Liver cirrhosis is a chronic, progressive disorder in which fibrous scar tissue progressively replaces functioning hepatic parenchyma, distorting normal architecture into regenerative nodules and culminating in impaired synthetic function and portal hypertension [1]. Hepatic encephalopathy (HE) — a reversible neuropsychiatric syndrome arising from the accumulation of gut-derived neurotoxins that the failing liver can no longer clear — is among the most serious and potentially fatal complications of this process [2,3]. Its clinical spectrum extends from minimal cognitive and psychomotor impairment detectable only on formal neuropsychometric testing, through overt confusion and disorientation, to deep coma [4]. The burden falls heavily on developing nations. In India, chronic liver disease is a leading contributor to premature mortality, driven by rising alcohol consumption, endemic viral hepatitis and an expanding prevalence of metabolic liver disease [5]. Every episode of overt encephalopathy carries prognostic weight: the appearance of HE in a cirrhotic patient marks the transition to decompensated disease and is associated with a substantial reduction in survival [6]. The pathophysiology is multifactorial. Ammonia, generated by intestinal bacterial degradation of nitrogenous substrate and by glutaminase activity in enterocytes, is normally converted to urea by the periportal hepatocyte. In cirrhosis this capacity is lost and portosystemic shunting delivers ammonia directly to the systemic circulation, where it crosses the blood–brain barrier to cause astrocyte swelling and glutamatergic dysfunction [7]. Superimposed on hyperammonaemia are systemic inflammation and oxidative stress, which act synergistically to lower the threshold at which a given ammonia concentration produces cerebral dysfunction [8]. Gut dysbiosis and increased intestinal permeability complete the gut–liver–brain axis, permitting translocation of bacteria and endotoxin that further amplifies the inflammatory response [9]. Critically, most episodes of HE in cirrhosis are not spontaneous but are triggered by an identifiable precipitating event [10]. Bacterial infection — particularly spontaneous bacterial peritonitis, urinary tract infection and pneumonia — provokes HE through systemic inflammatory activation as well as increased ammonia generation [11,12]. Gastrointestinal bleeding, usually variceal, delivers a large protein load into the gut lumen while simultaneously producing hypovolaemia and renal hypoperfusion that impair ammonia clearance [7,13]. Constipation prolongs intestinal transit and increases colonic ammonia absorption [14]. Electrolyte disturbances, especially hyponatraemia and hypokalaemia arising from diuretic use or renal dysfunction, promote cerebral oedema and lower the encephalopathic threshold [15,16]. Sedatives, opioids and benzodiazepines may precipitate or deepen encephalopathy through direct neurotransmitter effects, and dehydration, malnutrition and continued alcohol use contribute further [4,17]. This distinction matters clinically. Unlike the underlying cirrhosis, precipitating factors are in large measure preventable and correctable, and outcome depends critically on their early identification and reversal [10]. Yet their relative frequency varies markedly between populations and healthcare systems: infection predominated in a Nepalese series [18], whereas variceal bleeding has led in several Indian reports. In resource-limited districts, late presentation and restricted access to endoscopy and intensive care may alter this distribution further. The present study was therefore undertaken to define the spectrum and frequency of precipitating factors of hepatic encephalopathy, together with the demographic profile and aetiology of cirrhosis, in patients presenting to a tertiary care teaching hospital in northern Karnataka.

