Advertisement
Mayo Clinic Proceedings Home

Refining the Ammonia Hypothesis

A Physiology-Driven Approach to the Treatment of Hepatic Encephalopathy

      Abstract

      Hepatic encephalopathy (HE) is one of the most important complications of cirrhosis and portal hypertension. Although the etiology is incompletely understood, it has been linked to ammonia directly and indirectly. Our goal is to review for the clinician the mechanisms behind hyperammonemia and the pathogenesis of HE to explain the rationale for its therapy. We reviewed articles collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar between October 1, 1948, and December 8, 2014, and by a manual search of citations within retrieved articles. Search terms included hepatic encephalopathy, ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, ammonia and lactulose, rifaximin, zinc, and nutrition. Ammonia homeostatsis is a multiorgan process involving the liver, brain, kidneys, and muscle as well as the gastrointestinal tract. Indeed, hyperammonemia may be the first clue to poor functional reserves, malnutrition, and impending multiorgan dysfunction. Furthermore, the neuropathology of ammonia is critically linked to states of systemic inflammation and endotoxemia. Given the complex interplay among ammonia, inflammation, and other factors, ammonia levels have questionable utility in the staging of HE. The use of nonabsorbable disaccharides, antibiotics, and probiotics reduces gut ammoniagenesis and, in the case of antibiotics and probiotics, systemic inflammation. Nutritional support preserves urea cycle function and prevents wasting of skeletal muscle, a significant site of ammonia metabolism. Correction of hypokalemia, hypovolemia, and acidosis further assists in the reduction of ammonia production in the kidney. Finally, early and aggressive treatment of infection, avoidance of sedatives, and modification of portosystemic shunts are also helpful in reducing the neurocognitive effects of hyperammonemia. Refining the ammonia hypothesis to account for these other factors instructs a solid foundation for the effective treatment and prevention of hepatic encephalopathy.

      Abbreviations and Acronyms:

      BCAA (branched-chain amino acids), BID (twice daily), GABA-A (γ-aminobutyric acid type A), HE (hepatic encephalopathy), MELD (Model for End-Stage Liver Disease), NMDA (N-methyl-d-aspartate receptor), q2-q4 (every 2-4 hours), ROS (reactive oxygen species), TID (3 times daily), TIPS (transjugular intrahepatic portosystemic shunt)
      Article Highlights
      • Ammonia is an important cause of hepatic encephalopathy (HE), but its levels do not correlate with symptoms, partly because of the additive effect of inflammation.
      • The kidney, muscle, brain, and gut all play critical roles in ammonia metabolism.
      • Muscle wasting (sarcopenia) is associated with HE.
      • Renal injury, hypokalemia, and acidosis can each precipitate HE.
      • Standard treatment for HE includes reducing ammonia and bacterial translocation from the gut, nutritional supplementation, and sedative or narcotic avoidance.
      • Second-line treatments for HE include probiotics, zinc, closure of portosystemic shunts, and ammonia scavengers, such as glycerol phenylbutyrate.
      Hepatic encephalopathy (HE) is a morbid and costly complication of cirrhosis that presents as a spectrum from mild inattention to coma.
      • Blei A.T.
      • Córdoba J.
      Hepatic encephalopathy.
      • Volk M.L.
      • Tocco R.S.
      • Bazick J.
      • Rakoski M.O.
      • Lok A.S.
      Hospital readmissions among patients with decompensated cirrhosis.
      It is independently associated with increased mortality and reduced quality of life.
      • Arguedas M.R.
      • DeLawrence T.G.
      • McGuire B.M.
      Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.
      • Cordoba J.
      • Ventura-Cots M.
      • Simón-Talero M.
      • et al.
      Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
      The etiology of HE is multifactorial and incompletely understood, but it has often been tied to ammonia.
      In patients with inborn defects of ammonia metabolism, hyperammonemia is directly linked to a spectrum of neuropathology inclusive of neuropsychiatric disorders, severe brain injury, coma, and death.
      • Diaz G.A.
      • Krivitzky L.S.
      • Mokhtarani M.
      • et al.
      Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.
      • Enns G.M.
      • Berry S.A.
      • Berry G.T.
      • Rhead W.J.
      • Brusilow S.W.
      • Hamosh A.
      Survival after treatment with phenylacetate and benzoate for urea-cycle disorders.
      For these patients, interventions to prevent hyperammonemia have proved lifesaving.
      • Enns G.M.
      • Berry S.A.
      • Berry G.T.
      • Rhead W.J.
      • Brusilow S.W.
      • Hamosh A.
      Survival after treatment with phenylacetate and benzoate for urea-cycle disorders.
      Patients with cirrhosis can develop similar neurocognitive phenomena in the context of measurably elevated blood ammonia levels, and therapies that demonstrably lower ammonia levels improve symptoms. These correlations underpin the ammonia hypothesis.
      This concept of ammonia in the pathogenesis of HE, however, is incomplete. Indeed, the ammonia hypothesis presents a clinical conundrum. On the one hand, although frequently assessed, the clinical utility of ammonia levels is unclear because they rarely correlate with symptoms, let alone outcomes.
      • Fichet J.
      • Mercier E.
      • Genée O.
      • et al.
      Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy.
      • Ong J.P.
      • Aggarwal A.
      • Krieger D.
      • et al.
      Correlation between ammonia levels and the severity of hepatic encephalopathy.
      • Shawcross D.
      • Sharifi Y.
      • Canavan J.
      • et al.
      Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
      • Stahl J.
      Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance.
      On the other hand, the ammonia hypothesis is a widely accepted premise that leads to frequent assessment of ammonia concentrations in general clinical practice.
      • Phillip S.G.
      • Runyon B.A.
      Serum ammonia level for the evaluation of hepatic encephalopathy.
      By refining the ammonia hypothesis to include the substantial contributions of inflammation, endotoxin, and interorgan ammonia trafficking involving the brain, kidney, and muscle, the true importance of ammonia may be clarified and the clinical power of the hypothesis may increase significantly.
      Ammonia is traditionally considered a gut-derived nitrogenous toxin produced by bacterial metabolism of amino acids, primarily glutamine.
      • Blei A.T.
      • Córdoba J.
      Hepatic encephalopathy.
      • Albrecht J.
      • Norenberg M.D.
      Glutamine: a Trojan horse in ammonia neurotoxicity.
      • Welbourne T.
      • Weber M.
      • Bank N.
      The effect of glutamine administration on urinary ammonium excretion in normal subjects and patients with renal disease.
      Normally, ammonia from the gut is efficiently handled by the liver through 2 main metabolic avenues: the urea cycle (also known as the ornithine cycle) and glutamine synthetase (which converts glutamate to glutamine). Cirrhosis, with its associated hepatocellular dysfunction and portosystemic shunting, reduces the efficiency of these “detoxification” mechanisms. The result is greater systemic distribution of ammonia.
      • Stahl J.
      Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance.
      • Butterworth R.F.
      Complications of cirrhosis III. Hepatic encephalopathy.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
      • Tarantino G.
      • Citro V.
      • Esposito P.
      • et al.
      Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins.
      • Warren K.S.
      • Reboucas G.
      • Baptista A.G.
      Ammonia metabolism and hepatic coma in hepatosplenic schistosomiasis patients studied before and after portacaval shunt.
      However, although the liver is a critical player in the ammonia story, it is far from the only one.
      Herein, we highlight the clinical importance of the multiple organs responsible for ammonia metabolism and the modifying effect of inflammation. We show how a refined ammonia hypothesis informs a complete approach to the patient with HE. This review examines the pathogenesis of HE with a focus on existing and evolving therapeutic targets.

      Methods

      A search of the representative literature was performed. Articles were collected through a search of MEDLINE/PubMed, Cochrane Database of Systematic Reviews, and Google Scholar and by a manual search of citations within retrieved articles. Search dates spanned October 1, 1948, to December 8, 2014. Search terms included hepatic encephalopathy [MeSH], ammonia hypothesis, brain and ammonia, liver failure and ammonia, acute-on-chronic liver failure and ammonia, cirrhosis and ammonia, portosytemic shunt, transjugular intrahepatic portosystemic shunt, portocaval shunt, ammonia and lactulose, rifaximin, zinc, and nutrition.
      The terminology used to describe HE has changed over time. We use the term overt HE to describe an episode of acute disorientation or coma. Controlled or resolved refers to patients who have recovered from overt HE. Secondary prophylaxis describes the use of therapies to prevent another episode of HE. Covert HE includes patients who have abnormal psychometric testing without overt confusion.
      • Leise M.D.
      • Poterucha J.J.
      • Kamath P.S.
      • Kim W.R.
      Management of hepatic encephalopathy in the hospital.

