833171 ANP ANZJP ArticlesFairbrother et al.

Review

Australian & New Zealand Journal of Psychiatry

Lithium can cause hyperthyroidism as 1­–19

https://doi.org/10.1177/0004867419833171
DOI: 10.1177/0004867419833171

well as hypothyroidism: A systematic © The Royal Australian and

New Zealand College of Psychiatrists 2019

review of an under-recognised Article reuse guidelines:

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association

Fiona Fairbrother1,*, Nicola Petzl2,*, James G Scott1,3,4 and

Steve Kisely2,5,6

Abstract
Objective: Hypothyroidism is a well-documented consequence of lithium treatment. Less well known is a possible
association between lithium therapy and hyperthyroidism. This may have clinical implications as rapid changes in thyroid
hormones may worsen a person’s affective state, while symptoms of hyperthyroidism can mimic those of mania. We
therefore systematically reviewed the published literature for evidence of lithium-induced hyperthyroidism.
Methods: We searched PubMed, Embase and CINAHL for articles where individuals developed biochemically confirmed
hyperthyroidism (with or without clinical symptoms), while on lithium therapy for an affective illness. We included case
reports, case series, cross-sectional, case control and cohort studies.
Results: We included 52 studies, 39 of which were individual case reports and 3 were case series. There were 10 cross-
sectional or case control or cohort studies. All the research designs suggested an association between the prescription
of lithium and hyperthyroidism. However, these findings were limited by the quality of the included studies, small number
of participants and the general lack of either a clear temporal relationship or dose response.
Conclusion: Hyperthyroidism is an uncommon side-effect of lithium compared to hypothyroidism but may have clinical
implications. However, large prospective studies are required to clarify this association and to further inform the man-
agement of patients treated with lithium where hyperthyroidism occurs.

Keywords
Lithium, hyperthyroidism, thyrotoxicosis, bipolar affective disorder, schizoaffective disorder

Introduction
Hypothyroidism caused by lithium treatment is now well 1Metro North Mental Health, Royal Brisbane and Women’s Hospital,
documented (Bocchetta et al., 2007b; Bocchetta and Herston, QLD, Australia
Loviselli, 2006; Bou Khalil and Richa, 2011; Kibirige 2West Moreton Health Service, Ipswich, QLD, Australia

et al., 2013). Less well known, and somewhat surprising 3Centre for Clinical Research, Faculty of Medicine, The University of

given its antithyroid mechanism of action, is an association Queensland, Brisbane, QLD, Australia
4Queensland Centre for Mental Health Research (QCMHR), The Park
between lithium therapy and hyperthyroidism.
Centre for Mental Health, Brisbane, QLD, Australia
The first case report appeared in 1974, and since then, a 5Metro South Mental Health, Woolloongabba, QLD, Australia

growing body of reports has added to the evidence base 6School of Medicine, The University of Queensland, Woolloongabba,

(Franklin, 1974). Although there is a causative relationship QLD, Australia

between lithium therapy and other forms of thyroid illness *Joint first authors
(goitre and hypothyroidism; Lazarus, 2009; Lazarus et al.,
Corresponding author:
1986), the nature of the association between lithium and
Steve Kisely, School of Medicine, The University of Queensland, Level 4,
hyperthyroidism is less clear. Possible mechanisms include Building 1, Princess Alexandra Hospital, Ipswich Road, Woolloongabba,
a direct toxic or immuno-stimulatory effect on the thyroid QLD 4102, Australia.
(Kibirige et al., 2013). Email: [email protected]

Australian & New Zealand Journal of Psychiatry, 00(0)

2 ANZJP Articles

One study identified thyrotoxicosis in 3.9% of women Ethical approval was not required for this systematic
and 1.8% of men treated with lithium therapy, which was review, as all included primary data had been previously
similar to rates of hyperthyroidism reported in a 20-year published with ethical approval.
study of the incidence of thyroid disease in a representative Two of the authors (F.B. and N.P.) independently
sample of the United Kingdom (Kirov et al., 2005; screened identified records and abstracts. The reference
Vanderpump et al., 1995). Incidence rates per 1000 survi- lists of all included studies were screened to identify addi-
vor years on lithium were 6.4 for women and 2.7 for men tional relevant studies that met inclusion criteria.
(Kirov et al., 2005). A further study reported an incidence
rate for lithium-associated thyrotoxicosis of 2.7 cases per
Inclusion criteria
1000 person-years, while that for silent thyroiditis was
approximately 1.3 cases per 1000 person-years (Miller and We included articles where individuals developed biochemi-
Daniels, 2001). The latter is a transient thyrotoxicosis with cally confirmed subclinical or clinical hyperthyroidism while
a very low 24-hour radioiodine uptake. Barclay et al. (1994) on lithium therapy for an affective illness (e.g. bipolar disor-
found that the number of cases of thyrotoxicosis in patients der, schizoaffective disorder and depression). Where older
on lithium was more than three times that predicted from psychiatric diagnostic terms were used, such as ‘manic psy-
the local thyrotoxicosis incidence rate. However, these cal- chosis’, these were converted into a standardised diagnosis
culations were made based on an estimate of the number of congruent with the International Classification of Diseases
patients in the area on lithium, which was derived by – 10th Revision (ICD-10) or the Diagnostic and Statistical
extrapolating from old data dating from 1974, and the Manual of Mental Disorders (5th Edition; DSM-5), based on
amount of lithium sold in the area in 1989 (Barclay et al., the reported clinical history. Patients were included if they
1994). More recently, a population-based cohort study had an existing thyroid illness such as a goitre or hypothy-
found that the rate of hyperthyroidism among lithium- roidism, unless they were hyperthyroid prior to commencing
treated patients increased compared to olanzapine and val- lithium therapy. The decision to include cases of premorbid
proate, but not quetiapine (Hayes et al., 2016). thyroid illness was made on the premise that lithium use
By contrast, a retrospective analysis of laboratory data could accelerate the patient’s transition to hyperthyroidism
(Shine et al., 2015) and a cross-sectional comparison of leading to illness in predisposed individuals (Chow et al.,
those exposed to lithium therapy and controls did not find 1993). We included the following study designs: case series,
any association between that lithium therapy in general and cohort studies, case control and cross-sectional studies.
hyperthyroidism (Kuman Tuncel et al., 2017). However, the
former study did report an association in patients with higher Exclusion criteria
than median lithium concentrations (Shine et al., 2015).
In summary, most case reports, case series and cohort We excluded papers where individuals developed hyper-
studies suggest that exposure to lithium treatment is associ- thyroidism after the withdrawal or cessation of lithium
ated with an increased risk of hyperthyroidism. However, therapy. This is because these cases may have had a pre-
some authors do not report any association. Although existing hyperthyroid illness that was masked by the thy-
uncommon, hyperthyroidism is an important and clinically roid-suppressing effects of lithium, and which then became
relevant phenomenon as rapid changes in thyroid hormones apparent on cessation of this treatment (Carmaciu et al.,
may worsen a person’s affective state while symptoms can 2003; Miller and Daniels, 2001).
mimic those of mania (Arlt et al., 2008; de Sousa Gurgel
et al., 2015; Iga et al., 2005; Szabadi, 1991). We therefore Study quality
systematically reviewed the published literature for evi-
dence of lithium-induced hyperthyroidism. We assessed the quality of cross-sectional, case control or
cohort studies using a modified version of the Newcastle–
Ottawa Scale (Mata et al., 2015). This scale assesses the
Methods quality of non-randomised studies included in systematic
Search strategy reviews and meta-analyses across the following domains:
sample representativeness and size, comparability between
The systematic review adhered to the Preferred Reporting respondents and non-respondents, ascertainment of hyper-
Items for Systematic Reviews and Meta-Analyses thyroidism and statistical quality (Mata et al., 2015). We
(PRISMA; Moher et al., 2009). We sought advice from a divided studies into those at low risk of bias (⩾3 points) or
research librarian prior to the commencement of the search. high risk of bias (<3 points).
Articles were located by searching PubMed (1964 to
January 2018), Embase (1947 to January 2018) and
Statistical analysis
CINAHL (1937 to January 2018). We restricted our search
to English-language articles. Table 1 shows the search The limited number of studies and their variations in meth-
terms. The review protocol is available from the authors. odology, particularly length of follow-up, meant that

Australian & New Zealand Journal of Psychiatry, 00(0)

Fairbrother et al. 3

Table 1. Search strategy.

