BackgroundAdvances in cancer immunotherapy have generated encouraging results in multiple malignancies refractory to standard chemotherapies. As the use of immune checkpoint inhibitors (ICI) proliferates, the incidence of autoimmune side effects associated with these agents, termed immune related adverse events (irAE), is expected to increase. The frequency of significant irAE in ICI treated patients is about 10–20% and early recognition is critical to prevent serious morbidity and even mortality. New onset autoimmune diabetes mellitus (DM) associated with immune checkpoint inhibitor treatment is extremely rare, occurring in less than 1% of patients. Autoimmune DM often presents as diabetic ketoacidosis, a medical emergency requiring immediate treatment. We describe the first reported case of a patient with lung cancer who developed autoimmune diabetes after nivolumab treatment and was found to have three diabetes related (islet) autoantibodies present before ICI treatment and seroconversion of another after ICI treatment and onset of autoimmune DM.Case PresentationA 34 year old African American woman with metastatic non-small cell lung cancer (NSCLC) was treated with nivolumab in the second line setting after disease progression following standard chemoradiation therapy. After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis. Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related (islet) autoantibodies and absolute insulin dependence. The patient eventually required use of continuous subcutaneous insulin infusion (insulin pump) due to erratic glycemic excursions and multiple readmissions for DKA. Human leucocyte antigen (HLA) genoyping revealed none of the high risk haplotypes associated with the development of type 1 diabetes. Interestingly, a frozen blood sample obtained prior to treatment with nivolumab tested positive for three of the four diabetes related (islet) autoantibodies despite no prior history of diabetes and no family history of diabetes. Notably, at the time of manuscript preparation, the patient is without evidence of NSCLC recurrence with no further treatment since the nivolumab therapy.ConclusionNew onset autoimmune diabetes mellitus associated with nivolumab has been described only in case reports and occurs at rates of < 1% in the large clinical trials which garnered FDA approval in the second line setting for NSCLC. As ICI use continues to expand across a wide variety of malignancies, clinicians must maintain a high index of suspicion for irAE, including autoimmune DM and other endocrinopathies. A multidisciplinary team and thorough education of the patient are recommended to optimize management of new onset adult autoimmune DM. Our patient may have been at greater risk for the development of ICI related autoimmune diabetes due to the presence of three diabetes related autoantibodies prior to therapy; however, about half of the reported cases of autoimmune DM aft...

Type B insulin resistance is a rare syndrome characterized by fluctuating glucose levels (ranging from hyperglycemia with extreme insulin resistance to intractable hypoglycemia without exogenous insulin administration), high serum insulin levels, and insulin receptor autoantibodies. Most cases occur in the African American population in association with other underlying autoimmune systemic diseases. Treatments with high-dose steroids, immunosuppressants, and plasmapheresis have been used, with variable outcomes, in patients without spontaneous remission. We report the case of a 60-year-old African American woman with history of systemic lupus erythematosus presenting with extreme fluctuations in glucose levels, ranging from severe hyperglycemia to refractory hypoglycemia, with high serum concentration of insulin in both phases. Her presentation and phenotype were very similar to those seen in known cases of type B insulin resistance associated with insulin receptor antibodies. Treatment in other reported cases used a combination of high-dose steroids and immunosuppressants. We tried high-dose steroids, azathioprine, and intravenous immunoglobulins, which resulted in improvement and barely detectable insulin receptor antibody. We present a case of type B insulin resistance with abnormally low titers of insulin receptor antibodies despite a typical clinical course and response. Future research is needed to improve diagnosis and treatment in this rare disease.

