The Gastrointestinal System

Oral Cavity Disorders

Salivary Gland Disorders

Esophageal Motility & Structural Disorders

Esophagitis — Causes by Category

• Reflux (erosive) esophagitis: the most common type, secondary to GERD
• Pill/medication-induced esophagitis: from prolonged mucosal contact with bisphosphonates, tetracyclines, NSAIDs, or iron/potassium supplements — usually prevented by taking pills with plenty of water while upright
• Eosinophilic esophagitis: chronic, immune-mediated eosinophilic infiltration linked to atopic disease (asthma, food allergy); endoscopy shows characteristic rings and linear furrows; presents with dysphagia and food impaction, especially in young patients, and doesn't respond to standard acid suppression alone
• Infectious esophagitis: Candida (white plaques/pseudomembranes, most common), HSV-1 (discrete "punched-out" ulcers), and CMV (larger linear ulcers) — all more common with immunosuppression
• Corrosive esophagitis: from caustic ingestion (acid or alkali), with risk of stricture formation during healing

• All types of esophagitis share the hallmark symptoms of odynophagia (painful swallowing) and/or dysphagia

GERD → Barrett → Adenocarcinoma Progression

Gastritis & Peptic Ulcer Disease

Localizing GI Bleeding — the Ligament of Treitz

• The ligament of Treitz (suspensory ligament of the duodenum) is the anatomic dividing line between upper and lower GI bleeding
• Upper GI bleed (proximal to the ligament): peptic ulcer disease and variceal hemorrhage are the leading causes; presents with hematemesis and/or melena (black, tarry stool — blood has been digested in transit)
• Lower GI bleed (distal to the ligament): diverticulosis, angiodysplasia, hemorrhoids, and colorectal cancer are common causes; presents with hematochezia (bright red or maroon blood, reflecting a shorter transit time)
• Caveat: a brisk upper GI bleed can also present as hematochezia if transit is fast enough, so hemodynamic instability should never be dismissed just because the blood looks "lower GI" in origin

Gastric Neoplasms

• Intestinal-type adenocarcinoma: associated with H. pylori, atrophic gastritis, nitrosamines/smoked foods, blood group A; forms a bulky ulcerating mass
• Diffuse-type (signet ring) adenocarcinoma: infiltrates the gastric wall diffusely → linitis plastica ("leather bottle" stomach); worse prognosis, not clearly H. pylori-linked
• Metastatic spread patterns: Virchow node (left supraclavicular), Krukenberg tumor (bilateral ovarian mets with signet ring cells), Sister Mary Joseph nodule (periumbilical)
• Leiomyoma: most common benign gastric tumor
• Leukoplakia: white mucosal patch that cannot be scraped off; common precursor lesion for oral squamous cell carcinoma

Dumping Syndrome

• Follows gastric surgery (e.g., vagotomy, gastrectomy) that bypasses normal pyloric regulation
• Hyperosmolar chyme dumps rapidly into the small bowel → fluid shifts intraluminally
• Early symptoms: bloating, cramping, diarrhea, tachycardia from volume shift
• Late symptoms (1–3 h): reactive hypoglycemia from an exaggerated insulin surge

Abdominal Pain Localization Logic

• Visceral peritoneum irritation → dull, poorly localized pain (referred to embryologic dermatome — e.g., early appendicitis = periumbilical)
• Parietal peritoneum irritation → sharp, well-localized pain (e.g., late appendicitis = RLQ / McBurney point)

Pain Character as a Diagnostic Clue

• Sharp, boring epigastric pain radiating straight to the back → suggests pancreatitis
• Burning, gnawing epigastric pain → suggests gastric or duodenal ulcer disease
• Pain that begins periumbilically and migrates/localizes to the right lower quadrant → suggests appendicitis

Common Structural & Ischemic Disorders

Mechanical vs Functional Obstruction

• Small-bowel obstruction: most often caused by postsurgical adhesions; also hernias, intussusception
• Large-bowel obstruction: most often caused by colorectal neoplasm; also volvulus, severe diverticular stricture
• Gallstone ileus: a gallstone erodes through a cholecystoenteric fistula and mechanically obstructs the bowel, classically at the ileocecal valve — a mechanical obstruction despite the name
• Ileus (adynamic/paralytic): temporary failure of coordinated peristalsis without a mechanical blockage; common postoperatively; distinguished from mechanical obstruction by diffusely decreased bowel sounds and absence of a transition point on imaging

