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🩺 Harrison's Section 6 - Alterations in GI Function

Chapters 47-53 | Master Study Guide

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CHAPTER 47 - DYSPHAGIA

The Big Picture in One Sentence

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🔑 Key Terminology - Learn These First

Memory trick: "Globus Doesn't Interfere" - globus is felt but doesn't actually block swallowing.

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🫁 Physiology of Swallowing - 3 Phases

VOLUNTARY (ORAL) → PHARYNGEAL → ESOPHAGEAL
     ↓                  ↓              ↓
Chew + mix        Centrally mediated   Peristalsis
with saliva       reflex; larynx       clears bolus
                  elevates + UES opens  to stomach

• Oral cavity: CN V (trigeminal) + CN VII (facial)
• Tongue: CN XII (hypoglossal)
• Pharynx: CN IX (glossopharyngeal) + CN X (vagus)
• UES = cricopharyngeus muscle (CN X)
• LES relaxes as food enters esophagus

1. Primary - triggered by swallow; runs full length
2. Secondary - triggered by local distention (e.g., reflux); starts at distention, goes distal
3. Tertiary - nonperistaltic, disordered, spontaneous (abnormal finding)

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🎯 The #1 Clinical Approach - Localization Framework

Step 1: Oropharyngeal vs. Esophageal?

Step 2: Solid only OR Solid + Liquid?

Memory Mnemonic: "SOS CAMP" - Solids Only = Structural (Cancer, A stricture, Mechanical, Peptic)

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Causes Table - Oropharyngeal Dysphagia

Causes Table - Esophageal Dysphagia

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🔑 High-Yield Specific Diagnoses

Achalasia

• LES fails to relax + absent peristalsis
• Barium swallow: "bird-beak" / "rat-tail" appearance
• Manometry: incomplete LES relaxation + aperistalsis
• Symptoms: dysphagia to solids AND liquids, regurgitation of undigested food, weight loss
• Treatment: pneumatic dilation, Heller myotomy, or POEM (peroral endoscopic myotomy)

Eosinophilic Esophagitis (EoE)

• Young men, history of atopy/allergies
• Intermittent solid dysphagia, food impaction
• Endoscopy: rings, furrows, whitish exudates
• Biopsy: ≥15 eosinophils/high-power field
• Treatment: proton-pump inhibitors, swallowed topical steroids, elimination diet

Schatzki Ring

• Lower esophageal mucosal ring
• Intermittent dysphagia to solids, "steakhouse syndrome"
• Treated with endoscopic dilation

Zenker's Diverticulum

• Posterior pharyngeal outpouching (Killian's triangle)
• Regurgitation of undigested food hours after eating, halitosis, gurgling neck sounds
• Elderly patients
• Diagnosed with barium swallow

Diffuse Esophageal Spasm

• Chest pain + intermittent dysphagia
• Manometry: simultaneous contractions >20% of swallows
• Barium: "corkscrew esophagus"

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Diagnostic Workup

1. Barium swallow - first step for structural lesions
2. Endoscopy (EGD) - direct visualization + biopsy
3. Esophageal manometry - gold standard for motility disorders
4. Video fluoroscopy - best for oropharyngeal dysphagia

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CHAPTER 48 - NAUSEA, VOMITING, AND INDIGESTION

The Big Picture

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🧠 Neural Control of Vomiting - The Circuit

Triggers (periphery, CTZ, cortex, vestibular)
              ↓
    VOMITING CENTER (brainstem)
    [Nucleus tractus solitarius + dorsal vagal complex]
              ↓
    Motor output → vomiting

• Located in the area postrema - floor of 4th ventricle
• Outside the blood-brain barrier (can detect blood-borne toxins/drugs)
• Key receptors: D2 (dopamine), 5-HT3 (serotonin), NK1 (substance P), opioid, cannabinoid

• Gut vagal afferents (distension, mucosal irritation)
• Vestibular system (motion sickness → histamine H1 + muscarinic M1)
• Higher cortical centers (anxiety, pain, noxious smells)

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🎯 Causes of Nausea/Vomiting by Category

Memory trick for "projectile vomiting + no nausea" = CNS (brain bypasses the nausea warning)

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⏰ Timing Clues That Diagnose

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Complications to Know

• Metabolic alkalosis + hypokalemia + hypochloremia - classic "contraction alkalosis" from losing HCl
• Mallory-Weiss tear - mucosal tear at GEJ from forceful retching (hematemesis)
• Boerhaave syndrome - full esophageal rupture (severe chest pain, subcutaneous emphysema) - EMERGENCY
• Aspiration pneumonia - especially in impaired consciousness
• Wernicke's encephalopathy - thiamine deficiency in prolonged vomiting

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💊 Antiemetic Pharmacology - Must Know

Memory: "DO NAAC" - Dopamine, Ondansetron/5-HT3, NK1, Antihistamine, Anticholinergic, Corticosteroids

• Also a prokinetic (speeds gastric emptying)
• Useful in gastroparesis
• Crosses BBB - can cause extrapyramidal side effects (tardive dyskinesia with long use)

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Indigestion (Dyspepsia)

Subtypes:

1. Epigastric pain syndrome (EPS) - burning/pain centered in epigastrium
2. Postprandial distress syndrome (PDS) - bothersome fullness after meals, early satiety

Causes:

• Peptic ulcer disease (~15%)
• GERD (~20%)
• Functional (idiopathic) dyspepsia (~60%) - most common; no structural cause found

Red Flags (Alarm Symptoms) - MUST REFER FOR ENDOSCOPY:

• Weight loss (unintentional)
• Anemia (iron deficiency)
• Vomiting (persistent)
• Evidence of bleeding (melena, hematemesis)
• Swallowing difficulty + age >60

