Ischemic colitis after weight-loss medication

Departments of 1Medicine (Gastroenterology) and 2Pathology, McMaster University, Hamilton, Ontario; 3Department of Medicine (Gastroenterology), University of Toronto, Toronto, Ontario Correspondence: Dr EJ Irvine, Division of Gastroenterology, St Michael’s Hospital, Room 16-052 Cardinal Carter Wing, 30 Bond Street, Toronto, Ontario M5B 1W8. Telephone 416-864-5060, fax 416-861-8378, e-mail irvinej@smh.toronto.on.ca Received for publication June 25, 2003. Accepted September 17, 2003 D Comay, J Ramsay, EJ Irvine. Ischemic colitis after weightloss medication. Can J Gastroenterol 2003;17(12):719-721 .

Phentermine, a commonly prescribed weight-loss drug, is currently approved for short term weight loss (4).It is an amphetamine derivative that stimulates norepinephrine release in the hypothalamus to suppress appetite centrally (5).Its use, in combination with fenfluramine, increased sharply following the publication of the fenfluramine-phentermine ("fen-phen") study, demonstrating its superiority to placebo for weight reduction (6).However, subsequent reports linking fenfluramine and dexfenfluramine to the development of pulmonary hypertension and cardiac valvular abnormalities led to a dramatic decline in their use, as well as that of phentermine (7-10).Both fenfluramine and dexfenfluramine were subsequently withdrawn from the market (11).
We report a case of ischemic colitis following the use of a common weight-loss drug, phentermine, in a patient without other risk factors for large bowel ischemia, and review the literature to illustrate a potential important consequence of this medication.

CASE PRESENTATION
A 59-year-old woman presented to the emergency department at Hamilton Health Sciences (McMaster University, Hamilton, Ontario) with a history of passing bright red loose stool that was preceded by several hours of severe, crampy, suprapubic abdominal pain.She had three bloody bowel movements that produced approximately 175 mL and a one-day history of nausea and bilious vomiting without blood or coffee-ground material.She denied having fevers or rigors and had noted an intentional weight loss of 12 kg (from 82 kg to 70 kg) over 10 weeks, after starting the phentermine.She had also experienced two self-limited episodes of suprapubic abdominal pain with nonbloody diarrhea four weeks and eight weeks after starting the drug, but did not seek medical attention.
She had no prior history or symptoms suggestive of inflammatory bowel disease and no recent history of antibiotic use, well-water consumption or eating commercially prepared meals.She had recently travelled to Virginia and eaten in a communal dining hall, but no known contacts had fallen ill and her travelling companion had remained well.
Her medical history was significant for inflammatory osteoarthritis, asthma, gastroesophageal reflux disease, mild hypertension and paroxysmal supraventricular tachycardia.She had no symptoms of ischemic heart disease, and an extensive cardiac work-up, performed one year previously for tachycardia, had been normal.Her mother had left-sided ulcerative colitis.
Her medications included prednisone 5 mg daily, verapamil 180 mg twice daily, albuterol puffer as needed, budesonide two puffs twice daily, esomeprazole 40 mg daily, acetominophen with codeine as needed for arthralgia and phentermine resin (Ionamin, Celltech Pharmaceuticals, USA) one 15 mg capsule taken daily before breakfast.She had previously taken estrogen replacement for postmenopausal symptoms but discontinued this medication on her physician's advice three months before her presentation.
She was a lifelong nonsmoker, rarely consumed alcohol and drank four to six cups of tea daily.She had a sedentary lifestyle with no high-endurance pursuits.She had a remote cholecystectomy and had an allergy to nonsteroidal anti-inflammatory drugs, which caused her to wheeze.
On arrival at the emergency department, her blood pressure was 144/80 mmHg, heart rate was 90 beats/min and regular, and there was no postural change in either.She was afebrile.Her cardiovascular and respiratory examinations were within normal limits.On examination of the abdomen, bowel sounds were present and she had mild left lower quadrant tenderness without rebound tenderness or guarding.A digital rectal examination revealed an empty rectal vault with bright red blood on the examining glove.
Blood chemistry panel and coagulation profiles were normal.Apart from a mildly elevated white blood cell count of 11.9×109/L, the complete blood count was normal.A selected panel of bloodwork to exclude vasculitis -including C-reactive protein, antinuclear antibodies, extractable nuclear antibodies, rheumatoid factor, and C3 and C4 levels -was normal.Screening for antineutrophilic cytoplasmic antibodies was not performed.
Stool examinations were performed to exclude the presence of pathogens and Clostridium difficile toxin.Abdominal x-rays revealed multiple fluid-filled loops of bowel without distension, thumb-printing, air-fluid levels or free intraperitoneal air.
A colonoscopy, performed within 12 h of hospitalization, demonstrated 10 cm of edematous, ulcerated, hemorrhagic mucosa at the splenic flexure with normal flanking mucosa.Biopsies showed features of both acute ischemic colitis (Figure 1) and chronic ischemic morphological features, such as fibrosis (Figure 2).

DISCUSSION
There are no published reports to date of phentermine use alone in association with ischemic colitis.There was, however, a single case report of a healthy 36-year-old woman who developed ischemic colitis while taking fenfluramine-phentermine (12).She had lost 14 kg while on a combination of fenfluramine 20 mg and phentermine 30 mg three times per day for three months.She had no risk factors for bowel ischemia, apart from remote birth-control pill use, rare nonsteroidal anti-inflammatory drug use and smoking five cigarettes per week.
Phentermine has also been described in association with ischemic neurological events in two patients (13).One patient had a seven-day hemisensory disturbance consistent with a transient ischemic attack, while the other patient had a right occipital infarct with multiple vascular abnormalities on cerebral angiogram.
The putative mechanism by which phentermine may cause ischemic colitis is based on its pharmacological properties.Phentermine is a beta-phenethylamine derivative of amphetamine and stimulates norepinephrine release from nerve terminals, such as in the intestinal vasculature (5).The resulting adrenergic stimulation may lead to mesenteric vasoconstriction and tissue ischemia (14).Other sympathomimetic agents, such as cocaine, methamphetamine and pseudoephedrine have been well documented to cause ischemic colitis through similar mechanisms (15)(16)(17)(18)(19)(20)(21)(22).

CONCLUSION
This case report describes a temporal association between the use of phentermine and the development of ischemic colitis.Heightened awareness and appropriate surveillance is warranted to determine whether the use of weight-loss drugs, such as phentermine, can lead to ischemic colitis.

Figure 1 )
Figure1) Acute ischemic colitis (biopsy magnification 100×).There is hemorrhage and a mixed inflammatory cell infiltrate in the lamina propria.The mucosa shows regenerative changes of increased basophilia and mucin depletion

Figure 2 )
Figure2) Remote ischemic injury (biopsy magnification 100×).There is marked fibrosis and loss of glandular mucosa (gland drop-out) in the lamina propria

TABLE 1
Selected risk factors for ischemic colitis