I read with interest the paper by Proot et al1 comparing two low-protein diets in the treatment of dogs with congenital portosystemic shunts (PSS). They reported a significant reduction in hepatic encephalopathy (HE) score in both the soy protein and chicken-based diets over the study period, and a significant reduction in fasting ammonia when the soy-based diet was fed but not when the chicken-based control diet was fed. They interpret the improvement in HE scores in both diets as being because of the low protein concentration and note “this underscores the importance of a low-protein diet, as expected.” Furthermore, they suggest that the explanation for the lower serum fasting ammonia in dogs on the soy-based test diet is most likely “that the higher digestibility of its protein source caused a higher absorption of amino acids and other derivatives in the small intestines, so that less nitrogen could reach the colon where they could be ammoniagenic.”
While the results of this study are significant and interesting, the conclusions are misleading and outdated in their focus on protein restriction and reduced colonic ammoniagenesis as the main beneficial effects of a hepatic diet. This is a shame because the authors miss an opportunity to stimulate wider debate and further experiments investigating the “ideal” diet to use in medical management of congenital PSS. There is no good experimental evidence that it is protein restriction which is important in dogs in medical management of congenital PSS, but the literature in dogs and humans remains littered with anecdotal insistence that protein restriction is the key to treatment of these patients, which hinders research. In fact, very much the opposite appears to be the case: studies in dogs with experimentally produced PSS anastomoses showed that they had the same (not lower) apparent dietary protein requirements as normal dogs and that dogs with an experimental PSS fed a very low protein diet (11% crude protein) showed a significant decrease in serum albumin and total protein concentrations, suggesting negative nitrogen balance.2 Furthermore, studies more than 30 years ago in germ-free dogs with experimental PSS suggested that colonic bacteria had a very limited role in producing ammonia.3 In my clinical experience, a number of dogs with medically managed PSS develop a clinically relevant hypoproteinemia when fed on just a manufactured protein-restricted liver diet. Consequently, I now always supplement these dogs' diets with extra high-quality protein (usually in the form of dairy protein) and have not used an unsupplemented protein-restricted diet in a dog with congenital PSS for the past 10 years. Anecdotally, I have not seen any increase in HE in these dogs in this time and their clinical outcomes have been excellent, but this needs testing with a properly designed trial of “normal” protein concentration diets in dogs with PSS. In Proot's paper, although neither total protein nor albumin changed significantly on either diet, Table 2 does show a disturbingly low serum albumin concentration in at least 1 dog on the control diet as the lower end of the range decreases from 16 g/L at the start of the study to 9 g/L on the control diet, and it is unknown what would happen to total protein and albumin concentrations if these dogs were fed the diets for more than 4 weeks.
Do the authors really consider that dogs fed a limited protein diet with a very digestible protein source (chicken) have a significant amount of undigested protein remaining in the colon to be converted by colonic bacteria to ammonia? Recent studies in animals and humans suggest that the main source of ammonia in the portal blood is in fact glutaminase activity by small intestinal enterocytes which use glutamine as their main energy source.4 This activity increases postprandially when enterocyte metabolic activity increases to allow digestion and absorption of food. The small intestine is a very extensive and metabolically active organ and this glutaminase activity is enough in itself to explain the postprandial HE in dogs with congenital PSS. The focus should shift to investigations of whether the test diet stimulates less small intestinal metabolic activity or less hepatic ammoniagenesis than the control diet. What would happen if a soy-based diet with normal protein concentrations were used, instead of a restricted protein diet? Is it the protein type or concentration that is important or some other aspect of the diet?
This was a lovely study but a big opportunity missed! I have been asking for the pet food companies to catch up with the science and produce a hepatic diet that is not protein restricted for many years now. The next study should use a soy-based diet with normal protein levels. To quote a review article from the Lancet4 (which also questions the evidence for the efficacy of lactulose in HE—but that is for another day): “We have entered an exciting phase in research into hepatic encephalopathy, with novel therapies evolving from the discovery of new targets. Lactulose and low-protein diets should no longer be part of standard care, but this does not necessarily mean that these therapies do not work in selected patients. Further trials of lactulose, protein restriction, and newer agents should be placebo-controlled … Current guidelines will need to be revised with strict attention being paid to treating the precipitating factors, with correction of dehydration, electrolyte and acid-base imbalance, constipation, and infection.”