Protein-Losing Enteropathy

Etiology

The three main groups of disorders that cause excess protein loss in stools are:

1. Primary Erosive/Ulcerative gastrointestinal Disorders

This group of conditions includes inflammatory bowel diseases (both ulcerative colitis and Crohn disease), gastrointestinal malignancies, any erosions or ulcers of stomach or duodenum, Clostridium difficile colitis, carcinoid syndrome, graft vs. host disease.

      2. Non-Erosive/Non-Ulcerative Gastrointestinal Disorders

This group includes topical Sprue, celiac disease, Menetrier disease, amyloidosis, cutaneous burns, eosinophilic gastroenteritis, bacterial overgrowth, Intestinal parasitic infections, Whipple disease, collagenous colitis, AIDS, mixed connective tissue diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA).[2][3]

      3. Disorders Causing Increased Interstitial Pressure or Lymphatic Obstruction

This grouping can be due to primary intestinal lymphangiectasia, right-sided heart failure, constrictive pericarditis, congenital heart disease, Fontan procedure for single ventricle, cirrhosis with portal hypertension gastropathy, hepatic venous outflow obstruction, mesenteric tuberculosis or sarcoidosis, retroperitoneal fibrosis, lymphoenteric fistula, lymphoma, and thoracic duct obstruction.[4][5][6]

Epidemiology

The incidence and prevalence of protein-losing enteropathy are not known. It can affect people of any age, race, or sex without any specific predilection.

Pathophysiology

This condition occurs when the loss of proteins through the gastrointestinal tract exceeds the synthesis of proteins by the body, leading to hypoproteinemia. Normally most of the proteins entering the gut are degraded into amino acids and are reabsorbed. In conditions causing inflammation and erosions of the gastrointestinal tract, the mucosal permeability increases, leading to excessive leakage of serum proteins into the gut, and poor reabsorption. This state leads to hypoproteinemia. In diseases causing increased lymphatic pressure and lymphatic obstruction, there is an increased leak of lymph into the gastrointestinal tract and decreased absorption of chylomicrons, resulting in a deficiency of fat-soluble vitamins and protein loss.[1]

Histopathology

Histopathology depends on the underlying cause. For example, In protein-losing enteropathy caused by Crohn disease, we can see granulomas and acute and chronic inflammation of the colonic wall. Crypt abscesses, crypt branching, increased lamina propria cellularity, basal plasmacytosis, basal lymphoid aggregates are present in ulcerative colitis. Various other mucosal abnormalities can be seen depending upon the etiology.[7]

History and Physical

The clinical features of protein-losing enteropathy depend on the underlying etiology. Loss of serum proteins leads to decreased oncotic pressure in capillaries, which, in turn, leads to peripheral edema (most common presenting symptom) due to transudation of fluids from capillaries to the subcutaneous tissue. Patients can also present with abdominal distension due to ascites and pleural effusions. In primarily gastrointestinal causes of protein loss, they can have diarrhea, bloating, abdominal pain, etc. This condition can cause loss of immunoglobulins and lymphocytes, which cause immunocompromised state leading to frequent infections, and also patients can get opportunistic infections. Patients with protein loss due to cardiac diseases can present with symptoms of heart failure like pitting edema, pleural effusion, shortness of breath, elevated jugular venous pressure.

Evaluation

Diagnosis of protein-losing enteropathy should be suspected in patients with hypoproteinemia once the other common causes like severe malnutrition, nephrotic syndrome, or chronic liver diseases have been ruled out. Since the protein loss in PLE occurs independent of their molecular weight, these patients have low albumin and low globulins in their serum. If there are isolated low serum albumin and normal serum globulins, then alternative causes should be considered.

Alpha 1 antitrypsin (A1AT) intestinal clearance is the primary and most common test performed to diagnose PLE. This protein has high molecular weight, is minimally degraded in the gut and is excreted intact. Its clearance is calculated by 24 hr stool collection and measuring A1AT in serum and stool.

Alpha 1-antitrypsin clearance = (stool volume) x (stool alpha 1-antitrypsin)/ (serum alpha-1 antitrypsin).

