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BACKGROUND AND AIM: Plasma exchange (PLEX) improves survival in patients with rodenticidal hepatotoxicity. However, predictors of treatment response are unknown. We aimed at assessing predictors of response to PLEX treatment in these patients. METHODS: Patients with rodenticidal hepatotoxicity from 2014 to 2023 managed in our department were included in this study. Kochi criteria (model for end-stage liver disease [MELD] score ≥ 36 or international normalized ratio [INR] ≥ 6 with hepatic encephalopathy [HE]) derived specifically for rodenticidal hepatotoxicity (PubMed IDentifier [PMID]: 26310868) were used to assess need for liver transplantation. We analyzed predictors of survival at one month. ∆Bilirubin, ∆MELD score and ∆INR were calculated as percentage change of the parameter after third PLEX session (or after last PLEX if < 3 PLEX sessions done) from baseline pre-PLEX value. RESULTS: Of 200 patients with rodenticidal hepatotoxicity, 114 patients were treated with low-volume PLEX (PLEX-LV). No patient had liver transplantation. Of 78 patients who fulfilled Kochi criteria, 32 patients were PLEX-LV eligible and underwent PLEX-LV (M: 10; age: 20.5, 7-70 years; median, range; acute liver failure: 24). Twenty-two (69%; acute liver failure: 14) of the 32 patients were alive at one month. Presence of HE (p = 0.03) and ∆MELD (p < 0.001) were significant predictors on univariate analysis, while ∆MELD (aOR = 0.88, 95% CI: 0.79-0.98, p = 0.01) was the only significant independent predictor of one-month transplant-free survival. Area under receiver operating characteristic (ROC) for ∆MELD was 0.93 (95% CI:0.85-1.00) and a decrease of ≥ 20% in MELD score while on PLEX-LV had 90% sensitivity and 90% specificity in predicting one-month survival. CONCLUSIONS: Decline in MELD while on PLEX-LV independently predicted one-month transplant-free survival in rodenticidal hepatotoxicity patients. This may help guide decision on stopping PLEX-LV in patients predicted to respond to treatment and to consider alternate treatment options in non-responders.
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The acute inflammatory milieu in patients with acute liver failure (ALF) results in 'toxic' blood in these patients. In vitro experiments have shown that the plasma obtained from ALF patients is toxic to rabbit hepatocytes and inhibits regeneration of rat hepatocytes. Treatments such as plasma exchange and continuous renal replacement therapy to cleanse the blood have improved survival in ALF patients. In the liver microcirculation, the exchange of fluid across fenestrae in liver sinusoidal endothelial cells (LSECs) is vital for proper functioning of hepatocytes. Clogging of the liver filter bed by inflammatory debris and cells ('traffic jam hypothesis') impeding blood flow in sinusoids may in turn reduce the exchange of fluid across LSEC fenestrae and cause dysfunction and necrosis of hepatocytes in ALF patients. In mouse model of paracetamol overdose, disturbances in microcirculation in the liver preceded the development of injury and necrosis of hepatocytes. This may represent a reversible pathophysiological mechanism in ALF which may be improved by the anti-inflammatory effect of plasma exchange. Wider access to urgent plasma exchange is a major advantage compared to urgent liver transplantation to treat ALF patients worldwide, especially so in resource constrained settings. Continuous hemo-filtration or dialysis is used to reduce ammonia levels and treat cerebral edema in ALF patients. In this review, we discuss the different modalities to cleanse the blood in ALF patients, with an emphasis on plasma exchange, from a hepatology perspective.
