Introduction

Graves’ disease (GD) is a prominent autoimmune thyroid disorder (AITD), distinguished by the disruption of immune tolerance towards thyroid antigens [1]. In GD, immune tolerance is compromised, leading to the infiltration of T lymphocytes into the thyroid and the activation of B lymphocytes. Additionally, there is elevated production and release of autoantibodies targeting the thyroid-stimulating hormone receptor (TSHR), which is a crucial immunological indicator for GD diagnosis [2]. Consequently, the interaction between the TSHR and its corresponding autoantibody thyrotropin receptor antibodies (TRAb) triggers an immune response, leading to the manifestation of goiter, hyperthyroidism and ophthalmopathy [1]. The typical biochemical profile observed in children with GD includes reduced levels of thyroid-stimulating hormone (TSH) and elevated concentrations of free thyroxine (FT4) and free triiodothyronine (FT3). While the exact cause of GD remains elusive, available evidence suggests a significant genetic influence coupled with occasional environmental factors that might trigger the condition in individuals with a predisposition to immune-related vulnerabilities [2, 3]. Although GD is an uncommon condition among children, constituting only 1% to 5% of all diagnosed cases across various age groups, the global occurrence of pediatric GD seems to be increasing, with reported incidences ranging from 1.5 to 6.5 per 100,000 individuals worldwide [2]. This condition can manifest at any point during childhood, with a female predominance, although its prevalence tends to rise with advancing age [3].

Autoimmune hepatitis (AIH) is a chronic, immunological liver disease characterized by the immune system’s targeting of the liver, resulting in the destruction of hepatocytes, leading to inflammation and fibrosis [4]. The hepatocyte destruction occurs due to an imbalance between proinflammatory cells and immunosuppressive cells, particularly a disparity between regulatory T cells and T helper cells [5]. A loss of tolerance to the patient’s own liver antigens is regarded as the main underlying pathogenetic mechanism, which is likely triggered by environmental agents such as pathogens and xenobiotics in genetically susceptible individuals [6]. Diagnosing AIH poses challenges due to the heterogeneity of its presentation, the lack of typical laboratory biomarkers, and the absence of pathognomonic symptoms of the disease. During clinical presentation, individuals may exhibit various scenarios, ranging from being asymptomatic to symptomatic, experiencing acute liver failure, or presenting with decompensated cirrhosis [4]. Histological examination remains the fundamental element in making a diagnosis, and to date, a biopsy is indispensable for this purpose [7]. The identification of AIH is based on elevated levels of serum transaminases and immunoglobulin G (IgG), the existence of autoantibodies, and the observation of characteristic changes in liver histology. Other causes of acute/chronic hepatitis must be excluded [8]. Recent analyses conducted in Europe have uncovered an elevated prevalence of AIH, with reported incidence rates ranging from 1.1 to 2.56 cases and a prevalence of 17.3 to 18.3 per 100,000 individuals (0.8 to 1.9 cases and 11.6 to 17 per 100,000 individuals in the pediatric group). Contemporary research indicates a potential rise in the incidence of the disease. AIH exhibits a predilection for females, with a male-to-female ratio ranging from 1:4 to 1:6.

In a noteworthy proportion of AIH cases, approximately 20%, comorbid autoimmune conditions such as thyroiditis, vitiligo, type 1 diabetes, and occasionally GD have been documented [9]. GD concomitant with AIH poses a complex clinical challenge, comprising three distinct manifestations: GD-associated AIH, GD concurrent with classical AIH, and GD complicated by autoimmune-like drug-induced liver injury (DILI), each characterized by unique clinical attributes. The co-occurrence of liver dysfunction with GD underscores the necessity of considering AIH as a potential diagnosis, even in pediatric patients.

Case report

We present a 13-year-old boy admitted to the Department of Pediatric Endocrinology with suspected hyperthyroidism. Written informed consent for publication of this case was obtained from the patient’s parents. According to local regulations, ethical approval was not required for this type of study (letter No. BNW/NWN/0052/KB/317/25). The boy had a history of ocular exophthalmos, tachycardia, decreased exercise tolerance, motor restlessness, and loose stools for the last four months. No weight loss or sleep disorders were observed. Hormonal tests performed on an outpatient basis, a couple of days before hospital admission, showed significantly reduced TSH values (< 0.008 µIU/ml; normal range: 0.27–4.2) and high FT3 (18.93 pg/ml; normal range: 2.89–4.33) and FT4 (2.12 ng/ml; normal range: 0.89–1.37) concentrations. Endocrine disorders were concomitantly accompanied by mildly elevated transaminases: aspartate aminotransferase (AST) 67 U/l (normal range: 0–40) and alanine aminotransferase (ALT) 102 U/l (normal range: 0–41).

