Clinical characteristics and risk factors of liver injury in COVID-19: a retrospective cohort study from Wuhan, China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly become a major international public health concern. This study was designed to evaluate the clinical characteristics and risk factors of COVID-19-associated liver injury. METHODS: A fraction of 657 COVID-19 patients were retrospectively analyzed. Clinical and laboratory data were derived from electronic medical records and compared between patients with or without liver injury. Multivariate logistic regression method was used to analyze the risk factors for liver injury. RESULTS: Among 657 patients, 303 (46.1%) patients had liver injury with higher rate in severe/critically ill patients [148/257 (57.6%)] than those in moderate cases [155/400 (38.8%)]. The incidence of liver injury was much higher in male [192/303 (63.4%)] than female [111/303 (36.6%)], and in severe/critical patients [148/303 (48.8%)] with percutaneous oxygen saturation ≤ 93% [89/279 (31.9%)] or peak body temperature ≥ 38.5 °C [185/301 (61.5%)] on admission. Liver injury-related inflammations included increased white blood cells, neutrophils and decreased lymphocytes. More patients with liver injury than without had increased serum IL-2R, TNFα, ferritin, hsCRP, PCT, ESR, γ-GT, and LDH. Multivariate regression analysis revealed that increasing odds of liver injury were related to male, higher serum hsCRP (≥ 10 mg/L), and neutrophil-to-lymphocyte ratio (NLR) (≥ 5). Moreover, more deceased patients (14/82 (17%)) had significantly elevated serum TBIL than discharged patients [25/532 (4.7%)]. CONCLUSION: Liver injury is a common complication in COVID-19 patients. The potential risk factors of liver injury include male, hsCRP and NLR score. A close monitor of liver function should be warned in COVID-19 patients, especially in severe/critical individuals.

Liver damage at admission is an independent prognostic factor for COVID-19.

OBJECTIVE: Abnormal liver function is a common form of extra-pulmonary organ damage in patients with coronavirus disease 2019 (COVID-19). Patients with severe COVID-19 have a higher probability and progression of liver injury than those without severe disease. We aimed to evaluate the prognosis of liver injury in patients with COVID-19. METHODS: We retrospectively included 502 patients with laboratory-confirmed SARS-CoV-2 infection. Clinical features and survival of patients with and without liver injury were compared. Cox proportional hazards models were used to determine the variables that might have an effect on survival. RESULTS: Among the 502 patients enrolled, 301 patients had abnormal liver function with increased neutrophil count, C-reactive protein, creatinine, troponin I (TnI), D-dimer, lactose dehydrogenase and creatine kinase. Patients with abnormal liver functions had a higher mortality rate (28.9% vs 9.0%, P < 0.001), a higher ratio of male sex (65.1% vs 40.8%, P < 0.001) and a higher chance of developing systemic inflammatory response syndrome (53.5% vs 41.3%, P = 0.007). Among patients with abnormal liver functions, patients with grade 2 liver damage (with both abnormal alanine aminotransferase or aspartate aminotransferase levels and abnormal alkaline phosphatase or gamma-glutamyl transpeptidase levels) had a higher ratio of male patients, elevated neutrophil count, procalcitonin, D-dimer levels and mortality rate. Multivariate Cox regression analyses suggested that the grade of liver damage (hazard ratio: 1.377, 95% confidence interval: 1.000-1.896, P = 0.049) was an independent predictor of death. CONCLUSIONS: Patients with COVID-19 and abnormal liver functions have a higher mortality than those with normal liver functions. Liver damage is an independent prognostic factor of COVID-19.

Biochemical recovery from exertional heat stroke follows a 16-day time course.

