- Vladan Milovic, MD, PhD
Vladan Milovic, MD, PhD
- Associate Professor of Medicine
- Head, Department of Gastroenterology & Oncology Reha-Zentrum Bad Reichenhall /
- Bayerisch Gmain Klinik Hochstaufen Bayerisch Gmain
- Bayern, Germany
- Richard J Grand, MD
Richard J Grand, MD
- Professor of Pediatrics
- Boston Children's Hospital
- Harvard Medical School
Protein-losing gastroenteropathies are characterized by an excessive loss of serum proteins into the gastrointestinal tract, resulting in hypoproteinemia, edema, and, in some cases, pleural and pericardial effusions. The diagnosis of protein-losing gastroenteropathy should be considered in patients with hypoproteinemia in whom other causes, such as malnutrition, heavy proteinuria, and impaired protein synthesis, due to liver diseases, have been excluded.
This topic will review the etiology, pathogenesis, clinical manifestations, diagnosis and management of protein-losing gastroenteropathy. Other causes of hypoalbuminemia are discussed elsewhere. (See "Clinical features and diagnosis of malabsorption", section on 'Protein malabsorption' and "Mechanisms of nutrient absorption and malabsorption", section on 'Protein absorption' and "Overview of heavy proteinuria and the nephrotic syndrome" and "Tests of the liver's biosynthetic capacity (eg, albumin, coagulation factors, prothrombin time)", section on 'Albumin'.)
The normal gastrointestinal tract does not contribute significantly to the catabolism of plasma proteins, accounting for only about 10 percent of the normal turnover of albumin and gamma globulin . Once plasma proteins pass into the gastrointestinal tract, they are degraded rapidly to amino acids and reabsorbed into the portal circulation.
Protein-losing gastroenteropathy can be caused by a diverse group of disorders (table 1). Intestinal leakage of plasma proteins occurs via one of the following mechanisms:
●Inflammatory exudation – Mucosal injury results in exudation of protein-rich fluids across the eroded epithelium. The degree of mucosal involvement typically correlates with the severity of protein loss.
- Schmidt PN, Blirup-Jensen S, Svendsen PJ, Wandall JH. Characterization and quantification of plasma proteins excreted in faeces from healthy humans. Scand J Clin Lab Invest 1995; 55:35.
- Davidson NO. Intestinal lipid absorption. In: Textbook of Gastroenterology, Yamada T, Alpers DH, Kaplowitz N (Eds), JB Lippincott, Philadelphia 2003. p.413.
- Acciuffi S, Ghosh S, Ferguson A. Strengths and limitations of the Crohn's disease activity index, revealed by an objective gut lavage test of gastrointestinal protein loss. Aliment Pharmacol Ther 1996; 10:321.
- Rybolt AH, Bennett RG, Laughon BE, et al. Protein-losing enteropathy associated with Clostridium difficile infection. Lancet 1989; 1:1353.
- Dansinger ML, Johnson S, Jansen PC, et al. Protein-losing enteropathy is associated with Clostridium difficile diarrhea but not with asymptomatic colonization: a prospective, case-control study. Clin Infect Dis 1996; 22:932.
- Stark ME, Batts KP, Alexander GL. Protein-losing enteropathy with collagenous colitis. Am J Gastroenterol 1992; 87:780.
- Ebert EC, Hagspiel KD. Gastrointestinal and hepatic manifestations of systemic lupus erythematosus. J Clin Gastroenterol 2011; 45:436.
- Molina JF, Brown RF, Gedalia A, Espinoza LR. Protein losing enteropathy as the initial manifestation of childhood systemic lupus erythematosus. J Rheumatol 1996; 23:1269.
- Jaeken J, Vanderschueren-Lodeweyckx M, Casaer P. Familial psychomotor retardation with markedly fluctuating serum prolactin, FSH and GH levels, partial TBG-deficiency, increased serum arylsulfatase A and increased CSF protein: a new syndrome. Pediatr Res 1980; 14:179.
- Hendriksz CJ, McClean P, Henderson MJ, et al. Successful treatment of carbohydrate deficient glycoprotein syndrome type 1b with oral mannose. Arch Dis Child 2001; 85:339.
- Kelly DG, Miller LJ, Malagelada JR, et al. Giant hypertrophic gastropathy (Ménétrier's disease): pharmacologic effects on protein leakage and mucosal ultrastructure. Gastroenterology 1982; 83:581.
