WHAT'S AT STEAK IN NUTRITION FOR HE?

Hepatic encephalopathy (HE) is a devastating complication of cirrhosis, posing a huge burden not only for patients but also for their caregivers and the healthcare system (1). Hyperammonemia is necessary for the development of HE. However, it is not sufficient. Systemic inflammation is likely a prerequisite and often potentiates the toxicity of circulating ammonia (2). Nevertheless, efforts to eliminate ammonia pharmacologically (using first line lactulose (3)) and support the body's means for ammonia metabolism form the standards of HE prophylaxis. The key strategy in support of one's ammonia metabolism is nutritional. In the setting of portal hypertension, the skeletal muscle takes up >50% of systemic ammonia and converts it to glutamine (4). This process is catabolic. Skeletal muscle's mechanism of ammonia metabolism consumes branched-chain amino acids. Unchecked, this process causes sarcopenia, resulting in a vicious cycle of hyperammonemia where the ammonia causes muscle loss and the muscle loss increases serum ammonia levels. Indeed, sarcopenia increases the risk of HE (5) while improvements in muscle mass reduce the risk of HE (6). Accordingly, for patients with cirrhosis and portal hypertension, a diet including 1 g dietary protein for each kilogram actual body weight is essential. Data regarding optimal method by which patients arrive at this total, however, are uncertain.

THE MEAT OF THE ISSUE

It must be acknowledged that ammonia levels rise after a high-protein meal. There persists, based on this observation, a myth that protein should be restricted in cirrhosis. Although protein restriction is unsafe and harmful, there is interest in studying diets that can increase protein consumption without even transient increases in ammonia levels. Specifically, many advocates suggest consuming plant-based protein sources than meat-based ones. Two small (N = 8 and 10) crossover studies suggested that vegetable protein results in better cognitive indices than animal protein diets (7,8). Another small trial compared 40 g of animal protein with neomycin and 80 g of vegetable protein with equivalent effects on cognition (9). These data, however, are inadequate to settle a debate between vegetable and animal protein.

ENTER THE BURGER KING

In this issue of Clinical and Translational Gastroenterology, Badal et al aimed to fill this gap with an elegant randomized trial (10). Thirty outpatients with cirrhosis were randomized 1:1:1 to eat a bland, condiment-free burger with 20 g protein from beef, vegan (soy/pea), or vegetarian (soy/egg/whey) sources. Serum ammonia only increased in the meat group (by 30%) and remained more elevated for 2 hours. Moreover, the vegan or vegetarian meals improved metabolites linked to ammoniagenesis and HE (decreased acylcarnitines, reduced branched-chain amino metabolism, and decreased lysophospholipids with the vegan meal). There was no difference between the vegan and vegetarian meals on ammonia levels and blood metabolites despite the presence of egg and whey in the vegetarian burger patty. No effects were observed on gut microbiota diversity. Dietary recalls from the prerandomization period were not different between the groups. However, ammonia levels were higher at baseline for those who received the beef burgers. Despite the limitations of this small, short-term study, the relative effects of vegetarian or vegan meal are appetizing—both for clinicians and researchers.

NEXT STEPS

Food is central to effective supportive care for cirrhosis generally and HE specifically. Yet there are so little data to guide clinicians. Patients deserve more studies like this. However, this trial is too small in scope to generalize widely: 30 patients, 3-hour observation, 3 specific burgers, only 1 meal. Furthermore, all subjects were men. Future studies should investigate longer term strategies in diverse subjects, effects of variable or consistent protein sources, and the clinical relevance of these changes on patients' cognitive function, quality of life, as well as the risk of developing overt HE. The present study generates enthusiasm for vegetarian/vegan protein, which may one day prove to be the best option. We are hopeful, therefore, that this excitement may compel others to conduct this type of research. Until then, unanswered is the question, “What should my patient with HE eat?”

CONFLICTS OF INTEREST

Guarantor of the article: Elliot B. Tapper, MD

Specific author contributions: C.L. and E.B.T.: drafting of the manuscript.

Financial support: None to report.

Potential competing interest: The authors disclose no potential financial or non-financial conflict of interests regarding this study.

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