Longitudinal changes in bone mineral density may be associated with long-term survival in patients with cirrhosis: A proof of concept of study.

INTRODUCTION: The impact of longitudinal changes in different body components measured via body composition analysis (BCA) on liver-related outcomes in patients with cirrhosis is poorly understood. We evaluated the prognostic relevance of longitudinal changes in body composition over one year in patients with cirrhosis. METHODS: This was a follow-up study of a randomized controlled trial evaluating changes in bone density measured via dual energy X-ray absorptiometry (DEXA) upon vitamin D supplementation. Patients with available anthropometric indices, fat mass (FM), fat-free mass (FFM), bone-density at lumbar spine (LD) and left femur-neck (FD) (assessed by T score) at two time points one year apart were assessed for outcomes. The prognostic relevance of change in parameters such as ΔFM, ΔFFM, ΔLD and ΔFD over one year was assessed and compared with baseline model for end-stage liver disease (MELD) score. RESULTS: Patients with cirrhosis (n=112) (mean age 41.8±12 years, 58.5% males) were followed up for median duration of 5.7 years interquartile range [IQR 3.5-5.7], with five-year survival rate of 77%. On serial BCA, ΔLD (p=0.029) and ΔFD (p=0.003) emerged as significant predictors of survival, whereas ΔFM (p=0.479), ΔFFM (p=0.245) and ΔBMI (p=0.949) were not. The area under curve of ΔLD and MELD score for predicting survival was 0.636 (0.5-0.773) and 0.664 (0.555-0.773), respectively. ΔFD<0.1 over one year had sensitivity and specificity of 70.4% and 56.5% to predict poor survival. The combination of ΔFD, MELD and ascites predicted five-year survival with an optimism-corrected c-statistic of 0.785. CONCLUSION: Among body composition parameters, changes in bone mineral density correlate best with survival and have prognostic relevance similar to that of ascites and MELD score.

Randomised clinical trial: effect of adding branched chain amino acids to exercise and standard-of-care on muscle mass in cirrhotic patients with sarcopenia.

BACKGROUND: The role of branched-chain amino acids (BCAA) in improving muscle mass in cirrhosis is presently debatable. AIMS: To evaluate the role of BCAA in improving muscle mass in a double-blind randomized placebo-controlled trial in patients with cirrhosis having sarcopenia. METHODS: Consecutive patients with cirrhosis with Child-Pugh score < 10 and sarcopenia were randomized to receive either 12 g/day of BCAA orally or a placebo (1:1) for 6 months in addition to a home-based exercise program (30 min/day), dietary counselling and standard medical therapy. Sarcopenia was defined according to gender-specific axial skeletal muscle index (SMI) cut-offs. The primary endpoint was a change in muscle mass based on CT scan (SMI) after 6 months of supplementation. RESULTS: Sixty patients [mean age 41.6 ± 9.9 years; males (66.6%) of predominantly viral (40%) and alcohol-related (31.7%) cirrhosis] were randomized. Baseline clinical and demographic characters were similar except MELD score (10.2 ± 2.8 vs. 12.2 ± 3.5, p = 0.02) and calorie intake (1838.1 kcal ± 631.5 vs. 2217.5 kcal ± 707.3, p = 0.03), both being higher in the placebo arm. After adjusting for both baseline confounders, baseline SMI and protein intake, the change in SMI at 6 months was similar in both groups [mean adjusted difference (MAD) + 0.84, CI - 2.9; + 1.2, p = 0.42] by intention-to-treat analysis. The secondary outcomes including change in handgrip strength (p = 0.65), 6-m gait speed (p = 0.20), 6-min walk distance (p = 0.39) were similar in both arms. Four patients had minor adverse events in each arm. CONCLUSION: Addition of BCAA to exercise, dietary counselling and standard medical therapy did not improve muscle mass in patients with cirrhosis having sarcopenia. (CTRI/2019/05/019269). TRIAL REGISTRATION NUMBER: CTRI/2019/05/019269 (Clinical Trials Registry of India).

Effect of Vitamin D Supplementation on Vitamin D Level and Bone Mineral Density in Patients With Cirrhosis: A Randomized Clinical Trial.

