The Effects of Heparins on the Liver: Application of Mechanistic Serum Biomarkers in a Randomized Study in Healthy Volunteers

Abstract

Heparins have been reported to cause elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) but have not been associated with clinically significant liver injury. The mechanisms underlying these benign laboratory abnormalities are unknown. Forty-eight healthy men were randomized to receive subcutaneous injections of unfractionated heparin (UFH; 150 U/kg), enoxaparin sodium (1 mg/kg), dalteparin sodium (120 IU/kg), or adomiparin sodium (125 IU/kg; a novel heparin) every 12 h for 4.5 days. Asymptomatic elevations in serum ALT or AST were observed in >90% of the subjects. Elevations were also observed in the levels of serum sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), miR-122, high-mobility group box-1 protein (including the acetylated form), full-length keratin 18, and DNA. Keratin 18 fragments, which are apoptosis biomarkers, were not detected. Biomarker profiles did not differ significantly across heparin treatments. We conclude that heparins as a class cause self-limited and mild hepatocyte necrosis with secondary activation of an innate immune response.

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

“…Time‐dependent elevations in levels of serum biomarkers specifically associated with liver injury, miR‐122 ( Figure 1 a ) and GLDH ( Figure 1 b ), were observed in four subjects, including the two subjects meeting Hy's Law criteria (Subjects 8 and 12 in Figure 1). The maximal observed values for miR‐122 and GLDH were comparable to those previously reported in healthy adults receiving therapeutic doses of acetaminophen12 and heparins13 and are, on average, 25× lower than elevations seen for serious DILI induced by acetaminophen overdose 14. In all subjects, the increase in miR‐122 returned to baseline values and GLDH appeared to be returning to baseline levels at the final measurement on Day 28.…”

“…DILIsym modeling in a simulated population of patients encompassing variability in relevant parameters predicted that the maximum percent hepatocyte loss was <13% in patients completing the phase I clinical trials. The estimated peak values for hepatocyte loss are in the range of what has been estimated to occur as a result of asymptomatic and reversible elevations in serum aminotransferases observed in healthy adults during recurrent therapeutic doses of acetaminophen12 or heparins13 rather than clinically important hepatotoxicity. It is of note that both of the putative Hy's Law cases did experience symptoms at the time of the biochemical abnormalities; one experienced nausea and abdominal pain and the other experienced flu‐like symptoms.…”

Influence of Fondaparinux Versus Nadroparin Calcium Thromboprophylaxis on Clinical Parameters Following Total Knee Arthroplasty

“…Our results showed an increase in AST and ALT levels immediately after the surgery in the patients receiving nadroparin calcium, while in the patients receiving fondaparinux the levels of AST and ALT decreased throughout their hospital stay. Although it is known that LMWH can lead to an increase of ALT level, it is hypothesized that this increase does not pose a problem for liver function, but is simply a reaction to direct stimulation of hepatocytes, immunoreaction, or a transient increase of LMWH half-life 19 . None of our patients developed any symptoms regarding liver function and no further examination was needed regarding this issue.…”

MicroRNAs in Liver Disease: Bench to Bedside

“…However, miR-122 alone may not be an ideal DILI biomarker because it does not distinguish benign clinical ALT elevations from serious liver injury potential. 105 It is also not specific enough to uniquely identify acetaminophen toxicity. 106 Future challenges will be to determine whether miR-122 can provide clinical prognostic value over current biomarkers of DILI in prospective clinical trials and real-life clinical situations with other etiologies of liver disease.…”