Asymptomatic thrombocytopenia after nintedanib initiation in a patient with progressive pulmonary fibrosis: a case report and review of literature.

BACKGROUND: Nintedanib is a primary antifibrosing medication available for idiopathic pulmonary fibrosis, systemic sclerosis-interstitial lung disease, and progressive pulmonary fibrosis, with scattered report of drug-induced thrombocytopenia. CASE REPORT: A 60-year-old Asian male with no history of thrombocytopenia was administered with nintedanib to treat progressive pulmonary fibrosis. The platelet count dropped rapidly after introduction of nintedanib and resolved gradually by withdrawal of the medication along with thrombopoietin receptor agonist. CONCLUSION: Based on experience from the limited reports, nintedanib-induced thrombocytopenia is typically reversible and manageable. Close monitoring of platelet counts in patients receiving this medication should be warranted.

Sertraline-Induced Hypoglycemia in Drug-Induced Liver Injury.

Sertraline, a selective serotonin reuptake inhibitor, is a medication recommended as a third line treatment of cholestatic liver injury pruritis. We report a case of a young male who developed liver injury secondary to self-administration of anabolic steroids and who complained of persistent pruritis leading to a treatment by sertraline. Two days later, the patient was admitted to the hospital with a severe hypoglycemia, while the liver function tests were in amelioration. Clinical and biological evaluation were in favor of sertraline-induced hypoglycemia, a side effect rarely reported in non-diabetic patients, and in the context of hepatic injury.

Docetaxel-Induced Pneumonitis in a Patient With Metastatic Lung Adenocarcinoma.

Docetaxel is a taxane anti-neoplastic agent commonly used in the treatment of solid-organ tumours. Here, we describe a case of a patient with metastatic lung adenocarcinoma who had disease progression following initial treatment with a combination of pembrolizumab, pemetrexed and carboplatin. She received three cycles of docetaxel and had a favourable oncological response but was admitted for breathlessness following the third cycle. A repeat computed tomography scan of the thorax showed predominantly right-sided ground-glass opacities and consolidation. The patient underwent high-risk bronchoscopy and bronchoalveolar lavage. Once infection was confidently ruled out, she was started on high-dose steroid therapy and responded to treatment.

Selective Androgen Receptor Modulators Leading to Liver Injury: A Case Report.

Selective androgen receptor modulators (SARMs) have gained popularity for their alleged ability to selectively target androgen receptors, potentially offering muscle-building benefits with fewer side effects than traditional steroids. However, the safety profile of SARMs, including RAD-140, is not fully understood. This case report presents a 29-year-old male who developed liver injury after taking RAD-140. The patient experienced jaundice and elevated liver enzymes after three months of RAD-140 use. A liver ultrasound revealed hepatic steatosis and a hyperechoic lesion. Symptoms resolved after discontinuing RAD-140. Similar cases of liver injury associated with RAD-140 have been reported, highlighting the potential hepatotoxicity of this SARM. Discontinuation of RAD-140 appears to reverse liver injury, but the long-term effects and risks of SARM use remain unclear. This case highlights the need for caution and monitoring when considering SARMs for performance enhancement.

Propensity score matching-based analysis of the effect of corticosteroids in treating severe drug-induced liver injury.

