A U.S. payer perspective, 3 %discount rate, and willingness to pay (WTP) threshold of $100,000/ QALY were used. Sensitivity analyses included pre-LT therapy length, cost & efficacy, selleck kinase inhibitor & scenarios with newer regimens. Results: Post-LT therapy resulted in 2.7-4.3 QALYs and costs of $275,000-$519,000 depending on MELD (Table). Pre-LT therapy extended QALYs and costs, with greater gains and costs at low MELDs. The ICERs were above the WTP threshold except for MELD=20-29 where the LT rate meant most

patients got <48 wks of SOF/RBV but enough to attain post-LT SVR. MELDs<20 had longer wait times with longer courses of pre-LT therapy while MELDs>30 either died or went to LT before SVR was achieved; both had high ICERs. Shorter durations reduced ICERs for MELDs<30; at a duration of 24 wks, any MELD<30 fell below the WTP threshold using SOF/RBV without change in ICERs for MELDs>30. Improved SVR rates for cirrhotics who complete therapy pre- LT & lower drug costs also reduced ICERs below the WTP threshold for low MELDs. Conclusion: SOF/RBV for up to 48 wks pre-LT provides good value for money with MELD=20-29 at listing. Future regimens with high SVR rates, shorter durations & lower costs may improve the economic appeal of pre-LT therapy for MELDs<30, but not those >30. Disclosures:

Alissa J. Wright – Grant/Research Support: Pfizer, Sunovion, Astellas Arthur Y. Kim – Consulting: Abbvie Pharmaceuticals, Gilead Pharmaceuticals; Grant/Research Support: Bristol-Myers Squibb, Gilead Pharmaceuticals Erlotinib solubility dmso Raymond T. Chung – Consulting: Abbvie; Grant/Research Support: Gilead, Mass Biologics The following people have nothing to disclose: Jay A. Fishman, Benjamin P. Linas medchemexpress Purpose: The current study aims at identifying demographics and clinical characteristics associated with high HRU and costs among patients with CHC. Methods:

Health insurance claims from 60 self-insured U.S companies from 01/2001-03/2013 were analyzed. Adult patients with ≥2 CHC claims (ICD-9: 070.44 or 070.54), ≥6 months of continuous insurance coverage before the first CHC diagnosis and ≥36 months of observation post-CHC were included. Patients diagnosed with HIV were excluded. Patients were categorized in four mutually exclusive groups based on quartile distribution of cumulative healthcare costs during the 36-month follow-up [i.e. 25th ($9,600), 50th ($25,092), and the 75th ($54,100) percentiles]. Demographics and baseline comorbidities including CHC-related and non-CHC conditions were described. A multinomial logistic regression model was estimated to identify baseline demographic and clinical characteristics associated with the highest quartiles of HRU and costs. Results: A total of 4,898 CHC patients formed the study population. The mean age was 53.3, 53.2, 51.3, and 51.

[17, 25] In this study, we found that the LGV diameter increased with the increasing

endoscopic grades of the varices, which suggested that the diameter of LGV or SV could have a potential association with the endoscopic grades of the varices. We confirmed that the diameters of the LGV or SV could be independent risk factors for the presence of esophageal varices, and be used to Cilomilast discriminate the grades of the varices. Based on the present data with the ROC analysis, the LGV and SV diameter measurements could be used as referential criteria to classify the endoscopic grades of esophageal varices except for discriminating grade 1 from 2. This indiscrimination between grade 1 and 2 may be because the endoscopic grading system for the varices used in our study is on the basis of the size and morphology of the largest varix, and the difference in the endoscopic grades between grade 1 and 2 is not so obvious. Patients between grades 0–1

and 2–3, which were defined as low-risk and high-risk varices, respectively, could be discriminated by the LGV and SV diameter measurements. According BMS-907351 manufacturer to the AUC which was used to assess the diagnostic performance of the cut-off diameters in classifying the endoscopic grades of esophageal varices, the cut-off diameter of the LGV was found to be better than that of the SV in classifying grades 0 from 1, grades 0 from 2, and grades 0–1 from 2–3. The potential explanation may be because the SV is not only the predominant originating vein of the LGV but also the originating vein of other shunts such as splenorenal shunt and gastric fundic varices, which may have an affect on the hemodynamics and diameter of the SV.[1, 23] On the other hand, the cut-off diameter of the SV was found to have similar diagnostic performance to that of the LGV in classifying grades 0 from 3, and grades 2 from 3; and

