Early effects of radioactive iodine (I-131) therapy on liver function in patients with Graves’ disease: a 48-h analysis

Abstract

Objective

Radioactive iodine (RAI) therapy is one of the most widely used and relatively safe treatments for Graves’ disease (GD). However, its effects on liver function tests (LFTs) remain incompletely understood. This study aimed to evaluate early changes in LFTs following RAI therapy and to identify potential risk factors.

Results

We conducted a retrospective review of 122 patients with GD who received RAI therapy at our department between January 2019 and July 2020. Following RAI treatment, significant changes in liver biochemical parameters were observed: levels of total protein (TP), albumin (ALB), globulin (GLO), direct bilirubin (DBIL), and gamma-glutamyl transpeptidase (GGT) increased, while total bilirubin (TBIL), indirect bilirubin (IBIL), and aspartate aminotransferase (AST) decreased. Our findings suggest that RAI therapy is associated with new, transient abnormalities in liver biochemical parameters in over a quarter of patients, involving alterations in ALB, DBIL, AST, alkaline phosphatase (ALP), or combinations of these markers. Multivariate analysis revealed that younger age and higher RAI dosage were independent predictors of liver function test abnormalities following treatment.

Introduction

Graves’ disease (GD) is the most common cause of hyperthyroidism and predominantly affects individuals between the ages of 30 and 50, with a lifetime risk of 2% in women and 0.2% in men [1–3]. GD presents with a wide spectrum of clinical manifestations that significantly impair patients’ quality of life, including heat intolerance, tremors, fatigue, anxiety, insomnia, unintentional weight loss, muscle weakness, palpitations, and ocular symptoms [2].

The primary treatment options for GD include antithyroid drugs (ATDs), radioactive iodine (RAI) therapy, and surgical thyroidectomy. In Europe and Asia, ATDs such as propylthiouracil (PTU) and methimazole (MMI) are generally used as first-line therapies. The standard duration of ATDs treatment ranges from 1.5 to 2 years, with approximately half of patients experiencing relapse after discontinuation. Recent evidence indicates that prolonging ATDs therapy beyond the conventional period may reduce recurrence rates compared to standard regimens [4, 5]. However, ATDs are associated with several adverse effects—including hepatotoxicity, agranulocytosis, rash, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which can limit their long-term use [6–8]. Hepatotoxicity is one of the most frequent and severe side effects associated with ATDs. The incidence of ATDs-induced liver injury varies significantly depending on the specific agent used. According to Suzuki et al., the overall prevalence of ATDs-related drug-induced liver injury was 2.5%, with methimazole (MMI) accounting for 1.4% and propylthiouracil (PTU) for 6.3% [9].

Due to its high efficacy and shorter treatment duration, RAI therapy is increasingly preferred by GD patients. As the number of patients receiving RAI therapy rises, concerns regarding its potential side effects have grown. Known complications of RAI therapy include transient worsening of thyrotoxicosis, onset or progression of ophthalmopathy, radiation-induced thyroiditis, local lymphadenitis, and uncertain risks of malignancy and mutagenesis [10–12]. However, there is a scarcity of research on the influence of liver function tests (LFTs) following RAI therapy among GD patients [13]. Previous studies have indicated that following the administration of RAI, the liver demonstrates a greater hepatic iodine uptake compared to other major organs, with the exception of the thyroid [14–16]. The majority of RAI is excreted from the body via urine, saliva, and feces within 48 h [17]. Therefore, in this study, LFTs were performed both before and 48 h after RAI therapy in patients with Graves’ disease. We hypothesized that RAI therapy may induce transient biochemical liver alterations independent of thyroid hormone changes.