INTRODUCTION: In patients with cirrhosis, highly prevalent vitamin D deficiency and low bone mineral density (BMD) increase the burden of disease, and role of vitamin D supplementation is not clear. So, our aim was to determine the effect of vitamin D supplementation on vitamin D level and BMD in patients with cirrhosis. METHODS: Patients with cirrhosis (18-60 years) of any etiology were enrolled. We measured serum 25(OH)D, parathyroid hormone, thyroid-stimulating hormone, free T4, bone-specific alkaline phosphatase, insulin-like growth factor (IGF)-1, and health-related quality of life at entry and at 1 year; however, serum calcium was measured at 3-month interval. BMD was measured by dual-energy x-ray absorptiometry at lumbar spine and left hip neck at entry and after 1 year. Statistical analysis was performed according to intention-to-treat analysis. RESULTS: Of 390 screened patients with cirrhosis, 164 participants (82 in each group) were randomized. There was significant increase in 25(OH)D levels in intervention group after 1 year (33.7 [24.3-45.7] ng/mL vs 23.1 [17-28.2] ng/mL; P < 0.001) when compared with placebo. The mean difference in BMD at lumbar spine and left hip neck was not significantly changed after 1 year of intervention with vitamin D between both groups. There was no significant change in both the groups in levels of calcium, thyroid-stimulating hormone, parathyroid hormone, free T4, IGF-1, and bone-specific alkaline phosphatase and quality of life. DISCUSSION: Supplementation with vitamin D for 1 year improves vitamin D levels but did not result in improvement in BMD at lumbar spine and left hip neck in patients with cirrhosis.

Antioxidants for Pancreatic Functions in Chronic Pancreatitis: A Double-blind Randomized Placebo-controlled Pilot Study.

BACKGROUND: Antioxidants (AO) supplementation in chronic pancreatitis (CP) has been evaluated for pain. But it is not clear whether AO in CP have an effect on pancreatic functions and other clinical outcomes. We evaluated effect of AO on endocrine function in CP. MATERIALS AND METHODS: Double-blind placebo (PL)-controlled randomized pilot study on 107 patients with CP assigned to receive daily combined AO or PL for 6 months. Primary outcome was: improvement in endocrine function (Homeostasis Model Assessment-Insulin Resistance). Secondary outcome measures were: improvement in C-peptide, Qualitative Insulin Sensitivity Check Index, exocrine pancreatic function (fecal elastase), surrogate markers of fibrosis (platelet-derived growth factor BB, transforming growth factor-ß1, α-smooth muscle actin), quality of life (QOL), pain, nutritional status, markers of oxidative stress (OS), AO status, and inflammation. RESULTS: There was an increase in levels of serum selenium (107.2±26.9 to 109.7±26.9 vs. 104.1±28.6 to 124.0±33.6 µg/L, P=0.022) and serum vitamin E [0.58 (range, 0.27-3.22) to 0.66 (range, 0.34-1.98) vs. 0.63 (range, 0.28-1.73) to 1.09 (range, 0.25-2.91) mg/dL, P=0.001] in the AO than the PL group. However, no significant differences were observed between groups in any of the primary or secondary outcome measures. CONCLUSIONS: Supplementation with AO to patients with CP causes a sustained increase in blood levels of AO; however, it has no addition benefit over PL on endocrine and exocrine functions, markers of fibrosis, OS and inflammation, nutritional status, pain and QOL. Further larger studies with adequate sample size are required.

Angle of His Accentuation Is a Viable Alternative to Dor Fundoplication as an Adjunct to Laparoscopic Heller Cardiomyotomy: Results of a Randomized Clinical Study.

BACKGROUND: There is no consensus regarding the type of anti-reflux procedure to be used as an adjunct to laparoscopic Heller cardiomyotomy (LHCM). The aim of this study was to compare Angle of His accentuation (AOH) with Dor Fundoplication (Dor) as an adjunct to LHCM. METHODS: A total of 110 patients with achalasia cardia presenting for LHCM from March 2010 to July 2015 were randomized to Dor and AOH. Symptom severity, achalasia-specific quality of life (ASQOL), new onset heartburn, and patient satisfaction were assessed using standardized scores preoperatively, at 3, 6 months, and then yearly. The primary outcome was relief of esophageal symptoms while secondary outcomes were new onset heartburn and ASQOL. RESULTS: Both groups were comparable with respect to the baseline demographic characteristics. There was no conversion to open and no mortality in either group. Median operative time was 128 min in AOH and 144 min in Dor group (p < 0.01). Mean follow-up was 36 months and was available in 98% patients. There was significant improvement in esophageal symptoms in both groups with no statistically significant difference between the two groups (p > 0.05). There was no difference in cumulative symptom scores between the two groups over the period of follow-up. New onset heartburn was seen in 11% in AOH and 9% in Dor group. Mean ASQOL score improved in both groups with no difference between the two groups (p = 0.83). Patient satisfaction was similar in both groups. CONCLUSION: AOH is similar to Dor as an adjunct to LHCM in safety and efficacy and can be performed in shorter time. CLINICAL REGISTRATION NUMBER: CTRI: REF/2014/06/007146.