the cut-off diameter of the SV was better in classifying grades 1 from 3. Therefore, recognition of the dilated LGV and SV may be an additional secondary 上海皓元 sign of esophageal varices, and the diameter measurements are crucial to classify endoscopic grades of the varices for guiding the therapy to prevent the potential hemorrhage.[24] However, there was a limitation in this study. The enrolled patients in this study had post-hepatitic cirrhosis secondary to chronic hepatitis B, but our findings are specific to liver cirrhosis in patients with hepatitis B. In conclusion, we used a portography with MR imaging to visualize the inflowing vessel and its originating vein of esophageal varices secondary to liver cirrhosis in patients with hepatitis B. On MR portography, the diameter of the LGV or SV could be associated with the presence and endoscopic grades of the varices, and could be used to discriminate the high-risk varices from the low-risk ones.

Our findings also underline the importance

of using a mixture of products in the assay and, if possible, a quantitative approach, as even a discrepant outcome for the FL-rFVIII products may be observed, as in the case of plasma No. 3. This consistent but surprising finding in repeated assays was IgG-mediated and specific, in that it was possible to inhibit with only the product it bound to. We cannot, however, rule out the possibility PF-01367338 mw that smaller amounts of antibodies towards the other full-length molecules were also present, and that these were simply not detected in our assay at the cut-off of +3 SD. The concern of a cut-off-related outcome should be further discussed when evaluating any antibody response, as in patients without an identified inhibitor as well as in those with or without

NNA, antibodies of both neutralizing and non-neutralizing capacity may be present, but at lower concentrations than those corresponding to the defined cut-off of the assay. There are discrepant data on the influence of the disease-causative mutation and NNA prevalence. The intron 22 inversion mutation of F8 was shown in one study to increase the risk of NNA response [7]; however, we found all genetic alterations represented in our cohort producing NNA. When comparing patients carrying one of the high-risk mutations for inhibitor development with patients this website carrying low-risk mutations, no significant difference in NNA prevalence was observed, a finding which agrees with other studies [3, 13]. In contrast

with the French study by Lebreton et al. we found, in the subgroup without a history of inhibitors (n = 122), a significant difference in median age of patients with NNA (30.0 years) compared with patients without NNA (14.0 years) (P = 0.021). Fifty-nine patients in our study had, according to the investigators caring for them, been successfully treated with ITI. However, 25.4% 上海皓元医药股份有限公司 still had detectable antibodies in the ELISA assays, but the binding specificity of these antibodies varied. In five patients, antibodies were detected although both half-life and in vivo recovery were considered normal. In addition, in three cases, the ELISA assay was only negative against the product used at detection of the inhibitor. Unfortunately, the specific drug used for ITI was not captured, but it is reasonable to believe that the product used for ITI was the same as that in use at time of inhibitor detection. This is more or less a general approach and may indicate an as yet uncharacterized and undefined clinical difference between the molecules. The risk for recurrence of the inhibitory antibodies after ITI among patients with NNA remains to be determined, but it is reasonable to believe that it may be higher than without a detectable response, although the characteristics of these remaining antibodies have been suggested to change during ITI [5].

13 Whereas 10% of the Caucasians had a variant genotype, these were seen in 2% of

the South West Asians and 4.7% of the Chinese. Variations in the TPMT*2 allele were seen in the Caucasians, but not in the other two groups. TPMT*3A was the only mutant allele found in the South West Asians, but was not seen in the Chinese. The Chinese individuals only had the TPMT*3C allele. Efrati and co-authors14 examined TMPT risk alleles within groups in an Israeli population: Druze individuals differed greatly from check details Jewish and Muslim groups. Allelic frequencies of TMPT varied between the three groups. Furthermore, two variants (TMPT*2 and TMPT*3B), were not found in any of the subpopulations. Further studies have also examined variations in TMPT enzyme activity. For Selleck RG7204 example, Cooper et al.15 defined TMPT enzyme activity in 1000 adults from various ethnic groups. Women, especially those of South-East Asian origin, had lower activity than men. Variations in XO activity are also described. Kudo et al.16 defined variations in a group of 96 Japanese. Several polymorphisms were defined, which correlated with individual differences in

