Hepatic encephalopathy (HE) is a neuropsychiatric complication of chronic liver disease (CLD), especially cirrhosis, and a potentially reversible syndrome.[1] It encompasses a range of neurological symptoms from subtle cognitive dysfunction and altered sleep cycles to disorientation, personality changes, and coma.[2] It is mainly due to impaired hepatic detoxification and portosystemic shunting, leading to the accumulation of toxic substances for the brain, such as ammonia.[3] Overt hepatic encephalopathy (OHE) is a frequent, major clinical problem that leads to frequent hospital admissions, loss of functional independence, decreased quality of life, and death.[4] The neurological effects of cirrhosis may be ongoing, even after an overt episode of cognitive dysfunction has been resolved.[5] Secondary prophylaxis is recommended for prevention of recurrent HE, and the guidelines from the European Association for the Study of the Liver (EASL) for 2022 stress the fact that the long-term burden of the disease is high in patients with HE.[6]

The progressive decrease in skeletal muscle mass, strength, and physical function, which is known as sarcopenia, is a growing extrahepatic complication of cirrhosis.[7] It is linked to chronic inflammation, malnutrition, hyperammonemia, changed protein metabolism, hormonal changes, and decreased physical activity.[8] Importantly, skeletal muscles are also involved in ammonia detoxification via synthesis of glutamine; thus, muscle depletion may further impair ammonia clearance and worsen hepatic encephalopathy.[9] This link may become a vicious circle, as muscle wasting leads to hyperammonemia and the latter to extrahepatic ammonia elimination, which in turn may lead to muscle wasting.[10]

Another important issue in recurrent HE is the possibility of cognitive dysfunction, which may occur after clinical recovery, following repeated HE episodes, and can result in persistent deficits in attention, memory, executive functioning, learning ability, and psychomotor speed.[2] In a 2023 systematic review and meta-analysis of 55 studies and 13,158 patients, the prevalence of sarcopenia was 40.1% in cirrhosis patients, and it was noted that sarcopenia was a significant predictor of poor outcomes such as HE.[11] The results indicate that the assessment of muscle health and cognitive capability should be integrated and not restricted to the assessment of recurrent HE as a neurological presentation of liver disease.

The pharmacologic treatment of recurrent HE consists of decreasing production and absorption of ammonia in the gut.[12] Lactulose, a non-absorbable disaccharide, is the first-line treatment and second-line prophylactic agent that works through colonic acidification and cathartic action, which decreases the absorption of ammonia from the intestine.[13] Rifaximin is an antibiotic with minimal intestinal absorption that alters the composition of intestinal bacteria and decreases the formation of ammonia and other neurotoxic metabolites.[14]

Although there are known therapeutic effects, the comparative relationship of the use of rifaximin and lactulose with sarcopenia and cognitive dysfunction in patients with recurrent HE is not fully characterized. While rifaximin has shown promise for muscle preservation and neurocognitive benefits, the studies conducted so far have largely assessed either the recurrence of HE or hospitalization or immediate neurological recovery, but not both muscle status and neurocognitive function. Furthermore, it is still unknown if the burden of sarcopenia and cognitive dysfunction differs between patients receiving rifaximin and patients receiving lactulose, especially in recurrent HE patients. A combined investigation of these outcomes could yield broader clinical implications of various HE treatment strategies and opportunities for more complete cirrhosis management. Therefore, the present study aimed to compare the association of rifaximin versus lactulose use with sarcopenia and cognitive dysfunction among patients with recurrent hepatic encephalopathy.

