INVITED REVIEW
Question of an Infectious Etiology or Contribution to the Pathogenesis of Infantile Hypertrophic Pyloric Stenosis Taher Modarressi
See ‘‘Infantile Hypertrophic Pyloric Stenosis: Closing In On the Cause’’ by Dassinger and Fuchs on page 545.
ABSTRACT Infantile hypertrophic pyloric stenosis is a concerning cause of nonbilious vomiting in the neonatal population. Although a number of etiological theories exist, its exact cause remains nebulous. The question of an infectious etiology (or contribution) has been previously examined in case reports and case series, with recent support through suggestions of seasonality and familial aggregation with unclear inheritance patterns. The present review discusses the published literature regarding infectious etiologies of infantile hypertrophic pyloric stenosis. Furthermore, it attempts to demonstrate that newer research regarding an NOS1 genetic etiology does not exclude, but rather can be consistent with, an infectious etiology. Key Words: Heliobacter pylori, infantile hypertrophic pyloric stenosis, infectious etiology, neuronal nitric oxide synthase, nitric oxide, NOS1, pyloric stenosis
(JPGN 2014;58: 546–548)
T
he exact etiology of infantile hypertrophic pyloric stenosis (IHPS) remains unclear. Reviews have summarized the vast number of genetic and environmental factors that may play a role in IHPS pathogenesis, including neuronal, hormonal, biochemical, and environmental effects (1,2). Additionally, a growing body of research has hinted at seasonality in IHPS epidemiology. Most investigations have observed a peak summer incidence (3–5). Others have found bimodal spring-autumn peaks (6), winter peak (7), or have failed to demonstrate seasonality at all (8,9). The topic is controversial and complicated by researchers’ inconsistencies in defining seasons: both technical months (‘‘summer’’ as June 21–September 21) and various calendar months (‘‘summer’’ as either May-June-July or June-July-August) are used in the literature. Notably, the studies were conducted in different countries and at different latitudes; a cursory review of average local temperatures during months claimed as months of peak incidence fails to reveal any overarching association between incidence and temperature. Theoretical IHPS seasonality and epidemiological research that
Received July 24, 2013; accepted November 19, 2013. From the Department of Internal Medicine, Massachusetts General Hospital, Boston, MA. Address correspondence and reprint requests to Taher Modarressi, MD, Department of Internal Medicine, 55 Fruit Street, GRB 740, Boston, MA 02114 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000261
demonstrate familial aggregation with unclear inheritance patterns, thereby suggesting possible intrafamilial transmission, however, raises the suspicion of infection. The hypothesis of an infectious etiology for IHPS has been the source of numerous studies, but no formal reviews. Various pathogens have been investigated in the etiologic model of IHPS, but not all are completely novel. Pyloric stenosis was correlated with duodenal ulcers in the adult patient population (10,11), but it was only after Nobel prize–winning research linked duodenal ulcers to Helicobacter pylori infection (12) that researchers considered H pylori in IHPS pathogenesis. A particularly strong supporting factor was investigations in the adult patient population demonstrating resolution of pyloric stenosis after eradication of H pylori via triple or quadruple pharmacotherapy (13,14). A Korean study in 1994 (15), however, found no evidence of a link between gastric infection with H pylori and IHPS. The theory was formally detailed in the English-language literature in 2000 (16), but further studies throughout the 2000s have found no causal link as measured by multiple methods such as antibody titer levels, rapid urease testing, H pylori stool antigen, and gastric mucosal biopsy (17–19). Unfortunately, the latter studies had limitations of small sample sizes (16, 20, and 39, respectively) and various irregularities, including the presence of ‘‘H pylori–like organisms’’ on gastric mucosal biopsy (18); interestingly, the