Asymptomatic Elevation Of Liver Enzymes Research Articles

ASSOCIATION COVID-19 AND LIVER INJURY : A SYSTEMATIC REVIEW

Background: Most COVID-19 patients present with typical respiratory symptoms (i.e., cough, dyspnea) and fever. However, abnormal liver function is often developed in patients with COVID-19, and liver injury has been related with severe disease. Liver damage ranges from mild asymptomatic elevation of liver enzymes to severe liver injury, while a few cases of acute liver failure have also been reported. The aim: This study aims to show association COVID-19 and liver injury. Methods: By comparing itself to the standards set by the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) 2020, this study was able to show that it met all of the requirements. So, the experts were able to make sure that the study was as up-to-date as it was possible to be. For this search approach, publications that came out between 2013 and 2023 were taken into account. Several different online reference sources, like Pubmed and SagePub, were used to do this. It was decided not to take into account review pieces, works that had already been published, or works that were only half done. Result: In the PubMed database, the results of our search brought up 44 articles, whereas the results of our search on SagePub brought up 334 articles. The results of the search conducted for the last year of 2013 yielded a total 7 articles for PubMed and 111 articles for SagePub. The result from title screening, a total 4 articles for PubMed and 46 articles for SagePub. In the end, we compiled a total of 10 papers. We included five research that met the criteria. Conclusion: COVID-19-associated liver injury is caused by the cumulative effects of multiple factors, including hepatotropic SARS-CoV-2, drug-induced liver injury, hypoxic reperfusion, immune stress and inflammatory factor storms.

Bismuth subcitrate, metronidazole and tetracycline – a rare cause of drug-induced liver injury

Drug-induced liver injury (DILI) is a liver condition caused by any drug or toxic substance. The spectrum of DILI manifestations can range from asymptomatic elevation of liver enzymes to acute liver failure. Antibiotics are one of the major causes of DILI. The authors report the case of a 37-year-old male with nausea, right hypochondrium pain and fever with history of bismuth subcitrate, metronidazole and tetracycline combination treatment in the previous five days. DILI was suspected and other aetiologies of acute hepatitis were excluded such as viral, autoimmune or even haemochromatosis and Wilson’s disease. Liver biopsy was performed, being compatible with the diagnosis of DILI; DILI is a diagnosis of exclusion. Bismuth subcitrate, metronidazole and tetracycline combination treatment is a rare cause of DILI.

Role of N-acetylcysteine in liver injury due to dengue fever.

Dengue fever (DF) is a common mosquito-borne viral infection which is endemic in Southeast Asia. Liver involvement may vary from asymptomatic elevation of liver enzymes to fulminant hepatitis. Although the valuable effects of N-acetylcysteine (NAC) in paracetamol toxicity and non-paracetamol liver failure have been extensively studied, its use in DF-associated hepatitis remains unclear. We made a literature search in an online format from libraries such as PubMed, Google Scholar, and EMBASE, and selected 33 articles including original research articles, case reports, and systemic analyses. The majority of the articles reviewed had a positive outcome but treatment strategies involved NAC together with supportive care. Hence, data on sole use of NAC from large randomised control trials remain unclear.

Assessment of effect statin-drug interactions in cardiology outpatient department in Teaching Hospital Surabaya

Background: HMG-CoA inhibitors, more commonly known as statins, are lipid-lowering agents that have benefits in cardiovascular therapy. Stains are associated with two significant side effects, asymptomatic elevations of liver enzymes and myopathy. Myopathy is the most likely to occur when statins are prescribed with other drugs. Objectives: To evaluate the effect of drug interactions between statins and concomitant drugs in outpatient cardiovascular patients. Methods: This study conducted in a prospective cohort. Checking drug interactions was done through the Lexicomp Drug Interactions software and patient’s complaints were taken thorough interviews. Results: There were 69 patients included in the study sample. A total of 16 patients received atorvastatin, and 53 patients received simvastatin. More than half of sample (59%) have statin-drug interactions. The most drug interactions were severe (41%), followed by moderate (22%) and mild (10%). The most interacting drugs were amlodipine and diltiazem. Based on the results of interview, there were no complaint of myopathy felt by patient. Conclusion: The effects of drug interactions still need to be considered even though the patients did not complain of myopathy in this study. Several factors can determine the impact of drug interactions not experienced by the patient.

