Acta Diabetologica
https://doi.org/10.1007/s00592-020-01560-2
CASE REPORT
Co‑existence of starvation ketoacidosis and hyperthyroidism in early
pregnancy: a case report
Djordje Marina1   · Elisabeth R. Mathiesen1,2 · Marianne Klose1 · Berit Woetmann Pedersen2,3 · Lene Ringholm1,2
Received: 11 May 2020 / Accepted: 17 June 2020
© Springer-Verlag Italia S.r.l., part of Springer Nature 2020
Introduction
Ketoacidosis is a potentially life-threatening complication of
diabetes characterised by hyperglycaemia, metabolic acido-
sis and increased ketone body concentration caused by an
absolute or relative lack of insulin [1]. During pregnancy, the
onset of diabetic ketoacidosis can occur at normal or only
slightly elevated glucose levels, and ketoacidosis progresses
more rapidly than in non-pregnant women with type 1 dia-
betes [1]. Ketoacidosis can result in intrauterine death, with
a fetal mortality of up to 35% [2].
Diabetes is often, but not always, diagnosed before onset
of ketoacidosis and other etiologies of ketoacidosis as
starvation ketoacidosis may be considered [2]. Hyperem-
esis gravidarum is a condition with extreme and persistent
nausea and vomiting in early pregnancy that may lead to
insufficient food and fluid intake and starvation ketosis [3].
Further, signs of hyperthyroidism with elevated thyroid hor-
mones and suppressed thyroid stimulating hormone (TSH)
are often concomitantly present in women with hyperemesis
gravidarum [3].
The co-existence of ketoacidosis and hyperthyroidism
was first described in 1957 [4]. Hyperthyroidism is asso-
ciated with increased metabolism, lipolysis, blood glucose
levels and insulin resistance which may further trigger the
development of ketogenesis and ketoacidosis in susceptible
individuals [4].
This article belongs to the topical collection Pregnancy and
Diabetes, managed by Antonio Secchi and Marina Scavini.
* Djordje Marina
dr.djordjemarina@gmail.com
1
Department of Endocrinology PE7562, Rigshospitalet,
Blegdamsvej 9 DK‑2100 Copenhagen, Denmark
2
Center for Pregnant Women with Diabetes, Rigshospitalet,
Blegdamsvej 9, DK‑2100 Copenhagen, Denmark
3
Department of Obstretics, Rigshospitalet, Blegdamsvej 9,
DK‑2100 Copenhagen, Denmark
Conditions where increased carbohydrate requirement
exceeding the carbohydrate intake leads to ketosis have been
described in both healthy women in late pregnancy [2] and
during lactation [5], but to our knowledge not in healthy
women in early pregnancy.
We report a case of a woman without known diabetes who
presented with signs and symptoms of ketoacidosis and ges-
tational hyperthyroidism in combination with hyperemesis
gravidarum in early pregnancy.
Case report
A 30-year-old otherwise healthy woman presented with
nausea for two weeks and frequent vomiting the last two
days. She had been unable to eat for 4–5 days and had an
unintended 5 kg weight loss within the last weeks (BMI
19.2 kg/m2). She described fatigue and slightly decreased
consciousness. She reported no intake of alcohol, ketogenic
diet or history with eating disorder. The patient had experi-
enced symptoms of hyperemesis gravidarum in two earlier
pregnancies, but not so pronounced as in this pregnancy and
previous episodes of ketoacidosis were not reported.
Blood tests revealed a capillary glucose level of
11.9 mmol/l. Arterial pH was 7.30 (reference 7.35–7.45),
bicarbonate concentration 16.7  mmol/l (reference
21.0–27.0  mmol/l) and lactate 1.8  mmol/l (reference
0.7–2.1  mmol/l). A urine test revealed severe ketonuria
(> 15.6 mmol/l, reference < 0.5 mmol/l). A pregnancy test
was positive, and an ultrasound scanning demonstrated a
singleton pregnancy with an intrauterine fetus at 9 gesta-
tional weeks.
According to our local treatment protocol for ketoaci-
dosis, the treatment was basically as follows: Intravenous
insulin treatment (6 IE/h) was given upon initiation of the
ketoacidosis regimen together with potassium chloride 0.3%/
sodium chloride 0.9% infusion (500 ml/h) and sodium chlo-
ride 0.9% infusion (250–500 mg/h) which was shifted to
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glucose 10% infusion when plasma glucose of 6.8 mmol/l
was detected. Insulin treatment was reduced to 0–3 IE/h
depending on the glucose level. Three hours after initia-
tion of the ketoacidosis regimen pH normalised to 7.36 and
bicarbonate was 17.2 mmol/l, and ketonuria was negative
after 5 h. The treatment was simplified to one drip of glu-
cose–insulin–potassium drip, including glucose 10%, 20 IE
insulin aspart and 20 mmol potassium. Thirty-six hours
after initial hospitalisation nausea and vomiting persisted
and was leading to insufficient oral food and fluid intake.
