Thyroid Dysfunctions in Patients with Hepatocellular Carcinoma Treated by Transarterial Chemoembolization

INTRODUCTION

Transarterial chemoembolization (TACE) emerged as a palliative therapeutic option for unresectable hepatocellular carcinoma (HCC) cases and has since established itself as one of the predominant modalities within interventional oncology [1]. Contemporary TACE techniques typically involve inserting a catheter into the hepatic segmental arteries that provide blood to HCC lesions. This targeted approach seeks to maximize the therapeutic effect on the tumor while minimizing damage to the adjacent non-neoplastic hepatic tissue. The treatment combines a chemotherapeutic drug with iodide—in the form of iodized oil—such as lipiodol, which is used as a radiopaque contrast medium (CM), to improve its effectiveness [2].

Through the process of incorporating iodine into the double bonds of unsaturated fatty acids derived from specific plant oils, particularly poppy seed oil, which contains a high proportion of unsaturated fatty acids, [3]. As an iodinated contrast medium (ICM), lipiodol introduces a substantial iodine burden to the patient. A single dose provides roughly 13,500 micrograms of free iodide, along with 15 to 60 grams of bound iodine, which could later be converted into free iodide following administration [4, 5].

This amount of iodide surpasses the advised daily intake for adults of 150 micrograms by a factor ranging from 90 times to several hundred thousand times [6, 7]. Given this significant iodine exposure, the current work was intended to assess the incidence and characteristics of thyroid dysfunction in patients with HCC undergoing TACE.

PATIENTS AND METHODS

Study Design:

This cross-sectional study was conducted at the HCC Clinic in the Tropical Medicine Department of Ain Shams University Hospitals from June 2014 to December 2014.

The study enrolled 30 patients with confirmed HCC diagnoses according to the Barcelona Clinic Liver Cancer 2010 criteria, all providing written informed consent before undergoing TACE procedures [8]. Exclusion criteria were established to minimize confounding factors. They included patients with a history of thyroid disorders, those who had received antiviral treatment, and individuals residing in iodine-deficient geographical areas.eg upper Egypt governorates like Suhag, Qena, Luxor and Aswan. Rural and desert communities (New Valley and North Sinai).  

Pre-TACE Clinical Assessment and Laboratory Investigations:

Before the TACE procedure, all patients underwent comprehensive clinical evaluations. A thorough medical history was obtained, and detailed physical examinations were performed, with particular attention devoted to manifestations of thyroid dysfunction. Laboratory investigations included CBC analysis, liver profile tests ALT and AST, renal function assessment (serum creatinine), and tumor marker evaluation (serum alpha-fetoprotein). Additionally, baseline thyroid function was assessed by measuring TSH, free T3, and free T4 levels.

Post-TACE Monitoring and Follow-up:

Following the TACE procedure, patients were systematically monitored for changes in thyroid function. The thyroid profile (TSH, free T3, and free T4) was re-evaluated at two distinct time points: one week and one-month post-procedure. Patients were re-examined clinically and questioned concurrently with laboratory tests about the development of manifestations indicative of thyroid dysfunction after TACE management.

Laboratory Methodology for Thyroid Function Assessment:

Thyroid function parameters were measured using B7K Architect free T3, free T4, and TSH reagent kits (U.S.A). The assay methodology employed was chemiluminescent microparticle immunoassay (CMIA), which enables quantitative determination of free T3, free T4, and TSH in human serum or plasma specimens.

Blood specimens were collected using standard venipuncture techniques in serum separator tubes or EDTA anticoagulant tubes for plasma. To ensure optimal assay performance, specimens were processed free of bubbles, fibrin, red blood cells, and other particulate matter. Full clot development in serum samples was confirmed before the centrifugation process began. For tests postponed beyond 24 hours, serum or plasma was isolated from the cellular elements. Specimens were stored at 2-8°C for up to 6 days; for longer storage periods, specimens were frozen at -10°C or below, which preserved assay performance characteristics.

Assay Calibration and Reference Ranges:

The free T3 assay utilized a calibrator range of 0.0-30.0 pg/ml, with results generated using a 4-parameter logistic curve fit data reduction approach (4PLC, Y-weighted). The default result unit was pg/ml; the formula concentration in pg/ml × 1.536 yields an alternative unit conversion to pmol/L. The accepted normal reference range was 1. 71–3. 71 pg/ml.

