Cirrhosis

Aka: Cirrhosis, Laennec's Cirrhosis, Portal Cirrhosis, Liver Fibrosis, Hepatic Fibrosis, Chronic Liver Failure

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II. Pathophysiology

  1. Irreversible liver injury and inflammation leads to Hepatic Fibrosis and altered hepatic architecture
    1. Diffuse fibrotic bands
    2. Nodular regeneration (Micronodular and Macronodular)
    3. Decreased hepatic metabolic and synthetic function
      1. Decreased Clotting Factors and Thrombocytopenia
      2. Increased Bilirubin
  2. Results in increased Portal Hypertension
    1. See Portal Hypertension
    2. Cirrhotic Ascites
    3. Esophageal Varices

III. Epidemiology

  1. Twelvth leading cause of death in United States
    1. Cirrhosis deaths: 12.8 per 100,000 U.S. population
  2. Alcohol was previously most common cause of Cirrhosis in U.S., but has been surpassed by Viral Hepatitis (esp. Hepatitis C)
  3. Genetic predisposition
  4. Incidence greatest in middle aged males
  5. More common in non-hispanic black and mexican americans in U.S.

IV. Risk Factors: Progression from Hepatitis to Cirrhosis (Alcohol, Viral Hepatitis, NAFLD)

  1. Advanced Age
  2. Medical Comorbidities (esp. comorbid HIV and Hepatitis C)
  3. Male gender (except for women in Alcoholic Hepatitis, who may rapidly progress to Cirrhosis)

V. Causes: Common

  1. Viral Hepatitis (most common cause of Cirrhosis)
    1. Hepatitis B (and Hepatitis D)
      1. Progresses to Cirrhosis in 20-30% of cases
    2. Hepatitis C
      1. Leading cause of Cirrhosis in U.S.
      2. Progresses to Cirrhosis in 5-20% of cases
  2. Alcohol Abuse (20%)
    1. Surpassed by Viral Hepatitis (esp. Hepatitis C) as most common cause of Cirrhosis
    2. Progresses from Alcoholic Steatosis to Alcoholic Hepatitis
    3. Ultimately results in hepatocellular necrosis and Cirrhosis
  3. Nonalcoholic Fatty Liver Disease (NASH)
    1. Increasing Prevalence and is trending to become the most common cause of Liver Transplant by 2035
    2. Associated with Type 2 Diabetes Mellitus, Metabolic Syndrome and Obesity
  4. Primary Biliary Cirrhosis
  5. Hemochromatosis (5-10%)
  6. Biliary obstruction (5-10%)
    1. Congenital: Biliary atresia, biliary cysts
    2. Cystic Fibrosis

VI. Causes: Less Common

  1. See Hepatotoxin (e.g. Amiodaron, Methotrexate)
  2. Autoimmune Chronic Hepatitis
  3. Hepatic venous outflow tract obstruction (Budd-Chiari Syndrome)
  4. Hepatic sinusoidal obstruction syndrome (Venoocclusive Disease)
  5. Primary Sclerosing Cholangitis
    1. Associated with Inflammatory Bowel Disease
  6. Genetic Disorders
    1. Wilson's Disease
    2. Alpha-1-Antitrypsin Deficiency
    3. Inborn Errors of Metabolism
      1. Glycogen Storage Disease
      2. Galactosemia
  7. Congestive Heart Failure
  8. Sarcoidosis
  9. Infections
    1. Brucellosis
    2. Tertiary Syphilis
    3. Echinococcosis
    4. Schistosomiasis

VII. Symptoms

  1. Often asymptomatic in compensated Cirrhosis
  2. General
    1. Weakness
    2. Fatigue
    3. Weight loss
    4. Anorexia and decreased appetite
  3. Gastrointestinal
    1. Nausea and Vomiting
    2. Diarrhea
  4. Endocrine
    1. Loss of libido
    2. Gynecomastia
    3. Impotence
    4. Infertility
    5. Amenorrhea

