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Prognostic Implications of Minimal/Covert Hepatic Encephalopathy: Large-scale Validation Cohort Studies

  • Christopher R. Flud
    Affiliations
    College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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  • Andres Duarte-Rojo
    Correspondence
    Address for correspondence: Andres Duarte-Rojo, University of Arkansas for Medical Sciences, Division of Gastroenterology and Hepatology, 4301 W Markham, Slot #567, Shorey Bldg S8/68, Little Rock, AR 72205, USA. Fax: +1 501 686 6248.
    Affiliations
    Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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      Minimal or Covert Hepatic Encephalopathy (MHE/CHE), the preclinical phase of Hepatic Encephalopathy (HE), is strongly associated with poorer Quality of Life (QOL), Overt HE (OHE), and death. Several diagnostic tests have been developed that have prognostic value in predicting clinical outcomes such as OHE, cirrhosis progression, and death. However, dispute among clinicians and HE researchers have kept its application largely underutilized. Current issues contributing to the confusion include: lack of a formal definition for CHE, uncertainty of which diagnostic tools to use, and whether one or two abnormal tests are required for a diagnosis. Due to this misunderstanding, the aims of this review were to consolidate large-scale (n ≥ 100) validation studies in order to discuss these obstacles and make recommendations for improving our approach to MHE/CHE. The studies included in this review are a great resource for initiating a unified effort for advancement in HE, and as such, it is our hope that this will drive progress toward common goals that will permanently improve the lives of patients with cirrhosis.

      Abbreviations:

      CHE (Covert Hepatic Encephalopathy), HE (Hepatic Encephalopathy), MHE/CHE (Minimal or Covert Hepatic Encephalopathy), OHE (Overt HE), QOL (Quality of Life)

      Keywords

      The current literature leaves little doubt regarding the importance of diagnosing Minimal or Covert Hepatic Encephalopathy (MHE/CHE). Several studies confirm MHE or CHE as predictors of Overt Hepatic Encephalopathy (OHE), decreased Quality of Life (QOL), and mortality. Missing from existing literature, however, is consistent proof of improved outcomes following resolution of MHE with anti-ammonia treatment. This has lowered enthusiasm among clinicians for pursuing MHE/CHE diagnoses via specialized testing. As such, less than 10% of clinicians routinely screen for MHE in patients with cirrhosis, a trend made worse by continued lack of agreement and understanding within the field (e.g., how Grade I Hepatic Encephalopathy [grade I HE] or CHE are addressed).
      • Laurisen M.M.
      • Bajaj J.S.
      Hepatic encephalopathy treatment and its effect on driving abilities: a continental divide.
      Since there is a disconnect between HE researchers and clinicians regarding the diagnosis, testing, and implications of MHE/CHE, we aimed to review and discuss published large-scale validation studies, outlining design variations affecting proper interpretation, and making recommendations for a unified clinical approach.
      Table 1 consolidates several large-scale (n ≥ 100) studies that assessed the ability of MHE/CHE to predict specific clinical outcomes. Results revealed variability in the prevalence of MHE/CHE, ranging from 14% to 70%, further illustrating the dependence of MHE/CHE diagnoses on the type of diagnostic test used and the concept that HE is a spectrum of related but distinct disorders. All studies included the Psychometric Hepatic Encephalopathy Score (PHES) to diagnose MHE. Neurophysiological tests (Electroencephalography [EEG] & Critical Flicker Frequency [CFF]) and neuropsychological tests (Stroop EncephalApp [StE], Inhibitory Control Test [ICT], Continuous Reaction Time [CRT], and Animal Naming Test [ANT1]) were included in varying degrees. The principal outcome linked to abnormal testing was OHE, although some studies included mortality as well.
      Table 1Prospective Large-scale Studies Addressing MHE/CHE Longitudinal Validation.
      Author, year & countryStudy designStudy results
      TargetPopulationTestsEndpointMHEOutcomes & follow-upValidation resultsComments
      Dhiman
      • Taneja S.
      • Dhiman R.
      • Khatri A.
      • et al.
      Inhibitory control test for the detection of minimal hepatic encephalopathy in patients with cirrhosis of liver.


