Browsing by Author "Samala, Niharika"
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Item A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish(Wiley, 2020-11) Hernandez-Perez, Marimar; Kulkarni, Abhishek; Samala, Niharika; Sorrell, Cody; El, Kimberly; Haider, Isra; Aleem, Ansari Mukhtar; Holman, Theodore R.; Rai, Ganesha; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of Medicine12-Lipoxygenase (12-LOX) is a key enzyme in arachidonic acid metabolism, and alongside its major product, 12-HETE, plays a key role in promoting inflammatory signaling during diabetes pathogenesis. Although 12-LOX is a proposed therapeutic target to protect pancreatic islets in the setting of diabetes, little is known about the consequences of blocking its enzymatic activity during embryonic development. Here, we have leveraged the strengths of the zebrafish-genetic manipulation and pharmacologic inhibition-to interrogate the role of 12-LOX in pancreatic development. Lipidomics analysis during zebrafish development demonstrated that 12-LOX-generated metabolites of arachidonic acid increase sharply during organogenesis stages, and that this increase is blocked by morpholino-directed depletion of 12-LOX. Furthermore, we found that either depletion or inhibition of 12-LOX impairs both exocrine pancreas growth and unexpectedly, the generation of insulin-producing β cells. We demonstrate that morpholino-mediated knockdown of GPR31, a purported G-protein-coupled receptor for 12-HETE, largely phenocopies both the depletion and the inhibition of 12-LOX. Moreover, we show that loss of GPR31 impairs pancreatic bud fusion and pancreatic duct morphogenesis. Together, these data provide new insight into the requirement of 12-LOX in pancreatic organogenesis and islet formation, and additionally provide evidence that its effects are mediated via a signaling axis that includes the 12-HETE receptor GPR31.Item Abnormal liver tests are not sufficient for diagnosis of hepatic graft‐versus‐host disease in critically ill patients(Wolters Kluwer, 2022) Yang, Alexander H.; Han, Mai Ai Thanda; Samala, Niharika; Rizvi, Bisharah S.; Marchalik, Rachel; Etzion, Ohad; Wright, Elizabeth C.; Patel, Ruchi; Khan, Vinshi; Kapuria, Devika; Venkat, Vikramaditya Samala; Kleiner, David E.; Koh, Christopher; Kanakry, Jennifer A.; Kanakry, Christopher G.; Pavletic, Steven; Williams, Kirsten M.; Heller, Theo; Medicine, School of MedicineHepatic graft-versus-host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15-day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = -0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period -30 (days 30 to 16 before death) to period -15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.Item Clinical Characteristics and Outcomes of Mild to Moderate Alcoholic Hepatitis(Wiley, 2019) Samala, Niharika; Gawrieh, Samer; Tang, Qing; Lourens, Spencer G.; Shah, Vijay H.; Sanyal, Arun J.; Liangpunsakul, Suthat; Chalasani, Naga; Medicine, School of MedicineIntroduction & Aim Much is known about alcoholic hepatitis (AH) that is severe enough to require hospitalisation. The characteristics of individuals with alcoholic hepatitis presenting with mild to moderate severity are not well understood. In this study, we investigated the risk factors, characteristics and outcomes of mild to moderate AH (M‐AH). Methods A total of 255 individuals with AH enrolled into a multicenter, prospective, observational study between 12/2014 and 4/2018 was included. Participants were seen at enrollment, 6 and 12 months. M‐AH was defined as MELD ≤20 at presentation, whereas severe AH as MELD ≥21. Results In total, 100 individuals had M‐AH, whereas 155 had severe AH. Individuals with M‐AH were older (49 vs 44 years, P = 0.01), had lower BMI (27 vs 31 kg/m2, P = 0.0007) and more likely to be male (68% vs 55%, P = 0.046) compared to the severe AH group. A higher proportion in the M‐AH group consumed coffee in the last 5 years compared to the severe AH group (29% vs 18%, P = 0.03), and fewer had PNPLA3 risk allele G (P = 0.019) compared to the severe AH group. Average drinks per drinking day (12.9 vs 10.7, P = 0.13) and total number of drinks in last 30‐day period (331 vs 280, P = 0.14) were not different between two groups. Compared to severe AH, patients with M‐AH had significantly lower mortality at 30 days (2% vs 13.6%), 90 days (3% vs 22.6%) and 12 months (10.4% vs 31.4%) (P < 0.001 for all). Conclusions Individuals with M‐AH