Increased Alanine Aminotransferase Levels Research Articles

Interferon γ-induced protein 10 kinetics in treatment-naive versus treatment-experienced patients receiving interferon-free therapy for hepatitis C virus infection: implications for the innate immune response.

We measured interferon γ-induced protein 10 (IP-10) levels in 428 patients at baseline, week 1, and week 2 of all-oral treatment for hepatitis C virus (HCV) infection. An increased baseline IP-10 level was associated with a T allele in the IL28B gene, an increased alanine aminotransferase level in treatment-naive but not experienced patients, and an increased body mass index. At week 1, the mean decline in plasma IP-10 levels was the same in treatment-naive and treatment-experienced patients (-49%), whereas during week 2 the mean decline in IP-10 levels in treatment-naive patients (-14%) was significantly larger than in treatment-experienced patients (-2%; P = .0176). IP-10 thus may be a surrogate marker of the rate of intracellular viral replication complex decay.

Administration of phospholipase D1 inhibitor attenuates aminoacetophenone-induced acute liver injury (CAM5P.245)

Abstract A phospholipase D1 (PLD1)-selective inhibitor, N-[2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-1-methylethyl]-2-naphthalenecarboxamide, strongly blocked aminoacetophenone-induced acute liver injury. Administration of 500 mg/kg aminoacetophenone strongly increased alanine transaminase levels in serum, which was markedly decreased by PLD1 inhibitor administration in a dose-dependent manner, showing almost complete inhibition by 4 mg/kg of the inhibitor. During the pathological progress of acute liver injury, GSH levels are decreased, which is recovered by the administration of PLD1 inhibitor. JNK mediates aminoacetophenone-induced oxidative stress and liver injury. PLD1 inhibitor administration strongly blocked JNK phosphorylation in aminoacetophenone-induced acute liver injury model. Several inflammatory cytokines including TNF-α, IFN-γ, CCL2, and IL-1β were strongly increased from liver in aminoacetophenone-induced acute liver injury, which were also markedly decreased by PLD1 inhibitor administration. Taken together, the results indicate that the PLD1 inhibitor strongly show therapeutic effects reverse the progression of acute liver injury, and PLD1 can be regarded as an important target molecule to develop therapeutic agents against acute liver injury.

Abstract 30: Body Mass Index Is Associated With Markers Of Inflammation And Liver Damage Among Healthy Adolescents

Objectives: Obesity is the main cause of non-alcoholic fatty liver disease. Clinical studies reported that adolescent obesity is also associated with elevated levels of inflammatory markers and liver enzymes. However, it is unclear whether adolescents’ body mass index (BMI) within the normal range is associated with inflammatory marker or liver enzyme levels. Thus we investigated the association of BMI with C-reactive protein (CRP) and alanine aminotransferase (ALT) levels in healthy Korean adolescents. Methods: The JSHS Study is a prospective cohort study to investigate the risk factors for vascular change in early life. The current cross-sectional analysis enrolled 540 boys and 506 girls, aged 15-16 years old, who participated in the baseline examinations between 2007 and 2012. Baseline measurements included anthropometrics, physical examinations, questionnaires, and fasting blood analysis. Spearman correlation and linear regressions analyses were used to investigate the association of BMI with CRP and ALT. All statistical analyses were performed separately for males and females. Results: CRP levels were positively correlated with BMI in males (correlation coefficient r=0.175, p<0.001) and females (r=0.206, p<0.001). After adjustment for age, smoking and alcohol consumption, higher BMI was positively associated with increased CRP levels (β=0.157, p<0.001 for male; β=0.195, p<0.001 for female). But this association was attenuated (β=0.091, p=0.074 for male; β=0.085, p=0.091 for female), when the analysis was limited to adolescents with normal range of BMI (18.5 to 25.0 kg/m2). ALT levels were positively correlated with BMI only in males (correlation coefficient r=0.337, p<0.001) but not in females (r=0.072, p=0.104). After adjustment for age, smoking and alcohol consumption, higher BMI was positively associated with increased ALT levels (β=0.436, p<0.001 for male; β=0.094, p=0.034 for female). But this association was significant only in males (β=0.190, p<0.001) not in females (β=0.074, p=0.143), when the analysis was limited to adolescents with normal range of BMI. Conclusion: Higher BMI was positively associated with increased levels of CRP and ALT among healthy Korean adolescents. The positive association between BMI and ALT levels was observed even in male adolescents with normal range of BMI.