Methods

Patients

This was a retrospective observational study, GD patients who underwent RAI therapy from January 2019 to July 2020 at our hospital were included and reviewed (as shown in Fig. 1). The inclusion criteria were as follows: (1) Diffuse enlargement of the thyroid gland. (2) Serum thyrotropin (TSH) levels lower than 0.55 µIU/mL, free triiodothyronine (FT3) levels higher than 6.5 pmol/L, and free thyroxine (FT4) levels higher than 22.7 pmol/L. (3) Elevated 24-h radioactive iodine uptake (24-h RAIU). (4) Elevated thyrotropin receptor antibody (TRAb) levels. The exclusion criteria were as follows: (1) Patients with hyperthyroidism due to causes other than GD, such as toxic multinodular goiter or Plummer’s disease; (2) Patients with abnormal LFTs (any value outside the reference range) prior to receiving RAI therapy; (3) Patients lacking LFTs before and/or after RAI therapy; (4) Patients with a history of RAI therapy; (5) Patients who had undergone surgical thyroidectomy; (6) Patients suffering from other conditions that may lead to abnormal LFTs, such as viral hepatitis, alcoholic hepatitis, and autoimmune hepatitis. After evaluation, a total of 396 patients were found not to meet the criteria, resulting in the inclusion of 122 patients in the study. Various risk factors were collected and analyzed, including gender, age, duration of GD disease, FT3, FT4, TSH, TRAb, thyroperoxidase antibody (TPOAb), 24-h RAIU, and the administered dosages of RAI. The study received approval from the ethics committee of Linyi People’s Hospital, affiliated with Shandong Second Medical University (Approval number: 30067). Given that this research constitutes a retrospective clinical study, our hospital’s ethics committee waived the requirement for obtaining written informed consent from all participants. All methods were conducted in accordance with the principles of the Declaration of Helsinki.

Fig. 1.

Patient selection process

Thyroid function tests

All thyroid function tests were conducted in the nuclear medicine laboratory of our hospital. The ADVIA Centaur XPT immunoassay system, along with its supporting reagents from Siemens, was utilized for the testing process. Prior to RAI therapy, all patients were required to fast for a minimum of 8 h. Subsequently, a volume of 3 to 5 milliliters of venous blood was extracted from the elbow in the morning. The blood samples were then centrifuged to separate the serum for further analysis. The normal ranges of the various indexes were as follows: FT3, 3.5–6.5 pmol/L; FT4, 11.5–22.7 pmol/L; TSH, 0.55–4.78 uIU/mL; TPOAb, 0–60 IU/mL; TRAb, 0–1.75 IU/L.

Liver function tests (LFTs)

All LFTs were conducted in the clinical biochemistry laboratory of our hospital. The AU5800 automatic biochemical analyzer, along with its supporting reagents from Beckman, was utilized for the testing process. The majority of radioactive iodine is excreted from the body within 48 h [17]. Therefore, in this study, LFTs were conducted both before and 48 h after RAI administration in GD patients. All patients were required to fast for at least 8 h prior to each blood sampling. Subsequently, a volume of 3 to 5 milliliters of venous blood was extracted from the elbow in the morning. The blood samples were then centrifuged to separate the serum for further analysis. The normal ranges of the various indexes were as follows: Total protein (TP): 60.0–80.0 g/L; Albumin (ALB): 34.0–48.0 g/L; Globulin (GLO): 20.0–35.0 g/L; Total bilirubin (TBIL): 2.0–24.0 µmol/L; Direct bilirubin (DBIL): 0.00–5.00 µmol/L; Indirect bilirubin (IBIL): 1.70–20.60 µmol/L; Alanine aminotransferase (ALT): 7.0–40.0 U/L; Aspartate aminotransferase (AST): 13.0–35.0 U/L; Alkaline phosphatase (ALP): 40.0–150.0 U/L; Gamma-glutamyl transpeptidase (GGT): 7.0–45.0 U/L.

RAI therapy

RAIU measurements, thyroid volume, thyroid weight estimation, and RAI dose calculation were performed as previously described [18, 19]. Briefly, all patients ceased taking ATDs and other iodine-containing medications for a minimum of 1 week and followed a low-iodine diet for at least 2 weeks before undergoing RAI therapy. After fasting for a minimum of 8 h, patients orally consumed the calculated RAI dose in the morning and then ate food 2 h later to ensure the optimal efficacy of RAI therapy.

