Atezolizumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis and Takotsubo cardiomyopathy

Abstract

Atezolizumab is a humanised monoclonal IgG1 antibody that is used in treating many solid malignancies. Endocrinopathies are known but a rare adverse event of these immunotherapeutic drugs. Autoimmune diabetes induced by atezolizumab has been rarely reported in the literature. We report the case of a woman in her eighth decade with no known history of diabetes who developed new-onset autoimmune diabetes and Takotsubo cardiomyopathy due to the adverse effects of atezolizumab therapy for hepatocellular carcinoma. We also review the characteristics and outcomes of cases previously reported in the literature.

Background

Atezolizumab is a humanised IgG1 monoclonal antibody that targets human programmed cell death-ligand 1 (PD-L1).¹ Immunotherapies such as atezolizumab have revolutionised modern oncological practice and are popular treatments of choice for several solid malignancies, including hepatocellular carcinoma (HCC). However, atezolizumab has known adverse effects ranging from easier-to-manage events like decreased appetite and fever to more serious, immune-mediated reactions such as colitis, hepatitis, thyroiditis, etc.² Type 1 diabetes/autoimmune diabetes is a rarely reported side effect of atezolizumab. In the literature, very few cases of diabetic ketoacidosis (DKA) secondary autoimmune diabetes due to this drug have been reported. We present a case of acute onset fulminant type 1 diabetes with subsequent Takotsubo cardiomyopathy (TCMP) in a woman in her eighth decade with unresectable HCC who was being treated with atezolizumab. This is the first-ever reported case of atezolizumab or an immunotherapeutic agent inducing Takotsubo’s secondary to acute onset DKA in a patient.

Case presentation

A Caucasian woman in her eighth decade with HCC on chemotherapy was referred by her oncologist to the emergency room with a blood glucose of 714 mg/dL. She had a history of clear cell variant of HCC for 8–9 months, confirmed by tissue biopsy. She was initially started on sorafenib due to the unresectable nature and stage of the disease. The clinical and radiological follow-up showed rapid progression of the disease; therefore, she was switched to an atezolizumab and bevacizumab combination regimen after three cycles. At presentation, she was on this chemotherapy regimen for 6 months. Her medical history included hypertension and osteoporosis. She had no history of diabetes mellitus (DM) and was not on any medications besides her chemotherapy regimen. At presentation, she reported a generalised feeling of being unwell and noticed watery, non-bloody diarrhoea for 5 days. She also reported confusion and increased fatigue. She denied headache, dizziness, chest pain, shortness of breath, abdominal pain, nausea, vomiting and urinary symptoms. On the physical exam, she was afebrile with a blood pressure of 134/84 mm Hg, heart rate of 90 beats per minute, respiratory rate of 22 breaths per minute and oxygen saturation of 100% on room air. On general appearance, she was drowsy and confused but arousable. She was oriented to self and place but not to time. Her pupils were equally dilated and reactive to light. She had a systolic murmur at her right sternal border. Her abdomen was soft, non-tender and non-distended. Her pulmonary examination was unremarkable. There was no oedema in her upper or lower extremities.

Investigations

The investigations showed a white cell count of 8.0×10³/µL, haemoglobin of 115 g/L, haematocrit of 34.4% and platelet count of 213.0×10³/µL. A basic metabolic panel showed sodium 123 mmol/L, potassium 5.4 mmol/L, chloride 85 mmol/L, carbon dioxide 11 mmol/L, anion gap 27 mmol/L, glucose 714 mg/dL, blood urea nitrogen (BUN) 54 mg/dL and creatinine 1.4 mg/dL. In liver function studies, alanine transaminase (ALT) was increased to 121 U/L, and aspartate aminotransferase (AST) was increased to 186 U/L. Beta-hydroxybutyrate levels were significant at 7.89 mmol/L. High-sensitivity troponin was elevated to 45 ng/L on admission and peaked at 60 956 ng/L 2 days later. HbA1c level was checked when the glucose levels were elevated and were in the prediabetic range of 6.5%. Urinalysis was positive for glucose, protein and ketones. A venous blood gas was performed due to the high suspicion of DKA and showed a pH 7.22, CO₂ 29 mm Hg and bicarbonate 13.0 mg/L indicative of metabolic acidosis. Blood cultures showed no growth after 5 days of incubation. The lack of history of DM, current HbA1c in the prediabetes range, no history of alcohol use, SGLT-2 inhibitors prescription and starvation, the possibility of autoimmune diabetes leading to DKA was considered. The patient’s glutamic acid decarboxylase 65-kilodalton (GAD-65) antibody test was negative.

