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Evaluation of Liver Function

Part 10: Disorders of the Gastrointestinal System · Part 10 – Gastrointestinal Disorders · Chapter 348

Key Clinical Points

  1. Liver function tests (LFTs) are a battery of tests (bilirubin, AST/ALT, Alk Phos, albumin, PT) used to detect disease, distinguish types of liver disorders, and gauge damage.
  2. No single biochemical test can accurately assess the liver's total functional capacity; they must be interpreted as a battery.
  3. Conjugated hyperbilirubinemia (direct fraction ≥15%) almost always implies liver or biliary tract disease.
  4. AST:ALT ratio >2:1 is suggestive of alcohol-related liver disease; >3:1 is highly suggestive.
  5. Alkaline Phosphatase (Alk Phos) elevation >4x normal suggests cholestatic, infiltrative, or bone conditions.
  6. Prothrombin time is the single best acute measure of hepatic synthetic function due to short half-lives of clotting factors.
  7. Child-Pugh score ≥7 indicates decompensated liver disease (Class B or C).
  8. MELD Score uses INR, serum bilirubin, and serum creatinine to predict mortality and prioritize liver transplants.
  9. Noninvasive fibrosis tests include FibroTest, ELF, FIB4, TE (FibroScan), and MRE.
  10. All patients with liver disease should receive Hepatitis A and B vaccinations.

DEFINITION & OVERVIEW

• Liver Function Tests (LFTs): Serum biochemical tests used to detect liver disease, distinguish types of disorders, gauge damage extent, and monitor treatment response. ◦ Components: include biochemical, radiologic, and pathologic tests. ◦ Limitations: Lack specific sensitivity/specificity; can be normal in severe disease or abnormal in non-hepatic conditions. ◦ Clinical Utility: They do not measure total functional capacity but indicate categories (e.g., hepatocellular vs. cholestatic). ◦ Assessment Strategy: Use as a battery; multiple abnormal findings or persistent abnormalities increase the probability of liver disease. ◦ Reliability: If all results are normal, the probability of missing occult liver disease is low.

• Child-Pugh Classification: Used to assess the severity of cirrhosis and predict outcomes. ◦ Score 5–6: Class A ◦ Score 7–9: Class B ◦ Score 10–15: Class C ◦ Decompensation: Defined as Child-Pugh score ≥7.

• MELD Score: Used to predict short-term mortality and for liver transplant prioritization. ◦ Components: INR, serum bilirubin, and serum creatinine.

Table 347-6: Child-Pugh Classification of Cirrhosis

• Serum Bilirubin: <2.0 mg/dL (1); 2.0–3.0 (2); >3.0 (3) [μmol/L: <34 (1); 34–51 (2); >51 (3)] • Serum Albumin: <30 g/L (1); 30–35 (2); >35 (3) • Prothrombin Time: <4 s (1); 4–6 (2); >6 (3) OR INR <1.7 (1); 1.7–2.3 (2); >2.3 (3) • Hepatic Encephalopathy: None (1); Minimal (2); Advanced (3)

ETIOLOGY & PATHOPHYYSOLOGY

• Bilirubin Metabolism: ◦ Conjugated (direct) vs. Unconjugated (indirect). ◦ Unconjugated: Insoluble in water, bound to albumin; rarely elevated in liver disease. ◦ Conjugated: Water-soluble; elevation almost always implies liver or biliary tract disease. ◦ Thresholds: → If direct fraction is <15%, bilirubin is considered all indirect. → Isolated unconjugated hyperbilirubinemia (less than 15% direct) suggests hemolysis or genetic conditions (Crigler-Najjar, Gilbert's). ◦ Urine Bilirubin: Any bilirubin in urine is conjugated; presence of bilirubinuria implies liver disease or obstructive jaundice.

