Summary
Background
Validated diagnostic tools that are accurate, cost effective and acceptable to patients are required for disease stratification and monitoring in NAFLD.
Aims
To investigate the ...performance and cost of multiparametric MRI alongside existing biomarkers in the assessment of NAFLD.
Methods
Adult patients undergoing standard of care liver biopsy for NAFLD were prospectively recruited at two UK liver centres and underwent multiparametric MRI, blood sampling and transient elastography withing 2 weeks of liver biopsy. Non‐invasive markers were compared to histology as the gold standard.
Results
Data were obtained in 50 patients and 6 healthy volunteers. Corrected T1 (cT1) correlated with NAFLD activity score (ρ = 0.514, P < .001). cT1, enhanced liver fibrosis (ELF) test and liver stiffness differentiated patients with simple steatosis and NASH with AUROC (95% CI) of 0.69 (0.50‐0.88), 0.87 (0.77‐0.79) and 0.82 (0.70‐0.94) respectively and healthy volunteers from patients with AUROC (95% CI) of 0.93 (0.86‐1.00), 0.81 (0.69‐0.92) and 0.89 (0.77‐1.00) respectively. For the risk stratification of NAFLD, multiparametric MRI could save £150,218 per 1000 patients compared to biopsy. Multiparametric MRI did not discriminate between individual histological fibrosis stages in this population (P = .068).
Conclusions
Multiparametric MRI accurately identified patients with steatosis, stratifies those with NASH or simple steatosis and reliably excludes clinically significant liver disease with superior negative predictive value (83.3%) to liver stiffness (42.9%) and ELF (57.1%). For the risk stratification of NAFLD, multiparametric MRI was cost effective and, combined with transient elastography, had the lowest cost per correct diagnosis.
Linked content
This article is linked to Ferraioli paper. To view this article visit https://doi.org/10.1111/apt.14501.
Glucose is the major fuel for fetal oxidative metabolism. A positive maternal–fetal glucose gradient drives glucose across the placenta and is sufficient to meet the demands of the fetus, eliminating ...the need for endogenous hepatic glucose production (HGP). However, fetuses with intrauterine growth restriction (IUGR) from pregnancies complicated by placental insufficiency have an early activation of HGP. Furthermore, this activated HGP is resistant to suppression by insulin. Here, we present the data demonstrating the activation of HGP in animal models, mostly fetal sheep, and human pregnancies with IUGR. We also discuss potential mechanisms and pathways that may produce and support HGP and hepatic insulin resistance in IUGR fetuses.
•Intrauterine growth restricted fetuses have increased hepatic glucose production.•Mechanisms include changes in hormone signals, insulin action, and substrate supply.•Increased hepatic glucose production is a complication in IUGR neonates.•Persistence across the lifespan is a hallmark of type 2 diabetes.
Key points
Adults who were affected by intrauterine growth restriction (IUGR) suffer from reductions in muscle mass, which may contribute to insulin resistance and the development of diabetes.
We ...demonstrate slower hindlimb linear growth and muscle protein synthesis rates that match the reduced hindlimb blood flow and oxygen consumption rates in IUGR fetal sheep. These adaptations resulted in hindlimb blood flow rates in IUGR that were similar to control fetuses on a weight‐specific basis.
Net hindlimb glucose uptake and lactate output rates were similar between groups, whereas amino acid uptake was significantly lower in IUGR fetal sheep.
Among all fetuses, blood O2 saturation and plasma glucose, insulin and insulin‐like growth factor‐1 were positively associated and norepinephrine was negatively associated with hindlimb weight.
These results further our understanding of the metabolic and hormonal adaptations to reduced oxygen and nutrient supply with placental insufficiency that develop to slow hindlimb growth and muscle protein accretion.
