Hyponatraemia due to hypothyroidism: a rare side effect from pomalidomide
- 1 Internal Medicine, Greater Baltimore Medical Center, Towson, Maryland, USA
- 2 Pulmonary and Critical Care Medicine, Greater Baltimore Medical Center, Towson, Maryland, USA
- Correspondence to Dr Ji Hyun Rhee; jrhee@gbmc.org
Abstract
Pomalidomide is an immunomodulatory drug used for relapsed and refractory multiple myeloma (RRMM). Hypothyroidism is an uncommon side effect of pomalidomide. We present a 70-year-old male patient with RRMM on daratumumab, pomalidomide and dexamethasone, who presented with 2 weeks of fatigue. Laboratory values showed sodium of 120 mEq/L, plasma osmolarity of 256 mOsm/kg, urine osmolarity of 648 mOsm/kg and urine sodium of 93 mEq/L. Adrenocorticotropic hormone (ACTH) stimulation test was within normal limits. Thyroid-stimulating hormone (TSH) was 88.6 IU/mL (0.380–4.700 IU/mL), total triiodothyronine (TT3) <21 ng/mL (0.8–2 ng/mL), free thyroxine (fT4) 0.10 ng/dL (0.93–1.70 ng/dL) and free triiodothyronine (fT3) <0.5 pg/mL (2.3–4.2 pg/mL). Antithyroid peroxidase antibody was 726 IU/mL (<9 IU/mL). TSH 1 year ago was 2.88 IU/mL and TT3 was 1.06 ng/mL. He was started on levothyroxine with improvement in his symptoms, sodium level and thyroid functions. The most likely culprit was pomalidomide. Checking thyroid functions before and periodically while on pomalidomide is important in screening for this possible side effect.
Background
Pomalidomide is an immunomodulatory drug (IMiDs) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). It is a thalidomide analogue that has immunomodulatory, antiangiogenic and tumouricidal effects. Like the other thalidomides, it has haematological and non-haematological side effects. Haematological side effects include thrombocytopenia, anaemia, leucopenia and neutropenia. Non-haematological side effects include infections, nausea, diarrhoea, constipation, fatigue and back pain.1 One of the least reported side effects of pomalidomide is hypothyroidism. Although hypothyroidism has been reported in other thalidomides with reported incidence of 20% in thalidomide and 5%–10% in lenalidomide, there have only been two cases of hypothyroidism reported in association with pomalidomide. Here, we report a patient with hyponatraemia found to have hypothyroidism due to pomalidomide used to treat his RRMM.
Case
A 70-year-old male patient with no significant medical history was diagnosed with stage II IgG kappa multiple myeloma (MM) in April 2016 when he presented with sudden onset left eye blindness. He received two sessions of plasmapheresis and was started on bortezomib, lenalidomide and dexamethasone. However, in October 2017, he developed right popliteal deep venous thrombosis and pulmonary embolism and underwent autologous stem cell transplant in November 2017. Since the transplant, he was maintained on lenalidomide. However, in January 2019, his M spike was found to be elevated with a repeat bone marrow biopsy showing 60%–70% increased plasma cells confirming RRMM. He was started on a new chemotherapy regimen with daratumumab, pomalidomide and dexamethasone. He was on eighth cycle of this regimen when he presented to his oncologist’s office with fatigue and decreased appetite for 2 weeks. Vital signs and physical examination including volume status and neurological examination were unremarkable. He had outpatient blood work, which is shown in table 1.
Outpatient laboratory work
| Significant labs | Patient value | Normal range |
| Sodium | 120 mEq/L | 133–145 mEq/L |
| Creatinine | 1.1 mg/dL | 0.5–1.2 mg/dL |
| Glucose | 172 mg/dL | 70–115 mg/dL |
| White cell count | 2.49×10³/µL | 4–11×10³/µL |
| Haemoglobin | 102 g/L | 135–180 g/L |
| Platelets | 72×109/L | 150–400×109/L |
| Total neutrophils | 1.2×10³/µL | 2.00–8.00×10³/µL |
| Total protein | 8.7 g/dL | 5.9–8.4 g/dL |
| Albumin | 4 g/dL | 3.2–5.2 g/dL |
| Globulin | 4.7 g/dL | 2–4 g/dL |
Due to significant hyponatraemia, he was sent to the emergency department where he was given 1 L of normal saline with worsening sodium down to 116 mEq/L. He was admitted to the progressive care unit for severe hyponatraemia.
