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Journal of Digestive Diseases 2014; 15; 331–333
doi: 10.1111/1751-2980.12139
Letter to the editor
Recurrent ischemic colitis associated with oral contraceptive therapy
Sirs, In an interesting article Mosli et al.1 methodically reported the risk factors associated with ischemic colitis, as well as characterizing the clinical features, endoscopic findings, complications and prognosis of this disease. They noted a female predominance, but interestingly reported no association with oral contraceptive (OC) use or hormone replacement therapy (HRT). However, they acknowledged that this lack of association might have resulted from the underreporting of OC use or HRT, because patients often failed to voluntarily disclose their use of these agents, and physicians must therefore directly query patients about such use. We emphasize the clinical relevance of this omission by reporting a case of recurrent severe ischemic colitis after failing to discontinue OC medications after the first episode. A 36-year-old woman administered a standard dose and regimen of OC with combination levonorgestrelethinyl-estradiol triphasic pills (Enpresse: Barr Laboratories, Pomona, NY, USA) for 15 years for dysfunctional uterine bleeding, presented with moderately severe acute lower abdominal pain and mild hematochezia (hematocrit 40.5%). Abdominal contrast-enhanced computed tomography (CT) with delayed imaging showed moderate left colonic mural thickening. Colonoscopy showed segmental colitis with edema, erythema and shallow ulcers in the proximal sigmoid colon, descending colon and splenic flexure (Fig. 1). The pathological examination of colonic biopsy specimens was consistent with ischemic Correspondence to: Palaniappan MANICKAM, Division of Gastroenterology and Hepatology, Department of Internal Medicine, William Beaumont Hospital, MOB 602, 3535 W. 13 Mile Road, Royal Oak, MI 48073, USA. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
colitis. Routine stool tests were negative for enteric infections. There were no recent cardiac arrhythmia or other apparent risk factors for ischemic colitis. The physician elected to continue OC therapy despite ischemic colitis because of the strong therapeutic indication. Five years later, the patient re-presented with moderately severe acute lower abdominal pain and mild hematochezia (hematocrit 38.5%), while still taking OC. Abdominal CT showed focal severe mural thickening, extending from the splenic flexure to the sigmoid colon, and dramatic streaky mesentery adjacent to these bowel segments (Fig. 2a). Colonoscopy revealed patchy, highly erythematous friable mucosa with erosions and hemorrhage extending from the splenic flexure to the sigmoid colon (Fig. 2b). The pathological examination of colonic biopsy specimens was consistent with ischemic colitis. Routine stool tests were negative for enteric infections. OC administration was then discontinued. OC use has been implicated in venous thromboembolism, myocardial infarction and cerebrovascular accidents.2 It has also been associated with gastrointestinal ischemia, but this association is inconsistently reported. An extensive literature review since 2000 revealed four other case reports of the association between OC use and ischemic colitis (Table 1).3–7 Although several prior case reports suggested this association, Deana and Dean8 in 1995 published a retrospective study showing a strong causal association between the two. They studied 18 young patients presenting with ischemic colitis, of whom 59% were taking low-dose estrogenic OC agents and reported a sixfold relative risk of ischemic colitis among patients taking OC compared with the general female population. This association also occurred in patients who had prior, but not current, OC use, and in young female patients taking HRT for gynecological indications. Preventza et al.9 further validated this association in 2001 by reporting 25 young female
331
18 years, female, Caucasian
26 years, female, unknown
36 years, female, Caucasian
41 years, female, Caucasian
Rasmussen et al.5 (2011)
Seon et al.6 (2011)
Current report (episode 1)
Current report (episode 2)
20 (i.e. 5 years after episode 1)
15
2
4
3
Unknown
None
None
Juvenile chronic polyarthritis. Irritable bowel syndrome None
Naratriptan therapy for migraine headaches
None
Other potential risk factors
Abdominal CT: focal, severe, mural thickening from splenic flexure to sigmoid colon with dramatic, streaky adjacent mesentery. Colonoscopy with biopsy: diagnostic for IC.