Reduced skeletal muscle mass in the fetus with intrauterine growth restriction (IUGR) persists into adulthood and may contribute to increased metabolic disease risk. To determine how placental insufficiency with reduced oxygen and nutrient supply to the fetus affects hindlimb blood flow, substrate uptake and protein accretion rates in skeletal muscle, late gestation control (CON) (n = 8) and IUGR (n = 13) fetal sheep were catheterized with aortic and femoral catheters and a flow transducer around the external iliac artery. Muscle protein kinetic rates were measured using isotopic tracers. Hindlimb weight, linear growth rate, muscle protein accretion rate and fractional synthetic rate were lower in IUGR compared to CON (P < 0.05). Absolute hindlimb blood flow was reduced in IUGR (IUGR: 32.9 ± 5.6 ml min−1; CON: 60.9 ± 6.5 ml min−1; P < 0.005), although flow normalized to hindlimb weight was similar between groups. Hindlimb oxygen consumption rate was lower in IUGR (IUGR: 10.4 ± 1.4 μmol min−1 100 g−1; CON: 14.7 ± 1.3 μmol min−1 100 g−1; P < 0.05). Hindlimb glucose uptake and lactate output rates were similar between groups, whereas amino acid uptake was lower in IUGR (IUGR: 1.3 ± 0.5 μmol min−1 100 g−1; CON: 2.9 ± 0.2 μmol min−1 100 g−1; P < 0.05). Blood O2 saturation (r2 = 0.80, P < 0.0001) and plasma glucose (r2 = 0.68, P < 0.0001), insulin (r2 = 0.40, P < 0.005) and insulin‐like growth factor (IGF)‐1 (r2 = 0.80, P < 0.0001) were positively associated and norepinephrine (r2 = 0.59, P < 0.0001) was negatively associated with hindlimb weight. Slower hindlimb linear growth and muscle protein synthesis rates match reduced hindlimb blood flow and oxygen consumption rates in the IUGR fetus. Metabolic adaptations to slow hindlimb growth are probably hormonally‐mediated by mechanisms that include increased fetal norepinephrine and reduced IGF‐1 and insulin.
Key points
Adults who were affected by intrauterine growth restriction (IUGR) suffer from reductions in muscle mass, which may contribute to insulin resistance and the development of diabetes.
We demonstrate slower hindlimb linear growth and muscle protein synthesis rates that match the reduced hindlimb blood flow and oxygen consumption rates in IUGR fetal sheep. These adaptations resulted in hindlimb blood flow rates in IUGR that were similar to control fetuses on a weight‐specific basis.
Net hindlimb glucose uptake and lactate output rates were similar between groups, whereas amino acid uptake was significantly lower in IUGR fetal sheep.
Among all fetuses, blood O2 saturation and plasma glucose, insulin and insulin‐like growth factor‐1 were positively associated and norepinephrine was negatively associated with hindlimb weight.
These results further our understanding of the metabolic and hormonal adaptations to reduced oxygen and nutrient supply with placental insufficiency that develop to slow hindlimb growth and muscle protein accretion.
Intrauterine growth restriction (IUGR) of the fetus, resulting from placental insufficiency (PI), is characterized by low fetal oxygen and nutrient concentrations that stunt growth rates of metabolic ...organs. Numerous animal models of IUGR recapitulate pathophysiological conditions found in human fetuses with IUGR. These models provide insight into metabolic dysfunction in skeletal muscle and liver. For example, cellular energy production and metabolic rate are decreased in the skeletal muscle and liver of IUGR fetuses. These metabolic adaptations demonstrate that fundamental processes in mitochondria, such as substrate utilization and oxidative phosphorylation, are tempered in response to low oxygen and nutrient availability. As a central metabolic organelle, mitochondria coordinate cellular metabolism by coupling oxygen consumption to substrate utilization in concert with tissue energy demand and accretion. In IUGR fetuses, reducing mitochondrial metabolic capacity in response to nutrient restriction is advantageous to ensure fetal survival. If permanent, however, these adaptations may predispose IUGR fetuses toward metabolic diseases throughout life. Furthermore, these mitochondrial defects may underscore developmental programming that results in the sequela of metabolic pathologies. In this review, we examine how reduced nutrient availability in IUGR fetuses impacts skeletal muscle and liver substrate catabolism, and discuss how enzymatic processes governing mitochondrial function, such as the tricarboxylic acid cycle and electron transport chain, are regulated. Understanding how deficiencies in oxygen and substrate metabolism in response to placental restriction regulate skeletal muscle and liver metabolism is essential given the importance of these tissues in the development of later lifer metabolic dysfunction.