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Falência Hepática Aguda , Troca Plasmática , Humanos , Troca Plasmática/métodos , Falência Hepática Aguda/terapia , Falência Hepática Aguda/etiologia , Animais , Terapia de Substituição Renal Contínua/métodos , Camundongos , Ratos , Modelos Animais de Doenças , Hepatócitos , Coelhos , Fígado/irrigação sanguínea , Microcirculação , AcetaminofenRESUMO
Background: Data on non-O1/non-O139 Vibrio cholera (NOVC) infection in liver disease is limited. We studied the clinical features and outcome of patients with cirrhosis with non-NOVC bacteraemia and/or spontaneous bacterial peritonitis (SBP) when compared to non-extended spectrum beta lactamase (non-ESBL) Escherichia coli (E. coli). Methods: Hospital information system of patients with cirrhosis admitted with bacteraemia and/or SBP from 2010 to 2020 was searched to include patients with NOVC infection. Non-ESBL E. coli bacteraemia/bacterascites were chosen as a comparator group, matched for the date of admission within 5 days of index case. Propensity score matching (PSM) was done for patient's age and Child score to compare outcome at discharge between NOVC-infected and E. coli-infected cirrhotic patients. Results: There were 2545 patients admitted with bacteraemia and/or SBP during the study period; 29 had NOVC isolated (M:F = 23:6; age: 39, 18-54 years; median, range; model for end-stage liver disease [MELD] score: 25, 12-38; Child score: 11, 10-12.5) from either blood (26), ascites (3), or both (8). Of these, 26 isolates were pan-sensitive to antibiotic sensitivity tests. Fifty-three patients with non-ESBL E. coli were isolated (M: F = 43:10; age: 48; 18-69 years; MELD score: 25, 20-32; Child score:12,11-13) from blood (31), ascites (17), or both (5) within the selected time frame. Of these, 48 isolates were sensitive to the empirical antibiotics initiated.After PSM, in comparison with 29 non-ESBL E. coli patients (age: 41, 18-55 years; MELD score: 24, 19-31; Child score: 12, 11-13), NOVC patients had higher incidence of circulatory failure at admission (14 [49 %] vs 4 [13 %]; P: 0.01) and significantly higher in-hospital mortality (15 [52 %] vs 6 [20 %];P: 0.028]. Conclusions: Bacteraemia due to non-O1/non-O139 strains of V. cholera, is an uncommon cause of bacteraemia or bacterascites in patients with cirrhosis and is associated with high incidence of circulatory failure and significant mortality.
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Background: Idiosyncratic drug-induced liver injury (iDILI) causing acute liver failure (ALF) carries high short-term mortality and patients who meet King's College criteria for liver transplantation have 1-month survival of 34% without liver transplantation (PMID: 20949552). We present our experience with low-volume plasma exchange (PLEX-LV, 50% of estimated plasma volume exchanged per session) and low-dose steroid to treat iDILI ALF. Methods: We retrospectively analysed data of patients with iDILI (diagnosed as per RUCAM score), treated with PLEX-LV and low-dose steroid (prednisolone: 10 mg OD, with rapid taper) in our department from 2016 to 2022. Baseline and dynamic parameters (post-PLEX) were assessed as predictors of 1-month liver transplantation-free survival. Results: Twenty-two iDILI patients [probable: possible iDILI: 20:2, males: 9, age: 30 (14-84) years, median (range); MELD score: 30.5 (19-43)] underwent PLEX-LV for ALF during the study period. Causative agents were complementary and alternative medications (36%), antiepileptics (18%) antimicrobials (14%), antitubercular drugs (14%), antifungal drugs (9%) and others (9%). All patients had jaundice and encephalopathy; 9 patients also had ascites. None of the patients underwent liver transplantation. Study patients underwent 3 (1-7) PLEX sessions and 1.4 (0.6-1.6) litres of plasma was exchanged per session. One-month transplant-free survival was 59% (13/22) in the study population and 63% (12/19) among patients who fulfilled Kings College criteria for liver transplantation. Reduction of ≥25% in plasma von Willebrand factor (VWF) levels after PLEX-LV predicted improved survival (HR: 0.09, 95% CI: 0.01-0.65; AUROC: 0.81; 95% CI: 0.6-1.0). Conclusion: Low-volume PLEX and low-dose steroid appears a promising treatment option in patients with iDILI-induced ALF not opting for liver transplantation. Dynamic changes in VWF level after PLEX predict 1-month survival in these patients.
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Plasma exchange (PLEX) to treat liver failure patients is gaining increasing momentum in recent years. Most reports have used PLEX to treat patients with acute liver failure (ALF) or acute on chronic liver failure (ACLF). Etiology of liver disease has an important bearing on the prognosis of the illness in these patients. The accruing data suggest survival benefit with PLEX compared with standard medical treatment to treat ALF and ACLF patients, in randomised controlled trials done world-over. The American College of Apheresis now recommends high-volume PLEX as first-line treatment for ALF patients. Most matched cohort studies done from India which recruited patients with a specific etiology of ALF or ACLF report survival benefit with PLEX compared to standard medical treatment. The survival benefit with PLEX appears more pronounced in ALF patients rather than in ACLF patients. Systematic analysis of the efficacy of PLEX to treat ALF and ACLF patients is needed. There is also a need to identify dynamic predictive scores to assess which patients with ALF or ACLF will respond to PLEX.
