2019, 66 (9), 769-775

Original

Liver dysfunction induced by Levothyroxine Sodium

Tablets (Euthyrox®) in a hypothyroid patient with
Hashimoto’s thyroiditis: case report and literature review
Hengcai Yu1), 2), Wen Zhang1), Chengwu Shen1), Haiqing Zhang3), Haochao Zhang2), Yahui Zhang1),
Dongna Zou1) and Xianwei Gong1)

1)
Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
2)
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy
of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3)
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China

Abstract. A 49-year-old woman with hypothyroidism developed liver dysfunction after increasing dose of levothyroxine (L-
T4) (Euthyrox®) from 25 μg to 50 μg. Viral hepatitis, autoimmune hepatitis and non-alcoholic steatohepatitis (NASH) were
ruled out with examinations. She had no concurrent medication and had no history of infectious, chronic or any other
autoimmune diseases. After cessation of Levothyroxine Sodium Tablets (Euthyrox®), liver enzymes gradually returned to
normal. She was diagnosed levothyroxine-induced liver injury, based on criteria proposed in “Diagnosis and treatment
guideline on drug-induced liver injury” issued by the Chinese Medical Association (2015). As an alternative 25 μg qod of
Levothyroxine Sodium Tablets (Letrox®) was tried and increased gradually up to 75 μg daily. Since then liver enzymes have
remained within normal range. The main difference of additive for both tablets is whether it contains lactose or not: Euthyrox®
contains lactose which caused no liver injury, thus excluding the possibility that an additive of Euthyrox® contributed to liver
injury. The relatively quicker and larger replacement with synthetic T4 for hypothyroidism inducing transient thyrotoxicosis
was suspected, although thyroid function was normal. Immune-mediated drug-induced liver injury (DILI) was also not
excluded. This is a rare case of drug-induced liver injury due to levothyroxine tablets. It reminded us that when replacement
with synthetic T4 for hypothyroidism is done, smaller-dose initiation and slower-speed increase may be useful for treatment of
cases similar to genetically susceptible individuals.

Key words: Drug-induced liver injury (DILI), Levothyroxine Sodium Tablets

HASHIMOTO’S THYROIDITIS, also known as especially oral administration of levothyroxine (L-T4)

chronic lymphocytic thyroiditis, a kind of autoimmune
thyroiditis, is increasing by 5% per year in China. Hypo‐
thyroidism, mainly caused by Hashimoto’s thyroiditis, is
mainly treated with replacement of thyroid hormones,
Submitted Feb. 24, 2019; Accepted Apr. 23, 2019 as EJ19-0078
Released online in J-STAGE as advance publication Jun. 18, 2019
Correspondence to: Hengcai Yu, Department of Pharmacy, Shan‐
dong Provincial Hospital Affiliated to Shandong University, 324,
Jing 5 Rd., Jinan 250021, China.
E-mail: yuhengcai200712761@163.com
Abbreviations: L-T4, Levothyroxine; TSH, Thyroid stimulating
hormone; AST, Aspartate aminotransferase; ALT, Alanine amino‐
transferase; LKM-1, Liver kidney microsomal autoantibody type 1;
NASH, Non-alcoholic steatohepatitis; RUCAM, Roussel Uclaf
Causality Assessment Method; DILI, Drug-induced liver injury;
BSEP, Bile salt export pump; ROS, Reactive oxygen species; DIO,
Deiodinase enzyme; UGTs, Uridine diphosphate glucuronosyl‐
transferases; SNP, Single nucleotide polymorphisms; THR, Thy‐
roid hormone receptor; DLST, Drug-induced lymphocyte stim‐
ulation test
[1, 2]. At present, two manufacturers of levothyroxine
tablets are on the market in China: Euthyrox® tablets
(Merck KGaA, Germany) and Letrox® tablets (Berlin-
Chemie AG, Germany) [3]. Inactive ingredients include
cornstarch, gelatin, magnesium stearate, and sodium
croscarmellose in both L-T4 tablets. The difference is
that Euthyrox® tablets contain lactose as an additive but
Letrox® tablets do not. In general, L-T4 is safe and well
tolerated by patients, except for the possibility of devel‐
oping osteoporosis as a result of L-T4 over-replacement,
particularly in post-menopausal women, as described in
the drug instructions. To our knowledge, liver dysfunc‐
tion induced by administration of L-T4 has not been
reported in China so far, and there are only six case
reports all from Japan by searching PubMed [4-9].
Recently we encountered a female hypothyroid patient
with Hashimoto’s thyroiditis, who developed liver injury
due to levothyroxine (Euthyrox®).

