Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

Enhanced Collagen Deposition in the Duodenum of Patients with Hyaline Fibromatosis Syndrome and Protein Losing Enteropathy.

Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C>T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE.

Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency.

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

Indoleamine-pyrrole 2,3-dioxygenase-1 (IDO-1) mRNA is over-expressed in the duodenal mucosa and is negatively correlated with serum tryptophan concentrations in dogs with protein-losing enteropathy.

INTRODUCTION: Dogs with protein-losing enteropathy (PLE) have decreased serum tryptophan concentrations, which may contribute to disease pathogenesis. Indoleamine-pyrrole 2,3-dioxygenase-1 (IDO-1) expression is associated with low serum tryptophan concentrations and is increased in the gastrointestinal tract of humans with inflammatory bowel disease (IBD). Therefore, the objective of our study was to determine if the mRNA expression of IDO-1 is increased in the duodenal mucosa of dogs with PLE as compared to dogs with chronic enteropathy (CE) and healthy dogs, and whether this expression is correlated with changes in serum tryptophan concentration. METHODS: Our study was a retrospective study using archived paraffin-embedded duodenal biopsy specimens from 8 healthy Beagle dogs from the Iowa State University Canine Service Colony and 18 and 6 client-owned dogs diagnosed with CE and PLE, respectively at the Bristol Veterinary School. A novel RNA in situ hybridization (ISH) technology, RNAscope, was used to identify IDO-1 mRNA mucosal expression in duodenal tissues. An IDO-1 specific probe was hybridized onto 10 duodenal biopsy sections from each dog whereby RNAscope signal (mRNA expression) was quantified by a single operator using light microscopy. RESULTS: Dogs with PLE had significantly higher mRNA expression of IDO-1 in the duodenal mucosa compared to healthy dogs (mucosal percentage IDO-1 positive: P = 0.0093, (mean ± S.D) control: 19.36 ± 7.08, PLE: 34.12 ± 5.98, average fold difference: 1.76 and mucosal IDO-1 H-score: P = 0.0356, (mean ± S.D) control: 45.26 ± 19.33, PLE: 84.37 ± 19.86, average fold difference: 1.86). The duodenal mucosal mRNA expression of IDO-1 was negatively correlated with serum tryptophan concentrations in dogs with PLE (mucosal IDO-1 H-score: Spearman's rank correlation coefficient = -0.94, P = 0.0048). CONCLUSIONS: In conclusion, our study suggests that decreased serum tryptophan concentrations in dogs with PLE is associated with increased intestinal IDO-1 expression. Further studies are needed to determine potential inflammatory pathways responsible for increased expression of IDO-1 in the intestinal tract of dogs with PLE.

Multisite measurement of regional oxygen saturation in Fontan patients with and without protein-losing enteropathy at rest and during exercise.

BACKGROUND: Protein-losing enteropathy (PLE) is a severe complication of Fontan circulation with increased risk of end-organ dysfunction. We evaluated tissue oxygenation via near-infrared spectroscopy (NIRS) at different exercise levels in Fontan patients. METHODS: Assessment of multisite NIRS during cycle ergometer exercise and daily activities in three groups: Fontan patients with PLE; without PLE; patients with dextro-transposition of the great arteries (d-TGA); comparing univentricular with biventricular circulation and Fontan with/without PLE. Renal threshold analysis (<65%;<55%;<45%) of regional oxygen saturation (rSO2) was performed. RESULTS: Fontan patients showed reduced rSO2 (p < 0.05) in their quadriceps femoris muscle compared with biventricular d-TGA patients at all time points. rSO2 in renal tissue was reduced at baseline (p = 0.002), exercise (p = 0.0062), and daily activities (p = 0.03) in Fontan patients with PLE. Renal threshold analysis identified critically low renal rSO2 (rSO2 < 65%) in Fontan patients with PLE during exercise (95% of monitoring time below threshold) and daily activities (83.7% time below threshold). CONCLUSION: Fontan circulation is associated with decreased rSO2 values in skeletal muscle and hypoxemia of renal tissue solely in patients with PLE. Reduced rSO2 already during activities of daily life, might contribute to comorbidities in patients with Fontan circulation, including PLE and renal failure.

