Myocardial Infarction

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

EPIDEMIOLOGY

• ~605,000 patients experience a new AMI each year
• ~200,000 experience a recurrent AMI each year
• About half of AMI-related deaths occur before the patient reaches the hospital
• In-hospital mortality has declined from ~10% to ~5%
• 1-year mortality after AMI is ~15%
• Mortality is approximately fourfold higher in patients aged >75 years

CLASSIFICATION: ACUTE CORONARY SYNDROMES

• ST-segment elevation → STEMI
• No ST-segment elevation → UA or NSTEMI (distinguished by biomarkers)

• Type 1 - Spontaneous MI from plaque rupture/erosion and thrombosis
• Type 2 - MI due to supply-demand mismatch (e.g., spasm, embolism, arrhythmia, anemia, hypotension)
• Type 3 - Cardiac death with symptoms of ischemia before biomarkers are available
• Types 4a/4b/4c - Procedure-related MI (PCI, stent thrombosis, restenosis)
• Type 5 - CABG-related MI

PATHOPHYSIOLOGY

Role of Acute Plaque Rupture/Erosion

• Slowly developing high-grade stenoses do NOT typically precipitate STEMI (due to collateral development)
• STEMI results from rapidly developing thrombus at a site of vascular injury
• Risk factors facilitating injury: cigarette smoking, hypertension, lipid accumulation, inflammation

• Rich lipid core
• Thin fibrous cap (thin-capped fibroatheroma)
• Expansive remodeling
• Neovascularization (angiogenesis)
• Plaque hemorrhage
• Adventitial inflammation
• "Spotty" pattern of calcification

Note: Despite these features, <5% of thin-capped fibroatheromas actually serve as a nidus for AMI during long-term follow-up.

Thrombosis Cascade

1. Initial platelet monolayer forms at the disrupted plaque
2. Agonists (collagen, ADP, epinephrine, serotonin) promote platelet activation
3. Thromboxane A2 (potent vasoconstrictor) is released - further platelet activation and resistance to fibrinolysis
4. Glycoprotein IIb/IIIa receptor undergoes conformational change - develops high affinity for fibrinogen
5. Fibrinogen bridges adjacent platelets, creating the platelet plug
6. The coagulation cascade is activated, and a fibrin-rich thrombus stabilizes the clot

Cellular Consequences

• Zone of injury - potentially salvageable myocardium
• Zone of ischemia - outer rim, often reversible

CLINICAL PRESENTATION

Symptoms

• Classic: Prolonged (>20-30 min), severe, crushing/pressure-like chest pain, not relieved by nitrates
• Radiation to the left arm, neck, jaw, back, or epigastrium
• Associated: diaphoresis, dyspnea, nausea, vomiting, light-headedness
• Atypical presentations (common in elderly, diabetics, women): epigastric pain, fatigue, dyspnea without chest pain ("silent MI")

Physical Examination

• Patient appears anxious and in distress
• Tachycardia (sinus), possible bradycardia with inferior MI (vagal effect)
• S4 gallop is nearly universal (reduced LV compliance)
• S3 gallop if significant LV dysfunction
• New mitral regurgitation murmur (papillary muscle dysfunction or rupture)
• Signs of LV failure: pulmonary rales, elevated JVP
• Signs of RV infarction (inferior STEMI): elevated JVP, Kussmaul's sign, hypotension with clear lungs

DIAGNOSIS

ECG

1. Hyperacute T waves - earliest finding (peaked, wide-based T waves)
2. ST-segment elevation - diagnostic of STEMI (>1 mm in ≥2 contiguous limb leads or >2 mm in ≥2 contiguous precordial leads)
3. Q waves - develop over hours to days, indicate transmural necrosis
4. T-wave inversion - as ST normalizes
5. Q waves persist in completed infarction

Cardiac Biomarkers

• Rise within 3-6 hours of myocyte necrosis
• Peak at 24-48 hours
• Remain elevated for 7-14 days (useful for late diagnosis)
• Levels rise to 20-50 times the upper reference limit in classic STEMI
• High-sensitivity troponins detect microinfarction even when CK-MB is normal

• Rises within 4-6 hours
• Returns to normal by 48-72 hours
• Useful for detecting reinfarction (rises again after normalization)
• Peaks earlier with successful reperfusion ("washout" phenomenon)

• Myoglobin: earliest rise (1-4 hrs) but non-specific
• WBC: rises within hours, peaks 12,000-15,000/μL, persists 3-7 days
• ESR: rises more slowly, peaks during first week

Cardiac Imaging

• Echocardiography: Wall motion abnormalities are nearly universal; cannot distinguish acute STEMI from old scar; useful for LV function assessment, RV infarction, pericardial effusion, LV thrombus, mechanical complications
• Cardiac MRI: Best delineates infarct size and viability
• Nuclear imaging: Technetium-sestamibi for perfusion

