eMedicine Specialties > Gastroenterology > Intestine

Protein-Losing Enteropathy

Naeem Aslam, MD, Fellow, Department of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine
Richard Wright, MD, Professor and Chief, Department of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine

Updated: Jul 11, 2008

Introduction

Background

Protein-losing enteropathy is characterized by the severe loss of serum proteins into the intestine. Normal protein loss in the gastrointestinal tract mainly consists of sloughed enterocytes and pancreatic and biliary secretions. Albumin loss through the gastrointestinal tract normally accounts for 2-15% of the total body degradation of albumin, but, in patients with severe protein-losing gastrointestinal disorders, the enteric protein loss may reach up to 60% of the total albumin pool.

The serum protein level reflects the balance between protein synthesis, metabolism, and protein loss. Protein-losing enteropathy is characterized by more loss of proteins via the gastrointestinal tract than synthesis leading to hypoalbuminemia. It is not a single disease, but an atypical manifestation of other diseases.

Pathophysiology

The pathophysiology of this disorder is directly related to the excessive leakage of plasma proteins into the lumen of the gastrointestinal tract. Mechanisms for gastrointestinal protein loss include lymphatic obstruction, mucosal disease with erosions, ulcerations, or increased mucosal permeability to proteins as a result of cell damage or death. Proteins entering the gastrointestinal tract are metabolized into constituent amino acids by gastric, pancreatic, and small intestinal enzymes and are reabsorbed. When the rate of gastrointestinal protein loss exceeds the body's capacity to synthesize new proteins, hypoproteinemia develops. 

Frequency

United States

The prevalence rate is not known.

International

The prevalence rate is not known.

Mortality/Morbidity

Morbidity and mortality of this condition directly relate to its cause, either primary gastrointestinal disease or a multisystem disorder.

Race

No racial predilection exists.

Sex

No sex predilection exists.

Age

No age predilection exists.

Clinical

History

• The most common presenting symptom is swelling of the legs or other areas due to peripheral edema secondary to decreased plasma oncotic pressure, with subsequent transudation of fluid from the capillary bed to the subcutaneous tissue.
• If the protein-losing gastroenteropathy is related to other systemic diseases (eg, congestive heart failure, constrictive pericarditis, connective-tissue disease, amyloidosis, protein dyscrasias), the clinical presentation may be that of the primary disease process.
• Patients with primary gastrointestinal disease present with diarrhea with or without bleeding, abdominal pain, and/or weight loss.
• Along with a loss of proteins, a significant loss of immunoglobulins and lymphocytes can also occur. This may lead to the development of an immunological deficiency, predisposing to infections.

Physical

• Physical examination reveals peripheral edema and, in rare cases, anasarca.
• Evidence of the underlying medical problem (eg, cardiac disease, amyloidosis) may exist.
• If a primary gastrointestinal etiology exists, the abdominal examination findings may be unremarkable. Hepatosplenomegaly may be present, depending on the underlying process.

Causes

• Primary gastrointestinal mucosal diseases (typically ulcerative/erosive) include the following:
  • Erosions or ulcerations of the esophagus, stomach, or duodenum
  • Regional enteritis
  • Graft versus host disease
  • Pseudomembranous colitis (Clostridium difficile)
  • Mucosal-based neoplasia
  • Carcinoid syndrome
  • Idiopathic ulcerative jejunoileitis
  • Amyloidosis
  • Kaposi sarcoma
  • Protein dyscrasia
  • Ulcerative colitis
  • Neurofibromatosis
  • Cytomegalovirus infection
• Increased interstitial pressure or lymphatic obstruction leading to protein loss can be caused by the following:
  • Tuberculosis
  • Sarcoidosis
  • Retroperitoneal fibrosis
  • Lymphoma
  • Intestinal endometriosis
  • Lymphoenteric fistula
  • Whipple disease
  • Cardiac disease (constrictive pericarditis or congestive heart failure)
  • Intestinal lymphangiectasia
• Nonerosive upper gastrointestinal diseases include the following:
  • Cutaneous burns
  • Whipple disease
  • Connective tissue disorders
  • Acquired immunodeficiency syndrome (AIDS)
  • Enteropathy, such as angioedema (idiopathic or hereditary) and Henoch-Schönlein purpura
  • Celiac sprue
  • Tropical sprue
  • Allergic gastroenteritis
  • Eosinophilic gastroenteritis
  • Giant hypertrophic gastritis (Ménétrier disease)
  • Bacterial overgrowth
  • Intestinal parasites
  • Microscopic colitis
  • Dientamoeba fragilis

Differential Diagnoses

Other Problems to Be Considered

Cutaneous burns
Parasitic infections
Viral enteritis

Workup

Laboratory Studies

• The most prominent laboratory abnormality is a decrease in serum albumin and globulin.
• A gastrointestinal disorder should be considered the cause of hypoalbuminemia after malnutrition, nephrotic syndrome, and chronic liver disease are excluded. The diagnostic workup can then be focused on gastrointestinal causes.
• The presence of alpha1-antitrypsin in the stool is an important diagnostic clue because it is not normally absorbed or secreted into the bowel.
  • In patients with hyperacidity syndromes, this study is not accurate because of the degradation of alpha1-antitrypsin in an environment where the pH is less than 3.  
  • Measuring stool volume and stool alpha1-antitrypsin concentration shows the plasma clearance (PC) of alpha1-antitrypsin. The plasma clearance of alpha1-antitrypsin can be used to monitor response to therapy.

