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Pathophysiology

Pancreatic Disease

Acute & chronic pancreatitis, diabetes mellitus types 1 & 2, and pancreatic cancer

Acute Pancreatitis

Pathophysiology

Acute pancreatitis results from premature activation of pancreatic proteases (particularly trypsinogen β†’ trypsin) within the pancreas, causing autodigestion. Trypsin activates other zymogens (elastase, phospholipase A2, chymotrypsin), leading to acinar cell necrosis, inflammatory cascade (IL-1, IL-6, TNF-Ξ±), and systemic inflammatory response.

🧠 Mnemonic β€” Causes: GET SMASH'DGallstones (most common, 40%) Β· Ethanol (35%) Β· Trauma Β· Steroids Β· Mumps/viral Β· Autoimmune Β· Scorpion sting Β· Hyperlipidemia/Hypercalcemia Β· ERCP Β· Drugs (azathioprine, furosemide, sulfa, valproate)

Diagnosis (Revised Atlanta Criteria)

Diagnosis requires 2 of 3: (1) Characteristic abdominal pain (epigastric, radiating to back, severe, constant); (2) Serum lipase or amylase β‰₯3Γ— ULN; (3) Characteristic CT findings. Lipase is more specific than amylase (remains elevated longer).

Severity Assessment β€” Ranson's Criteria

At AdmissionAt 48 Hours
Age >55Hct drop >10%
WBC >16,000BUN rise >5 mg/dL
Glucose >200 mg/dLCa <8 mg/dL
LDH >350 IU/LPO2 <60 mmHg
AST >250 IU/LBase deficit >4 mEq/L
β€”Fluid sequestration >6L

Score 0–2: mild (<5% mortality); 3–4: moderate (15%); 5–6: severe (40%); >6: >99% mortality

Complications

  • Local: Pancreatic necrosis (sterile vs. infected), pseudocyst (4+ weeks), abscess, walled-off necrosis
  • Systemic: ARDS, acute kidney injury, shock, GI bleeding, hypocalcemia (saponification), DIC
πŸ₯ ManagementAggressive IV hydration (lactated Ringer's preferred; 250–500 mL/hr initially). NPO β†’ advance diet as tolerated (early enteral nutrition via NG/NJ tube preferred over TPN). Analgesia (opioids). Treat etiology (ERCP for gallstone pancreatitis with cholangitis). Antibiotics ONLY for confirmed infected necrosis (not prophylactically).

Chronic Pancreatitis

Pathophysiology

Repeated episodes of acute pancreatitis or chronic ductal hypertension β†’ progressive parenchymal fibrosis β†’ loss of exocrine (acinar cells) and endocrine (islet cells) function. Most common cause in adults: alcohol abuse (70%). Other causes: hereditary (PRSS1 mutation), autoimmune, idiopathic, tropical, obstructive (stricture, tumor).

Clinical Features

  • Recurrent epigastric pain: chronic, often radiates to back; worse after eating
  • Exocrine insufficiency: steatorrhea (malabsorption of fat, fat-soluble vitamins A, D, E, K), weight loss β€” occurs when >90% of exocrine function lost
  • Endocrine insufficiency: type 3c diabetes mellitus (pancreatogenic); brittle, hypoglycemia-prone
  • Imaging: CT shows calcifications (pathognomonic), ductal dilation, atrophy
🎯 Boards PearlCalcifications on CT/X-ray = chronic pancreatitis. Secretin-stimulated MRCP or EUS are most sensitive early tests. Treat exocrine insufficiency with pancreatic enzyme replacement (lipase >40,000–50,000 units per meal with fatty meals). Pain management: analgesic ladder β†’ celiac plexus block β†’ surgery (Whipple or lateral pancreatojejunostomy). Screen for pancreatic cancer.

Diabetes Mellitus Type 1

Pathophysiology

Type 1 DM is an autoimmune disease resulting in T-cell mediated destruction of pancreatic beta cells, causing absolute insulin deficiency. Associated with HLA-DR3 and HLA-DR4 antigens. Autoantibodies: anti-GAD65, anti-insulin antibodies (IAA), anti-islet cell antibodies (ICA), anti-IA-2. Without insulin, cells cannot take up glucose β†’ hyperglycemia, and lipolysis is unchecked β†’ free fatty acids β†’ ketone bodies (DKA).