TREATMENT

Initial Management: The "Time is Muscle" Principle

• First medical contact to balloon (FMC-to-balloon) goal: ≤90 minutes at PCI-capable hospitals
• If transfer required: ≤120 minutes
• If PCI not achievable within 120 min: fibrinolysis within 30 min of hospital arrival

1. Aspirin 160-325 mg (chewed for rapid absorption) - inhibits cyclooxygenase-1, reduces thromboxane A2
2. IV access, continuous ECG monitoring, supplemental O2 only if SpO2 <90%
3. 12-lead ECG within 10 minutes of presentation

Control of Discomfort

• Sublingual 0.4 mg, up to 3 doses at 5-minute intervals
• Reduces preload and increases myocardial O2 supply
• Contraindicated when: systolic BP <90 mmHg, suspected RV infarction, phosphodiesterase-5 inhibitor use within 24 hours

• 2-4 mg IV every 5 minutes
• Effective analgesic; causes venodilation (can reduce preload)
• Side effects: bradycardia, hypotension, vagotonic effects (treat with atropine)
• May slow GI absorption of oral antiplatelet agents but no proven adverse outcomes

• Metoprolol 5 mg IV every 2-5 min, up to 3 doses
• Conditions for safe use: HR >60 bpm, systolic BP >100 mmHg, PR interval <0.24 s, no acute HF
• Reduce myocardial O2 demand, lower risk of reinfarction and ventricular fibrillation

Antiplatelet Therapy

• Clopidogrel: 600 mg loading, 75 mg daily (for fibrinolysis or where newer agents unavailable)
• Prasugrel: 60 mg loading, 10 mg daily (more potent; avoid with prior TIA/stroke, age >75, weight <60 kg)
• Ticagrelor: 180 mg loading, 90 mg twice daily (reversible; avoid with prior intracranial hemorrhage, active bleeding)

Anticoagulation

• Unfractionated heparin (UFH): IV bolus; titrated to ACT
• Bivalirudin: Direct thrombin inhibitor; alternative to UFH
• Fondaparinux: Not recommended as sole anticoagulant for primary PCI

• UFH or enoxaparin for minimum 48 hours

Reperfusion Therapy

Primary PCI (preferred)

• Most effective reperfusion strategy when available in time
• Goal: door-to-balloon ≤90 min at PCI-capable hospitals
• Drug-eluting stents (DES) preferred over bare metal stents
• Restores TIMI 3 flow in >90% of patients

Fibrinolytic Therapy

• Alteplase (tPA): 15 mg IV bolus, then 0.75 mg/kg (max 50 mg) over 30 min, then 0.5 mg/kg (max 35 mg) over 60 min
• Reteplase: Two 10-unit IV boluses 30 min apart
• Tenecteplase: Single weight-based IV bolus (most convenient)
• Streptokinase: Non-fibrin-specific; risk of allergic reactions

• Absolute: Prior intracranial hemorrhage, ischemic stroke within 3 months, intracranial neoplasm/AVM, active bleeding, suspected aortic dissection, significant head/facial trauma within 3 months
• Relative: Severe uncontrolled hypertension (>180/110), prior ischemic stroke >3 months, anticoagulant therapy, traumatic CPR, recent internal bleeding within 2-4 weeks, pregnancy, active peptic ulcer

• Resolution of chest pain
• ≥50% reduction in ST elevation at 60-90 minutes
• Reperfusion arrhythmias (accelerated idioventricular rhythm)
• Early peak of cardiac biomarkers ("washout")

Long-Term Medical Therapy

• Begin within first 24 hours (oral) if no contraindications
• Continue indefinitely (reduce mortality, sudden death, reinfarction)
• Metoprolol succinate or carvedilol preferred

• Begin within 24 hours in all patients with STEMI with EF ≤40%, anterior MI, pulmonary congestion
• Reduce LV remodeling, prevent HF, reduce mortality
• ARBs (valsartan) if ACE inhibitor intolerant

• Eplerenone or spironolactone in patients with EF ≤40% and either HF symptoms or diabetes
• Reduce mortality by ~15-17%
• Avoid if creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women), or K+ >5.0 mEq/L

• High-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) in all patients without contraindication
• Target LDL <70 mg/dL (or <55 mg/dL in very high risk)
• Begin in-hospital before discharge

COMPLICATIONS

Hemodynamic Complications: Killip Classification

Left Ventricular Failure and Pulmonary Edema

• Results from extensive myocardial necrosis
• Management: loop diuretics (furosemide), nitrates (preload reduction), ACE inhibitors (afterload reduction)
• Digitalis has unimpressive benefit in post-MI HF
• Inotropic support (dobutamine, milrinone) for refractory cases

