Neurofilament Light Chain Protein in Plasma and Extracellular Vesicles Is Associated with Minimal Hepatic Encephalopathy and Responses to Rifaximin Treatment in Cirrhotic Patients.

Neurofilament light chain protein (NfL) levels reflect neuronal damage in several neurological diseases and have been proposed as a possible biomarker. Plasma extracellular vesicles (EVs) could play an important role as mediators of the inflammatory changes associated with inducing minimal hepatic encephalopathy (MHE) in cirrhotic patients. This study investigated the association of NfL levels in plasma and EVs with the presence of MHE in cirrhotic patients, and with responses to rifaximin treatment. The NfL levels in plasma and EVs were assessed in 71 patients with liver cirrhosis (40 with MHE and 31 without MHE) and 26 controls. A total of 31 patients with MHE received rifaximin treatment. We examined changes in NfL levels in plasma and EVs before and after 6 months of rifaximin treatment. The NfL measures were correlated with cognitive alterations and plasma inflammatory cytokines. MHE patients showed increased plasma levels of NfL, which were reverted after rifaximin treatment in patients who responded to treatment. The NfL content in EVs also showed a reversal pattern in MHE patients treated with rifaximin. In multivariable analyses, NfL levels were independently associated with the presence of MHE. We also showed that patients with high levels of both ammonia and fractalkine had significantly higher NfL levels than patients with low levels of least one of these parameters. Rifaximin treatment in MHE patients showed promising results in improving axonal damage, suggesting that rifaximin may have therapeutic benefits against disease progression in MHE.

Anti-inflammatory and immunomodulating effects of rilpivirine: Relevance for the therapeutics of chronic liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mechanisms involved, focusing on its anti-inflammatory and immunomodulating properties. They were evaluated in vitro (human hepatic cell lines of the major hepatic cell types), in vivo (liver samples from a murine nutritional model of NAFLD) and ex vivo (peripheral blood mononuclear cells -PBMC- from patients with CLD). Transcriptomic analysis of liver samples from NAFLD mice showed RPV down-regulated biological processes associated with the inflammatory response (NF-κB/IκB signaling and mitogen-activated protein kinase -MAPK- activity) and leukocyte chemotaxis and migration. We observed a decrease in Adgre1 and Ccr2 expression and in the number of CCR2 + cells in the periportal areas of RPV-treated NAFLD mice. This RPV-induced effect on the CCL2/CCR2 axis was confirmed in vitro. A similar result was also obtained with CXCL10/IP10, one of the main chemokines in the liver. RPV also diminished activation of MAP kinases p38 and JNK. In addition, RPV inhibited the NLRP3 inflammasome pathway in vitro, decreasing NLRP3 protein expression, caspase-1 activation and IL-1ß gene expression. RPV was also proven anti-inflammatory in PBMC from patients with CLD treated ex vivo. In conclusion, beyond its well-described role in antiretroviral therapy, RPV manifests anti-inflammatory and immunoregulatory effects, a finding that could be of great relevance for the search of novel targets or repositioning strategies for CLD.

Biological treatment interruption in inflammatory bowel disease: Motivation and predictive factors.