Diabetic Ketoacidosis (DKA)

FeatureDKA (T1DM)HHS (T2DM)
Glucose>250 mg/dL (often 300–500)>600 mg/dL
pH<7.3>7.3
Bicarb<18 mEq/L>15 mEq/L
Anion gapElevated (>12)Normal or mildly elevated
KetonesModerate–large (serum and urine)Minimal
OsmolalityVariable>320 mOsm/kg
MortalityLow if treated (<5%)Higher (10–20%)
πŸ₯ DKA ManagementIV fluids (0.9% NS, then 0.45% NS + dextrose when glucose <250). IV insulin infusion. Potassium replacement (do not start insulin if K <3.3 mEq/L). Identify precipitant (infection, missed insulin, new-onset T1DM). Bicarbonate only if pH <6.9. Transition to subcutaneous insulin when anion gap closed, patient eating, and gap closing.

Diabetes Mellitus Type 2

Pathophysiology

Type 2 DM involves progressive insulin resistance (peripheral tissues fail to respond to insulin) combined with beta cell dysfunction and eventual decline. Key mediators: excess visceral adiposity β†’ elevated free fatty acids and adipokines (TNF-Ξ±, IL-6, resistin) β†’ impaired insulin signaling (IRS-1 serine phosphorylation). Beta cells compensate with hyperinsulinemia until they fail (~50% beta cell loss at diagnosis).

Diagnostic Criteria

TestNormalPrediabetesDiabetes
Fasting glucose<100 mg/dL100–125β‰₯126 (Γ—2)
2-hr OGTT (75g)<140 mg/dL140–199β‰₯200
HbA1c<5.7%5.7–6.4%β‰₯6.5% (Γ—2)
Random glucoseβ€”β€”β‰₯200 + symptoms

Microvascular & Macrovascular Complications

  • Nephropathy: microalbuminuria β†’ macroalbuminuria β†’ ESRD; ACE inhibitor/ARB for protection
  • Retinopathy: non-proliferative β†’ proliferative; VEGF drives neovascularization; anti-VEGF therapy
  • Neuropathy: symmetric distal polyneuropathy (stocking-glove); autonomic neuropathy (gastroparesis, orthostatic hypotension)
  • Cardiovascular: 2–4Γ— increased risk of MI, stroke, PAD
  • Foot disease: neuropathy + PVD β†’ ulcers, infections, amputations
🎯 Boards Pearl β€” HbA1c TargetsGeneral: <7% (ADA). Individualize: <6.5% in young/healthy; <8% in elderly/comorbidities/hypoglycemia-prone. Screening: q3 years in average risk; annual if at risk. Metformin remains first-line unless contraindicated (eGFR <30). Add GLP-1 agonist (liraglutide, semaglutide) or SGLT-2 inhibitor (empagliflozin, canagliflozin) for CVD/HF/CKD benefit.

Pancreatic Adenocarcinoma

Epidemiology & Risk Factors

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the US with 5-year survival ~12%. Most arise in the head of the pancreas (60–70%). Risk factors: age >60, smoking (2Γ— risk), chronic pancreatitis, T2DM, obesity, family history, hereditary syndromes (BRCA2, Lynch, FAMM, Peutz-Jeghers), new-onset DM in older adult with weight loss.

Clinical Presentation

LocationClassic Presentation
Head (60–70%)Painless obstructive jaundice, Courvoisier's sign (palpable non-tender GB), steatorrhea, weight loss
Body/Tail (30–40%)Epigastric/back pain (invasion of celiac plexus), weight loss, new-onset DM β€” usually late presentation, unresectable

Diagnosis & Staging

  • CT abdomen with triple-phase contrast (imaging of choice)
  • ERCP or EUS + biopsy for tissue diagnosis
  • CA 19-9: tumor marker (not used for screening; elevated in cholangiocarcinoma, pancreatitis)
  • Only ~20% are resectable at diagnosis
🎯 Boards PearlCourvoisier's sign = palpable, non-tender gallbladder in the setting of painless jaundice β†’ suggests pancreatic head mass (or other periampullary tumor) compressing CBD. Trousseau's sign (migratory thrombophlebitis) is associated with visceral cancers including pancreatic cancer. New-onset DM + weight loss in a patient >50 β†’ rule out pancreatic cancer. Resectable: Whipple procedure (pancreaticoduodenectomy); adjuvant chemotherapy (FOLFIRINOX or gemcitabine + capecitabine).