were older, less obese, drank coffee more often and carried more favourable PNPLA3 genotype compared to severe AH, despite similar alcohol consumption. M‐AH had substantial mortality with one in ten dying by 12 months.Item Decreased Quality of Life is Significantly Associated with Body Composition in Patients with Nonalcoholic Fatty Liver Disease(Elsevier, 2020) Samala, Niharika; Desai, Archita; Vilar, Eduardo; Smith, Emily R.; Gawrieh, Samer; Kettler, Carla D.; Pike, Francis; Chalasani, Naga; Medicine, School of MedicineBackground & Aims We studied impaired quality of life (QOL) and its determinants among individuals with nonalcoholic fatty liver disease (NAFLD). Methods We collected data from 341 patients with NAFLD who completed the short form 36 (SF-36) questionnaire. Body composition and liver fibrosis were assessed in patients with NAFLD using bioelectrical impedance and transient elastography, respectively. Advanced fibrosis was defined as liver stiffness measurements (LSMs) of 12.1 kPa or greater. SF-36 scores of patients with NAFLD were compared with SF36 scores of individuals with chronic medical illnesses and the general population obtained from the published literature. Results Among patients with NAFLD, percent body fat was negatively associated with scores from all 8 SF-36 scales, whereas lean body mass was positively associated with scores from 5 of 8 SF-36 scales. On multivariable analysis, SF-36 PF scores were negatively associated with type 2 diabetes, body mass index, and LSM and positively associated with lean body mass and level of alanine aminotransferase. Patients with NAFLD, and even those without advanced fibrosis, had significantly lower mean QOL scores than the control group or the general population. Conclusions Individuals with NAFLD, even those without advanced fibrosis, have lower QOL than controls. Body composition associates with QOL in patients with NAFLD; both of the modifiable factors independently associated with QOL are related to body composition. Further studies are needed to investigate if interventions to improve body composition can increase QOL for patients with NAFLD.Item Health-related quality of life is dynamic in alcohol hepatitis and responds to improvement in liver disease and alcohol consumption(Wiley, 2022) Madathanapalli, Abhishek; Tang, Qing; Lammert, Craig; Samala, Niharika; Shah, Vijay H.; Sanyal, Arun; Chalasani, Naga; Desai, Archita P.; Biostatistics, School of Public HealthBackground: The impact of alcoholic hepatitis (AH) on health-related quality of life (HRQOL) remains inadequately described. We aimed to characterize HRQOL in AH and heavy drinkers (HD), and its associations with clinical variables and outcomes. Methods: This is a post hoc analysis of participants in the Translational Research and Evolving Alcoholic Hepatitis Treatment 001 study (NCT02172898). HRQOL was measured using Short Form Health Survey (SF-36). Mean SF-36 scores were compared in AH and HD with two-sample t-tests. Associations among clinical characteristics, 30-day mortality, and SF-36 mental and physical component scores (MC, PC) were investigated with generalized linear and logistic multivariate regression models. Trends of MC and PC scores were analyzed using one-way ANOVA. Results: Participants with AH (n = 258) and HD (n = 181) were similar demographically. AH cases had a mean Model for End-stage Liver Disease (MELD) score of 23 (7). AH cases had lower PC scores [37 (10) vs. 48 (11), p < 0.001] but higher MC scores [37 (13) vs. 32 (13), p < 0.001]. MC scores were independently associated with age, male gender, and daily alcohol consumption; PC scores were independently associated with age, BMI, alanine aminotransferase concentration, alkaline phosphatase concentration, white blood cell counts, and the presence of ascites. With each 5-point decrease in the baseline PC score, the adjusted odds of dying within 30 days increased by 26.7% (95% CI 1% to 46%). Over time, HRQOL in AH improved (day 0 to day 180 delta PC score: 4.5 ± 1.7, p = 0.008; delta MC score: 9.8 ± 2.0, p < 0.001). Participants with a MELD score <15 by day 180 had greater increases in PC scores than those with MELD score ≥15 (delta PC score 7.1 ± 1.8 vs. -0.7 ± 2.3, p = 0.009), while those abstinent by day 180 had greater increases in MC scores than those who were not abstinent (delta MC score 9.1 ± 1.8 vs. 2.8 ± 2.4, p = 0.044). Conclusions: HRQOL is poor in AH and HD in a domain-specific