original Korean study (15) also noted an irregularity, with slight differences in H pylori– specific immunoglobulin G antibody levels. Although no direct link between IHPS and H pylori has thus far been discovered, investigators of the above studies are in general agreement that further research with larger sample sizes is necessary to fully analyze this theory. Viral etiologies of IHPS have also been the subject of investigation. In 1956, Alarotu (20) observed perivascular and intraganglionic leukocytes on histopathology of pyloric biopsies. Herweg et al (21) thereafter examined 44 pyloric biopsies, and, after initially isolating coxsackie B in 2, were unable to replicate these results or isolate any other viral infection. Researchers later turned their attention to Epstein-Barr virus, which has been associated with infection in smooth muscle cells leading to leiomyomas and leiomyosarcomas in immunocompromised patients (22,23). In an investigation again limited by small sample size (10 patients), Epstein-Barr virus was not found to be correlated with IHPS (24). Furthermore, a study (25) seeking to correlate any of the common neonatal respiratory and gastrointestinal viruses with IHPS found no evidence of association. A number of additional theoretical infectious etiologies exist for hypertrophic pyloric stenosis as supported by case reports from the adult patient population, although none have been investigated in the pediatric context. A case report described stenotic change in the gastric pylorus of a 69-year-old man infected with invasive gastric candidiasis (26). Notably, gastric fungal colonization has been reported due to hypoacidity secondary to the use of proton pump inhibitors (27). The neonatal stomach, which is pH neutral at birth and lowest in acid at 3 weeks of age (16,28,29), would therefore theoretically be more hospitable to Candida. Another
546 JPGN Volume 58, Number 5, May 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 58, Number 5, May 2014
case report described a case of a 37-year-old woman infected with the parasite Strongyloides stercoralis who exhibited pyloric narrowing on endoscopy secondary to inflammatory mucosal infiltration (30). Although it is improbable that a fungal or helminthic infection is solely responsible for IHPS, these case reports suggest that many different infectious processes may theoretically contribute to the postnatal development of stenosis. Studies suggest that the male predominance in IHPS incidence, reported to be 4 to 6 times that of female infants (9,31,32), is indicative of a primary genetic etiology. Male neonates have, however, long been thought to be at increased susceptibility to infectious diseases (16,33–35), which has since been demonstrated in bacterial (36–38) and viral (33,39) infections. Neonatal, Gramnegative urinary tract infections, for example, occur in the same 4:1 ratio as IHPS (40). Animal studies have shown the same skewing for parasitic infections (41). Research has shown that susceptibility depends more on the particular infection and that female-predominant infectious diseases do occur (42), but most pathogens manifest predominantly in men. This phenomenon has been theorized to be the result of X chromosome–mediated immunity, with the tradeoff that women experience autoimmune diseases more than men (43). Detractors of the theory of an infectious etiology point to a growing body of literature that implicates neuronal nitric oxide synthase (nNOS) gene NOS1 in IHPS pathogenesis (44–48). Polymorphisms in NOS1 yield a deficiency of nitric oxide (NO), an inhibitory neurotransmitter of the gastrointestinal system, leading to the inability of myenteric plexus smooth muscle to relax and thus resulting in hypertrophy and pyloric stenosis. Although the model is appealing, the immunological role of nNOS cannot be ignored. nNOS-derived NO has been shown to regulate dendritic cell maturation and the T-cell response, and inhibiting nNOS was demonstrated to interfere with the antigen-presenting function of dendritic cells, yielding subsequent T-cell anergy with decreases in interferon-g, interleukin-5, and interleukin-13 (49). Studies