17. Hepatic Encephalopathy, Sarcopenia, and Frailty
KeywordsHepatic encephalopathyChronic liver diseaseMuscleSarcopeniaFrailtyAmmoniaTherapeutics
Hepatic encephalopathy (HE), a complex neuropsychiatric syndrome, and sarcopenia (muscle mass loss) are serious complications observed in as many as 80% of patients with end-stage liver disease (i.e., cirrhosis). The impact of these complications is significant as they affect survival and quality of life and lead to poor outcome following liver transplantation. Chronic liver disease leads to hyperammonemia, which is a major factor in the development of HE. Recent data suggest ammonia acts as a metabolic stressor and impairs other organs (in addition to the brain) including muscle. During the setting of chronic liver disease, the muscle plays a vital compensatory role in detoxifying ammonia as it contains an ammonia-removing enzyme, namely, glutamine synthetase. Accordingly, sarcopenia, which is part of the frailty syndrome, may be an important driver of HE development. The goal of this chapter is to provide an updated description of the interplay between HE, sarcopenia, and physical and cognitive frailty. Firstly, HE will be presented in terms of definition, pathogenesis, and therapeutics. Secondly, sarcopenia and frailty will be tackled with regard to definitions and relevance for cirrhosis and HE. Then, evidence-based recommendations for sarcopenia and frailty in the context of HE will be elaborated. Suggestions to inform future research will conclude the chapter.
Assessment tools for HE (Weissenborn et al. 2019)
Psychometric Hepatic Encephalopathy Score (PHES)
Number Connection Test (NCT) A and B
Digit symbol test
Serial dotting test
Line drawing test
Five paper-pencil tests evaluating cognitive/psychomotor processing speed and visuomotor coordination
Psychometric measures for the assessment of early HE
Assesses visuoconstructive abilities
Assesses visuomotor coordination and speed
Assesses speed and accuracy
Animal Naming Test (ANT)
Number of animals listed in 60 s
Continuous Reaction Time (CRT)
Relies on repeated registration of the motor reaction time to auditory stimuli
Inhibitory control test
Computerized test of response inhibition and working memory
Evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name
Montreal Cognitive Assessment (MoCA)
Paper-pencil test measuring mild cognitive impairment
Computerized test that measures speed and accuracy to perform a digit recognition memory task of increasing complexity
Can detect changes in cortical cerebral activity across the spectrum of HE
Critical flicker frequency
Frequency at which a flickering light appears to be flickering to the observer
Repeatable Battery for the Assessment of Neuropsychological Status
Assesses cognition across specific domains including immediate memory, visuospatial/constructional, language, attention, and delayed memory
The neuropathology of HE in chronic liver disease reveals primarily morphological changes in astrocytes, including Alzheimer type II astrocytosis  and cytotoxic cell swelling, which, consequently, lead to brain edema . This common feature is observed in cirrhotic patients suffering from HE , an observation that was also confirmed in cirrhotic rats with minimal HE . However, the pathophysiological consequences of brain edema (astrocyte swelling) in HE remain elusive. The pathological basis of HE is multifactorial, and ammonia is believed to play a pivotal role [14, 15]. Furthermore, since astrocytes are the only cells in the brain capable of clearing ammonia via the enzyme glutamine synthetase, it has been postulated that the accumulation of glutamine in astrocytes subsequent to ammonia detoxification results in increased osmotic forces and swelling. There is ample evidence suggesting that lactate may also be implicated in the pathogenesis of HE . Other factors implicated in the pathophysiology of HE include inflammation and oxidative stress. In fact, hyperammonemia and systemic oxidative stress act synergistically to induce cognitive impairment in HE .
Currently, treatment for HE is based on strategies aimed at reducing the concentration of circulating blood ammonia, by lowering its production, increasing its removal, or combining the two strategies. One obvious approach is to target the source of ammonia production, with the gut being a primary candidate. Reducing ammonia production in the gut will minimize its absorption into the systemic circulation and hence the brain from high ammonia exposure. However, because interorgan ammonia metabolism is altered during the onset of liver disease , additional organs, such as skeletal muscle, become important players in the metabolism of ammonia. Skeletal muscle, which contains the ammonia-removing enzyme glutamine synthetase, makes up approximately 40% of total body mass. Therefore, increasing the capacity of skeletal muscle to remove ammonia is a potential approach for the treatment of HE. The following paragraphs depict different therapeutic approaches for the treatment of HE.
