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Cirrhosis

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Cirrhosis, Laennec's Cirrhosis, Portal Cirrhosis

  • Pathophysiology
  1. Irreversible liver inflammation
    1. Diffuse fibrotic bands
    2. Nodular regeneration (Micronodular and Macronodular)
  2. Results in increased Portal Vein pressure
    1. See Portal Hypertension
  • Epidemiology
  1. Fifth leading cause of death in United States
    1. Cirrhosis deaths: 8.8 per 100,000 U.S. population
  2. Alcohol most common cause
    1. Cirrhosis occurs in 25% of Alcoholics
  3. Genetic predisposition
  4. Incidence greatest in middle aged males
  • Causes
  • Common
  1. Alcohol Abuse (60-70%)
    1. Progresses from Alcoholic Steatosis to Alcoholic Hepatitis
    2. Ultimately results in hepatocellular necrosis and Cirrhosis
  2. Viral Hepatitis (10%)
    1. Hepatitis B (and Hepatitis D)
      1. Progresses to Cirrhosis in 20-30% of cases
    2. Hepatitis C
  3. Primary Biliary Cirrhosis
  4. Hemochromatosis (5-10%)
  5. Biliary obstruction (5-10%)
    1. Congenital: Biliary atresia, biliary cysts
    2. Cystic Fibrosis
  6. Nonalcoholic Fatty Liver Disease (NASH)
  • Causes
  • Less common
  1. See Hepatotoxin (e.g. Methotrexate)
  2. Autoimmune Chronic Hepatitis
  3. Venoocclusive Disease (Budd-Chiari Syndrome)
  4. Genetic Disorders
    1. Wilson's Disease
    2. Alpha-1-Antitrypsin Deficiency
    3. Inborn Errors of Metabolism
      1. Glycogen Storage Disease
      2. Galactosemia
  5. Congestive Heart Failure
  6. Sarcoidosis
  7. Infections
    1. Brucellosis
    2. Tertiary Syphilis
    3. Echinococcosis
    4. Schistosomiasis
  • Symptoms
  1. General
    1. Weakness
    2. Fatigue
    3. Weight loss
    4. Anorexia
  2. Gastrointestinal
    1. Nausea and Vomiting
    2. Diarrhea
  3. Endocrine
    1. Loss of libido
    2. Gynecomastia
    3. Impotence
    4. Infertility
    5. Amenorrhea
  • Signs
  1. Eyes
    1. Scleral Icterus
    2. Kayser-Fleischer Ring (Wilson's Disease)
  2. Chest
    1. Gynecomastia
    2. Pleural Effusion
  3. Abdomen
    1. Liver span
      1. Initial: Hepatomegaly
        1. Large firm, nontender palpable liver
      2. Later: Liver shrinks in size
    2. Splenomegaly
    3. Ascites
    4. Testicular atrophy
  4. Skin
    1. Jaundice
    2. Purpura
    3. Palmar erythema
    4. Spider nevi or Caput Medusa
      1. Superficial veins dilate on Abdomen and chest
    5. Telangiectases
    6. Nail changes
      1. Muehrcke's Lines
      2. Terry's Nails
      3. Clubbing
    7. Loss of Axillary and pubic hair
  5. Musculoskeletal
    1. Lower extremity edema
    2. Dupuytren's Contracture
  6. Neurologic
    1. Asterixis
    2. Tremor
    3. Delirium
    4. Coma
  7. Genitourinary
    1. Testicular atrophy
  8. Other
    1. Fetor hepaticus (sweet, pungent breath odor)
  • Labs
  • Initial
  1. See Liver Function Test Abnormality
  2. Complete Blood Count (CBC)
    1. Microcytic Anemia from blood loss
    2. Macrocytic Anemia from Folate Deficiency
    3. Pancytopenia from hypersplenism
    4. Thrombocytopenia (<160,000 sensitive for Cirrhosis)
  3. Liver Function Tests
    1. Prolonged Prothrombin Time (INR)
    2. Hypoalbuminemia
    3. Bilirubin elevated
    4. Alkaline Phosphatase elevated
    5. Gamma-Glutamyltransferase (GGT) increased
    6. Alanine transaminase (ALT)
    7. Aspartate transaminase (ALT)
