38.4 Endocrinology: Diabetes Mellitus Diagnosis, Treatment and Complications, DKA and HHS, Thyroid Disease, Pituitary Disorders, Adrenal Disorders (Cushing, Aldosteronism, Addison, Pheochromocytoma), Calcium and Parathyroid Disorders, Obesity and Metabolic Syndrome

Why this area matters

Diabetes affects a large and growing share of Filipino adults, and many are diagnosed only when complications appear. Thyroid disease (especially Graves disease and goiter) is common in women. The PLE tests diagnostic thresholds, first-line drugs, emergencies and the stepwise testing of endocrine syndromes.

Diabetes mellitus

• Classification:
  • type 1: autoimmune beta-cell destruction (GAD and other antibodies), absolute insulin deficiency, prone to DKA;
  • type 2: insulin resistance with relative insulin deficiency, linked to obesity;
  • gestational diabetes;
  • other types: monogenic (MODY), pancreatic disease, drugs (steroids).
• Prediabetes: fasting glucose 100 to 125 mg/dL, 2-hour OGTT 140 to 199 mg/dL, or HbA1c 5.7% to 6.4%. Lifestyle change (about 7% weight loss and 150 minutes of exercise a week) prevents progression, and metformin helps selected patients.
• Treatment of type 2 diabetes:
  • lifestyle, diabetes education and weight management;
  • metformin first-line in most patients (avoid if eGFR is below 30, and stop for iodinated contrast in patients at risk);
  • SGLT2 inhibitors for heart failure or CKD and GLP-1 receptor agonists for ASCVD or weight loss, chosen regardless of HbA1c;
  • other options: DPP-4 inhibitors, sulfonylureas (cheap but cause hypoglycemia and weight gain), pioglitazone and insulin (for HbA1c above 10% or glucose of 300 mg/dL or more with symptoms, or catabolic features);
  • general target HbA1c below 7%, less strict in the elderly or those prone to hypoglycemia.
• Chronic complications and screening:
  • retinopathy: annual dilated eye exam; laser or anti-VEGF for proliferative disease and macular edema;
  • nephropathy: yearly urine albumin-to-creatinine ratio and eGFR; ACE inhibitor or ARB for albuminuria, and an SGLT2 inhibitor;
  • neuropathy: annual monofilament foot exam; foot care and footwear to prevent ulcers and amputation;
  • cardiovascular disease: statins, BP control below 130/80 mmHg, stopping smoking.
• Hypoglycemia (glucose below 70 mg/dL):
  • sweating, tremor, palpitations, then confusion and seizures;
  • "rule of 15": 15 g of fast-acting glucose, recheck in 15 minutes;
  • unconscious patients get IV dextrose (D50 or D10) or glucagon;
  • sulfonylurea-induced hypoglycemia can recur, so observe for longer.

Endocrine Emergencies: Diabetes, Thyroid & Adrenal Disorders

Diabetes Mellitus ADA Diagnostic Criteria

1. Fasting Plasma Glucose (FPG) $\ge 126\text{ mg/dL}$ ($7.0\text{ mmol/L}$) after an 8-hour fast.
2. 2-Hour Plasma Glucose $\ge 200\text{ mg/dL}$ ($11.1\text{ mmol/L}$) during a standard $75\text{ g}$ Oral Glucose Tolerance Test (OGTT).
3. Glycated Hemoglobin (HbA1c) $\ge 6.5\%$ ($48\text{ mmol/mol}$) using an NGSP-certified assay.
4. Classic symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, unexplained weight loss) plus a random plasma glucose $\ge 200\text{ mg/dL}$ ($11.1\text{ mmol/L}$).