This prospective, descriptive, hospital-based observational study was conducted in the Department of General Medicine, Ballari Medical College and Research Centre (formerly Vijayanagar Institute of Medical Sciences), Ballari, Karnataka, a tertiary care teaching hospital serving a predominantly rural catchment population. Ethical considerations: Institutional Ethics Committee clearance was obtained before commencement. Written informed consent was obtained from every participant, or from a legally acceptable representative where the level of consciousness precluded personal consent. Study population and eligibility: All patients with hepatic encephalopathy admitted during the study period were screened. Patients were eligible if aged above 12 years, of either sex, with established cirrhosis of any aetiology, presenting with hepatic encephalopathy of any grade including minimal hepatic encephalopathy. Patients with a known psychiatric disorder or on psychiatric treatment, those whose altered sensorium was attributable to metabolic disorder or head injury, and those in acute alcoholic intoxication or alcohol withdrawal were excluded, since these confound the clinical diagnosis of encephalopathy. Sample size estimation: The sample size was calculated using nMaster software version 2.0, applying the formula for a single proportion. The expected proportion was derived from the study of Poudyal et al., in which the commonest precipitant of hepatic encephalopathy was infection (49.2%), followed by electrolyte imbalance (41%), constipation (33.33%) and gastrointestinal bleeding (16%) [18]. Taking an expected proportion of 0.333, a two-sided alpha of 0.05 and a precision of 10% at 95% confidence, the required sample size was 85 subjects. Data collection: A structured questionnaire captured present and past illness, with specific enquiry into haematemesis and melaena, constipation, vomiting, diarrhoea, oliguria, fever, bleeding manifestations, high-protein dietary intake, recent paracentesis, trauma and surgery. Personal history of alcohol, smoking and intravenous drug use was recorded, and use of sedatives, diuretics, tranquillisers, analgesics and cough preparations documented in detail. Clinical examination: All patients were examined with particular attention to jaundice, pallor, fever, asterixis, hydration status, pedal oedema and ascites. A detailed abdominal and neurological examination was performed in every case. Hepatic encephalopathy was graded from grade 1 to grade 4 according to standard clinical criteria. Investigations: Every patient underwent complete blood count, liver and renal function tests, random blood sugar, serum electrolytes, serum albumin and coagulation profile. Ascitic fluid analysis was performed where ascites was present. Abdominal ultrasonography assessed liver and splenic size, parenchymal echogenicity, portal vein diameter and ascites; where ascites was detected, an ascitic tap excluded spontaneous bacterial peritonitis. Cirrhosis severity was graded by the Child–Pugh score [19]. Definition of precipitating factor: The precipitating factor was assigned as the clinically apparent event temporally related to the onset of encephalopathy and identified on the basis of history, examination and investigation. Infections were confirmed microbiologically or by ascitic fluid polymorphonuclear count where applicable. Statistical analysis: Data were entered and analysed using IBM SPSS Statistics version 23.0. Categorical variables were summarised by frequency and percentage analysis and continuous variables by mean and standard deviation. Associations between categorical variables were tested using the chi-square test, or Fisher's exact test where expected cell counts were small. A probability value below 0.05 was taken as statistically significant.

Eighty-five patients with cirrhosis presenting with hepatic encephalopathy were studied. Table 1. Age distribution of study participants (n = 85) Age group (years) Frequency (n) Percentage (%) 21–30 7 8.2 31–40 31 36.5 41–50 27 31.8 51–60 13 15.3 61–70 4 4.7 71–80 1 1.2 81–90 2 2.4 Total 85 100.0 The distribution was strikingly weighted towards the productive middle years of life. Fifty-eight patients (68.3%) were aged between 31 and 50 years, and the 36–46 year band alone accounted for approximately 45% of the cohort. The single most frequently represented ages were 38 years (8 patients, 9.4%) and 45 years (7 patients, 8.2%). Only 7 patients (8.2%) were above 60 years. This youthful age profile is markedly lower than that reported from Western series and reflects the early onset and rapid progression of alcohol-related liver disease in this population; it also implies that the elderly are under-represented because relatively few patients survive long enough with decompensated cirrhosis to present in later decades. Table 2. Sex distribution of study participants (n = 85) Sex Frequency (n) Percentage (%) Male 78 91.8 Female 7 8.2 Total 85 100.0 There was a