©The Japan Endocrine Society

770
Case Report
A 49-year-old woman had been diagnosed with
Hashimoto’s thyroiditis on June 25, 2017 when her
serum levels of FT4 was 9.12 pmol/L (11.5–22.7
pmol/L), FT3 was 3.4 pmol/L (3.5–6.5 pmol/L) and thy‐
roid stimulating hormone (TSH) was 79.58 μIU/mL
(0.55–4.78 μIU/mL), with normal liver function. Both
antithyroglobulin antibody and antithyroid peroxidase
antibody were seropositive at >500.00 IU/mL (0–60
IU/mL) and >1,300.0 IU/mL (0–60 IU/mL), respectively.
Her thyroid hormone was in hypothyroidism and oral
replacement therapy with 25 μg/day of L-T4 (Euthyrox®)
was initiated on June 26, 2017. On July 3, 2017, 7 days
later, the dosage was increased to 50 μg/day. However, at
a regular visit on August 4, 2017, despite levels of FT4
(18.59 pmol/L), FT3 (4.63 pmol/L), and TSH (0.970
μIU/mL) being within normal range, she was found to
have increased aspartate aminotransferase (AST) and
alanine aminotransferase (ALT) in blood tests, sugges‐
tive of liver dysfunction. The patient complained of
fatigue and loss of appetite. Physical examination was
unremarkable, and she did not have fever, jaundice, or
any skin abnormality.
Laboratory findings on August 4, 2017 were as fol‐
lows: white blood cells, 3.99 × 109/L (eosinophil 7.5%);
total bilirubin, 27.2 umol/L (3.5–23.5 umol/L); AST,
1,252 IU/L (7–40 IU/L); ALT, 1,507 IU/L (13–35 IU/L);
alkaline phosphatase (ALP), 85 IU/L (23–140 IU/L);
gamma-GT, 28 IU/L (7–45 IU/L); and Hepatitis A virus
antibody IgM, Hepatitis B virus antigen, Hepatitis B
virus antibody, Hypersensitive Hepatitis C RNA quanti‐
fication, Hepatitis E immunoglobulin M antibodies,
Cytomegalovirus DNA quantification and Epstein-Barr
virus DNA quantification were all negative. Moreover,
anti-soluble liver antigen/hepatopancreatic antigen anti‐
bodies, anti-cytoplasmic liver antigen type 1 antibodies,
anti-mitochondrial M2 antibody, anti-liver kidney micro‐
somal autoantibody type 1 (LKM-1), anti-double-
stranded DNA antibodies, SM, SSA and SSB were also
negative. She had no history of drinking alcohol. Liver
injury induced by either viral hepatitis, autoimmune hep‐
atitis, Sjogren syndrome, systemic lupus erythematosus
or non-alcoholic steatohepatitis (NASH) were excluded.
Her serum levels of FT4 and FT3 were 18.59 pmol/L
(11.5–22.7 pmol/L) and 4.63 pmol/L (3.5–6.5 pmol/L),
respectively, and serum TSH was 0.970 μIU/mL (0.55–
4.78 μIU/mL). Therefore, liver injury induced by hyper‐
thyroidism due to overdose of levothyroxine was rejec‐
ted. Meanwhile, she denied having a history of chronic
diseases such as hypertension, coronary heart disease,
diabetes, or a history of infectious diseases such as tuber‐
culosis and close contact history. She denied major
Yu et al.