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BACKGROUND AND AIM: Monocytes and macrophages play a crucial role in the pathogenesis of acute liver failure (ALF). We aimed to study reticuloendothelial activation and its correlation with disease severity in commonly encountered yellow phosphorus (rodenticide)-induced hepatotoxicity patients. We also studied peripheral monocyte phenotype in a subset of patients. METHODS: Reticuloendothelial activation markers were analyzed and correlated with disease severity score in a prospectively collected database of yellow phosphorus-related hepatoxicity patients between 2018 and 2021. In a prospective cohort of these patients and age-matched healthy controls, peripheral blood monocyte phenotyping was performed. RESULTS: Reticuloendothelial activation markers were analyzed in 67 patients [Age: 23(12-64) years; median (range), men: 25, acute liver injury (ALI): 38, ALF: 29, model for end-stage liver disease (MELD) score: 28 (7-40)] of yellow phosphorus-induced hepatotoxicity. Serum ferritin (927; 10.3-34 807 ng/mL), sCD163 (4.59; 0.11-12.7 µg/mL), sCD25 (3050; 5.6-17 300 pg/mL) and plasma von Willebrand factor (423.5, 103-1106 IU/dL) were increased and showed significant correlation with liver disease severity assessed by MELD score (ρ = 0.29, ρ = 0.6, ρ = 0.56 and ρ = 0.46 respectively). Phenotyping and serum immune markers were performed in seven patients (M: 4; age: 27, 15-37 years; median, range; MELD score: 36, 21-40) and compared with eight healthy controls. Increase in classical monocytes and decrease in patrolling and intermediate monocyte subsets were observed in ALF cohort. HLA-DRlow CD163hi (immune exhaustion), CD64hi (immune complex-mediated response), and CCR2hi (liver homing) monocyte phenotype was noted. CONCLUSION: Altered peripheral monocyte phenotype with enhanced liver homing and macrophage activation, suggests important role of innate immune activation, and provides a potential therapeutic target, in yellow phosphorus-induced hepatotoxicity.
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Doença Hepática Induzida por Substâncias e Drogas , Doença Hepática Terminal , Falência Hepática Aguda , Humanos , Monócitos/patologia , Estudos Prospectivos , Índice de Gravidade de Doença , Fenótipo , Biomarcadores , Falência Hepática Aguda/induzido quimicamente , Doença Hepática Induzida por Substâncias e Drogas/patologiaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease globally and in India. The already high burden of NAFLD in India is expected to further increase in the future in parallel with the ongoing epidemics of obesity and type 2 diabetes mellitus. Given the high prevalence of NAFLD in the community, it is crucial to identify those at risk of progressive liver disease to streamline referral and guide proper management. Existing guidelines on NAFLD by various international societies fail to capture the entire landscape of NAFLD in India and are often difficult to incorporate in clinical practice due to fundamental differences in sociocultural aspects and health infrastructure available in India. A lot of progress has been made in the field of NAFLD in the 7 years since the initial position paper by the Indian National Association for the Study of Liver on NAFLD in 2015. Further, the ongoing debate on the nomenclature of NAFLD is creating undue confusion among clinical practitioners. The ensuing comprehensive review provides consensus-based, guidance statements on the nomenclature, diagnosis, and treatment of NAFLD that are practically implementable in the Indian setting.
