Endocrine Board Review 2021

Serge A Jabbour

• Publisher: Endocrine Society
• Year: 2022
• eBook ISBN: 9781936704088
• Edition: 1
• Topic: Medicine
• Subtopic: Clinical Medicine

Endocrine Board Review (EBR) Reference Edition 2021 is a board examination preparation book designed for endocrine fellows who have completed or are nearing completion of their fellowship and are preparing to sit for the board certification exam, and for practicing endocrinologists in search of a comprehensive self-assessment of endocrinology, either to prepare for recertification or to update their practice. EBR consists of approximately 240 case-based, American Board of Internal Medicine (ABIM) style, multiple-choice questions. Each section follows the ABIM Endocrinology, Diabetes, and Metabolism Certification Examination blueprint, covering the breadth and depth of the certification and recertification examinations. Each case is discussed in detail with comprehensive answer explanations and references provided. CME, MOC, online module not included. Updated annually.

ANSWERS

ENDOCRINE
BOARD
REVIEW 2021

Adrenal Board Review

Tobias Else, MD

1 ANSWER: D) Homocysteine and methylmalonic acid measurement
Autoimmune polyendocrine syndromes (APS) can be grouped into APS type 1 and APS type 2. APS type 1 is an autosomal recessive disorder caused by pathogenic variants in the AIRE gene. The main manifestations are primary adrenal insufficiency, hypoparathyroidism, and mucocutaneous candidiasis, but other autoimmune endocrinopathies can also occur (eg, hypothyroidism [20%], pernicious anemia [15%]). This patient lacks the core manifestations of hypoparathyroidism and mucocutaneous candidiasis, but she most likely has 2 manifestations of APS type 2. The main manifestations of APS type 2 in patients with adrenal insufficiency are hypothyroidism (40%), type 1 diabetes mellitus (10%), vitamin B₁₂ deficiency (10%), and vitiligo (10%).

Further evaluation for atrophic gastritis and vitamin B₁₂ deficiency will most likely identify this reversible cause of the patient’s neurologic symptoms. While values well below the lower limit of normal are often diagnostic for B₁₂ deficiency, borderline levels (200-300 pg/mL) are best followed up by homocysteine and methylmalonic acid level measurement (Answer D). Methylmalonic acid is the most specific and sensitive marker for vitamin B₁₂ deficiency. Treatment consists of vitamin B₁₂ supplementation, either with initially intramuscular B₁₂ or high oral doses. Atrophic gastritis and vitamin B₁₂ deficiency can present with neurologic symptoms without any hematologic or gastrointestinal symptoms or signs.

Celiac disease is best diagnosed with esophagogastroduodenoscopy and deep duodenal biopsies (Answer C). Celiac disease coexists in about 5% of patients with APS type 2. Celiac disease is associated with a broad spectrum of neurologic manifestations, but other symptoms or signs are commonly present as well. Assessing for tissue transglutaminase-IgA antibodies (Answer E) is the screening of choice for celiac disease. IgA deficiency can lead to false-negative screening, but in this case tissue transglutaminase-IgG was also negative.

Diminished ankle reflexes, particularly with a delayed relaxation phase, are associated with hypothyroidism. However, there is no concern in this patient that the slightly increased/upper-limit TSH reflects current severe underreplaced hypothyroidism and no other hypothyroid symptoms are present. Thus, free T₄ measurement (Answer B) is not necessary.

Adrenoleukodystrophy (Answer A) is an X-linked recessive disorder and can initially present with adrenal insufficiency and later with myelopathy with the neurologic manifestations of sensory ataxia and neurogenic bladder dysfunction. Although female carriers can develop myelopathy, adrenal insufficiency in female carriers is exceedingly rare.

EDUCATIONAL OBJECTIVE

Identify atrophic gastritis as an autoimmune disorder that occurs with adrenal insufficiency.

REFERENCE(S)

Erichsen MM, Løvås K, Skinningsrud B, et al. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry. J Clin Endocrinol Metab. 2009;94(12):4882-4890. PMID: 19858318

Bruserud O, Oftedal BE, Landegren N, et al. A longitudinal follow-up of autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2016;101(8):2975-2983. PMID: 27253668

Green R, Allen LH, Bjørke-Monsen A-L, et al. Vitamin B₁₂ deficiency. Nat Rev Dis Primers. 2017;3:17040. PMID: 28660890

Kemp S, Huffnagel IC, Linthorst GE, Wanders RJ, Engelen M. Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history. Nat Rev Endocrinol. 2016;12(10):606-615. PMID: 27312864

