Pathophysiology and management of hepatic encephalopathy 2014 update: Ammonia toxicity and hyponatremia

Hyperammonemia is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia elicits astrocyte swelling and causes brain edema. In addition, hyponatremia, a condition frequently observed in hepatic cirrhosis, also exacerbates brain edema, potentially becoming a factor that exacerbates HE. Therefore, as a treatment strategy for HE, alleviating ammonia toxicity is essential. In addition to restricting protein intake, synthetic disaccharides such as lactulose and lactitol, probiotics that improve gut flora, and rifaximin, an antibiotic with poor bioavailability, are also administrated. Additionally, branched‐chain amino acids and carnitine have also been administrated. Moreover, we investigated the current trend in the concomitant use of drugs with different mechanisms of action. In Japan, the V2 receptor antagonist tolvaptan can be administrated to hepatic cirrhosis patients with fluid retention. This drug is also useful as a countermeasure for hyponatremia in hepatic cirrhosis, and elucidating its effects in HE patients may therefore become an agenda in the future. These observations indicate that ammonia toxicity, gut flora control and low sodium control are major focuses in HE improvement and long‐term prognosis.     

乳果糖治疗肝性脑病和亚临床肝性脑病149例临床观察

目的 进一步评估乳果糖对肝硬化肝性脑病和亚临床肝性脑病的疗效。方法 观察乳果糖治疗前后患者的精神状态、扑翼状震颤、脑电图、静脉血氨浓度和数字连接试验的改善情况。结果 乳果糖对肝性脑病组的脑病表现总有效率达96.5％,治疗前后静脉血氨浓度和数字连接试验的改善均有非常显著性差异(P<0.01);亚临床肝性脑病组治疗前后血氨有非常显著性差异(P<0.01),数字连接试验有显著性差异(P<0.05)。在乳果糖治疗观察期间,无一例亚临床肝性脑病患者发展为肝性脑病。结论 乳果糖适合于肝硬化肝性脑病和亚临床肝性脑病患者长期服用,可作为预防和治疗肝性脑病的常规用药。     

Management of hepatic encephalopathy in patients with cirrhosis

The term hepatic encephalopathy encompasses a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of hepatic encephalopathy in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. In patients with acute-on-chronic liver failure the pathophysiology remains undefined. Ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. Recent studies suggest that inflammation and it modulators may play a synergistic role with ammonia in the pathogenesis of hepatic encephalopathy. Therapy of hepatic encephalopathy is directed primarily at reducing ammonia generation and increasing its detoxification. The currently accepted regimens to treat hepatic encephalopathy such as lactulose and protein restricted diets need further clinical trials and therefore placebo controlled clinical trials in hepatic encephalopathy are justified. In liver failure, ammonia metabolism involves multiple organs and therefore ammonia reduction will require simultaneous targeting of these organs. The present review describes the pathophysiological basis of hepatic encephalopathy and evaluates the available therapies.     

Helicobacter pylori infection, plasma ammonia levels, and psychometric testing in cirrhotic patients

OBJECTIVE: The role of Helicobacter pylori (H. pylori) infection as a cause of hepatic encephalopathy is still debated. This study focused on the relationship between H. pylori, plasma ammonia levels, and intellectual function in cirrhotic patients. METHODS: Forty-seven cirrhotics with latent or mild hepatic encephalopathy were enrolled in the study, upon H. pylori assessment at endoscopy. Plasma ammonia level determinations and psychometric testing were performed at entry in all patients. Patients with H. pylori infection received a 2-wk standard dual therapy and bacterial eradication was assessed at endoscopy 6-8 wk later. On this occasion, plasma ammonia levels and psychometric assessments were repeated. Patients without H. pylori infection at entry were also studied after 6-8 wk for ammonia level assessment and psychometric testing, as a control group. Patients receiving lactulose therapy and those without therapy were grouped separately for statistical analysis. RESULTS: Among 21 patients without lactulose therapy (group A), basal plasma ammonia levels and psychometric testing scores did not significantly differ between 13 infected and eight uninfected patients. Similarly, among 26 patients undergoing lactulose therapy (group B), basal plasma ammonia concentration and psychometric testing scores did not significantly differ between 13 infected and 13 uninfected patients. Moreover, in group B, both the prevalence of previous overt hepatic encephalopathy episodes and the mean daily dose of lactulose therapy were similar between infected and uninfected patients. In addition, no significant reduction in the plasma ammonia concentrations and in psychometric testing scores emerged in both groups A and B after bacterial eradication. CONCLUSIONS: This study failed to find a relationship between H. pylori, plasma ammonia levels, and psychometric testing scores in cirrhotic patients with latent or mild hepatic encephalopathy.     

