A previously healthy 61-year-old man comes to the physician because of a 6-month history of morning headaches. He also has fatigue and trouble concentrating on his daily tasks at work. He sleeps for 8 hours every night; his wife reports that he sometimes stops breathing for a few seconds while sleeping. His pulse is 71/min and blood pressure is 158/96 mm Hg. He is 178 cm (5 ft 10 in) tall and weighs 100 kg (220 lb); BMI is 31.6 kg/m2 . Which of the following is the most likely cause of this patient's hypertension?

Nocturnal upper airway obstruction

Proliferation of adrenal chromaffin cells

A 21-year-old male college student is very anxious about having thyroid cancer as he found a lump in his neck a few days ago. He has also had diarrhea and a feeling of warmth on his face for 3 days now. His father and uncle both have been diagnosed with thyroid cancer. The lump is about 1 cm in diameter and is fixed and nontender on palpation. Physical examination is otherwise unremarkable. Ultrasound shows a non-cystic cold nodule that requires fine needle aspiration for diagnosis. Thyroid functions tests are normal, and his calcitonin level is 346 ug/ml. Which of the following genetic mutations would warrant thyroidectomy in this patient?

Down expression of the Ras protooncogene

Activating mutation of the BRAF gene

A 51-year-old African American man with a history of poorly controlled hypertension presents to the emergency room with blurry vision and dyspnea. He reports rapid-onset blurred vision and difficulty breathing 4 hours prior to presentation. He takes lisinopril, hydrochlorothiazide, and spironolactone but has a history of poor medication compliance. He has a 50 pack-year smoking history and drinks 4-6 shots of vodka per day. His temperature is 99.2°F (37.3°C), blood pressure is 195/115 mmHg, pulse is 85/min, and respirations are 20/min. On exam, he is ill-appearing and pale. He is intermittently responsive and oriented to person but not place or time. Fundoscopic examination reveals swelling of the optic disc with blurred margins. A biopsy of this patient’s kidney would most likely reveal which of the following?

Concentrically thickened arteriolar tunica media with abundant nuclei

Calcific deposits in the arterial media without luminal narrowing

Fibrous atheromatous plaques in the arterial intima

Endothelial proliferation and luminal narrowing with a chronic inflammatory infiltrate

A 38-year-old woman with type 1 diabetes for 20 years presents with diabetic ketoacidosis. She is treated and recovers. Six months later, she develops progressive fatigue, nausea, and hyperpigmentation. Laboratory studies show morning cortisol 3 μg/dL, ACTH 180 pg/mL, TSH 8.2 mIU/L, free T4 0.6 ng/dL, and positive anti-thyroid peroxidase antibodies. She also has positive 21-hydroxylase antibodies. Her 12-year-old daughter was recently diagnosed with type 1 diabetes. Evaluate the pathologic process and most critical monitoring recommendation for the daughter.

Autoimmune polyglandular syndrome type 2; screen daughter for adrenal antibodies and thyroid function annually

Multiple endocrine neoplasia syndrome; screen for pheochromocytoma and medullary thyroid cancer

Schmidt syndrome with isolated sporatic occurrence; routine diabetes management only for daughter

Autoimmune polyglandular syndrome type 1; screen for mucocutaneous candidiasis and hypoparathyroidism

Secondary endocrine failure from diabetes complications; optimize glycemic control in daughter

A 29-year-old man presents with severe headaches and episodic palpitations, sweating, and anxiety. During an episode, blood pressure is 240/130 mmHg. Between episodes, blood pressure is 135/85 mmHg. 24-hour urine shows metanephrines 4.2 mg (normal: <1.0). MRI reveals a 4 cm right adrenal mass. His brother died suddenly at age 25 from an intracranial hemorrhage, and his father had thyroid cancer. Genetic testing reveals a RET proto-oncogene mutation. Evaluate the pathologic syndrome and preoperative management priority.

MEN 2A with pheochromocytoma; alpha-blockade then beta-blockade before thyroid evaluation and surgery

MEN 2A with pheochromocytoma; screen for medullary thyroid cancer before any surgery

Isolated familial pheochromocytoma; genetic counseling after tumor resection

MEN 2B with pheochromocytoma; proceed directly to adrenalectomy for blood pressure control

Von Hippel-Lindau syndrome; screen for CNS hemangioblastomas before surgery

A 62-year-old man presents with confusion and severe muscle weakness. He recently started treatment for small cell lung cancer. Laboratory studies show sodium 118 mEq/L, serum osmolality 245 mOsm/kg, urine osmolality 520 mOsm/kg, and urine sodium 85 mEq/L. He is clinically euvolemic with blood pressure 125/80 mmHg. Serum cortisol and TSH are normal. Evaluate the pathophysiologic mechanism and most appropriate initial management given the clinical context.

