What are the diagnostic and treatment approaches for common endocrinological disorders?

Diagnostic and Treatment Approaches for Common Endocrinological Disorders

Primary Adrenal Insufficiency (Addison's Disease)

Diagnostic Approach

Suspect primary adrenal insufficiency in any patient with unexplained fatigue, weight loss, hypotension, or hyponatremia, and immediately measure morning plasma ACTH and cortisol levels. 1

• Laboratory findings at presentation: Hyponatremia occurs in 90% of cases, but the classic combination of hyponatremia and hyperkalemia is present in only 50% of patients 1
• Diagnostic gold standard: Short cosyntropin test (250 μg) with serum cortisol measurement at 30 and/or 60 minutes; cortisol should exceed 550 nmol/L to be normal 1, 2
• Initial screening when cosyntropin test unavailable: Morning plasma ACTH (elevated) and cortisol (low) levels 1
• Critical point: If acute adrenal crisis is suspected, administer IV hydrocortisone 100 mg immediately and start 0.9% saline infusion without waiting for diagnostic confirmation 1

Establishing Etiology

• First step: Measure serum 21-hydroxylase autoantibodies, as autoimmunity is the predominant cause in Europe 1
• If autoantibodies negative: Obtain CT imaging of adrenals 1
• In male patients: Assay very long-chain fatty acids to exclude adrenoleukodystrophy 1
• In children/young adults with PAI plus hypoparathyroidism or candidiasis: Consider APS-1 and test for anti-interferon omega antibodies or AIRE gene mutations 1

Treatment Protocol

Initiate hydrocortisone 15-25 mg daily (or cortisone acetate 20-35 mg daily) in 2-3 divided doses, with the first dose immediately upon waking and last dose at least 6 hours before bedtime. 1, 2

• Pediatric dosing: Hydrocortisone 6-10 mg/m² body surface area daily 1
• Mineralocorticoid replacement: Fludrocortisone 50-200 μg once daily; children and younger adults may require higher doses 1, 2
• Salt intake: Advise patients to take salt and salty foods ad libitum; avoid liquorice and grapefruit juice 1
• Patient education essentials: All patients must wear medical alert identification, carry a steroid card, and have supplies for self-injection of parenteral hydrocortisone 1

Acute Adrenal Crisis Management

Administer IV or IM hydrocortisone 100 mg immediately, followed by 100 mg every 6-8 hours until recovery. 1

• Fluid resuscitation: Isotonic (0.9%) sodium chloride solution at initial rate of 1 L/hour until hemodynamic improvement 1
• Identify precipitant: Search for underlying infection or other triggers once treatment initiated 1
• Mineralocorticoid restart: Resume fludrocortisone when hydrocortisone dose falls below 50 mg/day 1

Follow-Up and Monitoring

• Annual review: Assess health, well-being, weight, blood pressure, and serum electrolytes 1
• Screen for associated autoimmune conditions: Monitor TSH, free T4, and TPO antibodies every 12 months for thyroid disease 1
• Additional annual screening: Plasma glucose, HbA1c, complete blood count, and vitamin B12 levels 1
• Bone health: Monitor bone mineral density every 3-5 years 1
• In women of reproductive age: Inform about risk of premature ovarian insufficiency, especially with positive SCC antibodies 1

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Secondary Adrenal Insufficiency (Hypopituitarism)

Diagnostic Approach

Low ACTH with low cortisol is diagnostic of secondary adrenal insufficiency, distinguishing it from primary adrenal insufficiency which presents with high ACTH. 3

• Initial evaluation: Morning ACTH and cortisol levels, plus basic metabolic panel for electrolyte abnormalities 3
• Assess other pituitary hormones: TSH, free T4, LH, FSH, testosterone (males)/estradiol (females) 1, 3
• Imaging indication: MRI brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities or new severe headaches 1, 3
• Common etiology: Immune checkpoint inhibitor therapy causing hypophysitis 1, 3

Treatment Algorithm

Initiate hydrocortisone 10-20 mg orally in the morning and 5-10 mg in early afternoon for mild symptoms. 3

• Critical sequencing: If multiple hormone deficiencies present, always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis 3
• Moderate symptoms: Consider higher initial dosing (hydrocortisone 20-30 mg morning, 10-20 mg afternoon), then taper to maintenance over 5-10 days 3
• Severe symptoms/crisis: IV normal saline plus IV stress-dose corticosteroids (hydrocortisone 100 mg or dexamethasone 4 mg), then taper to maintenance over 7-14 days after discharge 3
• Patient education: Stress dosing (doubling or tripling doses during illness, surgery, or significant stress) 3
• Medical alert: Provide bracelet for adrenal insufficiency to trigger stress-dose corticosteroids by emergency services 3

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Thyroid Disorders

Hypothyroidism Diagnosis

• Screening tests: TSH and free T4 before starting any treatment 1
• Primary hypothyroidism: Elevated TSH with low free T4 1
• Central hypothyroidism (secondary/tertiary): Low TSH with low free T4, suggesting pituitary or hypothalamic etiology 1, 3
• Repeat monitoring: TSH and free T4 before each treatment cycle 1

Hypothyroidism Treatment

Administer levothyroxine once daily on an empty stomach, one-half to one hour before breakfast with a full glass of water. 4

