Download Diapositive 1

PTU hepatotoxicity :
the dilemma
Daniel Glinoer
University Hospital Saint-Pierre (ULB)
(Brussels – Belgium)
AOTA Meeting (Bali) - October 2012
BACKGROUND INFORMATION
 Maternal Hyperthyroidism: 1/500 to 1/2.000
(subclinical hyperthyroidism: ~1/500; GD: ~1/1.000 - 1/2.000)
 Maternal Hyperthyroidism due to non-autoimmune GTT (
related to elevated hCG levels) is ~10-fold more frequent than GD
(but is much less severe and seldom requires active treatment).
 Health risks to mother and fetus are associated with poor control
of HR (miscarriage, placental abruption, congestive heart failure, thyroid
storm, preeclampsia, preterm delivery, prematurity & IUGR, fetal abnormalities
& death).
 If the mother has previously been treated with ATD, she may still
be at risk of a relapse. In mothers previously treated with surgery
or RI131 (even when taking L-T4 for HO), the fetus/newborn is still
at risk of developing HR due to the possible persistence of TSHRAbs.
Side effects of Antithyroid Drugs (ATD)*
Minor (rash, fever)
PTU
MMI
5 – 20 %
5 – 20 %
(dose-related)
Agranulocytosis
Hepatic toxicity
0.2 – 0.5 %
(not clearly dose-related)
0.2 – 0.5 %
(dose-related)
Hepatitis 25 %
Cholestasis
(< 1% severe)
Vasculitis
Antineutrophil cytoplasmic
antibody positive (ANCA +)
(few death)
Very rare
* From David Cooper, In: Proc. of the ‘Eunice Kennedy Shriver’ Symposium, October 2008
(Rockville, MD)
Localized or diffuse skin and accessory structures loss,
especially on scalp (affects 3/10.000 newborns)
A
P
L
A
S
I
A
C
U
T
I
S
A case of aplasia cutis seen in Lyon (Jacques Orgiazzi)
Picture taken at 3 weeks old
Mother taking 60 mg MMI for GD at onset of pregnancy
Barbero P et al., Am J Med Gen (2008)
Multicenter Argentinian case-control study. Prenatal exposure to maternal hyperthyroidism
treated with MMI was identified in 10/61 cases (16.4%) compared to 2/183 (1.1%) in the
control group (OR = 18; CI95% = 3.5–121.4).
Facial features in exposed cases showed some similarities such as broad arched eyebrows
(8/10), broad forehead (7/10), broad nasal bridge (7/10), and/or hypoplastic nasal alae
(4/10). Other associated anomalies were hypothelia, bilateral cryptorchidism,
microcephaly, ventricular septal defect, and branchial fistula.
FDA Alert (April 6, 2009)
Information for Healthcare Professionals on
Propylthiouracil-Induced Liver Failure
“FDA is notifying healthcare professionals of the risk of serious liver
injury, including liver failure and death, with the use of propylthiouracil
in adult and pediatric patients”.
FDA Drug Safety Communication (April 21, 2010)
“Black Box Warning” on severe liver injury with PTU
“Dear Colleague,
The United States FDA has added a Boxed Warning to the label for PTU,
to include information about reports of severe liver injury and acute liver
failure, some of which have been fatal, in adult and pediatric patients
using this medication”.
Question 1:
Why has it taken so long (> half a century!) for
this issue to reach the front line?
HISTORICAL VIGNETTE
 WWII: discovery of the goitrogenic effects of thioureas;
Thiouracil is proposed for the treatment of hyperthyroidism
in 1943 (Astwood).
 July 1947: PTU (6-propyl-2-thiouracil) was officially
introduced for clinical use in Graves’ Disease (& for
pregnant women in 1951).
 Isolated instances of liver toxicity have been reported almost
as soon as the use of PTU had started.
“Toxic manifestations of thiouracil therapy”
(F.D. Moore: JAMA, 130:315, 1946)
WILLIAMS ET AL., JCEM 1997
 1997: was this ...a ‘forgotten’ study’ .... although published in
JCEM? (Dept Endocrinology & Pediatrics; Pittsburgh)
 Report of 2 personal cases (1 liver transplantation & 1 death).
