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Alterations in Function of the Gallbladder and Exocrine Pancreas

Structure and Function of the Pancreaticobiliary System

  • Components
    • Gallbladder and cystic duct
    • Intrahepatic, hepatic, and common bile ducts
    • Endocrine & exocrine pancreas
    • Extra-hepatic biliary tree + gallbladder = tightly regulated conduit delivering bile to the duodenum
  • Illustrated anatomy (slide)
    • Common bile duct joins pancreatic duct before entering duodenum (ampulla)
    • Pancreatic acini = exocrine cells → digestive juice
    • Islets of Langerhans:
      • \alpha cells → glucagon
      • \beta cells → insulin
      • \delta cells → somatostatin
      • PP (pancreatic polypeptide) cells
    • Dense capillary network for endocrine hormone dispersal

Embryology of the Pancreaticobiliary System

  • Weeks 3\text{–}4 gestation: primitive foregut forms dorsal pancreatic bud (dorsal pancreas)
  • Week 5 gestation:
    • Cranial bud → liver
    • Caudal bud → gallbladder
    • Basal bud → ventral pancreas (later rotates to fuse with dorsal pancreas)

Physiology of Bile & Gallbladder

  • Bile composition: bile acids, pigments (bilirubin), cholesterol, phospholipids
  • Bile salts: indispensable for emulsifying fat & facilitating intestinal absorption
  • Bile as a waste route: bilirubin, excess cholesterol, xenobiotics excreted via feces
  • Gallbladder functions:
    • Receives hepatic bile
    • Concentrates by water re-absorption
    • Contracts (stimulated by cholecystokinin, CCK) → propels bile through common bile duct into duodenum

Functional Anatomy & Physiology of the Pancreas

  • Dual organ:
    • Endocrine: insulin, glucagon, somatostatin directly into blood
    • Exocrine: ~ 1!\text{–}!1.5\,\text{L} enzyme-rich fluid/24 h into duodenum
  • Enzymes
    • Secreted active: amylase, lipase
      • Serum amylase & lipase rise almost simultaneously in pancreatitis
    • Secreted as pro-enzymes: trypsinogen, chymotrypsinogen, pro-carboxypeptidase, etc.; enterokinase in duodenal brush-border converts trypsinogen → trypsin, initiating cascade
  • Hormonal control of secretion: CCK (from I-cells, stimulated by fat/protein in chyme) & secretin (from S-cells, stimulated by acid chyme) → potentiate enzyme & bicarbonate secretion respectively

Pathophysiology of Cholesterol Gallstone Formation (Cholelithiasis)

  • Three indispensable factors:
    1. Supersaturation of bile with cholesterol (↓ bile acid:cholesterol ratio)
    2. Nucleation of cholesterol crystals (accelerated by mucin, gallbladder stasis, bacterial β-glucuronidase)
    3. Hypomotility of gallbladder (↓ CCK response → prolonged residence time → stone growth)

Gallbladder Disorders

Epidemiology & Risk

  • Gallstones:
    • 2\times more common in women
    • Prevalence: highest in Native Americans (e.g., Pima), intermediate in European Caucasians, lowest in Asians

Cholelithiasis

  • Presence of stones; may be silent or cause biliary colic (intermittent RUQ/epigastric pain, precipitated by meals or nocturnal)

Cholecystitis

  • Acute:
    • Inflammation of gallbladder wall, usually calculus-related cystic duct obstruction
    • Severe RUQ pain radiating to back, fever, leukocytosis
    • Risk of gangrene & perforation if untreated
  • Chronic:
    • Recurrent low-grade inflammation → fibrosis, wall thickening
    • Complication: porcelain gallbladder (calcified wall) → ↑ carcinoma risk

Biliary malignancy

  • Rare (≈ 1\text{–}2/100{,}000 yr US)
  • Presentation: RUQ pain + obstructive jaundice (tumor at neck/cystic duct/common bile duct)
  • Poor prognosis due to late detection

Pancreatic Disorders

Acute Pancreatitis (AP)

  • Etiology (top causes):
    • Alcohol (~ 66\% first attacks in US)
    • Gallstones obstructing ampulla
    • Hypertriglyceridemia (> 1000\,\text{mg/dL})
    • Trauma, ERCP, drugs, infections, genetic PRSS1/SPINK1 mutations
  • Pathogenesis:
    • Acinar cell injury or duct obstruction → inappropriate intracellular activation of trypsin → autodigestion, inflammation, necrosis, systemic cytokine storm
  • Clinical spectrum: mild interstitial → severe necrotizing (multi-organ failure)
  • Serology: rise in serum amylase & lipase (lipase remains elevated longer)
  • Aftermath: transient or prolonged impairment of endocrine & exocrine function