trauma and blood transfusion history. She had no history
of drug allergy, and was allergic to seafood. She did not
take any other medication except L-T4 (Euthyrox®) due
to Hashimoto’s thyroiditis at least in the past 90 days.
The clinical course of this case after admission is
shown in Fig. 1. On August 4, 2017, administration of L-
T4 (Euthyrox®) was discontinued immediately due to the
suspicion that the liver dysfunction may have been due
to the 50 μg tablet. On August 10, 2017, abdominal
ultrasonography was performed and revealed normal
results. However, serum AST and ALT were still high on
the same day, 665 IU/L and 961 IU/L, respectively.
Therefore, Reduced Glutathione for Injection (Atomo‐
lam) 3 g ivdrip qd + 0.9% NaCl injection 100 mL, Bicy‐
clol Tablets (Bacenol) 50 mg po tid, Silybin Meglumine
Tablets (Cilipine) 200 mg po tid were prescribed to
quickly recover liver function. On August 18, 2017, liver
function test results showed AST was 193 IU/L (7–40
IU/L) and ALT was 156 IU/L (13–35 IU/L) and Reduced
Glutathione for Injection was discontinued considering
the improvement of liver function. On September 3,
2017, FT4 was 8.96 pmol/L, FT3 was 2.72 pmol/L, TSH
was 106.163 μIU/mL which showed the patient was in
hypothyroid state again, and liver function showed
improved test results with AST 123 IU/L (7–40 IU/L)
and ALT 80 IU/L (13–35 IU/L). On September 14, 2017,
AST was 104 IU/L (7–40 IU/L) and ALT was 39 IU/L
(13–35 IU/L) which demonstrated the further improved
liver function.
On September 18, 2017, 25 μg qod of Levothyroxine
Sodium Tablets (Letrox ®) was restarted with hepatic pro‐
tection drugs including Bicyclol Tablets and Silybin
Meglumine Tablets. On October 8, 2017, FT4 was 5.84
pmol/L, FT3 was 2.13 pmol/L, TSH was 150 μIU/mL,
still in hypothyroidism, and L-T4 (Letrox®) was care‐
fully increased up to 25 μg qd. On November 3, 2017,
L-T4 (Letrox®) was increased up to 50 μg qd. On
November 22, 2017, AST and ALT was within normal
range and drugs to protect the liver including Bicyclol
Tablets and Silybin Meglumine Tablets were discontin‐
ued. At the same time, FT4 was 12.5 pmol/L, FT3 was
3.55 pmol/L, TSH was 54.42 μIU/mL and L-T4
(Letrox®) was carefully increased up to 75 μg qd. The
patient was followed up since then and L-T4 dosage was
adjusted according to her thyroid function.
On June 12, 2018, her serum levels of FT4 and FT3
were 19.37 pmol/L and 3.41 pmol/L, and serum TSH
was 3.65 μIU/mL, showing the thyroid function was in
the normal range with 75 μg daily of L-T4 (Letrox®).
There has been no recurrence of liver dysfunction. The
patient was followed up to January 4, 2019 and the
thyroid and liver function findings were always within
normal range with 75 μg daily of L-T4 (Letrox®). We
 Levothyroxine induced liver dysfunction 771