 Review of literature (+ their own): 30 cases of PTU-associated
hepatotoxicity (between 1947 and 1997).
KIM’S STUDY (Am J Gastroenterology, 2001)







912 adult patients (1990-98); 415 excluded; 497 treated with PTU
Clinically overt hepatitis developed in 6/497 patients (1.2%)
Age: 43 + 11 years
Onset after 12 - 49 days with PTU
Type of hepatitis: cholestatic (3); hepatocellular injury (1); mixed (2)
No role of age, sex, PTU dose, initial T4 or T3 levels
Liver function tests normalized in ALL patients between 16 & 145 days after
PTU withdrawal
Liver Transplantation for Acute Liver Failure
from Drug-Induced Liver Injury in the U.S.
(Mark Russo et al.; Liver Transplantation, 2004)
- Total (1990-2002): 2.291 hepatic transplantations.
- Total: 357 (15%) for acute hepatic necrosis due to drugs.
- Total: 270 recipients included in the study, with a single
drug implicated in 258 cases.
- Mean age : 33 years (76% female).
- Pediatric recipients (<18 yrs): 41 cases  4 due to PTU.
- Acetaminophen hepatotoxicity: 124 recipients (46%).
- Other drugs: 137 recipients (51%):
- Isoniazid (INH) 
24 cases (18%)
- PTU

13 cases (10%)
- Phenytoin

10 cases (7%)
- Valproate

10 cases (7%)
Question 3:
Attempting to reassess the epidemiology
of PTU-induced liver injury from
literature and databases ?
Pediatric Population
 Adults
 Pregnancy
7/23 = 30%
2009
From Scott Rivkees & Donald Mattison (Intern J Pediat Endocrinol, 2009)
Int J Ped Endo
dose/d duration total (gr)
1234567891011121314-
300 mg
300
300
450
300
300
300
300
300
300
250
450
450
300
0.5 mth
4.5
2
18
1.2
11
2
27
1
9
4
36
7
63
3
27
4*
36
14
126
4
30
4
54
6*
81
9*
81
Dose: 330 mg/d
Duration: 4.4 months
Total: ~ 43 gr
PTU
FDA-AERS/Medwatch
PTU
dose/d
12345678910111213-
300 mg
600
50
300
225
450
300
450
300
150
450
200
?
duration
120 days
75
458
135
120
120*
66
183*
210*
60
120
150
?
Dose: 300 mg
Duration: 5 months
Total: 38 gr
total (gr)
36
32
23
41
30
41
20
81
63
9
54
30
?
COMMENTS ON PTU DOSES
From FDA-AERS/Medwatch files:
(duration of PTU admin.)
2-3 months:
4-5 months:
6-7 months:
> 1 year:
3/13
6/13
2/13
1/13
unknown:
1/13
The duration of PTU administration was extremely variable:
25% after a few months; the majority after 4-5 months; others
occurring after half a year or longer.
Concerning the total amount of PTU, 38 grams (average) during 5
months (average) represent 250 mg/d (average), which is a rather
large dose for an average 10-year old child.
CONCLUSIONS  Children/Adolescents
Use of PTU can result in tragic consequences and should never
be used as a first-line antithyroid drug in children:
•
Children are 5-fold more prone (than adults) to develop DILI and
PTU is the 3rd most frequent cause of drug-induced liver transplant
in the U.S. The expected rate of severe liver injury and death is 17
times higher in those exposed to PTU compared with non-exposed.
•
Because of the natural history of GD in children, ATD therapy must
often be prolonged during several years. Thus, MMI is the logical
ATD alternative, not to mention the possibility to use radioiodine or
surgery to ensure a cure of the disease.
•
However, my review of FDA files leaves me with the clinical
impression that liver function testing during PTU treatment could
(perhaps?) have avoided some of the deleterious evolutions
observed, by reducing PTU dose or withdrawing PTU as soon as
abnormal liver tests were found.
