Smartphone-based Stroop Test, EncephalApp: What is the optimal cutoff for diagnosing minimal hepatic encephalopathy?

Abstract

Jiang et al explored the diagnostic capabilities of EncephalApp, a smartphone-based Stroop Test, in patients with nonalcoholic liver disease. The study included 160 patients with nonalcoholic cirrhosis and utilized the psychometric hepatic encephalopathy score as a benchmark for diagnosing minimal encephalopathy. The identified optimal cutoff times were > 101.93 seconds for the "off" time and > 205.86 seconds for the combined "on + off" time, demonstrating sensitivities of 0.84 and 0.90, and specificities of 0.77 and 0.71, respectively. The findings suggest the necessity of employing different cutoffs for patients with alcoholic vs nonalcoholic liver cirrhosis, reflecting the distinct pathophysiologies underlying each condition. Additionally, alcohol consumption itself may influence Stroop test outcomes. Therefore, it is reasonable to establish separate benchmarks for alcoholic and nonalcoholic cirrhotic patients. Further validation in larger patient cohorts with clinical outcomes is essential. The demand for noninvasive liver disease assessments remains high in clinical practice.

Key Words: Minimal encephalopathy; Liver cirrhosis; Portal hypertension; Stroop test; Alcohol-related liver disease; Metabolic dysfunction-associated liver disease

Core Tip: Jiang et al examined the diagnostic performance of EncephalApp, a smartphone-based Stroop Test, in patients with nonalcoholic liver disease. Different etiologies manifest distinct liver damage pathophysiologies, justifying the use of varied cutoffs for alcoholic and nonalcoholic cirrhotic patients. These findings should be confirmed through validation in larger patient cohorts, ideally correlated with clinical outcomes. The clinical need for noninvasive liver disease evaluations continues to be significant.

TO THE EDITOR

In this issue of the World Journal of Hepatology, Jiang et al[1] explored the diagnostic capabilities of EncephalApp, a smartphone-based Stroop Test, in patients with nonalcoholic liver disease[1]. Liver cirrhosis is the leading cause of liver-related deaths worldwide and is a primary concern in the management of chronic liver disease[2,3]. Patients with cirrhosis may develop ascites, esophagogastric varices, hepatic encephalopathy, and hepatocellular carcinoma. Hepatic encephalopathy encompasses a spectrum of neurophysiological impairments, including mental deterioration, psychomotor dysfunction, disorientation, memory loss, and coma. Minimal or covert encephalopathy represents a less severe form, distinct from overt encephalopathy.

Despite advancements in the treatment of advanced hepatocellular carcinoma using immune checkpoint inhibitors and tyrosine kinase inhibitors, these therapies are generally limited to cirrhotic patients classified as Child-Pugh A[4]. The challenges of preventing disease progression and reversing impaired liver function remain unmet. Early diagnosis and treatment of complications in cirrhotic patients are crucial for preserving liver function reservoir. Overt hepatic encephalopathy is typically diagnosed through clinical symptoms, such as flapping tremors and elevated plasma ammonia levels. Recently, attention has turned to minimal encephalopathy, a less severe condition that significantly impacts quality of life and daily functioning, and is associated with an increased risk of traffic accidents[5]. The recurrence of hepatic encephalopathy is linked to high hospitalization rates and poor prognosis, making prophylaxis and early diagnosis essential[6]. Due to its subtle symptoms, minimal encephalopathy often goes undiagnosed in clinical settings. Its diagnosis involves a combination of cognitive and psychometric evaluations, neurological and neurophysiological assessments, imaging tests, biochemical markers, clinical risk factors, and patient history. Several guidelines recommend psychometric hepatic encephalopathy score (PHES), Stroop test, Scan test, critical flicker frequency (CFF) test, electroencephalogram, and brain magnetic resonance imaging[7-9]. Among these, the PHES is considered the most reliable method for diagnosing minimal encephalopathy. The PHES is a pencil-and-paper test consisting of five tasks designed to assess cognitive functions. These tasks include the number connection test-A, where participants connect numbers in sequential order, and the number connection test-B, which requires alternating between numbers and letters in order, both as quickly as possible. the serial dotting test involves placing dots in the center of 10 circles. The line tracing test requires participants to draw a line between two parallel borders without touching them. Finally, the digit symbol test evaluates the ability to match symbols with their corresponding numbers, with speed being a critical factor in all tasks[10]. The Stroop test, originally devised by Dr. Stroop[11], is also regarded as a reliable measure for diagnosing hepatic encephalopathy. This test involves two components: "on" and "off" states, which are determined by the presence of color and word discordance.

