Pediatric Protein-Losing Enteropathy Workup

Updated: Jul 25, 2017
  • Author: Simon S Rabinowitz, MD, PhD, FAAP; Chief Editor: Carmen Cuffari, MD  more...
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Workup

Approach Considerations

Patients with edema and documented hypoalbuminemia but without clinical or biochemical evidence of liver or renal disease should have a thorough evaluation for protein-losing enteropathy (PLE). In the past, PLE was often considered a diagnosis of exclusion; however, several approaches for determining abnormal protein loss in the GI tract are currently noted. The ideal test for PLE would detect a serum protein in the stool that is not secreted, digested, or reabsorbed in the GI tract. However, no ideal test is available.

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Laboratory Studies

Three established types of tests have been used to evaluate for PLE. The earliest tests involved the intravenous administration of a radiolabeled substrate followed by the determination of radioactivity in the feces. The second type of test directly measures endogenous proteins in the feces. A third approach is the use of nuclear scintigraphy, not only for diagnosis, but also to identify potential regional or localized areas of protein loss. A recent publication described the use of MRI as an alternative method to diagnose and localize this condition. [43]

Radiolabeled proteins

  • Use of radiolabeled proteins to measure albumin turnover dates back to 1950 with Kinsell. [44]  
  • In the late 1950s, Swartz, and later Citrin, administered iodine 131–albumin to patients in an attempt to measure albumin turnover. In a patient with hypertrophic gastritis and PLE, Citrin reported that the 131 I-albumin lost in the stomach was degraded and the free 131 I was then absorbed and excreted in the urine, making the measurement of 131 I in the stools unreliable.
  • In 1957, Gordon reported the use of polyvinylpyrrolidone iodine I 125 ( 131 I-PVP) as a marker for protein metabolism. [45]  PVP is a macromolecule that is not digested by intestinal enzymes and is poorly absorbed when taken by mouth. In patients with PLE, intravenously administered 131 I-PVP results in detectable levels of radioactivity in the stool. The problem with this substance is that it is not a normal metabolite, has a wide range of molecular weights, and can be partially absorbed and secreted. More importantly, the 131 I is easily released from the carrier, which then can be absorbed and excreted in the urine. This is problematic if urine contamination of the stool occurs as in pediatric patients.
  • In 1961, the next radioactive substrate used was chromium 51–albumin. This method had several advantages. The 51 Cr bound tightly to albumin and was poorly absorbed from the GI tract. Thus, little or no radioactivity was detectable in the urine.
  • In practice, approaches using radiolabeled compounds are now rarely used because 48-72 hours of stool collection is required in the hospital, care must be taken to avoid contamination of stool collection with urine, and the tests involve radiation exposure.
  • Endogenous Proteins
    • In 1977, Crossley and Elliot demonstrated that the stools of patients with PLE as determined by51 Cr-albumin excretion also had high levels of alpha-1-antitrypsin, (A1-AT).
    • A1-AT is an endogenous protein not present in the diet; the molecular weight is similar to albumin. It is normally not actively secreted, absorbed, or digested.
    • A1-AT is stable in feces at 37°C, allowing collection over several days.
    • Because A1-AT is not excreted in urine, urine contamination of the stool sample does not alter the spot determination of fecal A1-AT.
    • Stool samples are simply lyophilized, and A1-AT is extracted by solubilization.
    • Fecal A1-AT can then be detected by immunoassay. Measurement of fecal A1-AT can be used as a spot determination or the clearance of A1-AT can be more formally calculated using the following formula:A1-AT clearance = [(fecal A1-AT concentration) (stool volume/24 h]/(A1-AT serum concentration).
    • Many studies have demonstrated the efficacy of using fecal A1-AT levels and A1-AT clearance for diagnosis and follow-up care in patients with PLE.
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Imaging Studies

Several radiopharmaceuticals tagged to proteins have been used to examine protein-losing enteropathy, including indium-111 (In-111)–transferrin, technetium-99m (Tc-99m)–human serum albumin, and 99mTc-dextran. The latter compound is reported to be superior for numerous technical reasons. Technetium Tc-99m MDP scintigraphy, an initial method of choice to detect skeletal metastases in cancer patients, was also reported to detect protein-losing enteropathy incidentally in a patient suspected of having bone metastases. [46]  Both Tc-99m and In-111 have been shown to have a high sensitivity for diagnosis and localization of protein-losing enteropathy; however, current evidence shows that low specificity may limit the usefulness of this imaging modality. Though this technique has been reported to be useful in the diagnosis of protein-losing enteropathy, no studies have compared the sensitivity of scintigraphy with fecal A1-AT determination. However, it may be extremely useful in identifying sites of involvement in protein-losing enteropathy (ie, stomach vs small intestine or even regional differences in the small bowel).

MRI has been used to identify lymphatic abnormalities yielding protein-losing enteropathy in both the intestine and mesentery, including dilated thoracic duct and mesenteric lymphatic as well as prominent subcutaneous lymphatics in the extremity. [43]  Specialized MRI lymphatic imaging, including dynamic contrast-enhanced magnetic resonance lymphangiography, intranodal lymphangiography, and liver lymphangiography, have been used to localize abnormal lymphatic leakage from the liver and duodenum. [47]

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Procedures

In addition to the investigations listed above to document and localize the PLE, a thorough orderly evaluation is required in the patient with PLE to determine the underlying etiology of the protein loss. This usually begins with cultures and other tests for the infectious causes listed above, serologic evaluation for the immune conditions listed above, and radiographic studies (nuclear medicine, contrast studies, CT scans, MRI) to localize the area of involvement and identify characteristic patterns.

Often, endoscopy is also performed to assess for specific mucosal features such as the hypertrophic gastric folds of Menetrier disease, the pseudomembranes of C difficile colitis, the scalloping of the duodenum in sprue, and the stigmata of inflammatory bowel disease. Nonerosive erythematous gastric mucosa is the most frequent endoscopic finding in PLE associated with SLE. [31]  At the time of endoscopy, biopsies are obtained to confirm the histological findings listed below.

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Histologic Findings

Intestinal and more rarely gastric, colonic, and esophageal biopsies are at times required to definitively diagnose the underlying diseases that are the cause of the protein-losing enteropathy. Examples include Crohn disease, ulcerative colitis, celiac disease, graft versus host disease, Whipple disease, lymphoma, Hirschsprung disease, pseudomembranous colitis, eosinophilic gastroenteritis, allergic enteropathy, and some infectious diseases.

Lymphangiectasia, dilated lacteals in the mucosa, is also a histologic diagnosis.

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