First Report of Lipoprotein X Formation in Methimazole-Induced Cholestatic Jaundice with Agranulocytosis

Dear Editor,

Lipoprotein X (Lp-X) is an abnormal lipoprotein typically found in the plasma of patients with cholestatic diseases or familial lecithin-cholesterol acyltransferase deficiency [1]. As Lp-X lacks apolipoprotein B (ApoB), it may be misidentified as LDL cholesterol (LDL-C) on electrophoresis [2]. We report a case of methimazole-induced cholestatic hepatitis with agranulocytosis in which marked Lp-X elevation posed diagnostic challenges. To our knowledge, this is the first report of concurrent methimazole-induced cholestatic hepatitis, agranulocytosis, and LP-X formation—a rare constellation of adverse drug reactions. This case report was approved by the Institutional Review Board of Soonchunhyang University Bucheon Hospital, Bucheon, Korea (IRB No. 2025-04-021). As this study involved a retrospective review of the patient’s medical records, the requirement for informed consent was waived by the IRB.

An 88-yr-old female patient was diagnosed as having Graves’ disease and was started on 10 mg methimazole (MTZ) twice daily immediately after the diagnosis. She developed generalized pruritus after 3 days of therapy, followed by jaundice after 10 days, prompting hospital admission at Soonchunhyang University Bucheon Hospital (Bucheon, Korea). Her medical history included hypertension and type 2 diabetes mellitus. Pre-treatment liver function tests (LFTs) and lipid panel were normal.

Upon admission, thyroid function tests revealed a mild hypothyroid state and presence of antithyroid antibodies, consistent with Graves’ disease suppressed by MTZ treatment. LFTs indicated acute hepatitis and cholestatic liver disease. Viral and autoimmune markers were negative. Hematologic evaluation revealed concurrent agranulocytosis. Lipid profiling revealed marked hypercholesterolemia. The LDL-C level was 1,063 mg/dL, and the serum ApoB concentration was 159 mg/dL, yielding an LDL-C/ApoB ratio of 6.69, which is markedly elevated compared with the physiological ratio (approximately 1:1). Serum phospholipid levels were markedly elevated, exceeding the upper limit of quantification (>2,000 mg/dL).

To investigate this marked elevation of cholesterol levels further, we performed lipoprotein electrophoresis, which revealed a predominant LDL peak (77.1%). Agarose gel electrophoresis revealed a broad band in the beta region, suggesting Lp-X presence (Fig. 1). High-resolution electrophoresis is required for definitive identification but was not feasible in our setting. Therefore, Lp-X was diagnosed based on clinical features of cholestasis, agarose gel electrophoresis, and elevated serum phospholipid levels.

Fig. 1. Agarose gel electrophoretic profiles of lipoproteins. (A) LDL sub-fraction electrophoretic profile. (B) The right lane represents the profile of a normal control sample, a serum specimen that demonstrated a typical lipoprotein distribution on agarose gel electrophoresis. The left lane represents the profile of the patient sample, demonstrating a broad, intense band in the Lp-X region in addition to the β fraction, consistent with Lp-X accumulation under cholestatic conditions.

Abbreviations: Lp-X, lipoprotein X; VLDL, very low-density lipoprotein.

The patient was diagnosed as having drug-induced liver injury with a cholestatic pattern and agranulocytosis attributed to MTZ. Marked dyslipidemia due to Lp-X accumulation was observed. The patient received conservative management, including hepatoprotective agents and granulocyte colony-stimulating factor. As statins can exacerbate hepatotoxicity, treatment for the abnormally elevated cholesterol level was deferred. By hospital day 11, LFT parameter levels and neutrophil counts normalized, and the patient was subsequently discharged. At the follow-up visit 1 month after discharge, dyslipidemia persisted. The patient was prescribed pravastatin with careful monitoring. Cholesterol levels improved during 4 months of follow-up, without deterioration of liver function (Fig. 2).

Fig. 2. Temporal trends in LFT results and lipid profile over time. The upper panel reveals that AST, ALT, ALP, γ-GT, and T.bil levels rapidly normalized following MTZ discontinuation. The lower panel demonstrates marked improvement in T.chol, TG, and LDL levels after pravastatin initiation, with stable liver function.

Abbreviations: LFT, liver function test; ALP, alkaline phosphatase; γ-GT, gamma-glutamyltransferase; T.bil, total bilirubin; MTZ, methimazole; TG, triglycerides; T.chol, total cholesterol.

This case represents an exceptionally rare constellation of adverse drug reactions, involving concurrent MTZ-induced cholestatic hepatitis and agranulocytosis, both of which are individually uncommon. The resulting interference in the lipoprotein profile, particularly, the markedly elevated LDL levels, was initially misinterpreted, posing significant diagnostic and therapeutic challenges.

We considered several possible mechanisms that might underlie the occurrence of Lp-X formation, including the marked severity of cholestasis, interindividual variability in lipid metabolism [3], and potential genetic predispositions [4]. Drug-related thyroid suppression may have contributed to dyslipidemia. MTZ-induced suppression of thyroid hormone production may indirectly affect lipid metabolism by downregulating hepatic LDL receptor expression, thereby impeding the metabolic clearance of LDL [5, 6]. These thyroid hormone-mediated effects, compounded by cholestasis-related impairment of lipoprotein clearance, may have synergistically caused marked lipid abnormalities and Lp-X formation.

Diagnostically, Lp-X can be mistaken for LDL on standard lipid panels as it has similar density and electrophoretic mobility. High-resolution electrophoresis and nuclear magnetic resonance-based lipoprotein profiling are considered diagnostic standards but are not feasible in most clinical laboratories [7]. In this setting, simple approaches such as agarose electrophoresis, ApoB measurement, and phospholipid quantification can facilitate diagnosis [8]. In the presence of Lp-X, the LDL-C/ApoB ratio becomes disproportionately elevated because Lp-X particles lack ApoB. These markers, combined with the clinical representation of cholestasis, provide practical alternatives for identifying Lp-X in routine practice [9, 10].

A limitation of our case study is that confirmatory tests such as high-resolution electrophoresis for Lp-X were not performed. Therefore, Lp-X diagnosis was based on indirect evidence, including the electrophoretic pattern, serum phospholipid elevation, and ApoB measurement, and should be interpreted with caution.

When managing patients with cholestatic liver injury exhibiting marked LDL-C elevation, clinicians should suspect Lp-X. A clearer understanding of the biochemical characteristics of Lp-X may help refine diagnostic approaches in cholestatic conditions and guide the development of standardized algorithms for distinguishing Lp-X–related dyslipidemia from true hypercholesterolemia.