Definition, Etiology, PathogenesisTop
Protein-losing enteropathy is a clinical syndrome characterized by excessive loss of plasma proteins from the gastrointestinal (GI) tract that leads to hypoproteinemia. Protein loss can occur from abnormalities in the lymphatic system resulting in loss of protein-rich lymph or from mucosal damage (with or without ulceration). The mostly affected proteins are those with long half-lives, such as albumin or immunoglobulins.
1) Loss of proteins with lymph:
a) Primary intestinal lymphangiectasia: Characterized by dilation of lymphatic vessels within the GI tract secondary to congenital obstruction of lymphatics. This leads to a high-pressure system and leakage of protein-rich lymph, causing hypoproteinemia, lymphopenia, and edema. Most patients present before the age of 3 years.
b) Secondary lymphatic vessel dilation (impaired lymph outflow): Cardiovascular diseases (right ventricular failure, constrictive pericarditis, long-term complications of Fontan procedure—a surgical procedure to correct congenital cardiac abnormalities), lymphatic dysfunction (eg, cancer, tuberculosis, sarcoidosis, radiotherapy and chemotherapy), cirrhosis, hepatic veno-occlusive disease or hepatic vein thrombosis, chronic pancreatitis with the formation of pseudocysts, Crohn disease, Whipple disease, intestinal lymphatic fistulas, congenital lymphatic malformations, arsenic poisoning, retroperitoneal fibrosis.
2) Mucosal erosions and ulcerations: Inflammatory bowel disease, tumors (gastric cancer, lymphomas, Kaposi sarcoma, heavy chain diseases), pseudomembranous colitis, multiple gastric ulcers or gastric erosions, enteropathy induced by nonsteroidal anti-inflammatory drugs or chemotherapy, ulcerative jejunoileitis, graft-versus-host disease.
3) Increased mucosal permeability: Celiac disease and tropical sprue, Ménétrier disease, lymphocytic gastritis, Helicobacter pylori gastritis, amyloidosis, common variable immunodeficiency–associated gastroenteropathy, infections (small intestinal bacterial overgrowth, complication of acute viral gastroenteritis, parasitic infections, Whipple disease), systemic connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease), hypertrophic hypersecretory gastropathy, allergic gastroenteropathy, eosinophilic gastroenteritis, collagenous colitis.
Proteins lost through the GI tract are usually digested (except for alpha1 antitrypsin, thus used as a diagnostic marker [see Diagnostic Tests, below]). In patients with lymphatic stasis, lymphocytes and immunoglobulins are also lost (although this usually does not lead to clinically apparent immunodeficiency) and malabsorption of long-chain triglycerides and fat-soluble vitamins ensues.
Clinical manifestations are diverse and largely depend on the underlying condition. The most common signs and symptoms include chronic diarrhea (frequently with steatorrhea), nausea, vomiting, edema (pitting, symmetric, affecting particularly the lower limbs), sometimes lymphedema of various locations, ascites, less frequently pleural or pericardial effusions (fluid may be milky due to the lymph content), malnutrition, cachexia in advanced cases, symptoms of vitamin A and D deficiencies.
1. Laboratory tests: Hypoalbuminemia; low levels of immunoglobulins (IgG, IgA, IgM), fibrinogen, transferrin, and ceruloplasmin; sometimes lymphopenia, hypocholesterolemia, anemia, and hypocalcemia.
2. Fecal alpha1-antitrypsin excretion is increased. Alpha1 antitrypsin is produced in the liver and does not undergo secretion, absorption, or digestion; thus, it is only detected intact in stool if there is loss from the GI tract. Alpha1 antitrypsin clearance is measured by collecting 24-hour alpha1 antitrypsin levels in stool and serum. A false-negative result may occur in conditions associated with hypersecretion of hydrochloric acid (as alpha1 antitrypsin undergoes proteolysis at a pH <3.5); in such cases a proton pump inhibitor should be administered 3 days before the test.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to evidence being based only on a case report. Takeda H, Nishise S, Furukawa M, Nagashima R, Shinzawa H, Takahashi T. Fecal clearance of alpha1-antitrypsin with lansoprazole can detect protein-losing gastropathy. Dig Dis Sci. 1999 Nov;44(11):2313-8. PubMed PMID: 10573380. Intestinal bleeding can increase alpha1-antitrypsin clearance.