Establishing the role of PLVAP in protein-losing enteropathy: a homozygous missense variant leads to an attenuated phenotype.

BACKGROUND: Intestinal integrity is essential for proper nutrient absorption and tissue homeostasis, with damage leading to enteric protein loss, that is, protein-losing enteropathy (PLE). Recently, homozygous nonsense variants in the plasmalemma vesicle-associated protein gene (PLVAP) were reported in two patients with severe congenital PLE. PLVAP is the building block of endothelial cell (EC) fenestral diaphragms; its importance in barrier function is supported by mouse models of Plvap deficiency. OBJECTIVE: To genetically diagnose two first-degree cousins once removed, who presented with PLE at ages 22 and 2.5 years. METHODS: Family-based whole exome sequencing was performed based on an autosomal recessive inheritance model. In silico analyses were used to predict variant impact on protein structure and function. RESULTS: We identified a rare homozygous variant (NM_031310.2:c.101T>C;p.Leu34Pro) in PLVAP, which co-segregated with the disease. Leu34 is predicted to be located in a highly conserved, hydrophobic, α-helical region within the protein's transmembrane domain, suggesting Leu34Pro is likely to disrupt protein function and/or structure. Electron microscopy and PLVAP immunohistochemistry demonstrated apparently normal diaphragm morphology, predicted to be functionally affected. CONCLUSIONS: Biallelic missense variants in PLVAP can cause an attenuated form of the PLE and hypertriglyceridaemia syndrome. Our findings support the role of PLVAP in the pathophysiology of PLE, expand the phenotypic and mutation spectrums and underscore PLVAP's importance in EC barrier function in the gut.

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy.

BACKGROUND: Protein-losing enteropathy (PLE) is characterised by gastrointestinal protein leakage due to loss of mucosal integrity or lymphatic abnormalities. PLE can manifest as congenital diarrhoea and should be differentiated from other congenital diarrhoeal disorders. Primary PLEs are genetically heterogeneous and the underlying genetic defects are currently emerging. OBJECTIVES: We report an infant with fatal PLE for whom we aimed to uncover the underlying pathogenic mutation. METHODS: We performed whole exome sequencing (WES) for the index patient. Variants were classified based on the American College of Medical Genetics and Genomics guidelines. WES results and our detailed clinical description of the patient were compared with the literature. RESULTS: We discovered a novel homozygous stop mutation (c.988C>T, p.Q330*) in the Plasmalemma Vesicle-Associated Protein (PLVAP) gene in a newborn with fatal PLE, facial dysmorphism, and renal, ocular and cardiac anomalies. The Q330* mutation is predicted to result in complete loss of PLVAP protein expression leading to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE. Recently, another single homozygous stop mutation in PLVAP causing lethal PLE in an infant was reported. CONCLUSIONS: Our findings validate PLVAP mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.

Protein-Amino Acid Metabolism Disarrangements: The Hidden Enemy of Chronic Age-Related Conditions.

