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148
B. H. Malik and M. S. Hameed
tissues and are responsible for all thyroid activities [12, 17]. Urinary protein losses are negligible under normal circumstances. In NS, however, substantial urinary pro­tein losses occur, including T4 and T3 along with their binding proteins, as well as the free fractions fT4 and fT3 to a lesser extent [2, 4, 5, 18, 19]. This explains why thyroid function abnormalities are so common in people with NS, which is a renal­endocrine illness [2]. Milder symptoms and normal levels of free hormones are seen early in the disease process [2, 4]. fT4 and fT3 are also dramatically lowered if the protein losing processes carry on for longer periods causing subclinical hypothyroid state [4, 19]. High urinary protein levels and increased serum creatinine were found to be independent risk factors for thyroid dysfunction in a study of individuals who had been ofcially diagnosed with NS, while a greater level of plasmatic albumin was found to be an independent protective factor [5]. In ve children with congeni­tal NS, lasting cure of hypothyroidism after bilateral nephrectomy had already been documented [14]. This nding demonstrates that hypothyroidism was not caused by an intrinsic abnormality in the thyroid gland. Corticosteroids may contribute to thy­roid dysfunction by suppressing serum TSH levels, impairing peripheral T4 to T3 conversion, and lowering TBG synthesis (which might be the contributory factor in this case) [9]. In addition to NS, hypothyroidism has been linked to some glomeru­lonephritides (GN) [2, 20, 21].

Conclusion

Renal disease evaluation should be commenced when diagnosis of hypothyroidism is made. Severity of thyroid dysfunction and treatment response are determined jointly by clinical circumstances and proteinuria severity. The necessity of a clearer understanding of the relationships between thyroid and renal functions is high­lighted in this case study. When nephrotic syndrome is rst identied, it is fair to evaluate thyroid function and then perform serial testing.