      1. Most cost effective screening for Cirrhosis
  4. Electrolytes
    1. Hyponatremia
    2. Hypokalemic alkalosis
    3. Glucose disturbance
  • Labs
  • Elucidate Cirrhosis Causes
  1. Viral Hepatitis Studies
    1. HBsAg
    2. xHBc IgM
    3. xHBs IgG
    4. xHCV IgG
    5. xHDV IgG
  2. Iron Studies (Rule out Hemochromatosis)
    1. Serum Iron
    2. Total Iron Binding Capacity (TIBC)
    3. Ferritin
  3. Autoimmune factors
    1. Antimitochondrial Antibody
    2. Smooth Muscle Antibody
    3. Antinuclear Antibody (ANA)
  4. Miscellaneous Cause evaluation
    1. Ceruloplasmin (Wilson's Disease)
    2. Alpha-1-Antitrypsin
  • Imaging
  1. Abdominal Ultrasound with Doppler
    1. Preferred first line imaging (preferred over CT)
    2. General findings suggestive of Cirrhosis
      1. Liver nodularity, irregularity
      2. Increased echogenicity
      3. Liver Atrophy
    3. Findings suggestive of advanced disease
      1. Liver small and nodular
      2. Ascites
      3. Decreased portal circulation by doppler flow
  2. Advanced imaging: CT Scan or MRI of liver
    1. Poor sensitivity for early Cirrhosis
    2. Identifies Nodules, lobar atrophy
  • Diagnostics
  1. Liver Biopsy
    1. Indicated where no cause on noninvasive evaluation
    2. Contraindicated in severe Coagulopathy
      1. Check CBC with platelets, INR before proecdure
      2. No NSAIDs or Aspirin for 7-10 days before procedure
    3. Benefit outweighs risk: Diagnosis improves course
    4. Test Sensitivity and Specificity: 80-100%
  2. Portal Venography
  3. Wedged hepatic vein pressure management
  • Evaluation
  • Complication Screening
  1. Endoscopic screen for Esophageal Varices q1-2 years
  2. Hepatocellular Carcinoma screening
    1. Serum Alpha-fetoprotein every six months
    2. Liver Ultrasound every 6 to 12 months
  • Evaluation
  • Coagulation abnormalities
  1. Pathophysiology
    1. End-stage liver disease patients have mixed Coagulation Disorders (both hypocoagulable and Hypercoagulable)
    2. Liver failure results in deficiency of pro-coagulant factors (increasing risk of bleeding)
      1. Procoagulant Factors: I (Fibrinogen), II (prothrombin), V, IX, X (thrombin) and XI
      2. Increased risk of Gastrointestinal Bleeding (especially Variceal Bleeding)
    3. Liver failure also results in deficiency of Anticoagulant factors (increasing risk of clotting)
      1. Anticoagulant Factors: Protein C, protein S and Antithrombin
      2. Increased risk of Portal Vein Thrombosis, Deep Vein Thrombosis
    4. INR is a poor marker for bleeding risk in liver failure
      1. INR is specific for Warfarin which affects all Vitamin K dependent factors (II, VII, IX and X) equally
      2. Liver failure, in contrast, affects both procoagulants and Anticoagulants inconsistently
    5. More accurate markers of bleeding risk in liver failure
      1. Fibrinogen
      2. Thromboelastogram (limited availability)
  2. Active bleeding management
    1. Replace blood losses with Packed Red Blood Cells
      1. Aim for systolic Blood Pressure >90 mmHg (permissive Hypotension)
      2. Exercise caution with blood replacement in Variceal Bleeding
        1. May increase bleeding due to increased pressure
        2. Villanueva (2013) N Engl J Med 368(1):11-21 [PubMed]
    2. Manage bleeding source (e.g. Variceal Bleeding)
    3. Reversal of Coagulopathy is based on expert opinion only