For free T4 assessment, the calibrator range was 0.0-6.0 ng/dl, also utilizing a 4PLC, Y-weighted data reduction method. The default result unit was ng/dl, with conversion to pmol/L available using the formula: concentration in ng/dl × 12.87 = concentration in pmol/L. The normal reference range was defined as 0.70-1.48 ng/dl.

The TSH assay employed a calibrator range of 0.0000-100.0000 μIU/ml, with the same 4PLC, Y-weighted calibration curve. The default unit was μIU/ml, with direct 1:1 conversion to mIU/ml available. The established normal reference range for TSH was 0.35-4.94 μIU/ml.

TACE Procedure Methodology:

The TACE procedure was performed using percutaneous endovascular techniques. Either 5-F catheters (Simmons 1 and Cobra; Mallinckrodt, St. José, USA or Hydrophilic Simmons 1 and Cobra; Terumo, Tokyo, Japan) or 3-F coaxial microcatheters (Tracker 18; Vascular Access System, Target, St. José, USA; SP Catcher; Terumo) selective catheterization of the hepatic segmental arteries supplying the lesions.

The TACE approach facilitated direct delivery of potent anticancer agents to tumor-feeding arteries, resulting in high intratumoral drug concentrations while minimizing systemic exposure. To guarantee uniform emulsion, 100 mg adriablastin powder was painstakingly made by mixing 10 cc salty, water-soluble CM and 10 cc oily CM (lipiodol ultra-fluid). Gelfoam particles—cut into tiny pledgets and suspended in water-soluble CM before treatment—were used during the embolization phase.

Sample Size Calculation:

Using PASS 15 program for sample size calculation, setting confidence level at 90% and margin of error at 12.5%, it is estimated that sample size of 30 patients were enough to detect an expected incidence rate of thyroid dysfunction of 20%.

Statistical Analysis:

Data was analyzed using IBM SPSS Statistics (Version 22.0, IBM Corp., USA, 2013). Quantitative parametric measures were expressed as mean ± standard deviation, while quantitative non-parametric measures were presented as median and percentiles. Categorical data were expressed as both numbers and percentages. Statistical evaluations were performed using Ranked Spearman correlation and Chi-square tests. Statistical significance was defined as a probability of error at 0.05, with values at 0.01 and 0.001 considered highly significant.

RESULTS

Demographic and clinical characteristics of the study participants are shown in table 1   Subclinical alterations in thyroid hormone concentrations were observed in a subset of patients following TACE, with levels demonstrating either an increase or decrease relative to baseline. Regarding TSH levels, one-week post-TACE, elevated concentrations were recorded in 4 patients (13.3%), reduced levels in 1 patient (3.3%), and normal levels maintained in 25 patients (83.3%). By the one-month follow-up, TSH levels in the 4 patients with previously elevated values had normalized, while the single patient with a low TSH level persisted in this state. Additionally, among patients with normal TSH levels at one week, 2 (8%) exhibited reduced levels at one month, with these changes achieving statistical significance (p < 0.05) (Table 2).

With respect to FT4 levels, one week after TACE, 5 patients (16.7%) displayed elevated concentrations, and 3 patients (10%) showed reduced levels. At the one-month assessment, the number of patients with elevated FT4 increased to 9 (30%), while the 3 patients with initially low levels had normalized, with these shifts demonstrating statistical significance (p < 0.05) (Table 3).

Similarly, FT3 levels exhibited changes: one-week post-TACE, 2 patients (6.7%) had elevated FT3 levels, and 2 patients (6.7%) had reduced levels. By one month, 4 patients (13.3%) presented with elevated FT3 levels, and 1 patient (3.3%) exhibited a reduced level but these shifts are not statistically significant (Table 4).

Furthermore, there were no notable correlations between the observed alterations in thyroid hormone levels and variables such as age, sex, residence, or baseline laboratory parameters (p > 0.05). These findings suggest that while TACE induces detectable changes in thyroid function, these variations are not consistently associated with demographic or clinical covariates in this cohort.

 Table 1: Demographic data of the studied group.

Data is presented as Mean ± SD& percentage.

 Tables 2: Changes in TSH levels.

Data is presented as percentage (%). TSH: Thyroid-Stimulating Hormone.

Tables 3: Changes in FT4 levels.

Data is presented as percentage (%). FT4: Free Thyroxine
Tables 4: Changes in FT3 levels.

Data is presented as percentage (%)