Histologic Changes in Liver Tissue From Patients With Chronic Hepatitis B and Minimal Increases in Levels of Alanine Aminotransferase: A Meta-analysis and Systematic Review

The level of alanine aminotransferase (ALT) is a marker of hepatitis B severity and response to treatment. However, measurements of ALT level may be of limited use during the immune clearance phase of chronic hepatitis B (CHB) and can be affected by age, weight, and concomitant liver disease. We performed a literature review to determine the proportion of CHB patients with ALT levels of 1- to 2-fold the upper limit of normal who also had significant underlying liver fibrosis (stage ≥2). We performed a Medline search of original articles published before June 2012, and their references; we also searched abstracts from the 2010 and 2011 annual meetings of the American Association for the Study of Liver Diseases and the 2011 and 2012 Digestive Disease Weeks. Studies were included that had 20 or more consecutive treatment-naive CHB patients with 6 months or more of follow-up evaluation, histologic data, and levels of ALT 1- to 2-fold the upper limit of normal. Study heterogeneity was assessed by a Forest plot and Q and I(2) analyses. Sensitivity was measured using 1-study removed analysis. Our analysis included 8 articles and 1 abstract, comprising 683 patients. Based on random-effects modeling, 48% of patients had stage 2 or higher fibrosis (95% confidence interval, 36%-61%). In a sensitivity analysis, exclusion of the study that caused the greatest deflection of the pooled estimate produced a revised estimate of 43%. A subgroup of hepatitis B e antigen-positive and hepatitis B e antigen-negative patients (n = 168 and 170, respectively) showed similar rates of fibrosis (41% vs 47%; P = nonsignificant). Despite heterogeneity in the literature, a substantial proportion of patients with slight increases in ALT level have significant fibrosis. Given the possibility of advanced liver disease, the threshold for antiviral treatment must be individualized. Further studies are needed to investigate patients with modest increases in ALT level.

Alanine aminotransferase and metabolic syndrome in adolescents: the Korean National Health and Nutrition Examination Survey Study

Adolescent NAFLD has increased in parallel with obesity. Elevated serum ALT level is a surrogate marker for NALFD. Increased ALT levels are closely related to NAFLD and metabolic syndrome. Increased ALT within normal range are associated with an increased risk of metabolic syndrome. All of the five components of metabolic syndrome were associated with high ALT within normal range. By elevation of ALT, the prevalence of metabolic syndrome increased in obese adolescents and normal-weight adolescents as well. The potential interactions between alanine aminotransferase (ALT) and components of metabolic syndrome (MetS) have not been fully investigated in healthy adolescents. This study investigated the impact of a mild ALT elevation on the risks of MetS in healthy Korean adolescents. From the Korean National Health and Nutrition Examination Surveys 1998-2009, the data of 5026 adolescents aged 10-18 years (2604 boys and 2422 girls) were analysed. Individuals who had ALT levels equal or more than 40 IU L(-1) were excluded. Subjects in the upper ALT tertile had higher mean values of body mass index (BMI), homeostasis model assessment-insulin resistance and prevalence of MetS than subjects in the lower tertile. The risk of each five components of MetS was significantly higher than subjects in the lower tertile. Compared with the subjects in the lower ALT tertile, the prevalence of MetS was higher in the upper tertile among obese adolescents (44.6-50.7% vs. 31.2-40.0%) as well as normal-weight adolescents (5.2-7.7% vs. 2.7-3.2%). Subjects in the upper ALT tertile were at a higher risk of MetS than those in the lower tertile (odds ratio [OR] = 1.95 for boys, OR = 2.00 for girls) after controlling for age and BMI. A high serum ALT within normal range increased the risk of all the components of MetS. The prevalence of MetS increased with the elevation of obesity level, and it increased further with the elevation of ALT tertile. Thus, serum ALT levels in addition to BMI might be useful as a marker for early detection of MetS.

