International Journal of Health & Allied Sciences

CASE REPORT
Year
: 2013  |  Volume : 2  |  Issue : 4  |  Page : 278--282

Orlistat-induced acute pancreatitis in a type II diabetic and hypothyroid young woman : A case report


Patralekha Ray Chaudhuri, Ranjita Santra, Shovan Palodhi, Somnath Mondal 
 Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India

Correspondence Address:
Ranjita Santra
Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata - 700 001, West Bengal
India

Abstract

Background: Orlistat is an anti-obesity drug that acts by inhibiting pancreatic and gastric lipase in the gastrointestinal tract. It has been linked to rare instances of acute pancreatitis, some of which have been severe. Case Report: A 31-year-old obese woman was prescribed orlistat 120-mg capsule three times a day with each main meal containing fat for 6 months. She developed acute abdominal pain and vomiting with epigastric tenderness 5 weeks after starting anti-obesity therapy. Serum lipase and computed Tomography (CT) scan of the patient suggested the presence of acute pancreatitis. The patient was hospitalized; orlistat was stopped and she was treated symptomatically. A diagnosis of drug-induced pancreatitis was made following exclusion of other possible factors precipitating pancreatitis. Conclusion: This case report suggests that orlistat can trigger drug-induced acute pancreatitis in some cases and clinicians should be vigilant about it. A total of 99 cases of orlistat-related pancreatitis have been reported to the US Food and Drug Administration (FDA), but no causative link has been found in the clinical trials. It is therefore not in the list of adverse drug reactions of orlistat.



How to cite this article:
Chaudhuri PR, Santra R, Palodhi S, Mondal S. Orlistat-induced acute pancreatitis in a type II diabetic and hypothyroid young woman : A case report.Int J Health Allied Sci 2013;2:278-282


How to cite this URL:
Chaudhuri PR, Santra R, Palodhi S, Mondal S. Orlistat-induced acute pancreatitis in a type II diabetic and hypothyroid young woman : A case report. Int J Health Allied Sci [serial online] 2013 [cited 2019 Oct 14 ];2:278-282
Available from: http://www.ijhas.in/text.asp?2013/2/4/278/126752


Full Text

 Introduction



Orlistat is a tetrahydrolipstatin, a saturated derivative of lipstatin which is a potent natural inhibitor of gastric and pancreatic lipase. Orlistat is a gastric and pancreatic lipase inhibitor used in obesity management, inhibiting the absorption of fat from the diet and causing a high fecal fat content. It binds to gastric and pancreatic lipase, thereby inactivating them; this inhibits the hydrolysis of dietary triglycerides consequently reducing the absorption of monoglycerides and free fatty acids. This causes some unpleasant gastrointestinal side effects including oily discharge, flatulence, fecal urgency, fatty/oily stool, fecal incontinence, abdominal and rectal pain, nausea, and vomiting. It is thought that these symptoms cause a behavior modification in the patient with avoidance of fat-rich foods to avoid the adverse effects. The product information reports abdominal pain as a common and cholelithiasis as a rare complication of orlistat but not pancreatitis.

Acute pancreatitis is an inflammatory disease with a wide spectrum of severity. [1] It is clinically characterized by acute constant abdominal pain and elevated pancreatic enzymes. [2] Alcoholism and biliary tract stone disease account for 95% of cases. [3] Acute pancreatitis is classified as mild, moderate, or severe; the differentiation of which is made by using disease severity scores such as Imrie, [1] Ranson, and more recently Acute Physiology and Chronic Health Evaluation (APACHE) II.

Drug-induced pancreatitis is less common, with routine prescription drugs, as an etiological factor, accounted for 3.4% of cases of acute pancreatitis. [4] The severity of drug-induced pancreatitis is variable; the majority of patients recover without any long-term morbidity, but 5-15% of patients experience life-threatening complications. [5] People at risk of drug-induced pancreatitis include elderly patients taking multiple medications, patients who are HIV positive, patients who have cancer, and patients receiving immunomodulatory agents. [6] Orlistat has been licensed in the UK since 1998, and gained National Institute of Clinical Excellence (NICE) approval in 2001. [4] It is licensed for use in the obese population with body mass index (BMI) ≥30 kg/m 2 or ≥27 kg/m 2 with other risk factors, e.g.hypertension, diabetes, or dyslipidemia. Our patient fitted these characteristics.