Nonabsorbable disaccharides, particularly lactulose, have been first-line therapy for patients with chronic liver disease and HE for past decades . Lactulose acts as both osmotic laxative, prebiotic, and gut-acidifying agent. Lactulose is a synthetic disaccharide composed of the monosaccharides fructose and galactose. It remains undigested until it reaches the colon, where it is metabolized by colonic bacteria into acetic acid and lactic acid. These carboxylic acids reduce the intraluminal pH, and the resulting acidification of the colon suppresses the growth of the intestinal urease bacteria (ammoniagenic bacteria), leaving the acid-resistant, nonammoniagenic bacteria. Lactulose also decreases the absorption of ammonia through a cathartic effect, clearing the gut of ammonia before it is systemically absorbed, resulting in increased fecal nitrogen excretion. Lactulose has also been shown to impede the uptake of glutamine by the intestinal wall, thus preventing glutamine from being metabolized into ammonia . Although lactulose is safe and beneficial in the treatment of HE, compliance is often underachieved, given the need to titrate the dose in order to reach two or three semisoft stools per day. In addition, lactulose treatment has been shown to cause abdominal cramping, bloating, nausea, vomiting, flatulence, and abdominal distension. Furthermore, lactulose treatment affects intestinal absorption, and this may amplify the nutritional deficits in patients with chronic liver disease, leading to a poorer outcome after liver transplantation .
Orally administered antimicrobial agents targeting the gut have long been utilized with the primary aim of inhibiting urease-containing bacteria in the colon, thereby decreasing ammonia production and preventing absorption through the gastrointestinal tract. Antibiotics such as neomycin, metronidazole, and vancomycin have all been demonstrated to lower blood ammonia in patients with chronic liver disease . Nonetheless, because of the systemic absorption of these antimicrobial agents, serious adverse effects have been reported, which have limited their widespread use. Rifaximin is an antibiotic, with a broad spectrum of antibacterial activity, that has proven to be efficient in lowering blood ammonia levels in patients with HE by reducing the growth of ammonia-producing bacteria . Rifaximin treatment has resulted in fewer adverse effects and a faster and greater decrease in blood ammonia in comparison with neomycin . Rifaximin was the first ever therapy that was approved by the FDA for the treatment of HE. The conclusive study demonstrated rifaximin reduces the recurrence of HE . In addition, an exploratory data analysis of a phase II/III clinical trials concluded that rifaximin may improve liver and neuropsychological functions through the regulation of the gut microbial consortia in patients with HE .
Probiotic therapy involves monocultures or mixed cultures of live microorganisms, administered orally to improve the properties of the intestinal microflora. Studies have shown that probiotics are beneficial in the treatment of HE, possibly by modulating intestinal bacteria via the colonization of non-urease bacteria and by lowering blood ammonia concentrations . Moreover, probiotic supplementation in patients with HE has been shown to be very well tolerated, and the compliance rates were excellent . Compared with placebo or no intervention, probiotics improve recovery and may lead to improvements in the development of OHE, quality of life, and plasma ammonia concentrations, but little effect on mortality has been shown . Furthermore, evidence regarding probiotics and HE is considered to be of low quality . Therefore, further studies evaluating the potential role of probiotics in HE are needed.
