Hypoglycaemia in lithium toxicity: A rare clinical entity presenting with a diagnostic dilemma

Dear Editor,

Some rare side effects of lithium include nephrotoxicity, neurotoxicity, and altered carbohydrate metabolism. A literature search revealed only two case reports of symptomatic hypoglycemia in patients treated with lithium.[1,2] whereas there is 01 population base cohort study that reports a positive association between maternal lithium use and neonatal hypoglycemia.[3]

A 65-year-old male with a case of BPAD since 2004, Type 2 diabetes mellitus, and hypertension since 2018 on Tab Lithium 900 mg/day, Tab Metformin 1 gm BD and Tab Telmisartan 40 mg/day was brought by his wife to emergency department with acute-onset dizziness, profuse sweating, and tremors since evening. He was found unconscious in his bedroom, drenched in sweat, and subsequently taken to a general physician. His capillary blood glucose (CBG) was recorded at 24 mg/dL. He was infused with 25% dextrose, following which he regained consciousness. Post-stabilization, he was referred to this center.

On presentation, he had confusion, profuse sweating, tremors, and difficulty walking without support. There was no history of any recent falls, head trauma, fasting, or psychotropic substance/medication ingestion. Clinical examination revealed a Glasgow Coma Scale of 11/15, pulse of 98/minute, blood pressure of 150/80 mmHg, SPO2 of 98% in room air, and respiratory rate of 18/minute. A central nervous system (CNS) examination revealed a drowsy individual with 5/5 tone and power and 3+ deep tendon reflexes in all limbs. Pupils were equal and reactive to light, with no gaze preference, facial asymmetry, or positive Babinski reflex. During the examination, he had profuse sweating and became unconscious. CBG revealed capillary glucose at 36 mg/dL. After a 25% dextrose infusion, he improved. Tab metformin was stopped, and he was shifted to the intensive care unit as a case of recurrent hypoglycemia. Laboratory investigations revealed hemoglobin of 12.5 g/100 mL (males: 15.5 ± 2.5), total leucocyte count of 16,600/cumm (4000–11,000/cumm), platelets of 4.04 L/cumm (1.5–4.0 L/mm³), urea of 17 mg/dL (10–50 mg/dL), creatinine of 1.9 mg/dL (0.7–1.3 mg/dL), uric acid of 9.3 mg/dL (3.5–7.2 mg/dL), bilirubin total of 0.8 mg/dL (0.2–1.0 mg/dL), bilirubin direct of 0.2 mg/dL (up to 0.2 mg/dL), aspartate aminotransferase of 48 IU/L (15–37 IU/L), alanine transaminase of 88 IU/L (16–63 IU/ L), alkaline phosphatase of 52 U/L (46–116 IU/L), albumin of 3.8 g/dL (3.4–5.0 g/dL), globulin of 2.4 g/dL (1.8–3.6 g/dL), sodium of 139 mEq/L (136–145 mEq/L), and potassium of 4.2 mEq/L (3.5–5.1 mEq/L). The ECG revealed sinus tachycardia. The urine toxicology screen was negative for benzodiazepine, amphetamine, morphine, cocaine, methamphetamine, and tetrahydrocannabinol. The non-contrast computed tomography head was normal. A psychiatric review revealed a history of elated mood, overtalkativeness, reduced need for sleep, and increased libido of 03 weeks duration, following which lithium was increased from 300 to 900 mg/day 2 days prior to current admission, with no hypoglycemic episodes in these 2 days. Tab lithium was withheld; serum lithium levels revealed 1.49 mmol/l. Input-output charts revealed a reduced urine output of 550 mL/day. The diagnosis was revised to lithium toxicity with AKI. Despite continuous dextrose infusion, he developed multiple episodes of hypoglycemia and generalized tonic-clonic seizures (GTCS) within a span of 24 hours. Lab investigations for plasma insulin and C-peptide levels were within normal limits. Additionally, transabdominal, endoscopic ultrasound, and CT abdomen were done to rule out insulinoma. After 02 cycles of CRRT, his serum lithium level was reduced to 0.80 mmol/l. The tremulousness of the hands reduced, and there were no further episodes of hypoglycemia or GTCS. Subsequently, he was shifted to the medical ward and observed without lithium. At the time of discharge, he was started on Tab Divalproex sodium 250 mg/day and gradually increased to 1500 mg/day over 01 week.

The minimum effective plasma level of lithium for prophylaxis is 0.4 mmol/L with the optimal range being 0.6–0.8 mmol/L.[4] With multimodal action, it inhibits dopamine, but promotes gamma-aminobutyric acid neurotransmission and downregulates N-methyl-D-aspartate receptors. It has modulatory action on the cellular signaling system. It inhibits protein kinase C, myristoylated alanine-rich C kinase substrate, and glycogen synthase kinase (GSK-3), which are raised in Mania. It also inhibits the inositol system, thereby depleting myoinositol. Its neuroprotective action is facilitated by the production of brain-derived neurotrophic factor.[5]

Symptoms of hypoglycemia are characterized by neurogenic symptoms, viz., trembling, palpitations, sweating, anxiety, hunger, nausea, and tingling, and neuroglycopenic symptoms, viz., confusion, weakness, drowsiness, blurred vision, headache, and dizziness. The symptomatology in the form of sweating, tremors, loss of consciousness, and seizures in a diabetic patient on oral hypoglycaemic agents (OHA) led to a diagnosis of recurrent hypoglycemia in our patient. Metformin, being the most widely used OHA, does not increase the risk of hypoglycemia.[6] Also, the patient continued to have recurrent hypoglycemic episodes and GTCS despite stopping metformin and giving dextrose infusions.

A temporal association of hypoglycemic episodes with an increased lithium dose, increased plasma lithium concentration known to be toxic, resolution of symptoms after CRRT, and the absence of any other contributory cause led to the diagnosis of lithium toxicity. However, lithium-associated hypoglycemia at therapeutic doses has rarely been described in the literature.[1] In a clinical setting, the evidence is scanty and mostly comes from case reports and case series.[2] In recent rat studies, GSK-3 inhibition has been shown to increase glucose uptake in insulin-insensitive muscle and adipose tissue, causing attenuation of cellular glucose uptake and glycogen storage, thus deemed beneficial in the hyperglycemic state of diabetes mellitus. The proposed mechanism of the hypoglycemia could be due to GSK-3 inhibition due to the toxicity of lithium.[7]

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