Original Article
Enteritis Necroticans (Pigbel) in a Diabetic Child
N Engl J Med 2000; 342:1250-1253April 27, 2000
- Abstract
Background
Enteritis necroticans (pigbel), an often fatal illness characterized by hemorrhagic, inflammatory, or ischemic necrosis of the jejunum, occurs in developing countries but is rare in developed countries, where its occurrence is confined to adults with chronic illnesses. The causative organism of enteritis necroticans is Clostridium perfringens type C, an anaerobic gram-positive bacillus.
Methods
In December 1998, enteritis necroticans developed in a 12-year-old boy with poorly controlled diabetes mellitus after he consumed pig intestines (chitterlings). He presented with hematemesis, abdominal distention, and severe diabetic ketoacidosis with hypotension. At laparotomy, extensive jejunal necrosis required bowel resection, jejunostomy, and ileostomy. Samples were obtained for histopathological examination. Polymerase-chain-reaction (PCR) assay was performed on paraffin-embedded bowel tissue with primers specific for the cpa and cpb genes, which code for the α and β toxins produced by C. perfringens.
Results
Histologic examination of resected bowel tissue showed extensive mucosal necrosis, the formation of pseudomembrane, pneumatosis, and areas of epithelial regeneration that alternated with necrotic segments — findings consistent with a diagnosis of enteritis necroticans. Gram's staining showed large gram-positive bacilli whose features were consistent with those of clostridium species. Through PCR amplification, we detected products of the cpa and cpb genes, which indicated the presence of C. perfringens type C. Assay of ileal tissue obtained during surgery to restore the continuity of the patient's bowel was negative for C. perfringens.
Conclusions
The preparation or consumption of chitterlings by diabetic patients and other chronically ill persons can result in potentially life-threatening infectious complications.
Media in This Article
Figure 1
Abdominal Radiograph Showing Dilated Loops of Small Bowel.Figure 3
Electrophoresis of DNA Fragments Produced by Polymerase Chain Reaction with the Use of Primers for the cpa and cpb Genes, Which Encode the α and β Toxins of Clostridium perfringens Type C.Article Activity
- Article
Enteritis necroticans, an often fatal illness characterized by hemorrhagic, inflammatory, or ischemic necrosis of the jejunum, was first described in northern Germany and Denmark after World War II.1,2 Most patients had been starved for long periods and then had eaten a voluminous meal. Enteritis necroticans was subsequently recognized in 1961 among children in Papua New Guinea, in whom it often followed a large feast of pork.3 There it was termed “pigbel,” in the dialect of Papua New Guinea, and has been a major public health problem.4 The clinical features of enteritis necroticans include abdominal distention and pain and hypotension. At laparotomy, dilated, thickened loops of bowel are found, with segments of necrosis often separated by normal segments of bowel. On histologic examination, necrotic villi and numerous bacteria are seen on the mucosal surface of affected tissue.5
The causative organism of enteritis necroticans is Clostridium perfringens, an anaerobic gram-positive bacillus. This species is divided into toxicogenic types A, B, C, D, and E on the basis of the production of four major toxins.6,7 All five types produce α toxin, which is a hemolytic, necrotizing, lethal phospholipase C. In addition, type B produces β and ε toxins, type C produces β toxin, type D produces ε toxin, and type E produces ι toxin. Enteritis necroticans is caused by the β toxin produced by type C,5-8 and immunization against this toxin has resulted in a decline in the incidence of the condition.4
Enteritis necroticans is recognized in other developing countries9-12 and, in rare instances, in developed countries, where its occurrence is confined to adults with chronic illnesses.13-15 We report here a case of enteritis necroticans in a boy with diabetes after he consumed pig intestines (chitterlings) in the United States.
Case Report
A 12-year-old boy who had been hospitalized frequently for poorly controlled type 1 diabetes mellitus during the previous two years was transferred to the emergency department of Children's Healthcare of Atlanta at Egleston because of diabetic ketoacidosis with altered mental status. Forty-eight to 72 hours before admission, he had consumed large quantities of food, including chitterlings, in three separate Christmas dinners. He had not traveled outside Atlanta and had had no contact with farm animals.