References

1. Bradley SE, Stephan F, Coelho JB, Reville P. The thyroid and the kidney. Kidney Int. 1974;6(5):346–65.
2. Dousdampanis P, Trigka K, Vagenakis GA, Fourtounas C.The thyroid and the kidney: a com­plex interplay in health and disease. Int J Artif Organs. 2014;37(1):1–12.
3. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of sub­clinical hypothyroidism in chronic kidney disease patients. Clin J Am Soc Nephrol. 2008;3(5):1296–300.
4. Jain D, Aggarwal HK, Pavan Kumar YM, Jain P.Evaluation of thyroid dysfunction in patients with nephrotic syndrome. Med Pharm Rep. 2019;92(2):139–44.
5. Li L-Z, Hu Y, Ai S-L, etal. The relationship between thyroid dysfunction and nephrotic syn­drome: a clinicopathological study. Sci Rep. 2019;9(1):6421.
22 Hypothyroidism withNephrotic Syndrome Misdiagnosed asCardiac Failure
6. Lo JC, Chertow GM, Go AS, Hsu C-Y.Increased prevalence of subclinical and clinical hypo­thyroidism in persons with chronic kidney disease. Kidney Int. 2005;67(3):1047–52.
7. Rhee CM, Kalantar-Zadeh K, Streja E, etal. The relationship between thyroid function and estimated glomerular ltration rate in patients with chronic kidney disease. Nephrol Dial Transplant. 2015;30(2):282–7.
8. Chandurkar V, Shik J, Randell E.Exacerbation of underlying hypothyroidism caused by pro­teinuria and induction of urinary thyroxine loss: case report and subsequent investigation. Endocr Pract. 2008;14(1):97–103.
9. Burch HB.Drug effects on the thyroid. N Engl J Med. 2019;381(8):749–61.
10. Fonseca V, Thomas M, Katrak A, Sweny P, Moorhead JF.Can urinary thyroid hormone loss cause hypothyroidism? Lancet. 1991;338(8765):475–6.
11. Jung SH, Lee JE, Chung WY. Changes in the thyroid hormone proles in children with nephrotic syndrome. Korean J Pediatr. 2019;62(3):85–9.
12. Maiden MJ, Torpy DJ.Thyroid hormones in critical illness. Crit Care Clin. 2019;35(2):375–88.
13. Benvenga S, Vita R, Di Bari F, Fallahi P, Antonelli A.Do not forget nephrotic syndrome as a cause of increased levothyroxine replacement therapy. Eur Thyroid J. 2015;4(2):138–42.
14. Chadha V, Alon US.Bilateral nephrectomy reverses hypothyroidism in congenital nephrotic syndrome. Pediatr Nephrol. 1999;13(3):209–11.
15. Karethimmaiah H, Sarathi V. Nephrotic syndrome increases the need for levothyroxine replacement in patients with hypothyroidism. J Clin Diagn Res. 2016;10(12):OC10.
16. Soh S, Aki O, Manabu O, Norimasa K, Hiroshi K, Masao N.A case of minimal change nephrotic syndrome with hypothyroidism deterioration. CEN Case Rep. 2016;5:95.
17. Bartalena L, Robbins J.Thyroid hormone transport proteins. Clin Lab Med. 1993;13(3):583–98.
18. Levey AS, Stevens LA, Schmidetal CH.A new equation to estimate glomerular ltration rate. Ann Intern Med. 2009;150(9):604–12.
19. Alam ABM, Hasan ANM, Khan AH, Quader MMU, Begum SA, Banik SK. Association between primary hypothyroidism and nephrotic syndrome: a case report. Chattagram Maa-o­Shishu Hosp Med College J. 2013;12(2):63–5.
20. Mariani LH, Berns JS. The renal manifestations of thyroid disease. J Am Soc Nephrol. 2012;23(1):22–6.
21. Connie MR. Thyroid and kidney disease interactions: a review of the evidence. Curr Opin Endocrinol Diabetes Obes. 2016;23(5):407–15.
149
Chapter 23
Adrenal Insufciency Misdiagnosed asSyndrome ofInappropriate ADH Secretion
IvanCancarevic
Learning Objectives
By the end of this presentation, the clinician will be able to:
1. Identify the clinical ndings associated with adrenal insufciency.
2. Discuss and enumerate the classication and common causes of hyponatremia.
3. Apply the aforementioned concepts in a clinical scenario.
4. Analyze the basics of hyponatremia management.
5. Discuss the potential for misdiagnosis of the cause of hyponatremia in the set­ting of adrenal insufciency.

Introduction

Hyponatremia is generally dened as a sodium level below 136mEq/L and can be seen in a variety of clinical settings. Pseudohyponatremia refers to a falsely low reading of serum sodium levels, usually due to the presence of very high amounts of protein or lipid in the blood, giving the appearance of a larger serum volume [1]. Real hyponatremia usually also indicates serum hyperosmolality. It is further divided based on the patient’s volume status into hypovolemic hyponatremia, euvolemic hyponatremia, and hypervolemic hyponatremia [2]. Hypovolemic hypo­natremia develops in the setting of a loss of both free water and sodium; however, the loss of sodium exceeds the loss of free water [2, 3]. Hypervolemic hyponatre­mia, on the other hand, develops in the setting of disproportionate retention of free water in comparison to sodium, leading to decreased concentration of serum sodium, typically in patients with underlying heart or liver disease [2, 4, 5]. Euvolemic
I. Cancarevic (*) Icahn School of Medicine at Mount Sinai, New York, NY, USA
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_23
151
152
I. Cancarevic
hyponatremia refers to the setting where the patient is euvolemic, but the serum concentration of sodium is low. The most common causes are the syndrome of inap­propriate antidiuretic hormone (SIADH), primary polydipsia, and endocrinopa­thies, such as hypothyroidism and adrenal insufciency [2, 6, 7].
Aldosterone, the end hormone of the renin-angiotensin-aldosterone system (RAAS), acts on the distal nephron stimulating potassium secretion and sodium reabsorption. Adrenal insufciency, therefore, tends to present with impairment of both processes resulting in hyponatremia and hyperkalemia [8]. Patients are typi­cally hypovolemic, although it can be difcult to assess since volume loss is not always signicant [2].
Clinically, there are a number of ways to assess volume status, although it is not always easy to do. Vital signs, physical exam, and even ndings on the point-of-care ultrasound testing all help get a sense of the patient’s volume status, but unless the volume decit is severe, it may go unnoticed [9]. Therefore, it is easy to understand why diagnosing the etiology of hyponatremia is challenging, and misdiagnosis is common.

