Maximum Alanine Aminotransferase Research Articles

Abstract 7094: Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations

Abstract AZD4573 is a highly potent and selective Cyclin-Dependent Kinase 9 inhibitor. The AZD4573 First-in-Human (FIH) study revealed variable alanine transaminase (ALT) and/or bilirubin elevation and a clear correlation to dose or PK exposure could not be defined. While concurrent ALT elevation ≥3x upper limit of normal (ULN) and bilirubin elevation ≥2x ULN (potential Hy’s law) is a biochemical finding indicating potential drug-induced liver injury, quantitative modeling disconnected ALT and bilirubin elevation demonstrating that the observations were not Hy’s Law cases. Furthermore, we implemented a targeted metabolomics workflow to investigate the ALT and bilirubin elevation mechanism and identify predictive biomarkers to better understand and/or predict any hepatic stress liabilities associated with AZD4573 clinical development. We implemented an established metabolomics methodology to 359 samples from 15 patients yielding 47,000 total data points. Data was separated into 98 different dosing intervals from the 15 patients to identify the ALT and bilirubin-associated metabolic changes conserved across all patients while incorporating metabolic differences in individual patents with ALT and bilirubin elevation in only a fraction of multiple doses. Orthogonal Partial Least Squares modeling identified several metabolites and pathways altered as a function of maximum ALT or bilirubin levels. Post-dose conjugated bile acids were elevated when ALT and bilirubin were elevated. Pre-dose creatine levels were decreased when ALT and bilirubin elevation occurred, and pre-dose glutamate levels were elevated when ALT elevation occurred. Pre-dose decreased total carnitines and kynurenine pathway activation were observed when ALT and bilirubin elevation occurred, but the effect did not reach statistical significance. Elevated bile acids are an established characteristic of cholestasis and suggest cholestasis as a probable mechanism for AZD4573-induced reversible liver stress. Interestingly, decreased creatine, glutamate elevation, decreased total carnitine, and kynurenine pathway activation are all associated with some form of liver stress or disfunction which may explain the irregular ALT and bilirubin elevations observed in patients receiving AZD4573; while ALT itself is a biomarker of liver damage, these pre-dose biochemical changes may illuminate potential preceding liver stress. Dosing patients already experiencing higher liver stress levels may be more susceptible to drug-induced ALT and bilirubin elevation, and patients with increasing in-study liver stress may only present at later doses. This work demonstrates metabolomics utility to elucidate possible mechanisms of liver toxicity as well as to identify potential predictive biomarkers for further investigation to explore individual patient risk in clinical studies. Citation Format: John K. Meissen, Kevin Contrepois, Sophie Regan, Jennifer Tan, Alison J. Foster, Jiaqi Yuan, Shringi Sharma, Dominic Williams, Anton I. Rosenbaum. Clinical metabolomics reveals baseline biomarkers of hepatic dysfunction correlating with irregular drug-induced ALT and bilirubin elevations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7094.

Characterizing a Cohort of Patients with Hemophilia B Treated with Fidanacogene Elaparvovec from the Phase 3 Benegene-2 Study Who Returned to Factor IX Prophylaxis

