Prospective Assessment of Treatment-Induced Liver Injury as a Cause of Diffuse Pathologic Hepatic Enhancement in Contrast-Enhanced Ultrasound.

OBJECTIVE: A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. METHODS: To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n = 20) or acute leukemia patients prior to IT (n = 20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. RESULTS: The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. CONCLUSION: Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE.

Pharmacokinetic assessment of rifampicin and des-acetyl rifampicin in carbon tetrachloride induced liver injury model in Wistar rats.

OBJECTIVES: Preclinical evidence is needed to assess drug-metabolite behaviour in compromised liver function for developing the best antitubercular treatment (ATT) re-introduction regimen in drug-induced liver injury (DILI). The pharmacokinetic behavior of rifampicin (RMP) and its active metabolite des-acetyl-rifampicin (DARP) in DILI's presence is unknown. To study the pharmacokinetic behavior of RMP and DARP in the presence of carbon tetrachloride (CCl4) plus ATT-DILI in rats. METHODS: Thirty rats used in the experiment were divided equally into six groups. We administered a single 0.5 mL/kg CCl4 intraperitoneal injection in all rats. Groups II, III, IV, and V were started on daily oral RMP alone, RMP plus isoniazid (INH), RMP plus pyrazinamide (PZA), and the three drugs INH, RMP, and PZA together, respectively, for 21-days subsequently. Pharmacokinetic (PK) sampling was performed at 0, 0.5, 1, 3, 6, 12, and 24 h post-dosing on day 20. We monitored LFT at baseline on days-1, 7, and 21 and sacrificed the rats on the last day of the experiment. RESULTS: ATT treatment sustained the CCl4-induced liver injury changes. A significant rise in mean total bilirubin levels was observed in groups administered rifampicin. The triple drug combination group demonstrated 1.43- and 1.84-times higher area-under-the-curve values of RMP (234.56±30.66 vs. 163.55±36.14 µg h/mL) and DARP (16.15±4.50 vs. 8.75±2.79 µg h/mL) compared to RMP alone group. Histological and oxidative stress changes supported underlying liver injury and PK alterations. CONCLUSIONS: RMP metabolism inhibition by PZA, more than isoniazid, was well preserved in the presence of underlying liver injury.

Risk assessment of micafungin-induced liver injury using spontaneous reporting system data and electronic medical records.

INTRODUCTION: There is limited information regarding antifungal-induced liver injuries, which have high mortality rates. Therefore, we used the Japanese Adverse Drug Event Report (JADER) database for signal detection associated with antifungal-induced liver injuries and medical records for risk assessment. METHODS: Reports of antifungal-induced liver injuries from JADER data were analyzed to calculate the reporting odds ratio (ROR) and 95% confidence interval (CI). A medical record-based study involving 109 adult patients treated with micafungin shows liver injury as the primary outcome in patients treated with micafungin. The albumin-bilirubin (ALBI) score was calculated based on albumin and total bilirubin levels. We selected five explanatory factors for multivariable logistic regression: alanine aminotransferase ≥20 IU/L, alkaline phosphatase ≥372 IU/L, aspartate aminotransferase ≥25 IU/L, ALBI score ≥ -1.290, and age ≥65 years. RESULTS: Signal detection for micafungin was observed in both, hepatocellular and cholestatic injuries, as per data from JADER. Univariate analyses performed on medical records suggest that alanine aminotransferase (p = 0.008), aspartate aminotransferase (p = 0.036), alkaline phosphatase (p = 0.045), and ALBI score (p = 0.028) may be factors associated with micafungin-induced liver injury. Based on multivariable logistic regression, the adjusted odds ratio for micafungin-induced liver injury in patients with ALBI score ≥ -1.290 was 2.78 (95% CI: 1.014-7.605, p = 0.047), suggesting that low hepatic functional reserve could be a risk factor for micafungin-induced liver injury. CONCLUSIONS: Careful monitoring of liver function may be necessary for micafungin administration in patients with low hepatic functional reserve.

Assessment of hepatic prostaglandin E2 level in carbamazepine induced liver injury.