pattern. Independent of MELD score, lower baseline HRQOL is associated with higher 30-day mortality. Over time, HRQOL improves with greater gains seen in individuals with improved MELD scores and those who were abstinent.Item Hemophagocytic Lymphohistiocytosis in the Medical ICU: A Single-Institution Cohort Study on Acute Liver Failure and Mortality(Wolters Kluwer, 2021-01-08) Al Nasrallah, Nawar; Al-Hader, Ahmad; Samala, Niharika; Sears, Catherine R.; Medicine, School of MedicineHemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disorder that is associated with high morbidity and mortality in the ICU. It has also been associated with acute liver failure. Design: Retrospective observational study. Setting: Tertiary-care medical ICU. Patients: Thirty-one patients critically ill with hemophagocytic lymphohistiocytosis. Interventions: None. Measurements and main results: We performed a comprehensive review of critically ill hemophagocytic lymphohistiocytosis patients admitted to a tertiary-care medical ICU from January 2012 to December 2018. Most patients presented with constitutional symptoms and elevated liver enzymes and thrombocytopenia were common upon hospital admission. ICU admission laboratory and clinical variables were used to calculate Acute Physiology and Chronic Health Evaluation II, hemophagocytic syndrome diagnostic score, and model for end-stage liver disease. Mean age of the cohort was 48.1 years, and 45% were male. The mortality rate was 65% at 28 days and 77% at 1 year. About 28-day survivors were younger, had lower mean Acute Physiology and Chronic Health Evaluation II score (16.5 vs 23.0; p = 0.004), and higher mean hemophagocytic syndrome diagnostic score (249.1 vs 226.0; p = 0.032) compared with nonsurvivors. Survivors were less likely to receive mechanical ventilation, renal replacement therapy, or vasopressor support and were more likely to receive chemotherapy for hemophagocytic lymphohistiocytosis. In this ICU cohort, 29% were diagnosed with acute liver failure, of whom only 22% developed acute liver failure early during their hospital stay. Acute liver failure was associated with a higher model for end-stage liver disease score upon hospital admission. Available histology in those that developed acute liver failure showed massive hepatic necrosis, or histiocytic or lymphocytic infiltrates. Conclusions: Patients admitted to the ICU with hemophagocytic lymphohistiocytosis have a high mortality. Those who survived had lower Acute Physiology and Chronic Health Evaluation scores, had higher hemophagocytic syndrome diagnostic scores, are more likely to receive hemophagocytic lymphohistiocytosis specific chemotherapy, and are less likely to have organ failure. Hemophagocytic lymphohistiocytosis can be associated with acute liver failure especially when model for end-stage liver disease score is elevated upon admission.Item High-quality diet, physical activity, and college education are associated with low risk of NAFLD among the US population(Wiley, 2021) Vilar‐Gomez, Eduardo; Nephew, Lauren D.; Vuppalanchi, Raj; Gawrieh, Samer; Mladenovic, Andrea; Pike, Francis; Samala, Niharika; Chalasani, Naga; Medicine, School of MedicineBackground and Aims The effects of diet quality (DQ), physical activity (PA), and socioeconomic status (SES) on the risk of NAFLD are unclear. We examined the association among DQ, PA, SES, and NAFLD risk. Approach and Results This is a cross-sectional analysis of the National Health and Nutrition Examination Surveys, 2017–2018, which included 3589 participants with reliable information on vibration-controlled transient elastography (VCTE) measurements, 24-h dietary recalls, PA, and SES. DQ was assessed by the Healthy Eating Index (HEI)-2015. PA was determined by the Global Physical Activity Questionnaire. SES was assessed by the educational attainment and family poverty income ratio (PIR). Risk of NAFLD was considered by means of a composite outcome using VCTE measurements: non-NAFLD versus NAFLD without clinically significant fibrosis (CSF) versus NAFLD with CSF. The NAFLD risk was lower in physically active (≥600 metabolic equivalent of task [MET] min/week) versus inactive participants (<600 MET min/week) (OR: 0.71, p = 0.043). A high-quality diet (HQD) (HEI > 56.64) was associated with a lower risk of NAFLD (OR: 0.58, p < 0.01) compared with a non-HQD. The lowest NAFLD risk was observed in those physically active with HQD (OR: 