Colorectal Adenocarcinoma

Carcinoid Tumor

• Arises from neuroendocrine (enterochromaffin/Kulchitsky) cells; most common site is the appendix
• Secretes serotonin and other vasoactive substances
• Carcinoid syndrome (flushing, diarrhea, bronchospasm, right-sided valvular lesions) occurs only once hepatic metabolism is bypassed — i.e., with liver metastases, since the liver normally clears serotonin from portal blood
• Diagnosis: elevated urinary 5-HIAA (serotonin metabolite)

Functional & Other Inflammatory Bowel Conditions

Functional Liver Anatomy

• Hepatic lobule: hexagonal unit centered on a central vein, with portal triads (hepatic artery, portal vein, bile duct branch) at the corners
• Zone 1 (periportal): first to receive oxygenated blood — most susceptible to viral hepatitis and toxin-mediated injury requiring bioactivation
• Zone 3 (pericentral): lowest oxygen tension — most susceptible to ischemia and to injury from metabolites generated by cytochrome P450 (e.g., acetaminophen toxicity, alcoholic injury)
• Kupffer cells: resident macrophages lining the sinusoids that clear bacteria and worn-out red blood cells
• Hepatic stellate (Ito) cells: store vitamin A while quiescent; become activated in chronic injury to lay down extracellular matrix — the main driver of hepatic fibrosis

Bile Acid Synthesis & Enterohepatic Circulation

• Colonic bacteria deconjugate/dehydroxylate a portion of bile salts into secondary bile acids
• ~95% of bile salts are actively reabsorbed at the terminal ileum and recycled to the liver (enterohepatic circulation)
• ~5% are lost in feces daily — this fecal loss is the route by which the body eliminates cholesterol, and it's the target of bile acid-binding resin therapy
• Terminal ileum disease or resection interrupts this cycle → bile salt malabsorption, diarrhea, and impaired fat-soluble vitamin absorption

Acetaminophen (APAP) Hepatotoxicity

• In overdose, glutathione stores are depleted → NAPQI accumulates and covalently binds hepatocyte proteins → centrilobular (zone 3) necrosis
• CYP450 inducers (chronic ethanol use, isoniazid, rifampin, phenytoin, barbiturates, carbamazepine) increase NAPQI generation and worsen toxicity risk
• Antidote: N-acetylcysteine — replenishes glutathione stores and can also directly detoxify NAPQI
• Activated charcoal / gastric decontamination may help if given soon after ingestion

Bilirubin Metabolism & Jaundice

Neonatal Hyperbilirubinemia

• Mild unconjugated hyperbilirubinemia is nearly universal in the first week of life, from a combination of high fetal RBC turnover, an immature (low-activity) UGT1A1 enzyme, and a sterile newborn gut that favors bilirubin reabsorption over excretion — this benign physiologic pattern typically resolves within 1–2 weeks without treatment
• Breastfeeding failure jaundice: insufficient milk intake in the first days of life slows gut transit and bilirubin elimination in stool, increasing enterohepatic recirculation
• Breast milk jaundice: a compound in breast milk increases intestinal deconjugation of bilirubin, appearing later (after the first week) and lasting longer than typical physiologic jaundice
• Severe, poorly controlled unconjugated hyperbilirubinemia risks kernicterus — deposition of lipid-soluble bilirubin in the basal ganglia and brainstem, causing permanent neurologic injury
• Treatment is phototherapy, which converts unconjugated bilirubin into water-soluble photoisomers that can be excreted without needing hepatic conjugation

Liver Enzyme Pattern Interpretation

• AST/ALT disproportionately elevated → hepatocellular injury pattern
• ALP/GGT disproportionately elevated → cholestatic/obstructive pattern
• AST:ALT ratio > 2:1 classically suggests alcoholic liver injury
• Synthetic function: prolonged PT/INR and low albumin indicate advanced hepatic dysfunction (not acute injury alone) — the liver synthesizes albumin and most coagulation factors, so significant hepatocyte loss (roughly >90%) is needed before synthetic capacity clearly declines

Viral Hepatitis

Cirrhosis — Common Causes & Signature Findings

Alcohol-Associated (and Metabolic) Liver Disease Spectrum

• Driven by excess NADH generation during alcohol metabolism, which favors fat synthesis and impairs fatty acid oxidation
• Mallory bodies are damaged, eosinophilic intracytoplasmic keratin clumps seen in steatohepatitis, whether from alcohol or metabolic disease
• Metabolic dysfunction–associated steatotic liver disease (MASLD, formerly "NAFLD") is the metabolic-syndrome counterpart — obesity-driven hepatic fat accumulation without significant alcohol use; its inflammatory stage (MASH, formerly NASH) can progress to cirrhosis and hepatocellular carcinoma through the same steatosis → steatohepatitis → fibrosis sequence