On admission, the patient was in good general condition. Physical examination revealed several symptoms suggestive of hyperthyroidism (mild eye exophthalmos, upper limb tremor, tachycardia approximately 100 beats per min), as well as other abnormalities, including an asthenic body type, adenoid facial appearance, malocclusion, dental caries, and distended palatine tonsils. Upon palpation of the neck, an enlarged thyroid gland was detected. Pubertal stage was assessed according to the Tanner scale: gonadarche 2, pubarche 1, axillarche 1. There was a family history of Hashimoto’s disease in the child’s mother, who also remains under the care of a cardiologist due to tachycardia. Laboratory tests confirmed thyrotoxicosis (TSH < 0.005 µIU/ml, normal range: 0.27–4.2; FT4 3.87 ng/dl, normal range: 0.93–1.7; FT3 7.99 pmol/l, normal range: 4.44–6.65). Thyroid peroxidase antibodies (TPOAb) and TRAb titers were significantly elevated (TPOAb > 600 IU/ml, normal range: 0–34; TRAb 35.64 IU/l, normal range: 0.3–1.58). Additionally, a normal diurnal cortisol profile was observed. Elevated transaminase levels, found during outpatient tests, were also confirmed (Table I). The ultrasound examination revealed a hypoechoic, slightly hypertrophied and hypervascularized thyroid gland. The right thyroid lobe measured 1.7 × 1.8 × 5.2 cm (volume of 8.2 ml) and the left lobe 1.6 × 1.7 × 4.3 cm (5.8 ml). Abdominal ultrasound showed no abnormalities: echotexture of the liver was normal, and the right lobe of the liver measured 11.4 cm in the craniocaudal dimension. The consulting cardiologist did not identify any heart abnormalities other than tachycardia.

In consideration of the overall clinical picture, the patient was diagnosed with thyrotoxicosis in the course of GD. Treatment with thyreostatics and β-blockers was initiated (thiamazole at a dose of 0.8 mg/kg of body weight, propranolol at a dose of 0.5 mg/kg of body weight), leading to clinical improvement and normalization of thyroid hormone concentrations. After 8 days, the patient was discharged home in good general condition with the recommendation of treatment with thiamazole at a dose of 0.5 mg/kg of body weight daily and propranolol 0.5 mg/kg of body weight. A hepatoprotective supplement (essential phospholipids) was included. Due to mild ocular exophthalmos, a follow-up at the Ophthalmology Clinic was also recommended.

After three weeks, the boy presented for a scheduled follow-up at the Pediatric Endocrinology Outpatient Clinic. Physical examination revealed a yellow discoloration of the skin and cornea. The tests performed during the visit showed increasing values of transaminases (AST 435.7 U/l, ALT 415.8 U/l) and inhibited thyroid hormone production (FT4 0.552 ng/dl). Two weeks before the visit, the patient had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The following day, he was readmitted to the Department of Pediatric Endocrinology for an extended diagnosis due to increasing liver parameters. On admission, he was in good general condition and reported no complaints. Laboratory tests showed elevated transaminases (ALT 435 U/l, AST 349 U/l), slightly elevated gammaglutamyl transpeptidase (GGTP 120 U/l; normal range: 10–78), and normal total bilirubin concentration. Total protein and IgG were also elevated (25.8 g/l; normal range: 7.59–15.4). Wilson disease and α1-antitrypsin deficiency were excluded on the basis of normal levels of ceruloplasmin and α1-antitrypsin SARS-CoV-2 IgG antibodies were reactive (2166.12 binding antibody units [BAU]/ml; reference threshold > 7.1 BAU/ml), while immunoglobulin M (IgM) was non-reactive. IgG antibodies to Cytomegalovirus and herpesviruses were also positive, with negative IgM values for both. According to negative serological test results, Epstein-Barr virus infection was excluded. Antibodies to hepatitis C virus and hepatitis B surface antigen were negative. Based on the low titer of anti-tissue transglutaminase antibodies in the immunoglobulin A class, celiac disease was ruled out. The abdominal ultrasound examination revealed a normal dimension and homogeneous echotexture of the liver; however, the spleen had a homogeneous appearance and a borderline size (12 cm; normal range ≤ 12 cm). Considering the overall condition of the disease (increasing liver enzymes and low FT4), the decision was made to reduce the previous dose of thiamazole to 0.27 mg/kg of body weight and recommend gradual discontinuation of propranolol. Due to elevated GGTP activity and serum levels of transaminases, ursodeoxycholic acid (dose: 750 mg/day) was added to the therapy. In the follow-up tests, 15 days after implementing the treatment modifications, there was only a slight decrease in transaminase levels, normalization of GGTP, and further reduction in FT4 values. Consequently, the thyrostatic dose was further reduced to 0.13 mg/kg of body weight (Table I). The patient was discharged home with a recommendation for further follow-up at the Endocrinology Clinic within 2 weeks, and a referral for gastroenterological evaluation was issued.