The chest X-ray showed bibasilar-dependent atelectasis but no acute disease. A CT scan of the head was done without contrast to evaluate the cause of confused state at admission. It showed no acute intracranial abnormalities, a small focus of chronic ischaemia to the left caudate body and putamen was stable since 2017, and additional mild chronic small vessel ischaemic change in the supratentorial white matter, which was also stable. A CT scan of the abdomen and pelvis revealed an interval improvement in tumour burden within the right hepatic lobe and medial segment of the left hepatic lobe, enlargement of the lateral segment of the left lobe, and an atrophic pancreas. The atrophic pancreas was not seen in a previous abdominal scans performed 7 months before this presentation.

She underwent cardiac catheterisation 1 day after her procedure due to concurrent ST-elevation myocardial infarction (STEMI), which was negative for any culprit vessels requiring stents. Instead, the imaging revealed left ventricular akinesis, which also involved inferoapical and anterior apical segments, with vigorous systolic contraction of mid zones and anterior and inferior walls, consistent with TCMP. In addition, an echocardiogram was performed on the day after admission, and the results showed an ejection fraction of 30%, grade 1 diastolic dysfunction and apical wall dyskinesis, further corroborating the diagnosis of TCMP.

Differential diagnosis

The patient presented with blood glucose >700 mg/dL, confusion and diarrhoea. DKA was the primary differential for the patient. On confirmation, she was started on an insulin as per the management protocol for DKA. We ruled out alcohol use, starvation and SGLT-2 use through history obtained from her family and discussions with the referring oncologist and primary care physician. The sudden onset of diabetes prompted testing for GAD-65 antibody to rule out latent autoimmune diabetes in adults, which was negative. A CT scan of her abdomen was performed to rule out any undiagnosed malignancies or progression of HCC. Instead, it revealed an atrophied pancreas (figure 1). A comprehensive chart review showed her HbA1c to be 5.3% 9 months ago. The patient’s primary care physician reported that the patient had normal blood glucose levels on routine visits up until this presentation. The sudden fulminant onset of diabetes with DKA prompted us to consider atezolizumab as the underlying cause behind this acute illness and hospitalisation. The atrophic pancreas visualised on imaging further corroborated this presentation to be linked to this novel immunotherapeutic agent.

Figure 1.

Axial view of CT of the abdomen with contrast demonstrating an atrophic pancreas (marked with red arrows).

Furthermore, the patient developed typical ST-segment elevations on her ECG with an acute rise in troponins prompting urgent catheterisation. Instead of a culprit vessel, the catheterisation revealed changes consistent with TCMP. All these changes were secondary to DKA and fulminant DM triggered by atezolizumab. Based on the acuteness of presentation, the events throughout hospitalisation and the findings on imaging, we diagnosed her with atezolizumab-induced autoimmune DM. Of note, an outpatient ophthalmology examination of her retina after discharge revealed age-related dry macular degeneration and no diabetes-related damage to ocular structures, further supporting the acuity in this case.

Treatment

After resolution of DKA with insulin drips, she was moved to a monitored floor, where she managed with a basal-bolus insulin regimen. However, the dosing remained challenging because her diabetes resulted in severe fluctuations in blood glucose levels. She was discharged to a skilled nursing facility on daily basal insulin and a customised insulin sliding scale created by the endocrinology team to tackle the sudden changes in blood glucose levels, and frequent telehealth follow-ups were scheduled to adjust the regimen. The decision to continue her atezolizumab therapy on discharge was made after a comprehensive multidisciplinary discussion considering her irreversible pancreatic damage and otherwise good tolerance to the immunotherapeutic agent.