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Background: In a prior report, no patient with rodenticidal hepatotoxicity who met Kochi criteria (MELD score ≥36 or baseline INR ≥6 with hepatic encephalopathy) (PMID: 26310868) for urgent liver transplantation survived with medical management alone. Plasma exchange (PLEX) may improve survival in these patients. Objectives: We describe our experience with low-volume PLEX (PLEX-LV) in treating rodenticide ingestion induced hepatotoxicity in children. Methods: From prospectively collected database of rodenticidal hepatotoxicity patients managed as in-patient with department of Hepatology from December 2017 to August 2021, we retrospectively studied outcomes in children (≤18 years). Hepatotoxicity was categorized as acute liver injury (ALI, coagulopathy alone) or acute liver failure (ALF, coagulopathy and encephalopathy). Kochi criteria was used to assess need for urgent liver transplantation. The primary study outcome was one-month survival. Results: Of the 110 rodenticidal hepatotoxicity patients, 32 children (females: 56%; age: 16 [4.7-18] years; median, range) constituted the study patients. The study patients presented 4 (1-8) days after poison consumption (impulsive suicidal intent:31, accidental:1). Twenty children (62%) had ALI [MELD: 18 (8-36)] and 12 (38%) had ALF [MELD: 37 (24-45)].All children received standard medical care, including N-acetyl cysteine; ALF patients also received anti-cerebral edema measures. None of the patient families opted for liver transplantation. Seventeen children (ALI: 6, ALF: 11) were treated with PLEX-LV (3 [1-5] sessions, volume of plasma exchanged per session: 26 [13-38] ml/kg body weight) and peri-procedure low dose prednisolone.At 1 month, 28 of the 32 children (87.5%) were alive (4 ALF patients died). Of 10 children who met Kochi listing criteria for urgent liver transplantation, two children were ineligible for PLEX-LV (due to hemodynamic instability) and of the remaining 8 children treated by PLEX-LV, 6 (75%) survived. Conclusions: PLEX-LV shows promise as an effective non-liver transplant treatment in children with rodenticidal hepatotoxicity.
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BACKGROUND AND AIMS: We hypothesized that artificial intelligence (AI) models are more precise than standard models for predicting outcomes in acute-on-chronic liver failure (ACLF). METHODS: We recruited ACLF patients between 2009 and 2020 from APASL-ACLF Research Consortium (AARC). Their clinical data, investigations and organ involvement were serially noted for 90-days and utilized for AI modelling. Data were split randomly into train and validation sets. Multiple AI models, MELD and AARC-Model, were created/optimized on train set. Outcome prediction abilities were evaluated on validation sets through area under the curve (AUC), accuracy, sensitivity, specificity and class precision. RESULTS: Among 2481 ACLF patients, 1501 in train set and 980 in validation set, the extreme gradient boost-cross-validated model (XGB-CV) demonstrated the highest AUC in train (0.999), validation (0.907) and overall sets (0.976) for predicting 30-day outcomes. The AUC and accuracy of the XGB-CV model (%Δ) were 7.0% and 6.9% higher than the standard day-7 AARC model (p < .001) and 12.8% and 10.6% higher than the day 7 MELD for 30-day predictions in validation set (p < .001). The XGB model had the highest AUC for 7- and 90-day predictions as well (p < .001). Day-7 creatinine, international normalized ratio (INR), circulatory failure, leucocyte count and day-4 sepsis were top features determining the 30-day outcomes. A simple decision tree incorporating creatinine, INR and circulatory failure was able to classify patients into high (~90%), intermediate (~60%) and low risk (~20%) of mortality. A web-based AARC-AI model was developed and validated twice with optimal performance for 30-day predictions. CONCLUSIONS: The performance of the AARC-AI model exceeds the standard models for outcome predictions in ACLF. An AI-based decision tree can reliably undertake severity-based stratification of patients for timely interventions.