Cardiogenic Shock

• Incidence reduced from ~20% to ~7% with modern reperfusion
• Only 10% present with shock on admission; 90% develop it during hospitalization
• Characterized by: SBP <90 mmHg, cardiac index <2.2 L/min/m², PCWP >18 mmHg
• Patients typically have severe multivessel CAD with "piecemeal necrosis" extending outward
• Treatment: emergency revascularization (PCI or CABG), intra-aortic balloon pump, vasopressors/inotropes, mechanical circulatory support

Right Ventricular Infarction

• ~1/3 of patients with inferior STEMI have some degree of RV necrosis
• Clinical triad: elevated JVP + Kussmaul's sign + hypotension with clear lungs
• ST elevation in right-sided leads (V4R) - present in first 24 hours
• Hemodynamic pattern: resembles constrictive pericarditis (steep RA "y" descent, dip-and-plateau in RV waveforms)
• Treatment: volume expansion to maintain RV preload; avoid nitrates and diuretics

Mechanical Complications

• Occurs 3-5 days post-MI (softening of necrotic myocardium)
• Presents with sudden cardiovascular collapse, electromechanical dissociation
• High mortality; requires emergency surgery

• Acute left-to-right shunt
• New harsh holosystolic murmur at left sternal border
• Confirmed by echocardiography / right heart catheterization (O2 step-up)
• Surgical repair or transcatheter closure required

• Causes acute severe mitral regurgitation
• Posteromedial papillary muscle (supplied by single coronary artery = RCA) more commonly ruptures than anterolateral (dual blood supply)
• Presents with acute pulmonary edema, new murmur
• Requires urgent surgical repair/replacement

• Late complication; occurs in 10-15% of STEMI (especially anterior)
• Persistent ST elevation weeks after STEMI
• Risk of thrombus, HF, arrhythmias
• Anticoagulation for LV thrombus; consider surgical repair

Arrhythmias

• Occurs in 3-5% of STEMI in first hour
• Treat with immediate DC defibrillation (unsynchronized, 200 J biphasic)
• Prophylactic lidocaine not recommended (increases mortality)
• Late VF (>48 h): associated with large infarct; consider ICD

• Sustained VT: DC cardioversion if hemodynamically unstable; IV amiodarone if stable
• Accelerated idioventricular rhythm (AIVR): benign reperfusion arrhythmia - no treatment needed
• Torsades de pointes: correct hypokalemia/hypomagnesemia; IV magnesium

• Common with inferior MI (vagal reflex - Bezold-Jarisch reflex)
• Treatment: atropine 0.5-1 mg IV; temporary pacing if refractory

• First-degree and Mobitz I (Wenckebach): usually inferior MI, reversible; atropine if needed
• Mobitz II and complete heart block with anterior MI: infra-Hisian; requires temporary pacing
• Complete heart block with inferior MI: often transient (due to AV nodal ischemia)

• Occurs in 15-20% of STEMI
• Rate control (beta-blockers, diltiazem, digoxin) or cardioversion if unstable
• Anticoagulation to prevent thromboembolic events

Recurrent Chest Pain

• Pericarditis (Dressler syndrome): weeks to months after MI; autoimmune; pleuritic chest pain, fever, pericardial friction rub; treat with aspirin/NSAIDs
• Early pericarditis: days 1-3 post-STEMI; due to epicardial inflammation
• Reinfarction: ECG changes + new biomarker rise
• Ischemia at a distance: residual stenosis in non-infarct artery

SECONDARY PREVENTION AND REHABILITATION

• Smoking cessation (most important single intervention)
• Cardiac rehabilitation (reduces mortality by ~20%)
• Diet low in saturated fat; Mediterranean diet
• Achieve and maintain BMI 18.5-24.9 kg/m²

• Aspirin 75-100 mg indefinitely
• DAPT for 12 months (then aspirin alone)
• Beta-blocker (especially if EF reduced)
• ACE inhibitor/ARB
• High-intensity statin
• Aldosterone antagonist if EF ≤40% with HF or diabetes

• Echocardiography to assess LV function
• Stress testing or functional imaging 4-6 weeks post-discharge
• ICD implantation if EF ≤35% persists at ≥40 days post-MI despite optimal medical therapy

PROGNOSIS

• LV ejection fraction (single most important factor)
• Infarct size and location
• Presence of residual ischemia
• Age and comorbidities
• Time to reperfusion
• Successful reperfusion (TIMI 3 flow)

