Clinical insights into levothyroxine overdose: A systematic review

Abstract

BACKGROUND

Levothyroxine (LTX) is one of the most commonly used medications due to the high prevalence of hypothyroidism in various age groups. Overdose (OD) with LTX, intentional or unintentional, is rare but can have clinically significant and even life-threatening consequences. Data on clinical outcomes of patients with LTX OD are limited, and guidelines on its management are suboptimal.

AIM

To compile all available data on the clinical characteristics, management, and outcomes of patients with LTX OD.

METHODS

A systematic literature search was conducted to identify English-language articles through PubMed, Scopus, and EMBASE that reported primary patient data on LTX OD in all age groups. All analyses were performed using STATA-18.

RESULTS

Forty-nine studies, comprising 95 individual cases and six larger retrospective studies (n = 11513), were analyzed. The median age of patients in case reports was 20 years (3.5-42), with a female preponderance (66.1%). The median ingested dose of LTX was 4250 μg (1250-10000), with a median time to presentation of 4.5 hours (1.5–24). Tachycardia (38.9%), confusion (23.2%), and fever (18.9%) were the most frequent symptoms. Severe complications included atrial fibrillation (5.3%), and one death was reported. Patients with intentional LTX OD were significantly older (median 35.5 vs 3.5 years, P < 0.001) and had higher diastolic blood pressure (P = 0.003), while non-intentional OD cases had higher heart rates (P = 0.02). Among the 11513 patients from larger studies, more than 90% experienced minimal or no symptoms, particularly in pediatric cohorts. Rarely severe outcomes, such as coma and cardiac failure, were observed in adults with high-dose ingestions, requiring interventions such as beta-blockers, corticosteroids, and plasmapheresis.

CONCLUSION

This study provides the first comprehensive dataset on LTX OD. Patients with non-suicidal/accidental LTX OD mainly belong to the pediatric age group, while those with suicidal intent belong to the older age group. Despite the risk of toxicity with ingestion of high doses of LTX, mortality is extremely rare.

Key Words: Levothyroxine; Overdose; Toxicity; Thyroid; Suicide; Thyroxine

Core Tip: This systematic review presents the most comprehensive data synthesis on levothyroxine (LTX) overdose (OD) across all age groups. It highlights key clinical patterns that distinguish unintentional pediatric OD from intentional adult OD, with the latter exhibiting more prominent symptom severity. Despite wide dose variability, mortality was rare. Most cases were managed conservatively. Extracorporeal modalities were employed in cases that were severe and refractory. This systematic review highlights the need for treatment protocols and prevention strategies for LTX toxicity, providing valuable insights for clinicians managing thyroid hormone toxicity.

INTRODUCTION

Levothyroxine (LTX), a synthetic form of thyroxine (T4), is the cornerstone of treatment for hypothyroidism and is among the most frequently prescribed endocrine medications worldwide[1]. It is available in different formulations, including oral tablets, liquid preparations, injections, suppositories, and transdermal patches[2]. LTX exerts its effect through peripheral conversion to the more potent liothyronine (T3), mirroring the physiological effects of endogenous thyroid hormone on the human body. Although generally considered a safe replacement hormone to prescribe, it carries the potential to exert toxic effects when taken in higher-than-required doses, with symptoms similar to overt hyperthyroidism. Although LTX toxicity is rare, it has been reported in the context of accidental, intentional, and iatrogenic overdose (OD). An acute ingestion of 5 mg or more of levothyroxine across all age groups is generally considered potentially toxic[3]. The spectrum of clinical manifestations after LTX OD is broad. Patients can present asymptomatic or with adrenergic symptoms such as fever, tachycardia, tremors, and heat intolerance[3]. In extreme situations, it has been reported to cause serious complications, including neurological compromise (such as coma and seizures) and even death[3,4].

Despite LTX’s narrow therapeutic index (NTI) and its potential for serious clinical outcomes such as atrial fibrillation, seizures, coma, and death, the existing literature is limited and fragmented. Consequently, there are many uncertainties concerning the clinical burden, course, and management of patients with LTX toxicity, and it remains a therapeutic challenge for treating physicians[5].

