Endocrinology Key Concepts
Diabetes Diagnosis
Diabetes is diagnosed using A1C ≥6.5%, fasting plasma glucose ≥126 mg/dL, 2-hour plasma glucose ≥200 mg/dL during OGTT, or random glucose ≥200 mg/dL with classic hyperglycemic symptoms. 1
Diagnostic Criteria
- A1C ≥6.5% (must be NGSP certified and standardized to DCCT assay) 1
- Fasting plasma glucose ≥126 mg/dL (no caloric intake for at least 8 hours) 1
- 2-hour plasma glucose ≥200 mg/dL during 75-g OGTT 1
- Random plasma glucose ≥200 mg/dL with classic symptoms (polyuria, polydipsia, unexplained weight loss) or hyperglycemic crisis 1
Confirmatory Testing
- In the absence of unequivocal hyperglycemia (e.g., hyperglycemic crises), two abnormal results are required from different tests obtained at the same time (e.g., A1C and FPG) or the same test at two different time points 1
Screening Recommendations
- Screen adults ≥35 years of age for prediabetes and diabetes 1
- Screen adults with overweight/obesity (BMI ≥25 kg/m²) who have one or more risk factors including physical inactivity, first-degree relative with diabetes, high-risk ethnicity, history of gestational diabetes, hypertension, HDL <35 mg/dL or triglycerides >250 mg/dL, polycystic ovary syndrome, or A1C ≥5.7% 1
- Repeat screening every 3 years if results are normal 1
- Screen pregnant women at 24-28 weeks gestation for gestational diabetes 1
Insulin Types by Onset of Action
Rapid-Acting Insulins (Bolus)
- Lispro, aspart, and glulisine have onset of action within 15 minutes, peak at 1-2 hours, and duration of 3-5 hours 1
- Administered immediately before meals to cover postprandial glucose excursions 1
Short-Acting Insulin
- Regular insulin has onset at 30 minutes, peak at 2-4 hours, and duration of 6-8 hours 1
Intermediate-Acting Insulin
- NPH (neutral protamine Hagedorn) has onset at 1-2 hours, peak at 4-8 hours, and duration of 12-16 hours 1
Long-Acting Insulins (Basal)
- Glargine and detemir provide relatively peakless insulin coverage over 24 hours 1
- Degludec provides ultra-long action beyond 24 hours 1
Basal vs. Bolus Insulins
Basal Insulins
Basal insulins include NPH, glargine, detemir, and degludec, which provide background insulin coverage throughout the day. 1
- NPH is intermediate-acting with some peak effect 1
- Glargine, detemir, and degludec are long-acting with minimal peak, providing steady 24-hour coverage 1
- Initiated at 10 units or 0.1-0.2 units/kg body weight 1, 2
- Titrated based on fasting glucose readings 3
Bolus Insulins
Bolus insulins include rapid-acting insulins (lispro, aspart, glulisine) and regular insulin, which cover mealtime glucose excursions. 1
- Rapid-acting analogues are preferred because they are faster-acting 1
- Administered 1-3 times daily immediately before meals 1
- Titrated based on pre-meal and post-meal glucose readings 3
Premixed Insulins
- Novolog 70/30 (70% protamine aspart/30% aspart) provides both basal and prandial coverage 3
- Administered twice daily, 30 minutes before breakfast and dinner 3
- Pharmacodynamic profiles make premixed insulins suboptimal for covering postprandial glucose compared to separate basal-bolus regimens 1
Dawn vs. Somogyi Effect
Dawn Phenomenon
The Dawn phenomenon is early morning hyperglycemia (typically 4-8 AM) caused by nocturnal surges in growth hormone, cortisol, and catecholamines that increase hepatic glucose production and decrease insulin sensitivity.
- Occurs without preceding hypoglycemia
- Managed by increasing evening basal insulin dose or timing adjustment
- Confirmed by checking glucose at 3 AM (which will be normal or elevated)
Somogyi Effect
The Somogyi effect is rebound hyperglycemia in the morning following unrecognized nocturnal hypoglycemia, triggered by counterregulatory hormone release (glucagon, epinephrine, cortisol, growth hormone).
- Occurs after nocturnal hypoglycemia (typically 2-3 AM)
- Managed by decreasing evening insulin dose or adding bedtime snack
- Confirmed by checking glucose at 3 AM (which will be low, <70 mg/dL)
- Patients with hypoglycemia unawareness should increase glycemic targets for several weeks to partially reverse the condition 1
Oral Hypoglycemic Agents
Metformin (Biguanide)
Metformin is first-line therapy for type 2 diabetes, reducing hepatic glucose production and improving insulin sensitivity. 4
- Contraindications: eGFR <30 mL/min/1.73 m², acute or chronic metabolic acidosis including DKA, severe hepatic impairment 4
- Adverse effects: Lactic acidosis (rare but serious), gastrointestinal symptoms (diarrhea, nausea), vitamin B12 deficiency 4
- Stop metformin before iodinated contrast procedures in patients with eGFR 30-60 mL/min/1.73 m², hepatic impairment, alcoholism, or heart failure; restart 48 hours after if renal function stable 4
- Avoid excessive alcohol intake as it potentiates lactate metabolism effects 4
- Monitor vitamin B12 levels every 2-3 years 4
Sulfonylureas
Sulfonylureas stimulate pancreatic beta-cell insulin secretion.
