Prior drug allergies are associated with worse outcome in patients with idiosyncratic drug-induced liver injury: A machine learning approach for risk stratification.

The impact of prior drug allergies (PDA) on the clinical features and outcomes of patients who develop idiosyncratic drug-induced liver injury (DILI) is largely unknown. We aimed to assess the clinical presentation and outcomes of DILI patients based on the presence or absence of PDA and explore the association between culprit drugs responsible for DILI and allergy. We analysed a well-vetted cohort of DILI cases enrolled from the Spanish DILI Registry. Bootstrap-enhanced least absolute shrinkage operator procedure was used in variable selection, and a multivariable logistic model was fitted to predict poor outcomes in DILI. Of 912 cases with a first episode of DILI, 61 (6.7%) had documented PDA. Patients with PDA were older (p = 0.009), had higher aspartate aminotransferase (AST) levels (p = 0.047), lower platelet count (p = 0.011) and higher liver-related mortality than those without a history of drug allergies (11% vs. 1.6%, p < 0.001). Penicillin was the most common drug associated with PDA in DILI patients (32%). A model including PDA, nR-based type of liver injury, female sex, AST, total bilirubin, and platelet count showed an excellent performance in predicting poor outcome in patients from the Spanish DILI Registry (area under the ROC curve [AUC] 0.887; 95% confidence interval [CI] 0.794 - 0.981) and the LATINDILI Network (AUC 0.932; 95% CI 0.884 - 0.981). Patients with suspected DILI should be screened for PDA as they would require a close monitoring for early detection of worsening clinical course.

Sarcoidosis with esophageal involvement: an uncommon clinical enigma.

We present the case of a 46-year-old male, a former smoker, with a medical history significant for morbid obesity grade III, hypothyroidism, hyperuricemia, and dyslipidemia. Four months ago, he was diagnosed with sarcoidosis involving mediastinal lymph nodes and is currently undergoing treatment with corticosteroids. The patient presented to the emergency department with persistent epigastric and thoracic pain lasting one week, accompanied by dysphagia and odynophagia intermittently. Laboratory tests showed elevated acute-phase reactants, with no other notable abnormalities. Chest X-ray revealed pre-existing mediastinal adenopathy. Despite an abdominal CT scan with contrast showing no significant findings, esophagogastroduodenoscopy revealed marked extrinsic compression of the esophagus between 25 and 32 cm from the dental arch, with less intensity distally. Although passage of the endoscope through this area caused significant pain, it did not hinder its advancement. A chest CT scan with oral contrast demonstrated filamentous narrowing of the esophagus in the middle third, along with concentric thickening of its walls and multiple paratracheal, parahilar, and periesophageal lymphadenopathies. Following a tapering regimen of corticosteroids, the patient was discharged with a clinical diagnosis of sarcoidosis with mediastinal and esophageal involvement secondary to extrinsic compression. Due to clinical improvement with the prescribed treatment, endoscopic ultrasound and biopsies to assess esophageal wall involvement were deemed unnecessary.

Changing perspectives: unveiling the risks of ashwagandha-induced hepatotoxicity.

Ashwagandha, an herb popular in Ayurvedic medicine, is renowned for its health-enhancing properties. However, its association with liver damage in recent years has raised significant concerns, necessitating careful assessment and management. This case underscores the dangers of Ashwagandha, particularly for individuals with preexisting liver conditions, where it can lead to life-threatening acute-on-chronic liver failure. The lack of solid clinical evidence supporting Ashwagandha's health claims emphasizes the need for an evidence-based approach. Public education is essential to raise awareness of the risks associated with herbal supplements and prevent liver diseases.

Interlobar Artery Resistive Index predicts Acute-on-Chronic Liver Failure Syndrome in Cirrhotic Patients with Acute Decompensation.

INTRODUCTION: Patients with acutely decompensated (AD) cirrhosis are at risk for developing acute-on-chronic liver failure (ACLF) syndrome. This syndrome is associated with a high short-term mortality rate. The aim of our study was to identify reliable early predictors of developing ACLF in cirrhotic patients with AD. PATIENTS AND METHODS: We assessed 84 cirrhotic patients admitted for AD without ACLF on admission. We performed routine blood testing and detailed ultrasound Doppler studies of systemic arteries and mayor abdominal veins and arteries. We also calculated liver-specific and intensive care unit predictive scores. The area under the ROC curve (AUROC) was calculated for all variables that were significantly different between patients who developed ACLF and those who did not. Sensitivity, specificity, positive and negative predictive values, as well as diagnostic accuracy predicting the short-term development of ACLF were determined. RESULTS: of the 84 patients, 23 developed ACLF whereas 61 did not. In the univariate analysis, serum levels of creatinine and urea, prothrombin time ratio, MELD score, portal vein and femoral artery flow velocity as well as the renal and interlobar artery resistive indices (RI) were associated with the short-term development of ACLF. However, only interlobar artery RI had independent predictive value in the multivariate analysis. The AUROC value for RI of the interlobar arteries was 0.9971. CONCLUSION: On the first day of admission, ultrasound measurement of the RI of the interlobar arteries recognizes with high predictive accuracy those cirrhotic patients admitted with AD who will develop ACLF during hospital admission.

Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.

UNLABELLED: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days. CONCLUSIONS: Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.

Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients. METHODS: Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use. RESULTS: The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis. CONCLUSIONS: The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients.

Experience of the endoscopist increases detection rates of smaller size and higher histological grade polyps.

BACKGROUND: Adenoma and polyp detection rates (ADR and PDR, respectively) are important indicators of endoscopy quality, particularly in colorectal carcinoma screening. OBJECTIVE: To assess the influence of the endoscopist's experience on the ADR and PDR. PATIENTS AND METHODS: In this study, 9635 colonoscopies were screened during a 5-year period. Only 5738 were finally analyzed due to exclusion criteria. The endoscopists were separated in three groups of experience according to the number of colonoscopies performed in the past (yearly and total). The number of polyps and adenomas, as well as the size and histology of these polyps were recorded. RESULTS: The ADR and PDR were similar regardless of the experience of the endoscopist, but those with more experience clearly found more polyps of less than 10 mm (P = 0.01) and of less than 3 mm (P < 0.0001). Most of the differences were due to a higher number of flat polyps detected by the experienced group. This study also shows that more experienced endoscopists detect adenomas with more advanced histology (P < 0.0001). CONCLUSION: Even though the ADR and PDR are similar in all groups of endoscopists, the less experienced endoscopists could be missing some of the smaller polyps, sometimes with more advanced histology.

Pioglitazone leads to an inactivation and disassembly of complex I of the mitochondrial respiratory chain.

BACKGROUND: Thiazolidinediones are antidiabetic agents that increase insulin sensitivity but reduce glucose oxidation, state 3 respiration, and activity of complex I of the mitochondrial respiratory chain (MRC). The mechanisms of the latter effects are unclear. The aim of this study was to determine the mechanisms by which pioglitazone (PGZ), a member of the thiazolidinedione class of antidiabetic agents, decreases the activity of the MRC. In isolated mitochondria from mouse liver, we measured the effects of PGZ treatment on MRC complex activities, fully-assembled complex I and its subunits, gene expression of complex I and III subunits, and [3H]PGZ binding to mitochondrial complexes. RESULTS: In vitro, PGZ decreased activity of complexes I and III of the MRC, but in vivo only complex I activity was decreased in mice treated for 12 weeks with 10 mg/kg/day of PGZ. In vitro treatment of isolated liver mitochondria with PGZ disassembled complex I, resulting in the formation of several subcomplexes. In mice treated with PGZ, fully assembled complex I was increased and two additional subcomplexes were found. Formation of supercomplexes CI+CIII2+CIVn and CI+CIII2 decreased in mouse liver mitochondria exposed to PGZ, while formation of these supercomplexes was increased in mice treated with PGZ. Two-dimensional analysis of complex I using blue native/sodium dodecyl sulfate polyacrylamide gel electrophoresis (BN/SDS-PAGE) showed that in vitro PGZ induced the formation of four subcomplexes of 600 (B), 400 (C), 350 (D), and 250 (E) kDa, respectively. Subcomplexes B and C had NADH:dehydrogenase activity, while subcomplexes C and D contained subunits of complex I membrane arm. Autoradiography and coimmunoprecipitation assays showed [3H]PGZ binding to subunits NDUFA9, NDUFB6, and NDUFA6. Treatment with PGZ increased mitochondrial gene transcription in mice liver and HepG2 cells. In these cells, PGZ decreased intracellular ATP content and enhanced gene expression of specific protein 1 and peroxisome-proliferator activated receptor (PPAR)γ coactivator 1α (PGC-1α). CONCLUSIONS: PGZ binds complex I subunits, which induces disassembly of this complex, reduces its activity, depletes cellular ATP, and, in mice and HepG2 cells, upregulates nuclear DNA-encoded gene expression of complex I and III subunits.

Hospital-based screening outperforms primary care screening as a means of achieving hepatitis C virus micro-elimination.