On the day of admission, his mother brought him to another emergency department because of somnolence and hematemesis. His blood glucose concentration was 1500 mg per deciliter (83.3 mmol per liter), the serum sodium concentration was 105 mmol per liter, the serum potassium concentration was 7.9 mmol per liter, the serum bicarbonate concentration was 6 mmol per liter, and the serum creatinine concentration was 5.8 mg per deciliter (513 μmol per liter). Arterial-blood gas values were as follows: pH, 7.08; partial pressure of carbon dioxide, 19 mm Hg; and partial pressure of oxygen, 175 mm Hg, with a base deficit of 22.7 mmol per liter. The initial white-cell count was 11,300 per cubic millimeter, with 55 percent segmented neutrophils and 24 percent band forms; the hemoglobin concentration was 9.9 g per deciliter, and the platelet count was 242,000 per cubic millimeter. Treatment with intravenous saline and insulin was initiated, and the patient was transferred to Children's Healthcare of Atlanta at Egleston. On arrival, he was confused and combative. His temperature was 34.1°C, the heart rate 118 beats per minute, the respiratory rate 22 breaths per minute, and the blood pressure 66/33 mm Hg. The physical examination revealed dry mucous membranes, an odor of acetone to the breath, and a tender, distended, soft abdomen. His height and weight were 156 cm (approximately the 75th percentile for age) and 39 kg (approximately the 50th percentile for age), respectively. The glycosylated hemoglobin value was 14.1 percent (normal range, 3.0 to 6.2), and the serum transthyretin (prealbumin) concentration was less than 7 mg per deciliter (normal range, 18 to 45).
The patient continued to have hematemesis, and his abdominal tenderness increased. In addition to intravenous fluids and insulin, he received cefotaxime, ticarcillin–clavulanate, and clindamycin. Hypotension persisted despite aggressive volume resuscitation; dopamine, norepinephrine, and epinephrine were given to maintain blood pressure. He was intubated for airway protection because of increasing respiratory effort and declining mental status. An abdominal radiograph showed dilated loops of small bowel, with gas in the bowel wall and in the intrahepatic branches of the portal vein (Figure 1Figure 1
Abdominal Radiograph Showing Dilated Loops of Small Bowel.). Exploratory laparotomy revealed bloody ascites and necrotic bowel from the proximal jejunum to the mid-ileum. The necrotic bowel was resected, leaving approximately 2 cm of jejunum and 36 cm of distal ileum. A jejunostomy and an ileostomy were created.Histologic examination of the resected bowel showed extensive inflammation and necrosis of the mucosa, with areas of pseudomembrane formation and pneumatosis (Figure 2AFigure 2
Photomicrographs of Resected Ileum from the Patient with Enteritis Necroticans.). Areas of epithelial regeneration alternated with necrotic segments (Figure 2B). Gram's staining revealed gram-positive bacteria, including large gram-positive bacilli whose features were consistent with those of clostridium species (Figure 2C); spores were seen at a magnification of 1000. Yeast forms consistent with the presence of candida species were also present. Bowel tissue was not cultured, and cultures of ascitic fluid (aerobic and anaerobic) yielded no growth. Polymerase-chain-reaction (PCR) assay was used to detect C. perfringens in paraffin-embedded bowel tissue.16,17 Primers specific for the cpa and cpb genes, which code for α and β toxins, respectively, were used for the detection of these genes; cpa is chromosomal and cpb is found on a plasmid. Although the β toxin (encoded by the cpb gene) is the primary virulent factor associated with enteritis necroticans, a primer pair for the cpa gene was included because all isolates of C. perfringens produce α toxin. The amplified products were then separated by electrophoresis in a 1.5 percent agarose gel and stained with ethidium bromide. The assay therefore detected amplification products of cpa and cpb, indicating the presence of C. perfringens type C (Figure 3Figure 3Electrophoresis of DNA Fragments Produced by Polymerase Chain Reaction with the Use of Primers for the cpa and cpb Genes, Which Encode the α and β Toxins of Clostridium perfringens Type C.).The patient had an extended hospital stay, with prolonged parenteral hyperalimentation before he was able to tolerate enteral nutrition. Six weeks after the laparotomy, he underwent surgery to reestablish the continuity of the intestinal tract. PCR assay of tissue obtained from the ileal fistula during the second operation did not show C. perfringens (Figure 3). PCR assay performed on paraffin-embedded bowel tissue that had been resected for another indication from another child was also negative for C. perfringens (data not shown).
