The "culprit" of repeated low blood sodium

preface

According to the 2014 European hyponatremia guidelines, serum sodium < 135mmol/L is hyponatremia, often accompanied by a decrease in plasma osmolality, severe cases can cause hyponatremic encephalopathy, early manifestations of headache, restlessness, convulsions, followed by indifference, lethargy, and even coma, respiratory arrest and death
.
Common reasons are: 1.
Insufficient intake, the patient's diet is too light, the salt intake is insufficient, hyponatremia, and patients often have fatigue, poor feeding and other manifestations
.
2.
Digestive diseases or excessive loss of other systems, such as long-term chronic diarrhea, vomiting, heavy sweating and other reasons
.
3.
Improper secretion of antidiuretic hormone syndrome (SIADH), such as severe brain infection or tumor, will cause inappropriate secretion of antidiuretic hormone, causing hyponatremia
.
4.
Cerebral salt wasting syndrome, due to central nervous system, head trauma and surgery, excessive release of natriuretic factors causes hyponatremia
.
Compared with hypokalemia, clinical hyponatremia seems to be less important, but it is more difficult to manage, and simple sodium supplementation can lead to wrong treatment and even endanger the patient's life
.

Case history

Patient, male, 73 years old
.
2022-4-21Due to "decreased appetite with vomiting fatigue", he was treated
in the Department of Integrated Traditional Chinese and Western Medicine in our hospital.
2022-05-06Hospitalized in the Department of Neurology at 05-16, 05-23, 05-30 and 06-07 respectively due to "weakness in limbs, slurred speech with convulsions of limbs"
, and then transferred to the Department of Neurology of our hospital for inpatient treatment.
Since 2022-04-01, the patient has decreased appetite, accompanied by vomiting and fatigue
without obvious triggers.
Slow walking, clumsiness, shaking, and uncoordinated hand posture are present, along with slurred speech and paroxysmal convulsions
of both lower extremities.
Repeated hyposodium during hospitalization, no obvious abnormalities
were seen.

Case study

01

Clinical case studies

2022-05-06Inpatient treatment in the Department of Neurology of our hospital, main complaint: weakness of limbs, slurred speech with limb convulsions
.
Present medical history: after surgery for liver tumors in the hospital (after targeting, immunization, interventional therapy), memory loss began to appear 7+ days ago, and 2+ days ago suddenly trembled limbs, manifested as "slow walking, clumsy, shaky", accompanied by slurred speech and thirst, and finally diagnosed as autoimmune encephalitis
.
The admitted neurology department diagnosed autoimmune encephalitis (positive for DPPX antibodies) and received rituximab infusion
.
Physical examination: BP: 101/64mmHg, clear mind, scarring of about 20cm after surgery on the abdomen, tenderness in the right upper quadrant, no obvious abnormal signs
on cardiopulmonary examination.
Decreased numeracy and memory
.

Diagnosis: 1.
Autoimmune encephalitis (positive DPPX antibody) 2.
Chronic non-atrophic erosive gastritis 3.
After liver cancer surgery 4.
Abdominal effusion 5.
Cirrhosis 6.
Portal hypertension 7.
Splenomegaly 8.
Pleural effusion 9.
Arrhythmia Atrial fibrillation One-degree atrioventricular block QT interval prolongation 10.
Left kidney cyst 11.
Abnormal glucose tolerance 12.
Electrolyte imbalance (hyponatremia and hypochloremia).

02

Test case studies

Table 1 Patient electrolyte results

The patient's low sodium and low chloride results (see Table 1 above) attracted the attention of the examiner, and after reviewing the patient's historical results, it was found that the patient has been recurrent hyponatremia since 4-21 (the first outpatient visit in our hospital), why has it been repeatedly hyposodium? What are the causes of low sodium? Continue to review the historical results and medical history data with doubts, the medical history shows that the fourth rituximab infusion was given for the diagnosis of autoimmune encephalitis (DPPX positive), the patient was liver cancer after surgery, and PD1 immunotherapy has been undergone 6 times in the hospital, and the long-term medical advice has been since June 8: concentrated sodium chloride injection (10ml 1q).

Why is long-term sodium supplementation ineffective? Where did sodium disappear? Recent changes in blood sodium levels in patients are shown in Figure 1
.

