Safety and efficacy of cyclin-dependent kinase inhibitor rechallenge following ribociclib-induced limiting hypertransaminasemia.

Cyclin-dependent kinase inhibitors (CDKIs) and endocrine therapy (ET) are the corner-stone of systemic therapy for patients with hormone-positive (HR+) HER2-negative metastatic breast cancer (MBC). However, limited data exist regarding rechallenge treatment strategies with CDKIs after limiting toxicity. In this report, we provide evidence of the safety and efficacy of sequential treatment with palbociclib or abemaciclib in 6 HR+/HER- MBC patients who experienced grade ≥3 ribociclib-induced hypertransaminasemia. Until results from large observational or randomized studies are communicated, empirical evidence may help make individualized decisions on CDKI rechallenge beyond ribociclib-induced unacceptable liver toxicity.

Interface dermatitis as an indicator of hepatic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS).

BACKGROUND: There are conflicting reports on the association between interface dermatitis and hepatic involvement in DRESS. METHODS: A cross-sectional analysis of the clinical and the histopathologic features of DRESS was performed to study the association between the histopathology of the skin rash and hepatic involvement. RESULTS: The clinical and the histopathologic findings were evaluated in 40 cases of DRESS. Thirty patients (75%) had a hepatic involvement. Thirty (75%) biopsy specimens showed a combination of different inflammatory patterns. The interface dermatitis was noted in 24 specimens (60%). Twenty-one patients with the interface dermatitis had a hepatic involvement (P = .04). CONCLUSIONS: The skin rash of DRESS often shows the coexistence of different inflammatory patterns. The interface dermatitis showed a statistically significant association with the hepatic involvement in DRESS.

Regorafenib induces lethal autophagy arrest by stabilizing PSAT1 in glioblastoma.

GBM (glioblastoma multiforme) is the most common and aggressive brain tumor with no curative options available. Therefore, it is imperative to develop novel potent therapeutic drugs for GBM treatment. Here, we show that regorafenib, an oral multi-kinase inhibitor, exhibits superior therapeutic efficacy over temozolomide, the first-line chemotherapeutic agent for GBM treatment both in vitro and in vivo. Mechanistically, regorafenib directly stabilizes PSAT1 (phosphoserine aminotransferase 1), a critical enzyme for serine synthesis, to trigger PRKAA-dependent autophagy initiation and inhibit RAB11A-mediated autophagosome-lysosome fusion, resulting in lethal autophagy arrest in GBM cells. Maintenance of PSAT1 at a high level is essential for regorafenib-induced GBM suppression. Together, our data provide novel mechanistic insights of regorafenib-induced autophagy arrest and suggest a new paradigm for effective treatment of GBM.Abbreviations: 3-MA: 3-methyladenine; ACACA: acetyl coenzyme A carboxylase alpha; ACTB/ß-actin: actin, beta; AMPK: adenosine monophosphate-activated protein kinase; ATG5: autophagy related 5; CTSD: cathepsin D; DN-: dominant-negative; GBM: glioblastoma multiforme; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PSAT1: phosphoserine aminotransferase 1; SQSTM1/p62: sequestosome 1; TKIs: tyrosine kinase inhibitors.

Local and systemic effects caused by Crotalus durissus terrificus, Crotalus durissus collilineatus, and Crotalus durissus cascavella snake venoms in swiss mice.

INTRODUCTION: Crotalus envenomations cause serious complications and can be fatal without appropriate treatment. Venom isoforms present and inter/intraspecific variations in the venom composition can result in different symptoms presented by bites by snakes from the same species but from different geographical regions. We comparatively evaluated the local and systemic effects caused by Crotalus durissus terrificus (Cdt), C.d. collilineatus (Cdcolli), and C.d. cascavella (Cdcasc) envenomation. METHODS: Venom chromatography was performed. Proteolytic, phospholipase, and LAAO activities were analyzed. Edema, myotoxicity, hepatotoxicity, nephrotoxicity, and coagulation alterations were evaluated. RESULTS: The venom SDS-PAGE analyses found the presence of convulxin, gyroxin, crotoxin, and crotamine in Cdt and Cdcolli venoms. Crotamine was not present in the Cdcasc venom. Cdt, Cdcollli, and Cdcasc venoms had no proteolytic activity. Only Cdcasc and Cdt venoms had phospholipase activity. LAAO activity was observed in Cdcolli and Cdcasc venoms. Cdcolli and Cdcasc venoms caused 36.7% and 13.3% edema increases, respectively. Cdt venom caused a 10% edema induction compared to those by other venoms. All venoms increased TOTAL-CK, MB-CK, and LDH levels (indicating muscle injury) and ALT, AST, GGT, and ALP levels (markers of liver damage) and were able to induce a neuromuscular blockade. Urea and creatinine levels were also altered in both plasma and urine, indicating kidney damage. Only Cdcolli and Cdcasc venoms increased TAPP and TAP. CONCLUSIONS: Together, these results allow us to draw a distinction between local and systemic effects caused by Crotalus subspecies, highlighting the clinical and biochemical effects produced by their respective venoms.