analyzing the contribution of pathological NO overproduction in lupus, rheumatoid arthritis, and other autoimmune diseases (50,51) lend further support to NO mediation of the immune response (although admittedly such studies have evaluated the contribution of NO produced from NOS2 [inducible NOS]). The mechanism of NOS1 mediation has been increasingly elucidated in recent years (52–54). Among other functions, nNOS maintains normal physiologic levels of NO, which suppresses nuclear factor-kB (55,56), a well-known transcription factor that modulates the immune and inflammatory responses. Lipopolysaccharide and interferon-g act to shift nNOS equilibrium toward the inactivated, phosphorylated form. The resulting decrease in intracellular NO subsequently disinhibits nuclear factor-kB. Two studies examining viral and prion diseases have demonstrated decreases in nNOS (57,58), even in the setting of prenatal infection (59). IHPS may, therefore, simply be a consequence, rather than a direct result, of neonatal infection. Notably, estrogens enhance nNOS activity (60), a possible contributor to epidemiologic male predominance. Therefore, the relation between NOS1 and IHPS is not incompatible with an infectious etiology. Although a possibility, further research is needed to propose and evaluate the role of specific pathogens and to examine whether an infectious explanation can account for the whole story. Acknowledgments: The author thanks Dr Philip Kahn (Department of Pediatrics, Division of Pediatric Rheumatology, New York University) for wondering aloud on rounds and providing the spark for this review, and Dr Linda Tewksbury (Department of Pediatrics, New York University) for kind words and encouragement. www.jpgn.org
Infectious Etiology or Contribution to Pathogenesis of IHPS
REFERENCES 1. Panteli C. New insights into the pathogenesis of infantile pyloric stenosis. Pediatr Surg Int 2009;25:1043–52. 2. Peeters B, Benninga MA, Hennekam RC. Infantile hypertrophic pyloric stenosis: genetics and syndromes. Nat Rev Gastroenterol Hepatol 2012;9:646–60. 3. Schechter R, Torfs CP, Bateson TF. The epidemiology of infantile hypertrophic pyloric stenosis. Paediatr Perinat Epidemiol 1997; 11:407–27. 4. Mackay AJ, Mackellar A. Infantile hypertrophic pyloric stenosis: a review of 222 cases. Austral N Z J Surg 1986;56:131–3. 5. Zamakhshary MF, Dutta S, To T, et al. Seasonal variation of hypertrophic pyloric stenosis: a population-based study. Pediatr Surg Int 2011;27:689–93. 6. Kwok RH, Avery G. Seasonal variation of hypertrophic pyloric stenosis. J Pediatr 1967;70:963–5. 7. Dodge JA. Infantile hypertrophic pyloric stenosis in Belfast, 1957-1969. Arch Dis Child 1975;50:171–8. 8. Habbick BF, To T. Incidence of infantile hypertrophic pyloric stenosis in Saskatchewan, 1970-85. CMAJ 1989;140:395–8. 9. Leong MM, Chen SC, Hsieh CS, et al. Epidemiological features of infantile hypertrophic pyloric stenosis in Taiwanese children: a nationwide analysis of cases during 1997-2007. PLoS One 2011;6:e19404. 10. Johnston D, Lyndon PJ, Smith RB, et al. Highly selective vagotomy without a drainage procedure in the treatment of haemorrhage, perforation, and pyloric stenosis due to peptic ulcer. Br J Surg 1973;60:790–7. 11. Rigler S, Oberhelman H Jr, Brasher P, et al. Pyloric stenosis and gastric ulcer. AMA Arch Surg 1955;71:191–5. 12. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;323:1311–5. 13. de Boer WA, Driessen WM. Resolution of gastric outlet obstruction after eradication of Helicobacter pylori. J Clin Gastroenterol 1995; 21:329–30. 14. Tursi A, Cammarota G, Papa A, et al. Helicobacter pylori eradication helps resolve pyloric and duodenal stenosis. J Clin Gastroenterol 1996;23:157–8. 15. Moon S, Shim Y, Lee N, et al. The relationship between Helicobacter pylori infection and infantile hypertrophic pyloric stenosis in infants. J Korea Surg Soc 1994;46:724–31. 16. Paulozzi LJ. Is Helicobacter pylori a cause of infantile hypertrophic pyloric stenosis? Med Hypotheses 2000;55:119–25. 17. Aslanabadi S, Rafeey M, Diaz D, et al. Role of Helicobacter pylori in the pathogenesis of infantile hypertrophic pyloric stenosis. Afr J Paediatr Surg 2011;8:172–5. 