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Minimal/Covert Hepatic Encephalopathy – Impact of Comorbid Conditions

  • Karin Weissenborn
    Correspondence
    Address for correspondence: Karin Weissenborn, Clinic for Neurology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Tel.: +49 511 532 2339; fax: +49 511 532 3115.
    Affiliations
    Clinic for Neurology, Hannover Medical School, Hannover, Germany
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Published:October 11, 2018DOI:https://doi.org/10.1016/j.jceh.2018.08.010
      Mild cognitive dysfunction as in minimal or covert hepatic encephalopathy (HE) can be found in a variety of metabolic disturbances, several neurological diseases, and even older age. Because liver cirrhosis usually is accompanied by one or the other of these, a differentiation between HE and cognitive decline because of comorbidities is difficult. Somehow discriminating is the impairment of motor speed and accuracy, which is more prominent in HE than in any of the comorbidities. The observation that, for example, diabetes mellitus, renal dysfunction, infections, or hyponatremia as well as older age increase the risk of developing HE indicates the interaction between these factors and liver dysfunction in the development of HE and the necessity to adjust the therapy accordingly.

      Keywords

      Abbreviations:

      DM (diabetes mellitus), HCV (hepatitis C virus), HE (hepatic encephalopathy), NCT B (number connection test B)
      Neither neuropsychological nor neurophysiological findings characteristic for hepatic encephalopathy (HE) are specific. Thus, consideration of comorbidities is mandatory in diagnosing HE. Montagnese et al. reported that 95 of 177 prospectively recruited patients with cirrhosis and HE in their center had comorbidities that could add to their symptoms besides HE.
      • Montagnese S.
      • Schiff S.
      • Amodio P.
      Quick diagnosis of hepatic encephalopathy: fact or fiction?.
      Most important are renal dysfunction, hyponatremia, diabetes mellitus (DM), infection, and thiamine deficiency. But, of course, also genuine neurological disorders such as dementia could play a role in an individual case. By analyzing the data of about 15.000 patients with alcoholic or cryptogenic cirrhosis, Jepsen et al. found a 10% prevalence of DM, while 5% of their patients had cerebrovascular disease and 1% had severe renal dysfunction.
      • Jepsen P.
      • Vilstrup H.
      • Andersen P.K.
      • Lash T.L.
      • Sørensen H.T.
      Comorbidity and survival of Danish cirrhosis patients: a nationwide population-based cohort study.
      The rate of diabetes and renal dysfunction in a population of patients with liver cirrhosis varies with the underlying liver disease and the severity of liver dysfunction. In patients with hepatitis C virus, cirrhosis diabetes was observed in up to 1/3 of the patients,
      • Zein N.N.
      • Abdulkarim A.S.
      • Wiesner R.H.
      • Egan K.S.
      • Persing D.H.
      Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease.
      and patients on the waiting list for transplantation showed significant renal dysfunction in about 20%.
      • Patt C.H.
      • Fairbanks K.D.
      • Thuluvath P.J.
      Renal insufficiency may partly explain chronic anemia in patients awaiting liver transplantation.
      Hyponatremia (serum sodium level < 135 mmol/l) was observed in 31% of patients with cirrhosis on the waiting list for liver transplantation in a survey in the United States and has been shown to be correlated with both HE and mortality.
      • Kim W.R.
      • Biggins S.W.
      • Kremers W.K.
      • et al.
      Hyponatremia and mortality among patients on the liver-transplant waiting list.
      • Cordoba J.
      • Garcia-Martinez R.
      • Simon-Talero M.
      Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence.
      The rate of bacterial infections in patients with liver cirrhosis has been reported as 25% to 35%
      • Jalan R.
      • Fernandez J.
      • Wiest R.
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL special conference 2013.
      and may rise to 45% in patients with gastrointestinal bleedings.
      • Tandon P.
      • Garcia-Tsao G.
      Bacterial infections, sepsis, and multiorgan failure in cirrhosis.
      Thiamine deficiency is usually considered in patients with alcohol-toxic cirrhosis presenting with the characteristic triad of neurological symptoms—ophthalmoplegia, ataxia, and confusion/memory loss. But thiamine deficiency may as well present with milder signs of brain dysfunction such as fatigue, apathy, difficulty in concentration, and memory and in these cases is at risk to be overlooked by clinical routine examination.
      • Butterworth R.F.
      Thiamine deficiency-related brain dysfunction in chronic liver failure.
      Of note, thiamine deficiency is not restricted to patients with alcoholic cirrhosis but may be present in other cirrhotic patients as well because of malnutrition and loss of hepatic thiamine stores.
      • Butterworth R.F.