Diarrhea

Harrison's Principles of Internal Medicine, 22nd Edition (2025) — Chapter 49

DEFINITION

• Acute diarrhea: <2 weeks
• Persistent diarrhea: 2-4 weeks
• Chronic diarrhea: >4 weeks

Conditions to Distinguish from True Diarrhea

EPIDEMIOLOGY

• Worldwide, >1 billion individuals suffer one or more episodes of acute diarrhea each year
• ~100 million persons in the U.S. are affected annually by acute diarrhea
  • ~half must restrict activities
  • 10% consult physicians
  • ~250,000 require hospitalization
  • ~5000 die (primarily the elderly)
• Acute infectious diarrhea is the second leading cause of death in children; ~525,000 children <5 years die per year globally (WHO)
• Prevalence of chronic diarrhea in the U.S.: 5.0%; women affected 1.5× more than men
• Accounts for ~50% of referrals to gastroenterologists

NORMAL PHYSIOLOGY

• Regulate secretion and absorption of water and electrolytes
• Store and transport intraluminal contents aborally
• Salvage short-chain fatty acids from bacterial metabolism of unabsorbed carbohydrate

Neural Control

• Intrinsic innervation: Enteric nervous system (ENS) - the "brain of the gut"
  • Myenteric plexus (Auerbach's) - controls motility
  • Submucosal plexus (Meissner's) - controls secretion and local blood flow
• Extrinsic innervation: Sympathetic (inhibits motility/secretion), parasympathetic (promotes motility/secretion), sensory afferents

Fluid and Electrolyte Balance

• Small intestine receives ~9-10 L/day (2 L ingested + 7 L secreted); absorbs ~8-9 L
• Colon receives ~1-2 L/day; reduces to ~100-200 mL fecal water
• Maximal colonic absorptive capacity: ~4-5 L/day; when exceeded, diarrhea results

• Na+/H+ exchangers (NHE): apical Na+ absorption
• CFTR (cystic fibrosis transmembrane conductance regulator): anion/Cl- secretion
• Aldosterone: enhances colonic Na+ absorption
• Short-chain fatty acids from fiber fermentation enhance colonic absorption

ACUTE DIARRHEA

Infectious Agents

1. Travelers - Up to 40% of U.S. tourists to endemic areas (Latin America, Africa, Asia) develop traveler's diarrhea:
   • Most common: enterotoxigenic and enteroaggregative E. coli
   • Also: Campylobacter, Shigella, Aeromonas, norovirus, Salmonella, Giardia, Cyclospora
2. Consumers of certain foods:
   • Salmonella, Campylobacter, Shigella - from chicken
   • Enterohemorrhagic E. coli O157:H7 - from undercooked hamburger
   • Bacillus cereus - from fried rice or reheated food
   • Staphylococcus aureus or Salmonella - from mayonnaise or creams
   • Salmonella - from eggs
   • Listeria - from fresh/frozen uncooked foods, mushrooms, dairy
   • Vibrio species - from raw seafood
   • Hepatitis A - from raw seafood
3. Immunocompromised persons - broader spectrum including opportunistic pathogens (Cryptosporidium, Microsporidium, CMV, MAC)
4. Institutionalized persons - nosocomial pathogens, especially Clostridioides difficile
5. Daycare attendees and their contacts - Giardia, rotavirus, Cryptosporidium, Shigella

Pathophysiologic Mechanisms of Infectious Diarrhea

Other Causes of Acute Diarrhea (the ~10%)

• Medications: Antibiotics (most common - C. difficile or direct), magnesium-containing antacids, colchicine, lactulose, metformin, misoprostol, NSAIDs, SSRIs, digoxin, chemotherapy
• Toxic ingestions: Heavy metals, organophosphates
• Ischemia: Ischemic colitis (typically left colon; presents with crampy pain and bloody diarrhea)
• Diet indiscretions: Excess fiber, artificial sweeteners (sorbitol, mannitol)
• Systemic illness: Thyrotoxicosis, adrenal insufficiency
• Overflow diarrhea: Fecal impaction with liquid seepage

EVALUATION OF ACUTE DIARRHEA

Clinical Assessment

• Profuse watery diarrhea with dehydration
• Passage of many small-volume bloody/mucoid stools with fever
• Systemic illness (fever >38.5°C, severe abdominal pain)
• Immunocompromised patient
• Elderly patient
• Recent antibiotics or hospitalization (suspect C. difficile)
• Duration >48 hours without improvement
• Outbreak scenario (public health concern)