The Joint Nonprescription Drugs Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee Meeting in Maryland in 2006, discussed orlistat as a new drug application for orlistat to become a nonprescription drug, had been applied for. [5] They state that there have been 99 raw reports of pancreatitis for orlistat, but say that placebo-controlled trials of orlistat in patients treated for 2 years showed no increase in incidence of pancreatitis. The Canadian Adverse Drug Reaction Newsletter reports incidences of pancreatitis secondary to orlistat. [6]

 Case Report



A 31-year-old female patient presented with severe vomiting and abdominal pain 5 weeks after starting anti-obesity therapy. Orlistat was being prescribed as the only drug for obesity in this case in the dose of 120 mg capsule thrice daily. No concomitant history of intake of any herbal or Ayurvedic drug was found while detailing the case history. She complained of severe upper abdominal burning pain radiating to the back, nausea, and vomiting that worsened with eating and change of posture. On admission, a detailed history and biochemical evaluation excluded other risk factors for pancreatitis gallstones, increased alcohol intake, recent endoscopic retrograde cholangiopancreatography (ERCP), hypercalcemia, hypercholesterolemia, or viral infections. The patient was also receiving metformin 500 mg twice daily for type-2 diabetes and thyroxine 50 μg once daily for hypothyroidism which were diagnosed 6 months back, when an ultrasonography (USG) of the uterus and adnexa revealed polycystic ovarian disease (PCOD). She weighed 110 kg with a BMI of 44. Type 1 diabetes in this case was ruled out by blood for autoantibody assay and urine sample for ketone bodies which were negative at the time of diagnosis. She had good control over hemoglobin A1C (HbA1c) levels: 6.2% and lipid profile, which revealed serum low density lipoprotein (LDL)-80 mg/dl, high density lipoprotein (HDL)-80 mg/dl, and triglycerides-110 mg/dl which was evident from the daily intake of low dose of atorvastatin (10 mg). She received 20 mg of atorvastatin once daily for 3 months initially, the dose of which was reduced to 10 mg after consecutive follow-up lipid profile assays.

Physical examination revealed temperature 38.5 C, pulse-99/min, and epigastric tenderness and fullness with no signs of peritonitis. Since this patient presented to the emergency department with severe epigastric pain, no evaluation of the baseline values could be performed. Complete hemogram showed Hb (9 g/dl), total WBC (14,000/mm 3 ) with neutrophils-65%, and adequate platelets. Laboratory investigations revealed blood sugar-250 mg/dl (postprandial), serum calcium (Ca ++ )-20 mmol/l, serum alkaline phosphatase (ALP)-350 μ/ml, serum lipase-150 IU/l, serum lactate dehydrogenase (LDH)-733 IU/l, and serum amylase-850 U/L. Serum urea and creatinine were within normal limits. Raised levels of markers for inflammation: ESR-110 mm/h and raised C-Reactive protein (CRP) were found. Arterial blood gas analysis revealed normal pH value with a pO 2 90 mmHg. Abdominal ultrasound revealed a normal, thin-walled, acalculus gallbladder with no evidence of hepatobiliary duct dilation. Further contrast-enhanced axial computed tomographic section of the upper abdomen demonstrated peripancreatic and retroperitoneal edema and stranding. The pancreas itself appeared relatively normal [Figure 1]. Large non-enhancing areas of necrosis were visible in the body and neck of the pancreas [Figure 2]. A well-defined fluid collection was seen in the retroperitoneum just below the level of the pancreas [Figure 3]. USG of abdomen, magnetic resonance cholangiopancreatography (MRCP) and esophagoscopy were normal. Scoring by Glasgow [7] severity score was 4 out of 7, indicating severe acute pancreatitis. Orlistat was stopped and the patient was treated symptomatically in intensive care unit (ICU). Patient improved (serum lipase: 50 IU/dl and serum amylase: 60 IU/dl on discharge) and was discharged from the hospital after 10 days.{Figure 1}{Figure 2}{Figure 3}

 Discussion



Acute pancreatitis remains a disease of uncertain pathogenesis and nonspecific therapy. The proportion of cases of pancreatitis caused by drugs is estimated to be around 2% in the general population, with much higher proportions in high risk groups, such as children and HIV positive patients. [8]

Specific criteria to support drug-induced illness was first described by Mallory and Kern in 1988; case reports with the strongest evidence are those that:

Clearly diagnose pancreatitis and exclude common etiologies,provide the dose and time interval between the start of treatment with the suspected drug and the development of pancreatitis,document response to withdrawal of the drug, anddemonstrate recurrent pancreatitis upon rechallenge with the drug. [9] The majority of cases are mild, [10] but severe and even fatal cases of drug-induced pancreatitis may occur, thus making identification of the offending agent critical. [8]