H. pylori:

• Test-and-treat strategy in patients without alarm features
• Testing: urea breath test (non-invasive, preferred), stool antigen, or serology
• Treatment: PPI + clarithromycin + amoxicillin (triple therapy); or bismuth quadruple if high resistance area

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CHAPTER 49 - DIARRHEA AND CONSTIPATION

The Big Picture

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🧬 Normal GI Physiology Review (Foundation)

• Intake (oral + secretions): ~9 L/day enters the gut
• Small bowel absorbs: ~6.5 L
• Colon absorbs: ~2-2.5 L
• Stool output: ~100-200 mL/day

• Enteric nervous system (ENS): Myenteric plexus (motor) + Submucosal plexus (secretion/absorption)
• Key neurotransmitters: ACh, VIP, NO, serotonin (5-HT), substance P
• Interstitial cells of Cajal - pacemaker cells modulated by myenteric plexus
• Parasympathetics (vagus): excitatory to gut
• Sympathetics: inhibitory to gut (slow it down)

• "Housekeeper" contractions during fasting
• Phase III = strong propulsive wave - clears gut between meals
• Absent in small intestinal bacterial overgrowth (SIBO)

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DIARRHEA

Definition:

• >200 g/day stool weight (or >3 loose stools/day)
• Acute: <4 weeks; Chronic: >4 weeks

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🎯 Pathophysiology Framework - The 4 Mechanisms

1. Osmotic Diarrhea

• Non-absorbable solutes draw water into gut lumen
• Stops with fasting
• Osmotic gap > 125 mOsm/kg (stool osmotic gap = 290 - 2×[Na+stool + K+stool])
• Examples: lactase deficiency, lactulose, Mg antacids, sorbitol

2. Secretory Diarrhea

• Active ion secretion or reduced absorption (often Cl- secretion)
• Persists with fasting (large volume, watery)
• Osmotic gap < 50 mOsm/kg
• Examples: VIPoma, carcinoid, cholera, bile acid malabsorption, microscopic colitis

3. Inflammatory Diarrhea

• Mucosal damage + loss of absorptive surface
• Blood, pus, mucus in stool
• Fever, abdominal pain
• Examples: Crohn's, UC, infectious colitis, radiation colitis

4. Malabsorptive Diarrhea

• Steatorrhea (fat in stool) - pale, bulky, oily, float, hard to flush
• Examples: celiac disease, Whipple's disease, pancreatic exocrine insufficiency

Memory Trick - "OSIM": Osmotic (stops with fasting), Secretory (persists with fasting), Inflammatory (blood/pus), Malabsorptive (fat/steatorrhea)

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⚡ Acute Diarrhea (< 4 weeks)

• Fever >38.5°C
• Bloody stools
• Duration >7 days
• Immunocompromised patient
• Severe dehydration
• Outbreak setting

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🔬 Chronic Diarrhea - Systematic Approach

Categories to Distinguish:

1. Fatty/malabsorptive - steatorrhea, weight loss
2. Inflammatory - blood, pus, fever, elevated CRP/ESR
3. Watery - secretory or osmotic

Key Diagnostic Tests:

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CONSTIPATION

Definition: < 3 spontaneous bowel movements/week, or straining, hard stools, incomplete evacuation

Prevalence: 8.8% in USA; women 1.5x more than men

Causes Framework:

PRIMARY (Functional)         SECONDARY
        |                          |
Normal transit         Slow transit        IBS-C
                                     
                    Medications    Metabolic    Structural
                    (opioids,      (hypothyroid, (colorectal  
                    iron, calcium   hypercalcemia, cancer,
                    channel        Parkinson's)  obstruction)
                    blockers)

Alarm Features for Constipation (need colonoscopy):

• Age >50 first presentation
• Rectal bleeding
• Unintentional weight loss
• Anemia
• Family history of colorectal cancer
• Recent change in bowel habit

Treatment Ladder:

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CHAPTER 50 - GASTROINTESTINAL BLEEDING

The Big Picture

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🎯 Rapid Localization Framework

Key Exception: Brisk UGIB can cause hematochezia! BUN:Cr ratio and NG lavage help differentiate.

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Upper GI Bleeding - Causes

Forrest Classification (Peptic Ulcer Bleeding - Endoscopic):

• Ia: Active spurting → highest rebleed risk → urgent endotherapy
• Ib: Active oozing
• IIa: Non-bleeding visible vessel → still high risk → endotherapy
• IIb: Adherent clot → intermediate risk
• IIc: Flat pigmented spot → low risk
• III: Clean base ulcer → lowest risk → discharge possible

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Lower GI Bleeding - Causes

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Management of UGIB - Resuscitation First!

1. ABC resuscitation: 2 large-bore IVs, type & cross, volume resuscitation
2. Transfusion threshold: Hgb <7 g/dL (restrictive strategy = better outcomes)
3. IV PPI: Bolus + infusion (reduces rebleed, surgery need for peptic ulcers)
4. Octreotide: If variceal bleed suspected (reduces portal pressure)
5. Antibiotics (ceftriaxone): If cirrhosis (SBP prophylaxis - reduces mortality)
6. Endoscopy within 24 hours (within 12 hrs if unstable or variceal suspected)
7. Endoscopic therapy: Epinephrine injection + hemoclip or thermal coagulation
8. TIPS/surgery if endoscopy fails

Scoring Systems:

• Glasgow-Blatchford Score - pre-endoscopy; guides need for hospital admission/intervention
• Rockall Score - post-endoscopy; predicts rebleed risk and mortality

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CHAPTER 51 - JAUNDICE

The Big Picture

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🧬 Bilirubin Metabolism - The Pathway

Heme → Biliverdin → Unconjugated bilirubin (indirect)
         (in RES)      [fat soluble, bound to albumin]
                              ↓ (hepatocyte)
                       Conjugated bilirubin (direct)
                       [water soluble]
                              ↓
                         Bile → Gut → Urobilinogen
                                       ↓          ↓
                                  Urine      Stercobilin (feces - brown color)

Key Point: Unconjugated bilirubin is NOT water soluble - it cannot be filtered by kidneys, so NO bilirubinuria in prehepatic jaundice.