Database Search terms

PubMed ‘Hyperthyroidism’[Mesh] OR Hyperthyroidism[tiab] OR ‘thyrotoxicosis’[MeSH Terms] OR

(n = 199) ‘thyrotoxicosis’[tiab] OR hyperthyroidism OR ‘silent thyroiditis’ OR thyroiditis
‘Adverse effects’[Subheading] OR harm[tiab] OR harms[tiab] OR side-effect[tiab] OR ‘side-effects’[tiab]
OR Undesirable effect[tiab] OR undesirable effects[tiab] OR undesirable reaction[tiab] OR undesirable
reactions[tiab] OR undesirable event[tiab] OR undesirable events[tiab] OR undesirable outcome[tiab]
OR undesirable outcomes[tiab] OR adverse effect[tiab] OR adverse effects[tiab] OR adverse
reaction[tiab] OR adverse reactions[tiab] OR adverse event[tiab] OR adverse events[tiab] OR adverse
outcome[tiab] OR adverse outcomes[tiab]
‘Lithium’[Mesh] OR lithium OR lithicarb OR eskalith OR lithobid OR lithane OR cibalith-s OR quilonum
OR hypnorm
Filter: Human, English language

Embase (‘hyperthyroidism’/exp OR Hyperthyroidism:ti,ab OR ‘thyrotoxicosis’/exp OR ‘thyrotoxicosis’:ti,ab

(n = 138) OR hyperthyroidism OR ‘silent thyroiditis’ OR thyroiditis) AND (‘adverse effects’/exp OR harm:ti,ab
OR harms:ti,ab OR side-effect:ti,ab OR ‘side-effects’:ti,ab OR ‘undesirable effect’:ti,ab OR ‘undesirable
effects’:ti,ab OR ‘undesirable reaction’:ti,ab OR ‘undesirable reactions’:ti,ab OR ‘undesirable event’:ti,ab
OR ‘undesirable events’:ti,ab OR ‘undesirable outcome’:ti,ab OR ‘undesirable outcomes’:ti,ab OR
‘adverse effect’:ti,ab OR ‘adverse effects’:ti,ab OR ‘adverse reaction’:ti,ab OR ‘adverse reactions’:ti,ab
OR ‘adverse event’:ti,ab OR ‘adverse events’:ti,ab OR ‘adverse outcome’:ti,ab OR ‘adverse
outcomes’:ti,ab) AND (‘lithium’/exp OR lithium OR lithicarb OR eskalith OR lithobid OR lithane OR
cibalith-s OR quilonum OR hypnorm)

CINAHL (MH‘Hyperthyroidism’ OR Hyperthyroidism OR MH ‘Thyrotoxicosis’ OR ‘thyrotoxicosis’ OR

(n = 12) hyperthyroidism OR ‘silent thyroiditis’ OR thyroiditis) AND (MH‘Adverse Drug Event’ OR harm OR
harms OR side-effect OR ‘side-effects’ OR ‘undesirable effect’ OR ‘undesirable effects’ OR ‘undesirable
reaction’ OR ‘undesirable reactions’ OR ‘undesirable event’ OR ‘undesirable events’ OR ‘undesirable
outcome’ OR ‘undesirable outcomes’ OR ‘adverse effect’ OR ‘adverse effects’ OR ‘adverse reaction’
OR ‘adverse reactions’ OR ‘adverse event’ OR ‘adverse events’ OR ‘adverse outcome’ OR ‘adverse
outcomes’) AND (MH‘Lithium’ OR lithium OR lithicarb OR eskalith OR lithobid OR lithane OR
cibalith-s OR quilonum OR hypnorm)

statistical pooling in a meta-analysis was neither possible Results

nor appropriate. Results were therefore restricted to a nar-
rative synthesis. We extracted descriptive statistics for each We identified 349 studies in the databases (199 in PubMed,
type of study design including the age, sex, psychiatric 138 in Embase and 12 in CINAHL), with a further 11 stud-
diagnosis, duration of lithium treatment prior to thyrotoxi- ies found via screening of references or other sources
cosis, lithium dose and level at the time of presentation (Figure 1). After assessing papers at the title and abstract
with thyrotoxicosis, and evidence of the following: (1) level, we included 52 studies, 39 of which were individual
clinical signs/symptoms of hyperthyroidism, (2) pre-exist- case reports and 3 case series (total n = 42). There were 10
ing thyroid illness and (3) presence of antithyroid antibod- cross-sectional, case control or cohort studies (Figure 1).
ies. Medical comorbidities were not included as they were The 39 case reports gave details on 45 patients (Table 2)
seldom recorded. (Altieri et al., 2015; Arlt et al., 2008; Bafaqeeh and Myers,
1976; Bandyopadhyay and Nielsen, 2012; Becerra-
Fernandez, 1995; Bernstein and Friedman, 2011; Byrne
Categorisation of study types and Delaney, 1993; Chalasani and Benson, 2014; Chow
Cohort studies were defined as observational studies, et al., 1993; Cubitt, 1976; Dalan et al., 2007; Dang and
where the sampling of study participants was based on Hershman, 2002; De Sousa Gurgel et al., 2015; Deardorff
exposure to lithium. The starting point for a cohort study et al., 2016; Dwarakanathan, 1998; El-Bakush et al., 2014;
may be all exposed or all unexposed patients, or both. Fauerholdt and Vendsborg, 1981; Franklin, 1974;
Notably, a comparison group is not a defining feature of Humphreys and Waddell, 1988; Kar et al., 2014; Law et al.,
a cohort study (Dekkers et al., 2012). By contrast, case 2004; McDermott et al., 1986; MacGregor, 1977; Merry,
studies/series case control studies were observational 1977; Mizukami et al., 1995; Numata et al., 2002; Onuigbo
designs, which consisted solely of participants who were et al., 2000; Pallisgaard and Frederiksen, 1978; Rabin and
sampled based on the presence of a disease or disease- Evans, 1981; Reus et al., 1979; Sato et al., 2013; Shimzu
related outcome (Dekkers et al., 2012). et al., 1997; Sinnott et al., 1992; Siyam et al., 2013; Tan

Australian & New Zealand Journal of Psychiatry, 00(0)

4 ANZJP Articles

Figure 1. PRISMA flow chart of included and excluded studies.