BACKGROUND: Loss-of-response and adverse events (AE) to biologics have been linked to HLA-DQA1*05 allele. However, the clinical factors or biologic used may influence treatment duration. Our objective was to evaluate the influence of clinical and therapeutic factors, along with HLA, in biological treatment discontinuation. METHODS: A retrospective study of consecutive IBD patients treated with biologics between 2007 and 2011 was performed. Main outcome was treatment discontinuation due to primary non-response (PNR), secondary loss of response (SLR) or AE. HLA-DQA1 genotyping was done in all patients. Regression analyses were used to assess risk factors of treatment discontinuation. RESULTS: One hundred fifty patients (61% male) with 312 biologic treatments were included. 147 (47%) were discontinued with a cumulative probability of 30%, 41% and 56% at 1, 2 and 5 years. The use of infliximab (p=0.006) and articular manifestations (p<0.05) were associated with treatment discontinuation. Considering cause of withdrawal, Ulcerative Colitis (UC) had a higher proportion of PNR (HR=4.99; 95% CI=1.71-14.63; p=0.003), SLR was higher if biologics had been indicated due to disease flare (HR=2.32; 95% CI=1.05-5.09; p=0.037) while AE were greater with infliximab (HR=2.46; 95% CI=1.48-4.08; p<0.001) or spondylitis (HR=2.46; 95% CI=1.78-6.89; p<0.001). According to the biological drug, HLA-DQA1*05 with adalimumab showed more SLR in cases with Crohn's disease (HR=3.49; 95% CI=1.39-8,78; p=0.008) or without concomitant immunomodulator (HR=2.8; 95% CI=1.1-6.93; p=0.026). CONCLUSIONS: HLA-DQ A1*05 was relevant in SLR of IBD patients treated with adalimumab without immunosupression. In patients treated with other biologics, clinical factors were more important for treatment interruption, mainly extensive UC or extraintestinal manifestations and having indicated the biologic for flare.

Caustic Ingestion: A Risk-Based Algorithm.

INTRODUCTION: Caustic ingestion management could be improved with a diagnostic approach based on risk factors. This study aimed to develop an algorithm derived from predictive factors of a poor clinical course, to evaluate its diagnostic accuracy and resource consumption, and to compare it with 2 other approaches, a radiological one based on computed tomography and a classical one based on symptoms and endoscopy. METHODS: All patients older than 15 years presenting with caustic ingestion in our tertiary care hospital between 1995 and 2021 were prospectively included. Adverse outcome was defined as intensive care unit admission, emergency surgery, or death. Ingestion characteristics, symptoms, and laboratory and endoscopic findings were analyzed to determine the most relevant risk factors. Diagnostic accuracy and the number of examinations required were estimated and compared with the other 2 algorithms applied to our series. RESULTS: The sample included 532 cases of caustic ingestion, 13.2% (95% confidence interval [CI]: 10.3-16.0) of which had adverse outcomes. Volume and type of caustic substance; presence of symptoms and pharyngolaryngeal involvement; and neutrophilia, acidosis, and endoscopic injury were combined to develop an algorithm that would provide the highest diagnostic odds ratio (167.2; 95% CI: 71.9-388.7). Following this approach, half of the patients (50.6%; 95% CI: 46.2-55.1) would not require any examination and, overall, the need for endoscopy (20.0%; 95% CI: 16.4-23.5) and computed tomography (16.3%; 95% CI: 13.0-19.5) would be lower than that for the other 2 algorithms. DISCUSSION: A risk-based algorithm could improve caustic ingestion management by maintaining high diagnostic accuracy while reducing diagnostic test requirements.

Metabolic syndrome is associated with poor response to rifaximin in minimal hepatic encephalopathy.

Patients with cirrhosis may show minimal hepatic encephalopathy (MHE), for which rifaximin is effective. Metabolic syndrome may be associated with cognitive impairment. Our aims were to evaluate the influence of metabolic syndrome features on response to rifaximin for neurological and inflammatory alterations in MHE. A prospective cohort study was conducted in 63 cirrhotic patients and 30 controls from two tertiary centres recruited between 2015 and 2019. Metabolic syndrome was defined according to the Adult Treatment Panel-III. Patients were classified into 31 without and 32 with MHE according to the Psychometric Hepatic Encephalopathy Score (PHES). All participants performed specific psychometric tests, and inflammatory parameters were studied. Patients with MHE received rifaximin (400 mg/8 h). Response was evaluated by PHES at 3 and 6 months. Response according to metabolic syndrome manifestations was compared. The response rate was 66%. Older age (p = 0.012) and all metabolic syndrome diseases (p < 0.05) were associated with non-response, plus an increase in risk as the number of manifestations rose (p < 0.001). Patients with metabolic manifestations exhibited worse processing speed (p = 0.011), working memory (p = 0.005), visual coordination (p = 0.013) and lower proportion of activated CD4+ lymphocytes (p = 0.039) at baseline, as well as worse concentration (p = 0.030), bimanual coordination (p = 0.004) and higher levels of intermediate monocytes (p = 0.026), CX3CL1 (p < 0.05), IL-17 (p = 0.022), AHR (p = 0.010) and IgG (p < 0.05) at 3 and/or 6 months of rifaximin. Patients with clinical signs of metabolic syndrome have poor response to rifaximin for MHE, with a higher proportion of neurological alterations associated with a pro-inflammatory environment.

