Cirrhosis and End-Stage Liver Disease

Complications of End-Stage Liver Disease

• End-stage liver disease (cirrhosis) is a chronic, irreversible degeneration of liver cells, followed by scarring and infiltration of tissues with fibrotic strands and regeneration nodules.
• This process leads to progressive liver function loss and circulatory obstruction (portal hypertension).
• Associated complications include gastroesophageal varices, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, and hepatorenal syndrome.
• Risk factors mainly include alcoholic liver disease and viral hepatitis, and to a lesser extent, biliary diseases, metabolic disorders, or drug reactions.

Pathogenesis of Cirrhosis

• Inflammation and necrosis of hepatocytes lead to the replacement of normal liver architecture with interconnecting fibrous scar tissue.
• Regenerative nodules, ranging from micronodules (less than 3 mm) to macronodules (greater than 3 mm) are formed by hepatocyte regeneration.

Manifestations of Cirrhosis

• Asymptomatic stage
• Early symptoms include weight loss (potentially masked by ascites), weakness, anorexia, hepatomegaly, jaundice, and abdominal pain.

Portal Hypertension

• Portal hypertension is characterized by increased resistance to blood flow in the portal venous system and sustained portal vein pressure above 10 mmHg (normal 5-10 mmHg).
• This results from both increased resistance to portal flow (fibrotic scars, regeneration nodules, and intrahepatic nitric oxide (NO)) and increased portal venous inflow (splanchnic vasodilation from increased NO production in extrahepatic circulation).
• Complications of portal hypertension include splenomegaly, ascites, portosystemic shunts (e.g., esophageal varices, anorectal varices, and caput medusae), bleeding (decreased clotting factors), thrombocytopenia (from splenomegaly), gynecomastia (altered testosterone and estrogen metabolism), spider angiomas, and palmar erythema, and hepatic encephalopathy
• Increased intrahepatic venous pressure and dilation of venous channels behind the obstruction.
• Collateral channels open, connecting portal and systemic circulation, leading to complications.
• Portal hypertension leads to increased pressure in peritoneal capillaries, resulting in ascites.

Classification of Cirrhosis

• Compensated cirrhosis: Portal pressure < 10 mmHg, no complications. Management focuses on treating the underlying cause and primary prevention.
• Decompensated cirrhosis: Portal pressure > 10 mmHg, with complications. Management focuses on treating complications and secondary prevention.

Laboratory Findings in Cirrhosis

• Conventional liver function tests may not fully reflect the extent of disease (necrosis, regeneration, scarring).
• Child-Turcotte-Pugh classification scores liver disease severity and predicts long-term mortality and quality of life.
• The model for end-stage liver disease (MELD) score is an alternate method to assess survival and prioritize patients for transplantation (predicts 90-day mortality).

Ascites

• Ascites is free fluid in the abdominal cavity, caused by increased resistance within the liver and reduced osmotic pressure in the bloodstream (hypoalbuminemia).
• Systemic compensation involves generalized vasodilation, increased cardiac output, and sodium/water retention through the renin-angiotensin-aldosterone system (RAAS).
• Clinical features: shifting dullness, fluid wave, bulging flanks, abdominal pain.
• Diagnosis includes medical history, clinical features, abdominal ultrasonography, and diagnostic paracentesis (serum-ascites albumin gradient).

Classification of Ascites

• Grade 1: Mild (detected only by ultrasound)
• Grade 2: Moderate (symmetric distension of abdomen)
• Grade 3: Large/Gross (marked distension of abdomen)
• Responsive ascites, Recurrent ascites, Refractory ascites, as determined by response to treatment.

Treatment of Ascites

• Alcohol cessation if alcohol induced
• Dietary sodium restriction (less than 2000 mg/day)
• Fluid restriction (less than 1.5 L/day if serum sodium is less than 120-125 mmoL/L)
• Diuretics (starting in grade 2). Combination of furosemide and spironolactone is preferred, with doses adjusted as needed; spironolactone substitution with amiloride might be required for some patient.
• Large-volume paracentesis (LVP) may manage tense ascites, and albumin administration during this procedure may help.
• Monitoring electrolytes and avoiding drugs that exacerbate sodium/water retention (e.g., NSAIDs) is key in the treatment.