Local and systemic effects caused by Crotalus durissus terrificus, Crotalus durissus collilineatus, and Crotalus durissus cascavella snake venoms in swiss mice

Abstract INTRODUCTION: Crotalus envenomations cause serious complications and can be fatal without appropriate treatment. Venom isoforms present and inter/intraspecific variations in the venom composition can result in different symptoms presented by bites by snakes from the same species but from different geographical regions. We comparatively evaluated the local and systemic effects caused by Crotalus durissus terrificus (Cdt), C.d. collilineatus (Cdcolli), and C.d. cascavella (Cdcasc) envenomation. METHODS: Venom chromatography was performed. Proteolytic, phospholipase, and LAAO activities were analyzed. Edema, myotoxicity, hepatotoxicity, nephrotoxicity, and coagulation alterations were evaluated. RESULTS: The venom SDS-PAGE analyses found the presence of convulxin, gyroxin, crotoxin, and crotamine in Cdt and Cdcolli venoms. Crotamine was not present in the Cdcasc venom. Cdt, Cdcollli, and Cdcasc venoms had no proteolytic activity. Only Cdcasc and Cdt venoms had phospholipase activity. LAAO activity was observed in Cdcolli and Cdcasc venoms. Cdcolli and Cdcasc venoms caused 36.7% and 13.3% edema increases, respectively. Cdt venom caused a 10% edema induction compared to those by other venoms. All venoms increased TOTAL-CK, MB-CK, and LDH levels (indicating muscle injury) and ALT, AST, GGT, and ALP levels (markers of liver damage) and were able to induce a neuromuscular blockade. Urea and creatinine levels were also altered in both plasma and urine, indicating kidney damage. Only Cdcolli and Cdcasc venoms increased TAPP and TAP. CONCLUSIONS: Together, these results allow us to draw a distinction between local and systemic effects caused by Crotalus subspecies, highlighting the clinical and biochemical effects produced by their respective venoms.

Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study.

Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR 47%); transaminase elevations the most frequent lab-abnormality AE (TN 33.3%, RR 30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3% for TN patients (all PRs); median response duration was 21.0 months in RR patients but was not reached for TN patients. Based upon phase 1 efficacy, pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further investigation in a phase 3 study in RR CLL/SLL.

Duvelisib, an oral dual PI3K-δ, γ inhibitor, shows clinical activity in indolent non-Hodgkin lymphoma in a phase 1 study.

Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients). Two dose-limiting toxicities (DLTs), Grade 3 transaminase elevations and Grade 3 rash, occurred at 100 mg BID, and the MTD was determined to be 75 mg BID. Across all doses, 58.1% of iNHL patients had a response (19.4% complete, 35.5% partial, and 3.2% minor); median time to response was 1.84 months and duration of response was 16.9 months. Median progression-free survival was 14.7 months, and the probability of overall survival at 24 months was 71.7%. Severe (Grade ≥ 3) adverse events included elevated liver enzymes (38.7%), diarrhea (25.8%), and neutropenia (29.0%). Three patients, all in the 75 mg BID cohort, experienced fatal AEs: E. coli sepsis, acute respiratory failure, and fungal pneumonia. No iNHL patients experienced Pneumocystis pneumonia. Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high-risk, heavily pretreated, relapsed/refractory iNHL patients, with 25 mg BID selected for further clinical development.

Fragment-based approaches to TB drugs.

Tuberculosis is an infectious disease associated with significant mortality and morbidity worldwide, particularly in developing countries. The rise of antibiotic resistance in Mycobacterium tuberculosis (Mtb) urgently demands the development of new drug leads to tackle resistant strains. Fragment-based methods have recently emerged at the forefront of pharmaceutical development as a means to generate more effective lead structures, via the identification of fragment molecules that form weak but high quality interactions with the target biomolecule and subsequent fragment optimization. This review highlights a number of novel inhibitors of Mtb targets that have been developed through fragment-based approaches in recent years.

Experimental Evolution of Diverse Strains as a Method for the Determination of Biochemical Mechanisms of Action for Novel Pyrrolizidinone Antibiotics.