1727. Phase 1b Dose-ranging Study Demonstrates Tolerability and Pharmacokinetics (PK) of Oral Epetraborole at the Predicted Therapeutic Dosage for Mycobacterium avium Complex (MAC) Lung Disease

Abstract Background Epetraborole (EBO) — an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria — is under clinical development for treatment of MAC lung disease. We conducted a Phase 1b dose-ranging study of EBO tablets in healthy adult volunteers, to inform dose selection in the treatment of MAC lung disease. Methods In this double-blind, placebo-controlled trial, EBO or placebo tablets were administered (n=8/cohort, 3:1 randomization) at dosages of 250-1000 mg q24h or 500 mg or 1000 mg q48h for up to 28 days. Standard Ph1 clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Based on prior human studies using significantly higher EBO daily doses, gastrointestinal (GI) events and anemia were predetermined AEs of special interest (AESIs). Plasma concentrations of EBO were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods. Results A total of 43 subjects were enrolled; the 1000 mg q24h cohort was terminated early due to local COVID restrictions. Overall, 80.6% EBO subjects and 83.3% placebo subjects experienced ≥1 TEAE, none of which was serious or severe (Table). Most TEAEs were mild in severity (90%), and the remainder were moderate (10%). No TEAE leading to withdrawal from study was reported. The most frequent types of TEAEs were GI events (48.4% EBO, 41.7% placebo subjects), the most common being mild nausea. Two subjects had premature discontinuation of EBO due to a TEAE (asymptomatic liver enzyme elevations in a 250 mg q24h subject and mild nausea in a 1000 mg q48h subject). One 1000mg q24h subject had a TEAE of anemia. No clinically significant findings or TEAEs were observed for physical examinations, ECGs, or urine laboratory tests. Plasma Cmax and AUC0-∞ of EBO increased in a linear, dose-proportional manner across cohorts. Tmax was observed at ∼1 h post dose; mean t1/2 ranged from 7.63 to 11.1 h. Conclusion Oral EBO administered for 28-day dosing was generally well tolerated at the predicted therapeutic dose (500mg q24h) Predictable PK characteristics facilitate its use in MAC lung disease Further evaluation in a Phase 2/3 treatment-refractory MAC lung disease study is planned Disclosures Paul B. Eckburg, MD, Paratek Pharmaceuticals, Inc.: Safety Review Board|Spero Therapeutics, Inc.: Advisor/Consultant Sanjay Chanda, PhD, AN2 Therapeutics: Stocks/Bonds George Talbot, MD, AN2 Therapeutics, Inc.: Advisor/Consultant|AN2 Therapeutics, Inc.: Co-founder Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support.

Protective Effect of Hydroalcoholic Extract of Clove on Thioacetamide-Induced Hepatotoxicity Animal Model: Effects Hydroalcoholic Extract of Clove Against Hepatotoxicity.

The drug-induced liver injury (DILI) has a wide range of clinical presentations, from asymptomatic liver enzyme elevations to cirrhosis. Herbal dietary supplements may be beneficial to reduce the risk of hepatotoxicity. This study aimed to evaluate the effects of different doses of clove extracts on humoral factors in rats with hepatotoxicity induced by thioacetamide. In this experimental study, rats were divided into nine groups (10 rats per each). The Control group received no treatment. The Sham group was treated with oral administration of distilled water (0.5 ml) for 21 days. The positive control group received thioacetamide (50 mg/kg for three days) intraperitoneally. The clove group was divided into three subgroups and given daily oral administrations of 50, 150, and 300 mg/kg of clove hydroalcoholic extracts (for 21 days). Rats in the experimental group were divided into three subgroups and subjected to 50 mg/kg thioacetamide injection after receiving hydroalcoholic extracts of clove (50, 150, and 300 mg/kg, respectively) for 21 days in the last three days. All rats were sacrificed after 48 hours to measure liver function parameters (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total plasma protein, and albumin). The rats that received thioacetamide showed liver damage by increased serum liver biomarkers and decreased levels of total plasma protein and albumin compared to the control group. The different doses of clove extract resulted in a significant improvement of liver damage by reduced serum liver enzymes levels and increased total plasma protein and albumin. Oral administration of the different doses of the clove extract (50, 150, and 300 mg/kg) for 21 consecutive days could significantly improve the changes associated with serum biomarkers of hepatotoxicity. [GMJ.2022;11:e1603].

