Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies, are novel therapeutic agents widely used in numerous malignancies. They are known to cause multiple immune-related endocrine adverse events (irAEs); however, anterior pituitary hypophysitis with secondary hypopituitarism is the most frequently reported irAE, especially in patients receiving anti-CTLA-4 treatment. By contrast, posterior pituitary involvement, such as central diabetes insipidus (CDI), is relatively rare and only few case reports have been published. The present report describes the case of a 53-year-old woman with metastatic melanoma treated with nivolumab an anti-PD-L1 monoclonal antibody. At 6 months after the initiation of nivolumab treatment, the patient was diagnosed with deficiency of the corticotrope and thyreotrope axes and in the following 2 months the patient was diagnosed with progressive development of polyuria-polydipsia syndrome. The diagnosis of partial CDI was retained based on plasma and urinary osmolalities, the water deprivation test and baseline copeptin levels as well as on the absence of the bright spot in the posterior pituitary in magnetic resonance imaging. Systematic research of the literature revealed a total of 13 cases reports (including 14 patients) presenting with CDI treated with monotherapy with CTLA-4 (n=5) or PD-1/PD-L1 Abs (n=6) or combined treatments (n=3). The improved understanding of the mechanisms of ICI action along with their extensive use should contribute to the early recognition of irAE symptoms. We hypothesized that clinicians should be aware of this clinical entity and its symptoms and treat it appropriately.
Immune check point inhibitors (ICI) are associated with immune related adverse events (irAEs) involving multiple endocrinological organs (
In a systematic review and meta-analysis including data from 38 randomized clinical trials comprising 7,551 patients investigating the use of ICIs in the treatment of various cancer types, hypophysitis incidence ranged from 1.5 to 13.3% in patients treated with CTLA-4 Abs and 0.3-3% in those with PD-1Abs. Recently, isolated cases reports have described the diagnosis of central diabetes insipidus (CDI) due to dysfunction of posterior pituitary/hypothalamus in patients treated with ICI (
According to data from the WHO global database of individual case safety reports (
Herein, we report the case of a patient diagnosed with simultaneous anterior and posterior hypophysitis (panhypophysitis) induced by nivolumab and discuss the emerging difference in the incidence of hypophysitis/CDI among subclasses of ICIs and the related pathogenic mechanisms.
A 53-year-old female patient was followed at Laikon General Hospital for metastatic melanoma of the left tibial treated with multiples surgeries due to local recurrences. A treatment with nivolumab-a PD-L1 Ab-was introduced at January 2021. The patient received 240 mg flat dose by intravenous infusion every 2 weeks and achieved a partial response (RECIST 1.1) within 6 months, based on computerised tomography (CT) scanning. Her other routine medication included venlafaxine. A thorough baseline work-up revealed normal electrolyte, hepatic, and renal function at the initiation of immunotherapy and before every session.
However, 6 months after the initiation of nivolumab she presented with extreme fatigue necessitating a precipitating hormonal work-up which revealed deficiency of the corticotrope and thyreotrope axis. The detailed biochemical work-up is shown in
Following these results, the patient eventually accepted to be hospitalised and a water deprivation test followed by desmopressin (DDAVP) administration test was performed (
Pituitary magnetic resonance imaging (MRI) did not show signs of hypophysitis (
The patient was started a replacement treatment with oral desmopressin (DDAVP) at 60 mg once daily with titration of the dose increasing to twice daily with evident improvement of her polyuria, nycturia, and polydipsia and re-initiation of nivolumab. Panhypopituitarism including CDI persisted after 6 months of follow up.