BACKGROUND AND AIM: There is no conventional treatment for patients with severe drug-induced liver injury (DILI) except for discontinuation of liver injury drugs and symptomatic supportive therapy. Opinions on whether corticosteroids can be used to treat severe DILI are conflicting, and most of the relevant clinical studies are case reports or retrospective studies, which still need to be supported by high-level evidence-based medical studies. This study aimed to evaluate the effect and tolerance of corticosteroids in patients with severe DILI. Risk factors associated with patient failure to cure were also explored. METHODS: Propensity score matching based on nearest-neighbor 1:1 matching was used to screen severe DILI patients in the corticosteroids and control groups. Severe DILI was defined as elevated serum ALT and/or ALP with TBIL≥5 ULN (5 mg/dL or 85.5 µmol/L) with or without INR ≥1.5. Patients were treated with conventional therapy combined with corticosteroids in the corticosteroids group and only conventional therapy in the control group. RESULTS: A total of 146 patients, 73 each in the corticosteroids and control groups, were included in this study. By analyzing the entire cohort, we found no significant difference in cure rates between patients in the corticosteroid group and control group (34.2% vs. 20.5%, p=0.095), and there was no significant difference in the incidence of adverse effects between the two groups (20.5% vs. 20.5%, p=1.000). However, TBIL decreased more in the corticosteroids group on day 7 (89.2 ± 107.6 µmol/L vs. 58.8 ± 70.7 µmol/L, p=0.046). In subgroup analyses, patients whose TBIL remained elevated despite conventional treatment had a higher TBIL decline on day 7,14 after use of corticosteroid (99.2 ± 98.5µmol/L vs. -23.3 ± 50.4µmol/L, p<0.001; 120 ± 119.1µmol/L vs. 61.2 ± 98.5µmol/L, p=0.047). The cure rate of patients in the corticosteroid group was significantly higher than that of the control group (36.1% versus 4.5%, p=0.016). The proportion of patients with TBIL <85.5 µmol/L was also significantly higher in the corticosteroid group than in the control group at day 7 (p=0.016) and day 14 (p=0.004) after treatment. In the subgroup analysis of patients with different clinical phenotypes, the causative agent was herbal, autoimmune antibody-positive and 40% < PTA ≤ 50% of patients, corticosteroid use did not increase the cure rate of the patients. Univariate and multifactorial analyses found corticosteroid use to be a protective factor for failure to cure in patients with severe DILI (p<0.001, OR:0.191,95% CI:0.072-0.470), and peak TBIL to be a risk factor (p=0.003, OR:1.016,95% CI:1.007-1.028). CONCLUSIONS: The addition of corticosteroids could not increase the cure rate in patients with severe DILI, but it could rapidly reduce the patient's TBIL at an earlier stage. Corticosteroids could also promote curing in patients with elevated TBIL after conventional treatment. Corticosteroid use was a protective factor for failure to cure in patients with severe DILI and peak TBIL was a risk factor.

Newer formulations of oral testosterone undecanoate: development and liver side effects.

INTRODUCTION: Testosterone deficiency is a clinical disorder due to either failure of the testes to produce testosterone or failure of the hypothalamus or pituitary to produce sufficient gonadotropins. Previous formulations of oral testosterone therapy, particularly methyltestosterone, have been associated with adverse liver effects. Many different routes of testosterone delivery have been developed, each with their own administrative benefits and challenges. Newer formulations of oral testosterone undecanoate (TU) provide a convenient administration option, although their use has been limited by hepatotoxicity concerns based on older methyltestosterone data, and prescribing physicians may still be concerned about adverse liver effects. OBJECTIVES: In this review, we discuss the history of oral testosterone development, clarify the mechanism of action of oral TU, and describe the relevant liver safety findings. METHODS: Relevant literature was allocated to present a review on the history of oral TU development and the mechanism of action of oral TU. We pooled data from individual studies of oral TU products to present a safety summary. RESULTS: Overall, safety results from studies of the newer formulations of oral TU showed that increased liver function test values are not generally associated with oral TU formulations and that no clinically significant liver toxicities were noted in clinical trials of oral TU. CONCLUSION: Continued research into the safety of oral TU will contribute to a better understanding of the potential risks in patients receiving this therapy, an outcome that highlights the importance of providing patient education and reassurance regarding oral TU safety.

Deciphering Paroxysmal Nocturnal Hemoglobinuria: An Unusual Paradigm of Hemolytic Anemia.

Paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematopoietic stem cell disorder, arises from the increased sensitivity of red blood cells (RBC) to complement due to an acquired deficiency of certain glycosylphosphatidylinositol (GPI)-linked proteins, resulting in chronic intravascular hemolysis, arterial and venous thrombotic phenomena, multi-organ damage, and failure. We present an intriguing case of hemolytic anemia, initially suspected to be drug-induced, and later found to be associated with PNH, despite being a subclinical clone. A clinician should not hesitate to repeat fluorescent-labeled aerolysin (FLAER) cytometry if the clinical picture strongly favors a diagnosis of PNH. This case marks the importance of testing for PNH clones in autoimmune hemolytic anemia (AIHA) since their prevalence is not negligible and may correspond to a prominent hemolytic pattern, a higher thrombotic risk, and a higher therapeutic indication, such as eculizumab. This underscores the significance of conducting a thorough evaluation for occult causes of treatment-unresponsive hemolytic anemia, paving options for an early and alternative therapeutic approach.

