Heparin-Associated, Sustained Hospital-Acquired Hyperkalemia: The Forgotten Culprit in the Inpatient Setting? A Case Report with Review of the Literature

Technical Summary: Heparin-Associated, Sustained Hospital-Acquired Hyperkalemia

Problem Statement
Hospital-acquired hyperkalemia is a clinically significant condition associated with cardiac arrhythmias, increased morbidity, and prolonged hospital stays. While drug-induced hyperkalemia is a common etiology in inpatients, heparin—a universally administered agent for deep vein thrombosis (DVT) prophylaxis—is frequently overlooked as a causative factor. Heparin-induced hyperkalemia (HIH) is a well-characterized but underdiagnosed adverse reaction where heparin suppresses aldosterone synthesis in the adrenal zona glomerulosa and reduces angiotensin II receptor affinity. Despite affecting an estimated 7–8% of heparin-treated patients, HIH is rarely included in the differential diagnosis for refractory hyperkalemia, leading to unnecessary diagnostic evaluations and treatment failures when standard therapies (e.g., insulin-dextrose, calcium gluconate) fail to address the underlying mineralocorticoid deficiency.

Methodology
This report utilizes a single-case study design combined with a narrative review of contemporary literature.

• Case Presentation: The authors present a 35-year-old male with Crohn's disease who developed sustained, refractory hyperkalemia (peak 6.6 mEq/L) following emergency exploratory laparotomy. The patient had normal baseline renal function and no history of diabetes or chronic kidney disease. The clinical course involved a temporal correlation between the initiation of prophylactic unfractionated heparin (UFH) and a progressive rise in serum potassium, despite initial hypokalemia.
• Diagnostic Approach: The diagnosis was established through the exclusion of other causes (e.g., renal failure, pseudohyperkalemia due to thrombocytosis, other offending medications) and the calculation of the transtubular potassium gradient (TTKG). A TTKG of 4.0 in the setting of hyperkalemia indicated impaired mineralocorticoid activity. Serum cortisol was normal, ruling out primary glucocorticoid deficiency.
• Intervention: The management strategy involved discontinuing heparin and switching to fondaparinux, administering fludrocortisone (a synthetic mineralocorticoid), and using furosemide to enhance kaliuresis.
• Literature Review: The authors contextualized the case by reviewing recent literature, including a 40-year systematic review (Singh et al., 2025) and a large retrospective comparative study (Naseralallah et al., 2024), to assess the prevalence and risk factors of HIH.

Key Results

• Clinical Outcome: In the reported case, serum potassium normalized over five days following the cessation of heparin and the administration of fludrocortisone. The TTKG remained low (4.6) two days after heparin discontinuation, consistent with the expected gradual recovery of zona glomerulosa function.
• Literature Findings:
  • A systematic review by Singh et al. (2025) identified 38 cases of heparin-induced hyperkalemia between 1983 and 2023, noting that only 13.2% of these cases utilized the Naranjo Adverse Drug Reaction Probability Scale for causality assessment.
  • A retrospective study by Naseralallah et al. (2024) involving 929 patients found hyperkalemia rates of 56.3% with UFH, compared to 15–17% with low molecular weight heparins (LMWH). Diabetes was identified as an independent risk factor.
  • Recent case reports confirm HIH can occur in diverse populations, including patients without classic risk factors (e.g., the young patient in this report) and in critical care settings (e.g., COVID-19, cardiac surgery).

Significance and Claims
The paper argues that HIH is a "forgotten culprit" in the inpatient setting that is likely far more prevalent than current estimates suggest. The authors claim that the condition is consistently underdiagnosed due to the routine nature of heparin prophylaxis, the temporal lag between drug initiation and hyperkalemia (typically days 2–7), and a lack of awareness among clinicians regarding heparin's effect on aldosterone.

The significance of this work lies in:

1. Raising Clinical Awareness: Emphasizing that HIH can occur in young, otherwise healthy patients without traditional risk factors like diabetes or chronic kidney disease, particularly when compounded by recent glucocorticoid cessation (as seen in this patient's history of abrupt budesonide withdrawal).
2. Diagnostic Utility: Highlighting the TTKG as a simple, non-invasive, and underutilized tool to differentiate mineralocorticoid deficiency from other causes of hyperkalemia.
3. Therapeutic Implications: Demonstrating that standard hyperkalemia management is insufficient if the underlying cause (heparin) is not removed. The paper asserts that the definitive treatment is heparin discontinuation and, if necessary, mineralocorticoid replacement (fludrocortisone).
4. Systemic Impact: The authors conclude that recognizing HIH is critical for patient safety, diagnostic efficiency, and cost reduction, urging clinicians across all disciplines to include HIH in the differential diagnosis for any unexplained or refractory inpatient hyperkalemia.