The continuing rise of multidrug resistant pathogens has made it clear that in the absence of new antibiotics we are moving toward a "postantibiotic" world, in which even routine infections will become increasingly untreatable. There is a clear need for the development of new antibiotics with truly novel mechanisms of action to combat multidrug resistant pathogens. Experimental evolution to resistance can be a useful tactic for the characterization of the biochemical mechanism of action for antibiotics of interest. Herein, we demonstrate that the use of a diverse panel of strains with well-annotated reference genomes improves the success of using experimental evolution to characterize the mechanism of action of a novel pyrrolizidinone antibiotic analog. Importantly, we used experimental evolution under conditions that favor strongly polymorphic populations to adapt a panel of three substantially different Gram-positive species (lab strain Bacillus subtilis and clinical strains methicillin-resistant Staphylococcus aureus MRSA131 and Enterococcus faecalis S613) to produce a sufficiently diverse set of evolutionary outcomes. Comparative whole genome sequencing (WGS) between the susceptible starting strain and the resistant strains was then used to identify the genetic changes within each species in response to the pyrrolizidinone. Taken together, the adaptive response across a range of organisms allowed us to develop a readily testable hypothesis for the mechanism of action of the CJ-16 264 analog. In conjunction with mitochondrial inhibition studies, we were able to elucidate that this novel pyrrolizidinone antibiotic is an electron transport chain (ETC) inhibitor. By studying evolution to resistance in a panel of different species of bacteria, we have developed an enhanced method for the characterization of new lead compounds for the discovery of new mechanisms of action.

Elevation of Kynurenine Metabolites in Rat Liver and Serum: A Potential Additional Mechanism of the Alcohol Aversive and Anti-cancer Effects of Disulfiram?

AIMS: The tryptophan metabolites 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) inhibit the liver mitochondrial low Km aldehyde dehydrogenase and possess alcohol-aversive and immunosuppressant properties. As the disulfiram (DS) metabolite carbon disulphide activates enzymes forming 3-HK and 3-HAA, we investigated if repeated disulfiram treatment increases the hepatic and serum levels of these 2 metabolites. METHODS: Livers and sera of male Wistar rats were analysed for tryptophan and kynurenine metabolites after repeated DS treatment for 7 days. RESULTS: DS increased liver and serum [3-HK] and [3-HAA] possibly by increasing the flux of tryptophan down the hepatic kynurenine pathway and activation of kynurenine hydroxylase and kynureninase. CONCLUSIONS: We provisionally suggest that elevation of some kynurenine metabolites may be an additional mechanism of the alcohol-aversive and anticancer effects of disulfiram.

A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis.

BACKGROUND: Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase. METHODS: We sought to obtain preliminary information on the therapeutic activity and safety of imetelstat in patients with high-risk or intermediate-2-risk myelofibrosis. Imetelstat was administered as a 2-hour intravenous infusion (starting dose, 9.4 mg per kilogram of body weight) every 1 to 3 weeks. The primary end point was the overall response rate, and the secondary end points were adverse events, spleen response, and independence from red-cell transfusions. RESULTS: A total of 33 patients (median age, 67 years) met the eligibility criteria; 48% had received prior JAK inhibitor therapy. A complete or partial remission occurred in 7 patients (21%), with a median duration of response of 18 months (range, 13 to 20+) for complete responses and 10 months (range, 7 to 10+) for partial responses. Bone marrow fibrosis was reversed in all 4 patients who had a complete response, and a molecular response occurred in 3 of the 4 patients. Response rates were 27% among patients with a JAK2 mutation versus 0% among those without a JAK2 mutation (P=0.30) and 32% among patients without an ASXL1 mutation versus 0% among those with an ASXL1 mutation (P=0.07). The rate of complete response was 38% among patients with a mutation in SF3B1 or U2AF1 versus 4% among patients without a mutation in these genes (P=0.04). Responses did not correlate with baseline telomere length. Treatment-related adverse events included grade 4 thrombocytopenia (in 18% of patients), grade 4 neutropenia (in 12%), grade 3 anemia (in 30%), and grade 1 or 2 elevation in levels of total bilirubin (in 12%), alkaline phosphatase (in 21%), and aspartate aminotransferase (in 27%). CONCLUSIONS: Imetelstat was found to be active in patients with myelofibrosis but also had the potential to cause clinically significant myelosuppression. (Funded by Geron; ClinicalTrials.gov number, NCT01731951.).

Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

The present study has been directed to investigate Ursodeoxycholic Acid (UDCA) effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis). This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

Olanzapine-induced triglyceride and aminotransferase elevations without weight gain or hyperglycemia normalized after switching to aripiprazole.