枯草杆菌二联活菌肠溶胶囊联合乳果糖治疗肝性脑病疗效分析

目的探讨枯草杆菌二联活菌肠溶胶囊联合乳果糖口服溶液治疗肝性脑病患者的临床疗效。方法将160例肝性脑病患者随机分为治疗组(84例)和对照组(76例)。治疗组给予枯草杆菌二联活菌肠溶胶囊联合乳果糖口服溶液口服,对照组给予谷氨酸钠、谷氨酸钾静脉输注。两组疗程均为14天。观察患者肝性脑病症状的改善及治疗前后血氨水平。结果治疗组总有效率为83.3%,其症状改善和降低血氨均优于对照组(P=0.044、0.038),差异有统计学意义。结论枯草杆菌二联活菌肠溶胶囊联合乳果糖治疗肝性脑病具有较好的疗效。     

Hepatic encephalopathy: pathophysiology and advances in therapy.

Hepatic encephalopathy is a major neuropsychiatric complication of cirrhosis. Hepatic encephalopathy can occur in patients with fulminant liver disease without evidence of portosystemic shunting. The syndromes are distinct in acute liver failure and cirrhosis. The pathogenesis of hepatic encephalopathy probably is multifactorial, although the predominant causative agent appears to be ammonia. Prevention and treatment of hepatic encephalopathy in cirrhotic patients continues to rely on ammonia lowering strategies which include assessment of dietary protein intake and the use of lactulose, neomycin, sodium benzoate and L-ornithine-aspartate. This review provides recent information on the classification of hepatic encephalopathy, current theories for pathophysiological basis and evaluates the available therapies.     

乳果糖治疗亚临床肝性脑病的临床研究

目的 前瞻性对比乳果糖长、短程治疗对亚临床肝性脑病(SHE)的效果及其对SHE病程的影响。方法 经智力测验(数字连接试验和数字符号试验之一异常)诊断的SHE 64例随机分入对照组(21例)、短程组(21例)和长程组(22例),后2组分别服乳果糖达8周和24周。治疗前以及治疗后每间隔8周行血氨、智力测验和体感诱发电位(SEP)等检查,共随访24周。结果 每组各有20例完成追踪。与对照组和治疗前相比,长程组血氨和智力测验显著改善(P＜0．05—0．01)且SEP的N50波潜伏期稳定不变,短程组治疗到第8周也有改善(P＜0．05),但停药后又逐渐恶化。对照组的血氨、智力测验和N50波潜伏期逐渐恶化,在16周时后2项与治疗前差异有显著性(P＜0．05—0．01);而长程组血氨持续降低,其肝性脑病(HE)患病率(5％)显著低于短程组(30％)和对照组(40％)(P＜0．05)。结论 乳果糖维持治疗能够降低血氨、改善智力测验结果并可能防止SEP的恶化,最终降低HE的患病率。     

Advances in the Evaluation and Management of Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy (MHE) is a neurocognitive disorder that affects up to 80% of cirrhotic patients. Similar to overt hepatic encephalopathy, ammonia and oxidative stress play key roles in the pathogenesis of MHE. However, MHE is characterized by subtle deficits and psychomotor abnormalities that can only be elicited by specialized psychometric tests. Although no gold standard exists for the diagnosis, MHE remains an important entity for clinicians to recognize because of its negative impact on a patient’s health-related quality of life and association with driving impairment and vehicle accidents. MHE has also been associated with an increased rate in the development of overt hepatic encephalopathy and increased mortality; therefore, identification and treatment should not be delayed. Treatment to date has been focused on reducing serum ammonia levels with agents such as lactulose, probiotics, and synbiotics. MHE is a real and growing problem that is epidemic in cirrhosis, and increasing awareness of this condition is necessary for adequate management of these patients.     

