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Cases & Commentaries

Delayed Diagnosis of Endocrinologic Emergencies

Two cases in which thyroid function tests were ordered appropriately but not acted upon in a timely fashion illustrate the challenges of thyroid emergencies. The patient in Case #1 had a history of hyperthyroidism and noted not taking his medications for months, yet no one addressed his abnormal thyroid function tests until hospital day 3. He had thyroid storm. In Case #2, providers neglected to follow up on the patient's abnormal thyroid function tests, even though she was taking a medication with a known risk of thyroid toxicity. She had myxedema coma. Cristiane Gomes-Lima, MD, and Kenneth D. Burman, MD, both of Medstar Washington Hospital Center, discuss thyroid storm and myxedema coma, cognitive biases that may lead to diagnostic errors, and strategies to enhance follow-up of test results.

Cases & Commentaries
Published November 2017

Delayed Diagnosis of Endocrinologic Emergencies

Commentary by Cristiane Gomes-Lima, MD, and Kenneth D. Burman, MD

The Cases

Case #1:

A 47-year-old man with a history of hyperthyroidism and hypertension presented to the emergency department (ED) with subjective symptoms of "not feeling himself." He told the ED clinician that he had been unable to take his medications for several months due to financial difficulties. Initial evaluation revealed low-grade fever, a heart rate of 170 beats per minute, and trace lower extremity edema bilaterally. There were possible infiltrates on his chest radiograph. An electrocardiogram revealed new-onset atrial fibrillation.

The patient was started on a diltiazem drip and admitted to the telemetry unit for management of his heart rhythm and possible pneumonia. He continued to have fevers and tachycardia during the first 2 hospital days despite antibiotics and fluids. On top of that, he developed lethargy and delirium.

A new hospitalist assumed care of the patient on the third hospital day. She reviewed the laboratory results and found that the patient had an undetectable thyroid-stimulating hormone (TSH) level and a high level of circulating thyroid hormone—indicating a diagnosis of thyroid storm (a severely overactive thyroid gland). These laboratory tests had been ordered in the ED. Although results were available the following day, they had not been noted or acted upon. The hospitalist realized that this life-threatening syndrome almost certainly explained the patient's clinical condition. She immediately discontinued intravenous fluids, started treatment with propranolol to control the heart rate and methimazole to suppress thyroid hormone production, and consulted an endocrinologist.

However, the patient remained lethargic and developed hypoxemia over the course of the day. An echocardiogram showed a diminished ejection fraction and dilated left ventricle, consistent with a tachycardia-induced cardiomyopathy (weakness of the heart muscle due to longstanding rapid heart rate). The patient was transferred to the intensive care unit (ICU) due to worsening respiratory status. Shortly after arrival in the ICU, he went into cardiac arrest and could not be resuscitated.

Case #2:

A 53-year-old woman with a history of chronic obstructive pulmonary disease (COPD) on home oxygen, congestive heart failure, atrial fibrillation, status post coronary artery bypass grafting and mechanical aortic valve replacement was admitted with shortness of breath and lower leg swelling for several days attributed to an acute exacerbation of congestive heart failure. On the second hospital day, she developed atrial fibrillation with rapid ventricular response, requiring transfer to the ICU for management. She was started on an amiodarone drip and reverted to normal sinus rhythm within 12 hours. She stabilized and was discharged home on oral amiodarone therapy.

Over the next 3 months, the patient had multiple hospital admissions for presumed COPD exacerbations requiring treatment with bronchodilators, antibiotics, and oral steroids. She also developed abnormal liver function tests and was diagnosed with fatty liver disease. Eventually, she was readmitted to the hospital with hypothermia, hypotension, delirium, and continued hypoxemia. She had bilateral infiltrates on her chest radiograph and was assessed as having septic shock due to pneumonia. She was admitted to the ICU and required noninvasive positive pressure ventilation. Her liver function worsened, and she developed pseudo-obstruction of her colon (Ogilvie syndrome) requiring decompression.

On a Saturday afternoon, well into her prolonged hospital stay, her condition worsened. The covering physician reviewed her old labs and found a very high TSH level and undetectable levels of thyroid hormone. This test had been ordered during a hospitalization one month previously, but the result was not documented in any progress notes, and there was no evidence that anyone had acted on the result. The physician realized that the result likely indicated myxedema coma—systemic illness due to lack of thyroid hormone. Her worsening respiratory status, liver abnormalities, and colonic pseudo-obstruction were all consistent with severe hypothyroidism. This thyroid dysfunction is a known complication of amiodarone therapy, but despite the patient's multiple hospitalizations and overall worsening clinical status, none of her prior physicians had recognized this diagnosis.

