Gastrointestinal Pharmacotherapy: Cirrhosis & Portal Hypertension

Gastrointestinal Disorders Pharmacotherapy: Cirrhosis & Portal Hypertension

• Cirrhosis: A late-stage, progressive form of liver fibrosis.
• Distortion of liver architecture creates regenerative nodules.
• Resulting from any chronic liver disease cause, including chronic viral hepatitis or alcoholic liver disease.
• Cirrhosis complications lead to significant morbidity and mortality.
• Common complications include ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, and hepatocellular carcinoma.

Portal Hypertension and Cirrhosis—Introduction

• Definition Of cirrhosis: A diffuse process characterized by fibrosis, converting normal hepatic architecture into structurally abnormal nodules.
• This process increases resistance to blood flow in portal hypertension leading to varices and ascites.
• Hepatocyte loss and intrahepatic shunting of blood diminish metabolic and synthetic function, causing hepatic encephalopathy (HE) and coagulopathy.
• Clinical Consequences:
  • Impaired hepatocyte function, increased intrahepatic resistance to portal hypertension, and hepatocellular carcinoma.
  • Circulatory imbalances, including splanchnic vasodilation, vasoconstriction, kidney hypoperfusion, water and salt retention, and increased cardiac output.

Pathophysiology and Etiology

• Cirrhosis elevates portal blood pressure due to fibrotic changes within hepatic sinusoids.
• Liver vasodilatory and vasoconstrictor mediators change.
• Splanchnic vasculature blood flow increases.
• Most common causes: Hepatitis, alcoholic liver disease, and hepatitis C + alcoholic disease.
• Miscellaneous causes include autoimmune hepatitis, primary biliary cirrhosis, secondary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, and drug-induced liver injury.

Fatty Liver (Steatosis) from Ethanol

• Fatty liver or steatosis is the first stage of alcohol-related liver injury.
• Characterized by lipid deposition in hepatocytes.
• Steatosis progresses to liver inflammation (steatohepatitis), hepatocyte death, and collagen deposition leading to fibrosis.
• Ethanol-induced oxidative stress on the liver is suggested as a driver of these mechanisms.

Consequences of Cirrhosis

• Pathophysiologic abnormalities result in ascites, portal hypertension, esophageal varices, hepatic encephalopathy, and coagulation disorders.

Clinical Presentation (Signs and Symptoms)

• Common symptoms include anorexia, nausea, abdominal discomfort, weight loss, malaise, ascites, peripheral edema, jaundice, palmar erythema, gynecomastia, testicular atrophy, amenorrhea, loss of pubic hair, hepatomegaly, splenomegaly, encephalopathy, and bleeding.

Laboratory Findings

• Elevated ALT and AST levels can normalize in later stages.
• Elevated bilirubin is common.
• Low albumin levels are common.
• Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) are often seen.
• Elevated serum creatinine and blood urea nitrogen (BUN) can occur.

Treatment: Cirrhosis

• The primary treatment goals include slowing or reversing liver disease progression, preventing further liver insults, managing complications, and determining the suitability and timing of liver transplantation.

Portal Hypertension

• Portal pressure depends on flow and resistance across the hepatic vasculature.
• Normal portal pressure is less than 6 mmHg, increasing to 7-9 mmHg in cirrhotic patients.
• Factors contributing to portal hypertension:
  • Increased intrahepatic resistance due to vasoconstriction, compression, and fibrosis.
  • Increased portal venous inflow due to splanchnic vasodilation.

Portal Hypertension and Varices

• Portal pressure increases by 5 mmHg more than inferior vena cava pressure.
• This leads to varices and alternative blood flow routes.
• A portal pressure exceeding vena cava pressure by more than 12 mmHg increases the risk of varices.
• Hemorrhage from varices impacts 25-40% of cirrhotic patients and carries a 30% mortality risk per episode.

How Varices Form

• Portal hypertension forces blood flow backward, enlarging and developing varices in the esophagus and stomach.
• Pressure buildup also enlarges the spleen.

Management of Varices

• Treatment focuses on primary and secondary prophylaxis as well as managing acute variceal hemorrhage.

Primary Prophylaxis of Varices

• Mainstay treatment is nonselective beta-adrenergic blockade (propranolol or nadolol).
• Mechanisms include decreasing cardiac output through beta-1 blockade and decreasing splanchnic blood flow through beta-2 blockade.
• A heart rate of 55 beats/minute or higher and a systolic blood pressure of 90 mmHg or higher are crucial to consider.
• Adverse effects are experienced by 27% of patients.
• • Continued use recommended for the duration of the patient's life, unless otherwise contraindicated.

Beta Blockers (BB) in Varices

• Only nonselective beta blockers have an adrenergic dilatory effect on mesenteric arterioles decreasing portal blood circulation and pressure.
• Propranolol or nadolol dosing: Start at 20 mg twice daily or 10 mg three times daily, titrating to a reduction in resting heart rate to 20-25% and an absolute rate of 55-60 beats/min or adverse effects develop.
• Selective beta-blockers such as atenolol or metoprolol have less impact and aren't considered suitable for primary prophylaxis.
• Isosorbide-5-mononitrate usage is mentioned, but no context provided.

Primary Prophylaxis for Varices Treatment Recommendations (Cont.)