Baseline High Viral Load and Unfavorable Patterns of Alanine Aminotransferase Change Predict Virological Relapse in Patients With Chronic Hepatitis C Genotype 1 or 2 Obtaining Rapid Virological Response During Antiviral Therapy

BackgroundRapid virological response (RVR) strongly predicts sustained virological response (SVR) in patients with chronic hepatitis C (CHC), and abbreviates antiviral therapy in some patients.ObjectivesTo identify factors predicting virological relapse (VR) in CHC patients who attained RVR.Patients and MethodsMedical records of 133 CHC patients with an RVR after completing 24 weeks of antiviral therapy (a combination of pegylated interferon-α and ribavirin) were analyzed. Baseline characteristics and on-treatment responses were compared between the patients with an SVR and those with VR. Patients with normal alanine aminotransferase (ALT) levels at weeks 4 and 12 and at the end-of-treatment (EoT) and patients with elevated, but constantly decreasing, ALT levels were classified as having favorable patterns of ALT change. A trend of increasing ALT levels either between weeks 4 and 12 or between weeks 12 and EoT was classified as unfavorable. A high viral load (HVL) was defined as a baseline HCV RNA ≥ 600000 IU/mL.ResultsIn total, 116 (87.2%) patients had a SVR and 14 (10.5%) had VR. The VR rates were comparable between patients with genotype-1 (13.1%) and genotype-2 infection (8.7%) (P = 0.572). Multivariate analysis revealed that HVL (P = 0.015; odds ratio [OR] = 14.754; 95% confidence interval (CI) = 1.671–130.240), and unfavorable ALT patterns (P = 0.039; OR = 4.397; 95% CI = 1.078–17.930) independently predicted VR. In subgroup analysis, low viral load (LVL) patients had a minimal VR rate (1.8%). Among the HVL patients, the VR rate of those using peg-IFN-α-2a was relatively low (9.1%). Patients using peg-IFN-α-2b had a slightly higher VR rate (23.8%; P = 0.128), and patients with favorable patterns of ALT changes had a lower VR rate (10.3%) compared to the 53.8% in patients with unfavorable ALT patterns (P = 0.005).ConclusionsIn southern Taiwan, 24 weeks of antiviral therapy achieved a high SVR rate in patients with CHC attaining RVR, except in the subgroup of patients treated with peg-IFN-α-2b with HVL and on-treatment unfavorable ALT patterns.

Phase I study of sunitinib plus capecitabine/cisplatin or capecitabine/oxaliplatin in advanced gastric cancer

We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC). Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity. Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively. At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

Long-term Safety and Tolerability of Twice-daily Balsalazide Disodium Tablets in Patients with Ulcerative Colitis

Purpose: Balsalazide disodium is an azo-bonded 5-aminosalicylic acid prodrug cleaved by colonic bacteria, providing direct drug delivery to the colon with efficacy in inducing and maintaining ulcerative colitis (UC) remission. This study evaluated long-term safety and tolerability of a new formulation, balsalazide disodium tablets (BDT), which was developed to allow less frequent dosing and enhance compliance in the treatment of UC. Methods: In a phase 3, multicenter, open-label extension study, adults in UC remission or with mild-to-moderate active UC received 3.3 g of BDT (dosed as three 1.1 g tablets) twice daily for up to 1.4 years. Eligible patients had participated in previous double-blind, phase 3 studies (a placebo-controlled or actively controlled [mesalamine] trial) of BDT for active UC. Patients were assessed in the clinic at baseline, months 1 and 3, every 3 months through the end of treatment (EOT), and at 2 weeks after EOT, with a telephone interview at week 2. Safety assessments included monitoring of AEs and clinical laboratory and vital sign measurements. Results: Of the 443 patients enrolled, 253, 142, and 48 had been treated with BDT, mesalamine, or placebo, respectively, during the double-blind studies. The safety population (n=440) was 50.9% male and 85.2% white, with a mean (SD) age of 43.1 (13.2) years. Median (range) duration of exposure was 277.5 days (1 to 495), with 317 (72.0%) and 84 (19.1%) patients receiving >6 and >12 months of treatment, respectively. The most common adverse events (AEs; in ≥5% of patients) were worsening UC (10.9%), diarrhea (6.1%), abdominal pain (5.9%), and headache (5.5%). The majority of patients (86.1%) reported AEs with mild or moderate severity. Gastrointestinal AEs were most commonly reported during the 0-8 and >8-26 week time periods; infection-related AEs (eg, upper respiratory tract infection) were most common at >26-52 weeks. Drug-related AEs occurred in 8.9% of patients; most common were worsening UC (1.6%) and headache (1.1%). Twenty-seven patients (6.1%) discontinued from the study due to an AE, including worsening UC in 18 patients (4.1%). Serious AEs occurred in 21 patients (4.8%), with one death that was not drug-related; only one serious AE (worsening UC) was drug-related. Pancreatic, renal, and hepatic AEs occurred in 13 patients (3.0%); all events were mild or moderate, and only one event (increased alanine aminotransferase levels) was drug-related. There were no clinically meaningful mean changes from baseline in clinical laboratory parameters. Conclusion: Twice-daily balsalazide disodium tablets were safe and well-tolerated for the long-term (up to 1.4 years) management of UC. This research was funded by Salix Pharmaceuticals, Inc., Raleigh, NC, USA. Disclosure - Ellen J Scherl: received grants from, served as a consultant for, and is on the speakers' bureau for Salix Pharmaceuticals, Inc.; received grants from and served as a consultant for Abbott, Centocor, Janssen Research and Development, PDL BioPharma, Prometheus Laboratories, and UCB; received grants from Elan, Millennium Pharmaceuticals, and Osiris Therapeutics; and served as a consultant for AstraZeneca, Axcan Pharma, Berlex Inc., Cerimon Pharmaceuticals, Hospira Inc., NPS Pharmaceuticals, Inc., Optimer Pharmaceuticals, Questcor Pharmaceuticals, Shire, Sigma Tau Pharmaceuticals, Inc., Solvay Pharmaceuticals, Inc., and TAP Pharmaceuticals. Ronald E. Pruitt: nothing to disclose. Shahriar Sedghi: nothing to disclose. Andrew C. Barrett: employee of and holds stock in Salix Pharmaceuticals, Inc. Enoch Bortey: employee of and holds stock in Salix Pharmaceuticals, Inc. Craig Paterson: employee of and holds stock in Salix Pharmaceuticals, Inc. William P. Forbes: officer and employee of and holds stock in Salix Pharmaceuticals, Inc.