Statistical analysis

Normally distributed variables were reported as mean ± standard deviation (SD) and analyzed using the paired t-test. Non-normally distributed variables were reported as median (interquartile range: P25, P75) and analyzed with the Wilcoxon signed-rank test or the Mann–Whitney U test. Categorical variables were presented as frequencies and percentages and analyzed using the chi-square test. Logistic regression analysis was conducted to evaluate the relationship between specific parameters and abnormal LFTs. An ROC curve analysis was conducted to evaluate the predictive power of these parameters on abnormal LFTs. Statistical significance was defined as P < 0.05. All statistical analyses were conducted using SPSS software (Version 22.0, USA).

Results

The demographic and clinical characteristics of the patients

Of the 122 patients included in the study, 108 (88.5%) were female, and the remaining 14 (11.5%) were male, as indicated in Table 1. The average age of the patients was 42.43 years, and the median duration of the disease was 12 months. The median levels of FT3, FT4, TSH, TPOAb, and TRAb were 18.39 pmol/L, 47.15 pmol/L, 0.006 uIU/mL, 1300 IU/mL, and 12.23 IU/mL, respectively. The average thyroid iodine uptake rate at 24 h was found to be 68.46%, and the median dose of RAI therapy administered to the patients was 7 mCi.

Table 1.

Basic demographic and clinical characteristics of patients in the study

Variables	Range
Male: Female	14(11.5%): 108(88.5%)
Age (years)	42.43 ± 13.60
Duration of GD (months)	12 (3, 48)
FT3 (pmol/L)	18.39 (10.86, 28.98)
FT4 (pmol/L)	47.15 (27.15, 64.66)
TSH (uIU/mL)	0.006 (0.002, 0.010)
TPOAb (IU/mL)	1300.00 (314.40, 1300.00)
TRAb (IU/mL)	12.23 (6.40, 26.96)
24-h RAIU	68.46 ± 11.51
Dose of RAI (mCi)	7.00 (5.00, 8.50)

Categorical variables were presented as frequencies and percentages. Normally distributed variables were presented as mean ± standard deviation (SD), while non-normally distributed variables were presented as median (interquartile range: P25, P75)

GD Graves’ disease, FT3 Free triiodothyronine, FT4 Free thyroxine, TSH Thyrotropin, TPOAb Thyroperoxidase antibody, TRAb Thyrotropin receptor antibody, RAIU Radioactive iodine uptake, RAI Radioactive iodine

Explore the risk factors affecting LFTs after radioactive iodine therapy

As shown in Table 2, the study demonstrated that the levels of TP, ALB, GLO, DBIL, and GGT increased after RAI therapy, while the levels of TBIL, IBIL, and AST decreased. Further gender-based analysis revealed that these trends were consistent in both male and female patients. However, due to the limited number of male participants, the statistical analysis did not reveal significant differences between genders.

Table 2.

Comparison of liver function tests before and after radioactive iodine (RAI) therapy

Variables	Before RAI	After RAI	The median change	Z	P value
TP (g/L)	67.2 (64.4, 70.4)	69.0 (66.2, 71.7)	1.8	− 3.474	0.001
ALB (g/L)	41.8 (39.7, 43.7)	42.7 (39.8, 44.6)	0.9	− 2.268	0.023
GLO (g/L)	25.3 (23.2, 27.7)	26.4 (24.1, 28.9)	1.1	− 3.007	0.003
TBIL (umol/L)	10.6 (8.8, 13.4)	8.4 (6.4, 10.1)	− 2.2	− 6.656	0.001
DBIL (umol/L)	3.2 (2.5, 3.8)	3.4 (2.9, 4.3)	0.2	− 4.703	0.001
IBIL (umol/L)	7.5 (5.8, 10.4)	4.7 (3.5, 6.0)	− 2.8	− 8.081	0.001
ALT (U/L)	20.9 (15.5, 27.2)	19.5 (14.5, 28.2)	− 1.4	− 0.515	0.607
AST (U/L)	20.3 (15.9, 24.1)	17.7 (14.6, 21.9)	− 2.6	− 4.000	0.001
ALP (U/L)	98.5 (80.9, 120.2)	100.0 (80.8, 117.3)	1.5	− 0.642	0.521
GGT (U/L)	16.8 (13.4, 23.9)	19.0 (14.0, 26.0)	2.2	− 4.376	0.001

