EASL Clinical Practice Guidelines

Diagnosis and testing

Clinical evaluation

Judging and measuring the severity of HE is approached as a continuum [65]. The testing strategies in place range from simple clinical scales to sophisticated psychometric and neurophysiological tools; however, none of the current tests are valid for the entire spectrum [[11], [66]]. The appropriate testing and diagnostic options differ according to the acuity of the presentation and the degree of impairment [67].

Diagnosis and testing for OHE

The diagnosis of OHE is based on a clinical examination and a clinical decision. Clinical scales are used to analyze its severity. Specific quantitative tests are only needed in study settings. The gold standard is the West Haven criteria (WHC;Table 2, including clinical description). However, they are subjective tools with limited interobserver reliability, especially for grade I HE, because slight hypokinesia, psychomotor slowing, and a lack of attention can easily be overlooked in clinical examination. In contrast, the detection of disorientation and asterixis has good inter-rater reliability and thus are chosen as marker symptoms of OHE [67]. Orientation or mixed scales have been used to distinguish the severity of HE [[68], [69]]. In patients with significantly altered consciousness, the Glasgow Coma Scale (GCS; Table 6) is widely employed and supplies an operative, robust description.

Table 5
GCS [169].



The scale comprises three tests: eyes, verbal, and motor responses. The three values separately as well as their sum are considered. The lowest possible GCS (the sum) is 3 (deep coma or death), whereas the highest is 15 (fully awake person). Abbreviation: n.a., not applicable.

Diagnosing cognitive dysfunction is not difficult. It can be established from clinical observation as well as neuropsychological or neurophysiological tests. The difficulty is to assign them to HE. For this reason, OHE still remains a diagnosis of exclusion in this patient population that is often susceptible to mental status abnormalities resulting from medications, alcohol abuse, drug use, effects of hyponatremia, and psychiatric disease (Table 4). Therefore, as clinically indicated, exclusion of other etiologies by laboratory and radio logical assessment for a patient with altered mental status in HE is warranted.

Testing for MHE and CHE

Minimal hepatic encephalopathy and CHE is defined as the presence of test-dependent or clinical signs of brain dysfunction in patients with CLD who are not disoriented or display asterixis. The term “minimal” conveys that there is no clinical sign, cognitive or other, of HE. The term “covert” includes minimal and grade 1 HE. Testing strategies can be divided into two major types: psychometric and neurophysiological [[70], [71]]. Because the condition affects several components of cognitive functioning, which may not be impaired to the same degree, the ISHEN suggests the use of at least two tests, depending on the local population norms and availability, and preferably with one of the tests being more widely accepted so as to serve as a comparator.

Testing for MHE and CHE is important because it can prognosticate OHE development, indicate poor quality of life and reduced socioeconomic potential, and help counsel patients and caregivers about the disease. The occurrence of MHE and CHE in patients with CLD seems to be as high as 50% [72], so, ideally, every patient at risk should be tested. However, this strategy may be costly [73], and the consequences of the screening procedure are not always clear and treatment is not always recommended. An operational approach may be to test patients who have problems with their quality of life or in whom there are complaints from the patients and their relatives [74]. Tests positive for MHE or CHE before stopping HE drug therapy will identify patients at risk for recurrent HE [[33], [75]]. Furthermore, none of the available tests are specific for the condition [76], and it is important to test only patients who do not have confounding factors, such as neuropsychiatric disorders, psychoactive medication, or current alcohol use.

Testing should be done by a trained examiner adhering to scripts that accompany the testing tools. If the test result is normal (i.e., negative for MHE or CHE), repeat testing in 6 months has been recommended [77]. A diagnosis of MHE or CHE does not automatically mean that the affected subject is a dangerous driver [78]. Medical providers are not trained to formally evaluate fitness to drive and are also not legal representatives. Therefore, providers should act in the best interests of both the patient and society while following the applicable local laws [78]. However, doctors cannot evade the responsibility of counseling patients with diagnosed HE on the possible dangerous consequences of their driving, and, often, the safest advice is to stop driving until the responsible driving authorities have formally cleared the patient for safe driving. In difficult cases, the doctor should consult with the authorities that have the expertise to test driving ability and the authority to revoke the license.

A listing of the most established testing strategies is given below. The test recommendation varies depending on the logistics, availability of tests, local norms, and cost [[65], [66], [71]].

