Background & Aims The drug-induced liver injury network (DILIN) is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study. Methods In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI. Results Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P=.09) and mortality was significantly higher (16% vs 5.2%; P<.001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared to those without liver disease (6.7% vs. 1.5%, p=0.006). Forty-one cases with latency ≤ 7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared to individuals younger than 65 y, individuals 65 y or older (n=149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died. Conclusion Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared to patients without. Further studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.

Sprouting angiogenesis is critical to blood vessel formation, but the cellular and molecular controls of this process are poorly understood. We used time-lapse imaging of green fluorescent protein (GF-P)-expressing vessels derived from stem cells to analyze dynamic aspects of vascular sprout formation and to determine how the vascular endothelial growth factor (VEGF) receptor flt-1 affects sprouting. Surprisingly, loss of flt-1 led to decreased sprout formation and migration, which resulted in reduced vascular branching. This phenotype was also seen in vivo, as flt-1 ؊/؊ embryos had defective sprouting from the dorsal aorta. We previously showed that loss of flt-1 increases the rate of endothelial cell division. However, the timing of division versus morphogenetic effects suggested that these phenotypes were not causally linked, and in fact mitoses were prevalent in the sprout field of both wild-type and flt-1 ؊/؊ mutant vessels. Rather, rescue of the branching defect by a soluble flt-1 (sflt- 1 IntroductionThe first step in the formation of most blood vessels is the production of an intricately branched vascular plexus. [1][2][3] This plexus is subsequently pruned and remodeled and in some cases coalesced to form larger vessels. The primary branched plexus forms by several processes, including the initial assembly of vascular precursor cells called vasculogenesis, and the subsequent migration of endothelial cells from the parent vessel called sprouting angiogenesis. The sprouts that form migrate until they reach another sprout or vessel, whereupon they most often form connections that are essential for elaborating and expanding the branched network. Although the formation of vascular sprouts has been described historically, 4-6 surprisingly little is known of the cellular processes and molecular controls of sprout formation, and even less is known about how these processes are integrated with other ongoing cellular events such as cell division.The vascular sprouts that form during embryonic development extend from primitive vessels. Individual endothelial cells send out filopodia, then migrate away from the parent vessel without breaking all contacts with surrounding cells, so that eventually multiple cells comprise the sprout. Cell numbers in the sprout are also increased by cell division behind the leading tip of the sprout. 6,7 Formation of a branched vascular plexus depends on the regulated expression of vascular endothelial growth factor-A (VEGF-A) by nonendothelial cells. This signal modulates intracellular signaling pathways that regulate endothelial cell division, migration, and survival. 8 This regulation is dose-dependent, as modest changes in the amount of available VEGF-A in either direction compromise vascular development, and loss of even one copy of the Vegf-A gene leads to vascular disruption and embryonic lethality. 9-13 Availability also seems to be regulated by the production of different isoforms of VEGF-A via alternative splicing. These isoforms have differing affinities for matrix componen...

Context Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. Objective Define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. Design Cross-sectional evaluation. Participants 23 patients (22 with familial, one acquired, 78.3% female, aged 12–64 years) with PL and non-alcoholic fatty liver disease (NAFLD). Measurements Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by MRI, histopathological and immunofluorescence examinations of liver biopsies. Results 7 patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691.3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1.5) of %fat trunk to %fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11.3+6.3%) and correlated positively with hemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78.3%), hypertension (56.5%) and mood disorders (52.2%) were highly prevalent. Mean NAFLD Activity Score (NAS) score was 5±1 and 78.3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. Conclusions PL is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

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Peribiliary glands (PBGs) are clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts (EHBDs). While their function is largely undefined, they may represent a stem cell niche. Here, we hypothesized that PBGs are populated by mature and undifferentiated cells capable of proliferation in pathological states. To address this hypothesis, we developed a novel whole-mount immunostaining assay that preserves the anatomical integrity of EHBDs coupled with confocal microscopy, and found that PBGs populate the entire length of the extrahepatic biliary tract, except the gallbladder. Notably, in addition to the typical position of PBGs adjacent to the duct mucosa, PBGs elongate and form intricate intramural epithelial networks that communicate between different segments of the bile duct mucosa. Network formation begins where the cystic duct combines with hepatic ducts to form the common bile duct, and continues along the common bile duct. The cells of PBGs and the peribiliary network stain positively for α-tubulin, mucins, and chromogranin A, as well as for endoderm transcription factors Sox17 and Pdx1, and proliferate robustly following duct injury induced by virus infection and bile duct ligation. Conclusion PBGs form elaborate epithelial networks within the walls of EHBDs, contain cells of mature and immature phenotypes, and proliferate in response to bile duct injury. The anatomical organization of the epithelial network in tubules and the link with PBGs support an expanded cellular reservoir with the potential to restore the integrity and function of the bile duct mucosa in diseased states.