Protein-Losing Enteropathy 

Updated: Dec 10, 2019
Author: Naeem Aslam, MD; Chief Editor: Burt Cagir, MD, FACS 

Overview

Background

Protein-losing enteropathy is characterized by the severe loss of serum proteins into the intestine.[1] 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.[2]

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.[3]

Etiology

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)[4]

  • Mucosal-based neoplasia

  • Carcinoid syndrome

  • Idiopathic ulcerative jejunoileitis

  • Amyloidosis[5]

  • Kaposi sarcoma

  • Protein dyscrasia

  • Ulcerative colitis

  • Neurofibromatosis

  • Cytomegalovirus infection[6]

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[7]

Nonerosive upper gastrointestinal diseases include the following:

  • Cutaneous burns[8]

  • Whipple disease

  • Connective tissue disorders

  • Acquired immunodeficiency syndrome (AIDS)[2]

  • Enteropathy, such as angioedema (idiopathic or hereditary) and Henoch-Schönlein purpura

  • Celiac sprue

  • Tropical sprue

  • Allergic gastroenteritis

  • Eosinophilic gastroenteritis

  • Giant hypertrophic gastritis (Ménétrier disease)[9, 10, 11]

  • Bacterial overgrowth

  • Intestinal parasites

  • Microscopic colitis

  • Dientamoeba fragilis[12]

Cases in which protein-losing enteropathy was the initial manifestation of systemic lupus erythematosus have been reported.[13, 14, 15]

Protein-losing enteropathy can also occur as a complication of the Fontan procedure, an operation for several congenital heart abnormalities; the surgery allows systemic venous blood to reach the lungs without circulating through a ventricle.[16, 17, 18, 19]  In children, protein-losing enteropathy may occur before or after the procedure, especially in the setting of hemodynamic disturbances.[20]

Epidemiology

United States statistics

The prevalence rate is not known.

International statistics

The prevalence rate is not known.

Race-, sex-, and age-related demographics

No racial, sexual, or age predilection exists.

Prognosis

A retrospective study by John et al indicated that the survival rate has increased for patients who develop protein-losing enteropathy as a complication of the Fontan procedure, an operation for the treatment of several types of congenital heart abnormalities. Although the 5-year mortality rate has been reported to be 50% for patients who develop protein-losing enteropathy following the surgery, the investigators found that in 42 such patients identified from Mayo Clinic clinical databases, the survival rate at 5 years after the diagnosis of enteropathy was 88%.[17]

The survival rate tended to be lower, however, in patients with a high Fontan pressure, reduced ventricular function (ejection fraction < 55%), and a New York Heart Association functional classification of greater than 2. Treatments associated with a higher survival rate included spironolactone, octreotide, and sildenafil, as well as the creation of fenestrae and Fontan obstruction relief.[17]

Mortality/Morbidity

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

 

Presentation

History

The most common presenting symptom of protein-losing enteropathy 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.[21]

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.[2]

Physical Examination

Physical examination reveals peripheral edema and, in rare cases, anasarca. Evidence of the underlying medical problem (eg, cardiac disease, amyloidosis) may exist.[5, 22]

If a primary gastrointestinal etiology exists, the abdominal examination findings may be unremarkable. Hepatosplenomegaly may be present, depending on the underlying process.

 

DDx

Diagnostic Considerations

Clinicians should have a high index of suspicion for protein-losing enteropathy as an uncommon complication of inflammatory bowel disease, particularly in the setting of hypoproteinemia without concomitant hepatic disease, severe malnutrition, or proteinuria.[23]  

The following conditions should also be considered in patients with suspected protein-losing enteropathy:

  • Cutaneous burns

  • Parasitic infections

  • Viral enteritis

Differential Diagnoses

 

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.[24]

The presence of alpha1-antitrypsin in the stool is an important diagnostic clue because it is not normally absorbed or secreted into the bowel.[25]  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.[25] The plasma clearance of alpha1-antitrypsin can be used to monitor response to therapy.

Alpha 1-AT PC = ((stool volume) x (stool alpha 1-AT)) / (serum alpha-1 AT)

Erythrocyte sedimentation rate and serum total cholesterol levels have reported to be significantly elevated in patients with lupus-related protein-losing enteropathy.{ref29)

Viral serologies may be helpful.

In a prospective study that evaluated the immunologic characteristics of patients with protein-losing enteropathy (PLE) following Fontan procedures and those without postoperative PLE, patients with postoperative PLE all had markedly low CD4 T cell counts compared to the control subjects.[26] Both groups had mildly decreased CD8 T cells and normal to slightly elevated natural killer and B cells.

Also see Alpha1-Antitrypsin Deficiency.

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.[27]

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.

T2-weighted magnetic resonance imaging shows promise in the evaluation of lymphatic abnormalities in patients following functional single-ventricle palliative surgery.[18] Lymphatic anomalies might play a role in protein-losing enteropathy in this setting.

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.[28]

Histologic Findings

Mucosal abnormalities can be observed with inflammatory (colitis) and infectious (viral tuberculosis) causes and in lymphatic obstruction (lymphangiectasia).[29, 30, 31]

 

Treatment

Medical Care

Focus treatment on correcting the underlying process causing the protein-losing gastroenteropathy.[21] 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.[10] 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.[10]

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.[32, 33]

Patients with celiac sprue typically respond to a gluten-free diet. A minority requires corticosteroids.

 

Medication

Medication Summary

Octreotide has limited benefit in treating patients with Ménétrier disease, but a therapeutic trial may be worthwhile.[34] 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

Class Summary

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.

 

Questions & Answers

Overview

What is protein-losing enteropathy?

What is the pathophysiology of protein-losing enteropathy?

Which GI mucosal diseases cause protein-losing enteropathy?

Which disorders cause increased interstitial pressure or lymphatic obstruction leading to protein-losing enteropathy?

Which nonerosive upper GI diseases cause protein-losing enteropathy?

What is the prevalence of protein-losing enteropathy?

What is the prognosis of protein-losing enteropathy?

Presentation

Which clinical history findings are characteristic of protein-losing enteropathy?

Which physical findings are characteristic of protein-losing enteropathy?

DDX

Which conditions should be considered in the differential diagnoses of protein-losing enteropathy?

What are the differential diagnoses for Protein-Losing Enteropathy?

Workup

What is the role of lab testing in the workup of protein-losing enteropathy?

What is the role of imaging studies in the workup of protein-losing enteropathy?

How is primary GI tract disease assessed in protein-losing enteropathy?

What is the role of endoscopy in the workup of protein-losing enteropathy?

Which histologic findings are characteristic of protein-losing enteropathy?

Treatment

How is protein-losing enteropathy treated?

What is the role of surgery in the treatment of protein-losing enteropathy?

Which dietary modifications are used in the treatment of protein-losing enteropathy?

Medications

What is the role of medications in the treatment of protein-losing enteropathy?

Which medications in the drug class Corticosteroids are used in the treatment of Protein-Losing Enteropathy?