---

Thyrotoxicosis

Definition

• Overt thyrotoxicosis - elevated T4/T3 + suppressed TSH; most patients are symptomatic
• Subclinical thyrotoxicosis - normal T4/T3 + low TSH; most patients asymptomatic
• T3 thyrotoxicosis - elevated T3 but normal T4 (more common in iodine-deficient regions and in toxic adenoma/recurrent Graves)

---

Causes / Etiology

Thyrotoxicosis WITH Hyperthyroidism (increased production)

Thyrotoxicosis WITHOUT Hyperthyroidism (release from destroyed tissue)

• Subacute (de Quervain) thyroiditis
• Silent (painless) thyroiditis, postpartum thyroiditis
• Drug-induced thyroid destruction: amiodarone, cytokines, tyrosine kinase inhibitors, immune checkpoint inhibitors (nivolumab, pembrolizumab)
• Radiation thyroiditis
• Factitious thyrotoxicosis (exogenous ingestion)

---

Epidemiology

• Overall prevalence: ~0.5-1 per 1,000 in the USA
• 10 times more common in women than men
• Graves disease: peak age 30-60 years
• Toxic multinodular goiter/adenoma: age 40-70 years, higher in iodine-deficient areas

---

Pathophysiology

1. Increased synthesis (TSH receptor stimulation by antibodies, autonomous nodules)
2. Destruction of thyroid tissue releasing stored hormone
3. Exogenous ingestion

---

Clinical Features

Symptoms (in descending order of frequency)

• Hyperactivity, irritability, dysphoria
• Heat intolerance and sweating
• Palpitations
• Fatigue and weakness
• Weight loss with increased appetite (weight gain in 5% due to hyperphagia)
• Diarrhea / increased stool frequency
• Polyuria
• Oligomenorrhea, loss of libido
• Fine tremor (best elicited at fingertips)
• Insomnia, impaired concentration

Signs

• Tachycardia (most common cardiovascular sign); atrial fibrillation especially in elderly
• Goiter
• Warm, moist skin; palmar erythema; onycholysis
• Proximal myopathy (without fasciculations)
• Lid retraction / lid lag
• Fine tremor
• Diffuse alopecia (up to 40%)
• Bounding pulse, widened pulse pressure
• Gynecomastia (males)
• Hyperreflexia

Apathetic (elderly) presentation

Cardiovascular complications

• Sinus tachycardia → supraventricular tachycardia → atrial fibrillation
• Systolic hypertension, widened pulse pressure
• High-output cardiac failure (in elderly or pre-existing cardiac disease)
• Worsening angina
• Osteoporosis, mild hypercalcemia (in up to 20%), fractures

---

Graves Disease - Specific Features

• TSI (IgG) binds and activates TSH receptors on follicular cells → continuous T4/T3 production independent of TSH
• Pituitary feedback loop is bypassed → TSH becomes profoundly suppressed (<0.01 mIU/L)
• TPO and Tg antibodies also present in up to 80%
• Genetic associations: HLA alleles, CTLA4

1. Ophthalmopathy (exophthalmos/proptosis) - TSH receptors expressed on orbital fibroblasts; activated T cells release IFN-γ, TNF, IL-1 → glycosaminoglycan accumulation → muscle swelling, increased retro-orbital fat → proptosis, diplopia, corneal injury, optic neuropathy
2. Pretibial myxedema (dermopathy) - scaly thickening/induration of skin over shins; glycosaminoglycan deposition
3. Thyroid acropachy - rare periosteal reaction of digits/toes
4. Diffuse goiter (>90% of patients) - symmetrically enlarged, soft, bruit audible over gland
5. Thyroid bruit - increased blood flow

---

Diagnosis

Laboratory Tests

Imaging

• Radioiodine uptake (RAIU) scan with 123I: differentiates causes - diffuse uptake (Graves) vs. hot nodule (toxic adenoma) vs. cold scan (thyroiditis)
• Thyroid ultrasound: goiter size, nodules

---

Treatment

1. Symptomatic / Immediate Control

• Beta-blockers (propranolol 20-40 mg q6h, or long-acting atenolol): first-line for symptomatic relief - controls tachycardia, tremor, anxiety, heat intolerance; also blocks T4→T3 peripheral conversion (at high doses of propranolol)
• Anticoagulation: consider for all patients with atrial fibrillation (CHA2DS2-VASc score); majority revert to sinus rhythm with treatment of thyrotoxicosis