18. Dahshan A, Donovan KG, Halabi IM, et al. Helicobacter pylori and infantile hypertrophic pyloric stenosis: is there a possible relationship? J Pediatr Gastroenterol Nutr 2006;42:262–4. 19. Sherwood W, Choudhry M, Lakhoo K. Infantile hypertrophic pyloric stenosis: an infectious cause? Pediatr Surg Int 2007;23:61–3. 20. Alarotu H. The histopathologic changes in the myenteric plexus of the pylorus in hypertrophic pyloric stenosis of infants (pylorospasm). Acta Paediatr Suppl 1956;45:1–131. 21. Herweg JC, Middelkamp JN, Thornton HK, et al. A search into the etiology of hypertrophic pyloric stenosis. J Pediatr 1962;61:309–10. 22. Dionne JM, Carter JE, Matsell D, et al. Renal leiomyoma associated with Epstein-Barr virus in a pediatric transplant patient. Am J Kid Dis 2005;46:351–5. 23. Hatano M, Takada H, Nomura A, et al. Epstein-Barr virus-associated bronchial leiomyoma in a boy with cellular immunodeficiency. Pediatr Pulmonol 2006;41:371–3. 24. Jenson HB, Gulley ML, Puri P. Absence of Epstein-Barr virus in smooth muscle cells of idiopathic hypertrophic pyloric stenosis. Arch Pathol Lab Med 2001;125:361–3. 25. McHeik JN, Dichamp I, Levard G, et al. Infantile hypertrophic pyloric stenosis: are viruses involved? J Med Virol 2010;82:2087–91. 26. Joo MK, Park JJ, Lee BJ, et al. A case of stenotic change from gastric candidiasis managed with temporary stent insertion. Gut Liver 2011; 5:238–41. 27. Goenka M, Kochhar R, Chakrabarti A, et al. Candida overgrowth after treatment of duodenal ulcer. A comparison of cimetidine, famotidine, and omeprazole. J Clin Gastroenterol 1996;23:7–10.
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Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Modarressi 28. Agunod M, Yamaguchi N, Lopez R, et al. Correlative study of hydrochloric acid, pepsin, and intrinsic factor secretion in newborns and infants. Am J Dig Dis 1969;14:400–13. 29. Avery GB, Randolph JG, Weaver T. Gastric acidity in the first day of life. Pediatrics 1966;37:1005–7. 30. Ozturk G, Aydinli B, Celebi F, et al. Gastric perforation caused by Strongyloides stercoralis: a case report. Ulus Travma Acil Cerrahi Derg 2011;17:90–2. 31. Cui W, Ma CX, Tang Y, et al. Sex differences in birth defects: a study of opposite-sex twins. Birth Defects Res A Clin Mol Teratol 2005;73:876– 80. 32. To T, Wajja A, Wales PW, et al. Population demographic indicators associated with incidence of pyloric stenosis. Arch Pediatr Adolesc Med 2005;159:520–5. 33. Green MS. The male predominance in the incidence of infectious diseases in children: a postulated explanation for disparities in the literature. Int J Epidemiol 1992;21:381–6. 34. Schlegel RJ, Bellanti JA. Increased susceptibility of males to infection. Lancet 1969;2:826–7. 35. Washburn TC, Medearis DN, Childs B. Sex differences in susceptibility to infections. Pediatrics 1965;35:57–64. 36. Fortunov RM, Hulten KG, Hammerman WA, et al. Communityacquired Staphylococcus aureus infections in term and near-term previously healthy neonates. Pediatrics 2006;118:874–81. 37. Shah S, Sharieff GQ. Pediatric respiratory infections. Emerg Med Clin North Am 2007;25:961–79. 38. Thompson DJ, Gezon HM, Rogers KD, et al. Excess risk of staphylococcal infection and disease in newborn males. Am J Epidemiol 1966;84:314–28. 39. Vergnano S, Menson E, Kennea N, et al. Neonatal infections in England: the NeonIN surveillance network. Arch Dis Child Fetal Neonatal Ed 2011;96:F9–14. 40. Biyikli NK, Alpay H, Ozek E, et al. Neonatal urinary tract infections: analysis of the patients and recurrences. Pediatr Int 2004;46:21–5. 41. Zuk M, McKean KA. Sex differences in parasite infections: patterns and processes. Int J Parasitol 1996;26:1009–24. 42. McClelland EE, Smith JM. Gender specific differences in the immune response to infection. Arch Immunol Ther Exp (Warsz) 2011;59:203–13. 43. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol 2010;10:594–604. 44. Chung E. Infantile hypertrophic pyloric stenosis: genes and environment. Arch Dis Childhood 2008;93:1003–4. 45. Friebe A, Koesling D. The function of NO-sensitive guanylyl cyclase: what we can learn from genetic mouse models. Nitric Oxide 2009; 21:149–56.