Safety of infliximab therapy in rheumatoid arthritis patients with previous exposure to hepatitis B virus

To evaluate the safety of tumor necrosis factor-α (TNF-α) monoclonal antibody (infliximab) therapy in patients with rheumatoid arthritis (RA) and previous exposure to hepatitis B virus (HBV) who had normal liver function. This is a retrospective study from a 26-week, prospective, multicenter trial in 234 patients with RA who received infusions of infliximab (3mg/kg at week 0, 2, 6, 14 and 22). The medical records of these patients were reviewed, including the information on disease duration, laboratory tests and HBV markers. The data on liver function during the study was analyzed, as well as comparison between patients with previous exposure to HBV and patients without such exposure. Forty-one patients with previous exposure to HBV were HBsAg(-). Forty patients had normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and only one patient with positive anti-HBc showed an elevated ALT level before administration of infliximab, and had a further increase of ALT level at week 14, but decreased thereafter. The average ALT and AST levels rose slightly during the treatment but remained in normal range and the differences were insignificant compared with baseline. There was no statistically significant difference in the incidence of liver function abnormalities during the treatment of infliximab between the patients with previous exposure to HBV and those without such exposure. In patients with RA and previous exposure to HBV but with a negative HBsAg and normal liver function at baseline, liver function abnormalities were not observed during infliximab treatment.

The Pharmacokinetics and Safety of a Fixed-Dose Combination of Acetylsalicylic Acid and Clopidogrel Compared With the Concurrent Administration of Acetylsalicylic Acid and Clopidogrel in Healthy Subjects: A Randomized, Open-Label, 2-Sequence, 2-Period, Single-Dose Crossover Study