VIII. Signs

  1. Eyes
    1. Scleral Icterus
    2. Kayser-Fleischer Ring (Wilson's Disease)
  2. HEENT
    1. Sublingual juandice
    2. Parotid hypertrophy
  3. Chest
    1. Gynecomastia
    2. Pleural Effusion
  4. 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
  5. 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. Digital Clubbing
    7. Loss of Axillary and pubic hair
  6. Musculoskeletal
    1. Lower Extremity Edema
    2. Dupuytren's Contracture
    3. Muscle Wasting
  7. Neurologic
    1. Asterixis (hand Tremor into wrist extension)
    2. Tremor
    3. Altered Mental Status (drowsy, confusion, Delirium to coma)
  8. Genitourinary
    1. Testicular atrophy
  9. Other
    1. Fetor hepaticus (sweet, pungent breath odor due to dimethyl sulfide)

IX. Labs: Initial

  1. 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)
  2. Liver Function Tests
    1. See Liver Function Test Abnormality
    2. Prolonged Prothrombin Time (INR)
    3. Hypoalbuminemia (Serum Albumin <3.5 g/L)
    4. Bilirubin elevated
    5. Alkaline Phosphatase elevated
    6. Gamma-Glutamyltransferase (GGT) increased
    7. Alanine transaminase (ALT)
    8. Aspartate transaminase (ALT)
      1. Most cost effective screening for Cirrhosis
  3. Electrolytes
    1. Hyponatremia
    2. Hypokalemic alkalosis
    3. Glucose disturbance

X. Labs: Evaluate Cirrhosis Causes

  1. Review Hepatotoxin exposure history
    1. Alcohol Abuse
    2. Hepatotoxic Medications
  2. Viral Hepatitis Studies
    1. HBsAg
    2. xHBc IgM
    3. xHBs IgG
    4. xHCV IgG
    5. xHDV IgG
  3. Non-Alcoholic Fatty Liver Risk Factors (NAFLD)
    1. Fasting Lipid Panel
    2. Hemoglobin A1C
  4. Iron Studies (Rule out Hemochromatosis)
    1. Serum Iron
    2. Total Iron Binding Capacity (TIBC)
    3. Ferritin
  5. Autoimmune factors
    1. Antimitochondrial Antibody
    2. Smooth Muscle Antibody
    3. Antinuclear Antibody (ANA)
  6. Miscellaneous Cause evaluation
    1. Ceruloplasmin (Wilson's Disease)
    2. Alpha-1-Antitrypsin

XI. Labs: Noninvasive Staging of Hepatic Fibrosis

  1. AST to Platelet Ratio Index Score
    1. Predicts low risk OR high risk of fibrosis, but does NOT differentiate intermediate risk
    2. Score <0.5 U/L: Good Negative Predictive Value (80% for Hepatitis CVirus related fibrosis)
    3. Score >0.7 U/L: Test Sensitivity 77%, Test Specificity 72% for F2 Fibrosis
    4. SCore >1.0 U/L: Test Sensitivity 61-76%, Test Specificity 64-72% for F3-4 Fibrosis
    5. Score >2.0 U/L: Test Specificity for Cirrhosis 91% (but only 46% Test Sensitivity)
  2. Fibrosis 4 Score
    1. See Fibrosis Probability Score (Fib-4 Score)
    2. Score <1.45: Good Negative Predictive Value (80% for Hepatitis CVirus related fibrosis)
    3. Score >3.25 (>2.67 in NAFLD): Positive Predictive Value >80%
  3. FibroSure (Combines FibroTest and Actitest)
    1. Score <0.30: Good Negative Predictive Value (90% for NAFLD related fibrosis)
    2. Score >0.70 (>0.48 in Viral Hepatitis): Positive Predictive Value >80%
  4. NAFLD Fibrosis Score
    1. Score <-1.455 has 88% Negative Predictive Value for advanced fibrosis in NAFLD
    2. Score >0.676 has 82% Positive Predictive Value for advanced fibrosis in NAFLD
  5. Direct Serum Markers
    1. Procollagen (Types 1, 3, 4)
    2. Matrix metalloproteinases
    3. Cytokines
    4. Chemokines