This systematic review compiles and synthesizes all available clinical data on LTX toxicity, focusing on its clinical course, management, and outcomes in all age groups. This study aims to quantify the clinical burden of LTX toxicity and optimize its management guidelines, ultimately enhancing clinical decision-making and improving patient safety.

MATERIALS AND METHODS

Literature search

We performed a literature search using electronic databases, including PubMed, Scopus, and EMBASE, to identify eligible articles published in English from any date to July 11, 2023. The study design and methodology adhered to PRISMA guidelines[6]. The search strategy was formulated using the following terms: "Thyroxine" OR "LTX" OR "T4" OR "levothyroxine" OR "thyroid replacement" OR "thyrotropin" OR "liothyronine" OR "hyperthyroid" AND "OD" OR "toxic" OR "toxicity" OR "suicide" OR "suicidal" OR "intoxication".

Study selection

Two study team members (Khan HA and Younas HW) independently screened the titles and abstracts of the articles using Rayyan AI Software, followed by a full-text screening of the articles to decide on inclusion/exclusion. Two reviewers reviewed each article, and in case of disagreement, a third reviewer (Ata F) independently reviewed the article to make a final decision regarding the inclusion or exclusion.

Inclusion criterion

The study included all the case series, case reports, prospective studies, retrospective studies, randomized control trials, abstracts, and letters to the editor discussing primary patient data regarding LTX OD. The patient population included individuals of all age groups and genders, with or without preexisting thyroid conditions. The OD criterion included both intentional or suicidal and unintentional ingestions, single or staggered overdosage. All patients fulfilling the inclusion criteria were analyzed, regardless of presenting symptoms.

Exclusion criterion

Excluded studies were those without primary patient data, such as review articles and primary studies with multiple drug ODs, where the individual effect of LTX toxicity could not be assessed.

Quality assessment

Two members (Khan HA and Younas HW) assessed the quality of the included studies. The Joanna Briggs Institute case report and series appraisal checklist were used to assess the quality of case reports/case series, whereas the Methodological Index for Non-randomized Studies scoring system was used to assess the quality of observational studies[7-9]. A third reviewer (Ata F) independently reviewed and resolved any quality assessment conflicts.

Data collection

Khan HA, Younas HW, Javed H, Umar R, and Ahmed B collected data in a pre-specified data collection sheet. In cases where individualized patient data were not available, the corresponding authors were contacted by Khan HA and Ata F. In the data collection sheet, the patient's demographics (including patient age and gender), comorbid conditions, presenting symptoms, pattern of overdosage, and hemodynamic data were extracted. Laboratory data included a thyroid hormone profile [thyroid-stimulating hormone (TSH), free thyroxine (fT4), total T3, and T4], a liver profile [aspartate aminotransferase (AST), alanine aminotransferase, alkaline phosphatase], and a complete blood count. Treatment strategies considered were the use of activated charcoal, gastric lavage, cholestyramine, beta-blockers, anti-thyroid medications (carbimazole, methimazole, and propylthiouracil), intubation, thyroidectomy, and lithium. The outcome considered was the time it took for the thyroid profile to normalize, along with consultations from endocrinology, psychiatry, toxicology, and mortality.

Statistical analysis

Descriptive statistics were used to summarize patient demographics, clinical features, and outcomes. Continuous variables were reported as medians with interquartile ranges (IQR), while categorical variables were expressed as frequencies and percentages. Comparative analyses between suicidal and non-suicidal OD groups were performed using the Mann-Whitney U test for continuous variables and the χ² or Fisher’s exact test for categorical variables. A P value of < 0.05 was considered statistically significant. All statistical analyses were conducted using STATA version 18 (StataCorp, College Station, TX, United States).