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Insuficiência Hepática Crônica Agudizada , Humanos , Insuficiência Hepática Crônica Agudizada/diagnóstico , Inteligência Artificial , Creatinina , Prognóstico , Fatores de TempoRESUMO
Aim of the study: To study the prevalence of risk factors for nonalcoholic fatty liver disease (NAFLD) in middle-aged (40-59 years) and elderly patients (≥60 years) with cryptogenic cirrhosis as compared to those with hepatitis B or C virus (HBV or HCV) related cirrhosis. Methods and materials: Between August 2013 and December 2014, cases (cryptogenic cirrhosis) and controls (HBV/HCV cirrhosis) above 40 years of age were prospectively recruited and assessed for the cause and prevalence of risk factors for NAFLD. Results: One hundred eighteen cases (male-74%; age 55 (40-74) years; median (range); Child's class A:B:C-46:38:16) and 59 controls (male-80%; age 55.5 (40-69) years; Child's class A:B:C-56:30:14) were enrolled. Obesity (53% v/s 39%, P-0.081), diabetes mellitus (DM) (52% v/s 27%; P-0.002), family history of DM (30% v/s 13%; P-0.016), family history of Obesity (21% v/s 3.5%; P-0.002) and metabolic syndrome (65% v/s 44%; P-0.01) were more among cases than controls. Lifetime weight as obese was also longer in cases than in controls (5.9 ± 6.2 years v/s 3.2 ± 5.1 years, P-0.002). On subgroup analysis, in elderly age group, DM (55% v/s 17%, P-0.006), family history of DM (40% v/s 11%, P-0.025), metabolic syndrome (76% v/s 44%, P-0.017) and family history of obesity (19% v/s 0, P-0.047) were more common in cases as compared to controls, where as in the middle-age group, family history of obesity was the only significant factor (22% v/s 5%, P-0.025). Lifetime weight as obese was longer in cases than controls in both middle and elderly age groups. Conclusion: Among middle-aged and elderly patients with cirrhosis, there was a higher prevalence of risk factors for NAFLD in those with cryptogenic cirrhosis, compared to those with HBV or HCV cirrhosis.
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BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is considered a main prognostic event in patients with chronic liver disease (CLD). We analyzed the 28-day and 90-day mortality in ACLF patients with or without underlying cirrhosis enrolled in the ACLF Research Consortium (AARC) database. METHODS: A total of 1,621 patients were prospectively enrolled and 637 (39.3%) of these patients had cirrhosis. Baseline characteristics, complications and mortality were compared between patients with and without cirrhosis. RESULTS: Alcohol consumption was more common in cirrhosis than non-cirrhosis (66.4% vs. 44.2%, p < 0.0001), while non-alcoholic fatty liver disease/cryptogenic CLD (10.9% vs 5.8%, p < 0.0001) and chronic HBV reactivation (18.8% vs 11.8%, p < 0.0001) were more common in non-cirrhosis. Only 0.8% of patients underwent liver transplantation. Overall, 28-day and 90-day mortality rates were 39.3% and 49.9%, respectively. Patients with cirrhosis had a greater chance of survival compared to those without cirrhosis both at 28-day (HR = 0.48; 95% CI 0.36-0.63, p < 0.0001) and 90-day (HR = 0.56; 95% CI 0.43-0.72, p < 0.0001), respectively. In alcohol CLD, non-cirrhosis patients had a higher 28-day (49.9% vs. 23.6%, p < 0.001) and 90-day (58.4% vs. 35.2%, p < 0.001) mortality rate than cirrhosis patients. ACLF patients with cirrhosis had longer mean survival than non-cirrhosis patients (25.5 vs. 18.8 days at 28-day and 65.2 vs. 41.2 days at 90-day). Exaggerated systemic inflammation might be the reason why non-cirrhosis patients had a poorer prognosis than those with cirrhosis after ACLF had occurred. CONCLUSIONS: The 28-day and 90-day mortality rates of ACLF patients without cirrhosis were significantly higher than those with cirrhosis in alcoholic CLD. The presence of cirrhosis and its stage should be evaluated at baseline to guide for management. Thai Clinical Trials Registry, TCTR20191226002.