The normal clearance of A1AT is under 13ml/24 hours. Clearance greater than 27 ml/ day indicates increased gastrointestinal protein loss and points towards the diagnosis of PLE. Clearance is affected by diarrhea. Any condition causing diarrhea leads to increased clearance of A1AT, so the higher threshold of more than 56ml/24 hr should be used in these conditions. Increased stomach acidity and decreased ph lead to increased degradation of A1AT, so the performance of this test should be while the patient is on antacids especially if there is suspicion of hypersecretory state causing increased protein loss. Gastrointestinal bleeding can also cause increased clearance of A1AT.

Other tests like 51Cr-labeled albumin clearance(considered gold standard), technetium 99 labeled serum albumin scintigraphy can also be performed if there is high clinical suspicion of PLE with negative A1AT clearance test. These tests have high sensitivity, but they are very cumbersome, expensive and not readily available so not routinely performed.[8]

Once the diagnosis of PLE is established with increased A1AT clearance, further workup is needed to find the underlying etiology and to guide treatment. Important consideration should be given to the history and physical examination of the patient. Detailed history helps in narrowing down the list of conditions causing hypoproteinemia and PLE and guides the approach towards further work up. Basic labs like complete blood count with differential, liver function tests, renal function tests should be performed in all patients. In cases where symptoms suggest gastrointestinal causes of protein loss, tests for celiac disease, infectious work for chronic intestinal infections, appropriate imaging of abdomen and pelvis, upper and lower gastrointestinal endoscopies with biopsies, capsule endoscopies (if upper and lower endoscopies are unremarkable) should be performed. Autoimmune workup should be ordered if SLE or RA is suspected. Echocardiogram and workup on the lines of heart failure should be done if cardiac causes of PLE is suspected. Fontan procedure in patients with congenital heart disease is a well-known cause of PLE and has been extensively studied

Treatment / Management

Treating the underlying pathology is the mainstay of treatment. Besides this, dietary modifications also play a critical role in the management of protein-losing enteropathy. Diet rich in protein and medium chain triglycerides and low in fat is considered the best diet in this condition. Patients may require 2 to 3g/kg/day of protein. Replacement of micronutrients, electrolytes, and vitamin deficiencies should occur as appropriate.

If heart failure is the cause of PLE, then optimization of heart failure medications needs to be done. Diuretics are an option for symptoms of anasarca and fluid overload. Pericardiectomy can help in constrictive pericarditis. Treatment with immunosuppressive medications should be the approach in inflammatory bowel disease, SLE, RA, and other inflammatory conditions. Treat parasitic infections if they are the cause of PLE. Surgical resection can be a consideration in Menetrier disease[9] and refractory inflammatory bowel disease. Octreotide has been considered beneficial in primary intestinal lymphangiectasia and Menetrier disease by decreasing lymphatic pressure and reducing intestinal protein loss. Budesonide and corticosteroids may be helpful in eosinophilic gastroenteritis and some cases of PLE due to Fontan procedure.[10](B3)

Routine monitoring is advisable after initiation of treatment in the form of checking micronutrients and vitamin deficiencies, serum protein levels, and A1AT clearance.

Differential Diagnosis

Any condition that leads to low serum proteins should be in the differential diagnosis of PLE. Differential diagnosis also varies depending on the primary underlying etiology causing PLE. Some common conditions are chronic liver diseases which lead to low serum albumin due to decreased synthesis, renal conditions causing significant proteinuria (like nephrotic syndrome), severe protein-calorie malnutrition, malabsorption syndromes, heart failure, cutaneous burns.[11]

Prognosis

Prognosis is variable and dependant on the underlying cause of protein-losing enteropathy. If there is a successful treatment of the underlying cause, then it can lead to complete resolution of PLE.

Complications

Complications depend mostly on the underlying disease causing protein-losing enteropathy. Patients with Inflammatory bowel disease can develop colon cancer, anemia, primary sclerosing cholangitis, and many other complications. PLE due to ulcerative diseases can have a perforation of ulcer and peritonitis. Patients with Clostridium difficile colitis can develop toxic megacolon. Patients can develop a deficiency of micronutrients and vitamins (particularly fat-soluble vitamins). Due to the loss of immunoglobulins and lymphocytes, patients get prone to recurrent and opportunistic infections.