Reye Syndrome

• Rare, potentially fatal pediatric hepatic encephalopathy triggered by giving aspirin during a viral illness (classically varicella or influenza)
• Aspirin metabolites reversibly inhibit mitochondrial enzymes → impaired beta-oxidation → microvesicular fatty liver, hyperammonemia, hypoglycemia, and progressive encephalopathy with cerebral edema
• This is why aspirin is avoided in children except for specific indications like Kawasaki disease

Consequences of Portal Hypertension

• Splenomegaly, ascites, hepatic encephalopathy (impaired ammonia clearance)
• Rising portal pressure forces blood through small collateral veins that normally connect the portal and systemic circulations — these collaterals dilate into varices at three classic sites:

• TIPS (transjugular intrahepatic portosystemic shunt) creates a direct channel between the portal vein and a hepatic vein to decompress portal pressure — effective for refractory varices/ascites, but by diverting blood around the liver's filtering capacity it can precipitate or worsen hepatic encephalopathy

Systemic Manifestations of Cirrhosis

Spontaneous Bacterial Peritonitis & Vascular Liver Emergencies

• Spontaneous bacterial peritonitis (SBP): infection of ascitic fluid without an obvious surgical source, seen in cirrhotic patients; often subtle (fever, abdominal pain, worsening encephalopathy) or even silent; diagnosed by paracentesis showing an ascitic fluid neutrophil count above roughly 250 cells/mm³; typically caused by gram-negative enteric organisms; treated empirically with a third-generation cephalosporin
• Budd-Chiari syndrome: thrombotic or compressive obstruction of hepatic venous outflow → painful hepatomegaly, ascites, and a mottled "nutmeg liver" from centrilobular congestion; linked to hypercoagulable states, polycythemia vera, and pregnancy; classically spares jugular venous pressure (no JVD), which helps distinguish it from right heart failure as a cause of congestive hepatomegaly
• Portal vein thrombosis: often clinically silent, but can cause portal hypertension, abdominal pain, and fever; risk factors include cirrhosis, malignancy, and pancreatitis

Focal Liver Lesions

• Hepatocellular adenoma: benign; associated with oral contraceptive/anabolic steroid use; risk of rupture and hemorrhage; regresses with cessation of hormone exposure
• Hepatocellular carcinoma: risk factors include cirrhosis (any cause), chronic HBV/HCV, aflatoxin exposure; elevated alpha-fetoprotein; spreads hematogenously
• Cholangiocarcinoma: malignancy of the bile duct epithelium, most often at the confluence of the right and left hepatic ducts; risk factors include primary sclerosing cholangitis and liver fluke infection (Clonorchis); presents late with jaundice and weight loss
• Metastatic disease is the most common cause of a liver mass overall — much more common than primary liver cancer

Gallbladder & Biliary Tract Disease

• Uncomplicated cholelithiasis and acute cholecystitis are managed surgically with cholecystectomy
• Choledocholithiasis and cholangitis are typically managed with endoscopic retrograde cholangiopancreatography (ERCP) to clear the duct; surgical common bile duct exploration is reserved for ERCP failure

Gallstone Composition

• Cholesterol stones: the majority of stones; risk factors include obesity, rapid weight loss, estrogen exposure (pregnancy/OCPs), age, female sex — classic "female, fertile, forty, fat" risk profile
• Pigment stones: form from excess bilirubin, seen with chronic hemolysis (e.g., sickle cell disease, hereditary spherocytosis) or biliary infection; pigment stones in a child or young adult without a hemolytic or infectious cause should raise suspicion for an underlying hemoglobinopathy

Esophageal Muscle Transition

• Upper esophageal sphincter: skeletal muscle, voluntary control of swallow initiation
• Lower esophageal sphincter (LES): smooth muscle, relaxes via vagal/NO/VIP signaling to admit the bolus, then contracts to prevent reflux

Gastric Motor Function

• Receptive relaxation: vagally-mediated fundic relaxation that accommodates incoming food without a large pressure rise
• Trituration: antral peristaltic waves (~3 per minute) grind food into chyme
• Migrating motor complex (MMC): motilin-driven "housekeeping" contractions that sweep undigested debris through the gut during fasting