BackgroundDual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is used for the treatment of acute coronary syndrome. A combined formulation of ASA and clopidogrel has been developed to provide dosing convenience and improve adherence. ObjectiveThis study was designed to compare the pharmacokinetic properties and safety profile of a fixed-dose combination formulation of ASA and clopidogrel with concurrent administration of each agent in healthy male Korean volunteers. MethodsThis single-dose, randomized, open-label, 2-period crossover study was conducted in 64 healthy Korean volunteers. Equal numbers of eligible participants were randomly assigned to receive either the fixed-dose combination of ASA 100 mg and clopidogrel 75 mg or the free combination of each agent followed by a 7-day washout period and then administration of the alternate formulation. Serial blood samples were collected immediately before and after dosing for 24 hours. The safety profile was evaluated by using adverse events (AEs), which were assessed by physical examination, vital signs, ECGs, clinical laboratory tests, and interviews. The 2 formulations were considered to be bioequivalent if the 90% CIs for the log-transformed Cmax and AUC0–last values were within the predetermined range of 0.8 to 1.25. ResultsSixty-four volunteers (mean [SD] age, 27.51 [8.15] years; weight, 68.55 [7.86] kg; height, 173.80 [5.94] cm) were enrolled, and 63 completed the study. For ASA, the 90% CIs for the geometric mean ratios of Cmax and AUC0–last were 0.9483 to 1.1717 and 0.9946 to 1.1020, respectively. For salicylic acid, the 90% CIs were 0.9614 to 1.0396 for Cmax and 0.9778 to 1.0163 for AUC0–last. For clopidogrel, the 90% CIs were 0.9809 to 1.2562 for Cmax and 0.9674 to 1.2073 for AUC0–last. Six of the 20 AEs reported were drug related: decreased hemoglobin levels (n = 2), fever (n = 1), and headache (n = 1) with the test formulation and increased alanine aminotransferase levels (n = 1) and dyspepsia (n = 1) with the reference formulation. All of the drug-related AEs were transient and mild in severity. ConclusionsThe fixed-dose combination of ASA and clopidogrel 100 mg/75 mg did not meet the regulatory criteria for bioequivalence as defined by the Korea Food and Drug Administration. Both formulations were well tolerated in these healthy male Korean subjects. ClinicalTrials.gov Identifier: NCT01448330

Liver Aminotransferases and Risk of Incident Type 2 Diabetes: A Systematic Review and Meta-Analysis

We evaluated the associations of liver aminotransferases with risk of type 2 diabetes (T2D) in general populations by conducting a systematic review and meta-analysis of published prospective studies. Studies were identified in a literature search of PubMed, EMBASE, and Web of Science from 1950 through October 2012. Of the 2,729 studies reviewed, 17 studies involving 60,359 participants and 3,890 incident T2D events were included. All of the studies assessed associations between alanine aminotransferase (ALT) level and T2D, with heterogeneous findings (I(2) = 88%, 95% confidence interval (CI): 82, 92; P < 0.001). The pooled fully adjusted relative risk of T2D was 1.26 (95% CI: 1.14, 1.41) per 1-standard-deviation change in log baseline ALT level. This association became nonsignificant after trim-and-fill correction for publication bias. Nine studies evaluated associations between aspartate aminotransferase (AST) levels and T2D risk, with a corresponding relative risk of 1.02 (95% CI: 0.99, 1.04). The relative risk of T2D per 5-IU/L increase in ALT level was 1.16 (95% CI: 1.08, 1.25). Available data indicate moderate associations of ALT with risk of T2D events, which may be attributable to publication bias. There was no evidence for an increased risk of T2D with AST. Large prospective studies may still be needed to establish the magnitude and nature of these associations.

Clinical Presentation, Outcome, and Response to Therapy Among Patients With Acute Exacerbation of Chronic Hepatitis C

The slow asymptomatic progression of chronic hepatitis C (CHC) can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of CHC. We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of CHC from January 2005 through June 2010; we followed them up for a median period of 36 months. These cases were hepatitis C virus (HCV) RNA positive, hepatitis B surface antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed up for at least 2 years. Liver biopsy specimens had been taken from 23 cases and 31 controls-once before enrollment in the study and once during the follow-up period. HCV genotype 2 was detected in 46.4% of cases, and HCV genotype 1 was detected in 43.9%. Among cases, the mean ALT level was 1063 ± 1038 IU/dL, and the mean total bilirubin level was 15.87 ± 7.15 mg/dL. A higher percentage of cases carried the interleukin-28B CC genotype than controls (40.2% vs 24.4%; P < .05). Among cases, 43.5% had a steady increase in ALT level (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsy specimens, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by more than 2 (P < .005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necroinflammation of more than 2 points (P < .005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained virologic response was achieved in 26 cases (81.2%) and 23 controls (60.5%). Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a sustained virologic response after treatment with pegylated interferon and ribavirin.