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🎯 Classification Framework

Memory: "PREHEPATIC = No Bilirubin in Urine" because unconjugated can't get through kidneys

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Common Causes by Category

Prehepatic (Unconjugated Hyperbilirubinemia):

• Hemolysis (spherocytosis, G6PD, sickle cell, transfusion reaction)
• Gilbert's syndrome - most common benign cause; UGT1A1 enzyme reduced; jaundice during fasting/illness; no treatment needed
• Crigler-Najjar syndrome (severe form - neonatal)
• Ineffective erythropoiesis (thalassemia)

Hepatocellular:

• Viral hepatitis (A, B, C, E)
• Alcoholic hepatitis
• Drug-induced liver injury (DILI)
• Autoimmune hepatitis
• Wilson's disease, hemochromatosis
• Non-alcoholic steatohepatitis (NASH)

Cholestatic (Obstructive):

• Intrahepatic: Primary biliary cholangitis (PBC), PSC, drug-induced cholestasis, pregnancy cholestasis
• Extrahepatic: Choledocholithiasis, pancreatic cancer (painless jaundice = classic!), cholangiocarcinoma, stricture

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Key Lab Patterns

ALP + GGT both elevated = cholestasis (GGT confirms liver origin of ALP elevation)

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Investigation Approach

1. History + clinical exam (scleral icterus = jaundice confirmed)
2. LFTs + CBC + bilirubin fractionation
3. Ultrasound abdomen - first imaging (dilated ducts = obstructive; stones; liver texture)
4. If obstructive: MRCP (non-invasive) → ERCP (therapeutic - stone removal)
5. If hepatocellular: Viral serologies, autoimmune markers, ferritin, ceruloplasmin

Courvoisier's Law:

• Painless jaundice + palpable gallbladder = malignant obstruction (usually pancreatic head cancer)
• If gallbladder NOT palpable + jaundice = likely stone disease (gallbladder contracted from chronic inflammation)

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CHAPTER 52 - ABDOMINAL SWELLING AND ASCITES

The Big Picture

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🎯 The 5 F's + 2 More (Causes of Abdominal Distension)

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SAAG - The Critical Formula

SAAG = Serum albumin - Ascites albumin

Memory: "HIGH SAAG = HIGH pressure = portal hypertension = cirrhosis"

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Ascites Exam Findings

• Shifting dullness - most sensitive clinical test (detects ~500 mL)
• Fluid thrill - for massive ascites
• Bulging flanks - visible on inspection

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Causes of Ascites

1. Cirrhosis (~75-80% of all ascites in Western countries) - portal hypertension + hypoalbuminemia + sodium retention
2. Malignancy (~10%)
3. Heart failure (~5%)
4. Tuberculosis - especially in developing countries
5. Pancreatitis (pancreatic ascites - amylase very high in fluid)
6. Nephrotic syndrome (low SAAG - low oncotic pressure)

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Diagnostic Paracentesis - Always Do This

• Cell count + differential (PMNs >250/mm³ = SBP diagnosis)
• Albumin (for SAAG)
• Total protein
• Culture + Gram stain
• Cytology (if malignancy suspected)
• Amylase (if pancreatitis suspected)
• Triglycerides (chylous ascites if milky)

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Spontaneous Bacterial Peritonitis (SBP)

• IV Ceftriaxone (3rd gen cephalosporin) × 5 days
• IV Albumin 1.5 g/kg on day 1 + 1 g/kg on day 3 - reduces hepatorenal syndrome and mortality
• Long-term prophylaxis: Norfloxacin or ciprofloxacin (after first episode)

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Management of Cirrhotic Ascites

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CHAPTER 53 - ABDOMINAL PAIN

The Big Picture

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🧠 Types of Abdominal Pain - Pathophysiology

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🎯 Classic Referred Pain Patterns - HIGH YIELD

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The Gut Embryological Regions - Visceral Pain Localization

Memory: "From top to bottom: Epi → Umbilical → Hypogastric = Fore → Mid → Hind"

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Acute Abdomen - The Critical Emergencies

Signs of Peritonitis (SURGICAL EMERGENCY):

• Guarding - voluntary muscle contraction
• Rigidity - involuntary board-like stiffness
• Rebound tenderness - pain on release of pressure
• Patient lies still, afraid to move
• Bowel sounds absent

Causes of Acute Abdomen:

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Appendicitis - Detailed Breakdown (Most Tested!)

1. Periumbilical visceral pain (first)
2. Anorexia, nausea
3. Migration to RLQ (McBurney's point = 1/3 from ASIS to umbilicus)
4. Fever
5. If perforated - brief pain relief, then diffuse peritonitis

• McBurney's point tenderness - most specific location
• Rovsing's sign - pressure on LLQ causes pain in RLQ
• Psoas sign - pain on right hip extension (retrocecal appendix)
• Obturator sign - pain on internal rotation of right hip (pelvic appendix)
• Dunphy's sign - pain on coughing

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Extra-Abdominal Causes of Abdominal Pain - Don't Miss!