Background: Fidanacogene elaparvovec (PF-06838435, formerly SPK-9001) is an adeno-associated virus (AAV)-based gene therapy designed to deliver a high-activity human factor IX (FIX) variant transgene, FIX-R338L, resulting in endogenous FIX production in people with hemophilia B. To date, 45 participants with moderately severe to severe (FIX:C ≤2%) hemophilia B have received fidanacogene elaparvovec as part of the ongoing phase 3 study, BENEGENE-2 (NCT03861273). Of these 45 participants, 6 returned to prophylaxis (RTP) of FIX after initially responding to treatment. We describe the characteristics of the RTP participants. Methods: Participants with baseline FIX activity ≤2% received a single dose of 5e11 vg/kg fidanacogene elaparvovec (AAVrh74 variant) as part of the phase 3 study (N=45). Participants suspended prophylaxis following vector infusion (1 participant continued for 2 weeks post infusion), which could be resumed per the investigator's discretion and the protocol provided guidance for when to consider resuming prophylaxis: ≥2 consecutive central laboratory FIX activity levels ≤2% at least 2 weeks apart and/or ≥2 spontaneous joints bleeds within 4 weeks and/or ≥3 spontaneous bleeds overall (joint and non-joint). Results: Prior to fidanacogene elaparvovec infusion, all 45 participants had completed at least 6 months of prophylaxis as part of the lead-in study (BENEGENE-1, NCT03587116). The mean age (range) of all 45 study participants was 33.2 y (18-62) and the 6 RTP participants had a mean age (range) of 28.3 y (18-47), of whom 4 were <30 y old. The region, race, and weight of the 6 RTP participants were representative of the entire study population (Table 1). All RTP participants initially responded to gene therapy and achieved peak FIX activity levels >5%, determined by one-stage actin-FSL (7-22.1%) and one-stage Synthasil (18.3-45.5%) across Days 36-97. Time to RTP from fidanacogene elaparvovec dose ranged from Days 155 to 623. The reasons reported for RTP were low FIX activity in 5 participants, of whom 1 had a prior history of intracerebral hemorrhage, and increased bleeds in 1 participant. Five participants recorded ≥1 bleeding event prior to resumption of prophylaxis. All RTP participants were treated with ≥1 course of corticosteroids for presumed cellular immune response. In all cases, maximum alanine aminotransferase was 1-2x upper limit of normal. Two RTP participants had an ELISPOT drawn within ±1 day of starting corticosteroids; both were negative for capsid peptides (Table 2). In comparison, 4 participants who took corticosteroids but did not resume prophylaxis were positive for capsid. All 6 RTP participants had a decline in FIX activity from peak levels in the absence of inhibitors, but displayed variable decline prior to and during corticosteroid treatment, or after completion of corticosteroid wean, with and without some elevation of liver enzyme at the time of the decline. Conclusion: The 6 RTP participants who received fidanacogene elaparvovec in the phase 3 study (BENEGENE-2) initially responded to therapy before a heterogenous decline in FIX activity. The limited number of participants and lack of consistent patterns and demographic features make identifying predictors of potential RTP challenging. Although all RTP participants were treated with corticosteroids during this study, not all participants treated with corticosteroids RTP of FIX. Predictors of loss of response have not been identified and further work is ongoing to potentially identify factors associated with increased risk of RTP.

Low Spontaneous Clearance Rates of Recently Acquired Hepatitis C Virus in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men (PROBE-C Study).

Using direct-acting antivirals (DAAs) for recently acquired hepatitis C virus (RAHCV) infections, particularly in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), dramatically reduced the incidence of hepatitis C. However, implementation into clinical practice is challenging. The aim of this study was to analyze spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC. The PROBE-C study is an observational European cohort on RAHCV infections in HIV-positive MSM. Between 2007 and 2017, RAHCV infections were documented with ≥12 months of follow-up. Fisher exact, χ2, and Mann-Whitney U tests were used for statistical analysis. A total of 464 RAHCV infections were documented; 457 of 464 patients (98%) were male, and the median age (interquartile range [IQR]) was 41 (38-46) years. The main risk group for hepatitis C virus (HCV) transmission was MSM (98.9%). Most participants were infected with HCV genotype 1 (78.3%). The median baseline HCV RNA level (IQR) was 230 000 (135 000-474 432) IU/mL, and the median CD4+ T-cell count was 574/µL (547-604/µL. Of all cases, 92% received combination antiretroviral therapy, with 91% showing suppressed HIV RNA levels (<200 copies/mL). The median maximum alanine aminotransferase level (IQR) was 445 (402-522) U/L. SC of RAHCV infection occurred in 55 of 464 cases (11.9%). A >2-log decline in HCV RNA levels 4 weeks after diagnosis of RAHCV infection was the strongest predictor of SC (P < .001; sensitivity, 96.4%; specificity, 97.5%; positive predictive value, 84.1%; negative predictive value, 99.5%). SC of RAHCV in HIV-positive MSM is found in only 11.9% of cases and a <2-log drop in HCV RNA level at week 4 after diagnosis should prompt early DAA-based treatment. However, immediate DAA treatment for RAHCV infection may also be favored in patients with ongoing transmission risk behavior.

Term Infant with Bilateral Parenchymal Brain Hemorrhages.

Term Infant with Bilateral Parenchymal Brain Hemorrhages.