Variables were presented as median (interquartile range: P25, P75) and analyzed with the Wilcoxon signed-rank test

TP Total protein, ALB Albumin, GLO Globulin, TBIL Total bilirubin, DBIL Direct bilirubin, IBIL Indirect bilirubin, ALT Alanine aminotransferase, AST Aspartate aminotransferase, ALP Alkaline phosphatase, GGT Gamma glutamyl transpeptidase

Upon reviewing the test results, it was found that thirty-two patients (26.2%) exhibited abnormal LFTs outside the reference range after RAI therapy. Most patients exhibited mild abnormalities in their LFTs; however, four patients (3.3%) showed significantly elevated ALT levels, exceeding 1.5 times the upper limit of the normal range. Interestingly, AST levels showed a small but statistically significant decline, suggesting transient hepatocellular adaptation rather than injury. Three patients exhibited a mild increase in albumin levels compared to pretreatment values, which may be associated with dehydration due to inadequate fluid intake. Among the thirty-two patients, eight exhibited two or more of these abnormalities. After taking liver-protective medications, all patients’ LFTs returned to normal within 3 months.

The age and administered dose of RAI differed significantly between patients with normal LFTs and those with abnormal LFTs (see Table 3). As indicated in Table 4, the binary logistic regression results revealed that younger age and higher doses of RAI were associated with abnormal LFTs. Finally, a combined ROC curve analysis indicated that the predictive ability of younger age and RAI dose for abnormal LFTs following RAI therapy was 0.701 (Fig. 2).

Table 3.

Comparison of the normal LFTs group and the abnormal LFTs group following radioactive iodine therapy

Variables	Normal LFTs group	Abnormal LFTs group	Test of significance	P value
Male: Female	9:81	5:27	0.735χ2	0.391
Age (years)	44.22 ± 13.58	37.38 ± 12.53	2.499T	0.014
Duration of GD (months)	12 (3, 48)	12 (3.75, 57)	− 0.758U	0.449
FT3 (pmol/L)	18.31 (11.43, 26.06)	19.70 (8.99, 30.80)	− 0.711U	0.477
FT4 (pmol/L)	45.52 (27.15, 63.95)	49.93 (25.56, 88.44)	− 0.704U	0.481
TSH (uIU/mL)	0.005 (0.002, 0.009)	0.008 (0.005, 0.011)	− 1.615U	0.106
TPOAb (IU/mL)	1300.00 (361.36, 1300.00)	1300.00 (239.98, 1300.00)	− 0.491U	0.623
TRAb (IU/mL)	12.23 (6.24, 27.36)	12.41 (6.54, 24.38)	− 0.041U	0.967
24-h RAIU	68.51 ± 11.76	68.36 ± 10.96	0.063T	0.950
Dose of RAI (mCi)	6.50 (5.00, 8.00)	8.00 (5.25, 11.50)	− 2.214U	0.027

Normally distributed variables were reported as mean ± standard deviation (SD) and analyzed using the independent samples t-test (T). Non-normally distributed variables were reported as median (interquartile range: P25, P75) and analyzed with the Mann–Whitney U test (U). Categorical variables were presented as frequencies and analyzed using the chi-square test (χ²)

GD Graves’ disease, FT3 Free triiodothyronine, FT4 Free thyroxine, TSH Thyrotropin, TPOAb Thyroperoxidase antibody, TRAb Thyrotropin receptor antibody, RAIU Radioactive iodine uptake, RAI Radioactive iodine

Table 4.

Logistic regression analysis of risk factors for abnormal liver function tests after radioactive iodine therapy

Variables	B	S.E.	Wald	P	OR	95% CI
						Lower	Upper
Age	− 0.035	0.017	4.240	0.039	0.966	0.935	0.998
Dose of RAI (mCi)	0.207	0.079	6.919	0.009	1.230	1.054	1.436

RAI Radioactive iodine, OR Odds ratio, CI Confidence interval

Fig. 2.