Abdominal CT: moderate left colonic mural thickening. Colonoscopy with biopsy: diagnostic for IC.
Abdominal/pelvis CT: sigmoid wall thickening. Colonoscopy with biopsy: diagnostic for IC. Abdominal CT: minimal ascites in pelvic cavity. Colonoscopy with biopsy: diagnostic for IC.
Mesenteric angiography: normal. Colonoscopy with biopsy: diagnostic for IC.
Colonoscopy: diagnostic for ischemic colitis in left colon.
Brief details
Managed conservatively with intravenous fluids and empiric antibiotics; OC discontinued; Discharged on day 2.
Managed conservatively with intravenous fluids and empiric antibiotics; OC continued after hospital discharge on day 2.
Managed conservatively with bowel rest, intravenous fluids, and empiric antibiotics; OC continued after hospital discharge on day 5.
Therapy not specified; OC discontinued. Repeat colonoscopy one week later was normal. Administered levofloxacin therapy; OC and naratriptan therapies discontinued. Discharged at the fourth hospital day. Managed conservatively with i.v. fluids; OC discontinued.
Treatment
IC recurred 2 months later while still taking OC; OC then discontinued. Recurrence of IC after 5 years while still taking OC (see Episode 2) No recurrence
No recurrence
No recurrence
No recurrence
Post-hospital course
None
None
None
None
None
None
Extra-colonic ischemic episodes
P. Manickam et al.
†Cases before 2000 are excluded because of changes in OC composition since the 1980s and improved recognition of alternative etiologies, such as hypercoagulable syndromes, since 2000.7 ‡Case 2 of Frossard et al. is associated with oral contraceptive use. Case 1 is not associated with such use and is not included in this table. CT, computed tomography; IC, ischemic colitis; i.v., intravenous; OC, oral contraceptive.
42 years, female, unknown
39 years, female, unknown
Age, gender, race
Charles et al.4 (2005)
Frossard et al. (2001)‡
3
Duration of OC use before IC (years)
Case reports published since 2000 of an association between oral contraceptive use and ischemic colitis†
First author (publication year)
Table 1.
332
Journal of Digestive Diseases 2014; 15; 331–333
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 331–333
(a)
(b)
Figure 1. The first episode of ischemic colitis. (a) Colonoscopy showing severe luminal narrowing in descending colon from multiple hemorrhagic nodules (endoscopic appearance corresponding to the radiographic findings of thumbprinting), which are pathognomonic for ischemic colitis. (b) Colonoscopic image showing erythema, spontaneous hemorrhage and mucosal exudate in descending colon, which is strongly suggestive of ischemic colitis.
(a)
(b)
Figure 2. The second episode of ischemic colitis. (a) Abdominal computed tomography at the level of transverse colon shows severe mural thickening (yellow bar) and streaky adjacent mesentery (red arrow) at the splenic flexure; findings compatible with segmental ischemic colitis. Nondifferential air fluid levels are present throughout the transverse colon, but there is no mural thickening in this noninvolved segment. (b) Colonoscopy of descending colon showing segmental colitis characterized by mucosal erythema, patchy spontaneous hemorrhage (upper left) and white mucopus (right side); all findings are highly consistent with ischemic colitis.
