Hypothyroidism-associated rhabdomyolysis: A new case report and review of the reported cases

Fahmi Yousef Khan; Theeb Osama Sulaiman; Raza Ali Akbar

doi:10.4103/ijas.ijas_14_21

CASE-BASED REVIEW

Year : 2021 | Volume : 6 | Issue : 2 | Page : 31-37

Hypothyroidism-associated rhabdomyolysis: A new case report and review of the reported cases

Fahmi Yousef Khan¹, Theeb Osama Sulaiman², Raza Ali Akbar¹
¹ Department of Medicine, Hamad General Hospital, Doha; Clinical Medicine, Weill Cornell Medical College, Ar-Rayyan, Qatar
² Department of Medicine, Hamad General Hospital, Doha, Qatar

Date of Submission	16-Nov-2021
Date of Acceptance	07-Jan-2022
Date of Web Publication	07-Oct-2022

Correspondence Address:
Dr. Fahmi Yousef Khan
Department of Medicine, Hamad General Hospital, Doha; Weill Cornell Medical College, P.O.Box: 3050, Ar-Rayyan
Qatar

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ijas.ijas_14_21

Abstract

Background: Hypothyroidism alone or in combination with other factors has the risk of triggering rhabdomyolysis. In this article, we aim to describe hypothyroidism-associated rhabdomyolysis and its outcomes.
Methods: We reported a new case of hypothyroidism-associated rhabdomyolysis and reviewed similar reported cases from the literature for in-depth knowledge.
Results: Eighty-one cases, including the one reported in this article, met the inclusion criteria for this review. The mean age of the patients was 45.6 ± 15.8 years. Out of these, 57 (70.4%) patients were males and 24 (29.6%) were females. The precipitating factor was absent in 45 (55.6%) cases. A total of 8 (9.9%) cases had chronic renal failure at time of presentation, while 25 (30.9%) had hypertension, 11 (13.6%) had diabetes mellitus, and 32 (39.5%) had dyslipidemia. The median creatine kinase (CK) level was 5885 U/L (Interquartile range: 3280.5–11550.5 U/L). Electromyography was performed in 12 patients with 10 (12.3%) cases showing myopathic changes including polyphasic potential and fiber necrosis. Muscle biopsy was performed in 7 (8.4%) cases, with Type II fiber atrophy observed in 4 (4.9%) biopsies. Sixty-two cases developed acute kidney injury, of which 14 (17.3%) required hemodialysis. All patients were treated with levothyroxine and most patients (67, 82.7%) were treated by hydration. All the reported patients made good recovery. A statistically nonsignificant correlation was found between CK and thyroid-stimulating hormone (r = 0.218; P = 0.052).
Conclusions: Rhabdomyolysis is a recognized complication of hypothyroidism even in the absence of additional risk factors. Clinicians should be aware of the impact of rhabdomyolysis and hypothyroidism on renal function and promptly initiate hormone replacement therapy and vigorous hydration to preserve the renal function.

Keywords: Acute kidney injury, hypothyroidism, myopathy, rhabdomyolysis

How to cite this article:
Khan FY, Sulaiman TO, Akbar RA. Hypothyroidism-associated rhabdomyolysis: A new case report and review of the reported cases. Imam J Appl Sci 2021;6:31-7

How to cite this URL:
Khan FY, Sulaiman TO, Akbar RA. Hypothyroidism-associated rhabdomyolysis: A new case report and review of the reported cases. Imam J Appl Sci [serial online] 2021 [cited 2023 May 28];6:31-7. Available from: https://www.e-ijas.org/text.asp?2021/6/2/31/358062

Introduction

Rhabdomyolysis is a potentially life-threatening syndrome characterized by the breakdown of skeletal muscle resulting in the subsequent release of intracellular contents into the circulatory system. The etiologic spectrum of rhabdomyolysis is extensive, including major causes such as toxins and medications, trauma, excessive muscular activity, heat-related, muscle ischemia, and infections. Other rarer causes include electrolyte disturbance, hereditary metabolic abnormalities or structural abnormalities of the skeletal muscle cell, connective tissue disorders, and endocrine abnormalities.^[1] Hypothyroidism-associated rhabdomyolysis is a clinical condition which is usually triggered by some precipitating factors, such as the simultaneous use of statins along with heavy exercise. However, rhabdomyolysis due to hypothyroidism with no apparent precipitating factors has also been reported in the literature.^{[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52]}

In this case report, we describe a similar patient with no apparent precipitating factors for hypothyroidism-associated rhabdomyolysis. To better understand the topic, we reviewed 73 published case reports^{[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75]} of rhabdomyolysis associated with hypothyroidism retrieved from different sources including MEDLINE, PubMed, search engine Google, and EMBASE.