DKA versus HHS: Comparison & Protocols

• Protocols for DKA and HHS Management:
  1. Fluid Resuscitation: Initial fluid of choice is $0.9\%$ normal saline infused at $1,000\text{ mL/hour}$ for the first 1 to 2 hours. Switch to $0.45\%$ NaCl ($250-500\text{ mL/hr}$) if corrected sodium is normal or high. Add $5\%$ to $10\%$ dextrose when blood glucose falls below $250\text{ mg/dL}$ (2024 consensus) to prevent hypoglycemia while allowing continuous insulin infusion to clear ketoacids.
  2. Potassium Repletion Protocol: Check serum potassium before administering insulin!
     • If $\text{K}^+ < 3.5\text{ mEq/L}$: Hold insulin and give IV potassium (about $10\text{ mEq/hour}$, more if severe) until $\text{K}^+ > 3.5\text{ mEq/L}$ (2024 consensus; the 2009 threshold was $3.3$), because insulin drives potassium into cells and will precipitate fatal ventricular arrhythmias or respiratory muscle arrest.
     • If $\text{K}^+ 3.5 - 5.0\text{ mEq/L}$: Add potassium to the IV fluids to keep serum potassium between $4.0\text{ and }5.0\text{ mEq/L}$.
     • If $\text{K}^+ > 5.0\text{ mEq/L}$: Do not give potassium; recheck 2 hours after starting insulin and then every 4 hours.
  3. Intravenous Regular Insulin: Continuous infusion at $0.1\text{ units/kg/hour}$ (or $0.14\text{ units/kg/hour}$ without bolus). Target glucose reduction of $50-75\text{ mg/dL/hour}$. In DKA, insulin is continued until resolution of ketoacidosis (2024 consensus: beta-hydroxybutyrate $< 0.6\text{ mmol/L}$ with venous $\text{pH} \ge 7.3$ or bicarbonate $\ge 18\text{ mEq/L}$), not merely glucose normalization. Overlap with subcutaneous basal insulin for 2 hours before terminating IV insulin.

Thyroid Storm versus Myxedema Coma

• Thyroid Storm: Extreme, life-threatening thyrotoxicosis precipitated by infection, surgery, trauma, or iodinated contrast. Characterized by hyperpyrexia ($39.0-41.0^\circ\text{C}$), marked tachycardia out of proportion to fever (atrial fibrillation common), agitation, delirium, jaundice, and high-output heart failure. Scored via the Burch-Wartofsky Point Scale (score $\ge 45$ diagnostic). Multi-agent management administered sequentially:
  1. Beta-Blocker: High-dose Propranolol ($60-80\text{ mg}$ PO q4h or $1-2\text{ mg}$ IV q4h) to suppress adrenergic hyperstimulation and block peripheral conversion of $T_4$ to active $T_3$.
  2. Thionamide: Propylthiouracil (PTU) ($200\text{ mg}$ PO q4h; preferred over methimazole in storm because PTU uniquely blocks peripheral $T_4$-to-$T_3$ conversion) or Methimazole.
  3. Inorganic Iodine Solution: Administer Lugol's iodine or Saturated Solution of Potassium Iodide (SSKI) at least 1 hour AFTER thionamide administration. Administering iodine earlier supplies substrate for accelerated de novo thyroid hormone synthesis.
  4. Corticosteroids: Intravenous Hydrocortisone ($100\text{ mg}$ IV q8h) to blunt peripheral $T_4$-to-$T_3$ conversion and treat concomitant relative adrenal insufficiency.
• Myxedema Coma: Decompensated severe hypothyroidism presenting with hypothermia ($< 35.0^\circ\text{C}$), bradycardia, hypotension, hypoventilation (hypercapnic respiratory failure), hyponatremia, and altered mental status or coma. Management: Intravenous Hydrocortisone ($100\text{ mg}$ IV q8h) must be administered FIRST (prior to levothyroxine) to prevent precipitating acute adrenal crisis; followed by intravenous loading dose of Levothyroxine ($200-400\text{ }\mu\text{g}$ IV) $\pm$ Liothyronine ($T_3$), passive external rewarming, and mechanical ventilation.