      2010

      India
      MHEn = 100

      No prior OHE
      PHES

      ≤−5

      CFF

      Z score < 2
      SurvivalPHES 48%

      CFF 21%
      Death 31%

      L2FU: 6%

      Approximately 2 years
      PHES ≤ −6 is an independent predictor of poor prognosis

      Abnormal CFF did not have any prognostic value on survival
      Mean survival of 645 days with PHES > −6

      Mean survival of 490 days with PHES ≤ −6
      Taneja
      • Dhiman R.
      • Kurmi R.
      • Thumburu K.
      • et al.
      Impact of minimal/Covert hepatic encephalopathy on patients with cirrhosis.


      2012

      India
      MHEn = 102

      No prior OHE
      PHES

      ≤−5

      ICT

      ≥14 lures
      OHE

      Survival
      PHES 40%

      ICT 52%
      OHE 12%

      Death 10%

      6 m (average)
      PHES independently predicted increased risk of death and OHE

      ICT did not predict OHE or survival
      87% patients were classified as CTP-A or CTP-B, which may have contributed low incidence of OHE
      Montagnese
      • Montagnese S.
      • Balistreri E.
      • Schiff S.
      • et al.
      Covert hepatic encephalopathy: agreement and predictive validity of different indices.


      2014

      Italy
      CHEn = 132, 58 ± 11

      Cirrhosis

      No baseline OHE

      (grade I HE in 36%)

      Prior OHE in 63%
      PHES

      ≤−4

      CFF

      <38/39

      EEG
      Defined as normal/abnormal based on proposed spectral criteria.
      OHE ≥ 2PHES 33%

      CFF

      21–31%

      EEG 42%
      OHE 22%

      Death 13%

      LT 13%

      11 ± 7 m (available in 79 patients)
      CHE by PHES or EEG predicted OHE

      CFF did not predict OHE
      CHE predicted OHE

      Grade I HE had worse prognosis compared to MHE

      Prior OHE associated to worse PHES & EEG

      71% had PSS
      Riggio
      • Riggio O.
      • Amodio P.
      • Farcomeni A.
      • et al.
      A model for predicting development of overt hepatic encephalopathy in patients with cirrhosis.


      2015

      Italy
      MHEn = 216, 63 ± 12

      Cirrhosis

      No baseline OHE

      (no grade I HE)

      Prior OHE in 22%
      PHES

      ≤−4
      OHE ≥ 2PHES 44%OHE 32%

      Death 26%

      L2FU 2%

      LT 7%

      15 ± 12 m
      MHE by PHES predicted OHE (with or without prior OHE)Multivariable: ↓ albumin and prior OHE predicted OHE

      TIPS or PSS in 22%

      Precipitated HE: 79%
      Lauridsen
      • Lauridsen M.M.
      • Schaffalitzky de Muckadell O.B.
      • Vilstrup H.
      Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests.


      2015

      Denmark
      MHEn = 129, 59 (40–79)

      Cirrhosis

      (no grade I HE)

      Prior HE in 27%
      PHES

      <−4

      CRT

      <1.9
      OHEPHES 34%

      CRT 53%
      OHE 19%

      Death 23%

      11 ± 6 m
      MHE by PHES or CRT predicted OHE

      MHE by PHES and CRT predicted death
      Study compared MHE definition by one or two tests
      Ampuero, 2015
      • Ampuero J.
      • Simon M.
      • Montoliu C.
      • et al.
      Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis.


      Spain
      MHEn = 117, 58 ± 11

      (validation, n = 114)

      Cirrhosis

      (no grade I HE)

      Prior HE in 13%
      PHES

       < -4

      CFF

       < 39
      OHE

      Survival
      PHES

      26%

      CFF

      37%
      OHE 31%

      Death 21%

      60 ± 34 m
      MHE by CFF predicted death

      MHE by CFF predicted OHE
      Multivariable: Age and MELD predicted mortality

      MELD-MHE Interaction
      Gupta
      • Gupta D.
      • Ingle M.
      • Shah K.
      • Phadke A.
      • Sawant P.
      Prospective comparative study of inhibitory control test and psychometric hepatic encephalopathy score for diagnosis and prognosis of minimal hepatic encephalopathy in cirrhotic patients in the Indian subcontinent.


