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Liver Function Tests and Disease: Comprehensive Study Notes (Markdown)

Liver Anatomy and Function

  • Dr Chanika Ariyawansa context: Genetic Pathology Registrar, Chemical Pathologist; focus on Liver Function Tests (LFTs) and liver disease patterns.

  • Core idea: LFT interpretation combines anatomy, physiology, and pattern recognition (hepatocellular vs cholestatic vs mixed) with clinical context.

LIVER ANATOMY

  • Liver components and vascular/pancreatic-adjacent landmarks:

    • Left hepatic duct

    • Right hepatic duct

    • Hepatic duct

    • Portal vein (branch of portal system)

    • Hepatic artery (branch of hepatic artery)

    • Inferior vena cava (IVC) via hepatic veins

    • Gallbladder with cystic duct

    • Common bile duct → Duodenum

    • Duodenum, Jejunum (part of GI tract involved in digestion/absorption)

    • Pancreatic duct

  • Blood flow and nutrient delivery sequence:

    • Small intestine absorbs products of digestion -> nutrients travel via hepatic portal vein to liver

    • Liver monitors blood content as it processes absorbed nutrients and toxins

    • Blood from liver drains into systemic circulation via hepatic veins into the IVC

  • Liver architecture (cross-section):

    • Liver Lobules with Hepatocytes arranged around a Central Vein; branches of Portal Vein and Hepatic Artery feed into sinusoids; Central Vein drains into hepatic vein

    • Sinusoids: capillary-like vessels where exchange occurs

  • Conceptual function: Liver is organized to process blood from the GI tract, metabolize nutrients, detoxify, store, synthesize, and secrete

LIVER FUNCTION OVERVIEW

  • STORAGE

    • Ferritin

    • Glycogen

    • Vitamins A, D, E, B12

  • EXCRETION

    • Bilirubin

    • Cholesterol

  • DETOXIFICATION

    • Endogenous: Ammonia to urea (via urea cycle)

    • Exogenous: Drugs and toxins

  • SYNTHETIC

    • Proteins: Albumin, Lipoproteins, IGF-1, Alpha-1-antitrypsin

    • Coagulation factors (Vitamin K dependent: II, VII, IX, X)

    • Bile acids

  • METABOLISM

    • Heme metabolism to bilirubin

    • Cholesterol, Carbohydrate, Protein metabolism

  • DIGESTION

    • Bile salts: fat emulsification

COMPLICATIONS OF LIVER FAILURE

  • STORAGE dysfunction leads to: ferritin elevation, glycogen storage impairment causing hypoglycaemia, vitamin deficiencies (A, D, E, B12)

  • EXCRETION dysfunction leads to: bilirubin accumulation causing encephalopathy, impaired bile acids, cholesterol imbalance

  • DETOXIFICATION dysfunction leads to: ammonia accumulation with widespread toxicity (encephalopathy, coma); drug/toxin accumulation

  • SYNTHETIC dysfunction causes: hypoalbuminaemia → oedema; decreased IGF-1, altered lipoproteins, reduced coagulation factors → bleeding tendency; bile acids buildup

  • METABOLISM dysfunction results in: impaired heme/cholesterol/ carbohydrate/protein metabolism leading to systemic effects

PROGRESSION OF LIVER DISEASE

  • Chronic injury factors: viral infection, alcohol, NASH (non-alcoholic steatohepatitis); autoimmune disorders; cholestatic disorders; genetic polymorphisms; epigenetic marks; obesity and metabolic diseases as cofactors

  • Disease trajectory:

    • Normal liver → inflammatory damage → matrix deposition (fibrosis) → early fibrosis with disrupted architecture

    • Loss of hepatocyte function; aberrant regeneration

    • Potential resolution if underlying cause is removed (anti-fibrotic therapies or cell therapy)

    • Regression possible; progression can lead to liver failure and portal hypertension

    • Outcomes: liver failure, liver transplant, cirrhosis, hepatocellular carcinoma (HCC)

STAGES OF LIVER DAMAGE

  • Liver steatosis: increased fat deposition within the liver

  • Fibrosis: scar tissue formation (increased connective tissue)

  • Cirrhosis: extensive scar tissue replacing healthy tissue, architecture disrupted

  • Liver cancer: formation of malignant tumors (HCC) or metastases

LIVER FUNCTION TESTS (LFTs)

