PTU hepatotoxicity : the dilemma Daniel Glinoer University Hospital Saint-Pierre (ULB)

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 TSHR-Abs.

Side effects of Antithyroid Drugs (ATD)* PTUMMI Minor (rash, fever) 5 – 20 % 5 – 20 % (dose-related) Agranulocytosis 0.2 – 0.5 % 0.2 – 0.5 % (not clearly dose-related) (dose-related) Hepatic toxicity Hepatitis 25 % Cholestasis (< 1% severe) (few death) Vasculitis Antineutrophil cytoplasmic Very rare antibody positive (ANCA +) * 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 PTU dose/ddurationtotal (gr) 1- 300 mg 0.5 mth 4.5 2- 300 2 18 3- 300 1.2 11 4- 450 2 27 5- 300 1 9 6- 300 4 36 7- 300 7 63 8- 300 3 27 9- 300 4* 36 10- 300 14 126 11- 250 4 30 12- 450 4 54 13- 450 6* 81 14- 300 9* 81 FDA-AERS/Medwatch PTU dose/ddurationtotal (gr) 1- 300 mg 120 days 36 2- 600 75 32 3- 50 458 23 4- 300 135 41 5- 225 120 30 6- 450 120* 41 7- 300 66 20 8- 450 183* 81 9- 300 210* 63 10- 150 60 9 11- 450 120 54 12- 200 150 30 13- ? ? ? Dose: 330 mg/d Duration: 4.4 months Total: ~ 43 gr Dose: 300 mg Duration: 5 months Total: 38 gr

Comments on PTU doses From FDA-AERS/Medwatch files: 2-3 months: 3/13 (duration of PTU admin.) 4-5 months: 6/13 6-7 months: 2/13 > 1 year: 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.

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/yrdevelop 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 contra-indication 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.

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 10-week 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: • Risks associated with both propylthiouracil (PTU) and methimazole (MMI) should be discussed; • PTU should be used in the first trimester of pregnancy, because of the risk of MMI embryopathy; and • 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 womenshould have been found in liver injury reports and databases (which was not the case; why?).

Epidemiology: pregnancy • Thus, 80–160 womenshould 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.

PTU hepatotoxicity : the dilemma Daniel Glinoer University Hospital Saint-Pierre (ULB)