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Liver Function Tests (LFTs) - Complete Guide

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1. Why the Liver is Tested

• Synthesis of serum proteins: albumin, coagulation factors (except von Willebrand factor), carrier proteins, hormonal and growth factors
• Bile production: bile acids, cholesterol, lecithin, phospholipids
• Nutrient regulation: glucose/glycogen storage, lipid and amino acid metabolism
• Drug/toxin metabolism: conjugation of bilirubin, drugs, and other lipophilic compounds for excretion
• Ammonia detoxification via the urea cycle (unique to the liver)
• Immune defense via Kupffer cells (resident macrophages)

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2. Components of the LFT Panel

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3. Bilirubin - The Metabolic Pathway

Production

• ~250-350 mg of bilirubin is produced daily in healthy adults
• ~85% comes from breakdown of senescent red blood cells in splenic macrophages
• Heme is cleaved by heme oxygenase → biliverdin + CO + Fe²⁺
• Biliverdin reductase (NADPH-dependent) converts biliverdin → unconjugated bilirubin
• Unconjugated bilirubin is lipid-soluble, toxic, and binds tightly to albumin in plasma

Hepatic Uptake and Conjugation

• Bilirubin-albumin complex is transported to the liver via the portal circulation
• Bilirubin enters hepatocytes through sinusoidal membrane transporters
• Inside the hepatocyte, bilirubin is conjugated with glucuronic acid by UDP-glucuronosyltransferase (UGT1A1) → conjugated (direct) bilirubin (water-soluble)
• Conjugated bilirubin is secreted into bile canaliculi via MRP2 transporters

Excretion

• Conjugated bilirubin passes through the bile ducts into the small intestine
• Gut bacteria convert it to urobilinogen; most is excreted in feces as stercobilin (brown color of stool)
• A small portion of urobilinogen is reabsorbed (enterohepatic circulation) and excreted in urine as urobilinogen

Delta Bilirubin

• In prolonged cholestasis, conjugated bilirubin covalently binds to albumin → delta bilirubin
• This explains prolonged jaundice after relief of biliary obstruction, as delta bilirubin has a long half-life (similar to albumin, ~18 days)

• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 365

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4. Aminotransferases (ALT and AST) - Markers of Hepatocellular Injury

Where they live in the cell (key diagram)

ALT (Alanine Aminotransferase / formerly SGPT)

• Catalyzes: Alanine + α-ketoglutarate → Pyruvate + Glutamate (requires vitamin B6/pyridoxal phosphate)
• Location: Entirely cytoplasmic - released only with membrane injury
• Tissue specificity: Highly liver-specific (much more than AST)
• Half-life: ~47 hours
• Elevated in: viral hepatitis, NAFLD/NASH, drug-induced liver injury, ischemic hepatitis
• Most sensitive marker of hepatocellular injury

AST (Aspartate Aminotransferase / formerly SGOT)

• Catalyzes: Aspartate + α-ketoglutarate → Oxaloacetate + Glutamate (also requires B6)
• Location: Both cytoplasmic and mitochondrial isoforms
• Found in: liver, heart muscle, skeletal muscle, kidney, brain - less liver-specific than ALT
• Half-life: cytoplasmic AST ~17 hours; mitochondrial AST ~87 hours
• Normal upper limit: ~40 IU/L for both

Clinical use of AST:ALT ratio

• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 533

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5. Alkaline Phosphatase (ALP) - Cholestatic Marker

• ALP is a canalicular membrane enzyme
• Mechanism of elevation in cholestasis: bile salt accumulation causes release of membrane fragments with attached canalicular enzymes into plasma
• Not liver-specific - also found in bone (osteoblasts), intestine, placenta, kidney
• To confirm hepatic origin, always check GGT - if GGT is also elevated, ALP is of hepatic origin

ALP Isoenzymes and Causes of Elevation

• Isolated ALP elevation (with normal GGT) usually points to a bone source
• ALP elevation with elevated bilirubin and GGT = cholestatic liver disease

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6. GGT (Gamma-Glutamyl Transferase)

• Found in: bile duct epithelium, hepatocyte canalicular membrane, also in kidneys, pancreas
• Very sensitive but not specific - elevated by:
  • Biliary obstruction / cholestasis
  • Alcohol use (microsomal enzyme induction - even without liver damage)
  • Enzyme-inducing drugs: phenytoin, phenobarbital, carbamazepine
  • NAFLD
  • Pancreatitis
• Primary clinical use: confirm that a raised ALP is of hepatic (not bone) origin
• GGT + ALP elevation = hepatobiliary cause confirmed
• Elevated GGT alone is a sensitive marker of alcohol use disorder

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7. Albumin - Synthetic Function Marker