Methods

Data sources

We reviewed the English-language literature and checked the relevant references from 1970 to 2019 to identify all known cases of rhabdomyolysis associated with hypothyroidism using multiple sources; MEDLINE, PubMed, search engine Google, and EMBASE using the terms “rhabdomyolysis and hypothyroidism,” “Hypothyroid myopathy,” “hypothyroidism-associated rhabdomyolysis,” and “hypothyroid rhabdomyolysis.” Manuscripts published in English were reviewed and relevant references were checked, and authors were contacted where possible. In addition, we also present a new case report.

Inclusion and exclusion criteria

All cases with biochemical diagnosis of primary hypothyroidism (with or without clinical signs) and serum creatine kinase (CK) level of more than ten times the upper limit of normal were included in this report.

We excluded cases if they fulfilled at least one of the following criteria: abstracts, insufficient clinical or laboratory data, serum CK level <10 times the upper limit of normal, endocrinopathies other than primary hypothyroidism (panhypopituitarism, Cushing syndrome), or presence of primary muscle disease.

Data extraction

For all reports of rhabdomyolysis caused by hypothyroidism, the information extracted included if available: patient's age and sex, clinical and laboratory features, concomitant drugs, associated medical conditions as well as therapeutic interventions and outcome.

Data analysis

The gathered information was transferred to the computer utilizing the with SPSS software (v 25; IBM Corp, Armonk, NY, USA). Descriptive statistics of qualitative and quantitative data were expressed as frequency along with percentage and mean (±SD). Pearson's Chi-square and exact tests were used to test the differences in the proportion of categorical variables, and independent t-tests were used for evaluating the difference between the means of two continuous variables. Pearson correlation analysis was performed to examine the linear relationship between serum CK and TSH level. P < 0.05 was considered statistically significant.

Case Report

A 35-year-old man was admitted to our hospital with a 2-day history of lower limb muscular pain. The patient also noted that his urine had turned dark brown for the preceding 24 h. On further questioning, he reported cold intolerance and somnolence for 6 months. Other medical history was unremarkable. He was not taking any medications and denied any abuse of alcohol or drugs including anabolic steroids. There was no personal or family history of muscle or thyroid disease. On physical examination, the patient was alert and oriented. There was no pedal edema or palpable goiter and the skin examination was normal. His temperature was 36.7°C, blood pressure was 120/70 mmHg, and pulse rate was 72 beats/min. The range of motion in the lower extremities was limited by the pain and tenderness and there was no delayed relaxation of ankle jerk. The rest of his clinical examination was unremarkable.

The laboratory investigations revealed a hemoglobin level of 12 g/dL (NR: 13–17 g/dl) and a total leukocyte count of 5.1 × 103/μL (4–10 × 10³/uL) with a normal differential and a platelet count of 153,000/μL (NR: 150–400 × 10³/uL). Blood chemistry revealed aspartate aminotransferase of 81 U/L (NR: 5–34 U/L); alanine aminotransferase, 75 U/L (NR: 0–55 U/L); blood urea nitrogen 8.8 mmol/L (NR: 1.17–3.64 mmol/L); and serum creatinine 210 μmol/L (NR: 64–100 μmol/L). An arterial blood gas analysis at room air was performed which showed H 7.2 (NR: 7.35–7.45), PaO₂88 mmHg (NR: 83–108 mmHg), and PaCO₂31 mmHg (NR: 35–45 mmHg). His fasting lipid profile showed a total cholesterol of 6.1 mmol/L (NR: <5.1 mmol/L), LDL cholesterol 4.2 mmol/L (NR: 3.36–4.12 mmol/L), and triglyceride 1.2 mmol/L (NR: <1.7 mmol/L). His myoglobin was elevated 1230 ng/ml (NR: 28–72 ng/ml) and the CK level was elevated (12331 U/L; NR: 22–100 U/L) with normal CK MB fraction and cardiac troponin levels. The urine myoglobin test result was positive. Urinalysis did not reveal any hematuria, pyuria, or ketonuria.

