Protein losing enteropathy due to congenital disorder of glycosylation: A case report

Abstract

Protein-Losing Enteropathy (PLE) is the loss of protein through the gastrointestinal tract, subsequently leading to low levels of protein in the serum. The differential diagnosis for PLE is broad, and treatment is based on identifying and appropriately treating the underlying cause of the PLE. A 2-year-old boy presented with diarrhea, vomiting, edema, anemia, hypoalbuminemia, low serum IgG, and elevated stool alpha-1-antitrypsin, concerning for PLE. Endoscopy/colonoscopy showed mild reactive changes in the gastric and duodenal mucosa and was otherwise normal with no evidence of autoimmune enteropathy. MRI abdomen was negative for mesenteric lymphatic malformations. Echocardiogram showed a structurally normal heart. Urine CMV PCR was positive, and he was treated with valganciclovir for suspected Menetrier’s disease, with no improvement in symptoms. He was incidentally noted to be hypoglycemic and subsequently admitted with profoundly labile blood glucose requiring glucagon and continuous glucose infusions. Further workup demonstrated hyperinsulinism, up-trending liver enzymes with normal international normalized ratio, and coagulopathy with low factor 11 and antithrombin with PICC-associated DVT. The constellation of PLE, transaminitis, hyperinsulinemic hypoglycemia, and coagulopathy was concerning for a congenital disorder of glycosylation (CDG). Transferrin glycosylation studies showed a CDG type I pattern and were confirmed via genetic testing with biallelic variants in the mannose phosphate isomerase (MPI) gene, which established the diagnosis of mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG). Mannose therapy resulted in complete resolution of his edema, diarrhea, hypoalbuminemia, transaminitis, and hypoglycemia. CDGs include over 100 monogenic diseases with defects in the synthesis of oligosaccharides. Though a rare cause of PLE, MPI-CDG is an important consideration in the differential given the availability of an effective therapy. Treatment is well-tolerated and highly effective. In the case presented, the patient began showing symptomatic and biochemical improvement within a week of initiating therapy.

Introduction

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) is part of a group of disorders characterized by abnormal glycosylation of proteins. MPI-CDG is an autosomal recessive condition due to mutations in the MPI gene. MPI-CDG is a multisystemic condition with common presenting symptoms including hepatomegaly, hypoglycemia, diarrhea, coagulopathy, and protein-losing enteropathy (PLE), among others. Treatment with mannose can help with symptom management and survival.^1–4

PLE can be a presenting symptom of MPI-CDG. PLE occurs when plasma proteins are lost from the gastrointestinal tract and can be due to conditions that lead to epithelial leakage, increased interstitial pressure, or lymphatic obstruction. Traditionally, PLE has been classified by etiology as primary or secondary PLE. Primary PLE can be due to lymphatic malformations or disordered lymphatic flow, such as from intestinal lymphangiectasia. Secondary PLE can be due to mechanical obstruction or mucosal disruption, such as from inflammatory bowel disease, celiac disease, or Menetrier syndrome.

Presenting clinical features vary depending on the underlying etiology of PLE, but individuals may present with symptoms of diarrhea, abdominal distension, bloating, as well as frequent infections due to gastrointestinal loss of immunoglobulins. The presence of alpha-1 antitrypsin in the stool is diagnostic of PLE, and alpha-1 antitrypsin intestinal clearance can be measured. Management of PLE is dependent on the underlying etiology, with a high protein, low-fat diet with medium-chain triglycerides recommended.^5–7

We present a case of a 22-month-old with PLE with symptoms of diarrhea and intermittent edema, also with coagulopathy and asymptomatic hypoglycemia, leading to the diagnosis of MPI-CDG.

Case report

A 22-month-old boy with no known medical conditions and a family history significant only for atopy presented with 3 months of persistent diarrhea and intermittent episodes of facial swelling and emesis in the setting of multiple courses of antibiotics for recurrent acute otitis media. There were no symptoms of vomiting, abdominal pain, constipation, fever, or weight loss. He had previously been evaluated by allergists without identification of an allergic food trigger. On screening labs, he had albumin of 1.7 g/dL, total protein 3.4 g/dL, hemoglobin 9.2 g/dL, and C-reactive protein 6.3 mg/dL. Infectious stool studies, including clostridium difficile toxin, bacterial, viral, and parasite panel were negative. Given the hypoalbuminemia, he had a stool alpha-1 antitrypsin level that was elevated at 355 mg/dL and combined with a low total Immunoglobulin G (IgG) at 67 mg/dL. Given his chronic diarrhea in the setting of no proteinuria, adequate dietary protein intake, and no evidence of synthetic liver dysfunction, he was diagnosed with PLE.