      1. Increased INR reversed with PCC4 or FFP is commonly used but may not alter bleeding risk
      2. Cryoprecipitate indications
        1. Fibrinogen <150 mg/dl
        2. Fibrinogen increases 100 mg/dl with 10 units of Cryoprecipitate
      3. Platelet indications
        1. Platelet Count <50,000
    4. Invasive procedures
      1. Bleeding complications are most reduced when procedure is performed by most skilled provider
        1. In contrast to risk based on degree of Coagulopathy
        2. Deloughery (1996) Transfusion 36(9): 827-31 [PubMed]
  3. Anticoagulation
    1. Consult hepatology and adjust regimen for severe liver disease (e.g. Child-Pugh C), Esophageal Varices
    2. Decreasing portal pressure (e.g. Beta Blockers) may reduce bleeding risk on Anticoagulation
    3. Warfarin may be used if baseline INR (before Warfarin) is <1.7
    4. Direct Oral Anticoagulants or DOACS (e.g. Apixaban) may be used in Child-Pugh A, and some Child-Pugh B cases
  4. References
    1. Orman and Deloughery in Herbert (2014) EM:Rap 14(4): 1
    2. Tripodi (2011) N Engl J Med 365(2): 147-56 [PubMed]
  • Management
  1. See Prevention of Liver Disease Progression
  2. Vaccination
    1. Hepatitis A Vaccine
    2. Hepatitis B Vaccine
    3. Annual Influenza Vaccine
    4. Polyvalent pneumococcal Vaccine
  3. Avoid exacerbating medications and substances
    1. See Hepatotoxic Medications
    2. Avoid Alcohol
    3. Avoid NSAIDS
      1. Risk of Upper GI Bleeding
      2. Risk of Renal Failure
  4. Maintain adequate nutrition
    1. Limit Sodium intake to <2 grams per day
    2. Frequent, high calorie meals and bedtime snack
    3. Check fat soluble Vitamins and zinc
    4. Adequate protein
      1. Early Cirrhosis: 1 to 1.5 grams/kg/day
      2. Advanced Cirrhosis: 1 gram/kg/day
  5. Previously tried to treat Cirrhosis (most ineffective)
    1. Penicillamine (inhibits collagen cross-links)
    2. Propylthiouracil (reduces hepatic hypermetabolism)
    3. Interferon alpha (inhibits liver fibrogenic activity)
  6. Manage complications specifically
    1. See Esophageal Varices
      1. Acute bleeding from Esophageal Varices
        1. ICU Admission with acute stabilization (pRBC, Somatostatin)
      2. Compensated Cirrhosis with large Varices
        1. Non-selective Beta Blocker (Propranolol, Nadolol)
        2. Consider endoscopic variceal ligation
      3. Compensated Cirrhosis with no Varices
        1. Upper endoscopy screening for Varices q2-3 years
      4. Compensated Cirrhosis with small Varices
        1. Upper endoscopy screening for Varices yearly
    2. See Cirrhotic Ascites
      1. Salt restriction and Diuretics
      2. Paracentesis (Treat if subacute Bacterial peritonitis identified)
    3. See Spontaneous Bacterial Peritonitis
    4. See Hepatic Encephalopathy
      1. Disaccharides or Rifaximin (Xifaxan)
      2. Do not drive
      3. Paracentesis (Treat if subacute Bacterial peritonitis identified)
    5. Acute Hyponatremia
      1. See Hypervolemic Hypoosmolar Hyponatremia
      2. Results from splanchnic vasodilation with renin-Angiotensin activation
        1. Antidiuretic hormone released with secondary free water retention
      3. Management
        1. See Hyponatremia Management
        2. Free water restriction limited to 1 to 1.5 Liters daily
        3. Avoid rapid correction outside severe acute Hyponatremia
    6. Hepatocellular Carcinoma screening
      1. Ultrasound liver every 6-12 months
