MEDICINE

Letters to the Editor

The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint
Inhibitors
by Prof. Dr. med. Knut Mai, Prof. Dr. med. Martin Fassnacht, Prof. Dr. med. Dr. rer. nat. Dagmar Führer-Sakel,
Prof. Dr. med. Jürgen B. Honegger, Prof. Dr. med. Matthias M. Weber, Prof. and Dr. med. Dr. rer. nat. Matthias Kroiss
in issue 23/2021

The Focus Should Be on “Vitally Important” not been surgically removed or affected by radiothera-
Hormone Axes peutic injury (2).
Thus far, about 30 cases have been reported/published Non-alcoholic fatty liver disease is common now-
of immune checkpoint inhibitor (CPI) induced autoim- adays and predisposes patients to developing cancer.
mune polyglandular syndrome, especially for treatment CPIs can make patients with pre-existing diabetes mel-
with programmed death cell protein 1 (PD-1) inhibitors litus (often detectable by means of an abnormally high
and in patients with the HLA-DR4-allele. Patients with HbA1c measurement) insulin dependent to a higher ex-
severe cancer disease often have gonadotropic insuffi- tent or completely, but they can also induce generalized
ciency / secondary hypogonadism and do not wish to lipodystrophy (3, 4). Immunosuppressive glucocorti-
have sex hormone replacement therapy during the coid therapy in CPI induced diabetes mellitus is usually
cancer therapy. The administration of testosterone is not beneficial. DOI: 10.3238/arztebl.m2021.0311
contraindicated in patients with active prostate cancer,
References
as is administration of estrogens in (hormone positive)
1. Yang Y, Liu J, Yang K, et al.: Endocrine adverse events caused by
breast cancer. Growth hormone treatment should be different types and different doses of immune checkpoint inhibitors in
avoided in patients having active cancer treatment. For the treatment of solid tumors: a meta-analysis and systematic review. J
Clin Pharmacol 2021; 61: 282–97.
this reason, testing for growth hormone and gonado-
2. Lutz A, Stojkovic M, Schmidt M, Arlt W, Allolio B, Reincke M:
tropins can be avoided in many patients with suspected Adrenocortical function in patients with macrometastases of the adrenal
CPI induced hypophysitis, at least during active cancer gland. Eur J Endocrinol 2000; 143: 91–7.
treatment and immunotherapy. The focus should be on 3. Haddad N, Vidal-Trecan T, Baroudjian B, et al.: Acquired generalized
lipodystrophy under immune checkpoint inhibition. Br J Dermatol 2020;
the “vitally important” hormone axes, such as that of 182: 477–80.
the thyroid and adrenals. A correlation with the dosage 4. Mai K, Fassnacht M, Führer-Sakel D, Honegger JB, Weber MM, Kroiss
of the CPI seems to exist for the development of M: The diagnosis and management of endocrine side effects of immune
checkpoint inhibitors. Dtsch Arztebl Int 2021; 118: 389–96.
hypophysitis, but less so for CPI induced hypo-
thyroidism, hyperthyroidism, and primary adrenal fail- Prof. Dr. med. habil. Christian A. Koch, FACP, MACE
ure (1). Cancer patients may also develop metastases in Department of Medicine
Fox Chase Cancer Center
the adrenals, unilaterally or bilaterally; the risk of Philadelphia, USA
primary adrenal insufficiency is higher for bilateral ad- [email protected]
renal metastases than for patients with unilateral adren- Conflict of interest statement
al metastases, as long as the second adrenal gland has The author declares that no conflict of interest exists.