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🔗 INTEGRATION TABLE - How the Chapters Connect

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📋 RAPID REVIEW - ONE-LINERS TO MEMORIZE

1. Globus ≠ Dysphagia - globus doesn't interfere with actual swallowing
2. Achalasia = bird beak + aperistalsis - both LES AND peristalsis fail
3. EoE = young man + atopy + ≥15 eos/HPF - treat with topical steroids
4. Vomiting center in brainstem; CTZ in area postrema (outside BBB)
5. Projectile vomiting + no nausea = raised ICP (bypasses nausea warning)
6. DO NOT give antibiotics in STEC (O157) - increases HUS risk
7. Osmotic diarrhea stops with fasting; secretory does not
8. BUN:Cr >20:1 = UGIB (blood digested = urea absorbed)
9. SAAG ≥1.1 = portal hypertension (cirrhosis, CHF, Budd-Chiari)
10. SBP: PMNs >250 = treat with ceftriaxone + albumin
11. Gilbert's = most common benign cause of jaundice - fasting/stress triggers
12. Courvoisier's law: painless jaundice + palpable GB = cancer (not stones)
13. Visceral pain = midline; parietal pain = localizes to lesion
14. Alvarado ≥7 = surgery for appendicitis
15. "Pain out of proportion to exam" = mesenteric ischemia until proven otherwise

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🫘 Harrison's Section 7 - Alterations in Renal & Urinary Tract Function

Chapters 54-58 | Master Study Guide

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CHAPTER 54 - AZOTEMIA AND URINARY ABNORMALITIES

The Big Picture in One Sentence

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🧬 Kidney Function Basics - What You Must Know First

• Normal: ~120 mL/min/1.73m²
• Best clinical estimate: CKD-EPI equation (replaces old MDRD)
• Serum creatinine alone is an unreliable GFR marker - affected by muscle mass, diet, drugs

• Normal: 8-20 mg/dL
• Elevated by: protein intake, GI bleeding, catabolic states, steroids, dehydration
• Decreased by: liver failure, low protein diet, SIADH

• Normal: 10-15:1
• >20:1 = pre-renal (urea reabsorbed with water in hypovolemia)
• <10:1 = intrinsic renal, rhabdomyolysis (creatinine disproportionately high), liver disease

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🎯 The Azotemia Classification - MASTER THIS

AZOTEMIA
    |
    ├── PRE-RENAL (reduced perfusion, kidneys intact)
    |       ↓
    |   Oliguria + concentrated urine + respond to fluids
    |
    ├── INTRINSIC RENAL (kidney itself damaged)
    |       ↓
    |   Specific urine findings help localize injury
    |
    └── POST-RENAL (obstruction below kidneys)
            ↓
        Anuria or alternating oliguria/polyuria

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Pre-Renal Azotemia

• True volume depletion: vomiting, diarrhea, bleeding, burns, diuretics
• Low cardiac output: heart failure, cardiogenic shock
• Altered vascular resistance: sepsis (distributive shock)
• Selective afferent constriction: NSAIDs block prostaglandin-mediated afferent dilation (critical in heart failure, cirrhosis)
• Selective efferent dilation: ACE inhibitors / ARBs - reduce GFR by dropping efferent resistance

FENa formula: FENa = (Urine Na × Plasma Cr) / (Plasma Na × Urine Cr) × 100

FENa <1% but still ATN? Yes - in contrast nephropathy, myoglobinuria, early obstruction, hepatorenal syndrome. Use FEUrea instead (FEUrea <35% = pre-renal) when diuretics given.

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Intrinsic Renal Azotemia - Localize by Nephron Segment

Glomerular Disease

• Hematuria + proteinuria + RBC casts = nephritic syndrome (glomerulonephritis)
• Massive proteinuria (>3.5 g/day) + edema + hypoalbuminemia = nephrotic syndrome
• Causes: IgA nephropathy, post-streptococcal GN, lupus nephritis, ANCA vasculitis

Tubular Disease (ATN - most common cause of AKI in hospital)

• Causes: ischemia (shock), nephrotoxins (aminoglycosides, contrast, cisplatin, myoglobin, hemoglobin)
• Urine findings: muddy brown granular casts (classic) + tubular epithelial cells
• Phases: oliguric (days-weeks) → polyuric (recovery) → complete recovery
• FENa >2%; isosthenuria

Interstitial Disease (Acute Interstitial Nephritis - AIN)

• Causes: drug hypersensitivity (NSAIDs, antibiotics - especially beta-lactams, rifampin, PPIs), infections
• Classic triad: fever + rash + eosinophilia (only in ~30% - do not rely on it)
• Urine: WBC casts + eosinophiluria (dipstick often negative for blood/protein)
• Biopsy confirms; Treatment: stop offending drug ± steroids

Vascular Disease

• Renal artery stenosis (bilateral - ACE inhibitor can precipitate AKI)
• Thrombotic microangiopathy (HUS, TTP - schistocytes + thrombocytopenia)
• Cholesterol emboli: livedo reticularis, eosinophilia, after vascular procedure

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Post-Renal Azotemia

• Prostate enlargement (BPH) - most common in elderly men
• Cervical/pelvic cancer - bilateral ureteric obstruction
• Kidney stones (usually requires bilateral or solitary kidney)
• Urethral stricture, neurogenic bladder

• Anuria (complete obstruction) or oliguria
• Palpable bladder (if bladder outlet obstruction)
• Post-obstructive diuresis after relief (watch for electrolyte losses!)
• Ultrasound: hydronephrosis (dilated collecting system)

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Urinary Abnormalities - Approach

Proteinuria

• Orthostatic (postural): protein only when upright, disappears when supine - benign in young
• Tubular: small proteins (beta-2 microglobulin, RBP) - from tubular injury
• Overflow: excess production (light chains in myeloma, myoglobin)

Hematuria

• Gross hematuria: visible blood
• Microscopic: >3 RBCs/hpf on two separate urinalyses

• Dysmorphic RBCs + RBC casts = GLOMERULAR origin (acanthocytes = pathognomonic)
• Normal-shaped RBCs = urological origin (stone, tumor, infection, trauma)