Outcome and follow-up

As the patient’s hospital course was protracted by presumed STEMI (later found to be TCMP via intracardiac catheterisation) and diabetes, she was discharged to a skilled nursing facility. After discharge, she followed up with her primary care physician, where she reported poor appetite and leg oedema and was found to be hyponatraemic (sodium: 129 mEq/L). She was then referred to a nephrologist for further management, who believed this hyponatraemia was multifactorial from her poor hepatic function, hypervolaemia and a direct effect of atezolizumab. She was started on sodium chloride tablets 1 g two times per day, along with fluid restriction. Her blood glucose was very strictly followed by the endocrinologists, who created a personalised blood glucose monitoring regimen for her and followed her with weekly telehealth visits along with regular in-office visits. Her insulin regimen was continuously altered based on her weekly blood glucose readings and fluctuations to maintain euglycaemia in our patient. She remains on atezolizumab and bevacizumab for treatment of HCC and has not developed any new signs of progression.

Discussion

Atezolizumab is a humanised monoclonal antibody immune checkpoint inhibitor (ICI) that selectively binds to PD-L1, inhibiting the interaction between PD-1 and B7.1 (ie, CD80 receptors). PD-L1 is an immune checkpoint protein expressed on tumour cells and infiltrating cells, and it downregulates antitumuor T cell function by binding to PD-1 and B7.1. The United States Food and Drug Administration (FDA) has approved it for treating an array of solid malignancies, including urothelial carcinoma and lung malignancies.² It has become the standard of care in combination with bevacizumab in unresectable HCC since the landmark Imbrave150 trial.³ The commonly seen adverse reactions include fatigue, nausea and decreased appetite. Rarely, immune-mediated adverse reactions are also seen in patients, which can be severe or fatal and involve multiple organ systems, and cause hepatitis, pneumonitis and colitis.²

Although infrequent, endocrinopathies have been observed following immunotherapy use. Thyroid or adrenal dysfunction, and hypophysitis are typically reported endocrinopathies that develop after immunotherapy.⁴ Autoimmune diabetes following immunotherapy has been reported a handful of times in literature so far (table 1). Although poorly understood, pancreatic damage with immunotherapy has several underlying hypotheses. PD-L1 is expressed on pancreatic islet cells and plays a crucial role in shielding against systemic autoimmunity. Administration of anti-PD-L1 therapy may lead to the development of autoimmune DM by disrupting this pathway.⁵ Moreover, pathogenesis of diabetes and DKA in immunotherapy use is due to a lack of insulin production. This occurs due to the destruction of pancreatic β-cells by autoreactive T cells and is termed ‘insulitis’ and has been successfully demonstrated in mouse models.^{6 7}

Table 1.

Summary of the case reports in the past 5 years reporting diabetic ketoacidosis (DKA) post-treatment with atezolizumab

Case report	Age at presentation (years)	Sex	Type of cancer	Pre-existing DM	Time to the presentation from starting atezolizumab (in weeks)	Presentation	Blood glucose (mg/dL)	C-peptide levels (ng/mL)	GAD-65 antibodies (U/mL)	Outcome
Way et al8	Not reported	M	Metastatic papillary urothelial cancer	No	9	DKA	336	0.6	28.4	Switched to gemcitabine and cisplatin and continued to require insulin therapy. Death from cancer 1 year later.
Hickmott et al 9	57	M	Metastatic urothelial carcinoma	No	15	DKA	432	0.65 (1.0–7.1)	Negative	Discharged on two times per week insulin. Chemo discontinued due to tumour progression and death 3 months later from metastasis.
Kapke et al 10	63	F	High-grade urothelial cancer	No	6	DKA	801	0.02	>250	Patient readmitted while arranging alternate therapy, death from acute hypoxic respiratory failure.
Patti et al11	70	F	Stage 4 non-small cell lung adenocarcinoma	No	9	DKA	1015	Not reported	Negative	Not reported.
Sothornwit et al(12)	52	F	Advanced non-small cell lung cancer	No	24	DKA	332	<0.03	7.2	Switched to paclitaxel and carboplatin with partial remission.
Lanzolla et al13	60	M	Metastatic lung adenocarcinoma	No	12	DKA	549	0.7	Negative	Immunotherapy stopped. Tumour progression in 3 months.
Nishioki et al14	73	F	Metastatic lung adenocarcinoma	No	22	DKA	962	Not reported	Negative	Discharge on daily insulin.
Wong et al15	55	F	Recurrent squamous cell lung carcinoma	No	8	Not reported	10.9 mmol/L	0.6	Not reported	Resumed atezolizumab, daily insulin regimen and tumour progress after 11 cycles.
Rahman et al16	64	M	Metastatic renal cell carcinoma	Yes	14	DKA	609	Not reported	>250	Resumed atezolizumab and basal bolus regimen on discharge.
Clontz et al17	74	F	Metastatic triple-negative breast cancer	No	52	DKA	845	0.1	<5	Discharged on basal-bolus insulin.

