August 2023 – Clinical Chemistry

New-onset Type I diabetes mellitus (T1DM).

Based on the potassium and glucose results, the patient was referred to the Emergency Department. Upon presentation to the ED, lab results are notable for sodium of 122 mmol/L, glucose of 896 mg/dL, lactate of 2.4 mmol/L, and beta-hydroxybutyrate of 1.6 mmol/L.

A diabetes diagnosis is confirmed by A1c of 18.0% and glucose of 896 mg/dL. At the time of presentation to the ED, the earlier hyperkalemia has resolved, but the patient is now hyponatremic.

New-onset T1DM, electrolyte abnormalities, and DKA/HHS

Are the observed electrolyte abnormalities consistent with the patient’s condition, or was some sort of laboratory or pre-analytical error involved? Significant electrolyte abnormalities can be associated with acute presentation of T1DM, especially in diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar state (HHS), which are often the first presentation in new-onset cases of Type I diabetes. Significant hyperkalemia is often seen in DKA/HHS,^1,2 and can be attributed to multiple mechanisms, all of which contribute to a shift of potassium from the intracellular to extracellular compartment.

First, the absence of insulin, which activates the Na/K-ATPase at cell membranes and is therefore responsible for maintaining the intracellular potassium gradient, allows the loss of potassium from the intracellular to the extracellular space. Second, the presence of increased extra-cellular osmolarity due to marked hyperglycemia causes efflux of water from cells, accompanied by additional intracellular potassium. Finally, the presence of metabolic acidosis, as in DKA, is associated with extracellular shunting of potassium as hydrogen ions accumulate intracellularly, displacing positively charged potassium ions to balance intracellular and extracellular charge.

The hyponatremia observed upon presentation to the ED would also be consistent with marked hyperglycemia and/or DKA/HHS; increased extracellular osmolarity results in an expansion of the extracellular fluid volume, resulting in a dilutional hyponatremia.³ While pseudohyperkalemia by hemoconcentration due to the combination of fist-clenching and prolonged tourniquet time  during phlebotomy is known to occur,⁴ this mechanism would not explain the other lab abnormalities seen in this case.

The diagnosis of T1DM was established by the presence of marked hyperglycemia, ketosis (urine ketones positive, beta-hydroxybutyrate elevated), and elevated A1c. The patient did not meet the criteria for DKA, not being frankly acidotic (venous pH 7.35) despite the presence of BOHB and an increased anion gap. The patient was also not classified as having HHS, having a calculated serum osmolality of 294 mOsm/kg (RI: 275-295); HHS is generally associated with osmolality in excess of 320 mOsm/kg. The patient was therefore admitted to pediatric general medicine and managed successfully with intravenous fluid administration and subcutaneous insulin. Prompt laboratory diagnosis and follow-up may have prevented a presentation of acute DKA, which can have significant associated morbidity and mortality.⁵

Additional testing for T1DM

The patient was also found to be positive for antibodies to islet antigen-2 (IA-2). While not necessary for the diagnosis of T1DM in most cases, autoantibodies against islet cell antigens including insulin, IA-2, glutamate decarboxylase 65 (GAD65) and zinc transporter ZnT8, can be helpful in determining an autoimmune etiology. Greater than 95% of patients with T1DM are positive for at least one of these auto-antibodies, and their presence can be helpful for distinguishing between Type 1 and Type 2 diabetes in ambiguous cases, such as late-onset diabetes, adolescent diabetes presenting without ketoacidosis, and adolescent onset diabetes in patients who are overweight or obese.^6,7

References

1. Adrogué HJ, Lederer ED, Suki WN, Eknoyan G. Determinants of plasma potassium levels in diabetic ketoacidosis. Medicine (Baltimore). 1986;65(3):163-72. Epub 1986/05/01.
2. Atchley DW, Loeb RF, Richards DW, Benedict EM, Driscoll ME. ON DIABETIC ACIDOSIS: A detailed study of electrolyte balances following the withdrawal and reestablishment of insulin therapy. J Clin Invest. 1933;12(2):297-326. Epub 1933/03/01.
3. Katz MA. Hyperglycemia-induced hyponatremia -- calculation of expected serum sodium depression. N Engl J Med. 1973;289(16):843-4. Epub 1973/10/18.
4. Don BR, Sebastian A, Cheitlin M, Christiansen M, Schambelan M. Pseudohyperkalemia caused by fist clenching during phlebotomy. New Engl J Med. 1990;322(18):1290-2.
5. Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child. 2004;89(2):188-94. Epub 2004/01/23.
6. Bingley PJ. Clinical applications of diabetes antibody testing. J Clin Endocr Met. 2010;95(1):25-33.
7. Winter WE, Schatz DA. Autoimmune markers in diabetes. Clin Chem. 2011;57(2):168-75.