Proteins are macro-molecules crucial for cell life, which are made up of amino acids (AAs). In healthy people, protein synthesis and degradation are well balanced. However, in the presence of hypercatabolic stimulation (i.e., inflammation), protein breakdown increases as the resulting AAs are consumed for metabolic proposes. Indeed, AAs are biochemical totipotent molecules which, when deaminated, can be transformed into energy, lipids, carbohydrates, and/or biochemical intermediates of fundamental cycles, such as the Krebs' cycle. The biochemical consequence of hyper-catabolism is protein disarrangement, clinically evident with signs such as sarcopenia, hypalbuminemia, anaemia, infection, and altered fluid compartmentation, etc. Hypercatabolic protein disarrangement (HPD) is often underestimated by clinicians, despite correlating with increased mortality, hospitalization, and morbidity quite independent of the primary disease. Simple, cheap, repeatable measurements can be used to identify HPD. Therefore, identification and treatment of proteins' metabolic impairment with appropriate measurements and therapy is a clinical strategy that could improve the prognosis of patients with acute/chronic hypercatabolic inflammatory disease. Here, we describe the metabolism of protein and AAs in hypercatabolic syndrome, illustrating the clinical impact of protein disarrangement. We also illustrate simple, cheap, repeatable, and worldwide available measurements to identify these conditions. Finally, we provide scientific evidence for HPD nutritional treatment.

Investigation of the Influence of Protein-Losing Enteropathy on Monoclonal Antibody Pharmacokinetics in Mice.

Protein losing enteropathy (PLE), which is characterized by substantial loss of plasma proteins into the gastrointestinal (GI) tract, is a complication of a variety of GI diseases, including inflammatory bowel disease. Clinical studies have found that the clearance of monoclonal antibodies (mAb) is often increased in subjects with diseases known to cause PLE; however, direct relationships between PLE and mAb pharmacokinetics have not been demonstrated. This study employed a murine model of colitis to examine the influence of PLE on mAb pharmacokinetics. Mice were given dextran sodium sulfate (DSS, 2% w/v) supplemented tap water as drinking source for 6 days to induce colitis and PLE. Mice were then intravenously injected with 8C2, a murine IgG1 mAb. 8C2 plasma concentrations were measured up to 14 days post injection. Fecal alpha-1-antitrypsin (A1AT) clearance was measured as biomarker for PLE. DSS-treated mice developed PLE of clinically relevant severity. They also showed a transient increase in 8C2 plasma clearance and a decrease in 8C2 plasma exposure. The area under the 8C2 plasma concentration-time curve for the length of the study (AUC0-14d) reduced from 1368 ± 255 to 594 ± 224 day µg/ml following DSS treatment (p = 0.001). A quantitative relationship between A1AT clearance and 8C2 clearance was obtained via population pharmacokinetic modeling. DSS treatment substantially increased 8C2 clearance and reduced 8C2 exposure. Increased mAb plasma clearance was highly correlated with A1AT fecal clearance, suggesting the possible utility of A1AT fecal clearance as a mechanistic biomarker to predict the pharmacokinetics of therapeutic antibodies.

Enteropatía perdedora de proteínas asociada a lupus eritematoso sistémico refractaria con buena respuesta a rituximab / Protein-losing enteropathy associated with refractory systemic lupus erythematosus with a good response to rituximab

Se presenta un caso de enteropatía perdedora de proteínas (EPP)como manifestación inicial del lupus eritematoso sistémico (LES). Se trata de una paciente de sexo femenino, de 17 años de edad, que consulta por síndrome ascítico edematoso e hipoalbuminemia. El diagnóstico de LES se estableció por la presencia de: rash malar, úlceras orales, trombocitopenia, anticuerpos antinucleares, anticardiolipinas IgM y anticoagulante lúpico positivos. Se descartó el compromiso renal y hepático como causa de hipoproteinemia. El diagnóstico de la pérdida enteral de proteínas se realizó con el Clearance de alfa 1 antitripsina. La EPP fue refractaria a distintas líneas de inmunosupresores, como corticoides, ciclofosfamida, azatioprina y ciclosporina, presentando respuesta satisfactoria y sostenida a rituximab, lo que posibilitó la reducción de corticoides y la remisión de la enfermedad por tiempo prolongado (AU)