XO enzyme activity. Ethnic variations in the frequencies of these polymorphisms may occur. To date, there are no data regarding ethnic differences in shunting of thiopurine metabolism or in differential responses to the combination of allopurinol with thiopurines. Variations in the frequencies of medchemexpress polymorphisms in TMPT and XO likely contribute and need to be considered in dosing of allopurinol and thiopurines. As emphasized

in the Safety Notice, the interactions between allopurinol and azathioprine can lead to serious adverse outcomes. However, the careful combination of these drugs, along with close monitoring of metabolites and blood counts can be efficacious and lead to much improved health outcomes. While there are no published guidelines in this area, we would advise weekly blood counts for at least four weeks when this combination is commenced and three monthly blood tests in the long term. Individual and ethnic variations in the key enzymes involved in the metabolism of these drugs are important to consider in prescribing and monitoring. Always check if a patient is on azathioprine before prescribing allopurinol “
“The aims of this study are to assess the antiviral effects, safety and telaprevir (TVR) pharmacokinetics in two cohorts given TVR every 8 h (q8h) at doses of 500 mg and 750 mg with peginterferon-α-2b and ribavirin in chronic hepatitis C patients. Twenty chronic hepatitis C (HCV) patients with genotype 1b in high viral loads were randomly assigned to two TVR-based regimens of 750 mg q8h (group A) and 500 mg q8h (group B) in combination with peginterferon-α-2b and ribavirin for 12 weeks.

The nuclear bile salt receptor FXR has been shown to protect against insulin resistance8 and fatty liver8, 9: antidiabetic effects were mechanistically linked to repressed Pepck8 and increased hepatic IRS-2 phosphorylation. Both mechanisms were also reported in DLPC-treated mice in the current study.1 Antisteatotic effects in the presented study might thus rely on bile salt-/FXR-mediated repression of Srebp-1.9 The membrane bile salt receptor TGR5 improves glucose homeostasis by release of GLP-110 and by increasing energy expenditure in brown adipose tissue.10, 11 Concertedly, these bile salt sensors might thus mediate antidiabetic and antisteatotic effects as a result

of DLPC-/LRH-1-induced stimulation of bile salt synthesis. To further explore its molecular mechanisms and the possible contribution of bile

VX 770 salt receptors to its antidiabetic and antisteatotic effects, studies of DLPC should be expanded to mouse models that lack Tgr5 or Fxr expression. As DLPC is now being administered in a clinical trial, potential risks should be considered BMS-777607 supplier that might be associated with DLPC treatment in men: The hydrophilic, nontoxic bile salt pool in mice differs markedly from the more hydrophobic, potentially toxic bile salt pool in humans. Human hydrophobic bile salts are potent inducers of hepatocellular apoptosis.12, 13 The DLPC-induced increase in hepatic bile salt levels could thus result in a potential risk in men. As hepatocellular steatosis increases bile salt toxicity,14 patients with steatosis and steatohepatitis might be at increased risk to develop bile salt-induced liver injury following DLPC administration. It is a limitation of the present study that the effect of DLPC on biochemical markers of liver injury was not assessed in mouse models of steatosis. DLPC induced expression of Oct4 in vitro in the present study. OCT4 has been implicated in tumorigenesis15 and was reported to be predictive of poor survival in HCC.16 Therefore, potential procarcinogenic 上海皓元医药股份有限公司 effects of DLPC should be considered in

further in vivo studies. In summary, the identification of DLPC as an antidiabetic and antisteatotic ligand of Lrh-1 in mice is highly intriguing and might prove to be a long-sought new therapeutic tool in metabolic disease in men. However, mice are not men, and careful monitoring of patients for DLPC-induced hepatic and extrahepatic side effects is warranted. “
“Appropriate organ allocation must balance minimizing waitlist mortality and maximizing post-transplant outcomes. While MELD predicts waitlist death, additional metrics are needed to identify transplant candidates at risk for poor outcomes. Frailty, a syndrome of decreased physiologic reserve associated with adverse health outcomes, may provide a novel measure of risk stratification among candidates for transplantation.