The patient was immediately started on levothyroxine and endocrinology was consulted. However, within 24 hours, she went into multi-organ failure and respiratory failure with hypoxia and hypercapnia. She required intubation and mechanical ventilation as well as institution of vasopressors due to shock. Although her condition improved slightly, she could not be weaned from the ventilator and developed a ventilator-associated pneumonia. She had previously stated her wishes to avoid resuscitative measures or a prolonged ICU course. After extensive discussions with her family, the goals of care were changed to comfort measures only. She died peacefully in the ICU after a 3-week hospitalization.

The Commentary

by Cristiane Gomes-Lima, MD, and Kenneth D. Burman, MD

Endocrinology is a medical specialty in which there are far fewer emergency situations than in many other specialties. But emergencies still do occur. Two of them are illustrated by these case reports: thyroid storm and myxedema coma. These are rare but life-threatening conditions that result from either decompensated thyrotoxicosis or severe thyroid hormone deficiency, respectively.(1)

It is difficult to determine accurately the incidence of thyroid storm because of considerable variability in its diagnostic criteria. However, it may occur in 1% to 2% of hospital admissions for thyrotoxicosis.(1) Burch and Wartofsky have proposed a semiquantitative scale for the diagnosis of thyroid storm (Table 1).(2). Applying these criteria to the patient from Case #1, it is highly likely he had thyroid storm on admission. Nonetheless, the emergency department (ED) clinician seems to have mistakenly attributed his symptoms and signs to pneumonia and treated him for this diagnosis. On the third hospital day, a different physician reviewed this diagnosis, noted elevated thyroid function tests, and began to act upon those results. Unfortunately, the delay in diagnosis was crucial for a condition that, even when diagnosed and treated in a timely manner, may result in death. The mortality rates for thyroid storm range from 10%–75% of hospitalized patients.(1)

Myxedema coma has an incidence rate of 0.22 per million per year.(1) It typically presents in older women—frequently in the winter months—but it can occur in both sexes and in younger patients as well.(1) The key diagnostic features are (i) altered mental status (not necessarily coma, notwithstanding the well known complication of myxedema coma), (ii) defective thermoregulation, and (iii) a precipitating event.(3) As with thyroid storm, a scoring system for myxedema has been proposed to improve diagnostic accuracy (Table 2).(4) Underlying diseases, such as congestive heart failure, and metabolic disturbances, particularly those associated with the use of medications such as amiodarone, are among the precipitating factors for myxedema coma in Case #2.(1,4) Amiodarone contains 37.25% iodine by weight, resulting in the release of large amounts of iodine in circulation during its metabolism. Overt amiodarone-induced thyrotoxicosis or amiodarone-induced hypothyroidism may develop in 14% to 18% of all patients treated with this drug. Amiodarone-induced hypothyroidism usually develops between 6 to 18 months of treatment, occurring preferentially in areas with sufficient iodine intake, in females, and in subjects with preexistent thyroid peroxidase antibodies. Amiodarone-induced thyrotoxicosis, on the other hand, is more prevalent in iodine-deficient areas.(5) The patient from Case #2 meets most criteria for the diagnosis of myxedema coma. Even with appropriate intensive care, the mortality rate for myxedema coma is 20% to 25%.(1)

The symptoms of thyroid decompensation are common and nonspecific. Thus, diagnosis can be difficult—especially in the ED, where external demands and internal stresses are often present. When an endocrinologist is brought in as the discussant at a Morbidity and Mortality conference or in a Medicine Grand Rounds, it may seem obvious that a series of nonspecific symptoms and signs pointed to an endocrine emergency. However, in the real world, the diagnosis is often not straightforward. Some of the cognitive biases and system biases that may lead to diagnostic errors are present in both of the reported cases.