Objective. Carbamazepine (CBZ), a widely used antiepileptic drug, is one major cause of the idiosyncratic liver injury along with immune reactions. Conversely, prostaglandin E2 (PGE2) demonstrates a hepatoprotective effect by regulating immune reactions and promoting liver repair in various types of liver injury. However, the amount of hepatic PGE2 during CBZ-induced liver injury remains elusive. In this study, we aimed to evaluate the hepatic PGE2 levels during CBZ-induced liver injury using a mouse model. Methods. Mice were orally administered with CBZ at a dose of 400 mg/kg for 4 days, and 800 mg/kg on the 5th day. Results. Plasma alanine transaminase (ALT) level increased in some of mice 24 h after the last CBZ administration. Although median value of hepatic PGE2 amount in the CBZ-treated mice showed same extent as vehicle-treated control mice, it exhibited significant elevated level in mice with severe liver injury presented by a plasma ALT level >1000 IU/L. According to these results, mice had a plasma ALT level >1000 IU/L were defined as responders and the others as non-responders in this study. Even though, the hepatic PGE2 levels increased in responders, the hepatic expression and enzyme activity related to PGE2 production were not upregulated when compared with vehicle-treated control mice. However, the hepatic 15-hydroxyprostaglandin dehydrogenase (15-PGDH) expression and activity decreased significantly in responders when compared with control mice. Conclusions. These results indicate that elevated hepatic PGE2 levels can be attributed to the downregulation of 15-PGDH expression under CBZ-induced liver injury.

Androgenic anabolic steroid-induced liver injury: two case reports assessed for causality by the updated Roussel Uclaf Causality Assessment Method (RUCAM) score and a comprehensive review of the literature.

BACKGROUND: Anabolic androgenic steroids (AAS) usage is widespread and increasing. AAS drug-induced liver injury (DILI) is recognised but its clinical course and management is poorly described. We report 2 cases of AAS DILI with associated renal dysfunction, managed successfully with oral corticosteroids. METHODS: A comprehensive review identified 50 further cases to characterise the clinical and biochemical course. Causality grading was calculated using the updated Roussel Uclaf Causality Assessment Method (RUCAM) score. Data are presented as median values. RESULTS: The most common AAS taken was methyldrostanolone. Patients commonly present with jaundice and pruritus but may exhibit other constitutional symptoms. Patients presented 56 days after starting, and bilirubin peaked 28 days after stopping, AAS. Causality assessment was 'unlikely' in 1 (2%), 'possible' in 31 (60%) and 'probable' in 20 (38%). Peak values were: bilirubin 705 µmol/L, alanine transaminase 125 U/L, aspartate transaminase 71 U/L, alkaline phosphatase 262 U/L, gamma-glutamyl transferase 52 U/L, international normalised ratio 1.1. Liver biopsies showed 'bland' canalicular cholestasis. 43% of patients developed kidney injury (peak creatinine 225 µmol/L). Therapies included antipruritics, ursodeoxycholic acid and corticosteroids. No patients died or required liver transplantation. CONCLUSIONS: Physicians are likely to encounter AAS DILI. Causality assessment using the updated RUCAM should be performed but defining indications and proving efficacy for therapies remains challenging.

Quantitative Assessment of Extracellular Volume in Doxorubicin-Induced Liver Injury in Beagle Models by Equilibrium Computed Tomography.

PURPOSE: The purpose of this study was to determine whether liver extracellular volume (ECV) measured using equilibrium computed tomography (EQ-CT) can be used to quantitatively assess doxorubicin-induced liver injury (DILI). METHODS: The ethical approval was obtained from the Institutional Animal Care and Use Committee regulations. Thirteen dogs administered with doxorubicin for 0 to 24 weeks were imaged by contrast-enhanced EQ-CT. The dogs were divided into 3 groups: the baseline (13 dogs), 16-week (10 dogs), and 24-week (7 dogs) groups. Pathological analysis of the liver was performed using hematoxylin-eosin and Masson staining. Liver ECV uptake was calculated for each group and correlated with the histopathological and serological findings of hepatic fibrosis (hyaluronic acid and procollagen type III). RESULTS: In the baseline group, the median ECVs of the right and left liver lobes were 21.78% (interquartile range [IQR], 16.78%-26.68%) and 20.91% (IQR, 16.39%-24.07%), respectively. In the 16- and 24-week groups, the median ECVs of these 2 liver lobes were 28.18% (IQR, 20.56%-34.61%) and 25.96% (IQR, 14.07%-41.38%) and 29.71% (IQR, 27.19%-35.25%) and 29.22% (IQR, 22.62%-38.67%), respectively. There were no significant differences in ECV between the left and right lobes in the 3 groups (P < 0.05). Both the 16- and 24-week groups showed significantly higher ECV than did the primary group (P = 0.001-0.0006). However, there were no significant differences in ECV between the 16-week group and 24-week group (P = 0.412). There was a positive correlation between the serum index and edema due to the inflammation and necrosis associated with DILI (R = 0.6534, R = 0.7129). CONCLUSIONS: Extracellular volume measured by EQ-CT imaging can accurately predict the potential DILI through the quantification of ECV changes.

