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The majority of reported cases of hepatotoxicity associated with anti-TNF agents
have been in women [ 69 – 71 ]. The mean age of patients with anti-TNF-associated
hepatotoxicity ranges from 32 to 46 years [ 68 , 70 , 71 ].
Pathophysiology
The pathophysiology of anti-TNF agent-induced liver injury has not been clearly
defined [ 71 ]. Liver biopsies in these cases often reveal hepatocellular injury with
features of autoimmunity [ 70 , 71 ]. Proposed mechanisms include increase in the
number of autoreactive immune cells leading to autoimmune hepatitis; induction of
an immune system imbalance due to cytokine blockade; a selective effect on T
helper cell subsets and immune complex formation, exposing an underlying disease
in a patient with genetic susceptibility; or a break in self-tolerance following the
exposure of hidden antigens [ 69 ].
Diagnosis and Management
Diagnosis of hepatotoxicity associated with anti-TNF therapy requires exclusion of
other underlying causes of liver disease. As discussed previously, hepatotoxicity
associated with anti-TNF therapy can occur after just one dose of the anti-TNF
agent [ 76 ], though the average latency described in the literature is 14–18 weeks
[ 68 , 70 , 71 ]. The majority of affected patients presents with progressive elevation in
transaminases (ALT or AST > 3x upper limit of normal), although a minority pres-
ents with bland cholestasis [ 70 , 71 ].
When hepatotoxicity is suspected after initiation of an anti-TNF therapy, a thor-
ough history including the use of alcohol and both prescription and over-the-counter
medications and supplements should be included in the evaluation. It is crucial to
exclude viral infections including acute hepatitis A, acute or reactivation of chronic
hepatitis B, hepatitis C, hepatitis E, cytomegalovirus, and Epstein-Barr infections [ 70 ,
71 ]. In addition, autoimmune serology including antinuclear antibody, anti- dsDNA,
anti-mitochondrial antibody, and anti-liver/kidney microsomal antibodies should be
obtained. Right upper quadrant ultrasound or cross-sectional imaging is recommended
to exclude biliary obstruction or structural abnormalities. A liver biopsy should be
considered if serology and imaging are unrevealing for other causes of liver injury.
Among the 34 patients with hepatotoxicity attributed to anti- TNF therapy, Ghabril
et al. noted that 22 had positive responses to ANA and/or anti-smooth muscle antibody
or had histological features of autoimmunity on liver biopsy (see Fig. 14.4) [ 70 ].
The prognosis of anti-TNF therapy-associated hepatotoxicity is generally good
[ 70 , 71 ]. The majority of patients recover from hepatotoxicity after discontinuation
of the implicated anti-TNF therapy, with or without the addition of corticosteroid
[ 70 – 72 ]. Among the six subjects from the DILI network who had hepatotoxicity
attributed to anti-TNF therapy, all patients recovered and were able to be withdrawn
U. Wong and R.K. Cross