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Protein-losing enteropathy (PLE) is a rare condition characterised by a loss of serum protein into the gastrointestinal (GI) tract, resulting in hypoproteinaemia which can be complicated by oedema, ascites, pleural and pericardial effusions and malnutrition.
PLE occurs in a number of GI conditions that cause excessive loss of serum proteins into the GI tract. Three main mechanisms are involved:
Mucosal disease with ulceration with protein loss across disrupted mucosal surface
- Chronic gastric ulcer.
- Gastric carcinoma.
- Inflammatory bowel disease.
- Idiopathic ulcerative jejunoileitis.
Lymphatic obstruction causing loss of protein-rich chyle
- Primary intestinal lymphangectasia.
- Secondary obstruction due to:
- Heart disease
- Retroperitoneal fibrosis
Idiopathic alterations in mucous capillary permeability
- Ménétrier's disease.
- Zollinger-Ellison syndrome.
- Acute viral or eosinophilic gastroenteritis.
- Coeliac disease.
- Allergic protein-losing enteropathy.
- Giardiasis and hookworm infections.
- Common variable immunodeficiency.
- Systemic lupus erythematosus (SLE).
Because the condition is so multifactorial, the prevalence rate is not known.
PLE is a common complication of Fontan's operation.This is a procedure carried out in children with severe congenital heart disease, in which venous blood is diverted from the right atrium to the pulmonary arteries without passing through the right ventricle.
The clinical presentation is very variable, depending on the underlying cause but mainly consists of oedema due to hypoproteinaemia.Consider PLE in any patient presenting with oedema, especially if this is against a background of GI disease.
- A dietary history should be taken to exclude malnutrition as a cause of reduced albumin synthesis.
- Check the patient's medical history for information about renal disease (increased protein loss) or hepatic disease (reduced albumin synthesis).
- Ask about GI symptoms, in particular any symptoms suggestive of enteritis (eg, diarrhoea, abdominal pain).
- Ask about alcohol intake.
- Check for a history of congenital heart disease, episodes of pericarditis, serious streptococcal infection, or prior heart surgery (increased interstitial pressure can be a cause).
- Check the general nutritional status of the patient - eg, height, weight, head circumference in children.
- Look for signs of acute liver disease (eg, enlarged liver, tenderness in the right upper quadrant).
- Look for signs of chronic liver disease (eg, jaundice, splenomegaly, prominent veins on the abdomen).
- Check for signs of right heart failure - eg, ascites and jugular vein distension.
- The finding of high blood pressure may suggest renal or cardiac disease.
- Look for signs of GI pathology - eg, abdominal tenderness, macroscopic or microscopic blood and mucus in the stool.
- Collagenous and lymphocytic colitis.
- Inflammatory bowel disease.
- Mycoplasma infections.
- Restrictive cardiomyopathy.
- Yersinia enterocolitica.
The initial step in the evaluation of any patient with hypoproteinaemia and/or hypoalbuminaemia is to exclude other, more common causes, such as malnutrition, liver and renal diseases.
- Serum proteins - by definition hypoalbuminaemia will be present.
- Liver and renal disease should be excluded by the appropriate function tests.
- Evidence of protein loss via the GI tract should be investigated in patients with oedema, hypoalbuminaemia and normal renal and liver function tests.
- Alpha-1-antitrypsin (A1AT):
- A1AT is a protein synthesised in the liver that is neither actively secreted nor absorbed.
- Raised A1AT levels in stools is a marker for protein loss but is not very specific as this is also seen in liver disease.
- However, the most commonly used and reliable method to determine enteric protein loss is to determine the clearance of A1AT from plasma.
- The measurement of A1AT clearance requires both a blood sample to determine plasma A1AT level and a 24-hour stool collection to determine stool volume and stool A1AT level.
- Viral serologies may be useful.
- Scintigraphy is a more accurate test. It involves the use of radio-labelled substances which are administered intravenously and then detected by the use of serial abdominal X-rays. The two common agents used are technetium Tc 99m labelled dextran or human serum albumin.