      2015

      India
      MHEn = 200, 47

      Cirrhosis

      (no grade I HE)

      No prior OHE
      PHES

      ≤−5

      ICT

      ≥14
      OHEPHES 68%

      ICT 70%
      OHE 26%

      Death 16%

      12 m
      MHE by PHES and ICT predict OHE

      MHE by PHES and ICT predict death
      OHE in non-MHE not reported
      Thomsen
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.


      2016

      United Kingdom
      CHEn = 106, 58 ± 10

      Cirrhosis

      (grade I HE in 42%)

      No prior OHE
      PHES

      <−4

      CFF

      <39

      EEG
      Defined as normal/abnormal based on proposed spectral criteria.
      OHE ≥ 2PHES 60%

      CFF 54%

      EEG 42%
      OHE 12%

      Death 12%

      L2FU 8%

      8 ± 8 m
      CHE by PHES did not predict OHE

      CHE by PHES and EEG predicted death
      Study compared CHE definition by one or two tests

      grade I HE associated with significantly more risk of future hospitalization and death
      Allampati
      • Allampati S.
      • Duarte-Rojo A.
      • Thacker L.R.
      • et al.
      Diagnosis of minimal hepatic encephalopathy using Stroop EncephalApp: a multicenter us-based, norm-based study.


      2016

      United States
      MHEn = 437, 57 ± 8

      Cirrhosis

      No baseline OHE

      (grade I HE unknown)

      Prior OHE in 36%
      PHES

      ≤−4

      ICT

      Norms

      StE

      Norms
      OHE ≥ 2PHES 37%

      ICT 35%

      StE 54%
      OHE 13%

      11 (8–15) m
      MHE by PHES, ICT, or StE predicted OHE (with or without prior OHE)Study evaluated 3 definitions for abnormal StE
      Campagna
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.


      2017

      Italy
      HE < Grade II

      (MHE/CHE)
      n = 327, 60 ± 13

      n = 200 (prospective)

      Cirrhosis

      grade I HE in 15%

      Prior OHE in 23%
      PHES

      ≤−4

      S-ANT1

      EEG (available in 146 patients)
      OHE ≥ 2

      Survival
      PHES 23%

      ANT1 14%
      Calculated by the number of patients classified as HE grade<II (to include MHE and grade I HE) with ANT1<10.


      EEG 42% (of 146)
      OHE 39%

      Death 23%

      12 m
      ANT1 predicted 1-year risk of OHE and deathStudy compared S-ANT1 against PHES and EEG

      S-ANT1 score was well-related to HE stage

      (unimpaired vs. MHE/grade I HE vs. grade II HE)
      Ampuero
      • Ampuero J.
      • Montoliú C.
      • Simón-Talero M.
      • et al.
      Minimal hepatic encephalopathy identifies patients at risk of faster cirrhosis progression.