Investigation
Repeat glucose level on admission was 129 mg/dL (70–115 mg/dL), creatinine 1.2 mg/dL (0.5–1.2 mg/dL), protein 7.8 g/dL (5.9–8.4 g/dL), albumin 3.6 g/dL (3.2–5.2 g/dL) and globulin 4.2 g/dL (2.0–4.0 g/dL). Hyponatraemia workup showed plasma osmolarity of 256 mOsm/kg (227–297 mOsm/kg), urine osmolarity of 648 mOsm/kg (50–1200 mOsm/kg) and urine sodium of 93 mEq/L. Further workup revealed normal adrenocorticotropic hormone (ACTH) stimulation test; initial cortisol of 12.5 μg/dL, then 21 μg/dL and 23.7 μg/dL at 30-minute and 60-minute intervals, respectively, after intravenous cosyntropin 250 mcg administration. Thyroid-stimulating hormone (TSH) was markedly elevated at 88.6 IU/mL (0.380–4.700 IU/mL), with total triiodothyronine (TT3) <21 ng/mL (0.8–2 ng/mL), free thyroxine (fT4) 0.10 ng/dL (0.93–1.70 ng/dL) and free triiodothyronine (fT3) <0.5 pg/mL (2.3–4.2 pg/mL). Antithyroid peroxidase (anti-TPO) antibody was 726 IU/mL (<9 IU/mL). In review, his baseline thyroid function test 1 year ago showed normal TSH of 2.88 IU/mL and TT3 of 1.06 ng/mL.
Differential diagnosis
Hyponatraemia is defined as having a sodium level of less than 135 mEq/L. History and physical examination along with other laboratory work help narrow down the aetiology. In this patient, his blood sugar level on admission was within normal range excluding hyperglycaemia-induced hyponatraemia as a cause. His protein level was slightly elevated, making hyperproteinaemia as a possible cause of hyponatraemia. However, his serum sodium level was out of proportionately lower than the degree of his elevated protein level so this was unlikely. He also had not had any recent prostate or bladder surgery, making pseudohyponatraemia unlikely. He did not have any psychiatric history, binge water drinking or beer potomania, and was not on tea and toast diet, making them unlikely as aetiology.
His plasma osmolarity was low and he did not have any signs of volume overload or depletion so what he had was a true hypotonic hyponatraemia with euvolaemia. Differentials for this include hypothyroidism, adrenal insufficiency and syndrome of inappropriate antidiuretic hormone secretion (SIADH). The patient was on dexamethasone as one of his chemotherapy regimens so it is possible that he had relative adrenal insufficiency. However, ACTH stimulation test showed appropriate response in his serum cortisol levels after ACTH, making adrenal insufficiency as a cause of hyponatraemia unlikely. SIADH was also a possibility but this is a diagnosis of exclusion and our patient had elevated TSH, low free T3, T4 and total T3, in addition to positive anti-TPO leading to the diagnosis of hypothyroidism, which was the most plausible aetiology of his hyponatraemia. Review of his medication list did not show any potential culprit such as hydrochlorothiazide and the only changes that had been made to his medication list was his chemotherapy regimen. Literature search revealed rare side effect of hypothyroidism associated with pomalidomide, which was thought to be the culprit for his presentation.
Treatment
He was seen by an endocrinologist and was recommended to stop pomalidomide and was started on 100 mcg of levothyroxine.
Outcome and follow-up
His sodium steadily improved to a level of 131 mEq/L on discharge and 138 mEq/L at 4-week follow-up. His follow-up TSH level dropped significantly to 5.06 IU/mL, which is shown in table 2.
