Fatal liver injury associated with clopidogrel

Kastalli, Sarrah; Aidli, Sihem El; Zaiem, Ahmed; Abdallah, H. Ben; Daghfous, Riadh

doi:10.1111/j.1472-8206.2009.00791.x

Cited by 12 publications

(12 citation statements)

References 10 publications

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“…In humans, at least one episode of idiosyncratic hepatotoxicity and progressive liver failure has been attributed to the antiplatelet drug clopidogrel (11). Millions of individuals take drugs that alter 5-HT homeostasis as treatments for depression and other neuropsychiatric disorders.…”

Section: Discussionmentioning

confidence: 99%

Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults

Omenetti

Yang

Gainetdinov

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β1. Increased TGF-β1, in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.

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Section: Discussionmentioning

confidence: 99%

Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults

Omenetti

Yang

Gainetdinov

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…increased with age [364]. Various side effects have been reported for both clopidogrel (bleeding, liver and bone injury, enhanced lipopolysaccharide-induced inflammation) [365,366] and ticagrelor (bleeding, dyspnoea) [367]. In more recent reports, it was suggested that there may be a role for endogenous adenosine in ticagrelor-induced dyspnoea [368,369].…”

Section: Thrombosismentioning

confidence: 99%

Blood cells: an historical account of the roles of purinergic signalling

Burnstock

2015

Purinergic Signalling

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The involvement of purinergic signalling in the physiology of erythrocytes, platelets and leukocytes was recognised early. The release of ATP and the expression of purinoceptors and ectonucleotidases on erythrocytes in health and disease are reviewed. The release of ATP and ADP from platelets and the expression and roles of P1, P2Y 1 , P2Y 12 and P2X1 receptors on platelets are described. P2Y 1 and P2X1 receptors mediate changes in platelet shape, while P2Y 12 receptors mediate platelet aggregation. The changes in the role of purinergic signalling in a variety of disease conditions are considered. The successful use of P2Y 12 receptor antagonists, such as clopidogrel and ticagrelor, for the treatment of thrombosis, myocardial infarction and stroke is discussed.

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“…3–9 These include eight men and four women, aged 56–89 years old, that developed liver injury 4 days to 6 months after clopidogrel intake. The pattern of liver injury was mainly mixed hepatocelullar-cholestatic, but hepatocellular liver injury and systemic inflammatory response syndrome with hepatic injury were also observed.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent case of clopidogrel liver injury with liver failure and fatal outcome was published. 3 …”

Section: Discussionmentioning

confidence: 99%