Fig. 1  Clinical course of the case. Changes in thyroid function and liver enzymes (AST and ALT). On September18, 2017, administration
of L-T4 (Letrox®) was started and carefully increased up to 75 μg daily. AST and ALT levels returned to normal range on
November 22, 2017 and there has been no recurrence of liver injury with administration of L-T4 (Letrox®) since then.

suspect these transient liver biochemical abnormalities
were related to the quickly increased thyroid hormone in
the hypothyroid patient which was similar to transient
thyrotoxicosis and impaired liver function.
Discussion
In general, L-T4 is safe and well tolerated by patients
at normal dosage. To date and to our knowledge, there
has been only six case reports of liver dysfunction
induced by administration of L-T4 in a literature search,
which are presented in Table 1 [4-9]. Drug-induced
hepatotoxicity remains a diagnosis of exclusion. In the
present case, according to “ Diagnosis and treatment
guideline on drug-induced liver injury” issued by the
Chinese Medical Association (2015), several factors are
able to potentiate the diagnosis of L-T4-induced hepato‐
toxicity, including timing of drug intake, clinical course
of liver injury, and exclusion of other causes of liver
injury. When the Roussel Uclaf Causality Assessment
Method (RUCAM) scale was applied to our patient, the
assessed score was consistent with probable drug-
induced liver injury (DILI) (Table 2) [10]. Therefore, we
concluded that liver injury in our case was probably
caused by administration of L-T4 (Euthyrox®).
According to the L-T4 (Euthyrox®) instructions, T4 is
slowly eliminated. The major pathway of thyroid hor‐
mone metabolism is through sequential deiodination.
Approximately 80% of circulating T3 is derived from
peripheral T4 by monodeiodination. The liver is the
major site of degradation for both T4 and T3. Approxi‐
mately 80% of the daily dose of T4 is deiodinated to
yield equal amounts of T3 and reverse T3 (rT3). T3 and
rT3 are further deiodinated to diiodothyronine. Thyroid
hormones are also metabolized via conjugation with glu‐
curonides and sulfates and excreted directly into the bile
and gut where they undergo enterohepatic recirculation.
García-Cortés et al. demonstrated that different risk fac‐
tors have been associated to the development of DILI
including host factors, drug-dependent factors, and envi‐
ronmental conditions [11]. Among drug-dependent risk
factors, daily dose greater than 50 mg, more than 50% of
hepatic metabolism, greater lipophilicity, and/or dual
inhibition of mitochondrial and bile salt export pump
 772
Table 1 Case reports of thyroxine-induced liver dysfunction
Liver functions at maximum
Patient’s Patient’s Symptoms of Probable causes of liver Publication
First author Initial diagnosis and the corresponding Initial dugs Final dugs Treatment process after liver injury Country Language
sex age liver injury injury year
thyroid function
L-T4 tablet was discontinued. Four
years after L-T4 cessation, L-T4
AST 269 IU/L, ALT 233 powder was increased at a rate of
No fever,
IU/L, ALP 395 IU/L; FT4 50-80-50 μg daily and stopped because
Subclinical jaundice, or L-T4 An additive in the L-T4 Japan,
Kang S [4] Female 54 1.24 ng/dL, FT3 2.46 L-T4 tablet of liver dysfunction; 25 μg L-T4 2015 English
hypothyroidism any skin powder tablet Kobe
pg/mL, TSH 3.51 uIU/mL, powder was restarted and was
abnormality
Normal carefully increased at a rate of
30-40-50-60-70 μg daily without liver
dysfunction.
L-T4 was discontinued. Dried thyroid
powder (T3 + T4) was administered,
A complex of L-T4 and
AST 670 IU/L, ALT 884 but ALT still elevated and jaundice
carrier protein may be easily
IU/L, ALP 458 IU/L; FT3 developed. Then liothyronine (T3) was
Primary recognized by immune Japan,
Kawakami T [5] Male 63 No jaundice 2.5 pg/mL and FT4 0.8 L-T4 T3 used instead of T4 and discontinued 2007 English
hypothyroidism system in genetically Tokyo
ng/dL, normal, serum TSH because of exacerbated total bilirubin
susceptible individuals,
150.6 μIU/mL high and jaundice. About four months later,
leading to liver injury.
T3 was reused and no liver injury
recurred.
Liver is a major site of
Primary AST 232 IU/L, and ALT
L-T4 was discontinued. T3 was degradation of thyroid
hypothyroidism Fever (37– 365 IU/L, ALP 629 IU/L;
gradually increased at a dose of hormone and L-T4 might Japan,
Ohmori M [6] Female 13 probably caused by 38°C), general FT3 5.5 pg/mL high, FT4 L-T4 T3 1999 English
5-10-15-50 μg per day without liver induce liver damage in Tochigi
Yu et al.