- Contraindications: Type 1 diabetes, DKA, severe renal or hepatic impairment
- Adverse effects: Hypoglycemia (major concern), weight gain
- Typically discontinued when complex insulin regimens are initiated 1
DPP-4 Inhibitors (Gliptins)
DPP-4 inhibitors enhance incretin activity, increasing insulin secretion and decreasing glucagon secretion in a glucose-dependent manner.
- Contraindications: History of pancreatitis (relative), severe renal impairment (dose adjustment needed)
- Adverse effects: Pancreatitis (rare), joint pain, increased infection risk
- Typically discontinued when complex insulin regimens are initiated 1
GLP-1 Receptor Agonists
GLP-1 receptor agonists enhance glucose-dependent insulin secretion, suppress glucagon, slow gastric emptying, and promote satiety. 3
- Contraindications: Personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2, history of pancreatitis
- Adverse effects: Nausea, vomiting, diarrhea, pancreatitis (rare), thyroid C-cell tumors (animal studies)
- Can be combined with basal insulin for treatment intensification with less weight gain and hypoglycemia than intensified insulin regimens 3
SGLT2 Inhibitors
SGLT2 inhibitors block renal glucose reabsorption, increasing urinary glucose excretion. 1
- Contraindications: eGFR <30 mL/min/1.73 m² (varies by agent), type 1 diabetes (relative)
- Adverse effects: Genital mycotic infections, urinary tract infections, euglycemic diabetic ketoacidosis (serious), volume depletion, hypotension, acute kidney injury 1
- Patients should stop SGLT2 inhibitors and seek immediate medical attention if symptoms of ketoacidosis develop 1
- May be used with insulin to improve glucose control and reduce total daily insulin dose 1
Thiazolidinediones (TZDs)
TZDs (primarily pioglitazone) improve insulin sensitivity in muscle and adipose tissue. 1
- Contraindications: NYHA Class III-IV heart failure, active liver disease, bladder cancer
- Adverse effects: Fluid retention, heart failure exacerbation, weight gain, bone fractures, bladder cancer (pioglitazone) 1
- Use with caution in patients with or at risk for congestive heart failure 1
- May be used with insulin to reduce total daily insulin dose 1
Pathophysiology of DKA
DKA results from absolute or relative insulin deficiency combined with elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone), leading to accelerated lipolysis, excessive fatty acid production, beta-oxidation, and ketogenesis. 5
Key Mechanisms
- Insulin deficiency prevents glucose utilization and promotes inappropriate gluconeogenesis and glycogenolysis, causing severe hyperglycemia 1
- Increased catecholamines accelerate lipolysis, producing excess free fatty acids 5
- Free fatty acids undergo beta-oxidation in the liver, generating ketone bodies (acetoacetate, beta-hydroxybutyrate, acetone) 5
- Ketone accumulation causes metabolic acidosis with elevated anion gap 5
- Osmotic diuresis from hyperglycemia leads to severe dehydration and electrolyte losses 6
Diagnostic Criteria for DKA
DKA is diagnosed by the triad of hyperglycemia (glucose >250 mg/dL), ketonemia/ketonuria, and metabolic acidosis (pH <7.3, bicarbonate <18 mEq/L). 6
Specific Criteria
- Blood glucose >250 mg/dL (though euglycemic DKA can occur with SGLT2 inhibitors) 6
- Arterial pH <7.3 6
- Serum bicarbonate <18 mEq/L 6
- Positive serum or urine ketones (moderate to large) 6
- Anion gap >10-12 mEq/L 6
Severity Classification
- Mild DKA: pH 7.25-7.30, bicarbonate 15-18 mEq/L 6
- Moderate DKA: pH 7.0-7.24, bicarbonate 10-14 mEq/L 6
- Severe DKA: pH <7.0, bicarbonate <10 mEq/L 6
Management of DKA
The pillars of DKA management are aggressive intravenous fluid resuscitation, continuous insulin infusion, electrolyte replacement (particularly potassium), and treatment of precipitating factors. 6
Fluid Resuscitation
- Initial fluid bolus: 1-1.5 L of 0.9% normal saline over the first hour 6
- Subsequent fluid rate: 250-500 mL/hour of 0.9% or 0.45% saline depending on hydration status and serum sodium 6