Discussion
Cleaned and boiled pig intestines (chitterlings) are part of traditional holiday meals, particularly in the southern United States.18 During the preparation of chitterlings, the cook and the other foods prepared at the same time may be exposed to the contents of pig bowels. We speculate that this patient ingested C. perfringens that produces β toxin, either in the chitterlings or in other foods contaminated during or after preparation of the chitterlings. Chitterlings have also been implicated in enteritis due to Yersinia enterocolitica 18 and in salmonella infections.19
That the epithelium was regenerating indicated that mucosal injury probably started about 48 to 72 hours before the laparotomy. The finding in the intestinal wall of numerous large gram-positive rods with spores consistent with the presence of clostridium and candida-like organisms on the necrotic mucosal surface suggested a dramatic alteration of the child's intestinal microflora.
The development of enteritis necroticans requires the action of the β toxin of C. perfringens. Antibody to the β toxin of C. perfringens type C is uncommon among persons from developed countries (less than 15 percent of the population), but high or rising titers are detected in most persons recovering from enteritis necroticans (56 percent to more than 80 percent).3,5,12,20 However, factors other than this toxin have an important role in the pathogenesis of enteritis necroticans. Among these factors are trypsin inhibitors, which prevent intestinal degradation of the toxin, and reduced intestinal motility, which favors the local accumulation of toxin.3,5,6 Protein malnutrition, which is associated with decreased activity of trypsin, and the ingestion of sweet potatoes, which contain trypsin inhibitors, have been associated with enteritis necroticans.3-6
Factors associated with enteritis necroticans in developed countries include the reduced gastric acidity and gastrointestinal motility associated with some chronic diseases and the frequent consumption of sweet potatoes or other foods that contain trypsin inhibitors13-15; one report described a diabetic patient who consumed pork before the onset of hypotension, hematemesis, and abdominal distention.14
Our patient was not obviously malnourished, but his glycosylated hemoglobin value indicated that his diabetes had recently been poorly controlled. Poor diabetic control is associated with protein malnutrition,21 and the patient had a low serum transthyretin concentration, a finding compatible with protein malnutrition. Diabetic patients may have delayed gastric emptying22 and reduced intestinal motility,23,24 which may contribute to the accumulation of toxins and the overgrowth of bacteria.
Cases of acute ischemic intestinal necrosis in patients with diabetic ketoacidosis in the United States have been attributed to mesenteric and portal venous thrombosis or nonocclusive bowel ischemia due to ketoacidosis and hypotension25,26; evidence of C. perfringens infection was not reported in these cases. This patient's hypotension and hyperosmolar state could have compromised blood flow to the small bowel but are unlikely to have initiated this process. Rather, the history and pathological findings implicate a state of intense infectious injury that lasted about two to three days. The diagnosis of enteritis necroticans was based on the clinical presentation, gross and microscopic lesions, and the presence of C. perfringens type C in the bowel. Chronically ill persons, as well as parents of infants, should be informed of the risks of infection related to the preparation and consumption of chitterlings and of the failure of heating to destroy some potential pathogens.27,28
We are indebted to Robert Pettignano, M.D., for his thoughtful review of the manuscript.
Source Information
From the Divisions of Critical Care Medicine (T.M.P., J.D.F.) and Endocrinology (L.M.), Children's Healthcare of Atlanta at Egleston, Atlanta; the National Center for Infectious Diseases (C.M.B.-S.) and the Epidemiology Program Office (A.G.D.), Centers for Disease Control and Prevention, Atlanta; the Department of Veterinary Science and Microbiology, University of Arizona, Tucson (J.G.S., D.M.B.); and the Divisions of Pediatric Pathology (C.A.), Surgery (H.L.), and Infectious Diseases, Epidemiology, and Immunology (C.M.B.-S., C.A., S.R.N.), Emory University, Atlanta.
Address reprint requests to Dr. Petrillo at the Division of Critical Care Medicine, Children's Healthcare of Atlanta at Egleston, 1405 Clifton Rd. NE, 3rd Fl. Annex, Atlanta, GA 30322, or at toni_petrillo@oz.ped.emory.edu.
- References
References
1
Fick KA ,Wolken AP . Necrotic jejunitis. Lancet 1949;1:519-521
CrossRef | Medline2
Zeissler J ,Rassfeld-Sternberg L . Enteritis necroticans due to Clostridium welchii type F. BMJ 1949;1:267-269
CrossRef | Web of Science | Medline3
Murrell TGC ,Roth L ,Egerton J ,Samels J ,Walker PD . Pig-bel: enteritis necroticans: a study in diagnosis and management. Lancet 1966;1:217-222
CrossRef | Web of Science | Medline4
Lawrence GW ,Lehmann D ,Anian G , et al. Impact of active immunisation against enteritis necroticans in Papua New Guinea. Lancet 1990;336:1165-1167
CrossRef | Web of Science | Medline5
Cooke RA. Pig Bel. In: Rosenberg HS, Bolande RP, eds. Perspectives in pediatric pathology. Vol. 5. New York: Masson Publishing, 1979:137-52.
