Platelets in chronic liver disease, from bench to bedside

Ramadori, Pierluigi; Klag, Thomas; Malek, Nisar P.; Heikenwälder, Mathias

doi:10.1016/j.jhepr.2019.10.001

Cited by 58 publications

(48 citation statements)

References 110 publications

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“…Possible causes include splenic sequestration of platelets, suppression of platelet production in the bone marrow, decreased thrombopoetin production in the liver and an autoimmune mediated destruction[ 5 ]. Additionally, platelets actively participate in pathophysiologic processes in the liver, resulting in fibrosis and cirrhosis; previous studies including animal models showed that platelets have a major role in liver inflammation via interactions with the hepatic sinusoidal endothelium and myeloid cells, inducing diverse hepatic processes ranging from liver repair and regeneration to necroinflammation and fibrosis[ 10 , 11 ]. Additionally, studies hypothesized that circulating platelet-neutrophil aggregates can induce neutrophil activation, thus driving end organ damage in patients with cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis

Gotlieb¹,

Schwartz²,

Zelber‐Sagi³

et al. 2020

WJG

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BACKGROUND Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension (HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts (PTC), when still within the normal range, and the risk of cirrhosis. AIM To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases. METHODS A nested case-control study utilizing a large computerized database. Cirrhosis cases ( n = 5258) were compared to controls ( n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores (fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated. RESULTS The mean age in both groups was 56 (SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who’s PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis (95%CI 1.25-1.35). CONCLUSION In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.

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Section: Introductionmentioning

confidence: 99%

Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis

Gotlieb¹,

Schwartz²,

Zelber‐Sagi³

et al. 2020

WJG

View full text Add to dashboard Cite

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“…The general downregulation of ‘Platelet activation’ (Additional File 5 ) broadly agreed with this scenario, since liver dysfunction is usually reported in combination with an activation of platelets, often considered dynamic sentinels interacting with immune cells [ 134 – 136 ]. In this context, the marked upregulation of M-SAA3.2 ( Mammary Serum Amyloid A3.2 ) [FC = 5.70] was noteworthy (Table 8 ).…”

Section: Discussionmentioning

confidence: 72%

Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows

et al. 2021

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Background Methionine (Met) supply during late-pregnancy enhances fetal development in utero and leads to greater rates of growth during the neonatal period. Due to its central role in coordinating nutrient and one-carbon metabolism along with immune responses of the newborn, the liver could be a key target of the programming effects induced by dietary methyl donors such as Met. To address this hypothesis, liver biopsies from 4-day old calves (n = 6/group) born to Holstein cows fed a control or the control plus ethyl-cellulose rumen-protected Met for the last 28 days prepartum were used for DNA methylation, transcriptome, metabolome, proteome, and one-carbon metabolism enzyme activities. Results Although greater withers and hip height at birth in Met calves indicated better development in utero, there were no differences in plasma systemic physiological indicators. RNA-seq along with bioinformatics and transcription factor regulator analyses revealed broad alterations in ‘Glucose metabolism’, ‘Lipid metabolism, ‘Glutathione’, and ‘Immune System’ metabolism due to enhanced maternal Met supply. Greater insulin sensitivity assessed via proteomics, and efficiency of transsulfuration pathway activity suggested beneficial effects on nutrient metabolism and metabolic-related stress. Maternal Met supply contributed to greater phosphatidylcholine synthesis in calf liver, with a role in very low density lipoprotein secretion as a mechanism to balance metabolic fates of fatty acids arising from the diet or adipose-depot lipolysis. Despite a lack of effect on hepatic amino acid (AA) transport, a reduction in metabolism of essential AA within the liver indicated an AA ‘sparing effect’ induced by maternal Met. Conclusions Despite greater global DNA methylation, maternal Met supply resulted in distinct alterations of hepatic transcriptome, proteome, and metabolome profiles after birth. Data underscored an effect on maintenance of calf hepatic Met homeostasis, glutathione, phosphatidylcholine and taurine synthesis along with greater efficiency of nutrient metabolism and immune responses. Transcription regulators such as FOXO1, PPARG, E2F1, and CREB1 appeared central in the coordination of effects induced by maternal Met. Overall, maternal Met supply induced better immunometabolic status of the newborn liver, conferring the calf a physiologic advantage during a period of metabolic stress and suboptimal immunocompetence.

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“…This common programme is very similar to human NAFLD and NASH (Teufel et al 2016). Downregulation of fatty acid metabolism and positive enrichment of platelets and haemostasis-related pathways is a hallmark of our data as well as transcriptomes of human NASH (Arendt et al 2015; Mardinoglu et al 2014; Moylan et al 2014; Ramadori et al 2019; Naguib et al 2020).…”

Section: Discussionmentioning

confidence: 76%

Common transcriptional programme of liver fibrosis in mouse genetic models and humans

Cokan

Urlep

Moškon

et al. 2020

Preprint

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Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden of modern societies and frequently present with no clearly defined molecular biomarkers. Herein we used systems medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways. Enrichment analyses of KEGG, Reactome and TRANSFAC databases complemented with genome-scale metabolic modelling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional programme with activated ERα signalling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or sex.

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Platelets in chronic liver disease, from bench to bedside

Cited by 58 publications

References 110 publications

Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis

Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis

Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows

Common transcriptional programme of liver fibrosis in mouse genetic models and humans

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