  • Major components on standard LFT panels:

    • Bilirubin (Bili)

    • Alkaline Phosphatase (ALP)

    • Gamma-glutamyl transferase (GGT)

    • Alanine transaminase (ALT)

    • Albumin (ALB)

    • Total protein (TP)

  • Hepatocyte damage markers (not true markers of function but reflect cell injury):

    • ALT (cytoplasm) with half-life t_{1/2} ext{(ALT)} = 47 ext{ hours}

    • AST (cytoplasm and mitochondria) with half-life t_{1/2} ext{(AST)} = 17 ext{ hours}

    • Note: not always included in routine LFTs in all labs

  • Excretion markers (bile flow and cholestasis):

    • ALP: present in bile duct epithelium; also found in bone, kidney, placenta, intestine, some cancers

    • GGT: present in bile ducts and other organs; not found in bone; helps distinguish liver vs bone sources

    • Bilirubin: breakdown product of heme from old RBCs; main bile pigment

  • Synthetic markers (liver functional capacity):

    • Albumin: main plasma protein responsible for oncotic pressure; long half-life (~21 days)

    • Coagulation factors: II, VII, IX, X (Vitamin K dependent)

    • Total protein = Albumin + Globulins

  • Bilirubin metabolism (summary):

    • Unconjugated bilirubin is produced from heme breakdown and binds to albumin

    • In the liver, unconjugated bilirubin is conjugated with glucuronic acid to form conjugated bilirubin

    • Conjugated bilirubin is excreted into bile and enters the biliary system

    • Intestinal bacteria convert bilirubin to urobilinogen; most urobilinogen is excreted in feces; a portion is reabsorbed and excreted in urine

    • Pathways: Extravascular/intravascular hemolysis increases unconjugated bilirubin; conjugation capacity is hepatocyte-dependent

  • Bilirubin metabolism pathway (schematic, simplified):

    • ext{Unconjugated bilirubin} + ext{glucuronic acid}
      ightarrow ext{Conjugated bilirubin}

    • Conjugated bilirubin enters biliary system → intestine; urobilinogen produced; some reabsorbed and excreted via kidney; majority excreted in feces as stercobilin

  • Additional tests of function and etiology markers (as per LFT workup):

    • AST, INR/Prothrombin time (PT) for synthetic function; bilirubin fractions; ALP isoenzymes to differentiate liver vs bone origin

    • Conjugated bilirubin measurements; bile acids (synthetic markers)

    • Ammonia for hepatic encephalopathy risk

    • Viral serology (HBV, HCV, EBV, CMV)

    • Copper studies for Wilson’s disease; ferritin/iron studies for hemochromatosis; A1AT activity/genotyping; autoimmune antibodies (ANA, SMA, LKM, AMA, pANCA); Ig levels

    • Tumor markers (HCG, AFP); fibrosis scores (Hepascore, APRI); imaging (US/CT/MRI)

  • Additional notes on interpretation:

    • Isolated patterns vs mixed patterns guide etiology

    • Mild abnormalities are common and may normalize on repeat testing

    • Abnormal LFTs do not always indicate liver pathology; some signs reflect extrahepatic disease or mechanical issues

    • Normal LFTs (AST/ALT) do not always exclude chronic liver disease

LATE-PART: HEPATOCYTE DAMAGE vs Cholestasis vs Mixed Patterns

  • Hepatocellular pattern: predominantly elevated AST/ALT (ALT typically favored when ALT > AST in many cases) with relatively modest ALP/GGT; often due to hepatocyte injury

  • Cholestatic pattern: elevated ALP and GGT with elevated bilirubin, reflecting bile flow obstruction or intra-/extrahepatic cholestasis

  • Mixed pattern: elevations in both hepatocellular and cholestatic markers

  • Key teaching: pattern recognition is essential for prioritizing differential diagnosis and management

HEPATIC DISEASE PATTERNS AND AETIOLOGY

  • HEPATOCELLULAR (hepatocyte destruction)

    • NAFLD/NASH, acute alcoholic hepatitis, acute viral hepatitis, acute on chronic viral hepatitis, drug-induced liver injury (e.g., phenytoin, isoniazid, diclofenac, paracetamol), ischemic hepatitis, autoimmune hepatitis, inherited diseases (e.g., alpha-1-antitrypsin deficiency)