patients with ischemic colitis, of whom 52% were using OC at the time of diagnosis. The pathophysiology for the association between OC use and ischemic colitis and the population at risk for this complication has not been conclusively established. Activated protein C resistance has been
OC pill associated ischemic colitis
333
postulated as a mechanism and the importance of evaluation for hypercoagulability has been suggested in this setting.10 This case, although representing anecdotal evidence, adds to the reported association between OC use and ischemic colitis by showing recurrent toxicity with drug rechallenge. OC use should be explored as a possible etiology in young women presenting with ischemic colitis by taking a thorough history, and these medications should be considered for discontinuation when implicated in the etiology to prevent recurrence. Palaniappan MANICKAM, Maryconi JAURIGUE, Mihaela BATKE & Mitchell S. CAPPELL Division of Gastroenterology and Hepatology, Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA REFERENCES 1 Mosli M, Parfitt J, Gregor J. Retrospective analysis of disease association and outcome in histologically confirmed ischemic colitis. J Dig Dis 2013; 14: 238–43. 2 Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012; 366: 2257–66. 3 Frossard JL, Spahr L, Queneau PE, Armenian B, Bründler MA, Hadengue A. Ischemic colitis during pregnancy and contraceptive medication. Digestion 2001; 64: 125–7. 4 Charles JA, Pullicino PM, Stoopack PM, Shroff Y. Ischemic colitis associated with naratriptan and oral contraceptive use. Headache 2005; 45: 386–9. 5 Rasmussen DK, Segars LW. Case of ischemic colitis in a young adolescent associated with triphasic hormonal contraceptive therapy: a case report and review of the literature. W V Med J 2011; 107: 22–5. 6 Seon CS, Park YS, Park SH et al. A case of oral-contraceptive related ischemic colitis in young woman. Clin Endosc 2011; 44: 129–32. 7 van Vliet HA, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 2006; (3): CD003553. 8 Deana DG, Dean PJ. Reversible ischemic colitis in young women. Association with oral contraceptive use. Am J Surg Pathol 1995; 19: 454–62. 9 Preventza OA, Lazarides K, Sawyer MD. Ischemic colitis in young adults: a single-institution experience. J Gastrointest Surg 2001; 5: 388–92. 10 Mann DE Jr, Kessel ER, Mullins DL, Lottenberg R. Ischemic colitis and acquired resistance to activated protein C in a woman using oral contraceptives. Am J Gastroenterol 1998; 93: 1960–2.
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 331–333
doi: 10.1111/1751-2980.12139
Letter to the editor
Recurrent ischemic colitis associated with oral contraceptive therapy
Sirs, In an interesting article Mosli et al.1 methodically reported the risk factors associated with ischemic colitis, as well as characterizing the clinical features, endoscopic findings, complications and prognosis of this disease. They noted a female predominance, but interestingly reported no association with oral contraceptive (OC) use or hormone replacement therapy (HRT). However, they acknowledged that this lack of association might have resulted from the underreporting of OC use or HRT, because patients often failed to voluntarily disclose their use of these agents, and physicians must therefore directly query patients about such use. We emphasize the clinical relevance of this omission by reporting a case of recurrent severe ischemic colitis after failing to discontinue OC medications after the first episode. A 36-year-old woman administered a standard dose and regimen of OC with combination levonorgestrelethinyl-estradiol triphasic pills (Enpresse: Barr Laboratories, Pomona, NY, USA) for 15 years for dysfunctional uterine bleeding, presented with moderately severe acute lower abdominal pain and mild hematochezia (hematocrit 40.5%). Abdominal contrast-enhanced computed tomography (CT) with delayed imaging showed moderate left colonic mural thickening. Colonoscopy showed segmental colitis with edema, erythema and shallow ulcers in the proximal sigmoid colon, descending colon and splenic flexure (Fig. 1). The pathological examination of colonic biopsy specimens was consistent with ischemic Correspondence to: Palaniappan MANICKAM, Division of Gastroenterology and Hepatology, Department of Internal Medicine, William Beaumont Hospital, MOB 602, 3535 W. 13 Mile Road, Royal Oak, MI 48073, USA. Email: [email protected] Conflict of interest: None. © 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