The clinical diagnosis of acute pancreatitis is based on characteristic abdominal pain and nausea, combined with elevated serum levels of pancreatic enzymes. The pathogenesis of acute pancreatitis relates to inappropriate activation of trypsinogen to trypsin (the key enzyme in the activation of pancreatic zymogens) and a lack of prompt elimination of active trypsin inside the pancreas. [11] Gallstones and ethanol account for over 80% of cases. Hypertriglyceridemia, hypercalcemia, and infection are rarer causes. Drugs are implicated in only 0.1-2% of cases. Certain subpopulations such as children, women, the elderly, and patients with advanced HIV infection or inflammatory bowel disease may be at higher risk. [12] The diagnosis of drug-induced pancreatitis is often challenging because there are no unique clinical characteristics to distinguish drugs from other causes of pancreatitis. The majority of cases are mild, but severe and even fatal cases may occur, thus making identification of the offending agent critical. Management of drug-induced acute pancreatitis requires withdrawal of the offending agent and supportive care. Prevention of drug-induced pancreatitis requires an up-to-date knowledge of drugs that have the strongest evidence linking their use to the development of pancreatitis as well as the proposed mechanisms through which they may cause the reaction. [12] The association between orlistat and pancreatitis has been reported to our knowledge only once in the literature. [13] In contrast with the previous report, our cases demonstrated significant increases in serum amylase. Pancreatitis is classically diagnosed in the presence of either raised serum amylase or lipase in the context of characteristic abdominal pain. [14] A raised amylase of over four times the upper limit is diagnostic, but is not mandatory to confirm the diagnosis. In this case, use of the Naranjo probability criteria suggests orlistat was the primary etiological agent. [15] Any purported causative mechanism most likely involves local effects on pancreatic enzymes/metabolites within the acinar ducts and duodenum. Direct destructive effects to intestinal villi have been reported in animal models, but not confirmed in human studies. [16] Like other cases of drug-induced pancreatitis, direct toxicity, or hypersensitivity may be relevant. Orlistat has a good safety profile, [17] but previous cases of serious adverse hepatic events have been reported: Hepatic cholestasis, subacute liver failure, and hepatic necrosis were described in previous reports. [18],[19],[20],[21] Placebo-controlled trials did not yet yield higher rates of pancreatitis. [22],[23] Orlistat is currently contraindicated in patients with chronic malabsorption syndromes, cholestasis, and breastfeeding; but not in cases of previous pancreatitis. [24] From our case it may be reasonable to suggest strong caution where there is a previous history of pancreatitis, alcohol excess, or serious predisposition to pancreatic injury. Autoimmune pancreatitis can also be considered as a differential diagnosis since the patient also had hypothyroidism which could be autoimmune as well. About 2% of episodes of acute pancreatitis are caused by drugs. Phenformin was repeatedly associated with acute pancreatitis, [25] but only two case reports highlighted a possible causative role for metformin. [26],[27] In one case, acute pancreatitis occurred for the coexistence of correct metformin treatment and acute renal failure; [26] in the other, metformin overdose was deemed responsible. [27] Hypothyroidism has a well-established association with hyperlipidemia. Atorvastatin 10 mg once daily does not reveal any association with pancreatitis in the existing literature unlike the higher doses. Elevations of triglyceride levels are observed in up to 35% of hypothyroid patients. Impaired LDL receptor activity may result in decreased clearance and thus an accumulation of LDL particles. A low circulating free thyroid hormone level may also impair lipoprotein lipase activity in adipose tissue. Replacement therapy with L-thyroxine treatment may reverse both of these defects. [28]

 Conclusion



Rising rates of obesity and the approval of nonprescription sale, suggests that the use of orlistat will rise markedly. Increased awareness and early detection of adverse clinical events will be of the crucial importance, as more complications are seen from increased use. Acute pancreatitis occurred soon after the commencement of orlistat therapy in this case. For any patient commenced on orlistat and presenting with new onset severe abdominal pain, the diagnosis of pancreatitis should be considered. Whilst the drug is generally safe, in groups with preexisting risk factors for pancreatitis, it should be introduced cautiously and both patients and clinicians should remain vigilant about the clinical features of pancreatic injury.

 Acknowledgement



We deeply acknowledge the patient for providing the details of her case history. We thank the faculty members in the Department of Medicine, Calcutta Medical College, Kolkata for their diagnosis and treatment of such a not so common case of drug-induced pancreatitis.

