Protein-Losing Enteropathy

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]

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]

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, 16]

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.[17, 18, 19, 20]  In children, protein-losing enteropathy may occur before or after the procedure, especially in the setting of hemodynamic disturbances.[21]  Children potententially more affected with protein-losing enteropathy and plastic bronchitis may be those who are older when undergoing Fontan procedure and have a dominant right single ventricle.[22]

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.

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%.[18]

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.[18]

Mortality/Morbidity

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

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.[23]

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 reveals peripheral edema and, in rare cases, anasarca. Evidence of the underlying medical problem (eg, cardiac disease, amyloidosis) may exist.[5, 24]

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

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.[28]

The presence of alpha1-antitrypsin in the stool is an important diagnostic clue because it is not normally absorbed or secreted into the bowel.[29]  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.[29] 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.[30] Both groups had mildly decreased CD8 T cells and normal to slightly elevated natural killer and B cells.

Also see Alpha1-Antitrypsin Deficiency.

Radionuclide-labeled serum albumin can be administered intravenously, and stool can be collected as a measure of protein exudation into the gastrointestinal tract.[31]

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.[19] Lymphatic anomalies might play a role in protein-losing enteropathy in this setting.

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.

Findings on endoscopic studies are usually normal unless primary gastrointestinal disease (eg, ulcerative colitis, Crohn disease, Ménétrier disease, viral mucosal ulcerations) is present.[32]

Mucosal abnormalities can be observed with inflammatory (colitis) and infectious (viral tuberculosis) causes and in lymphatic obstruction (lymphangiectasia).[33, 34, 35]

Focus treatment on correcting the underlying process causing the protein-losing gastroenteropathy.[23] 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. 

CHAPLE disease

Pozelimab is indicated for treatment of CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and severe protein-losing enteropathy (CHAPLE) syndrome in patients aged 1 year and older.[36] Pozelimab is an immunoglobulin (Ig) antibody that is directed against terminal complement protein C5. The role of C5 is to inhibit terminal complement activation by blocking cleavage of C5 into C5a (anaphylatoxin) and C5b. This action blocks formation of the membrane-attack complex (C5b-C9), a structure mediating cell lysis. 

FDA approval was based on results from an open-label phase 2/3 trial (N = 10).[37] All 10 patients achieved normalization of serum albumin and serum IgG concentrations by week 12 and maintained these concentrations through at least 72 weeks of treatment. Five of the 10 patients received a total of 60 albumin transfusions in the 48 weeks preceding treatment. In the 48 weeks after starting treatment, one patient received a single albumin transfusion. Nine of the 10 patients were hospitalized for a total of 268 days in the 48 weeks before treatment, whereas two patients were hospitalized for a total of 7 days in the 48 weeks after starting treatment.[37]  

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]

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.[38, 39]

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

Octreotide has limited benefit in treating patients with Ménétrier disease, but a therapeutic trial may be worthwhile.[40] 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. 

Pozelimab, a monoclonal antibody targeting C5, has been approved for treatment of CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and severe protein-losing enteropathy (CHAPLE) syndrome in patients aged 1 year and older.[36]  

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.

Class Summary

In protein-losing enteropathy related to CHAPLE disease, pozelimab, a monoclonal antibody targeting C5, has been shown to normalize serum albumin and serum IgG concentrations as well as reduce hospitalizations and albumin infusions.[37]

Pozelimab (Veopoz)

Indicated for treatment of CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and severe protein-losing enteropathy (CHAPLE) syndrome in patients aged 1 year and older. Pozelimab is an immunoglobulin antibody directed against terminal complement protein C5. The role of C5 is to inhibit terminal complement activation by blocking cleavage of C5 into C5a (anaphylatoxin) and C5b. This action blocks formation of the membrane-attack complex (C5b-C9), a structure mediating cell lysis.