et al., 2013; Todd and Jerram, 1978; Valenta et al., 1981; hyperthyroid but clinically asymptomatic. Autoantibodies
Yamagishi and Yokoyama-ohta, 1999; Yassa et al., 1988). were positive in 9 cases, negative in 15 and not reported in
Lithium was used for a range of diagnoses including 21 cases.
bipolar disorder (n = 30 patients), depression (n = 10 The three case series described 46 patients with some
patients), schizoaffective disorder (n = 2 patients) and form of hyperthyroidism while on lithium treatment
cyclothymic personality disorder (n = 1 patient). Diagnoses (Table 3) (Barclay et al., 1994; Brownlie and Turner, 2011;
were missing for two patients. The mean age at presenta- Sirota et al., 1992). In terms of socio-demographic features,
tion was 46 (standard deviation = 14, range = 19–68) years, 36 were females and 10 males, with a mean age of 45 years.
with the majority female (66%). The median lithium dose The mean duration of treatment was 5.3 (range = 0.5–
was 900 (range = 600–1500) mg/day, and the mean and 25) years. Thyroid illness was treated in 24 patients (52%)
median duration of lithium therapy before developing thy- and not treated in 9 (19.6%), with no information on treat-
rotoxicosis was 3 years (range = 9 days to 18 years). Almost ment in 13 patients (28.3%).
all patients (44 of 45) were biochemically and clinically There were nine cross-sectional or cohort studies
hyperthyroid with only one case being chemically (Table 4) that described 2674 patients who were treated

Australian & New Zealand Journal of Psychiatry, 00(0)

 Table 2. Case reports.

Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment
Fairbrother et al.

1 Franklin 45/F Depres- 4 year Li Not re- Tremor, sweating, Not re- Not re- Not re- Not reported Histology toxic Thyroidec-
(1974) sion, therapy, pre- ported heat intolerance, ported ported ported goitre tomy
20 years existing non- weight loss, firm
toxic goitre goitre
– euthyroid
1g

2 Cubitt 59/F Cyclo- Not re- Not re- Tremor, no goitre Not re- Not re- Not re- Total = Thyrotoxicosis Carbimazole
(1976) thymic ported ported ported ported ported 19.5–24.4
PD umol/L (5.6–
14.3), Free
T4 index =
0.170–0.231
(0.049–0.138)

3 Bafaqeeh 50/M BPAD 3 year 0.6 mmol/L Agitated, tremulous, Not re- Not re- 210 nmol/L Not reported Thyrotoxicosis Not re-
and Myers duration, sweating, tachy- ported ported (55–150) ported
(1976) 0.5–1.0 g cardia, perceptual
disturbance and
paranoia

4 MacGregor 39/F Depres- 5 years Not re- Weight loss, Negative Not re- Not re- T4 210 Hyperthyroidism Carbimazole
(1977) sion ported tremor, lid lag, no ported ported mmol/L
goitre

5 Merry 54/M Depres- 1200 mg (2 Not re- Shakiness, dizziness, Not re- Not re- 1.47 nmol 257 nmol Thyrotoxicosis Carbimazole
(1977) sion years) ported palpitations, weight ported ported (0.8–1.5) (50 to
loss 1–154 nmol)

6 Todd and (a) 36/F Depres- 800 mg, 0.58 0.58, sec- Weight loss, Negative 55 U/mL >5 ng/mL >200 ng/mL Thyrotoxicosis Partial thy-
Jerram sion ond level excessive sweating, roidectomy
(1978) 0.36 proptosis, goitre,
pigmentation, brisk
reflexes, wasting/
weakness muscles
(b) 48/F Depres- 800 mg 0.9–1.28, Goitre bruit, exoph- Positive Not re- Not re- Not reported Thyrotoxicosis; Li reduction,
sion (reduced to 0.71 at thalmos, proximal ported ported eventually hypo- carbimazole,
600 mg due 600 mg myopathy, brisk thyroid propranolol
to tremors) reflexes, agitated,
paranoid

Australian & New Zealand Journal of Psychiatry, 00(0)

5

(continued)
 6
Table 2. (Continued)
Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment

7 Pallis- 50/F BPAD 900 mg Not re- Enlarged non-tender Not re- Not re- Not re- 11.9 ug/dL Thyrotoxicosis Methima-
gaard and ported goitre, fatigue, ported ported ported (3.7–6.0) (non-specific zole, Li
Frederiksen anxiety, palpitations, thyroiditis); continued,
(1978) diarrhoea, weight euthyroid after Al-triiodo-
loss, hyperhidrosis therapy thyronine

8 Reus et al. 22/F BPAD 1500 mg 0.9–1.0 Mania, heat intoler- Present Not re- 284ng100ml 16.5 ug/100 Thyrotoxic Li continued
(1979) mmol ance, tremor, anxi- ported mL self-resolved; at 1500 mg
ety, palpitations repeat episode
1 year later;
similar circum-
stances; transient
thyrotoxicosis
(silent thyroidi-
tis) related to Li

Australian & New Zealand Journal of Psychiatry, 00(0)

therapy

9 Fauerholdt 63/M BPAD Nil dose, 3 Not re- Developed goitre Not re- Not re- Not re- Not reported Thyrotoxicosis 2 months
and Vends- year dura- ported after 3 years ported ported ported antithyroid
borg (1981) tion and clinical and drug and
biochemical signs of partial thy-
thyrotoxicosis roidectomy

10 Rabin and 62/M BPAD 600–900 mg 0.3–1.0 Weight loss, heat Not re- 5.6 uU Normal 17.2 ug/dL Euthyroid initial- Cessation
Evans (1981) intolerance, stare ported (4.5–11.5) ly; hyperthyroid of Li
with bilateral lid lag, with Li; euthyroid
proptosis on cessation

11 Valenta 49/F BPAD 600 mg 0.4–0.6 Hyperhidrosis, Antimicro- Blunted 270–571 ng/ 18.7–27.6 Euthyroid; hyper- Propylthi-
et al. (1981) mEq/L fine tremor, brisk somal Ab TRH dL (80–190) ug/dL thyroidism post ouracil
reflexes positive, response Li; euthyroid
Antithy-
roglobulin
Ab negative

12 McDermott 57/F BPAD 900 mg (8 0.7 mmol/L Tachycardia, lid lag, Antithy- 3.6 uU/ Not re- Elevated = 1. Primary hypo- Radioiodine;
et al. (1986) years) diffuse goitre roglobulin mL ported 14.7–16.9 ug/ thyroidism Remained
positive, dL, Free thy- 2. Hyperthyroid on Li
antimi- roxine index 3. Hypothyroid
crosomal = 6.5–7.9 (spontaneous
negative change from
Hashimoto’s to
Graves’ disease)
ANZJP Articles

(continued)
 Table 2. (Continued)
Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment
Fairbrother et al.

13 Humphreys 50/M Depres- 1250 mg Not re- Headache, chest Not re- Not re- Not re- Recorded as 1. Thyrotoxicosis Radioiodine
and Waddell sion ported pain, thirst, weight ported ported ported elevated 2. Hypothyroid – and carbima-
(1988) loss, sweating, fine post treatment zole; Li not
tremor, palpable ceased
goitre, tachycardia
brisk reflexes

14 Yassa et al. (a) 68/F Not 3 years Not re- No clinical evidence Not re- 0.5 uU/ Not re- 14.6 mcg/100 Euthyroid after Li not
(1988) reported ported of hypothyroidism ported mL ported mL 2 months; tran- ceased; no
sient hyperthy- intervention
roidism

(b) 61/F Not Not re- Not re- Exophthalmos, lid Negative Not re- Not re- 16.5 mcg/100 Thyrotoxic Li ceased,
reported ported ported lag, warm skin, dif- ported ported mL nodular goitre; radioactive
fuse nodular goitre euthyroid iodine