A Double-Blind, Placebo-Controlled, Crossover Study of Magnesium Supplementation in Patients with XMEN Disease.

X-linked MAGT1 deficiency with increased susceptibility to Epstein-Barr virus (EBV) infection and N-linked glycosylation defect (XMEN) disease is an inborn error of immunity caused by loss-of-function mutations in the magnesium transporter 1 (MAGT1) gene. The original studies of XMEN patients focused on impaired magnesium regulation, leading to decreased EBV-cytotoxicity and the loss of surface expression of the activating receptor "natural killer group 2D" (NKG2D) on CD8+ T cells and NK cells. In vitro studies showed that supraphysiological supplementation of magnesium rescued these defects. Observational studies in 2 patients suggested oral magnesium supplementation could decrease EBV viremia. Hence, we performed a randomized, double-blind, placebo-controlled, crossover study in 2 parts. In part 1, patients received either oral magnesium L-threonate (MLT) or placebo for 12weeks followed by 12weeks of the other treatment. Part 2 began with 3days of high-dose intravenous (IV) magnesium sulfate (MgSO4) followed by open-label MLT for 24weeks. One EBV-infected and 3 EBV-naïve patients completed part 1. One EBV-naïve patient was removed from part 2 of the study due to asymptomatic elevation of liver enzymes during IV MgSO4. No change in EBV or NKG2D status was observed. In vitro magnesium supplementation experiments in cells from 14 XMEN patients failed to significantly rescue NKG2D expression and the clinical trial was stopped. Although small, this study indicates magnesium supplementation is unlikely to be an effective therapeutic option in XMEN disease.

Acute liver failure secondary to Ayurvedic Herbal medication in a child: a case report

Ayurvedic and Herbal medicine induced liver injury is rarely reported in children. The injury can range from mild asymptomatic elevation of liver enzymes to severe presentation with acute liver failure leading to death. The diagnosis is by exclusion and relies on accurate history and clinical examination supported by laboratory investigations. Various causality assessments such as council for international organizations of medical sciences (CIOMS) and Roussel Uclaf Causality Assessment Method (RUCAM) have been reported to be useful in reaching the diagnosis of Herbal Induced Liver Injury (HILI). However, these scales have not been validated specifically for pediatric age group. In this report, we present a case of a child who was presented to our department with acute liver failure after taking unlabeled ayurvedic medicine for jaundice and loss of appetite. The child was examined for age specific causes of hepatic injury and acute liver failure and he was managed conservatively. Despite extensive search, we did not find any etiology and suspected herbal medicine induced hepatic injury. She recovered completely after stopping the offending medicines. This case highlights the paradoxical hepatotoxic effect of such medications, widely considered safe and natural by the masses. Pediatric hepatologists and general practitioners should be well aware about such adverse effects of herbal medications when encountered with patients with abnormal liver functions. The health authorities need to establish strict quality check and regulations both in the production and sale of ayurvedic medications.