XII. Imaging

  1. Abdominal Ultrasound with Doppler
    1. Preferred first line imaging (preferred over CT)
    2. Efficacy
      1. Steatosis (94% Test Sensitivity, 84% Test Specificity)
      2. Fibrosis or Cirrhosis (<57% Test Sensitivity)
    3. General findings suggestive of Cirrhosis
      1. Liver nodularity, irregularity
      2. Increased echogenicity
      3. Liver Atrophy
    4. Findings suggestive of advanced disease and Portal Hypertension
      1. Liver small and nodular
      2. Ascites
      3. Decreased portal circulation by doppler flow
      4. Portosystemic collateral vessels
      5. Splenomegaly
    5. Repeat Ultrasound every 6 months in Cirrhosis and Hepatitis C
      1. Evaluate for Hepatocellular Carcinoma
  2. Transient Elastography (via Ultrasound Fibroscan)
    1. Office based point-of-care procedure performed in 5 minutes
    2. Liver stiffness evaluated in kilopascals via measured velocity of low frequency elastic shear waves through liver
    3. Efficacy
      1. Score >12.5 kPa has Test Sensitivity 87% and Test Specificity 91% for Cirrhosis
      2. Negative Predictive Value >90%
      3. Test Sensitivity: 81%
      4. Test Specificity: 88%
      5. False Positives in Bone Marrow disease, Hemolysis, medications
      6. Less accurate in obese patients, excessive Alcohol, extrahepatic cholestasis
  3. Advanced imaging: CT Scan or MRI of liver
    1. Poor sensitivity for early Cirrhosis
    2. Identifies Nodules, lobar atrophy

XIII. 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%
    5. However error rate in fibrosis staging still occurs in 20% of cases
  2. Portal Venography
  3. Wedged hepatic vein pressure management

XIV. Staging

  1. See Child-Pugh Score
  2. See MELD Score
  3. See Metavir Scoring System

XV. Evaluation: Complication Screening

  1. Endoscopic screen for Esophageal Varices every 1 to 2 years
  2. Hepatocellular Carcinoma screening
    1. Serum Alpha-fetoprotein every six months
    2. Liver Ultrasound every 6 to 12 months

