Coexistence of VLCAD deficiency and Hashimoto’s thyroiditis: a rare case report

Abstract

Background

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a mitochondrial fatty acid oxidation disorder caused by mutations in the acyl-CoA dehydrogenase very long chain (ACADVL) gene. Hashimoto’s thyroiditis is the most common autoimmune thyroid disease. To the best of our knowledge, their coexistence has not been reported. This case highlights a potential mechanistic link between mitochondrial dysfunction, chronic inflammation, and endocrine autoimmunity.

Case presentation

A 33-year-old woman presented with acute-onset generalized myalgia, fatigue, and dark-colored urine. Laboratory findings confirmed severe rhabdomyolysis. Thyroid tests revealed primary hypothyroidism with elevated anti-TPO and anti-Tg levels, and ultrasonography demonstrated chronic autoimmune thyroiditis. The patient had a history of recurrent unexplained rhabdomyolysis without identifiable external triggers. Therefore, genetic testing was performed to evaluate for an underlying metabolic myopathy. Genetic testing identified a homozygous ACADVL c.1097G>A (p. Arg366His) variant, confirming VLCAD deficiency. Treatment included intravenous hydration, L-carnitine supplementation, a medium-chain triglyceride (MCT)-enriched diet, and levothyroxine. The patient showed marked improvement and remained stable without recurrence for one year.

Conclusions

To the best of our knowledge, this appears to be the first report describing the coexistence of VLCAD deficiency and Hashimoto’s thyroiditis. Chronic mitochondrial dysfunction may potentially contribute to systemic inflammation and immune activation associated with autoimmune thyroid disease. Increased awareness of this association may facilitate earlier clinical recognition and encourage comprehensive evaluation.

Background

VLCAD deficiency is an autosomal recessive disorder caused by pathogenic variants in the ACADVL gene, resulting in impaired mitochondrial β-oxidation of long-chain fatty acids [1]. The clinical spectrum ranges from severe neonatal cardiomyopathy to childhood hypoketotic hypoglycemia, and an adult myopathic form characterized by exercise-induced rhabdomyolysis [1, 2]. During metabolic stress—such as fasting, infection, or physical exertion—patients may experience acute energy deficiency and muscle breakdown.

Beyond its metabolic effects, emerging evidence supports a broader immunometabolic role for VLCAD deficiency. Studies have shown that the accumulation of long-chain acyl-CoA intermediates promotes oxidative stress, which in turn activates inflammatory pathways including NF-κB and NLRP3 inflammasome signaling. For example, Vallejo et al. [3] demonstrated elevated pro-inflammatory cytokines such as IL-6 and TNF-α in VLCAD patients. Additional studies have reported increased serum CRP levels and evidence of systemic inflammation [4]. These findings support the hypothesis that VLCAD deficiency induces chronic low-grade inflammation.

More broadly, mitochondrial dysfunction is increasingly recognized as a contributor to autoimmunity. Mitochondrial ROS production and impaired mitophagy can lead to neoantigen formation, immune cell activation, and tissue-specific autoimmunity [5].

Hashimoto’s thyroiditis, the most common autoimmune thyroid disease, is characterized by lymphocytic infiltration, follicular destruction, and elevated anti-thyroid antibodies [6]. Oxidative stress and impaired mitochondrial function have been implicated in its pathophysiology, potentially enhancing immune-mediated thyroid injury.

In autoimmune thyroiditis specifically, oxidative stress within thyrocytes may enhance antigen presentation and drive anti-TPO and anti-Tg antibody production [7]. Thus, VLCAD-induced mitochondrial dysfunction may serve as a bridge linking metabolic disturbance with autoimmune processes.

We were unable to identify any previous reports describing the coexistence of VLCAD deficiency and Hashimoto’s thyroiditis in the literature. This case therefore provides a unique opportunity to explore potential mechanistic interactions between metabolic myopathies and endocrine autoimmunity.

Case presentation

A 33-year-old woman presented with acute-onset generalized myalgia, fatigue, and dark-colored urine. She denied strenuous exercise, trauma, alcohol use, or medication triggers. She had experienced similar episodes in the past, though less severe. Her medical history included no prior diagnosis of thyroid disease or metabolic disorders. Family history was negative for autoimmune conditions, myopathies, or thyroid dysfunction.

On admission, physical examination revealed diffuse muscle tenderness without focal neurologic deficits. Laboratory testing showed severe rhabdomyolysis: Creatine kinase (CK) 28,265 U/L; AST 912 U/L; ALT 314 U/L; LDH 1,373 U/L. Renal function was preserved. The differential diagnosis for rhabdomyolysis included exertional, traumatic, drug-induced, infectious, autoimmune, and metabolic causes. There was no history of exertion, trauma, alcohol or illicit drug use, or statin therapy. Viral serologies and autoimmune panels were negative. Genetic testing was initiated due to recurrent rhabdomyolysis (Table 1).

Table 1.

Laboratory findings

Parameter	At Admission	At Discharge*	3-Month follow up	Reference Range
CK (U/L)	28,265	2,413	180	< 170
AST (U/L)	912	89	24	0–32
ALT (U/L)	314	204	35	0–33
LDH (U/L)	1,373	782	185	135–214
Creatinine (mg/dL)	0.40	0.63	0.65	0.5–0.9
TSH (µIU/mL)	8.5	8.5	2.1	0.27–4.2
Free T4 (ng/dL)	0.65	0.65	1.2	0.92–1.68
Anti-TPO (IU/mL)	308	-	104	< 34
Anti-Tg (IU/mL)	264	-	150	< 115

*: Discharge values were measured on the 7th day of hospitalization

Further history revealed symptoms compatible with hypothyroidism, including cold intolerance and fatigue. Thyroid function tests showed TSH 8.5 µIU/mL and free T4 0.65 ng/dL. Autoantibodies were markedly elevated: anti-TPO 308 IU/mL and anti-Tg 264 IU/mL. Thyroid ultrasonography demonstrated diffuse hypoechogenicity and pseudonodularity, consistent with Hashimoto’s thyroiditis. Levothyroxine 50 µg/day was initiated.