In a sheep model of intrauterine growth restriction (IUGR) produced from placental insufficiency, late gestation fetuses had smaller skeletal muscle mass, myofiber area, and slower muscle protein ...accretion rates compared with normally growing fetuses. We hypothesized that IUGR fetal muscle develops adaptations that divert amino acids (AAs) from protein accretion and activate pathways that conserve substrates for other organs. We placed hindlimb arterial and venous catheters into late gestation IUGR (
= 10) and control (CON,
= 8) fetal sheep and included an external iliac artery flow probe to measure hindlimb AA uptake rates. Arterial and venous plasma samples and biceps femoris muscle were analyzed by mass spectrometry-based metabolomics. IUGR fetuses had greater abundance of metabolites enriched within the alanine, aspartate, and glutamate metabolism pathway compared with CON. Net uptake rates of branched-chain AA (BCAA) were lower by 42%-73%, and muscle ammoniagenic AAs (alanine, glycine, and glutamine) were lower by 107%-158% in IUGR hindlimbs versus CON. AA uptake rates correlated with hindlimb weight; the smallest hindlimbs showed net release of ammoniagenic AAs. Gene expression levels indicated a decrease in BCAA catabolism in IUGR muscle. Plasma purines were lower and plasma uric acid was higher in IUGR versus CON, possibly a reflection of ATP conservation. We conclude that IUGR skeletal muscle has lower BCAA uptake and develops adaptations that divert AAs away from protein accretion into alternative pathways that sustain global energy production and nitrogen disposal in the form of ammoniagenic AAs for metabolism in other organs.
The prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic ...disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.
Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to increasing prevalence of these diseases, yet ...mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro-inflammatory phenotypes at the transcriptional, metabolic, and functional levels in bone marrow-derived macrophages (BMDMs) from 3-year-old juvenile offspring and in hematopoietic stem and progenitor cells (HSPCs) from fetal and juvenile bone marrow and fetal liver. mWSD exposure is also associated with increased oleic acid in fetal and juvenile bone marrow and fetal liver. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling of HSPCs and BMDMs from mWSD-exposed juveniles supports a model in which HSPCs transmit pro-inflammatory memory to myeloid cells beginning in utero. These findings show that maternal diet alters long-term immune cell developmental programming in HSPCs with proposed consequences for chronic diseases featuring altered immune/inflammatory activation across the lifespan.
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•Maternal Western-style diet (mWSD) produces pro-inflammatory macrophages in juvenile non-human primates•Metabolism/functional potential of mWSD-exposed fetal HSPCs mirrors juvenile HSPCs•mWSD increases chromatin accessibility in juvenile HSPC and BMDM inflammatory genes•Oleic acid increases in bone marrow of mWSD-exposed fetuses and juveniles
Using nonhuman primate models, Nash et al. show that maternal Western-style diet provokes reprogramming of fetal hematopoietic stem and progenitor cells to transmit pro-inflammatory memory to myeloid cells for years after weaning, even when offspring are fed a conventional diet, predisposing these offspring to inflammatory disease across the lifespan.
•Chemotherapy induces microbiome disruption, inflammation, and cognitive decline.•The resulting microbiome disruption relates to cognitive decline and inflammation.•Those cognitively impaired have ...unique chemotherapy-induced microbiome alterations.
