Introduction

Hepatic encephalopathy (HE) represents one of the most significant complications of liver diseases. It is a neurocognitive, psychiatric, and musculoskeletal disorder that is associated with both acute and chronic liver insufficiency as well as portal‑systemic shunting. While potentially reversible, HE is strongly linked to a high risk of recurrence and significantly reduces survival rate.^1,2 As excessive alcohol consumption is the primary cause of liver cirrhosis (up to 50% of cases) in several Western European countries, including Poland,³ it is essential to assess the frequency of HE occurrence in this population, alongside the patients with nonalcoholic etiology of cirrhosis.

HE encompasses a broad spectrum of conditions, ranging from mild symptoms to coma, and confers a high risk of mortality. According to the definitions provided by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases,⁴ the division and assessment of HE are influenced by 4 key factors: the severity of clinical manifestations, underlying disease, disease duration, and presence of triggers. Minimal HE (MHE) represents the mildest form of HE, characterized by subtle neurological symptoms that may not be immediately apparent on a routine examination, but lead to cognitive deficits detectable through specific psychometric or neuropsychological tests.⁴ Due to the mild nature of its symptoms, MHE remains the most under‑recognized and underdiagnosed form of HE. This oversight negatively impacts both the patient health and the health care system, leading to progression to more severe complications in undiagnosed individuals.^4-6

Patients with MHE exhibit deficits in psychomotor speed, visual perception, and attention, while their verbal abilities remain largely unaffected.³ Over the years, several studies have documented the negative effects of MHE on driving skills, work capacity, sleep efficiency, and social interactions.^2,7 Overall, the accumulated evidence suggests that MHE significantly impairs health‑related quality of life.⁸ Moreover, this condition has a relatively high prevalence, with studies indicating that 20%–50% of patients with cirrhosis and up to 80% of those with chronic liver disease develop MHE, depending on the diagnostic criteria and population studied.^5,8-10

Given the subtle symptoms and their significant clinical implications, the use of dedicated diagnostic tests is crucial for detecting MHE.¹ In general, they can be classified into several categories, including psychometric, neurophysiological, neuroimaging, and laboratory tests.⁴ This paper focuses on the Psychometric Hepatic Encephalopathy Score (PHES) and its application in patients with alcoholic and nonalcoholic etiology of liver cirrhosis.

PHES is a paper‑and‑pencil test that is internationally regarded as the gold standard for diagnosing MHE^4,10; it was specifically designed and later refined to detect this condition. It consists of 5 components that assess motor speed, motor accuracy, concentration, attention, visual perception, visual construction, and memory within a 20‑minute time frame. A PHES score of 4 or below is indicative of MHE. Of note, PHES is not only a diagnostic tool but also a prognostic instrument that helps identify high‑risk patients.^4,9,11 Furthermore, to improve its diagnostic accuracy, PHES has been standardized for the population of several countries, including Poland,^12,13 which is important in the context of cultural and socioeconomic differences.

The aim of the study was to determine the prevalence of MHE in patients hospitalized for cirrhosis, and to analyze selected laboratory parameters (levels of creatinine, total bilirubin, total protein, albumin, and sodium, as well as aminotransferase activity, prothrombin time, and the international normalized ratio [INR]) in the individuals diagnosed with MHE.

Patients and methods

A total of 100 patients with a confirmed diagnosis of liver cirrhosis, hospitalized at the Department of Gastroenterology and Hepatology of the University Clinical Hospital in Wrocław, Poland, were assessed for inclusion in the study. The study protocol was approved by the Bioethics Committee of the Wroclaw Medical University (409/2020). Informed consent was obtained from all participants included in the study.

Cirrhosis was caused by toxic (excessive alcohol consumption) or nontoxic factors (metabolic and autoimmune conditions). Due to the profile of the department, individuals with cirrhosis caused by hepatotropic viral infections were not included in the study. Patients with cryptogenic cirrhosis were also excluded.

All patients were assessed according to the classification of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). Those meeting the criteria for overt HE (grades 1–4 according to the ISHEN classification) were excluded. To rule out cognitive deficits of other etiologies in the patients without overt HE, the Mini‑Mental State Examination was conducted. This standardized, 11‑question test evaluates 5 key cognitive domains: orientation, memory, attention and calculation, repetition, and language skills. Patients scoring below 25 points were not included in the study.

Based on the above criteria, a total of 68 patients were included in the final analysis.