Fig.
1 Recent changes in serum sodium levels

Where did sodium go? Is it excessive vomiting loss or renal sodium loss? With such doubts, continue to look for the cause, clinically applied for a 24-hour urine electrolyte test for the patient, and the patient's 24-hour urine electrolyte results are as follows:

Table 2 24-hour urine electrolyte results

Table 2 results show that patients do develop renal sodium loss, and the causes of renal sodium loss are: (1) the use of diuretics; (2) adrenal insufficiency; (3) Glucocorticoid deficiency, etc.
, the patient did not use diuretics
.
So what is the cause of renal sodium loss?

Continue to review the patient's examination results and find that the patient has adrenocorticosteroid-related tests in the early stage (Table 3).

Table 3 Results of adrenal cortex-related examinations in patients

The results of Table 3 showed that the patient's cortisol and adrenocorticotropic hormone (ACTH) were very low, and the cause of renal sodium loss was originally caused by adrenal insufficiency, while the cause of adrenal hypofunction was decreased pituitary ACTH secretion
.

After the above in-depth analysis of the medical history and test results, considering that the true cause of low blood sodium has not been clarified clinically, we issued a test analysis opinion report for the clinic: the patient has long-term hyponatremia, the urine sodium level is elevated, the patient's PTC and ACTH levels are extremely low, the patient has a history of long-term use of anti-PD-1, there may be immune encephalitis caused by anti-PD-1 use, and the secondary adrenal insufficiency caused by insufficient ACTH secretion leads to renal hypernatremia caused by hyponatremia, please combine clinical judgment
。

After the report was issued, the clinic accepted our opinion and immediately prescribed a long-term medical order for the patient: methylprednisolone sodium succinate for injection
.
6-17 re-check blood sodium elevation, 6-18 ask endocrinology department consultation: the patient has adrenal insufficiency
.
Suggestion:? Continue to use methylprednisolone, adjust the dose according to your disease, and contact our department to evaluate the glucocorticoid supplement regimen
before your department intends to stop methylprednisolone.
The re-examination sodium was further increased, and the patient's nausea and vomiting symptoms disappeared after the blood sodium returned to normal 6-21, and the patient was discharged from the hospital at 6-22, and the patient was discharged with 5mg q.
d orally with 5mg Q.
d with prednisone tablets (5mg×100 tablets
).
The change in blood sodium level after exogenous glucocorticoid supplementation on June 16 is shown in Figure 2
below.

Fig.
2 Changes in blood sodium level after exogenous glucocorticoid supplementation

In the process of follow-up of the patient, it was found from the doctor's order on June 16 that the patient only supplemented with glucocorticoids exogenously, but did not receive sodium exogenously, and the level of blood sodium increased
.
Again, it shows that the patient's hyponatremia is not a decrease in the source, but excessive loss, which prevents the loss of sodium and the blood sodium rises
.
More miraculous is that after the recovery of low blood sodium, the patient's vomiting symptoms disappeared, it turned out that vomiting was not the cause of sodium loss, but the symptoms caused by increased intracranial pressure caused by low blood sodium, low blood sodium is the cause of vomiting, after the correction of low blood sodium, vomiting symptoms disappeared
.

Knowledge expansion

The pathogenesis of secondary adrenal insufficiency stems from insufficient secretion of CRH and ACTH, and the common causes of pituitary tumors, pituitary inflammation, pituitary infections, etc.
lead to pituitary damage [1].

In addition, for patients who use glucocorticoids in high-dose doses for a long time, acute adrenal insufficiency will occur after abrupt discontinuation of ACTH, because exogenous glucocorticoids can inhibit the secretion of ACTH by hypothalamic pituitary gland due to negative feedback[2].

After reviewing all of the patient's medical records and historical results and reviewing the literature, it is speculated that the patient may be hypoadenal adrenal function secondary to immunopituitary inflammation due to PD-1 immunotherapy
.
Patients have undergone 6 courses of PD-1 immunotherapy, and a large number of literature has clearly pointed out that anti-PD-1 monoclonal antibody drugs can cause damage to systemic multi-organ systems including the endocrine system, causing endocrine-related adverse reactions, such as hypothyroidism, hyperthyroidism, pituitary inflammation and adrenal dysfunction, pneumonia, nephritis, hepatitis, enteritis, myositis, autoimmune myocarditis, pancreatitis, etc.
[3-4].

With the wide application of immune checkpoint inhibitors, the resulting immune-related adverse events (irAEs) have also received more and more attention, among which endocrine-related adverse events (such as thyroid dysfunction, pituitary inflammation, adrenal insufficiency, etc.
) are insidious at the onset and are not easy to detect, resulting in delayed treatment, often bringing serious adverse consequences and even endangering the life
of patients.
In one retrospective study, the most common symptoms of PD1-induced pituitary inflammation were headache and fatigue [5].