AIM: To assess the respective performances of a HCV screening program in a hospital setting and a HCV screening model applied concomitantly in a primary care centre. METHODS: Adult patients consecutively admitted to hospital for ambulatory surgery were screened for anti-HCV antibodies (hospital screening cohort, HPSC), as were patients receiving blood tests for medical reasons in a primary care centre (primary care screening cohort, PCSC). Serum anti-HCV and HCV RNA levels were tested by ELISA and real-time PCR, respectively. RESULTS: Seroprevalence of HCV infection was 2.2 % in the HPSC and 1.4 % in the PCSC (p = 0.044). All viraemic patients (0.2 % in HPSC and 0.1 % in PCSC) were treated with direct-acting antivirals and 85.7 % experienced a sustained virological response. CONCLUSIONS: Hospital-based HCV screening outperformed primary care-centered screening, significantly increasing HCV case findings.

Protein-tyrosine phosphatases are involved in interferon resistance associated with insulin resistance in HepG2 cells and obese mice.

Insulin resistance is a risk factor for non-response to interferon/ribavirin therapy in patients with chronic hepatitis C. The aim of this study was to determine the role played by protein-tyrosine phosphatases (PTPs) in the absence of interferon-α (IFNα) response associated with insulin resistance. We induced insulin resistance by silencing IRS-2 or by treating HepG2 cells with tumor necrosis factor-α (TNFα) and analyzed insulin response by evaluating Akt phosphorylation and IFNα response by measuring Stat-1 tyrosine phosphorylation and 2',5'-oligoadenylate synthase and myxovirus resistance gene expression. The response to IFNα was also measured in insulin-resistant obese mice (high fat diet and ob/ob mice) untreated and treated with metformin. Silencing IRS-2 mRNA induces insulin resistance and inhibits IFNα response. Likewise, TNFα suppresses insulin and IFNα response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFNα response. Both silencing IRS-2 and TNFα treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFNα response in insulin-resistant cells. Insulin-resistant ob/ob mice have increased PTP-1B gene expression and activity in the liver and do not respond to IFNα administration. Treatment with metformin improves this response. In HepG2 cells, insulin resistance provokes IFNα resistance, which is associated with an increased PTP-1B activity in the liver. Inhibition of PTP-1B activity with pervanadate and metformin or knocking down PTP-1B reestablishes IFNα response. Likewise, metformin decreases PTP-1B activity and improves response to IFNα in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFNα/ribavirin therapy.

Mitochondrial respiratory chain activity is associated with severity, corticosteroid response and prognosis of alcoholic hepatitis.

BACKGROUND AND AIMS: Little is known about the extent of mitochondrial respiratory chain (MRC) activity dysfunction in patients with alcoholic hepatitis (AH). We aimed to assess the hepatic MRC activity in AH patients and its potential impact on the severity and prognosis of this life-threatening liver disease. METHODS: MRC complexes were measured in liver biopsies of 98 AH patients (non-severe, 17; severe, 81) and in 12 histologically normal livers (NL). Severity was assessed according to Maddrey's Index and MELD score. Corticosteroid response rate and cumulative mortality were also evaluated. RESULTS: The activity of the five MRC complexes was markedly decreased in the liver of AH patients compared with that of NL subjects, being significantly lower in patients with severe AH than in those with non-severe AH. There was a negative correlation between the activity of all MRC complexes and the severity of AH. Interestingly, only complex I and III activities showed a significant positive correlation with the corticosteroid response rate and a significant negative correlation with the mortality rate at all-time points studied. In a multivariate regression analysis, besides the MELD score and the corticosteroid response rate, complex I activity was significantly associated with 3-month mortality (OR = 6.03; p = 0.034) and complex III activity with 6-month mortality (OR = 4.70; p = 0.041) in AH patients. CONCLUSION: Our results indicate that MRC activity is markedly decreased in the liver of AH patients, and, particularly, the impairment of MRC complexes I and III activity appears to have a significant impact on the clinical outcomes of patients with AH.

Melatonin improves mitochondrial respiratory chain activity and liver morphology in ob/ob mice.

In previous studies, we have shown that mitochondrial respiratory chain (MRC) activity is decreased in patients with nonalcoholic steatohepatitis and in ob/ob mice and that peroxynitrite plays a pathogenic role. The present study examined whether melatonin, a peroxynitrite scavenger, prevents: (i) the in vitro effects of peroxynitrite on normal mitochondrial proteins and (ii) the development of nonalcoholic liver disease, MRC dysfunction and proteomic changes found in the mitochondrial complexes from ob/ob mice. We studied MRC activity, assembly of mitochondrial complexes and its subunits in normal mitochondrial proteins exposed to peroxynitrite in the absence and presence of melatonin. The same studies were done in mitochondrial proteins from ob/ob mice untreated and treated with melatonin. Preincubation of mitochondrial proteins from wild-type mice with melatonin prevented 3-tyrosine nitration of these proteins, eliminated the reduction in the MRC activity, the defect in the assembly of mitochondrial complexes and degradation of their subunits induced by peroxynitrite in vitro. Moreover, treatment of ob/ob mice with 10 mg/kg/day melatonin for 12 wk reduced oxidative and nitrosative stress, prevented the loss of MRC activity, protected their complexes and subunits from degradation, and favored assembling of mitochondrial complexes. In addition, this treatment improved fatty liver, decreased hepatic triglyceride concentration and increased apolipoprotein B100 in liver tissue. In conclusion, melatonin prevents the effects of peroxynitrite on mitochondrial proteins in vitro and administration of melatonin to ob/ob mice normalizes liver morphology, mitochondrial dysfunction and assembly of MRC complexes.