P062 COVID-19 hyperinflammation can be predicted using routine clinical laboratory markers

Abstract Background/Aims Since early in the COVID-19 pandemic, there has been interest in the concept that some morbidity and mortality may be due to excessive inflammation. Several definitions of COVID-19 hyperinflammation (COV-HI) have been proposed, including Manson criteria (C-reactive protein, CRP ≥150mg/L or doubling above 50mg/L in 24 hours and/or ferritin 1500ug/L); and Webb criteria (includes CRP ≥150mg/L or ferritin ≥750ug/L). A consistent finding has been worse outcomes. Little is known regarding the underlying pathologies separating these patients from others. Aim To investigate whether machine learning using standard laboratory features can identify a distinguishing ‘COV-HI signature’. Methods A database of daily clinical and laboratory features was collected from 611 patients admitted to hospital with confirmed COVID-19 during the first wave of community-acquired infection at University College London Hospitals, Sheffield Teaching Hospitals, Newcastle upon Tyne Hospitals and Royal Wolverhampton. All data prior to mechanical ventilation were interrogated. Patients were categorised as COV-HI based on Webb thresholds (CRP &amp;gt;150 mg/L or ferritin ≥750ug/L). Laboratory features (peak or nadir depending on recognised predictors of illness severity) included: minimum lymphocyte count 10^9/L; minimum monocyte count 10^9/L; minimum haemoglobin g/dL, minimum albumin g/L; maximum neutrophils count 10^9/L; maximum alanine aminotransferase IU/L; maximum platelet count 10^9/L and maximum creatinine μmol/L. The data were analysed using unsupervised clustering and supervised machine learning models (logistic regression, support vector machine, decision trees, random forest classification (RF), naïve bayes and k-nearest neighbours) using Orange 3.29.1 software. Results 463 patients had sufficient data to determine Cov-HI status: 361 met COV-Hi definition at any point pre- ventilation during admission (median age 71, 65.93% male), 102 patients did not (median age 73, 51% male). In keeping with our previous work, COV-HI was associated with increased mortality (p &amp;lt; 0.0001), Odds ratio 3.506 (CI 1.871-6.916), relative risk 2.708 (CI 1.600-4.734). Multiple logistic regression revealed no significant relationship between sex and mortality (p 0.6673, Male Odds ratio 0.90). Unsupervised hierarchical clustering using laboratory features identified two clusters: Cluster-1, comprising 72.8% patients without hyperinflammation; and Cluster-2, comprising 73.3% COV-HI. Supervised machine learning models were tested using the same features. All models predicted COV-HI with good accuracy; the RF model performed best (area under the curve 0.818, classification accuracy 0.803, F1 0.79, Precision 0.85, Recall 0.74) and identified maximum neutrophil count and minimum albumin level as the most important features contributing to the classification. Conclusion Patients with hyperinflammation defined by CRP and ferritin thresholds share other global derangements in laboratory markers, suggesting shared pathology. Outcomes are less good in this patient group. The importance of neutrophils to the models is consistent with an association with COVID-19 disease severity and the possible contribution of neutrophil extracellular traps to pathology, while albumin is a known marker of inflammation. Disclosure M. Hutchinson: None. R. Tattersall: None. E.C. Jury: None. E. Hawkins: None. J. Manson: None.

Dreigend leverfalen en ernstige hypoglykemie bij een jonge vrouw met anorexia nervosa

Impending liver failure and severe hypoglycemia in a young woman with anorexia nervosa Anorexia nervosa (AN) is a complex psychosomatic disease that may lead to life-threatening conditions such as acute liver failure and hypoglycemia. This article discusses the case of a 28-year-old woman with a BMI (weight/length2) of 10.6 kg/m2 who presented generally unwell to the emergency department with diffuse abdominal cramps. During her hospitalization, she repeatedly developed a profound hypoglycemia (which was associated with a significant decline in the level of consciousness). She also showed a significant increase of her transaminases to a maximum alanine aminotransferase (ALT) of 1,219 U/L and a maximum aspartate aminotransferase (AST) of 512 U/L. Enteral feeding was gradually started, resulting in both the prevention of another episode of hypoglycemia and normalisation of the transaminases. Mildly elevated liver enzymes are frequent in AN. A rise of ALT/AST, however, only occurs in patients with a very low BMI and is a sign of impending liver failure. Most likely, this is caused by autophagy-induced hepatitis, although this remains a subject of debate. Severe AST/ALT abnormalities are associated with the development of a profound hypoglycemia due to impairment of the gluconeogenesis and the limited reserve of glycogen in the hepatocytes. Both impending liver failure and hypoglycemia can best be treated by supervised nutritional rehabilitation.

Outcome of Living-Donor Liver Transplantation Using Grafts from Donors Treated for Fatty Liver.