15 Sinnott et al. 42/F BPAD 750 mg (2 0.6 mmol Tremor, proximal Antimicro- Un-de- 10.7 pmol/L 40 pmol/L 1. Thyrotoxicosis Li continued
(1992) years) muscle weakness, somal Abs tectable (2.5–7.5) (12–28) 2. Hypothyroid-
mildly tender diffuse positive, ism
goitre antithy- Li continued;
roglobulin consistent with
Abs nega- granulomatous
tive thyroiditis

16 Byrne and 63/M BPAD 9 years Not re- Exophthalmos, lid Not re- Not re- Not re- Not reported Hyperthyroidism Carbima-
Delaney 900 mg – ported lag, unable to close ported ported ported – treated with zole; Li
(1993) reduced to right eye carbimazole, ceased
600 mg after hypothyroid
first episode – treated with
hyperthy- thyroxine;
roidism. second episode
Poorly hyperthyroid-
compliant ism – ceased Li.
– ceased Marked improve-
ment within 72
hours – resolved

17 Chow et al. (a) 40/F BPAD 1250 mg (3 0.7 mmol/L Clinically euthyroid Not re- Not re- 12.9 pmol/L Total = 1. Transient Li continued
(1993) years) but small diffuse ported ported 173 nmol/L, thyrotoxicosis
goitre FT4 = 2. transient hypo-
40.9 pmol/L thyroidism
3. Euthyroidism

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7

(continued)
 8
Table 2. (Continued)
Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment

(b) 37/F Recurrent Not re- Positive <0.02 7 pmol/L 27.5 pmol/L 1. Hypothyroid- Li continued
depres- ported (12 antimico- ulU/L (normal) (elevated) ism
sion year hx Li globulin Ab, 2. Euthyroidism
therapy) negative on thyroxine
antisomal 3. Transient
Ab thyrotoxicosis
after stopping
thyroxine
4. Hypothyroid-
ism
5. Euthyroidism

(c) 22/F BPAD 750 mg 0.45 Hand tremor, heat Negative <0.02 16.4 pmol/L >67 pmol/L 1. Transient Li continued
intolerance, weight ulU/L thyrotoxicosis
loss 2. Transient

Australian & New Zealand Journal of Psychiatry, 00(0)

hypothyroidism
3. Euthyroidism

18 Becerra- 48/F BPAD 2 years, 1.12 mEq/L Diffuse goitre Negative 0.06 3.34 ng/dL 283 ng/dL Hashimoto’s dis- Li ceased;
Fernandez 600 mg (0.2–1.2) uIU/mL (0.8–2.67) (80–180) ease; Li ceased; propranolol;
(1995) (0.32– propranolol and carbimazole
5.56) carbimazole;
euthyroid, anti-
bodies remained
undetectable;
Li-induced or un-
derlying disease,
but antibody
negative suggests
role of Li

19 Mizukami 26/F BPAD 800 mg, 2 Not re- Sweating, palpita- Negative <0.2 FT3 = FT4 = Li-associated Li ceased;
et al. (1995) year dura- ported tions, anorexia, (TG and M) uU/L 13.6 pmol/L 87.5 pmol/L autoimmune propranolol
tion diffusely enlarged (3.4–8.2) thyroiditis
goitre, no pre-
existing thyroid
dysfunction

20 Shimzu et al. 29/F BPAD 600 mg, 27 Not re- Palpitations, irrita- Positive <0.05 3.6 nmol/L 233 nmol/L Euthyroid ini- Methi-
(1997) month dura- ported tion, weight loss, no TSH binding uIU/mL (1.2–3.1) (58–155) tially; developed mazole;
tion pre-existing thyroid inhibitor Ig (0.03– Graves’ disease; eventually
dysfunction 5.00) euthyroid with thyroidec-
treatment tomy
ANZJP Articles

(continued)
 Table 2. (Continued)
Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment
Fairbrother et al.

21 Dwara- (a) 31/F BPAD 900 mg Not re- Tachycardia, Not re- >0.2 Not re- 15.4 uU/dL Li-induced hyper- Propylthi-
kanathan – depres- ported anxiety, diffusely ported uU/mL ported (4.4–10.7) thyroidism ouracil PTU
(1998) sion enlarged thyroid (0.71– therapy
7.5) 100 mg TDS,
radioactive
iodine
(b) 48/F Depres- 7 months Not re- Tremor, weight Not re- >0.03 Not re- 19 uU/dL Li-induced hyper- Radioactive
sion ported loss, heat intoler- ported uU/mL ported thyroidism iodine
ance, anxiety, (0.38–
palpitations, diffusely 0.615)
enlarged thyroid
(c) 50/F Depres- 17 years Not re- Itching, gastroin- Not re- >0.03 Not re- 24 uU/dL Li-induced hyper- Radioactive
sion ported testinal symptoms, ported uU/mL ported (4.4–10.7 thyroidism iodine
tremor, anxiety, (0.38–
diffusely enlarged 0.615)
thyroid

22 Yamagi- 50/F BPAD 800 mg daily, 1.0 mmol Symptomatic 3 Negative <0.03 27.10 pmol/L 81.72 pmol/L Pre-Li TFTs Not re-
shi and 5 month months uIU/ml (3.39–6.31) (10.3–21.88) normal; Graves’ ported
Yokoyama- duration (0.4–5.0) disease
ohta (1999)

23 Onuigbo 47/M BPAD 1200 mg, 10 1.9 mmol/L Tremor, ataxia, Negative <0.06 Increased T3 Free T4 = Euthyroid pre-Li; Atenolol; Li
et al. (2000) year dura- tachycardia, in- uU/mL uptake 5.7nh/dL painless thyroidi- ceased
tion creased reflexes (0.38– (2.3–4.2) tis (Li-associated
4.7) thyrotoxicosis)

24 Dang and 52/M BPAD 900 mg for >0.1 Delusional mania, Negative 0.06 Not re- 6.17 ng/dL Silent thy- Atenolol,
Hershman 15 years, anxious, weight loss, uU/mL ported (0.8–2) roiditis – atypical prednisone;
(2002) ceased tachycardia (0.6–4.6) granulomatous ceased Li
3 months thyroiditis
before
admission

25 Numata 48/F Depres- 600 mg for 0.55–0.63 Perspiration Not detect- 0.01 ng/ 6.5 ng/dL 2.4 ng/dL Thyrotoxicosis Lithium
et al. (2002) sion 9 days mEq/L able dL (0.65– (2.3–3.7) (0.93–1.75) caused by silent ceased and
5.55) thyroiditis thyroid
function
normalised

(continued)

Australian & New Zealand Journal of Psychiatry, 00(0)

9
 Table 2. (Continued)
10

Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment

26 Law et al. 39/M BPAD No dose Therapeu- Weight loss, tachy- Not re- <0.1 7.2 (0.7– 53 pmol/L Li associated Propranolol
(2004) recorded, 18 tic cardia, tremor ported (0.4–5.0 2.1 nmol/L) (10–23) thyrotoxicosis;
year dura- uIU/L) normalised with
tion treatment

27 Dalan et al. 65/F BPAD Not re- 0.6 Delirious, restless Negative 0.05 415.6 pg/ 1.24 ng/dL Subclinical hyper- Ceased Li,
(2007) ported dehydrated, multi- uIU/L dL (279.2– thyroidism carbimazole
nodular goitre (0.29– 538.96)
0.377)

28 Arlt et al. 56/F BPAD 4 months, 1.0 After iodine con- Negative 0.47 uU/L Normal on Normal on Thyrotoxicosis Thiamazole
(2008) 1125 mg trast medium, weak- (0.35–4.5) admission, admission, and pred-
ness, numbness, gait – dropped 222 ng/dL 8.1 then nisolone;
disturbance, weight less than increased to ceased Li
loss, depressed 0.01 14.7 ug/dL and symp-