      2017

      Spain
      MHEn = 320

      Cirrhosis

      Prior OHE
      PHES

      <−4

      CFF

      ≤39
      Cirrhosis progressionPHES 31%

      CFF 43%
      Cirrhosis progression 38%

      Death 19%

      LT 11%

      3.5 ± 1.8 years
      MHE linked to cirrhosis progression(65% in MHE vs. 32% non-MHE)Study showed MHE by PHES and CFF has accelerated disease progression in patients with compensated and decompensated cirrhosis
      CFF: Critical Flicker Frequency; CHE: Covert Hepatic Encephalopathy; CRT: Continuous Reaction Time; EEG: Electroencephalogram; grade I HE: Grade I Hepatic Encephalopathy; ICT: Inhibitory Control Test; L2FU: Lost to Follow-up; LT: Liver Transplantation; m: Months; MELD: Model for End Stage Liver Disease; MHE: Minimal Hepatic Encephalopathy; NR: Not Reported; OHE: Overt Hepatic Encephalopathy; PHES: Portosystemic Hepatic Encephalopathy Score; PSS: Portosystemic Shunts; StE: Stroop EncephalApp; TIPS: Transhepatic Portosystemic Shunt.
      a Defined as normal/abnormal based on proposed spectral criteria.
      b Calculated by the number of patients classified as HE grade < II (to include MHE and grade I HE) with ANT1 < 10.
      Nearly all studies concluded that patients with MHE/CHE had a poorer QOL and an increased risk of OHE and death. Although several studies mentioned QOL, this was specifically assessed using the Sickness Impact Profile (SIP) by Lauridsen et al.
      • Lauridsen M.M.
      • Schaffalitzky de Muckadell O.B.
      • Vilstrup H.
      Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests.
      Regardless of the diagnostic test used, episodes of OHE were reported in all studies and found to be strongly correlated with MHE/CHE. In 2015, Ampuero et al. used survival as the primary endpoint; however, several other authors also confirmed the association between MHE/CHE and mortality.
      • Lauridsen M.M.
      • Schaffalitzky de Muckadell O.B.
      • Vilstrup H.
      Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests.
      • Ampuero J.
      • Simon M.
      • Montoliu C.
      • et al.
      Minimal hepatic encephalopathy and critical flicker frequency are associated with survival of patients with cirrhosis.
      • Gupta D.
      • Ingle M.
      • Shah K.
      • Phadke A.
      • Sawant P.
      Prospective comparative study of inhibitory control test and psychometric hepatic encephalopathy score for diagnosis and prognosis of minimal hepatic encephalopathy in cirrhotic patients in the Indian subcontinent.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.
      • Taneja S.
      • Dhiman R.
      • Khatri A.
      • et al.
      Inhibitory control test for the detection of minimal hepatic encephalopathy in patients with cirrhosis of liver.
      • Dhiman R.
      • Kurmi R.
      • Thumburu K.
      • et al.
      Impact of minimal/Covert hepatic encephalopathy on patients with cirrhosis.
      Of note, Ampuero et al. later assessed the effects of MHE using a novel approach of monitoring cirrhosis progression via a prognostic staging model. Patients were stratified based on major clinical manifestations (e.g. variceal bleeding, ascites, jaundice, HE) and monitored for transition to subsequent stages. The study concluded that MHE at baseline not only was associated with accelerated cirrhosis progression but also confirmed the utility of MHE to predict future development of OHE.
      • Ampuero J.
      • Montoliú C.
      • Simón-Talero M.
      • et al.
      Minimal hepatic encephalopathy identifies patients at risk of faster cirrhosis progression.
      Another variation in study design worth noting is how patients with grade I HE were addressed: they were either excluded, analyzed separately, or combined with MHE into a single entity (i.e. CHE). The rationale behind the CHE construct is to apply the objective features of MHE diagnostic tests to grade I HE from West Haven criteria, thus reducing diagnostic subjectivity. As seen in the table, of eleven studies surveyed, three included CHE in their study design.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.
      • Montagnese S.
      • Balistreri E.
      • Schiff S.
      • et al.
      Covert hepatic encephalopathy: agreement and predictive validity of different indices.
      Montagnese et al., and Thomsen et al. reaffirmed the heterogeneity of CHE by showing significant differences in clinical outcomes in patients with MHE vs. grade I HE.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      • Montagnese S.
      • Balistreri E.
      • Schiff S.
      • et al.
      Covert hepatic encephalopathy: agreement and predictive validity of different indices.
      Undisputedly, the identification of grade I HE in clinical trials is relevant, but it is unlikely most clinicians will consistently apply the subjective criteria for its identification as reliably as it is done within the context of research, thus affecting its prognostic implications in clinical practice. Also, although a couple of studies excluded patients with prior episodes of OHE,
      • Gupta D.
      • Ingle M.
      • Shah K.
      • Phadke A.
      • Sawant P.
      Prospective comparative study of inhibitory control test and psychometric hepatic encephalopathy score for diagnosis and prognosis of minimal hepatic encephalopathy in cirrhotic patients in the Indian subcontinent.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      • Taneja S.
