Molar Pregnancy-Induced Thyroid Storm

The Journal of Emergency Medicine, Vol. 38, No. 5, pp. e71– e76, 2010 Copyright © 2010 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$–see front matter

doi:10.1016/j.jemermed.2009.08.053

Clinical Communications: OB/GYN MOLAR PREGNANCY-INDUCED THYROID STORM Joshua B. Moskovitz,

MD, MPH

and Michael C. Bond,

MD, FACEP, FAAEM

Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland Reprint Address: Joshua B. Moskovitz, MD, MPH, Department of Emergency Medicine, University of Maryland School of Medicine, 110 South Paca Street, 6th Floor, Suite 200, Baltimore, MD 21201

e Abstract—Background: Molar pregnancy is a rare form of pregnancy, affecting approximately 1 in 1000 pregnancies in the United States. Hyperthyroidism is a rare complication of molar pregnancy; thyroid storm occurs even less frequently. Objectives: To discuss a rare cause of thyroid storm in a woman of reproductive age. Case Report: A 17-year-old girl presented to a community hospital’s Emergency Department (ED) after experiencing 1 week of palpitations and tachycardia. The tachycardia partially responded to administration of calcium channel blockers and ␤-blockers. The patient was transferred to a tertiary care center for further evaluation. At the tertiary center, pregnancy was confirmed, thyroid storm was diagnosed, and ultrasound examination yielded a snowstorm image, indicating a molar pregnancy. The patient was admitted to the intensive care unit for management. Dilatation and curettage resolved her symptoms, and after a 9-day hospital stay, she was discharged home on atenolol therapy. Conclusions: Thyroid storm induced by gestational trophoblastic disease should be considered in any woman of childbearing age who presents with symptoms suggestive of hyperthyroidism. © 2010 Elsevier Inc.

refractory to initial treatment, and typically requires treatment of the underlying cause (e.g., fever, dehydration, anxiety, pulmonary embolus). In this case report, we describe a patient with significant sinus tachycardia induced by an uncommon illness, thyroid storm, precipitated by an even more uncommon underlying condition, molar pregnancy.

CASE REPORT A 17-year-old girl presented to the Emergency Department (ED) of a community hospital after experiencing palpitations and chest discomfort for a duration of 1 week. The symptoms had worsened during the night of presentation. The vital signs on arrival were: temperature 36.6°C (97.8°F), heart rate 200 beats/min, respiratory rate 20 breaths/min, blood pressure 147/105 mm Hg, and SpO2 96% on room air. She had experienced intermittent abdominal pain with nausea and vomiting, and was unable to tolerate any food or liquids. She described a fast, pounding heartbeat and had shortness of breath and diaphoresis. She had a family history of hypertension and asthma, but she did not have any medical or surgical history relevant to the current condition. She was not taking any medications, and had no known medication allergies. She did not use tobacco, alcohol, or illicit drugs. The patient had experienced a 15-pound weight loss over the prior week. She had a headache and a cough, but she had not experienced fevers. The last menses was approximately 1 month prior, although she recently noticed some vaginal bleeding. One or 2 weeks earlier, at a local clinic, she had learned that she was pregnant.

e Keywords—molar pregnancy; hyperthyroidism; thyrotoxicosis; gestational trophoblastic disease; thyroid storm

INTRODUCTION Tachycardia has many causes and is a common presentation among the pediatric population. Sinus tachycardia can be Presented at the Clinical Pathologic Case Conference, Council of Emergency Medicine Residency Directors, Washington, DC, May 2008.

RECEIVED: 14 April 2009; FINAL ACCEPTED: 2 August 2009

SUBMISSION RECEIVED:

22 June 2009; e71

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J. B. Moskovitz and M. C. Bond

Figure 1. Initial electrocardiogram upon arrival in the community hospital emergency department.

On physical examination, the patient was noted to be restless. She had no respiratory distress. The examination was remarkable for tachycardia and suprapubic tenderness, with guarding evident on the abdominal examination. The initial work-up at the community hospital included a normal chest X-ray study, a blood glucose concentration of 86 mg/dL, an electrocardiogram (ECG) (Figure 1), and laboratory assessment (Tables 1–3). The ECG was initially interpreted as an undifferentiated supraventricular tachycardia, and the patient was given adenosine, 6 mg i.v., followed by 12 mg i.v., which yielded no response. She was then given serial doses of

Table 1. Complete Blood Count from the Community Hospital Emergency Department Test

