Cirrhosis

Pathophysiology

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
Results in increased Portal Hypertension

Epidemiology

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

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

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

Causes
Common

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
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
Nonalcoholic Fatty Liver Disease (NASH)
1. Increasing Prevalence and is trending to become the most common cause of liver transplant by 2035
Primary Biliary Cirrhosis
Hemochromatosis (5-10%)
Biliary obstruction (5-10%)
1. Congenital: Biliary atresia, biliary cysts
2. Cystic Fibrosis

Causes
Less Common

See Hepatotoxin (e.g. Amiodaron, Methotrexate)
Autoimmune Chronic Hepatitis
Venoocclusive Disease (Budd-Chiari Syndrome)
Genetic Disorders
Congestive Heart Failure
Sarcoidosis
Infections

Symptoms

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

Signs

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

Labs
Initial

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)
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
Electrolytes
1. Hyponatremia
2. Hypokalemic alkalosis
3. Glucose disturbance

Labs
Elucidate Cirrhosis Causes

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

Labs
Noninvasive Staging of Hepatic Fibrosis

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 C Virus 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)
Fibrosis 4 Score
1. See Fibrosis Probability Score (Fib-4 Score)
2. Score <1.45: Good Negative Predictive Value (80% for Hepatitis C Virus related fibrosis)
3. Score >3.25 (>2.67 in NAFLD): Positive Predictive Value >80%
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%
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
Direct Serum Markers
1. Procollagen (Types 1, 3, 4)
2. Matrix metalloproteinases
3. Cytokines
4. Chemokines

Imaging

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
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
Advanced imaging: CT Scan or MRI of liver
1. Poor sensitivity for early Cirrhosis
2. Identifies Nodules, lobar atrophy

Diagnostics

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
Portal Venography
Wedged hepatic vein pressure management

Staging

See Child-Pugh Score
See MELD Score
See Metavir Scoring System

Evaluation
Complication Screening

Endoscopic screen for Esophageal Varices q1-2 years
Hepatocellular Carcinoma screening
1. Serum Alpha-fetoprotein every six months
2. Liver Ultrasound every 6 to 12 months

Evaluation
Coagulation abnormalities

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)
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]
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
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

See Prevention of Liver Disease Progression
Vaccination
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
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)
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
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)
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. 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
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

Management
Peri-operative risk assessment

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
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

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)
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
Availability
1. Candidates: 18,000 per year for 4000 available livers
2. Wait time for liver Transplantation: 2-3 years
Efficacy
1. One year survival: 85%
2. Five year survival: 75%
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

Portal Hypertension
1. Esophageal Varices with bleeding
2. Hemorrhagic Gastritis
Cirrhotic Ascites
Spontaneous Bacterial Peritonitis
Hepatic Encephalopathy
Liver Failure
Coagulation Abnormalities
Hepatorenal Syndrome
Hepatocellular Carcinoma (Relative Risk: 22.9)
Cholelithiasis
Pericardial Effusion
Hyposplenism
Osteoporosis
Abdominal Wall Hernia

Prognosis
Advanced Cirrhosis

See Child-Pugh Score
See Model for End-Stage Liver Disease (MELD Score)
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)
Overall mortality
1. Two year mortality: 50%
2. Five year mortality: 65%
Factors associated with worse prognosis
1. Unfavorable signs
2. Additional Risk factors for worse prognosis
  1. Black race
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