Fluconazole-induced hepatotoxicity in a tertiary care hospital among patients with dermatophytosis

Background: Fluconazole is being used commonly to treat onychomycosis. Although the risk of liver injury is comparatively less with fluconazole, the severity among immunocompromised individuals is high. There are only a few studies available regarding fluconazole-induced drug-induced liver injury for Indian population. The purpose of this study is to investigate the incidence rate of fluconazole-induced liver injury among general population and to identify other adverse drug reaction (ADR) associated with the use of fluconazole in dermatophytosis. Aims and Objectives: This study aims to study the incidence and severity of liver injury caused by fluconazole and to assess the other adverse effects. Materials and Methods: After obtaining the Institutional Ethical Committee clearance, this study was conducted at the Outpatient Department of Dermatology, RGGH, Chennai. One hundred patients with dermatophytosis, on oral fluconazole 150 mg, biweekly were included and data were collected regarding duration of therapy and adverse effects. The causality assessment was done by the World Health Organization assessment scale and severity assessment using modified Hartwig severity assessment scale. Results: Of the 100 patients, 58% developed ADR. About 64% of patients had ADR and they were on therapy for more than 12 weeks. Increase in serum transaminases was noted in 8% of patients. Abdominal pain was the most common adverse drug effect documented followed by headache. Most of the ADRs were in possible category of causality assessment scale. In severity assessment, most of the ADRs were in mild category. Conclusion: From this study, we conclude that asymptomatic elevations of liver enzymes were observed in patients on fluconazole therapy for more than 12 weeks duration. Liver functions are to be monitored periodically among the patients taking fluconazole for longer periods so that we can avoid the unwanted effects.

Cholestatic hepatitis with ciprofloxacin therapy: A Case Report

Ciprofloxacin has generally been well-tolerated and is the commonly prescribed fluoroquinolone antibiotic for treatment of urinary tract and gastrointestinal infection. The adverse effects on the liver usually range from asymptomatic elevation of liver enzymes to fulminant hepatitis. However, acute fulminant hepatitis and cholestatic hepatitis are reported rarely in literature. Here, we report a case of ciprofloxacin induced cholestatic hepatitis in a 52 year old woman following intravenous ciprofloxacin for acute gastroenteritis.

2480 Nivolumab-Induced Hepatitis and Vesiculopustular Skin Rash in a Patient With Metastatic Melanoma

INTRODUCTION: The advent of immunotherapy has been hailed as a breakthrough in cancer treatment. However, it comes with a multitude of immune mediated adverse effects. Gastrointestinal adverse effects include hepatitis and colitis. Immunotherapy related hepatitis can range from asymptomatic elevation of liver enzymes (grade 1) to decompensated liver failure (grade 4). CASE DESCRIPTION/METHODS: 82 years old male with stage IIC Malignant Melanoma of right posterior diagnosed in 2014, treated with wide excision. In December 2016, PET scan revealed right chest wall lesion, treated with re-excision. c-kit and BRAF were negative. In June 2017, PET scan showed metastatic disease involving lung, pancreas, gluteus maximus and left flank. The patient was started on Nivolumab. After 7 cycles, the PET scan became negative for any metastatic lesions. After 8 cycles, he had a severe morbilliform, vesiculopustular rash secondary to Nivolumab. Skin Biopsy showed a lymphocytic infiltrate with scattered eosinophils and numerous neutrophils. High dose prednisone was started with tapering for 3 months. Nivolumab was temporarily held and resumed after a good response to steroids. After 14 cycles, the patient developed malaise, fatigue, nausea and mild abdominal pain. ALT was 393, AST 302, ALK 164. Bilirubin was 1.1. Hepatitis A, B, and C testing were negative, anti-liver kidney microsomal antibody and anti-mitochondrial antibody was negative, acetaminophen level was normal, CT and Ultrasound of the liver were negative for metastatic lesions or other hepatic pathology. No recent change in medication or alcohol use was reported. As per ASCO guidelines, hepatitis was classified as Grade III (ALT and AST >5-20 times the upper limit of normal). The patient was started on 100 mg prednisone daily with tapering for 2 months. Liver enzymes normalized and symptoms resolved. Nivolumab was discontinued. PET scan 6 months from the last cycle showed disease in remission. DISCUSSION: Treatment of immunotherapy induced hepatitis depends on severity. Immunotherapy can be continued in grade 1, temporarily held in grade 2, and permanently discontinued in grade 3 and 4 as per guidelines. High dose steroids (prednisone 1-2 mg/kg) with tapering serve as the mainstay of treatment. Mycophenolate or azathioprine can be considered in refractory cases. However, it needs further research whether immunotherapy can be re-trialed in patients with grade 3 toxicity, who have responded well to the steroids, and would potentially benefit from a repeat trial.