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Insuficiência Hepática Crônica Agudizada , Transplante de Fígado , Humanos , Cirrose Hepática/complicações , PrognósticoRESUMO
BACKGROUND: Etiology of and outcomes following idiosyncratic drug-induced liver injury (DILI) vary geographically. We conducted a prospective study of DILI in India, from 2013 to 2018 and summarize the causes, clinical features, outcomes and predictors of mortality. METHODS: We enrolled patients with DILI using international DILI expert working group criteria and Roussel Uclaf causality assessment method. Follow-up was up to 3 months from onset of DILI or until death. Multivariate logistics regression was carried out to determine predictors of non-survival. RESULTS: Among 1288 patients with idiosyncratic DILI, 51.4% were male, 68% developed jaundice, 68% required hospitalization and 8.2% had co-existing HIV infection. Concomitant features of skin reaction, ascites, and encephalopathy (HE) were seen in 19.5%, 16.4%, and 10% respectively. 32.4% had severe disease. Mean MELD score at presentation was 18.8 ± 8.8. Overall mortality was 12.3%; 65% in those with HE, 17.6% in patients who fulfilled Hy's law, and 16.6% in those that developed jaundice. Combination anti-TB drugs (ATD) 46.4%, complementary and alternative medicines (CAM) 13.9%, anti-epileptic drugs (AED) 8.1%, non-ATD antimicrobials 6.5%, anti-metabolites 3.8%, anti-retroviral drugs (ART)3.5%, NSAID2.6%, hormones 2.5%, and statins 1.4% were the top 9 causes. Univariate analysis identified, ascites, HE, serum albumin, bilirubin, creatinine, INR, MELD score (p < 0.001), transaminases (p < 0.04), and anti-TB drugs (p = 0.02) as predictors of non-survival. Only serum creatinine (p = 0.017), INR (p < 0.001), HE (p < 0.001), and ascites (p = 0.008), were significantly associated with mortality on multivariate analysis. ROC yielded a C-statistic of 0.811 for MELD and 0.892 for combination of serum creatinine, INR, ascites and HE. More than 50 different agents were associated with DILI. Mortality varied by drug class: 15% with ATD, 13.6% with CAM, 15.5% with AED, 5.8% with antibiotics. CONCLUSION: In India, ATD, CAM, AED, anti-metabolites and ART account for the majority of cases of DILI. The 3-month mortality was approximately 12%. Hy's law, presence of jaundice or MELD were predictors of mortality.
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Of the currently available drugs tested to treat nonalcoholic fatty liver disease (NAFLD), the most efficacious drugs are pioglitazone (an insulin sensitizer) and vitamin E (an antioxidant). By targeting insulin resistance, the key pathogenic mechanism underlying metabolic syndrome and NAFLD, pioglitazone maybe the preferred drug to treat NAFLD. As we await the results of research trials into multiple new drugs to treat NAFLD, when should we use the currently available patients to treat NAFLD at the present time? To date, no drug has been approved by regulatory agency specifically to treat NAFLD. However, many drugs have been approved to treat other components of metabolic syndrome such as diabetes mellitus and dyslipidemia. Are we underutilizing the currently available drugs to treat NAFLD? Herein, we review the benefits and concerns of the use of these currently available drugs to treat NAFLD and suggest clinical scenarios, wherein the clinician should consider using these drugs.
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BACKGROUND: Overactivation of reticuloendothelial cells lining liver sinusoids - Kupffer cells (macrophages) and sinusoidal endothelial cells - may narrow the sinusoidal lumen, impair perfusion in liver microcirculation and contribute to disease severity in alcoholic hepatitis. AIM: The aim of the article was to assess reticuloendothelial activation in patients with severe alcoholic hepatitis (SAH). METHODS: In SAH patients, we prospectively studied baseline reticuloendothelial activation markers [serum ferritin, sCD163 and plasma von Willebrand factor (VWF) antigen] and Macrophage Activation Syndrome (MAS) criteria, correlated them with disease severity scores [model for end-stage liver disease (MELD) and Sequential Organ Failure Assessment (SOFA) scores] and analyzed their ability to predict survival over a 90-day follow-up period. RESULTS: A total of 50 SAH patients [45 (37-49) years, median (interquartile range), 49 males, discriminant function, 76.2 (54.5-106.6); MELD score, 30 (26.2-36)] were studied. 41 SAH patients (82%) had ferritin >500 ng/mL, and all (100%) had markedly raised sCD163 and VWF levels. The median sCD163 level was 10-fold higher than healthy controls and the median VWF level was 5-fold above the upper limit of normal. In total, 37 SAH patients (74%) met MAS criteria. Reticuloendothelial activation markers correlated with MELD and SOFA scores (P < 0.05). VWF was an independent marker to predict mortality in SAH [adjusted hazard ratio, 1.002 (1.000-1.004)]. CONCLUSIONS: The reticuloendothelial system was markedly activated and correlated with disease severity scores in SAH patients.VWF predicted short-term mortality independent of MELD and sCD163. Further larger multicentric studies are needed to validate these findings.
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Doença Hepática Terminal , Hepatite Alcoólica , Adulto , Biomarcadores , Células Endoteliais , Feminino , Ferritinas , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Fagocitário Mononuclear , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Fator de von WillebrandRESUMO
Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 × 10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.