• Young adult: IgA nephropathy (post-exercise gross hematuria), thin basement membrane disease
• Middle-aged woman: UTI, bladder tumor
• Older man: prostate disease, bladder cancer

Casts

Memory: "Red cells = Renal glomerular; White cells = infection/interstitial; Muddy brown = ATN; Waxy = CKD"

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CHAPTER 55 - INTERSTITIAL CYSTITIS / BLADDER PAIN SYNDROME (IC/BPS)

The Big Picture

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Definition and Epidemiology

• Predominantly affects women (female:male ~5:1)
• Peak age: 40-60 years
• Prevalence: 2-7% of women

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Pathophysiology - 3 Key Mechanisms

1. Defective glycosaminoglycan (GAG) layer of urothelium - normally protects bladder wall from urine irritants; when defective, urine constituents (especially potassium) penetrate into submucosa and trigger inflammation
2. Neurogenic inflammation - activation of bladder mast cells → release of histamine, prostaglandins, substance P → suburothelial inflammation
3. Central sensitization - chronic pain processing in CNS leads to allodynia and hyperalgesia beyond the bladder (overlap with IBS, fibromyalgia, vulvodynia)

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🎯 Clinical Features - The Hallmark Triad

1. Pelvic/suprapubic pain - worse with bladder filling, relieved by voiding
2. Urinary urgency and frequency (often 8-60 voids/day)
3. Nocturia

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Diagnosis

1. UTI (urine culture negative)
2. Bladder cancer (cystoscopy + biopsy if hematuria or risk factors)
3. STIs
4. Endometriosis
5. Overactive bladder

• Urinalysis + culture (must be negative)
• Potassium sensitivity test (Parson's test): Intravesical instillation of KCl solution - positive (pain) supports IC/BPS but not widely used now
• Cystoscopy + hydrodistension (under anesthesia): reveals petechiae ("glomerulations") after distension - supportive but not pathognomonic
• Bladder biopsy: Rules out carcinoma in situ; may show mast cell infiltration

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Treatment - Stepwise

Memory for treatment: "EAT PAIN" - Education, Amitriptyline, Training (bladder), PPS, Antihistamines, Intravesical, Neuromodulation

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CHAPTER 56 - FLUID AND ELECTROLYTE DISTURBANCES

The Big Picture

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SODIUM DISORDERS

Normal Physiology

• Normal serum Na+: 136-145 mEq/L
• Sodium is the major extracellular osmole - it determines plasma osmolality
• Plasma osmolality = 2[Na+] + Glucose/18 + BUN/2.8 (normal ~285-295 mOsm/kg)
• ADH (vasopressin) controls water reabsorption in collecting duct
• High osmolality → ADH secretion → water retained → dilutes Na+ back to normal

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HYPONATREMIA (Na+ < 136 mEq/L)

Step 1: Assess Plasma Osmolality

Correction for hyperglycemia: For every 100 mg/dL rise in glucose above 100, Na+ drops by ~1.6-2.4 mEq/L (corrected Na+ = measured Na+ + 1.6 × [(glucose - 100)/100])

Step 2: Assess Volume Status (for Hypotonic Hyponatremia)

HYPOVOLEMIC (total body Na+ LOW)
    Urine Na <20 = extrarenal loss (vomiting, diarrhea, sweating)
    Urine Na >20 = renal loss (diuretics, Addison's, salt-wasting nephropathy)

EUVOLEMIC (total body Na+ normal, excess water)
    Most common: SIADH
    Also: hypothyroidism, adrenal insufficiency, psychogenic polydipsia

HYPERVOLEMIC (total body Na+ HIGH, even more water)
    Urine Na <20 = heart failure, cirrhosis, nephrotic syndrome
    Urine Na >20 = CKD/AKI

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SIADH - The Most Tested Cause of Hyponatremia

1. Hypotonic hyponatremia (serum osmolality <275)
2. Urine inappropriately concentrated (urine osmolality >100; usually >300)
3. Urine Na+ >40 mEq/L (kidneys not conserving Na+ despite low plasma Na+)
4. Normal volume status (no edema, no dehydration)
5. Normal renal, adrenal, thyroid function
6. No diuretics

• CNS disorders: meningitis, SAH, stroke, head trauma, psychosis
• Neoplasms: small cell lung cancer (most common tumor cause), pancreas, lymphoma
• S - surgery (post-op)
• Pulmonary: pneumonia, TB, COPD, mechanical ventilation
• Unknown (idiopathic - elderly)
• Medications: carbamazepine, SSRIs, opioids, chlorpropamide, cyclophosphamide, oxytocin
• Pain
• Drugs (others): NSAIDs (enhance ADH action), tricyclics

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Treatment of Hyponatremia - CRITICAL to Know

Rate of Correction (The Most Important Rule in Electrolytes):

Never correct Na+ faster than 8-10 mEq/L per 24 hours (max 12 mEq/L/24hr)

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HYPERNATREMIA (Na+ > 145 mEq/L)

1. Water loss > Na+ loss:
   • Renal: Diabetes insipidus (central or nephrogenic), loop diuretics, osmotic diuresis
   • Extrarenal: diarrhea, sweating, fever, burns, mechanical ventilation
2. Inadequate water intake: elderly, altered consciousness, intubated patients
3. Na+ gain: hypertonic saline, sodium bicarbonate, hyperaldosteronism (rare)

Diabetes Insipidus (DI)

Treatment of Hypernatremia:

• Replace free water deficit
• Formula: Free water deficit = 0.6 × weight(kg) × ([Na+/140] - 1)
• Correct slowly: no faster than 10-12 mEq/L per 24 hours
• Rapid correction → cerebral edema
• Route: oral (preferred) or D5W IV; avoid isotonic saline (contains Na+)