• Aminotransferases (AST/ALT): ◦ Reflect damage to hepatocytes (increased membrane permeability). ◦ Correlation: Poor correlation between degree of damage and absolute level; not useful for prognosis in acute disorders. ◦ Specificity: → <300 IU/L: Non-specific, found in many liver disorders. → >1000 IU/L: Suggests extensive injury (viral hepatitis, ischemic injury, toxin/drug-induced). → Obstructive Jaundice: Usually not elevated, except during acute phase of gallstone passage (briefly 1000–2000 IU/L). ◦ Alcohol-related Liver Disease: → AST:ALT ratio ≥2:1 is suggestive; >3:1 is highly suggestive. → AST rarely >300 IU/L; ALT often normal due to pyridoxal phosphate deficiency.

• Alkaline Phosphatase (Alk Phos): ◦ Reflects cholestasis or other conditions. ◦ Thresholds: → <3x normal: Seen in almost any type of liver disease. → >4x normal: Suggests cholestatic liver disorders, infiltrative diseases (cancer, amyloidosis), or bone conditions (e.g., Paget's). ◦ Verification: GGT and 5'-nucleotidase confirm liver origin of Alk Phos.

• Albumin: ◦ Synthesized by hepatocytes; long half-life (18–20 days). ◦ Clinical Use: Not a good indicator of acute/mild dysfunction; hypoalbuminemia reflects chronic disease (cirrhosis) or other causes (malnutrition, nephrotic syndrome).

• Globulins: ◦ γ Globulins: Increased in chronic liver disease (e.g., cirrhosis due to failure to clear bacterial antigens). ◦ Specific Patterns: → IgM increase: Common in primary biliary cholangitis. → IgA increase: Common in alcoholic liver disease.

• Coagulation Factors: ◦ Produced by hepatocytes (except Factor VIII). ◦ Clinical Use: Best acute measure of hepatic synthetic function due to short half-lives. ◦ Prothrombin Time: Measures factors II, V, VII, and X; reflects Vitamin K status. ◦ Prognosis: PT >5 s above control (not corrected by Vitamin K) is a poor prognostic sign in acute liver disease.

• Ammonia: ◦ Detoxified by liver to urea; also partially detoxified by muscle. ◦ Clinical Use: Poor correlation with encephalopathy severity or hepatic function; useful only for identifying occult liver disease in patients with mental changes.

CLINICAL FEATURES

• Diagnostic Utility: Liver tests do not provide specific diagnoses but categorize the nature of the disease. ◦ Categorization: Identifies hepatocellular vs. cholestatic patterns. ◦ Assessment Strategy: Must be used as a battery; multiple abnormal findings or persistent abnormalities increase probability of liver disease. ◦ Reliability: If all results are normal, the probability of missing occult liver disease is low.

DIFFERENTIAL DIAGNOSIS

• Isolated Unconjugated Bilirubin: → Hemolytic disorders. → Genetic conditions (Crigler-Najjar, Gilbert's). → Gilbert's: Diagnosis if no hemolysis is present in an otherwise healthy patient.

• Conjugated Hyperbilirubinemia: → Always implies liver or biliary tract disease.

• Isolated Alkaline Phosphatase: → <3x normal: Non-specific; seen in many liver diseases. → >4x normal: Cholestatic, infiltrative (cancer, amyloidosis), or bone conditions (Paget's). → Other causes: Primary biliary cholangitis, sclerosing cholangitis, Hodgkin's, diabetes, hyperthyroidism, heart failure.

• Aminotransferase Elevations: → Viral hepatitis; Ischemic injury; Toxin/drug-induced; Sepsis; Transplant rejection. → Obstructive Jaundice: Usually not elevated, except during acute phase of gallstone passage (briefly 1000–2000 IU/L).

• Obstructive Jaundice: → Cancer; Common duct stone; Sclerosing cholangitis; Bile duct stricture.