Clinical Case Presentation

A 53-year-old female with a past medical history of hypothyroidism managed with a stable dose of levothyroxine was admitted to the hospital for a syncopal episode, which happened while walking to the bathroom in her apartment. The patient also reported a recent history of fatigue, nonspecic abdominal discomfort, and anorexia. Vitals signs on admission were signicant for blood pressure of 100/64mmHg and heart rate of 105/min. Initial laboratory tests revealed hemoglobin of 10.7g/dL (the patient at the time still had regular periods), sodium of 126mEq/L, and potassium of 5.1mEq/L.Initial EKG showed sinus rhythm. A head CT was ordered, and it was unrevealing. The physical exam was unremarkable, and there was no evidence of volume depletion– skin turgor was normal, and the patient’s mucosal surfaces were not appearing to be dry. Due to the patient’s apparent euvolemic state and lack of clinical ndings suggestive of acute hyponatremia, the admitting resident initially diagnosed the patient with SIADH-induced euvolemic hyponatremia, and water restriction was ordered. The resident feared that, in the setting of low hemoglobin levels, the patient might have an underlying malignancy that may have triggered the SIADH, and he recommended pursuing a malignancy workup in this patient. Additionally, in order to rule out a cardiogenic cause of syncope, the patient was placed on telemetry monitoring. The next day, the patient got dizzy when she attempted to go to the bathroom, and her morning sodium level was 124mEq/L despite having less than 1200mL of water the previous day. Thyroid-stimulating hormone (TSH) levels obtained on admission were found to be within normal range, effectively ruling out thyroid disease causing any of the patient’s symptoms or nd­ings. On the physical exam, her volume status was notably changing, and her muco­sal surfaces appeared much drier than on admission. Telemetry revealed no abnormal
23 Adrenal Insufciency Misdiagnosed asSyndrome ofInappropriate ADH Secretion
rhythms at any time, although sinus tachycardia was noted around the time when the patient went to the bathroom and became dizzy. Supine blood pressure remained stable. Orthostatic vital signs were obtained, and the patient became hypotensive to 74/52mmHg, and a 1L bolus of normal saline was administered, leading to mild symptomatic improvement and blood pressure elevation. Urine electrolytes were obtained and showed sodium of 45mmol/L with markedly decreased urine potas­sium, indicating simultaneous sodium wasting and potassium retention. Those nd­ings, combined with postural hypotension, generalized fatigue, and anorexia, were consistent with the diagnosis of adrenal insufciency, and an endocrine workup was initiated. Aldosterone levels were found to be markedly decreased with elevated levels of renin, indicating primary adrenal disorder. The patient was subsequently started on udrocortisone which led to the normalization of her electrolyte levels.
153

Differential Diagnosis

1. Adrenal insufciency– it is frequently diagnosed late because the symptoms are
highly nonspecic, and even the laboratory ndings, other than decreased hor­mone levels, can be seen with a number of other conditions– notably, a combi­nation of hyponatremia and hyperkalemia is characteristic.
2. Hyponatremia– rarely symptomatic unless acute and/or severe, in which case
patients usually present with neurological symptoms. It can be caused by a num­ber of factors and is classied according to the patient’s volume status.
3. SIADH– a common cause of euvolemic hyponatremia, frequently in the setting
of another disease or condition, such as malignancies or brain or lung disease, and is typically managed with water restriction.