Stool Examination

• Fecal leukocytes (or lactoferrin): Indicates inflammatory/invasive etiology; not present in toxigenic or viral causes
• Fecal occult blood: Present with invasive pathogens or mucosal inflammation
• Stool culture: For invasive pathogens (Salmonella, Shigella, Campylobacter, E. coli O157)
• Ova and parasites: For travelers, immunocompromised patients, prolonged illness
• C. difficile toxin assay (PCR): If recent antibiotics, hospitalization, or outbreak
• Rotavirus/norovirus antigen: In outbreak settings or pediatric cases

Treatment of Acute Diarrhea

• Mild-moderate dehydration: Oral rehydration solution (ORS) - WHO formula: Na+ 75 mmol/L, K+ 20 mmol/L, Cl- 65 mmol/L, citrate 10 mmol/L, glucose 75 mmol/L
• Severe dehydration: IV crystalloid (normal saline or Ringer's lactate)
• Early refeeding encouraged; avoid lactose temporarily if lactase-deficient

• Loperamide: 4 mg initially, then 2 mg after each loose stool (max 16 mg/day)
  • Opioid receptor agonist; reduces gut motility and secretion
  • Avoid in febrile dysentery, bloody diarrhea, suspected invasive infection
• Bismuth subsalicylate: Reduces stool frequency; antibacterial and antisecretory properties

• Not required in most cases of acute, self-limiting diarrhea
• Indicated for: dysenteric illness, traveler's diarrhea, immunocompromised host, severe systemic illness
• C. difficile: oral vancomycin 125 mg QID × 10 days (preferred); or fidaxomicin 200 mg BID × 10 days; metronidazole for mild cases only
• Campylobacter: azithromycin
• Shigella: fluoroquinolone or azithromycin
• Salmonella (non-typhoidal): antibiotics ONLY if severe/bacteremic - may prolong carrier state
• Traveler's diarrhea: rifaximin, ciprofloxacin, or azithromycin (3-day course)

CHRONIC DIARRHEA

Pathophysiologic Classification

1. Secretory Diarrhea

• Stimulant laxatives: senna, cascara, bisacodyl, castor oil
• Chronic alcohol: enterocyte injury, impaired Na+/water absorption, rapid transit
• Olmesartan (ARB): sprue-like enteropathy
• Rarely: ACE inhibitors (intestinal angioedema)
• GLP-1 receptor agonists (e.g., semaglutide): infrequent adverse effect

• Accounts for ~40% of unexplained chronic diarrhea
• ~1% of general population (same prevalence as celiac disease)
• Mechanism: Reduced negative feedback of bile acid synthesis by FGF-19 (produced by ileal enterocytes) → excess bile acids overwhelm ileal reabsorption → colon secretion
• With <100 cm terminal ileum disease/resection: dihydroxy bile acids escape, stimulate colonic secretion (cholereic diarrhea)
• Diagnosis: elevated fasting serum 7αC4 (C4) or fecal primary/total bile acids
• Features: severe diarrhea, urgency, impaired quality of life

• Carcinoid tumors: serotonin, histamine, prostaglandins, kinins → episodic flushing, wheezing, right-sided valvular heart disease, diarrhea; pellagra-like skin lesions (niacin depletion)
• VIPoma (pancreatic cholera, WDHA syndrome): VIP and other peptides → massive watery diarrhea (>3 L/day, up to 20 L/day), hypokalemia, achlorhydria, flushing, hyperglycemia
• Gastrinoma (Zollinger-Ellison): hypersecretion of gastric acid → inactivates pancreatic enzymes → diarrhea in ~1/3 of cases; sole presentation in 10%
• Medullary carcinoma of thyroid: calcitonin, prostaglandins → watery diarrhea; poor prognosis with metastases
• Systemic mastocytosis: histamine and other mediators
• Addison's disease: adrenal insufficiency → secretory diarrhea

2. Osmotic Diarrhea

• Osmotic laxatives: Mg2+, PO4³-, SO4²- (commonly seen with over-the-counter antacids, laxative abuse)
• Lactase deficiency (most common disaccharidase deficiency):
  • Primary (adult-onset, genetic): progressive loss of brush-border lactase; highly prevalent in Asians, Africans, Native Americans
  • Secondary: post-infectious, IBD, celiac disease
  • Symptoms: bloating, flatulence, watery diarrhea after dairy consumption
• Nonabsorbable carbohydrates: fructose (excess fruit/soft drinks), sorbitol (chewing gum, diet candy), lactulose, polyethylene glycol
• FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols): wheat intolerance, IBS-related

3. Steatorrheal (Malabsorptive) Diarrhea

• Pancreatic exocrine insufficiency (PEI): chronic pancreatitis, pancreatic cancer, CF; lipase deficiency → fat maldigestion
• Bacterial overgrowth (SIBO): deconjugation of bile salts by bacteria → impaired fat solubilization; associated with diabetes, scleroderma, strictures, blind loops
• Liver disease/cholestasis: reduced bile acid secretion → impaired fat emulsification
• Bariatric surgery: Roux-en-Y bypass → fat maldigestion