- Bayerdörffer E, Ritter MM, Hatz R, et al. Healing of protein losing hypertrophic gastropathy by eradication of Helicobacter pylori--is Helicobacter pylori a pathogenic factor in Ménétrier's disease? Gut 1994; 35:701.
- Groisman GM, George J, Berman D, Harpaz N. Resolution of protein-losing hypertrophic lymphocytic gastritis with therapeutic eradication of Helicobacter pylori. Am J Gastroenterol 1994; 89:1548.
- Yamada M, Sumazaki R, Adachi H, et al. Resolution of protein-losing hypertrophic gastropathy by eradication of Helicobacter pylori. Eur J Pediatr 1997; 156:182.
- Farahat K, Hainaut P, Jamar F, et al. Lymphocytic gastritis: an unusual cause of hypoproteinaemia. J Intern Med 1993; 234:95.
- Wolber RA, Owen DA, Anderson FH, Freeman HJ. Lymphocytic gastritis and giant gastric folds associated with gastrointestinal protein loss. Mod Pathol 1991; 4:13.
- Suzuki C, Higaki S, Nishiaki M, et al. 99mTc-HSA-D scintigraphy in the diagnosis of protein-losing gastroenteropathy due to secondary amyloidosis. J Gastroenterol 1997; 32:78.
- Umar SB, DiBaise JK. Protein-losing enteropathy: case illustrations and clinical review. Am J Gastroenterol 2010; 105:43.
- Ozen A, Comrie WA, Ardy RC, et al. CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis. N Engl J Med 2017; 377:52.
- Malek NP, Ocran K, Tietge UJ, et al. A case of the yellow nail syndrome associated with massive chylous ascites, pleural and pericardial effusions. Z Gastroenterol 1996; 34:763.
- Peters B, Schuurs-Hoeijmakers JH, Fuijkschot J, et al. Protein-losing enteropathy in camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome. Pediatr Rheumatol Online J 2016; 14:32.
- Yang C, Dehner LP. Protein-losing enteropathy with intestinal lymphangiectasia in skeletal dysplasia with Lys650Met mutation. Am J Med Genet A 2016; 170:2993.
- Stephen J, Vilboux T, Haberman Y, et al. Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations. Eur J Hum Genet 2016; 24:1268.
- Elkadri A, Thoeni C, Deharvengt SJ, et al. Mutations in Plasmalemma Vesicle Associated Protein Result in Sieving Protein-Losing Enteropathy Characterized by Hypoproteinemia, Hypoalbuminemia, and Hypertriglyceridemia. Cell Mol Gastroenterol Hepatol 2015; 1:381.
- Pollack SF, Geffrey AL, Thiele EA, Shah U. Primary intestinal lymphangiectasia treated with rapamycin in a child with tuberous sclerosis complex (TSC). Am J Med Genet A 2015; 167A:2209.
- Meadows J, Jenkins K. Protein-losing enteropathy: integrating a new disease paradigm into recommendations for prevention and treatment. Cardiol Young 2011; 21:363.
- Müller C, Globits S, Glogar D, et al. Constrictive pericarditis without typical haemodynamic changes as a cause of oedema formation due to protein-losing enteropathy. Eur Heart J 1991; 12:1140.
- Wilkinson P, Pinto B, Senior JR. Reversible protein-losing enteropathy with intestinal lymphangiectasia secondary to chronic constrictive pericarditis. N Engl J Med 1965; 273:1178.
- Feldt RH, Driscoll DJ, Offord KP, et al. Protein-losing enteropathy after the Fontan operation. J Thorac Cardiovasc Surg 1996; 112:672.
- de Koning TJ, Dorland L, van Berge Henegouwen GP. Phosphomannose isomerase deficiency as a cause of congenital hepatic fibrosis and protein-losing enteropathy. J Hepatol 1999; 31:557.
- Bernier JJ, Florent C, Desmazures C, et al. Diagnosis of protein-losing enteropathy by gastrointestinal clearance of alpha1-antitrypsin. Lancet 1978; 2:763.
- Florent C, L'Hirondel C, Desmazures C, et al. Intestinal clearance of alpha 1-antitrypsin. A sensitive method for the detection of protein-losing enteropathy. Gastroenterology 1981; 81:777.
- Strygler B, Nicar MJ, Santangelo WC, et al. Alpha 1-antitrypsin excretion in stool in normal subjects and in patients with gastrointestinal disorders. Gastroenterology 1990; 99:1380.
- Florent C, Vidon N, Flourié B, et al. Gastric clearance of alpha-1-antitrypsin under cimetidine perfusion. New test to detect protein-losing gastropathy? Dig Dis Sci 1986; 31:12.