Diagnostic and prognostic assessment of suspected drug-induced liver injury in clinical practice.

Idiosyncratic drug-induced liver injury (DILI) is a challenging liver disorder because it can present with a range of phenotypes, mimicking almost every other hepatic disease, and lacks specific biomarkers for its diagnosis. Hence, a confident DILI diagnosis is seldom possible as it relies on the precise establishment of a temporal sequence between the exposure to a given prescription drug or sometimes hidden herbal product/over the counter medication as well as the exclusion of other aetiologies of liver disease. However, an accurate diagnosis is of most importance, as prompt withdrawal of the causative agent is essential in DILI management. Indeed, DILI can be severe and even fatal or in a fraction of cases evolve to chronic damage, but specific biomarkers for predicting mortality/liver transplantation or a chronic outcome in the very early phases of DILI are not yet available. In this article, we discuss the best diagnostic and prognostic approach of a DILI suspicion by judiciously choosing and interpreting the standard tests currently used in clinical practice.

Assessment of Serious Acute and Chronic Idiosyncratic Drug-Induced Liver Injury in Clinical Practice.

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF) in developed countries. The extremely variable phenotype of DILI, both in presentation and in severity, is one of the distinctive characteristics of the disease and one of the major challenges that hepatologists face when assessing hepatotoxicity cases. A new Hy's law that more accurately predicts the risk of ALF related to DILI has been proposed and validated. Other prognostic scoring algorithms for the early identification of DILI patients who may go on to develop ALF have been developed as it is of most clinical relevance to stratify patients for closer monitoring. Recent data indicate that acute DILI often presents a more prolonged resolution or evolves into chronicity at a higher frequency than other forms of acute liver injury. Risk factors for chronicity, specific phenotypes, and histological features are discussed in this study. Biomarkers to predict DILI outcome are in need.

Drug and herb-induced liver injury: A critical review of Brazilian cases with proposals for the improvement of causality assessment using RUCAM.

INTRODUCTION AND OBJECTIVES: Although hepatotoxicity accounts for 10% of adverse drug reactions, it remains poorly understood and underreported. This study aimed to summarize case reports of herb- and drug-induced liver injury in Brazil. METHODOLOGY: Systematic review in the following databases: PubMed, SciELO, Science Direct, CAPES, and gray literature. RESULTS: Twenty-seven studies reporting 32 cases were identified. Brazilian cases were primarily detected in hospitals, and occurred mainly in young males suffering from chronic diseases. Drugs (n=29) were a more frequent cause of liver injury than herbs (n=3). Almost a third of these drugs were anticonvulsants, and 15 appear in the Brazilian List of Essential Medicines. In 50% of the cases, clinical manifestations started within 30 days of drug ingestion. Regarding the decline of liver enzymes, 50% of the cases reached normality after drug withdrawal. However, 7 deaths and 2 liver transplantations were reported. Only one study assessed causality using RUCAM. CONCLUSION: Given the severe outcomes of DILI and HILI, early detection and management of hepatotoxicity to increase drug safety are necessary, as well as pharmacotherapeutic monitoring of patients with chronic diseases. Moreover, the application of the RUCAM algorithm in clinical practice has to be further disseminated.

A multicenter assessment of liver toxicity by MRI and biopsy in IBD patients on 6-thioguanine.