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POTASSIUM DISORDERS

Normal Physiology

• Normal serum K+: 3.5-5.0 mEq/L
• 98% of body K+ is intracellular (mainly muscle) - only 2% extracellular
• K+ shifts between compartments rapidly (acidosis → K+ out of cells; alkalosis → K+ into cells)
• Each 0.1 unit drop in pH → ~0.6 mEq/L rise in serum K+ (and vice versa)
• Kidneys control long-term K+ balance via principal cells of collecting duct (aldosterone-regulated)

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HYPOKALEMIA (K+ < 3.5 mEq/L)

Causes Framework:

• Insulin administration (drives K+ into cells via Na/K-ATPase)
• Beta-2 agonists (albuterol, ritodrine/tocolytic)
• Alkalosis
• Thyrotoxicosis (thyrotoxic periodic paralysis - especially Asian/Latin patients)
• Familial hypokalemic periodic paralysis - attacks of weakness at night/early morning

• GI losses: Vomiting (metabolic alkalosis + low Cl-), diarrhea, fistulas, NG drainage
  • Urine K+ <20 mEq/day = GI loss
• Renal losses:
  • Diuretics (most common cause overall!) - especially loop + thiazides
  • Mineralocorticoid excess (Conn's syndrome, Cushing's) - aldosterone drives K+ excretion
  • Renal tubular acidosis type 1 and 2
  • Hypomagnesemia (blocks tubular K+ reabsorption - must correct Mg2+ to correct K+!)
  • Bartter's syndrome (loop-like defect), Gitelman's syndrome (thiazide-like defect)
  • Urine K+ >20 mEq/day = renal loss

Clinical Features of Hypokalemia:

ECG Memory: "Low K = Low T + U waves appear" - U wave is positive deflection after T wave, best seen V2-V3

Treatment of Hypokalemia:

• Mild (3.0-3.5): oral KCl replacement; increase dietary K+ (banana, orange, potato)
• Moderate-severe (<3.0 or symptomatic): IV KCl at maximum 10-20 mEq/hr (never faster - cardiac arrest risk)
• Always correct hypomagnesemia first - hypomagnesemia causes refractory hypokalemia
• If on diuretics: switch to K+-sparing (spironolactone, amiloride, triamterene)

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HYPERKALEMIA (K+ > 5.0 mEq/L)

Causes Framework - "3 D's": Don't, Dilute, Dump

1. Pseudohyperkalemia (lab artifact): hemolysis of blood sample, thrombocytosis, leukocytosis - repeat test
2. Transcellular shift (out of cells):
   • Acidosis (metabolic or respiratory) - each 0.1 pH drop → +0.6 mEq/L K+
   • Insulin deficiency (DKA)
   • Hyperkalemic periodic paralysis
   • Beta-blocker overdose
   • Tissue necrosis (rhabdomyolysis, tumor lysis, hemolysis, burns)
   • Succinylcholine (depolarizing neuromuscular blocker) - causes dangerous K+ release in burn, crush, denervation patients
3. Reduced renal excretion (most common true cause):
   • AKI / CKD
   • Hypoaldosteronism: Addison's disease, type 4 RTA (hyporeninemic hypoaldosteronism - common in diabetic nephropathy)
   • Drugs: ACE inhibitors, ARBs, K+-sparing diuretics (spironolactone, amiloride), NSAIDs, trimethoprim, heparin
4. Excess intake: IV potassium, blood transfusion (old stored blood), salt substitutes

Clinical Features - Cardiac Danger!

K+ 5.5-6.5: Peaked (tall, narrow, symmetric) T waves
K+ 6.5-7.5: Prolonged PR, wide QRS
K+ >7.5:    Loss of P waves, sine wave pattern
K+ >8-9:    Ventricular fibrillation / asystole → DEATH

Memory: "Peaked T → PR long → QRS wide → No P → Sine wave → VF"

Treatment of Hyperkalemia - Know the "CBDIG" Protocol:

The order: Calcium first (protects heart) → Shift K+ in (bicarb/insulin/beta-agonist) → Remove K+ from body (resins/dialysis)

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CHAPTER 57 - HYPERCALCEMIA AND HYPOCALCEMIA

The Big Picture

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Normal Calcium Physiology

• Normal total calcium: 8.5-10.5 mg/dL (ionized Ca2+ = 4.6-5.1 mg/dL)
• ~50% bound to albumin, ~10% complexed (citrate, phosphate), ~40% ionized (biologically active)
• Correct for albumin: For every 1 g/dL drop in albumin below 4, add 0.8 mg/dL to measured calcium
• Calcium regulation:
  • PTH: raises Ca2+ (bone resorption + renal Ca2+ reabsorption + activates Vit D)
  • 1,25-(OH)2D (calcitriol): raises Ca2+ (intestinal absorption)
  • Calcitonin: lowers Ca2+ (used acutely; long-term effect minimal)
  • FGF-23: lowers phosphate (opposite of PTH on phosphate)

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HYPERCALCEMIA (Calcium > 10.5 mg/dL)

Causes - The "CHIMPANZEES" Mnemonic

Two Giants: Primary Hyperparathyroidism vs. Malignancy

1. Humoral (most common ~80%): PTHrP secretion (squamous cell lung, breast, renal, bladder)
2. Osteolytic metastases: Myeloma, breast cancer - local bone destruction
3. Ectopic 1,25-D production: Lymphomas (like sarcoid mechanism)
4. Ectopic PTH: Extremely rare

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Clinical Features of Hypercalcemia - "Bones, Stones, Groans, Psychic Moans, Thrones"

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Treatment of Hypercalcemia

Acute Severe Hypercalcemia (Ca2+ > 14 mg/dL or symptomatic):

Memory: "Saline First - then add Furosemide - then Bisphosphonate - then Calcitonin (quick bridge)"

Primary Hyperparathyroidism:

• Symptomatic (stones, fractures, neurocognitive): Parathyroidectomy (curative)
• Asymptomatic indications for surgery: Ca2+ >1 mg/dL above ULN, T-score <-2.5 at any site, age <50, 24-hr urine Ca >400 mg, CrCl <60 mL/min
• Medical management if not surgical candidate: Cinacalcet (calcimimetic - activates calcium-sensing receptor → suppresses PTH)

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HYPOCALCEMIA (Calcium < 8.5 mg/dL)

Causes Framework - "PTH? Then Vitamin D? Then Other?"