Effect of oral glutamine supplementation on gut permeability and endotoxemia in patients with severe acute pancreatitis: a randomized controlled trial.

OBJECTIVE: The aim of this study is to evaluate the effect of oral glutamine (GL) supplementation on gut permeability and endotoxemia (surrogate end point) in patients with severe acute pancreatitis. METHODS: In a randomized controlled trial, patients were randomized to be given placebo or GL for 7 days. The primary outcome measures include the effect on gut permeability (assessed by lactulose/mannitol excretion in urine and endotoxemia assessed by endotoxin core antibodies type IgG and IgM (EndoCab IgG and IgM). The secondary outcome measures include infectious complications, mortality, total hospital/intensive care unit stay, C-reactive protein, and prealbumin levels. RESULTS: Patients were assigned to GL (n = 41) and placebo (n = 39) groups. There was no change in gut permeability after the intervention. However, the EndoCab IgM levels increased significantly (33 [4, 175] to 40 [8, 350] GMU/mL; P = 0.0164) and the C-reactive protein levels decreased significantly (133 [1, 287] to 88 [1, 267] ng/mL; P = 0.0236) in the GL group. No difference was observed in infectious complication, prealbumin value, hospital/intensive care unit stay, and mortality in both groups. CONCLUSIONS: No significant trend was identified for an effect of GL on gut permeability. Decreased inflammation and endotoxemia did not translate into reduced infectious complications in severe acute pancreatitis. However, the study was underpowered to detect the aforementioned difference (trial registration: CTRI/2009/000945).

Effect of antioxidant supplementation on surrogate markers of fibrosis in chronic pancreatitis: a randomized, placebo-controlled trial.

OBJECTIVES: This study aimed to determine the effect of antioxidant (AO) supplementation on surrogate markers of fibrosis in patients with chronic pancreatitis (CP). METHODS: In a randomized, placebo (PL)-controlled trial, patients with CP were randomized to groups that were given PL or AO for 3 months. Outcome measures were change in serum levels of transforming growth factor ß1 and platelet-derived growth factor AA (PDGF-AA) (primary outcome) as well as blood markers of oxidative stress (thiobarbituric acid-reactive substances) and AO status (ferric-reducing ability of plasma) (secondary outcome). Pain relief and analgesic requirement was also recorded. RESULTS: Patients (n = 61; mean [SD] age, 35.2 [10.0]; male patients, 43) were assigned to AO (n = 31) and PL (n = 30) groups. The median (range) percent reduction from baseline to 3 months in levels of PDGF-AA (17.1% [-25.3% to 88.7%] vs 2.8% [-243.1% to 30.2%]; P = 0.001), transforming growth factor ß1 (P = 0.573), and thiobarbituric acid-reactive substances (P = 0.207) as well as percent increment from baseline to 3 months in ferric-reducing ability of plasma (P = 0.003) were higher in the AO group compared with the PL group. Proportion of patients who had both reduced PDGF-AA and reduced pain was greater in AO as compared with PL group (17/31 vs 9/30, P = 0.05) CONCLUSIONS: Reduction in markers of fibrosis (PDGF-AA) translated into clinical outcome (reduction in pain and analgesic requirements) in those supplemented with AOs in CP (trial registration, CTRI/2011/05/001747).

A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis.