References

1Blamey SL, Imrie CW, O′Neill J, Gilmour WH, Carter DC. Prognostic factors in acute pancreatitis. Gut 1984;25:1340-6.
2Underwood TW, Frye CB. Drug-induced pancreatitis. Clin Pharm 1993;12:440-8.
3Sekimoto M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, et al. JPN Guidelines for the management of acute pancreatitis: Epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis. J Hepatobiliary Pancreat Surg 2006;13:10-24.
4Barreto SG, Tiong L, Williams R. Drug-induced acute pancreatitis in a cohort of 328 patients. A single-centre experience from Australia. JOP 2011;12:581-5.
5Kale-Pradhan PB, Conroy JL. Pancreatitis. In: Tisdale JE, Miller DA, editors. Text Book of Drug-Induced Diseases: Prevention, Detection, and Management. Bethesda: American Society of Health-System Pharmacists, Inc.; 2005. p. 537-47.
6Boyd IW. The role of the Australian Adverse Drug Reactions Advisory Committee (ADRAC) in monitoring drug safety. Toxicology 2002;181-182:99-102.
7Woo SM, Noh MH, Kim BG, Hsing CT, Han JS, Ryu SH, et al. Comparison of serum procalcitonin with Ranson, APACHE-II, Glasgow and Balthazar CT severity index scores in predicting severity of acute pancreatitis. Korean J Gastroenterol 2011;58:31-7.
8Wilmink T, Frick TW. Drug-induced pancreatitis. Drug Saf 1996;14:406-23.
9Mallory A, Kern F. Drug-induced pancreatitis. Bailliere′s Clin Gastroenterol 1988;2:293-307.
10Lankisch PG, Drogue M, Gottesleben F. Drug induced acute pancreatitis: Incidence and severity. Gut 1995;37:565-7.
11Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med 2006;354:2142-50.
12Balani AR, Grendell JH. Drug-induced pancreatitis: Incidence, management and prevention. Drug Saf 2008;31:823-37.
13Napier S, Thomas M. 36 year old man presenting with pancreatitis and a history of recent commencement of Orlistat case report. Nutr J 2006;5:19.
14Working Party of the British Society of Gastroenterology, Association of Surgeons of Great Britain and Ireland, Pancreatic Society of Great Britain and Ireland, Association of Upper GI Surgeons of Great Britain and Ireland. UK guidelines for the management of acute pancreatitis. Gut 2005;54:1-9.
15Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.
16Caner M, Dogruman H, Taskin E, Kandil A, Demirci C. Effects of orlistat and its relationship with nitric oxide in the small intestinal mucosa. Chin J Physiol 2005;48:217-22.
17Filippatos TD, Derdemezis CS, Gazi IF, Nakou ES, Mikhailidis DP, Elisaf MS. Orlistat-associated adverse effects and drug interactions: A critical review. Drug Saf 2008;31:53-65.
18Kim DH, Lee EH, Hwang JC, Jeung JH, Kim do H, Cheong JY, et al. A case of acute cholestatic hepatitis associated with orlistat. Taehan Kan Hakhoe Chi 2002;8:317-20.
19Montero JL, Muntane J, Fraga E, Delgado M, Costán G, Serrano M, et al. Orlistat associated subacute hepatic failure. J Hepatol 2001;34:173.
20Thurairajah PH, Syn WK, Neil DA, Stell D, Haydon G. Orlistat (Xenical)-induced subacute liver failure. Eur J Gastroenterol Hepatol 2005;17:1437-8.
21Lau G, Chan CL. Massive hepatocellular [correction of hepatocullular] necrosis: Was it caused by Orlistat? Med Sci Law 2002;42:309-12.
22Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: A randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155-61.
23Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: A randomized controlled trial. JAMA 1999;281:235-42.
24Joint Formulary Committee, British Medical Association and the Royal Pharmaceutical Society of Great Britain. 58th ed. London: British National Formulary; September 2009.
25Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: An update. J Clin Gastroenterol 2005;39:709-16.
26Mallick S. Metformin induced acute pancreatitis precipitated by renal failure. Postgrad Med J 2004;80:239-40.
27Ben MH, Thabet H, Zaghodoudi I, Amamou M. Metformin associated acute pancreatitis. Vet Hum Toxicol 2002;44:47-8.
28Gan SI, Edwards AL, Symonds CJ, Beck PL. Hypertriglyceridemia-induced pancreatitis: A case-based review. World J Gastroenterol 2006;12:7197-202.