2. Antithyroid Drugs (ATDs)

• Methimazole (MMI): preferred in most patients; blocks thyroid peroxidase → inhibits thyroid hormone synthesis
• Propylthiouracil (PTU): preferred in first trimester of pregnancy (MMI associated with embryopathy); also blocks peripheral T4→T3 conversion
• Dosing for storm: PTU 500-1000 mg loading, then 250 mg q4h; MMI 60-80 mg/day
• Side effects: Rash, urticaria, fever, arthralgia (1-5%); agranulocytosis (<1%, abrupt onset - warn patients about sore throat/fever); hepatitis (PTU - avoid in children)

3. Radioiodine (131I) Ablation

• Progressive destruction of thyroid cells
• Treatment of choice for toxic multinodular goiter and toxic adenoma
• For Graves: widely used after ATD control; dose 370-555 MBq (10-15 mCi)
• Absolutely contraindicated in pregnancy
• Pre-treat with ATD for ≥1 month to prevent thyrotoxic crisis post-RAI; stop methimazole 2-3 days before; restart 3-7 days after if at risk
• Most patients ultimately develop hypothyroidism and require lifelong T4 replacement

4. Surgery (Total/Near-Total Thyroidectomy)

• Indicated for large goiters, suspected malignancy, ophthalmopathy, pregnancy (after first trimester if ATDs fail), patient preference
• Requires pre-operative ATD to achieve euthyroid state
• Complications: hypoparathyroidism, recurrent laryngeal nerve injury

---

Thyroid Storm (Thyrotoxic Crisis)

Precipitants

Clinical Features

• Marked pyrexia: 104-106°F (40-41°C)
• Extreme tachycardia (disproportionate to fever)
• Altered mental status: agitation → delirium → psychosis → coma
• Cardiovascular collapse: CHF, hypotension, AF
• GI: nausea, vomiting, diarrhea, abdominal pain; hepatic failure (poor prognosis)

Burch-Wartofsky Score (1993) - Scoring for Thyroid Storm Diagnosis

Treatment of Thyroid Storm (order matters - iodine MUST follow thionamide by ≥1 hour)

---

Special Situations

Pregnancy

• PTU preferred in first trimester (methimazole associated with aplasia cutis, choanal atresia)
• Switch to methimazole in 2nd/3rd trimester (PTU hepatotoxicity risk)
• High maternal TSI can cross placenta → neonatal thyrotoxicosis; TRAb levels should be monitored
• RAI absolutely contraindicated
• Graves disease has 3x higher relapse rate postpartum

Subclinical Thyrotoxicosis

• Treat if: TSH <0.1 mIU/L with age >65, cardiac disease, osteoporosis, or symptoms; or TSH persistently suppressed
• Observe with close monitoring if TSH 0.1-0.4 mIU/L and asymptomatic

Atrial Fibrillation

• Occurs in 10-20% of thyrotoxic patients, more common >50 years
• Up to 75% revert to sinus rhythm with treatment of thyrotoxicosis alone
• Warfarin dose requirements are decreased in thyrotoxic state
• Digoxin doses need to be increased (increased clearance)

---

Recent Evidence (2025-2026)

---

Diabetes Mellitus - Comprehensive Notes

---

1. Diabetes Mellitus - Overview

Diagnostic Criteria (ADA)

Glycemic Targets (ADA 2024)

---

2. Type 2 Diabetes Mellitus (T2DM)

Pathophysiology - The "Ominous Octet" (DeFronzo)

1. Insulin resistance - skeletal muscle, liver, adipose tissue
2. Beta-cell failure - progressive, irreversible over time
3. Increased hepatic glucose production (fasting hyperglycemia)
4. Impaired incretin effect - reduced GIP/GLP-1 activity
5. Alpha-cell hypersecretion of glucagon
6. Increased renal glucose reabsorption (raised renal threshold)
7. Increased lipolysis - elevated free fatty acids worsen insulin resistance
8. Neurotransmitter dysfunction - central appetite dysregulation

Risk Factors

• Obesity (especially central/visceral adiposity)
• Family history (strong genetic component)
• Physical inactivity
• Age >45 years
• Dyslipidemia (low HDL, high triglycerides)
• Hypertension
• Prior gestational diabetes
• Polycystic ovary syndrome (PCOS)
• Ethnicity (South Asian, African, Hispanic)

Clinical Features

• Often asymptomatic for years (insidious onset)
• Polyuria, polydipsia, polyphagia
• Fatigue, blurred vision
• Recurrent infections (candidal, UTIs, skin)
• Acanthosis nigricans (insulin resistance marker)
• Peripheral neuropathy / foot ulcers may be first presentation
• No ketoacidosis typically (residual insulin prevents lipolysis)