BackgroundThe aim of this study was to determine the efficacy of treating donors’ fatty liver (FL) and to assess early graft function in recipients who received treated FL grafts in living-donor liver transplantation (LDLT).Material/MethodsData were collected for adult-to-adult LDLTs. Donors diagnosed with FL (FL group) received diet–exercise and pharmacological treatment. The perioperative findings and early transplanted graft function were compared with those of donors without FL (non-FL group) during the same period.ResultsOf 30 donors, 8 were determined to have FL. The median duration of treatment for FL was 58 days. The liver-to-spleen attenuation ratios on CT scan in the FL group were significantly improved after treatment: 0.95 (0.62–1.06) to 1.2 (1.12–1.46) (P=0.003). Liver biopsy prior to donor surgery showed ≤10% fatty infiltration. Postoperative laboratory findings of the donors in the FL group were comparable to those in the non-FL group: maximum alanine transaminase (189.6±94.7 IU/L vs. 196.8±57.4) and maximum total bilirubin (2.2±1.1 mg/dL vs. 1.7±0.5 mg/dL). No major complications were observed after donor hepatectomy in either group. There were no significant differences between the 2 groups in early graft function, as evaluated by laboratory data, ascites volume, and bile production 2 weeks postoperatively. Graft and patient survival were 100% in both groups at 3 months.ConclusionsPreoperative intentional treatment for FL was effective. Early graft function and donor postoperative course were comparable in the 2 groups. These results suggest that well-treated steatotic grafts can be used without jeopardizing donor safety.

Spontaneous Fluctuations in Liver Biochemistries in Patients with Compensated NASH Cirrhosis: Implications for Drug Hepatotoxicity Monitoring.

Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed.

Preoperative 5-aminolevulinic acid administration for brain tumor surgery is associated with an increase in postoperative liver enzymes: a retrospective cohort study.

Besides 5-aminolevulinic acid (5-ALA), liver enzyme elevation after brain tumor surgery can be caused by anesthesia and medications. In this retrospective study, we determined whether preoperative 5-ALA administration is associated with postoperative elevation of liver enzymes (PELE) in brain tumor patients and identified predictive factors for PELE in patients treated with 5-ALA. In 179 patients undergoing brain tumor surgery with preoperative normal values of liver enzymes, laboratory data on serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and total bilirubin (T.bil) levels were collected preoperatively and through postoperative day (POD) 45. Ninety-nine PELEs (ALT, 56; AST, 34; ALP, 5; and TB, 4) were observed in 62 (34.6%) patients. Four (4.2%) patients treated with 5-ALA showed grade 3 elevation of transaminases based on the Common Terminology Criteria for Adverse Effects. Preoperative 5-ALA treatment was predictive of PELE (odds ratio [95% confidence interval], 2.30 [1.14-4.67]; P = 0.021). In patients treated with 5-ALA (n = 95), 70 PELEs (ALT, 39; AST, 22; ALP, 5; and TB, 4) were observed in 41 (43.2%) patients and significant predictive factors for PELE were preoperative ALT level (1.10 [1.04-1.17]; P = 0.001) and body mass index (BMI, 1.29 [1.08-1.56]; P = 0.006). In patients treated with 5-ALA, 13 and 36 patients, of 39 patients whose maximum postoperative ALT levels > 40U/L, showed the normal value of serum ALT on PODs 14 and 45, respectively. Only three patients showed ALT elevation > 40U/L on PODs 15-45, with a downward trend. The use of 5-ALA for brain tumor surgery in patients with preoperative normal values of liver enzymes was associated with increased transient PELE, but a low incidence of severely elevated liver transaminases levels. When 5-ALA is administered to patients with the upper normal value of preoperative serum ALT and overweight, attention is paid to PELE.

Single nucleotide polymorphisms associated with elevated alanine aminotransferase in patients receiving asunaprevir plus daclatasvir combination therapy for chronic hepatitis C.

AimsDrug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy.MethodsSubjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected.ResultsAmong the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2–4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023).ConclusionsCYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.

Indices of muscle and liver dysfunction after surviving hemorrhage and prolonged hypotension.