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46. Huang LT, Tiao MM, Lee SY, et al. Low plasma nitrite in infantile hypertrophic pyloric stenosis patients. Dig Dis Sci 2006;51:869–72. 47. Kusafuka T, Puri P. Altered messenger RNA expression of the neuronal nitric oxide synthase gene in infantile hypertrophic pyloric stenosis. Pediatr Surg Int 1997;12:576–9. 48. Vanderwinden JM, Mailleux P, Schiffmann SN, et al. Nitric oxide synthase activity in infantile hypertrophic pyloric stenosis. N Engl J Med 1992;327:511–5. 49. Adler HS, Simon A, Graulich E, et al. Neuronal nitric oxide synthase modulates maturation of human dendritic cells. J Immunol 2010; 184:6025–34. 50. Nagy G, Clark JM, Buza´s EI, et al. Nitric oxide, chronic inflammation and autoimmunity. Immunol Lett 2007;111:1–5. 51. Jarazo-Dietrich S, Jacobo P, Pe´rez CV, et al. Up regulation of nitric oxide synthase–nitric oxide system in the testis of rats undergoing autoimmune orchitis. Immunobiology 2012;217:778–87. 52. Colasanti M, Cavalieri E, Persichini T, et al. Bacterial lipopolysaccharide plus interferon-gamma elicit a very fast inhibition of a Ca2þdependent nitric-oxide synthase activity in human astrocytoma cells. J Biol Chem 1997;272:7582–5. 53. Colasanti M, Persichini T, Cavalieri E, et al. Rapid inactivation of NOSI by lipopolysaccharide plus interferon-gamma-induced tyrosine phosphorylation. J Biol Chem 1999;274:9915–7. 54. Colasanti M, Suzuki H. The dual personality of NO. Trends Pharmacol Sci 2000;21:249–52. 55. Matthews JR, Botting CH, Panico M, et al. Inhibition of NF-kB DNA binding by nitric oxide. Nucl Acids Res 1996;24:2236–42. 56. Togashi H, Sasaki M, Frohman E, et al. Neuronal (type I) nitric oxide synthase regulates nuclear factor kappaB activity and immunologic (type II) nitric oxide synthase expression. Proc Natl Acad Sci U S A 1997;94:2676–80. 57. Akaike T, Weihe E, Schaefer M, et al. Effect of neurotropic virus infection on neuronal and inducible nitric oxide synthase activity in rat brain. J Neurovirol 1995;1:118–25. 58. Ovadia H, Rosenmann H, Shezen E, et al. Effect of scrapie infection on the activity of neuronal nitric-oxide synthase in brain and neuroblastoma cells. J Biol Chem 1996;271:16856–61. 59. Fatemi SH, Cuadra AE, El-Fakahany EE, et al. Prenatal viral infection causes alterations in nNOS expression in developing mouse brains. Neuroreport 2000;11:1493–6. 60. Hayashi T, Yamada K, Esaki T, et al. Effect of estrogen on isoforms of nitric oxide synthase: possible mechanism of anti-atherosclerotic effect of estrogen. Gerontology 1997;43 (suppl 1):24–34.
www.jpgn.org
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Question of an Infectious Etiology or Contribution to the Pathogenesis of Infantile Hypertrophic Pyloric Stenosis Taher Modarressi
See ‘‘Infantile Hypertrophic Pyloric Stenosis: Closing In On the Cause’’ by Dassinger and Fuchs on page 545.