Role of circulating neurotoxins in the pathogenesis of hepatic encephalopathy: potential for improvement following their removal by liver assist devices

Abstract Both acute and chronic liver failure result in impaired cerebral function known as hepatic encephalopathy (HE). Evidence suggests that HE is the consequence of the accumulation in brain of neurotoxic and/or neuroactive substance including ammonia, manganese, aromatic amino acids, mercaptans, phenols, short‐chain fatty acids, bilirubin and a variety of neuroactive medications prescribed as sedatives to patients with liver failure. Brain ammonia concentrations may attain levels in excess of 2 mm , concentrations which are known to adversely affect both excitatory and inhibitory neurotransmission as well as brain energy metabolism. Manganese exerts toxic effects on dopaminergic neurones. Prevention and treatment of HE continues to rely heavily on the reduction of circulating ammonia either by reduction of gut production using lactulose or antibiotics or by increasing its metabolism using l ‐ornithine‐l ‐aspartate. No specific therapies have so far been designed to reduce circulating concentrations of other toxins. Liver assist devices offer a potential new approach to the reduction of circulating neurotoxins generated in liver failure. In this regard, the Molecular Absorbents Recirculating System (MARS) appears to offer distinct advantages over hepatocyte‐based systems.     

Effects of Alcohol on the Brain in Cirrhosis: Beyond Hepatic Encephalopathy

Recent advances have led to a greater understanding of how alcohol alters the brain, both in acute stages (intoxication and alcohol withdrawal) and in chronic misuse. This review focuses on the current understanding of how alcohol affects the brain in cirrhosis patients with and without hepatic encephalopathy (HE). Chronic alcohol use is associated with nutritional deficiencies, dementia, cirrhosis, and decompensating events such as HE. Direct toxicity on brain tissue, induction of neuro‐inflammation, and alcohol's alterations of the gut microbiome are possible mechanisms for the clinical features of HE associated with alcohol use. Acute management of the alcoholic cirrhosis patient with altered mental status should focus on ruling out other causes, best intensive care, and use of gut‐based therapies such as lactulose and rifaximin. Long‐term management centers on optimizing treatment of concurrent mood disorders, nutritional support, and medical management of complications associated with cirrhosis. Future studies are needed to clarify mechanisms of brain injury in concomitant alcohol misuse and HE in addition to designing treatment interventions in order to improve outcomes in these patients.     

Lactitol in the treatment of chronic hepatic encephalopathy: an open comparison with lactulose.

Lactulose is currently the drug of choice for the treatment of hepatic encephalopathy. It is, however, only available as a syrup which is contaminated with other sugars. Consequently patients may express aversion to its excessively sweet taste and many experience nausea because of its hyperosmolarity. Lactitol is a disaccharide analogue of lactulose which can be produced as a pure crystalline powder with a low relative sweetness. Theoretically it should have the same therapeutic effects as lactulose but fewer side effects. Five patients with chronic hepatic encephalopathy on maintenance lactulose were monitored clinically, psychometrically, and by measurement of venous blood ammonia, electroencephalogram mean cycle frequency, and cerebral blood flow during three months treatment with lactulose and a similar period on lactitol. Lactitol was at least as efficacious as lactulose but was more acceptable because its cathartic effect was more predictable, its formulation was more convenient and its less sweet taste preferred. Lactitol is the ideal successor to lactulose for treatment of this condition.     

