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For medical professionals only
Mild symptoms cannot be ignored!
Written by | On weekend mornings, Xu Junrong
received a call from a man he had recently met, saying that he had vomited frequently in the past two weeks, could not eat, and now he could not walk, and wanted to be hospitalized in our department
.
I wondered in my heart, when I first saw him a month ago, he was alive, spirited, and a thousand cups of courage, how could he suddenly become so sick?
Hyponatremia, blood sodium value does not rise but decreases after sodium infusion.
.
.
frequently.
After taking medical history, he learned that he had discovered malignant mesothelioma of the abdominal cavity 4 years ago, underwent two surgeries, six cycles of chemotherapy after surgery, and also used immuno-oncology
.
Six months ago, he underwent surgery for papillary thyroid cancer, but recovered well
after surgery.
A
B
Fig.1 Electrolyte results of patients A.
at the time of admission B.
After admission
, after infusion sodium supplementation, although the patient's symptoms improved, the results of re-examination of blood sodium did not rise but decreased, and the blood sodium value became 123mmol/L
.
After intra-abdominal mesothelioma surgery, stubborn hyponatremia, hyponatremia should not be related to tumors, right?
Clinically, patients with hyponatremia should first determine their blood volume status and determine whether they are hypovolaemic hyponatremia, isovolaemic hyponatremia, or hypervolaemic hyponatremia
.
My patient is considered isovolemic hyponatremia
as a result of a lack of extracellular fluid (thirst, orthostatic hypotension, tachycardia) or an increase (edema, serosal effusion, pulmonary edema).
The overall fluid volume of isovolaemic hyponatremia increases, while the total sodium in the body is basically normal or slightly decreases, resulting in decreased blood osmolality and dilution hyponatremia
.
The osmolality of 260 mmol/L is significantly lower than normal, and the hematocrit is also low, thus meeting the characteristics of
isovolemic hyponatremia.
In isovolaemic hyponatremia, syndrome with abnormal antidiuretic hormone secretion is the most common
.
Syndrome of abnormal antidiuretic hormone secretion refers to syndromes such as abnormal secretion of antidiuretic hormone in the body or its abnormal activity, which is not limited by blood volume, resulting in water retention, increased urinary sodium excretion, and dilution hyponatremia
.
The common cause of abnormal antidiuretic hormone secretion syndrome is first malignant tumor, the most common is lung oat cell carcinoma, and abdominal malignant mesothelioma has also been reported
to cause abnormal secretion of antidiuretic hormone.
This patient has an underlying disorder that can lead to abnormal antidiuretic hormone secretion, and there are multiple findings to support the presentation of the syndrome with abnormal antidiuretic hormone secretion, but a 24-hour urine electrolyte test and urine osmolality are required to confirm the diagnosis
.
Figure 2: In
addition to abnormal secretion of antidiuretic hormone, glucocorticoid deficiency and severe hypothyroidism can also cause isovolemic hyponatremia
.
Given that blood glucose was also low on admission, we checked hormone levels and thyroxine levels to rule out hyponatremia
caused by these two factors.
The patient's thyroid hormone levels were not abnormal, but cortisol levels were significantly reduced, adrenocorticotropic hormone (ACTH) was lower than normal, and the results of 24-hour urine electrolyte examination showed no abnormalities in urinary sodium and low urine osmolality
.
It appears that the cause of low sodium in patients is not abnormal secretion of antidiuretic hormone due to tumors, but is related
to reduced cortisol levels.
Since both cortisol and ACTH levels are low, problems may arise in the
pituitary gland.
However, we did an MRI of the pituitary gland and did not find any abnormalities
.
So what exactly causes hypopituitarity? Why does this patient have so many problems with malignant mesothelioma, thyroid cancer, hypopituitary function, and severe hyponatremia at the same time? Can monism be used to explain all the clinical manifestations of patients?
What is the cause? Is it related to tumors?
A
B
Figure 3: Cortisol rhythm of patients A.8 a.
m.
B.
4
p.
m.
In order to unravel these mysteries, I carefully questioned the patient's medical history and reviewed all the medical records of the patient hospitalized in the hospital for the past four years, and found that the patient did not show hyponatremia before tumor immunotherapy, and after the application of nivolumab and ipilimumab, two immune checkpoint inhibitors, blood sodium and cortisol levels were reduced in multiple hospitalizations.
However, because the symptoms are not obvious, they have not attracted the attention
of patients and doctors.
Patients also developed rashes and autoimmune pneumonia after using both drugs, and thyroid nodules, which had been monitored for many years, were class III and quickly turned into thyroid cancer
.
That is, patients with these two drugs experienced a variety of immune-related adverse effects
.