Efficacy and Safety of Bacillus coagulans LBSC in Drug Induced Constipation Associated With Functional Gastrointestinal Disorder: A Double-Blind, Randomized, Interventional, Parallel, Controlled Trial a Clinical Study on Bacillus coagulans LBSC for Drug Induced Constipation Associated With FGIDs.

Background: Active drugs and nutraceutical supplements commonly induce various gastrointestinal illnesses, and constipation is a major gastrointestinal symptom accompanied with functional gastrointestinal disorders. Drug-induced imbalance in gut microbiota may play critical role in such physiological disturbances. Probiotics have been known for resuming normal and healthy gut microbiome. Objective: To investigate the clinical efficacy and safety of Bacillus coagulans LBSC in the treatment of drug induced constipation associated with functional gastrointestinal disorder (FGID) symptoms. Methods: A prospective, interventional, randomized, double-blind, parallel, multi-arm, controlled trial with 168 patients experiencing drug induced constipation associated with FGID symptoms (DICAWFGID) screened through Rome IV criteria were randomized into 2 arms, i.e. placebo arm (n = 28) and atorvastatin, atenolol, metformin, amitriptyline, and calcium in test arm (n = 28/arm). Patients in both arms received similar dosages (1 g sachet, 3 times a day) for 35 days. The occurrence of constipation using Bristol Stool Form Scale, assessment of degree of constipation on 4-point Likert scale, occurrence of hard stool and degree of stool expulsion on 3-point scale, and defecation frequency were primary endpoints. While, secondary outcomes consisted of the changes in severity of FGID symptoms, visual analogue scale and tolerance to IP, along with reports of adverse events (AEs) and severe adverse events (SAEs). Results: There was a significant reduction in occurrence of constipation (≥98.6% and P-value <0.05) in test arm over the placebo arm. Assessment of co-primary endpoints showed significant improvements in degree of stool consistency (P-value 0.0232; CI: 0.1870, 1.1629), borderline significantly superior in degree of stool expulsion (P-value 0.0553; CI: 0.0378, -0.4939), while the other co-primary efficacy endpoints displayed considerably improved advancement (non-significant, P-value ≥0.05). The intra group analysis of symptoms at start of treatment (SOT) and end of treatment (EOT) revealed a significant reduction in scores for occurrence of constipation and degree of constipation, whereas significant improvement in the scores for degree of stool consistency and degree of stool expulsion (P-value <0.001) after the intervention period. In secondary endpoints, the processed responses clearly signified a considerable positive improvement (non-significant, P-value ≥0.05) in other symptoms of constipation associated with FGIDs as determined by the changes in the EOT-SOT score. The study data also highlighted the safety of Bacillus coagulans LBSC at the studied dose. No AEs and/or SAEs were documented during the investigation. Conclusion: At the studied dose, Bacillus coagulans LBSC was safe for oral consumption and effective in the management of the drug induced constipation associated with FGIDs symptoms.

Pregabalin-Induced Bullous Pemphigoid: A Case Report of a Rare Drug-Triggered Autoimmune Skin Disorder.

Bullous pemphigoid (BP) is a common autoimmune blistering disorder primarily affecting the elderly, characterized by intense pruritus and tense bullae on the skin. We report the case of a 75-year-old female with a history of breast cancer who developed BP on both feet following the initiation of pregabalin for pain management. Histopathological examination confirmed BP, and symptoms improved with topical corticosteroid treatment and discontinuation of pregabalin. This case highlights the potential of pregabalin to induce BP and underscores the importance of recognizing medication-induced bullous diseases for prompt diagnosis and management.

Management of Pulmonary Toxicities Associated with Systemic Therapy in Non Small Cell Lung Cancer.

