Metabolic Brain Disease

, Volume 32, Issue 2, pp 595–605 | Cite as

Sleep disturbances in patients of liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy

  • Jatinderpal Singh
  • Barjesh Chander SharmaEmail author
  • Vinod Puri
  • Sanjeev Sachdeva
  • Siddharth Srivastava
Original Article


Sleep disturbances are common in patients of cirrhosis with minimal hepatic encephalopathy (MHE) and affect health related quality of life (HRQOL). No study has evaluated effect of lactulose on sleep disturbances and correlation with HRQOL in patients with MHE. We assessed sleep disturbances in cirrhosis with MHE and effect of lactulose on sleep disturbances and HRQOL. One hundred patients of cirrhosis [MHE; (n = 50, age 45.3 ± 11.2 years, 45 males) no-MHE (n = 50, age 46.3 ± 10.4 years, 44 males)] were included. MHE was diagnosed with psychometric hepatic encephalopathy score (PHES) ≤ −5. All patients underwent laboratory parameters including arterial ammonia and critical flicker frequency (CFF) Sleep disturbances were measured with Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and polysomnography. HRQOL was measured with SF-36(v2) questionnaire. Patients with MHE were given lactulose therapy for 3 months and all the parameters were repeated. Poor quality of sleep and excessive day time sleepiness were more common in patients with MHE, compared to without MHE. With lactulose therapy there was improvement in MHE in 21 patients and arterial ammonia levels (93.74 ± 14.8 vs. 71.44 ± 18.8 μmol/L: p < 0.001), CFF (34.83 ± 3.54 vs. 39.44 ± 4.95 Hz: p < 0.001), PHES (−7.64 ± 2.1 vs. -5.58 ± 2.09: p < 0.001), PSQI (8.6 ± 3.3 vs. 5.2 ± 1.5: p < 0.001), ESS (12.52 ± 3.01 vs. 9.24 ± 2.27: p < 0.001) and HRQOL (p = 0.01). Excessive day time sleepiness and impaired sleep quality are common in patients with MHE and correlate with neuropsychiatric impairment. Improvement in MHE with lactulose also leads to improvement in sleep disturbances and HRQOL.


Hepatic encephalopathy Lactulose 



Minimal hepatic encephalopathy


Hepatic encephalopathy


Psychometric hepatic encephalopathy score


Child turcotte pugh


Model for end stage liver disease


Critical flicker frequency




Epworth sleepiness scale


Pittsburg sleep quality index


Health related quality of life


Confidence interval


Correlation coefficient


Compliance with ethical standards

Conflict of interest

All authors have no conflicts (financial, professional, or personal) that are relevant to the manuscript.

Funding source


Grant support


Supplementary material

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Table S6 (DOCX 14 kb)


