This document discusses antithyroid drugs and their potential to cause liver injury. It provides background on the common antithyroid drugs propylthiouracil (PTU) and methimazole, and their uses and side effects. The mechanisms of antithyroid drug-induced liver injury are not fully understood, but may involve reactive metabolites, genetic factors, and immune responses. Factors like age, gender, concomitant medications, and underlying thyroid conditions can also influence the risk of liver injury. Therapeutic strategies discussed include drug cessation, monitoring liver function, and potential protective treatments in experimental models.
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Antithyroid Drugs and Liver Injury Risk Factors
1. Antithyroid drugs and liver
Alaa Wafa. MD
Associate Professor of Internal Medicine
Diabetes and Endocrine unit
Mansoura university
Thyroalex ( 8 May 2015)
3. Anti thyroid drugs
• An antithyroid agent is a hormone
antagonist acting upon thyroid hormones.
• (also called thionamides)
• Mostly used to treat hyperthyroidism
caused by Graves' disease.
• Antithyroid drugs block the formation , so
decrease the levels of the two hormones
produced by the thyroid, thyroxine (T4) and
triiodothyronine (T3)
4. short-term TTT in people with
Graves' to prepare for thyroid
surgery or radioiodine.
long-term TTT, approximately 30 %
of people with Graves' disease will
have a remission after prolonged
TTT with antithyroid drugs.
TTT of hyperthyroidism associated
with TMNG or a toxic adenoma
("hot nodule"), usually to prepare
for thyroid surgery or radioiodine.
TTT of hyperthyroidism during
pregnancy.
Antithyroid
drugs may
be used as
5. TYPES OF ANTITHYROID DRUGS
• propylthiouracil (PTU)
• methimazole(MMI, Tapazole).
In USA
• propylthiouracil (PTU)
• Carbimazole (which is
converted into MMI in the
body)
In Europe
A less common antithyroid agent is potassium
perchlorate.
6. Methimazole
• Reverses hyperthyroidism more
quickly than PTU
• Fewer side effects.
• It requires an average of six weeks to lower
T4 levels to normal
• Often given before radioactive iodine
treatment.
• Can be taken once per day.
7. Propylthiouracil
• Does not reverse hyperthyroidism
as rapidly as MMI
• Has more side effects.
• Because of its potential for liver damage,
it is used only when MMI or carbimazole are
not appropriate.
• PTU must be taken two to three times per
the day.
8. • The drug of choice during pregnancy
• Experts now recommend that PTU be given
during the first trimester only.because there
have been rare cases of liver damage in
people taking PTU.
• Women who are nursing, methimazole is a
better choice than PTU (to avoid liver side
effects).
Propylthiouracil
10. Side effects of antithyroid drugs
• Mostly are minor, but major side effects can
occur.
• No way to predict who will experience side
effects
• It is important to discuss all possible side
effects before starting treatment.
• If antithyroid treatments cannot be tolerated,
we can consider radioiodine treatment or
surgery.
11. • It can occur in up to 15 % of people who take
an antithyroid drug in Both MMI and PTU:
itching
rash
joint pain and swelling
fever
changes in taste
nausea, and vomiting.
Minor side effects
12. If one drug another
causes
side effects drug
Switch to
13. Fortunately, the major side effects of
antithyroid drugs are very rare.
• Agranulocytosis
• liver damage
• aplastic anemia
• vasculitis
Major side effects
14. Fortunately, the major side effects of
antithyroid drugs are very rare.
• Agranulocytosis
• liver damage
• aplastic anemia
• vasculitis
Major side effects
15.
16.
17.
18. mechanism of antithyroid drug associated liver damage
• The mechanism is not clear
• this type of drug induced liver injury
(DILI) is uncommon
• Not obviously related to drug dose
• multifactorial dependent
• Therefore, these reactions are termed 'idiosyncratic'
DILI (IDILI).
19. Mechanism of antithyroid drug associated liver damage
• Despite the great effects of these drugs
in controlling hyperthyroidism, their administration is
associated with hepatotoxicity as a serious side
effect.
• Hepatic injury induced by these agents
could be so severe that might lead to
hepatic failure and requirement for liver
transplantation,and even death has been reported in
some cases.
20.
21. Propylthiouracil was approved for
marketing in 1947.
Its frequency is approximately 0.1% based
on the available data.
PTU associated liver damage typically
occurs within three months of starting the
drug.
Patients should be counseled to recognize
and report symptoms suggestive of hepatic
dysfunction (especially in first 6 months of
treatment), which should prompt
immediate discontinuation
22. • The FDA's Adverse Event Reporting
System
A total of 32(22 adult & 10 pediatric)
cases of serious liver injury associated
with the use of PTU were reported to
since that system was established in
1969 through October 2008
Of the 22 adult cases, the FDA
identified 12 deaths and five liver
transplants.
Of the 10 pediatric cases, there was
one death and six reports of liver
transplant.