Olanzapine induced a marked elevation in triglyceride and cholesterol levels and in liver transaminase enzymes after 12 weeks of treatment in a patient with schizophrenia. These changes were not seen in an earlier 10-week course of treatment with risperidone, and improved substantially 1 week after the patient stopped olanzapine and began treatment with aripiprazole. The patient did not exhibit weight gain or hyperglycemia with any of the medications. This case and a review of the literature suggest that olanzapine may have unique properties that affect hepatic enzyme pathways, independent of any effects on weight and glucose, that may lead to hyperlipidemia and transaminitis in some patients.

Good tolerability, long-term survival and easy management of side effects in a patient with metastatic renal cell carcinoma treated with pazopanib.

In recent years many new agents have been introduced into clinical practice to treat metastatic renal cell carcinoma. Some of these agents are tyrosine kinase inhibitors, which have different adverse events compared to chemotherapy or immunotherapy. We describe the case of a man treated with pazopanib as first-line therapy for metastatic disease, demonstrating the efficacy, good tolerability and easy management of some side effects of this tyrosine kinase inhibitor. The patient, who presented with lung metastases, started therapy in November 2012 and was alive and in continuous response at the time of writing (November 2014). We controlled the elevation of transaminase levels with low-dose corticosteroid administration. The patient had no other significant adverse events (apart from dysgeusia and grade 1 diarrhea), he had good quality of life, and his performance status throughout the treatment was very good (ECOG 0).

Hepatotoxicity evaluation of aqueous extract from Scutia buxifolia.

Nowadays there is an increase in the number of people taking herbals worldwide. Scutia buxifolia is used for the treatment of hypertension, but little is known about its action on liver. Thirty-two Wistar rats were divided into four groups: control and groups treated during 30 days with 100, 200 and 400 mg of lyophilized aqueous extract of S. buxifolia (SBSB)/kg of body weight. This study was planned to explore hepatotoxic effect of SBSB, which was assessed by serum transaminases (ALT and AST). Thiobarbituric acid reactive substances (TBARS) levels were determined in liver, along with thiols content (NPSH), catalase (CAT) activity and, superoxide dismutase (SOD) enzymes. Histopathological studies of liver tissue were performed. Flavonoids and phenolics were quantified in SBSB by high performance liquid chromatography with diode array detection (HPLC/DAD). We did not observe alterations on redox status (TBARS, NPSH, CAT and, SOD) in the control and experimental groups. An increase on AST activity was only observed at 200 mg of SBSB, whereas ALT score was not affected by SBSB. Moreover, no morphological alterations were observed on the hepatocytes, matching the analysed biochemical parameters. This way, we conclude that SBSB was not toxic.

Ursodeoxycholyl lysophosphatidylethanolamide improves steatosis and inflammation in murine models of nonalcoholic fatty liver disease.

UNLABELLED: Hepatic fat accumulation and changes in lipid composition are hallmarks of nonalcoholic fatty liver disease (NAFLD). As an experimental approach for treatment of NAFLD, we synthesized the bile acid-phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). Previous work demonstrated profound hepatoprotective properties of the conjugate in vitro and in vivo. Here we investigated the effects of UDCA-LPE in two nutritional mouse models of NAFLD. C57BL/6 mice were fed a high-fat diet (HFD) for 28 weeks, resulting in steatosis with hyperlipidemia. In a second model, mice received a methionin-choline-deficient (MCD) diet for up to 11 weeks, which induced advanced nonalcoholic steatohepatitis (NASH). Establishment of liver injury was followed by intraperitoneal injections of 30 mg/kg UDCA-LPE three times a week for different time periods. UDCA-LPE ameliorated both HFD- and MCD-induced increases in alanine aminotransferase (ALT) values near to normalization. As for metabolic parameters, UDCA-LPE reduced elevated serum triglyceride and cholesterol values in HFD mice. Liver histology showed improvement of steatosis in HFD and MCD mice concomitant with reductions in hepatic triglyceride and cholesterol levels. Additionally, the conjugate lowered serum caspase-8 activity in both models and decreased lipid hydroperoxides in MCD mice. Abundance of proinflammatory lysophosphatidylcholine (LPC), which was detectable in both HFD and MCD mice, was reduced by UDCA-LPE. Quantitative reverse transcriptase-polymerase chain reaction qRT-PCR of liver specimens revealed that UDCA-LPE strongly down-regulated inflammatory genes and modified the expression of genes involved in lipid metabolism. CONCLUSION: The current study demonstrates that UDCA-LPE improves hepatic injury at different stages of NAFLD. By concurrently lowering hepatic lipid overloading as well as susceptibility of hepatocytes toward inflammatory stimuli, the conjugate may be able to ameliorate disease progression. Thus, UDCA-LPE represents a promising compound suitable for the treatment of NAFLD.