6
Songer JG . Clostridial enteric diseases of domestic animals. Clin Microbiol Rev 1996;9:216-234
Web of Science | Medline7
Sterne M ,Warrack GH . The types of Clostridium perfringens. J Pathol Bacteriol 1964;88:279-283
CrossRef | Web of Science | Medline8
Allen SD. Pig-bel and other necrotizing disorders of the gut involving Clostridium perfringens. In: Connor DH, Chandler FW, Schwartz DA, Manz HJ, Lack EE, eds. Pathology of infectious diseases. Vol. 1. Stamford, Conn.: Appleton & Lange, 1997:717-24.
9
Murrell TGC . Enteritis necroticans in Nepal. Lancet 1979;1:279-279
CrossRef | Web of Science | Medline10
Wright DH ,Stanfield JP . Enteritis necroticans in Uganda. J Pediatr 1967;71:264-268
CrossRef | Web of Science | Medline11
Shann F ,Lawrence G ,Jun-Di P . Enteritis necroticans in China. Lancet 1979;1:1083-1084
CrossRef | Web of Science | Medline12
Johnson S ,Echeverria P ,Taylor DN , et al. Enteritis necroticans among Khmer children at an evacuation site in Thailand. Lancet 1987;2:496-500
CrossRef | Web of Science | Medline13
Williams MR ,Pullan JM . Necrotizing enteritis following gastric surgery. Lancet 1953;2:1013-1018
CrossRef14
Severin WPJ ,de la Fuente AA ,Stringer MF . Clostridium perfringens type C causing necrotising enteritis. J Clin Pathol 1984;37:942-944
CrossRef | Web of Science | Medline15
Farrant JM ,Traill Z ,Conlon C , et al. Pigbel-like syndrome in a vegetarian in Oxford. Gut 1996;39:336-337
CrossRef | Web of Science | Medline16
Songer JG ,Meer RR . Genotyping of Clostridium perfringens by polymerase chain reaction is a useful adjunct to diagnosis of clostridial enteric disease in animals. Anaerobe 1996;2:197-203
CrossRef | Web of Science17
Meer RR ,Songer JG . Multiplex polymerase chain reaction assay for genotyping Clostridium perfringens. Am J Vet Res 1997;58:702-705
Web of Science | Medline18
Lee LA ,Gerber AR ,Lonsway DR , et al. Yersinia enterocolitica O:3 infections in infants and children, associated with the household preparation of chitterlings. N Engl J Med 1990;322:984-987
Full Text | Web of Science | Medline19
Cornell J ,Neal KR . Protracted outbreak of Salmonella typhimurium definitive phage type 170 food poisoning related to tripe, `pig bag,' and chitterlings. Commun Dis Public Health 1998;1:28-30
Medline20
Johnson S . Antibody responses to clostridial infections in humans. Clin Infect Dis 1997;25:Suppl 2:S173-S177
CrossRef | Web of Science | Medline21
Arbona C ,Ascaso JF ,Martinez-Valls J ,Perez-Lazaro A ,Sanchez C ,Carmena R . Malnutrición proteica en la diabetes mellitus insulinodependiente o tipo I: relación con el grado de control metabólico. Med Clin (Barc) 1990;95:572-575
Web of Science | Medline22
Cucchiara S ,Franzese A ,Salvia G , et al. Gastric emptying delay and gastric electrical derangement in IDDM. Diabetes Care 1998;21:438-443
CrossRef | Web of Science | Medline23
Camilleri M ,Malagelada JR . Abnormal intestinal motility in diabetics with the gastroparesis syndrome. Eur J Clin Invest 1984;14:420-427
CrossRef | Web of Science | Medline24
Spengler U ,Stellaard F ,Ruckdeschel G ,Scheurlen C ,Kruis W . Small intestinal transit, bacterial growth, and bowel habits in diabetes mellitus. Pancreas 1989;4:65-70
CrossRef | Web of Science | Medline25
Chan-Cua S ,Jones KL ,Lynch FP ,Freidenberg GR . Necrosis of the ileum in a diabetic adolescent. J Pediatr Surg 1992;27:1236-1238
CrossRef | Web of Science | Medline26