Rifaximin, a nonabsorbed oral antibiotic, in the treatment of hepatic encephalopathy: antimicrobial activity, efficacy, and safety

The nonabsorbed (< 0.4%) oral antibiotic rifaximin, which has been available for enteric bacterial conditions for more than a decade in several countries outside the United States, was recently introduced in the United States for the treatment of travelers' diarrhea, and is being evaluated in clinical trials for possible introduction for hepatic encephalopathy and other conditions involving enteric bacteria. This article discusses the antimicrobial activity, efficacy, and safety of rifaximin in hepatic encephalopathy. Rifaximin is a nonsystemic antibiotic with antibacterial activity against enteric pathogens for gastrointestinal infections. In 15 studies, several of which were adequately powered to assess efficacy, rifaximin was at least as effective as lactulose/lactitol (the current mainstay of pharmacologic treatment for hepatic encephalopathy) and neomycin and paromomycin (the antibiotics most commonly prescribed for hepatic encephalopathy) in improving neurologic signs and symptoms and reducing blood ammonia levels. The results of studies employing small samples are similar to those of the larger studies. Finally, rifaximin has a good tolerability profile in patients with hepatic encephalopathy, and thus appears to constitute a promising new option for this disorder. The current database on rifaximin would be strengthened by results of placebo-controlled studies to quantify more precisely the benefits of therapy.     

Minimal hepatic encephalopathy: time to recognise and treat

Minimal hepatic encephalopathy represents a part of the spectrum of hepatic encephalopathy and is the mildest form. While patients with hepatic encephalopathy have impaired intellectual functioning, personality changes, altered levels of consciousness, and neuromuscular dysfunction, patients with minimal hepatic encephalopathy have no recognisable clinical symptoms of hepatic encephalopathy but have mild cognitive and psychomotor deficits. The prevalence of minimal hepatic encephalopathy has been reported to vary between 30% and 84% in patients with liver cirrhosis and is higher in patients with poor liver function. The diagnosis is usually made by neuropsychological and/or neurophysiological testing in cirrhotic patients who are otherwise normal on neurological examination. Minimal hepatic encephalopathy is a clinically significant disorder that impairs the health-related quality of life, predicts the development of overt encephalopathy and is probably associated with a poor prognosis. Thus screening all patients with cirrhosis for minimal hepatic encephalopathy using psychometric testing is recommended. Pharmacologic therapy is recommended for patients diagnosed with minimal hepatic encephalopathy. The pathogenesis of minimal hepatic encephalopathy is considered similar to that of overt hepatic encephalopathy and ammonia plays a key role. Thus ammonia lowering agents such as lactulose, L-ornithine and L-aspartate that have good safety profiles are recommended. Future studies will better define the role of probiotics, levocarnitine and sodium benzoate.     

Systematic review and meta-analysis of randomized trials on probiotics for hepatic encephalopathy

Aim: The objective of this systematic review and meta‐analysis was to assess the efficacy of probiotics and synbiotics in patients with hepatic encephalopathy. Methods: Eligible trials were identified by searching electronic databases including MEDLINE, the Cochrane Library, Science Citation Index and Embase, abstract proceedings, reference lists and ongoing trial registers until 13 October 2010. We included randomized controlled trials comparing probiotics and synbiotics with no intervention, placebo or lactulose in patients with hepatic encephalopathy. The primary outcome measure was improvement in hepatic encephalopathy. Results were expressed as risk rates (RR) with confidence intervals (CI) and intertrial heterogeneity as I². Results: Seven trials with a total of 393 patients were analyzed. Compared to placebo or lactulose, treatment with probiotics or synbiotics significantly improved hepatic encephalopathy (RR = 1.40, 95% CI = 1.05–1.86, I² = 5%). Probiotics decreased arterial ammonia (weighted mean difference 15.95; 95% CI = 26.72–3.28; I² = 68%), but not venous ammonia (weighted mean difference 5.23; 95% CI = 21.77–11.30; I² = 89%). Treatment with probiotics or synbiotics did not significantly affect the psychometric tests. Overall adverse events were reported in four trials with no difference between probiotics and placebo groups (RR = 0.32, 95% CI = 0.04–2.57; I² = 59%). Regression analysis showed evidence of small‐study effects. Conclusion: The present meta‐analysis suggests that probiotics may be an effective treatment of hepatic encephalopathy, though rigorous evaluation in standardized, randomized, clinical trial with clinically relevant outcomes is still needed.     