Hashimoto’s fatigue 1.11 ng/dL, TSH 0.6

dysfunction. primary hypothyroid
thyroiditis μIU/mL
patients.
T3 was discontinued. L-T4, 25 μg per
day for four days and liver injury
recurred. For the following four Hypersensitivity induced by
Hypothyroidism
General AST 704 IU/L, ALT 1,044 months no medication was taken. Then exogenous administration of Japan,
Shibata H [7] Female 63 with Hashimoto’s T3, L-T4 T3 1986 English
malaise IU/L T3 was administered with a dose of 5 T3, L-T4 and desensitization Tokyo
thyroiditis
μg per day, increased gradually up to a to T3 at last
daily dose of 35 μg without liver
dysfunction.
Hashimoto’s
Inui A [8] — — — — — — — Allergic hepatitis Japan 1983 Japanese
thyroiditis
Toki M [9] Female 65 — — — — — — Additive of Thyradin (L-T4) Japan 2003 Japanese
The larger initial dose and
the faster increased dose
AST 1,252 IU/L, ALT 1,507 L-T4 (Euthyrox®) was discontinued.
resulted to oxidative stress,
Hypothyroidism IU/L, ALP 85 IU/L; FT4 45 days later, L-T4 (Letrox®) was
Fatigued, L-T4 L-T4 and mitochondrial China,
Our case Female 49 with Hashimoto’s 18.59 pmol/L, FT3 4.63 gradually increased at a dose of 2019 English
anorectic (Euthyrox®) (Letrox®) dysfunction of liver and Jinan
thyroiditis pmol/L, TSH 0.970 12.5-25-50-75 μg daily no liver injury
liver injury occurred in
μIU/mL, normal recurred.
genetically susceptible
individuals.