Question 3:
Attempting to reassess the epidemiology
of PTU-induced liver injury from
literature and databases ?
Pediatric Population
 Adults
 Pregnancy
FDA-AERS/MEDWATCH FILES REVIEWED
 17 cases analyzed + 2 pregnancy-related adverse events (+ 5 unreadable




files + 4 MMI-related files)  Total of 28 files enlisted between 1982 &
2008 (70% < 2000)
Sex: 17/19 females (90%)
Age: 19-73 years (2 ?)  mean age 35 yrs (except for 1 case aged 73 yrs,
all others were young patients)
PTU dose/day highly variable: 100 - 600 mg  mean dose of 320 mg/d
Duration of PTU treatment: between 1 month (3 cases) and 1-2 years (4
cases),  mean duration of 187 days * (* 3-4 cases were unpredictable DILI
(30%) but for the others monitoring liver function test could (perhaps?) have prevented the
dreadful outcome).
 Total PTU dose given: between 6 g and 200 g  mean: 59 g **
(** excluding 4 cases with rapid DILI, the total PTU dose received is 80 g).
 Outcome: 10/17 deaths (2 after LT); 7 survivors (2 after successful LT)
*** (*** nothing known about liver function in survivors (except 1 with cirrhosis).
EPIDEMIOLOGY :
ADULT POPULATION
USA: population of 311 million individuals,
with 230 million adults (2011)
 In 2008, 101.000 individuals were prescribed PTU
(from R. Bahn et al. Thyroid, 2008).
 About 60.000 adults develop hyperthyroidism each year.
 About 25-50% of these patients are treated with PTU.
(from D. Cooper; In: Proc. ‘Eunice Symposium’, 2008).
 Depending on these relative percentages, the range of
PTU-treated adult patients becomes 15.000 to 30.000.
(adapted from D. Cooper; In: JCEM, 2009).
EPIDEMIOLOGY:
ADULT POPULATION
 PTU-treated adult patients = 15.000 to 30.000/yr
 If the incidence of PTU-related severe liver damage is ~1%,
 ~150-300 adults/yr develop severe hepatic injury each year.
 It is assumed that patients will recover from liver injury (totally
or partially?) after PTU withdrawal ~10-fold more frequently.
Thus, if ~10% of these cases (incidence of 1/1.000) develop liver
failure resulting in transplantation,  10-30 individuals/yr with
Graves’ disease in the U.S. should be found in transplantation
or ALF databases.
 This estimate is NOT concordant with the data: 18 PTU-related
liver transplants over the past 17 years (and 9 deaths).
Liaw et al., Annals Internal Medicine 118:424, 1993 (Taipei, Taiwan)
- 95 patients with hyperthyroidism screened for
for AST & ALT before treatment: 60/95 (63%) had
normal liver tests.
- 54 patients monitored during PTU administration:
15 of them (28%) showed ALT elevation 2 months
after PTU initiation with 300 mg/day.
- After dosage reduction to 100-150 mg/day , ALT
levels returned to normal in 13/15 cases within
3 months (the other 2 cases ??).
- ALT elevation asymptomatic (with normal biblirubin) in all cases.
- Liver biopsy done in 3 patients: patches of hemorrhagic necrosis or ill-defined
granulomas in the perivenular region.
Conclusion: PTU-induced subclinical liver injury is frequent and remains
usually transient and asymptomatic. Therapy with PTU may be continued with
caution in the absence of symptoms and hyperbilirubinemia.
CONCLUSIONS  Adults
The same conclusion applies to adults (i.e. do not prescribe PTU) with the
exception of rare patients for whom no other therapeutic option would
be available, such as those with toxic reactions to MMI or contraindication for surgery or RII31.
However, several items remain to be elucidated further:
•
Most cases recover spontaneously after PTU withdrawal.
•
Monitoring liver function tests may benefit patients who might
develop severe liver injury. Since most cases with DILI remain mild
to moderate, liver function tests may be useful for instance to reduce
PTU dosage to a strict minimum or withdraw the drug.