ABSTRACT Infantile hypertrophic pyloric stenosis is a concerning cause of nonbilious vomiting in the neonatal population. Although a number of etiological theories exist, its exact cause remains nebulous. The question of an infectious etiology (or contribution) has been previously examined in case reports and case series, with recent support through suggestions of seasonality and familial aggregation with unclear inheritance patterns. The present review discusses the published literature regarding infectious etiologies of infantile hypertrophic pyloric stenosis. Furthermore, it attempts to demonstrate that newer research regarding an NOS1 genetic etiology does not exclude, but rather can be consistent with, an infectious etiology. Key Words: Heliobacter pylori, infantile hypertrophic pyloric stenosis, infectious etiology, neuronal nitric oxide synthase, nitric oxide, NOS1, pyloric stenosis
(JPGN 2014;58: 546–548)
T
he exact etiology of infantile hypertrophic pyloric stenosis (IHPS) remains unclear. Reviews have summarized the vast number of genetic and environmental factors that may play a role in IHPS pathogenesis, including neuronal, hormonal, biochemical, and environmental effects (1,2). Additionally, a growing body of research has hinted at seasonality in IHPS epidemiology. Most investigations have observed a peak summer incidence (3–5). Others have found bimodal spring-autumn peaks (6), winter peak (7), or have failed to demonstrate seasonality at all (8,9). The topic is controversial and complicated by researchers’ inconsistencies in defining seasons: both technical months (‘‘summer’’ as June 21–September 21) and various calendar months (‘‘summer’’ as either May-June-July or June-July-August) are used in the literature. Notably, the studies were conducted in different countries and at different latitudes; a cursory review of average local temperatures during months claimed as months of peak incidence fails to reveal any overarching association between incidence and temperature. Theoretical IHPS seasonality and epidemiological research that
Received July 24, 2013; accepted November 19, 2013. From the Department of Internal Medicine, Massachusetts General Hospital, Boston, MA. Address correspondence and reprint requests to Taher Modarressi, MD, Department of Internal Medicine, 55 Fruit Street, GRB 740, Boston, MA 02114 (e-mail: [email protected]). The author reports no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000261
demonstrate familial aggregation with unclear inheritance patterns, thereby suggesting possible intrafamilial transmission, however, raises the suspicion of infection. The hypothesis of an infectious etiology for IHPS has been the source of numerous studies, but no formal reviews. Various pathogens have been investigated in the etiologic model of IHPS, but not all are completely novel. Pyloric stenosis was correlated with duodenal ulcers in the adult patient population (10,11), but it was only after Nobel prize–winning research linked duodenal ulcers to Helicobacter pylori infection (12) that researchers considered H pylori in IHPS pathogenesis. A particularly strong supporting factor was investigations in the adult patient population demonstrating resolution of pyloric stenosis after eradication of H pylori via triple or quadruple pharmacotherapy (13,14). A Korean study in 1994 (15), however, found no evidence of a link between gastric infection with H pylori and IHPS. The theory was formally detailed in the English-language literature in 2000 (16), but further studies throughout the 2000s have found no causal link as measured by multiple methods such as antibody titer levels, rapid urease testing, H pylori stool antigen, and gastric mucosal biopsy (17–19). Unfortunately, the latter studies had limitations of small sample sizes (16, 20, and 39, respectively) and various irregularities, including the presence of ‘‘H pylori–like organisms’’ on gastric mucosal biopsy (18); interestingly, the original Korean study (15) also noted an irregularity, with slight differences in H pylori– specific immunoglobulin G antibody levels. Although no direct link between IHPS and H pylori has thus far been discovered, investigators of the above studies are in general agreement that further research with larger sample sizes is necessary to fully analyze this theory. Viral etiologies of IHPS have also been the subject of investigation. In 1956, Alarotu (20) observed perivascular and intraganglionic leukocytes on histopathology of pyloric biopsies. Herweg et al (21) thereafter examined 44 pyloric biopsies, and, after initially isolating coxsackie B in 2, were unable to replicate these results or isolate any other viral infection. Researchers later turned their attention to Epstein-Barr virus, which has been associated with infection in smooth muscle cells leading to leiomyomas and leiomyosarcomas in immunocompromised patients (22,23). In an investigation again limited by small sample size (10 patients), Epstein-Barr