pronounced male preponderance, with a male-to-female ratio of approximately 11:1. Only 7 women (8.2%) were represented. This disparity is far greater than the twofold to threefold male excess typically described for cirrhosis in general and is attributable chiefly to the very high prevalence of alcohol use among men in this region, compounded by differences in health-seeking behaviour and in the social acceptability of alcohol consumption among women. Table 3. Aetiology of cirrhosis among study participants (n = 85) Aetiology Frequency (n) Percentage (%) Alcoholic 70 82.4 Hepatitis B 8 9.4 Cryptogenic 4 4.7 Hepatitis C 3 3.5 Total 85 100.0 Alcohol was overwhelmingly the dominant cause, responsible for 70 of 85 cases (82.4%). Chronic viral hepatitis together accounted for a further 11 cases (12.9%), hepatitis B being roughly three times as frequent as hepatitis C. Cryptogenic cirrhosis, in which no aetiology was identified despite full investigation, comprised 4 cases (4.7%); this category probably conceals a proportion of non-alcoholic steatohepatitis and burnt-out autoimmune disease that formal histology or metabolic profiling might have identified. The near-total dominance of alcohol identifies it as the single most modifiable determinant of the disease burden in this catchment area. Table 4. Precipitating factors of hepatic encephalopathy (n = 85) Precipitating factor Frequency (n) Percentage (%) Gastrointestinal bleeding 33 38.8 Constipation 19 22.4 Infection — spontaneous bacterial peritonitis 10 11.8 Electrolyte imbalance 9 10.6 Infection — pneumonia 5 5.9 Overdiuresis 3 3.5 Infection — urinary tract infection 3 3.5 Paracentesis 2 2.4 Large-volume paracentesis 1 1.2 Total 85 100.0 This table addresses the primary objective of the study. Gastrointestinal bleeding was the single commonest precipitant, identified in 33 patients (38.8%) — more than one in every three episodes. Constipation followed in 19 patients (22.4%). Among infections, spontaneous bacterial peritonitis was the leading individual entity (10 patients, 11.8%), ahead of pneumonia (5, 5.9%) and urinary tract infection (3, 3.5%). Electrolyte imbalance accounted for 9 episodes (10.6%). Procedure- and treatment-related causes were uncommon: overdiuresis precipitated 3 episodes (3.5%), and paracentesis, including one large-volume tap, a further 3 (3.5%). Table 5. Precipitating factors grouped by mechanistic category (n = 85) Category Constituent factors Frequency (n) Percentage (%) Gastrointestinal bleeding Variceal and non-variceal haemorrhage 33 38.8 Constipation — 19 22.4 Infection SBP (10), pneumonia (5), UTI (3) 18 21.2 Electrolyte imbalance Hyponatraemia, hypokalaemia 9 10.6 Iatrogenic / procedure-related Overdiuresis (3), paracentesis (2), large-volume paracentesis (1) 6 7.1 Total 85 100.0 When the individual infective entities are aggregated, infection rises to become the third commonest category at 21.2%, only marginally behind constipation. The three leading categories — gastrointestinal bleeding, constipation and infection — together accounted for 70 of 85 episodes (82.4%). All three are amenable to well-established preventive measures: endoscopic variceal surveillance with beta-blockade or band ligation, regular lactulose therapy titrated to two or three soft stools daily, and prophylactic antibiotics with prompt diagnostic paracentesis in patients with ascites. The 7.1% of episodes attributable to iatrogenic causes is a small but wholly avoidable fraction, underlining the importance of cautious diuretic titration and adequate albumin replacement after large-volume paracentesis. Table 6. Distribution of encephalopathy grade by precipitating factor (percentages as reported) Precipitating factor Grade 1 Grade 2 Grade 3 Grade 4 Constipation 0.00% 57.14% 28.57% 14.29% Electrolyte imbalance 6.45% 54.84% 22.58% 16.13% Gastrointestinal bleeding 33.33% 33.33% 22.22% 11.11% Infection 2.63% 50.00% 28.95% 18.42% Note: percentages are reproduced exactly as reported in the source dataset. The implied denominators do not reconcile with the case counts in Table 4 (see Discussion, Limitations) and require verification against the primary records before publication. Grade 2 encephalopathy predominated across every precipitant, accounting for half or more of episodes triggered by constipation (57.14%), electrolyte imbalance (54.84%) and infection (50.00%). Infection was associated with the highest proportion of grade 4 (comatose) presentations at 18.42%, followed by electrolyte imbalance at 16.13%, consistent with the synergistic effect of systemic inflammation and hyponatraemia on cerebral function. Gastrointestinal bleeding showed the most even spread across grades, with an equal 33.33% at grades 1 and 2 and the lowest proportion of grade 4 disease (11.11%), suggesting that haemorrhage frequently declares itself clinically — through haematemesis or melaena — before encephalopathy has progressed to its deepest stages, thereby prompting earlier presentation.

