443Drug Induced Liver Injury at a Tertiary Hospital in India. - PDF document

443Drug Induced Liver Injury at a Tertia
443Drug Induced Liver Injury at a Tertiary Hospital in India. 2017; 16 (3): 442-450 Abdominal ultra-tients were followed up for at least 6 months or until Patients with pre-exist- MELD score was calculated (creatinine mg/dL) + 3.8 x log (international normal- According Summary of demographic and laboratory variables in patients with DILI (n = 82).VariableNMinimumMaximumMeanSDAge (years)82137639.515.3Duration of Hospitalization (days)5735015.512.1Duration of drug exposure (days)82118033.629.1s)8234513.511.4)8216.631.122.72.9Total protein (g/dL)824.88.06.30.6Albumin (g/dL)8224.53.30.5Total bilirubin (mg/dL)820.537.05.16.7Direct bilirubin (mg/dL)820.120.02.63.8INR820.92.91.40.4AST (IU/L)82211918314.8343ALT (IU/L)82181892301315ALP (IU/L)8280680218.1140.9Creatinine (mg/dL)820.531.050.45MELD score8263514.66.9Hemoglobin (g/dL)824.116.310.82.1/dL)820.85.42.60.9/dL)822,60021,7008,993.83,904.1ALP: Alkaline phosphatase. AST: Aspartate transaminase. ALT: Alanine transaminase. DILI: Drug induced liver injury. INR: International normalized ratio.MELD: Model for End stage Liver Disease. WBC: White blood cell count. SD: Standard deviation.Rathi C, et al. 2017; 16 (3): 442-450 test for parametric data. Analysis of varianceHepatocellularCholestaticMixedP value(n = 41)(n = 12)(n = 29)38.3±15.240.2±13.341±16.60.75Female (%)24 (58.5)5 (41.6)12 (41.4)0.3)23.2±2.723.3±3.

522± 30.2228.4±29.444±2536.5±29.50.2Alco
522± 30.2228.4±29.444±2536.5±29.50.2Alcohol intake (%)10 (24.4)4 (33.3)5 (17.2)0.5Jaundice (%)18 (43.9)11 (91.7)16 (55.2)Nausea (%)40 (97.6)10 (83.3)25 (86.2)0.1Anorexia (%)33 (80.5)10 (83.3)14 (48.3)0.008Itching (%)8 (19.5)6 (50)8 (27.6)0.1Skin Rash (%)7 (17.1)2 (16.7)4 (13.8)0.9Dark urine (%)18 (43.9)12 (100)18 (62.1)Abdominal pain (%)32 (78)7 (58.3)21 (72.4)0.4Acute kidney injury (%)2 (4.9)1 (8.3)2 (6.9)0.8Ascites (%)4 (9.7)3 (25)6 (20.7)0.3Encephalopathy (%)6 (14.6)1 (8.3)3 (10.3)0.7Total bilirubin, mean ± SD (mg/dL)3.1±3.38.5±9.36.5±8.20.01457.5±378.278.2±35.9171.8±88.2453.8±428.382.2±56.5214.6±123.4 ALP, mean ± SD (IU/L)190±107.9250.9±186.8244.1±157.40.019I0NR, mean ± SD1.4±0.41.4±0.31.4±0.50.9Creatinine, mean ±SD (mg/dL)1±0.341±0.611±0.520.64MELD score, mean ± SD13±5.717.6±5.715.5±8.40.09Mild21 (51.2)1 (8.3)12 (41.4)Moderate8 (19.5)5 (41.7)4 (13.8)Severe and/or Fatal12 (29.3)6 (50)13 (44.8)Possible1 (2.4)2 (16.7)1 (3.4)0.3Probable33 (80.5)7 (58.3)23 (79.3)Highly probable7 (17.1)3 (25)5 (17.2)Overall deaths (%)4 (10%)2 (17%)7 (24%)Liver related deaths (%)3 (7.3%)1 (8.3%)4 (13.8%)ALP: Alkaline phosphatase. AST: Aspartate transaminase. ALT: Alanine transaminase. BMI: Body mass index. INR: International Normalized Ratio. MELD:Model for End Stage Liver Disease. SD: Standard deviation. P values compare hepatocellular, cholestatic and mixed categories.445Dru