This cross-sectional comparative study aimed to evaluate the correlation between the use of rifaximin and lactulose and sarcopenia and cognitive dysfunction in patients suffering from recurrent hepatic encephalopathy. The study was conducted at the Department of Medicine, Jinnah Medical and Dental College, Karachi, Pakistan. The study was conducted over six months, from 1st November 2025 to 30th April 2026. The sample size was calculated using the OpenEpi online sample size calculator with two independent proportions for comparison. Asghar et al. (2025) conducted a study to compare the use of rifaximin vs lactulose monotherapy in secondary prevention of HE and reported recurrence rates of 16.1% vs 34.8%, respectively.[15] These proportions were used as reference estimates for the sample size calculation. The sample size for each group was calculated as 83 patients at a 95% level of confidence, 80% study power, and a 1:1 allocation ratio. The final sample size was 184 patients (92 in each group) after applying a 10% increase to account for incomplete evaluation or missing data. A non-probability sampling technique of consecutive sampling was employed. Patients were recruited consecutively, starting from the first eligible patient admitted to medical wards or seen in the outpatient department of the hospital during the study period until the desired number of patients was reached. Patients were included if they were adult male or female patients aged 18 years and older who had been diagnosed with chronic liver disease or cirrhosis, and had a history of recurrent hepatic encephalopathy. Recurrent HE was defined as 2 or more episodes of overt HE in 6 months. Patients taking rifaximin therapy or lactulose therapy for secondary prophylaxis for at least 4 weeks before enrolment were included. Patients had to be clinically stable at the time of evaluation, have to have informed consent, and have to be in good mental condition. Acute overt hepatic encephalopathy on assessment, HCC, prior stroke, Parkinson's disease, dementia, major psychiatric disorders, neuromuscular diseases, or other diseases that affect muscle mass or cognition independently were excluded from the study. Recent major surgery or severe acute infection, advanced malignancy, or incomplete medical records were also exclusion criteria. Additional factors that could affect cognitive performance were minimized by excluding patients with a history of alcohol and substance dependence. After obtaining approval from the institutional ethical review committee, eligible patients were enrolled after obtaining written informed consent. A structured proforma was completed for demographic and clinical data, such as age, gender, BMI, duration and etiology of liver disease, number of previous HE episodes, comorbidities, medication history, and length of treatment. Laboratory data (serum bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase, creatinine, sodium, and platelet count) were retrieved from medical records or laboratory investigations. Disease severity was assessed using the Child-Pugh classification and Model for End-Stage Liver Disease (MELD) score.[16] All patients were divided into two groups based on their secondary prophylactic treatment. Group A comprised patients who were started on rifaximin-based therapy (rifaximin 550 mg twice daily), and group B comprised patients who were started on lactulose-based therapy, typically two to three times daily, intending to produce two to three soft stools per day. The actual treatment regimens used, including the use of concomitant lactulose within the rifaximin group, were described and shown to differentiate combination therapy from monotherapy. Sarcopenia was evaluated through the measurement of skeletal muscle mass and muscle strength. Skeletal muscle mass was evaluated using computed tomography (CT) images at the third lumbar vertebral level (L3), where available, and skeletal muscle index was calculated by dividing the total skeletal muscle area by height squared. The cutoffs for sarcopenia were sex-specific. The handgrip strength was measured with a calibrated hand dynamometer, and decreased muscle strength was documented by reference values for sex. Cognitive dysfunction was examined by the Psychometric Hepatic Encephalopathy Score, which included standardized neuropsychological tests of attention, concentration, visuomotor coordination, and psychomotor speed.[17] Patients with abnormal PHES results according to appropriate reference values were classified as having cognitive dysfunction. To minimize the effects of acute encephalopathy episodes on cognitive performance, all assessments were carried out during clinical stability. The data were analyzed with SPSS Statistics version 26 software from IBM. Quantitative variables, including age, body mass index, laboratory parameters, skeletal muscle index, handgrip strength, and PHES, were assessed for normality using the Shapiro–Wilk test. Normally distributed variables were presented as mean ± standard deviation, whereas non-normally distributed variables were presented as median and interquartile range. Data for categorical variables such as gender, sarcopenia, cognitive dysfunction, Child-Pugh class, and clinical characteristics were expressed in frequencies and percentages. Independent-samples t-test and Mann–Whitney U test were used to compare quantitative variables between the two treatment groups, as appropriate. The chi-square test and Fisher's exact test were used to compare categorical variables. Binary logistic regression analysis was performed to determine the independent association of treatment group with sarcopenia and cognitive dysfunction after adjusting for potential confounders, including age, gender, body mass index, Child-Pugh class, MELD score, serum albumin, and duration of liver disease. Results were reported as odds ratios with 95% confidence intervals. A p-value < 0.05 was taken as significant.

