Liver Injury Induced by Levothyroxine Tablets in a Patient with Hypothyroidism
A 31-year-old woman with a history of thyroid cancer surgery experienced drug-induced liver injury (DILI) following treatment with levothyroxine tablets. This case highlights the potential role of pharmaceutical additives in triggering adverse reactions, emphasizing the need for clinical vigilance when managing patients on thyroid hormone replacement therapy.
Clinical Presentation and Initial Management
The patient underwent left thyroidectomy for micro-papillary carcinoma on February 5, 2018. Preoperative laboratory assessments revealed normal liver function: total bilirubin (T-BIL) 21.5 mmol/L, direct bilirubin (D-BIL) 6.3 mmol/L, alanine transaminase (ALT) 27.5 U/L, aspartate transaminase (AST) 22.7 U/L, and alkaline phosphatase (ALP) 48.9 U/L. Thyroid function tests showed mild hypothyroidism: free triiodothyronine (FT3) 3.95 pmol/L, free thyroxine (FT4) 15.57 pmol/L, and thyroid-stimulating hormone (TSH) 2.56 mU/L. Postoperatively, she was prescribed levothyroxine tablets (LTA, Merck KGaA) 100 µg daily and calcium carbonate D3 (CC-D3) 600 mg daily.
Onset of Liver Dysfunction
During a follow-up evaluation on March 9, 2018—26 days after initiating LTA—laboratory tests revealed significant liver injury: ALT 325.2 U/L (10× upper limit of normal [ULN]), AST 144.9 U/L (4× ULN), T-BIL 16.2 mmol/L, and D-BIL 4.10 mmol/L. Thyroid function had normalized (FT3 5.50 pmol/L, FT4 20.13 pmol/L, TSH 0.035 mU/L), indicating adequate hormone replacement. Viral hepatitis serologies (hepatitis B and C) and autoimmune markers (ANA, AMA-M2, ASMA, LKM-1, SLA/LP, LC-1) were negative, ruling out common causes of acute hepatitis. The Roussel Uclaf Causality Assessment Method (RUCAM) scored 6 points, supporting a probable diagnosis of DILI (hepatocellular injury type, acute, severity grade 1).
Therapeutic Interventions and Clinical Course
LTA was reduced to 75 µg daily, and liver-protective therapies were initiated: magnesium isoglycyrrhizinate (100 mg IV daily) and reduced glutathione (2.4 g IV daily). By March 14, transaminases showed improvement (ALT 126.2 U/L, AST 43.3 U/L). Upon discharge, the patient continued LTA 75 µg and CC-D3, supplemented with oral glycyrrhizic acid diamine (GAD) and polyene phosphatidylcholine (PPC) capsules. Despite this, liver enzymes remained elevated (ALT 126.2 U/L, AST 43.3 U/L on March 14), prompting further action.
Transition to Alternative Levothyroxine Formulation
On March 25, LTA was discontinued and replaced with levothyroxine tablets from a different manufacturer (LTB, Berlin Chemie AG) at 75 µg daily. This switch coincided with gradual normalization of liver function: by April 6, ALT and AST decreased to 63.5 U/L and 32.6 U/L, respectively, and bilirubin levels normalized (T-BIL 10.70 mmol/L, D-BIL 3.00 mmol/L). LTB was incrementally increased to 100 µg daily by June 19, with sustained improvement in liver parameters (T-BIL 13.00 mmol/L, D-BIL 3.30 mmol/L by August 7). Abdominal ultrasounds throughout treatment showed no structural abnormalities.
Analysis of Causative Factors
The temporal relationship between LTA initiation and liver injury, coupled with recovery after switching to LTB, strongly implicated LTA as the causative agent. Both LTA and LTB contain levothyroxine sodium as the active ingredient but differ in excipients: LTA includes corn starch, gelatin, lactose, and magnesium stearate, while LTB uses calcium bicarbonate, dextrin, and microcrystalline cellulose. Additives in LTA, particularly lactose and magnesium stearate, were hypothesized to act as haptens, forming antigenic complexes that trigger immune-mediated hepatotoxicity. This mechanism aligns with prior case reports linking levothyroxine excipients (e.g., ferric oxide) to DILI.
Clinical Implications and Mechanistic Insights
Levothyroxine-induced liver injury is rare, with fewer than five documented cases since 1986. The latency period varies: triiodothyronine (T3) caused injury after 4 months in one case, whereas levothyroxine induced damage within 4 days to 2 months in others. The proposed mechanism involves T-cell activation against hapten-carrier complexes derived from drug excipients. This case underscores the importance of considering non-active ingredients in drug formulations when investigating idiosyncratic DILI.
Management Strategies
- Early Recognition: Unexplained transaminase elevation in patients on levothyroxine should prompt RUCAM assessment.
- Excipient Screening: Switching to alternative formulations with distinct additives may resolve liver injury.
- Therapeutic Monitoring: Regular liver function tests are advised during dose escalation or formulation changes.
Conclusion
This case illustrates the critical role of pharmaceutical additives in levothyroxine-associated hepatotoxicity. Clinicians should maintain a high index of suspicion for excipient-driven DILI and consider alternative formulations when standard treatments provoke adverse reactions. The patient’s successful transition to LTB highlights the utility of pharmacovigilance in optimizing individualized therapy.
doi.org/10.1097/CM9.0000000000000340
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