BACKGROUND: The aim of this study was to characterize the time-resolved progression of clinical laboratory disturbances days-following an exertional heat stroke (EHS). Currently, normalization of organ injury clinical biomarker values is the primary indicator of EHS recovery. However, an archetypical biochemical recovery profile following EHS has not been established. METHODS: We performed a retrospective analysis of EHS patient records in US military personnel from 2008-2014 using the Military Health System Data Repository (MDR). We focused on commonly reported clinical laboratory analytes measured on the day of injury and all proceeding follow-up visits. RESULTS: Over the prescribed period, there were 2,529 EHS episodes treated at 250 unique treatment locations. Laboratory results, including a standardized set of blood, serum and urine assays, were analyzed from 0-340 days following the initial injury. Indicators of acute kidney injury, including serum electrolyte disturbances and abnormal urinalysis findings, were most prevalent on the day of the injury but normalized within 24-48hours (creatinine, blood urea nitrogen, and blood and protein in urine). Muscle damage and liver function-associated markers peaked 0-4 days after injury and persisted outside their respective reference ranges for 2-16 days (alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, myoglobin, prothrombin time). CONCLUSION: Biochemical recovery from EHS spans a 16-day time course, and markers of end-organ damage exhibit distinct patterns over this period. This analysis underscores the prognostic value of each clinical laboratory analyte and will assist in evaluating EHS patient presentation, injury severity and physiological recovery.

The Effects of Special Patient Population Plasma on Pharmacokinetic Quantifications Using LC-MS/MS.

BACKGROUND: Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations. METHODS: EMA and FDA bioanalytical method validation guidance have recommended studying matrix effects on quantitation if samples from special patient populations are to be analyzed. In addition to lesinurad (plasma protein binding 98.2%), the matrix effects from special population plasma on the quantitation of verapamil (PPB 89.6%), allopurinol and oxypurinol (PPB negligible) were also investigated. RESULTS: The plasma from special population patients had no matrix effects on the three quantification methods with stable isotope labeled internal standard, protein precipitation extraction, and LC-MS/MS detection. The validated lesinurad plasma quantification method was successfully applied for the pharmacokinetic evaluations to support the clinical studies in renal impaired patients. CONCLUSION: Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations.

A Phase 1 Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Patients With Hepatic Impairment and Healthy Matched Controls.

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection. Liver disease is a major cause of morbidity and mortality in HIV-infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30-mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least-squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50-1.06) for AUC0-∞ , 0.69 (0.51-0.93) for Cmax , 1.40 (0.80-2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82-2.94) for CU at 24 hours, 2.14 (1.57-2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14-3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment.

Selective Associations of Recent Low Concentrations of Perfluoroalkyl Substances With Liver Function Biomarkers: NHANES 2011 to 2014 Data on US Adults Aged ≥20 Years.

OBJECTIVE: Perfluoroalkyl substances (PFAS) and liver function biomarkers were reexamined for relatively lower serum concentrations of PFAS observed in recent years. METHODS: National Health and Nutrition Examination Survey 2011 to 2014 data were analyzed for obese and nonobese participants for serum perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA) as well as four liver function biomarkers in risk-adjusted analysis. RESULTS: Among obese participants only, alanine aminotransferase (ALT) was positively associated with PFOA (ß = 0.07065, P < 0.01), PFHxS (ß = 0.051349, P < 0.01), and with PFNA (ß = 0.072742, P < 0.01). PFOA (ß = 0.07422, P = 0.03) and PFNA (ß = 0.077995, P < 0.01) were associated with gamma glutamyl transferase (GGT) in obese participants. CONCLUSIONS: Recent lower levels of PFOA, PFHxS, and PFNA are associated with higher serum liver functions but only among obese participants. The findings are consistent with PFAS animal toxicology concerning steatosis.

Pharmacokinetic Analysis of Propofol Target-Controlled Infusion Models in Chinese Patients with Hepatic Insufficiency.

BACKGROUND Effects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency. MATERIAL AND METHODS We assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 µg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software. RESULTS In the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained. CONCLUSIONS Propofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.

Effects of Intrinsic Factors on the Clinical Pharmacokinetics of Vortioxetine.

