Protein losing enteropathy: comprehensive review of the mechanistic association with clinical and subclinical disease states

Abstract

Protein losing enteropathy (PLE) has been associated with more than 60 different conditions, including nearly all gastrointestinal diseases (Crohn's disease, celiac, Whipple's, intestinal infections, and so on) and a large number of non-gut conditions (cardiac and liver disease, lupus, sarcoidosis, and so on). This review presents the first attempt to quantitatively understand the magnitude of the PLE in relation to the associated pathology for three different disease categories: 1) increased lymphatic pressure (e.g., lymphangiectasis); 2) diseases with mucosal erosions (e.g., Crohn's disease); and 3) diseases without mucosal erosions (e.g., celiac disease). The PLE with lymphangiectasis results from rupture of the mucosal lymphatics, with retrograde drainage of systemic lymph into the intestinal lumen with the resultant loss of CD4 T cells, which is diagnostic. Mucosal erosion PLE results from macroscopic breakdown of the mucosal barrier, with the epithelial capillaries becoming the rate-limiting factor in albumin loss. The equation derived to describe the relationship between the reduction in serum albumin (C_P) and PLE indicates that gastrointestinal albumin clearance must increase by at least 17 times normal to reduce the C_P by half. The strengths and limitations of the two quantitative measures of PLE (⁵¹Cr-albumin or α₁-antitrypsin [αAT] clearance) are reviewed. αAT provides a simple quantitative diagnostic test that is probably underused clinically. The strong, unexplained correlation between minor decreases in C_P and subsequent mortality in seemingly healthy individuals raises the question of whether subclinical PLE could account for the decreased C_P and, if so, could the mechanism responsible for PLE play a role in the increased mortality? A large-scale study correlating αAT clearance with serum albumin concentrations will be required in order to determine the role of PLE in the regulation of the serum albumin concentration of seemingly healthy subjects.

Keywords: Crohn’s; albumin; antitrypsin; celiac; enteropathy; lymphangiectasis.

Figure 1

Schematic diagram of normal intestinal mucosa. Notes: The epithelial cells present a diffusion barrier between the interstitial space and the lumen. The albumin that slowly leaks from the plasma (concentration=C_P) to the interstitial space (C_Tis) is removed by the lymphatics. The luminal albumin concentration (C_Lumen) is zero.

Figure 2

The predicted relationship between the increase in GI albumin clearance and the resulting steady-state serum albumin (serum albumin/normal albumin) in a PLE subject with normal renal and hepatic functions. Abbreviations: GI, gastrointestinal; PLE, protein losing enteropathy.

Figure 3

Schematic diagram illustrating the pathophysiology for the PLE produced by increased lymphatic pressure resulting from increased venous pressure (P_Vein). Note: The lymphatic ruptures into the intestinal lumen, allowing decompression and retrograde drainage of the systemic lymph. Abbreviation: PLE, protein losing enteropathy.

Figure 4

Fecal α-antitrypsin clearance in various disease states. Notes: The “normal” clearance corresponds to the control data for the Crohn’s disease study (mean=8.3 mL/day, range of 1.5–19.2 mL/day). In patients with heart failure, the clearance is normal except for one patient. In contrast, most subjects with Crohn’s or celiac disease have a statistically significant increase in clearance.

Figure 5

Schematic diagram of the PLE occurring in diseases with mucosal erosions. Note: Because of the large breaks in the epithelial permeability barrier, the capillaries become the rate-limiting step in the leak of serum albumin and the interstitial albumin (C_Tis) locally equilibrates with the lumen (C_Tiss=C_Lumen=0). Abbreviation: PLE, protein losing enteropathy.

Figure 6

The lactulose/mannitol permeability ratio in Crohn’s and celiac diseases.

Figure 7

Schematic diagram of the PLE occurring in diseases without mucosal erosions. Notes: It is assumed that the increased permeability results from a defect in the epithelial tight junctions. The epithelium is the rate-limiting step in the albumin leak and the interstitial albumin (C_Tis) is greater than that in the lumen (C_Lumen=0). Abbreviation: PLE, protein losing enteropathy.