Alternative Diagnoses

Initially, due to the lack of obvious signs of hypovolemia, an inexperienced clinician diagnosed the patient with SIADH and placed the patient on uid restriction, which made her symptoms worse.

Discussion

As illustrated in this case, determining the etiology of hyponatremia is not always straightforward, and the consequences of inaccurate diagnosis and treatment can be life-threatening for the patient. The initial step in the assessment of hyponatremia is to ensure that it is not pseudohyponatremia by doing the appropriate corrections. Afterward, as previously stated, carefully assessing volume status is crucial in
154
I. Cancarevic
patients with newly diagnosed hyponatremia. Moreover, analysis of osmolality and electrolyte levels both in the blood and in the urine is necessary to determine the exact etiology. For example, hypovolemic patients are likely to have very low levels of urinary sodium, whereas someone like the patient presented in this case, who has adrenal insufciency, will have higher levels of urinary sodium, indicating sodium wasting. Serum potassium levels are important, in particular, to assess adrenal func­tion since adrenal or aldosterone receptor diseases have the opposite effects on sodium and potassium. Treatment, importantly, also varies based on the etiology of hyponatremia. Volume repletion is generally needed in cases of hypovolemia, while water restriction is encouraged with euvolemic and hypervolemic hyponatremia [10]. In cases of euvolemic hyponatremia, psychogenic polydipsia needs to be ruled out– usually by assessing urine osmolality and, as needed, doing a water depriva­tion test which will result in a prompt increase in urine osmolality [11]. Frequently, in the hospital setting, SIADH becomes the “default” diagnosis even before the entire workup has been completed, which, like in this case, increases the probability that subtler presentations of other conditions may be missed. Another thing worth mentioning is that, in this case, the patient already had a history of hypothyroidism, which predisposes her to other autoimmune endocrine disorders, such as adrenal insufciency. Moreover, hypothyroidism itself could be a cause of hyponatremia in some patients, although this patient’s current TSH level is normal, so it is not a likely cause in her. Obtaining hormone levels if there is any suspicion of endocrine disease needs to be part of the workup since the condition can progress and become life-threatening [12]. For instance, had this patient not been diagnosed, it is feasible that in the near future, she could have developed an adrenal crisis. Treatment of adrenal insufciency depends on the hormones that are affected (which depends on the zones of the adrenal gland that are affected) but typically involve glucocorti­coids, such as hydrocortisone or prednisone, as well as udrocortisone. Hormonal supplementation should lead to the normalization of electrolyte levels.

Conclusion

When a patient is found to be hyponatremic, it is extremely important not to assume the diagnosis without performing an adequate workup. Moreover, assessment of vol­ume status is essential and should include vital orthostatic signs. Endocrine disor­ders, such as hypothyroidism or adrenal insufciency, should not be overlooked as a possible cause of hyponatremia. Treatment depends on the underlying etiology, and misdiagnosing and incorrectly treating hyponatremia can have dire consequences.
23 Adrenal Insufciency Misdiagnosed asSyndrome ofInappropriate ADH Secretion
155