Management of patients with Intestinal Bowel Disease and COVID-19: A review of current evidence and future perspectives.

The COVID-19 pandemic has been a challenge for countries and health professionals worldwide. Viral entry by ACE-2 receptor and an excessive activation of the immune system are key to understand both incidence and severity of disease. Inflammatory Bowel Disease (IBD) represents a special condition associated with an inordinate response of the immune system to external agents. IBD treatments have been associated to an increased risk of bacterial and viral infections. This has raised the question of possible higher incidence and severity of COVID-19 infection in IBD patients. Several papers have been published during this year of pandemic to answer that question. Moreover, COVID-19 vaccination offers great promise in controlling infection in patients with IBD. Based on current evidence, patients with IBD do not have a higher incidence of COVID-19 than the general population, and they do not have worse disease evolution. Advanced age and presence of a greater number of comorbidities have been associated with worse outcomes, similar to the general population. Corticosteroids are associated to an increased risk of COVID-19 infection, higher hospitalization rate and higher risk of severe COVID-19. 5-ASA/Sulfasalazine and Thiopurines have a possible increased risk of severe COVID-19, although studies are lacking. On the other hand, Anti-TNF may have a possible protective effect. It is recommended to maintain the treatment. Anti-IL-12/23, anti-integrins and tofacitinib have results comparable to anti-TNF. Based on the efficacy, expert recommendations, and the absence of other evidence, it is recommended that patients with IBD be vaccinated.

NNRTI and Liver Damage: Evidence of Their Association and the Mechanisms Involved.

Due to the improved effectiveness and safety of combined antiretroviral therapy, human immunodeficiency virus (HIV) infection has become a manageable, chronic condition rather than a mortal disease. However, HIV patients are at increased risk of experiencing non-AIDS-defining illnesses, with liver-related injury standing out as one of the leading causes of death among these patients. In addition to more HIV-specific processes, such as antiretroviral drug-related toxicity and direct injury to the liver by the virus itself, its pathogenesis is related to conditions that are also common in the general population, such as alcoholic and non-alcoholic fatty liver disease, viral hepatitis, and ageing. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of combined anti-HIV treatment due to their unique antiviral activity, high specificity, and acceptable toxicity. While first-generation NNRTIs (nevirapine and efavirenz) have been related largely to liver toxicity, those belonging to the second generation (etravirine, rilpivirine and doravirine) seem to be generally safe for the liver. Indeed, there is preclinical evidence of rilpivirine being hepatoprotective in different models of liver injury, independently of the presence of HIV. The present study aims to review the mechanisms by which currently available anti-HIV drugs belonging to the NNRTI family may participate in the development of liver disease.

A New Score Unveils a High Prevalence of Mild Cognitive Impairment in Patients with Nonalcoholic Fatty Liver Disease.

Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The neurological functions affected remain unclear. The aims were to: (1) Characterize the neuropsychological alterations in NAFLD patients; (2) assess the prevalence of impairment of neurological functions evaluated; (3) develop a new score for sensitive and rapid MCI detection in NAFLD; (4) assess differences in MCI features between patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH); and (5) compare neuropsychological alterations in NAFLD patients with cirrhotic patients with MCI. Fifty-nine NAFLD patients and 53 controls performed psychometric tests assessing different neurological functions: PHES (Psychometric Hepatic Encephalopathy Score) battery, d2, Stroop, Oral SDMT (Symbol Digit Modalities Test), Digit Span, number-letter test, and bimanual and visual-motor coordination tests. NAFLD patients show impairment in attention, mental concentration, psychomotor speed, cognitive flexibility, inhibitory mental control, and working memory. We developed a new, rapid, and sensitive score based on the most affected parameters in NAFLD patients, unveiling that 32% of NAFLD show MCI. Prevalence was similar in NAFL (36%) or NASH (27%) patients, but lower in NAFLD than in cirrhosis (65%). MCI prevalence is significant in NAFLD patients. Psychometric testing is warranted in these patients to unveil MCI and take appropriate measures to reverse and prevent its progression.