Chemotherapy is notorious for causing behavioral side effects (e.g., cognitive decline). Notably, the gut microbiome has recently been reported to communicate with the brain to affect behavior, including cognition. Thus, the aim of this clinical longitudinal observational study was to determine whether chemotherapy-induced disruption of the gut microbial community structure relates to cognitive decline and circulating inflammatory signals. Fecal samples, blood, and cognitive measures were collected from 77 patients with breast cancer before, during, and after chemotherapy. Chemotherapy altered the gut microbiome community structure and increased circulating TNF-α. Both the chemotherapy-induced changes in microbial relative abundance and decreased microbial diversity were related to elevated circulating pro-inflammatory cytokines TNF-α and IL-6. Participants reported subjective cognitive decline during chemotherapy, which was not related to changes in the gut microbiome or inflammatory markers. In contrast, a decrease in overall objective cognition was related to a decrease in microbial diversity, independent of circulating cytokines. Stratification of subjects, via a reliable change index based on 4 objective cognitive tests, identified objective cognitive decline in 35% of the subjects. Based on a differential microbial abundance analysis, those characterized by cognitive decline had unique taxonomic shifts (Faecalibacterium, Bacteroides, Fusicatenibacter, Erysipelotrichaceae UCG-003, and Subdoligranulum) over chemotherapy treatment compared to those without cognitive decline. Taken together, gut microbiome change was associated with cognitive decline during chemotherapy, independent of chemotherapy-induced inflammation. These results suggest that microbiome-related strategies may be useful for predicting and preventing behavioral side effects of chemotherapy.
IGF-1 is a critical fetal growth-promoting hormone. Experimental infusion of an IGF-1 analog, human recombinant LR3 IGF-1, into late gestation fetal sheep increased fetal organ growth and skeletal ...muscle myoblast proliferation. However, LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), thus reducing physiologic regulation of IGF-1 bioavailability. The peptide sequences for LR3 IGF-1 and sheep IGF-1 also differ. To overcome these limitations with LR3 IGF-1, we developed an ovine (sheep) specific recombinant IGF-1 (oIGF-1) and tested its effect on growth in fetal sheep. First, we measured
myoblast proliferation in response to oIGF-1. Second, we examined anabolic signaling pathways from serial skeletal muscle biopsies in fetal sheep that received oIGF-1 or saline infusion for 2 hours. Finally, we measured the effect of fetal oIGF-1 infusion versus saline infusion (SAL) for 1 week on fetal body and organ growth,
myoblast proliferation, skeletal muscle fractional protein synthetic rate,
expression in skeletal muscle and liver, and IGF-1 signaling pathways in skeletal muscle. Using this approach, we showed that oIGF-1 stimulated myoblast proliferation
. When infused for 1 week, oIGF-1 increased organ growth of the heart, kidney, spleen, and adrenal glands and stimulated skeletal myoblast proliferation compared to SAL without increasing muscle fractional synthetic rate or hindlimb muscle mass. Hepatic and muscular gene expression of
was similar between oIGF-1 and SAL. We conclude that oIGF-1 promotes tissue and organ-specific growth in the normal sheep fetus.
Studying fetal hematopoiesis is challenging as hematopoiesis transitions from the liver to bone marrow. Obtaining human samples is not possible, and small animal models may not provide sufficient ...biological material. Here, we present a protocol for isolating hematopoietic cells from the nonhuman primate fetal liver and bone. We describe steps for using cells from the same fetus for fluorescence lifetime imaging microscopy to measure metabolism, assessing cellular function, and flow cytometry for immunophenotyping at the single-cell level.
For complete details on the use and execution of this protocol, please refer to Nash et al. (2023).1
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•Instructions for isolation of mononuclear cells from NHP fetal liver and bone marrow•Instructions for separating CD34+ and CD34- cells using column enrichment•Descriptions of downstream immunophenotypic, functional, and metabolic assays
Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
Studying fetal hematopoiesis is challenging as hematopoiesis transitions from the liver to bone marrow. Obtaining human samples is not possible, and small animal models may not provide sufficient biological material. Here, we present a protocol for isolating hematopoietic cells from the nonhuman primate fetal liver and bone. We describe steps for using cells from the same fetus for fluorescence lifetime imaging microscopy to measure metabolism, assessing cellular function, and flow cytometry for immunophenotyping at the single-cell level.
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