Digestion of Proteins in the Stomach

Categories of Vomiting Triggers

• Vestibular/labyrinthine disturbance (motion sickness, vertigo)
• Vagally-mediated visceral stimulation (obstruction, distention)
• Opioid and other drug exposure (direct chemoreceptor trigger zone stimulation)
• Migraine
• Metabolic derangement (diabetic ketoacidosis, gastroparesis, hypercalcemia, uremia)
• Infection (gastroenteritis, systemic illness)
• Toxin exposure
• Increased intracranial pressure and alcohol intoxication
• Neurogenic/psychogenic causes
• Pregnancy

Major GI Hormones — Source, Trigger, Action

Autonomic Modulation of the Gut

Three Phases of Gastric Acid Secretion

Macronutrient Digestion Pathways

Site-Specific Absorption Map

• The colon can absorb roughly 2–3 L of water per day; once this daily capacity is exceeded, the excess is excreted as diarrhea
• The stomach itself absorbs very little of anything except a small amount of ethanol and water
• Defecation is coordinated by both an involuntary rectosphincteric reflex (internal anal sphincter relaxation with rectal distention) and voluntary control of the external anal sphincter

Lipoprotein Trafficking Overview

• High LDL is an independent risk factor for atherosclerosis and coronary artery disease
• Statins (HMG-CoA reductase inhibitors) are first-line for lowering LDL; monitor liver enzymes for hepatotoxicity
• Bile acid-binding resins (cholestyramine, colestipol) bind intestinal bile acids and prevent their reabsorption, forcing the liver to divert more cholesterol into new bile acid synthesis — net effect is lowered LDL
• Niacin (nicotinic acid) suppresses hepatic release of VLDL, secondarily lowering LDL and raising HDL; flushing is a common side effect

Diarrhea Mechanisms

• Osmotic: unabsorbed solutes pull water into the lumen (e.g., lactase deficiency); resolves with fasting
• Secretory: active ion (Cl⁻) secretion drives obligatory water loss (e.g., cholera toxin); persists with fasting
• Inflammatory/exudative: mucosal damage causes protein/blood/pus leakage into lumen (e.g., invasive bacteria, IBD)
• Motility-related: altered transit time (e.g., IBS, hyperthyroidism, diabetic autonomic neuropathy)

Bacterial Causes

Viral & Protozoal Causes

Acute vs Chronic Pancreatitis

Pancreatic Exocrine Neoplasm

• Ductal adenocarcinoma
  • Risk factors: smoking, chronic pancreatitis, age, diabetes
  • Over half arise in the pancreatic head → obstructive jaundice (often painless)
  • Trousseau sign (migratory superficial thrombophlebitis) is a classic paraneoplastic clue
  • Elevated CA 19-9 (tumor marker); poor overall prognosis due to late presentation

Pancreatic Endocrine (Islet Cell) Tumors

Nonneoplastic Polyps

• These lack significant malignant potential on their own — worth recognizing so they aren't confused with the neoplastic types below

Neoplastic Polyp Types (by malignant potential)

• Villous adenomas tend to be sessile (flat-based) with fingerlike projections and carry the greatest malignant potential
• Tubular adenomas are the most common polyp type overall and are usually pedunculated
• Larger size and higher villous component both increase cancer risk
• Serrated polyps are a separate neoplastic pathway (distinct from the tubular/tubulovillous/villous adenoma spectrum) — they carry a "saw-tooth" crypt pattern on biopsy and silence mismatch repair genes through promoter methylation, feeding into the same microsatellite instability route discussed below

Hereditary Polyposis Syndromes

Two Molecular Roads to Colorectal Cancer

Screening & Diagnostic Pearls

• Average-risk screening starts at age 45 with colonoscopy (or an alternative such as fecal immunochemical testing, FIT-DNA, or CT colonography)
• A first-degree relative with colon cancer moves screening up to age 40, or 10 years before that relative's age at diagnosis, whichever is earlier
• Patients with longstanding IBD begin screening about 8 years after disease onset
• An "apple core" napkin-ring lesion on barium enema reflects an annular, obstructing left-sided tumor
• Streptococcus gallolyticus (formerly S. bovis) bacteremia or endocarditis is a classic clue prompting a colonoscopy to look for an underlying colorectal tumor
• CEA is used to monitor for recurrence after treatment, not as a screening test

Acid-Suppressing & Mucosal-Protective Agents

H. pylori Eradication Concept

Antiemetics

Octreotide

• Long-acting somatostatin analog — suppresses release of gastrin, VIP, and other splanchnic vasodilatory hormones, and reduces splanchnic blood flow
• Used for acute variceal bleeding, acromegaly, carcinoid syndrome, and VIPoma
• Adverse effects: nausea, cramping, steatorrhea; increases gallstone risk by inhibiting CCK-mediated gallbladder emptying

