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Pathophysiology – Liver Diseases (Lecture Review)

Structure and Function of the Liver

  • Anatomical Location & Gross Anatomy

    • Situated in the right upper abdominal quadrant immediately beneath the diaphragm.
    • Four lobes identified on gross inspection (right, left, caudate, quadrate) separated by peritoneal reflections (e.g., falciform, round, triangular, venous ligaments).
    • Receives a dual blood supply
    • Hepatic artery (oxygen-rich arterial blood).
    • Portal vein (nutrient-rich venous blood from intestines, spleen, pancreas).
    • Portal circulation & venous drainage return blood via right, middle, and left hepatic veins → inferior vena cava.
    • Possesses a rich lymphatic network to drain interstitial fluid.

  • Digestive Functions

    • Secretes bile salts for emulsification & absorption of dietary fats.
    • Processes & stores macronutrients absorbed from intestines:
    • Fats: β-oxidation, lipoprotein synthesis, triglyceride storage.
    • Carbohydrates: glycogenesis, glycogenolysis, gluconeogenesis.
    • Proteins: transamination, deamination, urea formation.
    • Vitamin & mineral handling (A, D, B$_{12}$, iron, copper, etc.).

  • Endocrine Functions

    • Metabolizes glucocorticoids, mineralocorticoids, sex hormones → maintains hormonal homeostasis.
    • Regulates systemic carbohydrate, lipid, and protein metabolism by adjusting plasma substrate concentrations.

  • Hematologic Functions

    • Temporary blood storage (acts as vascular capacitance reservoir).
    • Extracts bilirubin produced from hemoglobin catabolism.
    • Capable of extramedullary hematopoiesis in certain disease states.
    • Synthesizes most coagulation factors (I, II, V, VII, IX, X, XI) and thrombopoietin.
    • Clinical correlations
    • ↓ Hepatic bilirubin clearance → ↑ indirect (unconjugated) serum bilirubin.
    • ↑ Urinary urobilinogen reflects hepatocellular dysfunction / hepatitis.
    • Bile acid transport defects ↔ hyperbilirubinemia.

  • Excretory & Detoxification Functions

    • Excretes bile pigments (bilirubin diglucuronide) & cholesterol in bile.
    • Converts ammonia → urea for renal excretion.
    • Biotransforms drugs, alcohol, xenobiotics via Phase I (CYP450) & Phase II (conjugation) pathways.

General Manifestations of Liver Disease

  • Hepatocellular Failure

    • Jaundice
    • Prehepatic, hepatic, posthepatic, or cholestatic patterns.
    • Muscle wasting from protein-energy malnutrition.
    • Ascites caused by portal hypertension & hypoalbuminemia.
    • Coagulopathy / excessive bleeding (↓ clotting factors, vitamin K malabsorption).
    • Hypoalbuminemia → edema, altered drug binding; vitamin deficiencies (fat-soluble).
    • Glucose imbalance (hypoglycemia in fulminant failure).
    • Endocrine disturbances (e.g., gynecomastia, testicular atrophy, amenorrhea).

  • Portal Hypertension

    • Result of ↑ intrahepatic resistance from fibrosis & regenerative nodules.
    • Complications: splenomegaly, ascites, portosystemic shunts.

  • Gastroesophageal Varices

    • Dilated submucosal veins secondary to portal hypertension—high rupture risk.
    • Early clinical triad: bleeding, anemia, shock.

  • Portosystemic (Hepatic) Encephalopathy

    • Neuropsychiatric syndrome graded 1–4; manifestations from mild confusion → coma.
    • Cerebral edema complicates grade 3–4, ↑ intracranial pressure.

  • Sequelae of Advanced Disease

    • Ascites (pathologic peritoneal fluid accumulation).
    • Spontaneous bacterial peritonitis (SBP)
    • Mono-microbial infection (usually Streptococcus pneumoniae, Escherichia coli).
    • Hepatorenal Syndrome
    • Functional renal failure due to profound renal vasoconstriction in advanced cirrhosis.

Disorders of the Liver

Acute Viral Hepatitis

  • General: diffuse inflammation of hepatic parenchyma; diagnosed by serology.

  • Hepatitis A (HAV)

    • RNA picornavirus; fecal–oral transmission.

  • Hepatitis B (HBV)

    • Partially double-stranded DNA hepadnavirus; spread via parenteral blood/body fluid exposure.
    • Vaccine: recombinant HBsAg; seroconversion rate 95\% in immunocompetent hosts.
    • Serologic course:
    • HBcAg appears first → anti-HBc.
    • HBsAg indicates active infection; conversion to anti-HBs may take ≤ 1 \text{ yr}.

  • Hepatitis C (HCV)

    • Single-stranded RNA, Flaviviridae; high propensity for chronicity.

  • Hepatitis D (HDV) – Delta agent

    • Defective RNA virus; requires HBV co-infection for replication.

  • Hepatitis E (HEV)

    • RNA virus; fecal–oral via contaminated water; severe in pregnancy.

Chronic Hepatitis (≥ 6 \text{ mo} inflammation)

  • Chronic Persistent (Triaditis/Transaminitis)

    • Low-grade portal inflammation; generally benign.

