L-ornithine L-aspartate in acute treatment of severe hepatic encephalopathy: A double-blind randomized controlled trial.

BACKGROUND AND AIMS: Data on the use of intravenous L-ornithine L-aspartate (LOLA) in the treatment of overt HE (OHE) is limited. We evaluated the role of intravenous LOLA in patients of cirrhosis with OHE grade III-IV. APPROACH AND RESULTS: In a double-blind randomized placebo-controlled trial, 140 patients were randomized to a combination of LOLA, lactulose, and rifaximin (n = 70) or placebo, lactulose, and rifaximin (n = 70). LOLA was given as continuous intravenous infusion at a dose of 30 g over 24 h for 5 days. Ammonia levels, TNF-α, ILs, and endotoxins were measured on days 0 and 5. The primary outcome was the improvement in the grade of HE at day 5. Higher rates of improvement in grade of HE (92.5% vs. 66%, p < 0.001), lower time to recovery (2.70 ± 0.46 vs. 3.00 ± 0.87 days, p = 0.03), and lower 28-day mortality (16.4% vs. 41.8%, p = 0.001) were seen in the LOLA group as compared with placebo. Levels of inflammatory markers were reduced in both groups. Significantly higher reductions in levels of blood ammonia, IL-6, and TNF-α were seen in the LOLA group. CONCLUSIONS: Combination of LOLA with lactulose and rifaximin was more effective than only lactulose and rifaximin in improving grades of HE, recovery time from encephalopathy, with lower 28-day mortality.

A double blind randomized controlled trial to assess efficacy of nutritional therapy for prevention of recurrence of hepatic encephalopathy in patients with cirrhosis.

BACKGROUND AND AIM: Overt hepatic encephalopathy (OHE) has high risk of recurrence and is associated with poor survival. The role of nutrition therapy is well documented in cirrhosis, but its efficacy in preventing the recurrence of OHE has not been studied. METHODS: In double blind RCT, we randomly assigned 150 patients with liver cirrhosis, with history of OHE in recent past to receive nutrition therapy (group I) or no nutrition therapy (group II) and followed up for 6 months. The primary efficacy end points were occurrence of breakthrough episodes and time to breakthrough episode of OHE. Secondary end points were OHE related hospitalizations and time to hospitalization involving OHE. Other parameters included anthropometry, changes in serum cytokines (IL-1, IL-6, IL-10, and TNF-α), endotoxin and myostatin. RESULTS: There was significant reduction in occurrence of breakthrough episodes of OHE in group I [10 vs 36, hazard ratio 0.20; P < 0.001], OHE-related hospitalization [8 vs 24, hazard ratio 0.27; P < 0.001)]. Times to breakthrough episode of OHE and OHE-related hospitalization were longer in group I. At the end of 6 months, inflammatory and anthropometry parameters showed significant improvement in group I compared with worsening of serum albumin, anthropometric parameters, IL-6, IL-10 and TNF-α in group II. At the end of 6 months, ascites (50 vs 66, P = 0.01), gastrointestinal bleed (2 vs 11, P = 0.007), and jaundice (16 vs 41, P < 0.001) were lower in group I. CONCLUSIONS: Treatment with nutrition therapy prevented recurrence of OHE and decreased OHE-related hospitalizations as compared with no nutrition therapy.

Nutritional therapy for persistent cognitive impairment after resolution of overt hepatic encephalopathy in patients with cirrhosis: A double-blind randomized controlled trial.