colitis. Routine stool tests were negative for enteric infections. There were no recent cardiac arrhythmia or other apparent risk factors for ischemic colitis. The physician elected to continue OC therapy despite ischemic colitis because of the strong therapeutic indication. Five years later, the patient re-presented with moderately severe acute lower abdominal pain and mild hematochezia (hematocrit 38.5%), while still taking OC. Abdominal CT showed focal severe mural thickening, extending from the splenic flexure to the sigmoid colon, and dramatic streaky mesentery adjacent to these bowel segments (Fig. 2a). Colonoscopy revealed patchy, highly erythematous friable mucosa with erosions and hemorrhage extending from the splenic flexure to the sigmoid colon (Fig. 2b). The pathological examination of colonic biopsy specimens was consistent with ischemic colitis. Routine stool tests were negative for enteric infections. OC administration was then discontinued. OC use has been implicated in venous thromboembolism, myocardial infarction and cerebrovascular accidents.2 It has also been associated with gastrointestinal ischemia, but this association is inconsistently reported. An extensive literature review since 2000 revealed four other case reports of the association between OC use and ischemic colitis (Table 1).3–7 Although several prior case reports suggested this association, Deana and Dean8 in 1995 published a retrospective study showing a strong causal association between the two. They studied 18 young patients presenting with ischemic colitis, of whom 59% were taking low-dose estrogenic OC agents and reported a sixfold relative risk of ischemic colitis among patients taking OC compared with the general female population. This association also occurred in patients who had prior, but not current, OC use, and in young female patients taking HRT for gynecological indications. Preventza et al.9 further validated this association in 2001 by reporting 25 young female
331
18 years, female, Caucasian
26 years, female, unknown
36 years, female, Caucasian
41 years, female, Caucasian
Rasmussen et al.5 (2011)
Seon et al.6 (2011)
Current report (episode 1)
Current report (episode 2)
20 (i.e. 5 years after episode 1)
15
2
4
3
Unknown
None
None
Juvenile chronic polyarthritis. Irritable bowel syndrome None
Naratriptan therapy for migraine headaches
None
Other potential risk factors
Abdominal CT: focal, severe, mural thickening from splenic flexure to sigmoid colon with dramatic, streaky adjacent mesentery. Colonoscopy with biopsy: diagnostic for IC.
Abdominal CT: moderate left colonic mural thickening. Colonoscopy with biopsy: diagnostic for IC.
Abdominal/pelvis CT: sigmoid wall thickening. Colonoscopy with biopsy: diagnostic for IC. Abdominal CT: minimal ascites in pelvic cavity. Colonoscopy with biopsy: diagnostic for IC.
Mesenteric angiography: normal. Colonoscopy with biopsy: diagnostic for IC.
Colonoscopy: diagnostic for ischemic colitis in left colon.
Brief details
Managed conservatively with intravenous fluids and empiric antibiotics; OC discontinued; Discharged on day 2.
Managed conservatively with intravenous fluids and empiric antibiotics; OC continued after hospital discharge on day 2.
Managed conservatively with bowel rest, intravenous fluids, and empiric antibiotics; OC continued after hospital discharge on day 5.
Therapy not specified; OC discontinued. Repeat colonoscopy one week later was normal. Administered levofloxacin therapy; OC and naratriptan therapies discontinued. Discharged at the fourth hospital day. Managed conservatively with i.v. fluids; OC discontinued.
Treatment
IC recurred 2 months later while still taking OC; OC then discontinued. Recurrence of IC after 5 years while still taking OC (see Episode 2) No recurrence
No recurrence
No recurrence
No recurrence
Post-hospital course
None
None
None
None
None
None
Extra-colonic ischemic episodes
P. Manickam et al.
†Cases before 2000 are excluded because of changes in OC composition since the 1980s and improved recognition of alternative etiologies, such as hypercoagulable syndromes, since 2000.7 ‡Case 2 of Frossard et al. is associated with oral contraceptive use. Case 1 is not associated with such use and is not included in this table. CT, computed tomography; IC, ischemic colitis; i.v., intravenous; OC, oral contraceptive.
42 years, female, unknown
39 years, female, unknown
Age, gender, race
Charles et al.4 (2005)
Frossard et al. (2001)‡
3
Duration of OC use before IC (years)
Case reports published since 2000 of an association between oral contraceptive use and ischemic colitis†
First author (publication year)
Table 1.