Australian & New Zealand Journal of Psychiatry, 00(0)

mood, progressed (4.5–11.5) toms largely
to tetraparesis, bul- resolved in
bar symptoms, diso- 3 weeks
rientation, paranoid/
nihilistic delusions
and cachexia

29 Bernstein 61/M BPAD 600 mg for 7 0.5 mmol/L Not symptomatic, Negative 0.03 uU/L 4.8 pg/mL 1.73 ng/dL Thyroiditis Lithium
and Fried- years no pre-existing (0.34– (2.4–4.2) (0.58–1.64) tapered
man (2011) thyroid illness 5.60) and ceased
– 4 weeks
later TFTs
normalised

30 Deardorff 38/F Schizoaf- 900 mg 0.8 mmol/L Akathisia, weight Not re- 0.004 Not re- 1.48 mIU/L Li-induced hyper- Beta block-
et al. (2016) fective loss ported mIU/L ported thyroidism ers; thyroid
status nor-
malised after
50 days from
Li cessation

(continued)
ANZJP Articles
 Table 2. (Continued)
Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment
Fairbrother et al.

31 Bandyopad- 46/F BPAD Not re- 3.6mEq/L Acute onset agita- Not re- 0.016 7.5 pg/mL 3.0 ng/dL Severe thyro- Haemodi-
hyay and ported (0.6–1.2), tion and delirium, ported uU/mL (1.8–4.6) (0.7–1.8) toxicosis and im- alysis; pro-
Nielsen Li toxic hyperhidrosis, de- (0.4–5.5) pending thyroid pylthiouracil;
(2012) hydrated, tachycar- storm propranolol
dia, bilateral pedal
oedema, coarse
tremor, brisk re-
flexes, no goitre

32 Sato et al. 64/F BPAD Maintenance Therapeu- Mild diarrhoea, ma- Antithyroid <0.01 8.12 pg/mL 4.45 ng/dL Thyrotoxicosis Li ceased
(2013) dose for 9 tic level laise and low-grade Ab negative, (1.71–3.71) (0.7–148) due to silent
years fever, drowsiness, peroxidase thyroiditis
proximal myopathy Ab positive

33 Siyam et al. 27/M Schizoaf- 1350 mg Denied diaphoresis, Negative Low = 4.6 pg/mL 1.57 ng/dL Acute thyroiditis; Li discon-
(2013) fective heat intolerance, 0.006 (2.0–4.4) (90.93–1.70) hyperthyroid- tinued on
disorder eye protrusion, mcU/mL ism resolved admission
(3 years tremor, weight gain, (0.270– during admission,
hx) tachycardia, AH/VH 4.2) 2 month post
– complete nor-
malisation TFT

34 Tan et al. 51/F BPAD (18 1350 mg 0.4–0.6 Symptomatic, no Not re- 0.02 Not re- 19 pmol/L Hyperthyroid- Carbima-
(2013) years hx) mmol/L pre-existing thyroid ported mIU/L ported (10–25) ism due to silent zole; Li
illness (0.5–4.0) thyroiditis continued;
symptoms
resolved
after 3
months then
hypothyroid-
ism

35 Chalasani 19/F BPAD – 1250 mg 0.75 2/52 hx headaches, Negative 0.01 Not re- 63.6 pmol/L Hyperthyroidism Li continued;
and Benson subclinical mmol/L lethargy, weight mU/L ported (12–22) improved when propranolol
(2014) hypothy- loss, tremor, (0.4–4.0) propranolol com-
roidism achycardia, diffuse menced, lithium
non-tender goitre, continued, hypo-
lid lag thyroid result

(continued)

Australian & New Zealand Journal of Psychiatry, 00(0)

11
 Table 2. (Continued)
12

Age
Author(s), (years)/ Auto-anti- Sequence thyroid
No. year sex Diagnosis Lithium dose Li level Symptoms bodies TSH T3 T4 dysfunction Treatment

36 El-Bakush 25/F BPAD Not report- 4.6 mmol/L Lithium toxicity Antithyroid <0.002 Not re- 1.96 ng/dL Lithium toxicity, Propylthi-
et al. (2014) – schizo- ed, recently peroxidase mU/mL ported (elevated) silent thyroiditis ouracil; hae-
phrenia, increased Ab positive (low) modialysis
pre-
existing
hypothy-
roidism

37 Kar et al. 61/F BPAD (23 18 year Therapeu- Thyrotoxic, no Not re- 0.01 Not re- Elevated Thyrotoxicosis; Li continued
(2014) years hx) duration on tic range at previous history of ported mU/L ported series of 3 after 5 months and titrated
lithium onset thy- thyroid illness (0.27– months = treatment, devel- according
rotoxicosis 4.20 57, 72 and oped hypothy- to serum Li
however mU/L) 40 pmol/L roidism levels; carbi-
fluctuated (12.0–22.0) mazole
up to 1.2

Australian & New Zealand Journal of Psychiatry, 00(0)

mmol/L

38 Altieri et al. Adult BPAD Not re- 2.7 mEq/L Tremors, reduced Not re- Low Elevated Elevated Thyroid storm; Methima-
(2015) female – recent ported (0.5–1.2), oral intake, emesis, ported TFTs normalised zole; pro-
sleeve Li Toxic agitated, tachycardia after treatment pranolol
gastrec- hypertensive, febrile
tomy

39 De Sousa 19/M Schizoaf- 1200 mg 0.61 Anxiety headaches, Not re- 0.61 Not re- FT4 = Thyrotoxicosis When Li
Gurgel et al. fective mmol/L restlessness that ported uUI/mL ported 3.13 ng/dL was ceased,
(2015) disorder progressed to se- (0.34– (0.54–1.24) symptoms
vere psycho-motor 5.6) elevated rapidly
agitation, tachycar- resolved
dia, tremor

TSH: thyroid stimulating hormone; BPAD: bipolar affective disorder; TFT: thyroid function test.
ANZJP Articles
Fairbrother et al. 13

Table 3. Case series studies.

Author(s), Study design and Psychiatric Outcomes No. of Duration of

year recruitment diagnosis measures participants Age/gender lithium therapy Findings

Brownlie Study of Thyrotoxicosis; TFTs, 99mTC 23 20 F, 3 M; 6 (0.6–25) 10 diffuse

and Turner hyperthyroid psychiatric pertechtenate median age years hyperplasia – 2
(2011) patients diagnosis not thyroid = 41 (19–75) of which Graves’
presenting to reported scintiscan years disease, 2 toxic
clinic who were multi-nodular
maintained on Li goitre, 9 painless
therapy between thyroiditis, 1 sub-
1999 and 2006 acute thyroiditis
(on Li for <1
year), 1 diffuse
goitre

Barclay et al. Retrospective Tc 14 9 F, 5 M; mean 4.3 (1–11) Scintiscans of 13

(1994) study identifying pertechtenate age = 49 years pts – identified
14 pts with thyroid scans, (17–72) years Mean Li 8 toxic diffuse
Li-associated serum T3, dose = 750 goitre, 2 toxic
thyrotoxicosis T4, free T4 (400–1250) mg multi-nodular
attending thyroid index, thyroid goitre, 1 toxic
clinic over microsomal uninodular
18-year period and goitre, 2 painless
(1973–1991) thyroglobulin thyroiditis
Ab titres