Hepatic Encephalopathy

• Hepatic encephalopathy is brain dysfunction due to liver insufficiency or portosystemic shunting, presenting in a spectrum from subtle changes to coma.
• Common causes are nitrogenous substance (NH3) accumulation from the gut, activation of GABA (by endogenous benzodiazepine-like substances), and zinc deficiency or altered cerebral metabolism.
• Precipitating factors can include constipation, bleeding, infection, dehydration, and use of CNS-active drugs (benzodiazepines and narcotics).
• Clinical features include altered mental status and progress to coma, with asterixis ("hand flap") as a common finding.
• Grading systems (e.g., West Haven Criteria (WHC)) are used to classify the severity.
• Subtypes of hepatic encephalopathy are classified based on underlying disease (Type A, B, or C), duration (Episodic, Recurrent, or Persistent), or presence/absence of precipitating factors.

Treatment of Hepatic Encephalopathy

• Assess and address precipitating factors (e.g., infection, bleeding).
• Non-pharmacologic management: dietary interventions (low-protein, high-carbohydrate diet, controlled protein intake, and late-evening CHO intake), and balanced supplementation like BCAA, zinc supplementation.
• Pharmacologic treatment includes lactulose (to reduce NH3 absorption), rifaximin (to reduce urease-producing bacteria), or other nonabsorbable antibiotics (Neomycin or Metronidazole).
• The continued use of diuretics is ineffective and should be avoided. Secondary prophylaxis with lactulose or rifaximin is often necessary after acute episodes.

Gastroesophageal Varices

• Variceal hemorrhage is caused by portal hypertension and resulting collateral blood vessel formation (e.g., esophageal, gastric varices).
• Risk of bleeding is significant (25–35% of patients with varices and 30–50% mortality rates per bleed). Recurrence of bleeding has high rates (70% within 6 months of an initial bleed).
• Acute variceal bleeding management involves fluid resuscitation, hemodynamic stabilization, vasoactive therapy, endoscopy and potential intervention (e.g., sclerotherapy, endoscopic variceal band ligation).
• Nondrug measures to control bleeding (e.g., balloon compression, TIPS) are used in medication-unresponsive cases.
• Prevention of bleeding includes endoscopy, and pharmacologic therapy including non-selective β-blockers in patients at high risk. Secondary prophylaxis includes a combination of endoscopic variceal band ligation and non-selective β-blockers for patients with a history of bleeding.

Spontaneous Bacterial Peritonitis (SBP)

• Infection in previously sterile ascitic fluid, often secondary to liver failure, portal hypertension, or suppression of hepatic reticuloendothelial cells.
• Associated with 20–40% of in-hospital mortality.
• Causes typically involve enteric gram-negative pathogens (mainly Escherichia coli).
• Clinical presentation includes fever, abdominal pain, nausea, vomiting, diarrhea, and altered mental status (encephalopathy).
• Diagnosis requires abdominal paracentesis to identify more than 250 polymorphonuclear cells/mm³.
• Treatment involves prompt empiric broad-spectrum antibiotic therapy (e.g., cefotaxime, ceftriaxone), potentially followed by culture-guided therapy, and supplemental albumin in patients who meet the criteria (renal failure; total bilirubin > 4 mg/dL), or high risk of liver failure.

Hepatorenal Syndrome (HRS)

• Development of renal failure secondary to liver cirrhosis, the primary mechanism being renal hypoperfusion.
• Criteria: SCr > 1.5 mg/dL (with no improvement after diuretics or albumin) and no shock, nephrotoxins, or parenchymal kidney disease.
• Treatment includes albumin plus octreotide or midodrine infusions.

This quiz covers the complications and pathogenesis of end-stage liver disease, particularly cirrhosis. It examines the irreversible degeneration of liver cells, resulting in various complications such as portal hypertension and hepatic encephalopathy. Understanding these concepts is crucial for studying liver pathology.