This study determined the long-term effects of prolonged hypotension (PH) on liver, muscle, and kidney dysfunction. The hypothesis was that longer duration of PH after hemorrhage will result in greater organ dysfunction. Baboons were sedated and hemorrhaged (30% blood volume). Systolic blood pressure greater than 80 mm Hg was maintained for 1 hour (1 hr-PH; n = 5), 2 hours (2 hr-PH; n = 5), or 3 hours (3 hr-PH; n = 5). After PH, hemorrhage volume was replaced. Animals were recovered and monitored for 21 days. Control animals were hemorrhaged and immediately resuscitated (0 hr-PH, n = 3). Data are Mean ± Standard Deviation, and analyzed by 2-way repeated measures ANOVA and Holm-Sidak test. Hemorrhage resulted in mild hypotension. Minimal resuscitation was required during the hypotensive phase, and survival rate was 100%. Significant increases (p < 0.001) in alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase, and lactate dehydrogenase occurred on Day 1 after PH, and were significantly greater (p < 0.001) in the 2 hr- and 3 hr-PH groups than the 0 hr-PH group. Maximum alanine aminotransferase levels (U/L) were 140 ± 56 (0 hr-PH), 170 ± 130 (1 hr-PH), 322 ± 241 (2 hr-PH), and 387 ± 167 (3 hr-PH). Maximum aspartate aminotransferase levels (U/L) were 218 ± 44 (0 hr-PH), 354 ± 219 (1 hr-PH), 515 ± 424 (2 hr-PH), and 711 ± 278 (3 hr-PH). Maximum creatine phosphokinase values (U/L) were 7834 ± 3681 (0 hr-PH), 24336 ± 22268 (1 hr-PH), 50494 ± 67653 (2 hr-PH), and 59857 ± 32408 (3 hr-PH). Maximum lactic acid dehydrogenase values (U/L) were 890 ± 396 (0 hr-PH), 2055 ± 1520 (1 hr-PH), 3992 ± 4895 (2 hr-PH), and 4771 ± 1884 (3 hr-PH). Plasma creatinine and blood urea nitrogen were unaffected by PH (p > 0.10). These results indicate that PH up to 3 hours in duration results in transient liver and muscle dysfunction that was most severe after 2 hr-PH and 3 hr-PH. Prolonged hypotension produced minimal effects on the kidney. Basic science research, Level of evidence not required for basic science research.

Indices of Organ Damage after Surviving Hemorrhage and Prolonged Hypotension

BACKGROUNDHypotensive resuscitation to raise systolic pressure to 80–90 mm Hg is the standard of care on the battlefield for hemorrhaging Soldiers, and is maintained until the casualty is transported to a surgical unit usually within one hour of injury. Prompt evacuations may not be possible in future conflicts, and hypotension will be required for longer periods of time. This study determined the long‐term effects of prolonged hypotension (PH) held for 0, 1, 2 and 3 hours on kidney, liver and muscle damage up to 21 days after PH, and tested the hypothesis that longer duration of hypotension after hemorrhage will result in greater organ damage.METHODSMale baboons were anesthetized and hemorrhaged until systolic blood pressure was 70 mmHg for 10 min. Systolic blood pressure of greater than 80 mm Hg with autologous blood was maintained for 1 hour (1hr PH; n=5), 2 hours (2hr PH; n=5), or 3 hours (3hr PH; n=5) hours. After the PH period, the hemorrhage volume of whole blood was replaced, and the animal was recovered and monitored for 21 days. Control animals were anesthetized, hemorrhaged and immediately resuscitated with hemorrhaged blood (0hr PH, n=3). Blood samples were obtained before and 1, 3, 7, 14 and 21 days after PH, and analyzed for blood chemistry profile. Data were analyzed with 2 way repeated measures ANOVA and Holm‐Sidak test, and expressed as Mean ± Standard Deviation.RESULTSPlasma creatinine and blood urea nitrogen were unaffected by PH and remained within normal limits in all PH groups. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine phosphokinase (CPK), and lactate dehydrogenase (LDH) values were significantly elevated after PH (time effect; P&lt;0.001; PH group effect; P=0.3). Maximum ALT levels were observed on Day 1 after PH in 0hr PH (140 ± 56 U/L), 1hr PH (170 ± 130 U/L), 2hr PH (322 ± 241 U/L), and 3hr PH (387 ± 167 U/L). Maximum AST levels were observed on Day 1 after PH in 0hr PH (218 ± 44 U/L), 1hr PH (354 ± 219 U/L), 2hr PH (515 ± 424 U/L), and 3hr PH (711 ± 278U/L). Maximum CPK values were observed on Day 1 after PH in 0hr PH (7834 ± 3681 U/L), 1hr PH (24336 ± 22268 U/L), 2hr PH (50494 ± 67653 U/L), and 3hr PH (59857 ± 32408 U/L). Maximum LDH values were observed on Day 1 after PH in 0hr PH (890 ± 396 U/L), 1hr PH (2055 ± 1520 U/L), 2hr PH (3992 ± 4895 U/L), and 3hr PH (4771 ± 1884 U/L). Max levels of ALT, AST, CPK, and LDH were positively correlated with the duration of PH (P&lt;0.05). All values returned to pre‐PH levels by 21 days after PH.CONCLUSIONSThese results indicate that PH up to 3 hours in duration results in transient liver and muscle damage that is correlated with the duration of PH in male baboons. PH of any duration produced minimal effects on the kidney. More studies are needed to determine if longer periods of PH result in permanent and more extensive organ damage.Support or Funding InformationThis study was funded by the United States Army, Medical Research and Materiel CommandThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Clinico-etiological profile of raised aminotransferases in hospitalized children with liver disease and correlation with their severity level