• Celiac disease: IgA anti-tissue transglutaminase (TTG), anti-endomysial antibodies; villous atrophy; gluten-free diet
• Whipple's disease: Tropheryma whipplei; malabsorption, arthralgias, lymphadenopathy, CNS involvement
• Tropical sprue: post-infectious; folate/B12 deficiency
• Crohn's disease: skip lesions, ileal involvement
• Radiation enteritis: mucosal damage after radiation therapy
• Short bowel syndrome: surgical resection
• Abetalipoproteinemia: congenital defect in chylomicron formation

• Primary intestinal lymphangiectasia
• Secondary lymphatic obstruction (lymphoma, carcinoid, Whipple's, amyloidosis)
• Protein-losing enteropathy with hypoproteinemia/edema

4. Inflammatory Diarrhea

• Crohn's disease: transmural inflammation; any part of GI tract; skip lesions, cobblestone mucosa, fistulas, strictures, perianal disease
• Ulcerative colitis (UC): mucosal inflammation; rectum always involved; continuous; bloody diarrhea; crypt abscesses; toxic megacolon
• Microscopic colitis (lymphocytic colitis, collagenous colitis): normal colonoscopy; diagnosis by biopsy; watery diarrhea; associated with NSAIDs, PPIs, SSRIs; more common in older women
• Radiation colitis: pelvic/abdominal radiation therapy
• Ischemic colitis: watershed areas (splenic flexure, rectosigmoid junction)
• Invasive pathogens: Shigella, C. difficile, E. histolytica, CMV (immunocompromised)
• Diverticulitis: left lower quadrant pain, fever, diarrhea
• Neoplasms: colon cancer, lymphoma

5. Motility-Related Diarrhea

• IBS with diarrhea (IBS-D): altered brain-gut interaction; diagnosis of exclusion; Rome IV criteria; abdominal pain relieved/associated with defecation; altered stool form/frequency
• Hyperthyroidism: thyroid hormone accelerates gut motility
• Diabetic autonomic neuropathy: impaired sympathetic inhibition → rapid transit or pseudo-obstruction with bacterial overgrowth
• Post-surgical: post-vagotomy diarrhea, post-cholecystectomy diarrhea (bile acid diarrhea)
• Hyperthyroidism/carcinoid: extrinsic endocrine stimulation of motility
• Scleroderma: dysmotility leading to SIBO, then malabsorption

EVALUATION OF CHRONIC DIARRHEA

History (Key Questions)

1. Onset, duration, pattern (continuous vs. episodic)
2. Stool characteristics: volume, consistency (Bristol Stool Form Scale), blood/mucus, fat/undigested food
3. Relationship to food, fasting (osmotic vs. secretory)
4. Nocturnal episodes (suggests organic rather than functional cause)
5. Abdominal pain: location, relationship to defecation
6. Medications: especially antibiotics, PPIs, NSAIDs, laxatives, olmesartan, metformin
7. Travel history, sick contacts
8. Family history of IBD, celiac disease, colon cancer
9. Systemic symptoms: weight loss, fever, arthralgias, rashes, flushing

Physical Examination

• Skin: dermatitis herpetiformis (celiac), erythema nodosum (UC), flushing (carcinoid), pyoderma gangrenosum (IBD)
• Eyes: episcleritis, uveitis (IBD)
• Joints: arthritis (IBD, Whipple's)
• Thyroid: mass (medullary thyroid cancer or hyperthyroidism)
• Heart: valvular disease (carcinoid)
• Abdomen: masses, hepatomegaly (metastases), tenderness
• Anus/rectum: perianal fistulas (Crohn's), sphincter laxity
• Lymphadenopathy: lymphoma, Whipple's

Laboratory Tests

• CBC: anemia (blood loss, B12/folate deficiency), leukocytosis (inflammation), eosinophilia (parasites, eosinophilic GE)
• ESR, CRP: elevated in inflammatory causes
• Electrolytes, BUN, creatinine: dehydration, renal function
• Liver function tests
• Thyroid function tests (TSH)
• IgA anti-tissue transglutaminase (TTG) antibodies with serum IgA level: celiac disease screening
• Stool: fecal leukocytes/lactoferrin, occult blood, ova and parasites, culture, C. difficile toxin

• Measured stool osmolality ~290 mOsm/kg
• Calculated gap = 290 - 2 × ([stool Na+] + [stool K+])
• Osmotic gap >125: osmotic diarrhea (carbohydrate malabsorption, osmotic laxatives)
• Osmotic gap <50: secretory diarrhea