BACKGROUND/AIMS: Although 6-thioguanine (6-TG) has been suggested as an effective treatment option for patients with inflammatory bowel disease (IBD), the recent description of its hepatotoxicity has led to the recommendation not to consider this drug. We initiated a multicenter safety study in IBD-patients treated with 6-TG to investigate hepatic changes by liver biopsy and magnetic resonance imaging (MRI). METHODS: Forty-five patients from three European centers treated with 6-TG (40-80 mg/d) at least for 8 weeks were enrolled. In all patients liver biopsy and MRI were performed. Slides and MR images were independently read by two pathologists and radiologists, respectively, and interpreted according to predefined criteria by consent. RESULTS: In 8 patients nodular regenerative hyperplasia (NRH) was diagnosed by liver biopsy, in 8 additional patients NRH could not be excluded due to equivocal pathological findings. MRI demonstrated a sensitivity of 77% and a specificity of 72% in the detection of pathohistological findings consistent with and/or possibly related to NRH. CONCLUSIONS: Our study suggests that 6-TG therapy in IBD patients is associated with NRH of the liver. Based on a special MRI protocol, non-invasive diagnosis of NRH with promising sensitivity and specificity was demonstrated.

Hepatotoxicity of antiretrovirals: incidence, mechanisms and management.

Hepatotoxicity is a relevant adverse effect derived from the use of antiretrovirals that may increase the morbidity and mortality among treated HIV-infected patients and challenges the treatment of HIV infection. Although several antiretrovirals have been reported to cause fatal acute hepatitis, they most often cause an asymptomatic elevation of transaminase levels. In addition to ruling out a variety of processes not related to the use of antiretrovirals or to the HIV infection, for appropriate management of the complication it is necessary to deduce the possible pathogenic mechanisms of the hepatotoxicity. Among these mechanisms, direct drug toxicity, immune reconstitution in the presence of hepatitis C virus (HCV) and/or hepatitis B virus (HBV) co-infections, hypersensitivity reactions with liver involvement and mitochondrial toxicity play a major role, although several other pathogenic pathways may be involved. Liver toxicity is more frequent among subjects with chronic HCV and/or HCB co-infections and alcohol users. Complex immune changes that alter the response against hepatitis virus antigens might be involved in the elevation of transaminase levels after suppression of the HIV replication by highly active antiretroviral therapy (HAART) in patients co-infected with HCV/HBV. The contribution of each particular drug to the development of hepatotoxicity in a HAART regimen is difficult to determine. The incidence of liver toxicity is not well known for most of the antiretrovirals. Although it is most often mild, fatal cases of acute hepatitis linked to the use of HAART have been reported across all families of antiretrovirals. Acute hepatitis is related to hypersensitivity reactions in the case of non-nucleosides and to mitochondrial toxicity in the case of nucleoside analogues. Alcohol intake and use of other drugs are other co-factors that increase the incidence of transaminase level elevation among HIV-infected patients. The management of liver toxicity is based mainly on its clinical impact, severity and pathogenic mechanism. Although low-grade HAART-related hepatotoxicity most often spontaneously resolves, severe grades may require discontinuation of the antiretrovirals, for example when there is liver decompensation, hypersensitivity reaction or lactic acidosis.

Latent tuberculosis in pregnancy: screening and treatment.

Currently, most cases of active tuberculosis in the United States are a result of activation of latent tuberculosis infection. In this article, the history of the epidemiology of tuberculosis and latent tuberculosis infection is reviewed. Previous and current recommendations for screening and treatment for latent tuberculosis during pregnancy and the postpartum period are discussed. A review of the literature regarding postpartum and antepartum treatment is included. Finally, the question of whether antepartum or postpartum treatment is the most beneficial is discussed.

Canal Saúde: [Programa de] Redução de Danos

Mostra um programa para apresentar um projeto do Ministério da Saúde na luta contra a AIDS, o Programa de Redução de Danos. Conta a história da descoberta da AIDS na década de 1980, e o surgimento de campanhas em todo mundo contra a epidemia desde então. Explica que o Programa de Redução de Danos do Ministério da Saúde visa fornecer seringas para os usuários de drogas na tentativa de diminuir o compartilhamento deste material. Informa que cerca de 50% dos usuários de drogas injetáveis são portadores do vírus HIV e grande parte transmite ou pegou o vírus através de seringas compartilhadas. Mostra que esse Programa é adotado no mundo todo e ao contrário do que muitos pensam o fornecimento de seringas descartáveis para usuários de drogas diminui a incidência de uso de drogas. O Programa, além de fornecer seringas descartáveis em troca das usadas, distribui camisinhas e informação para a população através de agentes diminuidores de danos, que vão até os locais indicados pela própria população como sendo um local para encontro de usuários. Discute com convidados que fazem parte do projeto os objetivos e resultados apresentados nos locais em que o Programa de Redução de Danos já está sendo implantado