Assessment of Hepatotoxicity

De La Iglesia FA, Sturgess JM, Feuer G. 1982. New approaches for the assessment of hepatotoxicity by means of quantitative functional-morphological interrelationships. In Plaa G, Hewitt WR, eds. Toxicology of the liver. NewYork, NY RavenPress, 47-102. 

Obviously, even with a combinatorial assessment of hepatotoxic mechanisms, a relatively simple in vitro system cannot recapitulate all of the mechanisms... 

In safety pharmacology, a number of renal functional tests, such as creatinine and electrolyte measurements, can be supported by most clinical chemistry laboratories (Kinter, Gossett, and Kerns 1994 Seuter 1996 ICH 2000). In some of the later chapters discussing assessments of hepatotoxicity and renal toxicity, a few functional tests are mentioned. Although it may be desirable to include function tests in repeated-dose toxicity studies, given the additional and sometimes invasive procedures, these tests may be better performed by incorporation into single-dose toxicity studies or separate additional studies (Matsuzawa et al. 1997). 

S-transferase in the assessment of hepatotoxicity—Its diagnostic utility in comparison with other recognized markers in the Wistar Han rat. Toxicological Pathology 30 365-372. 

Marchant CA, Fisk L, Note RR, Patel ML, Suarez D (2009) An expert system approach to the assessment of hepatotoxic potential. Chem Biodivers 6, 2107-14. 

Xu, J.J., Diaz, D. and O Brien, P.J. (2004) Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential. Chemico-Biological Interactions, 150, 115—128. 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

New biomarkers will be useful in hepatotoxicity risk assessment if the data quality and validity can be established. The FDA defines a valid biomarker as one that can be measured in an analytical test system with well-established performance characteristics and has an established scientific framework or body of evidence that elucidates the significance of the test results [160]. Although there is no formerly agreed upon path, biomarker validation should include appropriate end-points for study (i.e., toxicology, histopathology, bioanalytical chemistry, etc.) and dose- and time-dependent measurements. An assessment of species, sex and strain susceptibility is also important to evaluate across species differences. More specific considerations for validation of gene and protein expression technologies are reviewed by Corvi et al. and Rifai et al. [144, 147]. 

Smialowicz RJ, Simmons JE, Luebke RW, et al. 1991. Immunotoxicologic assessment of subacute exposure of rats to carbon tetrachloride with comparison to hepatotoxicity and nephrotoxicity. Fund AppI Toxicol 17 186-196. 

Recommended testing should include a white blood cell count and differential to permit assessment of neutropenic side effects. The total lymphocyte count as a measure of ART treatment response is unreliable and not generally recommended. Serum alanine or aspartate aminotransferase (ALT, AST) level determinations are recommended to monitor for hepatotoxicity. Creatinine and phosphate should be measured 4 weeks after initiation of tenofovir. 

Assessment of the hepatotoxicity of acute and short-term exposure to inhaled / -xylene in F-... 

Campbell, D.L., Lawton, L.A., Beattie, K.A. and Codd, G.A. (1994) Comparative assessment of the specificity of the brine shrimp and Microtox assays to hepatotoxic (microcystin-LR-containing) cyanobacteria, Environmental Toxicology and Water Quality 9 (1), 71-77. 

Relevant adverse effects are discussed in Chapter 6. It is important to determine whether the drug you are considering can cause any of these effects, and if so, the severity and the likelihood of those effect(s) occurring. This information will influence the risk-benefit assessment of the use of the medication in your patient. In addition, if you choose to use a drug that has potential associated risks, you will need to know which adverse effects to look out for, to ensure safe treatment. For example, which side effects suggest accumulation, which signs/symptoms/test results suggest hepatotoxicity ... 

There is a theoretical concern that chronic alcoholics are at an increased risk of paracetamol hepatotoxicity. However, from the shortterm data available in controlled situations, there seems to be no increased risk of hepatotoxicity when these patients are administered therapeutic doses of paracetamol. Some evidence suggests that the potential increased risk of hepatotoxicity may be related more to poor diet and fasting than to the effects of the alcohol. Longer-term controlled studies are still needed to assess the risks of chronic therapeutic dosing in alcoholics. 

Many centres prefer to avoid using NSAIDs in any patient with liver disease because of their side-effect profile. However, if the liver disorder is purely cholestatic in origin and the disease has not progressed to cirrhosis and portal hypertension, NSAIDs may be an option. Any risk-benefit assessment should consider the potential risk of hepatotox-icity, albeit rare. There are no specific contraindications in this patient because they are not cirrhotic, do not have deranged clotting, and are unlikely to be at increased risk of deteriorating renal function. If deemed necessary an NSAID could be used cautiously. 

Two small studies have examined the effect of HRT on liver function tests in healthy women. The women had regular assessment of their liver function tests during therapy. Hepatotoxicity and cholestasis were not observed [10, 11]. 

Penicillin-induced hepatotoxicity may not be as uncommon as has been thought. There have been three reviews. The first was a comparison of the assessment of drug-induced liver injury obtained by two different methods, the Council for International Organizations of Medical Sciences (CIOMS) scale and the Maria Victorino (M V) clinical scale (66). Three independent experts evaluated 215 cases of hepatotoxicity reported using a structured reporting form. There was absolute agreement between the two scales in 18% of cases, but there was no agreement in cases of fulminant hepatitis or death. The authors concluded that the CIOMS instrument is more likely to lead to a conclusion compatible with the specialist s empirical approach. 

Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La Cuesta F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001 33(l) 123-30. 

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