- Switch to dextrose-containing fluids (D5-0.45% saline) when glucose reaches 200-250 mg/dL to prevent hypoglycemia while continuing insulin 6
Insulin Therapy
- Do NOT give insulin bolus if potassium <3.3 mEq/L; replete potassium first to avoid life-threatening hypokalemia and cardiac arrhythmias 6
- Continuous IV regular insulin infusion at 0.1 units/kg/hour (or 0.14 units/kg/hour without bolus) 6
- Goal: decrease glucose by 50-75 mg/dL/hour 6
- Continue insulin infusion until anion gap closes (pH >7.3, bicarbonate >18 mEq/L, anion gap <12) 6
- Overlap subcutaneous insulin with IV insulin for 1-2 hours before discontinuing IV insulin to prevent recurrent ketoacidosis 6
Potassium Replacement
- **If K+ <3.3 mEq/L: hold insulin and give 20-30 mEq/hour potassium** until K+ >3.3 mEq/L 6
- If K+ 3.3-5.2 mEq/L: add 20-30 mEq potassium to each liter of IV fluid 6
- If K+ >5.2 mEq/L: do not give potassium but check levels every 2 hours 6
- Monitor potassium every 2-4 hours as insulin drives potassium intracellularly 6
Bicarbonate Administration
Sodium bicarbonate is indicated ONLY when arterial pH <6.9. 6
- Give 100 mEq sodium bicarbonate in 400 mL sterile water with 20 mEq KCl over 2 hours if pH <6.9 6
- Repeat every 2 hours until pH >7.0 6
- Bicarbonate is NOT recommended for pH ≥6.9 as it may worsen hypokalemia, paradoxical CNS acidosis, and delay ketone clearance 6
Treatment of Precipitating Factors
- Identify and treat underlying causes: infection (most common), insulin omission, myocardial infarction, stroke, pancreatitis, medications 6
- Broad-spectrum antibiotics if infection suspected 6
DKA vs. HHS
DKA is characterized by severe hyperglycemia with ketoacidosis, while HHS presents with extreme hyperglycemia and hyperosmolality but minimal or no ketosis. 5, 6
Key Differences
| Feature | DKA | HHS |
|---|---|---|
| Glucose | >250 mg/dL [6] | >600 mg/dL (often >1000 mg/dL) [6] |
| pH | <7.3 [6] | >7.3 [6] |
| Bicarbonate | <18 mEq/L [6] | >18 mEq/L [6] |
| Ketones | Moderate to large [6] | Absent to small [6] |
| Serum osmolality | Variable (usually <320 mOsm/kg) [6] | >320 mOsm/kg [6] |
| Anion gap | >10-12 [6] | Variable, usually <12 [6] |
| Mental status | Alert to drowsy [6] | Stupor to coma common [6] |
| Dehydration | Moderate (5-10% body weight) [6] | Severe (10-15% body weight) [6] |
| Mortality | 3.4-4.6% [5] | ~15% [5] |
| Typical patient | Young, type 1 diabetes [6] | Elderly, type 2 diabetes [6] |
Pathophysiologic Distinction
- In DKA, complete insulin deficiency allows unrestrained lipolysis and ketone production 5
- In HHS, residual beta-cell function is adequate to prevent lipolysis (thus no significant ketosis) but insufficient to prevent severe hyperglycemia 5
- Both conditions can coexist with features of ketoacidosis and hyperosmolality 6
Thyroid Storm Management
Thyroid storm requires immediate multi-drug therapy with thionamides, iodine (given at least 1 hour after thionamides), beta-blockers, corticosteroids, and supportive care; definitive management is thyroidectomy or radioactive iodine ablation after stabilization. 7, 8
Acute Medical Management
Thionamides (Block New Hormone Synthesis)
- Propylthiouracil (PTU): 500-1000 mg loading dose, then 250 mg every 4 hours orally or via nasogastric tube 7
- Methimazole: 60-80 mg loading dose, then 20 mg every 4-6 hours orally 7
- PTU is preferred as it also blocks peripheral T4 to T3 conversion 7
Iodine (Blocks Hormone Release)
- Potassium iodide (Lugol solution): 5 drops (0.25 mL) every 6 hours orally 7
- Saturated solution of potassium iodide (SSKI): 5 drops every 6 hours 7
- MUST give at least 1 hour after thionamide to prevent iodine from being used as substrate for new hormone synthesis 7
Beta-Blockers (Control Sympathetic Symptoms)
- Propranolol: 40-80 mg every 4-6 hours orally, or 1-2 mg IV every 5 minutes (also blocks T4 to T3 conversion) 7
- Esmolol: 250-500 mcg/kg loading dose, then 50-100 mcg/kg/min infusion for critically ill patients 7
Corticosteroids (Block T4 to T3 Conversion, Treat Relative Adrenal Insufficiency)
Supportive Care