Objective: The aim of this study was to analyze the clinico-etiological profile of raised aminotransferases in children with their severity level. Materials and Methods: We retrospectively analyzed 65 admitted children aged 1 month to 18 years with raised aminotransferases levels from January 2015 to July 2015. We divided them into three groups based on more liver specific, alanine aminotransferase (ALT) levels as mild (1-3 times of normal), moderate (3-20 times of normal), and severe if ALT ?20 times. Results: Total 65 children were retrospectively studied with a mean age of 72±52 months (range 1 month - 18 years), and male: Female ratio of 1.5/1. These patients were divided into three groups on the basis of their maximum ALT levels. Average levels of deranged ALT (mean±standard deviation) in mild, moderate, and severe groups were 78.8±27, 289±153, and 1938±861 IU/L, respectively. Out of 65 children, the clinical presentation was acute hepatitis in 35 (53%), acute liver failure in 15 (23%), acute on chronic liver failure in 7, and chronic liver disease in 8 patients. The etiologies were acute infective hepatitis in 41% (27) followed by metabolic in 15% (10), extra hepatic obstruction (7), autoimmune hepatitis (5), ischemic causes (7), neonatal hepatitis (2), hemophagocytic lymphohistiocytosis (HLH) (2), drug induced (2), cryptogenic (2), and diabetic ketoacidosis (1). Mild elevation of aminotransferases (n=17) was most commonly seen in metabolic liver disease (35%) followed by biliary tract obstruction (28%). Moderate elevation of aminotransferases levels (n=24) was seen in acute infective (29%) followed by metabolic liver disease (16%). In patients with severe elevations (n=24), the most common etiological diagnosis was acute infective hepatitis in (70%) followed by ischemic hepatitis (20%). The most common cause of acute infective hepatitis was acute viral hepatitis A. Conclusion: On the correlation of raised ALT with etiology, we suggest that severity grading of deranged aminotransferases can guide toward etiological diagnosis and narrow down the specific investigation required. Thus, it may help in early diagnosis and cost-effective management.

Elevated Preoperative Serum Bilirubin Improves Reperfusion Injury and Survival Postliver Transplantation.

BackgroundThe cytoprotective effects of hemeoxygenase-1 and its product biliverdin/bilirubin are widely acknowledged in experimental transplant medicine. However, its potentially beneficial effect during organ reperfusion is not established.MethodsIn a matched study, we compared markers of reperfusion injury (alanine aminotransferase/aspartate aminotransferase) and transplantation outcome (complication rates, liver function, and survival) between recipient groups with “normal” versus “increased” preoperative bilirubin values. Groups were matched for donor and recipient age, liver disease, year of transplantation, and recipient’s preoperative condition (modified model for end-stage liver disease score excluding bilirubin).ResultsThe postoperative transaminase peak was significantly higher when comparing the “normal” to the “increased” bilirubin group (maximum aspartate aminotransferase “normal” 2013 [325-13 210] U/L vs “increased” 1360 [221-15 460] U/L, P = 0.006; maximum alanine aminotransferase “normal” 1151 [82-6595] U/L vs “increased” 820 [66-5382] U/L, P = 0.01). Grafts in the “increased” bilirubin group had faster recovery of graft function with faster decrease in international normalized ratio at days 3 and 7 posttransplantation in the “increased” vs “normal” bilirubin group. Although long-term functional parameters (international normalized ratio and bilirubin posttransplantation) as well as surgical and biliary complication rates were similar in both groups, 1-year survival rates were significantly higher in the group with increased preoperative bilirubin (graft survival, “normal” 86% vs “increased” 97%; P = 0.006).ConclusionsIncreased bilirubin levels of liver graft recipients before transplantation are associated with reduced reperfusion injury and improved survival after transplantation.

Investigation of liver dysfunction: who should we test for hepatitis E?