3. Intestinal scintigraphy and magnetic resonance imaging (MRI) may provide additional information and document the loss of radioactively labelled material in some situations (eg, primary protein-losing enteropathy in children with intestinal lymphangiectasia), although the evidence is anecdotal and clinical utility of these tests is not clear. Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to evidence being based on an isolated case report only. Liu NF, Lu Q, Wang CG, Zhou JG. Magnetic resonance imaging as a new method to diagnose protein losing enteropathy. Lymphology. 2008 Sep;41(3):111-5. PubMed PMID: 19013878.
Increased fecal alpha1-antitrypsin excretion in a patient with hypoalbuminemia and edema in whom other causes have been excluded. A fecal clearance >27 mL/24 hours is considered abnormal. In the setting of diarrhea, a fecal clearance >56 mL/24 hours is abnormal.
1. Treatment of the underlying condition. In patients with primary lymphangiectasia involving a limited portion of the intestine, resection of the affected segment may be needed.
2. Nutritional management:
1) Restriction of fats containing long-chain triglycerides, as these are mostly absorbed through lymphatic vessels. Alternatively, recommend the use of formulas containing medium-chain triglycerides (MCTs) (eg, MCT oils, which are absorbed directly through the portal vein) to reduce the malabsorption of fats as well as to lower the lymphatic pressure and reduce the leakage of lymph to the intestinal lumen in patients with impaired lymphatic drainage.
2) Protein-rich diet (2-3 g/kg/d), sometimes supplemented with high-protein formulas.
3) Vitamin and trace element supplementation (calcium, iron, magnesium, zinc).
4) Parenteral nutrition if necessary.
3. Medications: Specific treatments are limited, and pharmacologic therapy is directed either at the underlying conditions or consequences (edema).
1) Patients after Fontan procedure: Certain medications showed potential benefit in very small randomized controlled trials (bosentan)Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Shang XK, Li YP, Liu M, et al. [Efficacy of endothelin receptor antagonist bosentan on the long-term prognosis in patients after Fontan operation]. Zhonghua Xin Xue Guan Bing Za Zhi. 2013 Dec;41(12):1025-8. Chinese. PubMed PMID: 24524605. or isolated case reports and small case series (sildenafil, budesonide, heparin) with corresponding major uncertainties regarding their usefulness.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data with a very small sample. John AS, Driscoll DJ, Warnes CA, Phillips SD, Cetta F. The use of oral budesonide in adolescents and adults with protein-losing enteropathy after the Fontan operation. Ann Thorac Surg. 2011 Oct;92(4):1451-6. doi: 10.1016/j.athoracsur.2011.03.103. Epub 2011 Jul 23. PubMed PMID: 21784410. Uzun O, Wong JK, Bhole V, Stumper O. Resolution of protein-losing enteropathy and normalization of mesenteric Doppler flow with sildenafil after Fontan. Ann Thorac Surg. 2006 Dec;82(6):e39-40. PubMed PMID: 17126088.
2) Other medications for protein-losing enteropathy tried in isolated cases:
a) Spironolactone 2.5mg/kg/d and furosemide 2 mg/kg/d:Evidence 5Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data, indirectness, and imprecision. Mizuochi T, Suda K, Seki Y, et al. Successful diuretics treatment of protein-losing enteropathy in Noonan syndrome. Pediatr Int. 2015 Apr;57(2):e39-41. doi: 10.1111/ped.12603. PubMed PMID: 25868959. A combination of diuretics aimed at decreasing fluid overload. Spironolactone may also reduce proteinuria.
b) Subcutaneous octreotide 0.1 mg tid:Evidence 6Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data, indirectness, and imprecision. Lee HL, Han DS, Kim JB, Jeon YC, Sohn JH, Hahm JS. Successful treatment of protein-losing enteropathy induced by intestinal lymphangiectasia in a liver cirrhosis patient with octreotide: a case report. J Korean Med Sci. 2004 Jun;19(3):466-9. PubMed PMID: 15201518; PubMed Central PMCID: PMC2816853. A somatostatin analogue that aims to reduce splanchnic blood flow and lymph secretion.