BACKGROUND AND AIM: Minimal hepatic encephalopathy (MHE) reflects cognitive impairment in patients with liver cirrhosis and is associated with poor prognosis. We assessed the effects of nutritional therapy on cognitive functions, health-related quality of life (HRQOL), anthropometry, endotoxins, and inflammatory markers in cirrhotic patients with MHE. METHODS: In a double-blind randomized controlled trial, cirrhotic patients with MHE were randomized to nutritional therapy (group I: 30-35 kcal/kg/day and 1.0-1.5 g of protein/kg/day) and no nutritional therapy (group II: diet as patients were taking before) for 6 months. MHE was diagnosed based on psychometric hepatic encephalopathy score (PHES). Anthropometry, ammonia, endotoxins, inflammatory markers, myostatin, and HRQOL were assessed at baseline and after 6 months. Primary endpoints were improvement or worsening in MHE and HRQOL. RESULTS: A total of 150 patients were randomized to group I (n = 75, age 46.3 ± 12.5 years, 58 men) and group II (n = 75, age 45.2 ± 9.3 years, 56 men). Baseline PHES (-8.16 ± 1.42 vs -8.24 ± 1.43; P = 0.54) was comparable in both groups. Reversal of MHE was higher in group I (73.2% vs 21.4%; P = 0.001) than group II. Improvement in PHES (Δ PHES 4.0 ± 0.60 vs -4.18 ± 0.40; P = 0.001), HRQOL (Δ Sickness Impact Profile 3.24 ± 3.63 vs 0.54 ± 3.58; P = 0.001), anthropometry, ammonia, endotoxins, cytokines, and myostatin levels was also significantly higher in group I than group II. Overt hepatic encephalopathy developed in 6 patients in group I and 13 in group II (P = 0.04). CONCLUSIONS: Nutritional therapy is effective in treatment of MHE and associated with improvement in nutritional status, HRQOL, ammonia, endotoxins, inflammatory markers, and myostatin levels.

Endoscopic retrograde cholangiopancreaticography-related complications - Experience from tertiary care teaching centre over half a decade.

Introduction: Endoscopic retrograde cholangiopancreaticography (ERCP) is an essential therapeutic procedure with a significant risk of complications. Data regarding the complications and predictors of adverse outcomes such as mortality are scarce, especially from India and Asia. We aimed to look at the incidence and outcome of complications in ERCP patients. Materials and Methods: This study is a retrospective analysis of prospectively collected data of all the patients who underwent ERCP and had a complication from January 2012 to December 2018. Data were recorded in predesigned pro forma. The data analysis was done by appropriate statistical tests. Results: : A total of 17,163 ERCP were done. A total of 570 patients (3.3%) had complications; perforation (n = 275, 1.6%) was most common followed by pancreatitis (n = 177, 1.03%) and bleeding (n = 60, 0.35%). The majorities of perforations were managed conservatively (n = 205, 74.5%), and 53 (19%) required surgery. Overall, 69 (0.4%) patients died. Of these, 30 (10.9%) patients died with perforation. Age (odds ratio [OR]: 1.04, 95% confidence interval [CI]: 1.005-1.07) and need of surgery (OR: 5.11, 95% CI: 1.66-15.77) were the predictors of mortality in patients with perforation. The majority pancreatitis were mild (n = 125, 70.6%) and overall mortality was 5.6% (n = 10). Conclusion: ERCP complications have been remained static over the years, with perforation and pancreatitis contributing the most. Most perforations can be managed conservatively with good clinical outcomes.

ERCP-related perforation: an analysis of operative outcomes in a large series over 12 years.

