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Case Reports
. 2009;44 Suppl 19(Suppl 19):1-7.
doi: 10.1007/s00535-008-2253-y. Epub 2009 Jan 16.

The enteropathy of prostaglandin deficiency

David H Adler  1 , John A Phillips 3rd, Joy D Cogan, Tina M Iverson, Nathalie Schnetz-Boutaud, Jeffrey A Stein, David A Brenner, Ginger L Milne, Jason D Morrow, Oliver Boutaud, John A Oates
Affiliations
Case Reports

The enteropathy of prostaglandin deficiency

David H Adler et al. J Gastroenterol. 2009.

Abstract

Background: Small intestinal ulcers are frequent complications of therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine.

Methods: Eicosanoids and metabolites were measured by isotope dilution with mass spectrometry. cDNA was obtained by reverse transcription and sequenced following amplification with RT-PCR.

Results: We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45-year-old man who was not taking any cyclooxygenase inhibitor. Prostaglandin metabolites in urine were significantly depressed. Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (P<0.006), and serum 12-HETE was 1.3% of controls (P<0.005). Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA). LTB4 biosynthesis by ionophore-activated leukocytes was only 3% of controls, and urinary LTE4 was undetectable. These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A2-alpha (cPLA2-alpha), which regulates cyclooxygenase- and lipoxygenase-mediated eicosanoid production by catalyzing the release of their substrate, AA. Sequencing of cPLA2-alpha cDNA demonstrated two heterozygous nonsynonymous single-base-pair mutations: Ser111Pro (S111P) and Arg485His (R485H), as well as a known single nucleotide polymorphism (SNP), Lys651Arg (K651R).

Conclusions: Characterization of this cPLA2-alpha deficiency provides support for the importance of prostaglandins in protecting small intestinal integrity and indicates that loss of prostaglandin biosynthesis is sufficient to produce small intestinal ulcers.

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Figures

Figure 1
Figure 1. Arachidonic acid cascade initiated by cPLA2α
P450, cytochrome P450; LOX, lipoxygenase; COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid.
See this image and copyright information in PMC

References

    1. Maiden L, Thjodleifsson B, Seigal A, Bjarnason II, Scott D, Birgisson S, et al. Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study. Clin Gastroenterol Hepatol. 2007;5:1040–5. - PubMed
    1. Matsumoto T, Kudo T, Esaki M, Yano T, Yamamoto H, Sakamoto C, et al. Prevalence of non-steroidal anti-inflammatory drug-induced enteropathy determined by double-balloon endoscopy: a Japanese multicenter study. Scandinavian Journal of gastroenterology. 2008;43:490–6. - PubMed
    1. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol. 2005;3:55–9. - PubMed
    1. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG. Video capsule endoscopy tp prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol. 2005;3:133–41. - PubMed
    1. Hayashi Y, Yamamoto H, Kita H, Sunada K, Sato H, Yano T, et al. Non-steroidal anti-inflammatory drug-induced small bowel injuries identified by double-balloon endoscopy. World J Gastroenterol. 2005;11:4861–4. - PMC - PubMed

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