Hepatitis E virus (HEV) is endemic in developed countries, but unrecognized infection is common. Many national guidelines now recommend HEV testing in patients with acute hepatitis irrespective of travel history. The biochemical definition of 'hepatitis' that best predicts HEV infection has not been established. This study aimed to determine parameters of liver biochemistry that should prompt testing for acute HEV. This was a retrospective study of serial liver function tests (LFTs) in cases of acute HEV (n=74) and three comparator groups: common bile duct stones (CBD, n=87), drug-induced liver injury (DILI, n=69) and patients testing negative for HEV (n=530). To identify the most discriminating parameters, LFTs from HEV cases, CBD and DILI were compared. Optimal LFT cutoffs for HEV testing were determined from HEV true positives and HEV true negatives using receiver operating characteristic curve analysis. Compared with CBD and DILI, HEV cases had a significantly higher maximum alanine aminotransferase (ALT) (P<0.001) and ALT/alkaline phosphatase (ALKP) ratio (P<0.001). For HEV cases/patients testing negative for HEV, area under receiver operating characteristic curve was 0.805 for ALT (P<0.001) and 0.749 for the ALT/ALKP ratio (P<0.001). Using an ALT of at least 300 IU/l to prompt HEV testing has a sensitivity of 98.6% and a specificity of 30.3% compared with an ALT/ALKP ratio higher than or equal to 2 (sensitivity 100%, specificity 9.4%). Patients with ALT higher than or equal to 300 IU/l should be tested for HEV. This is simple, detects nearly all cases and requires fewer samples to be tested than an ALT/ALKP ratio higher than or equal to 2. Where clinically indicated, patients with an ALT less than 300 IU/l should also be tested, particularly if HEV-associated neurological injury is suspected.

Risk factors for elevated liver enzymes during refeeding of severely malnourished patients with eating disorders: a retrospective cohort study.

BackgroundThere are few previous reports regarding the cause and evolution of liver injury in patients with anorexia nervosa (AN) during the refeeding process, and its management remains controversial. This study aimed to determine the risk factors for elevated liver enzymes during refeeding and their effect on the therapeutic process in severely malnourished patients with eating disorders.MethodsIn a retrospective cohort study of 167 female inpatients in a single hospital from January 2004 to March 2015, 67 who had normal alanine aminotransferase (ALT) levels on admission were divided into two groups according to the presence or absence of elevated ALT levels during refeeding, and then compared.ResultsThe median age and body mass index (BMI) of the patients on admission were 22 [interquartile range (IQR), 16–33] years and 12.2 (IQR, 11.1–13.0) kg/m2, respectively. Compared with their cohorts, significantly more patients in the early onset age group (<15 years old) had elevated ALT levels during refeeding (67% vs. 33%, p = 0.033), as did patients with longer median time to nadir BMI (3.0 vs. 0 days, p = 0.03). In addition, onset age [odds ratio (OR): 0.274; 95% confidence interval (CI): 0.077–0.981; p = 0.047] and time to nadir BMI (OR: 1.271; 95% CI: 1.035–1.56; p = 0.022) were significantly associated with the odds of elevated ALT levels during refeeding.ConclusionsThe results of this study suggest that early age at onset may be a potential risk factor for elevated ALT levels during refeeding in severely malnourished patients with eating disorders. Furthermore, elevated ALT levels during refeeding were significantly associated with delay in the start of weight gain. No significant relationship was found between the amount of initial prescribed calories and elevated ALT levels during refeeding. The median time to maximum ALT was 27 (IQR, 21–38) days after the refeeding process started.Electronic supplementary materialThe online version of this article (doi:10.1186/s40337-016-0127-x) contains supplementary material, which is available to authorized users.

Results of the TOP Study: Prospectively Randomized Multicenter Trial of an Ex Vivo Tacrolimus Rinse Before Transplantation in EDC Livers.