Overt Hepatic Encephalopathy: Current Pharmacologic Treatments and Improving Clinical Outcomes

Overt hepatic encephalopathy is a generally reversible neurologic complication of cirrhosis. Overt hepatic encephalopathy has been associated with poor hospitalization- and mortality-related outcomes, which is important given increasing hepatic encephalopathy-related hospitalizations over time. The aim of this narrative review is to provide an overview of hospital- and mortality-related outcomes in patients with overt hepatic encephalopathy and the pharmacologic therapies that may improve these outcomes. Guideline-recommended prophylaxis with lactulose (first-line therapy) or secondary prophylaxis with rifaximin plus lactulose decreases hospital admissions and mortality rates. Rifaximin or lactulose treatment was beneficial for reducing the hospitalization rate in patients with hepatic encephalopathy compared with no treatment. Further, retrospective studies have shown that rifaximin with or without lactulose was effective for decreasing the number of hepatic encephalopathy episodes, hepatic encephalopathy-related hospitalizations, and duration of hospitalization. Ornithine phenylacetate, an ammonia-reducing agent currently in development, is also being investigated in hospitalized patients with hepatic encephalopathy. Overall, data support that prophylaxis for the prevention of hepatic encephalopathy recurrence improves outcomes in patients with cirrhosis and a history of hepatic encephalopathy.     

Can Lactobacillus acidophilus improve minimal hepatic encephalopathy? A neurometabolite study using magnetic resonance spectroscopy

Background and study aimsMinimal hepatic encephalopathy (MHE) is diagnosed when hepatic patients perform worse on psychometric tests compared to healthy controls. This study aimed to evaluate probiotics as alternative therapy in MHE.Patients and methodsThis is an open-label randomised controlled trial, performed in the Department of Tropical Medicine and Infectious Diseases, Tanta University Hospitals, from March 2010 to January 2012. A total of 90 patients with MHE were allocated by simple randomisation to three parallel equal groups. Group A received lactulose, group B a probiotic (Lactobacillus acidophilus) and group C served as the control. After informed consent, patients were tested for gut micrecology, fasting blood ammonia, liver functions and magnetic resonance spectroscopy (MRS) examination to study brain metabolites, mainly choline (Cho), myo-inositol (mI), glutamine + glutamate (Glx) and creatinin (Cre). Patients who developed overt encephalopathy were excluded from analysis. The whole battery of investigations was repeated in the same order after 4 weeks.ResultsThe probiotic was better tolerated than lactulose. The relative risk reduction (RRR) of developing overt encephalopathy was 60% in the case of lactulose and 80% in the case of probiotic, with a number needed to treat (NNT) of 2.4 and 2.3, respectively. The differential but not total microecology count was significantly shifted towards saccharolytic rather than proteolytic bacteria. The mI/Cre and (Cho + mI)/Glx ratios were significantly increased and the Glx/Cre ratio was significantly reduced after 1 month-follow-up in the probiotic group compared to the lactulose group and in both treatment groups compared to the control group.ConclusionBoth probiotic and lactulose therapy can improve blood ammonia and psychometric tests in MHE and reduce the risk of developing overt encephalopathy. MRS showed more improvement in the levels of brain neurometabolites in the probiotic group.     

Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial.

A prospective randomized double-blind study was conducted to evaluate the efficacy of sodium benzoate in the treatment of acute portal-systemic encephalopathy. Seventy-four consecutive patients with cirrhosis or surgical portasystemic anastomosis and hepatic encephalopathy of less than 7 days duration were randomized to receive lactulose (dose adjusted for 2 or 3 semiformed stools/day) or sodium benzoate (5 gm twice daily). Assessment of response included mental status, asterixis, arterial ammonia level, electroencephalogram and number-connection test. Each was given a score between 0 and 4+. A portal-systemic encephalopathy index was calculated with these scores. Visual, auditory and somatosensory evoked potentials and a battery of psychometric tests for intelligence and memory were also performed to assess improvement. Thirty-eight patients received sodium benzoate; 36 took lactulose. Thirty patients (80%) receiving sodium benzoate and 29 (81%) receiving lactulose recovered; the remaining patients died. Improvement in portal-systemic encephalopathy parameters occurred in both treatment groups and was similar (p greater than 0.1). Electroencephalogram and evoked potentials were not as helpful as mental status in assessing of recovery. Psychometric test scores remained abnormal after recovery of mental status (21 to 42 days) and were probably too sensitive for monitoring of these patients. The incidence of side effects was similar in the two treatment groups. The cost of lactulose for one course of therapy was 30 times that of sodium benzoate. We conclude that sodium benzoate is a safe and effective alternative to lactulose in the treatment of acute portasystemic encephalopathy.     

Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis

Background/Aims: Minimal hepatic encephalopathy (MHE) impairs health‐related quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients. Lactulose is effective in the treatment of MHE. However, not all patients respond to lactulose. We evaluated predictors of nonresponse to lactulose. Patients and methods: Consecutive 110 cirrhotic patients without HE were evaluated for MHE by psychometry, P300 auditory event‐related potential (P300ERP), venous ammonia and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry and P300ERP (>2 SD). MHE patients were treated with lactulose for 1 month. Response was defined by normalization of the abnormal test parameters (both psychometric tests and P300ERP). Results: Sixty patients (54.5%) were diagnosed as having MHE: 17/39 (44%) in Child's A, 21/42 (50%) Child's B and 22/29 (76%) in Child's C. There was a significant difference between Child's C's vs Child's A's and B's (P<0.05). Abnormal psychometric tests and abnormal P300ERP were seen in 74 (67%) and 74 (67%) patients respectively. Of 60 patients with MHE, after treatment, psychometry remained abnormal in 22 (36.6%) and P300ERP in 21 (35%) patients. CFF was<38 Hz in 34 (57%) and 11 (18%) patients, respectively, before and after treatment in MHE patients. There was a significant difference between the baseline serum sodium level (134.7±2.6 vs 131.1±2.2 mmol/L, P=0.001) and the venous ammonia level (76.6±20.7 vs 113.4±22.8 μmol/L, P=0.001) between responders vs nonresponders. Receiver operating characteristic analysis was performed to identify the cutoff for venous ammonia [cutoff 93.5 mmol/L, area under the curve (AUC) 0.892 (0.814–0.970)] and for the serum sodium level [cutoff 132.5 mmol/L, AUC 0.874 (0.779–0.998)]. Taking a cutoff of 93.5 mmol/L for ammonia patient had a sensitivity of 88.5% and a specificity of 79.4%, respectively, and a cutoff of 132.5 mmol/L for serum sodium patient had a sensitivity of 76.5% and a specificity of 88.5% for nonresponse to lactulose. On univariate analysis and multivariate analysis, serum sodium and venous ammonia were the only two parameters associated with nonresponse to lactulose. Conclusion: The prevalence of MHE was 55% and MHE improved in 57% patients with lactulose. Baseline low serum sodium and high venous ammonia were highly predictive of nonresponse to lactulose therapy.     

Diagnosis and treatment of hepatic encephalopathy

Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia's key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.     

Ammonia and Hepatic Encephalopathy: The More Things Change,the More They Remain the Same

Ammonia is thought to be central in the pathogenesis of hepatic encephalopathy and has been of importance to generations dating back to the early Egyptians. Hippocrates 2500 years ago described ‘encephalopathy’ simply translated as ‘inside head suffering.’ Over 1500 papers have been written on hepatic encephalopathy since 1966, but only a minority of these actually refer to the original observation of hepatic encephalopathy and the link with ammonia made by Marcel Nencki and Ivan Pavlov in 1893 with very little acknowledgement being made to the early landmark studies which described the importance of the muscle and kidneys in maintaining ammonia homeostasis as well as the liver and gut. Furthermore, infection was recognized as being an important modulator of brain function by the ancient Greek physicians and philosophers. This review focuses upon the original experiments of Nencki and Pavlov and describes how they fit into what we understand about the pathophysiology and treatment of hepatic encephalopathy today.