Vortioxetine is an antidepressant agent with multimodal activity that is approved for the treatment of major depressive disorder at doses of 5 to 20 mg once daily. Vortioxetine is a medium-clearance drug that undergoes extensive metabolism via several cytochrome P450 isozymes. A series of single- and multiple-dose pharmacokinetic studies were performed to evaluate the impact of intrinsic (ie, subject-related) factors, such as age, sex, race, and renal and hepatic function, on the pharmacokinetics of vortioxetine. The point estimates on the ratios and their 90% confidence intervals (CIs) for the central values of AUC (area under the concentration-time curve) and Cmax (maximum plasma concentration) were obtained by taking the antilog of the differences and 90%CIs in the log-transformed least-squares means. The results demonstrate that there were no clinically meaningful differences (defined as exposure difference between 50% and 2-fold change) in the exposure to vortioxetine (as assessed by AUC and Cmax ) between elderly and younger subjects, men and women, and blacks and whites and among subjects with varying degrees of renal or hepatic impairment. These results suggest that no dosing adjustments of vortioxetine are required for the intrinsic factors investigated in these studies.

Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment.

BACKGROUND: The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients. METHODS: In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis]. RESULTS: In the phase I study, plasma exposures (area under the concentration-time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration-time curve over the 24-h dosing interval; AUCtau) was similar and sofosbuvir exposures were higher (~ 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant. CONCLUSIONS: No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.

[Predictors of hepatic insufficiency in obstructive jaundice]. / Prediktory pechenochnoi nedostatochnosti pri mekhanicheskoi zheltukhe.

AIM: To develop predictive model for hepatic insufficiency in obstructive jaundice. MATERIAL AND METHODS: Obstructive jaundice was modeled by the author's method on 48 mini pigs, while morpho-functional features of erythrocytes were studied by using of INTEGRA Aura atomic force microscope (NT-MDT, Zelenograd, Russia). Histological specimens were stained with hematoxylin and eosin. Discriminant analysis was used to create predictive model for hepatic insufficiency. RESULTS: Mathematical model of hepatic insufficiency prediction has been developed. Sensitivity and specificity of this model were 94.1% and 74.2% respectively. Total percentage of correct predictions was 81.3%. CONCLUSION: Severe obstructive jaundice contributes erythrocyte's transformation from biconcave to dome-shaped followed by changes of its physical properties. Erythrocyte's volume and activity of cytolysis enzymes are the most informative to predict hepatic insufficiency. Our model allows us to diagnose this complication at early stages and to correct pre-, intra- and postoperative therapy.

Agrimonia eupatoria L. (Agrimony) Extract Alters Liver Health in Subjects with Elevated Alanine Transaminase Levels: A Controlled, Randomized, and Double-Blind Trial.

Agrimonia eupatoria L. has been shown to protect against liver injury due to its lipid lowering and antioxidant activities. The aim of this research was to evaluate the effect of A. eupatoria L. aqueous extract (AEE) on 80 subjects with elevated alanine transaminase (ALT) levels in a randomized, double-blind, placebo-controlled, 8-week study. This trial was conducted between January 2013 and July 2013 at the Oriental Medical Hospital (Jecheon) of Semyung University. The trial included subjects aged 20 years or older who were diagnosed with mildly to moderately elevated ALT levels (between 45 and 135 IU/L). Subjects received two capsules of placebo or AEE twice a day for 8 weeks. Adverse events were recorded. Eighty subjects were randomized to placebo or AEE groups who had similar baseline characteristics. During the 8 weeks of treatment, 11 subjects were excluded from the analysis for protocol violation or consent withdrawal; efficacy of treatment was, therefore, evaluated in 69 subjects (placebo = 35, AEE = 34). The AEE group showed a significant reduction in ALT and serum triglyceride (TG) at 8 weeks compared with the placebo group (ALT P = .044, TG P = .020). Significant group and time interactions were found in ALT (P = .038), aspartate aminotransferase (P = .040), and TG (P = .010). Alkaline phosphatase, total bilirubin, and gamma-glutamyl transferase levels were not different between the two groups. There were no reported severe adverse events during this study, and total protein, albumin, blood urea nitrogen, creatine, and total cholesterol levels were normal in both groups. AEE consumption was safe and generally well tolerated without severe adverse events.

Troponin-T as a biomarker in neonates with perinatal asphyxia.