ROC curve analysis of younger age and RAI dose combined as predictors of abnormal liver function tests

To investigate the impact of changes in thyroid function on abnormal LFTs following RAI therapy, thyroid function and LFTs were measured simultaneously in 16 patients from the same cohort 48 h after RAI administration. As shown in Fig. 3, no significant changes in thyroid function were observed before and after RAI treatment (pre-FT3 vs. post-FT3, T = − 0.275, P = 0.787; pre-FT4 vs. post-FT4, T = 0.586, P = 0.566). These findings suggest that LFT changes are not solely due to fluctuating thyroid hormone levels.

Fig. 3.

Thyroid function tests before and after radioactive iodine therapy

Discussion

To date, limited research has been conducted on changes in LFTs following radioactive iodine therapy for Graves’ disease, and no studies have specifically examined alterations in liver function within the first 48 h post-treatment. Our study demonstrated that the levels of TP, ALB, GLO, DBIL, and GGT increased following RAI therapy, whereas the levels of TBIL, IBIL, and AST decreased. Upon review of the test results, 32 patients (26.2%) were found to exhibit abnormal LFTs outside the reference range after RAI therapy. Among them, four patients (3.3%) showed significantly elevated ALT levels, exceeding 1.5 times the upper limit of the normal range. Younger age and higher doses of RAI were significantly associated with post-treatment LFT abnormalities.

In general, the bidirectional interaction between the thyroid and the liver reveals a close and complex relationship, whether in states of health or disease. As the primary participant in the transport and metabolism of thyroid hormones, the liver not only synthesizes the major thyroid hormone transport proteins but also plays a crucial role in regulating the concentrations of circulating thyroid hormones. Meanwhile, thyroid hormones influence hepatocyte metabolic functions and bilirubin production by partially regulating lipid metabolism modulation processes [20].

Although radioactive iodine primarily exerts toxicity on thyroid cells that uptake iodine from the bloodstream, it can also be distributed throughout the body and accumulate in other organs. It is well known that the liver is a common organ where RAI accumulation following RAI therapy [16, 21]. Given that RAI treatment induces oxidative stress in patients, the substantial hepatic uptake of RAI results in radiation exposure to the liver, potentially leading to varying degrees of hepatotoxicity [22]. Bilirubin has been recognized as an endogenous antioxidant and a protective agent against oxidative damage in liver injury [23–25]. In our study, the significant decrease in both unconjugated bilirubin and total bilirubin levels after RAI treatment suggests that bilirubin is consumed during the defense against oxidative stress, highlighting its important role in mitigating oxidative damage and indicating a potential protective function in Graves’ disease (GD) patients undergoing RAI therapy.

Currently, research on the effects of RAI therapy on LFTs remains limited, and findings across studies are inconsistent. A study conducted by Allyson et al. investigated the impact of RAI treatment on LFTs in cats. They found that 6 weeks following RAI therapy, the levels of ALT, AST, and serum alkaline phosphatase (SAP) significantly decreased [26]. However, in that study, cats exhibited varying degrees of pre-existing liver function abnormalities prior to radioactive iodine treatment, which distinguishes them from the inclusion criteria of our study. Furthermore, early changes in liver function were not assessed, and potential interspecies differences in physiological responses between cats and humans may limit the generalizability of the findings.

In 2013, Qu et al. reported two cases in which patients exhibited normal LFTs prior to RAI therapy but subsequently developed severe LFT abnormalities [13]. This indicates that RAI therapy may potentially induce significant hepatotoxicity. In our study, we also observed that four patients had markedly elevated ALT levels. These findings are consistent with those reported by Qu et al. However, Piantanida et al. suggested that the severe LFT abnormalities were more likely associated with uncontrolled thyrotoxicosis rather than with RAI therapy per se [20]. To explore the potential relationship between LFT changes and thyroid function, we concurrently measured both parameters in a cohort of 16 patients 48 h after RAI administration. As shown in Fig. 3, no statistically significant differences in thyroid function were observed before and after treatment. These findings suggest that alterations in LFTs are not solely driven by changes in thyroid hormone levels.