• Synthesized exclusively in the liver (~10-15 g/day)
• Half-life: ~18-20 days (long half-life makes it a marker of chronic rather than acute liver disease)
• Normal: 3.5-5.0 g/dL
• Low albumin (hypoalbuminaemia) in liver disease indicates:
  • Reduced hepatic synthetic capacity
  • Advanced/chronic liver disease (cirrhosis)
• Caveat: albumin is also lowered by protein malnutrition, nephrotic syndrome (urinary loss), protein-losing enteropathy, catabolism (infection, burns), and dilution (IV fluids)
• Not useful in acute liver failure (half-life too long to reflect acute changes)

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8. Prothrombin Time (PT) / INR - Synthetic Function Marker

• The liver synthesizes all coagulation factors except von Willebrand factor (factors I, II, V, VII, VIII, IX, X, XI, XII, XIII)
• Factors II, VII, IX, X are vitamin K-dependent (require hepatic gamma-carboxylation)
• PT measures the extrinsic and common coagulation pathways
• PT/INR elevation in liver disease = reduced synthetic function
• Factor VII has the shortest half-life (~6 hours) → PT is the most sensitive and early synthetic function marker
• Acute liver failure causes rapid PT prolongation (within hours)
• PT elevation in liver disease must be distinguished from vitamin K deficiency (given IM vitamin K and recheck in 24h - if PT corrects, vitamin K deficiency; if it doesn't correct, liver synthetic failure)

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9. Additional Tests Sometimes Included

• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 366

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10. Patterns of LFT Abnormality - Interpreting the Panel

Pattern 1: Hepatocellular Pattern

• Predominant elevation: ALT and AST (often >5x-10x upper limit of normal)
• Bilirubin elevated (mixed or indirect predominance)
• ALP relatively normal or mildly elevated
• Causes: viral hepatitis (A, B, C, D, E), ischemic hepatitis ("shock liver"), drug toxicity (acetaminophen, isoniazid), autoimmune hepatitis, Wilson disease, acute fatty liver
• Massive elevation of ALT/AST (>1000 IU/L) = ischemic hepatitis, acute viral hepatitis, acute drug/toxin injury

Pattern 2: Cholestatic Pattern

• Predominant elevation: ALP and GGT (often >3-4x upper limit of normal)
• Bilirubin elevated (direct/conjugated predominant)
• ALT/AST normal or mildly elevated
• Causes: biliary obstruction (gallstones, cholangiocarcinoma, pancreatic cancer), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), intrahepatic cholestasis of pregnancy, drug-induced cholestasis (methyltestosterone, anabolic steroids), sepsis

Pattern 3: Mixed Pattern

• Elevations of both aminotransferases and biliary enzymes
• Causes: drug-induced liver injury (sulfonamides, phenytoin), cholestatic viral hepatitis, overlap syndromes

Pattern 4: Isolated Hyperbilirubinemia

• Unconjugated (indirect) hyperbilirubinemia with normal enzymes: hemolysis, Gilbert syndrome (UGT1A1 polymorphism - benign), Crigler-Najjar syndrome
• Conjugated (direct) hyperbilirubinemia with normal enzymes: Dubin-Johnson syndrome, Rotor syndrome
• Jaundice is clinically detectable when serum bilirubin > 2.5 mg/dL (43 μmol/L)

Pattern 5: Synthetic Dysfunction Pattern

• Low albumin + prolonged PT + elevated bilirubin (hepatic decompensation)
• Normal or mildly elevated enzymes (burned-out cirrhosis)
• Causes: end-stage cirrhosis, acute liver failure, fulminant hepatic failure

• Tietz Textbook of Laboratory Medicine, 7th Edition
• Harrison's Principles of Internal Medicine 22nd ed.

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11. Specific Disease Patterns

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12. Causes of Liver Disease (from Harrison's)

• Inherited hyperbilirubinemia: Gilbert, Crigler-Najjar, Dubin-Johnson, Rotor syndrome
• Viral hepatitis: A, B, C, D, E; EBV, CMV, HSV
• Immune/autoimmune: Primary biliary cholangitis, autoimmune hepatitis, PSC
• Genetic: Wilson disease, hemochromatosis, alpha-1 antitrypsin deficiency, Gaucher's disease
• Alcohol: Acute fatty liver, alcoholic hepatitis, Laennec's cirrhosis
• Non-alcoholic fatty liver disease (NAFLD/NASH)
• Drug-induced: Hepatocellular (isoniazid, acetaminophen), cholestatic (methyltestosterone), mixed (sulfonamides, phenytoin)
• Cholestatic: Gallstones, extrahepatic obstruction, biliary atresia
• Vascular: Budd-Chiari syndrome, sinusoidal obstruction syndrome, ischemic hepatitis
• Systemic disease: Sarcoidosis, amyloidosis, celiac disease, glycogen storage diseases
• Mass lesions: HCC, metastases