Increased alanine aminotransferase levels and associated characteristics among newly diagnosed type 2 diabetes patients: results from the DD2 study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Increased alanine aminotransferase levels and associated characteristics among newly diagnosed type 2 diabetes patients: results from the DD2 study

Increased alanine aminotransferase levels and associated characteristics among newly diagnosed type 2 diabetes patients: results from the DD2 study

Safety of Fondaparinux Versus Enoxaparin After TKA in Japanese Patients

Fondaparinux and enoxaparin are useful for preventing venous thromboembolism after total knee arthroplasty (TKA), but both drugs have associated complications. The purpose of this study was to clarify the risks associated with use of these drugs in Japanese patients who underwent TKA.A total of 575 patients (935 knees) underwent TKA and were retrospectively reviewed; 277 patients (454 knees) were treated with fondaparinux and 298 patients (481 knees) were treated with enoxaparin. The authors investigated the incidences of deep venous thrombosis of the lower limbs and pulmonary embolism to evaluate venous thromboembolism, knee enlargement compared with the preoperative size, incidence of subcutaneous knee hematoma, and other complications. No significant differences were observed between the 2 drugs regarding the incidences of deep venous thrombosis and pulmonary embolism. However, fondaparinux use resulted in knee enlargement (P<.0005) and subcutaneous hematoma of the knee (P=.035) significantly more often than enoxaparin use. Conversely, enoxaparin use significantly caused the elevation of alanine aminotransferase (one of the liver enzymes) at a higher rate than fondaparinux (30.1% vs 8.3%, respectively; P<.0001). However, the increased alanine aminotransferase levels were transient, and no patient exhibited symptoms of abnormal liver function, such as jaundice or cutaneous pruritus.Fondaparinux and enoxaparin were both effective in preventing venous thromboembolism in Japanese patients undergoing elective TKA. However, both drugs had some adverse effects. It is important to be aware of these potential risks when prescribing these drugs.

Prospective Study of Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: An Asian Cooperative Study between Japan and Korea

PurposeTo evaluate the safety and efficacy of transcatheter arterial chemoembolization used for the treatment of unresectable hepatocellular carcinoma (HCC) with an Asian cooperative prospective study between Japan and Korea. Materials and MethodsPatients with unresectable HCC unsuitable for curative treatment or with no prior therapy for HCC were enrolled. The patients underwent transcatheter arterial chemoembolization with emulsion of Lipiodol and anthracycline agent, followed by embolization with gelatin sponge particles, which was repeated on an as-needed basis. The primary endpoint was 2-year survival rate, and the secondary endpoints were adverse events and response rate. ResultsThe 2-year survival rate of 99 patients was 75.0% (95% confidence interval, 65.2%–82.8%). The median time-to-progression was 7.8 months, and the median overall survival period was 3.1 years. Of 99 patients, 42 (42%) achieved a complete response, and 31 (31%) had a partial response. The response rate was 73% using modified Response Evaluation Criteria in Solid Tumors. The grade 3–4 toxicities included increased alanine aminotransferase level in 36%, increased aspartate aminotransferase level in 35%, thrombocytopenia in 12%, and abdominal pain in 4% of patients. All other toxicities were generally transient. ConclusionsAsian transcatheter arterial chemoembolization demonstrated sufficient safety and reasonable efficacy as a standard treatment for unresectable HCC. These results could be useful as reference data for future trials of transcatheter arterial chemoembolization.

Association Between Variants in or Near PNPLA3, GCKR, and PPP1R3B With Ultrasound-Defined Steatosis Based on Data From the Third National Health and Nutrition Examination Survey

A genome-wide association study associated 5 genetic variants with hepatic steatosis (identified by computerized tomography) in individuals of European ancestry. We investigated whether these variants were associated with measures of hepatic steatosis (HS) in non-Hispanic white (NHW), non-Hispanic black, and Mexican American (MA) participants in the US population-based National Health and Nutrition Examination Survey III, phase 2. We analyzed data from 4804 adults (1825 NHW, 1442 non-Hispanic black, and 1537 MA; 51.7% women; mean age at examination, 42.5 y); the weighted prevalence of HS was 37.3%. We investigated whether ultrasound-measured HS, with and without increased levels of alanine aminotransferase (ALT), or level of ALT alone, was associated with rs738409 (patatin-like phospholipase domain-containing protein 3 [PNPLA3]), rs2228603 (neurocan [NCAN]), rs12137855 (lysophospholipase-like 1), rs780094 (glucokinase regulatory protein [GCKR]), and rs4240624 (protein phosphatase 1, regulatory subunit 3b [PPP1R3B]) using regression modeling in an additive genetic model, controlling for age, age-squared, sex, and alcohol consumption. The G allele of rs738409 (PNPLA3) and the T allele of rs780094 (GCKR) were associated with HS with a high level of ALT (odds ratio [OR], 1.36; P = .01; and OR, 1.30; P = .03, respectively). The A allele of rs4240624 (PPP1R3B) and the T allele of rs2228603 (NCAN) were associated with HS (OR, 1.28; P = .03; and OR, 1.40; P = .04, respectively). Variants of PNPLA3 and NCAN were associated with ALT level among all 3 ancestries. Some single-nucleotide polymorphisms were associated with particular races or ethnicities: variants in PNPLA3, NCAN, GCKR, and PPP1R3B were associated with NHW and variants in PNPLA3 were associated with MA. No variants were associated with NHB. We used data from the National Health and Nutrition Examination Survey III to validate the association between rs738409 (PNPLA3), rs780094 (GCKR), and rs4240624 (PPP1R3B) with HS, with or without increased levels of ALT, among 3 different ancestries. Some, but not all, associations between variants in NCAN, lysophospholipase-like 1, GCKR, and PPP1R3B with HS (with and without increased ALT level) were significant within subpopulations.