References

1. Weisberg LS.Pseudohyponatremia: a reappraisal. Am J Med. 1989;86(3):315–8. https://doi.
org/10.1016/0002- 9343(89)90302- 1.
2. Bufngton MA, Abreo K.Hyponatremia: a review. J Intensive Care Med. 2016;31(4):223–36.
https://doi.org/10.1177/0885066614566794.
3. Mohottige D, Lehrich RW, Greenberg A. Hypovolemic hyponatremia. Front Horm Res.
2019;52:93–103. https://doi.org/10.1159/000493240.
4. Solà E, Ginès P.Hypervolemic hyponatremia (liver). Front Horm Res. 2019;52:104–12. https://
doi.org/10.1159/000493241.
5. Rodriguez M, Hernandez M, Cheungpasitporn W, et al. Hyponatremia in heart failure:
pathogenesis and management. Curr Cardiol Rev. 2019;15(4):252–61. https://doi.org/10.217
4/1573403X15666190306111812.
6. Garrahy A, Thompson CJ. Hyponatremia and glucocorticoid deciency. Front Horm Res.
2019;52:80–92. https://doi.org/10.1159/000493239.
7. Verbali G. Euvolemic Hyponatremia Secondary to the Syndrome of Inappropriate Antidiuresis.
Front Horm Res. 2019;52:61–79. https://doi.org/10.1159/000493238.
8. Meneton P, Lofng J, Warnock DG. Sodium and potassium handling by the aldosterone-sen-
sitive distal nephron: the pivotal role of the distal and connecting tubule. Am J Physiol Renal
Physiol. 2004;287(4):F593–F601. https://doi.org/10.1152/ajprenal.00454.2003.
9. Scott MC, Mallemat H. Assessing volume status. Emerg Med Clin North Am.
2014;32(4):811–822. https://doi.org/10.1016/j.emc.2014.07.007.
10. Hoorn EJ, Zietse R. Diagnosis and Treatment of Hyponatremia: Compilation of the Guidelines.
J Am Soc Nephrol. 2017;28(5):1340–1349. https://doi.org/10.1681/ASN.2016101139.
11. Kotagiri R, Kutti Sridharan G. Primary Polydipsia. [Updated 2022 Apr 30]. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK562251/.
12. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insuf-
ciency. Lancet Diabetes Endocrinol. 2015;3(3):216–226. https://doi.org/10.1016/
S2213-8587(14)70142-1.
Chapter 24
Pheochromocytoma Misdiagnosed asCOVID-19
AllisonFoster
Learning Objectives
By the end of this presentation, the clinician will be able to:
1. Discuss the clinical ndings associated with pheochromocytoma.
2. Enumerate the clinical ndings associated with COVID-19.
3. Apply the aforementioned knowledge to clinical scenarios.
4. Analyze the risk of misdiagnosis of pheochromocytoma.
5. Discuss the initial management of said conditions.

Introduction

Pheochromocytoma is an uncommon tumor of the adrenal medulla that secretes catecholamines. It typically presents with hypertension, headaches, diaphoresis, and palpitations, which may be constant or intermittent [1]. Those symptoms, how­ever, are not specic and can be suggestive of a variety of other cardiac or pulmo­nary diseases. Therefore, the condition is frequently diagnosed late or misdiagnosed [1, 2]. In those cases, it can become life-threatening [1, 2]. Symptoms are caused by catecholamine overproduction, and the best diagnostic test is to measure metaneph­rines or normetanephrine in the urine [3]. It is managed with alpha-blockers, as well as other appropriate treatments for hypertension and arrhythmias [3]. The denitive and often curative treatment is surgery [3]. Excess catecholamines or adrenergic agonists can lead to the development of cardiomyopathy [4, 5]. In fact, in many cases, an underlying pheochromocytoma has been discovered in patients with car­diomyopathies even without characteristic symptoms of catecholamine excess [5].
A. Foster (*) Icahn School of Medicine at Mount Sinai, New York, NY, USA
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. Tohid et al. (eds.), The Misdiagnosis Casebook in Clinical Medicine,
https://doi.org/10.1007/978-3-031-28296-6_24
157
158
A. Foster
COVID-19 is the most talked-about disease of 2020 and 2021 since it created a global pandemic, the likes of which have not been seen in decades. It is spread through the respiratory route, and it typically presents with a combination of upper and lower respiratory symptoms, such as cough, shortness of breath, and fever [6]. Importantly, a number of atypical presentations of COVID-19 involving almost any other organs and systems have been reported. Myocarditis is one of the most fre­quently reported ones [7, 8]. It typically presents with chest discomfort and dys­pnea, although more dramatic presentations, including sudden cardiac death, can occur [9]. Precise diagnosis often requires either advanced imaging, such as cardiac MRI or even myocardial biopsy [8]. In patients suffering from COVID-19 who are short of breath at baseline, the diagnosis of myocarditis may be delayed even fur­ther. Therefore, for a patient with acute shortness of breath and chest discomfort, COVID-19 would likely be one of the rst differential diagnoses a clinician would think about, while many will not even think about pheochromocytoma.