Other rare symptoms include neuropsychiatric symptoms (confusion, hallucinations, memory loss, and mood swings), visual disturbances, insomnia, anorexia, nausea, diarrhea, chills, chills, erectile dysfunction, and decreased libido
.
Because the above symptoms are not typical, they are often mistaken clinically for related to the primary disease or other diseases and misdiagnosed
.
Therefore, baseline assessment of TSH, FT3, FT4, ACTH, cortisol, IGF-1, electrolytes, and glucose is necessary
before initiating immune checkpoint inhibitors (ICIs).

Case summary

The patient had developed electrolyte abnormalities (low sodium and low chloride) at 1+ months, and several visits to our hospital showed hyponatremia, and all were treated with supplementation of high-concentration sodium chloride, but the low sodium was not corrected
.
In this case, the patient developed symptoms of fatigue and poor appetite after treatment with PD-1 monoclonal antibody, but within two months of symptom onset, multiple hospital visits failed to confirm the diagnosis, and the difficulty in diagnosis was that the symptoms of adrenal insufficiency (AI) patients lacked specificity, and the hyponatremia caused by it may delay treatment
due to different clinical symptoms, complex differential diagnosis.
The literature suggests that at 110~125mmol/L, the patient's symptoms are obvious and severe, and the mortality rate is greatly increased, so timely and accurate diagnosis and reasonable treatment are very important
.
It is also important to improve the diagnosis
of AI by routinely screening patients with persistent unexplained nausea, fatigue, and hypotension for hemocortisol and ACTH.
On the other hand, standardizing the diagnostic ideas of hyponatremia is also helpful for the diagnosis
of AI.
Patients treated with immune checkpoint inhibitors (ICIs) should be closely monitored before, during, and after treatment for early diagnosis and treatment
.
This case also reminds us that if the examiner can pay attention to the patient's sustained low sodium earlier, carefully discover, carefully analyze, effectively communicate with the clinic, and further improve the relevant examination, the diagnosis can be earlier
.
As a tester, strive to improve, learn from clinical, imaging, pathology, etc.
, comprehensively judge and analyze the real meaning behind the numbers, and better reflect the value of the examiner and benefit patients
.

Expert reviews

Professor Li Guixing, Department of Experimental Medicine, West China Hospital, Sichuan University

In this case, repeated low sodium, the examiner did not simply issue a report, but paid attention to why there was repeated low sodium, step by step, actively reviewed the data and found that the patient had a history of PD-1 inhibitors, further understood the mechanism of action of the drug, adverse reactions, etc.
, combined with the patient's medical history, clinical manifestations and experimental results, it was found that the patient may be due to immunoencephalitis caused by medication, secondary adrenal insufficiency caused by insufficient ACTH secretion leading to renal hypersodium loss caused by hyponatremia , seems to be a single indicator, but has important significance, but leaving the disease is meaningless, as a tester we are not only to issue a report, but should actively communicate with the clinic, from the perspective of testing with clinical thinking to explore the truth
behind the numbers.

【References】

[1] LIN Guowei, WANG Jyao, GE Junbo, et al.
Practical Internal Medicine[M].
15th ed.
Beijing:People's Medical Publishing House,2018:2205-2219.

[2] CHEN Liqun, XU Mingming.
Research progress on immune checkpoint inhibitor-related endocrine adverse reactions[J].
Chinese Clinical Oncology,2020,47(17):906-911.
)

[3] CAO Ling, LI Xiaomu.
Immune checkpoint inhibitor-related endocrine adverse events[J].
Chinese Journal of Clinical Medicine,2020,27(6):931-937.
)

[4] Immunoendocrinology Group, Endocrinology Branch, Chinese Medical Association.
Expert consensus on immune-related adverse reactions of endocrine system caused by immune checkpoint inhibitors(2020)[J].
Chinese Journal of Endocrinology and Metabolism,2021,37(1):1-16.
)

[5] YU Mincheng, HU Bo, FU Peiyao, YANG Zhangfu, TANG Weiguo, SUN Haixiang, XU Yang.
Research progress on adverse reactions in clinical treatment of anti-PD-1/PD-L1 antibody[J].
Chinese Journal of Clinical Medicine,2018,25(04):625-631.
)