virus was not found to be correlated with IHPS (24). Furthermore, a study (25) seeking to correlate any of the common neonatal respiratory and gastrointestinal viruses with IHPS found no evidence of association. A number of additional theoretical infectious etiologies exist for hypertrophic pyloric stenosis as supported by case reports from the adult patient population, although none have been investigated in the pediatric context. A case report described stenotic change in the gastric pylorus of a 69-year-old man infected with invasive gastric candidiasis (26). Notably, gastric fungal colonization has been reported due to hypoacidity secondary to the use of proton pump inhibitors (27). The neonatal stomach, which is pH neutral at birth and lowest in acid at 3 weeks of age (16,28,29), would therefore theoretically be more hospitable to Candida. Another
546 JPGN Volume 58, Number 5, May 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 58, Number 5, May 2014
case report described a case of a 37-year-old woman infected with the parasite Strongyloides stercoralis who exhibited pyloric narrowing on endoscopy secondary to inflammatory mucosal infiltration (30). Although it is improbable that a fungal or helminthic infection is solely responsible for IHPS, these case reports suggest that many different infectious processes may theoretically contribute to the postnatal development of stenosis. Studies suggest that the male predominance in IHPS incidence, reported to be 4 to 6 times that of female infants (9,31,32), is indicative of a primary genetic etiology. Male neonates have, however, long been thought to be at increased susceptibility to infectious diseases (16,33–35), which has since been demonstrated in bacterial (36–38) and viral (33,39) infections. Neonatal, Gramnegative urinary tract infections, for example, occur in the same 4:1 ratio as IHPS (40). Animal studies have shown the same skewing for parasitic infections (41). Research has shown that susceptibility depends more on the particular infection and that female-predominant infectious diseases do occur (42), but most pathogens manifest predominantly in men. This phenomenon has been theorized to be the result of X chromosome–mediated immunity, with the tradeoff that women experience autoimmune diseases more than men (43). Detractors of the theory of an infectious etiology point to a growing body of literature that implicates neuronal nitric oxide synthase (nNOS) gene NOS1 in IHPS pathogenesis (44–48). Polymorphisms in NOS1 yield a deficiency of nitric oxide (NO), an inhibitory neurotransmitter of the gastrointestinal system, leading to the inability of myenteric plexus smooth muscle to relax and thus resulting in hypertrophy and pyloric stenosis. Although the model is appealing, the immunological role of nNOS cannot be ignored. nNOS-derived NO has been shown to regulate dendritic cell maturation and the T-cell response, and inhibiting nNOS was demonstrated to interfere with the antigen-presenting function of dendritic cells, yielding subsequent T-cell anergy with decreases in interferon-g, interleukin-5, and interleukin-13 (49). Studies analyzing the contribution of pathological NO overproduction in lupus, rheumatoid arthritis, and other autoimmune diseases (50,51) lend further support to NO mediation of the immune response (although admittedly such studies have evaluated the contribution of NO produced from NOS2 [inducible NOS]). The mechanism of NOS1 mediation has been increasingly elucidated in recent years (52–54). Among other functions, nNOS maintains normal physiologic levels of NO, which suppresses nuclear factor-kB (55,56), a well-known transcription factor that modulates the immune and inflammatory responses. Lipopolysaccharide and interferon-g act to shift nNOS equilibrium toward the inactivated, phosphorylated form. The resulting decrease in intracellular NO subsequently disinhibits nuclear factor-kB. Two studies examining viral and prion diseases have demonstrated decreases in nNOS (57,58), even in the setting of prenatal infection (59). IHPS may, therefore, simply be a consequence, rather than a direct result, of neonatal infection. Notably, estrogens enhance nNOS activity (60), a possible contributor to epidemiologic male predominance. Therefore, the relation between NOS1 and IHPS is not incompatible with an infectious etiology. Although a possibility, further research is needed to propose and evaluate the role of specific pathogens and to examine whether an infectious explanation can account for the whole story. Acknowledgments: The author thanks Dr Philip Kahn (Department of Pediatrics, Division of Pediatric Rheumatology, New York University) for wondering aloud on rounds and providing the spark for this review, and Dr Linda Tewksbury (Department of Pediatrics, New York University) for kind words and encouragement. www.jpgn.org
Infectious Etiology or Contribution to Pathogenesis of IHPS
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