SIADH from ectopic ADH production; restrict fluids and use vaptans

Primary polydipsia with sodium restriction; liberalize sodium intake

Cerebral salt wasting from brain metastases; treat with hypertonic saline

Adrenal insufficiency from lung cancer; administer hydrocortisone

Reset osmostat from chemotherapy; observation only

Pheochromocytoma and paraganglioma for USMLE Step 1: High-Yield Pathology Lessons

Pheochromocytoma 101 - The Rule of 10s

📌 A classic mnemonic for pheochromocytoma characteristics, though some figures are now considered higher with modern testing.

10% Extra-adrenal (paraganglioma)
10% Bilateral (consider genetic syndromes)
10% Malignant
10% Occur in children
10% Are not associated with hypertension (can be normotensive or have episodic HTN)

⭐ Modern studies, especially with increased genetic screening, suggest that the rates of malignancy (15-20%) and heritability (30-40%) are significantly higher than the classic 10% rule suggests.

Clinical Picture - The Catecholamine Cascade

Classic Triad: Episodic Headache, Sweating, Tachycardia.
Mnemonic (📌 The 5 P's):
- Pressure (paroxysmal hypertension)
- Pain (headache)
- Perspiration (diaphoresis)
- Palpitations (tachycardia)
- Pallor (vasoconstriction)
Episodes are paroxysmal, lasting minutes to hours. Can be triggered by surgery, trauma, or medications (e.g., TCAs, MAOIs).

⭐ While the classic presentation is episodic, the most common sign is sustained hypertension.

Lab & Imaging Dx - Finding the Pheo

Biochemical Confirmation First:
- Initial test: Plasma free metanephrines (high sensitivity) or 24-hr urinary fractionated metanephrines.
- Positive if levels are >3-4x the upper limit of normal.
- Equivocal results? Consider clonidine suppression test (pheo won't suppress).
Tumor Localization (Post-Biochemical Dx):
- 1st line: Abdominal/pelvic CT with contrast or MRI (T2-bright).
- Functional Imaging: For extra-adrenal, metastatic, or multifocal disease.
  - ¹²³I-MIBG Scintigraphy
  - ⁶⁸Ga-DOTATATE PET/CT (higher sensitivity)

⭐ Warning: Percutaneous biopsy is contraindicated! It can provoke a hypertensive crisis from massive catecholamine release.

Pathology & Genetics - Code Blue Genes

Germline mutations are present in ~30-40% of cases. Key syndromes dictate genetic testing.
📌 MEN have Very Nice Pheos: MEN2A/2B, Von Hippel-Lindau, Neurofibromatosis 1, Paraganglioma Syndromes (SDHx).
Syndromic Associations:
- MEN 2A & 2B: RET proto-oncogene.
- Von Hippel-Lindau: VHL gene; often bilateral pheochromocytomas.
- Neurofibromatosis Type 1: NF1 gene.
- Familial Paraganglioma: Succinate dehydrogenase (SDHx) genes (SDHB, SDHD).

⭐ SDHB mutations carry the highest risk for malignant transformation and extra-adrenal tumors (paragangliomas).

Genetic Syndromes Associated with Pheochromocytoma

Treatment - Alpha Before Beta

Pre-operative medical management is crucial to prevent intraoperative hypertensive crisis. The sequence is key.

📌 Mnemonic: Give Alpha-blockers Before Beta-blockers.

Alpha-Blockade (10-14 days pre-op):
- Irreversible: Phenoxybenzamine (preferred)
- Reversible: Phentolamine, Doxazosin
- Goal: Control blood pressure and vasoconstriction.
Beta-Blockade (2-3 days pre-op):
- Initiate only after adequate alpha-blockade.
- Goal: Control reflex tachycardia.

⭐ Warning: Giving β-blockers first causes unopposed α₁-receptor stimulation, leading to severe, refractory hypertension and potential pulmonary edema. This is a classic exam trap!

Epinephrine effects with beta-blockade

Pheochromocytomas are catecholamine-secreting tumors from adrenal chromaffin cells; extra-adrenal tumors are paragangliomas.

Presents with the classic triad: episodic headaches, sweating, and tachycardia (palpitations).

Diagnose with ↑ 24-hour urinary metanephrines and catecholamines.

Associated with MEN 2A/2B, VHL, and NF1 syndromes.

Crucial management step: preoperative α-blockade (e.g., phenoxybenzamine) before β-blockade and surgery.

Histology shows characteristic "Zellballen" nests of cells.

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