A case is presented of a protein-losing enteropathy (PLE) as the initial manifestation of systemic lupus erythematosus (SLE) in a 17 year-old female patient, who presented with ascites, edema and hypoalbuminemia. The diagnosis of SLE was based on the presence of: malar rash, oral ulcers, thrombocytopenia, antinuclear antibodies, IgM anticardiolipin antibody, and lupus anticoagulant. Renal and liver diseases were ruled out. The PLE diagnosis was confirmed with fecal alpha 1-antitrypsin clearance. The PLE was refractory to different lines of immunosuppressive agents like glucocorticoids, cyclophosphamide, azathioprine, and cyclosporine, showing a satisfactory and sustained response with rituximab, allowing steroid sparing and long term remission (AU)

Sjögren's syndrome associated with protein losing gastroenteropathy manifested by intestinal lymphangiectasia successfully treated with prednisolone and hydroxychloroquine.

Protein-losing gastroenteropathy (PLGE), a rare manifestation of primary Sjögren's syndrome (SS), is characterized by profound edema and severe hypoalbuminemia secondary to excessive serum protein loss from the gastrointestinal tract and is clinically indistinguishable from nephrotic syndrome. We report a case of a 30-year-old Taiwanese woman with PLGE-associated SS. In addition to a positive Schirmer's test, she had eye-dryness, thirst, and high levels of anti-SSA antibodies, fulfilling SS criteria. PLGE diagnosis was highly appropriate given the clinical profile of hypoalbuminemia, hypercholesterolemia, pleural effusion, and ascites, with absent cardiac, hepatic, or renal disease. We were unable to perform technetium-99 m-labeled human serum albumin scintigraphy ((99m)Tc-HAS). However, the patient's edema and albumin level improved dramatically in response to a 3-month regime of oral prednisolone followed by oral hydroxychloroquine.

In-111 transferrin scintigraphy in cirrhosis with hypoalbuminemia: evidence for protein-losing enteropathy in a small group of selected cases.

BACKGROUND: Hypoalbuminemia commonly observed in cirrhosis is considered to be mainly related to hepatocellular dysfunction. However, the correlation between the decrease in serum albumin and liver function is far from linear and arguments in favor of an additive role of protein-losing enteropathy have been brought by a few studies. AIM: To assess the potential role of protein-losing enteropathy in a group of patients with cirrhosis, portal hypertension, and hypoalbuminemia. DESIGN AND METHODS: Eleven patients with documented cirrhosis, portal hypertension, and a low serum albumin level compared to liver function underwent an (111)In-transferrin scintigraphy. RESULTS: Using this sensitive method of investigation, nine exhibited features suggestive of exudative enteropathy. Serum albumin level and digestive protein loss were even correlated (Pearson's coefficient = -0.529, one-sided p = 0.047). Protein loss were however not correlated with the degree of portal hypertension or with the extent of liver dysfunction evaluated by the aminopyrine breath test. CONCLUSIONS: Our preliminary data obtained in a small group of selected patients with cirrhosis, portal hypertension, and hypoalbuminemia indicate that protein-losing enteropathy may represent an appreciable and underestimated cause of hypoproteinemia.

Evaluation of performance of measurement of faecal α(1)-antitrypsin clearance and technetium-99m human serum albumin scintigraphy in protein-losing enteropathy.

BACKGROUND AND AIM: Our study aimed to compare the performance of faecal α(1)-antitrypsin clearance (AATC) and radiolabelled human serum albumin (HSA) scintigraphy in protein-losing enteropathy (PLE). METHODS: Patients studied by both AATC and technetium-99m ((99m)Tc)-labelled HSA scintigraphy were recruited and categorized into PLE and non-PLE groups based on clinical and laboratory findings. The performance of AATC and (99m)Tc-labelled HSA scintigraphy was evaluated using clinical diagnosis of PLE as a gold standard. RESULTS: 29 patients were recruited and 13 patients were considered to have definite PLE (PLE group). In the PLE group, all patients had a positive HSA scinigraphy and 10 (77%) had demonstrable positive tracing in the early phase. Conversely, only 6 of them (46%) had elevated AATC level (>13 m/day). Results of (99m)Tc-labelled HSA scan (but not AATC) showed significant agreement with the clinical diagnosis (κ 0.35, p = 0.013). (99m)Tc-labelled HSA scintigraphy carried higher sensitivity (100 vs. 46%) and negative predictive value (100 vs. 63%) compared to AATC in diagnosing PLE. The correlation between the results of these two investigations was only modest (κ 0.27, p = 0.04). The area under the receiver operating characteristic curve of AATC level showed no optimal diagnostic cut-off for PLE. CONCLUSION: (99m)Tc-labelled HSA scintigraphy was superior to AATC in diagnosing PLE.