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Objective To compare patients with DKA, hyperglycaemic hyperosmolar syndrome (HHS), or mixed DKA-HHS and COVID-19 [COVID (+)] to COVID-19-negative (−) [COVID (−)] patients with DKA/HHS from a low-income, racially/ethnically diverse catchment area. Methods A cross-sectional study was conducted with patients admitted to an urban academic medical center between 1 March and 30 July 2020. Eligible patients met lab criteria for either DKA or HHS. Mixed DKA-HHS was defined as meeting all criteria for either DKA or HHS with at least 1 criterion for the other diagnosis. Results A total of 82 participants were stratified by COVID-19 status and type of hyperglycaemic crisis [26 COVID (+) and 56 COVID (−)]. A majority were either Black or Hispanic. Compared with COVID (−) patients, COVID (+) patients were older, more Hispanic and more likely to have type 2 diabetes (T2D, 73% vs 48%, p < .01). COVID(+) patients had a higher mean pH (7.25 ± 0.10 vs 7.16 ± 0.16, p < .01) and lower anion gap (18.7 ± 5.7 vs 22.7 ± 6.9, p = .01) than COVID (−) patients. COVID (+) patients were given less intravenous fluids in the first 24 h (2.8 ± 1.9 vs 4.2 ± 2.4 L, p = .01) and were more likely to receive glucocorticoids (95% vs. 11%, p < .01). COVID (+) patients may have taken longer to resolve their hyperglycaemic crisis (53.3 ± 64.8 vs 28.8 ± 27.5 h, p = .09) and may have experienced more hypoglycaemia <3.9 mmol/L (35% vs 19%, p = .09). COVID (+) patients had a higher length of hospital stay (LOS, 14.8 ± 14.9 vs 6.5 ± 6.0 days, p = .01) and in-hospital mortality (27% vs 7%, p = .02). Discussion Compared with COVID (−) patients, COVID (+) patients with DKA/HHS are more likely to have T2D. Despite less severe metabolic acidosis, COVID (+) patients may require more time to resolve the hyperglycaemic crisis and experience more hypoglycaemia while suffering greater LOS and risk of mortality. Larger studies are needed to examine whether differences in management between COVID (+) and (−) patients affect outcomes with DKA/HHS.

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Introduction: Under steady-state conditions, measurement of TSH is accepted as the best assessment of thyroid function. The widely used TSH chemiluminometric assays have very low limits of detection and can help distinguish between the various causes of subnormal TSH. However, when evaluating a patient with abnormal thyroid tests but without thyroid symptoms, an appraisal of the test should be considered. Clinical Case: A 63-year-old South Asian man was referred to endocrinology for evaluation of a non-detectable TSH (&lt;0.01 µIU/mL) that was reproduced on repeat testing, both using Siemens ADVIA Centaur TSH3-UL immunoassay. The patient was clinically euthyroid and denied taking biotin supplements. Testing of thyroid hormone showed normal values for free T3, total T3, free T4, and total T4. Additional labs included normal studies for free thyroxine by equilibrium dialysis, thyroid stimulating immunoglobulin, and heterophilic antibodies. Thyroid uptake and scan showed uniform uptake of 5.1% and 15.1% at 2-hours and 24-hours, respectively, with no dominant nodules. Hypothalamic-pituitary hormonal testing and MRI pituitary were both normal as well. When TSH testing was repeated on a separate platform, Roche’s eCLIA immunoassay, detectable values were obtained (TSH 6.48 µIU/mL). Conclusions: Testing of serum TSH by commercially available immunoassays is based on the sandwich method in which one antibody binds to the β-subunit of TSH and the other to the α-β interface. Most assays use monoclonal antibody pairs to achieve high selectivity. Immunoassay tests are prone to interferences, particularly by way of altering the measurable concentration of the analyte or by altering antibody binding (1). In this case, the presence of detectable TSH depended on the platform by which it was measured. This finding suggests a TSH-β variant with impaired immunoreactivity but functionally normal bioactivity. Such a mutation has been previously reported to occur five times more frequently among South Asian individuals than the general population (2). Genetic testing was offered to the patient to confirm this suspicion but was declined. It is incumbent on the clinician to reconcile a test result that is discordant with the clinical presentation. Having a fundamental understanding of the principles of the testing platform can assist in identifying potential sources of error. Failing to recognize a possible interference can lead to unnecessary healthcare expenditures, misdiagnosis and inappropriate management, potentially at a cost to the patient’s wellbeing. When faced with an undetectable TSH with otherwise normal thyroid hormones and unremarkable clinical picture, it is best to repeat the TSH test using a different available platform. References: (1)Favresse J et al. Endocr Rev. 2018;39(5):830-850(2)Pappa T et al. Thyroid. 2015 Aug;25(8):869-76