      The Ammonia Hypothesis: The Brain

      Multiple organs contribute to absolute ammonia concentrations in the blood, but the symptoms of HE are driven mainly by ammonia’s effect on the brain. These effects are mediated by the three critical determinants of HE neuropathology: ammonia, glutamine, and inflammation (Figure 1).
      • Butterworth R.F.
      Complications of cirrhosis III. Hepatic encephalopathy.
      • Butterworth R.
      Effects of hyperammonaemia on brain function.
      • Norenberg M.D.
      Astroglial dysfunction in hepatic encephalopathy.
      Figure thumbnail gr1
      Figure 1The neuropathology of hepatic encephalopathy reflects the interplay of ammonia, glutamine, and inflammation. GABA-A = γ-aminobutyric acid type A; NMDA = N-methyl-d-aspartate receptor.
      Astrocytes are the principle brain cells affected in states of hyperammonemia.
      • Norenberg M.D.
      Astroglial dysfunction in hepatic encephalopathy.
      They are the primary carrier of glutamine synthetase in the brain, which converts ammonia and glutamate to glutamine.
      • Albrecht J.
      • Norenberg M.D.
      Glutamine: a Trojan horse in ammonia neurotoxicity.
      • Norenberg M.D.
      • Martinez-Hernandez A.
      Fine structural localization of glutamine synthetase in astrocytes of rat brain.
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      • Jayakumar A.R.
      • Rama Rao K.
      • Schousboe A.
      • Norenberg M.D.
      Glutamine-induced free radical production in cultured astrocytes.
      • Norenberg M.D.
      Astrocyte responses to CNS injury.
      • Yudkoff M.
      • Nissim I.
      • Pleasure D.
      Astrocyte metabolism of [15N] glutamine: implications for the glutamine-glutamate cycle.
      Glutamine plays a significant role in the neurotoxicity of ammonia in HE, contributing to the brain dysfunction associated with hyperammonemia in 2 ways. First, glutamine, generated in the cytosol, is, in turn, actively metabolized by astrocyte mitochondria via glutamine hydrolysis (by the mitochondrial protein phosphate-activated glutaminase), leading to the production of ammonia and the accumulation of reactive oxygen species (ROS). Under physiologic conditions, low intra-astrocyte concentrations of glutamine trigger very low levels of hydrolysis. However, with elevated systemic ammonia concentrations, increased glutamine leads to increased hydrolysis and ammonia production in mitochondria, generating increased ROS.
      • Yudkoff M.
      • Nissim I.
      • Pleasure D.
      Astrocyte metabolism of [15N] glutamine: implications for the glutamine-glutamate cycle.
      In turn, ROS leads to mitochondrial dysfunction and triggers inflammatory cascades.
      • Albrecht J.
      • Norenberg M.D.
      Glutamine: a Trojan horse in ammonia neurotoxicity.
      • Jayakumar A.R.
      • Rama Rao K.
      • Schousboe A.
      • Norenberg M.D.
      Glutamine-induced free radical production in cultured astrocytes.
      • Yudkoff M.
      • Nissim I.
      • Pleasure D.
      Astrocyte metabolism of [15N] glutamine: implications for the glutamine-glutamate cycle.
      Second, cytosolic glutamine is osmotically active. In the presence of hyperammonemia and elevated glutamine concentrations, astrocyte osmoregulatory mechanisms, including the degradation of cytosolic myo-inositol to maintain water balance, do not seem to suffice.
      • Cordoba J.
      • Gottstein J.
      • Blei A.T.
      Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema.
      Astrocyte swelling and, therefore, cerebral edema ensue, leading to reactive transcriptional changes that result in gliosis and cellular dysfunction.
      • Norenberg M.D.
      Astroglial dysfunction in hepatic encephalopathy.
      • Norenberg M.D.
      Astrocyte responses to CNS injury.
      Glutamine, therefore, causes cerebral dysfunction indirectly (through ROS generation) and directly (through astrocyte swelling).
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      • Norenberg M.D.
      Astrocyte responses to CNS injury.
      • Balata S.
      • Damink S.W.
      • Ferguson K.
      • et al.
      Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.
      In addition to astrocyte injury via glutamine, ammonia is directly neurotoxic. In brief, ammonia enhances inhibitory signaling by modifying neurotransmission through multiple mechanisms, including γ-aminobutyric acid, glutamate, and monoaminergic signal modulation.
      • Albrecht J.
      • Norenberg M.D.
      Glutamine: a Trojan horse in ammonia neurotoxicity.
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      • Balata S.
      • Damink S.W.
      • Ferguson K.
      • et al.
      Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.
      • Bachmann C.
      Mechanisms of hyperammonemia.
      • Lockwood A.H.
      • McDonald J.M.
      • Reiman R.E.
      • et al.
      The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia.
      There is strong evidence for many pathologic changes involving signaling molecules, although their precise impact remains unclear. These changes include stimulation of the peripheral-type benzodiazepine receptor, which leads to enhanced neurosteroid production and increased γ-aminobutyric acid type A expression; an increased synaptic glutamate concentration with resultant N-methyl-d-aspartate receptor stimulation; and increased serotonin signaling and metabolism.
      • Felipo V.
      • Butterworth R.F.
      Neurobiology of ammonia.
      The net effect of these alterations in neurotransmission is a combination of overstimulation and transcriptional deregulation, leading to neuronal degeneration and cell death.
      • Llansola M.
      • Rodrigo R.
      • Monfort P.
      • et al.
      NMDA receptors in hyperammonemia and hepatic encephalopathy.
      Progressive brain damage manifests in the long-term, which may persist after liver transplantation.
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      • Balata S.
      • Damink S.W.
      • Ferguson K.
      • et al.
      Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.
      • Garcia-Martinez R.
      • Rovira A.
      • Alonso J.
      • et al.
      Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume.
      The effect of inflammation and gut-derived endotoxemia on blood-brain barrier integrity and cerebral blood flow are of paramount importance in modulating the effects of systemic ammonia on cerebral dysfunction. Gut-derived endotoxemia and infection frequently occur in the setting of cirrhosis and have been independently associated with increased mortality and morbidity.
      • Shawcross D.
      • Sharifi Y.
      • Canavan J.
      • et al.
      Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      • Tranah T.H.
      • Vijay G.K.M.
      • Ryan J.M.
      • Shawcross D.L.
      Systemic inflammation and ammonia in hepatic encephalopathy.
      Inflammatory cytokines, primarily interleukins 1-β and 6 and tumor necrosis factor-α, and endotoxins potentiate ammonia neurotoxicity. This effect is exerted by enhancing diffusion of ammonia across the blood-brain barrier and by independently contributing to neuronal dysfunction.
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      • Bachmann C.
      Mechanisms of hyperammonemia.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      • Tranah T.H.
      • Vijay G.K.M.
      • Ryan J.M.
      • Shawcross D.L.
      Systemic inflammation and ammonia in hepatic encephalopathy.
      • Shawcross D.L.
      • Shabbir S.S.
      • Taylor N.J.
      • Hughes R.D.
      Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis.
      Acute liver failure is accompanied by particularly high levels of inflammatory cytokines, much higher relative to patients with cirrhosis. These cytokines disrupt the natural function of the blood-brain barrier and may explain why acute liver failure with hyperammonemia and HE is associated with a higher prevalence of clinically apparent cerebral edema and brain herniation compared with the HE that accompanies decompensated cirrhosis.
      • Shawcross D.
      • Sharifi Y.
      • Canavan J.
      • et al.
      Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      • Shawcross D.L.
      • Shabbir S.S.
      • Taylor N.J.
      • Hughes R.D.
      Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis.
      • Clemmesen J.O.
      • Larsen F.S.
      • Kondrup J.
      • Hansen B.A.
      • Ott P.
      Cerebral herniation in patients with acute E liver failure is correlated with arterial ammonia concentration.
      Targeted neurospecific therapies are not yet available for HE. However, glutamate uptake by mitochondria may prove a valid target.
      • Pichili V.
      • Rao K.
      • Jayakumar A.
      • Norenberg M.
      Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity.
      The focus then is aimed at reducing the passage of ammonia across the blood-brain barrier by reducing systemic inflammation, preventing and treating infections,
      • Polson J.
      • Lee W.M.
      AASLD position paper: the management of acute liver failure.
      scavenging of ROS during albumin dialysis,
      • Hassanein T.I.
      • Tofteng F.
      • Brown R.S.
      • et al.
      Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.
      and enhancing ammonia clearance and metabolism by other organs.
      • Bajaj J.
      • Heuman D.
      • Hylemon P.
      • et al.
      Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      • Rockey D.C.
      • Vierling J.M.
      • Mantry P.
      • et al.
      Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.
      To prevent the exacerbation of inhibitory signaling, benzodiazepines should be avoided if possible.
      • Assy N.
      • Rosser B.G.
      • Grahame G.R.
      • Minuk G.Y.
      Risk of sedation for upper GI endoscopy exacerbating subclinical hepatic encephalopathy in patients with cirrhosis.
      • Bajaj J.
      Review article: the modern management of hepatic encephalopathy.
      Last, systemic inflammation and endotoxemia, powerful determinants of ammonia-induced neuropathology, can be reduced by prevention and treatment of infection and modulation of the gut microbiome, as discussed later.