Result

Reference Range

WBC Hbg Hct Plat PT INR PTT

14.9 K/␮L 14.8 g/dL 40.9% 295 K/␮L 14 s 1.4 36.3 s

4.5–13.0 K/␮L 12.0–16.0 g/dL 36–46% 153–367 K/␮L 11.9–14.5 s 25–38 s

WBC ⫽ white blood cell count; Hbg ⫽ hemoglobin; Hct ⫽ hematocrit; Plat ⫽ platelets; PT ⫽ prothrombin time; INR ⫽ international normalized ratio; PTT ⫽ partial thromboplastin time.

diltiazem (20 mg, 25 mg, and 25 mg), which decreased her heart rate to the 160s. Treatment continued with 2 L normal saline, ranitidine, and promethazine, which had

Table 2. Chemistry Values from the Community Hospital Emergency Department Test

Result

Reference Range

Sodium Potassium Chloride Bicarbonate BUN Creatinine Glucose Calcium Magnesium ␤eta-hCG AST (SGOT) ALT (SGPT) Alkaline phosphotase Total bilirubin Total protein Amylase Lipase LDH CPK

138 mmol/L 3.3 mmol/L 91 mmol/L 31 mmol/L 41 mg/dL 1.0 mg/dL 82 mg/dL 10.8 mg/dL 2.5 mg/dL Positive 243 units/L 278 units/L 150 units/L 1.7 mg/dL 7.6 g/dL 161 units/L 425 units/L 335 units/L 43 units/L

136–145 mmol/L 2.6–6.0 mmol/L 98–107 mmol/L 21–30 mmol/L 6–20 mg/dL 0.5–1.0 mg/dL 70–99 mg/dL 8.6–10.0 mg/dL 1.6–2.6 mg/dL Negative 10–41 units/L 14–54 units/L 50–130 units/L 0.4–1.5 mg/dL 6.1–8.0 g/dL 27–131 units/L 22–51 units/L 100–190 units/L 30–135 units/L

BUN ⫽ blood urea nitrogen; Beta-hCG ⫽ beta-human chorionic gonadotropin; AST (SGOT) ⫽ aspartate aminotransferase; ALT (SGPT) ⫽ alanine aminotransferase; LDH ⫽ lactate dehydrogenase; CPK ⫽ creatine phosphokinase.

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Table 3. Urinalysis Results and Urine Toxicology Screen from the Community Hospital Emergency Department Test

Result

Reference Range

Glucose Bilirubin Specific gravity Blood pH Urobilinogen Nitrate Leuk est WBCs RBCs Epithelial cells Bacteria Amphetamines Barbiturates Benzodiazepines Cocaine PCP Opiates

Negative Moderate 1.025 Moderate 5.5 4.0 mg/dL Negative Trace 0–1 hpf 0–1 hpf 1–5 hpf Moderate Negative Negative Negative Negative Negative Negative

Negative Negative 1.002–1.030 Negative 4.5–8.0 0.2–1.0 mg/dL Negative Negative 0–5 hpf 0–2 hpf 0–50 hpf Negative Figure 2. Transabdominal ultrasound longitudinal uterus demonstrating molar pregnancy.

WBC ⫽ white blood cell count; hpf ⫽ high-powered field; RBC ⫽ red blood cell count; PCP ⫽ phencyclidine; Leuk est ⫽ leukocyte esterase.

no effect on the symptoms. Two 5-mg doses of metoprolol decreased her heart rate to the 130s. The patient was then transferred to our tertiary care facility, with a diltiazem infusion at 5 mg/h, for further evaluation and treatment. Upon arrival, the vital signs were: temperature 36.8°C (98.3°F), heart rate 135 beats/min, respiratory rate 29 beats/min, blood pressure 140/85 mm Hg, and SpO2 100% on room air. Additional pertinent physical examination findings included an enlarged uterus, equivalent to approximately 17 weeks of gestation. Further work-up included additional laboratory tests and diagnostic imaging. The patient had a significantly elevated triiodothyronine (T3)/thyroxine (T4) level and a decreased thyroid-stimulating hormone (TSH) level (Table 4). The beta-human chorionic gonadotropin (␤hCG) concentration was immeasurably high. Ultrasound demonstrated a snowstorm image consistent with a molar pregnancy (Figures 2, 3). An esmolol drip was initiated

in the ED, and the patient was admitted to the intensive care unit for stabilization. Endocrine and Gynecology consults were obtained. She was diagnosed with thyroid storm and was treated with propylthiouracil (PTU) and potassium iodine. Her headache and cough resolved with treatment. Once clinically stable, she was taken to the operating room for dilatation and curettage (D&C). Pathologic examination of the aborted tissue revealed a complete molar pregnancy with cytogenetic analysis of 46XX. The symptoms of thyroid storm resolved postoperatively. She was weaned off the esmolol drip and placed on atenolol. The PTU and potassium iodine were discontinued before discharge from the hospital. After a total length of stay of 9 days, the patient was discharged home, on atenolol. The ␤-hCG fell rapidly after the D&C. She was advised to have weekly ␤-hCG levels drawn until it was undetectable, and then every 1 to 2 months for a year. She was counseled to avoid pregnancy for at least 1 year. DISCUSSION Gestational trophoblastic diseases (GTDs) are neoplastic disorders arising from the trophoblastic epithelium of the