      Thiamine deficiency-related brain dysfunction in chronic liver failure.
      Data on the prevalence of thiamine deficiency in patients with cirrhosis are missing.
      The mentioned comorbidities may significantly affect brain function themselves (Table 1), but—even more importantly—they enhance the effect of metabolic and inflammatory alterations associated with end-stage liver disease on brain function.
      Table 1Pattern of (Subclinical) Cognitive Dysfunction That has Been Observed in Various Comorbidities of Liver Cirrhosis.
      DisorderAttentionMemoryExecutive functionVisuoconstructionProcessing speedMotor speedMotor accuracy
      Hepatic encephalopathyXXXXXX
      Diabetes mellitusXXXXX
      Renal dysfunctionXXXXX
      HyponatremiaXX
      Sepsis
      Data referring to septic encephalopathy were achieved after the patients' recovery.
      XXXXX
      Wernicke's encephalopathyXXXXXX
      HE, hepatic encephalopathy.
      The table lists those domains that may be affected in HE compared with various comorbidities. Obviously there is a significant overlap regarding the domains affected in the different conditions. Especially attention, executive function, and processing speed are impaired, irrespective of the underlying disorder. Although also patients with diabetes mellitus, renal dysfunction, and Wernicke's encephalopathy show alterations of motor function, these are less pronounced than in patients with HE.
      a Data referring to septic encephalopathy were achieved after the patients' recovery.
      Attention, executive function, and memory are significantly altered in patients with chronic kidney disease grade 4 and 5 and further decline in patients on hemodialysis.
      • Tryc A.B.
      • Alwan G.
      • Bokemeyer M.
      • et al.
      Cerebral metabolic alterations and cognitive dysfunction in chronic kidney disease.
      • Sanchez-Roman S.
      • Ostrosky-Solis F.
      • Morales-Buenrostro L.E.
      • Nogues-Vizcaino M.G.
      • Alberu J.
      • McClintock S.M.
      Neurocognitive profile of an adult sample with chronic kidney disease.
      The psychometric profile of patients with liver cirrhosis and renal dysfunction has not been separately studied in detail. But Kalaitzakis and Björnssen were able to show that, for example, the time needed to perform the number connection test B correlated with serum creatinine levels in their patients with liver cirrhosis and that serum creatinine was independently related to the presence of HE.
      • Kalaitzakis E.1
      • Björnsson E.
      Renal function and cognitive impairment in patients with liver cirrhosis.
      Serum creatinine levels have also been shown to indicate the risk for the development of HE.
      • Guevara M.
      • Baccaro M.E.
      • Ríos J.
      • et al.
      Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration.
      In subjects with type 2 DM, global cognition, semantic and episodic memory, working memory, and visuospatial ability were found to be impaired.
      • Arvanitakis Z.
      • Wilson R.S.
      • Bienias J.L.
      • Evans D.A.
      • Bennett D.A.
      Diabetes mellitus and risk of alzheimer disease and decline in cognitive function.
      In patients with type 1 DM, visual attention and perception, psychomotor efficiency, speed of information processing, and cognitive flexibility were affected.
      • Brands A.M.
      • Biessels G.J.
      • de Haan E.H.
      • Kappelle L.J.
      • Kessels R.P.
      The effects of type 1 diabetes on cognitive performance: a meta-analysis.
      Both, type 1 and type 2 DM increase the risk of developing dementia.
      • Ott A.
      • Stolk R.P.
      • van Harskamp F.
      • Pols H.A.P.
      • Hofman A.
      • Breteler M.M.B.
      Diabetes mellitus and the risk of dementia : the Rotterdam Study.
      • Biessels G.J.
      • Staekenborg S.
      • Brunner E.
      • Brayne C.
      • Scheltens P.
      Risk of dementia in diabetes mellitus: a systematic review.
      In regard to HE, an association with diabetes has been shown for minimal and overt HE.
      • Ampuero J.
      • Ranchal I.
      • del Mar Díaz-Herrero M.
      • del Campo J.A.
      • Bautista J.D.
      • Romero-Gómez M.
      Role of diabetes mellitus on hepatic encephalopathy.
      • Elkrief L.
      • Rautou P.E.
      • Sarin S.
      • Valla D.
      • Paradis V.
      • Moreau R.
      Diabetes mellitus in patients with cirrhosis: clinical implications and management.
      Considering possible mechanisms behind this association, the hypothesis that diabetes could increase ammonia production by enhancing small intestine glutaminase type K is of special interest.
      • Elkrief L.
      • Rautou P.E.
      • Sarin S.
      • Valla D.
      • Paradis V.
      • Moreau R.
      Diabetes mellitus in patients with cirrhosis: clinical implications and management.
      Metformin, which reduces glutaminase activity in vitro, has been shown to decrease the incidence of HE in patients with cirrhosis. Another important factor is the increased release of proinflammatory cytokines in type 2 DM and insulin resistance. Several studies indicate a relationship between the levels of proinflammatory cytokines and severity of HE in patients with cirrhosis and in acute liver failure.