• Prophylaxis for patients with small varices (< 5 mm) without bleeding or increased bleeding risk.
• Patients with small varices plus risk factors.
• Medium to large varices (varices > 5 mm) with or without bleeding plus high risk factors.
  • Endoscopic variceal ligation may be preferred instead of BB if applicable.
  • Use precaution in individuals with intolerance or contraindications to BB treatment.

Acute Variceal Hemorrhage

• An urgent and life-threatening consequence of cirrhosis.
• Treatment priorities include volume restoration, acute bleeding management, and prevention of recurrence.
• Packed red blood cells are used to increase Hemoglobin (Hb) to 10 g/dL.
• Fresh-frozen plasma and platelets are often required to correct coagulation abnormalities.
• Airway protection from blood aspiration is critical
• Antibiotics to prevent SBP and Gram-negative systemic infections.
• Control of immediate bleeding.
• Prevention of rebleeding, and liver function preservation

Drug Therapy for Acute Variceal Bleeding

• Somatostatin analogues (octreotide or vapreotide) and vasopressin/terlipressin are used to decrease portal blood flow and pressures by functioning as splanchnic vasoconstrictors.
• Endoscopic variceal banding (EVL) procedures may be necessary.

Infection Prophylaxis: Short-Term Antibiotics

• Norfloxacin (400 mg twice daily) for seven days or no treatment for SBP incidence or mortality.
• No significant differences in mortality between treatment and control groups.

Secondary Prophylaxis for Preventing Rebleeding

• Combination of beta-blockers and repeated endoscopic variceal ligation is frequently the most effective course of action.
• Initiation of beta-blockers may not occur until after initial variceal hemorrhage stabilization.
• Patients who abstain from bleeding for at least 24 hours or are ready for discharge follow-up may be candidates for beta-blocker treatment.

Ascites and Spontaneous Bacterial Peritonitis (SBP)

• Ascites is the accumulation of fluid within the peritoneal cavity, a common complication of cirrhosis.
• SBP is an infection of pre-existing ascitic fluid without an intra-abdominal source, frequently seen in end-stage liver disease.

Ascites Management

• Therapy aims to mobilize ascitic fluid, reduce abdominal discomfort, and prevent complications like SBP.
• Non-pharmacological methods include sodium and water restriction and therapeutic paracentesis.
• Pharmacological methods commonly include diuretics.
  • Combination of spironolactone and furosemide is a standard regimen.

Treatment Objectives of Cirrhosis

• Reduce complication rates.
• Treat complications.
• Reduce hospitalizations.

Non-Pharmacological Management of Ascites

• Salt restriction is frequently less than 2g/day.
• Regular weight monitoring provides essential information.
• Bed rest is a regular recommendation to promote patient well-being and reduce potential complications.
• Diet with restricted protein intake can be recommended for those suffering from hepatic encephalopathy.
• Endoscopic sclerotherapy or banding are used for managing variceal bleeding associated with ascites.

Pharmacologic Treatment of Ascites

• First-line treatment, including spironolactone.
• Starting dose: 100 mg daily, increasing every few days by 100mg every 3-7 days up to maximum of 400 mg daily.
• Serum potassium levels must be monitored every step of the way.
• Furosemide is considered an add-on or alternative option for those who do not respond to spironolactone or exhibit hyperkalemia or impaired kidney function at baseline, increasing the dose by 40mg/day.

Add-on Therapy for Ascites

• Furosemide can be added in those failing to respond to spironolactone alone
• Weight loss below 2 kg in one week of using spironolactone alone would typically indicate the need for an add-on therapy to increase efficacy.
• Beginning dose is 20 mg twice daily and can increase every few days by 40mg/day up to maximum dose of 160mg(twice daily).

Hepatic Encephalopathy (HE)

• A neuropsychiatric syndrome caused by liver disease.
• Symptoms include confusion, memory loss, personality changes, and coma.

HE Management Techniques

• Treat any underlying causes.
• Reduce or avoid protein intake.
• Reduce ammonia production in the gut.
• Treat with lactulose (15-30 mL every 8 hours) or other drugs such as metronidazole, rifaximin, or neomycin to reduce ammonia in the blood.
• Zinc replacement may also improve these symptoms.

Evaluation of Therapeutic Outcomes

• Assess ascites by monitoring weight
• Detect signs of SBP development
• Examine signs of clinical deterioration in patients (e.g., fever, abdominal pain, anorexia, malaise, fatigue)
• Evaluate cirrhosis severity and overt variceal bleeding response to treatment.
• Assess hepatic encephalopathy severity using EEG, psychological testing, and mental status evaluation, also considering concurrent drug therapy.

Outcome Assessment

• Preventing and eliminating ascites and its consequences.
• Preventing or treating SBP to decrease mortality.
• Managing variceal bleeding for decreased mortality.
• Appropriate methods to control portal pressure in acute or chronic variceal bleeding cases.
• Maintaining hepatic function, reducing hospitalizations in those with hepatic encephalopathy, decreasing ammonia levels, and offering adequate nutrition.

Further Reading:

• References to specific publications provide options for further research related to cirrhosis management.

This quiz focuses on the pharmacotherapy of gastrointestinal disorders, particularly cirrhosis and portal hypertension. It covers the causes, complications, and physiological effects of these conditions on the liver. Test your knowledge on the management and therapeutic approaches related to these serious health issues.