• Harrison's Principles of Internal Medicine 22nd ed., Table 347-1

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13. Key Clinical Pearls

1. ALT is more liver-specific than AST; an elevated AST could be from heart or skeletal muscle
2. AST:ALT > 2:1 + elevated GGT + elevated ALP = alcoholic liver disease until proven otherwise
3. Isolated elevated GGT in an otherwise normal panel = alcohol use or enzyme-inducing drug (phenytoin, phenobarbital)
4. ALP elevated in isolation (GGT normal) = likely bone disease or normal pregnancy
5. Low albumin + prolonged PT = significant hepatic synthetic failure; marker of prognosis
6. Delta bilirubin explains why jaundice persists even after biliary obstruction is relieved
7. >80% of liver must be destroyed before liver function is abolished due to massive regenerative capacity
8. Vitamin B6 deficiency (common in alcoholics) can cause falsely low ALT and AST - always consider
9. A single reading of any enzyme is less useful than serial measurements showing a trend (rising vs. falling)
10. Liver biopsy remains the gold standard for staging fibrosis, but carries risks: serious morbidity 0.6%, mortality 0.01%; sampling error in up to 20% of biopsies

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14. Noninvasive Markers of Fibrosis

• FIB-4 score (age × AST / platelet count × √ALT) - widely used
• APRI (AST to Platelet Ratio Index)
• FibroTest / FibroSure - commercial panel
• Transient elastography (FibroScan) - measures liver stiffness

• Tietz Textbook of Laboratory Medicine, 7th Edition, p. 2022

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Liver Function Tests - Completion

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15. Diagnostic Algorithm for Abnormal LFTs

Step-by-Step Approach

• AST > 3× URL AND ALP < 2× URL → Hepatocellular pattern
• AST < 3× URL AND ALP > 2× URL → Cholestatic pattern
• Both elevated → Mixed pattern (assume cholestatic and rule out biliary obstruction first)

• Hepatocellular + normal albumin → Acute hepatitis
• Hepatocellular + low albumin → Chronic hepatitis (albumin takes weeks to fall)
• Cholestatic + normal albumin → Acute cholestasis
• Cholestatic + low albumin → Chronic cholestasis

• Dilated bile ducts → Extrahepatic (mechanical) obstruction - stone, stricture, malignancy
• Normal bile ducts → Intrahepatic cholestasis - drug, PBC, PSC, intrahepatic causes

• Check PT/INR: prolonged = synthetic failure (poor prognosis marker)
• Check bilirubin trend: higher bilirubin correlates with poorer prognosis in most chronic liver diseases
• Check albumin trend: falling albumin = progressive synthetic failure

• Tietz Textbook of Laboratory Medicine, 7th Edition, p. 2020

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16. Non-Hepatic Causes of Abnormal LFTs

• Tintinalli's Emergency Medicine, p. 559

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17. Inherited Hyperbilirubinaemia Syndromes

Unconjugated (Indirect) Hyperbilirubinaemia

Conjugated (Direct) Hyperbilirubinaemia

• Goldman-Cecil Medicine, p. 1552-1557

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18. Hereditary Cholestatic Syndromes

• Odevixibat (apical bile salt transporter blocker) - for PFIC patients ≥3 months
• Maralixibat - for Alagille syndrome cholestasis ≥1 year
• Partial biliary external diversion as surgical option

• Goldman-Cecil Medicine, p. 1557

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19. Prognostic Scoring Systems Using LFT Components

Child-Pugh Score (Child-Turcotte-Pugh / CTP)

MELD Score (Model for End-Stage Liver Disease)

• Range: 6 (less ill) to 40 (gravely ill)
• Best predictor of short-term (3-month) mortality in cirrhosis
• Used for organ allocation for liver transplantation in the US
• MELD-Na adds sodium concentration (hyponatraemia worsens prognosis)
• MELD < 16 = lower postoperative mortality; MELD > 16 = substantially higher surgical risk
• PELD (Pediatric MELD) used for children under 12

• Harrison's Principles of Internal Medicine 22nd ed., p. 2675
• Sabiston Textbook of Surgery

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20. Ammonia and Hepatic Encephalopathy

• Ammonia is a byproduct of amino acid metabolism and is detoxified exclusively by the liver via the urea (Krebs-Henseleit) cycle
• In liver failure or portosystemic shunting: ammonia accumulates → hepatic encephalopathy (HE)
• Serum ammonia is used to confirm a diagnosis of HE - but it does not reliably correlate with encephalopathy grade (brain sensitivity to ammonia varies)
• Best measured on a rapidly processed iced arterial blood sample (ammonia is unstable ex-vivo)
• Elevated ammonia also from: intestinal bacterial overgrowth, GI bleeding (blood in gut → ammonia source), metabolic alkalosis, hypokalemia (renal ammonia production), rare urea cycle enzyme deficiencies
• Management: lactulose (traps ammonia in colon), rifaximin (reduces gut bacteria ammonia production), protein restriction (no longer recommended routinely)

