Liver Function Tests (LFTs)

from : https://www.ncbi.nlm.nih.gov/books/NBK482489/

Liver Anatomy and Function

• Located in the right upper quadrant of the body, below the diaphragm.
• Responsible for:
  • Primary detoxification of various metabolites.
  • Synthesizing proteins.
  • Producing digestive enzymes.
  • Metabolism regulation.
  • Regulation of red blood cells (RBCs).
  • Glucose synthesis and storage.

Liver Function Tests (LFTs)

• Tests typically include:
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Alkaline phosphatase (ALP)
  • Gamma-glutamyl transferase (GGT)
  • 5’nucleotidase
  • Total bilirubin
  • Conjugated (direct) bilirubin
  • Unconjugated (indirect) bilirubin
  • Prothrombin time (PT)
  • International normalized ratio (INR)
  • Lactate dehydrogenase
  • Total protein
  • Globulins
  • Albumin
• These tests help determine the area of hepatic injury and organize a differential diagnosis.

Patterns of Liver Injury

• Hepatocellular Disease: Elevated ALT and AST out of proportion to ALP and bilirubin.
• Cholestatic Pattern: Elevated ALP and bilirubin out of proportion to ALT and AST.
• Mixed Injury Pattern: Elevation of both ALP and AST/ALT levels.
• Isolated Hyperbilirubinemia: Elevation of bilirubin with normal ALP and AST/ALT levels.

Etiology and Epidemiology

• Elevated liver function tests are found in ~8% of the general population.
• Transient elevations may resolve after three weeks in asymptomatic patients.
• Interpretation should be cautious to avoid unnecessary testing.
• Borderline AST and/or ALT elevation: <2 times the upper limit of normal (ULN).
• Mild elevation: 2-5 times ULN.
• Moderate elevation: 5-15 times ULN.
• Severe elevation: >15 times ULN.
• Massive elevation: >10,000 IU/L.

Differential Diagnosis Based on Elevated LFTs

• Hepatocellular Pattern: Elevated aminotransferases out of proportion to alkaline phosphatase.
  • ALT-Predominant Causes:
    • Acute or chronic viral hepatitis
    • Steatohepatitis
    • Acute Budd-Chiari syndrome
    • Ischemic hepatitis
    • Autoimmune hepatitis
    • Hemochromatosis
    • Medications/toxins
    • Alpha1-antitrypsin deficiency
    • Wilson disease
    • Celiac disease
  • AST-Predominant Causes:
    • Alcohol-related liver disease
    • Steatohepatitis
    • Cirrhosis
    • Non-hepatic causes (hemolysis, myopathy, thyroid disease, exercise)

• Cholestatic Pattern: Elevated alkaline phosphatase + gamma-glutamyl transferase + bilirubin out of proportion to AST and ALT.
  • Hepatobiliary Causes:
    • Bile duct obstruction
    • Primary biliary cirrhosis
    • Primary sclerosing cholangitis
    • Medication-induced cholestasis
    • Infiltrating diseases (sarcoidosis, amyloidosis, lymphoma)
    • Cystic fibrosis
    • Hepatic metastasis
  • Non-Hepatic Causes:
    • Bone disease
    • Pregnancy
    • Chronic renal failure
    • Lymphoma or other malignancies
    • Congestive heart failure
    • Childhood growth
    • Infection or inflammation

Components of Liver Function Test

Hepatocellular Labs

• Aminotransferase:
  • Includes AST (Aspartate Aminotransferase) and ALT (Alanine Aminotransferase).
  • Markers of hepatocellular injury.
  • Participate in gluconeogenesis:
    • AST: Catalyzes transfer of amino group from aspartic acid to ketoglutaric acid, producing oxaloacetic acid.
    • ALT: Catalyzes transfer of amino group from alanine to ketoglutaric acid, producing pyruvic acid.
• AST (Aspartate Aminotransferase):
  • Exists as cytosolic and mitochondrial isoenzymes.
  • Found in liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and red cells.
  • Less sensitive and specific for liver injury compared to ALT.
  • Elevation may occur due to nonhepatic causes.
  • AST activity is higher in neonates and infants, declining to adult levels by approximately six months.
• ALT (Alanine Aminotransferase):
  • Cytosolic enzyme, highly concentrated in the liver.
  • Half-life: Approximately 47 ± 10 hours.
  • Typically higher than AST in most liver diseases where enzyme activity is from hepatocyte cytosol.
  • Hepatocellular injury (not necessarily cell death) triggers the release of these enzymes into circulation.
  • Higher values in normal males compared to females.
  • Correlates with obesity; normal reference range higher in individuals with higher body mass index.

