9. Hepatic encephalopathy

Cirrhosis

• Definition: Irreversible formation of fibrosis, restricting hepatic cell regeneration, forming nodules of poorly-functioning cells.

• Ultrasound Findings: Nodular/shrunken liver.

• Transient Elastography: Increased liver stiffness.

• Biopsy Findings: Diffuse fibrosis with nodular regeneration.

• Impact on Blood Flow: Fibrotic liver increases resistance to blood flow leading to:

  • Portal Hypertension: Increased pressure in portal venous circulation.

  • Portosystemic Shunts: Increased flow to esophageal, rectal, and splenic veins resulting in:

    • Varices: Dilated veins in the esophagus, stomach, or rectum.

    • Variceal Bleed: Caused by vascular stretching and endothelial vasodilator release (e.g., NO).

Pathophysiological Changes

• Inflammation and Genetic Changes: Inflammation can lead to epigenetic changes, including oncogene mutations, contributing to malignancies like hepatocellular carcinoma.

  • Indicators: Increased serum alpha-fetoprotein (sensitivity 50%, specificity 99%).

• Blood Flow Dynamics: Backflow of blood into the spleen and altered blood flow to kidneys can lead to:

  • Hypotension: Due to increased vasodilators entering systemic circulation.

  • Splenomegaly: Enlarged spleen due to increased hydrostatic pressure and sequestration of blood cells.

  • Hepatopulmonary Syndrome: Rare syndrome due to decreased sonication time for gas exchange in pulmonary vasculature.

• Clinical Manifestations of Cirrhosis:

  • Cytopenias: Risk of thrombocytopenia, anemia, and associated petechiae/bruising.

  • Hepatic Insufficiency:

    • Decreased liver synthetic functions affecting clotting factors and anticoagulants leading to:

      • Unpredictable hemostatic imbalance evidenced by elevated INR.

      • Ascites: Fluid accumulation in the peritoneal cavity.

      • Peripheral Edema: Due to fluid retention and hypoalbuminemia.

Hepatic Metabolism and Complications

• Toxin Management Failures: Impaired metabolism of metabolites like ammonia, leading to:

  • Hepatic Encephalopathy: Accumulation leads to neuropsychological symptoms, day-night reversal, asterixis, and delirium.

• Bilirubin Management Issues: Reduced conjugation and secretion causing:

  • Jaundice: Serum bilirubin >30 μmol/L, with scleral icterus and jaundiced frenulum.

Pathophysiology of GI Tract Disorders

• Disorders related to swallowing, gastric emptying, ulcer disease, and overall liver function including detoxification leading to jaundice and portal hypertension.

Hepatic Encephalopathy (HE)

• Etiology: Multiple causes including cirrhosis, intra- or extra-hepatic cholestasis, toxins (e.g., CCl4, mushrooms, alcohol).

• Precipitating Factors:

  • High protein intake, infections, TIPS, GI bleed, AKI, and electrolyte derangements can exacerbate HE.

Ammonia Metabolism and its Role in HE

• Normal Pathway: Ammonia from protein metabolism is converted to urea via the urea cycle in the liver.

• Disruption of Ammonia Management:

  • Shunting of ammonia bypasses the liver leading to increased levels in the brain.

  • Elevated ammonia provokes brain edema and neurotransmitter alterations, contributing to neuronal dysfunction.

Other Factors in Hepatic Encephalopathy

• Increased BBB Permeability: Leads to non-specific elevation due to various metabolites and neurotoxins like GABA and aromatic acids.

• Altered Neurotransmissive Mechanisms: Increased production of false neurotransmitters and shifts in neurotransmitter activity, contributing to excitotoxicity and neuronal damage.

• GABA Hypothesis: Suggests increased GABAergic tone in the brain could be linked to the pathophysiology of HE.

Clinical Manifestations

• Grades of HE:

  • Grade I: Mild altered sleep patterns, decreased attention span.

  • Grade II: Asterixis, disorientation.

  • Grade III: Hyperactive reflexes, stupor.

  • Grade IV: Coma status indicating severe dysfunction.

Cirrhosis Clinical Manifestation and Complications

• Portal Hypertension Consequences:

  • Ascites, increased risk for spontaneous bacterial peritonitis, potential sepsis, varices, splenomegaly, and thrombocytopenia.

• Liver Cell Failure Effects:

  • Jaundice, coagulopathy, hepatic coma, and hyperestrogenemia, resulting in various systemic complications such as hematemesis and ascites.

• Other Complications of Cirrhosis:

  • Hepatorenal syndrome, hepatocellular carcinoma, and hepatopulmonary syndrome.