2 ANSWER: D) Measure plasma free metanephrines, calcitonin, and carcinoembryonic antigen
This patient has a germline pathogenic variant in the RET gene conferring an increased risk for manifestations related to multiple endocrine neoplasia (MEN) type 2A, such as primary hyperparathyroidism, medullary thyroid cancer, and pheochromocytoma. The p.V804M variant is associated with a moderate risk for medullary thyroid cancer (American Thyroid Association guidelines), and recent studies have shown a lower risk for medullary thyroid cancer than previously estimated. Therefore, the best initial screening and lifelong surveillance for this patient is annual biochemical screening with calcium (currently normal), metanephrines (plasma or urine), calcitonin, and carcinoembryonic antigen (CEA) (Answer D). Catecholamines, epinephrine, and norepinephrine should not be used for pheochromocytoma screening due to lack of sensitivity and specificity. Measurement of plasma or urinary metanephrines is the standard of care. Only in the case of elevated or increased levels of metanephrines or calcitonin/CEA would imaging be indicated to evaluate for a pheochromocytoma or medullary thyroid cancer, respectively.

Thyroidectomy (Answer A) should not be immediately recommended, but it is definitely indicated if there is evidence for disease. Preoperatively, pheochromocytoma must be excluded. Imaging (Answers B and E) is not part of regular screening for MEN 2A because all manifestations are best surveilled biochemically. While PTH and 25-hydroxyvitamin D (Answer C) are often measured along with calcium, a calcium level is sufficient to screen for primary hyperparathyroidism.

EDUCATIONAL OBJECTIVE

Guide tumor surveillance for a patient with RET-related multiple endocrine neoplasia type 2A.

REFERENCE(S)

Loveday C, Josephs K, Chubb D, et al. p.Val804Met, the most frequent pathogenic mutation in RET, confers a very low lifetime risk of medullary thyroid cancer. J Clin Endocrinol Metab. 2018;103(11):4275-4282. PMID: 29590403

Wells SA Jr, Asa SL, Dralle H, et al; American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. PMID: 25810047

3 ANSWER: D) Perform CT of the chest, abdomen, and pelvis
This patient has a 1.8-cm carotid body tumor. While carotid body tumors can produce catecholamines, the greater than 28-fold elevation of normetanephrine in this case is far out of proportion. Only a 2- to 3-fold elevation would be expected maximally. The same range of normetanephrine elevation can be seen with tricyclic antidepressants. However, holding them for a few days is usually enough time to obtain reliable plasma metanephrine values. Thus, holding cyclobenzaprine for at least 4 weeks (Answer A) is not necessary. Urinary metanephrines (Answer B) would most likely show the same result with frank elevation and this would not be helpful in further management. The significant increase in plasma normetanephrine suggests the coexistence of another functional paraganglioma or pheochromocytoma as part of a hereditary paraganglioma syndrome. Most of these tumors are discovered in the abdomen, and therefore cross-sectional imaging (Answer D) is the best next step. If no tumor is obvious on abdominal imaging, additional cross-sectional chest imaging should be considered. With a 28-fold elevation of normetanephrine, one would expect a tumor size of at least 4 cm, which would not be missed by any cross-sectional imaging. Functional imaging (Answer C) is not useful. Indeed, MIBG scans should only be conducted when ¹³¹I-MIBG therapy is planned. Once a decision has been made to proceed with surgery, α-blockade (Answer E) is a reasonable approach. However, surgery should be considered for the most morbid lesion first, which, in this case, is probably an abdominal paraganglioma or pheochromocytoma.

EDUCATIONAL OBJECTIVE

Construct the differential diagnosis for a patient with elevated metanephrine levels.

REFERENCE(S)

Lenders JW, Duh Q-Y, Eisenhofer G, et al; Endocrine Society. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. PMID: 24893135

Rao D, van Berkel A, Piscaer I. Impact of 123 I-MIBG scintigraphy on clinical decision making in pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2019:jc.2018-02355. PMID: 30822354

Eisenhofer G, Deutschbein T, Constantinescu G, et al. Plasma metanephrines and prospective prediction of tumor location, size and mutation type in patients with pheochromocytoma and paraganglioma. Clin Chem Lab Med. 2020;59(2):353-363. PMID: 33001846

4 ANSWER: C) SDHD
The presence of 4 paragangliomas and a pheochromocytoma in this family, as well as the patient’s personal history of a paraganglioma and pheochromocytoma, is highly suggestive of a hereditary predisposition to paraganglioma/pheochromocytoma. Genes associated with paraganglioma and pheochromocytoma are shown in the table (see following page). The predominance of head and neck paragangliomas is more suggestive of a variant in SDHD, SDHC, or SDHB. Pathogenic variants in the VHL gene (Answer D) and RET gene (Answer E) (multiple endocrine neoplasia type 2) are mainly associated with adrenal pheochromocytomas and are less likely to be the etiology in this case. Pathogenic variants in SDHC (Answer A) have a much lower penetrance, rarely affect more than 1 or 2 family members, and rarely affect the adrenal glands. The inheritance of all of these genetic conditions is autosomal dominant. The risk of tumor development associated with SDHD pathogenic variants (Answer C), however, depends on the sex of the transmitting parent. Because of maternal imprinting, if the variant is inherited from the father, there is risk for paraganglioma and pheochromocytoma, while if the variant is inherited from the mother, the individual will be a carrier but is not at risk for tumor development. This is the inheritance pattern observed in this patient’s family.