BACKGROUND: Perforation is a rare but serious adverse event of endoscopic retrograde cholangiopancreatography (ERCP). The aim of this study was to determine the predictors of morbidity and mortality after surgical management of ERCP-related perforation (EP). METHODS: The records of patients with EP requiring surgical intervention at a tertiary referral center in a 12-year period (2004-2016) were retrospectively analyzed for demography, indications for ERCP, risk factors, timing and type of surgical repair, post-operative course, hospital stay, and outcome. Multiple logistic regression was used to identify the parameters predicting survival. RESULTS: Of 25,300 ERCPs, 380 (1.5%) had EP. Non-operative management was successful in 330 (86.8%) patients. 50 (13.2%) patients were operated for EP. Out of 50, the perforation was detected during ERCP (intra-procedure) in 32 patients (64%). In 30 patients (60%), the surgery was performed within 24 h of ERCP. Twenty patients underwent delayed surgery (after 24 h of ERCP) following the failure of initial non-operative management. The delayed surgery after an unsuccessful medical treatment had a detrimental effect on morbidity, mortality and hospital stay. Post-operative duodenal leak was the only independent predictor of 90-day mortality (p = 0.02, OR = 9.1, 95% CI 1.52-54.64). Addition of T-tube duodenostomy (TTD) to the primary repair for either type I or type II perforations increased post-operative duodenal leak (type I, p = 0.048 and type II; p = 0.001) and mortality (type I, p = 0.009 and type II, p = 0.045). CONCLUSION: Although EP is a rare event, it has a serious impact on morbidity and mortality. Delaying of surgery following failed non-operative management worsens the prognosis. Addition of TTD to the repair is not helpful in these patients.

Endoscopic cystogastrostomy versus surgical cystogastrostomy in the management of acute pancreatic pseudocysts.

Background: Studies comparing surgical versus endoscopic drainage of pseudocyst customarily include patients with both acute and chronic pseudocysts and the endoscopic modalities used for drainage are protean. We compared the outcomes following endoscopic cystogastrostomy (ECG) and surgical cystogastrostomy (SCG) in patients with acute pseudocyst. Methods: Seventy-three patients with acute pseudocyst requiring drainage from 2011 to 2014 were analysed (18 patients excluded: transpapillary drainage n = 15; cystojejunostomy n = 3). The remaining 55 patients were divided into two groups, ECG n = 35 and SCG n = 20, and their outcomes (technical success, successful drainage, complication rate and hospital stay) were compared. Results: The technical success (31/35 [89%] vs. 20/20 [100%] P = 0.28), complication rate (10/35 [28.6%] vs. 2/20 [10%]; P = 0.17) and median hospital stay (6.5 days [range 2-12] vs. 5 days [range 3-12]; P = 0.22) were comparable in both the groups, except successful drainage which was higher in surgical group (27/35 [78%] vs. 20/20 [100%] P = 0.04). The conversion rate to surgical procedure was 17%. The location of cyst towards tail of pancreas and presence of necrosis were the main causes of technical failure and failure of successful endoscopic drainage, respectively. Conclusion: Surgical drainage albeit remains the gold standard for management of pseudocyst drainage; endoscopic drainage should be considered a first-line treatment in patients with acute pseudocyst considering the reasonably good success rate.

L-ornithine L-aspartate in bouts of overt hepatic encephalopathy.

High-quality data on the efficacy of L-ornithine L-aspartate (LOLA) in patients with cirrhosis and bouts of overt hepatic encephalopathy (OHE) are missing. We evaluated the efficacy of intravenous LOLA in the reversal of bouts of OHE in patients with cirrhosis. In this prospective, double-blind, randomized, placebo-controlled trial conducted at two tertiary care institutes in India, 370 patients with cirrhosis and bouts of OHE were screened. After exclusion, 193 (52.16%) patients were randomized to receive either intravenous infusions of LOLA (n = 98), 30 g daily, or placebo (n = 95) for 5 days. Standard of care treatment (including lactulose and ceftriaxone) was given in both groups. Randomization was done centrally (http://www.sealedenvelope.com/). All study personnel were blinded to the treatment assignment. Fasting venous ammonia levels were estimated daily from 0 to 5 days. Serum tumor necrosis factor-alpha, interleukins, hemogram, and liver and renal function tests were performed at days 0 and 5. Primary outcome was mental state grade at day 5 of treatment. The grade of OHE was significantly lower in the LOLA group (compared to placebo) on days 1-4 but not on day 5. The mean time taken for recovery was lower in the LOLA group compared to the placebo group (1.92 ± 0.93 versus 2.50 ± 1.03 days, P = 0.002; 95% confidence interval -0.852 to -0.202). Venous ammonia at day 5 and length of hospital stay were significantly lower in the LOLA group. No significant difference in interleukins was seen between the groups. Conclusion: In patients with bouts of OHE, intravenous LOLA (as an add-on therapy to lactulose and ceftriaxone) significantly improves the grade of OHE over days 1-4, but not on day 5, and decreases venous ammonia, time of recovery, and length of hospital stay. (Hepatology 2018;67:700-710).

