HTHSCI 1DT3 Lecture Notes - Lecture 12: Azathioprine, Alcohol Dehydrogenase, C4A
23 Jun 2018
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Clinical problem
Idiosyncratic drug reactions are difficult to predict, as only seen when 100s of individuals take
the drug i.e. after trials
With unfractionated heparin, 30% get a rise in transaminases but no one gets a drug reaction c.f.
in isoniazid, 15% get raised trasnsaminases, 1% get jaundice and 0.1% die from LI
The answer is to detect sensitization
This is possible in sensitised individuals via lymphocyte proliferation test or Patch test for:
omeprazole, abacavir, methotrexate and clarithromycin (etc)
It is possible for abacavir in non-
sensitised individuals, but only in those
with certain HLA restrictions e.g. HLA-
B*5701 (but not non-HLA-B*5701). This
is detected via in vitro exposure of Px
CTLs to drug and subsequent
monitoring of IFN-gamma levels
Examples of HLAs predisposing to DILI
However, other genetic factors aside
from HLA status have a role as not all HLA+ get the DILI
Wei, 2012: if you add antibody against the HLA class 1 in the presence of the drug you can
prevent hepatotoxicity (in carbamazepine) – implicating the drug-TCR reaction
Factors allowing prediction of which drugs may cause DILIs
A number of HLA alleles that confer risk have been identified, as have other genetic
polymorphisms e.g. in P450, metabolisers, transporters
Biochemical / metabolic analysis can analyse how far the drug is causing mitochondrial
damage / danger signals and if these factors exhibit inter-individual differences is telling
Demonstration of in vitro sensitisation in non-sensitised subjects
Importance of the innate immune system in DILI
Involved in all DILI
The direct liver injury is exacerbated by downstream activation of the innate system: the
damaged hepatocytes release cytokines which trigger Kupffer cells, NK cells and T cells
How far the innate immune response mediates damage is due to a balance: either injurious
response mediated by IFN-gamma, Fas, TNF-alpha (injurious) vs. IL-10, IL-6, MIP-2, MCP-1, IP-10
(protective)
CYPs = important autoantigens associated with DILI
genetic background of individual and innate immunity shown to be increasingly important
Pathology of AIH – Rob Goldin
AIH is an acute clinical problem but histology shows chronic damage thus its classification is
controversial
Presentation: moderate-severe hepatitis, increased ALT and AST, normal to moderately-raised
alk phosph and GGT
IgG is raised, c.f. IgA in ALD
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Idiosyncratic drug reactions are difficult to predict, as only seen when 100s of individuals take the drug i. e. after trials. With unfractionated heparin, 30% get a rise in transaminases but no one gets a drug reaction c. f. in isoniazid, 15% get raised trasnsaminases, 1% get jaundice and 0. 1% die from li. This is possible in sensitised individuals via lymphocyte proliferation test or patch test for: omeprazole, abacavir, methotrexate and clarithromycin (etc) It is possible for abacavir in non- sensitised individuals, but only in those with certain hla restrictions e. g. hla- This is detected via in vitro exposure of px. Ctls to drug and subsequent monitoring of ifn-gamma levels. However, other genetic factors aside from hla status have a role as not all hla+ get the dili. Wei, 2012: if you add antibody against the hla class 1 in the presence of the drug you can prevent hepatotoxicity (in carbamazepine) implicating the drug-tcr reaction.