Sirota et al. Case series Psychiatric TFTs, physical 9 7 F, 2 M; Average All 9 had goitres,
(1992) report of illness stigmata average age = duration = 8 eye findings, 7
hyperthyroidism 50 years 59 months (6 clinical Graves’
in pts on Lithium months–15 disease, 1 toxic
years) multi-nodular
goitre, 1 solitary
toxic nodule

TFT: thyroid function test.

with lithium (Bocchetta et al., 2007a, 2007b; Calabrese The majority of the studies included involved very small
et al., 1985; Caykoylu et al., 2002; Hayes et al., 2016; numbers of participants, with only four studies having more
Kirov, 1998; Kirov et al., 2005; Kuman Tuncel et al., 2017; than 200 participants (Hayes et al., 2016; Kirov, 1998;
Shine et al., 2015). Of these patients, 58% were females. Miller and Daniels, 2001; Shine et al., 2015). However, two
The mean age was 46.5 years, and the mean duration of further studies had large numbers of patients treated with
lithium therapy was 2.8 years. Of these, 2.6% (n = 72) were lithium (n = 1916 with 234,035 matched controls and
hyperthyroid. Only one study reported the mean lithium n = 2148 patients, respectively) (Hayes et al., 2016; Shine
dose (Kuman Tuncel et al., 2017). One further large study et al., 2015). Length of follow-up was highly variable, both
of laboratory results (n = 235, 951) was not included in the within and between studies, and in a single study was inad-
descriptive statistics in the absence of usable raw data and equately defined (Kirov, 1998). Inclusion and exclusion
measures of either lithium duration or dosage (Shine et al., criteria also differed between studies and were not stated in
2015). In this study, lithium levels were not associated with two studies (Calabrese et al., 1985; Kirov et al., 2005).
hyperthyroidism after adjustment for age, sex and comor- However, they were more extensive and better elaborated
bidity (Shine et al., 2015). However, there was an increased in more recent studies (Caykoylu et al., 2002; Hayes et al.,
risk in patients with lithium levels that were higher than the 2016; Kuman Tuncel et al., 2017). Three studies took into
median for the sample (0·6 mmol/L). account possible confounders in their statistical analysis
There was only one case control study of 400 patients (Hayes et al., 2016; Kuman Tuncel et al., 2017; Shine et al.,
referred to Massachusetts General Hospital, 30 of whom 2015).
had Graves’ disease and 100 silent thyroiditis (Miller and In the case of cross-sectional, case control or cohort
Daniels, 2001). The odds of lithium exposure was increased studies where we were able to use the modified Newcastle–
4–7 fold in patients with silent thyroiditis compared to Ottawa scale, 8 of the 10 studies were judged as being at
those with Graves’ disease (95% confidence interval [CI] = low risk of bias (Bocchetta et al., 2007a, 2007b; Caykoylu
[1.3, 17.1]). et al., 2002; Hayes et al., 2016; Kirov, 1998; Kuman Tuncel

Australian & New Zealand Journal of Psychiatry, 00(0)

 Table 4. Cross-sectional and cohort studies.
14

Author(s), Psychiatric No. of Duration of

year Study design and recruitment diagnosis Outcome measures participants Gender/age lithium therapy Findings

Bocchetta Prospective study of clinically Not stated At least one TSH 118 out of 150 66% F at Up to 1 case of hyperthyroidism = an
et al. relevant thyroid dysfunction in a level, thyroid pts on lithium baseline; median 15 years; mean annual incidence rate of 0.1%
(2007b) cohort of patients on long-term circulating antibodies, age = 40.0 = 8.3 years
lithium treatment hypothyroidism/ years: F, 39.0
hyperthyroidism requiring years, M at
treatment baseline

Bocchetta Prospective comparison of BPAD1, Hyperthyroidism Of 110 pts, 58 73% F at 6 years; age 2 new cases of hyperthyroidism
et al. (2007a) thyroid and renal function of BPAD2 requiring antithyroid still on lithium, 20 baseline. range =
patients who had started on or major medication died, 32 lost to 65–84 years
lithium before and after 65 years depression follow-up
of age

Kuman Cross-sectional study design BPAD Thyroid hormone 84 patients 53.6% F; mean Mean duration 1.2% of lithium pts (1 case) of
Tuncel et al. with patients recruited from an antibodies, thyroid ultra treated with age = 43.1 of lithium subclinical hyperthyroidism.
(2017) affective disorders outpatient sonography lithium matched years therapy = No statistical difference

Australian & New Zealand Journal of Psychiatry, 00(0)

unit and controls recruited from and 65 gender 139.4 months; between cases and controls.
hospital staff and age similar mean dose =
controls 1088.8 mg/day

Hayes et al. Propensity score adjusted BPAD1 Identified adverse 2148 pts on 59.92% F; Pts were 41 events of hyperthyroidism.
(2016) longitudinal cohort study using outcomes including lithium median age = included if Rate per 100 patient year at risk
nationally representative UK hyperthyroidism, 46.28 years they had (PYAR) = 0.78.
electronic health records from TSH < 0.1 mU/L received Rate increased compared
January 1995 to December 2013 at least a to valproate (p = 0.003) and
of pts on olanzapine, quetiapine, 1-month olanzapine (p = 0.007) but not
valproate and lithium prescription of quetiapine (p = 0.096).
lithium

Kirov et al. Cohort study. BPAD1, TFTs, Ab assays 57 33 F, 24 M; Mean = 1 thyrotoxicosis (Graves’
(2005) Patients were recruited from BPAD2 or mean age = 53.1 (14–87) disease)
a lithium clinic or as part of a unipolar 49.3 (24–87) months
genetic association study with a depression years
14–87 month follow-up period.

Caykoylu Cross-sectional study of clinic BPAD1 TFTs 42 17 F, 25 M; Duration 3 M subclinical hypothyroidism;

et al. (2002) patients with diagnosis of BPAD mean age: F, range = 3 F subclinical hyperthyroidism;
and on lithium. 36.7 ± 15.3 4–156 months; 1 M hyperthyroidism; toxic
Exclusion of previous thyroid years; M, dose between goitre 16 pts (10 F)
dysfunction or augmenting 29.1 ± 11.7 600 and
psychotropic agents. years 1200 mg/day
ANZJP Articles

(continued)
 Fairbrother et al. 15

et al., 2017; Miller and Daniels, 2001; Shine et al., 2015)

TSH: thyroid stimulating hormone; BPAD: bipolar affective disorder; MDD: major depressive disorder; DSM-III: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition; TFT: thyroid function test.
(Table 5).

positive thyroid microsomal

Lithium not associated with

suppression of thyrotropin
2 (1 M and 1 F) developed

1 patient with pre-existing

hyperthyroidism based on
Discussion

antibodies developed

activity (p = 0.1010)
Lithium therapy is commonly associated with hypothyroid-

hyperthyroidism
thyrotoxicosis

ism. By contrast, hyperthyroidism is a very low prevalence

adverse event associated with lithium therapy. To our
Findings

knowledge, this is the first systematic review of all pub-

lished reports of hyperthyroidism associated with lithium
therapy. We found 52 studies, 39 of which were individual
lithium therapy

of information
due to source
case reports and 3 case series. There were 10 cross-sec-
Unable to be
Duration of

determined
tional, case control or cohort studies.