• Normal: <7 g/day on 100 g fat/day diet
• Steatorrhea: >7 g/day → malabsorption workup
• Sudan stain of stool: qualitative screening

• 7αC4 (7α-hydroxy-4-cholesten-3-one) or fecal bile acids: bile acid diarrhea
• Fecal elastase or secretin stimulation test: pancreatic exocrine insufficiency
• Hydrogen breath test: SIBO (glucose breath test), lactose intolerance (lactose breath test)
• Fecal calprotectin: non-invasive marker of intestinal inflammation; high in IBD; low in IBS
• Serum VIP, gastrin, 5-HIAA (24-hour urine), calcitonin: for hormone-secreting tumors
• Serum protein electrophoresis: lymphoma, myeloma

Endoscopy

• Colonoscopy with biopsies: if inflammatory or neoplastic cause suspected; essential for diagnosis of microscopic colitis (biopsies must be taken even with normal-appearing mucosa)
• Upper endoscopy with small bowel biopsies (duodenum/jejunum): celiac disease, Whipple's disease, tropical sprue, SIBO
• Capsule endoscopy: small bowel Crohn's, lymphoma, bleeding lesions

Imaging

• CT/MRI enterography: small bowel Crohn's, fistulas, masses, lymphadenopathy
• Abdominal CT: pancreatic disease, liver metastases, mesenteric ischemia
• Mesenteric angiography: ischemia

TREATMENT OF CHRONIC DIARRHEA

Non-Specific (Symptomatic) Treatment

• Loperamide: 2-4 mg up to 4× daily; preferred for mild-to-moderate diarrhea; does not cross BBB; safe
• Diphenoxylate/atropine: opiate-atropine combination
• Bismuth subsalicylate: mild antisecretory and antibacterial
• Cholestyramine (bile acid sequestrant): bile acid diarrhea (BAD), post-cholecystectomy diarrhea
• Octreotide (somatostatin analogue): secretory diarrhea from carcinoid, VIPoma; reduces secretion and slows transit
• Clonidine (α2-agonist): reduces secretion; useful in diabetic diarrhea and opioid-withdrawal diarrhea
• Codeine, tincture of opium: reserved for refractory diarrhea

Condition-Specific Treatment

SPECIAL SITUATIONS

Traveler's Diarrhea

• Prevention: safe food/water practices; bismuth subsalicylate prophylaxis (not routinely recommended)
• Treatment: rifaximin (non-absorbable, preferred for non-invasive), ciprofloxacin, or azithromycin (3-day course); loperamide as adjunct
• Self-treatment approach recommended for travelers to high-risk areas

Clostridioides difficile (CDI)

• Spore-forming, toxin-producing organism
• Risk factors: antibiotics, hospitalization, age >65, PPI use, immunosuppression
• Toxin A (enterotoxin) + Toxin B (cytotoxin) → mucosal damage
• Presentation: watery diarrhea, abdominal cramps, fever; severe: pseudomembranous colitis, toxic megacolon
• Diagnosis: stool PCR (highly sensitive) or GDH + toxin immunoassay
• Treatment: discontinue offending antibiotic; oral vancomycin 125 mg QID × 10 days; fidaxomicin 200 mg BID × 10 days; FMT for ≥3 recurrences; bezlotoxumab (anti-toxin B antibody) to reduce recurrence

Diarrhea in HIV/AIDS

• CD4 >200/μL: usual pathogens
• CD4 <200/μL: Cryptosporidium, Microsporidium, Isospora belli, CMV, MAC, Cyclospora
• Treatment: HAART (most effective); pathogen-specific therapy
• HIV enteropathy: direct viral effect on enterocytes with CD4 <100/μL

Microscopic Colitis

• Normal colonoscopy, abnormal biopsies
• Two subtypes: collagenous colitis (thickened subepithelial collagen band >10 μm) and lymphocytic colitis (increased intraepithelial lymphocytes >20 per 100 epithelial cells)
• Clinical: watery, non-bloody diarrhea; predominantly older women
• Associations: NSAIDs, PPIs, SSRIs, lansoprazole (especially)
• Treatment: stop offending drug; budesonide 9 mg/day × 6-8 weeks (most effective); bismuth, cholestyramine for mild cases

Diarrhea vs. Dysentery

Laboratory Diagnosis of Dengue

Overview

The Three Pillars of Dengue Lab Diagnosis

1. Virological Tests (Days 1-7 of illness)

A. NS1 Antigen Detection

• NS1 = nonstructural protein 1, secreted in large amounts during active viremia
• Detectable from Day 1 to Day 7-10 after illness onset
• Detected by ELISA or rapid immunochromatographic assay (RDT)
• Available as bedside rapid test
• Sensitivity: ~70-90% in primary infection; lower (~60-80%) in secondary infection (due to NS1-anti-NS1 immune complexes clearing NS1 faster)
• Does not cross-react with other flaviviruses as problematically as antibody tests
• Advantage: Very early diagnosis; positive even before IgM appears