      The Pathogenesis of Hyperammonemia

      The Gut

      Without question, the gut is a critical component in the pathogenesis of HE. Dietary nitrogen (particularly glutamine) is converted to ammonia by gut enzymes and urease-containing bacteria. Glutamine is metabolized by intestinal epithelial glutaminase, converting more than one-third of its nitrogen to ammonia, which diffuses into the portal circulation.
      • Welbourne T.
      • Weber M.
      • Bank N.
      The effect of glutamine administration on urinary ammonium excretion in normal subjects and patients with renal disease.
      For unclear reasons, patients with cirrhosis and portosystemic shunting have highly active phosphate-activated glutaminase, which leads to greater ammonia production from glutamine.
      • Souba W.W.
      • Smith R.J.
      • Wilmore D.W.
      Glutamine metabolism by the intestinal tract.
      • Romero-Gómez M.
      • Ramos-Guerrero R.
      • Grande L.
      • et al.
      Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy.
      Ammonia is then freely absorbed across the gut epithelial membrane. The gut is also the principle source of bacterial endotoxin, which contributes to HE.
      • Shawcross D.
      • Sharifi Y.
      • Canavan J.
      • et al.
      Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      • Tranah T.H.
      • Vijay G.K.M.
      • Ryan J.M.
      • Shawcross D.L.
      Systemic inflammation and ammonia in hepatic encephalopathy.
      In the 1960s, McDermott and Sherlock evaluated total colectomy for refractory HE. This approach is effective as a proof of principle but is ill-advised.
      • McDermott Jr., W.V.
      • Victor M.
      • Point W.W.
      Exclusion of the colon in the treatment of hepatic encephalopathy.
      • Walker J.
      • Emlyn-Williams A.
      • Craigie A.
      • Rosenoer V.
      • Agnew J.
      • Sherlock S.
      Treatment of chronic portal-systemic encephalopathy by surgical exclusion of the colon.
      Inhibitors of intestinal glutaminase have been shown to reduce portal ammonia levels even after treatment with lactulose and antibiotics.
      • Díaz-Herrero M.M.
      • del Campo J.A.
      • Carbonero-Aguilar P.
      • et al.
      THDP17 decreases ammonia production through glutaminase Inhibition: a new drug for hepatic encephalopathy therapy.
      However, these have never been studied in humans. Accordingly, direct elimination of ammonia from the gut via purgatory treatments and reduction of proteolytic bacterial flora, as well as reduction of inflammation secondary to gut translocation of bacterial by-products, form the mainstay of HE therapy.
      Nonabsorbable synthetic disaccharides, such as lactulose and lactitol, were first introduced in 1966
      • Müller J.B.
      • Guggenheim P.
      • Haemmerli U.
      Treatment of chronic portal-systemic encephalopathy with lactulose.
      and constitute first-line therapy for HE.
      • Blei A.T.
      • Córdoba J.
      Hepatic encephalopathy.
      Their mechanism of action is likely multifactorial. First, they decrease colonic transit time, reducing the opportunity for absorption of gut-derived ammonia, ie, the purgatory effect. The purgatory effect was recently reinforced in a trial of high-dose polyethylene glycol and in a study of high-volume lactulose for the treatment of overt HE.
      • Rahimi R.S.
      • Singal A.G.
      • Cuthbert J.A.
      • Rockey D.C.
      Lactulose vs polyethylene glycol 3350–electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial.
      • Al-Osaimi A.
      • Quatrara B.
      • Melo I.
      • et al.
      In-patient hepatic encephalopathy protocol improves in-patient outcome measures: interim analysis.
      Second, nonabsorbable disaccharides lower colonic pH. This effect converts ammonia to a nonabsorbable ammonium ion (preventing the production of ammonia by gut urealysis and inhibiting ammonia absorption).
      • van Thiel D.H.
      • Fagiuoli S.
      • Wright H.I.
      • Chien M.C.
      • Gavaler J.S.
      Gastrointestinal transit in cirrhotic patients: effect of hepatic encephalopathy and its treatment.
      • Wolpert E.
      • Phillips S.
      • Summerskill W.
      Transport of urea and ammonia production in the human colon.
      • Vince A.
      • Dawson A.
      • Park N.
      • O'Grady F.
      Ammonia production by intestinal bacteria.
      Lactulose is the first-line therapy for patients with overt HE, where the focus is on rapid laxation. However, beyond the readily apparent efficacy of lactulose in the acute setting, it has been difficult to prove its value for secondary prophylaxis of overt HE in rigorous trials.
      • Als-Nielsen B.
      • Gluud L.L.
      • Gluud C.
      Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.
      • Brown H.
      • Trey C.
      • McDermott W.V.
      Lactulose treatment of hepatic encephalopathy in outpatients.
      • Conn H.
      • Leevy C.
      • Vlahcevic Z.
      • et al.
      Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double blind controlled trial.
      • Elkington S.
      • Floch M.
      • Conn H.
      Lactulose in the treatment of chronic portal-systemic encephalopathy: a double-blind clinical trial.
      • Heredia D.
      • Caballeria J.
      • Arroyo V.
      • Ravelli G.
      • Rodes J.
      Lactitol versus lactulose in the treatment of acute portal systemic encephalopathy (PSE): a controlled trial.
      • Heredia D.
      • Teres J.
      • Orteu N.
      • Rodes J.
      Lactitol vs. lactulose in the treatment of chronic recurrent portal-systemic encephalopathy.
      • Sharma B.C.
      • Sharma P.
      • Agrawal A.
      • Sarin S.K.
      Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.
      As noted by Leise and colleagues,
      • Leise M.D.
      • Poterucha J.J.
      • Kamath P.S.
      • Kim W.R.
      Management of hepatic encephalopathy in the hospital.
      these studies were old and included mixed study populations of patients with covert, chronic, and overt HE. The most recent trial from a leading group of HE investigators, however, did show significant benefit for lactulose in the secondary prevention of overt HE.
      • Sharma B.C.
      • Sharma P.
      • Agrawal A.
      • Sarin S.K.
      Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.
      Conventional therapy with lactulose involves administration 2 to 3 times daily, with the absolute amount titrated to 3 to 4 daily soft bowel movements. When patients are admitted to the hospital with overt encephalopathy, however, a rapid bowel purge by high-dose, high-frequency lactulose therapy may rapidly improve symptoms.
      • Al-Osaimi A.
      • Quatrara B.
      • Melo I.
      • et al.
      In-patient hepatic encephalopathy protocol improves in-patient outcome measures: interim analysis.
      Further study is required to determine the relative benefits of strictly osmotic laxatives compared with agents such as lactulose that also alter gut pH.
      Efficacy aside, the overarching problem with nonabsorbable disaccharides has always been patient tolerability vis-à-vis taste and displeasure with the inconvenience of its purgatory effects. Accordingly, there is substantial interest in therapies directed at the bacterial species responsible for ammonia generation and the reduction of proinflammatory mediators.
      Antibiotic drugs are a conventional and effective treatment. Many have been studied—neomycin, vancomycin, and metronidazole—but none are as proven as rifaximin.
      • Als-Nielsen B.
      • Gluud L.L.
      • Gluud C.
      Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      • Sharma B.C.
      • Sharma P.
      • Lunia M.K.
      • Srivastava S.
      • Goyal R.
      • Sarin S.
      A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
      • Tarao K.
      • Ikeda T.
      • Hayashi K.
      • et al.
      Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy.
      A rifamycin derivative with poor bioavailability (ie, nonabsorbable), rifaximin acts by disrupting bacterial ribonucleic acid polymerase function. These 2 traits lend rifaximin a truly broad spectrum of action without the toxicities of previously evaluated antimicrobial agents.
      • Eltawil K.M.
      • Laryea M.
      • Peltekian K.
      • Molinari M.
      Rifaximin vs conventional oral therapy for hepatic encephalopathy: a meta-analysis.
      The precise mechanism of rifaximin's efficacy for the treatment of HE is unclear. It is likely multimodal and involves the modulation (not the reduction) of the small intestinal and colonic microbiome with a shift toward less pathogenic bacterial composition and metabolism.
      • Bajaj J.S.
      • Heuman D.M.
      • Sanyal A.J.
      • et al.
      Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      • McGee R.G.
      • Bakens A.
      • Wiley K.
      • Riordan S.M.
      • Webster A.C.
      Probiotics for patients with hepatic encephalopathy.
      • Bauer T.M.
      • Schwacha H.
      • Steinbrückner B.
      • et al.
      Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia.
      The result is decreased ammonia production and systemic endotoxemia. Both effects likely play important roles.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      • Shawcross D.
      • Wright G.
      • Damink S.O.
      • Jalan R.
      Role of ammonia and inflammation in minimal hepatic encephalopathy.
      • Shukla S.
      • Shukla A.
      • Mehboob S.
      • Guha S.
      Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy.
      • Wright G.
      • Jalan R.
      Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora's box?.
      Although rifaximin monotherapy may be effective, it has not been rigorously studied.
      • Neff G.W.
      • Jones M.
      • Broda T.
      • et al.
      Durability of rifaximin response in hepatic encephalopathy.
      Rifaximin is best studied in conjunction with lactulose, and the combination seems superior to lactulose alone for the prevention of overt HE.
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      • Sharma B.C.
      • Sharma P.
      • Lunia M.K.
      • Srivastava S.
      • Goyal R.
      • Sarin S.
      A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
      Further study is needed to determine the role of rifaximin in the treatment of overt HE.
      Similarly, probiotics have been assessed in the treatment of HE, albeit with mixed results.
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      • McGee R.G.
      • Bakens A.
      • Wiley K.
      • Riordan S.M.
      • Webster A.C.
      Probiotics for patients with hepatic encephalopathy.
      • Shukla S.
      • Shukla A.
      • Mehboob S.
      • Guha S.
      Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy.
      • Dhiman R.K.
      • Rana B.
      • Agrawal S.
      • et al.
      Probiotic VSL# 3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.
      The beneficial effects observed have been obtained from small trials of adherent patients. One such trial examining the primary prevention of overt HE in patients taking a probiotic yogurt was remarkably successful.
      • Bajaj J.S.
      • Saeian K.
      • Christensen K.M.
      • et al.
      Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
      • McGee R.G.
      • Bakens A.
      • Wiley K.
      • Riordan S.M.
      • Webster A.C.
      Probiotics for patients with hepatic encephalopathy.
      A recent randomized trial showed that in patients taking neither lactulose nor rifaximin, a commercially available probiotic reduced the risk of HE hospitalization and the severity of liver disease.
      • Dhiman R.K.
      • Rana B.
      • Agrawal S.
      • et al.
      Probiotic VSL# 3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.
      The mechanism of probiotic effect is not entirely clear, although there is evidence that at least some strains of bacteria (eg, Lactobacillus GG) modulate the gut microbiome, with a shift away from proteolytic and pathogenic bacteria. As with rifaximin, the result is a reduction in peripheral ammonia, endotoxin, and inflammatory cytokine levels.
      • Bajaj J.
      • Heuman D.
      • Hylemon P.
      • et al.
      Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.
      • Dhiman R.K.
      • Rana B.
      • Agrawal S.
      • et al.
      Probiotic VSL# 3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.
      Beyond probiotics, it is conceivable that well-selected stool transplantation may play a role for this indication by this mechanism.
      In summary, the gut is a major source of ammonia and inflammation related to bacterial endotoxin. Effective therapy for HE, therefore, should address both aspects. Finally, agents that slow bowel motility, such as opiates, facilitate ammonia absorption and may precipitate overt HE and preclude recovery despite adequate therapy during overt HE episodes.
      • Bajaj J.
      Review article: the modern management of hepatic encephalopathy.