Cholestasis Labs

• Alkaline Phosphatase (ALP):
  • Family of zinc metalloenzymes concentrated in the microvilli of the bile canaliculus and other tissues (bone, intestines, placenta).
  • Four isozymes:
    • Placental ALP (hPLALP)
    • Germ Cell ALP (GCALP or PLALP-like)
    • Intestinal ALP (IALP)
    • Tissue-Nonspecific ALP (TNALP)
  • Heat stability:
    • PLALP and GCALP: Most heat stable at 65°C.
    • Bone ALP: Least heat stable.
  • In healthy non-smokers, PLALP and GCALP < 1% of total ALP activity in serum.
  • Benign transient hyperphosphatasemia:
    • Marked rise in ALP, often several thousand IU/L.
    • Associated with concurrent infections in >60% of cases.
    • Characteristic pattern on polyacrylamide gel electrophoresis.
    • Benign condition, ALP returns to normal in 6-8 weeks.
• Gamma-Glutamyltransferase (GGT):
  • Located on cell membranes with high secretory or absorptive activities.
  • Catalyzes the transfer of a gamma-glutamyl group from peptides to other amino acids.
  • Specific for biliary disease, not present in bone.
  • Increased in obstructive liver disease (average 12-fold compared to ALP’s 3-fold increase).
  • Useful in distinguishing idiopathic cholestasis with or without bile duct involvement.
  • Levels affected by breastfeeding due to high GGT in breast milk postpartum.
  • Higher levels in individuals with BMI > 30 kg/m² due to liver fat deposition (steatosis).
  • Raised in liver diseases causing fibrosis/cirrhosis, space-occupying lesions, granulomatous disease.
• 5′-Nucleotidase (5′NT):
  • Associated with canalicular and sinusoidal plasma membranes.
  • Found in intestine, brain, heart, blood vessels, and endocrine pancreas.
  • Identifies the organ source of isolated ALP elevation.
  • Not increased in bone disease, primarily elevated in hepatobiliary disease.
• Lactate Dehydrogenase (LDH):
  • Commonly included in liver panels.
  • Poor diagnostic specificity for liver disease.
  • Markedly increased in hepatocellular necrosis, shock liver, lymphoma, or hemolysis associated with liver disease.
• Bilirubin:
  • End product of heme catabolism (80% from hemoglobin).
  • Unconjugated bilirubin:
    • Transported to the liver bound to albumin.
    • Water-insoluble, not excreted in urine.
  • Conjugated bilirubin:
    • Water-soluble, appears in urine.
    • Conjugated to bilirubin glucuronide in the liver, secreted into bile and gut.

Synthetic Function Tests

• Albumin:
  • Synthesized by hepatic parenchymal cells.
  • Synthesis rate dependent on colloidal osmotic pressure and dietary protein intake.
  • Feedback regulation by plasma albumin concentration.
  • Maintenance possible with only 10% of normal hepatocyte mass.
  • Half-life: 21 days.
  • Found in almost all extracellular body fluids.
  • Catabolized in various tissues via pinocytosis and intracellular proteolysis.
  • Low serum albumin in liver disease indicates decreased synthesis.
  • Normal liver function with low serum albumin may indicate:
    • Poor protein intake (malnutrition).
    • Protein loss (nephrotic syndrome, malabsorption, protein-losing enteropathy).
• Prothrombin Time (PT):
  • Measures rate of conversion of prothrombin to thrombin.
  • Dependent on factors II, V, VII, and X, all synthesized in the liver.
  • Delayed PT with normal liver function may indicate:
    • Warfarin treatment.
    • Consumptive coagulopathy (e.g., disseminated intravascular coagulopathy).
    • Vitamin K deficiency.

Serological Tests

• Autoantibodies for Autoimmune Liver Diseases:
  • Autoimmune Hepatitis Type 1 (AIH-1):
    • Anti-nuclear antibody (ANA).
    • Smooth muscle antibody (SMA).
  • Autoimmune Hepatitis Type 2 (AIH-2):
    • Antibody to liver kidney microsomal antigen type-1 (anti-LKM1).
    • Anti-liver cytosol type 1 (anti-LC1).
  • Primary Biliary Cirrhosis (PBC):
    • Antimitochondrial antibodies (AMA).
    • ANA reacting with nuclear pore gp210 and nuclear body sp100.
  • Sclerosing Cholangitis:
    • Primary Sclerosing Cholangitis (PSC): Atypical perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA).
    • Autoimmune Sclerosing Cholangitis (ASC): Serological features resembling AIH-1.

Secondary Biochemical Liver Tests

• Alpha-Fetoprotein (AFP):
  • Tumor marker for primary hepatocellular malignancies (e.g., hepatoblastoma, HCC).
  • Raised in regenerating liver, especially in chronic viral hepatitis.
• Carbohydrate Deficient Transferrin:
  • High-specificity test for detecting excess alcohol intake causing liver damage.
• Carbohydrate Antigen CA19-9:
  • Monitors activity of PSC, which may progress to cholangiocarcinoma.
• Serum Ferritin:
  • Useful for identifying hemochromatosis.
  • Positive acute phase reactant, raised in many illnesses and acute hepatic failure due to hepatocyte damage.