After 3 days, the boy was admitted to the Department of Pediatric Gastroenterology for further diagnostic investigations. Upon admission, the patient did not report any complaints. According to his mother, motor restlessness decreased, loose stools resolved, and the eye protrusion diminished. In laboratory tests, elevated transaminase levels, positive cholestasis biomarkers, and significantly increased IgG levels were found, accompanied by elevated total protein levels. The liver autoantibody panel revealed a positive result for anti-liver kidney microsomal antibodies (anti-LKM) and a weakly positive result for antinuclear antibodies (ANA). During the stay in the department, the diagnostic process was expanded to include a liver biopsy under general anesthesia. The histopathologic description of the biopsy indicated disrupted organ architecture, visibly thickened septa, the boundary plate interrupted by inflammatory infiltrate for half of its circumference, expanded portal spaces, a significant degree of lymphoid inflammatory infiltrate, numerous plasma cells, features of fatty degeneration in hepatocytes, isolated necrotic foci, and portal fibrosis. Considering the clinical picture of the disease, biochemical parameters, serological test results and histopathological findings, AIH was diagnosed. Treatment with oral glucocorticoid (1.0 mg/kg of body weight of prednisone per day) was applied, and choleretic therapy was maintained. The thiamazol treatment was continued at the previous dosage (0.13 mg/kg of body weight).

In the follow-up tests after 2 months of treatment, liver parameters normalized (AST 23.2 U/l; ALT 15.9 U/l), and total protein concentration decreased. Due to the positive response to glucocorticoid therapy, the introduction of azathioprine treatment was initially postponed. After discharge, the patient remains under regular follow-up by gastroenterology and endocrinology. Due to the rapid improvement in liver parameters, a gradual reduction of prednisone was recommended. Changes in TSH, FT3, and FT4 values require appropriate modification of thiamazole dosage.

However, one year after the AIH diagnosis, azathioprine (1.0 mg/kg/day) was introduced to align with standard AIH management guidelines and minimize the adverse events of glucocorticoid treatment. Due to its immunosuppressive effects, azathioprine allowed for a reduction not only in prednisone but also in the thyreostatic dose. Two years after diagnosis, the boy continues treatment with azathioprine 0.85 mg/kg/day and thiamazole and glucocorticoid in a minimal dose.

Discussion

GD is the most common cause of pediatric hyperthyroidism. Children constitute only 1–5% of all patients with GD. Comorbidity of AITD and liver dysfunction, usually mild, is not rare in pediatric patients; however, hypothyroidism prevails in this group. We present the first case of the simultaneous manifestation of GD and AIH in a teenage patient.

The cause of liver abnormalities in GD is unclear and is proposed to be multifactorial, including the effects of thyroid hormone excess on hepatocytes, which leads to oxidative stress and apoptosis of liver cells. Numerous pathophysiological connections exist between the liver and the thyroid gland, with liver anomalies noted in a significant proportion, ranging from 45% to 90%, of hyperthyroidism patients. Hepatotoxicity represents a prevalent and severe adverse effect associated with antithyroid drugs (ATD), with the incidence varying based on the specific ATD used. Elevated transaminase levels before and during the treatment may result from the patient’s underlying disease. Notably, GD-associated AIH is exceedingly uncommon, and this variant of AIH typically resolves following successful treatment of hyperthyroidism. Conversely, the coexistence of GD with classical AIH presents significant therapeutic complexities. Long-term administration of corticosteroids alongside anti-thyroid medication or radioactive iodine ablation represents a cornerstone in management. Nonetheless, despite effective hyperthyroidism control, AIH may persist, and discontinuation of steroid therapy can precipitate AIH recurrence [8].

In the course of the diagnosis and treatment of our patient, who presented with hyperthyroidism and mildly elevated transaminases, we first suspected hyperthyroidism per se as a reason for the increase of ALT and AST levels. The abnormal levels of thyroid hormones must be considered as a possible reason for hypertransaminasemia. Thyrotoxicosis results in higher oxygen demands on the liver, but without an increase in hepatic blood flow, resulting in hepatocyte ischemia. Furthermore, 80% of triiodothyronine is synthesized by the 5′-iodination of thyroxine in the liver and kidneys, which additionally contributes to liver overload [10].