RESULTS

Baseline demographics and clinical characteristics

This systematic review included a total of 49 studies, including case reports, series, and 6 larger retrospective studies[4,5,10-56] (Figure 1). A total of 95 patients with levothyroxine toxicity were identified from published case reports and series. The patients ranged in age from 0.75 to 92 years (mean 26.5 years, median 20 years, IQR: 3.5-42 years), with a majority being female (66.13%). Comorbid conditions were present in a subset of patients, with psychiatric disorders being the most common (9.47%), followed by diabetes mellitus (4.21%), chronic kidney disease (3.16%), heart failure (2.11%), and chronic obstructive pulmonary disease/asthma (1.05%) (Table 1). The highest recorded heart rate among the patients was 110 beats per minute (IQR: 89-128), with systolic and diastolic blood pressures reaching medians of 115 mmHg (IQR: 100-130) and 70 mmHg (IQR: 61.5-80), respectively. Biochemical analysis showed a median lowest potassium level of 3.6 mmol/L (IQR: 2.4-4.3) and a median highest creatinine level of 0.039 mmol/L (IQR: 0.026-0.057). The cumulative amount of levothyroxine ingested varied widely, with a median of 4250 μg (IQR: 1250-10000), and the median time from OD to presentation was 4.5 hours (IQR: 1.5-24).

Figure 1 Prisma flowchart of the inclusion and exclusion process of studies.

Table 1 Baseline demographics and clinical characteristics of 95 patients with levothyroxine toxicity from published case reports, series, and more extensive studies with individualizable data, n (%)/median (25^th-75^th percentiles).

Characteristic	n	Results
Age (years)	87	20 (3.5-42)
Gender	62
Female		41 (66.13)
Male		21 (33.87)
Comorbidities	95
Psychiatric disorder		9 (9.47)
Diabetes mellitus		4 (4.21)
Chronic kidney disease		3 (3.16)
Heart failure		2 (2.11)
COPD/asthma		1 (1.05)
Highest heart rate (beats/minute)	47	110 (89-128)
Highest systolic blood pressure (mm Hg)	41	115 (100-130)
Highest diastolic blood pressure (mm Hg)	40	70 (61.5-80)
Lowest potassium level (mmol/L)	7	3.6 (2.4-4.3)
Highest temperature (°C)	29	36.7 (36.4-37)
Highest creatinine (mmol/L)	16	0.039 (0.026-0.057)
Cumulative amount of levothyroxine (μg)	54	4250 (1250-10000)
Time from overdose to presentation (hours)	48	4.5 (1.5-24)

COPD: Chronic obstructive pulmonary disease.

Symptoms and complications

The clinical presentations varied widely among the patients (Table 2). The most common symptom was tachycardia, reported in 37 patients (38.95%), followed by confusion in 22 patients (23.16%), and fever in 18 patients (18.95%). Tremors were observed in 13 patients (13.68%), and palpitations in 12 patients (12.63%). Other less common symptoms included diarrhea (10.53%), vomiting (8.42%), heat intolerance (7.37%), sweating (6.32%), and shortness of breath (6.32%). Severe complications such as atrial fibrillation were noted in 5 patients (5.26%), while 2 patients each (2.11%) experienced bradycardia and heart failure. Ophthalmopathy was rare, occurring in only one patient (1.05%), and there was a single case of in-hospital mortality (1.05%).

Table 2 Symptoms and complications in 95 patients with levothyroxine toxicity from published case reports and series¹.

Variable	Frequency (%)
Tachycardia	37 (38.95)
Confusion	22 (23.16)
Fever	18 (18.95)
Tremors	13 (13.68)
Palpitations	12 (12.63)
Diarrhea	10 (10.53)
Vomiting	8 (8.42)
Heat intolerance	7 (7.37)
Sweating	6 (6.32)
Shortness of breath	6 (6.32)
Atrial fibrillation	5 (5.26)
Dizziness	4 (18.18)
Weight loss	3 (3.16)
Periodic paralysis	3 (3.16)
Bradycardia	2 (2.11)
Heart failure	2 (2.11)
Ophthalmopathy	1 (1.05)
In-hospital mortality	1 (1.05)

¹Some patients experienced multiple symptoms or complications; therefore, the total percentage exceeds 100%.