To identify studies and determine their eligibility, a systematic research was conducted in the PubMed Database on June 10, 2022. Research included the following keywords: ‘diabetes insipidus’, ‘immunotherapy’, ‘immune check-point inhibitors’, ‘posterior hypophysitis’, ‘pituitary’. The above keywords were also combined with the Boolean operators AND and OR. PICOT (population, intervention, comparison, outcomes, time) criteria were used in order the irrelevant articles to be excluded. Articles that do not align with the PICOT format were dismissed. More specifically, studies including population without malignancy (irrelevant population) or population presenting CDI induced by other causes than immunotherapy (irrelevant intervention) as well as studies including ICI-treated patients with hypophysitis without data on CDI (irrelevant outcome) were also excluded. Additionally, we excluded not original studies (Reviews or systematic reviews/meta-analysis) or
PubMed research revealed 583 English written reports; n=13 of them concerned
This is the case of a 53 year old woman treated with nivolumab for metastatic melanoma, presenting with a syndrome of polyuria-polydipsia, 6 months post-initiation of immunotherapy and 2 months after the diagnosis of the anterior pituitary deficiency (insufficiency of the corticotrope and thyreotrope axes). The diagnosis of partial CDI was retained based on biochemical findings that included inappropriately low urine osmolality for serum osmolality increased less than 50% after desmopressin administration in combination with low baseline copeptin levels. CDI induced by nivolumab treatment was confirmed through the medical history of the patient, the pituitary MRI and the water deprivation tests which allowed to exclude nephrogenic DI (NDI) and primary polydipsia.
DI is a rare condition that affects one in 25,000 persons (
In our patient the exclusion of metastatic disease was also challenging. Indeed, the posterior pituitary is most frequently affected by metastases, due to its vascularisation by the inferior hypophyseal artery (
Secondary hypophysitis related to ICI has a reported incidence ranging from 8 to 13% in patients treated with CTLA-4 Abs therapy (
Patients treated with ICIs rarely develop CDI secondary to an autoimmune process involving the hypothalamo-posterior pituitary region. Dysregulation of the posterior pituitary-hypothalamic axis induced by ICI has been reported in 13 case reports that are available in the current literature (summarized in
The pathophysiological mechanism for ICI-induced CDI remains unclear and may be linked to multiple pathways (
In many cases of patients with suspected DI, the diagnosis may be obvious based on serum and urinary osmolalities. If the serum osmolality is greatly increased, with concomitant low urinary osmolality, no further testing may be necessary. The diagnostic challenge arises when there are symptoms of polyuria and polydipsia with inappropriate normal or ‘almost normal’ serum osmolality or sodium levels or when NDI or primary polydipsia should be excluded. In such cases, dynamic test such as water deprivation test is required since direct measurement of plasma AVP is seldomly performed because of its rapid clearance. However, yet even under optimal conditions water deprivation test often require long periods of observation, and still is of low sensitivity (86%) and specificity (70%) (
Recently, copeptin-C-terminal peptide of pro-vasopressin-levels, either baseline or after stimulation (with hypertonic saline infusion or with L-arginine stimulation), has proven to be the most convenient and accurate way for the diagnosis of DI. Copeptin is co-secreted with AVP and is a surrogate of its secretion as it is a more stable compound (
In the MRI, CDI generally manifests as a pituitary ‘bright spot’ absence with or without enlargement (2-3 mm) of the pituitary stalk, although this finding alone is not necessarily sufficient to support CDI diagnosis. The posterior pituitary bright spot is a manifestation of stored vasopressin and although it is missing in 20% of the general population (
In conclusion, the recent widespread use of ICIs in oncology could explain why clinicians should be aware of the potential risk for developing CDI. For normoglycemic patients presenting with persistent polyuria/polydipsia syndrome during ICI therapy and in particular anti-PD-1/PD-L1, testing for DI via serum and urine specific osmolalities, urine specific gravity, and, if needed, a water deprivation test are required. Patients' symptoms of CDI can be easily controlled with DDAVP. As ICI are relatively new agents, rare side effects such as DI should be reported to the Food and Drug Administration adverse event reporting system (FAERS) to better understand their side effects and effective management of drug related adverse events.
Not applicable.
All data generated or analyzed during this study are included in this published article.
HG and AA conceived and designed the study. MM, DM, AA, PP, AK and DZ collected and interpreted all relevant clinical and laboratory data. AA, PP and HG prepared the manuscript. HG and AA confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Not applicable.
Written informed consent was obtained from the patient for publication of this case report and the accompanying images.
The authors declare that they have no competing interests.
MRI of our patient's pituitary gland. (A) Non-contrast T1 sagittal sequence showing the absence of the bright spot of the posterior pituitary gland (white arrow). (B) Post-contrast T1 sagittal sequence showing a normal posterior pituitary gland (white arrow). (C) Pre-contrast T1 coronal sequence showing a normal posterior pituitary gland (white arrow).