•
If patients develop evocative symptoms or signs (jaundice, fatigue,
nausea), the drug should be stopped and liver function tests obtained.
•
Severe liver injury is likely to be an idiosyncratic phenomenon.
Could these individuals be identified before starting treament ?
•
Is there a PTU dosage or duration effect? PTU (200 mg/d) given for 2
years represents a total amount of 150 gr of PTU.
Question 3:
Attempting to reassess the epidemiology
of PTU-induced liver injury from
literature and databases ?
Pediatric Population
 Adults
 Pregnancy
PREGNANCY:
THE FDA-ALERT FILES
Case N° 1 (reported in 2000; published by Morris – Texas – in 1989): fulminant
hepatic failure with encephalopathy at 25-weeks gestation. Liver transplantation
during pregnancy followed by Caesarian section (fetus did not survive). Several
complications after transplantation, but patient survived. PTU given 3 months before
pregnancy (PTU treatment duration was ~9 months). PTU dose quoted in article &
FDA report was extremely elevated (800 mg/day), although it was not clear whether
this very high dose was given from GD’s onset or when hospitalized.
Case N° 2 (reported in 2003; published by Ruiz – Valparaiso – 2003): literature
report from Chile concerning 2 women with PTU-related DILI. The second case was
a 32-yr old woman treated for GD with PTU (200 mg/d) for 3-4 months before
developing acute liver failure. Upon hospitalization, it was found that she was 10week pregnant. Outcome: death.
Personal Note: I was disappointed by the paucity of cases related to pregnancy.
The 2 patients are almost incidental findings of a pregnancy in women treated
with PTU for GD.
Recalculating the epidemiological frequency of PTU-related
severe adverse effects in pregnancy indicates that 1 woman would
be affected every 2.5–5 years, i.e. among 160 million pregnancies
and encompassing 80.000-160.000 women with Graves’ disease.
In press (ETJ): A case of propylthiouracil-induced hepatitis during pregnancy,
requiring cessation of propylthiouracil and subsequent successful treatment
with carbimazole.
P.. T… et al. (Royal United Hospital, XXX, UK)
- 32-yr old woman: GD diagnosed at 4-wk pregnant.
- PTU (300 mg/d), then reduced ‘steadily’ …
- At 20-wks, jaundice: PTU-induced DILI; PTU discontinued and replaced by CMZ
because hyperthyroidism recurred
- At 36-wks, CMZ was withdrawn; normal delivery with healthy baby
Taken from Patil-Sisodia & Mestman (Endo Pract., 2010)
ATA Guidelines (2011)
Antithyroid drugs. If the patient chooses ATD therapy, the
following recommendations should be given:
1) Risks associated with both propylthiouracil (PTU) and
methimazole (MMI) should be discussed;
2) PTU should be used in the first trimester of pregnancy,
because of the risk of MMI embryopathy; and
3) Consideration should be given to discontinuing PTU after
the first trimester and switching to MMI in order to
decrease the incidence of liver disease.
RECOMMENDATION 28
PTU is preferred for the treatment of hyperthyroidism in the first
trimester. Patients on MMI should be switched to PTU if pregnancy
is confirmed in the first trimester. Following the first trimester,
consideration should be given to switching to MMI. Level I-USPSTF
CONCLUSIONS  Pregnancy
For the special case of pregnancy, it is reasonable to
propose the use of PTU in the 1st trimester because
of MMI’s known teratotogenic effects during
organogenesis.
However, it should be kept in mind that this may not be as
staightforward as it may seem:
•
•
•
•
•
Fetal organogenesis is not fully achieved in the first trimester.
Switching from MMI to PTU will practically require some time
and women may well be into the 1st trimester before the pregnancy
is diagnosed and confirmed.
After this switch, the dosage of PTU needs to be reassessed with
repeated thyroid function tests.
The same « jeu sur une corde raide » applies to switching back
from PTU to MMI in the 2nd trimester.
Today, there is no evidence that the switch back from PTU to MMI
will eventually be proven to be beneficial.