So, is his hypopituitarism also associated with immune checkpoint inhibitors?
After reviewing the literature, it was learned that immune checkpoint inhibitors do have the side effect of causing pituitary inflammation, and this inflammation of the pituitary gland is termed immune checkpoint inhibitor-associated autoimmune hypophysitis
.
Figure 4: Results of adrenocorticotropic hormone test in patients
Immune checkpoint inhibitors
Immune checkpoint inhibitors (ICIs) are novel antitumor drugs
that work by activating the body's immune response to tumors 。 ICIs mainly include three categories, one is cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, and the representative drug is ipilimumab; the second is programmed cell death receptor 1 (PD-1) inhibitors, representative drugs are pembrolizumab and nivolumab; The third is PD-1 ligand (PD-L1/PD-L2) inhibitors, and the representative drugs are atezolizumab, durvalumab and averumab
.
Although these drugs have good antitumor activity, immune-related adverse events
can occur due to their reactivation of the immune response.
Common immune-related adverse events include skin lesions and thyroiditis, more common and severe immune-related adverse events include pneumonia, gastrointestinal reactions, hepatitis, nephritis, pituitary inflammation, adrenadenitis, and myositis, and rare immunotoxicity can lead to immune diabetes, cardiac and neuro-related toxicity
.
Autoimmune hypophysitis is a classic immune-related adverse event
.
Immune checkpoint inhibitor-associated autoimmune hypophysitis
Most immune checkpoint inhibitor-associated autoimmune hypophysitis involves the anterior pituitary lobe, with hypothyroidism of pituitary origin and adrenal insufficiency being the most common, and central diabetes insipidus due to posterior pituitary involvement less common
.
Immune checkpoint inhibitor-associated autoimmune hypophysitis tends to occur in patients
receiving CTLA-4 inhibitors alone or in combination with other ICIs.
Our patient is symptomatic of hypophysitis following the combination of the CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab
.
There are two main types of pituitary immune-related adverse events, isolated adrenocorticotropic hormone deficiency without pituitary enlargement and anterior pituitary hormone deficiency hypophysitis
with pituitary enlargement.
Our patient had no abnormalities on pituitary MRI, and hormone testing only showed adrenocorticotropic hormone deficiency and cortisol deficiency, making it an isolated adrenocorticotropic hormone deficiency without pituitary enlargement
.
Grade of immune checkpoint inhibitor-associated autoimmune hypophysitis
Autoimmune hypophysitis associated with immune checkpoint inhibitors is classified as grade
1 to 4 depending on disease severity.
Grade 1: asymptomatic or mildly symptomatic; Grade 2: moderate symptoms with unrestricted daily activities; Grade 3: severe symptoms that affect daily activities; Grade 4: Severe symptoms, life-threatening, inability to perform daily activities
.
The reason why our patient misdiagnosed many times in the outer hospital is because at first his symptoms were mild, only grade 1, and did not attract the attention
of doctors.
Treatment of immune checkpoint inhibitor-associated autoimmune hypophysitis
The treatment of immune checkpoint inhibitor-related autoimmune hypophysitis mainly needs to consider two aspects: hormone replacement therapy for the affected hypothalamic-pituitary axis, and whether ICIs need to be suspended or discontinued
.
Continuous ICIs are recommended for patients with grade 1 to 2; For grade 3 to 4 patients, discontinuation of ICIs is recommended if the patient has a pituitary crisis
.
Since our patients have ended treatment with immune checkpoint inhibitors and have only clinical manifestations of adrenal insufficiency, only oral prednisone replacement therapy
is currently required.
After taking the hormones, the patient's symptoms completely disappeared and the blood sodium returned to normal
.
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👇👇👇 References:[1] Li Jiayi, Xing Bing.
Research progress of immune checkpoint inhibitor-related autoimmune pituitary inflammation[J].
Basic Medicine and Clinic,2020,40(3):403-406.
)
[2] ZHANG Fang,XIE Xiaodong.
Current status and research progress in diagnosis and treatment of hypophysitis associated with tumor immunotherapy[J].
Chinese Journal of Cancer Prevention and Treatment,2021,13(6):602-606.
)
[3] NGUYEN H，SHAH K，WAGUESPACK S G，et al.
Immune checkpoint inhibitor related hypophysitis：diagnostic criteria and recovery patterns［J］.
Endocr Relat Cancer，2021，28（7）：419-431.
[4］IGLESIAS P.
Cancer immunotherapy induced endocrinopathies：Clinical behavior and therapeutic approach［J］.
Eur J Intern Med，2018，47：6-13.
This article reviewed: Yang Health Deputy Chief Physician of Jingdezhen Second People's Hospital Responsible Editor: Wen Jiaxin
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