• Viral serologies may be helpful.

Imaging Studies

• Radionuclide-labeled serum albumin can be administered intravenously, and stool can be collected as a measure of protein exudation into the gastrointestinal tract.
• Computed tomography scanning may suggest lymphatic obstruction. This needs to be confirmed with lymphangiography.
• Chest radiography, echocardiography, and radionuclide scanning of the heart detect cardiac disease.
• Erosive or ulcerative conditions are diagnosed using radiographic contrast studies or, when possible, endoscopy and mucosal biopsies.

Other Tests

• Primary gastrointestinal tract disease can be detected by endoscopy and biopsy, barium radiography, stools for ova and parasites, and culture. Primary gastrointestinal tract disease can be suggested by fecal occult blood.
• Perform a hydrogen breath test for bacterial overgrowth in the small intestine.

Procedures

• Findings on endoscopic studies are usually normal unless primary gastrointestinal disease (eg, ulcerative colitis, Crohn disease, Ménétrier disease, viral mucosal ulcerations) is present.

Histologic Findings

Mucosal abnormalities can be observed with inflammatory (colitis) and infectious (viral tuberculosis) causes and in lymphatic obstruction (lymphangiectasia).

Treatment

Medical Care

Focus treatment on correcting the underlying process causing the protein-losing gastroenteropathy. For example, the patient with congestive heart failure may respond to digitalis and diuretics, whereas the patient with intestinal parasites should be treated with the appropriate medication for the infestation.

Surgical Care

• Surgery for giant hypertrophic gastropathy (Ménétrier disease) and localized lymphatic obstruction has been suggested. Surgical lymphovenous anastomosis may also be of benefit in these patients.
• Eradicating Helicobacter pylori has also been shown to decrease gastric protein loss in some patients with giant hypertrophic gastropathy.

Diet

• A low-fat diet with supplementation with medium-chain triglycerides is theoretically of benefit in patients with lymphangiectasias. However, in practice, ingesting a diet containing medium-chain triglycerides results in increased blood flow with no reduction in fecal protein loss.
• Patients with celiac sprue typically respond to a gluten-free diet. A minority requires corticosteroids.

Medication

Octreotide has limited benefit in treating patients with Ménétrier disease, but a therapeutic trial may be worthwhile. A monoclonal antibody against the epidermal growth factor receptor has been shown to be effective in treating Ménétrier disease. External elastic support is helpful in reducing peripheral edema.

Prednisone may be used in patients with total villous atrophy that is unresponsive to gluten restriction. Prednisone rapidly reverses the symptoms and signs of eosinophilic gastroenteritis and returns the serum albumin to the reference range. Medium-chain triglycerides are not helpful in hereditary intestinal lymphangiectasia. Specific treatment of infectious enteritides is indicated when present.

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and by suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocyte and antibody production.

Dosing

Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk, as symptoms resolve, to 5-10 mg PO qd

Pediatric

Not established

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI bleeding or ulceration

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose and treat

References

1. Akgün A, Tani Acar E, Taner MS, et al. Scintigraphic diagnosis of protein-losing enteropathy secondary to amyloidosis. Turk J Gastroenterol. Mar 2005;16(1):41-3. [Medline].

2. Albright F, Bartter FC, Forbes AP. The fate of human serum albumin administered intravenously to a patient with idiopathic hypoalbuminemia and hypoproteinemia. Trans Assoc Am Physicians. 1949;204:62.

3. Bindl L, Buderus S, Bindl C, Lentze MJ. Protein-losing enteropathy: report of four cases and review of etiology, diagnostic work-up and treatment. Klin Padiatr. 2005;217:201-210.

4. Cheong JL, Cowan FM, Modi N. Gastrointestinal manifestations of postnatal cytomegalovirus infection in infants admitted to a neonatal intensive care unit over a five year period. Arch Dis Child Fetal Neonatal Ed. Jul 2004;89(4):F367-9. [Medline].

5. Citrin Y, Sterling K, Halsted JA. The mechanism of hypoproteinemia associated with giant hypertrophy of the gastric mucosa. N Engl J Med. Nov 7 1957;257(19):906-12. [Medline].

