Download causality assessment in drug induced liver injury

Arie Regev M.D.
Chair, Liver and GI Safety Committee
Global Patient Safety
Eli Lilly & Company
Global
Patient
roduct
Safety
Drug Induced Steatosis
and Steatohepatitis
Arie Regev, M.D.
Global Patient Safety
Eli Lilly and Company
Hepatic Steatosis
Definitions and Nomenclature (I)


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Hepatic steatosis is defined as fat deposition within
hepatocytes.
It is seen microscopically as vacuoles of fat in a
microvesicular or macrovesicular distribution.
Stetohepatitis is defined as fat deposition WITH
inflammation/ liver cell damage (i.e. ballooning) or hepatic
fibrosis
Liver Disorders Associated with Steatosis

Hepatic steatosis is associated with various liver disorders:
 alcoholic liver disease
 nonalcoholic fatty liver disease (NAFLD)
nonalcoholic steatohepatitis (NASH)
 hepatitis C
 Wilson’s disease
 acute fatty liver of pregnancy
 drug induced steatosis
NAFLD/NASH Versus Drug Induced
Steatosis/Steatohepatitis (I)
 NAFLD/NASH ≠ drug induced steatosis/steatohepatitis!!
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Nonalcoholic liver disease (NAFLD) is defined by the
presence of hepatic steatosis in people who do not consume
alcohol in high quantities and do not take drugs that may
cause steatosis.
Nonalcoholic steatohepatitis (NASH) is a subgroup of
NAFLD patients that show features of steatohepatitis
(inflammation/ ballooning/ fibrosis)
Studies on NAFLD and NASH exclude patients who drink
high quantities of alcohol or take drugs that are known to
cause steatosis.
Based on abundant evidence, clinical manifestations and
prognosis of NAFLD/NASH is generally different from drug
induced steatosis/steatohepatitis
Pathogenesis of NAFLD/NASH
Pathogenesis