      The Liver

      The liver processes ammonia and gut-derived bacterial products that are received from the systemic and portal circulation. Hepatic contributions to the hyperammonemia of cirrhosis are a function of decreased intrinsic hepatic function and portosystemic shunting.

      Intrinsic Liver Function

      The liver handles ammonia through 2 principle mechanisms. The first is the urea cycle, whereby carbon dioxide and ammonia are ultimately converted to urea and water. This process occurs primarily in the periportal hepatocytes. Beyond being affected by hepatocyte volume, urea cycle efficiency is reduced by 2 factors common in cirrhosis. First, portosystemic shunting bypasses periportal hepatocytes. Second, as a function of increased catabolism and inflammation, malnutrition is a hallmark of advanced liver disease.
      • O'Brien A.
      • Williams R.
      Nutrition in end-stage liver disease: principles and practice.
      The urea cycle requires the presence of specific amino acids (eg, ornithine, alanine, and arginine) and zinc-dependent enzymes, all of which are less available in the setting of malnutrition.
      Patients with cirrhosis and particularly those with HE should receive a nutritional assessment and nutritional supplementation if they cannot achieve adequate protein intake.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      Protein restriction is not recommended because it may exacerbate sarcopenia, which has deleterious effects on ammonia metabolism (see later). On the contrary, patients with cirrhosis and HE benefit from nutritional supplementation and can tolerate high-protein diets.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      • Uribe M.
      • Márquez M.A.
      • Ramos G.G.
      • et al.
      Treatment of chronic portal: systemic encephalopathy with vegetable and animal protein diets.
      Based on a randomized controlled trial, 1.2 g/kg of daily protein did not exacerbate HE and prevented muscle breakdown.
      • Córdoba J.
      • López-Hellı́n J.
      • Planas M.
      • et al.
      Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
      In general, patients with decompensated cirrhosis are recommended to receive a daily intake of 1.5 g of protein and 35 to 40 kilocalories per kilogram.
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      Beyond protein and calories, it is unclear whether specific nutrients should be supplemented. The European Society for Clinical Nutrition and Metabolism recommends that nutritional supplements include branched-chain amino acids (BCAA) for patients with HE.
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      Supplementation with BCAA (the rationale for which is discussed later) seems to support the cirrhotic patient’s nutritional status and may be associated with lower rates of clinical deterioration, albeit with generally mixed results and without reducing the risk of overt HE.
      • Marchesini G.
      • Bianchi G.
      • Merli M.
      • et al.
      Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.
      • Muto Y.
      • Sato S.
      • Watanabe A.
      • et al.
      Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis.
      To specifically combat HE, investigators have assessed diets enriched with BCAA, also with mixed results.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      • Als-Nielsen B.
      • Koretz R.L.
      • Kjaergard L.
      • Gluud C.
      Branched-chain amino acids for hepatic encephalopathy.
      • De Bruijn K.
      • Blendis L.
      • Zilm D.
      • Carlen P.
      • Anderson G.
      Effect of dietary protein manipulation in subclinical portal-systemic encephalopathy.
      • Horst D.
      • Grace N.D.
      • Conn H.O.
      • et al.
      Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial.
      • Les I.
      • Doval E.
      • García-Martínez R.
      • et al.
      Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study.
      Similarly, zinc supplementation has been studied. Zinc is an important cofactor for urea cycle enzymes. It is also frequently deficient in cirrhotic patients, particularly those with alcoholic liver disease.
      • Bode J.C.
      • Hanisch P.
      • Henning H.
      • Koenig W.
      • Richter F.W.
      • Bode C.
      Hepatic zinc content in patients with various stages of alcoholic liver disease and in patients with chronic active and chronic persistent hepatitis.
      Controlled, if small, trials have examined zinc supplementation, with largely positive results. However, the generalizability of these results is uncertain because no trial has evaluated zinc supplementation with the current standard of care for HE.
      • Foeken K.
      • De Jong G.
      Overt hepatic encephalopathy precipitated by zinc deficiency.
      • Marchesini G.
      • Fabbri A.
      • Bianchi G.
      • Brizi M.
      • Zoli M.
      Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis.
      • Riggio O.
      • Ariosto F.
      • Merli M.
      • et al.
      Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy.
      • Takuma Y.
      • Nouso K.
      • Makino Y.
      • Hayashi M.
      • Takahashi H.
      Clinical trial: oral zinc in hepatic encephalopathy.
      • Reding P.
      • Duchateau J.
      • Bataille C.
      Oral zinc supplementation improves hepatic encephalopathy: results of a randomised controlled trial.
      In summary, adequate nutritional intake is paramount to maintain liver function. Beyond that, supplementation with BCAA or zinc is a safe, viable option but requires further study in patients receiving the current standard of care.

      Portosystemic Shunting

      Portosystemic shunting exposes the brain to ammonia and bacterial products—the toxins associated with HE neuropathology. The disruption of the hepatic architecture seen in cirrhosis leads to spontaneous portosystemic shunting in 2 ways. First, portal hypertension mechanically forces blood flow from the gut away from the liver through portosystemic collaterals. Second, sinusoidal fibrosis disrupts the normal interaction between hepatocytes and blood contents, leading to intrahepatic portosystemic shunting.
      Shunts that lead to encephalopathy can be spontaneous or postsurgical, selective or unselective.
      • Henderson J.M.
      • Boyer T.D.
      • Kutner M.H.
      • et al.
      Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: a randomized trial.
      Eck and Pavlov first demonstrated episodic stupor as a function of surgical portosystemic shunts (Eck fistula) in dogs.
      • Shawcross D.
      • Jalan R.
      The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
      McDermott later confirmed this pattern in humans and implicated ammonia after he described similar postprandial stupor in a patient without liver disease with a mesenteric vein-inferior vena cava anastamosis made during a pancreaticoduodenectomy.
      • McDermott Jr., W.V.
      • Adams R.D.
      Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia.
      • McDermott Jr., W.V.
      • Adams R.D.
      • Riddell A.G.
      Ammonia metabolism in man.
      Even modern selective shunt procedures, namely, transjugular intrahepatic portosystemic shunts (TIPSs), can precipitate or exacerbate HE.
      • Fanelli F.
      • Salvatori F.M.
      • Rabuffi P.
      • et al.
      Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft.
      • Riggio O.
      • Angeloni S.
      • Salvatori F.M.
      • et al.
      Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts.
      Indeed, the familiar risk stratification scoring systems pertinent to cirrhosis, including the Child-Pugh and the Mayo Clinic Model for End-Stage Liver Disease (MELD), were developed to assess patient risks after shunt procedures, and they remain valid today.
      • Riggio O.
      • Angeloni S.
      • Salvatori F.M.
      • et al.
      Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts.
      • Kamath P.S.
      • Wiesner R.H.
      • Malinchoc M.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      Based on previous study, guidelines recommend that TIPS not be offered to patients with difficult-to-control HE or a MELD score greater than 18.
      • Boyer T.D.
      • Haskal Z.J.
      The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009.
      Symptoms of patients with refractory HE can be improved with closure of portosystemic shunts. Well-selected patients (ie, MELD score < 16) with spontaneous shunts complicated by symptomatic HE refractory to medical therapy can obtain relief from embolization procedures that reduce portosystemic shunting.
      • Singh S.
      • Kamath P.S.
      • Andrews J.C.
      • Leise M.D.
      Embolization of spontaneous portosystemic shunts for management of severe persistent hepatic encephalopathy.
      • Laleman W.
      • Simon-Talero M.
      • Maleux G.
      • et al.
      Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
      Similarly, patients with TIPS can undergo shunt revisions to reduce flow.
      • Fanelli F.
      • Salvatori F.M.
      • Rabuffi P.
      • et al.
      Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft.
      • Riggio O.
      • Angeloni S.
      • Salvatori F.M.
      • et al.
      Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts.

