The utilization of liver transplantation in the management of acute liver failure: Comparison between acetaminophen and non-acetaminophen etiologies

Simpson, Kenneth J.; Bates, C.M.; Henderson, Neil C.; Wigmore, Stephen J.; Garden, O. J.; Lee, Alistair; Pollok, Antony; Masterton, George; Hayes, Peter

doi:10.1002/lt.21681

Cited by 91 publications

(93 citation statements)

References 40 publications

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“…Laboratory investigations were repeated at daily intervals or more frequently in patients with rapidly progressive liver failure. Patients admitted to the SLTU are managed using a standard protocol as previously described, with patients with paracetamol poisoning treated with a continuous NAC infusion (6.25 mg kg -1 h -1 ) until the international normalized ratio (INR) is less than 2 [11]. The main therapeutic goals of this protocol have remained similar over the 16 years of this cohort study.The modified King's College Hospital poor prognostic criteria (KCC) are used in this unit and throughout the UK to determine patients who will most likely die without OLT [12].…”

Section: Patientsmentioning

confidence: 99%

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Craig¹,

Bates²,

Davidson³

et al. 2012

Brit J Clinical Pharma

Self Cite

143

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WHAT IS ALREADY KNOWN ON THIS SUBJECT• Paracetamol hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK.• Relatively little is known regarding the impact of staggered overdose pattern or delayed hospital presentation upon subsequent mortality or need for emergency liver transplantation.WHAT THIS STUDY ADDS• Staggered paracetamol overdoses, frequently taken to relieve pain, are strongly associated with reduced survival compared with single time point overdose.• Staggered paracetamol overdoses should be treated as high risk for the development of multiorgan failure, and should be considered for N‐acetyl cysteine treatment irrespective of admission serum paracetamol concentrations.• The King's College poor prognostic criteria may have reduced sensitivity in staggered overdose patients.AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose.RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol‐induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P= 0.025), although this overdose pattern did not independently predict death. The King's College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P= 0.009).CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi‐organ failure and should be considered for early transfer to specialist liver centres.

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Section: Patientsmentioning

confidence: 99%

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Craig¹,

Bates²,

Davidson³

et al. 2012

Brit J Clinical Pharma

Self Cite

143

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“…A recent study from the UK suggested that OLT is a more favorable approach to managing patients with non-APAP induced ALF compared to patients with APAP induced ALF. This was predominantly due to the frequent psychosocial contraindications in patients with APAP induced ALF (Simpson et al, 2009).…”

Section: Etiologymentioning

confidence: 99%

“…In the United Kingdom, about 30% of patients initially considered for OLT ultimately become untransplantable following the development of complications (i.e., cerebral edema, sepsis, hemodynamic abnormalities, multiorgan system failure) (Bernal et al, 1998). Additionally, many patients have medical or psychosocial contraindications to transplantation, including irreversible brain injury, underlying cardiovascular disease, infection/sepsis, alcohol or drug abuse, poorly controlled psychiatric disease, or inadequate family support (Simpson et al, 2009). Thus, it is important to identify and delist patients who are too ill to benefit from OLT.…”

Section: Prognosis and Prognostic Modelsmentioning

confidence: 99%

Role of Liver Transplantation in Acute Liver Failure

Liou

Larson

2008

Semin Liver Dis

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“…Its overdose, however, can be life threatening, causing severe liver and kidney damage (2)(3)(4)(5). In Western countries, acetaminophen-induced hepatotoxicity is a leading cause of acute liver failure requiring liver transplantation (6). Due to a widespread availability of acetaminophen and potentially lethal consequences of its overdose, the mechanisms of acetaminophen hepatotoxicity have been in focus of a large number of investigations (7).…”

mentioning

confidence: 99%

TRPM2 channels mediate acetaminophen-induced liver damage

Kheradpezhouh

Morphett

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

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Acetaminophen (paracetamol) is the most frequently used analgesic and antipyretic drug available over the counter. At the same time, acetaminophen overdose is the most common cause of acute liver failure and the leading cause of chronic liver damage requiring liver transplantation in developed countries. Acetaminophen overdose causes a multitude of interrelated biochemical reactions in hepatocytes including the formation of reactive oxygen species, deregulation of Ca 2+ homeostasis, covalent modification and oxidation of proteins, lipid peroxidation, and DNA fragmentation. Although an increase in intracellular Ca 2+ concentration in hepatocytes is a known consequence of acetaminophen overdose, its importance in acetaminophen-induced liver toxicity is not well understood, primarily due to lack of knowledge about the source of the Ca 2+ rise. Here we report that the channel responsible for Ca 2+ entry in hepatocytes in acetaminophen overdose is the Transient Receptor Potential Melanostatine 2 (TRPM2) cation channel. We show by whole-cell patch clamping that treatment of hepatocytes with acetaminophen results in activation of a cation current similar to that activated by H 2 O 2 or the intracellular application of ADP ribose. siRNA-mediated knockdown of TRPM2 in hepatocytes inhibits activation of the current by either acetaminophen or H 2 O 2 . In TRPM2 knockout mice, acetaminophen-induced liver damage, assessed by the blood concentration of liver enzymes and liver histology, is significantly diminished compared with wildtype mice. The presented data strongly suggest that TRPM2 channels are essential in the mechanism of acetaminophen-induced hepatocellular death.

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The utilization of liver transplantation in the management of acute liver failure: Comparison between acetaminophen and non-acetaminophen etiologies

Cited by 91 publications

References 40 publications

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

Role of Liver Transplantation in Acute Liver Failure

TRPM2 channels mediate acetaminophen-induced liver damage

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