A double-blind randomized controlled trial to assess efficacy of bromocriptine in cirrhotic patients with hepatic parkinsonism.

BACKGROUND: Parkinsonism like features can be seen in cirrhotics, possibly related to alterations in brain dopamine metabolism, transport and receptor integrity at basal ganglia. Hepatic parkinsonism is often not suspected and only ammonia-reducing therapies are given to such patients. We investigated the efficacy and safety of bromocriptine, a dopaminergic agent, in patients with hepatic parkinsonism. PATIENTS AND METHODS: Cirrhotics were screened for the presence of extrapyramidal symptoms and were diagnosed as hepatic parkinsonism if any two of tremor, bradykinesia and/or rigidity were present, supported by MRI brain showing T1 hyperintensities in basal ganglia and substantia nigra. Patients were randomized to receive placebo (Gr A, n = 22) or bromocriptine (Gr B, n = 24) for 12 weeks. Complete, partial and non-response were defined as 30%, 10%-30% and <10% reduction,respectively, in Unified Parkinson's Disease Rating Scale motor score. RESULTS: Of 1016 cirrhotics, 50 (4.9%) had hepatic parkinsonism. Patients in two treatment groups were comparable for MELD score, arterial NH3 and frequency of portosystemic shunts. Bromocriptine therapy for 12 weeks resulted in improvement in rigidity, tremors, bradykinesia and gait compared to placebo with complete and partial response in seven vs none (29.1%, 0%, P < 0.01) and 12 vs one (50%, 4.5%, P < 0.01) patients. Prolonged and more severe motor symptoms were associated with non-response to bromocriptine therapy. There were no major side effects in either treatment group. CONCLUSIONS: Hepatic parkinsonism is seen in ~5% cirrhotics. Bromocriptine is a safe and effective therapy for these patients and is more effective in mild to moderate hepatic parkinsonism.

Immune correlates of hepatitis B surface antigen spontaneous seroconversion in hepatitis B e antigen negative chronic hepatitis B patients.

BACKGROUND: Hepatitis B surface antigen (HBsAg) seroconversion in HBeAg -ve chronic hepatitis B (CHB) infection is rare, possibly due to poor antigen processing and impaired humoral response. We investigated the role of dendritic cells (DCs), T follicular helper (TFH) cells and plasma B cells in seroconversion. METHODS: HBeAg -ve (n=135) CHB patients with raised ALT at baseline were followed up. Patients undergoing HBsAg seroconversion (Gr. I, n=11) were compared with non-converters with low (Gr. II, n=17, HBV DNA<2000 IU/mL) or high HBV DNA (Gr. III, HBV DNA >2000 IU/mL, n=17). We measured cell phenotypes (TFH, B and DCs), HBV specific T-cell functionality [using pooled overlapping surface and core peptides], IL21 levels and gene expression analysis by qRT-PCR. RESULTS: Patients in Gr. I compared to Gr. II and III, had higher IL-21 levels (865 vs 276 vs 111 pg/mL, P=<.0001), TFH (CD4+ CXCR5+ ) cells (12.3 vs 4.67 vs 2.77, P=<.001), inducible T-cell co-stimulator (ICOS) expression on TFH cells (20.0 vs 13.0 vs 13.68, P=.01), HBsAg specific IL-17 (9.40 vs 2.33 vs 2.61, P=<.001) and TNF-α secreting TFH17 cells (82 vs 1.43 vs 2.33, P=<.001), plasma B (CD19+ CD38+ ) cells (15.0 vs 5.08 vs 5.57, P=<.001), myeloid (17.80 vs 5.39 vs 2.70, P=<.001) and plasmocytoid DCs (2.6 vs 0.43 vs 0.21, P=<.001). Plasma B-cell frequency (R2 =.64, P=.01) and IL-21 levels (R2 =.52, P=.003) correlated with anti-HBs titres in patients with HBsAg seroconversion. CONCLUSIONS: Dendritic cell and TFH cell mediated responses regulate humoral responses against HBV and play a major role in HBsAg seroconversion in CHB patients.

