Protein-losing enteropathy (PLE) is not an actual diagnosis, but a descriptive term used to encompass small intestinal disease (dogs > cats) severe enough for protein leakage into the gut lumen to exceed production from the liver. Associated consequences (hypovolaemia, third-spacing, peripheral oedema, hypercoagulable state through concurrent loss of antithrombin) and clinical signs (chronic weight loss, muscle wastage, small intestinal diarrhoea, vomiting, extended abdomen [ascites], pleural effusions, signs associated with thrombus formation) ensue. Causes of PLE are listed in the table below. Dog breeds predisposed to PLE include the Basenji, Yorkshire Terrier, Lundehund, Rottweiler, SCWT, and Shar Pei. Besides hypoalbuminaemia, hypoglobulinaemia is common (exceptions: Basenji enteropathy, histoplasmosis, occasionally in alimentary lymphoma), as is hypocholesterolaemia, lymphopenia, hypocalcaemia, and hypomagnesaemia. Often extensive investigations (laboratory assessment, diagnostic imaging) are necessary to rule out other causes of hypoalbuminaemia (protein-losing nephropathy, hepatic failure) or extra-gastrointestinal (GI) causes (e.g., exocrine pancreatic insufficiency, renal/endocrine disease [i.e., hypoadrenocorticism]). Serum cobalamin should be assessed to ascertain the presence of malabsorption, as hypocobalaminaemia has a prognostic and therapeutic consequence. Specialised tests for intestinal permeability and absorption (“sugar tests,” ⁵¹Cr-EDTA excretion) or advanced imaging to localise protein loss sites (⁵¹Cr or ⁶⁷Cu labelled albumin/ceruloplasmin scintigraphy) are not often performed routinely.

Intestinal biopsies are necessary to characterise the underlying pathology further and to rule out or diagnose intestinal neoplasia. In severe IBD or alimentary lymphoma, 3 basic mechanisms contribute to protein loss: lymphatic obstruction leading to lymphangiectasia and lacteal rupture, increased mucosal permeability due to mucosal infiltrations, and mechanical causes (ulcers, erosions, congestion). Lymphatic leakage leads to the formation of lipogranulomas in the intestinal wall or mesentery, which in turn contribute to the obstructive process. The latter are difficult to assess on endoscopic pinch biopsies, which is why some dogs with severe PLE can have minimal mucosal inflammation. Poor prognostic indicators in inflammatory PLE are a high canine inflammatory bowel disease (CIBDAI) or chronic enteropathy clinical activity index (CCECAI), and hypocobalaminaemia. Prognostic value of third-spacing or thromboembolic events is unclear. Treatment of PLE is generally aimed at the underlying cause (e.g., chemotherapy for lymphoma). For PLE due to IBD, traditionally an aggressive “step-down” approach is used, combining hypoallergenic or ultra-low-fat diet, antimicrobials, cobalamin, clopidogrel, steroids, and early administration of second-line immunosuppressants (SLI) like cyclosporine or chlorambucil. We have recently challenged this by a retrospective analysis of dogs with inflammatory PLE, showing that when using a “step-up” approach to immunosuppression, only 1/3 of dogs needed a SLI, while treatment requirements or outcome could not be predicted by routine clinicopathological data. It is difficult to translate these findings to the population of dogs with PLE presenting as emergency cases due to sudden deterioration or complications.

Interestingly, there might be a condition with significant protein loss via the intestinal epithelium that does not conform to traditional definitions of PLE, but combines some of its features with acute haemorrhagic diarrhoea syndrome (AHDS). AHDS (previously termed haemorrhagic gastroenteritis; HGE) has originally been described to be typical for small breed dogs (i.e., Yorkshire Terrier, Maltese, Pekingese), presenting with acute onset of haemorrhagic small intestinal diarrhoea (see figure below). The most consistent laboratory abnormality is haemoconcentration due to dehydration. Evidence for the cause of AHDS is conflicting, with possible associations with Clostridia sp. infections, but antimicrobial treatment is not indicated. Based on this, hypoalbuminaemia can be a potential - but not predominant - feature of AHDS (due to blood loss). However, we and others are observing an increasing number of dogs with no history of chronic GI disease, presenting with AHDS-like clinical signs that lead to rapid and drastic loss of serum proteins. The speaker has termed this condition “acute protein-losing syndrome” (APLS) for the purpose of this talk (see figure below). In comparison to dogs with “classic” AHDS, dogs with APLS do not respond favourably or quickly to symptomatic and supportive treatment. There is continuation of severe diarrhoea (often with significant GI ileus), hypovolaemia and hypotension, prompting empirical additional treatment.

Figure 1 Description of typical features of acute haemorrhagic diarrhoea syndrome (AHDS) and chronic protein-losing enteropathy (PLE), in comparison to “mixed” features of APLS.

As it can be difficult to differentiate AHDS from APLS initially, the ideal time point for more aggressive treatment is unclear. Furthermore, no consensus exists on what type of treatment would be appropriate. Often, antimicrobials (e.g., metronidazole) and immunosuppression (e.g., steroids) are administered, and measures for general support (colloids, albumin, plasma, pressors) as well as nutrition (enteral/tube feeding, partial parenteral nutrition) intensified. It is unclear if and at what stage these patients would benefit from GI biopsies. No infectious agent has been identified as a causative agent as far as the speaker is aware, and histology of GI biopsies is not consistently performed (speaker has seen one case with eosinophilic duodenitis/ileitis and marked ulcerative colitis with suppurative exudate, involving clusters of invasive Enterococci on fluorescent in situ hybridisation [FISH]). Routine assessment of biopsies (including FISH, immunohistochemistry, electron microscopy) or an intensified search for infectious agents might be needed in the future to characterise this disease further (figure 2). Outcome of APLS seems to be variable, with some dogs needing prolonged treatment, some recovering without the need for long-term medication, and some being euthanized for intractable disease. The speaker would like to invite a discussion on how frequently these types of cases are seen in other centres, if different approaches and outcomes are observed and what speculations there might be on potential causes.

Figure 2 Description of typical treatments of acute haemorrhagic diarrhoea syndrome (AHDS) and chronic protein-losing enteropathy (PLE), and suggestions for further workup and treatment of APLS.