The concentration of cases in the fourth and fifth decades, with 68.3% of patients aged 31–50 years and approximately 45% falling within the 36–46 year band, indicates that hepatic encephalopathy in this setting is predominantly a disease of middle age. This is somewhat younger than the mean ages of 52 and 54 years reported by Romero-Gómez et al. and Bustamante et al. respectively [20,21], a difference plausibly explained by earlier initiation of heavy alcohol use and the near-absence of non-alcoholic fatty liver disease as a competing aetiology in this cohort. The relative scarcity of cases beyond 60 years reflects both shorter exposure duration in the young and attrition from cirrhosis-related mortality before old age is reached. The male preponderance of 91.8% exceeded the 72% reported by Bustamante et al. [21] and is consistent with the observation of Sherlock and Dooley that men are disproportionately affected by cirrhosis and its complications [22]. Higher rates of hazardous alcohol consumption among men are the principal explanation [23]; sex differences in hepatic metabolism and in the immune response to viral hepatitis may contribute further [24]. Gastrointestinal bleeding emerged as the leading precipitant at 38.8%, closely comparable with the 44% reported by Cordoba et al. [10]. Luminal blood constitutes a substantial nitrogenous load that gut flora degrade to ammonia, while hypovolaemia simultaneously compromises renal ammonia clearance. This finding contrasts sharply with the series of Poudyal et al. from Nepal, in which infection led at 49.2% and gastrointestinal bleeding accounted for only 16% [18], and underscores how markedly the spectrum shifts with the aetiological mix of the underlying cirrhosis and with local access to variceal surveillance. Constipation ranked second at 22.4%, in keeping with the recognition by Ferenci et al. of impaired bowel transit as a frequent precipitant [25]. Prolonged colonic transit increases both the generation and the absorption of ammonia, and this factor is arguably the most easily corrected of all. Infections, at 21.2% when aggregated, approached the 25% reported by Ginès et al. [26], with spontaneous bacterial peritonitis the leading single organism-related entity. Electrolyte imbalance accounted for 10.6%, consistent with the emphasis placed by Riggio et al. on meticulous electrolyte management in preventing encephalopathy [27]. Alcoholic cirrhosis dominated at 82.4%, a proportion higher than in most Western series and reflecting regional drinking patterns; O'Shea et al. identified alcohol-related liver disease as a leading global cause of cirrhosis [28]. Hepatitis B at 9.4% and hepatitis C at 3.5% together confirm the continuing contribution of viral hepatitis described by Perz et al. [29], while cryptogenic cirrhosis at 4.7% probably includes unrecognised non-alcoholic steatohepatitis, as Bedossa and Paradis have argued [30]. Limitations: The single-centre design and sample of 85 restrict generalisability. Assignment of a single precipitating factor per patient may oversimplify episodes with more than one contributing trigger. Minimal hepatic encephalopathy was diagnosed clinically without formal psychometric testing, and covert cases were therefore likely under-ascertained. Most importantly, the percentages in Table 6 imply denominators inconsistent with the case counts in Table 4 and must be re-derived from the primary dataset before these grade-specific findings are relied upon.

