemia and should be added to the differential diagnosis of this condition. ROY C. ZIEGELSTEIN, M.D. BARRY K. RAYBURN, M.D. DAVID M. QUINL~, M.B., F.R.C.S.I.
Johns Hopkins Unwerstty School of Medicine Baltimore, Maryland
ACKNOWLEDGMENT We would like to express our gratitude to the housestaff of the Barker and Thayer Firms for their excellent care of these patients.
1. Wintrobe MM, Lee GR. Boggs DR, Bithell TC, Athens J. Foerster J. Clinical hematology. 8th ed. Philadelphia: Lea & Febiger, 1981: 617-45. 2. Fairbanks VF, Beutler E. Iron deficiency. In: Williams WJ. Beutler E, Erslev AJ, Rundles RW, editors. Hematology. 3rd ed. New York McGraw-Hill, 1983: 466-89. 3.Beveridge BR. Bannerman RM. Evanson JM, Witts LJ. Hypochromic anaemia: a retrospective study and follow-up of 378 inpatients. Q J Med 1965; 34: 145-61. 4. American Cancer Society. Americans look at cancer and the check-up. New York: Lieberman Research, Inc.. 1966. 5. Kutner B, Gordan G. Seeking care for cancer.
with octreotide (100 pg subcutacystectomy with external biliary neously, three times a day) was diversion and peritoneal washing started, followed 6 weeks later by were performed. The course was a combination of octreotide uneventful. Octreotide treatment (same regimen) and bromocripwas not subsequently resumed tine (5 mg orally three times a and GH levels have since reday). Headaches and the visual mained within normal limits. field defect improved dramatiTreatment with bromocriptine cally; insulin requirements de- (2.5 mg/day) had to be resumed clined to a complete termination. in order to keep PRL levels withSix months later, GH and PRL in the normal range. Twenty levels were less than 15 pg/L and months after octreotide withdrawal, MRI showed no evidence less than 100 pg/L, respectively; MRI showed a dramatic shrinkof tumor relapse. age of the tumor. One year after Besides the dramatic tumor the start of octreotide adminisshrinkage, this case highlights tration, GH and PRL levels were the potentially hazardous effect in the normal range and MRI re- of long-term octreotide use. Invealed a complete regression of deed, the occurrence of gallstones the tumor. The excellent out]2-71, and even of symptomatic come allowed us to discontinue, cholelithiasis [4], has been previfirst, octreotide, and later on (1 ously documented in anecdotal or month) bromocriptine. prospective reports. However, The result of abdominal ultraour case is, to our knowledge, the sound examination at 6 months first report of pancreatitis in such of treatment was unremarkable. a therapeutic setting. Although Examination at 12 months (i.e., ultrasound examination was not when octreotide was discontindefinitely conclusive, it is likely ued) disclosed a slight thickening that small calculi or sludge was of the gallbladder walls with a present at the end of treatment in narrowing of its lumen, but withour patient. We would like to sugout detectable sludge or calculi. gest that the progressive restoraThree weeks after octreotide tion of gallbladder motility rewithdrawal, the patient comsulting from octreotide withplained of right upper quadrant drawal was the main event that abdominal pain. This episode re- made the small calculi migrate solved with common analgesics, into the main bile duct, eventualbut a relapse occurred twice in ly causing pancreatitis. Indeed, the next 2 weeks. Finally, a fourth acute [8] and chronic [9] inhibitoepisode, 2 months after octreory effects of octreotide upon galltide withdrawal, prompted ad- bladder motility have been demmission of the patient to the hos- onstrated. These effects may expital. He had clinical and biologic plain both the development of evidence of acute cholecystitis. asymptomatic cholelithiasis durUltrasound examination dising the course of long-term occlosed intrahepatic biliary dilatatreotide therapy and the occurtion and multiple small calculi of rence of complications (e.g., panthe gallbladder; the main bile creatitis in our case) following the duct was slightly dilated (7 mm), drug’s withdrawal. Since longA surgical procedure was per- term treatment with high doses formed. The surgeon found an of bromocriptine in prolactinoedematous pancreatic area with mas or Parkinson’s disease has diffuse small cytosteatonecrotic not been reported to result in bilpatchy lesions and an amylaseiary side effects, it is reasonable rich peritoneal effusion. Chole- to ascribe the occurrence of gall-
June
1991
The American
Journal
of Medicine
Volume
90
763
BRIEF CLINICAL
OBSERVATIONS
stones in our patient to octreotide treatment, although we cannot exclude the possibility that the combined use of the two drugs may have reinforced the effects of octreotide. In conclusion, a careful ultrasonographic search for direct (sludge or gallstones) and indirect (thickened gallbladder walls) warning features is warranted not only before and during octreotide administration but also after octreotide withdrawal. JEAN-LOUIS SADOUL, M.D. DANIEL BENCHIMOL, M.D. ANTOINE THYSS, M.D. PIERRE FREYCHET, M.D.