Mitochondrial complex I subunits are decreased in murine nonalcoholic fatty liver disease: implication of peroxynitrite.

We investigate the cause of the low activity of mitochondrial complex I found in ob/ob mice with nonalcoholic fatty liver disease. In mitochondrial proteins from ob/ob mice, we assessed complex I activity, fully assembled complex I, and its subunits, oxygen consumption, gene expression of complex I subunits, and oxidative damage to DNA. In mitochondrial proteins from the liver of ob/ob mice, complex I activity, fully assembly of this complex and complex I subunits were markedly reduced. Likewise, gene expression of mitochondrial DNA-encoded subunits was significantly decreased in obese mice, but not nuclear DNA-encoded subunits. Treatment of obese mice with uric acid, anti-TNFalpha antibody or a mimic of manganese superoxide dismutase normalized all these abnormalities. "In vitro" addition of peroxynitrite to mitochondrial proteins from wild-type mice reproduced the abnormalities found in ob/ob mice (decreased complex I activity, the amount of fully assembled complex I, and its subunits, and mitochondrial oxygen consumption). Low activity of complex I found in ob/ob mice can be ascribed to a reduced amount of fully assembled complex, which may be attributed to degradation and reduced synthesis of its subunits by peroxynitrite. Exposure of mitochondrial proteins from normal mice to peroxynitrite reproduced the proteomic abnormalities present in ob/ob mice.

Fibronectin increases survival of rat hepatic stellate cells--a novel profibrogenic mechanism of fibronectin.

UNLABELLED: The aims of this study were to determine whether fibronectin increases survival of hepatic stellate cells (HSCs) in starving conditions, and to identify the signal transduction pathways involved in this effect. METHODS: Primary culture of rat HSCs were plated on fibronectin-uncoated or coated culture wells, and grown in the presence of 0.2% or 20% fetal calf serum. Cell apoptosis was measured by an ELISA procedure. Signal transduction pathways were analyzed by inhibiting major intracellular transduction pathways with appropriated inhibitors and by detecting phosphorylated proteins. RESULTS: Fibronectin increased survival of serum deprived HSCs. This effect was abrogated by the presence of the RGD peptide, by silencing FAK expression, and by inhibiting PI3K with LY294002 or wortmannin. Growth of HSCs on fibronectin induced integrin alpha5beta1 expression, tyr397, ser473, and ser136 phosphorylation of FAK, Akt, and Bad, respectively, and the binding of phosphorylated Bad to 14-3-3 proteins. Likewise, fibronectin increased Bcl2/Bax ratio and reduced release of mitochondrial cytochrome c into the cytoplasm, formation of apoptosome, and caspase 9 and 3 activity. These effects were avoided by treatment of cells with PI3K inhibitors. CONCLUSION: Fibronectin increases survival of HSCs via a pathway involving integrin alpha5beta1 receptors, FAK, PI3K, Akt and proteins of Bcl2 family.

Omentectomy Prevents Metabolic Syndrome By Reducing Appetite and Body Weight In A Diet-Induced Obesity Rat Model.

Visceral fat deposition is associated with impairment of glucose and lipid metabolism while leptin levels are frequently related to subcutaneous fat area. At present, there is considerable controversy regarding the role of visceral adipose tissue accumulation in the development of metabolic syndrome (MS). Here we show the effects of omentectomy on the liver and MS in a diet induced obesity rat model. Our results reveal that undergoing omentectomy previously the establishment of the diet-induced-obesity reduced significantly body weight gain and avoid the development of MS, including non-alcoholic fatty liver disease. Intriguingly, the significantly lower body weight gain was due to decreased food intake. Omentum drives obesity progression through leptin resistance mediated by C-reactive protein, Interleucin (IL)-6 and high lipolysis activity. Omentum removal reversed immediately the increased plasma levels of CRP and IL-6 and gradually food intake, weight gain, and features of MS in diet-induced-obesity. Omentectomy caused no changes in normal-weigh-rats. This report displays causal mechanism by which omentum promotes obesity and propose omentectomy as a promising procedure in MS prevention.