Workup for causes of PLE included an elevated fecal calprotectin of 1877 mg/g with subsequent upper endoscopy and colonoscopy that showed ulceration in the duodenal bulb, with mild reactive changes in the gastric and duodenal mucosa on pathology, and was otherwise normal with no evidence of autoimmune enteropathy. The MRI abdomen was negative for mesenteric lymphatic malformations. Echocardiogram showed a structurally normal heart. Ultimately, he was found to have a positive urine CMV PCR, and he was treated with valganciclovir for suspected Menetrier’s disease, with no improvement in diarrhea, edema, or hypoalbuminemia. Repeat upper endoscopy 1 month later showed no evidence of hypertrophic gastropathy and negative CMV immunohistochemistry. On follow-up labs a week after the upper endoscopy, he was incidentally noted to be hypoglycemic with a blood glucose level of 43 mg/dL, and he also had elevated transaminases with AST 102 U/L and ALT 116 U/L. He was subsequently admitted for management of labile blood sugars. Endocrinology was consulted and found to have hyperinsulinism. During the admission, he required a central line and developed a deep vein thrombosis shortly after line placement. Subsequent hematology workup showed a normal international normalized ratio of 1.01 but low factor 11 and antithrombin levels.

The constellation of PLE, transaminitis, hyperinsulinemic hypoglycemia, and coagulopathy was suggestive of a congenital disorder of glycosylation (CDG). Metabolism was consulted, and transferrin glycosylation studies showed a CDG type I pattern, with elevated mo-oli/di-oligosaccharide-CDG, A-oli-di-oligosaccharide-CDG, and tri-sialo/di-oligosaccharide-CDG. Genetic testing revealed biallelic variants in the MPI gene (c.656 G>A and c.602 T>C), which established the diagnosis of MPI-CDG. Mannose therapy was initiated with d-mannose 6000 mg daily, divided every 6 hours, which he tolerated well and resulted in complete resolution of his edema, diarrhea, hypoalbuminemia, transaminitis, and hypoglycemia (Table 1). He has been on mannose for over 4 years and continues to do well with normal transferrin studies, aminotransferases, albumin, and clotting factors, with his only complication while on mannose therapy being an elevated hemoglobin A1C.

Table 1.

Laboratory values at initial presentation, post-CMV treatment, and post-mannose treatment.

Time of Evaluation	Alpha-1-Antitrypsin(<54 mg/dL)	AST(<47 U/L)	ALT(<60 U/L)	Alk Phos(85 –270 U/L)	Albumin(3.5–4.7 g/dL)	Glucose(70–99 mg/dL)	Insulin(3–25 uIU/mL)	Factor XI (11)(65–150%)	Antithrombin III(0.86–1.18 U/mL)
Initial Work-up	335↑	75↑	36	90	1.6↓	78	-	-	-
Post-CMV treatment	563↑	156↑	129↑	128	1.8↓	31↓	6 *	41↓	0.36↓
Post-Mannose Therapy	<4	29	30	114	3.9	91	-	131	1.39↑

AST: aspartate aminotransferase; ALT: alanine aminotransferase; Alk Phos: alkaline phosphatase; CMV: cytomegalovirus.

*

Insulin values should be undetectable in the setting of hypoglycemia.

Discussion

PLE should be considered in individuals with hypoalbuminemia or hypoproteinemia, especially if other etiologies of low protein, such as synthetic liver dysfunction, urinary loss, and malnutrition, are excluded. Low serum protein leads to decreased oncotic pressure, which results in symptoms such as edema, ascites, or pleural effusions. GI symptoms such as diarrhea, abdominal pain, and bloating are also common. Some individuals may present with frequent infections as a consequence of the GI loss of immunoglobulins. The diagnosis of PLE is made based on the presence of alpha-1 antitrypsin in the stool, as seen in our patient. Alpha-1 antitrypsin protein is minimally degraded in the intestine, and as such,alpha-1 antitrypsin clearance is a reliable biomarker of gastrointestinal protein loss. The clinical presentation of PLE varies based on the underlying etiology. The key to the management of PLE is identification of the underlying etiology.^5–8