332
Journal of Digestive Diseases 2014; 15; 331–333
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Journal of Digestive Diseases 2014; 15; 331–333
(a)
(b)
Figure 1. The first episode of ischemic colitis. (a) Colonoscopy showing severe luminal narrowing in descending colon from multiple hemorrhagic nodules (endoscopic appearance corresponding to the radiographic findings of thumbprinting), which are pathognomonic for ischemic colitis. (b) Colonoscopic image showing erythema, spontaneous hemorrhage and mucosal exudate in descending colon, which is strongly suggestive of ischemic colitis.
(a)
(b)
Figure 2. The second episode of ischemic colitis. (a) Abdominal computed tomography at the level of transverse colon shows severe mural thickening (yellow bar) and streaky adjacent mesentery (red arrow) at the splenic flexure; findings compatible with segmental ischemic colitis. Nondifferential air fluid levels are present throughout the transverse colon, but there is no mural thickening in this noninvolved segment. (b) Colonoscopy of descending colon showing segmental colitis characterized by mucosal erythema, patchy spontaneous hemorrhage (upper left) and white mucopus (right side); all findings are highly consistent with ischemic colitis.
patients with ischemic colitis, of whom 52% were using OC at the time of diagnosis. The pathophysiology for the association between OC use and ischemic colitis and the population at risk for this complication has not been conclusively established. Activated protein C resistance has been
OC pill associated ischemic colitis
333
postulated as a mechanism and the importance of evaluation for hypercoagulability has been suggested in this setting.10 This case, although representing anecdotal evidence, adds to the reported association between OC use and ischemic colitis by showing recurrent toxicity with drug rechallenge. OC use should be explored as a possible etiology in young women presenting with ischemic colitis by taking a thorough history, and these medications should be considered for discontinuation when implicated in the etiology to prevent recurrence. Palaniappan MANICKAM, Maryconi JAURIGUE, Mihaela BATKE & Mitchell S. CAPPELL Division of Gastroenterology and Hepatology, Department of Internal Medicine, William Beaumont Hospital, Royal Oak, Michigan, USA REFERENCES 1 Mosli M, Parfitt J, Gregor J. Retrospective analysis of disease association and outcome in histologically confirmed ischemic colitis. J Dig Dis 2013; 14: 238–43. 2 Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012; 366: 2257–66. 3 Frossard JL, Spahr L, Queneau PE, Armenian B, Bründler MA, Hadengue A. Ischemic colitis during pregnancy and contraceptive medication. Digestion 2001; 64: 125–7. 4 Charles JA, Pullicino PM, Stoopack PM, Shroff Y. Ischemic colitis associated with naratriptan and oral contraceptive use. Headache 2005; 45: 386–9. 5 Rasmussen DK, Segars LW. Case of ischemic colitis in a young adolescent associated with triphasic hormonal contraceptive therapy: a case report and review of the literature. W V Med J 2011; 107: 22–5. 6 Seon CS, Park YS, Park SH et al. A case of oral-contraceptive related ischemic colitis in young woman. Clin Endosc 2011; 44: 129–32. 7 van Vliet HA, Grimes DA, Lopez LM, Schulz KF, Helmerhorst FM. Triphasic versus monophasic oral contraceptives for contraception. Cochrane Database Syst Rev 2006; (3): CD003553. 8 Deana DG, Dean PJ. Reversible ischemic colitis in young women. Association with oral contraceptive use. Am J Surg Pathol 1995; 19: 454–62. 9 Preventza OA, Lazarides K, Sawyer MD. Ischemic colitis in young adults: a single-institution experience. J Gastrointest Surg 2001; 5: 388–92. 10 Mann DE Jr, Kessel ER, Mullins DL, Lottenberg R. Ischemic colitis and acquired resistance to activated protein C in a woman using oral contraceptives. Am J Gastroenterol 1998; 93: 1960–2.
© 2014 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