Management of marked liver enzyme increase during olanzapine treatment: a case report and review of the literature.

OBJECTIVES: Atypical antipsychotics commonly cause isolated asymptomatic increase in the aminotransferase levels. Furthermore, the strategy in the choice of antipsychotic agent must take into account hepatic tolerance because of the non-negligible incidence of liver disorders among the psychiatric population. The aim of this article is to better understand the strategy to adopt during an increase of liver enzymes in a psychotic patient under atypical neuroleptic treatment. METHOD: A clinical case is presented of a female patient treated for psychotic decompensation with increase of liver enzymes (Olanzapine). Her treatment was changed several times over a period of 7 years and laboratory investigations were conducted simultaneously. RESULTS: It seems that the increase of liver enzymes is slightly more frequent with Clozapine and Olanzapine than Risperidone, Perazine and Haloperiol. CONCLUSION: The different mechanisms of hepatotoxicity are unknown at present but it seems that the hypersensibility mechanism is likely to be dose dependent. During an increase of enzymes, it is important to combine a control of hepatic enzymes with a reduction of neuroleptic dosage. Discontinuation should be considered if a continued increase of enzymes above certain values is shown or if a clinical symptom appears. We note also that some risk factors were found, including geriatric or pedopsychiatric age, obesity, and association with active ingredients or addictive substances responsible for hepatic disorders.

Lindane-induced biochemical perturbations in rat serum and attenuation by omega-3 and Nigella sativa seed oil.

Lindane (gamma-hexachlorocyclohexane, gamma-HCH), a highly persistent organochlorine insecticide is neurotoxic at acute doses and has been reported to induce oxidative stress in cells and tissues. In this study, we investigated the antioxidant property of Nigella sativa seed oil (N.O) and omega-3 polyunsaturated fatty acids (omega3) against gamma-HCH-induced oxidative hepatic and renal damage in male rats serum. Rats were orally given sublethal dose of gamma-HCH (12 mg/kg, 24 h prior to decapitation), while N.O (0.3 ml/kg) and omega3 (20 mg/kg) were given every 48 h for 20 days single or together, or also combined with gamma-HCH. gamma-HCH caused a significant increase in the levels of serum total lipids, cholesterol, and triglycerides by 49, 61 and 30% respectively, while HDL-cholesterol decreased by 45% compared to control group. Pretreatment with omega3 and N.O prior gamma-HCH administration re-established the altered biochemical features and alleviated the harmful effects of gamma-HCH on lipid profile. The concentration of serum total protein and albumin was significantly decreased by 35 and 45% respectively in rats treated with gamma-HCH compared to control. gamma-HCH also caused hepatic and renal damage, as observed from the elevated serum levels of urea, creatinine, total bilirubin and uric acid contents and aminotransferases (AST and ALT), phosphatases (ACP and ALP) and lactate dehydrogenase (LDH) activities. Co-administration of omega3 and N.O reversed the hazardous effects induced by gamma-HCH on the liver and kidney and also protected acetylcholinesterase from the inhibitory action of gamma-HCH as well as suppressed the lipid peroxidation. Thus, the results show that omega3 and N.O might prevent oxidative stress and attenuate the changes in the biochemical parameters induced by gamma-HCH in male rats.

Liver function tests and statins.

PURPOSE OF REVIEW: To discuss recent data on statins in patients with elevated liver tests. RECENT FINDINGS: As a result of the obesity epidemic in Western societies, conditions associated with metabolic syndrome are increasing, including nonalcoholic fatty liver disease (NAFLD). Because most patients with metabolic syndrome have indications for statins, clinicians will be confronted with prescribing statins to patients with elevated liver tests. Statins are associated with elevations in aminotransferases in up to 3% of treated patients, but statins rarely lead to serious drug-induced liver injury (DILI), chronic liver disease, or acute liver failure. Data have emerged demonstrating that not only are statins well tolerated to use in most patients with elevated liver tests but also they may have a beneficial therapeutic effect in treating the underlying liver disease. Studies demonstrate that statins may increase response rates of antiviral therapy for hepatitis C. In a study of 437 patients with moderate elevations in baseline aminotransferases, patients on statins were more likely to have a decline in aminotransferases compared with untreated patients. SUMMARY: Data support using statins in patients with elevated liver tests, especially patients with NAFLD, who may be at particularly high risk for cardiovascular disease.