      • Dhiman R.
      • Khatri A.
      • et al.
      Inhibitory control test for the detection of minimal hepatic encephalopathy in patients with cirrhosis of liver.
      • Dhiman R.
      • Kurmi R.
      • Thumburu K.
      • et al.
      Impact of minimal/Covert hepatic encephalopathy on patients with cirrhosis.
      those including subjects with prior OHE episodes found these patients are more susceptible for repeated OHE episodes, therefore reducing the clinical usefulness of MHE/CHE diagnosis when OHE is used as the endpoint. Interpretation of neuropsychometric tests also needs to be adjusted for patients with prior OHE. For example, Campagna et al. found that Simplified Animal Naming Test (S-ANT1) scores were lower in patients with previous history of OHE compared to those without prior overt episodes.
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.
      Three publications studied whether the combination of two abnormal tests was more valuable in predicting OHE and mortality than a single test.
      • Lauridsen M.M.
      • Schaffalitzky de Muckadell O.B.
      • Vilstrup H.
      Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      • Ampuero J.
      • Montoliú C.
      • Simón-Talero M.
      • et al.
      Minimal hepatic encephalopathy identifies patients at risk of faster cirrhosis progression.
      Per the EASL/AASLD recommendations, each study included PHES as one of the two tests. Thomsen et al. found that patients with two abnormal tests had an increased risk of developing OHE (60%) when compared to EEG or PHES alone (30% and 27%, respectively). Furthermore, the risk of death was 21% in patients diagnosed with CHE using the two-test strategy vs. 0% for either EEG and PHES alone.
      • Thomsen K.L.
      • Macnaughtan J.
      • Tritto G.
      • Mookerjee R.P.
      • Jalan R.
      Clinical and pathophysiological characteristics of cirrhotic patients with grade 1 and minimal hepatic encephalopathy.
      Lauridsen et al. shared this conclusion in that abnormalities in PHES paired with the CRT had more severe cirrhosis and 40% short-term mortality compared to 20% short-term mortality in patients with a single abnormal test.
      • Lauridsen M.M.
      • Schaffalitzky de Muckadell O.B.
      • Vilstrup H.
      Minimal hepatic encephalopathy characterized by parallel use of the continuous reaction time and portosystemic encephalopathy tests.
      Two studies introduced novel testing strategies. In a study by Allampati et al., StE was confirmed as a simple and reliable point-of-care tool to diagnose MHE. StE was validated against its norms as well as normative values generated by using PHES and ICT as gold standards. StE showed utility in predicting future occurrences of OHE as well as good agreement in a multicenter study.
      • Allampati S.
      • Duarte-Rojo A.
      • Thacker L.R.
      • et al.
      Diagnosis of minimal hepatic encephalopathy using Stroop EncephalApp: a multicenter us-based, norm-based study.
      Another novel diagnostic strategy was proposed by Campagna et al., finding the ANT1 to be well received by patients, rapidly administered, and easily scored. The authors produced a simplified three-level score (0 for S-ANT1 ≥ 15, 1 for 10 ≤ S-ANT1 < 15, and 2 for S-ANT1 < 10), which is associated with each HE stage, as well as the risk of subsequent episodes of OHE and death. Furthermore, S-ANT1 can be used over time to monitor changes in mental performance, provided that the new values are different than previous values by 20% or more.
      • Campagna F.
      • Montagnese S.
      • Ridola L.
      • Senzolo M.
      • Schiff S.
      • De Rui M.
      • et al.
      The animal naming test: an easy tool for the assessment of hepatic encephalopathy.
      Despite the variability in study design, these large-scale cohort studies provide an excellent framework for future progress in HE, including completion of clinical trials aiming to improve prognosis through timely intervention. Regardless of whether MHE or CHE is being considered, both strategies have shown utility in identifying high-risk patients, and, until the dispute on which to use is settled, grade I HE should be addressed both clinically and through specialized testing (i.e. neuropsychological and/or neurophysiological, etc.) in order to make data usable to all investigators. In the end, clinicians need consistent methodologies to bridge the gaps between point-of-care screening, further testing, and appropriate treatment. Realization of this goal can only be accomplished via international coordination and unified efforts providing an ultimate definition of the early stages of HE and the diagnostic toolbox to diagnose them. Once such a definition exists, consolidation of future research toward common data-driven goals will provide clinicians with well-supported tests and therapies that will have a lasting impact on patients with cirrhosis.

      Funding Sources

      This work is partially supported by the University of Arkansas for Medical Sciences College of Medicine Clinician Scientist Program.

      Presentations

      This work was presented at ISHEN Symposium, New Delhi, India, in March 2017.

      Conflicts of Interest

      The authors have none to declare.

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