Shear wave elasticity imaging (SWEI) has found success in liver fibrosis staging. However, technical failure and unreliable shear wave speed (SWS) estimation have been reported to increase both with ...elevated patient body mass index (BMI) and in the presence of significant hepatic fibrosis. Elevated BMI results in a significant amount of subcutaneous fat which attenuates acoustic radiation force (ARF) and abberates tracking beams. Advanced fibrosis results in small displacement amplitudes in stiff livers. This work evaluates hepatic SWEI measurement success as a function of push pulse energy using 2 Mechanical Index (MI) values (1.6 and 2.2) over a range of pulse durations. The rate of successful SWS estimation for 8 repeated measurements is linearly proportional to the push energy level. As expected, elevated push energy in SWEI measurements results in higher displacement signal-to-noise ratio (SNR). SWEI measurements with elevated push energy are successful in patients for whom standard push energy levels failed. Deep liver capsule is shown to be an indicator for lower yield of SWS estimation. Patients with deep liver capsules are likely to benefit from elevated push energies. We conclude that there is clinical benefit to using elevated acoustic output for hepatic SWS measurement in "difficult to image" patients.
Background & Aims Repair responses define the ultimate outcomes of liver disease. This study evaluated the hypothesis that fibrogenic repair in nonalcoholic fatty liver disease (NAFLD) is mediated by ...Hedgehog (Hh) pathway activation and consequent induction of epithelial-to-mesenchymal transitions (EMT) in ductular-type progenitors. Methods Immature ductular cells were exposed to Sonic hedgehog (Shh) in the presence or absence of the Hh inhibitor cyclopamine to determine whether Hh-pathway activation directly modulates EMT in liver progenitors. Potential biologic correlates of progenitor cell EMT were assessed using mice fed methionine-choline-deficient + ethionine (MCDE) diets with or without cyclopamine. The effects of increased Hh signaling on EMT and fibrogenic repair during diet-induced NAFLD were also compared in wild-type (WT) and Patched haplo-insufficient (Ptc+/− ) mice. Finally, evidence of Hh-pathway activation and EMT was examined in liver sections from patients with NAFLD. Results In cultured progenitors, Shh repressed expression of epithelial genes and EMT inhibitors but induced genes that are expressed by myofibroblasts. Cyclopamine reversed these effects. In mouse NAFLD models, Hh-pathway activation, EMT, expansion of myofibroblastic populations, and liver fibrosis occurred. Cyclopamine inhibited Hh-pathway activation and induction of EMT. Ptc+/− mice, which have an overactive Hh pathway, exhibited sustained overinduction of Hh target genes and more EMT, myofibroblast accumulation, and fibrosis than WT mice. Numbers of Shh-producing cells and Hh-responsive ductular cells that expressed EMT markers increased in parallel with liver fibrosis in patients with NAFLD. Conclusions Hh-mediated EMT in ductular cells contributes to the pathogenesis of cirrhosis in NAFLD.
Abstract Background & Aims Elafibranor is an agonist of the peroxisome proliferator activated receptor-α (PPARA) and peroxisome proliferator activated receptor-δ (PPARD). Elafibranor improves insulin ...sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy of elafibranor in an international, randomized, double-blind placebo-controlled trial of patients with non-alcoholic steatohepatitis (NASH). Methods Patients with NASH without cirrhosis were randomly assigned to groups given elafibranor 80 mg (n=93), elafibranor 120 mg (n=91), or placebo (n=92) each day for 52 weeks at sites in Europe and the United States. Clinical and laboratory evaluations were performed every 2 months over this 1 year period. Liver biopsies were then collected and patients were assessed 3 months later. The primary outcome was resolution of NASH without fibrosis worsening, using protocol-defined and modified definitions. Data from the groups given the different doses of elafibranor were compared with those from the placebo group using step-down logistic regression, adjusting for baseline nonalcoholic fatty liver disease activity score (NAS). Results In intention-to-treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, NASH resolved without fibrosis worsening in a higher proportion of patients in the 120 mg elafibranor group vs the placebo group (19% vs 12%; odds ratio OR, 2.31; 95% confidence interval CI, 1.02–5.24; P =.045), based on a post-hoc analysis for the modified definition. In post-hoc analyses of patients with NAS ≥4 (n=234), elafibranor 120 mg resolved NASH in larger proportions of patients than placebo based on the protocol definition (20% vs 11%; OR=3.16; 95% CI, 1.22–8.13; P =.018) and the modified definitions (19% vs 9%; OR=3.52; 95% CI, 1.32–9.40; P =.013). Patients with NASH resolution after receiving elafibranor 120 mg had reduced liver fibrosis stages compared to those without NASH resolution (mean reduction of 0.65 + 0.61 in responders for the primary outcome vs an increase of 0.10 + 0.98 in non-responders; P <.001). Liver enzymes, lipids, glucose profiles, and markers of systemic inflammation were significantly reduced in the elafibranor 120 mg group vs the placebo group. Elafibranor was well tolerated and did not cause weight gain or cardiac events, but did produce a mild, reversible increase in serum creatinine (effect size vs placebo: increase of 4.31±1.19 μmol/L, P <.001). Conclusions A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/day for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH. However, the predefined endpoint was not met in the intention to treat population. Elafibranor was well tolerated and improved patients’ cardiometabolic risk profile. Clinicaltrials.gov number: NCT01694849
We describe 2 patients presenting with polyarthritis in whom the synovial fluid (1 patient) or synovial tissue (1 patient) was positive for Tropheryma whippelii, the Whipple's disease–associated ...bacillus, when examined by polymerase chain reaction (PCR) and DNA sequencing. Histopathologic findings were consistent with articular Whipple's disease in the synovial fluid of 1 patient and the synovial tissue of the other. In both patients, bowel mucosal specimens were negative for Whipple's disease features by histologic and PCR methods. One patient was positive for T whippelii in the peripheral blood. Control synovial fluid specimens from 40 patients with other arthritides, including Lyme arthritis, were negative. Sequencing of a 284‐basepair region of the 16S ribosomal RNA gene confirmed that the sequence is closely related to the known T whippelii sequence. Both patients responded to treatment with antibiotics.
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