BACKGROUND: Troponin-T is a commonly used cardiac biomarker, which could be useful in perinatal asphyxia. We aimed to analyze troponin-T concentrations in asphyxiated neonates and to correlate the concentrations with clinical outcomes. METHODS: Data were collected from electronic medical records of neonates diagnosed with perinatal asphyxia over a period of four years. RESULTS: There were 63 neonates with moderate to severe encephalopathy, in whom serial troponin-T concentrations had been done on days 1, 3, and 7. 53 (84%) asphyxiated infants had troponin-T concentration >100 pg/ml at 2-4 h of life.The difference in troponin-T concentrations between moderate and severe encephalopathy was not statistically significant (173 vs. 263 pg/ml, p value 0.40). The difference in the concentrations at 72 hours between cooled and non-cooled neonates was not significant (48.5 vs. 62.5 pg/ml, p value 0.22). Troponin-T concentration was significantly higher in babies with hypotensive shock and hepatic injury, but not acute kidney injury. There was no significant correlation between troponin-T and the extent of resuscitation needed.Troponin-T concentration on day 1 of life was significantly higher in babies who died than who survived (407 vs. 168 pg/ml, p value 0.03). ROC curve for troponin-T to predict mortality had an area under the curve (AUC) of 0.803; the best cut-off value (190 pg/ml) had 82% sensitivity and 80% specificity. CONCLUSION: There was no significant difference in troponin-T concentrations between cooled and non-cooled neonates. Troponin-T concentration had a good predictive accuracy for mortality before discharge.

Preoperative Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Perioperative Liver-Related Complications Following Liver Resection for Colorectal Cancer Metastases.

BACKGROUND AND AIMS: There are limited data on the potential role of preoperative non-invasive markers, specifically the aspartate-to-alanine aminotransferase ratio and the aspartate aminotransferase-to-platelet ratio index, in predicting perioperative liver-related complications after hepatectomy for colorectal cancer metastases. METHODS: Patients undergoing liver resection for colorectal cancer metastases in a European institution during 2003-2010 were retrospectively enrolled. Relevant data, such as neoadjuvant chemotherapy, preoperative liver function tests, and perioperative complications, were collected from medical records. The nontumorous liver parenchyma in the surgical specimens of 31 patients was re-evaluated. RESULTS: Overall, 215 patients were included. In total, 40% underwent neoadjuvant chemotherapy and 47% major resection, while 47% had perioperative complications (6% liver-related). In multivariate regression analysis, the aspartate aminotransferase-to-platelet ratio index was independently associated with liver-related complications (odds ratio: 1.149, p = 0.003) and perioperative liver failure (odds ratio: 1.155, p = 0.012). The latter was also true in the subcohort of patients with neoadjuvant chemotherapy (odds ratio: 1.157, p = 0.004) but not in those without such therapy (p = 0.062). The aspartate-to-alanine aminotransferase ratio was not related to liver-related complications (p = 0.929). The area under the receiver operating characteristics curve for the aspartate aminotransferase-to-platelet ratio index as a predictor of liver-related complications was 0.857 (p = 0.008) in patients with neoadjuvant chemotherapy. Increasing aspartate aminotransferase-to-platelet ratio index was observed with an increase in degrees of sinusoidal obstruction syndrome (p = 0.01) but not for fibrosis (p = 0.175) or steatosis (p = 0.173) in the nontumorous liver in surgical specimens. CONCLUSION: The preoperative aspartate aminotransferase-to-platelet ratio index, but not the aspartate-to-alanine aminotransferase ratio, predicts perioperative liver-related complications following hepatectomy due to colorectal cancer metastases, in particular after neoadjuvant chemotherapy. The aspartate aminotransferase-to-platelet ratio index is related to sinusoidal obstruction syndrome in the nontumorous liver.

Biomarkers of hepatic injury and function in neonatal hypoxic ischemic encephalopathy and with therapeutic hypothermia.

Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p < 0.001). Infants treated with TH had lower peak alanine aminotransferase (ALT) concentrations (p = 0.025) and a delay in reaching peak CRP concentration (p < 0.001). CONCLUSION: We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury. What is Known: • Ischemic hepatic injury occurs frequently as a part of multiorgan dysfunction in infants with hypoxic ischemic encephalopathy (HIE). • The neuroprotective role of therapeutic hypothermia in management of infants with HIE is well recognized, but the potential hepato-protective effects of hypothermia are unclear. What is New/What this study adds: • Therapeutic hypothermia was associated with lower alanine aminotransferase and albumin concentrations and a delayed C-reactive protein (CRP) response and so may have the potential to modulate hepatic injury. • An elevated CRP concentration during the first postnatal week may be regarded as an expected finding in moderate and severe HIE and, in the overwhelming majority of cases, occurs secondary to hepatic hypoxia-ischemia in the absence of blood culture-positive sepsis.