g Induced Liver Injury at a Tertiary Hos
g Induced Liver Injury at a Tertiary Hospital in India. 2017; 16 (3): 442-450iate analysis by logistic regression was performed to iden-tify independent predictors of mortality, using all varia-bles found to be clinically significant on univariateanalysis. All reported P values are 2-tailed. The level ofsignificance was set at 0.05.RESULTS)sion in the study. The youngest patient was 13 years old andthe oldest patient was 76 years old. Most common symp-toms were nausea (91%), vomiting (85%), abdominal pain(73%) and anorexia (69%). Jaundice and dark colored urinewas presenting feature in 55% and 58%, respectively. Themedian duration of drug exposure was 28 days (range, 1-180days). 57 patients were hospitalized (69%) for a median of10 days (range, 3-50 days). 4 patients (5%) had underlyingliver disease in the form of alcoholic liver disease, nonalco-holic steatohepatitis, chronic hepatitis B and C (1 each).Two patients had diabetes with dyslipidemia. Summary ofthe clinical and laboratory variables is shown in Table 1.By using the RUCAM model for drug causality assess-ment,10,11 4 patients (5%) were classified as possible, 63 asThe most commonly implicated drugs were antitubercu-Number of patientsNumber of patients on(%)drug who died (%)Anti-tuberculous drugs (Rifampicin, Isoniazid, Pyrazinamide)40(49%)9Antiepileptic drugs (Phenytoin, Valproic acid)10(12%)2

(20%)8(10%)0Antiretroviral drugs (Zidovu
(20%)8(10%)0Antiretroviral drugs (Zidovudine, Stavudine, Nevirapine)7(9%)1(14.3%)Etoricoxib, Indomethacin, Nimesulide (1 each)5(6%)0Methotrexate3(4%)0Atorvastatin2(2%)1Anti-leprosy drugs (Dapsone, Clofazimine)2(2%)0Other drugs5(6%)0CAM: complementary and alternative medicine.Rathi C, et al. 2017; 16 (3): 442-450inflammatory drugs (6%), methotrexate (4%), atorvastatin(6%) (Table 3). thoseSurvivorsNon-survivorsP valueOR (N = 69)(N = 13)Males34(49.3%)7(53.8%)11.2 Jaundice33120.00513(1.6, 106.3)Nausea631211.1(0.1, 10.4)Vomiting58120.682.3 Anorexia4980.520.6Itching2020.490.4Fever3170.761.4Skin rashes1210.680.4Dark urine36120.0111Encephalopathy190.001153Acute kidney injury05 0.0019.6Ascites77Abdominal pain49110.492.2Alcohol intake16310.9(0.2, 4)Smoking420.242.9ATT3190.142.7 Demographic and laboratory variables for survivors and non-survivors (overall mortality).SurvivorsNon-survivorsP (N = 69)(N = 13)38.4±15.145.5±15.715.1±12.316.7±11.8)22.6±2.923.7±3.0Duration of drug exposure (days)33±2837±340.658Total protein (g/dL)6.3±0.65.9±0.5Albumin (g/dL)3.3±0.53.1±0.4Total Bilirubin (mg/dL)4.7±6.67.1±6.8Direct Bilirubin (mg/dL)2.4±3.73.9±4.3AST (IU/L)330±360233±219ALT (IU/L)322±329185±197ALP (IU/L)212±136250±165INR1.4±0.41.5±0.30.530Creatinine (mg/dL)0.94±0.131.68±0.87MELD score13.5±5.920.4±9.1Hemoglobin (g/dL)11±2.19.4±2.1TLC (per cmm)8840±39719807±3554Platelet