Diabetes Insipidus Should Be Included MRI scanning showed a thickening of the pituitary stalk
For completeness’s sake, diabetes insipidus (DI) should and contrast medium enhancement of the stalk as well as
be added as an entity to this very clear and balanced de- the posterior pituitary/neurohypophysis. A case of nivol-
scription of the endocrine side affects of immune umab induced CDI was reported in a man with advanced
checkpoint inhibitors. lung cancer, who developed the disease five months after
Central diabetes insipidus (CDI) is extremely rare the treatment had been initiated (3). The man died before
during treatment with immune checkpoint inhibitors (1). treatment for CDI was started. Symptomatic treatment
CDI has been described in only five cases of such treat- of CDI was given by means of administering 1-
ment. Two of these cases occurred during treatment for desamino-8-D-arginin-vasopressin (DDAVP) as tablets
prostate carcinoma using ipilimumab; in both cases the or nasal drops at an adequate dosage.
CDI was cured by administering high-dose glucocorti- The question of why CDI as an expression of
coids. In a further case, CDI developed during treatment lymphocytic infundibuloneurohypophysitis is rare
for Merkel cell carcinoma after three months of avelu- compared with lymphocytic adenohypophysitis during
mab. In this case, CDI disappeared spontaneously once treatment with immune checkpoint inhibitors remains
avelumab was stopped (2). In another case, during treat- unanswered. It is possible that the diagnosis of incom-
ment of metastatic melanoma with a combination of ni- plete CDI with mild polyuria is made only rarely in
volumab and ipilimumab, CDI, lymphocytic adenohypo- view of the often severe underlying disorder.
physitis, and type 1 diabetes developed. In all four cases, DOI: 10.3238/arztebl.m2021.0312

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References 4. Mai K, Fassnacht M, Führer-Sakel D, Honegger JB, Weber MM, Kroiss

1. Scherbaum WA: Autoimmune diabetes insipidus. In: Aminoff MJ, Boller M: The diagnosis and management of endocrine side effects of immune
rd checkpoint inhibitors. Dtsch Arztebl Int 2021; 118: 389–96.
F, Swaab DF, eds.: Handbook of clinical neurology, 3 series. The
human hypothalamus. Vol III, 25, Elsevier 2021.
Prof. (em.) Dr. med. Werner A. Scherbaum
2. Zhao C, Tella SH, Del Rivero J, et al.: Anti-PD-L1 treatment induced Heinrich-Heine-Universität Düsseldorf, Universitätsklinikum
central diabetes insipidus. J Clin Endocrinol Metab 2018; 103: 365–9. [email protected]
3. Deligiori MV, Siasos G, Vergadis C, et al.: Central diabetes insipidus
related to anti-programmed cell-death 1 protein active immunotherapy. Conflict of interest statement
Int Immunopharmacol 2020; 83: 106427. The author declares that no conflict of interest exists.

Associations of Endocrine Functions and courses of the primary disorder, such as weight gain.
Hormone Axes For this reason, some authors refer to abnormalities of
In my opinion, an article about the endocrine side the thyroid function tests (3). They also point out that
effects of immune checkpoint inhibitors should necess- thyroid dysfunction in patients being treated with im-
arily mention important associations of endocrine func- mune checkpoint inhibitors is associated with a better
tions and hormone/hormonal axes. response to the treatment and survival.
For example, primary adrenal cortex insufficiency Regarding immune checkpoint inhibitor-induced
can bring about higher concentrations of thyroid stimu- diabetes mellitus, some authors deem regular blood
lating hormone, reversible after cortisol substitution. glucose monitoring irrelevant because of the fulminant
On the other hand, cortisol substitution can unmask disease course (4). In this sense, there can be no talk of
central diabetes insipidus. An already existing failure of uncharacteristic symptoms.
the thyrotropic axis would have in painless thyroiditis a DOI: 10.3238/arztebl.m2021.0313
dampening effect on the TSH rise upon conversion into
References
hypothyroidism. I also miss for the diagnosis of a new
1. Mai K, Fassnacht M, Führer-Sakel D, Honegger JB, Weber MM, Kroiss
hypopituitarism a corticotropin releasing hormone test M: The diagnosis and management of endocrine side effects of immune
to check the corticotropic axis. The adrenocorticotropic checkpoint inhibitors. Dtsch Arztebl Int 2021; 118: 389–96.
hormone test with the remark “Beware of false posi- 2. Nguyen, Shah K, Waguespack SG, et al: Immune checkpoint inhibitor
related hypophysitis: diagnostic criteria and recovery patterns.
tives in acute pituitary insufficiency” shown in Figure 3 Endocrine-Related Cancer 2021; 28: 419–31.
of the article is obsolete, in my opinion. 3. Ferreira JL, Costa C, Marques B, et al: Improved survival in patients
Imaging diagnostics should have an important role with thyroid function test abnormalities secdondary to immune-
in suspected hypophysitis. A recently published study checkpoint inhibitors. Cancer Immunol Immunother 2021; 70: 299–309.
pointed out that (2) only laboratory diagnostics plus 4. Magis Q, Gaudy-Marqueste C, Basire A, et al: Diabetes and blood
glucose disorders under anti-PD1. J Immunother 2018; 41: 232–40.
headache or fatigue without magnetic resonance im-
aging would miss a third of cases. Obviously, imaging Dr. med. Athanasios Alexopoulos
is also important for the differential diagnostic evalu- Inne Medizin, Kurparkklinik
ation of other processes in the pituitary region. Bad Nauheim
[email protected]
Metastases, however, are rare in this setting.
Thyroid dysfunction, especially hypothyroidism, is Conflict of interest statement
not accompanied by the typical clinical signs in severe The author declares that no conflict of interest exists.