Clinical outcome after anti-tumour necrosis factor therapy discontinuation in 1000 patients with inflammatory bowel disease: the EVODIS long-term study.

BACKGROUND: The long-term outcome of patients after antitumour necrosis factor alpha (anti-TNF) discontinuation is not well known. AIMS: To assess the risk of relapse in the long-term after anti-TNF discontinuation. METHODS: This was an extension of the evolution after anti-TNF discontinuation in patients with inflammatory bowel disease (EVODIS) study (Crohn's disease or ulcerative colitis patients treated with anti-TNFs in whom these drugs were withdrawn after achieving clinical remission) based in the same cohort of patients whose outcome was updated. Clinical remission was defined as a Harvey-Bradshaw index ≤4 points in Crohn's disease, a partial Mayo score ≤2 in ulcerative colitis and the absence of fistula drainage despite gentle finger compression in perianal disease. RESULTS: This was an observational, retrospective, multicenter study. A total of 1055 patients were included. The median follow-up time was 34 months. The incidence rate of relapse was 12% per patient-year (95% confidence interval [CI] = 11-14). The cumulative incidence of relapse was 50% (95% CI = 47-53): 19% at one year, 31% at 2 years, 38% at 3 years, 44% at 4 years and 48% at 5 years of follow-up. Of the 60% patients retreated with the same anti-TNF after relapse, 73% regained remission. Of the 75 patients who did not respond, 48% achieved remission with other therapies. Of the 190 patients who started other therapies after relapse, 62% achieved remission with the new treatment. CONCLUSIONS: A significant proportion of patients who discontinued the anti-TNF remained in remission. In case of relapse, retreatment with the same anti-TNF was usually effective. Approximately half of the patients who did not respond after retreatment achieved remission with other therapies.

Serum cholesterol predicts transplant-free survival in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt.

BACKGROUND: Malnutrition is frequent in patients with cirrhosis and has been associated with poor prognosis. The Model for End-stage Liver Disease (MELD) score was created to predict survival after Transjugular Intrahepatic Porto-systemic Shunt (TIPS) but lacks a nutritional parameter. AIMS: To evaluate the prognostic value of serum cholesterol in patients with cirrhosis undergoing TIPS and to develop a prognostic score to predict survival. METHODS: An explorative cross-sectional study was conducted of cirrhotic patients undergoing TIPS from 2008 until 2019. Exclusion criteria were liver transplantation or hepatocellular carcinoma before TIPS. Risk analysis was used to compare survival according to clinical and analytical data. The diagnostic performance of serum cholesterol added to MELD was evaluated and confirmed in an external validation cohort. RESULTS: The final cohort of 100 patients had a mean MELD score of 14±5 and cholesterol of 122±51 mg/dL. MELD (p < 0,05) and both cholesterol (p < 0,05) and low-density lipoprotein levels (LDL-C) (p < 0,05) were independent predictors of post-TIPS transplant-free survival with an optimal cut-off of 106 mg/dL for serum cholesterol. The combined MELD-cholesterol risk score improved diagnostic accuracy of each parameter separately, and this was confirmed in the external cohort. CONCLUSION: Serum cholesterol and LDL-C are independent predictors of transplant-free survival in cirrhotic patients undergoing TIPS. The MELD-cholesterol score slightly improved prognostic accuracy. LAY SUMMARY: As an objective and easily measured indicator of both nutritional status and hepatic function, serum cholesterol could be useful to predict transplant-free survival in patients with cirrhosis undergoing TIPS. It can enable health care providers to identify high-risk patients and to optimize nutritional status before TIPS.