The potential mechanism underlying abnormal liver function after RAI treatment may involve varying degrees of iodine-131 uptake in the liver among certain patients, as well as direct radiation-induced hepatic injury mediated by iodine-131. Among patients with thyroid cancer, the frequency of diffuse hepatic uptake has been reported to range from 12.0% to 22.0% when the diagnostic iodine-131 scan was performed 2 days after the administration of 2–10 mCi of iodine-131 [27, 28]. Some studies further demonstrated that the grade of hepatic uptake were associated with abnormal levels of ALT and/or AST [16, 29]. These findings largely supports the hypothesis that abnormal hepatic iodine uptake over a short period may lead to elevated transaminase levels.

Several studies have reported that patients who undergo high-dose RAI ablation following total thyroidectomy for papillary thyroid carcinoma may experience abnormal LFTs, and there appears to be a correlation between the iodine-131 dose and these abnormalities [29–31]. Our study also identified a similar correlation between the dosage of iodine-131 and abnormal LFTs in patients with GD. This suggests that physicians should pay more attention to changes in LFTs among GD patients treated with higher doses of iodine-131.

In our study, we observed that 48 h after receiving RAI therapy, 26.2% of the patients exhibited abnormal LFTs outside the reference range. Although severe liver toxicity following RAI treatment is relatively rare, clinicians should remain vigilant for this potential adverse effect and routinely monitor hepatic function post-treatment.

Limitations

However, the present study also has some limitations. First, it was a non-randomized, retrospective, single-center study with a limited sample size and, therefore, may suffer from participant selection bias. Second, our exploration was limited to LFTs conducted 48 h following RAI therapy, and we did not examine the long-term consequences of these liver abnormalities. Third, our study may be subject to potential unmeasured confounders, including baseline nutritional status or viral infection levels. Therefore, the clinical implications of our findings are limited. Recognizing these limitations, further research is necessary to gain a more comprehensive understanding of the relationship between RAI therapy and liver function test abnormalities.

Conclusions

Our findings suggest that RAI therapy is associated with new, transient abnormalities in liver biochemical parameters in over a quarter of patients, with younger age and higher RAI dosage identified as the primary risk factors.

Abbreviations

RAI

Radioactive iodine

GD

Graves’ disease

TP

Total protein

ALB

Albumin

GLO

Globulin

TBIL

Total bilirubin

DBIL

Direct bilirubin

IBIL

Indirect bilirubin

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

ALP

Alkaline phosphatase

GGT

Gamma glutamyl transpeptidase

ATDs

Anti-thyroid drugs

PTU

Propylthiouracil

MMI

Methimazole

FT3

Free triiodothyronine

FT4

Free thyroxine

TSH

Thyrotropin

RAIU

Radioactive iodine uptake

TRAb

Thyrotropin receptor antibody

TPOAb

Thyroperoxidase antibody

ANCA

Anti-neutrophil cytoplasmic antibody

SD

Standard deviation

ROC curve

Receiver operator characteristic curve

SAP

Serum alkaline phosphatase

Author contributions

BL and RH conceived and designed the study, BL collected and entered the data. RH performed the statistical analysis and wrote the paper. BL reviewed the paper. All authors read and approved the manuscript.

Funding

This work was funded by the Natural Science Foundation of Shandong Province, China (Project No. ZR2014HP026), the Shandong Province Traditional Chinese Medicine Science and Technology Development Plan Project (Project No. 2017 − 466), and the Shandong Province Medical and Health Science and Technology Development Plan Project ((Project No. 2017WS498).

Data availability

The data used in this study is available from the corresponding author upon request.

Declarations

Ethics approval and consent to participate

This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki for research involving human participants. The study received approval from the ethics committee of Linyi People’s Hospital, affiliated with Shandong Second Medical University (Approval number: 30067). Given that this research constitutes a retrospective clinical study, our hospital’s ethics committee waived the requirement for obtaining written informed consent from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.