Adrenal Insufficiency & Adrenal Crisis

• Primary Adrenal Insufficiency (Addison Disease): Direct destruction of the adrenal cortex (autoimmune adrenalitis in $> 80\%$; tuberculosis in endemic developing countries). Results in deficiency of both cortisol and aldosterone. Hallmark laboratory findings: Hyponatremia, hyperkalemia, non-anion gap metabolic acidosis, and hypoglycemia. Physical examination reveals diffuse cutaneous hyperpigmentation (in palmar creases, buccal mucosa, vermilion border) due to uninhibited pro-opiomelanocortin (POMC) and ACTH synthesis stimulating melanocyte MC1 receptors.
• Secondary Adrenal Insufficiency: Hypothalamic-pituitary failure or chronic exogenous corticosteroid suppression. Aldosterone secretion is preserved (regulated by RAAS); hence, hyperkalemia is absent, and hyperpigmentation does NOT occur (ACTH is suppressed).
• Diagnosis: Confirmed by the Cosyntropin (synthetic ACTH) Stimulation Test ($250\text{ }\mu\text{g}$ IV/IM; failure of serum cortisol to peak $\ge 18\text{ }\mu\text{g/dL}$ at 30 or 60 minutes establishes adrenal insufficiency).
• Acute Adrenal Crisis: Life-threatening hypovolemic shock refractory to fluids and vasopressors, accompanied by abdominal pain, vomiting, fever, and severe hypoglycemia. Emergency management: Immediate intravenous Hydrocortisone ($100\text{ mg}$ IV bolus, followed by $100\text{ mg}$ q6-8h) and rapid volume resuscitation with $0.9\%$ saline and $5\%$ dextrose. Never withhold treatment for diagnostic testing.

Thyroid disease

• Thyrotoxicosis causes:
  • Graves disease: diffuse goiter with bruit, ophthalmopathy (proptosis, lid lag), pretibial myxedema, and TSH receptor antibodies;
  • toxic multinodular goiter and toxic adenoma (patchy or hot nodule on scan);
  • thyroiditis (subacute painful, silent, postpartum): low radioiodine uptake;
  • exogenous thyroid hormone (low thyroglobulin) and amiodarone or iodine.
• Treatment of Graves disease:
  • beta-blockers for symptoms;
  • methimazole (first-line), or propylthiouracil in the first trimester of pregnancy and in thyroid storm;
  • both can cause agranulocytosis: stop the drug and check a CBC if fever or sore throat develops;
  • radioactive iodine (contraindicated in pregnancy and breastfeeding, and may worsen eye disease) or thyroidectomy for relapse or large goiters.
• Subacute (de Quervain) thyroiditis: painful tender thyroid after a viral illness, high ESR, low uptake, and a thyrotoxic then hypothyroid phase. Treated with NSAIDs (or steroids) and beta-blockers; antithyroid drugs do not help.
• Hypothyroidism:
  • usually Hashimoto thyroiditis (anti-TPO antibodies), or after radioiodine or surgery;
  • fatigue, weight gain, cold intolerance, constipation, dry skin, slow reflexes, menstrual changes and hyponatremia or high cholesterol;
  • high TSH with low free T4 (in central hypothyroidism, TSH is low or normal);
  • treated with levothyroxine (about 1.6 µg/kg a day), starting at 25 to 50 µg in the elderly or those with CAD, and rechecking TSH after 6 to 8 weeks;
  • doses rise in pregnancy (by about 25% to 30%).
• Iodine deficiency goiter persists in some areas despite the salt iodization law (RA 8172, ASIN).

Pituitary disorders

• Prolactinoma: galactorrhea, amenorrhea and infertility in women; low libido and later mass effect in men. Treated with cabergoline (or bromocriptine), even for large tumors. Exclude pregnancy, hypothyroidism and drugs (antipsychotics, metoclopramide).
• Acromegaly: enlarging hands, feet and jaw, sweating, diabetes and hypertension. Screen with IGF-1; confirm by failure of GH suppression after an oral glucose load. Treated by transsphenoidal surgery, with somatostatin analogs if needed.
• Hypopituitarism:
  • causes: tumors, surgery, radiation, Sheehan syndrome (postpartum hemorrhage, failure to lactate) and apoplexy;
  • replace cortisol before thyroid hormone, to avoid adrenal crisis.
• Water balance:
  • diabetes insipidus: polyuria with dilute urine and high-normal sodium; central DI responds to desmopressin, nephrogenic DI (lithium, hypercalcemia) does not;
  • SIADH: euvolemic hyponatremia with inappropriately concentrated urine and urine sodium above 30 mmol/L, from lung disease, CNS disease, drugs or small cell cancer. Treated with fluid restriction, salt tablets or tolvaptan; correct chronic hyponatremia by no more than 8 to 10 mmol/L in 24 hours to avoid osmotic demyelination.