The condition was judged as hyperemesis gravidarum. Glu-
cose 10% infusion (60 ml/h) and subcutaneous insulin treat-
ment with insulin aspart was given as required. Blood glu-
cose levels were measured every 2 h and were between 6.3
and 10.1 mmol/l. Two days after initial hospitalisation, the
patient initiated basal bolus insulin treatment with insulin
aspart at meals and insulin detemir before bedtime. Glucose
10% infusion (60 ml/h) was continued due to persistent nau-
sea and vomiting.
Despite antiemetic therapy with Metoclopramide, Ondan-
setron and Meclozine, the patient continuously suffered from
hyperemesis precluding oral food and fluid intake and paren-
teral nutritional therapy was initiated 10 days after the initial
episode of ketoacidosis, while basal bolus insulin treatment
continued. Analysis of urine ketones was performed at hos-
pitalisation, after 5 and 7 h, once daily for 4 days and then
with longer intervals.
The diagnosis of type 1 diabetes was excluded due to a
normal haemoglobin A1c (HbA1c) level of 5.4%/35 mmol/
mol (reference < 6.5%/48 mmol/mol), negative Glutamic
Acid Decarboxylase autoantibodies (GAD-65) and fasting
serum C-peptide levels above reference range (1800 pmol/l;
reference 379–1630 pmol/l).
At 18 gestational weeks, the antiemetic treatment was
intensified with oral Prednisolone 50 mg daily. Thereafter,
nausea and vomiting decreased leading to discontinuation
of parenteral nutritional therapy, and the patient was dis-
charged with glucose levels between 4 and 8 mmol/l and
HbA1c 5.5%/37 mmol/mol without insulin treatment. Oral
antiemetic therapy was gradually reduced and discontinued
within six weeks.
From 22 gestational weeks onwards, the patient reported
sufficient food intake on a normal diet with home-monitored
glucose levels within normal range and no need for insulin
treatment. On a few occasions of the biweekly visits to the
outpatient clinic, ketonuria was present and the patient was
recommended extra oral carbohydrates. One episode with
relapse of frequent vomiting and ketosis (blood ketones
5.5  mmol/l) led to treatment with intravenous glucose
with good effect on ketosis and vomiting. New episodes of
ketoacidosis did not occur.
At the initial hospitalisation, routine testing of thyroid
function revealed hyperthyroidism with TSH < 0.01 IU/l
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Acta Diabetologica
(reference 0.40–4.80 IU/l), free thyroxine 40.1 pmol/l (ref-
erence 12.0–22.0 pmol/l), total thyroxine 299 nmol/l (refer-
ence 70–140 nmol/l) and total triiodothyronine 4.6 nmol/l
(reference 1.4–2.8  nmol/l), with negative Thyrotropin
Receptor Antibodies (TRAb) and Thyroid Peroxidase Anti-
bodies (TPOAb). Ultrasound scanning revealed a multi-
nodular goiter. Gestational hyperthyroidism was suspected
and observed without treatment for 3 weeks. Due to the
severe hyperemesis and persisting hyperthyroidism, a treat-
ment trial with a low dose of Propylthiouracil was initiated.
As thyroid function tests normalised within 2 weeks and
nausea and vomiting persisted, the Propylthiouracil was
consequently stopped. In the second trimester the free thy-
roxine levels had normalised (16.5–17.0 pmol/l, reference
local 2nd trimester specific range 9.6–17.0 pmol/l) while
TSH remained fully suppressed (< 0.01 IU/l). During the
third trimester free thyroxine levels remained within normal
range (10–10.5 pmol/l, reference local 3rd trimester spe-
cific range 8.4–16.0 pmol/l) and TSH became measurable.
Five days before delivery, both free thyroxine and TSH lev-
els were within normal range (10.0 pmol/l and 0.44 IU/l,
respectively).
At 28, 32 and 35 gestational weeks ultrasound estimated
fetal weight was normal, the patient still reported nor-
mal glucose levels before and after meals with HbA1c of
5.4%/36 mmol/mol. The patient gave birth to a healthy boy
at 37 gestational weeks after induction of labour.
Discussion
We present a case of ketoacidosis in early pregnancy in a
woman without known diabetes in combination with ges-
tational hyperthyroidism and hyperemesis gravidarum with
insufficient food and fluid intake.