Clinical Case Presentation

A 42-year-old female presented to the emergency department with new-onset acute shortness of breath. She had also experienced intermittent chest discomfort that she could not describe any further, nausea, vomiting, and generalized malaise for several days prior to this presentation. On physical exam, she was mildly febrile with a tem­perature of 38.2 °C (equivalent to 100.8°F), heart rate was 102 per minute, and blood pressure was normal, but the patient desaturated on room air and was placed on 12L of oxygen via OxyMask in order to achieve saturation of 97%. Initial lab work was signicant for a white blood cell (WBC) count of 25,000/uL with lympho­penia. Troponin and pro-BNP were markedly elevated. Chest CT was signicant for diffuse ground-glass opacities with septal thickening, a nding frequently associated with COVID-19 pneumonia. EKG was signicant for ST depression in leads II, III, and aVF.At the time, PCR testing for the SARS-CoV-2 virus took 48h, and patients were typically treated for COVID-19 based on clinical ndings alone, pending results of the nasal swab PCR.The patient was, therefore, diagnosed with COVID-19 pneumonia and COVID-19-related non-ST elevation myocardial infarction (NSTEMI) . She was initially treated with broad-spectrum antibiotics for possible secondary bacterial pneumonia and aspirin and heparin for NSTEMI.Corticosteroids were not given. She was provided symptomatic treatment for COVID-19. Interestingly, the PCR test for COVID-19 was negative. It was subsequently repeated and returned negative again, so COVID-19 was ruled out as a differential diagnosis, and another cause of pneumonia was suspected. In the meantime, pro-BNP contin­ued trending up, tachycardia persisted, and the patient became hypotensive. An echocardiogram was performed, which showed an ejection fraction of 25% with segmental wall motion abnormalities. No previous echocardiograms were available, but the patient-reported unlimited exercise tolerance and no history of chest pain or dyspnea. A repeat CT scan was performed a week after the presentation, and
24 Pheochromocytoma Misdiagnosed asCOVID-19
ground-glass opacities mostly resolved, which supported the idea that the patient had suffered from pneumonia that improved with treatment. At the time, the working diagnosis became idiopathic acute heart failure. The patient started developing wors­ening volume overload. Overnight, 10 days after the admission, the patient com­plained of worsening abdominal discomfort, and the covering physician ordered a CT scan of the abdomen which incidentally showed a mass in the left adrenal gland. Blood pressure was on the lower end of the reference range throughout the hospital­ization. Renin and aldosterone levels were within normal range.
Urine metanephrines were minimally elevated. Left adrenalectomy was per­formed, and the tissue biopsy conrmed the diagnosis of pheochromocytoma. All symptoms resolved, and cardiac function returned to baseline 3 months after the surgery. The patient was subsequently followed for a year and remained symptom-free.
159

Differential Diagnosis

COVID-19– it is nowadays one of the most common respiratory infections that can affect both upper and lower airways, with the most common symptoms being dys­pnea, cough, and fever, although a number of nonspecic symptoms and atypical presentations have been reported.
Myocarditis– inammation of the myocardium, frequently viral, presenting with symptoms which can be confused for COVID-19, including shortness of breath and cough.
Pheochromocytoma– tumor of the adrenal medulla that secretes catecholamines and presents with constant or intermittent hypertension, headache, and palpitations.

Alternative Diagnoses

Due to the similarity of the clinical presentation and high prevalence of COVID-19in the general population, the patient had been initially diagnosed with COVID-19 based on the clinical picture and missed the actual diagnosis of pheochromocytoma­induced myocarditis.

Discussion

This case clearly illustrates many of the issues faced by providers in clinical prac­tice. Initially, the patient presented with nonspecic symptoms, which could be explained by a number of different cardiovascular or pulmonary conditions. At the