In this prospective observational study of 85 cirrhotic patients presenting with hepatic encephalopathy at a tertiary centre in northern Karnataka, gastrointestinal bleeding was the single commonest precipitating factor, responsible for 38.8% of episodes, followed by constipation (22.4%), infection (21.2%, of which spontaneous bacterial peritonitis alone contributed 11.8%), electrolyte imbalance (10.6%) and iatrogenic causes (7.1%). Together, the three leading categories accounted for more than four-fifths of all episodes. The cohort was young, with over two-thirds aged between 31 and 50 years, overwhelmingly male (91.8%), and alcohol was the underlying aetiology of cirrhosis in 82.4% of cases. Every one of the principal precipitants identified is preventable or correctable. These findings therefore argue for a defined package of secondary prevention in every patient with cirrhosis: endoscopic variceal screening with beta-blockade or band ligation, standing lactulose therapy titrated to bowel frequency, a low threshold for diagnostic paracentesis and empirical antibiotics when ascites is present, and cautious diuretic titration with electrolyte monitoring. At a population level, the dominance of alcohol identifies reduction of harmful drinking among young and middle-aged men as the intervention with the greatest potential to reduce the burden of hepatic encephalopathy in this region. Larger multicentre studies with formal psychometric assessment of covert encephalopathy are needed to confirm these observations.

1. Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383(9930):1749–61. 2. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715–35. 3. Butterworth RF. Pathogenesis of hepatic encephalopathy in cirrhosis: the concept of synergism revisited. Metab Brain Dis. 2016;31(6):1211–5. 4. Ferenci P. Hepatic encephalopathy. Gastroenterol Rep (Oxf). 2017;5(2):138–47. 5. Mondal D, Das K, Chowdhury A. Epidemiology of liver diseases in India. Clin Liver Dis (Hoboken). 2022;19(3):114–7. 6. Romero-Gómez M, Montagnese S, Jalan R. Hepatic encephalopathy in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure. J Hepatol. 2015;62(2):437–47. 7. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc. 2015;90(5):646–58. 8. Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40(2):247–54. 9. Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut. 2016;65(12):2035–44. 10. Cordoba J, Ventura-Cots M, Simón-Talero M, Amorós À, Pavesi M, Vilstrup H, 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(2):275–81. 11. Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol. 2014;60(6):1310–24. 12. Bunchorntavakul C, Chamroonkul N, Chavalitdhamrong D. Bacterial infections in cirrhosis: a critical review and practical guidance. World J Hepatol. 2016;8(6):307–21. 13. Rahimi RS, Rockey DC. Complications of cirrhosis. Curr Opin Gastroenterol. 2012;28(3):223–9. 14. Pande C, Kumar A, Sarin SK. Small-intestinal bacterial overgrowth in cirrhosis is related to the severity of liver disease. Aliment Pharmacol Ther. 2009;29(12):1273–81. 15. Guevara M, Baccaro ME, Torre A, Gómez-Ansón B, Ríos J, Torres F, et al. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol. 2009;104(6):1382–9. 16. Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology. 2008;48(3):1002–10. 17. Sharma P, Sharma BC. Lactulose for minimal hepatic encephalopathy in patients with cirrhosis. Aliment Pharmacol Ther. 2014;39(7):689–94. 18. Poudyal NS, Chaudhary S, Kc S, Paudel BN, Basnet BK, Mandal A, et al. Precipitating factors and treatment outcomes of hepatic encephalopathy in liver cirrhosis. Cureus. 2019;11(4):e4363. 19. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9. 20. Romero-Gómez M, Córdoba J, Jover R, del Olmo JA, Ramírez M, Rey R, et al. Value of the critical flicker frequency in patients with minimal hepatic encephalopathy. Hepatology. 2007;45(4):879–85. 21. Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V, et al. Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol. 1999;30(5):890–5. 22. Sherlock S, Dooley J. Sherlock's diseases of the liver and biliary system. 11th ed. Oxford: Blackwell Science; 2002. 23. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet. 2009;373(9682):2223–33. 24. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–4. 25. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy — definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35(3):716–21. 26. Ginès P, Quintero E, Arroyo V, Terés J, Bruguera M, Rimola A, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987;7(1):122–8. 27. Riggio O, Angeloni S, Salvatori FM, De Santis A, Cerini F, Farcomeni A, 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(11):2738–46. 28. O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. Hepatology. 2010;51(1):307–28. 29. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–38. 30. Bedossa P, Paradis V. Cryptogenic cirrhosis and non-alcoholic fatty liver disease. Clin Liver Dis. 2003;7(1):175–85.