DM, diabetes mellitus; F, female; M, male.

Although new-onset autoimmune DM caused by ICI therapy is relatively rare, it often presents as DKA (table 1), a medical emergency that requires prompt and intensive management.^8–17 For these reasons, the treating physicians should be thorough with previous reports, and we also recommend monitoring fasting glucose every 3 months (or sooner if clinical indications appear) in patients on atezolizumab.¹² It is imperative to check blood ketone levels if blood glucose levels are higher than 250 mg/dL. The GAD antibodies should be screened in the laboratory testing of these individuals.^{12 16} Antibodies to IA2, IAA and ZnT8 are positive in similar case reports and may be tested in the absence of GADA. However, in patients treated with ICIs, the absence of characteristic autoantibodies should not prevent the diagnosis of autoimmune diabetes with the typical clinical presentation.

Pancreatic atrophy has been seen in up to 7.7% of patients on immunotherapy. It is irreversible and inconsistently related to exocrine pancreatic insufficiency in these individuals.¹⁸ Although not implicated before in literature, it may also preclude or coexist with the onset of autoimmune diabetes in these patients. Our case is unique in presenting radiographic evidence of this pancreatic atrophy with the onset of autoimmune diabetes in our patient (figure 1). Given that this damage is irreversible, a multidisciplinary discussion was undertaken, and the patient is currently doing well on combination chemotherapy and a personalised insulin regimen with frequent follow-ups.

TCMP, or stress cardiomyopathy, mimics acute coronary syndrome and presents as reversible left ventricular apical ballooning and dyskinesis in the absence of angiographically noted significant coronary stenosis.¹⁹ Although the exact pathophysiology is not completely understood, its association with physical and emotional stresses is postulated to be catecholamine mediated, leading to diffuse microvascular spasms, dysfunction and stunning.²⁰ The association between DM, DKA and TCMP has been reported previously in the literature. Several retrospective studies report a prevalence of DM in 11.5%–13.1% of patients with TCMP.^21–23 Other probable explanations include direct glucose poisoning and severe acidosis impairing excitation-contraction uncoupling.²⁴

Learning points.

• Autoimmune diabetes presenting as diabetic ketoacidosis is a rare but potentially life-threatening manifestation of atezolizumab therapy. Patients who are on this therapy require close monitoring of their blood glucose levels (preferably every 3 months) as early identification of the development of autoimmune diabetes can prevent hospitalisations. The HbA1c levels and appropriate antibodies should be checked in the setting of elevated blood glucose in these patients.

• Patients on atezolizumab presenting with fulminant diabetic ketoacidosis require interdisciplinary decision making involving primary care physicians, hospitalists, endocrinologists and oncologists. The threshold to check this adverse event should be low, and all providers involved in the care of these individuals should remain vigilant for signs and symptoms of hyperglycaemia and diabetic ketoacidosis in these patients.

• Once diagnosed with autoimmune diabetes, the patients should have tailored insulin regimens and close, frequent follow-ups. In addition, more advanced devices like insulin sensors can be a possible way of glucose monitoring in these patients.

• If laboratory tests are equivocal or indeterminate, imaging can be used to evaluate pancreatic changes/atrophy and serve as a supportive tool to clinch this life-threatening diagnosis.

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Consent obtained directly from patient(s).