EDUCATIONAL OBJECTIVE

Identify the pattern of inheritance of pathogenic variants in the SDHD gene.

REFERENCE(S)

Benn DE, Robinson BG, Clifton-Bligh RJ. 15 years of paraganglioma: clinical manifestations of paraganglioma syndromes types 1-5. Endocr Relat Cancer. 2015;22(4):T91-T103. PMID: 26273102

Table. Genes Associated With Paraganglioma and Pheochromocytoma

Syndrome	Gene(s)	Tumor locations	Hormone products	Other features
Familial paraganglioma type 1	SDHD	Head and neck paraganglioma, multiple; mediastinal paraganglioma; rarely adrenal medulla	Normetanephrine, metanephrine, dopamine, or none	Clear cell renal cell carcinoma, gastrointestinal stromal tumor, pituitary adenoma
Familial paraganglioma type 2	SDHAF2	Head and neck paraganglioma, multiple; rarely adrenal medulla	Unknown	Unknown
Familial paraganglioma type 3	SDHC	Head and neck paraganglioma; mediastinal paraganglioma	Normetanephrine or none	Unknown
Familial paraganglioma type 4	SDHB	Abdominal and pelvic paraganglioma; mediastinal paraganglioma; rarely adrenal medulla	Normetanephrine, dopamine, or none	Often malignant paraganglioma; clear cell renal cell carcinoma, gastrointestinal stromal tumor, pituitary adenoma
Familial paraganglioma	SDHA	Head and neck or other paraganglioma; adrenal medulla	Unknown	Unknown
Multiple endocrine neoplasia type 2A and 2B	RET	Adrenal medulla, bilateral	Metanephrine >> normetanephrine	Medullary thyroid carcinoma, hyperparathyroidism; marfanoid habitus and mucosal ganglioneuromas (2B only)
Neurofibromatosis type 1	NF1	Adrenal medulla	Metanephrine or metanephrine and normetanephrine	Café-au-lait spots, neurofibromas, peripheral nerve sheath tumors
von Hippel–Lindau syndrome	VHL	Adrenal medulla, bilateral; rarely paraganglioma	Normetanephrine	Retinal and central nervous system hemangioblastomas, clear cell renal cell carcinoma, pancreatic islet-cell tumors, other
Familial pheochromocytoma	TMEM127	Adrenal medulla	Normetanephrine and metanephrine	Renal cell carcinoma
Familial pheochromocytoma	MAX	Adrenal medulla, bilateral	Normetanephrine and metanephrine	Unknown
Fumarate hydratase deficiency	FH	Head and neck paraganglioma; adrenal medulla	Normetanephrine	Papillary renal cell carcinoma, uterine fibroids, cutaneous leiomyoma

5 ANSWER: C) Perform transesophageal echocardiography and blood cultures Cushing syndrome remains first and foremost a clinical diagnosis. This patient does not have any expected clinical features other than weakness, which can be seen as the only symptom with fast-progressing hypercortisolism. However, fast-progressing hypercortisolism usually occurs with either adrenocortical carcinoma (excluded by the normal abdominal CT in this vignette) or paraneoplastic ectopic ACTH. However, a fast-growing tumor as a source would be visible on a CT of the chest, abdomen, and pelvis. Weight loss would be very unusual with any kind of Cushing syndrome. Therefore, this patient most likely has another cause of hypercortisolism, such as infection, and the most likely source is endocarditis associated with the artificial heart valve. Thus, transesophageal echocardiography and blood cultures (Answer C) would be the best steps now.

In patients with severe illness, cortisol production becomes partially independent of ACTH, which therefore is normal or at least inadequately normal. Severe nonendocrine disease could also explain the other endocrine abnormalities, such as the thyroid and gonadal changes. With physiologic response of the hypothalamic-pituitary-adrenal axis to a stress stimulus (endocarditis and sepsis in this patient), there is no need for further evaluation such as salivary cortisol measurement (Answer B) or petrosal sinus sampling (Answer E) or even for treatment of hypercortisolism (Answer A). The abnormality on pituitary MR...

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