Chronic Pancreatitis (CP)

  • Definition: chronic irreversible inflammatory fibrosis leading to loss of acini, strictured ducts, calcifications
  • Clinical picture:
    • Recurrent/constant epigastric pain (may burn out)
    • Eventually manifests as pancreatic insufficiency: steatorrhea, malabsorption, weight loss, diabetes mellitus in 10\text{–}15\% patients
  • Causes: chronic alcohol use (most), genetic (CFTR, PRSS1), autoimmune, obstructive strictures/tumors, idiopathic tropical pancreatitis

Pancreatic Cancer

  • Epidemiology:
    • Accounts for \approx 2\% of all cancers yet #4 in cancer deaths
    • Median survival ≈ 12\,\text{months}; 5-year survival < 10\%
  • Clinical signs: painless jaundice (head tumors), weight loss, new-onset diabetes, migratory thrombophlebitis (Trousseau)
  • Risk factors: chronic pancreatitis, smoking, long-standing diabetes, genetic (BRCA2, PALB2, Peutz-Jeghers)

NGN Case Study – Acute Necrotizing Pancreatitis

  • Patient profile: 50-y/o male, 20-year alcohol misuse, family history (father + brother CP)
  • Presentation: steady “boring” LUQ pain radiating to back ×12 h, nausea, low-grade fever (100.4 °F), distended tender abdomen, hypoactive bowel sounds
  • Vitals: RR 20 (labored), HR 94, BP 140/80
  • Labs/Imaging ordered: serum pancreatic enzymes, LFTs (ALT/AST), ALP, bilirubin, CBC, electrolytes, abdominal CT/X-ray
  • Confirmed diagnosis: acute necrotizing pancreatitis
  • Priority complications to prevent/monitor (from slide answer):
    • Hypocalcemia
    • Hyperglycemia
    • Hypomagnesemia
    • Acute renal failure
    • Intra-abdominal sepsis
    • Acute respiratory distress syndrome (ARDS)
  • Rationales:
    • Severe AP triggers fat saponification → ↓ serum Ca^{2+}; aggressive fluid resuscitation/diuretics → (Mg^{2+}) loss
    • Islet cell injury + stress hormones → hyperglycemia
    • Systemic inflammation can precipitate ARDS & acute tubular necrosis
    • Infected necrosis → intra-abdominal sepsis = major mortality driver

Hormonal & Neural Regulation (Connections)

  • CCK: released from duodenal I-cells when fat/protein enter; causes gallbladder contraction, Oddi sphincter relaxation, pancreatic enzyme secretion
  • Secretin: released from S-cells when acid chyme enters; stimulates pancreatic & biliary ductal cells to secrete HCO_3^--rich fluid
  • Vagus (parasympathetic): potentiates during cephalic & gastric phases of digestion

Laboratory/Diagnostic Nuggets

  • Serum lipase/amylase: ↑ in tandem; lipase more specific, remains elevated longer
  • ALP & conjugated bilirubin: disproportionally ↑ suggest biliary obstruction/cancer
  • CT (contrast-enhanced): gold standard to grade necrosis, identify complications (pseudocyst, walled-off necrosis)
  • ERCP: diagnostic & therapeutic for choledocholithiasis → sphincterotomy

Risk Factors & Preventive Considerations

  • Female sex hormones (estrogen, pregnancy, OCPs) → ↑ cholesterol saturation
  • Rapid weight loss/TPN → gallbladder stasis
  • Hypertriglyceridemia (> 1000\,\text{mg/dL}) → pancreatic lipase release intracapillary → FFAs → injury
  • Avoid excessive alcohol & manage lipids to reduce AP risk

Clinical Correlations & Real-World Relevance

  • Gallstone “5 F’s” mnemonic: Female, Forty, Fat, Fertile, Fair (Caucasian)
  • Pain pattern: pancreatitis classically relieved by leaning forward, worsened supine
  • Porcelain gallbladder mandates prophylactic cholecystectomy due to carcinoma risk
  • Ethical: early identification of high-risk alcohol users, counseling & resources -> reduces incidence

Summary Equations/Statistics

  • Stone prevalence hierarchy: \text{Native American} > \text{Caucasian} > \text{Asian}
  • Alcohol role in AP first attacks: \approx 66\%
  • Pancreatic cancer mortality: \text{median survival} = 12\,\text{months}; \text{5-yr survival} < 10\%