  • Chronic Active

    • Progressive necro-inflammation extending beyond portal triads into lobules; can progress to cirrhosis.

  • Autoimmune Hepatitis

    • Progressive inflammation with characteristic auto-antibodies (ANA, SMA, LKM-1) & polyclonal hyper-γ-globulinemia.

Cirrhosis

  • Biliary Cirrhosis

    • Result of prolonged cholestasis & bile duct inflammation/obstruction → periportal fibrosis, nodular regeneration.

  • Biliary Flukes

    • Parasitic infection diagnosed by repeated stool ova exams ± serology.
    • Primary Sclerosing Cholangitis: autoimmune, often in ulcerative colitis patients.

  • Alcoholic Liver Disease (ALD)

    • Alcoholic Fatty Liver (Steatosis / Steatohepatitis)
    • Excessive triglyceride accumulation within hepatocytes due to ↑ delivery or impaired β-oxidation.
    • Alcoholic Hepatitis
    • Centrilobular necrosis, neutrophilic infiltrates, Mallory bodies (cytokeratin aggregates).

Toxic Liver Disorders

  • Metal Storage Diseases

    • Hereditary Hemochromatosis
    • Mutation in HFE gene → uncontrolled intestinal iron absorption → iron overload.
    • Wilson Disease (Hepatolenticular Degeneration)
    • Autosomal recessive ATP7B defect → copper accumulation (liver, brain, cornea).

  • Drug / Chemical Injury

    • Acetaminophen (Paracetamol) Toxicity
    • Accounts for 39\% of US acute hepatic failure.
    • Toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) normally conjugated with glutathione.
    • Acute ingestion ≥ 140 \text{ mg/kg} saturates pathway → hepatic necrosis.

Other Structural Liver Conditions

  • Liver Abscess

    • Common US etiologies: ascending cholangitis ± gallstones, portal vein seeding from intra-abdominal infection, or hematogenous spread.

  • Trauma

    • Suspect with upper abdominal / lower thoracic injuries (penetrating or blunt).
    • Massive hemorrhage possible due to vascularity.

  • Malignancy

    • Primary (rare): hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma, hepatoblastoma (pediatric).
    • Secondary (Metastatic): common spread from GI tract, breast, lung.

Liver Transplantation

  • ~8000 transplants annually; waiting list ≈ 3× supply.

  • Evaluation: physiologic reserve, psychosocial suitability.

  • Post-Transplant Management

    • Immunosuppression (calcineurin inhibitors, steroids, antimetabolites).
    • Acute rejection window: POD 4–10.
    • Clinical signs: tachycardia, fever, RUQ/flank pain, ↓ or discolored bile, rising jaundice.
    • Monitor & treat drug toxicities, metabolic derangements, infections.

Age-Related Considerations

Neonates & Pediatrics

  • Physiologic Jaundice: benign, up to 2 weeks.
    • Hyperbilirubinemia not physiologic if >5 \text{ mg/dL} (day 1), >10 \text{ mg/dL} (day 2), or >13 \text{ mg/dL} any time.
  • HAV in Children: often mild/asymptomatic; incidence inversely related to sanitation.
  • Congenital Disorders: enzyme deficiencies, inborn errors (e.g., galactosemia), intra/extra-hepatic cholestasis (biliary atresia).

Geriatrics

  • Altered pharmacokinetics → prolonged drug half-life.
  • Greater incidence of HCC & ischemic hepatitis.
  • Metabolic genetic diseases rarely present de novo in elderly.
  • Longstanding alcohol abuse → advanced cirrhosis in older adults; viral hepatitis may present atypically.

NGN Clinical Case – Ascites Management

  • Baseline: 78-year-old with chronic alcoholic cirrhosis + ascites; initial paracentesis removed 4 \text{ L}; started on spironolactone 100 \text{ mg/day} + furosemide 40 \text{ mg/day} and sodium restriction 2000 \text{ mg/day}.

  • Follow-Up (home visit)

    • Diuretics titrated to furosemide 160 \text{ mg} + spironolactone 400 \text{ mg} daily.
    • Weight ↓ from 104.5 kg → 97.3 kg.
    • Electrolytes: serum K^{+}=4.0\,\text{mEq/L}, urine K^{+}=60\,\text{mEq/L}; serum Na^{+}=140\,\text{mEq/L}, urine Na^{+}=110\,\text{mEq/L}—all within expected/therapeutic targets.
    • Vitals stable (BP 112/60 mmHg, HR 80 bpm, RR 12, SpO$_2 98\%).
    • Improvement markers: reduced abdominal distension, no peripheral edema, normal respiratory parameters.

Clinical & Ethical/Practical Implications

  • Early identification of portal hypertension enables prophylaxis against variceal bleeding (non-selective β-blockers, endoscopic banding).
  • Recognition of drug dosing adjustments in cirrhotics prevents iatrogenic toxicity (e.g., acetaminophen, benzodiazepines).
  • Vaccination (HBV) & harm-reduction (needle exchange) are critical public-health measures.
  • Transplant allocation ethics: balancing organ scarcity, prognosis, and social factors.
  • Screening for HCC in cirrhotic patients (ultrasound ± AFP every 6$$ mo) improves survival via early detection.