A sub-chronic Xysmalobium undulatum hepatotoxicity investigation in HepG2/C3A spheroid cultures compared to an in vivo model

Ethnopharmacology relevanceTraditional herbal medicines are utilized by 27 million South Africans. Xysmalobium undulatum (Uzara) is one of the most widely used traditional medicinal plants in Southern Africa. A false belief in the safety of herbal medicine may result in liver injury. Herb-induced liver injury (HILI) range from asymptomatic elevation of liver enzymes, to cirrhosis and in certain instances even acute liver failure. Various in vitro and in vivo models are available for the pre-clinical assessment of drug and herbal hepatotoxicity. However, more reliable and readily available in vitro models are needed, which are capable of bridging the gap between existing models and real human exposure. Three-dimensional (3D) spheroid cultures offer higher physiological relevance, overcoming many of the shortcomings of traditional two-dimensional cell cultures. Aims of this studyThis study investigated the hepatotoxic and anti-prolific effects of the crude X. undulatum aqueous extract during a sub-chronic study (21 days), in both a 3D HepG2/C3A spheroid model and the Sprague Dawley rat model. MethodsHepG2/C3A spheroids were treated with a known hepatotoxin, valproic acid, and crude X. undulatum aqueous extract for 21 days with continuous evaluation of cell viability and proliferation. This was done by evaluating cell spheroid growth, intracellular adenosine triphosphate (ATP) levels and extracellular adenylate kinase (AK). Sprague Dawley rats were treated with the same compounds over 21 days, with evaluation of in vivo toxicity effects on serum chemistry. ResultsThe results from the in vitro study clearly indicated hepatotoxic effects and possible liver damage following treatment with valproic acid, with associated growth inhibition, loss of cell viability and increased cytotoxicity as indicated by reduced intracellular ATP levels and increased AK levels. These results were supported by the increased in vivo levels of AST, ALT and LDH following treatment of the Sprague Dawley rats with valproic acid, indicative of hepatic cellular damage that may result in hepatotoxicity. The in vitro 3D spheroid model was also able to predict the potential concentration dependant hepatotoxicity of the crude X. undulatum aqueous extract. Similarly, the results obtained from the in vivo Sprague Dawley model indicated moderate hepatotoxic potential. ConclusionThe data from both the 3D spheroid model and the Sprague Dawley model were able to indicate the potential concentration dependant hepatotoxicity of the crude X. undulatum aqueous extract. The results obtained from this study also confirmed the ability of the 3D spheroid model to effectively and reliably predict the long-term outcomes of possible hepatotoxicity.

THE NUCLEAR FACTOR OF HEPATOCYTES 1β (HNF1β)–ASSOCIATED DISEASE. CLINIC, DIAGNOSTIC, TREATMENT (LITERATURE REVIEW AND CLINICAL OBSERVATION)