0.43, p < 0.01). Body mass index and waist circumference significantly mediated the effect of DQ and PA on NAFLD risk. Education (college or above) (OR: 0.65, p = 0.034), but not PIR, was associated with a reduced NAFLD risk. HQD and increased PA partially mediated the effect of education on NAFLD risk. The total effect of education on NAFLD risk mediated by DQ was 29% and by PA was 8%. Conclusions HQD, increased physical activity, and college education were associated with lower NAFLD risk in the US population.Item Inhibition of Secretin/Secretin Receptor Axis Ameliorates NAFLD Phenotypes(Wiley, 2021-10) Chen, Lixian; Wu, Nan; Kennedy, Lindsey; Francis, Heather; Ceci, Ludovica; Zhou, Tianhao; Samala, Niharika; Kyritsi, Konstantina; Wu, Chaodong; Sybenga, Amelia; Ekser, Burcin; Dar, Wasim; Atkins, Constance; Meadows, Vik; Glaser, Shannon; Alpini, Gianfranco; Surgery, School of MedicineBackground & Aims Human non-alcoholic fatty liver disease (NAFLD) is characterized at early stages by hepatic steatosis, which may progress to nonalcoholic steatohepatitis (NASH) when the liver displays microvesicular steatosis, lobular inflammation, and pericellular fibrosis. The secretin (SCT)/secretin receptor (SCTR) axis promotes biliary senescence and liver fibrosis in cholestatic models through downregulation of miR-125b signaling. We aim to evaluate the effect of disrupting biliary SCT/SCTR/miR-125b signaling on hepatic steatosis, biliary senescence and liver fibrosis in NAFLD/NASH. Approach & Results In vivo, 4 wk male WT, Sct-/- and Sctr-/- mice were fed a control diet (CD) or high-fat diet (HFD) for 16 wks. The expression of SCT/SCTR/miR-125b axis was measured in human NAFLD/NASH liver samples and HFD mouse livers by immunohistochemistry (IHC) and qPCR. Biliary/hepatocyte senescence, ductular reaction and liver angiogenesis were evaluated in mouse liver and human NAFLD/NASH liver samples. miR-125b target lipogenesis genes in hepatocytes were screened and validated by custom RT2 Profiler PCR array and luciferase assay. Biliary SCT/SCTR expression was increased in human NAFLD/NASH samples and in livers of HFD mice, whereas the expression of miR-125b was decreased. Biliary/hepatocyte senescence, ductular reaction, and liver angiogenesis were observed in human NAFLD/NASH samples as well as HFD mice, which were decreased in Sct-/- and Sctr-/- HFD mice. Elovl1 is a lipogenesis gene targeted by miR-125b, and its expression was also decreased in HFD mouse hepatocytes following Sct or Sctr knockout. Bile acid profile in fecal samples have the greatest changes between WT mice and Sct-/-/Sctr-/- mice. Conclusion The biliary SCT/SCTR/miR-125b axis promotes liver steatosis by upregulating lipid biosynthesis gene Elovl1. Targeting the biliary SCT/SCTR/miR-125b axis may be key for ameliorating phenotypes of human NAFLD/NASH.Item Is Fasting Necessary for Individuals With Nonalcoholic Fatty Liver Disease to Undergo Vibration-Controlled Transient Elastography?(Wolters Kluwer, 2019-06) Vuppalanchi, Raj; Weber, Regina; Russell, Sarah; Gawrieh, Samer; Samala, Niharika; Slaven, James E.; Harden, Lauren; Chalasani, Naga; Medicine, School of MedicineOBJECTIVES: To investigate the effect of meal intake on liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) in patients with biopsy-proven nonalcoholic fatty liver disease undergoing vibration-controlled transient elastography. METHODS: LSM and CAP were assessed at baseline and serially for 6 hours after meal intake in 24 patients. RESULTS: A significant increase in LSM was seen up to the 2-hour time point (26 ± 25%, P = 0.02). The CAP scores changed minimally with a maximal change of 3% (P > 0.1). CONCLUSIONS: Three hours of fasting is necessary before evaluation with vibration-controlled transient elastography.Item Liver Stiffness Measurements in Patients with Non‐cirrhotic Portal Hypertension – The Devil is In the Details(AASLD, 2018) Vuppalanchi, Raj; Mathur, Karan; Pyko, Maximillian; Samala, Niharika; Chalasani, Naga; Medicine, School of MedicineNon‐cirrhotic portal hypertension (NCPH) is often a diagnostic challenge due to signs and symptoms of portal hypertension that overlap with cirrhosis. The etiology of NCPH is broadly classified as prehepatic, hepatic (pre‐sinusoidal and sinusoidal) and post‐hepatic.1 Some common etiologies of NCPH encountered in clinical practice include portal vein thrombosis (prehepatic) and nodular regenerative hyperplasia (NRH) (hepatic).