BACKGROUND & AIMS: Oxidative stress has been implicated in the pathophysiology of chronic pancreatitis (CP). We evaluated the effects of antioxidant supplementation on pain relief, oxidative stress, and antioxidant status in patients with CP. METHODS: In a placebo-controlled double blind trial, consecutive patients with CP were randomized to groups that were given placebo or antioxidants for 6 months. The primary outcome measure was pain relief, and secondary outcome measures were analgesic requirements, hospitalization, and markers of oxidative stress (thiobarbituric acid-reactive substances [TBARS]) and antioxidant status (ferric-reducing ability of plasma [FRAP]). RESULTS: Patients (age 30.5+/-10.5 years, 86 male, 35 alcoholic, and 92 with idiopathic CP) were assigned to the placebo (n=56) or antioxidant groups (n=71). After 6 months, the reduction in the number of painful days per month was significantly higher in the antioxidant group compared with the placebo group (7.4+/-6.8 vs 3.2+/-4, respectively; P< .001; 95% CI, 2.07, 6.23). The reduction in the number of analgesic tablets per month was also higher in the antioxidant group (10.5+/-11.8 vs 4.4+/-5.8 respectively; P= .001; 95% CI, 2.65, 9.65). Furthermore, 32% and 13% of patients became pain free in the antioxidant and placebo groups, respectively (P= .009). The reduction in the level of TBARS and increase in FRAP were significantly higher in the antioxidant group compared with the placebo group (TBARS: placebo 1.2+/-2.7 vs antioxidant 3.5+/-3.4 nmol/mL; P= .001; 95% CI 0.96, 3.55; FRAP: placebo -5.6+/-154.9 vs antioxidant 97.8+/-134.9 microMFe(+2) liberated, P= .001, 95% CI 44.98, 161.7). CONCLUSIONS: Antioxidant supplementation was effective in relieving pain and reducing levels of oxidative stress in patients with CP.

Effect of antioxidant therapy on hospital stay and complications in patients with early acute pancreatitis: a randomised controlled trial.

BACKGROUND: Oxidative stress (OS) in acute pancreatitis (AP) has been pathologically linked with the systemic inflammatory response and antioxidant supplementation may have a clinical benefit. METHODS: In this prospective, randomised open label, controlled pilot study, patients admitted within 72 hours of onset of pain were randomised to receive either placebo (only standard medical treatment; SMT) or antioxidants (vitamin C 500 mg, N-acetyl cysteine 200 mg 8 hourly and antoxyl forte 1 capsule hourly with standard medical treatment; SMT + AO) daily, following informed consent. Patients with co-morbid illness and pregnancy were excluded. Primary efficacy measures were length of hospital stay and complications whilst secondary measures were biochemical markers of oxidative stress (thiobarbituric acid reactive substances [TBARS] and superoxide dismutase [SOD] and total antioxidant capacity [TAC] and vitamin C) at Days 1, 3 and 7. RESULTS: Of 53 patients, 30 patients were randomised to SMT and 23 patients to SMT + AO. The mean duration of hospital stay in the SMT group (10.3 +/- 7 days) was more compared to SMT + AOT (7.2 +/- 5 days), but was not statistically significant (p=0.07), complications were similar in the 2 groups. At Day 7, OS was significantly lower in the SMT + AO group when compared with the SMT group (TBARS, p=0.05; SOD, p=0.03) with a significant increase in FRAP and vitamin C (p=0.01). CONCLUSIONS: Antioxidant supplementation may decrease the length of hospital stay and complication rate in patients with AP, but a larger clinical trial is needed to support this hypothesis. Further, it decreased the OS and improved the antioxidant status in patients with AP.

Micronutrient antioxidant intake in patients with chronic pancreatitis.

Increased oxidative stress has been postulated to be an important mechanism in the pathophysiology of chronic pancreatitis (CP). Micronutrient deficiency may increase the oxidative stress as they assist in free radical clearance. The present study was undertaken to assess the intake of micronutrients, i.e. vitamins E and C, carotene, selenium, copper, zinc, manganese, magnesium, sulphur, riboflavin, methionine and choline in patients with CP. All consecutive patients with CP attending the Pancreas Clinic at the All India Institute of Medical Sciences were enrolled in the study. The usual dietary intake was estimated by the 24-hour dietary recall method and food frequency questionnaire. Dietary restrictions, if any, were also noted. The micronutrient intake of patients not on any nutritional supplements (n=75, 65 males and 10 females, mean age 31.06 +/- 10.64 years) was compared with age- and sex- matched healthy controls (n=75). The micronutrients were calculated as per the Nutritive value of Indian Foods given by the National Institute of Nutrition, Indian Council of Medical Research, India and the US dietary intake guidelines as applicable. It was found that the Body Mass Index (BMI) of patients was significantly lower than that of healthy controls. The total intake in terms of calorie was lower in patients when compared to controls. The dietary intake of vitamin E, riboflavin, choline, magnesium, copper manganese and sulfur was significantly lower than that of controls as well as the Recommended Dietary Allowance (RDA). Dietary intake of selenium and vitamin C was within the limits of the RDA but was lower than that of controls, while the intake of carotene was similar in both the groups and met the RDA. We conclude that patients with CP had significantly decreased micronutrient intake owing to diet modification due to pain. Micronutrient deficiency might contribute to increased oxidative stress in these patients.