  1. Portosystemic encephalopathy (PSE) syndrome test. This test battery consists of five paper-pencil tests that evaluate cognitive and psychomotor processing speed and visuomotor coordination. The tests are relatively easy to administer and have good external validity [76]. The test is often referred to as the Psychometric Hepatic Encephalopathy Score (PHES), with the latter being the sum score from all subtests of the battery. It can be obtained from Hannover Medical School (Hannover, Germany), which holds the copyright (Weissenborn.karin@mh-hannover.de). The test was developed in Germany and has been translated for use in many other countries. For illiterate patients, the figure connection test has been used as a subtest instead of the number connection test [79].
  2. The Critical Flicker Frequency (CFF) test is a psychophysiological tool defined as the frequency at which a fused light (presented from 60 Hz downward) appears to be flickering to the observer. Studies have shown its reduction with worsening cognition and improvement after therapy. The CFF test requires several trials, intact binocular vision, absence of red-green blindness, and specialized equipment [[80], [81]].
  3. The Continuous Reaction Time (CRT) test. The CRT test relies on repeated registration of the motor reaction time (pressing a button) to auditory stimuli (through headphones). The most important test result is the CRT index, which measures the stability of the reaction times. The test result can differentiate between organic and metabolic, brain impairment and is not influenced by the patient's age or gender, and there is no learning or tiring effect. Simple software and hardware are required [82].
  4. The Inhibitory Control Test (ICT) is a computerized test of response inhibition and working memory [83] and is freely downloadable at www.hecme.tv. The ICT test has been judged to have good validity, but requires highly functional patients. The norms for the test have to be elaborated beyond the few centers that have used it.
  5. The Stroop test evaluates psychomotor speed and cognitive flexibility by the interference between recognition reaction time to a colored field and a written color name. Recently, mobile application software (“apps” for a smartphone or tablet computer) based on the test has been shown to identify cognitive dysfunction in cirrhosis compared to paper-pencil tests [84]. Further studies are under way to evaluate its potential for screening for MHE and CHE.
  6. The SCAN Test is a computerized test that measures speed and accuracy to perform a digit recognition memory task of increasing complexity. The SCAN Test has been shown to be of prognostic value [85].
  7. Electroencephalography examination can detect changes in cortical cerebral activity across the spectrum of HE without patient cooperation or risk of a learning effect [70]. However, it is nonspecific and may be influenced by accompanying metabolic disturbances, such as hyponatremia as well as drugs. Possibly, the reliability of EEG analysis can increase with quantitative analysis. This specifically should include the background frequency with mean dominant frequency or spectral band analysis [60]. Also, in most situations, EEG requires an institutional setup and neurological expertise in evaluation, and the cost varies among hospitals.

Although the above-described tests have been used to test for MHE and CHE, there is, most often, a poor correlation between them because HE is a multi dimensional dysfunction [86]. Learning effect is often observed with psychometric tests and it is unclear whether current HE therapy plays a role in the test performance. Therefore, interpretation of these tests and consideration of the results for further management need an understanding of the patient's history, current therapy, and effect on the patient's daily activities, if signs of HE are found. For multicenter studies, the diagnosis of MHE or CHE by consensus should utilize at least two of the current validated testing strategies: paper-pencil (PHES) and one of the following: computerized (CRT, ICT, SCAN, or Stroop) or neurophysiological (CFF or EEG) [66]. In the clinical routine or single-center studies, investigators may use tests for assessing the severity of HE with which they are familiar, provided that normative reference data are available and the tests have been validated for use in this patient population [66].

Laboratory testing

High blood-ammonia levels alone do not add any diagnostic, staging, or prognostic value in HE patients with CLD [87]. However, in case an ammonia level is checked in a patient with OHE and it is normal, the diagnosis of HE is in question. For ammonia-lowering drugs, repeated measurements of ammonia may be helpful to test the efficacy. There may be logistic challenges to accurately measure blood ammonia, which should be taken into consideration. Ammonia is reported either in venous, arterial blood, or plasma ammonia, so the relevant normal should be used. Multiple methods are available, but measurements should only be employed when laboratory standards allow for reliable analyses.

Brain scans

Computed tomography (CT) or magnetic resonance (MR) or other image modality scans do not contribute diagnostic or grading information. However, the risk of intracerebral hemorrhage is at least 5-fold increased in this patient group [88], and the symptoms may be indistinguishable, so a brain scan is usually part of the diagnostic workup of first-time HE and on clinical suspicion of other pathology.

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