In Reply: cepts in earlier tumor stages in individual tumor

We thank Prof. Koch for his additional comments entities.
regarding the development of autoimmune diabetes We thank Prof. Scherbaum for his comment regard-
mellitus in existing type 2 diabetes and of polyglandu- ing rare CPI induced diabetes insipidus (CDI), which
lar autoimmune syndrome, especially during anti-PD-1 we—in view of space restrictions to our manu-
based therapy (1), which underlines the need for com- script—have only been able to hint at. Especially in the
prehensive endocrine evaluation in patients treated differentiation from polydipsia/polyuria symptoms in
with checkpoint inhibitors (CPI). CPI induced diabetes mellitus, awareness of this entity
Even though the diagnostic emphasis in CPI in- is important.
duced hypophysitis from a therapeutic perspective is In the authors’ experience, the development of dia-
sure to lie on the analysis of the corticotroph and betes mellitus during CPI therapy is variable and does
thyrotroph function, the evaluation of gonadotropic not always take a fulminant course with diabetic ke-
dysfunction makes sense. While contraindications toacidosis (2). For this reason we think—in contrast to
should be considered, sexual hormone supplemen- the explanations of Dr Alexopoulos—that simple blood
tation can be relevant in terms of wellbeing, anabolic glucose measurement, which is ubiquitously available
effects, and therapy of concomitant anemia in tumor as a point of care test, is very helpful, among others
patients, especially in the setting of increasing CPI in the context of hypoglycemic tendencies due to
use in the context of neoadjuvant therapeutic con- corticotropic insufficiency. The differential diagnostic