collection
6.4 years

14.5 ± 4
months

The mechanisms by which lithium induces a hyperthy-

roid state are unclear, with several different theories pro-
posed by researchers. One explanation is an underlying
M, 122 F; mean

mean age = 44

autoimmune mechanism, especially in patients with diffuse

age = 49 (35–
66) years; 864
(22–94) years

(17–61) years

= 49 (37–61)
Caucasian; 87

1052 F, mean

M, mean age

hyperplasia of the thyroid (Dang and Hershman, 2002). For

Gender/age

age = 52.8

10 F, 6 M;

instance, lithium leads to increased immunoglobulin pro-

years

duction in in-vitro studies (Deardorff et al., 2016). There is

also an increase in B-cell activity and a decrease in ratios of
cytotoxic T-cells among lithium-treated patients, as well as
with 234,035 non
lithium exposed
unipolar MDD,

increases in antithyroid antibodies (either antimicrosomal

levels matched
serum lithium
1916 pts with
63 recurrent
108 BPAD1,
participants

or antithyroglobulin) among lithium-treated patients with

19 BPAD2,
Total 209:

19 SCAD

controls

affective disorders (20%) compared to those not on lithium

No. of

(7.5%) (Wilson et al., 1991). A further study found that

16

lithium increased the titre of antithyroid antibodies in

patients who already possessed them, but not in control
calcium, HbA1c or lithium
measurements of serum
creatinine, thyrotropin,
4 months from 4 to 20

subjects exposed to lithium, suggesting that at the very least

TFTs, Ab assays every
Outcome measures

that lithium can exacerbate pre-existing thyroid autoim-

munity (Rapaport, 1994). Finally, autoimmunity is sug-
At least two

gested by the occurrence of exophthalmos among

lithium-treated patients, which resolves on cessation
months

(El-Bakush et al., 2014).

TFTs

level

However, an autoimmune process cannot be the sole

explanation given that antibodies were positive in less than
BPAD (DSM-III)
schizoaffective

of information
due to source
Unable to be

50% of patients in the case reports we identified where it

determined
Psychiatric

BPAD1/2,

collection
diagnosis

was measured (Table 2). Another possible mechanism is

disorder
(SCAD)
MDD,

iodide retention and expansion of intra-thyroidal iodide

stores secondary to inhibition of thyroid hormone synthesis
and release. This increase in intra-thyroidal iodide may pre-
between 1 October 1985 and 31
4–20 month period of follow-up
catchment area of the Maudsley

cipitate thyrotoxicosis in patients who are genetically pre-

laboratory information systems
short prospective arm of 3–20

Retrospective cohort study of

lithium naïve outpatients with
Study design and recruitment

routinely collected data from

of patient records within the

disposed to Graves’ disease, or nodular goitres, and thus

Hospital, London. Includes a

Prospective cohort study of

Retrospective study design

particularly sensitive to the effects of iodide (Barclay et al.,

1994; McDermott et al., 1986). Finally, lithium may exert a
direct toxic effect on the thyroid gland (Altieri et al., 2015;
Humphreys and Waddell, 1988), although evidence is
March 2014

weaker given the low numbers of patients involved and the

months

absence of any histological evidence of direct toxic changes

Table 4. (Continued)

in their thyroid gland cells (Miller and Daniels, 2001).

The time course from first exposure to lithium to the
Kirov (1998)

development of hyperthyroidism is highly variable, ranging

et al. (1985)

Shine et al.
Author(s),

Calabrese

from weeks to years. Thus, lithium can have an immediate

(2015)

or a delayed effect, and the reason for this is unclear. It may

year

be that when hyperthyroidism occurs shortly after the

Australian & New Zealand Journal of Psychiatry, 00(0)

16 ANZJP Articles

Table 5. Modified Newcastle–Ottawa scale.

Study Representativeness Size Comparability Outcome Statistics Total

Bocchetta et al. (2007b) 0 0 1 1 1 3

Bocchetta et al. (2007a) 0 0 1 1 1 3

Kuman Tuncel et al. (2017) 0 0 1 1 1 3

Hayes et al. (2016) 1 1 1 1 1 5

Shine et al. (2015) 1 1 1 1 0 4

Kirov et al. (2005) 0 1 0 1 0 2

Caykoylu et al. (2002) 0 0 1 1 1 3

Miller and Daniels (2001) 0 1 1 1 1 4

Kirov (1998) 0 1 0 1 1 3

Calabrese et al. (1985) 0 0 0 1 0 1

introduction of lithium, there is a direct toxic reaction or Silent thyroiditis is characterised by thyrotoxicosis with
destructive thyroiditis, akin to amiodarone-induced toxicity a very low 24-hour radioiodine uptake, and spontaneously
type II, while a delay of months or years suggests an auto- resolves, but may be followed by a hypothyroid phase
immune process (Siyam et al., 2013). (Woolf, 1980). In most cases, it is detected on routine test-
ing due to its transient nature and less obvious clinical fea-
tures when compared to Graves’ disease (Brownlie and
Clinical significance Turner, 2011). For this reason, silent thyroiditis is more
There are a number of important clinical considerations. likely to elude diagnosis altogether. It is also possible that
For instance, sudden changes in thyroid hormone levels in some patients diagnosed with lithium-induced hypothy-
may precipitate a psychiatric relapse (Arlt et al., 2008), roidism, what is actually being identified is the hypothyroid
while thyrotoxicosis in a patient with an affective disorder phase of silent thyroiditis, where the thyrotoxic phase has
may mimic the symptoms of their psychiatric illness and been missed (Miller and Daniels, 2001).
therefore be easily missed (De Sousa Gurgel et al., 2015). By contrast, Graves’ disease is more likely to present
This underscores the importance of checking thyroid func- symptomatically and the thyrotoxicosis is typically char-
tion in acutely ill psychiatric patients, particularly if they acterised by a diffuse goitre, elevated radioiodine uptake
are on lithium therapy and not responding to treatment. and homogeneous findings on scanning (McDermott
Furthermore, hyperthyroidism may also alter the renal et al., 1986). As it is an autoimmune disorder, it is unclear
clearance of lithium, leading to toxicity. Four cases of lith- what role, if, any lithium plays in the pathogenesis of this
ium toxicity in patients with thyrotoxicosis have been condition in lithium-treated patients. Graves’ disease is a
reported (Bandyopadhyay and Nielsen, 2012; Oakley et al., relatively common condition, and therefore, a proportion
2000; Sato et al., 2013). All required haemodialysis to treat of lithium-treated patients will develop the disease coinci-
their lithium toxicity, and one experienced serious compli- dentally to their lithium treatment (Thompson and Baylis,
cations of cardiac arrest, quadriplegia and coma, although 1986). However, as discussed above, there are researchers
she ultimately made a full recovery (Sato et al., 2013). It is who suggest a link between lithium therapy and autoim-
possible that in hyperthyroid patients, altered tubular func- munity, either by precipitating illness in an already predis-
tion due to induction of sodium–hydrogen counter-trans- posed individual or perhaps by a direct effect (Fauerholdt
port increases proximal tubule absorption of lithium, while and Vendsborg, 1981; Miller and Daniels, 2001).
simultaneously reducing the fractional excretion of lithium Interestingly, the case reports included four cases of
(Oakley et al., 2000). It is therefore important for clinicians ‘Hashitoxicosis’, three described by Chow et al. (1993)
to be aware that not only patients receiving lithium therapy (one of these was not included in our table as it followed
may be at an increased risk of thyrotoxicosis but that this lithium discontinuation) and one described by McDermott
state can also induce lithium toxicity. In patients where and colleagues (Chow et al., 1993; McDermott et al.,
there is a suspicion of lithium toxicity, thyroid function 1986). ‘Hashitoxicosis’ is used to describe the phenome-
tests and lithium level should therefore be performed as a non whereby Hashimoto’s thyroiditis (with or without
routine part of the initial evaluation (Sato et al., 2013). hypothyroidism) spontaneously evolves into Graves’