- Vardy PA, Lebenthal E, Shwachman H. Intestinal lymphagiectasia: a reappraisal. Pediatrics 1975; 55:842.
- Freeman HJ, Nimmo M. Intestinal lymphangiectasia in adults. World J Gastrointest Oncol 2011; 3:19.
- Abramowsky C, Hupertz V, Kilbridge P, Czinn S. Intestinal lymphangiectasia in children: a study of upper gastrointestinal endoscopic biopsies. Pediatr Pathol 1989; 9:289.
- Laor T, Hoffer FA, Burrows PE, Kozakewich HP. MR lymphangiography in infants, children, and young adults. AJR Am J Roentgenol 1998; 171:1111.
- Yueh TC, Pui MH, Zeng SQ. Intestinal lymphangiectasia: value of Tc-99m dextran lymphoscintigraphy. Clin Nucl Med 1997; 22:695.
- Bhatnagar A, Lahoti D, Singh AK, et al. Scintigraphic diagnosis of protein losing enteropathy using Tc-99m dextran. Clin Nucl Med 1995; 20:1070.
- JEFFRIES GH, CHAPMAN A, SLEISENGER MH. LOW-FAT DIET IN INTESTINAL LYMPHANGIECTASIA. ITS EFFECT ON ALBUMIN METABOLISM. N Engl J Med 1964; 270:761.
- Tift WL, Lloyd JK. Intestinal lymphangiectasia. Long-term results with MCT diet. Arch Dis Child 1975; 50:269.
- Heimburger DC, Weinsier RL. Therapeutic diets. In: Handbook of Clinical Nutrition, 3rd ed, Heimburger DC, Weinsier RL (Eds), Mosby, St. Louis 1997. p.235.
- Alpers DH, Stenson WF, Bier DM. Nutritional planning for patients with protein and calorie deficiency. In: Manual of Nutritional Therapeutics, 3rd ed, Alpers DH, Stenson WF, Bier DM (Eds), Little, Brown, and Co., Boston, MA 1995. p.265.
- Jacobs ML, Rychik J, Byrum CJ, Norwood WI Jr. Protein-losing enteropathy after Fontan operation: resolution after baffle fenestration. Ann Thorac Surg 1996; 61:206.
- Donnelly JP, Rosenthal A, Castle VP, Holmes RD. Reversal of protein-losing enteropathy with heparin therapy in three patients with univentricular hearts and Fontan palliation. J Pediatr 1997; 130:474.
- Masetti P, Marianeschi SM, Cipriani A, et al. Reversal of protein-losing enteropathy after ligation of systemic-pulmonary shunt. Ann Thorac Surg 1999; 67:235.
- Dousset B, Legmann P, Soubrane O, et al. Protein-losing enteropathy secondary to hepatic venous outflow obstruction after liver transplantation. J Hepatol 1997; 27:206.
- Stanley AJ, Gilmour HM, Ghosh S, et al. Transjugular intrahepatic portosystemic shunt as a treatment for protein-losing enteropathy caused by portal hypertension. Gastroenterology 1996; 111:1679.
- Sunagawa T, Kinjo F, Gakiya I, et al. Successful long-term treatment with cyclosporin A in protein losing gastroenteropathy. Intern Med 2004; 43:397.
- Mistilis SP, Skyring AP. Intestinal lymphangiectasia: Therapeutic effect of lymph venous anastomosis. Am J Med 1966; 40:634.
- Yeaton P, Frierson HF Jr. Octreotide reduces enteral protein losses in Ménétrier's disease. Am J Gastroenterol 1993; 88:95.
- Ballinger AB, Farthing MJ. Octreotide in the treatment of intestinal lymphangiectasia. Eur J Gastroenterol Hepatol 1998; 10:699.
- Kurolap A, Eshach-Adiv O, Hershkovitz T, et al. Loss of CD55 in Eculizumab-Responsive Protein-Losing Enteropathy. N Engl J Med 2017; 377:87.
- Erosive gastrointestinal diseases
- Nonerosive gastrointestinal diseases
- Diseases with lymphatic obstruction
- CLINICAL FEATURES
- Clinical manifestations
- Laboratory findings
- POST-DIAGNOSTIC EVALUATION
- Our approach
- History and physical examination
- Laboratory studies
- Abdominal imaging
- Endoscopy and biopsy
- Additional testing
- DIFFERENTIAL DIAGNOSIS
- Dietary therapy
- Treatment of the underlying disease
- SUMMARY AND RECOMMENDATIONS