Hepatocyte nuclear factor 1β (HNF1β)-associated disease is a rare autosomal dominant disease caused by various mutations in the HNF1β gene coding the hepatocyte nuclear factor 1β. HNF1β is a transcription factor that is critical for the development of kidney urogenital tract, pancreas, liver, brain, and parathyroid gland. Renal phenotype or HNF1β- nephropathy appeared to be extremely heterogenic: multicystic renal dysplasia, renal hypoplasia, unilateral renal agenesis, horseshoe kidney, atypical familial juvenile hyperuricemic nephropathy, urinary tract malformations and tubular dysfunction. Extrarenal phenotype of HNF1β-associated disease could be maturity-onset diabetes of the young (MODY), pancreatic atrophy and exocrine pancreatic dysfunction, elevated liver enzymes, neonatal cholestasis, congenital abnormalities of the genital tract, hyperparathyroidism, neurological symptoms. The multisystem phenotype makes clinical verification of the diagnosis extremely difficult. In this article, we present a clinical observation of a child with HNF1β – associated disease. The first clinical presentation of HNF1β-associated disease was ultrasound changes in the kidneys (hyperechogenic kidneys?), which were detected by prenatal ultrasonography in pregnancy. Renal ultrasound revealed polycystic kidney disease in the first days of life and bilateral medullary nephrocalcinosis by the age of three. The clinical examination showed a reduced renal function and developed Fanconi syndrome (glycosuria, low molecular proteinuria, hypophosphatemia, aminoaciduria, hyperuricosuria) in the first year of life. Also the child had a non-constant asymptomatic elevation of liver enzymes, hyperparathyroidism, osteoporosis. The diagnosis was confirmed by the results of next generation sequencing which revealed novel heterozygous mutation in exon 4 of the HNF1b gene (chr17: 36091813C>T), p.Cys273Tyr (c.818G>A). The identified mutation was validated by Sanger sequencing. Validation by Sanger sequencing did not reveal a chr17: 36091813C>T mutation in parents, which suggested the appearance of a mutation in the child de novo.

Clinicolaboratory profile of expanded dengue syndrome - Our experience in a teaching hospital.

Introduction:Classic dengue fever presentation has expanded its horizon by involving various organ systems and is named as expanded dengue syndrome. This changing presentation and rising burden across the globe may lead to delayed diagnosis and under reporting of this syndrome.Aim of Study:To analyze clinicolaboratory profile of patients with expanded dengue syndrome.Materials and Methods:About 520 cases of expanded dengue syndrome as per World Health Organization definition criteria 2012 were studied with their informed consent. Detailed history, thorough clinical examination, and relevant investigations were done. Their clinical and laboratory parameters were analyzed. Standard treatment guidelines were followed in all cases.Observation:About 301 patients were male and 219 were female with male-to-female ratio of 3:2. Their age varied from 12 to 76 years with the average age of 47.5 years. About 92% of cases presented with various gastro hepatic manifestations. The commonest gastrohepatic manifestation was transaminitis (57.5%) that is asymptomatic elevation of liver enzymes followed by acalculous cholecystitis (21%) and acute pancreatitis (13.9%). Twenty-nine patients presented with various neurological manifestations. Three patients presented with acute kidney injury and eight patients had coinfection with malaria. Fever with nausea and vomiting was the most common presentation. About 15% of patients presented with bleeding manifestations. About 40.6% of patients presenting as abdominal manifestations had platelet count <20,000/mm3 and needed platelet transfusion versus 9.8% with other system involvement (central nervous system, cardiovascular system (CVS), renal). Hepatomegaly was the most common ultrasonography (USG) finding being present in 57.5% of patients followed by acalculous cholecystitis in 21.3%. Total mortality was 1.9% in our series. We lost eight patients presenting with neurological manifestations and two patients with coinfection with malaria.Conclusion:Atypical presentations should prompt us to investigate for dengue especially during ongoing epidemics so that expanded dengue syndrome can be diagnosed and treated early.

Real-World Lab Data in Natalizumab Treated Multiple Sclerosis Patients Up to 6 Years Long-Term Follow Up.