In this patient, the decision to pursue genetic testing was based on a systematic exclusion of common rhabdomyolysis triggers, including trauma, infections, seizures, medications, and electrolyte disturbances. The patient experienced recurrent, unexplained episodes of rhabdomyolysis without identifiable external factors. These clinical features raised suspicion for an underlying inherited metabolic myopathy. Although intermediate metabolic tests such as plasma acylcarnitine profiling could not be performed due to technical limitations, the severity and recurrence of symptoms justified comprehensive genetic evaluation. A broad next-generation sequencing-based myopathy gene panel was performed, which identified a homozygous pathogenic ACADVL c.1097G > A (p. Arg366His) variant, confirming the diagnosis of VLCAD deficiency.

Treatment included continued hydration, L-carnitine supplementation, and a diet low in long-chain fats and enriched with medium-chain triglycerides (MCT). CK levels decreased progressively by ~ 92% (from 28,265 to 2,413 U/L), and the patient’s symptoms improved. The patient was discharged on the 7th day of hospitalization. At 3-month follow-up, CK and TSH levels were within normal range. She remained asymptomatic during one year of follow-up.

Investigations

Laboratory testing confirmed primary autoimmune hypothyroidism with elevated thyroid autoantibodies. Thyroid ultrasonography showed characteristic features of chronic autoimmune thyroiditis.

Treatment

Management included:

• Intravenous hydration.

• L-carnitine supplementation.

• MCT-rich diet with avoidance of prolonged fasting.

• Levothyroxine 50 µg/day.

Outcome and follow-up

The patient demonstrated full clinical recovery with normalization of thyroid function and CK levels. She remained asymptomatic with no recurrence of rhabdomyolysis during one year of follow-up.

Discussion

VLCAD deficiency leads to impaired mitochondrial β-oxidation and accumulation of long-chain lipid intermediates, which promote oxidative stress and activation of inflammatory pathways such as NF-κB and NLRP3 inflammasome signaling. Mitochondrial ROS production and impaired mitophagy are increasingly recognized contributors to immune dysregulation and autoimmunity. In Hashimoto’s thyroiditis, oxidative stress within thyrocytes enhances antigen presentation and drives anti-TPO and anti-Tg antibody production. These shared mitochondrial-inflammatory mechanisms provide a biologically plausible framework linking metabolic dysfunction with autoimmune thyroid disease. Recent reviews have emphasized the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of Hashimoto’s thyroiditis [8].

It should also be acknowledged that this coexistence may be coincidental, given the high prevalence of autoimmune thyroid disease among adult women. Therefore, while a mechanistic link is biologically plausible, the present case alone cannot establish causality, and the association should be interpreted with caution.

Though a single case report cannot prove causality, we estimated the probability of coincidental coexistence using population prevalence data. Historically, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) was estimated to affect between 1 in 100,000 to 1 in 120,000 individuals [9], whereas Hashimoto’s thyroiditis affects ~ 8–10% of the general population [10]. Assuming independence, the chance of both disorders coexisting by coincidence is ~ 1.6 per million individuals. This estimation is theoretical and intended only as illustrative context.

However, the observed coexistence of VLCAD deficiency and Hashimoto’s thyroiditis in this patient does not, by itself, establish a definitive causal or mechanistic relationship.

Hypothyroidism itself can cause myopathy and, in rare cases, rhabdomyolysis. However, in this patient, rhabdomyolysis was recurrent, occurred during periods of metabolic stress, and was associated with a confirmed pathogenic ACADVL mutation. These features are characteristic of VLCAD deficiency rather than primary hypothyroid myopathy, which is typically mild and slowly progressive [11].

Rapid improvement in muscle enzyme levels was achieved with fluid replacement and L-carnitine therapy.

The coexistence of VLCAD deficiency and Hashimoto’s thyroiditis in this patient raises the possibility of a mechanistic association involving mitochondrial dysfunction, oxidative stress, and immune dysregulation. However, this observation should be interpreted cautiously and viewed as hypothesis-generating rather than evidence of causality.

Learning points

• VLCAD deficiency and Hashimoto’s thyroiditis may share mitochondrial-inflammatory pathways.

• Chronic mitochondrial stress may predispose individuals to autoimmune activation.

• Hypothyroidism should be considered in rhabdomyolysis, but marked CK elevation and genetic confirmation support VLCAD as the primary cause.

• Multidisciplinary management—including hydration, dietary modification, carnitine supplementation, and thyroid hormone replacement—is essential.

• This case highlights the importance of autoimmune screening in patients with metabolic myopathies.

• Further studies are warranted to explore mitochondrial dysfunction as a contributor to autoimmune thyroid disease.

Author contributions

All authors made individual contributions to authorship. Y.E.G., G.A and A.C.D was involved in acquisition of the data and drafting the manuscript. Y.E.G. was involved in the diagnosis and management of the patient. All authors reviewed and approved the final draft.

Funding

The authors declare that no specific funding was received for this work.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.