SX-Ella Stent Danis Effectively Controls Refractory Variceal Bleed in Patients with Acute-on-Chronic Liver Failure.

BACKGROUND AND AIMS: Almost 10% of bleeding episodes are refractory to combination of vasoactive agent and endotherapy, and are associated with a mortality up to 50%. Severity of liver disease and high portal pressure are mainly responsible for it. TIPS cannot be used in these patients due to high MELD score. We aimed to evaluate the efficacy of self-expandable DE stents for control of refractory variceal bleeds in patients with ACLF. METHODS: Acute-on-chronic liver failure patients (n = 88, mean age 47.3 ± 10.9 years) with refractory variceal bleeds received either DE stent (Gr. A, n = 35) or continued with repeat endotherapy and vasoactive drug (Gr.B, n = 53). Matching by propensity risk score (PRS) was done to avoid selection bias. Competing risk Cox regression analysis was done to identify event-specific, i.e., gastrointestinal bleed-related death. RESULTS: Majority (78.4%) of patients were alcoholic with MELD score of 45.9 ± 20.1. Control of initial bleeding was significantly more in the DE stent group as compared to controls in both pre-match (89 vs. 37%; p < 0.001) and PRS-matched cohorts (73 vs. 32%; 0.007). Further, bleed-related death was also significantly lower in DE group as compared to controls in both pre-match (14 vs. 64%; p = 0.001) and PRS-matched cohorts (6 vs. 56%; p = 0.001). In a multivariate competing risk Cox model, patients who underwent DE stenting had reduced mortality in both pre-match (p = 0.04, HR 0.36, 95% CI 0.13-0.96) and PRS-matched cohorts (p < 0.001, HR 0.21, 95% CI 0.08-0.51). CONCLUSIONS: Self-expandable DE stents are very effective in control of refractory variceal bleeding and reduced mortality in patients with severe liver failure.

Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts. CONCLUSIONS: The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.

Randomized controlled trial comparing lactulose plus albumin versus lactulose alone for treatment of hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is associated with poor prognosis and treatment of HE is primarily directed at the reduction of the blood ammonia levels. The study evaluated the efficacy and safety of albumin plus lactulose versus lactulose alone for treatment of overt HE. METHODS: In prospective randomized controlled trial, 120 patients with overt HE were randomized in two groups: group A lactulose plus albumin (n = 60) and group B lactulose alone (n = 60). Primary end point was complete reversal of HE, and secondary end points were mortality and hospital stay. RESULTS: A total of 120 patients (mean age 40.4 ± 9.3 years) were included in this study. Thirty-six (30%) patients were in Child-Turcotte-Pugh (CTP) class B, and 84 (70%) were in CTP Class C. Mean CTP score was 9.8 ± 2.1, and model for end-stage liver disease score was 26.1 ± 5.3. Twenty seven (22.5%) had grade 2, 57 (47.5%) had grade 3, and 36 (30%) had grade 4 HE at the time of admission. Forty-five (75%) patients in group A compared with 32 (53.3%) patients in group B had complete reversal of HE (P = 0.03). Mortality was significantly lower in lactulose plus albumin group (11[18.3%]) versus lactulose alone (19 [31.6%], [P < 0.05]). There was significant decrease in levels of arterial ammonia, interleukin-6, interleukin-18, tumor necrosis factor-alpha, and endotoxins after treatment in both groups; however, the delta decrease was significantly higher in group A compared with group B. Hospital stay was shorter in group A. CONCLUSIONS: Combination of lactulose plus albumin is more effective than lactulose alone in treatment of overt HE.