DIAGNOSTIC APPROACH

  1. Initial Assessment of Liver Test Patterns (Figure 348-1): Identify the primary presentation: Isolated Bilirubin, Cholestatic pattern, or Isolated Alk Phos.
  2. Bilirubin Fractionation Analysis: • If Bilirubin is elevated → Determine if >15% is Direct. → Yes (>15%) → Dubin-Johnson or Rotor syndrome (if W/U negative). → No (<15%) → Evaluate for hemolysis. → W/U Positive → Hemolysis. → W/U Negative → Rule out other causes: Review drug list, Hep C/B antibodies, Iron, TIBC, ferritin, ANA, SPEP, Ceruloplasmin (Note: Ceruloplasmin <40).
  3. Cholestatic Pattern Evaluation: • Assess for ductal dilation via Ultrasound. → Ducts Not Dilated → Check AMA status. → AMA Negative → ERCP/Liver Bx. → AMA Positive → Liver Bx. → Ducts Dilated → CT/MRCP/ERCP → Liver Bx.
  4. Hepatocellular Pattern Evaluation: • Assess for ductal dilation and AMA status. → Ducts not dilated and/or AMA positive → Ultrasound, Review drug list, Check AMA → Liver biopsy. → Dilated ducts → MRCP.
  5. Isolated Alk Phos Evaluation: • Determine origin via GGT or 5'-nucleotidase. → Alk Phos of liver origin → Ultrasound, Review drug list, Check AMA → Liver biopsy. → Alk Phos of bone origin → Bone evaluation.
  6. Noninvasive Fibrosis Assessment: • FibroTest: Uses haptoglobin, bilirubin, GGT, A1, and α-macroglobulin. • ELF: Uses procollagen, hyaluronic acid, and TIMP-1. • FIB4: Calculated from age, ALT, AST, and platelets. • Imaging: Transient Elastography (TE/FibroScan) or Magnetic Resonance Elastography (MRE).
  7. Imaging for Obstruction: • Ultrasound is the first step to assess for dilated intrahepatic or extrahepatic bile ducts.

MANAGEMENT & TREATMENT

  1. Vaccination Protocol: • All patients with liver disease must receive Hepatitis A and B vaccines if not previously vaccinated.
  2. Surveillance for Complications: • HCC Surveillance: Ultrasound of the liver at 6- to 12-month intervals for patients with cirrhosis.
  3. Biopsy Decision Logic: • Indications: Uncertain cause, prolonged hepatitis (possible autoimmune), unexplained hepatomegaly/splenomegaly, uncharacterized lesions, staging lymphoma. • Contraindications: Significant ascites or prolonged INR → Use transjugular approach.

PROGNOSIS & COMPLICATIONS

• Prognostic Indicators: → Prothrombin time >5 s above control (not corrected by Vitamin K) → Poor prognosis in acute liver disease. → MELD Score: Used to predict mortality and allocate organs for transplant.

SPECIAL CONSIDERATIONS

• Patients with AIDS: → May present with hepatobiliary disorders (e.g., cytomegalovirus or cryptosporidial infection).

KEY PEARLS & CLINICAL TRAPS

• Bilirubin Rule: Any bilirubin in urine is conjugated; its presence implies liver disease or obstructive jaundice. • Alk Phos Rule: >4x normal indicates cholestatic, infiltrative, or bone issues; GGT/5'-nucleotidase confirm liver origin. • AST:ALT Ratio: >3:1 is highly suggestive of alcohol-related liver disease. • Fibrosis Tools: FibroTest and ELF are multi-parameter blood tests; FIB4 is a simple calculation (Age, ALT, AST, Platelets). • Acute vs. Chronic: Prothrombin time/INR are best for acute assessment; Albumin is only useful for chronic assessment.

Reference Tables

TABLE 347-6 Child-Pugh Classification of Cirrhosis FACTOR Serum bilirubin Serum albumin Prothrombin time

Harrison's 22e, p.2633

FACTOR POINTS TOWARD TOTAL SCORE
UNITS 1 2 3
Serum bilirubin μmol/L <34 34–51 >51
mg/dL <2.0 2.0–3.0 >3.0
g/L
g/dL		 >35
>3.5		 30–35
3.0–3.5
Prothrombin time Seconds
prolonged		 <4 4–6 >6
INRa <1.7 1.7–2.3 >2.3
None Easily
controlled
Hepatic
encephalopathy		 None Minimal Advanced
348 Evaluation of Liver
Function
Emily D. Bethea, Daniel S. Pratt