The patient was admitted to the intensive care unit with a provisional diagnosis of acute kidney injury (AKI) secondary to rhabdomyolysis. Early and aggressive hydration was initiated and urinary output was measured hourly with cautious monitoring of serum potassium and other electrolytes levels. During hospitalization, the patient's thyroid function tests were obtained which showed thyroid-stimulating hormone (TSH) of 100 mIU/L (NR: 0.45–4.5) and serum-free thyroxin (FT4) of 4.2pmol/L (NR: 9–20). Both serum antithyroglobulin antibody and antimicrosomal antibody were positive at high titers, consistent with primary autoimmune hypothyroidism. The antinuclear antibody was negative.

The patient was diagnosed with primary autoimmune hypothyroidism associated with rhabdomyolysis and AKI. Vigorous hydration was continued with cautious monitoring of serum potassium and other electrolyte levels to treat rhabdomyolysis and AKI, whereas hypothyroidism was treated with L-thyroxin at a dosage of 100 μg/day.

In the following days, the patient significantly improved with levels of CK and serum creatinine declining considerably towards normalization. The patient was subsequently discharged 16 days after hospitalization. He was then seen in the medical outpatient's clinic 12 weeks after discharge. He remained clinically asymptomatic and his labs revealed normal CK and serum creatinine levels.

Results Of The Case Reviews

In addition to our case, 74 reports with 80 cases meeting the criteria were included in this review. [Table 1] describes all of the 81 cases of hypothyroidism-associated rhabdomyolysis including our current reported case. The mean age of the patients was 45.6 ± 15.8 (9–75 years), out of which 57 (70.4%) were males and 24 (29.6%) were females. Precipitating factor was absent in 55 cases (67.9%). A total of 8 patients (9.9%) had chronic kidney disease chronic renal failure at time of presentation, while 25 (30.9%) had hypertension, 11 (13.6%) had diabetes mellitus, and 32 (39.5%) had dyslipidemia [Table 2].

Table 1: Summary of reported cases of rhabdomyolysis associated with hypothyroidism

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Table 2: Summary of reported cases of rhabdomyolysis associated with hypothyroidism

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The clinical manifestations of rhabdomyolysis associated with hypothyroidism include muscle pain, muscle swelling, muscle tenderness, backache, darkened urine, and generalized muscle weakness [Table 1].

The median CK level was 5885 U/L (Interquartile range: 3280.5–11550.5 U/L). Detection of blood/urine myoglobin was reported in 48 patients, with 41 positives. Electromyography was performed in 12 patients with 10 (12.3%) cases showing myopathic changes including polyphasic potential and fiber necrosis. Two cases (2.5%) exhibited normal electromyography. Muscle biopsy was performed in 7 (8.4%) cases, with Type II fiber atrophy observed in 4 (4.9%) biopsies, while 3 (3.7%) biopsies were reported normal.

Sixty-two cases of rhabdomyolysis were complicated with AKI, of which 14 (17.3%) required dialysis. All patients were treated with levothyroxine, and most patients, 67 (82.7%), were treated by hydration. All the reported patients made good recovery.

There were no significant differences between patients with and without AKI regarding the age, serum CK, and TSH levels [Table 3]. Moreover, a statistically nonsignificant correlation was found between CK and TSH (r = 0.218; P = 0.052), CK and FT4 (r = −0.109; P = 0.363), and CK and FT3 (r = −0.035; P = 0.827).

Table 3: Demographic and clinical characteristics of the patients with and without acute renal failure

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Discussion

Myopathy is a common clinical feature of patients with hypothyroidism, affecting approximately 79% of the cases. It presents with nonspecific symptoms of myalgias, muscle cramps, fatigue, and muscle weakness, particularly exacerbated with exertion and exercise. If hypothyroidism is left untreated, the patient may develop significant muscle disease such as rhabdomyolysis resulting in severe functional limitations.^[76] The most common laboratory finding in patients with hypothyroid myopathy is elevated serum CK, which occurs in 57%–90% of cases.^{[77],[78],[79],[80]} In asymptomatic patients, CK elevation is usually mild, <10 times the upper normal limits.^[81] Although the diagnostic CK level for rhabdomyolysis should be >10 times the upper normal limit, it is not clear whether or not the severity of rhabdomyolysis is related to the degree of CK elevation.^[80]

Our case, as well as the cases reviewed, highlights several important points.

First, rhabdomyolysis can occur in patients with primary hypothyroidism of various etiologies, with autoimmune thyroiditis being the most common etiology. Moreover, we found rhabdomyolysis can precede or follow the diagnosis of hypothyroidism. In our review, 60 cases, including ours, had rhabdomyolysis at presentation and retrospectively diagnosed with hypothyroidism. Accordingly, thyroid status should be evaluated when treating a patient suffering from unexplained rhabdomyolysis and AKI.