Antidiarrheals & IBD Therapeutics

• Loperamide and diphenoxylate: both are peripheral opioid-receptor agonists that slow gut motility; loperamide has essentially no CNS penetration (low abuse potential), while diphenoxylate is combined with atropine specifically to discourage misuse at high doses
• Sulfasalazine (sulfapyridine + 5-ASA): anti-inflammatory, activated by colonic bacteria; used in UC and Crohn colitis; adverse effects include reversible oligospermia and sulfonamide-related reactions
• Glucocorticoids (e.g., budesonide): induce remission in an IBD flare but are not used for long-term maintenance given their side-effect burden
• Azathioprine / 6-mercaptopurine: steroid-sparing immunomodulators for maintenance therapy in both Crohn disease and UC; bone marrow suppression is the main risk, worsened by concurrent allopurinol (both are metabolized by xanthine oxidase)
• Infliximab / adalimumab (anti-TNF monoclonal antibodies): used for moderate-to-severe Crohn disease and UC; screen for latent TB and hepatitis B before starting, since anti-TNF therapy can reactivate both

Laxative Classes

Orlistat

• Inhibits gastric and pancreatic lipase, blocking breakdown and absorption of dietary fat
• Used for weight loss, taken with fat-containing meals
• Adverse effects: abdominal cramping, flatulence, oily/frequent stools, and reduced absorption of fat-soluble vitamins

Foregut-Midgut-Hindgut Framework

Tongue Development & Pharyngeal Arch Origins

Digestive Tract Histology by Segment

GI Tract Wall — Histologic Layers

• Submucosal (Meissner) plexus: primarily regulates secretion and local blood flow
• Myenteric (Auerbach) plexus: sits between the two muscle layers, primarily controls motility
• Loss of myenteric ganglion cells is the defect underlying both Hirschsprung disease (colon) and achalasia (esophagus)

Epiploic Foramen of Winslow

• Natural opening connecting the greater and lesser peritoneal sacs
• Anterior border: hepatoduodenal ligament (contains the common bile duct, proper hepatic artery, and portal vein — the "portal triad in miniature")
• Superior border: caudate lobe of the liver
• Inferior border: first part of the duodenum
• Posterior border: inferior vena cava

Key Peritoneal Ligaments

Pectinate Line, Hemorrhoids & Anal Fissure

• The pectinate (dentate) line marks where hindgut endoderm meets ectoderm — it's the developmental hinge for how the anal canal is innervated, drained, and supplied

• Anal fissure: a tear in the anoderm below the pectinate line, classically in the posterior midline (the most poorly perfused area) — causes pain with defecation and bright red blood on the toilet paper; linked to constipation and low-fiber diets

Arterial Watersheds & Vascular Compression Syndromes

• GI-supplying arteries branch off the aorta anteriorly and are unpaired (celiac, SMA, IMA); non-GI arteries (renal, gonadal, lumbar) branch laterally/posteriorly and are paired
• Two colonic "watershed" zones receive overlapping supply from the terminal branches of two different arteries, making them most vulnerable to ischemia during hypotension or embolism:
  • Splenic flexure — junction of SMA and IMA territory
  • Rectosigmoid junction — junction of the last sigmoid branch and the superior rectal artery (both IMA branches)

Abdominal Wall, Inguinal Canal & Hernias

• Hesselbach triangle is bordered by the inferior epigastric vessels (lateral), rectus abdominis (medial), and inguinal ligament (inferior) — it's the weak spot for direct hernias
• Spermatic cord layers, outside-in from the internal oblique/external oblique/transversalis fascia: external spermatic fascia, cremasteric muscle/fascia, internal spermatic fascia

• Diaphragmatic/hiatal hernia: in infants, usually a congenital defect of the pleuroperitoneal membrane causing left-sided herniation into the thorax; in adults, laxity of the phrenoesophageal membrane allows the stomach to herniate through the esophageal hiatus (sliding type is far more common than paraesophageal, and is linked to GERD)

Rotation Errors & Clinical Correlates

• Incomplete rotation → malrotation, predisposes to midgut volvulus
• Failure of herniated gut to return → omphalocele (bowel covered by peritoneum/amnion)
• Failure of body wall closure (not a rotation defect) → gastroschisis (uncovered bowel, lateral to umbilicus)

Peritoneal Attachment Quick Reference

Congenital GI Malformations