The use of oral budesonide in adolescents and adults with protein-losing enteropathy after the Fontan operation.

BACKGROUND: Approximately 5% to 15% of patients develop protein-losing enteropathy (PLE) after the Fontan operation. Oral controlled release (CR) budesonide has been used as a treatment strategy, but its use in the older Fontan population has not been described. METHODS: Seven patients with refractory PLE after the Fontan operation were started on oral CR-budesonide at 9 mg. After 3 to 9 months, the dose was weaned to 3 mg. Response to treatment was assessed by clinical evaluation, serum albumin levels, and fecal α-1 antitrypsin clearance when available. RESULTS: Median age at last evaluation was 20 years (range, 16 to 32 years). Six patients had increases in serum albumin levels but only 4 patients had symptomatic improvement. Systemic side effects included: cushingoid features (5), adrenal insufficiency (4), and new-onset type 2 diabetes mellitus (2). One patient had improvement in cushingoid features after weaning CR-budesonide to 3 mg. Older patients (ages 27 to 32 years) had the worst side effect profiles and were the most refractory to treatment. These patients had sonographic evidence of hepatic cirrhosis but normal serum liver function tests. Two deaths occurred: 1 from sepsis 1 month after CR-budesonide initiation and 1 from respiratory arrest 5 months after CR-budesonide discontinuation. CONCLUSIONS: CR-budesonide can be used to treat PLE in certain patients, but careful assessment of hepatic function should be performed before initiation of therapy as systemic side effects can limit treatment. Normal serum liver function tests do not preclude hepatic dysfunction in the Fontan patient, and it is important to perform radiographic assessments as well.

Intestinal uptake of (99m)Tc-MDP: a case report of protein-losing enteropathy correlated with pathology findings from autopsy.

We present a case of a 60-year-old man with a history of severe hypoproteinemia and constitutional syndrome, suspected to have protein-losing enteropathy (PLE). Bone scintigraphy ((99m)Tc-MDP) performed to rule out the presence of bone metastases incidentally showed abnormal uptake in abdominal soft tissue. The patient unexpectedly died of heart failure, and autopsy revealed microscopic alterations consistent with PLE exclusively in the right colon, corresponding to the area of abnormal uptake. Few similar cases have been published, but none of them reported correlative pathological findings affecting the area of abnormal tracer uptake. In this case of PLE, (99m)Tc-MDP scintigraphy was a useful imaging method for localizing the site of protein loss, showing a focal area of alteration in the right colon. This finding could also have been of great help in case that surgery had been finally performed to control the protein loss.

Heterogeneity and atypical presentation in infantile systemic hyalinosis with severe labio-gingival enlargement: first Egyptian report.

Infantile systemic hyalinosis (ISH) (MIM 236490) is a rare, progressive, fatal autosomal recessive condition characterized by widespread deposition of hyaline material in many tissues. Our proband was a 4-year-old male with growth retardation, severe labio-gingival enlargement, generalized stiff skin, joint contractures, and intractable diarrhea. We discovered a history of a brother and sister who suffered a more severe disease course. A final diagnosis of systemic hyalinosis was made; we report this case and discuss the clinical and orodental heterogeneity among these siblings in the first report of an Egyptian family with ISH. We present a very rare entity, infantile systemic hyalinosis, a cause of joint contracture, protein-losing enteropathy, and growth retardation in infancy with a review of the relevant literature.

