Pituitary
https://doi.org/10.1007/s11102-018-0880-8
Immunotherapy-induced autoimmune diabetes and concomitant
hypophysitis
Melissa Sum1   · Franco Vallejo Garcia1
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Combination therapy with nivolumab, an anti-programmed
cell death-1 antibody, and ipilimumab, an anti-cytotoxic
T-lymphocyte-associated antigen4 compared to ipilimumab
alone leads to significantly longer overall survival in patients
with advanced melanoma [1].
Endocrinopathies associated with immunotherapy include
hypophysitis, thyroid dysfunction, adrenal insufficiency, and
autoimmune diabetes. Recent studies suggest that approxi-
mately 10–15% of patients receiving ipilimumab may
develop hypophysitis [2]. In a recent study that included 945
randomized patients [1], 7% of subjects in the combination
nivolumab and ipilimumab arm developed hypophysitis, and
none developed diabetes. Indeed, the development of immu-
notherapy-associated autoimmune diabetes is uncommon.
We report a highly unusual case of immunotherapy-induced
autoimmune diabetes and hypophysitis in the same patient.
A 75 year-old man with a history of acute lymphoblastic
leukemia and cranial irradiation in 1978 with subsequent
remission and treated melanoma in situ in 1988 presented
with recurrent melanoma. Twenty-nine years after his ini-
tial treatment for localized nasal melanoma, he noticed an
enlarged right cervical lymph node. Fine needle aspiration
was consistent with metastatic melanoma. Imaging studies
showed cervical and bulky mediastinal adenopathy consist-
ent with metastatic disease without evidence of intraabdomi-
nal or intracranial neoplasm. The patient initiated treatment
with combination nivolumab and ipilimumab. He tolerated
the first and second cycles and reported only minor itching
relieved by oral anti-histamines. Nine days after receiving
his third cycle of therapy, he reported malaise, polyuria,
polydipsia, fatigue, blurry vision and presented for urgent
medical evaluation.
* Melissa Sum
Melissa.Sum@nyumc.org
Franco Vallejo Garcia
Franco.VallejoGarcia@nyumc.org
1
NYU Langone Health, New York, NY, USA
In the emergency department, the patient appeared as a
thin man with fair skin in mild distress with dry mucous
membranes. He had normal mentation without acanthosis
nigricans or skin tags. Laboratory evaluation showed: glu-
cose 678 mg/dL (74–106), sodium 134 mmol/L (137–145),
carbon dioxide 26 mmol/L (25–32), anion gap 19 mmol/L
(8–16), pH 7.39, large degree of ketonuria, and calculated
serum osmolality of 315 mOsm/kg (275–295). He received
intravenous fluids and insulin, resulting in normalization
of glucose, osmolality and anion gap. Further investigation
revealed c-peptide 0.3 mg/mL (0.8–3.5), anti-glutamic acid
decarboxylase (GAD65) > 250 IU/mL (0–5), anti-islet cell
antibody titer < 1:4, insulin antibody 0.4 U/mL (0–0.4),
hemoglobin A1C 7.6%, normal cortisol, ACTH, and thyroid
hormone levels. He was diagnosed with immunotherapy-
induced autoimmune diabetes and prescribed basal–bolus
insulin.
At his follow-up appointment, he reported feeling well
while utilizing a stable dose of 0.15 units/kg basal insulin
and a carbohydrate ratio of 1 unit short-acting insulin for
15 g of carbohydrates along with an insulin sensitivity factor
of 50 mg/dL. Imaging showed marked improvement in his
cervical and mediastinal lymphadenopathy consistent with
anatomical response. His brain MRI showed new mild dif-
fuse prominence of the pituitary gland (Fig. 1), and repeat
labs showed normal cortisol, ACTH, and thyroid hormone
levels.
Two weeks later, the patient began to experience hypo-
glycemia unrelated to increase in activity, decrease in food
consumption, or infection, and his insulin dose was lowered.
Four days later, he reported ongoing hypoglycemia as well
as significant malaise even when euglycemic. Laboratory
evaluation showed: morning cortisol 0.8 mcg/dL (4.5–23),
ACTH 6 pg/mL (7–69), TSH 7.120 mIU/L (0.4–4.0), free T4
1.1 ng/dL (0.7–2.2), and he was diagnosed with central adre-
nal insufficiency in the setting of immunotherapy-induced
hypophysitis and subclinical hypothyroidism. He was
treated with replacement corticosteroids and subsequently,
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recurrent hypoglycemia in a patient with recently diagnosed

immunotherapy-induced autoimmune diabetes. To date,
only one other case of concurrent diabetes and hypophysitis
has been reported in a patient who received nivolumab for
an advanced pulmonary pleomorphic carcinoma [3]. That
patient also developed autoimmune diabetes first, and was
diagnosed with hypophysitis approximately 1 month later,
during an admission for nausea and hypotension. Inter-
estingly, despite initial normal routine pituitary labs, our
patient’s brain MRI showed evidence of a mildly prominent
pituitary. Subsequently, his sudden hypoglycemia provided a
clue regarding development of hormonal deficiencies, allow-
ing for diagnosis of hypophysitis prior to a more dramatic
presentation. Clinicians should be aware of the possibility
of this rare dual manifestation of immunotherapy-induced
diabetes and hypophysitis, which can manifest as hypogly-
cemia in a patient previously on a stable insulin regimen.

Compliance with ethical standards 

Conflict of interest  The authors declare that they have no conflict of

interest.

Fig. 1  Prominent pituitary on brain MRI

References
levothyroxine. With treatment of his adrenal insufficiency,
his hypoglycemia resolved and his insulin requirements
returned to the previously stable dosage. Three and a half
months after his last dose of nivolumab and ipilumumab,
immunotherapy continues to be on hold given his near com-
plete response.
In conclusion, we report a highly unusual case of
immunotherapy-induced hypophysitis that manifested with
1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob
JJ et al (2017) Overall survival with combined nivolumab and
ipilimumab in advanced melanoma. N Engl J Med 377:1345–1356
2. Faje A (2016) Immunotherapy and hypophysitis: clinical presenta-
tion, treatment, and biologic insights. Pituitary 19:82–92
3. Marchand L, Paulus V, Fabien N, Perol M, Thivolet C, Vouil-
larmet J, Saintigny P (2017) Nivolumab-induced acute diabetes
mellitus and hypophysitis in a patient with advanced pulmonary
pleomorphic carcinoma with a prolonged tumor response. J
Thorac Oncol 12(11):e182–e184

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