BackgroundOrgan shortage results in the transplantation of extended donor criteria (EDC) livers which is associated with increased ischemia-reperfusion injury (IRI). Experimental studies indicate that an organ rinse with the calcineurin inhibitor tacrolimus before implantation protects against IRI. The tacrolimus organ perfusion study was initiated to examine the effects of ex vivo tacrolimus perfusion on IRI in transplantation of EDC livers.MethodsA prospective randomized multicenter trial comparing ex vivo perfusion of marginal liver grafts (≥2 EDC according to Eurotransplant manual) with tacrolimus (20 ng/mL) or histidine-tryptophane-ketoglutarate solution (control) was carried out at 5 German liver transplant centers (Munich Ludwig-Maximilians University, Berlin, Heidelberg, Mainz, Regensburg) between October 2011 and July 2013. Primary endpoint was the maximum alanine transaminase (ALT) level within 48 hours after transplantation. Secondary endpoints were aspartate transaminase (AST), prothrombine ratio, and graft-patient survival within an observation period of 1 week. After an interim analysis, the study was terminated by the scientific committee after the treatment of 24 patients (tacrolimus n = 11, Control n = 13).ResultsTacrolimus rinse did not reduce postoperative ALT peaks compared with control (P = 0.207; tacrolimus: median, 812; range, 362-3403 vs control: median, 652; range, 147-2034). Moreover, ALT (P = 0.100), prothrombine ratio (P = 0.553), and bilirubin (P = 0.815) did not differ between the groups. AST was higher in patients treated with tacrolimus (P = 0.011). Survival was comparable in both groups (P > 0.05).ConclusionsContrary to experimental findings, tacrolimus rinse failed to improve the primary endpoint of the study (ALT). Because 1 secondary endpoint (AST) was even higher in the intervention group, the study was terminated prematurely. Thus, tacrolimus rinse cannot be recommended in transplantation of EDC livers.

Tacrolimus therapy causes hepatotoxicity in patients with a history of liver disease.

Tacrolimus is known to have little hepatotoxicity. Nevertheless, a few case studies have shown liver toxicities of tacrolimus, particularly in patients on multiple medications. This study is a retrospective data analysis on the potential of tacrolimus hepatotoxicity. A data analysis was conducted on the electronic medical records (EMRs) of 2,462 Korean patients taking tacrolimus or cyclosporine from 2002 through to 2008. Alanine aminotransferase (ALT) and total bilirubin level (TBL) were also monitored. The maximum ALT, time to reach ALTmax (TALTmax), and TBL(ALTmax) were compared between the tacrolimus and cyclosporine groups. Other possible factors that may aggravate liver function were also investigated. ALTmax and TBL(ALTmax) were higher in the tacrolimus group compared to the cyclosporine group (i.e., 50 IU/L vs. 41 IU/L and 1 mg/dL vs. 0.9 mg/dL, respectively), and TALTmax was shorter (i.e., 101 days vs. 142 days) in the tacrolimus group. In addition, the frequency of ALTmax > 3x upper limit of normal (ULN) (i.e., ALTmax > 120) was significantly increased in the tacrolimus group compared to the cyclosporine group (30% vs. 21%). The severity of tacrolimusinduced liver damage was greater in patients with history of liver disease, as indicated by > two-fold greater ALTmax than that of cyclosporine (i.e., 153 IU/L vs. 65 IU/L). Moreover, the ALTmax was significantly lowered by switching from tacrolimus to cyclosporine in patients with a history of liver disease. In patients with preexisting renal disease, neither tacrolimus nor cyclosporine showed any effect on ALTmax. Results indicate that tacrolimus may have a higher risk of inducing liver injury in Korean patients with a history of liver disease and may require close monitoring.

Chronic hepatitis B virus infection in children and adolescents in Japan.

Hepatitis B e antigen (HBeAg) seroconversion is an important event in patients with chronic hepatitis B virus (HBV) infection. This study aimed to clarify the outcome of long-term follow-up of chronic HBV infection and the factors affecting HBeAg seroconversion in children in Japan. Patients who were first examined at our institution between 1980 and 2012, who were <20 years of age at the time of this initial visit, and who were positive for hepatitis B surface antigen for at least 6 months were identified retrospectively. Sex, age at diagnosis, HBV genotype, maximum serum alanine aminotransferase (ALT) level, occurrence of hepatitis flare-ups (yes/no), and transmission route were evaluated to identify the predictors of HBeAg seroconversion. A total of 205 children with chronic HBV were enrolled. Among them, 192 were positive for HBeAg upon diagnosis of chronic HBV infection. Out of this group, 95 (49%) achieved HBeAg seroconversion and 43 (21%) received treatment during the follow-up period. Only the maximum serum ALT level was significantly associated with the achievement of HBeAg seroconversion by multivariate analysis (P < 0.05). Kaplan-Meier analysis showed that the median times to HBeAg seroconversion (50% achievement of HBeAg seroconversion) of the treated and untreated children were 10.2 and 12.0 years, respectively. The cumulative proportion of HBeAg seroconversion was significantly higher in the treated children than in the untreated children (P = 0.02). A higher serum ALT level was a predictor for HBeAg seroconversion. Antiviral treatment could accelerate the achievement of HBeAg seroconversion in HBV-infected children.

Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study.

Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.