Adrenal disorders

• Cushing syndrome:
  • central obesity, moon face, purple striae, proximal weakness, easy bruising, hypertension, diabetes and osteoporosis;
  • the most common cause is exogenous steroids;
  • screening: overnight 1 mg dexamethasone suppression test, late-night salivary cortisol or 24-hour urinary free cortisol;
  • localization: low ACTH means an adrenal tumor; high ACTH means pituitary (Cushing disease, suppresses with high-dose dexamethasone) or ectopic ACTH (small cell lung cancer, with severe hypokalemia).
• Primary aldosteronism (Conn syndrome):
  • hypertension with or without hypokalemia and metabolic alkalosis;
  • aldosterone-renin ratio to screen, then confirmatory tests, adrenal CT and adrenal vein sampling;
  • adenoma: laparoscopic adrenalectomy; bilateral hyperplasia: spironolactone or eplerenone.
• Pheochromocytoma:
  • paroxysms of headache, sweating and palpitations with hypertension;
  • plasma free metanephrines or 24-hour urine metanephrines, then CT or MRI;
  • alpha-blockade first (phenoxybenzamine), then a beta-blocker, then surgery; a beta-blocker alone can trigger a hypertensive crisis;
  • linked to MEN 2, VHL and NF1.
• Adrenal insufficiency (Addison disease and adrenal crisis): see the endocrine emergencies above. TB is an important cause in the Philippines.

Calcium and parathyroid disorders

• Hypercalcemia:
  • PTH-mediated: primary hyperparathyroidism (most common in outpatients);
  • PTH-independent: malignancy (PTHrP from squamous cancers, bone metastases, myeloma; most common in hospitalized patients), vitamin D excess, granulomas (TB, sarcoidosis) and thiazides;
  • symptoms: polyuria, dehydration, constipation, confusion and a short QT;
  • treatment of severe hypercalcemia: IV normal saline first, calcitonin for rapid effect, and IV bisphosphonate (zoledronic acid) or denosumab; dialysis if refractory.
• Hypocalcemia:
  • causes: post-thyroidectomy hypoparathyroidism, vitamin D deficiency, CKD, hypomagnesemia, pancreatitis;
  • Chvostek and Trousseau signs, tetany, seizures and a long QT;
  • treated with IV calcium gluconate for symptoms and oral calcium with calcitriol; correct magnesium first.
• Correct the calcium for albumin: add 0.8 mg/dL for each 1 g/dL that albumin is below 4 g/dL, or measure ionized calcium.

Obesity and metabolic syndrome

• BMI cut-offs for Asians (WHO Asia-Pacific): overweight 23 to 24.9, obese 25 or more. Asians develop diabetes and heart disease at lower BMIs.
• Metabolic syndrome (harmonized criteria): any 3 of 5:
  • waist circumference of 90 cm or more in Asian men and 80 cm or more in Asian women;
  • triglycerides of 150 mg/dL or more;
  • HDL below 40 mg/dL in men or below 50 mg/dL in women;
  • BP of 130/85 mmHg or more;
  • fasting glucose of 100 mg/dL or more (or treatment for any of these).
• Treatment of obesity:
  • diet, exercise and behavior change, aiming for 5% to 10% weight loss;
  • drugs such as GLP-1 receptor agonists (semaglutide) and dual GIP/GLP-1 agonists (tirzepatide), and orlistat;
  • bariatric surgery for severe obesity (see surgery);
  • look for secondary causes (hypothyroidism, Cushing syndrome, drugs).