      The Kidney

      Recognizing the kidney’s role in ammonia metabolism is critical for clinicians caring for patients with HE. Even in healthy patients, sharp increases in ammonia concentrations are handled in large part by renal processes.
      • Owen E.E.
      • Johnson J.H.
      • Tyor M.P.
      The effect of induced hyperammonemia on renal ammonia metabolism.
      The principle mechanism by which the kidney disposes of ammonia is through the formation of glutamine by renal tubular enzymes.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
      • Owen E.E.
      • Johnson J.H.
      • Tyor M.P.
      The effect of induced hyperammonemia on renal ammonia metabolism.
      • Dejong C.
      • Deutz N.
      • Soeters P.
      Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.
      • Gabuzda G.
      • Hall III, P.
      Relation of potassium depletion to renal ammonium metabolism and hepatic coma.
      Although renal insufficiency clearly limits these processes, there is still a limit to the functional kidney’s ability to eliminate ammonia. Indeed, the kidney requires glutamine to perform 2 of its essential functions, potassium and acid homeostasis, both of which lead to ammonia production.
      • Dejong C.
      • Deutz N.
      • Soeters P.
      Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.
      • Damink S.W.
      • Jalan R.
      • Redhead D.N.
      • Hayes P.C.
      • Deutz N.E.
      • Soeters P.B.
      Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS.
      • Damink S.W.O.
      • Dejong C.H.
      • Deutz N.E.
      • et al.
      Kidney plays a major role in ammonia homeostasis after portasystemic shunting in patients with cirrhosis.
      As a result, renal contributions to the levels of ammonia and glutamine, 2 key neurotoxins, depend on the patient’s clinical status.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
      • Baertl J.M.
      • Sancetta S.M.
      • Gabuzda G.J.
      Relation of acute potassium depletion to renal ammonium metabolism in patients with cirrhosis.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
      In the service of acid-base balance and eukalemia, the kidney takes up approximately half of all glutamine in the bloodstream as a substrate for tubular enzymes. In the setting of metabolic acidosis or hypokalemia, the production of renal glutaminase is increased, and glutamine is used to facilitate the disposal of acid into or recovery of potassium from the glomerular filtrate. Each glutamine used for either purpose generates 2 ammonium ions, some of which result in ammonia that then diffuses into circulation.
      • Welbourne T.
      • Weber M.
      • Bank N.
      The effect of glutamine administration on urinary ammonium excretion in normal subjects and patients with renal disease.
      • Lockwood A.H.
      • McDonald J.M.
      • Reiman R.E.
      • et al.
      The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia.
      • Mpabanzi L.
      • Damink S.W.O.
      • van de Poll M.C.
      • Soeters P.B.
      • Jalan R.
      • Dejong C.H.
      To pee or not to pee: ammonia hypothesis of hepatic encephalopathy revisited.
      • Tannen R.L.
      Relationship of renal ammonia production and potassium homeostasis.
      • Han K.-H.
      Mechanisms of the effects of acidosis and hypokalemia on renal ammonia metabolism.
      Through this mechanism, potassium depletion enhances renal ammoniagenesis and increases arterial ammonia levels.
      • Gabuzda G.
      • Hall III, P.
      Relation of potassium depletion to renal ammonium metabolism and hepatic coma.
      • Baertl J.M.
      • Sancetta S.M.
      • Gabuzda G.J.
      Relation of acute potassium depletion to renal ammonium metabolism in patients with cirrhosis.
      In the setting of hypokalemia, the proximal tubule conserves potassium via a proton-potassium antiporter that facilitates potassium recovery from glomerular filtrate. To support this process, renal glutaminase generates an ammonium ion from glutamine that donates a proton to be exchanged across the membrane for the potassium ion. The end result is recovered potassium, acidified urine, and ammonia, a by-product that diffuses into the serum. Acidosis, similar to hypokalemia, can occur in patients with cirrhosis presenting with overdiuresis, alcohol excess, or infections. Here, again, the renal tubule uses glutamine to maintain homeostasis through the disposal of acid (protons) in the urine using glutamine.
      • Han K.-H.
      Mechanisms of the effects of acidosis and hypokalemia on renal ammonia metabolism.
      • Jones J.W.
      • Sebastian A.
      • Hulter H.N.
      • Schambelan M.
      • Sutton J.M.
      • Biglieri E.G.
      Systemic and renal acid-base effects of chronic dietary potassium depletion in humans.
      • Lee Hamm L.
      • Hering-Smith K.S.
      • Nakhoul N.L.
      Acid-base and potassium homeostasis.
      Fortunately, acidosis and hypokalemia are often correctable.
      • Tannen R.L.
      Relationship of renal ammonia production and potassium homeostasis.
      • Tannen R.L.
      The effect of uncomplicated potassium depletion on urine acidification.
      • Zavagli G.
      • Ricci G.
      • Bader G.
      • Mapelli G.
      • Tomasi F.
      • Maraschin B.
      The importance of the highest normokalemia in the treatment of early hepatic encephalopathy.
      Furthermore, patients with HE and high normokalemia (potassium level, 5.4-5.5 mEq/L [to convert to mmol/L, multiply by 1]) show an earlier improvement in mental status and longer event-free survival than those with low normokalemia (potassium level, 3.5-3.6 mEq/L).
      • Tannen R.L.
      Relationship of renal ammonia production and potassium homeostasis.
      • Zavagli G.
      • Ricci G.
      • Bader G.
      • Mapelli G.
      • Tomasi F.
      • Maraschin B.
      The importance of the highest normokalemia in the treatment of early hepatic encephalopathy.
      Gastrointestinal bleeding is a major trigger for hyperammonemia, also through a renal mechanism. During hemorrhage, hemoglobin and albumin are digested in the gut. As pointed out in elegant studies by Olde Damink and colleagues,
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
      these proteins contain glutamine but lack isoleucine, an essential amino acid. In the absence of isoleucine, glutamine is absorbed from the gut but cannot be used for protein synthesis.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
      It, therefore, persists in the circulation, where it leads to ammonia production by renal glutaminase. Indeed, during gastrointestinal bleeding, ammonia production by the kidney swells to rival that of the gut.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
      Intravascular volume status is also an important determinant of systemic ammonia concentrations. The renin-angiotensin system, which responds to intravascular volume changes, is linked to ammonia hemostasis. The interactions are complex and incompletely characterized but are most likely related to angiotensin II levels. Angiotensin II increases ammonia production, whereas angiotensin receptor blockers markedly reduce urinary excretion of ammonia.
      • Nagami G.T.
      Enhanced ammonia secretion by proximal tubules from mice receiving NH4Cl: role of angiotensin II.
      As such, states of volume depletion, such as gastrointestinal bleeding and diuresis, could enhance renal ammonia production. Conversely, a volume challenge can increase ammonia excretion possibly by lowering angiotensin II levels.
      • Nagami G.T.
      Enhanced ammonia secretion by proximal tubules from mice receiving NH4Cl: role of angiotensin II.
      • Jalan R.
      • Kapoor D.
      Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver.
      Similarly, a reduction in the diuretic dose or temporary suspension may aid in the treatment of patients with HE taking diuretics.
      Recently, a novel pathway for renal ammonia elimination was tested in clinical trials. Glycerol phenylbutyrate is an orally administered odorless molecule. It can lower arterial ammonia levels in patients without effective urea cycles, namely, those with inborn metabolic defects and cirrhosis.
      • Diaz G.A.
      • Krivitzky L.S.
      • Mokhtarani M.
      • et al.
      Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.
      Glycerol phenylbutyrate is metabolized to phenylacetate and is subsequently conjugated with glutamine into a water-soluble molecule that is readily eliminated by the kidney, reducing available glutamine, preventing its metabolism by tissue glutaminases, and thereby reducing the risk of overt HE.
      • Rockey D.C.
      • Vierling J.M.
      • Mantry P.
      • et al.
      Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.
      • McGuire B.M.
      • Zupanets I.A.
      • Lowe M.E.
      • et al.
      Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.
      A similar mechanism was previously leveraged in a trial using sodium benzoate.
      • Sushma S.
      • Dasarathy S.
      • Tandon R.K.
      • Jain S.
      • Gupta S.
      • Bhist M.S.
      Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial.
      However, the utility of sodium benzoate is limited given the salt load of its required doses. Finally, there are ongoing trials of intravenous ornithine phenylacetate for the treatment of severe overt HE. The elimination product of ammonia and orthnithine phenylacetate is a water-soluble conjugate (phenylacetylglutamine) that is renally excreted.
      • Jalan R.
      • Wright G.
      • Davies N.
      • Hodges S.
      l-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy.

      Muscle

      Muscle is a significant site of ammonia metabolism for patients with cirrhosis, particularly those with portosystemic shunting, gastrointestinal bleeding, and sepsis.
      • Lockwood A.H.
      • McDonald J.M.
      • Reiman R.E.
      • et al.
      The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia.
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      • Holecek M.
      Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy: therapeutic perspectives.
      • Merli M.
      • Giusto M.
      • Lucidi C.
      • et al.
      Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study.
      • Montano-Loza A.J.
      • Meza-Junco J.
      • Prado C.M.
      • et al.
      Muscle wasting is associated with mortality in patients with cirrhosis.
      Ammonia is taken up by muscle and converted to glutamine via its glutamine synthetase, a process that is upregulated in the setting of portal hypertension.
      • Lockwood A.H.
      • McDonald J.M.
      • Reiman R.E.
      • et al.
      The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia.
      • Damink S.W.
      • Jalan R.
      • Redhead D.N.
      • Hayes P.C.
      • Deutz N.E.
      • Soeters P.B.
      Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS.
      Glutamine synthesis demands the availability of glutamate, which is derived in the cytoplasm from α-ketoglutarate that is harvested, in turn, from BCAA.
      • Uribe M.
      • Márquez M.A.
      • Ramos G.G.
      • et al.
      Treatment of chronic portal: systemic encephalopathy with vegetable and animal protein diets.
      • Holecek M.
      Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy: therapeutic perspectives.
      • Holecek M.
      • Kandar R.
      • Sispera L.
      • Kovarik M.
      Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle.
      The paucity of BCAA in cirrhotic patients with malnutrition leads to a reduced ability to convert ammonia to glutamine in skeletal muscle cells.
      • Olde Damink S.W.
      • Jalan R.
      • Deutz N.E.
      • et al.
      Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
      • Holecek M.
      Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy: therapeutic perspectives.
      The clinical relevance of skeletal muscle's role in ammonia metabolism is heightened further when one examines the consequences of sarcopenia in patients with cirrhosis. Indeed, muscle wasting has been associated with an increased risk of HE, both covert and overt.
      • Merli M.
      • Giusto M.
      • Lucidi C.
      • et al.
      Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study.
      • Kalaitzakis E.
      • Olsson R.
      • Henfridsson P.
      • et al.
      Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis.
      Accordingly, as described previously above, efforts to maintain nutritional status and forestall the development of clinically significant sarcopenia are crucial for patients with cirrhosis.
      • Blei A.T.
      • Córdoba J.
      Hepatic encephalopathy.
      • Amodio P.
      • Bemeur C.
      • Butterworth R.
      • et al.
      The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
      Maintaining the nutritional status by ensuring appropriate dietary intake and supplementation is paramount and is the shared responsibility of all providers involved in the care of cirrhotic patients.