  1. Arguedas MR, DeLawrence TG, McGuire BM (2003) Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci 48:1622–1626CrossRefPubMedGoogle Scholar
  2. Bajaj JS (2008) Minimal hepatic encephalopathy matters in daily life. World J Gastroenterol 14(23):3609–3615CrossRefPubMedPubMedCentralGoogle Scholar
  3. Balata S, Damink SW, Ferguson K et al (2003) Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis. Hepatology 37:931–939CrossRefPubMedGoogle Scholar
  4. Bernsmeier C, Weisskopf DM, Pflueger MOL et al (2015) Sleep disruption and daytime sleepiness correlating with disease severity and insulin resistance in non-alcoholic fatty liver disease: a comparison with healthy controls. PLoS One 17:10(11)Google Scholar
  5. Bersagliere A, Raduazzo ID, Nardi M et al (2012) Induced hyperammonemia may compromise the ability to generate restful sleep in patients with cirrhosis. Hepatology 55(3):869–878CrossRefPubMedGoogle Scholar
  6. Butterworth RF (2002) Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 17:221–227CrossRefPubMedGoogle Scholar
  7. Buysse DJ, Reynolds CF, Monk TH et al (1989) The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res 28:193–213CrossRefPubMedGoogle Scholar
  8. Cordoba J (2011) New assessment of hepatic encephalopathy. J Hepatol 54(5):1030–1040CrossRefPubMedGoogle Scholar
  9. Cordoba J, Cabrera J, Lataif L et al (1998) High prevalence of sleep disturbance in cirrhosis. Hepatology 27:339–345CrossRefPubMedGoogle Scholar
  10. Cordoba J, Alonso J, Rovira A et al (2001) The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol 35:598–604CrossRefPubMedGoogle Scholar
  11. Das A, Dhiman RK, Saraswat VA et al (2001) Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 16:531–535CrossRefPubMedGoogle Scholar
  12. De Rui M, Schiff S, Aprile D et al (2013) Excessive daytime sleepiness and hepatic encephalopathy: it is worth asking. Metab Brain Dis 28(2):245–248CrossRefPubMedGoogle Scholar
  13. De Rui M, Middleton B, Sticca A et al (2015) Sleep and circadian rhythms in hospitalized patients with decompensated cirrhosis: effect of light therapy. Neurochem Res 40(2):284–292CrossRefPubMedGoogle Scholar
  14. Dhiman RK, Kurmi R, Thumburu KK et al (2010) Diagnosis and prognostic significance of minimal hepatic enceph-alopathy in patients with cirrhosis of liver. Dig Dis Sci 55:2381–2390CrossRefPubMedGoogle Scholar
  15. Ferenci P, Lockwood A, Mullen K et al (2002) Hepatic encephalopathy– definition, nomenclature, diagnosis, and quantification:final report of the working party at the 11th world congress of gastroenterology, Vienna, 1998. Hepatology 35:716–721CrossRefPubMedGoogle Scholar
  16. Groeneweg M, Quero JC, De Bruijn I et al (1998) Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 28(1):45–49CrossRefPubMedGoogle Scholar
  17. Groeneweg M, Moerland W, Quero JC et al (2000) Screening of subclinical hepatic encephalopathy. J Hepatol 32:748–753CrossRefPubMedGoogle Scholar
  18. Heeren M, Sojref F, Schuppner RAB et al (2014) Active at night, sleepy all day--sleep disturbances in patients with hepatitis C virus infection. J Hepatol 60(4):732–740CrossRefPubMedGoogle Scholar
  19. Horsmans Y, Solbreux PM, Daenens C et al (1997) Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 11:165–170CrossRefPubMedGoogle Scholar
  20. Johns MW (1991) A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 14:540–545CrossRefPubMedGoogle Scholar
  21. Kharbanda PS, Saraswat VA, Dhiman RK (2003) Minimal hepatic encephalopathy: diagnosis by neuropsychological and neurophysiologic methods. Indian J Gastroenterol 22(Suppl. 2):S37–S41PubMedGoogle Scholar
  22. Llansola M, Cantero JL, Hita-Yañez E et al (2012) Progressive reduction of sleep time and quality in rats with hepatic encephalopathy caused by portacaval shunts. Neuroscience 201:199–208CrossRefPubMedGoogle Scholar
  23. Lockwood AH, Yap EW, Wong WH (1991) Cerebral ammonia metabolism in patients with severe liver disease and minimal HE. J Cereb Blood Flow Metab 11:337–341CrossRefPubMedGoogle Scholar
  24. Marchesini G, Bianchi G, Amodio P et al (2001) Italian study Group for Quality of life in cirrhosis. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 120:170–178CrossRefPubMedGoogle Scholar
  25. Mittal VV, Sharma BC, Sharma P et al (2011) A randomized controlled trial comparing lactulose, probiotics, and L-ornithine L-aspartate in treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 23(8):725–732CrossRefPubMedGoogle Scholar
  26. Montagnese S, Middleton B, Skene DJ et al (2009) Nighttime sleep disturbance does not correlate with neuropsychiatric impairment in patients with cirrhosis. Liver Int 29(9):1372–1382CrossRefPubMedGoogle Scholar
  27. Montagnese S, De Pittà C, De Rui M et al (2014) Sleep-wake abnormalities in patients with cirrhosis. Hepatology 59(2):705–712CrossRefPubMedGoogle Scholar
  28. Mostacci B, Ferlisi M, Baldi Antognini A et al (2008) Sleep disturbance and daytime sleepiness in patients with cirrhosis: a case control study. Neurol Sci 29(4):237–240CrossRefPubMedGoogle Scholar
  29. Prasad S, Dhiman RK, Duseja A et al (2007) Lactulose improves cognitive functions and health- related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 45:549–559CrossRefPubMedGoogle Scholar
  30. Rechtschaffen A, Kales A (1968) Manual of standardized terminology, techniques, and scoring system for sleep stages of human subjects. Los Angeles, Brain Information Service/ Brain Research Institute/UCLAGoogle Scholar
  31. Rikkers L, Jenko P, Rudman D, Freides D (1978) Subclinical hepatic encephalopathy: detection, prevalence, and relationship to nitrogen metabolism. Gastroenterology 75:462–469PubMedGoogle Scholar
  32. Samanta J, Dhiman RK, Khatri A et al (2013) Correlation between degree and quality of sleep disturbance and the level of neuropsychiatric impairment in patients with liver cirrhosis. Metab Brain Dis 28(2):249–259CrossRefPubMedGoogle Scholar
  33. Schomerus H, Hamster W (2001) Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab Brain Dis 16:37–41CrossRefPubMedGoogle Scholar
  34. Schomerus H, Hamster W, Blunck H et al (1981) Latent portasystemic encephalopathy. I. Nature of cerebral functional defects and their effect on fitness to drive. Dig Dis Sci 26:622–630CrossRefPubMedGoogle Scholar
  35. Sharma P, Sharma BC, Puri V et al (2007) Critical flicker frequency: diagnostic tool for minimal hepatic encephalopathy. J Hepatol 47:67–73CrossRefPubMedGoogle Scholar
  36. Sherlock S, Summerskill WH, White LP et al (1954) Portal-systemic encephalopathy; neurological complications of liver disease. Lancet 267(6836):454–457PubMedGoogle Scholar
  37. Takano T, Tian GF, Peng W et al (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–270CrossRefPubMedGoogle Scholar
  38. Teodoro VV, Bragagnolo MA Jr, Lucchesi LM et al (2013) Polysomnographic sleep aspects in liver cirrhosis: a case control study. World J Gastroenterol 14;19(22):3433–3438CrossRefGoogle Scholar
  39. Vaquero J, Chung C, Blei AT (2003) Brain edema in acute liver failure. A window to the pathogenesis of hepatic encephalopathy. Ann Hepatol 2:12–22PubMedGoogle Scholar
  40. Ware JE Jr, Sherbourne CD (1992) The MOS 36-item short-form health survey (SF-36) I. Conceptual framework and item selection. Med Care 30:473–483CrossRefPubMedGoogle Scholar
  41. Watanabe A, Sakai T, Sato S et al (1997) Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 26:1410–1414CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Jatinderpal Singh
    • 1
  • Barjesh Chander Sharma
    • 1
    Email author
  • Vinod Puri
    • 2
  • Sanjeev Sachdeva
    • 1
  • Siddharth Srivastava
    • 1
  1. 1.Department of GastroenterologyG. B. Pant Institute of Postgraduate Medical Education and ResearchNew DelhiIndia
  2. 2.Department of NeurologyG. B. Pant Institute of Postgraduate Medical Education and ResearchNew DelhiIndia

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