Comparative analysis of non-suicidal vs intentional suicidal levothyroxine ingestions

Table 3 shows the comparison of outcomes among suicidal intent and non-intentional OD of levothyroxine. Patients who ingested levothyroxine intentionally for suicide were older, with a median age of 35.5 years (IQR: 19-49) compared to 3.5 years (IQR: 1.5-18) in those who ingested the drug for non-suicidal reasons (P < 0.001). The highest heart rate was significantly lower in the intentional suicide group, with a median of 100 beats per minute (IQR: 85-120) compared to 119 beats per minute (IQR: 100-140) in the non-suicidal group (P = 0.02). Diastolic blood pressure was also higher in the suicide group, with a mean of 78.35 mmHg (SD 12.05) compared to 66.39 mmHg (SD 11.74) in the non-suicidal group (P = 0.003). AST/serum glutamic-oxaloacetic transaminase levels were slightly higher in the non-suicidal group (median: 35.5 U/L, IQR: 31-40) compared to the suicide group (median: 22 U/L, IQR: 17.5-47.5), although this difference was not statistically significant (P = 0.05). There were no significant differences in the cumulative dose of levothyroxine ingested or in mortality between the groups, with one death occurring in the non-suicidal group.

Table 3 Comparative analysis of patient characteristics and clinical outcomes based on levothyroxine use for non-suicidal vs intentional suicidal purposes, n (%)/median (25^th-75^th percentiles)/mean ± SD¹.

Characteristic/outcome	Not for suicide (n = 47)	Intentional for suicide (n = 46)	P value
Age (years)	3.5 (1.5-18)	35.5 (19-49)	< 0.001
Highest heart rate (beats/minute)	119 (100-140)	100 (85-120)	0.02
Highest systolic BP (mm Hg)	110 (95-123)	120 (110-132)	0.06
Highest diastolic BP (mm Hg)	66.39 ± 11.74	78.35 ± 12.05	0.003
Highest AST/SGOT (U/L)	35.5 (31-40)	22 (17.5-47.5)	0.05
Highest ALT/SGPT (U/L)	18 (13-24)	13 (11-19)	0.25
Cumulative levothyroxine dose (μg)	4054 (1000-14000)	4250 (1485-9700)	0.802
Treatment
Activated charcoal	15 (31.91)	12 (26.09)	0.53
Gastric lavage	4 (8.51)	1 (2.17)	0.36
Cholestyramine	1 (2.13)	3 (6.52)	0.36
Steroids	11 (23.4)	6 (13.04)	0.19
Beta blockers	20 (42.55)	11 (23.91)	0.057
Methimazole	2 (4.26)	1 (2.17)	1
Propylthiouracil	3 (6.38)	3 (6.52)	1
Plasmapheresis	7 (14.89)	0
Intubation	2 (4.26)	0
In hospital mortality	1 (2.13)	0

¹Some patients received more than one treatment, resulting in a total treatment count exceeding the total number of patients in the respective groups.

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; SGOT: Serum glutamic-oxaloacetic transaminase; SGPT: Serum glutamic-pyruvic transaminase; BP: Blood pressure.

Summary of clinical characteristics and outcomes in larger-scale studies

The analysis of data from larger-scale studies related to the toxicity of levothyroxine is summarized in Table 4. Of the 11513 patients across six larger included studies, most levothyroxine ODs resulted in minimal or no clinical effects. In pediatric groups, most cases were without any symptoms (94.9% in Litovitz et al[35], with 78 patients; 84.5% in Nygaard et al[41], with 181 patients; and > 95% in Roth et al[39], with 11189 patients), irrespective of the dose range. Symptoms, when present, included vomiting, tachycardia, and restlessness, with fewer than 5% requiring medical intervention. Binimelis et al[4] reported six adult patients with high-dose intentional ingestions (70–1200 mg) who developed significant complications, including coma, cardiac failure, rhythm disturbances, and one mortality. Treatments included beta blockers, corticosteroids, antithyroid medications, and plasmapheresis. On the other hand, data from Kandasam et al[26] suggested benign outcomes at doses up to 500 μg, with no active treatment.