Thirty patients with chronic hepatitis C virus (HCV) genotype 1 infection were randomized to receive a 14-day course of BMS-790052 (1, 10, 30, 60, or 100 mg once daily or 30 mg twice daily) or placebo in a ratio of 4:1. The mean maximum decline from find more baseline in HCV RNA ranged from 2.8 to 4.1 log10 IU/mL; the placebo group showed no evidence of antiviral activity. Most patients experienced viral rebound on or before day 7 of treatment with BMS-790052 monotherapy; viral rebound was associated with viral variants that had been previously implicated in resistance development in the in vitro replicon system. The PK profile was supportive of once-daily dosing with

median peak plasma concentrations at 1-2 hours postdose and mean terminal half-life of 12-15 hours. Steady state was achieved following 3-4 days of daily dosing.

BMS-790052 was well tolerated in all dose groups, with adverse events occurring with a similar frequency in BMS-790052- and placebo-treated groups. There were no clinically relevant changes in vital signs, laboratory, or electrocardiogram parameters. Conclusion: BMS-7590052 is the first NS5A replication complex inhibitor with multiple dose proof-of-concept in clinic. At doses of 1-100 mg daily, BMS-790052 was well tolerated, had a PK profile supportive of once-daily dosing, and produced a rapid and substantial decrease in HCV-RNA levels in patients chronically infected with HCV genotype 1. (HEPATOLOGY 2011 The current treatment R788 cell line of chronic hepatitis C virus (HCV) infection, a regimen of

pegylated interferon alpha (PEG-IFN)-2a or -2b, and ribavirin MCE公司 (RBV) remains unsatisfactory, particularly in the large number of patients with HCV genotype 1 infection, whose sustained viral response rates are currently ≈40%.1 However, treatment for HCV infection is rapidly evolving with the introduction of direct-acting antiviral (DAA) agents.2, 3 The combination of telaprevir, an HCV NS3 protease inhibitor, with PEG-IFN alpha-2a and RBV has been associated with sustained viral response rates of 61%-67% in patients with genotype 1 infection.2 Telaprevir is administered three times a day and has been associated with adverse events (AEs) such as rash and anemia.4 There continues to be an unmet medical need for additional DAA agents with different mechanisms of action and resistance patterns that are easy to administer, more effective, and well tolerated. Focusing on the critical importance of nonstructural protein 5A (NS5A) for HCV replication, BMS-790052 was identified as a potent and highly selective inhibitor of HCV based on inhibitor binding and mapping, inhibitor-induced resistant substitutions, and crystal structure modeling. In vitro data have shown that BMS-790052 inhibits HCV genotype 1 replicons with a median 50% effective concentration of ≤50 pM, whereas BMS-790052-resistant variants remain fully sensitive to interferon alpha and small-molecule inhibitors of HCV protease and polymerase.

28 Importantly, patients who already have active HBV disease (with significant levels of HBV DNA and raised ALT) when first identified at pre-chemotherapy screening should have their disease treated immediately, with the aim of minimizing viral replication and disease activity before chemotherapy is given. In patients at high risk of HBV reactivation, it is preferable that antiviral therapy be started pre-emptively

prior to chemotherapy, since this reduces the incidence and severity of reactivation hepatitis and allows chemotherapy to be completed.28,83 In contrast, deferring lamivudine treatment until HBV DNA levels become elevated is ineffective. In one randomized prospective study of patients receiving chemotherapy for lymphoma, HBV reactivation occurred Dasatinib supplier in 87% of find more patients in whom lamivudine therapy was delayed in this manner.84 More recently, a multi-center randomized prospective trial in patients with non-Hodgkin’s lymphoma receiving CHOP examined the effect of prophylactic lamivudine versus therapeutic lamivudine (delaying antiviral therapy until

elevations of ALT were observed). Hepatitis B reactivation occurred in 11.5% of patients treated pre-emptively, compared to 56% of patients treated therapeutically.21 A number of recent meta-analyses have now confirmed that pre-emptive lamivudine therapy reduces reactivation of HBV with a risk reduction estimated to be between 79% and 89%.74,75,85 Furthermore, the number of HBsAg positive patients needed to be treated with lamivudine to avoid medchemexpress a single reactivation is estimated to be three.74 Pre-emptive antiviral therapy is not routinely recommended in HBsAg negative/HBcAb positive patients with undetectable HBV-DNA, since these patients are at much lower risk of reactivation than HBsAg-positive patients. However, patients with detectable HBV DNA (occult HBV infection) are at greater risk of seroreversion and subsequent reactivation hepatitis