Nicol KK ,Davis GJ . An unusual complication of diabetes mellitus: the zebra that became a horse. South Med J 1997;90:83-85
CrossRef | Web of Science | Medline27
Yersinia enterocolitica infections during the holidays in black families -- Georgia. MMWR Morb Mortal Wkly Rep 1990;39:819-821
Medline28
Bien JP . Anticipatory guidance and chitterlings. J Pediatr 1998;133:712-712
Web of Science | Medline
- Citing Articles (13)
Citing Articles
1
Jorge E. Vidal, Menglin Ma, Julian Saputo, Jorge Garcia, Francisco A. Uzal, Bruce A. McClane. (2012) Evidence that the Agr-like quorum sensing system regulates the toxin production, cytotoxicity and pathogenicity of Clostridium perfringens type C isolate CN3685. Molecular Microbiologyno-no
CrossRef2
F.A. Uzal, B.A. McClane. (2011) Recent progress in understanding the pathogenesis of Clostridium perfringens type C infections. Veterinary Microbiology 153:1-2, 37-43
CrossRef3
J. Glenn Songer. (2010) Clostridia as agents of zoonotic disease. Veterinary Microbiology 140:3-4, 399-404
CrossRef4
Jorge E. Vidal, Kaori Ohtani, Tohru Shimizu, Bruce A. McClane. (2009) Contact with enterocyte-like Caco-2 cells induces rapid upregulation of toxin production by Clostridium perfringens type C isolates. Cellular Microbiology 11:9, 1306-1328
CrossRef5
Barbara M. Lund. 2008. Properties of Microorganisms that Cause Foodborne Disease. , 12-233.
CrossRef6
Sameera Sayeed, Francisco A. Uzal, Derek J. Fisher, Juliann Saputo, Jorge E. Vidal, Yue Chen, Phalguni Gupta, Julian I. Rood, Bruce A. McClane. (2008) Beta toxin is essential for the intestinal virulence of Clostridium perfringens type C disease isolate CN3685 in a rabbit ileal loop model. Molecular Microbiology 67:1, 15-30
CrossRef7
Tomomichi Matsuda, Yuji Okada, Eiji Inagi, Yasushi Tanabe, Yozo Shimizu, Kazuo Nagashima, Jun Sakurai, Masahiro Nagahama, Shinya Tanaka. (2007) Enteritis necroticans ?pigbel? in a Japanese diabetic adult. Pathology International 57:9, 622-626
CrossRef8
R. San Juan Garrido, C. Díaz Pedroche, F. López Medrano. (2006) Infecciones por anaerobios. Medicine - Programa de Formación Médica Continuada Acreditado 9:51, 3319-3328
CrossRef9
Jeremy Sobel, Charles G. Mixter, Priti Kolhe, Amita Gupta, Jeannette Guarner, Sherif Zaki, Neil A. Hoffman, J. Glenn Songer, Maurice Fremont-Smith, Marc Fischer, George Killgore, Phyllis H. Britz, Clifford MacDonald. (2005) Necrotizing Enterocolitis Associated with Clostridium perfringens Type A in Previously Healthy North American Adults. Journal of the American College of Surgeons 201:1, 48-56
CrossRef10
Filip Van Immerseel, Jeroen De Buck, Frank Pasmans, Gerard Huyghebaert, Freddy Haesebrouck, Richard Ducatelle. (2004) Clostridium perfringens in poultry: an emerging threat for animal and public health. Avian Pathology 33:6, 537-549
CrossRef11
Ding-You Li, Ann O. Scheimann, J. Glenn Songer, Richard E. Person, Marshall Horwitz, Linda Resar, Kathleen B. Schwarz. (2004) Enteritis Necroticans with Recurrent Enterocutaneous Fistulae Caused by Clostridium perfringens in a Child With Cyclic Neutropenia. Journal of Pediatric Gastroenterology and Nutrition 38:2, 213-215
CrossRef12
Ronald L. Coulter, Mary K. Coulter, Jim L. Murrow. (2002) The Food Animal Supply and Its Related Concerns. Journal of Food Products Marketing 8:2, 33-64
CrossRef13
Osterholm, Michael T., . (2000) Emerging Infections — Another Warning. New England Journal of Medicine 342:17, 1280-1281
Full Text