Table 4. Select Laboratory Values on Admission and Discharge from Teritiary Hospital Test

Admission Value

Discharge Value

Reference Range

TSH Total T3 Total T4 Quantitative ␤-Hcg AST ALT

0.90 ␮IU/mL ⬎ 800 ng/dL ⬎ 29.6 ␮g/dL ⬎ 200,000 mIU/mL 243 units/L 278 units/L

0.15 ␮IU/mL 68 ng/dL 10.6 ␮g/dL 15,501 mIU/mL 33 units/L 45 units/L

0.34–5.60 ␮IU/mL 45–137 ng/dL 4.5–12.0 ␮g/dL ⱕ 2 mIU/mL 10–41 units/L 14–54 units/L

TSH ⫽ thyroid-stimulating hormone; T3 ⫽ triiodothyronine; T4 ⫽ thyroxine; ␤-Hcg ⫽ beta-human chorionic gonadotropin; AST ⫽ aspartate aminotransferase; ALT ⫽ alanine aminotransferase.

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Figure 3. Transvaginal ultrasound transverse uterus demonstrating molar pregnancy.

placenta. They are associated with approximately 121 per 100,000 pregnancies in the United States (1,2). GTDs can be classified into four histologically distinct types: hydatiform mole (complete or partial), persistent invasive gestation trophoblastic neoplasia, choriocarcinoma, and placental site trophoblastic tumors. All four types produce quantities of ␤-hCG higher than in normal pregnancies. Each GTD produces a different quantity of ␤-hCG, with a progression in concentrations from the hydatiform mole (least) to the placental site trophoblastic tumors (most). The diagnosis of GTD should be considered in individuals who have a uterus larger than expected for gestational age and a highly elevated ␤-hCG concentration (3). Complicating the diagnosis of this condition is the fact that the ultrasound detection rate is only 30% to 50%, and the majority of hydatidiform moles appear as a missed or incomplete miscarriage (4). The symptoms of hyperthyroidism associated with GTD are caused by the high concentrations of ␤-hCG acting on the thyroid TSH receptor and inducing release of thyroid hormones. Laboratory studies have shown that normal ␤-hCG has weak thyrotopic activity on thyroid TSH receptors (5). One unit of ␤-hCG has the equivalent reactivity of 0.0013 ␮U of TSH. The bioreactivity of ␤-hCG on the TSH receptor is related to its level of sialylation: the higher the degree of sialylation, the less activity the ␤-hCG will have. The ␤-hCG produced by hydatiform moles has more thyrotropic activity than normal ␤-hCG due to its decreased sialylation (6). Additionally, the extent of desialylation of ␤-hCG varies with each molar pregnancy. The thyrotopic activity of 1 unit of ␤-hCG produced by a GTD ranges from 3.72 to 46.8 ␮U equivalents of TSH (7). Furthermore, the addition of normal TSH to desalyliated ␤-hCG has synergistic effects.

J. B. Moskovitz and M. C. Bond

By elevating the ␤-hCG concentration, a normal pregnancy causes a weak hyperthyroid state. The degree of hyperthyroidism is exacerbated by molar pregnancy, with higher levels of ␤-hCG and decreased levels of sialylation. The level of ␤-hCG, the amount of desialylation, and the duration of the molar pregnancy each has a role in the extent and development of hyperthyroidism, thyrotoxicosis, and thyroid storm. Serum levels of TSH may appear falsely elevated due to cross reactivity of ␤-hCG with the immunoassay. This is minimized with current third-generation TSH tests and normal ␤-hCG, but it is unclear whether desalyliated ␤-hCG has a higher affinity for the immunoassay. Normally, the cross-reactivity for hCG is ⬍ 0.001% (8). In the patient described in this report, TSH values over the first 12 h were reported as 0.90 ␮IU/mL and then 0.05 ␮IU/mL, showing significant variability. Patients with trophoblast-induced hyperthyroid states typically lack the characteristic features associated with Graves’ disease (ophthalmic disease, pretibial myxedema, and acropachy) because this type of thyrotoxicosis is usually of shorter duration (9). Thyrotoxicosis and thyroid storm exist on a continuum, and there is no general consensus on the definition of thyroid storm. Most definitions include elevated temperature, heart rate ⬎ 140 beats/min, and accentuated signs and symptoms of thyrotoxicosis. Only some authors include the need for dysfunction in one or more organ systems (central nervous, cardiovascular, or gastrointestinal system) to make the diagnosis (10). Furthermore, the thyrotoxicosis–thyroid storm continuum includes the potential for central nervous system effects (agitation, delerium, psychosis), gastrointestinal or hepatic dysfunction (nausea, vomiting, diarrhea, abdominal pain, and unexplained jaundice), cardiovascular dysfunction (tachycardia, congestive heart failure, atrial fibrillation), and thermoregulatory dysfunction (10). According to the scoring system by Burch & Wartofsky (Table 5), our patient’s presentation of tachycardia, agitation, abdominal pain, and precipitant history gave her a score of 55, which is highly suggestive of thyroid storm (10). The limited response of our patient’s profound sinus tachycardia to calcium channel blockers, ␤-blockers, and intravenous fluids prompted the treating clinicians to consider the diagnosis. Emergency treatment of thyrotoxicosis or thyroid storm is based on neutralizing the four major elements involved: the thyroid gland; the peripheral effects of thyroid hormone; systemic decompensation, if any; and the precipitating event. The precipitating event in the case presented here is the molar pregnancy, with the definitive treatment being evacuation; therefore, early Obstetrics and Gynecology evaluation was required. Hormone synthesis can be impeded with PTU or methimazole, and hormone release can be decreased with