A total of 184 patients were included in the study, 92 patients in each treatment group. The demographic and clinical characteristics were comparable between the groups, with no statistically significant differences in age, gender, BMI, etiology or duration of liver disease, previous HE episodes, or associated comorbidities (p > 0.05). The most frequent underlying cause was hepatitis C for both groups and male gender for the majority of patients (Table 1).

Laboratory findings and indicators of liver disease severity were also comparable between the treatment groups. No statistically significant differences were observed in serum bilirubin, albumin, ALT, AST, creatinine, sodium, platelet count, or MELD scores. There was also a well-balanced distribution of patients between Child-Pugh Class A and Class B in both groups (Table 2).

In terms of treatment characteristics, 76.1% of patients in the rifaximin group also received lactulose, compared with 100% of patients in the lactulose group. The recommended dose of rifaximin was 550 mg twice daily. There was no significant difference in treatment duration between any treatment group, including treatment for at least 3 or 6 months (Table 3).

Sarcopenia assessment showed that the prevalence of sarcopenia was significantly lower in patients treated with rifaximin than in patients treated with lactulose. Although skeletal muscle index and handgrip strength were comparatively higher in the rifaximin group, these differences were not statistically significant. However, the overall difference in sarcopenia prevalence between the groups was statistically significant (p = 0.047) (Table 4).

Patients receiving rifaximin-based therapy showed significantly better cognitive assessment scores in the Psychometric Hepatic Encephalopathy Score (PHES). There was a statistically significant between-group difference in the frequency of cognitive dysfunction, with this group having a lower frequency (p = 0.040) (Table 5).

Multivariable logistic regression analysis showed that treatment with rifaximin was significantly predictive of cognitive dysfunction after adjusting for potential confounding factors. However, its association with sarcopenia did not reach statistical significance. Older age and higher Child-Pugh class were associated with both outcomes, while lower BMI and serum albumin were associated with sarcopenia. Cognitive dysfunction was also more strongly correlated with higher MELD scores (Table 6).

Table 1. Demographic and clinical characteristics of the study participants

Table 2. Comparison of laboratory parameters and severity of liver disease

Table 3. Comparison of treatment characteristics between the study groups

Table 4. Comparison of sarcopenia-related parameters between the treatment groups

Table 5. Comparison of cognitive dysfunction between the treatment groups

Table 6. Binary logistic regression analysis of factors associated with sarcopenia and cognitive dysfunction