Results, Reporting, and Critical Findings

Correlation with Patient History and Physical Examination

• Important aspects to review:
  • Patient’s age
  • Past medical history (e.g., diabetes, obesity, hyperlipidemia, inflammatory bowel disease, celiac sprue, thyroid disorders, autoimmune hepatitis, acquired muscle disorders)
  • Alcohol use disorder
  • Medication use
  • Toxin exposure
  • Family history of genetic liver conditions (Wilson disease, alpha-1-antitrypsin deficiency, hereditary hemochromatosis)
• Review of systems for signs and symptoms of chronic liver disease:
  • Jaundice
  • Ascites
  • Peripheral edema
  • Hepatosplenomegaly
  • Gynecomastia
  • Testicular hypotrophy
  • Muscle wasting
  • Encephalopathy
  • Pruritus
  • Gastrointestinal bleeding
• Additional tests to determine cause of elevated transaminase levels:
  • Fasting lipid levels
  • Hemoglobin A1C level
  • Fasting glucose
  • Complete blood count with platelets
  • Complete metabolic panel
  • Iron studies
  • Hepatitis C antibody
  • Hepatitis B surface antigen testing

Reference Ranges for Liver Function Tests (LFTs)

• Variations depending on laboratory, sex, and body mass index (BMI)
• Each laboratory should establish its own reference interval based on methodology
• Typical reference ranges:
  • Alanine transaminase (ALT): 4 to 36 IU/L
  • Aspartate transaminase (AST): 5 to 30 IU/L
  • Alkaline phosphatase (ALP): 30 to 120 IU/L
  • Gamma-glutamyltransferase (GGT): 6-50 IU/L
  • Bilirubin: 2 to 17 µmol/L
  • Direct bilirubin: 0 to 6 µmol/L
  • Prothrombin time (PT): 10.9 to 12.5 seconds
  • Albumin: 35-50 g/L
  • Total protein: 60 to 80 g/L
  • Lactate dehydrogenase (LDH): 50 to 150 IU/L

Clinical Significance

• Alcohol:
  • AST to ALT ratio ≥ 2:1 suggests alcoholic liver disease
  • Elevated GGT also suggests alcohol abuse, but GGT alone is not specific
• Medications:
  • Many medications can cause liver damage (e.g., NSAIDs, antibiotics, statins, anti-seizure drugs, tuberculosis treatment drugs)
  • Acute hepatocellular injury linked to drugs like acetaminophen, allopurinol, NSAIDs, anti-tuberculosis medications, statins, antifungals, antibiotics, anti-seizure drugs, antidepressants, antipsychotics, antivirals
  • Acute cholestasis linked to drugs like anabolic steroids, NSAIDs, tricyclic antidepressants, alcohol, antibiotics
  • Long-term use of certain drugs (e.g., methotrexate) can lead to chronic liver damage
• Viral Hepatitis:
  • Common cause of hepatitis and elevated LFTs
  • Hepatitis B, C, and D can cause chronic hepatitis; Hepatitis A and E cause acute hepatitis
  • Other viruses (HIV, EBV, CMV) can also cause hepatitis
• Autoimmune Hepatitis:
  • Chronic disease with ongoing hepatocellular inflammation, necrosis, potential progression to cirrhosis
  • More common in young women
  • Positive autoantibodies (ANA, SMA, anti-LKM1, anti-LC1)
• Hepatic Steatosis and Nonalcoholic Steatohepatitis (NASH):
  • Overweight individuals, type II diabetes, dyslipidemia
  • Elevated AST and ALT with a 1:1 ratio, other liver function tests normal
• Hemochromatosis:
  • Abnormal iron accumulation leading to organ toxicity
  • Clinical manifestations: diabetes, liver disease, cutaneous hyperpigmentation
  • Diagnosis: Raised serum ferritin, transferrin saturation > 45%, HFE mutations
• Wilson Disease:
  • Autosomal-recessive disorder of copper metabolism
  • Clinical clue: Kayser-Fleischer rings (not always present)
  • Diagnosis: Low serum ceruloplasmin, 24-hour urinary copper excretion, liver biopsy
• Alpha-1 Antitrypsin Deficiency (AATD):
  • Genetic condition leading to obstructive pulmonary disease and liver disease
  • Common among Caucasians, often undiagnosed
• Celiac Disease:
  • Gluten sensitivity disorder with modest elevations in liver transaminases
  • Screening: tissue transglutaminase IgA, serum IgA level, anti-deamidated gliadin peptide IgG
• Thyroid Disorders:
  • Hypothyroidism and hyperthyroidism associated with abnormal liver enzymes
  • Screening: thyroid stimulating hormone, selective testing of free T4 and free/total T3