FIN
Use of ultrasound to distinguish between fetal hyperthyroidism
and hypothyroidism on discovery of a goiter.
C. HUEL, J. GUIBOURDENCHE, E. VUILLARD, J. OUAHBA, M. PIKETTY, J. F.
OURY and D. LUTON (Ultrasound Obstet Gynecol 2009; 33:412-420)
Ultrasound score to distinguish hypo- from hyperthyroidism in fetuses with goiter
• Vascularization
Peripheral or absent 0
Central 1
• Fetal heart rate
Normal 0
Tachycardia 1
• Bone maturation
Delayed −1
Normal 0
Accelerated 1
• Fetal movements
Normal 0
Increased 1
An overall score ≥ 2 is suggestive of hyperthyroidism and
a score < 2 is indicative of hypothyroidism.
Mechanisms … personal communication from Pr. Bernard Fromenty
(INSERM U-991, Faculty of Pharmacy, Rennes, France)
- Over 1.000 hepatotoxic molecules identified.
- Mechanisms of hepatotoxicity well studied & understood for some
(paracetamol, etc.), while unknown for most others.
- Recently, in vitro experiments (mice liver mitochondria) showed that PTU
tested positive for mitochondrial toxicity (among 100 other
molecules) .
- PTU increased O2 consumption with substrates that give their electrons to
complexes I & II of the mitochondrial respiratory chain.
- Toxic effects observed for concentrations <100 µM/L (within the range of
in vivo therapeutic Cmax).
- The hypothesis is that uncoupling of oxidative phosphorylation led to
decreased ATP, cell death and liver cytolysis.
- Thus, some individuals may have partial enzymatic deficiency in the mitochondrial
respiratory chain which remains entirely asymptomatic life long, unless
submitted to an additional mitochondrial ‘stress’ when receiving PTU.
- No known predictive test available.
- Eperimental data also showed that, even with idiosyncratic DILI (which is presumably
the case for PTU), an abnormally elevated dose and/or prolonged period of
administration increases the risk of hepatotoxicity. It is probably useful to
monitor liver function tests.
General Conclusions
 The management of Grave’ hyperthyroidism remains a clinical challenge.
However, following relatively simple rules of ‘good behavior’ allows to minimize
risks for both mother and fetus.
 Hepatotoxicity of PTU has long been underestimated. Thanks to our
colleagues pediatricians, awakening has taken place recently. While clear for
children/adolescents with GD, it is much less clear for adults in general and
complicates even further the specific case of GD in pregnancy.
 DILI due to PTU remains a rare event and because of « the principle of
precaution », true risks have probably been overestimated.
 One innovation could be the potential benefit of monitoring liver function
tests when using PTU.
 The use of PTU during the 1st trimester seems reasonable (MMI embryopathy
and fetal organogenesis). Thereafter, the choice remains open between
maintaining PTU (with monitoring of LFT) or switching back to MMI, whilst
one should strive to use the smallest possible dose of either ATD for the shortest
possible period of time.
EPIDEMIOLOGY :
PREGNANCY
USA: 4 million births/year
 Incidence of GD in pregnancy: ~1/1.000 – 1/2.000
 Over the past 40 years, there was a total of ~160 million births,
thus encompassing ~80.000 – 160.000 women with active GD.
 It is likely that ~100% of them were treated with PTU for
highly various periods of time since GD usually pre-exists the
ongoing pregnancy  ~80.000 – 160.000 women with potential
PTU side effects.
 If the incidence of severe drug-induced liver injury is ~1/1.000,
~80-160 women should have been found in liver injury reports
and databases (which was not the case; why?).
EPIDEMIOLOGY:
PREGNANCY
 Thus, 80–160 women should be found in literature and/or
databases on liver injury (Which was not the case; Why? Under-reporting
probable but not enough to explain the discrepancy).
 If the incidence of severe – irreversible – liver failure is 10% of
the above (i.e., final incidence of 1/10.000), 8–16 women should
be found in the FDA-AERS MedWatch alert on liver failure
due to PTU. However, there were only 2 reports of severe
maternal injury due to PTU.