OPINION STATEMENT: Drug-induced pneumonitis is a common adverse event that may occur during lung cancer systemic therapy. The incidence/prevalence of this side effect has increased due to recent extensive use of immunotherapy. Although pneumonitis prevalence is increased with the use of immune checkpoint inhibitors, it is also associated with chemotherapy and targeted therapy. Pneumonitis can occur early after drug exposure or present after several cycles of treatment. Its severity can range from insidious to fulminant, leading to hospitalization. In most cases, the diagnosis is made based on medical history, temporal correlation with use of lung cancer systemic therapy, and computed tomography (CT) findings. In the majority of cases, stopping the offending drug and use of corticosteroids is the sufficient treatment; however, patients with more severe forms of pneumonitis require additional immunosuppressive agents. In this review, we address pneumonitis caused by chemotherapy, antibody-drug conjugates, targeted therapy, or immunotherapy, and provide a detailed management approach.

Acute Liver Failure Induced by Provitalize: A Menopause Supplement Concocted From Herbs & Probiotics.

Drug-induced liver injury is one of the most common causes of acute liver failure in the Western world. Despite discontinuation of the offending agent, it can still tax a grim prognosis. We describe a case of a menopausal woman taking a herbal supplement called "Provitalize" to relieve hot flashes and bloating. This is the first case report of liver injury from this supplement. She initially presented with mild jaundice and elevated transaminases. Unfortunately, she rapidly progressed to encephalopathy, experienced multiorgan failure, and then died.

Triptolide-induced acute liver injury and its mechanism with estradiol in regulating macrophage-mediated inflammation and hepatocyte function.

Triptolide (TP), a diterpene from Tripterygium wilfordii, exhibits potent anti-inflammatory, immunomodulatory, and antitumor properties but is limited by severe hepatotoxicity. This study investigates sex differences in TP-induced liver injury and the protective role of estradiol (E2) in modulating macrophage-mediated inflammation and hepatocyte function. An acute liver injury model was established in male and female Balb/c mice using intraperitoneal TP injection. Liver function tests, histological analyses, and immunohistochemical staining were performed. THP-1 macrophage and various liver cell lines were used to study the effects of TP and E2 in vitro. Virtual screening, molecular docking, luciferase assays, and qPCR were employed to identify potential targets and elucidate underlying mechanisms. TP caused more severe liver injury in female mice, evidenced by increased liver indices, aspartate aminotransferase (AST) levels, and extensive hepatocyte damage. TP promoted M1 macrophage polarization, enhancing inflammation, particularly in female mice. E2 mitigated TP-induced inflammatory responses by downregulating pro-inflammatory cytokines and macrophage activation markers. Molecular docking and functional assays identified Nuclear receptor subfamily 1 group I member 2 (NR1I2) as a key target mediating the protective effects of E2. The study highlights significant sex differences in TP-induced hepatotoxicity, with females being more susceptible. E2 exerts protective effects against TP-induced liver injury by modulating immune responses, presenting a potential therapeutic approach to mitigate drug-induced liver injury (DILI). Further research on NR1I2 could lead to targeted therapies for reducing drug-induced liver damage.

Tofacitinib-Induced Acute Pancreatitis in a Patient with Rheumatoid Arthritis: A Case Report and Review of the Literature.

BACKGROUND: Acute Pancreatitis (AP) is an uncommon complication that rarely occurs during Rheumatoid Arthritis (RA). Among the varied etiologies of AP, Drug-induced Pancreatitis (DIP) remains a rare entity and a rather challenging condition. A large panel of drugs have been reported to cause pancreatitis; however, there are no cases of tofacitinib-induced pancreatitis reported in the literature. CASE PRESENTATION: We have, herein, reported the case of a Tunisian 58-year-old woman with a four-year history of RA who experienced two episodes of AP; the first one occurred on the second day of a 3-day series of methylprednisolone intravenous injections, and the second episode occurred on the sixth-day of tofacitinib administration. Each time, she presented acute abdominal pain with characteristic radiation to the back. Symptoms resolved spontaneously once the suspected drug was discontinued. In the event of a negative investigation, including abdominal ultrasonography and magnetic resonance imaging, and assessment of albumin, calcemia, triglyceridemia, serum ferritin, and IgG4 levels, DIP was the most likely diagnosis. CONCLUSION: Although DIP is still a rare condition, it remains serious with an increased risk of mortality. We intended to alert clinicians that in addition to the known side effects of tofacitinib, pancreatitis may be induced by this drug, especially in predisposed patients.