The present study compared the association of rifaximin-based and lactulose-based therapy with sarcopenia and cognitive dysfunction among patients with recurrent hepatic encephalopathy. The results showed that treatment with rifaximin was associated with a decreased prevalence of sarcopenia and cognitive dysfunction. However, after adjustment for potential confounders, only the association with cognitive dysfunction remained statistically significant. These results suggest a possible connection between HE treatment, muscle health, and neurocognitive function. In terms of sarcopenia, the prevalence in the present study is similar to the results of Tuo et al. (2023), who performed a systematic review and meta-analysis of 55 studies across 13,158 patients with cirrhosis, with a pooled prevalence of 40.1%.[18] Likewise, Cui et al. (2024) reviewed 40 studies and found that the prevalence of diabetes was 41%. Their findings also demonstrated a significant association between sarcopenia and hepatic encephalopathy.[19] The prevalence in the present study is within the range reported in these investigations, which confirms the significance of muscle assessment in patients with cirrhosis. Sarcopenia also showed its association with adverse outcomes, as Tantai et al. (2022) found that the mortality risk was about 2-fold higher for cirrhotic patients with sarcopenia. Their meta-analysis also demonstrated that sarcopenia prevalence increased with greater disease severity.[20] In this current study, they found that sarcopenia was independently associated with advanced Child-Pugh class, which confirms the link between the liver's poor function and diminished muscle health. However, the cross-sectional design is not a causal one. An important comparison can be made with Worland et al. (2025), who investigated the relationship between rifaximin use and skeletal muscle mass in 142 patients with cirrhosis and previous HE. They identified a retrospective cohort study that revealed that the use of rifaximin was an independent risk factor for an improvement in skeletal muscle area over the use of lactulose alone (p = 0.029).[21] This finding is consistent with the lower prevalence of sarcopenia observed in the rifaximin-based group in the present study. In our analysis, however, this relationship between sarcopenia and rifaximin-based therapy was not statistically significant after multivariable adjustment. This variation may be partially due to differences in study design and outcome assessment. In the same way, Wongtrakul et al. (2025) studied the association between sarcopenia and MHE in 210 patients with cirrhosis. They found that sarcopenia was significantly higher in the minimal HE group compared with the non-minimal HE group (45.9% vs. 21.4%). They found sarcopenia to be an independent risk factor for minimal HE in their multivariable analysis as well.[22] The results of this study support the clinical relevance of assessing muscle health in conjunction with cognitive function, as done in the study. Regarding cognitive dysfunction, the present results are similar to those of Han et al. (2021), who performed a systematic review and meta-analysis of 28 randomized controlled trials that included 2,979 patients. The authors reported that the effects of rifaximin on cognitive impairment in patients with minimal HE were superior to control treatment and the incidence of recurrent HE was lower.[23] This evidence supports the findings of lower cognitive dysfunction prevalence in patients receiving rifaximin-based therapy in this study. Tan et al. (2022) provided further support in the study of low- and high-dose rifaximin in patients with covert hepatic encephalopathy. Their randomized study demonstrated significantly higher rates of HE reversal in both rifaximin groups compared with the control group. In addition, improvements in health-related quality of life were reported. The results are consistent with the improved PHES that we found in the rifaximin group, but there may be differences in treatment duration, dose, and patient population.[24] The potential neurocognitive benefits of rifaximin were also investigated by Patel et al. (2022) in the RIFSYS randomized controlled trial involving 38 patients with cirrhosis and HE. The investigators noted that the HE grade also improved significantly after rifaximin therapy, as did the PHES, while the systemic inflammatory markers decreased. This finding may account for the enhanced cognitive functioning noted in our rifaximin group.[25] The present study, however, did not directly assess inflammatory markers nor explore the underlying biological mechanisms. More recently, Inada et al. (2026) conducted a multicentre randomized controlled trial involving 50 patients with covert HE. They found that their patients who were treated with rifaximin performed significantly better on the Stroop test after the treatment; however, the difference in overall improvement was not statistically significant between the two groups. This is another indication of a possible neurocognitive advantage of rifaximin and underscores the possibility that responses to treatment may be different depending on the assessment tool and patient characteristics. The improved PHES scores in the current research are generally consistent with this evidence.[26] The present study compared the association of rifaximin-based and lactulose-based therapy with sarcopenia and cognitive dysfunction among patients with recurrent hepatic encephalopathy. The results showed that treatment with rifaximin was associated with a decreased prevalence of sarcopenia and cognitive dysfunction. However, after adjustment for potential confounders, only the association with cognitive dysfunction remained statistically significant. These results suggest a possible connection between HE treatment, muscle health, and neurocognitive function. In terms of sarcopenia, the prevalence in the present study is similar to the results of Tuo et al. (2023), who performed a systematic review and meta-analysis of 55 studies across 13,158 patients with cirrhosis, with a pooled prevalence of 40.1%.