Natural History

Pharmacological Treatment Summary

---

3. Diabetic Ketoacidosis (DKA)

Definition

• D = Hyperglycemia (glucose ≥250 mg/dL) - or history of diabetes
• K = Ketonemia (β-hydroxybutyrate ≥3.0 mmol/L) or ketonuria ≥2+
• A = Acidosis (arterial/venous pH <7.3)

Pathophysiology

• Liver: Substrates (amino acids, lactate, free fatty acids, glycerol) delivered → glucose and ketone bodies (β-hydroxybutyrate, acetoacetate, acetone) released into circulation faster than utilization
• Adipose: Unrestrained lipolysis → free fatty acids → ketogenesis
• Osmotic diuresis: Hyperglycemia → dehydration, electrolyte loss → hemoconcentration → worsens hyperglycemia

DKA vs HHS

Precipitants of DKA

• Infections (most frequent - UTI, pneumonia)
• Inadequate insulin or non-adherence
• New-onset diabetes
• Acute coronary syndrome

• Cerebrovascular accident, pulmonary embolism
• Acute pancreatitis, alcohol intoxication
• Endocrinopathies: Cushing, thyrotoxicosis, acromegaly
• Drugs: Corticosteroids, SGLT2 inhibitors, clozapine, olanzapine, cocaine, thiazides

DKA Classification

Treatment of DKA

Step 1 - IV Fluid Resuscitation

• 0.9% Normal saline: 1 L bolus, then 500-1000 mL/h (to restore circulating volume)
• Switch to 0.45% saline (150-500 mL/h) once hemodynamics stable
• Aim for positive fluid balance over 12-24 h; no faster than 3 mOsm/kg/h
• Total-body water deficit is usually 7-9% body weight
• When glucose reaches 200 mg/dL → add Dextrose 5% to prevent hypoglycemia while continuing insulin

Step 2 - Insulin

• Regular insulin IV infusion: 0.1 units/kg/h (standard) or 0.05 units/kg/h (in hypokalemia)
• Some protocols: 0.1 units/kg IV bolus, then 0.1 units/kg/h infusion
• Target glucose reduction: 50-70 mg/dL/hour
• Switch to subcutaneous insulin when: pH >7.3, bicarbonate >18, patient eating, anion gap closed
• Do NOT stop insulin until ketoacidosis is fully resolved (even if glucose is normal)
• Continuous infusion of regular or short-acting insulin (lispro/aspart) allows frequent adjustment

Step 3 - Potassium Replacement

Other Measures

• Bicarbonate: NOT routinely given; only if pH <6.9 (50 mEq NaHCO3 over 1 hour)
• Phosphate: Not routinely supplemented
• ECG: Obtain to evaluate electrolyte abnormalities and rule out ACS (a precipitant)
• Search for and treat precipitating cause (broad-spectrum antibiotics if infection suspected)
• ICU monitoring preferred; non-ICU for mild-moderate DKA with close monitoring

---

4. Non-Pharmacological Management of Diabetes

A. Medical Nutrition Therapy (MNT)

• Emphasis on high-quality, nutrient-dense foods
• Individualized - consider personal, cultural, religious preferences

• Monitor carbohydrate intake to reduce postprandial glycemia
• Avoid fructose- and sucrose-containing beverages
• Minimize foods with added sugar
• Use glycemic index to predict postprandial glucose impact
• Carbohydrate counting for insulin dosing (1 unit per 10-15g carbohydrate)

• Mediterranean-style diet (monounsaturated and polyunsaturated fats)
• Minimal/no trans fats

• Optimal percentage individualized

• Sodium <2,300 mg/day
• Minimize sleep disruption (shift work and sleep deprivation increase insulin resistance)
• Religious fasting (Ramadan) - risk-stratify; close monitoring required
• Reduced-calorie sweeteners may be useful; routine vitamin supplements are not evidence-based

B. Physical Activity / Exercise

• 150 min/week of moderate aerobic activity, distributed over at least 3 days
• No gaps longer than 2 consecutive days
• Plus: Resistance training, flexibility, balance training
• Reduce sedentary behavior throughout the day

• Lowers plasma glucose (during and after exercise)
• Increases insulin sensitivity
• Cardiovascular risk reduction
• Reduced blood pressure
• Maintenance of muscle mass, reduction in body fat
• Weight loss

• Monitor glucose before, during, and after exercise
• Delay exercise if glucose >250 mg/dL with ketones present
• Ingest carbohydrate if glucose <90 mg/dL before exercising
• Reduce insulin doses before/after exercise
• Inject insulin into a non-exercising area
• Untreated proliferative retinopathy = relative contraindication (risk of vitreous hemorrhage)