23. Pathologic findings of PTU-induced hepatic
injury in human subjects
Parenchymal necrosis with hemorrhage,
Collapse of lobular architecture,
Preportal mixed inflammatory infiltrate.
24. • The pattern of hepatic injury by PTU
Hepatocellular type in most cases
Hepatic reactions: in the form of
hepatitis
Severe liver injury (some fatal)
acute liver failure (some cases requiring
transplantation) have been reported
25. Liver transaminase abnormality
o indicate subclinical liver injury which
considered a common event after PTU
administration
o incidence with PTU is very high compared
with methimazole .
asymptomatic elevation of serum ALT
developed in 14.3% of investigated patients
in a single center retrospective study.
PTU therapy might be continued with
caution in the presence of elevated liver
transaminases, without hyperbilirubinemia .
27. • Methimazole-induced hepatotoxicity
usually develops in the first few weeks
of drug consumption with an estimated
incidence of 0.1-0.2%.
• The pattern of liver injury induced by
methimazole is predominantly as
cholestatic type
• Pathhologic findings
oedema and inflammation of portal
tract with intracanalicular cholestasis
and moderate microvascular steatosis
34. • PTU is metabolized by glucuronidation in liver
• No PTU-related reactive metabolite(s) has been
suggested yet to induce hepatotoxic reactions.
But, it has been founded that myeloperoxidase
(MPO)-mediated metabolism of PTU led to a
reactive metabolite formation which covalently
bounded to leukocytes proteins.
• This reactions might be responsible for
agranulocytosis as a deleterious adverse effect
of PTU
35. • The exact CYP enzyme involved in methimazole
and/or PTU metabolism is not characterized yet,
• hence further investigations are required to
elucidate the possible role of enzyme variation
in the hepatotoxicity induced by these drugs.
• Moreover, future investigations could focus on
the possibility of reactive metabolite formation
during PTU biotransformation in liver.
37. • Sulfenic acids may have a role in
methimazole-induced hepatotoxicity.
• N-methylthiourea is proposed to be the main
methimazole reactive metabolite responsible
for the hepatotoxicity induced by this drug.
• glyoxal also might has an important role in
cellular injury induced by methimazole
38. • As methimazole is suspected to metabolized
to reactive intermediate(s) which might
involve in the hepatic injury induced by this
drug
• polymorphism in drug metabolizing enzymes
might has a role in the idiosyncratic nature of
the hepatic injury induced by this antithyroid
medication.
39. • As mentioned, glucuronidation is a one of the
metabolic pathways for antithyroid drugs
(especially PTU) to preparing them for
excretion
• The polymorphism in uridine
diphosphoglucuronosyl transferase enzymes
(UGTs) activity is also identified between
human populations.
40. • Hence, another proposed mechanism for
hepatotoxicity induced by antithyroid agents
could be attributed to their impaired
detoxification process, due to lower activity
of UGTs.
• Consequently, some populations might be at
a greater risk for these drugs to induce
hepatic injury
41. • Since some investigations mentioned a potential
role for "sulfur" atom in antithyroid agents to
induce toxicity during metabolism,substituting
"sulfur" with "selenium" might reduce the risk
of antithyroid drugs-induced liver injury.
• However, the possibility if their serious adverse
effects such as hepatotoxicity is lower than
conventional drugs, remains to be elucidated in
more future investigations
42. • Some investigations mentioned the critical
role of cellular defense mechanisms such as
glutathione (GSH) in preventing antithyroid
drugs induced hepatotoxicity.
• On the other hand, the liver GSH content
might be variable in different situations.
43. • Hence, particular attention should be given
to the possibility that unexpected toxic
reactions may be encountered under
conditions of tissue GSH depletion.
• Physicians might advise their patient to
avoiding alcohol consumption during
antithyroid therapy.
44.
45. • Immune-mediated reactions are suggested to
play a role in antithyroid drug-induced
hepatotoxicity.
• Although the mechanism(s) underlying this
event is not fully elucidated yet but cytokines
are thought to play a role in
immunemediated liver injury caused by
methimazole.
46. • The release of cytokines and autoantibodies are
reported in antithyroid drugs-treated patients
• Lymphocyte sensitization in a patient with
neonatal liver injury probably by placental
transfer of PTU has been reported.
All these reports are in line with the
hypothesis that patient immune system might
play a role in the pathogenesis of hepatic injury
induced by antithyroid medications.
47. • The presence of autoantibodies :
- preneuclear antineutrophil cytoplasmic
antibody
- antimyeloperoxidase antineutrophil
cytoplasmic antibody
All indicate that the immune system might
be involved in antithyroid drugs side effects
48. • the reactive metabolites of antithyroid
agents are capable of interacting with
different targets including proteins. Hence,
these modified proteins might act as haptens
and consequently stimulate the immune
system this is called (hapten hypothesis).
49.