Alanine Aminotransferase Is Associated with an Adverse Nocturnal Blood Glucose Profile in Individuals with Normal Glucose Regulation

ObjectiveAlthough the association between alanine aminotransferase (ALT) levels and risk of type 2 diabetes is well-studied, the effects of slightly increased ALT levels within the normal range on the temporal normal glucose profile remains poorly understood.MethodsA total of 322 Chinese subjects without impaired glucose tolerance or previous diagnoses of diabetes were recruited for study from 10 hospitals in urban areas across China. All subjects wore a continuous glucose monitoring (CGM) system for three consecutive days. The diurnal (06∶00–20∶00) and nocturnal (20∶00–06∶00) mean blood glucose (MBG) levels were calculated. Subjects were stratified by ALT quartile level and correlation analyses were performed.ResultsThe median ALT level was 17 IU/L, and subjects with ALT ≥17 IU/L had higher nocturnal MBG level than those with ALT <17 IU/L (P<0.05). Nocturnal MBG was positively correlated with ALT levels (Pearson correlation analysis: r = 0.187, P = 0.001), and the correlation remained significant after correction for the homeostatic model assessment of insulin resistance index (HOMA-IR) (r = 0.105, P = 0.041). No correlations were found between diurnal MBG and ALT, and nocturnal or diurnal MBG and aspartate aminotransferase or gamma-glutamyltransferase (all, P>0.05). Multivariate stepwise regression analysis of elevated nocturnal MBG identified increased HOMA-IR, elevated ALT levels, and decreased homeostatic model assessment of ß-cell function as independent factors (all, P<0.05).ConclusionsMildly elevated ALT levels, within the normal range, are associated with unfavorable nocturnal glucose profiles in Chinese subjects with normal glucose regulation.

The best-laid plans

The best-laid plans

Aminotransferase Levels Are Associated With Cardiometabolic Risk Above and Beyond Visceral Fat and Insulin Resistance

We sought to characterize associations between aminotransferase levels and cardiometabolic risk after accounting for visceral adipose tissue and insulin resistance. Participants (n=2621) from the Framingham Heart Study (mean age 51, 49.8% women) were included. Sex-specific linear and logistic regressions were used to evaluate associations between aminotransferase levels and cardiometabolic risk factors. In multivariable models, increased alanine aminotransferase levels were associated with elevated blood pressure, fasting plasma glucose, and triglycerides and lower high-density lipoprotein levels (all P≤0.007). Furthermore, each 1-SD increase in alanine aminotransferase corresponded to an increased odds of hypertension, diabetes mellitus, the metabolic syndrome, impaired fasting glucose, and insulin resistance estimated by the homeostasis model assessment of insulin resistance (odds ratio, 1.29-1.85, all P≤0.002). Associations with alanine aminotransferase persisted after additional adjustment for visceral adipose tissue, insulin resistance, and body mass index with the exception of high-density lipoprotein cholesterol in both sexes and blood pressure in women. Results were materially unchanged when moderate drinkers were excluded, when the sample was restricted to those with alanine aminotransferase <40 U/L, and when the sample was restricted to those without diabetes mellitus. Similar trends were observed for aspartate aminotransferase levels, but associations were more modest. Aminotransferase levels are correlated with multiple cardiometabolic risk factors above and beyond visceral adipose tissue and insulin resistance.