Second, contrary to what is known among researchers, regarding the significant role of some factors such as lipid-lowering drugs, alcohol, or exercise in triggering rhabdomyolysis in patients with hypothyroidism, rhabdomyolysis occurred in 55 (67.9%) of the cases reviewed, including ours, in the absence of additional precipitating factors. This indicates that rhabdomyolysis due to hypothyroidism alone is not as rare as some authors have previously suggested. The precise pathophysiology of rhabdomyolysis in hypothyroidism is currently not clear. Skeletal muscle has been recognized as a key thyroid hormone target for contractile function, regeneration, and transport as well as for metabolism and glucose disposal. Thyroid hormone deficiency leads to a reduced mitochondrial oxidative capacity, abnormal glycogenolysis, and an insulin-resistant state of the cell.^[82] This leads to selective atrophy of Type 2 muscle fibers (fast-twitching type) as they are dependent on glycolysis for energy, causing a switch to slow-twitching Type 1 fibers, low myosin ATPase activity, and low adenosine triphosphate that was seen clinically as slowing of muscle contraction.^{[31],[82],[83]} Moreover, decreased muscle carnitine, which was found in patients with hypothyroid myopathy, could also be a possible mechanism underlying hypothyroid myopathy.^[8] All these changes might sensitize muscle cells to other factors related to muscle injury and increase the risk of rhabdomyolysis.^[68]

Third, we only found that 14 (17.3%) cases presented with dark urine; otherwise, the clinical presentation of hypothyroidism-associated rhabdomyolysis was nonspecific and generally indistinguishable from hypothyroid myopathy. Therefore, a high index of suspicious is needed to detect this complication as early as possible. Unexplained muscle pain or weakness in hypothyroid patients must raise the suspicion of rhabdomyolysis, and therefore, CK level, being the most sensitive indicators of myocyte injury in rhabdomyolysis,^[1] should be evaluated.

Fourth, in general, AKI develops in almost a third to half (33%–45%) of all patients with rhabdomyolysis.^[1],[32] However, our review showed that over three-quarter (76.5%) of patients with hypothyroidism-associated rhabdomyolysis developed AKI, which is higher than the range reported for AKI in rhabdomyolysis patients in general. Based on some reports that showed an association between hypothyroidism and impaired renal function,^{[84],[85],[86]} the increased number of AKI among the reviewed cases can be attributed to the dual effect of hypothyroidism and rhabdomyolysis on the kidney, which may aggravate the occurrence of AKI. Hence, clinicians should be aware of the impact of rhabdomyolysis and hypothyroidism on renal function and initiate hormone replacement and vigorous hydration as early as possible to preserve renal function.

Fifth, we did not find a significant correlation between CK level and thyroid function tests such as TSH, FT4, and FT3 levels, which dispute any significant relation between the degree of muscle involvement and the severity of hypothyroidism. This is consistent with the findings of Hartl et al.^[87] but contrary to the findings of Hekimsoy and Oktem.^[80]

Finally, our review showed that the overall outcome of hypothyroid-associated rhabdomyolysis is generally good as all the reviewed patients recovered. In general, rapid remission of symptoms is achieved after the initiation of thyroxin. In addition, early and vigorous hydration to preserve renal function, and treating the underlying causes, played a crucial role in the safe outcome of the reviewed cases. Around one in 6 cases (17.3%) with AKI required dialysis. All patients suffering from AKI secondary to hypothyroid-associated rhabdomyolysis achieved a premorbid health status which they had prior to their presentation.

Conclusions

Rhabdomyolysis is a recognized complication of hypothyroidism even in the absence of additional risk factors. The clinical presentation of hypothyroidism-associated rhabdomyolysis is nonspecific and a high index of suspicious is needed to detect it as early as possible. Measurement of CK, therefore, has an important role in the evaluation of all hypothyroid patients presenting with muscular weakness. AKI is a serious potential consequence of hypothyroidism-associated rhabdomyolysis which needs early identification, prevention, and aggressive management. Hence, clinicians should be aware of the impact of rhabdomyolysis and hypothyroidism on renal function and promptly initiate hormone replacement and vigorous hydration to preserve the renal function.

Ethical approval

This study was approved by MRC (Project Ref. No: MRC-04-21-436).

Declaration of patient consent:

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The Guardian understands that names and initials will not be published, and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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