WHEN A TOXIC THYROID MAKES THE LIVER TOXIC: A CASE OF THYROID STORM COMPLICATED BY ACUTE LIVER FAILURE

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1 Case Report WHEN A TOXIC THYROID MAKES THE IVER TOXIC: A CASE OF THYROID STORM COMPICATED BY ACUTE IVER FAIURE Sanna Fatima, MD 1 ; Ritika Puri, MD 1 ; Soumya Patnaik, MD 1 ; Jorge Mora, MD 2 ABSTRACT Objective: Thyroid storm is a rare life-threatening medical emergency. It is associated with high mortality (10 to 30%). Though there may be mild derangements in liver function tests (FTs), acute liver failure (AF) is infrequently reported and its pathophysiology is poorly understood. We hereby report a case of AF in a patient with thyroid storm. Methods: A 41-year-old female with history of Graves disease (non-compliant with treatment) complicated by multiple episodes of thyroid storm and atrial fibrillation (Afib) presented with exertional dyspnea and productive cough. She was found to be in Afib with rapid ventricular rate and new-onset cardiomyopathy (left ventricular ejection fraction of <20%). She was noted to have a large, nontender thyroid gland with bruit; thyroid function tests were consistent with uncontrolled hyperthyroidism. Results: Two days after initiating treatment with methimazole and propranolol, she became increasingly lethargic, confused, and developed asterixis and icterus. FTs were consistent with AF. Methimazole was stopped due to potential hepatotoxicity. Steroids, cholestyramine, and ugol iodine were started for thyroid storm. iver ultrasound showed heterogeneous liver texture consistent with Submitted for publication July 17, 2016 Accepted for publication September 8, 2016 From the 1 Department of Internal Medicine, and 2 Department of Pulmonary and Critical Care Medicine, Einstein Medical Center, Philadelphia, Pennsylvania. Address correspondence to Dr. Sanna Fatima, Albert Einstein Medical Center, 5501 Old York Road, Klein 363, Philadelphia, PA fatimasa@einstein.edu DOI: /EP CR To purchase reprints of this article, please visit: acute inflammation. The patient subsequently improved with conservative management and control of thyroid storm. Once clinically stable, she underwent thyroidectomy as a definitive treatment of her Graves disease. Conclusion: The occurrence of AF in patients with thyroid storm has rarely been reported in the literature and is associated with high mortality. Hyperthyroidism has been hypothesized to injure the liver through several mechanisms which we will discuss in this case report. (AACE Clinical Case Rep. 2017;3:e200-e204) Abbreviations: AF = acute liver failure; FTs = liver function tests INTRODUCTION Thyroid storm is a rare life-threatening medical emergency. It is associated with high mortality (10 to 30%). Though there may be mild derangements in liver function tests (FTs), acute liver failure (AF) is infrequently reported (1-4) and its pathophysiology is poorly understood. We hereby report a case of AF in a patient with thyroid storm. CASE REPORT A 41-year-old African American female with history of uncontrolled Graves disease due to non-compliance with treatment, multiple previous episodes of thyroid storm, and atrial fibrillation (Afib) presented with exertional dyspnea and productive cough. Though normotensive, she was noted to be in Afib with a rapid ventricular rate of 120 beats per minute (bpm). A bedside 2D echocardiogram revealed a new-onset decompensated cardiomyopathy with left ventricular ejection fraction of <20% and normal right ventricular systolic function. She was e200 AACE CINICA CASE REPORTS Vol 3 No. 3 Summer 2017

2 Thyroid Storm and iver Failure, AACE Clinical Case Rep. 2017;3(No. 3) e201 found to have a large, non-tender thyroid gland with a bruit. Thyroid function tests were consistent with uncontrolled hyperthyroidism (thyroid-stimulating hormone 0.02 miu/, free thyroxine [T4] 5.25 ng/m); the remainder of her laboratory workup including FTs were normal. Ultrasound of the thyroid gland suggested acute diffuse thyroiditis consistent with Graves disease. She was started on methimazole (20 mg orally every 12 hours) and propranolol (60 mg orally every 8 hours). Over the next few days, she became increasingly lethargic, developed confusion, asterixis, and icterus, and was admitted to the intensive care unit. On day 2 after admission, FTs were noted to be significantly abnormal with alkaline phosphatase of 128 U/, total bilirubin of 2.9 mg/d, direct bilirubin of 2.2 mg/d, alanine aminotransferase of 948 U/, aspartate aminotransferase of 2,976 U/, and an international normalized ratio of 3.2, consistent with AF. Her methimazole was stopped because of its potential hepatotoxicity. Steroids (hydrocortisone 100 mg intravenously every 8 hours), cholestyramine (4 g orally every 6 hours), and ugol iodine (5% iodine, 10% potassium iodide; 10 drops every 8 hours) were started for thyroid storm. The dose of propranolol was also increased (80 mg every 6 hours). aboratory tests for viral hepatitis, autoimmune hepatitis, and Wilson disease were negative. iver ultrasound showed heterogeneous liver texture, consistent with acute inflammation without cirrhosis. iver transplant workup was initiated; however, she was deemed to be a high risk candidate for transplant due to the uncontrolled thyrotoxicosis. Fortunately, FTs started to improve on day 5 of admission (Fig. 1 and 2) and the patient remarkably improved with conservative management and control of thyroid storm. The trend of free T4 levels is shown in Figure 3. Thyroid function improved with treatment of Graves disease. Once clinically stable, she underwent thyroidectomy as a definitive treatment of her Graves disease. She continued to improve post-surgery and at the time of discharge she had normal FTs. DISCUSSION The balance between thyroid hormones and liver function is essential for normal metabolism. Thyroid hormones are important for normal hepatic function, while the liver is responsible for metabolism of thyroid hormones; they are glucuronidated and sulfated within the liver and subsequently excreted into the bile (5). Thyroid hormones are lipophilic and readily enter cell membranes, increasing cellular metabolism by acting directly on mitochondria and also the hepatocyte nucleus (6,7). iver dysfunction in thyroid disease can range from asymptomatic enzyme elevations to AF. In patients with hyperthyroidism, there can be several explanations for liver dysfunction. In vitro studies in animals have shown that excess triiodothyronine (T3) activity can induce hepatocyte apoptosis through a mitochondrial-dependent pathway (8). In addition, T3 is responsible for regulating enzymes involved in bilirubin metabolism, and excess levels can result in the accumulation of bilirubin precursors. Since thyroid hormones are glucuronidated and sulfated in the liver, excess thyroid hormones can overwhelm the hepatic machinery and injure hepatocytes (5). Furthermore, hyperthyroidism causes increased cardiac output and can lead to right-sided heart failure. The liver congestion associated with right-sided heart failure can contribute to abnormalities in liver function such as elevated transaminases, hyperbilirubinemia, and coagulopathy (9-11). Studies have shown that patients with hyperthy- Fig. 1. Patient liver function tests.