(lakhs/cmm)2.6±0.92.5±1.1ALP: Alkaline
(lakhs/cmm)2.6±0.92.5±1.1ALP: Alkaline phosphatase. AST: Aspartate transaminase. ALT: Alanine transaminase. BMI: Body Mass Index. INR: International Normalized Ratio. MELD:447Drug Induced Liver Injury at a Tertiary Hospital in India. 2017; 16 (3): 442-450bercular meningitis (1 patient each). The mean dura-not (Table 5). However, majority of the laboratory param- Laboratory variables for survivors and non-survivors at one week (overall mortality).SurvivorsNon-survivorsP (N = 69)(N = 13)Total protein (g/dL)6.3±0.55.8± 0.5Albumin (g/dL)3.3±0.42.8±0.5Total Bilirubin (mg/dL)4.6±6.911.9±8.9Direct Bilirubin (mg/dL)2.5±4.36±4.4AST (IU/L)185±354275±259ALT (IU/L)174±209241±238ALP (IU/L)188 ±111324±146INR1.2±0.32.5±1.3Creatinine (mg/dL)0.94±0.132.1±1.10.0001MELD score11.7±5.628.7±13.6ALP: Alkaline phosphatase. AST: Aspartate transaminase. ALT: Alanine transaminase. BMI: Body Mass Index. INR: International Normalized Ratio. MELD:Model for End Sliver Disease. SD: Standard deviation.Table 7. The details of liver related death cases (n = 8).MeanSD48.39.818.313.327.216)23.73Total Protein (g/dL)5.80.3Albumin (g/dL)2.90.4Total Bilirubin (mg/dL)9.37.9Direct Bilirubin (mg/dL)5.54.9INR1.50.4AST (IU/L)200172ALT (IU/L)13365ALP (IU/L)195100Creatinine (mg/dL)2.10.8MELD score24.59.4Hemoglobin (g/dL)8.92.4/dL)2.31.3/dL)8.73.4Total Protein (g/dL)5.60.4Albumin (g/dL)2.60.5Tota

l Bilirubin (mg/dL)15.98.1Direct Bilirub
l Bilirubin (mg/dL)15.98.1Direct Bilirubin (mg/dL)83.9INR31.2AST (IU/L)278212ALT (IU/L)210122ALP (IU/L)298153MELD score378ALP: Alkaline phosphatase. AST: Aspartate transaminase. ALT: Alaninetransaminase. DILI: Drug induced liver injury. INR: International NormalizedRatio. MELD: Model for End stage Liver Disease. WBC: White blood cellcount.Drug induced liver injury still remains a challenge inmodern day hepatology. Although it is relatively rare causeof liver injury, the overall mortality associated with DILIRathi C, et al. 2017; 16 (3): 442-450Table 9. Independent variables associated with mortality in patients with DILI after adjusting for laboratory variables at one week.VariableCoefficientOR (95% CI)P4.48588.69(4.85-162)0.002week)1.710(1.16-26.25)0.032ALP (1 week)1.986(1.31-40.56)0.023ALP: Alkaline phosphatase. CI: Confidence interval. MELD: Model for End Stage Liver Disease. OR: Odds ratio. Constant = - 3.798.Table 8. Independent variables associated with mortality in patients with DILI after adjusting for initial laboratory variables at recogni-tion of DILI.VariableCoefficientOR (95% CI)P5.720305(1.92-484.3)0.0273.64138(1.55-93.5)0.026is significant across all regions of the world. In our series, In our series, 8 deaths were reported 2.4%), which was also reported However, there was nomost commonly implicated drugs, as observed by other Althou