The differential diagnosis of PLE is broad. The causes can be grouped into disorders of the lymphatic system, such as lymphangiectasia or congenital heart disease, and disorders causing injured or abnormal intestinal mucosa, such as inflammatory bowel disease, infection, hypertrophic gastropathies (Menetrier’s disease), food-induced enteropathies, or Celiac disease. ⁸ In our case, prior to the presentation with hypoglycemia and coagulopathy, inflammatory bowel disease was high on the differential given the diarrhea and elevated fecal calprotectin. There was no colitis on colonoscopy to suggest chronic inflammation. On upper endoscopy, there was no histopathologic evidence of an enteropathy, celiac disease, or lymphatic malformation, but mild gastritis was noted. As other workups for etiologies of PLE were unremarkable, including a normal echocardiogram and abdominal MRI, Menetrier’s disease was considered a possibility given the mild gastritis and positive urine CMV PCR, and he was treated with a course of valganciclovir without improvement of symptoms (Table 1).

Ultimately, the incidental finding of hypoglycemia and coagulopathy lead to the diagnosis of MPI-CDG (Table 1). Congenital disorders of glycosylation (CDG) are caused by defects in the production of oligosaccharides and include more than 100 monogenic diseases. MPI-CDG is a rare cause of PLE and is due to a defect in the MPI enzyme resulting in a disorder of protein N-glycosylation, which can affect multiple organ systems. In MPI-CDG, symptoms typically present in infancy, and often manifest with hypoalbuminemia, PLE, and hyperinsulinemic hypoglycemia. Other symptoms which can be seen include diarrhea, vomiting, elevated liver enzymes, hepatomegaly, anemia, and coagulopathy with decreased Factors V, IX, XI, antithrombin III, Protein C and Protein S. The etiology of PLE in MPI-CDG is suspected to be caused by either lymphangiectasia or damage to the integrity of the intestinal mucosa due to fewer glycoproteins on enterocyte membranes. ¹

Diagnosis of MPI-CDG consists of screening via transferrin glycosylation studies with a confirmatory enzyme assay or gene analysis. Treatment with oral mannose supplementation bypasses the enzymatic defect in the MPI enzyme. The recommended dose of oral mannose is 150–170 mg/kg/dose four to five times daily. Mannose therapy has been shown to lead to resolution of hypoglycemia and diarrhea within 2 weeks of starting therapy. In addition, significant improvement in biochemical markers of disease has been noted. However, a limitation is that mannose therapy does not prevent or treat liver disease and persistent hepatic involvement, including hepatic fibrosis and portal hypertension with its sequelae such as splenomegaly with thrombocytopenia. While on mannose therapy, routine monitoring of liver function tests and ultrasound of the liver with elastography is recommended to monitor for liver disease.^1,2,9

In addition, venous thrombosis, altered kidney function, and “mannose diabetes” have been reported.^1,2,9,10 Treatment with mannose may result in elevated serum mannose, and hemoglobin modified by the addition of mannose can raise the hemoglobin A1c. Elevated point-of-care glucose testing could actually reflect elevated mannose levels. Routine screening of hemoglobin A1c is recommended for individuals with MPI-CDG on mannose therapy. Lowering the dose of mannose may be indicated if the hemoglobin A1c remains elevated. Another consideration in MPI deficiency is that high fructose intake can lead to the accumulation of fructose-1-phosphate with resultant symptoms like those in hereditary fructose intolerance. A fructose-restricted diet can be considered if there is hepatic fibrosis.^10,11

Conclusion

PLE is characterized by the loss of protein through the gastrointestinal tract, leading to low protein in the serum. As the differential diagnosis for PLE is broad and as treatment is based on the underlying etiology, it is important to be aware of the symptoms associated with potential etiologies of PLE. Though a rare cause of PLE, MPI-CDG should be considered in the setting of hypoglycemia, hypoalbuminemia, and coagulopathy with PLE, in the absence of underlying liver disease or proteinuria. Transferrin glycosylation studies should be checked if there is clinical suspicion of MPI-CDG, followed by confirmatory genetic testing or enzyme assay. Treatment of MPI-CDG with mannose can help with improvement in most of the associated symptoms and biochemical abnormalities, aside from hepatic involvement. Overall, this case highlights the importance of expanding the differential diagnosis and the effectiveness of a multidisciplinary team approach, which ultimately led to the diagnosis of MPI-CDG.