      • Ampuero J.
      • Ranchal I.
      • del Mar Díaz-Herrero M.
      • del Campo J.A.
      • Bautista J.D.
      • Romero-Gómez M.
      Role of diabetes mellitus on hepatic encephalopathy.
      • Elkrief L.
      • Rautou P.E.
      • Sarin S.
      • Valla D.
      • Paradis V.
      • Moreau R.
      Diabetes mellitus in patients with cirrhosis: clinical implications and management.
      Proinflammatory cytokines are related to cognitive dysfunction also apart from HE. Alterations of cognition and consciousness have been observed even in patients with uncomplicated infections of the urinary tract, although predominantly in subjects with pre-existing brain disorder.
      • Hufschmidt A.
      • Shabarin V.
      • Rauer S.
      • Zimmer T.
      Neurological symptoms accompanying urinary tract infections.
      And, up to 70% of patients with bacteremia and fever show neurological symptoms ranging from lethargy and mild inattention to coma.
      • Chaudhry N.
      • Duggal A.K.
      Sepsis associated encephalopathy.
      • Lamar C.D.1
      • Hurley R.A.
      • Taber K.H.
      Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome.
      Of note, the incidence of sepsis-associated encephalopathy is highest with biliary or intestinal infections and pneumonia, and sepsis-associated encephalopathy carries the risk of long-term cognitive impairments, including alterations in mental processing speed, executive function, memory, attention, and visuospatial abilities.
      • Chaudhry N.
      • Duggal A.K.
      Sepsis associated encephalopathy.
      • Lamar C.D.1
      • Hurley R.A.
      • Taber K.H.
      Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome.
      These findings are of interest regarding the strong association between infection and HE on the one side and the ongoing discussion on the reversibility of cognitive dysfunction in patients with HE after successful liver transplantation on the other.
      • Merli M.
      • Lucidi C.
      • Pentassuglio I.
      • et al.
      Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      • Tryc A.B.
      • Pflugrad H.
      • Goldbecker A.
      • et al.
      New-onset cognitive dysfunction impairs the quality of life in patients after liver transplantation.
      In patients with liver cirrhosis, infections are considered as significant risk factors for the development of HE.
      • Merli M.
      • Lucidi C.
      • Pentassuglio I.
      • et al.
      Increased risk of cognitive impairment in cirrhotic patients with bacterial infections.
      Shawcross et al. showed that hyperammonemia induced by administration of an amino acid solution to cirrhotic patients results in a deterioration in neuropsychological function in the presence of a systemic inflammatory response but not after resolution of the infection.
      • Shawcross D.L.
      • Davies N.A.
      • Williams R.
      • Jalan R.
      Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
      Hyponatremia is another significant risk factor for the development of HE.
      • Cordoba J.
      • Garcia-Martinez R.
      • Simon-Talero M.
      Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence.
      • Guevara M.
      • Baccaro M.E.
      • Ríos J.
      • et al.
      Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration.
      Per se hyponatremia may stay without any symptoms or may lead to severe neurological complications including disorientation, seizures, and disturbance of consciousness depending on the rate and extent of alterations.
      • Adrogué H.J.
      • Madias N.E.
      Hyponatremia.
      But, even mild hyponatremia may affect cognitive function, especially attention.
      • Renneboog B.
      • Musch W.
      • Vandemergel X.
      • Manto M.U.
      • Decaux G.
      Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.
      In patients with liver cirrhosis, hyponatremia adds to the ammonia effect on astrocyte volume and exacerbates astrocytic swelling because of a loss of organic osmolytes, such as myo-inositol.
      • Cordoba J.
      • Garcia-Martinez R.
      • Simon-Talero M.
      Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence.
      Finally, the most frequent comorbidities present in patients with liver cirrhosis share neurological symptoms with HE and tend to add to the mechanisms behind the development of HE, thus increasing the risk for HE. The significant alteration of motor speed and accuracy together with increased plasma ammonia levels helps differentiate HE from other metabolic encephalopathies. But even if these motor deficits are present, the impact of comorbidities on other domains such as attention, for example, cannot be determined. Thus, HE therapy has to consider the comorbidities as well.

      Conflicts of interest

      The author has none to declare.

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