Natalizumab inhibits the transmigration of immune cells across the blood-brain barrier thus inhibiting inflammation in the central nervous system. Generally, this blockade at the blood-brain barrier has significant influence on the circulating lymphocytes. Up to date, only short-term data on peripheral blood parameters are available which are mostly from controlled clinical trials and not from real-world experience. Real-world lab data of 120 patients diagnosed with highly active disease course of relapsing-remitting multiple sclerosis (RRMS) were analyzed during natalizumab treatment. Patient sampling was performed by consecutive recruitment in the Multiple Sclerosis Center Dresden. Lab testing was performed before and at every third infusion up to 72 months follow-up. After first natalizumab infusion, absolute numbers of all major lymphocyte populations including CD4+ T-cells, CD8+ T-cells, CD19+ B-cells, and NK-cells significantly increased and remained stable during the whole observation period of 72 months. Upon lymphocyte subsets, CD19+ B-cells presented a disproportionate increase up to levels higher than normal level in most of the treated patients. Neutralizing antibodies to natalizumab abrogated the described changes. Intra-individual variation of lymphocytes and its subsets remained in a narrow range for the whole treatment period. CD4/CD8 ratio did not change compared to baseline measurement up to 6 years of natalizumab treatment. Monocytes, eosinophils, and basophils, but not neutrophils persistently increased during natalizumab treatment. Hematological parameters including erythrocyte, platelet count, hemoglobin, and hematocrit remained unchanged compared to baseline. Interestingly, immature precursor cells including erythroblasts were detectable in 36,8% of the treated patients during natalizumab therapy, but not in the pretreatment period. Asymptomatic elevations of liver enzymes were rare, mostly only transient and lower than 3x upper normal limit. Kidney function parameters remained stable within physiological ranges in most patients. CRP levels >20 mg/dl were recognized only in 10 patients during natalizumab therapy and were mostly linked to respiratory tract infections. In our present analysis, we report persistent, but stable increases of peripheral immune cell subtypes in natalizumab treated patients. Additional serological analyses confirm excellent tolerability and safety even 6 years after natalizumab initiation in post-marketing experience.

Wilson's disease or hepatolenticular degeneration

Wilson's disease or hepatolenticular degeneration Abstract. Wilson's disease, or hepatolenticular degeneration, is a rare inherited disorder of copper metabolism. The most common clinical presentations are liver disease and / or neuro-psychiatric manifestations. Pathophysiologically, Wilson's disease is caused by mutations in the ATP7B gene, which lead to defective biliary excretion of copper and subsequent accumulation of copper in the liver and in other organs. Its prevalence is approximately 1:30 000, however its penetrance, clinical presentation and disease severity vary widely, ranging from asymptomatic elevation of liver enzymes to cirrhosis or acute liver failure with or without neuro-psychiatric symptoms. For this reason, Wilson's disease should be suspected and ruled out in cases of indeterminate liver disease or neuropsychiatric disturbances. The diagnostic algorithms are complex and involve clinical tests, ophthalmologic examination (Kayser-Fleischer rings in split-lamp examination), blood and urine tests, genetic testing, imaging and histology. In compensated liver disease, treatment of Wilson's disease by copper depletion (chelators, zinc) is usually effective. In case of liver failure liver transplantation may be needed, which corrects the underlying error of copper metabolism. New drugs with improved efficacy and tolerability are in clinical development.

Disease Modification in Multiple Sclerosis by Flupirtine-Results of a Randomized Placebo Controlled Phase II Trial.

Central nervous system inflammation and neurodegeneration are the pathophysiological hallmarks of multiple sclerosis (MS). While inflammation can readily be targeted by current disease modifying drugs, neurodegeneration is by far less accessible to treatment. Based on suggested additional neuroprotective capacities of the orally available non-opioid and centrally acting analgesic drug flupirtine maleate we hypothesized that treatment with flupirtine maleate might be beneficial in MS patients. The flupirtine as oral treatment in multiple sclerosis (FLORIMS) study was a multi-center, randomized and stratified, placebo-controlled double-blind phase II trial to investigate safety and efficacy in terms of clinical and radiographical activity of flupirtine maleate (300 mg per day) given orally for 12 months, add-on to interferon beta 1b subcutaneously in patients with relapsing remitting MS. Due to a substantial delay in recruitment, enrolment of patients was prematurely terminated after randomization of only 30 of the originally planned 80 patients. Of these, 24 regularly terminated study after 12 months of treatment. Data were analyzed as originally planned. Treatment with flupirtine maleate was overall well tolerated. We observed moderate and asymptomatic elevations of liver enzymes in several cases but no overt hepatotoxicity. Neither the intention to treat nor the per protocol analysis revealed any significant treatment effects of flupirtine maleate with respect to occurrence of MS relapses, disability progression, or development of new lesions on cranial MRI. However, substantial methodological limitations need to be considered when interpreting these results. In conclusion, the results of the FLORIMS study neither add further evidence to nor argue against the hypothesized neuroprotective or disease modifying effects of flupirtine maleate in MS.