In Case #1, by focusing on the early diagnosis of pneumonia, the physician fell victim to an anchoring bias. This was later complicated by confirmation bias, characterized by a tendency to ignore evidence that refutes the initial diagnosis, such as continued fever and tachycardia in spite of the use of antibiotics, as well as the development of lethargy and delirium. Gender biasmay also have contributed to the misdiagnosis, as evidenced by the failure to consider thyroid storm in a man (as thyroid disease is more prevalent in women).(6,7)

In Case #2, each time the patient was admitted for a presumed COPD exacerbation, different physicians demonstrated anchoring bias and, possibly, framing effect. This latter bias is present when diagnosticians are strongly influenced by the way in which the problem is framed.(6,7) Once a diagnostic label is attached to a patient, it becomes increasingly difficult to consider alternative diagnoses, another common bias known as diagnosis momentum.(6)

In addition to these biases, in both cases thyroid function tests that were ordered appropriately had not been noted and acted upon in a timely fashion. The patient in Case #1 had a history of hyperthyroidism and noted not taking his medications for months, yet no one addressed his abnormal thyroid function tests until hospital day 3. In Case #2, providers neglected to follow up on the patient's abnormal thyroid function tests, even though she was taking a medication with a known risk of thyroid toxicity. These gaps may have occurred as a consequence of lack of effective communication among different provider groups, poor handoffs, or delayed turnaround time of some laboratory tests.(7) In a prospective study, the implementation of the handoff program I-PASS was associated with a reduction of medical errors and in preventable adverse events. The I-PASS mnemonic stands for Illness severity, Patient summary, Action list, Situation awareness and contingency plans, and Synthesis by receiver.(8)

In the presented cases, it is unclear whether thyroid function tests were ordered as part of the ED/hospitalization routine laboratory tests or as a consequence of rational differential diagnostic reasoning. It is a basic premise in medicine that laboratory tests should be ordered as part of a Bayesian reasoning process to guide testing. In other words, the clinicians should predict the probability of a specific disease given a test result. Unnecessary (particularly "shotgun") testing risks missing important findings and confounding the diagnostic process.(9,10) In general, thyroid function tests and hormone assay results are not available as quickly as more routine tests such as complete blood counts or chemistry panels, and this timing may have contributed to follow-up failures in both cases. In our institution, the turnaround time of thyroid-stimulating hormone is 1 to 2 days, while free thyroxine and total triiodothyronine turnaround time is generally about 1 to 3 days. As thyroid function tests are not considered emergency tests with potential life-threatening consequences, they are not typically run on a stat basis. Clinicians should be able to request faster thyroid function tests and other hormonal results, either by flagging the laboratory or by directly calling it. In addition, laboratory phone calls to the attending physician for markedly abnormal tests would likely decrease delays in care delivery.

System errors reflect latent flaws in the health care system, which need to be addressed through attention to system design and performance.(11) For instance, in the case of laboratory tests the use of an alert notification system in the electronic health record (EHR), as well as electronic acknowledgement of test review, may be useful in the follow-up of pending diagnostic studies. However, a study in the outpatient setting demonstrated that provider acknowledgment of receipt of the test result does not automatically result in timely follow-up.(12) Missing results might be related to information overload from alert notifications, electronic handoffs of care, or poor usability of the EHR.(13) Follow-up failures (missed results) are more prone to occur in the outpatient than in the inpatient setting due to the fragmented nature of the visits. However, the cases presented here are examples that this situation may also occur in the inpatient setting.

Frequently, diagnostic errors are a combination of cognitive and system-related factors. In a retrospective study, both factors contributed to diagnostic error in 46% of the cases.(14) In both case reports presented, a lack of mechanisms to ensure follow-up of abnormal test results negatively reinforced cognitive biases in diagnostic reasoning, contributing to the delayed diagnosis of these endocrinologic emergencies.

Take-Home Points

Thyroid storm and myxedema coma are rare endocrine emergencies that require high suspicion and immediate treatment.
Cognitive biases may lead to diagnostic errors in endocrine emergencies, especially anchoring bias, confirmation bias, and framing effect.
Hormone tests, in general, have a longer turnaround time than routine laboratory tests that may contribute to follow-up failures (missed results).
Measures to prevent follow-up failures should include improved handoffs, alert notifications, electronic acknowledgement of receipt of pending tests, and laboratory phone calls to the attending physician on specific situations.