Flow diagram of the research strategy for the identification of cases reporting immunotherapy-induced DI. COVID-19, coronavirus disease 2019; DI, diabetes insipidus; ICI, immune checkpoint inhibitor; PICOT, population, intervention, comparison, outcomes, time.
Baseline biochemical parameters of the patient at diagnosis and post-treatment of DI.
Biochemical parameter | Onset of DI diagnosis | After the treatment of DI | Normal range |
---|---|---|---|
Blood | |||
Sodium, mmol/l | 143 | 139 | 136-143 |
Potassium, mmol/l | 4.9 | 4.4 | 3.7-4.9 |
Calcium, mmol/l | 9.4 | 9.6 | 8-10 |
Creatinine, mg/dl | 1.11 | 1.03 | 0.7-1.2 |
Osmolality, mOsmol/kg H2O | 309.92 | 294 | 280-295 |
Urine | |||
Urine specific gravity | 1.004 | 1.020 | 1.010-1.030 |
Osmolality, mOsmol/kg H2O | 184 | 757 | 500-800 |
Sodium, mEq/24 h | 175 | nd | 40-200 |
Potassium, mEq/24 h | 87 | nd | 25-120 |
Calcium, mEq/24 h | 138 | nd | 100-300 |
Serum | |||
TSH, µIU/ml | 0.98 | 0.99 | 0.27-4.7 |
FT4, ng/dl | 0.80 | 1.13 | 0.7-2 |
ACTH, pg/ml | <3.0 | <2.9 | 7.0-64 |
Prolactin, ng/ml | 31.0 | 32 | 4.8-23.3 |
Cortisol, µg/dl | 1.04 | 0.7 | 6.2-19.4 |
LH, IU/l | 49.7 | 51 | 7.7-58.5 |
FSH, IU/l | 87.9 | 89 | 25.8-134.8 |
DI, diabetes insipidus; TSH, thyrotropin hormone; FT4, free T4; ACTH, adrenocorticotropic hormone; LH, luteinizing hormone; FSH, follicle stimulating hormone; nd, no data.
Differential diagnosis of the polyuria syndrome based on the water deprivation test and copeptin levels.
Biochemical parameters | Normal | Central DI | NDI | Primary polydipsia | Partial CDI |
---|---|---|---|---|---|
Baseline urinary osmolality, (mOsm/kg) | >300 | <300 | <300 | 300-800 | 300-800 |
Urinary osmolality after water derivation |
800-1,200 | <300 | <300 | 300-800 | 300-800 |
Urine osmolality after administration of desmopressin, mOsm/kg | Increase >50% | No response | Normal | Increase <50% | |
Baseline copeptin levels |
Normal | <4.9 | >21.4 | Normal | Normal/low |
aSensitivity, 86%; specificity, 70%.
bSensitivity, 100%; specificity, 100%. DI, diabetes insipidus; NDI, nephrogenic diabetes insipidus; CDI, central diabetes insipidus.
Description of the water deprivation test.
Steps to follow | Parameters or criteria to evaluate |
---|---|
Before any measurement: Correction of any electrolyte abnormalities, including serum potassium and calcium and discontinuation of any medications that can affect urine output for at least 24 h | Diuretics, SGLT-2 inshibitors, DDAVP, carbamazepine, chlorpropamide, glucocorticoids and non-steroidal anti-inflammatory drugs; smoking and caffeine |
Baseline measurements (every 2 h) | Weight, blood pressure, heart rate prior to initiation of dehydration, plasma osmolality, serum sodium, urine osmolality; urine output and urine osmolality, serum sodium and plasma osmolality |
Criteria of discontinuation | i) Loss of >3% of body weight; ii) elevation of serum sodium to above normal limits (≥146-150 mmol/l); and iii) orthostatic hypotension or orthostatic symptoms or intractable thirst |
Administration of DDVAP (2 µg intravenous or intramuscular) | When DDVAP is administrated: i) Dehydration phase is completed for 8 h; or ii) two consecutive urine osmolality measurements do not differ by >10% and there is loss of 2% body weight; or iii) premature termination of dehydration phase due to loss of >3% of body weight, elevation of serum sodium to above normal limits, or intractable |
Measurement post-DDAVP administration | Urine and serum/plasma measurements are obtained hourly for 1-2 h after the injection. In patients with complete forms of DI, the test can be performed in <8 h while in those with partial DI the test could last longer (even 18 h) |
DDAVP, desmopressin; DI, diabetes insipidus; SGLT-2, sodium-glucose cotransporter-2.