Ciprofloxacin—Induced Cholestatic Jaundice in Setting of Chronic Liver Disease

Ciprofloxacin is a frequently prescribed fluoroquinolone antibiotic for its broad—spectrum coverage. It is commonly used for spontaneous bacterial peritonitis (SBP) prophylaxis in patients with cirrhosis. Severe adverse effects associated with its use include tendon rupture, Stevens—Johnson syndrome, interstitial nephritis, and liver injury. Liver injury associated with ciprofloxacin can cause mild asymptomatic elevation of liver enzymes, although rarely it can cause acute liver injury or cholestatic jaundice. We present a case of a 69 year—old male with a past medical history of alcoholic liver cirrhosis diagnosed in 1995, (has been sober since then with stable liver function) who was admitted for evaluation of hyperbilirubinemia reaching 27.4 mg/dl from 0.9 mg/dl in the time span of 5 weeks. 5 weeks back the patient had presented with small bowel obstruction managed by bowel resection and diverting ileostomy, which was complicated by him developing a pelvic abscess. CT scan showed minimal ascites. The abscess was drained by Interventional Radiology, treated with levofloxacin and metronidazole. The patient was discharged on ciprofloxacin daily for spontaneous bacterial peritonitis prophylaxis. Extensive viral and autoimmune panels were negative. Ceruloplasmin levels, transferrin saturation, and a—1 anti—trypsin level were normal. ERCP was unremarkable. Liver biopsy showed established cirrhosis and hepatocytes showed marked intracellular and intracanalicular cholestasis with proliferation along with scattered eosinophils suggesting drug—induced liver injury (DILI). Ciprofloxacin—induced cholestasis was suspected by exclusion, and ciprofloxacin was discontinued with gradual improvement of the bilirubin to 14 mg/dl over a period of 4 weeks. This case demonstrates the potential for cholestasis from ciprofloxacin use. The gradual resolution of liver function after the withdrawal of ciprofloxacin supports the diagnosis. We aim to highlight the increased risk of cholestasis and worsening liver function in patients with chronic liver disease with ciprofloxacin use. Chronic liver disease patients should be closely monitored when prescribed ciprofloxacin, and should be discontinued promptly at the first signs of liver injury.3044_A.tif Figure 1: No Caption available.3044_B.tif Figure 2: High Power showing eosinophils indicating Drug induced Liver Injury.3044_C.tif Figure 3: No Caption available.

Liver injury with drugs used for multiple sclerosis: A contemporary analysis of the FDA Adverse Event Reporting System

Background: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. Objective: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. Methods: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. Results: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12–2.52; and 2.53; 2.40–2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09–1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). Conclusion: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.

Clinical Profile of Diabetic Patients with Liver Dysfunction

The spectrum of clinical disease in fatty liver with steatohepatitis varies from the asymptomatic elevation of liver enzymes to severe liver disease with fibrosis and nodular regeneration. Patients with nonalcoholic steatohepatitis can develop progressive liver disease and complications to the point that they may need liver transplantation.Nonalcoholic steatohepatitis should be considered as a cause for chronically elevated liver enzymes in asymptomatic diabetic patients particularly if they are obese and have hyperlipidemia.This study was carried out among 100 diabetic patients diagnosed to be with hepatic dysfunction attending tertiary care hospital during the study period. Maximum number of patients had diabetic nephropathy (17%), followed by diabetic retinopathy (15%), peripheral neuropathy (11%) and peripheral vascular disease (4%). Neuropathy, Nephropathy, PVD and Retinopathy were present in patients who had diabetes for more than 10 years.