3 e202 Thyroid Storm and iver Failure, AACE Clinical Case Rep. 2017;3(No. 3) Fig. 2. Patient bilirubin levels. Fig. 3. Patient free thyroxine (T4) levels.

4 Thyroid Storm and iver Failure, AACE Clinical Case Rep. 2017;3(No. 3) e203 roidism and heart failure are more likely to manifest more severe hepatic dysfunction (10,11). Thyroid storm is a rare condition. In a nationwide survey conducted in Japan, its incidence in hospitalized patients was reported as 0.20 per 100,000 per year (12). Our patient fulfilled the criteria of definite thyroid storm as described by Akamizu et al (12), satisfying the combination of central nervous dysfunction manifestation (confusion and lethargy), gastrointestinal and hepatic manifestation (icterus, bilirubin >3mg/d), and tachycardia (heart rate >130 bpm). Most cases of noniatrogenic thyrotoxicosis are often seen in association with Graves disease. The literature related to liver dysfunction in acute thyrotoxicosis remains limited to case reports (1-3). Patients with acute thyrotoxicosis may demonstrate a wide spectrum of liver enzyme abnormalities. The pattern of liver injury in thyroid storm ranges from mild transaminitis to profound cholestatic liver dysfunction (2,11). There appears to be no direct correlation between the degree of thyroid dysfunction and liver abnormalities. Risk factors for profound liver disease in patients with acute thyrotoxicosis remain incompletely understood (13). The incidence of jaundice in thyroid storm has been reported to be between 17.6 and 21.3% in nationwide surveys (12). In addition, medications used to treat hyperthyroidism are also associated with hepatotoxicity. Thioamides are known to cause hepatotoxicity with an incidence ranging from 0.1 to 0.2%, with patterns of liver injury that may be either cholestatic or hepatocellular (14-16). Methimazole has typically been associated with transient asymptomatic elevation of serum aminotransferases that are often not clinically significant; however, it has been reported to cause an idiosyncratic liver injury with onset of hepatotoxicity within 2 to 12 weeks of initiation. The pattern of enzyme elevations is typically cholestatic or mixed. Fatal cases are rare, and rapid recovery is seen within 2 to 8 weeks of stopping therapy (17-19). Similarly, propylthiouracil has been associated with hepatotoxicity. The average duration of propylthiouracil therapy before the onset of hepatotoxicity is approximately 3 months (20). Propylthiouracil-related hepatotoxicity is thought to be a hypersensitivity reaction. The most common abnormality noted is asymptomatic elevation of aminotransferases (21). Acute hepatitis is seen in 0.2% of patients (22). The pattern of enzyme elevations is typically hepatocellular, although cholestatic and mixed patterns have also been described. Immediate cessation of propylthiouracil along with expectant management of the potential complications of hepatic failure is the mainstay of treatment (21-23). The mortality rate from propylthiouracil-induced hepatotoxicity is about 25% (22). In our patient, the most likely cause of AF was thyrotoxicosis. She was started on methimazole only 2 days prior to the onset of AF, thereby making it an unlikely etiology. Additionally, she did not have any signs of right sided heart failure. She never had hypotension or shock during her hospital stay, ruling out the possibility of ischemia from shock liver. Her remarkable recovery with the control of her thyroid storm indicates that thyrotoxicosis was the most probable cause. CONCUSION Though uncommon, hepatic derangements can occur in patients with uncontrolled thyroid storm and severe thyrotoxicosis. Medications used for treatment for hyperthyroidism can sometimes be the underlying etiology of liver failure and, therefore, it is critical to stop the possible inciting agents and quickly initiate management of the thyroid storm with alternative means, which may include an emergent thyroidectomy. iver transplant may be considered in rapidly worsening AF, irrespective of the underlying etiology of the AF, soon after the initiation of medical management. However, AF from thyroid storm may sometimes respond to conservative measures as noted in our patient. In addition, the management of our case was challenging as thyroid storm and AF are independently associated with high mortality. Our case should compel physicians to be cautious of liver function abnormalities in patients with thyrotoxicosis, as rapid decline in liver function can be a harbinger of AF. DISCOSURE The authors have no multiplicity of interest to disclose. REFERENCES 1. Choudhary AM, Roberts I. 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