- Upper and/or lower endoscopy and mucosal biopsies may be needed to elucidate underlying causes.
There is no specific treatment for PLE and so management is directed at the underlying cause and treatment for malnutrition and micronutrient deficiencies.
A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of primary intestinal lymphangiectasia medical management.
- The importance of treating the underlying cause cannot be overestimated. One study reported the resolution of PLE by the simple measure of treating the patient's chronic diarrhoea with loperamide. The use of diuretics for congestive heart failure is another example.
- Octreotide has been shown to be useful in some patients. It is a potent inhibitor of many hormones affecting the gut and has a marked effect on reducing blood flow to the intestines.
- Supplementation with fat-soluble vitamins may be helpful.
- PLE is a common complication of Fontan's operation.Heparin produces benefits independent of its anticoagulant effect. Steroids can be an effective therapy but must be continued long-term at a low dose.
- In patients who have undergone Fontan's procedure, making a window in the baffle that separates the systemic venous pathway from the pulmonary venous atrium has helped to resolve PLE, presumably due to a reduction in systemic venous pressure.
- In patients whose PLE is secondary to a cardiac cause (eg, restrictive cardiomyopathy, constrictive pericarditis, tricuspid valvar stenosis and insufficiency), restoration of the unobstructed flow of blood in the superior or inferior caval vein may be curative. Post-Fontan patients may benefit but are unlikely to be cured.
- Cardiac transplant is occasionally used to treat intractable PLE in patients who have had previous heart surgery.
- PLE after Fontan's operation associated with lymphangiectasia (blockage of the intestinal lymphatics) has been successfully treated by resection of the affected area of bowel.
This depends on the underlying disease but improved management techniques are reducing mortality and morbidity of many causes.
Further reading and references
Umar SB, DiBaise JK; Protein-losing enteropathy: case illustrations and clinical review. Am J Gastroenterol. 2010 Jan105(1):43-9
Freeman HJ, Nimmo M; Intestinal lymphangiectasia in adults. World J Gastrointest Oncol. 2011 Feb 153(2):19-23.
Meadows J, Gauvreau K, Jenkins K; Lymphatic obstruction and protein-losing enteropathy in patients with congenital heart disease. Congenit Heart Dis. 2008 Jul3(4):269-76.
Braamskamp MJ, Dolman KM, Tabbers MM; Clinical practice. Protein-losing enteropathy in children. Eur J Pediatr. 2010 Oct169(10):1179-85. Epub 2010 Jun 23.
Khalesi M, Nakhaei AA, Seyed AJ, et al; Diagnostic accuracy of nuclear medicine imaging in protein losing enteropathy : systematic review and meta-analysis of the literature. Acta Gastroenterol Belg. 2013 Dec76(4):413-22.
Vignes S, Bellanger J; Primary intestinal lymphangiectasia (Waldmann's disease). Orphanet J Rare Dis. 2008 Feb 223:5.
Windram JD, Clift PF, Speakman J, et al; An Unusual Treatment for Protein Losing Enteropathy. Congenit Heart Dis. 2011 Mar 21. doi: 10.1111/j.1747-0803.2011.00484.x.
Ryerson L, Goldberg C, Rosenthal A, et al; Usefulness of heparin therapy in protein-losing enteropathy associated with single ventricle palliation. Am J Cardiol. 2008 Jan 15101(2):248-51.
Thacker D, Patel A, Dodds K, et al; Use of oral budesonide in the management of protein-losing enteropathy after the Fontan operation. Ann Thorac Surg. 2010 Mar89(3):837-42.
Menon S, Hagler D, Cetta F, et al; Role of caval venous manipulation in treatment of protein-losing enteropathy. Cardiol Young. 2008 Jun18(3):275-81. Epub 2008 Mar 7.
Connor FL, Angelides S, Gibson M, et al; Successful resection of localized intestinal lymphangiectasia post-Fontan: role of (99m)technetium-dextran scintigraphy. Pediatrics. 2003 Sep112(3 Pt 1):e242-7.