All participants were assessed with the PHES test, which consists of 5 subtests: the number connection tests A and B (NCT‑A and NCT‑B), the serial dotting test (SDT), the digit symbol test (DST), and the line tracing test (LTT). The NCT‑A requires connecting randomly arranged numbers in order from 1 to 25, while the NCT‑B involves alternating between numbers (1 to 13) and letters (A to L). The results of both tests are recorded in seconds, including the time needed for completion and any necessary corrections. The SDT assesses psychomotor speed and precision by requiring patients to place a dot in the center of each of 100 circles as quickly as possible. The DST measures processing speed by instructing patients to copy as many coded symbols as possible within 90 seconds. The LTT evaluates visuospatial and motor coordination by having patients trace a line through a maze without crossing its boundaries, with errors affecting the final score. Overall, the PHES components assess visuospatial orientation, psychomotor speed, attention‑switching ability, precision, and visuoconstructive skills.

The PHES test was administered in the morning, at least 1 hour after the patient’s awakening. Prior to completing each section, the participants were provided with detailed instructions and had a trial run to ensure comprehension.

In addition to PHES testing, all patients underwent laboratory evaluations, including biochemical analyses of creatinine, total bilirubin, total protein, albumin, and sodium levels, aminotransferase activity, as well as coagulation parameters, including prothrombin time and INR. Blood samples were collected in the morning under fasting conditions.

Results

The study included 68 patients (43 men at a median age of 48 years [range, 24–79 years] and 25 women at a median age of 55 years [range, 28–74 years]). Overall, 43 patients had alcohol‑induced liver cirrhosis (32 men, 11 women). In the remaining 25 patients (14 men and 11 women), cirrhosis was caused by other factors.

The PHES scores ranged from –12 to 4, with a median of –5. Based on the test results, MHE was diagnosed in 46 patients (13 women [52%] and 33 men [75%]), which accounted for 68% of the study group.

According to etiology, MHE was diagnosed in 31 individuals with alcohol‑related cirrhosis, representing 72% of all patients in this group. Among the patients with nonalcoholic cirrhosis, MHE was diagnosed in 15 individuals, accounting for 60% of the group (Table 1).

The patients with a PHES‑based diagnosis of MHE had a higher Model for End‑Stage Liver Disease‑sodium (MELD‑Na) score than those without MHE, regardless of cirrhosis etiology (P <⁠0.001). The mean (SD) MELD‑Na score in the patients with MHE was 23.18 (9.43) points in the alcohol‑related cirrhosis group, and 21 (9.44) points in the nonalcoholic cirrhosis group. In the patients without MHE, the respective values were 15.36 (6.43) and 10.27 (3.47) points.

In the group with alcohol‑related liver cirrhosis, mean (SD) prothrombin time was longer in the individuals with MHE, as compared with those without this diagnosis (18.64 [4.86] vs 15.09 [2.03] s, respectively; P = 0.01). The total protein and albumin levels were lower in the patients with MHE than in those without this condition (P <⁠0.001 for both). No significant relationship was found with respect to aminotransferase activity or creatinine, bilirubin, and sodium levels.

Among the patients with nonalcoholic liver cirrhosis, higher serum levels of creatinine (P = 0.02) and bilirubin (P = 0.02) were observed in those diagnosed with MHE, as compared with the individuals without this diagnosis. The patients with MHE also had lower serum levels of sodium (P = 0.04) and albumin (P = 0.04) than the individuals without MHE.

We observed no differences in aminotransferase activity in either group, nor did we find a relationship between MHE and patient age.

Discussion

MHE is a common complication observed in patients with cirrhosis and other liver diseases. Currently, PHES is considered the gold standard in diagnosing MHE. However, the role of this test and other diagnostic methods remains a subject of discussion. Due to diagnostic challenges and the variability of symptoms, the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recommends the use of 2 independent diagnostic tests.⁴ Nevertheless, a 2019 study¹⁴ suggested there was no significant advantage of using 2 independent tests over a single test—either PHES or the Stroop EncephalApp.

According to a previous study,¹⁵ MHE may affect 30%–80% of patients with liver cirrhosis. The results of our study align with these values, as 68% of the included patients met the criteria for MHE diagnosis.

The detrimental impact of MHE on patient quality of life and prognosis has been described multiple times.^16,17 A recent multicenter study¹⁸ demonstrated that the occurrence of MHE was associated with a higher risk of progression to overt HE and poorer survival rates. Patients with MHE also more often required liver transplant.

According to literature data, early therapeutic intervention in patients with MHE can improve prognosis and even lead to resolution of the disease.¹⁹ For this reason, the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recommends testing all patients with diagnosed cirrhosis for MHE. In the patients with a test result not indicative of MHE, screening should be repeated every 6 months.²⁰

The results of this study confirm the frequent occurrence of MHE among patients with liver cirrhosis who do not have overt HE. We also demonstrated a more severe disease course, expressed by the MELD‑Na score, in the patients with MHE, regardless of the etiology of cirrhosis. This highlights the necessity of conducting MHE tests in all patients with liver cirrhosis.

Further research involving larger patient groups is needed to expand our understanding of MHE and its impact on the disease progression, prognosis, and patient quality of life.