TSH course
| Baseline; 1 year before admission | 2.88 IU/mL (0.380–4.700 IU/mL) |
| On admission | 88.6 IU/mL |
| 8 months after discharge | 5.06 IU/mL |
Discussion
MM is the second most common haematological malignancy in the USA, with an annual incidence rate of about 32 270 new cases (17 530 in men and 14 740 in women) diagnosed in 2020, according to the American Cancer Society. It is treated with a combination of IMiDs, proteasome inhibitors, alkylating agents, histone deacetylase inhibitors, steroids and stem cell transplant if deemed eligible. Majority of patients respond to a combination regimen. However, some patients do not respond to initial treatment, having refractory disease or have progression of disease despite conventional regimen, called RRMM. For patients with RRMM, pomalidomide, a thalidomide analogue and an oral third-generation IMiD, is used as either monotherapy or in combination with dexamethasone. It has direct tumouricidal, antiangiogenic and immune modulating effect.2 3 Like the other thalidomides, it has haematological and non-haematological side effects. Haematological side effects include neutropenia, leucopenia, anaemia and thrombocytopenia. Non-haematological side effects include fatigue, constipation, nausea, diarrhoea, asthenia, back pain, peripheral neuropathy, dyspnoea and infections such as pneumonia.1
Hypothyroidism has been reported in other thalidomides, with reported incidence of 20% in thalidomide and 5%–10% in lenalidomide.4 There have only been two cases of hypothyroidism reported in association with pomalidomide but none related with hyponatraemia from hypothyroidism. Hamadeh et al reported a 51-year-old woman with RRMM who presented with fatigue, cold intolerance, weight gain and extremity swelling after 4 cycles of pomalidomide, found to have hypothyroidism.4 Ali et al reported an 83-year-old woman with RRMM who presented with worsening fatigue after 4 weeks of pomalidomide, found to have hypothyroidism.5 Both of these patients showed improvement in their symptoms and thyroid functions after starting levothyroxine and discontinuing pomalidomide.4 5 Our patient presented with fatigue, decreased appetite and hyponatraemia with workup showing hypothyroidism as the most likely aetiology, and had improvement in his symptoms, sodium level and thyroid functions with levothyroxine.
Thalidomide and lenalidomide have been associated with thyroid abnormalities. Hypothyroidism caused by IMiDs usually occur via T-cell stimulation, antiangiogenic activity, inhibition of iodine uptake and release of thyroid hormones and other cytokines (interleukins).6 Case series by Figaro et al showed that, of the 170 patients treated with lenalidomide for MM, 6% had thyroid dysfunctions.7 Patients with previous thyroid dysfunctions had higher incidence of thyroid function test abnormalities with addition of thalidomide; 17% vs 6% in patients with previously normal thyroid functions (p=0.0001).7
Specific mechanism by which pomalidomide causes hypothyroidism has not been studied but it is probably similar to that seen in other thalidomides. Table 3 describes possible mechanisms of hypothyroidism by various anticancer drugs including IMiDs.4 5
Mechanisms of hypothyroidism by antineoplastic drugs
| Antineoplastic drugs | Mechanism of hypothyroidism |
| Tyrosine kinase inhibitors | Increases clearance of thyroxine and decrease iodine uptake by thyroid gland |
| Immunotherapies (such as interferon-alpha, alemtuzumab, ipilimumab) | Stimulates autoimmunity |
| Immunomodulatory drugs (such as thalidomide, lenalidomide) | Stimulates T-cells, has antiangiogenic activity and induces cytokine release |
In our patient, his anti-TPO antibody was elevated raising question about possible autoimmune mechanism. Further studies are needed to find out the exact pathogenesis of pomalidomide-induced hypothyroidism.
Learning points
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Hypothyroidism is an uncommon adverse effect of pomalidomide and it is imperative that physicians are aware of this rare side effect.
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Screening thyroid functions before and periodically during therapy is important in screening for this potential side effect.
Acknowledgments
We would like to thank Dr Christine Zhang for reviewing the abstract.
Footnotes
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Contributors Dr AQ wrote the initial case report description as well as discussion on the manuscript, and edited per corresponding author’s comments. Also did literature search and did the initial revision after the reviewer’s comments. Dr JHR reviewed, edited and revised the manuscript, corrected grammar, answered reviewer's comments, with final approval for submission and agreed to answer any questions regarding the case report. After revision per reviewer’s comments by Dr AQ, re-revised the manuscript and finalised the last version.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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