• Post-surgical (most common): thyroidectomy, parathyroidectomy, radical neck dissection
• Autoimmune: DiGeorge syndrome (22q11 deletion), autoimmune polyglandular syndrome type 1
• Hypomagnesemia (<1.2 mg/dL): blocks PTH secretion AND causes PTH resistance - must correct Mg2+ first!
• Radiation, infiltrative (hemochromatosis, Wilson's, malignancy)

• PTH high but kidneys don't respond (Gs protein defect)
• Type 1a: "Albright's hereditary osteodystrophy" - short stature, round face, short 4th metacarpal, subcutaneous calcifications

• Nutritional deficiency (most common worldwide)
• Malabsorption (Crohn's, celiac, bariatric surgery)
• CKD: impaired 1α-hydroxylase → cannot activate Vit D
• Vitamin D resistance (type II rickets)

• Hyperphosphatemia (binds Ca2+ → precipitates): AKI, rhabdomyolysis, tumor lysis, excess phosphate
• Pancreatitis (fat saponification consumes Ca2+)
• Alkalosis (increases albumin binding of Ca2+ → reduces ionized Ca2+)
• Osteoblastic metastases (prostate, breast cancer): Ca2+ deposited into bone
• Hungry bone syndrome (after parathyroidectomy - bones avidly take up Ca2+)

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Clinical Features of Hypocalcemia - Neuromuscular Excitability

• Convulsions
• Arrhythmias (prolonged QTc → Torsades de pointes)
• Tetany (carpopedal spasm, laryngospasm, bronchospasm)
• Spasms and stridor

• Chvostek's sign: Tap facial nerve (anterior to ear) → ipsilateral facial twitch (present in ~10% of normal - low specificity)
• Trousseau's sign: BP cuff inflated 20 mmHg above systolic for 3 min → carpal spasm (thumb adduction + wrist flexion) - more specific than Chvostek's

• Cataracts (subcapsular)
• Calcification of basal ganglia (parkinsonism, choreoathetosis)
• Dental enamel hypoplasia
• Papilledema (pseudotumor cerebri)
• Prolonged QTc on ECG

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Treatment of Hypocalcemia

Acute (Symptomatic - Tetany/Seizures):

• IV Calcium gluconate (10-20 mL of 10% = 90-180 mg elemental Ca2+) over 10-20 minutes
• Followed by calcium infusion (calcium gluconate in D5W)
• Caution: IV calcium precipitates with bicarbonate/phosphate - use separate lines

Chronic (Hypoparathyroidism):

• Oral calcium carbonate (with food - acid needed for absorption) OR calcium citrate (without food)
• Active vitamin D: Calcitriol (1,25-OH2D) - bypass need for renal activation; start 0.25 mcg BID
• Target Ca2+ at low-normal (8-8.5 mg/dL) to avoid hypercalciuria + nephrolithiasis
• Recombinant PTH (Natpara/palopegteriparatide) for refractory hypoparathyroidism

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CHAPTER 58 - ACIDOSIS AND ALKALOSIS

The Big Picture

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Foundation: The pH Equation

• pH: 7.35-7.45
• PaCO2: 35-45 mmHg
• HCO3-: 22-26 mEq/L

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🎯 The 5-Step Systematic Approach (Use Every Time)

Step 1: Is pH acidemic or alkalemic?

• pH <7.35 = Acidemia
• pH >7.45 = Alkalemia

Step 2: Is the primary disorder respiratory or metabolic?

• Metabolic acidosis: pH ↓ + HCO3- ↓
• Metabolic alkalosis: pH ↑ + HCO3- ↑
• Respiratory acidosis: pH ↓ + PaCO2 ↑
• Respiratory alkalosis: pH ↑ + PaCO2 ↓

Step 3: Is compensation appropriate?

Chronic compensation is always greater than acute - the kidney has had time to respond

Step 4: Calculate Anion Gap (if metabolic acidosis present)

AG = Na+ - (Cl- + HCO3-) Normal = 8-12 mEq/L (some labs 3-11 if different normal albumin)

Step 5: If high AG acidosis, calculate Delta-Delta ratio

Delta-Delta (Δ/Δ) = (AG - 12) / (24 - HCO3-)

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METABOLIC ACIDOSIS

High Anion Gap (AG > 12) - "MUDPILES / GOLDMARK"

• Methanol
• Uremia (AKI/CKD)
• Diabetic ketoacidosis (most common)
• Propylene glycol (IV lorazepam, other drugs)
• Isoniazid / Iron toxicity
• Lactic acidosis
• Ethylene glycol
• Salicylates

• Glycols (ethylene glycol, propylene glycol)
• Oxoproline (acetaminophen toxicity - chronic, often missed)
• Lactic acidosis
• D-lactic acidosis (short bowel)
• Methanol
• Aspirin (salicylates)
• Renal failure (uremia)
• Ketoacidosis (DKA, alcoholic, starvation)

Lactic Acidosis (Most Important High AG Cause in Hospital)

• Sepsis, cardiogenic shock, mesenteric ischemia, severe anemia, CO poisoning

• Metformin (especially in AKI), liver failure, thiamine deficiency, HIV drugs (NRTIs), malignancy, alcohol, cyanide

Key point: Metformin must be held when GFR <30 - accumulates and causes type B lactic acidosis

Normal Anion Gap (Hyperchloremic) Metabolic Acidosis

• Hyperalimentation (TPN)
• Addison's disease (hypoaldosteronism)
• RTA (renal tubular acidosis)
• Diarrhea (loss of HCO3- in stool - most common cause worldwide)
• Ureteral diversion (uretero-sigmoidostomy)
• Pancreatic fistula
• Saline infusion excess (dilutional)

Renal Tubular Acidosis (RTA) - High Yield Table

Type 3 RTA is obsolete/rarely used.