• Hepatic encephalopathy: 20-40% cumulative 1-year survival; 15% at 3 years
• Ascites: 2-year median survival (non-malignant); 4-month survival (malignant)
• Hepatorenal syndrome type 1: median survival 2 weeks; type 2: 4-6 months

• Goldman-Cecil Medicine, p. 1560

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21. LFTs in Specific Clinical Contexts

In Acute Liver Failure (ALF)

• Daily monitoring required
• PT/INR is the most sensitive early marker (factor VII - 6h half-life)
• Rising bilirubin + falling ALT/AST in the context of clinical deterioration = liver necrosis (enzymes are "used up" - a paradox called the "enzyme burnout" sign)
• ALF criteria: acute onset, encephalopathy, PT > 15-20 sec (or INR > 1.5) in a patient without pre-existing liver disease

In Alcoholic Liver Disease

• AST:ALT ratio > 2:1 (classically > 2) - key diagnostic clue
• GGT markedly elevated
• AST rarely > 300 IU/L in pure alcoholic hepatitis (values > 1000 IU/L suggest another cause like acetaminophen toxicity added to alcohol injury)
• Low AST/ALT despite severe alcoholic hepatitis can occur with pyridoxine (B6) deficiency

In NAFLD/NASH

• ALT typically > AST (early disease)
• When AST > ALT in NAFLD → suggests progression to cirrhosis
• GGT elevated (correlates with metabolic syndrome)
• GGT is an independent prognostic indicator of cardiovascular and all-cause mortality

In Drug-Induced Liver Injury (DILI)

• Hepatocellular pattern: isoniazid, acetaminophen, statins, antivirals
• Cholestatic pattern: methyltestosterone, anabolic steroids, amoxicillin-clavulanate, chlorpromazine
• Mixed pattern: sulfonamides, phenytoin
• Roussel Uclaf Causality Assessment Method (RUCAM) is used to score probability of DILI

In Cardiac Disease ("Cardiac Hepatopathy")

• Right heart failure → hepatic congestion → elevated ALP + mild elevation of aminotransferases + elevated bilirubin
• Acute right heart failure or shock → "ischemic hepatitis" or "shock liver": massive rise in AST/ALT (often > 1000-10,000 IU/L), resembles acute viral hepatitis
• AST often rises faster than ALT in ischemic hepatitis (cardiac AST contributing)

In Pregnancy

• Physiological: ALP elevated (placental isoenzyme) from 2nd trimester - normal finding
• Albumin mildly falls (dilutional)
• Abnormal: intrahepatic cholestasis of pregnancy (raised bile acids + ALP + GGT + bilirubin + pruritus), HELLP syndrome (Haemolysis + Elevated Liver enzymes + Low Platelets), acute fatty liver of pregnancy

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22. Urine Tests Related to LFTs

• Tintinalli's Emergency Medicine, p. 559

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23. Imaging Investigations After Abnormal LFTs

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24. Summary Table: Complete LFT Reference

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25. One-Line Rules to Remember

1. ALT > AST = viral hepatitis, NAFLD (liver-dominant injury)
2. AST > ALT (> 2:1) = alcoholic hepatitis (mitochondrial injury + B6 deficiency)
3. ALP + GGT both up = hepatobiliary cholestasis
4. ALP up, GGT normal = bone or placental source
5. GGT up alone = alcohol use or enzyme-inducing drug - not necessarily liver disease
6. Low albumin + high INR + high bilirubin = decompensated liver failure
7. Jaundice visible at bilirubin > 2.5 mg/dL (43 μmol/L)
8. Dark urine + pale stools + itching = conjugated (obstructive) jaundice
9. Isolated indirect hyperbilirubinaemia in young person = think Gilbert syndrome first
10. Massive ALT/AST (>1000 IU/L) = ischemic hepatitis, acetaminophen toxicity, or acute viral hepatitis
11. Normal LFTs do not exclude significant liver disease - cirrhosis can exist with a near-normal panel
12. Trend matters more than any single value - rising or falling values predict trajectory

Sources: Harrison's Principles of Internal Medicine 22nd Ed., Henry's Clinical Diagnosis and Management by Laboratory Methods, Tietz Textbook of Laboratory Medicine 7th Ed., Goldman-Cecil Medicine, Tintinalli's Emergency Medicine, Sabiston Textbook of Surgery, Sleisenger and Fordtran's GI and Liver Disease