H6pital Pasteur Nice, France
1. Lamberts SWJ. The role of somatostatin in the regulation of anterior pituitary hormone secretion and the use of its analogs in the treatment of human pituitary tumors. Endocr Rev 1988; 9: 417-36. 2. Tauber JP, BabinTH, Tauber MT, eta/. Long term effects of continuous subcutaneous infusion of the somatostatin analog octreotide in the treatment of acromegaly. J Clin Endocrinol Metab 1989; 68: 917-24. 3. Ho KY, Weissberger AJ, Marbach P, Lazarus L. Therapeutic efficacy of the somatostatin analogue SMS 201-995 (octreotide) in acromegaly. Effects of dose and frequency and long-term safety. Ann Intern Med 1990; 112: 173-81. 4. Comi RJ. Pharmacology and use in pituitary tumors, pp 36-41. In: Gorden P, moderator. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic disease of the gut. Ann Intern Med 1989; 110: 35-50. 5. McKnight JA, McCance DR, Grothers JG. Atkinson AB. Changes in glucose tolerance and development of gallstones during high dose treatment with octreotide for acromegaly. BMJ 1989; 299: 604-5. 6. Wass JAH. Anderson JV, Besser GM, Dowling RH. Gallstones and treatment with octreotide in acromegaly. BMJ 1989; 299: 1162-3. 7. PueCBousquet C, Buscaill L, Harris AG, Ribet A, Bayard F, Tauber JP. Incidence de la microlithiase vesiculaire lors du traitement par Sandostatine (SMS) en infusion sous cutanee continue (ISCC). Ann Endocrinol 1989; 50 (46 A): 22. 6. Lembcke B. Creutzfeldt W, Schleser S, Ebert R, Shaw C, Koop I. Effect of the somatostatin analogue Sandostatin (SMS 201-995) on gastrointestinal, pancreatic and biliary function and hormone release in normal men. Digestion 1987; 36: 108-24. 9. Van Liessum PA, Hopman WPM. Pieters GFFM, et al. Postprandial gallbladder motility duringlongterm treatment with the long-acting somatostatin analog SMS 201-995 in acromegaly. J Clin Endocrinol Metab 1989; 69: 557-62. Submitted
764
August 8, 1990, and accepted form January
June
1991
The American
in revised 12, 1991
Journal
GROSSLYNEGLECTED HEMATURIA:A RARECAUSE OF IRON-DEFICIENCYANEMIA Hematuria is not generally thought of as a cause of iron-deficiency anemia. One major textbook of hematology [l] does not even include it as a potential cause, whereas idiopathic pulmonary hemosiderosis and Goodpasture’s syndrome are included. Iron-deficiency anemia not due to menstrual blood loss is most often due to gastrointestinal blood loss [l-3], undoubtedly because of its chronic, occult nature. Because occult blood loss from the urinary tract is insufficient to produce iron deficiency and because gross hematuria usually prompts a visit to a physician within several months, the development of iron-deficiency anemia due to blood loss from the urinary tract appears to be rare. We report two patients who were admitted to the Osler Medical Service of the Johns Hopkins Hospital with gross hematuria that had been neglected long enough to produce severe irondeficiency anemia. The first patient was a 48yearold homeless man with gross hematuria for 1 year. He denied hematemesis, melena, hematochezia, or a history of anemia. His stool was brown and tested negative for occult blood. Urinalysis showed reddish-colored urine with too numerous to count red blood cells (RBCs). The hemoglobin level was 23 g/L, the hematocrit was 7.1%, and the mean corpuscular volume (MCV) was 57.3 fL. Cystoscopy with biopsy revealed transitional cell carcinoma of the bladder. The second patient, a 34-yearold man with paranoid schizophrenia, was brought by his sister for evaluation of more than 4% months of gross hematuria and 2 weeks of pica. His stool was brown and tested negative for occult blood. Urinalysis revealed of Medicine
Volume
90
slightly reddish urine with too numerous to count RBCs. The hemoglobin level was 30 g/L, the hematocrit was 10.6%, and the MCV was 58.0 fL. Cystoscopy with biopsy revealed transitional cell carcinoma of the bladder. A thorough evaluation of both patients disclosed no other etiology for their anemias. Iron-deficiency anemia in this country is almost exclusively caused by blood loss from the genital tract of women and from the gastrointestinal tract of both sexes. “Unusual bleeding or discharge” is considered one of the warning signs of cancer by the American Cancer Society [4]. Most individuals appear aware of this association [5] and would promptly seek medical attention for these symptoms. Unfortunately, this assumption may not be true for patients who are impaired by socioeconomic status or mental illness. The two cases reported here illustrate that gross hematuria, if neglected, can indeed produce iron-deficiency anemia and should be added to the differential diagnosis of this condition. ROY C. ZIEGELSTEIN, M.D. BARRY K. RAYBURN, M.D. DAVID M. QUINL~, M.B., F.R.C.S.I.
Johns Hopkins Unwerstty School of Medicine Baltimore, Maryland
ACKNOWLEDGMENT We would like to express our gratitude to the housestaff of the Barker and Thayer Firms for their excellent care of these patients.
1. Wintrobe MM, Lee GR. Boggs DR, Bithell TC, Athens J. Foerster J. Clinical hematology. 8th ed. Philadelphia: Lea & Febiger, 1981: 617-45. 2. Fairbanks VF, Beutler E. Iron deficiency. In: Williams WJ. Beutler E, Erslev AJ, Rundles RW, editors. Hematology. 3rd ed. New York McGraw-Hill, 1983: 466-89. 3.Beveridge BR. Bannerman RM. Evanson JM, Witts LJ. Hypochromic anaemia: a retrospective study and follow-up of 378 inpatients. Q J Med 1965; 34: 145-61. 4. American Cancer Society. Americans look at cancer and the check-up. New York: Lieberman Research, Inc.. 1966. 5. Kutner B, Gordan G. Seeking care for cancer.