Table 4 Summary of clinical characteristics, treatment strategies, and outcomes in larger-scale studies of levothyroxine toxicity.

Ref.	n	Age group	Key presentations	Reason for ingestion	LTX dose ingested	Treatment and complications
Litovitz et al[35]	78	0-12 years (0-5: 75; 5-12: 3)	74 Asymptomatic (94.9%), 3 fever, 1 vomiting, 1 diarrhea	Not specified	0.5 mg or less: 35 patients; 0.6-3.0 mg: 27 patients; > 3.0 mg: 6 patients	75 (96.1%) managed at home; 26 (33.3%) received no treatment; 38 (48.7%) received ipecac; 3 patients were hospitalized, 1 required propranolol treatment (2.5 mg every 6 hours)
Binimelis et al[4]	6	46-74 years	6 fever, tremors, heat intolerance, tachycardia	Unintentional	70-1200 mg ingested over 2-12 days	All patients received propranolol (120-140 mg/day) and hydrocortisone (400 mg/day). Patients 4-6 received propylthiouracil (400-1200 mg/day) and plasmapheresis. All patients developed neurological complications (e.g., coma, hemiparesis, aphasia). Patients 1-2 had left ventricular failure; others had rhythm disturbances. 1 patient died
Seidel et al[40]	54	< 28 days	42 Asymptomatic (77.8%). 1 tachypnea, 1 weight loss, 3 diarrhea, 6 restlessness	Not specified	< 30 µg/kg: 36 patients (87% asymptomatic); 30-50 µg/kg: 14 patients (79% asymptomatic); 50-60 µg/kg: 4 patients (75% asymptomatic)	Gastric lavage, Beta-blockers
Kandasamy et al[26]	5	Not specified	3 asymptomatic (60%). 2 hypertension with transient ECG changes	Unintentional	Maximum dose: 500 μg	No active treatment
Nygaard et al[41]	181	1-14 years	153 asymptomatic (84.5%)	Suicide: 44 (24.3%); unintentional: 134 (74.0%)	300-18000 μg	Not available
Roth et al[39]	11189	0-5 years: 6668 (59.6%); > 5 years: 4521 (40.4%)	112 vomiting (1.0%), 78 restlessness (0.7%), 123 tachycardia (1.1%)	10742 (96.0%) unintentional	Not specified	Activated charcoal in 392 patients (3.5%); gastric decontamination: Ipecac-induced emesis followed by activated charcoal administration in 134 patients (1.2%)

LTX: Levothyroxine; ECG: Electrocardiogram.

DISCUSSION

This systematic review offers valuable insights into the clinical manifestations and management of LTX OD across diverse patient populations. Around 11.7% of the United States population suffers from hypothyroidism, with more than 78% of those diagnosed being managed by thyroxine (T4), making levothyroxine one of the most prescribed medications in endocrinology[57-59]. Patterns of OD vary by age. In children, ingestion is usually accidental, and most remain symptom-free, whereas in adults, OD is more often intentional and associated with underlying psychiatric conditions or suicide attempts[5,35]. Remarkably, nearly half of the 95 individual cases analyzed in this systematic review involved intentional intake. Findings from this study aim to contribute to a better understanding of its clinical implications and facilitate the formulation of evidence-based treatment protocols.

Data from this review suggest that acute LTX OD is more common than chronic ingestion. Doses of up to 4mg/day were typically well-tolerated and produced minimal or no symptoms, which may delay recognition and medical evaluation[60]. The median time from OD to presentation was 4.5 hours (IQR: 1.5–24), and the most common reported clinical features were tachycardia (38.95%), confusion (23.16%), fever (18.95%), and tremors (13.68%). Other symptoms included palpitations (12.63%), diarrhoea (10.53%), and vomiting (8.42%). The In-hospital mortality rate was 1.05%, reflecting the generally favourable prognosis with timely management. The only death reported in this systematic review was in a pediatric patient due to septic shock. While the patient had received a supratherapeutic levothyroxine dose, the terminal event appeared multifactorial.