[18] Likewise, Cui et al. (2024) reviewed 40 studies and found that the prevalence of diabetes was 41%. Their findings also demonstrated a significant association between sarcopenia and hepatic encephalopathy.[19] The prevalence in the present study is within the range reported in these investigations, which confirms the significance of muscle assessment in patients with cirrhosis. Sarcopenia also showed its association with adverse outcomes, as Tantai et al. (2022) found that the mortality risk was about 2-fold higher for cirrhotic patients with sarcopenia. Their meta-analysis also demonstrated that sarcopenia prevalence increased with greater disease severity.[20] In this current study, they found that sarcopenia was independently associated with advanced Child-Pugh class, which confirms the link between the liver's poor function and diminished muscle health. However, the cross-sectional design is not a causal one. An important comparison can be made with Worland et al. (2025), who investigated the relationship between rifaximin use and skeletal muscle mass in 142 patients with cirrhosis and previous HE. They identified a retrospective cohort study that revealed that the use of rifaximin was an independent risk factor for an improvement in skeletal muscle area over the use of lactulose alone (p = 0.029).[21] This finding is consistent with the lower prevalence of sarcopenia observed in the rifaximin-based group in the present study. In our analysis, however, this relationship between sarcopenia and rifaximin-based therapy was not statistically significant after multivariable adjustment. This variation may be partially due to differences in study design and outcome assessment. In the same way, Wongtrakul et al. (2025) studied the association between sarcopenia and MHE in 210 patients with cirrhosis. They found that sarcopenia was significantly higher in the minimal HE group compared with the non-minimal HE group (45.9% vs. 21.4%). They found sarcopenia to be an independent risk factor for minimal HE in their multivariable analysis as well.[22] The results of this study support the clinical relevance of assessing muscle health in conjunction with cognitive function, as done in the study. Regarding cognitive dysfunction, the present results are similar to those of Han et al. (2021), who performed a systematic review and meta-analysis of 28 randomized controlled trials that included 2,979 patients. The authors reported that the effects of rifaximin on cognitive impairment in patients with minimal HE were superior to control treatment and the incidence of recurrent HE was lower.[23] This evidence supports the findings of lower cognitive dysfunction prevalence in patients receiving rifaximin-based therapy in this study. Tan et al. (2022) provided further support in the study of low- and high-dose rifaximin in patients with covert hepatic encephalopathy. Their randomized study demonstrated significantly higher rates of HE reversal in both rifaximin groups compared with the control group. In addition, improvements in health-related quality of life were reported. The results are consistent with the improved PHES that we found in the rifaximin group, but there may be differences in treatment duration, dose, and patient population.[24] The potential neurocognitive benefits of rifaximin were also investigated by Patel et al. (2022) in the RIFSYS randomized controlled trial involving 38 patients with cirrhosis and HE. The investigators noted that the HE grade also improved significantly after rifaximin therapy, as did the PHES, while the systemic inflammatory markers decreased. This finding may account for the enhanced cognitive functioning noted in our rifaximin group.[25] The present study, however, did not directly assess inflammatory markers nor explore the underlying biological mechanisms. More recently, Inada et al. (2026) conducted a multicentre randomized controlled trial involving 50 patients with covert HE. They found that their patients who were treated with rifaximin performed significantly better on the Stroop test after the treatment; however, the difference in overall improvement was not statistically significant between the two groups. This is another indication of a possible neurocognitive advantage of rifaximin and underscores the possibility that responses to treatment may be different depending on the assessment tool and patient characteristics. The improved PHES scores in the current research are generally consistent with this evidence.[26] LIMITATIONS This study has several limitations. First, the cross-sectional design does not allow for establishing a causal relationship between treatment type, sarcopenia, and cognitive dysfunction. Second, this study took place in a single tertiary care centre, and the results may not be applicable to other populations. Thirdly, selection bias may have been introduced due to the selection method (non-probability sampling) used, consecutive sampling. In addition, co-administration of lactulose with patients treated with rifaximin might have affected the results obtained and made it difficult to compare the treatment groups directly. The results may have been influenced by residual confounding from nutrition, physical activity, dietary protein intake and other clinical factors. Last, the lack of longitudinal assessments precluded assessment of changes over time in muscle mass and/or cognitive performance. Long-term prospective multicentre studies are thus recommended.

Patients treated with rifaximin-based therapy had a lower prevalence of sarcopenia and cognitive dysfunction compared to those treated with lactulose-based therapy. However, after adjustment for potential confounding factors, only the association with cognitive dysfunction remained statistically significant. These results indicate that treatment with rifaximin may be associated with improved cognitive function in RE patients.