Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus

doi:10.3945/ajcn.2008.27092

ORIGINAL RESEARCH COMMUNICATION

Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus

Beatrice Amadi¹^,2^,3^,4, Andrew O Fagbemi¹^,2^,3^,4, Paul Kelly¹^,2^,3^,4, Mwiya Mwiya¹^,2^,3^,4, Franco Torrente¹^,2^,3^,4, Camilla Salvestrini¹^,2^,3^,4, Richard Day¹^,2^,3^,4, Michael H Golden¹^,2^,3^,4, Erik A Eklund¹^,2^,3^,4, Hudson H Freeze¹^,2^,3^,4 and Simon H Murch¹^,2^,3^,4

¹ From the Department of Paediatrics and Child Health, UniversityTeaching Hospital of Lusaka, Lusaka, Zambia (BA and MM); theCentre for Paediatric Gastroenterology, Royal Free & UniversityCollege School of Medicine, London, United Kingdom (AOF, FT,and CS); the Tropical Gastroenterology and Nutrition Group,University of Zambia School of Medicine, Lusaka, Zambia (PK);the Queen Mary, University of London, London, United Kingdom(PK); the Centre for Gastroenterology and Nutrition, UniversityCollege London, London, United Kingdom (RD); the Universityof Aberdeen, Aberdeen, United Kingdom (MHG); the Burnham Institutefor Research, La Jolla, CA (EAE and HHF); and the Clinical SciencesResearch Institute, Warwick Medical School, University of Warwick,Coventry, United Kingdom (SHM).

² BA and AOF are joint first authors.

³ PK was supported by The Wellcome Trust, and HHF and SHM weresupported by the Children's Heart Fund for research into protein-losingenteropathy.

⁴ Address correspondence and reprint requests to SH Murch, WarwickMedical School, Clinical Sciences Research Institute, CliffordBridge Road, Coventry CV2 2DX, United Kingdom. E-mail: s.murch{at}warwick.ac.uk.

Background: Kwashiorkor, a form of severe malnutrition withhigh mortality, is characterized by edema and systemic abnormalities.Although extremely common, its pathophysiology remains poorlyunderstood, and its characteristic physical signs are unexplained.

Objective: Because kwashiorkor can develop in protein-losingenteropathy, which is caused by a loss of enterocyte heparansulfate proteoglycan (HSPG), and previous observations suggestabnormal sulfated glycosaminoglycan (GAG) metabolism, we examinedwhether intestinal GAG and HSPG are abnormal in children withkwashiorkor.

Design: Duodenal biopsy samples collected from Zambian childrenwith marasmus (n = 18), marasmic kwashiorkor (n = 8), and kwashiorkor(n = 15) were examined for expression of HSPG, GAGs, and immunologicmarkers and compared against reference samples from healthyUK control children. GAG and HSPG expression density and inflammatorycell populations were quantitated by computerized analysis.

Results: The kwashiorkor group was less wasted and had a lowerHIV incidence than did the other groups. All duodenal biopsysamples showed inflammation compared with the histologicallyuninflamed control samples. Biopsy samples from marasmic childrenhad greater inflammation and greater CD3⁺ and HLA-DR (humanleukocyte antigen DR)–positive cell densities than didsamples from children with kwashiorkor. Expression of both HSPGand GAGs was similar between marasmic and well-nourished UKchildren but was markedly lower in children with kwashiorkorin both the epithelium and lamina propria. Although underglycosylatedand undersulfated, epithelial syndecan-1 protein was normallyexpressed in kwashiorkor, which confirmed that abnormalitiesarise after core protein synthesis.

Conclusions: Intestinal HSPG loss occurs in kwashiorkor, whichmay precipitate protein-losing enteropathy to cause edema. Ifoccurring systemically, impaired HSPG expression could causeseveral previously unexplained features of kwashiorkor. We speculatethat a genetic predisposition to reduced HSPG biosynthesis mayoffer a contrasting selective advantage, by both diminishingprotein catabolism during transient undernutrition and protectingagainst specific infectious diseases.