Sleep disturbances in patients of liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy.

Sleep disturbances are common in patients of cirrhosis with minimal hepatic encephalopathy (MHE) and affect health related quality of life (HRQOL). No study has evaluated effect of lactulose on sleep disturbances and correlation with HRQOL in patients with MHE. We assessed sleep disturbances in cirrhosis with MHE and effect of lactulose on sleep disturbances and HRQOL. One hundred patients of cirrhosis [MHE; (n = 50, age 45.3 ± 11.2 years, 45 males) no-MHE (n = 50, age 46.3 ± 10.4 years, 44 males)] were included. MHE was diagnosed with psychometric hepatic encephalopathy score (PHES) ≤ -5. All patients underwent laboratory parameters including arterial ammonia and critical flicker frequency (CFF) Sleep disturbances were measured with Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and polysomnography. HRQOL was measured with SF-36(v2) questionnaire. Patients with MHE were given lactulose therapy for 3 months and all the parameters were repeated. Poor quality of sleep and excessive day time sleepiness were more common in patients with MHE, compared to without MHE. With lactulose therapy there was improvement in MHE in 21 patients and arterial ammonia levels (93.74 ± 14.8 vs. 71.44 ± 18.8 µmol/L: p < 0.001), CFF (34.83 ± 3.54 vs. 39.44 ± 4.95 Hz: p < 0.001), PHES (-7.64 ± 2.1 vs. -5.58 ± 2.09: p < 0.001), PSQI (8.6 ± 3.3 vs. 5.2 ± 1.5: p < 0.001), ESS (12.52 ± 3.01 vs. 9.24 ± 2.27: p < 0.001) and HRQOL (p = 0.01). Excessive day time sleepiness and impaired sleep quality are common in patients with MHE and correlate with neuropsychiatric impairment. Improvement in MHE with lactulose also leads to improvement in sleep disturbances and HRQOL.

Efficacy of Nutritional Therapy for Patients With Cirrhosis and Minimal Hepatic Encephalopathy in a Randomized Trial.

BACKGROUND & AIMS: Minimal hepatic encephalopathy (MHE) impairs health-related quality of life (HRQOL), leads to the development of overt HE, and is associated with poor outcome. We performed a randomized controlled trial to assess the effects of nutritional therapy on cognitive functions and HRQOL in patients with cirrhosis with MHE. METHODS: In a tertiary care setting in New Delhi, India, patients with cirrhosis with MHE were assigned randomly to groups given nutritional therapy (30-35 kcal/kg/d, 1.0-1.5 g vegetable protein/kg/d; n = 60; age, 42.1 ± 10.3 y; 48 men) or no nutritional therapy (patients continued on their same diet; n = 60; age, 42.4 ± 9.6 y; 47 men) for 6 months in 2014. MHE was diagnosed based on their psychometry hepatic encephalopathy score (PHES). HRQOL was assessed by a sickness impact profile (SIP) questionnaire. Primary end points were improvement or worsening in MHE and improvement in HRQOL. RESULTS: There was no significant difference in baseline PHES (-8.12 ± 1.32 vs -8.53 ± 1.38; P = .08) or SIP (14.25 ± 5.8 vs 15.44 ± 5.03; P = .85) scores. After the 6-month study period, a higher proportion of patients in the nutritional therapy group had reversal of MHE (71.1% vs 22.8%; P = .001). Patients in the nutritional therapy group also had larger increases in PHES (3.86 ± 3.58 vs 0.52 ± 4.09; P = .001) and HRQOL (improvement in SIP score of 3.24 ± 3.63 vs 0.54 ± 3.58; P = .001). Overt HE developed in 10% of patients in the nutritional therapy group vs 21.7% of the control group (P = .04). CONCLUSIONS: Based on a randomized controlled trial performed in India, nutritional therapy is effective in the treatment of MHE and is associated with improvement in HRQOL. Clinical Trial Registry-India registration no: CTRI/2013/07/003851.