Cristiane Gomes-Lima, MD
Endocrinology Research Fellow
MedStar Washington Hospital Center
MedStar Health Research Institute

Kenneth D. Burman, MD
Professor of Medicine, Georgetown University
Director of the Endocrine Section
MedStar Washington Hospital Center

References

1. Klubo-Gwiezdzinska J, Wartofsky L. Thyroid emergencies. Med Clin North Am. 2012;96:385-403. [go to PubMed]

2. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. 1993;22:263-277. [go to PubMed]

3. Wiersinga WM. Adult hypothyroidism. In: De Groot LJ, Beck-Peccoz P, Chrousos G, Dungan K, Grossman A, Hershman JM, et al., eds. Endotext. South Dartmouth, MA: MDText.com, Inc.; 2000.[go to PubMed]

4. Popoveniuc G, Chandra T, Sud A, et al. A diagnostic scoring system for myxedema coma. Endocr Pract. 2014;20:808-817. [go to PubMed]

5. Eskes SA, Wiersinga WM. Amiodarone and thyroid. Best Pract Res Clin Endocrinol Metab. 2009;23:735-751. [go to PubMed]

6. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003;78:775-780. [go to PubMed]

7. Mull N, Reilly JB, Myers JS. An elderly woman with 'heart failure': cognitive biases and diagnostic error. Cleve Clin J Med. 2015;82:745-753. [go to PubMed]

8. Starmer AJ, Spector ND, Srivastava R, et al; I-PASS Study Group. Changes in medical errors after implementation of a handoff program. N Engl J Med. 2014;371:1803-1812. [go to PubMed]

9. Field MH. To the Editor: Cognitive bias and diagnostic error. Cleve Clin J Med. 2016;83:407-408. [go to PubMed]

10. Mull N, Reilly JB, Myers JS. In Reply: Cognitive bias and diagnostic error. Cleve Clin J Med. 2016;83:408. [go to PubMed]

11. Graber M, Gordon R, Franklin N. Reducing diagnostic errors in medicine: what's the goal? Acad Med. 2002;77:981-992. [go to PubMed]

12. Singh H, Thomas EJ, Sittig DF, et al. Notification of abnormal lab test results in an electronic medical record: do any safety concerns remain? Am J Med. 2010;123:238-244. [go to PubMed]

13. Singh H, Spitzmueller C, Petersen NJ, Sawhney MK, Sittig DF. Information overload and missed test results in electronic health record-based settings. JAMA Intern Med. 2013;173:702-704. [go to PubMed]

14. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. Arch Intern Med. 2005;165:1493-1499. [go to PubMed]

Tables

Table 1. Diagnostic Criteria for Thyroid Storm.(Adapted From 2)

Thermoregulatory Dysfunction	Score
Temp °F (°C)
99–99.9 (37.2–37.7)	5
100–100.9 (37.8–38.2)	10
101–101.9 (38.3–38.8)	15
102–102.9 (38.9–39.4)	20
103–103.9 (39.5–39.9)	25
≥104.0 (≥40)	30
Central Nervous System Effects
Absent	0
Mild (agitation)	10
Moderate (delirium, psychosis, extreme lethargy)	20
Severe (seizure, coma)	30
Gastrointestinal-Hepatic Dysfunction
Tachycardia
90–109	5
110–119	10
120–129	15
129–139	20
≥140	25
Congestive Heart Failure
Absent	0
Mild (pedal edema)	5
Moderate (bibasilar rales)	10
Severe (pulmonary edema)	15
Atrial Fibrillation
Absent	0
Present	10
Precipitant History
Negative	0
Positive	10

Score <25: unlikely; 25–44: suggestive of impending storm; ≥45: highly suggestive of thyroid storm.

Table 2. Diagnostic Criteria for Myxedema Coma.(Adapted From 4)

Thermoregulatory Dysfunction	Score
Temp °F (°C)
>95 (35)	0
89.6–95 (32–35)	10
<89.6 (<32)	20
Central Nervous System Effects
Absent	0
Somnolent/lethargic	10
Obtunded	15
Stupor	20
Coma/seizures	30
Gastrointestinal Findings
Anorexia/abdominal pain/constipation	5
Decreased intestinal motility	15
Paralytic ileus	20
Cardiovascular Dysfunction
Bradycardia
Absent	0
50–59	10
40–49	20
<40	30
Other ECG changes*	10
Pericardial/pleural effusions	10
Pulmonary edema	15
Cardiomegaly	15
Hypotension	20
Metabolic Disturbances
Hyponatremia	10
Hypoglycemia	10
Hypoxemia	10
Hypercarbia	10
Decrease in GFR	10
Precipitant Event
Negative	0
Positive	10