Chronic OD, on the other hand, results from prolonged use at supratherapeutic doses due to over-prescription, non-compliance, or misuse for weight loss[61]. This leads to an insidious symptom onset, such as insomnia, anxiety, atrial fibrillation, osteoporosis, and menstrual irregularities[62]. Chronic cases typically show more pronounced thyrotoxicosis and higher morbidity and mortality[63].

Several demographic factors influence the risk and severity of LTX OD. Our data showed a median patient age of 20 years (IQR: 3.5–42), indicating a broad age range affected by LTX toxicity. The incidence of hypothyroidism increases with age[64]. In elderly patients, factors such as reduced drug absorption, polypharmacy, and comorbidities can offset the effects of decreased thyroid metabolism, resulting in levothyroxine dosing comparable to that of the younger population[65]. Moreover, these patients are more vulnerable to adverse effects such as atrial fibrillation and osteoporotic fractures[66-68]. Therefore, careful dosing and gradual titration are essential to avoid iatrogenic thyrotoxicosis. According to the analysis of NHANES data, thyroid disease is more prevalent in females[69]. This trend was also reflected in the current systematic review, with 66.13% of the cases involving females, compared to 33.87% involving males. Intentional OD was more frequently reported among women, possibly linked to a higher prevalence of psychiatric conditions such as depression and anxiety[70,71]. It is worth noting that although gender-based differences in incidence exist, severity of symptoms, and outcomes did not vary significantly between males and females.

Pediatric populations composed a substantial proportion of the cases in our review, with LTX OD typically resulting from accidental ingestion and exhibiting a largely asymptomatic course[72]. For example, Litovitz et al[35] reported 94.9% asymptomatic cases among 78 children, Nygaard et al[41] observed 84.5% asymptomatic cases among 181 patients, and Roth et al[39] documented over 95% asymptomatic cases in a cohort of 11189 children[35,39,56]. In contrast, adults are more prone to developing symptomatic toxicity, likely due to the presence of comorbidities such as cardiac, hepatic, or renal disorders[4,70]. Additionally, adults are also likely to use other medications with LTX, complicating clinical presentation with drug-drug interactions.

Although most LTX ODs follow a mild clinical course, rare cases involving massive ingestion may lead to life-threatening complications. Neuropsychiatric effects such as coma and delirium are presumably due to excess catecholamines and metabolic imbalance. Cardiovascular manifestations are frequent. For instance, Binimelis et al[4] reported cardiac disturbances, including refractory tachycardia, atrial fibrillation, and ventricular arrhythmias in all six patients studied. Five developed coma within 7–10 days post-ingestion, with one fatality due to acute renal failure and septic shock[4]. Similarly, Hack et al[73] reported a case involving severe agitation, which required intubation, and was accompanied by 20 kg weight loss during hospitalization, with treatment-resistant thyrotoxicosis for 12 days.

Levothyroxine is an NTI drug due to the high sensitivity of the hypothalamic-pituitary axis to minor fluctuations in T4, which can lead to significant variations in TSH secretion[74]. To keep euthyroid status intact, it is essential to carefully adjust the dosage to keep TSH in the normal range[65]. In patients with LTX OD, serum T4 concentrations do not always correlate with clinical presentation. Nyström et al[42] suggested decisions should be based on clinical presentation rather than serum hormone assays, a view supported by later studies from Tunget et al[75] and Nygaard et al[41]. Similarly, Litovitz et al[35] reported three patients with peak T4 levels above 26 μg/dL, of whom two were asymptomatic.