Effectiveness and safety of methotrexate monotherapy in patients with Crohn's disease refractory to anti-TNF-α: results from the ENEIDA registry.

BACKGROUND: Methotrexate can be used to maintain remission in Crohn's disease patients who are intolerant to thiopurines. Data on its use as monotherapy in other scenarios are limited. AIM: To assess the effectiveness of methotrexate monotherapy in Crohn's disease patients after previous failure to anti-tumour necrosis factor (anti-TNFα) drugs. METHODS: A retrospective, observational multicentre study of data from the Spanish ENEIDA registry. Participants were patients with active Crohn's disease and previous failure to anti-TNFα started on methotrexate monotherapy. Short-term effectiveness was assessed at 12-16 weeks based on Harvey-Bradshaw index (HBI): clinical remission as HBI ≤ 3 points and clinical response as HBI drop of ≥ 3 points over baseline. Long-term effectiveness was defined as steroid-free methotrexate persistence from 12 to 16 weeks until maximum follow up. Adverse events were recorded. RESULTS: Data were compiled for 110 patients treated with methotrexate after a failed response to one (39%) or two (55.6%) anti-TNFα agents. Short-term clinical response and remission rates were 60% and 30.9% respectively. Of 74 patients who continued after week 16, long-term effectiveness was achieved in 82% and 74% at 12 and 24 months respectively. In the multivariate analysis, non-remission at short term (vs remission) was associated with long-term failure (HR 2.58, 95%CI 1.95-3.68, P = 0.028). Adverse events (evaluated in 100 patients) were recorded in 44%, and in 30.4% of these patients, they led to methotrexate discontinuation. CONCLUSIONS: The benefits observed suggest methotrexate monotherapy could be a valid option in Crohn's disease patients with previous failure to anti-TNFα.

Transjugular intrahepatic portosystemic shunt reduces hospital care burden in patients with decompensated cirrhosis.

BACKGROUND AND AIMS: Patients with decompensated cirrhosis frequently require hospital admissions, which are associated with worse prognosis. The aim of this study was to analyze the effect of TIPS on the need for hospital care. Secondary objectives were to assess the clinical and biological impact of TIPS and to identify predictors of post-TIPS hospital care. METHODS: An observational, retrospective study of patients with decompensated cirrhosis treated with TIPS from January 2008 until March 2019. Exclusion criteria were TIPS placed for non-cirrhotic portal hypertension (PH) and patients referred from another hospital without prior or subsequent follow-up at our Unit. Hospital care, PH-related complications, and laboratory data were compared before and after TIPS. RESULTS: The final cohort comprised 104 patients (72% male) with a mean age of 60 (± 10) years. Follow-up from first decompensation until TIPS and that from procedure to study completion were 7 (4.2-9.8) and 20 (4.6-35.4) months, respectively. TIPS was indicated mainly for refractory ascites (50%) and variceal bleeding (39%). Hemodynamic and clinical success rates were 97% and 92%, respectively. The number of emergency department visits and hospital admissions decreased after the procedure (p < 0.001). Improvement was seen in MELD and Child-Pugh scores, renal function, hyponatremia, and anemia after TIPS. Variceal bleeding as the indication for TIPS (OR 0.047; 95 CI 0.006-0,39; p < 0.05) together with early creation of the shunt (stage 3 vs 5; p < 0.05) were associated with a reduction in risk of post-TIPS hospital care. CONCLUSION: TIPS is a safe and effective procedure that reduces hospital care burden by improving PH-related complications, hepatic, renal function, hyponatremia, and anemia. Variceal bleeding as the indication and early placement of the device were associated with a reduction in post-TIPS hospital care. These findings support a role for this treatment, predominantly in the early stages of cirrhosis.

Patients with Minimal Hepatic Encephalopathy Show Altered Thermal Sensitivity and Autonomic Function.