and it has been suggested that these patients be treated with lamivudine prior to chemotherapy.37,86 In occult infection, the alternative approach of deferring antiviral treatment until seroreversion and/or a significant rise in HBV-DNA has not been adequately assessed in clinical trials. Given the relative safety of oral antiviral therapy and the serious consequences of HBV reactivation, deferring treatment no longer can be recommended.37,87 The duration of antiviral prophylaxis is also contentious. Experience is limited to the use of lamivudine. It is likely that the optimal timing and duration of prophylaxis will depend in part on the antiviral drug used as well as the intensity of the immunosuppression together with a number of host and viral factors. In patients without evidence of active hepatitis B disease prior to chemotherapy, the most logical approach would be to provide antiviral cover until the immune system has fully recovered.

cAMP levels are tightly regulated by the phosphodiesterase (PDE) family of enzymes. Our recent work demonstrated that increased expression of hepatic PDE4, which specifically hydrolyzes and decreases cAMP levels, plays a pathogenic role in the development of liver injury. Hence, the aim of this study was to examine the effect of alcohol on PDE4 expression in the liver and its Doxorubicin potential role in the development of alcoholic steatosis. Methods: C57Bl/6 wild type and

Pde4b knockout (pde4b−/−) mice were pair-fed control or ethanol liquid diets for 4 weeks. One group of wild type mice received rolipram, a PDE4 specific inhibitor, during alcohol feeding. Liver steatosis was evaluated by Oil-Red-O staining and documented by biochemical assessment of hepatic triglycerides and free fatty acids. Expression of hepatic PDE4 and the effect of PDE4 inhibition on protein expression and activity of key enzymes involved in lipid metabolism were evaluated at both mRNA and protein levels. Results: We demonstrate for the first time that the early increase in the lipogenic genes Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) in alcohol fed wild type mice coincides with the

significant up-regulation of hepatic PDE4 expression. Notably, pde4b−/− mice and mice treated with rolipram had significantly lower hepatic free fatty acid content compared to wild type mice fed alcohol for 4 上海皓元 weeks. PDE4 inhibition did not affect alcohol metabolism as demonstrated by unaltered CYP2E1 expression in both pde4b−/− and mice treated with rolipram. Importantly, PDE4 inhibition in alcohol fed mice: (i) selleck compound prevented the decrease in hepatic sirtuin 1 (SIRT-1) levels; (ii) decreased hepatic ACC activity; and (iii) increased hepatic CPT1 a expression. Conclusion: These results demonstrate that alcohol induced increase in hepatic PDE4 expression

is a significant pathogenic mechanism underlying dysregulated lipid metabolism and the development of hepatic steatosis. Moreover, these data also suggest that hepatic PDE4 is a clinically relevant therapeutic target for the treatment of alcohol induced hepatic steatosis. Disclosures: Craig J. McClain – Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco, Abbott, Genentech; Grant/Research Support: Ocera, Merck, Glaxo SmithKline; Speaking and Teaching: Roche Shirish Barve – Speaking and Teaching: Abbott The following people have nothing to disclose: Diana Avila, Jingwen Zhang, Leila Gobejishvili Excess alcohol consumption is a leading cause of liver disease worldwide. In its severe form, alcoholic steatohepatitis (ASH) has a dismal prognosis with short-term mortality rates approaching 40%, in part due to only modestly effective medical therapies. As such, an urgent need exists to better understand the pathogenesis of ASH in order to develop more effective therapies.

cAMP levels are tightly regulated by the phosphodiesterase (PDE) family of enzymes. Our recent work demonstrated that increased expression of hepatic PDE4, which specifically hydrolyzes and decreases cAMP levels, plays a pathogenic role in the development of liver injury. Hence, the aim of this study was to examine the effect of alcohol on PDE4 expression in the liver and its RGFP966 purchase potential role in the development of alcoholic steatosis. Methods: C57Bl/6 wild type and