Benzoate and phenylacetate/phenylbutyrate
Sodium benzoate and sodium phenylacetate/phenylbutyrate (prodrug of phenylacetate) are metabolically coupled to glycine and glutamine and thus increase the excretion of these two ammoniagenic amino acids . Specifically, sodium benzoate conjugates with the amino acid glycine to form hippuric acid, which is excreted by the kidneys. Glycine is metabolized through the glycine cleavage system, an enzyme complex that consists of four proteins and generates ammonia as an end product. Sodium benzoate is administered to prevent glycine metabolism and thereby prevent the production of ammonia. In the context of chronic liver disease, sodium benzoate reduces blood ammonia levels and attenuates the symptoms of HE as effectively as lactulose . Sodium phenylbutyrate could be effective in reducing ammonia levels and might be effective in improving neurological status and intensive care unit discharge survival . However, the sodium load associated with these treatments, which could lead to fluid retention and exacerbates ascites, has limited its use in patients with chronic liver disease. Glycerol phenylbutyrate improves the organoleptic properties of sodium phenylbutyrate and is not associated with sodium load. A multicenter, randomized, double-blind, placebo-controlled phase II trial revealed that glycerol phenylacetate decreased the likelihood of hospitalization of cirrhotic patients with recurrent HE when compared with placebo, by lowering ammonia levels . Overall, glycerol phenylbutyrate was considered to be safe among cirrhotic patients with recurrent HE; however, larger randomized trials are needed to further establish the role of glycerol phenylbutyrate in patients with HE.
LOLA is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its efficacy for the treatment of HE is a subject of debate. A systematic review and meta-analysis of randomized controlled trials revealed that LOLA appears to improve mental state and lower ammonia in patients with HE or minimal HE . Furthermore, results of randomized controlled trials and meta-analyses provide support for the use of LOLA in the treatment of HE. Nevertheless, future trials should focus on the use of LOLA for prophylaxis .
Ornithine phenylacetate (OP)
The hypothesis behind the combination of ornithine and phenylacetate is that ornithine stimulates glutamine synthetase, generating glutamine and removing ammonia. Preventing glutamine from being metabolized by glutaminase and thereby regenerating ammonia, glutamine combines with phenylacetate to form phenylacetylglutamine which is eliminated in the urine . A phase IIa study including 47 patients with acute liver injury or failure found OP to be safe and well tolerated . Presently, there is no clinical evidence of a significant HE-ameliorating effect despite the fact that OP may have a potential for dose-dependent ammonia lowering [37, 38].
Branched-chain amino acids
Cirrhotic patients have an increased whole-body clearance of branched-chain amino acids (BCAA) compared to healthy subjects . This may reflect an increased metabolic demand of BCAA in skeletal muscle where the BCAA are primarily metabolized . This is in contrast to the majority of amino acids, which are metabolized mainly in the liver. BCAA enhance ammonia detoxification in skeletal muscle and thereby reduce plasma ammonia concentration. This leads to the assumption that external replenishment of BCAA further enhances the detoxification of ammonia in muscle. Treatment with BCAA has been shown to lower blood ammonia and improve the mental status of patients with cirrhosis . Moreover, a Cochrane meta-analysis showed that BCAA had beneficial effects on HE and there is evidence to support clinical benefits of BCAA .
L-Acetylcarnitine, a metabolite produced by the degradation of the essential amino acid lysine, serves as a carrier for short-chain fatty acids across the mitochondrial membrane. Treatment with L-acetylcarnitine (the acetylated form of L-carnitine, known to increase its bioavailability) significantly reduced serum ammonia levels and improved mental status as compared with placebo in cirrhotic patients with HE . However, a Cochrane systematic review analyzed a heterogeneous group of five trials at high risk of bias and with a high risk of random errors conducted by only one research team . The authors rated all evidence as of very low quality due to pitfalls and execution, inconsistency, and small sample sizes. The harms profile of L-acetylcarnitine is presently unclear. Accordingly, further randomized clinical trials to assess L-acetylcarnitine versus placebo are needed.
Acarbose, an approved treatment for diabetes, is an inhibitor of α-glucosidase that prevents the conversion of carbohydrates into monosaccharides. Furthermore, it has been demonstrated that acarbose can decrease colonic proteolytic flora and dietary nitrogenous substances. In a double-blind, crossover, randomized study, 107 cirrhotic patients with OHE and type 2 diabetes received acarbose treatment and demonstrated a significant reduction in serum ammonia levels and attenuation of HE . Acarbose is well tolerated and is not associated with serious adverse effects. Additional studies are required to further evaluate the role and mechanism of action of acarbose in the treatment of HE.