C. Weight Management

• Weight loss of even 5-10% body weight significantly improves glycemic control in T2DM
• Caloric restriction + exercise
• Very low calorie diets / bariatric surgery in selected obese patients

D. Self-Monitoring of Blood Glucose (SMBG) / Continuous Glucose Monitoring (CGM)

• CGM: provides real-time glucose data, time-in-range, and trends
• "Smart" pens record and report insulin injection data
• Closed-loop (artificial pancreas) systems: CGM + pump; automate insulin delivery

E. Psychosocial Care

• Patient should be an active member of the diabetes care team
• Screen for depression, anxiety, "diabetes distress"
• Address eating disorders (binge eating, bulimia, anorexia - more common in DM)
• Emotional stress disrupts adherence to diet, exercise, and medications
• Mental health specialist referral if needed

F. Smoking Cessation

• Smoking worsens insulin resistance, accelerates cardiovascular disease and nephropathy

G. Foot Care Education

• Daily inspection, proper footwear, podiatry referral
• Critical for preventing ulceration and amputation

---

5. Types of Insulin

Molecular Structure of Insulin Analogues

---

Complete Insulin Pharmacokinetics Table

Mechanism Modifications - How Analogues Work

• Reduce self-association (prevent hexamer formation)
• Lispro: swap B28-Pro and B29-Lys → rapid monomer dissociation
• Aspart: replace B28-Pro with aspartic acid → rapid dissociation
• Glulisine: B29-Lys→Glu, B3-Asn→Lys → rapid dissociation

• Glargine: add 2 Arg to C-terminus of B chain + replace A21-Asn with Gly → precipitates at SC pH 7.4 → slow absorption; peakless; cannot mix with acidic solutions
• Detemir: add myristoyl fatty acid to Lys-B29 → albumin binding → slows vascular transport
• Degludec: delete Thr-B30 + hexadecanedioyl acid via γ-Glu spacer at Lys-B29 → multi-hexamer depot SC → albumin binding → duration >42 h

Concentrated Insulins

Insulin Delivery Methods

1. Subcutaneous injection - syringes, pen devices
2. Smart pens - record dose and timing, connect to CGM
3. Continuous Subcutaneous Insulin Infusion (CSII / Insulin Pump) - uses rapid-acting analogues only; programmable basal rates + prandial boluses
4. Closed-loop (Artificial Pancreas) - CSII + CGM + algorithm; automates delivery; reduces hypoglycemia
5. IV infusion - regular insulin only; for DKA, perioperative, ICU (target 140-180 mg/dL in critically ill)
6. Inhaled - Afrezza; used pre-prandially with long-acting insulin

---

6. New and Emerging Insulins

A. Once-Weekly Basal Insulin - Insulin Icodec

• Class: Ultra-long-acting basal insulin analogue
• Dosing: Once weekly subcutaneous injection
• Mechanism: Modified to bind reversibly to albumin with very high affinity → extremely prolonged half-life (~196 hours = ~8 days)
• Clinical evidence: 14 clinical trials reviewed; majority showed non-inferiority and in some cases superiority vs daily basal insulins for HbA1c reduction; mild hypoglycemia slightly more frequent vs comparator in select studies
• Use: T1DM and T2DM (FDA approval sought)
• Advantage: Fewer injections → improved adherence, improved compliance, potentially improved glycemic control

B. Insulin Efsitora (BIF - Basal Insulin Fc)

• Second once-weekly insulin in late-stage clinical trials (2025)
• Fc fusion protein approach for prolongation
• Results of registration studies becoming available

C. Faster-Acting Insulin Aspart (Fiasp)

• Formulated with niacinamide and L-arginine
• Even faster absorption than standard aspart
• Allows injection at meal start or up to 20 min after

D. Biosimilar Insulins

• Glargine biosimilars (e.g., Basaglar, Semglee, Rezvoglar) - lower cost alternatives
• Lispro biosimilar available
• Important for cost-accessibility

E. Smart Closed-Loop (Artificial Pancreas) Systems

• Combine CGM + insulin pump + automated dosing algorithm
• Modern systems: Suspend delivery predicted hypoglycemia; increase delivery for predicted hyperglycemia
• User input still required for meal boluses in current-generation devices

F. Oral Insulin (in development)

• Bioavailability challenges remain; several formulations in clinical trials
• Hepato-preferential delivery would mimic physiologic portal insulin delivery - a key limitation of SC injection

---

Quick Summary Table