Spectral electroencephalogram in liver cirrhosis with minimal hepatic encephalopathy before and after lactulose therapy.

BACKGROUND AND AIM: Minimal hepatic encephalopathy (MHE) represents the mildest form of hepatic encephalopathy. Spectral electroencephalogram (sEEG) analysis improves the recognition of MHE by decreasing inter-operator variability and providing quantitative parameters of brain dysfunction. We compared sEEG in patients with cirrhosis with and without MHE and the effects of lactulose on sEEG in patients with MHE. METHODS: One hundred patients with cirrhosis (50 with and 50 without MHE) were enrolled. Diagnosis of MHE was based on psychometric hepatic encephalopathy score (PHES) of ≤ -5. Critical flicker frequency, model of end-stage liver disease score, and sEEG were performed at baseline in all patients. The spectral variables considered were the mean dominant frequency (MDF) and relative power in beta, alpha, theta, and delta bands. Patients with MHE were given 3 months of lactulose, and all parameters were repeated. RESULTS: Spectral electroencephalogram analysis showed lower MDF (7.8 ± 1.7 vs 8.7 ± 1.3 Hz, P < 0.05) and higher theta relative power (34.29 ± 4.8 vs 24 ± 6.7%, P = 001) while lower alpha relative power (28.6 ± 4.0 vs 33.5 ± 5.3%, P = .001) in patients with MHE than in patients without MHE. With theta relative power, sensitivity 96%, specificity 84%, and accuracy of 90% were obtained for diagnosis of MHE. After lactulose treatment, MHE improved in 21 patients, and significant changes were seen in MDF (7.8 ± 0.5 vs 8.5 ± 0.6), theta (34.2 ± 4.8 vs 23.3 ± 4.1%), alpha (28.6 ± 4.0 vs 35.5 ± 4.5%), and delta relative power (13.7 ± 3.5 vs 17.0 ± 3.3%) after treatment (P ≤ 0.05). CONCLUSIONS: Spectral EEG is a useful objective and quantitative tool for diagnosis and to assess the response to treatment in patients with cirrhosis with MHE.

Probiotics in management of hepatic encephalopathy.

Gut microflora leads to production of ammonia and endotoxins which play important role in the pathogenesis of hepatic encephalopathy (HE). There is relationship between HE and absorption of nitrogenous substances from the intestines. Probiotics play a role in treatment of HE by causing alterations in gut flora by decreasing the counts of pathogen bacteria, intestinal mucosal acidification, decrease in production and absorption of ammonia, alterations in permeability of gut, decreased endotoxin levels and changes in production of short chain fatty acids. Role of gut microbiota using prebiotics, probiotics and synbiotics have been evaluated in the management of minimal hepatic encephalopathy (MHE), overt HE and prevention of HE. Many studies have shown efficacy of probiotics in reduction of blood ammonia levels, treatment of MHE and prevention of HE. However these trials have problems like inclusion of small number of patients, short treatment durations, variability in HE/MHE related outcomes utilized and high bias risk, errors of systematic and random types. Systematic reviews also have shown different results with one systematic review showing clinical benefits whereas another concluded that probiotics do not have any role in treatment of MHE or HE. Also practical questions on optimal dose, ideal combination of organisms, and duration of treatment and persistence of benefits on long term follow-up are still to be clarified. At present, there are no recommendations for use of probiotics in patients with HE.

Malnutrition in cirrhosis increases morbidity and mortality.