Our patient presented initially with pronounced hyperem-
esis gravidarum and symptoms and signs of ketoacidosis, but
with preserved insulin production based on fasting plasma
C-peptide and negative GAD-65, excluding the diagnosis
of type 1 diabetes. Despite hyperglycaemia during intrave-
nous treatment with glucose, gestational diabetes mellitus
as a major contributor to the episode with ketoacidosis was
not regarded plausible due to normal glucose levels while
on a regular diet and a stable HbA1c below 40 mmol/mol,
which is well within the lower normal range from 9 to 35
gestational weeks [6]. However, the oral glucose test was
not performed. The relation between ketoacidosis and auto-
immune hyperthyroidism is well known, mostly in patients
with type 1 diabetes [4]. Severe hyperthyroidism was pre-
sent, but autoimmune hyperthyroidism was excluded, since
TPOAb and TRAb were both negative and the thyroid func-
tion normalised in the second trimester and remained normal
after discontinuation of anti-thyroid treatment. However, we
Acta Diabetologica
speculate that gestational hyperthyroidism may have con-
tributed to increased metabolism, lipolysis, ketogenesis and
insulin resistance.
In patients with hyperemesis gravidarum, hyperthyroid-
ism is often concomitantly present and the relation between
transient hyperthyroidism and symptoms of nausea and vom-
iting is well known [3]. Due to the persistent vomiting lead-
ing to parenteral nutritional therapy and concomitant hyper-
thyroidism, a low-dose anti-thyroid treatment was tentatively
initiated in order to reduce the nausea and vomiting. Despite
normalisation of the thyroid function, nausea and vomit-
ing remained pronounced. Further, no clinical effect was
obtained with approved antiemetics. Therefore, treatment
with Prednisolone was added under the careful observa-
tion of plasma glucose levels. Only thereafter, symptoms of
nausea and vomiting decreased. After 22 gestational weeks,
antiemetic therapy was discontinued.
It is important to be aware of the risk of ketosis at any
stage of pregnancy because ketoacidosis in pregnancy is
related to intrauterine death [2]. Pregnant women with type
1 diabetes are at high risk of developing ketoacidosis, mainly
in second and third trimesters when insulin resistance is pre-
sent, and both normal and elevated plasma glucose levels
can be seen in diabetic ketoacidosis in pregnancy [1]. The
increased risk of developing ketoacidosis during pregnancy
may be related to a tendency towards higher occurrence of
ketosis in both healthy women and women with diabetes
[1]. Hyperthyroidism may further increase the susceptibil-
ity of ketoacidosis by aggravating ketogenesis due to lipol-
ytic effects on adipocytes promoting hepatic beta-oxidation,
increased gluconeogenesis and intestinal glucose absorption
as well as insulin resistance [4]. Despite less insulin resist-
ance in early compared to late pregnancy, our patient was
probably having increased insulin resistance due to hyper-
thyroidism with the need for transient insulin therapy. We
conclude therefore that the patient developed ketoacidosis
induced by starvation, and that pregnancy per se and gesta-
tional hyperthyroidism were aggravating ketone production
and insulin resistance. Other causes of ketoacidosis were
excluded by lack of history of other precipitating factors
(diabetes, alcohol intake or ketogenic diet) and no previous
events with ketoacidosis (i.e., genetic defect predisposing for
ketoacidosis). In order to prevent relapse of ketoacidosis, the
patient was initially treated with intravenous glucose or par-
enteral nutritional therapy, when nausea and vomiting was
prevalent. After discharge, the patient was regularly tested
for ketonuria, which successfully prevented new episodes of
ketoacidosis. We did not find indication of any eating dis-
order. However, we acknowledge that pregnancy in women
with eating disorders may not be rare [7].
This case demonstrates that insufficient food and fluid
intake in combination with gestational hyperthyroidism
can lead to the development of starvation ketoacidosis in
early pregnancy. In order to prevent starvation ketoaci-
dosis, it is important to regularly test for the presence
of ketone bodies in pregnant women who present with
severe nausea and vomiting regardless stage of pregnancy.
If ketone bodies are present, treatment with intravenous
fluids and carbohydrates may be considered to prevent
starvation ketoacidosis.
Author contributions  All authors contributed to the study conception
and design. Material preparation and data collection were performed
by Djordje Marina, Lene Ringholm and Elisabeth R Mathiesen. The
first draft of the manuscript was written by Djordje Marina, and all
authors commented on the following versions of the manuscript. All
authors read and approved the final version of manuscript.
Funding  Not applicable.
Compliance with ethical standards 
Conflict of interest  The authors declare they have no conflict of in-
terest.
Human and animal rights  The patient was informed about her inclu-
sion in case report and has signed informed consent. The study was
performed in accordance with the ethical standards as laid down
in the 1964 Declaration of Helsinki and its later amendments or
comparable ethical standards. Anyway anonymity is guaranteed in
the case report. This case report does not contain any studies with
animals performed by any of the authors.
Ethical approval  This article does not contain any studies with
humanparticipants or animals performed by any of the authors.
Informed consent  A written informed consent was obtained from
the patient.
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