“—”: Inui A [8] and Toki M [9] were published in Japanese and detailed information was not obtained.
 Levothyroxine induced liver dysfunction
Table 2 Patient’s score on the Roussel Uclaf Causality Assessment Method scale
Variable
Liver injury type
Time of onset of the event
Time from drug intake until reaction onset
Course of reaction
Alcohol or pregnancy
Age
Concomitant therapy
Exclusion of non-drug-related causes
Previous information on hepatotoxicity
Response to re-administration
Total score
(BSEP) are properties of the drug that can contribute to a
risk for idiosyncratic DILI [12-16]. As the major site of
metabolism for both T4 and T3 is the liver, this brings a
possibility of liver damage. Mosedale and Watkins
reviewed the key components that lead to DILI, includ‐
ing oxidative stress, mitochondrial dysfunction and
changes within bile acid homeostasis [17]. The present
patient had signs of hypothyroidism and the relatively
quicker and larger replacement with synthetic T4
increased the oxygen demand on hepatocytes, which
could increase reactive oxygen species (ROS) accumula‐
tion. When the processes that exist to regulate cellular
levels of ROS are exceeded, oxidative stress can result in
damage to critical cellular components and eventually
cell death. Additionally, the possibility was not excluded
that L-T4, as a hapten protein forming covalent adducts,
was taken up by antigen-presenting cells or stimulated
the production of danger signals, hence triggering a
pathogenic adaptive immune response and leading to
immune-mediated DILI [18]. To our knowledge, only a
few patients have experienced L-T4-induced liver injury,
and so genetic factors, associated with individual risk of
developing liver injury on exposure to medications, may
alter the nature or the magnitude of immune-mediated
liver injury and increase the likelihood of DILI in sus‐
ceptible individuals [18].
The concentration of thyroid hormones in tissues is
regulated by deiodinases and thyroid hormone transport‐
ers. Deiodinase enzyme isoforms (DIO1, DIO2, and
DIO3) mainly control intracellular thyroid hormone con‐
centrations. DIO enzymes convert T4 to biologically
active T3. Activities of DIO1 and DIO2 play a pivotal
role in the negative feedback regulation of pituitary TSH
secretion [19, 20]. The DIO2 activity in the rs225104 TT
genotype was higher than that in the CC genotype [21].
773
Clinical results Score
Hepatocellular
First exposure
5–90 days +2
ALT descending by ≥50% in 30 days +2
Absent 0
<55 years 0
Absent 0
Ruled out +2
Reaction published but unlabeled +1
Not available 0
Probable 7
Arici et al. reported it should be given in lower dose to
the patients with rs225014 TT and rs225015 GG geno‐
types in DIO2 in order to provide proper treatment with
higher effectivity and lower toxicity [22]. Uridine
diphosphate glucuronosyltransferases (UGTs) are
responsible for T4 metabolism in human liver as thyro‐
xine glucuronide. Two common UGT1A subfamily
enzymes, UGT1A1 and UGT1A3, provide T4 glucuroni‐
dation in humans [23]. UGT1A1 has a higher affinity
than UGT1A3 for T4 in T4 glucuronidation while
UGT1A3 has a higher capacity for T4 glucuronidation.
It was reported that there is a significant correlation
between UGT1A1*28 and T4 glucuronidation [24].
Yoder Graber et al. pointed out that hypothyroid patients
with homozygous UGT1A1*28 variant should receive a
lower L-T4 dose [24]. Therefore, our present case may
have the rs225104 TT genotype or rs225015 GG geno‐
types in DIO2 or homozygous UGT1A1*28 variant. Liu
et al. suggested single nucleotide polymorphisms (SNP)
mutations coded in thyroid hormone receptor (THR)
influenced individual susceptibility to triiodothyronine
[25]. Therefore, the balance of thyroid hormones in
human is affected by multiple gene loci and gene poly‐
morphism.
In the six published case reports, three of which in the
English literature on liver injury was suspected allergic
reactions to L-T4 itself [5-7]. Drug-induced lymphocyte
stimulation test (DLST) was performed, but two of the
reported cases showed negative response to L-T4 [5, 6]
and the remaining one showed positive results for both
L-T4 and T3 [7]. Therefore, the statement that the mech‐
anism of liver injury is hypersensitivity induced by exog‐
enous administration of L-T4 will need to be further
clarified. There are two case reports in the Japanese liter‐
ature of liver injury suspected due to L-T4 [8, 9]. Inui et
774 Yu et al.
al. reported a case of allergic hepatitis although the cause
of allergy was not clarified [8]. Toki et al. reported a case
of liver dysfunction due to Fe2O3 of Thyradin-S® [9]. In
2015, Kang et al. presented a case report of liver dys‐
function due to some additive other than Fe2O3 in L-T4
tablet form [4]. In all the above literature, four showed
the mechanism of liver injury is hypersensitivity [5-8]
and two showed the additive in the L-T4 tablet induced
liver dysfunction [4, 9]. By reading the above English lit‐
erature carefully, we knew that the treatment process
after liver injury was as follows: discontinue L-T4 tablet
firstly, and then a few months or years later, restart 25 μg
L-T4 powder [4] or 5 μg T3 [6, 7] and carefully increase
up to the proper dosage at a very slow rate without liver
dysfunction, which may be a way of drug desensitization
or induced immune tolerance of the body.
Taking into account the above factors, after 45 days
discontinuation of L-T4 (Euthyrox®), 12.5 μg daily L-T4
(Letrox®) was restarted and gradually increased up to 75
μg daily, and no liver injury recurred. The difference is
that Euthyrox® tablets contain lactose as an additive
which generally causes no liver dysfunction but Letrox®
tablets do not contain. Therefore, this excluded the possi‐
bility that an additive of Euthyrox® contributed to liver
injury. We suspect that the relatively quicker and larger
replacement with synthetic T4 for hypothyroidism
induced transient thyrotoxicosis and impaired liver func‐
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In conclusion, we reported a case with levothyroxine-
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quicker and larger replacement with synthetic T4 for
hypothyroidism inducing transient thyrotoxicosis, al‐
though the patient had normal thyroid function. The
present case should remind us that when replacement
with synthetic T4 for hypothyroidism is done, smaller-
dose initiation and slower-speed increase should be con‐
sidered to the genetically susceptible individuals.
Disclosure
None of the authors have any potential conflicts of
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