BACKGROUND AND AIMS: Malnutrition is frequent in patients with cirrhosis and is associated with complications like ascites, hepatic encephalopathy, infections, and death. We determined the prevalence of malnutrition by various methods and its clinical importance in patients with cirrhosis. METHODS: Consecutive patients of cirrhosis from August 2013 to February 2015 were assessed. Nutritional status was assessed by traditional model (mid-arm circumference, triceps skinfold thickness, serum albumin, creatinine height index, total lymphocyte count), handgrip, and body composition analysis measuring skeletal muscle mass and body fat mass. All patients were followed up for 12 months to assess the outcome. RESULTS: 247 patients (age 42.10 ± 10.14 years, 81% male) were included in the study. Etiology of cirrhosis was alcohol in 53% patients. Prevalence of malnutrition was 59.5% according to traditional model, 66.8% by body composition analysis and 71.4% by handgrip. Nutritional status was poor in alcoholic cirrhotics versus nonalcoholics as assessed by triceps skinfold thickness (9.33 ± 2.9 vs 11.64 ± 3.5 mm; P = 0.001), serum albumin (25.1 ± 4 vs 28.1 ± 4 g/L; P = 0.001), and body fat mass (7.6 ± 3.1 vs 8.7 ± 3.3 kg; P = 0.008). Prevalence of malnutrition was 12/27 (44.5%), 96/131 (73.3%) and 84/89 (94.4%) in Child's class A, B, and C respectively. Complications requiring hospitalization (71.3% vs 38.2%; 0.002) and mortality (41.1% vs 18.2%; P = 0.001) were more in malnourished patients compared to well nourished. Nutritional assessment parameters significantly correlated with the liver disease severity (P < 0.05). CONCLUSIONS: Prevalence of malnutrition is high in patients with cirrhosis. It is associated with increased complications and mortality.

Probiotics prevent hepatic encephalopathy in patients with cirrhosis: a randomized controlled trial.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with a poor prognosis in patients with advanced liver disease. Probiotics alter the intestinal microbiota with non-urease-producing organisms that reduce production of ammonia. We investigated the efficacy of probiotics for the primary prophylaxis of HE. METHODS: We conducted a prospective trial at a tertiary care referral institute in New Delhi, India, from January 2012 through March 2013, of patients with cirrhosis without overt HE (age, 48.6 ± 11.1 y; 96 men and 64 women); 25 were Child-Turcotte-Pugh (CTP) class A, 51 were CTP class B, and 84 were CTP class C. Subjects were assigned randomly to groups given probiotics (1 × 10(8) colony-forming units, 3 times daily; n = 86, 42 with minimal HE) or no test article (control, n = 74; 33 with minimal HE). All subjects underwent psychometric analyses, critical flicker fusion (CFF) threshold assessments, glucose hydrogen breath tests to identify small intestinal bacterial overgrowth (SIBO), and lactulose hydrogen breath tests to measure orocecal transit time (OCTT). The primary end point was the development of overt HE. RESULTS: At baseline, subjects in each group had comparable CTP score, model for end-stage liver disease scores, CFF assessments, psychometric hepatic encephalopathy scores, and OCTT. After a mean follow-up period of 38.6 ± 8.80 weeks for patients given probiotics and 40.3 ± 9.8 weeks for controls, 6 patients given probiotics and 7 controls died (P = .81). Three months of probiotic administration significantly reduced levels of arterial ammonia, SIBO, and OCTT; increased psychometric hepatic encephalopathy scores; and increased CFF thresholds, compared with baseline. Seven subjects in the probiotic group and 14 controls developed overt HE (P < .05; hazard ratio for controls vs probiotic group, 2.1; 95% confidence interval, 1.31-6.53). Psychometric hepatic encephalopathy scores, CTP scores, and SIBO correlated with the development of overt HE. CONCLUSIONS: In a prospective, randomized controlled trial, probiotics were found to be effective in preventing HE in patients with cirrhosis. Trial registration No: CTRI/2012/07/002807.