However, after three weeks of treatment, we observed hyperthyroidism resolution and a rapid increase in the ALT and AST levels with jaundice. Our first thought about the cause of hypertransaminasemia was the side effect of thyrostatics. Suzuki et al. [11] reported an overall prevalence of ATD-related DILI at 2.5%, with methimazole (MMI) accounting for 1.4% and propylthiouracil (PTU) for 6.3%. MMI/carbimazole typically induces a cholestatic pattern of DILI, while PTU more commonly leads to hepatocellular liver injury [12]. The spectrum of DILI severity varies widely, from asymptomatic transaminase elevation to symptomatic hepatitis, in severe cases necessitating liver transplantation or resulting in mortality. Treatment primarily involves the immediate discontinuation of the implicated ATD. However, cases of reinitiating an alternate ATD have been reported, with variable outcomes, underscoring the importance of tailored management strategies [12]. In our patient, despite the use of a hepatoprotective supplement and reduction of the ATD dose, transaminase levels did not decrease. This situation might be due to both the GB disease and the coexistence of liver pathology.

In our case, the cause of elevated transaminases, apart from hypertransaminases resulting from ATD, may have been a SARS-CoV-2 infection that occurred after the boy’s first hospitalization, confirmed by a positive antibody titer. Morita et al. [13] presented a case report of a boy with severe acute hepatitis, five weeks after a self-limiting SARS-CoV-2 infection. The underlying cause of this hepatitis is an increase in T lymphocyte activation with predominance of cluster of differentiation 8 positive T cells in the course of COVID-19 infection [13]. In our patient, we also excluded other viral infections as a potential cause of hypertransaminasemia. However, additional diagnostics revealed high IgG levels, positive anti-LKM antibodies, weakly positive ANA, and a specific biopsy pattern, leading to the diagnosis of AIH and subsequent treatment with glucocorticoids.

Since 2008, a scoring system comprising four parameters (liver histology, autoantibody titers, serum levels of γ-globulin or IgG, and absence of viral hepatitis) has been used to diagnose AIH. AIH is distinguished by histological features such as interface hepatitis, portal plasma cell infiltration, hypergammaglobulinemia, and the presence of autoantibodies. An increased incidence of AITD has been noted among adult patients diagnosed with autoimmune liver disease (AILD). In a retrospective analysis conducted by Zeng et al. [14], adult individuals with AIH exhibited a higher propensity for developing AITD (45.8%), followed by AIH-primary biliary cholangitis overlap syndrome (39.5%) and primary biliary cholangitis (22.6%). Patients with concomitant AILD and AITD displayed elevated levels of IgG and γ-globulin. IgG levels exhibited a positive correlation with thyroid antibodies, including thyroglobulin antibody and TPOAb. Among individuals with concurrent AIH and AITD, a greater prevalence of homogeneous nuclear pattern ANA positivity was observed compared to those with AIH alone. Hashimoto’s thyroiditis (65.5%) predominantly characterized thyroid dysfunction in AILD patients with concurrent AITD, with diffuse lesions frequently identified via thyroid ultrasound (53.1%) [14]. Reports in the literature on the co-occurrence of GD and liver pathology due to AIH in the pediatric population are limited. Mogahed et al. [15] focused on the pediatric group and analyzed 58 children with AIH. Forty patients had type I AIH (69%), 15 patients had type II (25.9%), and 3 patients had seronegative AIH. In the whole group, 28 patients had associated autoimmune diseases – the most common was AITD, detected in 10 children (17.2%). In this group of children, 6 patients were euthyroid, 3 had subclinical hypothyroidism, but only 1 child had hyperthyroidism [15]. Similarly, other studies have reported AITD as the most common comorbidity associated with AIH in adults [16, 17]. This demonstrates the importance of screening AIH patients for early detection of thyroid dysfunction.

Yamada et al. [9] described a 12-year-old patient with GD who developed liver dysfunction after two months of MMI treatment, accompanied by histological features indicative of AIH upon initial biopsy examination. The case underscores that early-stage AIH may manifest with necrosis and inflammation predominantly localized to the centrilobular area, later extending to involve the portal area as liver dysfunction progresses. Consequently, in pediatric patients presenting with GD-associated liver dysfunction, AIH could be a contributory factor [9]. Our case report is the first to describe simultaneous manifestation of GD and AIH in a teenage patient, indicating the necessity to be vigilant in patients with hyperthyroidism and elevated transaminase levels.

Conclusions

This case underscores the importance of considering the possibility of dual autoimmune disorders in patients presenting with overlapping clinical features. Timely recognition and a multidisciplinary treatment approach are crucial for achieving optimal outcomes in such complex cases. Further research is warranted to explore the potential immunological links between GD and AIH, as well as the implications for tailored therapeutic interventions in pediatric populations.