Hypothyroidism During Immune Checkpoint Inhibitor Therapy That Is Not Responsive to Thyroxin Substitution. A Peripheral T4-T3 Conversion Block?
Authors: Verelst Faro , Beyens Michiel , Vandenbroucke Elke , Forceville Kathleen , Twickler Theodorus Bartholomeus 
Published: May 2021

Abstract
Hypothyroidism is a frequently occurring side effect in patients under treatment with immune checkpoint inhibitors. Recently, we were confronted with three patients who were treated with a checkpoint inhibitor expressing clinically overt hypothyroidism that could not be corrected with progressive Thyroxin substitution. The first case, a 90 -year-old man with a solid low differentiated invasive urothelial carcinoma with multiple regional lymph node metastases (cT2N2M0) started with Pembrolizumab. Afterwards, TSH levels increased significantly (TSH 112 mU/l, n &lt; 4.7 mU/l) with reduction in free T4 (1,6 pmol/l, n &gt; 11.5 pmol/l)). L-thyroxine (T4) was started (50 μg OD). After a few weeks, he deteriorated with significantly elevated brain natriuretic peptide (BNP), heart failure (NYHA III). His therapeutic compliance was optimal. No absorption hindrance (diarrhoea or vomiting). His TSH levels remained elevated (103 mU/l). Subsequently, the T4 dose was increased to 100 μg once a day. Due to T4 ineffectiveness and, in parallel, life-threatening heart failure, Cytomel®️ (Liothyronine; T3) was started (12,5 μg twice a day). After two weeks, TSH normalized and in parallel BNP decreased. The second case, an 82-year-old man diagnosed with a non-small cell lung carcinoma (stage: type IIIb; T1bN3M0). Nivolumab was started and hypothyroidism developed (TSH 27 mU/l and fT4 11.3 pmol/l). T4 (50 µg once a day) was promptly started. Despite T4 substitution, TSH rose progressively (towards 51 mU/L), with a further decline in free T4 (8,7 pmol/l). T4 dose was increased to 75 µg OD. However, no beneficial effect was seen on TSH and fT4 levels. Due to our prior experience, Cytomel®️ (Liothyronine) 25 μg three times per day was added to T4 75 µg with a subsequent improvement in thyroid profile. The third case, a 76-year-old woman with low differentiated urothelial carcinoma with diffuse metastasis to liver, lung and bone marrow. After the initiation of pembrolizumab the patient developed hypothyroidism: TSH 52 mU/l and fT4 7.6 pmol/l. Therefore, T4 was started (50 µg daily). At the check-up, 2 months later, TSH rose further to 73.1 mU/l. In this patient, T3 was not started, due to no availability and entering palliative care. We described 3 cases with overt hypothyroidism after the start with immune checkpoint inhibitors unresponsive to thyroxin substitution. In literature, we did not find similar cases. Interestingly, after adding T3, a good clinical and biochemical response was obtained suggesting a peripheral T4-T3 conversion block. The mechanism behind is unknown, but we hypothesize an inhibiting effect of checkpoint inhibitors on expression/activity of tissue deiodinases, intrinsically being affected by a not yet elucidated mutation (heterozygous carriers). Our observation could give rise to novel clinical considerations for those patients successfully treated with immune checkpoint inhibitors.