Gas chromatography-mass spectrometry assay for determination of Ntau-methylhistamine concentration in canine urine specimens and fecal extracts.

OBJECTIVE: To develop and validate a gas chromatography-mass spectrometry (GC-MS) method for determination of Ntau-methylhistamine (NMH) concentration in canine urine and fecal extracts and to assess urinary NMH concentrations in dogs with mast cell neoplasia and fecal NMH concentrations in dogs with protein-losing enteropathy. SAMPLE POPULATION: Urine specimens were collected from 6 healthy dogs and 7 dogs with mast cell neoplasia. Fecal extracts were obtained from fecal specimens of 28 dogs with various severities of protein-losing enteropathy, as indicated by fecal concentration of alpha1-proteinase inhibitor. PROCEDURES: NMH was extracted directly from urine, and fecal specimens were first extracted into 5 volumes of PBSS containing 1% newborn calf serum. Ntau-methylhistamine in specimens was quantified via stable isotope dilution GC-MS. The assay was validated via determination of percentage recovery of known amounts of NMH and interassay coefficients of variation. Urinary excretion of NMH was evaluated by means of NMH-to-creatinine concentration ratios. RESULTS: Recovery of NMH in urine and fecal extracts averaged 104.6% and 104.5%, respectively. Interassay coefficients of variation ranged from 5.4% to 11.7% in urine and 12.6% to 18.1% in fecal extracts. Urinary NMH excretion was significantly increased in dogs with mast cell neoplasia, compared with that in healthy dogs. No correlation was detected between severity of protein-losing enteropathy and fecal NMH concentration. CONCLUSIONS AND CLINICAL RELEVANCE: This method provided a sensitive, reproducible means of measuring NMH in canine urine and fecal extracts. High urinary NMH-to-creatinine concentration ratios in dogs with mast cell neoplasia are consistent with increased histamine release in this disease.

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

BACKGROUND: Kwashiorkor, a form of severe malnutrition with high mortality, is characterized by edema and systemic abnormalities. Although extremely common, its pathophysiology remains poorly understood, and its characteristic physical signs are unexplained. OBJECTIVE: Because kwashiorkor can develop in protein-losing enteropathy, which is caused by a loss of enterocyte heparan sulfate proteoglycan (HSPG), and previous observations suggest abnormal sulfated glycosaminoglycan (GAG) metabolism, we examined whether intestinal GAG and HSPG are abnormal in children with kwashiorkor. DESIGN: Duodenal biopsy samples collected from Zambian children with marasmus (n = 18), marasmic kwashiorkor (n = 8), and kwashiorkor (n = 15) were examined for expression of HSPG, GAGs, and immunologic markers and compared against reference samples from healthy UK control children. GAG and HSPG expression density and inflammatory cell populations were quantitated by computerized analysis. RESULTS: The kwashiorkor group was less wasted and had a lower HIV incidence than did the other groups. All duodenal biopsy samples showed inflammation compared with the histologically uninflamed control samples. Biopsy samples from marasmic children had greater inflammation and greater CD3+ and HLA-DR (human leukocyte antigen DR)-positive cell densities than did samples from children with kwashiorkor. Expression of both HSPG and GAGs was similar between marasmic and well-nourished UK children but was markedly lower in children with kwashiorkor in both the epithelium and lamina propria. Although underglycosylated and undersulfated, epithelial syndecan-1 protein was normally expressed in kwashiorkor, which confirmed that abnormalities arise after core protein synthesis. CONCLUSIONS: Intestinal HSPG loss occurs in kwashiorkor, which may precipitate protein-losing enteropathy to cause edema. If occurring systemically, impaired HSPG expression could cause several previously unexplained features of kwashiorkor. We speculate that a genetic predisposition to reduced HSPG biosynthesis may offer a contrasting selective advantage, by both diminishing protein catabolism during transient undernutrition and protecting against specific infectious diseases.