B. RT-PCR (Reverse Transcriptase Polymerase Chain Reaction)

• Detects dengue viral RNA in serum/plasma
• Window: Days 1-7 (same as NS1)
• Most sensitive and specific virological method
• Can serotype the virus (DEN-1, 2, 3, or 4) - important for epidemiology
• Gold standard for early diagnosis and confirmation
• Limitations: expensive, needs specialized lab, not widely available in endemic areas
• RT-PCR becomes negative after day 7 when viremia clears

C. Viral Culture / Isolation

• Inoculation of serum into mosquito cell lines (C6/36) or Vero cells
• Only done in reference/research labs
• Slow (takes days to weeks), impractical clinically
• Useful for serotyping, research, and vaccine studies

2. Serological Tests (From Day 3-5 onwards)

A. IgM ELISA (Anti-DENV IgM)

• IgM appears 3-5 days after illness onset
• 99% of patients have IgM by Day 10
• Peaks at 2 weeks, then declines to undetectable over 2-3 months
• Detected by MAC-ELISA (IgM antibody capture ELISA) - most widely used
• Cross-reacts with IgM from Zika virus, West Nile, Japanese encephalitis, yellow fever - major limitation
• A single positive IgM with compatible clinical picture = presumptive diagnosis of dengue

B. IgG ELISA (Anti-DENV IgG)

• IgG remains elevated for life after dengue infection
• Useful for distinguishing primary vs. secondary infection:

• Fourfold or greater rise in IgG titers between acute (≤5 days) and convalescent (>15 days) samples = confirms recent infection
• False positives: prior immunization or infection with other flaviviruses (West Nile, Japanese encephalitis, yellow fever, Zika)

C. Hemagglutination Inhibition (HI) Test

• Older classical test; still used in reference labs
• Dengue antibodies inhibit hemagglutination of goose RBCs by dengue antigen
• Primary infection: HI titre <1:1280 (low)
• Secondary infection: HI titre ≥1:2560 (high "anamnestic" boosting)
• Cross-reactive with all flaviviruses - low specificity

D. Plaque Reduction Neutralization Test (PRNT)

• Most specific serological test; gold standard for serology
• Measures neutralizing antibodies that reduce dengue plaques in cell culture
• PRNT₅₀ or PRNT₉₀ titres used
• Can confirm serotype
• Limitations: slow (takes days), expensive, requires BSL-2 conditions, research/reference lab only

3. Rapid Diagnostic Tests (RDTs) - Combined Approach

• Single-strip or cassette rapid test
• Testing for NS1 antigen + anti-dengue IgM in a single specimen collected during the first 10 days of illness accurately identifies ≥90% of dengue primary and secondary cases
• This combined approach is now recommended by WHO as the standard for clinical settings

Timing Guide: When to Use Which Test

Day of Illness →   1   2   3   4   5   6   7   8   9   10  11  12+
────────────────────────────────────────────────────────────────────
RT-PCR / NS1    ██████████████████████████████████░░░░░░░░░░
IgM (ELISA)     ░░░░░░░░████████████████████████████████████
IgG (ELISA)     ░░░░░░░░░░░░░████████████████████████████████
────────────────────────────────────────────────────────────────────
                ◄─ Viremic phase ─►◄────── Immune phase ──────►

• Days 1-5 (febrile phase): Use RT-PCR or NS1 antigen; can add IgM
• Day 5 onwards: IgM becomes the primary test
• Days 1-10: NS1 + IgM combo covers both phases with >90% sensitivity

Haematological and Biochemical Findings

WHO Diagnostic Criteria Summary

1. Virus isolation
2. Positive RT-PCR
3. Positive NS1 antigen
4. Fourfold rise in IgG between acute and convalescent samples
5. Positive IgM in a single sample (in the right clinical context)

Key Points to Remember

1. NS1 + RT-PCR - early (days 1-7); NS1 is the bedside-friendly option
2. IgM ELISA - from day 3-5; remains positive for 2-3 months
3. IgG - distinguishes primary (low) from secondary (high/rapid rise) infection
4. PRNT - gold standard for serology; confirms serotype; reference lab only
5. Combined NS1 + IgM on a single sample (days 1-10) captures ≥90% of cases
6. IgM cross-reacts with Zika, West Nile, Japanese encephalitis - always interpret in clinical context
7. Leukopenia + thrombocytopenia + fever = classic haematological triad; rising haematocrit = early warning of plasma leakage