• Drug interactions: Administer at least 4 hours before or after phosphate binders (calcium carbonate, ferrous sulfate), bile acid sequestrants, proton pump inhibitors, sucralfate, and antacids 4
• Monitoring in secondary hypothyroidism: Follow free T4 for dose titration as TSH is not accurate 3
• Critical warning: In patients with concomitant adrenal insufficiency, treat with replacement glucocorticoids prior to initiating levothyroxine to avoid precipitating adrenal crisis 4
• Diabetes management: Levothyroxine may worsen glycemic control; carefully monitor glucose after starting, changing, or discontinuing therapy 4

Hyperthyroidism Recognition

• Clinical presentation: Routine thyroid testing may show suppressed TSH with elevated free T4 1
• Immune checkpoint inhibitor-related: Thyroiditis can present as transient hyperthyroidism before progressing to hypothyroidism 1

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Adrenocortical Carcinoma (ACC)

Diagnostic Workup

Every patient with suspected ACC requires comprehensive hormonal evaluation to assess glucocorticoid, mineralocorticoid, sex steroid, and catecholamine excess. 1

• Glucocorticoid excess (minimum 3 of 4 tests): Dexamethasone suppression test (1 mg at 23:00h), 24-hour urinary free cortisol, basal serum cortisol, basal plasma ACTH 1
• Sex steroids and precursors: DHEA-S, 17-OH-progesterone, androstenedione, testosterone, 17-beta-estradiol (in men and postmenopausal women), 24-hour urine steroid metabolites 1
• Mineralocorticoid excess: Serum potassium, aldosterone/renin ratio (only in hypertensive or hypokalemic patients) 1
• Exclude pheochromocytoma: Plasma normetanephrine, metanephrine, and methoxytyramine (or 24-hour urinary fractionated metanephrines) 1

Imaging Protocol

• Initial imaging: CT or MRI of abdomen and CT thorax 1
• Staging: Full-body FDG-PET-CT (vertex to toe) to determine biopsy site and assess metastases 1
• Bone involvement: Bone scintigraphy when skeletal metastases suspected 1
• CT characteristics of ACC: Hounsfield units >10 in unenhanced CT, inhomogeneous appearance with irregular margins 1

Tissue Diagnosis

• Biopsy requirement: Obtain lesional tissue for histopathologic confirmation 1
• Molecular testing: BRAF V600E mutational testing (tissue); consider next-generation sequencing for MAP-kinase pathway mutations 1

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Pheochromocytoma and Paraganglioma (PPGL)

Diagnostic Approach

Systematically assess for pheochromocytoma in all adrenal masses by measuring plasma-free or urinary-fractionated metanephrines. 1

• Malignancy biomarker: Plasma methoxytyramine provides useful information to assess likelihood of malignancy 1
• High-risk features for metastases: Tumor size ≥5 cm, any extra-adrenal paraganglioma, known SDHB germline mutation, or plasma methoxytyramine more than threefold above upper reference limit 1

Imaging for PPGL

• Functional imaging indications: (1) Best tumor staging in patients with suspected metastases or high metastatic risk; (2) Evaluate option for radionuclide-based therapy in nonresectable PPGL 1
• Modality selection: MIBG scintigraphy, DOTA-TATE-PET, Dopa/Dopamine PET, or FDG-PET depending on availability and clinical context 1

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Histiocytic Neoplasms with Endocrine Manifestations

Erdheim-Chester Disease (ECD)

Diabetes insipidus is the most common presenting endocrine disorder in ECD (25-50% prevalence) and may precede diagnosis by many years. 1

• Anterior pituitary deficiencies: Gonadotropin (22%), thyrotropin (10%), corticotropin (3%); growth hormone deficiency most common (79%) 1
• Key association: More than 50% of patients with diabetes insipidus have anterior pituitary hormonal deficiencies 1
• Endocrine evaluation: Morning urine and serum osmolality, FSH, LH with testosterone (males)/estradiol (females), corticotropin with morning cortisol, thyrotropin and free T4, prolactin, IGF-1 1

Langerhans Cell Histiocytosis (LCH)

• Endocrine involvement: 50-70% of cases, most commonly diabetes insipidus which often precedes diagnosis 1
• Baseline and follow-up: All LCH patients require endocrine evaluation at baseline and during follow-up 1
• Dynamic testing: Growth hormone and corticotropin deficiencies may require dynamic testing for definitive diagnosis 1

Diagnostic Algorithm for Histiocytic Neoplasms

• Initial imaging: Full-body FDG-PET-CT (vertex to toe) to guide biopsy site 1
• Tissue confirmation: Biopsy of lesional tissue with BRAF V600E mutational testing 1
• Brain imaging: MRI brain with gadolinium contrast to assess hypothalamic/pituitary involvement 1
• Cardiac evaluation: Cardiac MRI to detect cardiovascular involvement 1

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Common Pitfalls and Caveats

• Adrenal crisis misdiagnosis: Never delay treatment for diagnostic testing; blood samples for cortisol and ACTH can be obtained before administering hydrocortisone 1
• Thyroid hormone in adrenal insufficiency: Starting levothyroxine before corticosteroid replacement can precipitate life-threatening adrenal crisis 3, 4
• Hypoglycemia in children: Between 10-20% of adult PAI patients have hypercalcemia at presentation, but children are particularly prone to hypoglycemia and seizures 1
• Pheochromocytoma exclusion: Always rule out pheochromocytoma before any adrenal intervention to prevent life-threatening hypertensive crisis 1
• Histiocytic disorders: Consider in any patient with "idiopathic" diabetes insipidus or anterior pituitary dysfunction, as these account for 10-15% of pituitary stalk lesions 5