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evaluation of occurring hyponatremia also requires measurement extent that we do not perform this test in this question in our
of blood glucose level. departments and would therefore rather not recommend it for
As we mentioned in our article, the symptoms of CPI induced non-endocrine centers either. DOI: 10.3238/arztebl.m2021.0314
endocrinopathies are often masked in the context of the underly-
ing severe disease and are therefore not always groundbreaking References
(3). Laboratory screening is therefore urgently required. 1. Shi Y, Shen M, Zheng X, et al.: ICPis-induced autoimmune polyendocrine syndrome
type 2: a review of the literature and a protocol for optimal management. J Clin
Magnetic resonance imaging (MRI) plays an important part, as Endocrinol Metab 2020; 105: dgaa553.
described, although it was not possible to assess the exclusive ad- 2. Tittel SR, Laubner K, Schmid SM, et al.: Immune-checkpoint inhibitor-associated
ditive value of MRI within the study design of the cited study, as diabetes compared to other diabetes types—a prospective, matched control study.
this was assessed as diagnostic only in combination with hor- J Diabetes 2021. doi: 10.1111/1753–0407.13215. Online ahead of print.
monal deficiency (1/3 asymptomatic). 3. Mai K, Fassnacht M, Führer-Sakel D, Honegger JB, Weber MM, Kroiss M: The
diagnosis and management of endocrine side effects of immune checkpoint inhibitors.
The diagnosis of corticotropic insufficiency can actually be Dtsch Arztebl Int 2021; 118: 389–96.
more complex. If it could not be excluded by basal hormone 4. Petersenn S, Quabbe HJ, Schofl C, Stalla GK, von Werder K, Buchfelder M:
measurement, the insulin tolerance test as the gold standard is The rational use of pituitary stimulation tests. Dtsch Arztebl Int 2010; 107: 437–43.
certainly not recommended outside endocrine centers. The 5. Maghnie M, Uga E, Temporini F, et al.: Evaluation of adrenal function in patients
with growth hormone deficiency and hypothalamic-pituitary disorders: comparison
metyrapone stimulation test requires an inpatient stay. The between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and
ACTH stimulation test has a high predictive value for excluding CRH stimulation tests. Eur J Endocrinol 2005; 152: 735–41.
corticotropic insufficiency (4) and—if its methodological
weaknesses are taken into consideration—has been found to be On behalf of the authors
Prof. Dr. med. Knut Mai
practical and safe. In view of the great variability of the cortisol Medizinische Klinik m.S. Endokrinologie, Diabetes und Stoffwechsel
response in the corticotropin releasing hormone (CRH) test, this Charite – Universitätsmedizin, Berlin
[email protected]
test may yield a pathological result in spite of normal pituitary
function (5). Further to the greater effort and higher costs, this Conflict of interest statement
limits the utility of the CRH test in our experience to such a clear Prof. Mai has received lecture honoraria from BMS and Eisai.

CLINICAL SNAPSHOT
Severe Diabetic Ketoacidosis Associated with Abdominal
Lipohypertrophy
A 23-year-old socially deprived man with a 15-year history of type 1 diabetes was brought
to our hospital after becoming somnolent and dehydrated with a blood glucose concentration
of 885 mg/dL. Arterial blood gas analysis (pH 7.05, bicarbonate 8.8 mmol/L) and the
presence of massive ketonuria confirmed the diagnosis of severe ketoacidosis.
The patient’s metabolism was chronically decompensated (HbA 18.7%), and he hardly
1c
ever measured his blood glucose concentration. He always injected his insulin into a large
abdominal lipohypertrophy (Figure). Careful inspection and palpation identify lipohypertrophies
in 20 to 40% of persons who inject themselves with insulin. These swellings (or hardenings)
of the subcutaneous fatty tissue make it impossible to calculate insulin absorption, thus Left periumbilical indurated lipohypertrophy, circa
risking hyperglycemia or hypoglycemia. Constant injection of insulin at the same site 7 × 6 cm in size, with small superficial abscesses
and microtrauma from the re-use of pen needles are predisposing factors. Mediated by following stab incision
insulin-like growth factor 1, insulin also stimulates growth at the local level. Lipohypertrophies
are often reversible if local insulin injection is strictly avoided, and can be prevented by adherence to correct injection technique with systematic
variation of sites. After initial intensive care, our patient received detailed diabetes training with a considerable reduction in insulin dose. He was
discharged to outpatient diabetological care.
Prof. Dr. med. Andreas Holstein, Milena Gehrig, Dr. med. (univ.) David J.F. Holstein, Medizinische Klinik I, Klinikum Lippe-Detmold, Detmold,
[email protected]
Conflict of interest statement: The authors declare that no conflict of interest exists.
Translated from the original German by David Roseveare.
Cite this as: Holstein A, Gehrig M, Holstein DJF: Severe diabetic ketoacidosis associated with abdominal lipohypertrophy.
Dtsch Arztebl Int 2021; 118: 682. DOI: 10.3238/arztebl.m2021.0074

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