Management of LTX OD is generally supportive in most cases. Typical interventions include activated charcoal, cholestyramine, beta-blockers, and corticosteroids[76]. This review found that the most commonly used treatment options in both non-suicidal and suicidal cases were beta blockers (42.55% vs 23.91%) and activated charcoal (31.91% vs 26.09%). In severe or refractory cases, extracorporeal treatment options, like plasmapheresis and hemoperfusion, have been explored. A study by Binimelis et al[4] found that plasmapheresis increased T4 clearance by 30 times, while hemoperfusion achieved 5 times increased clearance when compared to medical therapy. However, plasmapheresis had little effect on T3 levels, whereas hemoperfusion reduced T3 by 6-fold[4]. This difference reflects the pharmacologic properties of LTX, which is extensively protein-bound. Plasmapheresis removes both free and bound hormones via plasma extraction, whereas hemoperfusion adsorbs only the free hormone. A study by Kreisner et al[31] found that hemoperfusion reduces T3, T4, and free T4 levels by approximately 50% per session due to saturation of the charcoal column; the lowest levels of hormones are reached within 1-2 hours. They suggested using continuous hemoperfusion with filter changes to improve outcomes further[31].

Preventive measures are crucial for reducing OD risk, especially in children. Use of childproof packaging of levothyroxine is strongly advised to reduce accidental ingestion and subsequent hospitalizations[26]. Hartman et al[22] proposed that children who have received more than 0.1 mg/kg show early symptoms or elevated fT4 levels (> 100 pmol/L), need close monitoring, and should be observed for 48-72 hours with follow-up lasting up to two weeks[22]. In addition to monitoring, patient education is vital to prevent levothyroxine OD. Counselling should emphasize adherence to prescribed doses, avoiding double dosing after a missed pill, and recognizing early OD symptoms like palpitations, anxiety, and sweating to ensure prompt medical care.

The primary strength of this systematic review lies in its novelty, as it compiles all available data on LTX OD for the first time to the best of our knowledge, providing essential insights into its clinical course, management, and outcomes. The review was able to gather data from a wide age range as LTX is a drug common to paediatric, adult, and geriatric populations. This review encompassed various study designs, including case reports, series, and retrospective studies, selected through a comprehensive database search, allowing for a comprehensive assessment of clinical features and outcomes. Subgroup analysis between suicide-related and non-suicide-related cases provided meaningful details of patient characteristics and treatment approaches. However, certain limitations should be acknowledged in reviewing the results from this study. The predominance of individualizable data from case reports and series may introduce potential publication and reporting biases, which can limit comparability and the strength of conclusions. Additionally, the retrospective nature of the data in all included studies, as well as the treatment variations, limited our ability to conduct a meta-analysis. Lastly, most data pertain to acute OD, with limited data and understanding about chronic LTX OD. Nevertheless, it is essential to recognize that conducting a prospective observational study or a randomized trial on LTX OD is impractical. Hence, this systematic review presents the most comprehensive evidence on the clinical course of LTX OD.

Future research should prioritize the improved clinical characterization of LTX OD through long-term retrospective analyses and registry-based studies to enhance understanding of its presentation, monitoring, and long-term outcomes. More data is required explicitly on chronic LTX OD. Reliable clinical biomarkers, other than serum T4, can be explored, which may correlate more closely with symptom severity and inform therapeutic decisions. Further research should be conducted on the selection of patients for extracorporeal techniques, such as plasmapheresis and hemoperfusion. Additionally, studies should investigate the effectiveness of preventive strategies, such as childproof packaging and patient education.

CONCLUSION

LTX OD is often clinically benign, particularly in the pediatric age group, and when taken unintentionally. However, it can result in significant morbidity in intentional high-dose ingestions, especially among adults with comorbid conditions. Despite a broad range of clinical presentations, mortality remains rare. Management of LTX OD is mainly supportive, with beta-blockers and activated charcoal as the most commonly reported therapies. More intensive treatments, such as extracorporeal therapies, are reserved for refractory or severe toxicity. This systematic review provides the most comprehensive synthesis to date, stressing the need for standardized treatment protocols and preventive strategies.