Cirrhotic patients may experience alterations in the peripheral nervous system and in somatosensory perception. Impairment of the somatosensory system could contribute to cognitive and motor alterations characteristic of minimal hepatic encephalopathy (MHE), which affects up to 40% of cirrhotic patients. We assessed the relationship between MHE and alterations in thermal, vibration, and/or heat pain sensitivity in 58 cirrhotic patients (38 without and 20 with MHE according to Psychometric Hepatic Encephalopathy Score) and 39 controls. All participants underwent attention and coordination tests, a nerve conduction study, autonomic function testing, and evaluation of sensory thresholds (vibration, cooling, and heat pain detection) by electromyography and quantitative sensory testing. The detection thresholds for cold and heat pain on the foot were higher in patients with, than those without MHE. This hyposensitivity was correlated with attention deficits. Reaction times in the foot were longer in patients with, than without MHE. Patients with normal sural nerve amplitude showed altered thermal sensitivity and autonomic function, with stronger alterations in patients with, than in those without MHE. MHE patients show a general decrease in cognitive and sensory abilities. Small fibers of the autonomic nervous system and thermal sensitivity are altered early on in MHE, before large sensory fibers. Quantitative sensory testing could be used as a marker of MHE.

Multi-omic analysis unveils biological pathways in peripheral immune system associated to minimal hepatic encephalopathy appearance in cirrhotic patients.

Patients with liver cirrhosis may develop minimal hepatic encephalopathy (MHE) which affects their quality of life and life span. It has been proposed that a shift in peripheral inflammation triggers the appearance of MHE. However, the mechanisms involved in this immune system shift remain unknown. In this work we studied the broad molecular changes involved in the induction of MHE with the goal of identifying (1) altered genes and pathways in peripheral blood cells associated to the appearance of MHE, (2) serum metabolites and cytokines with modified levels in MHE patients and (3) MHE-regulated immune response processes related to changes in specific serum molecules. We adopted a multi-omic approach to profile the transcriptome, metabolome and a panel of cytokines of blood samples taken from cirrhotic patients with or without MHE. Transcriptomic analysis supports the hypothesis of alternations in the Th1/Th2 and Th17 lymphocytes cell populations as major drivers of MHE. Cluster analysis of serum molecules resulted in six groups of chemically similar compounds, suggesting that functional modules operate during the induction of MHE. Finally, the multi-omic integrative analysis suggested a relationship between cytokines CCL20, CX3CL1, CXCL13, IL-15, IL-22 and IL-6 with alteration in chemotaxis, as well as a link between long-chain unsaturated phospholipids and the increased fatty acid transport and prostaglandin production. We found altered immune pathways that may collectively contribute to the mild cognitive impairment phenotype in MHE. Our approach is able to combine extracellular and intracellular information, opening new insights to the understanding of the disease.

Caustic ingestion: development and validation of a prognostic score.

BACKGROUND: Caustic ingestion is a potentially severe condition and early identification of poor outcome is essential to improve management; however, prediction based on endoscopy alone can overestimate severity. This study aimed to develop and validate a prognostic score. METHODS: A prospective cohort study was designed to include all consecutive patients aged > 15 years who presented with caustic ingestion between 1995 and 2017. Adverse outcome was defined by intensive care unit admission, urgent surgery, or death. The predictive value of clinical, analytical, and endoscopic variables was assessed in the first cohort (derivation cohort) and a prognostic score based on the resulting risk factors was developed by logistic regression. Internal validation (bootstrapping) was performed and then external validation was checked in an independent sample of patients (validation cohort). RESULTS: 469 cases of caustic ingestion were included, 265 in the derivation cohort and 204 in the validation cohort. Ingestion of acidic substances (odds ratio [OR] 3.13, 95 % confidence interval [CI] 2.33 - 4.21), neutrophil count (OR 1.05, 95 %CI 1.04 - 1.06), metabolic acidosis (bicarbonate value, OR 0.82, 95 %CI 0.78 - 0.85), and endoscopic injury (OR 3.81, 95 %CI 3.35 - 4.34) were independent risk factors for poor outcome. The prognostic score based on these variables provided better accuracy than endoscopy alone (P = 0.04), with high sensitivity, specificity, positive and negative predictive values (93.3 %, 92.7 %, 72.7 %, 98.5 %, respectively), and area under the curve (0.976, 95 %CI 0.973 - 0.979; P < 0.001). CONCLUSIONS: This score allowed a reliable prognosis of caustic ingestion and was more accurate than endoscopy-based evaluation.