XVI. 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]

XVII. 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. Acetaminophen is safe (max 2000 mg total per day)
    3. Avoid Alcohol
      1. In Alcohol cessation, avoid Naltrexone and acomprosate in Child-Pugh Grade C Cirrhosis or worse
      2. Baclofen 5-10 mg three times daily is safe at any stage of liver disease
    4. Avoid NSAIDS
      1. Risk of Upper GI Bleeding
      2. Risk of Renal Failure
    5. Avoid raw fish consumption and brackish or salt water exposure
      1. Risk of Vibrio vulnificus infection
    6. Avoid unpasteurized dairy
      1. Risk of Listeria infection
  4. Review medications needing adjustment in Child-Pugh Class B and C (moderate to severe Cirrhosis)
    1. Drugs primarily metabolized by the liver
    2. Highly Protein bound medications (increased effects in hypoalbuminemia)
  5. Maintain adequate nutrition
    1. Optimize Diabetes Mellitus management
    2. Weight loss of 10% is recommended if obese with NAFLD
    3. Limit Sodium intake to <2 grams per day
    4. Frequent, high calorie meals and bedtime snack
    5. Check fat soluble Vitamins and zinc
    6. Adequate Protein
      1. Early Cirrhosis: 1 to 1.5 grams/kg/day
      2. Advanced Cirrhosis: 1 gram/kg/day
  6. 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)
  7. 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
        2. Targeted screening of those with findings suggestive of Portal Hypertension is replacing general screening
      4. Compensated Cirrhosis with small Varices
        1. Upper endoscopy screening for Varices every 1-2 years
    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. Hyponatremia (Serum Sodium <130 mEq/L)
      1. Chronic Hyponatremia
        1. Chronic Hyponatremia is present in 25% of Cirrhosis
        2. Asymptomatic in most patients and typically does not require treatment
        3. Results from splanchnic vasodilation with renin-Angiotensin activation
          1. Antidiuretic Hormone released with secondary free water retention
          2. Typically Hypervolemic Hypoosmolar Hyponatremia (see below)
      2. Acute Hyponatremia
        1. See Hyponatremia Management
        2. Hypovolemic Hypoosmolar Hyponatremia (most common acutely)
          1. Stop Diuretics
          2. Gentle rehydration with Intravenous Fluid
        3. Hypervolemic Hypoosmolar Hyponatremia (typically chronic)
          1. Free water restriction limited to 1 to 1.5 Liters daily
          2. Avoid rapid correction outside severe acute Hyponatremia
          3. Consider albumin infusion
    6. Hepatocellular Carcinoma screening
      1. Ultrasound liver every 6-12 months
      2. Also consider alpha fetoprotein test every 6-12 months
    7. Coagulopathy
      1. Results from impaired hepatocyte synthetic function of both Anticoagulant and procoagulant factors
      2. Elevated INR (aside from Warfarin use) does not reflect bleeding or Hypercoagulable risk in Cirrhosis
        1. Do NOT correct INR with FFP or PCC prior to procedures in patients not on Warfarin
        2. Increased INR without Warfarin does not protect against Venous Thromboembolism
  8. Comorbid conditions and symptoms
    1. Leg Cramps are common (esp. with Diuretic use)
      1. Monitor serum Electrolytes
      2. Baclofen 5-10 mg up to three times daily
    2. Major Depression
      1. SSRI medications appear safe in Cirrhosis

XVIII. 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]

XIX. Management: Liver Transplant

  1. See Liver Transplant (includes Liver Transplant Center Referral Indications)

XX. 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 (hepatic hydrothorax)
    1. Most common on right side
  11. Hyposplenism
  12. Osteoporosis
  13. Abdominal Wall Hernia
  14. Hyponatremia

XXI. Prognosis: Advanced Cirrhosis

  1. See Child-Pugh Score
  2. See Model for End-Stage Liver Disease (MELD Score)
  3. Progression from compensated to decompensated Cirrhosis (e.g. Ascites, encephalopathy)
    1. Ranges from 4-10% per year (variable depending on cause, treatment, ongoing liver injury)
    2. Compensated Cirrhosis is associated with a 12 year median survival (contrast with 2 years once decompensated)
  4. Overall mortality
    1. Two year mortality: 50%
    2. Five year mortality: 65%
  5. Factors associated with worse prognosis
    1. Unfavorable signs
      1. Hematemesis
      2. Jaundice
      3. Ascites
    2. Additional Risk factors for worse prognosis
      1. Black race
  6. 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]

XXII. References

  1. Swencki (2015) Crit Dec Emerg Med 29(11):2-10
  2. Swencki (2023) Crit Dec Emerg Med 37(8):4-12
  3. Habib (2001) Postgrad Med 109(3):101-13 [PubMed]
  4. Heidelbaugh (2006) Am Fam Physician 74(5):756-76 [PubMed]
  5. Maness (2021) Am Fam Physician 104(6): 626-35 [PubMed]
  6. Mcguire (1998) Postgrad Med 103(2):209-224 [PubMed]
  7. Menon (2000) Mayo Clin Proc 75(5):501-9 [PubMed]
  8. Riley (2001) Am Fam Physician 64(10):1735-40 [PubMed]
  9. Smith (2019) Am Fam Physician 100(12):759-70 [PubMed]
  10. Starr (2011) Am Fam Physician 84(12): 1353-9 [PubMed]

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