Pde4b knockout (pde4b−/−) mice were pair-fed control or ethanol liquid diets for 4 weeks. One group of wild type mice received rolipram, a PDE4 specific inhibitor, during alcohol feeding. Liver steatosis was evaluated by Oil-Red-O staining and documented by biochemical assessment of hepatic triglycerides and free fatty acids. Expression of hepatic PDE4 and the effect of PDE4 inhibition on protein expression and activity of key enzymes involved in lipid metabolism were evaluated at both mRNA and protein levels. Results: We demonstrate for the first time that the early increase in the lipogenic genes Acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) in alcohol fed wild type mice coincides with the

significant up-regulation of hepatic PDE4 expression. Notably, pde4b−/− mice and mice treated with rolipram had significantly lower hepatic free fatty acid content compared to wild type mice fed alcohol for 4 MCE公司 weeks. PDE4 inhibition did not affect alcohol metabolism as demonstrated by unaltered CYP2E1 expression in both pde4b−/− and mice treated with rolipram. Importantly, PDE4 inhibition in alcohol fed mice: (i) BI 6727 prevented the decrease in hepatic sirtuin 1 (SIRT-1) levels; (ii) decreased hepatic ACC activity; and (iii) increased hepatic CPT1 a expression. Conclusion: These results demonstrate that alcohol induced increase in hepatic PDE4 expression

is a significant pathogenic mechanism underlying dysregulated lipid metabolism and the development of hepatic steatosis. Moreover, these data also suggest that hepatic PDE4 is a clinically relevant therapeutic target for the treatment of alcohol induced hepatic steatosis. Disclosures: Craig J. McClain – Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco, Abbott, Genentech; Grant/Research Support: Ocera, Merck, Glaxo SmithKline; Speaking and Teaching: Roche Shirish Barve – Speaking and Teaching: Abbott The following people have nothing to disclose: Diana Avila, Jingwen Zhang, Leila Gobejishvili Excess alcohol consumption is a leading cause of liver disease worldwide. In its severe form, alcoholic steatohepatitis (ASH) has a dismal prognosis with short-term mortality rates approaching 40%, in part due to only modestly effective medical therapies. As such, an urgent need exists to better understand the pathogenesis of ASH in order to develop more effective therapies.

Third, anti-M3R antibodies may play important

roles in the pathogenesis of PBC. Interestingly, M3R is expressed in biliary tracts as well as in exocrine glands and smooth muscles,[1] and vagal nerve stimulation via M3R is known to induce the growth of bile duct epithelial cells.[15] Moreover, we showed previously that anti-M3R antibodies could alter Ca influx in human salivary glands cells after stimulation of M3R by specific agonists.[6, 16] Anti-M3R antibodies may react to M3R on bile duct epithelial cells LEE011 ic50 and could affect M3R signaling in these cells. In addition to such a pathogenic role, anti-M3R antibodies could explain the organ-specificity of PBC. Finally, the results in this study indicated that antibodies reactive to the first loop had the high specificity (80.0–100%) between PBC and CHC, NASH, PSC, obstructive jaundice, drug-induced liver injury and controls. Therefore, autoimmune response against the first extracellular loop of M3R may have specific pathogenic roles in the generation of PBC. In conclusion, we demonstrated in the present study that the majority of patients with PBC carry anti-M3R antibodies, similar to AMA, and that anti-M3R antibodies especially against the first extracellular loop are a potentially useful diagnostic

marker of CAL-101 order PBC. The study also clarified that anti-M3R antibodies had several B-cell epitopes on the extracellular domains of M3R, and that many PBC patients carried anti-M3R antibodies that recognized several extracellular domains of M3R. Moreover, the pathogenic roles of anti-M3R antibodies in PBC are expected to be clarified in the near future. WE THANK DR F. G. Issa for the critical reading of the manuscript. “
“Obesity

is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Steatosis, the hallmark feature of NAFLD, occurs when the rate of hepatic fatty acid uptake from plasma and de novo fatty acid synthesis is greater than the rate of fatty acid oxidation and export (as triglyceride within very low-density lipoprotein). Therefore, an excessive amount of intrahepatic triglyceride (IHTG) represents an imbalance between complex interactions of metabolic events. MCE The presence of steatosis is associated with a constellation of adverse alterations in glucose, fatty acid, and lipoprotein metabolism. It is likely that abnormalities in fatty acid metabolism, in conjunction with adipose tissue, hepatic, and systemic inflammation, are key factors involved in the development of insulin resistance, dyslipidemia, and other cardiometabolic risk factors associated with NAFLD. However, it is not clear whether NAFLD causes metabolic dysfunction or whether metabolic dysfunction is responsible for IHTG accumulation, or possibly both. Understanding the precise factors involved in the pathogenesis and pathophysiology of NAFLD will provide important insights into the mechanisms responsible for the cardiometabolic complications of obesity.