6. Ferrante M, De Hertogh G, Penninckx F, et al. Protein-losing enteropathy in Crohn's disease. Clin Gastroenterol Hepatol. Jun 2005;3(6):A25. [Medline].

7. 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. Oct 1981;81(4):777-80. [Medline].

8. Gordon RS Jr. Exudative enteropathy: abnormal permeability of the gastrointestinal tract demonstrable with labelled polyvinylpyrrolidone. Lancet. Feb 14 1959;1(7068):325-6. [Medline].

9. Ito R, Sakagami J, Kataoka K, et al. Chronic diarrhea and protein-losing gastroenteropathy caused by Dientamoeba fragilis. J Gastroenterol. Nov 2004;39(11):1117-9. [Medline].

10. Jeffries GH, Chapman A, Sleisenger MH. Low-fat diet in intestinal lymphagiectasia: its effect on albumin metabolism. N Engl J Med. 1964;270:761-4.

11. Laine L, Garcia F, McGilligan K, et al. Protein-losing enteropathy and hypoalbuminemia in AIDS. AIDS. Jun 1993;7(6):837-40. [Medline].

12. Lee YT, Sung JJ. Protein-losing enteropathy. Gastrointest Endosc. Nov 2004;60(5):801-2. [Medline].

13. Overholt BF, Jeffries GH. Hypertrophic, hypersecretory protein-losing gastropathy. Gastroenterology. Jan 1970;58(1):80-7. [Medline].

14. Pratz KW, Dingli D, Smyrk TC, et al. Intestinal lymphangiectasia with protein-losing enteropathy in Waldenstrom macroglobulinemia. Medicine (Baltimore). Jul 2007;86(4):210-4. [Medline].

15. Rybolt AH, Bennett RG, Laughon BE, et al. Protein-losing enteropathy associated with Clostridium difficile infection. Lancet. Jun 17 1989;1(8651):1353-5. [Medline].

16. Samarkos M, Vaiopoulos G, Andreopoulos A, et al. Association of protein-losing enteropathy and cryoglobulinaemia. Scand J Gastroenterol. Mar 2003;38(3):334-6. [Medline].

17. Stark ME, Batts KP, Alexander GL. Protein-losing enteropathy with collagenous colitis. Am J Gastroenterol. Jun 1992;87(6):780-3. [Medline].

18. Venkatesh B, Gough J, Ralston DR, et al. Protein losing enteropathy in critically ill adult patients with burns: a preliminary report. Intensive Care Med. Jan 2004;30(1):162-6. [Medline].

19. Vyas H, Driscoll DJ, Cetta F, et al. Gastrointestinal bleeding and protein-losing enteropathy after the fontan operation. Am J Cardiol. Sep 1 2006;98(5):666-7. [Medline].

20. Waldmann TA. Protein-losing gastroenteropathy. Gastroenterology. 1966;50:422.

21. Waldmann TA, Wochner RD, Strober W. The role of the gastrointestinal tract in plasma protein metabolism. Studies with 51Cr-albumin. Am J Med. Feb 1969;46(2):275-85. [Medline].

22. Yeaton P, Frierson HF Jr. Octreotide reduces enteral protein losses in Ménétrier's disease. Am J Gastroenterol. Jan 1993;88(1):95-8. [Medline].

Keywords

protein losing enteropathy, protein loss, protein deficiency, GI protein loss, gastrointestinal protein loss, protein-losing gastroenteropathy, protein losing gastroenteropathy, gastroenteropathy, gastric protein loss, giant hypertrophic gastropathy, Menetrier disease, Ménétrier disease, loss of plasma proteins from the gastrointestinal tract, excessive leakage of plasma proteins into the lumen of the gastrointestinal tract, lymphatic obstruction, mucosal disease with erosions, ulcerations, swelling of the legs, peripheral edema, decreased plasma oncotic pressure

Contributor Information and Disclosures

Author

Naeem Aslam, MD, Fellow, Department of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine
Naeem Aslam, MD is a member of the following medical societies: American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Coauthor(s)

Richard Wright, MD, Professor and Chief, Department of Medicine, Division of Gastroenterology/Hepatology, University of Louisville School of Medicine
Richard Wright, MD is a member of the following medical societies: American College of Physician Executives, American College of Physicians, American Gastroenterological Association, American Medical Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Medical Editor

Terence David Lewis, MBBS, FRACP, FRCPC, FACP, Program Director, Internal Medicine Residency, & Assistant Chairman, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, Loma Linda University Medical Center
Terence David Lewis, MBBS, FRACP, FRCPC, FACP is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, California Medical Association, Royal College of Physicians and Surgeons of Canada, and Sigma Xi
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Noel Williams, MD, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
Noel Williams, MD is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)