      Putting it All Together

      By focusing on the determinants of ammonia metabolism and neurotoxicity, clinicians may develop an effective multimodal therapeutic strategy for their patients with HE. In patients with cirrhosis and portosystemic shunting, amino acid bypass of the liver in the postabsorptive state and loss of intrinsic hepatic function significantly raise the importance of alternative sites of ammonia metabolism. Namely, the muscle and kidney are critical for maintaining ammonia homeostasis (Figures 1 and 2). With further potentiation and enhanced diffusion of ammonia across the blood-brain barrier by endotoxemia and systemic inflammation, early and aggressive treatment of infection, preservation of muscle mass and renal function, and maximal elimination of gut-derived ammonia and bacterial products should form the cornerstones of optimal HE treatment.
      Figure thumbnail gr2
      Figure 2Sources of hyperammonemia and ammonia toxicity: multiorgan mechanisms.
      A refined, multiorgan view of the ammonia hypothesis is instructive for all clinicians interested in the care of patients with cirrhosis. Ammonia levels may not reliably correlate with HE symptoms or outcomes in chronic liver disease.
      • Fichet J.
      • Mercier E.
      • Genée O.
      • et al.
      Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy.
      • Ong J.P.
      • Aggarwal A.
      • Krieger D.
      • et al.
      Correlation between ammonia levels and the severity of hepatic encephalopathy.
      • Stahl J.
      Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance.
      • Neff G.W.
      • Jones M.
      • Jonas M.
      • et al.
      Lack of Clostridium difficile infection in patients treated with rifaximin for hepatic encephalopathy: a retrospective analysis.
      However, as we described, serum ammonia and its ill-effects are a function of not only intrinsic liver disease and portosystemic shunting but also malnutrition, sarcopenia, renal injury, and gastrointestinal bleeding. Each factor requires special attention from the team of clinicians with whom these patients follow. To maximize the power of the refined ammonia hypothesis, clinicians should consider the following therapeutic framework (Figures 3 and 4).
      Figure thumbnail gr3
      Figure 3Target-based treatment of hepatic encephalopathy suggested by a refined ammonia hypothesis. TIPS = transjugular intrahepatic portosystemic shunt.
      Figure thumbnail gr4
      Figure 4A physiology-driven protocol for the treatment of hepatic encephalopathy. BID = twice daily; q2 - q4 = every 2-4 hours; TID = 3 times daily; TIPS = transjugular intrahepatic portosystemic shunt.

      Overt HE

      On admission, the hospitalized patient with acute HE should be broadly assessed for infection (from the urinary tract to a sampling of the ascites) and be treated for any infections promptly and aggressively. In addition, patients should receive a volume challenge if dehydrated, potentially with albumin (although not necessarily), and should have their diuretics discontinued at least temporarily, as well as any narcotics and benzodiazepines. Deficits in potassium should be repleted. Beyond that, all patients should receive lactulose. Consider albumin dialysis for refractory HE.
      • Leise M.D.
      • Poterucha J.J.
      • Kamath P.S.
      • Kim W.R.
      Management of hepatic encephalopathy in the hospital.
      Ammonia levels do not need to be assessed. Before hospital discharge, a nutrition consultation should be arranged, previous authorization to cover rifaximin for secondary prophylaxis should be considered, and the risks of driving should be explained. A referral for transplant evaluation should be pursued if not already undertaken. For a review of the stepwise in-hospital management of HE, please refer to the study by Leise and colleagues.
      • Leise M.D.
      • Poterucha J.J.
      • Kamath P.S.
      • Kim W.R.
      Management of hepatic encephalopathy in the hospital.

      Covert or Resolved HE After an Acute Episode

      Clinicians should maintain patients on lactulose or rifaximin therapy if their symptoms are mild and should consider combination therapy when their symptoms have been overt, required hospitalization, or did not respond to lactulose alone. Routine examinations should include assessments of volume status, especially for patients taking diuretics to guide dosing decisions. Efforts should be undertaken to ensure eukalemia and consider supplementation, especially for those with a history of hypokalemia. Clinicians should carefully track and address the patient's nutritional status, supplementing macronutrients and micronutrients as needed with consideration of BCAAs. For patients who are not candidates for first-line therapies or for those who do not completely respond, consideration of probiotics, zinc supplementation, or, when available, glycerol phenylbutyrate or l-ornithine l-aspartate is reasonable. Hepatic encephalopathy should be viewed as a contraindication for the prescription of sedatives and narcotics. Finally, the risks of driving must be explained.

      Conclusion

      In summary, the ideal therapeutic approach to patients with HE can be guided by a refined ammonia hypothesis. This refined and up-to-date view of the ammonia hypothesis is one that acknowledges the contribution of inflammation to the neurotoxicity of serum ammonia and underscores the importance of multiple organ systems, namely, the gut, kidney, and skeletal muscle, in achieving ammonia homeostasis.