“The dogma of sequential progression from NAFL to
NASH has grown out of favor”1
1. Paredes AH, et al. Clin Liver Dis 2012;16:397-419
NAFLD Pathogenesis
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The vast majority of NAFLD cases occur in the setting of
insulin resistance1
The pathogenesis of NAFLD involves multiple
interactions between the liver and peripheral adipose
tissue1,2
Insulin resistance promotes hepatic triglyceride
accumulation by causing imbalance between
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
factors that favor hepatic lipid accumulation AND
factors that decrease lipid build-up
1. Feldstein A, et al. Seminars in Liver Disease 2012;30:391
2. Smith BW, et al. Nat Rev Endocrinol 2011;7:456-465
NASH Pathogenesis
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In a subgroup of patients an adipose tissue inflammatory
response results in secretion of proinflammatory cytokines1
Suspected mechanism:
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inability to appropriately expand adipose tissue in the setting of
obesity leads to local hypoxia2
activation of adipocyte cell death signaling and apoptosis leads to
accumulation of adipose tissue macrophages 3
Adipose tissue secretes inflammatory cytokines (e.g. IL-6,
TNF) and reduced amounts of adiponecting
Inflammatory cytokines together with steatosis induce
oxidative stress and activate fibrogenic hepatic stellate cells
to cause NASH
1. Feldstein A, et al. Seminars in Liver Disease 2012;30:391
2. Ye J, et al. Am J Physiol Endocrinol Metab
2007;293:E1118–1128
3. Alkhouri N, et al. J Biol Chem 2010;285(5):3428–3438
Drug Induced Steatosis
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Drugs associated with hepatic steatosis:
 aspirin
 methotrexate
 amiodarone
 glucocorticoids
 tamoxifen
 5-fluorouracil
 valproate
 NRTIs* (zidovudine and didanosine)
*NRTIs, nucleoside reverse transcriptase inhibitors
Patel and Sanyal. Clin Liver Dis 2013:17;533–546
Mechanisms of Drug Induced Steatosis
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The mechanisms leading to DIS and steatohepatitis are not well
understood and often extrapolated from NASH literature.
In some cases the pathogenesis of liver damage is thought to
include:
 mitochondrial dysfunction
 increased reactive oxygen species (ROS) formation
 Endoplasmic Reticulum (ER) stress that induces
Inflammation
 liver cell death
 hepatic fibrosis
Patel and Sanyal. Clin Liver Dis 2013:17;533–546
Stravitz and Sanyal .Clin Liver Dis 2003;7:435–51.
Farrell GC. Semin Liver Dis 2002;22:185–94.
Suspected Mechanisms of Drug Induced Steatosis/steatohepatitis
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•
•
•
•
Inhibition of entry of long chain fatty acids (FFA) via the carnitine palmitoyl shuttle (CPT)
Inhibition of ß-oxidation leading to increased free fatty acids which are esterified to TG
Blocked transport of TG as very low density lipoprotein (VLDL)
Blocked flow of electrons through the electron transport chain (ETC)
Accumulation of electrons can lead to direct interaction with oxygen to produce reactive
oxygen species (ROS).
• Damage to mtDNA can induce mitochondrial permeability transition (MTP) pore formation
Patel and Sanyal. Clin Liver Dis 2013:17;533–546
Clinical Manifestations and Suspected Mechanisms
Drug
Clinical Manifestations
Pathologic
Findings
Suspected
Mechanisms
Aspirin
Reye syndrome: lactic acidosis
and hepatic dysfunction with
encephalopathy, hypoglycemia,
but mild increase in TBL. In
children with viral infection.
Develops within a few days.
Often rapidly fatal.
Microvesicular
steatosis
Arrests ß oxidation
by consuming CoA.
Increases
mitochondrial
permeability by MPT
pore formation.
Methotrexate Asymptomatic steatosis after a
long term treatment. May lead to
fibrosis and cirrhosis. Increased
risk with higher cumulative doses.
Macrovesicular
steatosis,
steatohepatitis,
fibrosis and
cirrhosis
Inhibits
mitochondrial
electron transport
chain
Amiodarone
Macrovesicular
steatosis,
steatohepatitis,
hepatic necrosis,
phospholipidosis
Decreases ß
oxidation; increases
lipid peroxidation,
ROS generation and
lipogenesis
Hepatocellular or cholestatic
injury. More common with
prolonged administration and
higher dose. May resemble
alcoholic liver disease
Patel and Sanyal. Clin Liver Dis 2013:17;533–546
NIDDK LiverTox.
Clinical Manifestations and Suspected Mechanisms
Drug
Clinical Manifestations
Pathologic
Findings
Suspected
Mechanisms
Corticosteroids
Hepatomegaly and steatosis,
with long term administration.
Usually due to worsening of
underlying NAFLD. Steatosis
is rapidly reversed with
discontinuation. Progressive
liver disease is rare.
Macrovesicular
steatosis. Can
also cause
hepatic
glycogen
accumulation.
Promote weight gain,
glucose intolerance;
inhibit mitochondrial
ß oxidation, decrease
hepatic triglyceride
secretion, and induce
lipid peroxidation
5-fluorouracil
Usually limited to transient
asymptomatic increases in
ALT. Clinically significant
liver injury is rare. Rare cases
of hyperammonemia and coma
with normal liver tests were
described with high IV doses.
Macrovesicular Unknown
steatosis.
Typically
isolated with no
steatohepatitis.
Tamoxifen
Steatosis after long term
therapy (years.) Typically
improves on withdrawal. Mild
or no ALT/AST changes.
Macrovesicular
steatosis and
steatohepatitis.
Rare cirrhosis
Patel and Sanyal. Clin Liver Dis 2013:17;533–546.
NIDDK LiverTox.
Promotes de novo
fatty acid synthesis.
Inhibits ß oxidation.
Worsens NAFLD.
Clinical Manifestations and Suspected Mechanisms (III)
Drug
Clinical Manifestations
Pathologic
Findings
Suspected Mechanisms
Valproate
May cause acute
hepatocellular injury or
Reye’s like syndrome. May
cause steatosis in a high
percentage of patients. May
worsen NAFLD through
weight gain and worsening
of insulin resistance.
Microvesicular
steatosis and
cirrhosis
Inhibits CPT-1 activity,
sequestering CoA;
arresting ETC and ATP
synthesis; promotes weight
gain
NRTIs
(zidovudine
and
didanosine)
May cause acute liver injury Microvesicular
steatosis and
which may lead to hepatic
steatohepatitis
failure and metabolic
acidosis. Serum enzymes
are only modestly elevated
and may initially be normal.
May worsen preexisting
NAFLD.
Mitochondrial dysfunction
by mtDNA depletion and
stimulation of autophagy
NRTIs, nucleoside reverse transcriptase inhibitors
Patel and Sanyal. Clin Liver Dis 2013:17;533–546
NIDDK LiverTox.
Diagnosis of Drug Induced Steatosis/Steatohepatitis
versus Typical Hepatocellular DILI
Different
 ALT/AST/ALP changes may
be milder or absent
 Time to onset typically longer
than hepatocellular DILI*
 Time to resolution often
longer (chronic injury)**
 Other common causes of
steatosis difficult to rule out
(NAFLD/NASH, alcoholic
liver disease)
 Hepatic imaging may help
make the diagnosis
* Rare examples of a rapid onset
Similar
 Rechallenge not
recommended
 No specific/diagnostic
biomarkers
 Histopathology generally not
specific and not diagnostic
(e.g. Reye syndrome)
** Rapid resolution less common but possible (e.g. corticosteroids.)
Detecting DIS During Drug Development
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Currently possible only when DIS is associated with:
 changes in basic hepatic biochemical tests:
ALT/AST/ALP/TBL
May be absent
 signs and symptoms of liver dysfunction
Rare and
 systemic manifestations (e.g. metab. acidosis) too late
May be detected only through hepatic imaging
(ultrasonography, CT, MRI, MRS) or liver biopsy
Not monitored in the majority of clinical trials
Asymptomatic DIS that is not associated with changes in
hepatic biochemical tests, may not be detected in today’s
clinical trials.
Summary (I)
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Drug induced steatosis/steatohepatitis (DIS) is a group of
heterogenous disorders which are characterized by fat
accumulation in hepatocytes
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In most known cases of DIS, clinical features, clinical course,
biomarkers and prognosis are different from those of
NAFLD/NASH
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In most cases, clinical features, biomarkers and clinical outcome
are different for different drugs
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There are currently no reliable biomarkers to predict the course,
severity or prognosis of DIS
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Although specific biomarkers of fibrosis and necrosis may be
useful for certain cases of NAFLD, there is no evidence that the
use of such markers can be extrapolated to DIS
Summary (II)
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In contrast with most cases of hepatocellular or cholestatic
DILI, DIS may not be associated with significant changes in
basic hepatic biochemical tests (ALT/AST/ALP/TBL)
There are currently no approved biomarkers which reliably
detect or predict DIS during drug development.
Liver imaging and liver biopsy are currently the only reliable
methods to detect drug induced steatosis
There are currently no approved biomarkers that reliably
differentiate between drug induced steatosis and
steatohepatitis.