Grading the range of hepatic encephalopathy from overt to covert: Animals to the rescue!
Authors: German Soriano, Jasmohan S. Bajaj
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article on Page 198 1 Hepatic encephalopathy (HE) includes a wide spectrum of neuropsychiatric abnormalities ranging from subclinical alterations only detectable by neuropsychological or neurophysiological testing to coma.1 As expected in such a continuous spectrum, attempts at classification are often artificial and have several limitations, especially in their mildest manifestations. In recent years, a new classification has been proposed: covert HE (including minimal HE and grade 1 HE) and overt HE (including grades 2‐4 of the West Haven classification).1 It should be kept in mind that HE is the complication of cirrhosis that determines the worst prognosis2 and the highest caregiver burden.3 Even in its earlier stages HE is associated with poor survival, predisposition to overt HE, traffic accidents, falls, and health‐related quality‐of‐life deterioration and presents a significant societal burden.3 Therefore, it is advisable to search for covert HE in the population of patients with cirrhosis.1 However, the differentiation between unimpaired and covert HE and between minimal HE and grade 1 HE is more difficult than the allocation of patients in one of the more severe grades included in overt HE.3 While some authors have questioned combining minimal HE and grade 1 HE under the umbrella of covert HE,6 most agree that reproducibly defining grade 1 HE remains an important goal.1 These difficulties are especially relevant in clinical practice outside specialized centers and in multicenter trials. In clinical practice it is difficult because the clinical manifestations are mild, their evaluation is highly subjective, and therefore highly specialized and time‐consuming tools requiring technical equipment and/or skilled staff are needed.1 While in multicenter trials, endpoints with high reproducibility are required for inclusion and defining endpoints; therefore, the relatively ephemeral grade 1 HE endpoint on its own does not pass muster. This issue with the lack of reproducibility in the earlier stages of the West Haven criteria has also garnered regulatory agency interest. As a result, newer multicenter overt HE trials are now required to have outcomes arising from the concept of the International Society of Hepatic Encephalopathy and Nitrogen Metabolism guidelines that define overt HE as a reproducible and clinically meaningful endpoint. However, regardless of the setting, the key clinical question is, does this grade of HE require treatment initiation or treatment change, or will it require further investigation before a management decision is made? To answer that question in practice, clinicians often rely on their prior knowledge of the patient's behavior or input from caregivers. This is unfortunately not always the case in practice or in clinical trials. Therefore, a simple tool that can contribute to identifying patients with covert HE and can be applied in practice is needed. In this issue of hepatology, Campagna et al.7 analyzed in patients with cirrhosis the usefulness of the Animal Naming Test (ANT) for detecting minimal HE and grade 1 HE. ANT is a semantic fluency test that can appraise the cognitive functions impaired in the early stages of HE, mainly executive functions. This elegant study was performed in two hospitals from Italy and enrolled 208 healthy controls and 327 patients with cirrhosis (including unimpaired patients and minimal HE, grade 1 HE, and overt HE [≥grade 2 HE] patients). Poor cognitive performance was defined by a Psychometric Hepatic Encephalopathy Score ≤–4. The authors defined the utility of the simplified ANT (S‐ANT1) score in the diagnosis of HE that was beyond grade 2 HE. The study team adjusted the results by educational level and age and importantly defined S‐ANT1 as an independent predictive factor of overt HE and death during follow‐up. Moreover, S‐ANT1 improved in grade ≥2 HE patients after the episode resolution. The authors designed a simple score with three categories of the S‐ANT1: ≥15, 10‐14, and <10 animals. Excluding patients with overt HE, the probability of being unimpaired for a patient with S‐ANT1 ≥15 was 80%, and the probability of having covert HE was 61% for a patient with S‐ANT1 <15 and 70% for a patient with S‐ANT1 <10 animals. Encouragingly, this study attempts to objectively define the poorly characterized grade 1 HE through the S‐ANT1 with some success. However, the problems mentioned above remain; i.e., this study was conducted in two very specialized centers with decades worth of experience in diagnosing grade 1 HE, which also have long‐term follow‐up and knowledge of the patients and caregivers. The two centers also did not critique the grade 1 HE assessment in each other's patients due to obvious privacy and geographical constraints but again used their clinical judgment. Therefore, the translation of these results into less specialized centers and in multicenter trials again needs to be seen. Another interesting finding was that even "unimpaired" patients with cirrhosis performed worse on the S‐ANT1 than healthy controls. As the authors comment, these results support the hypothesis that patients with cirrhosis often show early cognitive abnormalities despite a normal Psychometric Hepatic Encephalopathy Score.8 The S‐ANT1 can be a useful, simple, and fast screening tool in the initial evaluation and follow‐up of covert HE. However, it also has some limitations. First, the accuracy is limited because using the 15‐animal cutoff narrows the range between impaired and unimpaired patients. The results show that using this cutoff, one third of unimpaired patients would be referred for unnecessary further neuropsychological studies and that one third of patients with minimal HE would not be referred for further evaluation. The <10‐animal cutoff can help further in grade 1 determination but again not in the differentiation between being unimpaired and being at the beginning of the impaired spectrum. Another potential limitation is the possible variability of the S‐ANT1 among different geographical and cultural settings. Finally, an abnormal result on the S‐ANT1 does not necessarily imply covert HE because other causes of cognitive dysfunction can explain or contribute to this finding.6 Given the relatively older age of this patient population, a potential overlap between age‐related and cirrhosis‐related neurocognitive changes, as has been shown in prior studies, cannot also be excluded as a potential cause.9 A flowchart with the current process for standardizing patients with cirrhosis with earlier stages of HE and the potential role of ANT is shown in Fig. 1. The analysis of S‐ANT1 has moved the discussion forward in the latest trend in making tools to diagnose covert HE without specialized tests.10Figure 1: Flowchart of decision‐making in a patient with possible HE based on clinical setting. Abbreviation: OHE, overt HE.Although the S‐ANT1 will not resolve all of the issues in the differentiation between unimpaired and covert and within the covert stages, it does represent a step forward through which HE grading can be uniform in the real world. However, further studies are needed to validate and evaluate this new tool in geographically and culturally diverse cohorts as well as in interventional clinical trials.