      Supplemental Online Material

      References

        • Blei A.T.
        • Córdoba J.
        Hepatic encephalopathy.
        Am J Gastroenterol. 2001; 96: 1968-1976
        • Volk M.L.
        • Tocco R.S.
        • Bazick J.
        • Rakoski M.O.
        • Lok A.S.
        Hospital readmissions among patients with decompensated cirrhosis.
        Am J Gastroenterol. 2012; 107: 247-252
        • Arguedas M.R.
        • DeLawrence T.G.
        • McGuire B.M.
        Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis.
        Dig Dis Sci. 2003; 48: 1622-1626
        • Cordoba J.
        • Ventura-Cots M.
        • Simón-Talero M.
        • et al.
        Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
        J Hepatol. 2014; 60: 275-281
        • Diaz G.A.
        • Krivitzky L.S.
        • Mokhtarani M.
        • et al.
        Ammonia control and neurocognitive outcome among urea cycle disorder patients treated with glycerol phenylbutyrate.
        Hepatology. 2013; 57: 2171-2179
        • Enns G.M.
        • Berry S.A.
        • Berry G.T.
        • Rhead W.J.
        • Brusilow S.W.
        • Hamosh A.
        Survival after treatment with phenylacetate and benzoate for urea-cycle disorders.
        N Engl J Med. 2007; 356: 2282-2292
        • Fichet J.
        • Mercier E.
        • Genée O.
        • et al.
        Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy.
        J Crit Care. 2009; 24: 364-370
        • Ong J.P.
        • Aggarwal A.
        • Krieger D.
        • et al.
        Correlation between ammonia levels and the severity of hepatic encephalopathy.
        Am J Med. 2003; 114: 188-193
        • Shawcross D.
        • Sharifi Y.
        • Canavan J.
        • et al.
        Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
        J Hepatol. 2011; 54: 640-649
        • Stahl J.
        Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance.
        Ann Intern Med. 1963; 58: 1-24
        • Phillip S.G.
        • Runyon B.A.
        Serum ammonia level for the evaluation of hepatic encephalopathy.
        JAMA. 2014; 312: 643-644
        • Albrecht J.
        • Norenberg M.D.
        Glutamine: a Trojan horse in ammonia neurotoxicity.
        Hepatology. 2006; 44: 788-794
        • Welbourne T.
        • Weber M.
        • Bank N.
        The effect of glutamine administration on urinary ammonium excretion in normal subjects and patients with renal disease.
        J Clin Invest. 1972; 51: 1852-1860
        • Butterworth R.F.
        Complications of cirrhosis III. Hepatic encephalopathy.
        J Hepatol. 2000; 32: 171-180
        • Olde Damink S.W.
        • Jalan R.
        • Deutz N.E.
        • et al.
        The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.
        Hepatology. 2003; 37: 1277-1285
        • Tarantino G.
        • Citro V.
        • Esposito P.
        • et al.
        Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins.
        BMC Gastroenterol. 2009; 9: 21
        • Warren K.S.
        • Reboucas G.
        • Baptista A.G.
        Ammonia metabolism and hepatic coma in hepatosplenic schistosomiasis patients studied before and after portacaval shunt.
        Ann Intern Med. 1965; 62: 1113-1133
        • Leise M.D.
        • Poterucha J.J.
        • Kamath P.S.
        • Kim W.R.
        Management of hepatic encephalopathy in the hospital.
        Mayo Clin Proc. 2014; 89: 241-253
        • Butterworth R.
        Effects of hyperammonaemia on brain function.
        J Inherit Metab Dis. 1998; 21: 6-20
        • Norenberg M.D.
        Astroglial dysfunction in hepatic encephalopathy.
        Metab Brain Dis. 1998; 13: 319-335
        • Norenberg M.D.
        • Martinez-Hernandez A.
        Fine structural localization of glutamine synthetase in astrocytes of rat brain.
        Brain Res. 1979; 161: 303-310
        • Shawcross D.
        • Jalan R.
        The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.
        Cell Mol Life Sci. 2005; 62: 2295-2304
        • Jayakumar A.R.
        • Rama Rao K.
        • Schousboe A.
        • Norenberg M.D.
        Glutamine-induced free radical production in cultured astrocytes.
        Glia. 2004; 46: 296-301
        • Norenberg M.D.
        Astrocyte responses to CNS injury.
        J Neuropathol Exp Neurol. 1994; 53: 213-220
        • Yudkoff M.
        • Nissim I.
        • Pleasure D.
        Astrocyte metabolism of [15N] glutamine: implications for the glutamine-glutamate cycle.
        J Neurochem. 1988; 51: 843-850
        • Cordoba J.
        • Gottstein J.
        • Blei A.T.
        Glutamine, myo-inositol, and organic brain osmolytes after portocaval anastomosis in the rat: implications for ammonia-induced brain edema.
        Hepatology. 1996; 24: 919-923
        • Balata S.
        • Damink S.W.
        • Ferguson K.
        • et al.
        Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis.
        Hepatology. 2003; 37: 931-939
        • Bachmann C.
        Mechanisms of hyperammonemia.
        Clin Chem Lab Med. 2002; 40: 653-662
        • Lockwood A.H.
        • McDonald J.M.
        • Reiman R.E.
        • et al.
        The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia.
        J Clin Invest. 1979; 63: 449
        • Felipo V.
        • Butterworth R.F.
        Neurobiology of ammonia.
        Prog Neurobiol. 2002; 67: 259-279
        • Llansola M.
        • Rodrigo R.
        • Monfort P.
        • et al.
        NMDA receptors in hyperammonemia and hepatic encephalopathy.
        Metab Brain Dis. 2007; 22: 321-335
        • Garcia-Martinez R.
        • Rovira A.
        • Alonso J.
        • et al.
        Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume.
        Liver Transpl. 2011; 17: 38-46
        • Shawcross D.L.
        • Davies N.A.
        • Williams R.
        • Jalan R.
        Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
        J Hepatol. 2004; 40: 247-254
        • Tranah T.H.
        • Vijay G.K.M.
        • Ryan J.M.
        • Shawcross D.L.
        Systemic inflammation and ammonia in hepatic encephalopathy.
        Metab Brain Dis. 2013; 28: 1-5
        • Shawcross D.L.
        • Shabbir S.S.
        • Taylor N.J.
        • Hughes R.D.
        Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis.
        Hepatology. 2010; 51: 1062-1069
        • Clemmesen J.O.
        • Larsen F.S.
        • Kondrup J.
        • Hansen B.A.
        • Ott P.
        Cerebral herniation in patients with acute E liver failure is correlated with arterial ammonia concentration.
        Hepatology. 1999; 29: 648-653
        • Pichili V.
        • Rao K.
        • Jayakumar A.
        • Norenberg M.
        Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity.
        Glia. 2007; 55: 801-809
        • Polson J.
        • Lee W.M.
        AASLD position paper: the management of acute liver failure.
        Hepatology. 2005; 41: 1179-1197
        • Hassanein T.I.
        • Tofteng F.
        • Brown R.S.
        • et al.
        Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.
        Hepatology. 2007; 46: 1853-1862
        • Bajaj J.
        • Heuman D.
        • Hylemon P.
        • et al.
        Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis.
        Aliment Pharmacol Ther. 2014; 39: 1113-1125
        • Bajaj J.S.
        • Heuman D.M.
        • Sanyal A.J.
        • et al.
        Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy.
        PloS One. 2013; 8: e60042
        • Rockey D.C.
        • Vierling J.M.
        • Mantry P.
        • et al.
        Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.
        Hepatology. 2014; 59: 1073-1083
        • Assy N.
        • Rosser B.G.
        • Grahame G.R.
        • Minuk G.Y.
        Risk of sedation for upper GI endoscopy exacerbating subclinical hepatic encephalopathy in patients with cirrhosis.
        Gastrointest Endosc. 1999; 49: 690-694
        • Bajaj J.
        Review article: the modern management of hepatic encephalopathy.
        Aliment Pharmacol Ther. 2010; 31: 537-547
        • Souba W.W.
        • Smith R.J.
        • Wilmore D.W.
        Glutamine metabolism by the intestinal tract.
        JPEN J Parenter Enteral Nutr. 1985; 9: 608-617
        • Romero-Gómez M.
        • Ramos-Guerrero R.
        • Grande L.
        • et al.
        Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy.
        J Hepatol. 2004; 41: 49-54
        • McDermott Jr., W.V.
        • Victor M.
        • Point W.W.
        Exclusion of the colon in the treatment of hepatic encephalopathy.
        N Engl J Med. 1962; 267: 850-854
        • Walker J.
        • Emlyn-Williams A.
        • Craigie A.
        • Rosenoer V.
        • Agnew J.
        • Sherlock S.
        Treatment of chronic portal-systemic encephalopathy by surgical exclusion of the colon.
        Lancet. 1965; 286: 861-866
        • Díaz-Herrero M.M.
        • del Campo J.A.
        • Carbonero-Aguilar P.
        • et al.
        THDP17 decreases ammonia production through glutaminase Inhibition: a new drug for hepatic encephalopathy therapy.
        PloS One. 2014; 9: e109787
        • Müller J.B.
        • Guggenheim P.
        • Haemmerli U.
        Treatment of chronic portal-systemic encephalopathy with lactulose.
        Lancet. 1966; 287: 890-893
        • Rahimi R.S.
        • Singal A.G.
        • Cuthbert J.A.
        • Rockey D.C.
        Lactulose vs polyethylene glycol 3350–electrolyte solution for treatment of overt hepatic encephalopathy: the HELP randomized clinical trial.
        JAMA Intern Med. 2014; 174: 1727-1733
        • Al-Osaimi A.
        • Quatrara B.
        • Melo I.
        • et al.
        In-patient hepatic encephalopathy protocol improves in-patient outcome measures: interim analysis.
        Hepatology. 2009; 50: 446A
        • van Thiel D.H.
        • Fagiuoli S.
        • Wright H.I.
        • Chien M.C.
        • Gavaler J.S.
        Gastrointestinal transit in cirrhotic patients: effect of hepatic encephalopathy and its treatment.
        Hepatology. 1994; 19: 67-71
        • Wolpert E.
        • Phillips S.
        • Summerskill W.
        Transport of urea and ammonia production in the human colon.
        Lancet. 1971; 298: 1387-1390
        • Vince A.
        • Dawson A.
        • Park N.
        • O'Grady F.
        Ammonia production by intestinal bacteria.
        Gut. 1973; 14: 171-177
        • Als-Nielsen B.
        • Gluud L.L.
        • Gluud C.
        Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials.
        BMJ. 2004; 328: 1046
        • Brown H.
        • Trey C.
        • McDermott W.V.
        Lactulose treatment of hepatic encephalopathy in outpatients.
        Arch Surg. 1971; 102: 25-27
        • Conn H.
        • Leevy C.
        • Vlahcevic Z.
        • et al.
        Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy: a double blind controlled trial.
        Gastroenterology. 1977; 72: 573-583
        • Elkington S.
        • Floch M.
        • Conn H.
        Lactulose in the treatment of chronic portal-systemic encephalopathy: a double-blind clinical trial.
        N Engl J Med. 1969; 281: 408-412
        • Heredia D.
        • Caballeria J.
        • Arroyo V.
        • Ravelli G.
        • Rodes J.
        Lactitol versus lactulose in the treatment of acute portal systemic encephalopathy (PSE): a controlled trial.
        J Hepatol. 1987; 4: 293-298
        • Heredia D.
        • Teres J.
        • Orteu N.
        • Rodes J.
        Lactitol vs. lactulose in the treatment of chronic recurrent portal-systemic encephalopathy.
        J Hepatol. 1988; 7: 106-110
        • Sharma B.C.
        • Sharma P.
        • Agrawal A.
        • Sarin S.K.
        Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo.
        Gastroenterology. 2009; 137: 885-891
        • Bass N.M.
        • Mullen K.D.
        • Sanyal A.
        • et al.
        Rifaximin treatment in hepatic encephalopathy.
        N Engl J Med. 2010; 362: 1071-1081
        • Sharma B.C.
        • Sharma P.
        • Lunia M.K.
        • Srivastava S.
        • Goyal R.
        • Sarin S.
        A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
        Am J Gastroenterol. 2013; 108: 1458-1463
        • Tarao K.
        • Ikeda T.
        • Hayashi K.
        • et al.
        Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy.
        Gut. 1990; 31: 702-706
        • Eltawil K.M.
        • Laryea M.
        • Peltekian K.
        • Molinari M.
        Rifaximin vs conventional oral therapy for hepatic encephalopathy: a meta-analysis.
        World J Gastroenterol. 2012; 18: 767-777
        • Bajaj J.S.
        • Saeian K.
        • Christensen K.M.
        • et al.
        Probiotic yogurt for the treatment of minimal hepatic encephalopathy.
        Am J Gastroenterol. 2008; 103: 1707-1715
        • McGee R.G.
        • Bakens A.
        • Wiley K.
        • Riordan S.M.
        • Webster A.C.
        Probiotics for patients with hepatic encephalopathy.
        Cochrane Database Syst Rev. 2011; 11: CD008716
        • Bauer T.M.
        • Schwacha H.
        • Steinbrückner B.
        • et al.
        Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia.
        Am J Gastroenterol. 2002; 97: 2364-2370
        • Shawcross D.
        • Wright G.
        • Damink S.O.
        • Jalan R.
        Role of ammonia and inflammation in minimal hepatic encephalopathy.
        Metab Brain Dis. 2007; 22: 125-138
        • Shukla S.
        • Shukla A.
        • Mehboob S.
        • Guha S.
        Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy.
        Aliment Pharmacol Ther. 2011; 33: 662-671
        • Wright G.
        • Jalan R.
        Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora's box?.
        Hepatology. 2007; 46: 291-294
        • Neff G.W.
        • Jones M.
        • Broda T.
        • et al.
        Durability of rifaximin response in hepatic encephalopathy.
        J Clin Gastroenterol. 2012; 46: 168-171
        • Dhiman R.K.
        • Rana B.
        • Agrawal S.
        • et al.
        Probiotic VSL# 3 reduces liver disease severity and hospitalization in patients with cirrhosis: a randomized, controlled trial.
        Gastroenterology. 2014; 147: 1327-1337
        • O'Brien A.
        • Williams R.
        Nutrition in end-stage liver disease: principles and practice.
        Gastroenterology. 2008; 134: 1729-1740
        • Amodio P.
        • Bemeur C.
        • Butterworth R.
        • et al.
        The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
        Hepatology. 2013; 58: 325-336
        • Uribe M.
        • Márquez M.A.
        • Ramos G.G.
        • et al.
        Treatment of chronic portal: systemic encephalopathy with vegetable and animal protein diets.
        Dig Dis Sci. 1982; 27: 1109-1116
        • Córdoba J.
        • López-Hellı́n J.
        • Planas M.
        • et al.
        Normal protein diet for episodic hepatic encephalopathy: results of a randomized study.
        J Hepatol. 2004; 41: 38-43
        • Plauth M.
        • Cabre E.
        • Riggio O.
        • et al.
        ESPEN guidelines on enteral nutrition: liver disease.
        Clin Nutr. 2006; 25: 285-294
        • Marchesini G.
        • Bianchi G.
        • Merli M.
        • et al.
        Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.
        Gastroenterology. 2003; 124: 1792-1801
        • Muto Y.
        • Sato S.
        • Watanabe A.
        • et al.
        Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis.
        Clin Gastroenterol Hepatol. 2005; 3: 705-713
        • Als-Nielsen B.
        • Koretz R.L.
        • Kjaergard L.
        • Gluud C.
        Branched-chain amino acids for hepatic encephalopathy.
        Cochrane Database Syst Rev. 2003; 2: CD001939
        • De Bruijn K.
        • Blendis L.
        • Zilm D.
        • Carlen P.
        • Anderson G.
        Effect of dietary protein manipulation in subclinical portal-systemic encephalopathy.
        Gut. 1983; 24: 53-60
        • Horst D.
        • Grace N.D.
        • Conn H.O.
        • et al.
        Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial.
        Hepatology. 1984; 4: 279-287
        • Les I.
        • Doval E.
        • García-Martínez R.
        • et al.
        Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study.
        Am J Gastroenterol. 2011; 106: 1081-1088
        • Bode J.C.
        • Hanisch P.
        • Henning H.
        • Koenig W.
        • Richter F.W.
        • Bode C.
        Hepatic zinc content in patients with various stages of alcoholic liver disease and in patients with chronic active and chronic persistent hepatitis.
        Hepatology. 1988; 8: 1605-1609
        • Foeken K.
        • De Jong G.
        Overt hepatic encephalopathy precipitated by zinc deficiency.
        Gastroenterology. 1991; 100: 1114-1118
        • Marchesini G.
        • Fabbri A.
        • Bianchi G.
        • Brizi M.
        • Zoli M.
        Zinc supplementation and amino acid-nitrogen metabolism in patients with advanced cirrhosis.
        Hepatology. 1996; 23: 1084-1092
        • Riggio O.
        • Ariosto F.
        • Merli M.
        • et al.
        Short-term oral zinc supplementation does not improve chronic hepatic encephalopathy.
        Dig Dis Sci. 1991; 36: 1204-1208
        • Takuma Y.
        • Nouso K.
        • Makino Y.
        • Hayashi M.
        • Takahashi H.
        Clinical trial: oral zinc in hepatic encephalopathy.
        Aliment Pharmacol Ther. 2010; 32: 1080-1090
        • Reding P.
        • Duchateau J.
        • Bataille C.
        Oral zinc supplementation improves hepatic encephalopathy: results of a randomised controlled trial.
        Lancet. 1984; 324: 493-495
        • Henderson J.M.
        • Boyer T.D.
        • Kutner M.H.
        • et al.
        Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: a randomized trial.
        Gastroenterology. 2006; 130: 1643-1651
        • McDermott Jr., W.V.
        • Adams R.D.
        Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia.
        J Clin Invest. 1954; 33: 1-9
        • McDermott Jr., W.V.
        • Adams R.D.
        • Riddell A.G.
        Ammonia metabolism in man.
        Ann Surg. 1954; 140: 539-556
        • Fanelli F.
        • Salvatori F.M.
        • Rabuffi P.
        • et al.
        Management of refractory hepatic encephalopathy after insertion of TIPS: long-term results of shunt reduction with hourglass-shaped balloon-expandable stent-graft.
        Am J Roentgenol. 2009; 193: 1696-1702
        • Riggio O.
        • Angeloni S.
        • Salvatori F.M.
        • et al.
        Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts.
        Am J Gastroenterol. 2008; 103: 2738-2746
        • Kamath P.S.
        • Wiesner R.H.
        • Malinchoc M.
        • et al.
        A model to predict survival in patients with end-stage liver disease.
        Hepatology. 2001; 33: 464-470
        • Boyer T.D.
        • Haskal Z.J.
        The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009.
        Hepatology. 2010; 51: 306
        • Singh S.
        • Kamath P.S.
        • Andrews J.C.
        • Leise M.D.
        Embolization of spontaneous portosystemic shunts for management of severe persistent hepatic encephalopathy.
        Hepatology. 2014; 59: 735-736
        • Laleman W.
        • Simon-Talero M.
        • Maleux G.
        • et al.
        Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: a multicenter survey on safety and efficacy.
        Hepatology. 2013; 57: 2448-2457
        • Owen E.E.
        • Johnson J.H.
        • Tyor M.P.
        The effect of induced hyperammonemia on renal ammonia metabolism.
        J Clin Invest. 1961; 40: 215-221
        • Dejong C.
        • Deutz N.
        • Soeters P.
        Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.
        J Clin Invest. 1993; 92: 2834-2840
        • Gabuzda G.
        • Hall III, P.
        Relation of potassium depletion to renal ammonium metabolism and hepatic coma.
        Medicine (Baltimore). 1966; 45: 481-490
        • Damink S.W.
        • Jalan R.
        • Redhead D.N.
        • Hayes P.C.
        • Deutz N.E.
        • Soeters P.B.
        Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS.
        Hepatology. 2002; 36: 1163-1171
        • Damink S.W.O.
        • Dejong C.H.
        • Deutz N.E.
        • et al.
        Kidney plays a major role in ammonia homeostasis after portasystemic shunting in patients with cirrhosis.
        Am J Physiol-Gastrointest Liver Physiol. 2006; 291: G189-G194
        • Baertl J.M.
        • Sancetta S.M.
        • Gabuzda G.J.
        Relation of acute potassium depletion to renal ammonium metabolism in patients with cirrhosis.
        J Clin Invest. 1963; 42: 696-706
        • Olde Damink S.W.
        • Jalan R.
        • Deutz N.E.
        • et al.
        Isoleucine infusion during “simulated” upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.
        Hepatology. 2007; 45: 560-568
        • Mpabanzi L.
        • Damink S.W.O.
        • van de Poll M.C.
        • Soeters P.B.
        • Jalan R.
        • Dejong C.H.
        To pee or not to pee: ammonia hypothesis of hepatic encephalopathy revisited.
        Eur J Gastroenterol Hepatol. 2011; 23: 449-454
        • Tannen R.L.
        Relationship of renal ammonia production and potassium homeostasis.
        Kidney Int. 1977; 11: 453-465
        • Han K.-H.
        Mechanisms of the effects of acidosis and hypokalemia on renal ammonia metabolism.
        Electrolyte Blood Press. 2011; 9: 45-49
        • Jones J.W.
        • Sebastian A.
        • Hulter H.N.
        • Schambelan M.
        • Sutton J.M.
        • Biglieri E.G.
        Systemic and renal acid-base effects of chronic dietary potassium depletion in humans.
        Kidney Int. 1982; 21: 402-410
        • Lee Hamm L.
        • Hering-Smith K.S.
        • Nakhoul N.L.
        Acid-base and potassium homeostasis.
        Semin Nephrol. 2013; 33: 257-264
        • Tannen R.L.
        The effect of uncomplicated potassium depletion on urine acidification.
        J Clin Invest. 1970; 49: 813-827
        • Zavagli G.
        • Ricci G.
        • Bader G.
        • Mapelli G.
        • Tomasi F.
        • Maraschin B.
        The importance of the highest normokalemia in the treatment of early hepatic encephalopathy.
        Miner Electrolyte Metab. 1992; 19: 362-367
        • Nagami G.T.
        Enhanced ammonia secretion by proximal tubules from mice receiving NH4Cl: role of angiotensin II.
        Am J Physiol-Renal Physiol. 2002; 282: F472-F477
        • Jalan R.
        • Kapoor D.
        Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver.
        Gut. 2003; 52: 1041-1045
        • McGuire B.M.
        • Zupanets I.A.
        • Lowe M.E.
        • et al.
        Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.
        Hepatology. 2010; 51: 2077-2085
        • Sushma S.
        • Dasarathy S.
        • Tandon R.K.
        • Jain S.
        • Gupta S.
        • Bhist M.S.
        Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial.
        Hepatology. 1992; 16: 138-144
        • Jalan R.
        • Wright G.
        • Davies N.
        • Hodges S.
        l-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy.
        Med Hypotheses. 2007; 69: 1064-1069
        • Holecek M.
        Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy: therapeutic perspectives.
        Metab Brain Dis. 2014; 29: 9-17
        • Merli M.
        • Giusto M.
        • Lucidi C.
        • et al.
        Muscle depletion increases the risk of overt and minimal hepatic encephalopathy: results of a prospective study.
        Metab Brain Dis. 2013; 28: 281-284
        • Montano-Loza A.J.
        • Meza-Junco J.
        • Prado C.M.
        • et al.
        Muscle wasting is associated with mortality in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2012; 10: 166-173
        • Holecek M.
        • Kandar R.
        • Sispera L.
        • Kovarik M.
        Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle.
        Amino Acids. 2011; 40: 575-584
        • Kalaitzakis E.
        • Olsson R.
        • Henfridsson P.
        • et al.
        Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis.
        Liver Int. 2007; 27: 1194-1201
        • Neff G.W.
        • Jones M.
        • Jonas M.
        • et al.
        Lack of Clostridium difficile infection in patients treated with rifaximin for hepatic encephalopathy: a retrospective analysis.
        J Clin Gastroenterol. 2013; 47: 188-192