gh CAM is increasingly older age and 56%
gh CAM is increasingly older age and 56% patients were females. The The median age in Thus, in our series, with comparatively Symptoms of nausea, vomiting,and abdominal pain could be related to DILI or merely re-could predict severity and outcome in DILI patients. authors found that hepa- However, the difference was very small. Similarly, The differences in observations made by several and the pattern of liver Hence, the usefulness of different patterns of449Drug Induced Liver Injury at a Tertiary Hospital in India. 2017; 16 (3): 442-450 In all these studies, various high MELD score or a com- presence of jaundice, he- female gender, high total bilirubin and high MELD and low hemoglobin. Besides, the R value The other reason for The natural course of DILICONCLUSIONSDILI results in significant overall mortality (15.85%).are leading causes of DILI in India. Presence of jaundice,phosphatase at one week are independent predictors ofmortality. The unique finding in our study was that thelaboratory variables at one week predicted mortality betterfurther evaluation in larger studies.ACKNOWLEDGEMENTAuthors are thankful to Dr. Harshad Devarbhavi, Pro-fessor and Head, Department of Gastroenterology, St.John’s Medical College Hospital, Bangalore, for his guid-ance during the study.ABBREVIATIONSDrug-induced liver injury. Gamma glutamyl transferase. Upper limit of

normal.DECLARATION OF FUNDING SOURCEN
normal.DECLARATION OF FUNDING SOURCENone.POTENTIAL COMPETING INTERESTS1.Bjornsson E, Bergmann OM, Bjornsson HK, Kvaran RB, Olaf- 2013; 144: 1419-25.2.Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Tal- 2015; 148: 1340-52.3.Stevens JL, Baker TK. The future of drug safety testing: ex- 2009; 14: 162-7.4.Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet 2002; 36:Rathi C, et al. 2017; 16 (3): 442-4505.Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Ka- 2010; 105:6.de Abajo FJ, Montero D, Madurga M, García Rodríguez LA.7.Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee 2014; 109: 950-6.8.Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria 2005; 129:9.Acute Kidney Injury Work Group. Kidney Disease: Improving 2012; 2: 1-138.10.Danan G, Benichou C. Causality assessment of adverse re- 1993; 46: 1323-30.11.Benichou C, Danan G, Flahault A. Causality assessment of 1993; 46: 1331-6.12.Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, 2011; 89: 806-15.13.Treeprasertsuk S, Huntrakul J, Ridtitid W, Kullavanijaya P, 2010; 31: 1200-7.14.Björnsson E, Olsson R. Outcome and prognostic markers insevere drug induced liver disease. 2005; 42:15.De Valle MB, Av Klinteberg V, Alem N, Olsson R, Björnsson 2006;16.Lucena MI, Andrade RJ, Kaplowitz N, García-Cortes M, 2009; 49:17.Li B, Wang Z, Fang JJ, Xu CY, Chen WX. Evaluation of prog- Wor

ld 2007; 13: 628-32.18.Navarro VJ, Senio
ld 2007; 13: 628-32.18.Navarro VJ, Senior JR. Drug-related hepatotoxicity. 2006; 354: 731-9.19.Assis DN, Navarro VJ. Human drug hepatotoxicity: a contem- 2009; 5: 463-73.20.Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina- 2014; 147: 109-18.21.Jeong R, Lee YS, Sohn C, Jeon J, Ahn S, Lim KS. Model for 2015; 50: 439-46.22.García-Cortés M, Stephens C, Lucena MI, Fernández- 2011; 55: 683-91.23.Andrade RJ, Lucena MI, Kaplowitz N, García-Muñoz B, Bor- 2006; 44:24.Shapiro MA, Lewis JH. Causality assessment of drug-in-Rathi C, et al. 2017; 16 (3): 442-450Drug Induced Liver Injury at a Tertiary Hospital in India:Etiology, Clinical Features and Predictors of MortalityChetan Rathi, Nirav Pipaliya, Ruchir Patel, Meghraj Ingle, Aniruddha Phadke, Prabha SawantORIGINAL ARTICLEINTRODUCTION AND AIMS DILI in Also, hepatotoxicity is one of the im- The real incidence of Overall mortality from 10 to 17.3% However, there is limited data from devel-MATERIAL AND METHODSMexican Association of Hepatology,Latin-American Association for Study of the Liver andManuscript received: June 10, 2016.Manuscript accepted: August 15, 2016.DOI:10.5604/16652681.1235488Introduction and aims. Material and methods. Results. We ed mortality better than those at the time of DILI recognition. On multivariate logistic regression analysis, jaundice, encephasion. DILI Key words. Acute