      2. Also consider alpha fetoprotein test every 6-12 months
  7. Comorbid conditions and symptoms
    1. Muscle cramps are common
      1. Quinine Sulfate 260 mg at bedtime was historically used
        1. As with other historical indications, efficacy and evidence are likely lacking
    2. Major Depression
      1. SSRI medications appear safe
  • Management
  • Peri-operative risk assessment
  1. Peri-operative risk factors
    1. High Child-Pugh Score (see below)
    2. Cirrhotic Ascites
    3. Increased Serum Creatinine
    4. Cirrhosis cause other than primary biliary Cirrhosis
    5. History of Upper Gastrointestinal Bleeding
  2. Abdominal surgery risk associated with Child-Pugh Score
    1. Child-Pugh Class A: 10% peri-operative mortality
    2. Child-Pugh Class B: 30% peri-operative mortality
    3. Child-Pugh Class C: 82% peri-operative mortality
    4. Mansour (1997) Surgery 122:730-5 [PubMed]
  • Management
  • Liver Transplantation
  1. Indications for evaluation
    1. MELD Score >15 (or significant complications)
    2. Fulminant Liver Failure
    3. Decompensated Cirrhosis
      1. Hepatorenal Syndrome
      2. Cirrhotic Ascites
      3. Child-Pugh Stage B
    4. Hepatocellular Carcinoma
      1. No single lesion >5 cm
      2. No more than 3 lesions (largest 3 cm or less)
  2. Contraindications
    1. Hepatocellular Carcinoma >5 cm
    2. Other active malignancy
    3. Active Alcohol Abuse or other Substance Abuse
    4. Chronic infection
    5. Advanced cardiopulmonary disease
  3. Availability
    1. Candidates: 18,000 per year for 4000 available livers
    2. Wait time for liver transplantation: 2-3 years
  4. Efficacy
    1. One year survival: 85%
    2. Five year survival: 75%
  5. Post-transplant care
    1. Expect on average up to 2 emergency department visits post-transplant (with 70% admission rate)
    2. Typical post-transplant ED presentations are related to gastrointestinal or infectious symptoms
  • Complications
  1. Portal Hypertension
    1. Esophageal Varices with bleeding
    2. Hemorrhagic Gastritis
  2. Cirrhotic Ascites
  3. Spontaneous Bacterial Peritonitis
  4. Hepatic Encephalopathy
  5. Liver Failure
  6. Coagulation Abnormalities
  7. Hepatorenal Syndrome
  8. Hepatocellular Carcinoma (Relative Risk: 22.9)
  9. Cholelithiasis
  10. Pericardial Effusion
  11. Hyposplenism
  12. Osteoporosis
  • Prognosis
  • Advanced Cirrhosis
  1. See Child-Pugh Score
  2. See Model for End-Stage Liver Disease (MELD Score)
  3. Overall mortality
    1. Two year mortality: 50%
    2. Five year mortality: 65%
  4. Factors associated with worse prognosis
    1. Unfavorable signs
      1. Hematemesis
      2. Jaundice
      3. Ascites
    2. Additional Risk factors for worse prognosis
      1. Black race
  5. Mortality in 90 days based on MELD Score
    1. MELD Score >40: 71.3%
    2. MELD Score 30-39: 52.6%
    3. MELD Score 20-29: 19.6%
    4. MELD Score 10-19: 6.0%
    5. MELD Score <9: 1.9%
    6. Kamath (2001) Hepatology 33(2): 464-70 [PubMed]
  • References
  1. Swencki (2015) Crit Dec Emerg Med 29(11):2-10
  2. Habib (2001) Postgrad Med 109(3):101-13 [PubMed]
  3. Heidelbaugh (2006) Am Fam Physician 74(5):756-76 [PubMed]
  4. Mcguire (1998) Postgrad Med 103(2):209-224 [PubMed]
  5. Menon (2000) Mayo Clin Proc 75(5):501-9 [PubMed]
  6. Riley (2001) Am Fam Physician 64(10):1735-40 [PubMed]
  7. Starr (2011) Am Fam Physician 84(12): 1353-9 [PubMed]