Prevalence of elevated liver enzymes in adults with type 1 diabetes: A multicentre analysis of the German/Austrian DPV database.

AIMS: To assess the prevalence of elevated liver enzymes in adults with type 1 diabetes mellitus (T1DM) in routine clinical care and the association with cardiovascular risk profile in the Diabetes-Prospective-Documentation (DPV) network in Germany and Austria. SUBJECTS AND METHODS: This cross sectional observational study from the DPV registry includes data from 45 519 adults with T1DM at 478 centres up to September 2016. Liver enzyme measurements were available in 9226 (29%) patients at 270 centres and were analysed for increased alanine aminotransferase (ALT; men >50 U/L, women >35U/L) and/or aspartate aminotransferase (AST; men >50 U/L, women >35U/L) and/or gamma-glutamyltransferase (GGT; men >60U/L, women >40 U/L). A subgroup analysis in patients for whom 2 or more ALT measurements were available (n = 2335, 25%) and whose ALT was increased at least twice (men >30 U/L, women >19U/L) was performed. Associations with glycaemic control, cardiovascular risk factors and late complications were investigated with multiple regression analyses. RESULTS: Twenty percent (19.8%, n = 1824) had increased liver enzyme(s) on one or more occasions. Increased liver enzymes were associated with worse glycaemic control and higher BMI (both P < .0001), dyslipidemia (OR, 1.75; 95% CI, 1.54-2.0), hypertension (OR, 1.48; 95% CI: 1.31-1.68), myocardial infarction (OR, 1.49; 95% CI, 1.17-1.91) and end stage renal disease (OR, 1.59; 95% CI, 1.17-2.17). ALT was increased twice in 29% and was associated with worse glycaemic control (P < .0001), higher BMI (P < .0001), hypertension (OR, 1.58; 95% CI, 1.26-1.97) and dyslipidemia (OR, 1.89; 95% CI, 1.51-2.37). CONCLUSIONS: In this clinical audit in adults with T1DM, elevated liver enzymes on routine assessment were associated with a less favourable cardiovascular risk profile and with poorer glycaemic control.

Effects of subchronic extremely low-frequency electromagnetic field exposure on biochemical parameters in rats.

The objective of the present study was to systematically determine the effects of 50 Hertz (Hz) magnetic fields (MFs) on biochemical parameters in rats. Sixty-four adult (5 weeks old, 140-165 g) male Sprague-Dawley rats were randomly divided into four groups: sham, 20 µTesla (µT), 100 µT, and 500 µT 50 Hz MF ( n = 16 in each group). The rats in the MF groups were exposed for 2 h daily for up to 4 weeks. Under these experimental conditions, body weight, organ coefficients, biochemical parameters (blood lipids, myocardial enzymes, liver function, and renal function) were measured. We found that 50 Hz MFs had no significant effects on growth or on the majority of blood biochemical parameters, with the exception of creatinine and cholesterol. However, the changes in creatinine and cholesterol were relatively small and unlikely to be clinically relevant.

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study
.

OBJECTIVE: To assess the pharmacokinetics (PK), safety, and tolerability of siponimod and major metabolites in subjects with mild, moderate, and severe hepatic impairment (HI) compared with demographically-matched healthy subjects (HS). METHODS: This open-label, parallel-group study enrolled 40 subjects (each HI group, n = 8; HS group, n = 16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by those with moderate and severe HI. All subjects received single oral doses of 0.25 mg siponimod on day 1; PK and safety data were collected during the 21-day follow-up. RESULTS: All subjects had similar baseline characteristics and completed the study. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in the mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2- to 5-fold increase, particularly in the moderate and severe HI groups vs HS. There were no clinically-relevant safety findings. CONCLUSIONS: Single oral doses of 0.25 mg siponimod were well tolerated, and HI did not significantly alter exposure to siponimod. Increase in the M3 and M5 metabolites requires further evaluation. These results do not warrant any dose adjustments of siponimod in subjects with HI.
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Parenteral fish oil and liver function tests in hospitalized adult patients receiving parenteral nutrition: A propensity score-matched analysis.