50. • Trials demonestrated that methimazole
administration caused less severe hepatotoxic
events and vasculitis in children than PTU.
• No reports of liver failure or liver
transplantation in association with methimazole
use in children in united states.
So methimazole is safer in management of
hyperthyroidism in children but this doesn't
mean that it is completely safe.
51. • More serious adverse events reported in FDA
database for PTU than methimazole.
• Hence, some investigators suggested that
PTU should no longer be used as a first line
treatment for Graves' disease in children
52. In older patients
The average consumption of drugs is higher including ;
*multiple medications
*the risk for an additional disease that could influence the
manifestation of idiosyncratic DILI is greater
Mitochondrial function (which is a frequent intracellular target of
many drugs) is gradually weakening with advancing age, and
cumulative oxidative damage to mitochondria keeps surging.
Thus, oxidative damage to mitochondria is a critical factor of
susceptibility.
53. In older patients
• In addition, the variability in the activity of
different enzymes which are responsible for
the detoxification process of electrophilic
species, namely glutathione transferase
enzymes (GSTs), might also be involved in the
different responses to antithyroid
medications between adults and children.
54. In older patients
• On the other hand, methimazole should be
administered cautiously in older persons with
an appropriate dose, not only because of the
concern for higher rate of agranulocytosis, but
also probably because of more susceptibility of
these patients to the hepatic injury induced by
this drug.
55.
56. • Generally, drugs-induced hepatotoxicity is
more prevalent in females.
• A large retrospective study has recognized that
76% of all patients who developed severe liver
failure due to drugs were females.
• No clear reason has been identified for this
increased susceptibility to many different drugs
in women.
57. • Some authors has found no sex differences
related to antithyroids-induced
hepatotoxicity
• Hyperthyroidism is more common in women
Hence, any probable relationship between
patients sex and antithyroid drugs-induced
hepatotoxicity might be simply due to the
more rate of antithyroid drug prescription in
females.
58.
59. • Drug-induced hepatotoxicity can be affected by
drug interactions.
• Generally, drug interactions occur when two
drugs are co-administered and both are
metabolized by the same CYP450.
• But, in another situation when a drug toxic
metabolite is responsible for hepatotoxic
reactions, coadministration of enzyme-inducing
agents might deteriorate its hepatotoxic
properties.
60. • other drugs with enzyme-inducing properties
such as carbamazepine, isoniazid, etc. might
interact with methimazole to lead
hepatotoxic reactions
• be cautious about coadministrating the drugs
with hepatic enzyme inducing properties,
such as phenobarbital, with antithyroid
medications.
61.
62. • Several different disorders can cause hyperthyroidism.
• Graves' disease (GD), is the most common cause of
hyperthyroidism in humans.
• Many investigations have been carried out on the
complications which occur in hyperthyroid patients with
GD. It has been shown that, the activity of different
enzymes which are involved in the antioxidant defense
mechanism of liver, are changed in hyperthyroidism.
• Komosinska et al. showed that glutathione reductase
(GR) activity, was lower in hyperthyroid patients.
63. • As antithyroid drugs induced hepatotoxicity is
deteriorated in experimental models with
defected liver protective mechanisms, the
question arises if GD can sensitize individuals
to the antithyroid medications' adverse hepatic
effects
• The hypothesis that GD itself has a role in
antithyroid drugs-induced hepatic injury, needs
more controlled and in depth investigations to
be clarified.
64.
65. Therpeutic stratigies
• No other medical intervention except for
drug cessation and liver function monitoring
• However, intra vascular glutathione was
founded to be an effective treatment in a
case of methimazole-induced hepatotoxicity
• In another study , corticosteroids might
alleviate methimazole induced hepatitis
66. Therpeutic stratigies
• In experimental models ; organosulfur compounds
and the amino acid, taurine, could ameliorate the
toxic insult caused by methimazole.
• In another in vivo study, Nacetyl cysteine (NAC)
successfully prevented methimazole-induced hepatic
injury
These new protective strategies might help to develop
a useful hepatoprotective agent against antithyroid
drugs-induced liver injury in humans.
67. • methimazole and PTU may be associated
with the serious side effect of hepatotoxicity.
• Methimazole has been the most prescribed
antithyroid drug these years
• methimazole is preferred due to Factors such
as higher potency, convenient daily dosing,
and the better toxic profile
68. • But, physicians should be aware that
methimazole can be associated with
hepatotoxicity.
• Patients who take antithyroid drugs should
be aware of possible susceptibility factors
such as alcohol consumption, which might
hasten liver damage induced by antithyroid
medications.
69. FDA
• An increased risk of liver injury with
propylthiouracil compared to methimazole
• Health care professionals should carefully
consider which drug to initiate in a patient
recently diagnosed with Graves' disease.
• If propylthiouracil therapy is chosen, the patient
should be closely monitored for symptoms and
signs of liver injury, especially during the first six
months after initiating therapy.