Australian & New Zealand Journal of Psychiatry, 00(0)

Fairbrother et al. 17

disease associated with hyperthyroidism. It is considered cross-sectional, cohort and case control studies on the asso-
rare, leading Chow et al. (1993) to argue that the associa- ciation between lithium therapy and hyperthyroidism.
tion with lithium therapy may be at least partly causal However, there are several limitations. Many of the papers
(Chow et al., 1993). were of variable quality as most were case studies or series of
Our findings on hyperthyroidism highlight the impor- small numbers of participants rather than cross-sectional,
tance of monitoring lithium levels closely both during ini- case control or cohort studies. While most of the latter
tiation and on-going management. For this and other designs had a low risk of bias, only one measured serum
reasons, lithium levels should be as low as possible while lithium. Psychiatric diagnoses, lithium dose and level, and
consistent with clinical gain given findings that higher lev- length of treatment were inconsistently reported. There was
els are associated with an increased risk of hyperthyroid- heterogeneity in the tests used to determine thyroid illness
ism. Clinical practice guidelines have generally converged reflecting changes in practice over time. In addition, thyroid
around recommended lithium levels of between 0.6 and 0.8 assays have become more sensitive and reference ranges for
mmol/L as maintenance therapy (Malhi et al., 2016). Given the diagnosis of illness have altered, leading to an increase in
that even at this level, there is the possibility of increased rates of detection (Kuman Tuncel et al., 2017). A clear diag-
risk (Shine et al., 2015), thyroid function tests and, if pos- nosis of thyroid illness was also not always available.
sible, thyroid antibodies should be measured at initiation Furthermore, not all studies reported thyroid function
and every subsequent 6 months (McKnight et al., 2017). prior to commencing lithium, so pre-existing thyroid illness
The ‘Lithiumeter’ was developed as a visual guide for could not be excluded thereby raising questions as to
determining lithium levels in the management of bipolar whether a temporal relationship exists in these cases. The
disorder and has recently been updated (Malhi et al., 2016). limited number of prospective studies meant that a clear
The treatment of hyperthyroidism, if it does occur, temporal relationship could not be established and there
depends on the aetiology. As patients with silent thyroiditis was no evidence of a dose response. A plausible alternative
are usually asymptomatic, it is appropriate not to institute explanation for any association might be that patients on
any therapy, but to perform serial monitoring of thyroid lithium are more likely to have their thyroid function moni-
function, as greater than 50% will subsequently develop tored as per clinical guidelines and thus incident cases are
hypothyroidism (Brownlie and Turner, 2011). As the course more likely to be detected (Malhi et al., 2015). There was
of silent thyroiditis (spontaneous remission, followed by also limited evidence of a dose response although it is
either euthyroid or hypothyroid state) seems to be inde- worth noting that the largest of the included papers (n = 235,
pendent of the decision to continue or withdraw lithium 951) reported an increased risk of hyperthyroidism at
therapy, it would seem reasonable to continue lithium ther- higher lithium levels that was not present at concentrations
apy in those patients for whom it has been helpful maintain- below the study median (Shine et al., 2015).
ing remission of their psychiatric symptoms (Chalasani and In addition, concomitant psychotropic medication was
Benson, 2014). The natural history of ‘Hashitoxicosis’ is seldom reported and it is possible that other medication
also transient and self-limiting, so antithyroid therapy may could be responsible for changes in thyroid function.
again not be necessary (Chow et al., 1993). Indeed, one study found that rates of hyperthyroidism
When indicated, antithyroid drugs such as carbimazole, increased in people prescribed lithium compared to val-
with or without steroids, are effective in cases of lithium- proate and olanzapine, but not quetiapine (Hayes et al.,
induced hyperthyroidism (Brownlie and Turner, 2011). For 2016). Together, these make it difficult to make any conclu-
patients with lithium-induced Graves’ disease, radioiodine sions regarding the nature of the association between lith-
or thyroidectomy may also be necessary, particularly if ium treatment and hyperthyroidism. Large prospective
patients are non-compliant with antithyroid drugs. In cases studies are required to clarify this and to inform clinical
of toxic nodular goitre, even in the absence of compressive management of patients treated with lithium where hyper-
symptoms, thyroidectomy is indicated (Brownlie and thyroidism occurs.
Turner, 2011). Common interventions in our case reports Finally, our search was limited to studies in English and
included antithyroid agents, and the reduction or cessation we were unable to undertake a meta-analysis because of the
of lithium. Three required surgery. Based on the case stud- heterogeneity of study populations and designs.
ies reported in this review, there is no universal recommen-
dation for either continuing or ceasing lithium therapy after Conclusion
hyperthyroidism is identified, although in recent years dis-
continuing lithium has been the most commonly reported. Hyperthyroidism is uncommon in patients on lithium com-
pared to hypothyroidism. Nonetheless, it has several clini-
cal implications. In the acute setting, it can complicate or
Strengths and limitations mimic mania and lead to lithium toxicity. Distinguishing a
By systematically reviewing the literature, we report the relapse of bipolar illness from thyroid dysfunction is criti-
largest collection to date of case reports, case series, cal, as it determines the most appropriate treatment and

Australian & New Zealand Journal of Psychiatry, 00(0)

18 ANZJP Articles

hence patient outcome. Given the high prevalence of any Carmaciu CD, Anderson CS and Lawton CA (2003) Thyrotoxicosis after
thyroid illness in patients receiving lithium and the signifi- complete or partial lithium withdrawal in two patients with bipolar
affective disorder. Bipolar Disorders 5: 381–384.
cant clinical complications, it is essential that all patients Caykoylu A, Capoglu I, Unuvar N, et al. (2002) Thyroid abnormalities
requiring mood stabilisation be advised of the potential in lithium-treated patients with bipolar affective disorder. Journal of
adverse effects of lithium so they can make informed International Medical Research 30: 80–84.
choices about their health care. Regular thyroid monitoring Chalasani S and Benson KA (2014) Lithium-induced thyrotoxicosis in
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Declaration of Conflicting Interests thyrotoxicosis in 4 Chinese women with autoimmune thyroiditis.
Australian and New Zealand Journal of Psychiatry 27: 246–253.
The author(s) declared no potential conflicts of interest with respect
Cubitt T (1976) Letter: Lithium and thyrotoxicosis. The Lancet 1: 1247–
to the research, authorship and/or publication of this article.
1248.
Dalan R, Leow MK and Jong M (2007) Multiple endocrinopathies associ-
Funding ated with lithium therapy. Endocrine Practice 13: 758–763.
Dang AH and Hershman JM (2002) Lithium-associated thyroiditis.
J.G.S. is supported by a National Health and Medical Research
Endocrine Practice 8: 232–236.
Council Practitioner Fellowship Grant (grant no. 1105807).
De Sousa Gurgel W, Dutra PE, Higa RA, et al. (2015) Hyperthyroid
rage: When bipolar disorder hides the real disorder. Clinical
ORCID iD’S Neuropharmacology 38: 38–39.
Deardorff OG, Gwozdziewycz N and Adusumilli N (2016) A case of mis-
James G Scott https://orcid.org/0000-0002-0744-0688
taken identity: Akathisia or lithium-induced hyperthyroidism? Primary
Steve Kisely https://orcid.org/0000-0003-4021-2924 Care Companion for CNS Disorders 18. Available at: https://www.
psychiatrist.com/PCC/article/Pages/2016/v18n05/15l01921.aspx
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