Drug-induced liver injury related to gene therapy: A new challenge to be managed.

Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno-associated virus vectors, which have been shown to be viable for use in in vivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X-linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler-Najjar disease, alpha-1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short- and long-term management currently proposed to prevent or correct liver reactions in clinical practice.

Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK/mTOR signaling pathway.

BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

A Case of Severe Thrombocytopenia, Aseptic Meningitis, and Hepatitis Caused by Trimethoprim-Sulfamethoxazole: A Triple Threat.

Trimethoprim-sulfamethoxazole (TMP-SMX), a widely used antibiotic, is associated with both predictable dose-dependent side effects and rare, idiosyncratic adverse reactions. Here, we report the case of a previously healthy, non-G6PD-deficient, 27-year-old male who developed three idiosyncratic reactions: severe thrombocytopenia, aseptic meningitis, and hepatitis concurrently following TMP-SMX administration. The Naranjo adverse reaction probability score was 7, implying TMP-SMX as the probable cause of the clinical presentation. After a comprehensive workup to rule out alternate etiologies, we have established TMP-SMX as the culprit. Our case highlights the importance of early recognition of TMP-SMX-induced rare adverse events for appropriate management to mitigate long-term sequelae and ensure favorable patient outcomes.

Pirfenidone-induced liver injury, a case report of a rare idiosyncratic reaction.

Nearly all medications carry the risk of drug-induced liver injury (DILI). Idiosyncratic reactions are rare and poorly predictable, and the mechanisms are not always well understood. Pirfenidone is an oral antifibrotic drug used to treat idiopathic pulmonary fibrosis. While elevation of liver enzymes is a common adverse reaction during therapy, it rarely leads to discontinuation or reduction of the drug. Although isolated cases of liver damage or liver failure have been reported, they are infrequent. This report presents the case of a 70-year-old woman with known idiopathic pulmonary fibrosis, depression, hypothyroidism, and hypercholesterolemia who presented at our emergency department with jaundice, anorexia, and asthenia. The patient's medication regimen included lamotrigine, simvastatin, levothyroxine, and pirfenidone, which had been introduced 6 months prior. Laboratory testing revealed elevated liver enzyme levels consistent with acute hepatocellular hepatitis. Following a medical workup, which included anamnesis, laboratory testing, iconographic investigations, and liver biopsy, we concluded that the patient had suffered from pirfenidone-induced liver injury. Pirfenidone was withdrawn, and liver tests gradually improved. The purpose of this clinical case report is to highlight this rare adverse reaction and to make clinicians aware of its assessment and management. In 2018, only one other case of severe liver failure leading to the death of the patient was reported. Early detection of potential DILI during the workup is crucial to discontinue the suspected medication promptly. Any drug-induced hepatitis must be reported for registration.

A case report of toxic hepatitis induced by drug (pirfenidone) in a patient with idiopathic pulmonary fibrosis • Drug-induced liver injury (DILI) is a type of hepatitis caused by medication, drugs, or even herbal and dietary supplements. • There are two types of DILI reactions: intrinsic and idiosyncratic. ○ The intrinsic reaction, such as acute hepatotoxicity due to acetaminophen overdose, is easily predictable and well-known. ○ The idiosyncratic reaction is more complex, unpredictable, and not well-understood. Therefore, diagnosing an idiosyncratic reaction can be challenging. • Pirfenidone is an immunosuppressive drug used to treat idiopathic pulmonary fibrosis by inhibiting collagen formation through anti-fibrotic and anti-inflammatory mechanisms. • Several adverse reactions of pirfenidone are well described, including temporary elevation of liver enzymes during treatment. This adverse reaction is mostly asymptomatic and resolves spontaneously with or without dose adjustment. • However, few cases of severe DILI due to pirfenidone have been reported, which may lead to liver dysfunction. • This paper reports on a rare idiosyncratic reaction related to pirfenidone that resulted in hepatic adverse reactions.