Water deprivation test/DDAVP administration in the present case.
Sampling time (t) | Weight, kg | Serum osmolality, mOsmol/kg H2O | Urine osmolality, mOsmol/kg H2O |
---|---|---|---|
08:00 | 84.5 | 304.73 | 351 |
09:00 | 356 | ||
10:00 | 83.5 | 306.59 | 291 |
11:00 | 294 | ||
12:00 | 84.5 | 306.76 | 334 |
13:00 | 332 | ||
14:00 | 83.5 | 304.07 | 327 |
After 2 µcg DDAVP IV administration | |||
15:00 (t=0) | 305 | 457 | |
15:30 (t=+30 min) | 84.5 | 303 | na |
16:00 (t=+60 min) | 300 | 683 | |
16:30 (t=+90 min) | 84.4 | 303 | na |
17:00 (t=+120 min) | 299 | 716 |
DDAVP, desmopressin; IV, intravenous; na, not applicable.
Cases in the literature presenting with ICI-induced central DI.
First author/s, year | Age, years | Sex | Malignancy | Drug | ICI category | Dysfunction of pituitary | Dysfunction of hypothalamus | Median time to onset of DI, days | Duration of DI | MRI findings | Grade of AE | Follow-up, days | (Refs.) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Dillard |
50 | M | Adenocarcinoma of prostate | Ipilimumab | CTLA-4 Ab | Panhypopituitarism | No | 84 | 3 weeks | Normal | III | ND | ( |
Nallapanemi |
62 | M | Melanoma | Ipilimumab | CTLA-4 Ab | Panhypopituitarism | No | 121 | 5 months | ND | II | 180 | ( |
Gunawan |
52 | M | Melanoma | Ipilimumab + nivolumab | CTLA-4 Ab (+) PD-1 Ab | Isolated posterior pituitary | No | 28 | ND | ND | I | ND | ( |
Zhao |
73 | M | Merkel cell carcinoma | Avelumab | PD-L1 Ab | Isolated posterior pituitary | No | 112 | 6 weeks | Normal | I | 240 | ( |
Tshuma |
74 | F | Bladder cancer | Atezolizumab | PD-L1 Ab | Panhypopituitarism | Yes | 270 | ΝD | Hypothalamic mass | I | 365 | ( |
Deligiorgi |
71 | M | Adenocarcinoma of the lung | Nivolumab | PD-L1 Ab | Isolated posterior pituitary | No | 90 | ND | Normal | IV | ( |
|
Barnabei |
64 | M | Melanoma | Ipilimumab | CTLA-4 Ab | Panhypopituitarism | No | 60 | 5 days | Normal | I | 1,230 | ( |
Grami |
30 | M | Acute myeloid leukemia | Ipilimumab + nivolumab | CTLA-4 Ab (+) PD-1 Ab | Panhypopituitarism | No | ND | ND | ND | III | ND | ( |
Brilli |
68 | M | Mesothelioma | Tremelimumab and durvalumab | CTLA-4 Ab (+) PD-L1 Ab | Isolated posterior pituitary | No | 60 | Persisted | Normal | ND | 570 | ( |
Yu |
60 | M | Hodgkin lymphoma | Sintilimab | PD-1Ab | Isolated posterior pituitary | No | Immediate | 3 months | Nodular signal | II | 90 | ( |
Fosci |
62 | M | Hypopharynx cancer | Nivolumab | PD-1 Ab | Panhypopituitarism | No | 35 | 50 days |
Stalk enlarged | I | 24 | ( |
Terán |
46 | M | Adenocarcinoma of the lung | Nivolumab | PD-1 Ab | Panhypopituitarism | No | 62 | ND | ND | I | ND | ( |
Amereller |
2 cases | 1F/1M | ND | Ipilimumab | CTLA-4 Ab | ND | ND | ND | ND | ND | ND | ND | ( |
aThe patient died before initiation of treatment with desmopressin.
bThe patient died 50 days after desmopressin initiation. Ab, antibody; AE, adverse events; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DI, diabetes insipidus; F, female; ICI, immune-check point inhibitor; M, male; ND, no data; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1.