BACKGROUND & AIMS: Intravenous fat emulsions are associated with liver disease and there is some evidence that the administration of intravenous fish oil (FO) may be useful in reversing it. The aim of our study was to assess whether there are differences in the changes of liver function tests (LFTs) in hospitalized adult patients with parenteral nutrition (PN) with FO and vegetal lipids vs patients without FO. The secondary aim was to study the relationship between impaired LFT and FO. METHODS: This was a 4-year, propensity score-matched analysis including patients aged ≥18 years treated with PN for ≥10 days. The exclusion criteria were previous liver disease, biliary disorders or pancreatic cancer, and altered initial LFT values. Patients were classified into 2 groups: FO cohort (patients who received FO - in addition to vegetal oil - after the first week of PN) and the vegetal oil cohort (patients who received only vegetal oil). A propensity score matched cohort design was developed. Univariate analyses were used to study the changes in LFTs. To evaluate whether LFT alterations vary with FO administration, four stepwise multiple linear regression models were conducted. RESULTS: 52 patients were included, 52% men, median 66 (55-75) years and 69 kg (61.7-78.8), with 18.5 (14-31.8) days of PN treatment. Maximum FO supplementation was 23%. During the first week with PN (none of the groups receiving FO), gammaglutamyl transferase (GGT), alkaline phosphatase (AP) and total bilirubin (BIL) increased significantly. Comparing LFT values at seven days of PN with at the end of PN treatment, the univariate analysis showed a better response for the FO group. The group without FO showed a significant increase for GGT and AP. In multivariate models, the percentage of FO administered was associated with a decrease in GGT, B = -0.33 [CI 95% = -0.54/-0.12], in AP, B = -0.12 [CI 95% = -0.20/-0.03] and ALT, B = -0.12 [CI 95% = -0.21/-0.024]. CONCLUSIONS: Lipid composition plays a significant role in LFT alteration associated with PN, and FO intravenous lipid emulsions (ILEs) minimize disturbance of LFTs in hospitalized adult patients.

Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis.

BACKGROUND AND AIMS: Vitamin D deficiency is frequent in patients with cirrhosis. The aims of this study were to evaluate the relation of vitamin D status to portal hypertension, degree of liver dysfunction and survival. METHODS: Patients with cirrhosis who have been tested for 25-OH-vitamin D levels were retrospectively included. Vitamin D deficiency was defined as 25-OH-vitamin D levels <10 ng/ml. Child-Pugh score, model for end-stage liver disease (MELD) and available hepatic venous pressure gradient (HVPG) were recorded. Mortality was documented during follow-up. RESULTS: A total of 199 patients were included. Prevalence of vitamin D deficiency (<10 ng/ml) was 40% (79/199), with 14% in Child-Pugh stage A, 39% in Child-Pugh stage B and 47% in Child-Pugh stage C (p = 0.001). Vitamin D deficiency was more common in patients with clinically significant portal hypertension (CSPH, HVPG ≥ 10 mm Hg) than in patients without (43.5% vs. 24.4%, p = 0.025). Significantly more deaths were observed in patients with vitamin D deficiency (32.9%, 26/79 vs. 13.3%, 16/120; p = 0.001). COX regression found presence of hepatocellular carcinoma (p < 0.001; HR: 5.763 95%CI:2.183-15.213), presence of CSPH (p = 0.026; HR: 5.487 95%CI: 1.226-24.55) and Child-Pugh stage C (p = 0.003; HR:5.429 95%CI: 1.771-16.638) as independent risk factors for mortality. Furthermore we could show a tendency towards group vitamin D deficiency being an independent risk factor (p = 0.060; HR: 1.86 95%CI:0.974-3.552). CONCLUSIONS: Vitamin D levels progressively decrease in more advanced Child stages and in patients with increasing HVPG. Vitamin D deficiency might be a valuable predictor of mortality in cirrhosis.