- Aggressive cooling measures (avoid aspirin as it displaces thyroid hormone from binding proteins) 7
- IV fluids for dehydration 7
- Treat precipitating factors (infection most common, also DKA, trauma, surgery) 7, 8
Definitive Management
- Thyroidectomy is the definitive treatment for Graves' disease causing thyroid storm 7
- Radioactive iodine ablation is an alternative after acute stabilization 7
- Definitive therapy should be performed after patient is euthyroid to avoid perioperative complications 7
Diagnostic Criteria
- Burch and Wartofsky score ≥45 suggests thyroid storm (score includes temperature, CNS effects, cardiovascular dysfunction, heart failure, GI symptoms, precipitating event) 7
- Japan Thyroid Association criteria are simpler and may identify broader range of cases: thyrotoxicosis + CNS manifestations + at least one of fever, tachycardia, heart failure, or GI symptoms 7
ECG Findings in Thyroid Storm
The most common ECG finding in thyroid storm is sinus tachycardia, though atrial fibrillation is also frequently seen. 7
Specific Findings
- Sinus tachycardia (most common, heart rate typically >140 bpm) 7
- Atrial fibrillation (second most common) 7
- Other supraventricular tachyarrhythmias 7
- Increased QRS voltage (left ventricular hypertrophy pattern) 7
- ST-T wave changes 7
Wolff-Chaikoff Effect vs. Jod-Basedow Phenomenon
Wolff-Chaikoff Effect
The Wolff-Chaikoff effect is the acute inhibition of thyroid hormone synthesis caused by high iodine levels, which temporarily blocks iodine organification in the thyroid gland.
- Protective mechanism preventing thyrotoxicosis from iodine excess
- Normal thyroid glands "escape" from this effect within 24-48 hours
- Used therapeutically in thyroid storm (giving iodine after thionamides)
- Basis for using iodinated contrast or potassium iodide before thyroid surgery
Jod-Basedow Phenomenon
The Jod-Basedow phenomenon is iodine-induced hyperthyroidism that occurs when patients with underlying thyroid autonomy (multinodular goiter, autonomous nodules) are exposed to excess iodine.
- Occurs in iodine-deficient populations or patients with pre-existing thyroid disease
- Autonomous thyroid tissue uses excess iodine to produce excessive thyroid hormone
- Can be triggered by iodinated contrast, amiodarone, or iodine supplementation
- Opposite effect of Wolff-Chaikoff (hyperthyroidism vs. hypothyroidism)
Thyroid Function Test Interpretation
Normal Thyroid Function (Euthyroid)
- TSH: 0.4-4.0 mIU/L (normal range)
- Free T4: normal
- Free T3: normal
Primary Hypothyroidism
- TSH: elevated (>4.0 mIU/L)
- Free T4: low
- Free T3: low or normal
- Indicates thyroid gland failure (most common: Hashimoto's thyroiditis)
Subclinical Hypothyroidism
- TSH: mildly elevated (4.5-10 mIU/L)
- Free T4: normal
- Free T3: normal
- Early thyroid failure; consider treatment if TSH >10 or symptomatic
Primary Hyperthyroidism
- TSH: suppressed (<0.1 mIU/L)
- Free T4: elevated
- Free T3: elevated
- Indicates thyroid gland overactivity (Graves' disease, toxic nodular goiter)
Subclinical Hyperthyroidism
- TSH: suppressed (<0.4 mIU/L)
- Free T4: normal
- Free T3: normal
- Mild thyroid overactivity; monitor or treat based on cardiovascular risk
Central (Secondary) Hypothyroidism
- TSH: low or inappropriately normal
- Free T4: low
- Free T3: low
- Indicates pituitary or hypothalamic dysfunction
T3 Toxicosis
- TSH: suppressed
- Free T4: normal
- Free T3: elevated
- Early Graves' disease or toxic nodular goiter
Sick Euthyroid Syndrome (Non-Thyroidal Illness)
- TSH: variable (usually low-normal)
- Free T4: low or normal
- Free T3: low
- Occurs in severe systemic illness; thyroid function normalizes with recovery
Algorithm for Interpretation
- Check TSH first as screening test
- If TSH abnormal, measure free T4 (and free T3 if indicated)
- If TSH and free T4 discordant (e.g., low TSH with low T4), consider central hypothyroidism or non-thyroidal illness
- If hyperthyroid, check TSH receptor antibodies (TRAb) to diagnose Graves' disease
- If hypothyroid, check thyroid peroxidase antibodies (TPO) to diagnose Hashimoto's thyroiditis