Oxidative and Nitrosative Pattern in Circulating Leukocytes of Very Early/Early Hepatocellular Carcinoma Patients.

BACKGROUND/AIM: In chronic liver disease, various immune cell subsets exert pro or anti-tumour effects by releasing reactive oxygen and nitrogen species (ROS, RNS). Here, we evaluated the oxidative and nitrosative pattern in peripheral blood leukocyte subpopulations of early hepatocellular carcinoma (HCC) patients compared with HCC-free cirrhotic patients. MATERIALS AND METHODS: Venous blood samples from 18 HCC-free cirrhotic patients and 17 early stage HCC patients were collected to determine ROS, RNS and reduced glutathione levels in isolated leukocytes analyzed by flow cytometry. RESULTS: Intracellular levels of ROS and glutathione were higher in lymphocytes, monocytes, and neutrophils from HCC patients as well as mitochondrial superoxide in neutrophils and monocytes whereas intracellular levels of nitric oxide were lower in lymphocytes, monocytes, and neutrophils. CONCLUSION: Early HCC alters intracellular levels of ROS and RNS of some circulating leukocytes subsets. This finding may represent a potential area of interest concerning the development of new treatments and prognostic markers.

Motor and Cognitive Performance in Patients with Liver Cirrhosis with Minimal Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) is associated with mild cognitive impairment and frailty. This study aims to identify cognitive and motor differences in cirrhotic patients with and without MHE, and the correlations between motor signs and cognitive performance. Gait, balance, hand strength and motor speed performance were evaluated in 66 cirrhotic patients (38 without and 28 with MHE, according to the Psychometric Hepatic Encephalopathy Score (PHES). Cognitive performance was measured with the Mini-Mental State Examination, Verbal Fluency Test, Aprendizaje Verbal España-Complutense Test (TAVEC), Wechsler Adult Intelligence Scale III, Hamilton Depression and Anxiety Rating Scale and Functioning Assessment Short Test (FAST). MHE patients performed worse than patients without MHE in cognitive and autonomous functioning, learning and long-term memory, and verbal fluency. The same pattern was found in gait, center of pressure movement, variability of hand strength performance and hand motor speed. In MHE patients, high correlations were found between balance and FAST test, gait velocity and verbal skills, hand strength variability and anxiety and depression, and motor speed and FAST and TAVEC. MHE patients showed worse motor and cognitive performance than patients without MHE. MHE patients could have impaired movement control expressed as bradykinesia, and this reduced motor performance could correlate with cognitive performance.

Clinical assessment of risk factors for infection in inflammatory bowel disease patients.

PURPOSE: Recognizing patients with inflammatory bowel disease who are prone to infection would enable the adjustment of the type and intensity of immunosuppressive treatment. The aim of this study was to identify a clinical profile of risk for infections in IBD patients, based on the interaction of immunosuppressive treatment with factors inherent to the patient. METHODS: A case-control study was performed among patients older than 18 years. Patients with any significant infection (any kind of severe or recurrent infection according to standard clinical criteria or a critical enough infection according to the patient) were defined as cases. Both cases and controls were randomly selected in a 1:3 ratio. All the period from diagnosis to the end of recruitment (June 2016) was analyzed. Risk factors for infection were identified by logistic regression analysis; the strength of association was reported by odds ratio (OR) with 95% confidence interval (95%CI). RESULTS: A total of 112 cases and 270 controls were included. The independent risk factors for significant infection are the number of immunosuppressants (one drug: OR 1.28, 95% CI 0.53-3.11, two drugs: OR 2.37, 95% CI 1.01-5,56, and three drugs: OR 5.84, 95% CI 1.57-21.72), body mass index (OR 1.08; 95 %CI 1,01-1,16), the degree of comorbidity (OR 1.52; 95% CI 1.04-2.21), and the intensity of inflammatory activity (OR 1.43; 95% CI 1.19-1.71). CONCLUSIONS: Regardless of immunosuppression, several patient factors such as comorbidity, body mass index, or the inflammatory activity of the disease determine the individual risk of infectious complications and should be considered for an adequate risk assessment.