Memory: "Type 1 = distal = can't drop pH (>5.5) = stones + nephrocalcinosis"

Treatment of Metabolic Acidosis:

• Treat underlying cause (primary goal)
• NaHCO3 for severe acidosis (pH <7.1 or HCO3- <10): formula: Bicarb deficit = 0.5 × weight × (desired HCO3- - actual HCO3-)
• DKA: Insulin + IV fluids + K+ replacement (not bicarb unless pH <6.9)
• Lactic acidosis: Treat cause; bicarb controversial (may worsen intracellular acidosis, increases CO2)

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METABOLIC ALKALOSIS

The Big Picture

Causes:

• Vomiting / NG suction (most common): lose HCl → bicarb generation; volume contraction → aldosterone → more H+ excretion
• Loop or thiazide diuretics (once stopped): volume contraction + K+ loss
• Post-hypercapnia: Chronic CO2 retention → renal HCO3- retention; if respiratory problem corrected rapidly, HCO3- remains

• Mineralocorticoid excess: Primary aldosteronism (Conn's), Cushing's, licorice (glycyrrhizin acts like mineralocorticoid), Liddle's syndrome
• Severe hypokalemia (K+ shift out of cells → H+ shifts in → bicarb generation)
• Bartter's syndrome / Gitelman's syndrome (hereditary tubular disorders)

Urine Cl- is the key test (not urine Na+ - misleading because large bicarb is being excreted, pulling Na+ with it)

Clinical Features:

• Often asymptomatic if mild
• Reduced ionized calcium → paresthesias, cramps, Chvostek's/Trousseau's signs (same as hypocalcemia)
• Hypoventilation (compensation - PaCO2 rises)
• Hypokalemia (often coexists)
• Cardiac arrhythmias

Treatment:

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RESPIRATORY ACIDOSIS

Causes - "CNS → Nerve → Muscle → Lung → Airway"

• Acute: rapid rise in CO2, HCO3- barely rises (non-renal buffering), pH drops severely
• Chronic: kidneys retain HCO3- over days, pH partially corrected

Caution: In COPD "CO2 retainers," DO NOT give high-flow O2 blindly - eliminates hypoxic drive → worsening CO2 retention; use controlled O2 to target SpO2 88-92%

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RESPIRATORY ALKALOSIS

Causes - "HAMPER"

• Hypoxia (PE, pneumonia, high altitude, severe anemia) - most important
• Anxiety / pain (psychogenic hyperventilation)
• Mechanical ventilation (iatrogenic over-ventilation)
• Pregnancy (progesterone stimulates respiratory center)
• Encephalopathy (hepatic, sepsis, CNS disease)
• Respiratory stimulants (salicylates - early; fever; sepsis)

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🔗 Mixed Acid-Base Disorders - Common Clinical Combinations

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📋 RAPID REVIEW - ONE-LINERS FOR CHAPTERS 54-58

1. FENa <1% = pre-renal; >2% = ATN (use FEUrea if on diuretics)
2. Muddy brown granular casts = ATN (most common cause of AKI in hospital)
3. RBC casts = glomerulonephritis; WBC casts = pyelonephritis or AIN
4. IC/BPS = bladder pain + frequency + negative culture - diagnosis of exclusion
5. Trousseau's sign is MORE specific for hypocalcemia than Chvostek's
6. SIADH: urine Na+ >40 + urine osm >100 + euvolemia - concentrated urine inappropriately
7. Correct Na+ no faster than 8-10 mEq/L/24 hr - risk of ODS/central pontine myelinolysis
8. Central DI: concentrates with desmopressin; Nephrogenic DI: does not
9. Lithium = most common cause of nephrogenic DI (drug-induced)
10. Hypokalemia ECG = U waves (best seen V2-V3); Hyperkalemia = peaked T waves first
11. Always correct hypomagnesemia before correcting hypokalemia - refractory otherwise
12. Calcium gluconate is the FIRST treatment for hyperkalemia ECG changes (membrane stabilization)
13. Primary hyperPTH = high PTH + hypercalcemia; Malignancy = suppressed PTH + high Ca2+
14. "Bones, Stones, Groans, Psychic Moans, Thrones" = hypercalcemia symptoms
15. Calcitonin works fast (hours) but tachyphylaxis in 48-72 hrs - use as bridge to bisphosphonate
16. Winter's formula: expected PaCO2 = 1.5 × HCO3- + 8 ± 2 (metabolic acidosis compensation)
17. DKA = high AG metabolic acidosis (most common cause in clinical practice)
18. Urine Cl- <20 = saline-responsive alkalosis (vomiting, diuretics); >20 = saline-resistant (hyperaldosteronism)
19. Type 4 RTA = hyperkalemia + normal AG acidosis = diabetic nephropathy
20. "Pain out of proportion + metabolic acidosis" = mesenteric ischemia / lactic acidosis

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🔗 CROSS-CHAPTER CONNECTIONS

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