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Table 5. Diagnostic Scoring System for Thyroid Storm Thermoregulatory dysfunction Temperature 37.2–37.72°C (99–99.9°F) 37.78–38.28°C (100–100.9°F) 38.33–38.83°C (101–101.9°F) 38.89–39.39°C (102–102.9°F) 39.44–39.94°C (103–103.9°F) ⱖ 40°C (104.0°F) Central nervous system effects Absent Mild Agitation Moderate Delirium Psychosis Extreme lethargy Severe Seizure Coma Gastrointestinal-hepatic dysfunction Absent Moderate Diarrhea Nausea/vomiting Abdominal pain Severe Unexplained jaundice Cardiovascular dysfunction Tachycardia 90–109 beats/min 110–119 beats/min 120–129 beats/min 130–139 beats/min ⱖ 140 beats/min Congestive heart failure Absent Mild Pedal edema Moderate Bibasilar rales Severe Pulmonary edema Atrial fibrillation Absent Present Precipitant history Negative Positive

5 10 15 20 25 30 0 10 20

30

0 10

30

5 10 15 20 25 0 5

thyroid hormone can be decreased with ␤-blockers, specifically propanolol and esmolol. Excess hormone, depending on the severity of illness, can be removed with plasmapheresis and charcoal plasma perfusion. Systemic decompensation, including hyperthermia, dehydration, nutrional deficits, and heart failure, are vital components to the resuscitation. Salicylates should be avoided for antipyresis because it can displace thyroid hormone from thyroid-binding protein. Glucose and thiamine should be supplemented because patients with thyrotoxicosis can be nutritionally deficient from the hypermetabolic state. Corticosteroids and vasopressors may be necessary for patients who do not respond to fluid resuscitation alone (10 –12). Molar pregnancies can be treated by dilatation and curettage. Most patients do not require adjunctive therapy with methotrexate or chemotherapy. Low morbidity and mortality are achieved by monitoring patients via serial hCG determinations and instituting chemotherapy only in patients with postmolar gestational trophoblastic neoplasm. Some fatalities have been associated with prophylactic chemotherapy use (13).

CONCLUSION GTD-induced thyroid storm is rare, but must be considered in any woman of childbearing age who presents with symptoms suggestive of hyperthyroidism. It can be ruled out quickly with a negative pregnancy test.

10 15 0 10

Acknowledgment—The manuscript was copyedited by Linda J. Kesselring, MS, ELS, the technical editor and writer in the Department of Emergency Medicine at the University of Maryland School of Medicine.

0 10

Scoring: ⬍ 25 ⫽ unlikely to be thyroid storm; 25– 44 ⫽ suggestive of impending storm; ⱖ 45 ⫽ highly suggestive of thyroid storm. Points are assigned to the highest weighted description applicable in each category and scores totaled. Adapted from (10): Burch HB, Wartofsky L. Life-threatening thyrotoxicosis: thyroid storm. Endo Metab Clin North Am 1993;22:263–77; with permission from Elsevier.

iodine or lithium. It is important not to initiate iodine therapy until 1 h after PTU administration (even though it is readily available in the ED in the form of oral contrast), because iodine can cause a reflex thyroid hormone release. The peripheral effects of thyroid hormone can be muted by decreasing the rate of conversion of T4 to the more active T3. PTU, labetolol, and glucocorticoids all affect this conversion. The peripheral effects of

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