Mechanism and diagnosis of hepatic encephalopathy

The liver, connected to the gut via the portal vein, plays a crucial role in metabolizing gut-derived neurotoxins. This gut-liver-brain axis is central to the development of hepatic encephalopathy, particularly in the presence of gut dysbiosis. He et al[12] reported that Ruminococcus gnavus could induce neuropsychiatric symptoms akin to hepatic encephalopathy through the action of phenylalanine decarboxylase and its metabolite phenylethylamine. In cases of alcohol-related liver disease (ALD), alcohol consumption disrupts gut barrier function, facilitating bacterial translocation and subsequent liver inflammation[13]. In metabolic dysfunction-associated liver disease (MASLD), fecal microbiota exhibits a reduction in beneficial microbes such as Faecalibacterium prausnitzii, Bifidobacterium, and Coprococcus, alongside an increase in potentially harmful microorganisms like Escherichia coli, Klebsiella pneumoniae, and fungi such as Candida, Mucor, and Penicillium[14,15]. These shifts in microbiota composition lead to the production of various neurotoxins that differently affect neurological functions. Furthermore, alcohol use contributes to functional brain abnormalities resulting from its neurotoxicity, thiamine deficiency, and metabolic disturbances, potentially affecting the severity of encephalopathy despite similar stages of cirrhosis[16].

Viral hepatitis often results in periportal (zone 1) inflammation, whereas alcohol-related and metabolic dysfunction-associated steatohepatitis (MASH) primarily affect the pericentral (zone 3) areas[17]. Zone 3 hepatitis is more susceptible to portal hypertension and is more likely to develop portosystemic shunt-related minimal encephalopathy. Patients with MASH and ALD often present at clinics with advanced symptomatic liver disease, a delay exacerbated by the absence of effective screening programs or medical interventions. Early diagnosis and intervention for minimal encephalopathy can be crucial for these patients. Goldbecker et al[18] reported that the sensitivity and specificity of the PHES for diagnosing overt hepatic encephalopathy (alcohol-toxic, 26.3%; hepatitis, 20.2%; primary sclerosing cholangitis, 20.2%; others, 33.3%) were 82% and 97%, respectively. Ortiz-Treviño et al[19] found that the Stroop test for minimal encephalopathy had a sensitivity and specificity of 74% each. Ehrenbauer et al[20] documented the sensitivity and specificity of the Stroop test and CFF test for minimal hepatic encephalopathy as 85% and 66%, and 33% and 79%, respectively. They noted that the diagnostic cutoffs were > 101.93 seconds for "off" time and > 205.86 seconds for "on + off" time, with sensitivities of 84% and 90% and specificities of 77% and 71%, respectively. Kaps et al[21] reported that a cutoff of > 224.7 seconds ("on + off" time) best discriminated between patients with and without minimal encephalopathy, achieving a sensitivity of 71% and a specificity of 88% in both alcohol-related (56%) and non-alcohol-related cirrhotic patients. Bajaj et al[22] also highlighted the diagnostic efficacy of the EncephalApp, noting the best separation at an “on + off” time cutoff of > 190 seconds, with a sensitivity of 89% and a specificity of 82% in cirrhotic patients (alcohol 17% and non-alcohol 83%). These cutoffs may vary by clinic due to differences in disease distribution and severity. While ALD can be considered a distinct entity associated with heavy alcohol use, MASLD often involves a mixed cohort with mild to moderate alcohol consumption. The presence of cardiometabolic factors may also influence test results. Larger, multicenter studies are necessary to determine the optimal cutoffs for diagnosing minimal encephalopathy.

EncephalApp offers significant advantages for clinical use. First, as a free app, it provides precise, time-based measurements of cognitive performance, offering an objective alternative to traditional pencil-and-paper tests. Second, its mobile nature allows it to be used virtually anywhere. Third, it enables continuous recording and monitoring of results over time, facilitating better management of cognitive functions and treatment efficacy. Lastly, EncephalApp is simple, user-friendly interface makes it accessible for both healthcare providers and patients to assess cognitive function.

CONCLUSION

Early diagnosis and treatment of hepatic encephalopathy represent crucial strategies for preserving liver function in patients with cirrhosis. These approaches require validation in larger patient cohorts and ideally should be correlated with clinical outcomes. The demand for noninvasive liver disease assessments remains high in clinical practice.