Long-term follow-up of patients treated with aminosalicylates for ulcerative colitis: Predictive factors of response: An observational case-control study.

Background: Knowing patients' ulcerative colitis history is essential to selecting the appropriate therapy according to risk stratification. Objective: To evaluate and identify predictive factors of non-response to aminosalicylates judged as the need for a step-up approach over time. Methods: A case-control study of ulcerative colitis patients treated with aminosalicylates after the diagnosis of disease flare included in the ENEIDA single-centre registry from 1997 to 2017. Long-term treatment maintenance with aminosalicylates and higher therapeutic requirements were recorded. The cumulative incidence of treatment escalation was estimated using Kaplan-Meier curves and compared by the log-rank test. Cox regression analysis was performed to identify predictive factors of treatment with immunomodulators, biological agents or surgery. Results: A total of 457 patients were included, of whom 28% (n = 126) were non-responders to aminosalicylates. The cumulative probability for a step-up approach within 20 years of follow up was 35%, mainly due to steroid-dependent colitis. Risk factors for treatment escalation were age ≤27 years (hazard ratio 2.31, 95% confidence interval 1.36-3.92), extensive colitis (hazard ratio 1.65, 95% confidence interval 1.04-2.60), Mayo endoscopic subscore ≥2 (hazard ratio 1.45, 95% confidence interval 1.02-2.06) and extraintestinal manifestations (hazard ratio 2.04, 95% confidence interval 1.03-4.05). Conclusions: Aminosalicylates represent an effective maintenance therapy. Younger age, extensive colitis, endoscopic disease severity and extraintestinal manifestations are risk factors for higher therapeutic requirements.

Selective improvement by rifaximin of changes in the immunophenotype in patients who improve minimal hepatic encephalopathy.

BACKGROUND: Minimal hepatic encephalopathy (MHE) in cirrhotic patients is associated with specific changes in parameters of the immune system reflecting a more pro-inflammatory environment than in patients without MHE. The aims of this work were to assess the effects of rifaximin treatment of cirrhotic patients with MHE on: (1) MHE; (2) intermediate (CD14++CD16+) pro-inflammatory monocytes; (3) expression of early activation marker CD69 in T lymphocytes; (4) autoreactive CD4+CD28- T lymphocytes; (5) differentiation of CD4+ T lymphocytes to Th follicular and Th22; (6) serum IgG levels; and (7) levels of some pro-inflammatory cytokines. METHODS: These parameters were measured by immunophenotyping and cytokine profile analysis in 30 controls without liver disease, 30 cirrhotic patients without MHE and 22 patients with MHE. Patients with MHE were treated with rifaximin and the same parameters were measured at 3 and 6 months of treatment. We assessed if changes in these parameters are different in patients who improve MHE (responders) and those who remain in MHE (non-responders). RESULTS: Rifaximin improved MHE in 59% of patients with MHE. In these responder patients rifaximin normalized all alterations in the immune system measured while in non-responders it normalizes only IL-6, CCL20, and differentiation of T lymphocytes to Th22. Non-responder patients do not show increased expression of CD69 before treatment. CONCLUSIONS: Rifaximin normalizes changes in the immune system in patients who improve MHE but not in non-responders. Some alterations before treatment are different in responders and non-responders. Understanding these differences may identify predictors of the response of MHE to rifaximin.