The Temporal Profile of Increased Transaminase Levels in Patients With Acetaminophen-Induced Liver Dysfunction

Singer, Adam J.; Carracio, Thomas R; Mofenson, Howard C.

doi:10.1016/s0196-0644(95)70237-7

Cited by 82 publications

(47 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The Plasma compartment represents systemic circulation. Creation of the Intermediate compartment was required to optimize serum ALT dynamics observed in clinical response to several hepatotoxic compounds15, 23, 24, 25 and may represent the ALT in the interstitial space, the Space of Disse, or the liver sinusoids. The clearance of ALT is driven by a specified half‐life 26.…”

Section: Methodsmentioning

confidence: 99%

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo

Generaux

Howell

et al. 2017

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa‐treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., “Hy's Law”). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug‐induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.

show abstract

Section: Methodsmentioning

confidence: 99%

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo

Generaux

Howell

et al. 2017

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

show abstract

“…4 In ischemic or toxic liver injury, AST levels usually peak before those of ALT because of the enzyme's peculiar intralobular distribution. [27][28][29] Zone 3 of the acinus is more vulnerable to both hypoxic (hepatocytes are exposed to an already oxygen-poor milieu) and toxic (hepatocytes are richer in microsomal enzymes) damage. Furthermore, in ischemic injury aminotransferase levels tend to decrease rapidly after peaking (Fig.…”

Section: Marked and Moderate Aminotransferase Increasementioning

confidence: 99%

Liver enzyme alteration: a guide for clinicians

Giannini

Testa

Savarino

2005

Canadian Medical Association Journal

1,542

1,038

View full text Add to dashboard Cite

ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

show abstract

“…13 Another study, which included only patients with some degree of toxicity, found that six of eight who developed severe toxic hepatitis had an elevated aspartate aminotransferase (AST) within 24 hours of ingestion. 14 The AST in the other two increased within 36 hours. Also, an elevated aminotransferase level prior to NAC initiation is a consistent finding in acetaminophen fatalities.…”

mentioning

confidence: 96%

Medical Fortune‐telling: Predicting Acetaminophen Toxicity

Donovan

1999

Academic Emergency Medicine

View full text Add to dashboard Cite

The Temporal Profile of Increased Transaminase Levels in Patients With Acetaminophen-Induced Liver Dysfunction

Cited by 82 publications

References 14 publications

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Liver enzyme alteration: a guide for clinicians

Medical Fortune‐telling: Predicting Acetaminophen Toxicity

Contact Info

Product

Resources

About