  • CHOLESTATIC (cholestasis)

    • Intrahepatic cholestasis, extrahepatic obstructions (gallstones, cholangitis, strictures), sepsis-associated cholestasis, primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced cholestasis (anabolic steroids, OCPs, antibiotics), mass lesions (HCC, metastases, granulomas, abscesses)

  • MIXED patterns reflect concurrent hepatocellular and cholestatic pathology or liver plus non-liver pathology (e.g., bone disease)

HEPATOCELLULAR PATTERN - RAISED ALT CAUSES (DIFFERENTIAL)

  • Nonhepatic diseases that can elevate AST/ALT mildly are listed; primary hepatic causes typically show ALT > ~ALT elevations:

    • Drug-induced liver injury (DILI) including acetaminophen toxicity

    • Alcoholic hepatitis (AST > ALT often, but both elevated)

    • Chronic viral hepatitis (HBV, HCV)

    • Occupational/toxin-related hepatocellular damage

    • Cirrhosis due to viral hepatitis or NAFLD

    • Wilson disease, Autoimmune hepatitis

    • NAFLD (non-alcoholic fatty liver disease); Alpha-1-antitrypsin deficiency; Hemochromatosis

    • Congestive hepatopathy; Muscle injury (macrole or macro-AST can mimic elevation)

    • Adrenal insufficiency, thyroid disease, anorexia nervosa, malnutrition

    • Macro-AST phenomenon; malignant liver infiltration

  • With ALT elevations, evaluate pattern and magnitude to gauge acuteness and severity

ISOLATED GGT INCREASE

  • GGT is a sensitive but not specific liver disorder indicator; induced by many substances

  • Common causes: alcohol, medications (e.g., phenytoin) and enzyme-inducing drugs

  • GGT elevation with ALP elevation suggests a liver source (not bone) while normal GGT with high ALP suggests bone origin

  • Prostate cancer can cause GGT elevations secondarily via bone metastases; interpret in context

ISOLATED BILIRUBIN INCREASE

  • When bilirubin is elevated with or without liver enzyme elevations:

    • If there are elevated liver enzymes: reflective of liver disease or biliary obstruction

    • If there are no elevated liver enzymes: consider hemolysis, Gilbert’s syndrome, severe liver disease

  • Unconjugated (indirect) hyperbilirubinaemia causes: Gilbert syndrome, Crigler-Najjar syndrome, neonatal jaundice, hemolysis, hematoma resorption, starvation, congestive failure

  • Conjugated (direct) hyperbilirubinaemia: can be measured; Dubin–Johnson syndrome; cholestatic disease; severe hepatocellular disease

ISOLATED ALP INCREASE

  • Causes: Liver cholestatic disease (partial biliary obstruction, PBC, PSC), drugs (anabolic steroids, OCPs, phenytoin), mass lesions (sarcoidosis, HCC, metastases), bone diseases (Paget’s, osteoblastic metastases, hyperparathyroidism, healing fracture), pregnancy (2-3x increase in 3rd trimester)

  • Intestinal sources and isoenzymes: ALP isoenzymes can differentiate liver vs bone vs intestinal sources; ALP isoenzymes analysis available

  • Age-related differences: physiological growth in children/adolescents can increase bone ALP

ALP ISOENZYMES – ELECTPHORESIS

  • Separation by charge; liver, bone, placental, intestinal isoenzymes

  • Liver isoenzyme migrates fastest toward the anode; bone slower; placental band if present; intestinal slowest

  • Use neuraminidase treatment to improve separation between bone and liver isoenzymes

ADDITIONAL TESTS AND AETIOLOGY MARKERS

  • AST (optional) and clotting tests (INR, prothrombin time) for chronic vs acute states

  • Conjugated bilirubin, bile acids (synthetic function), ammonia (hepatic encephalopathy risk)

  • Viral serology for hepatitis viruses and EBV/CMV

  • Wilson’s disease workup: caeruloplasmin, 24-hour urinary copper, liver copper

  • Haemochromatosis workup: iron studies, HFE genotyping, liver iron

  • Alpha-1-antitrypsin disease workup: A1AT activity, genotyping

  • Autoimmune hepatitis screen: Anti-mitochondrial Ab, Anti-smooth muscle Ab, Anti-LKM Ab, ANA, pANCA, Ig levels

  • UGT1A1 genotyping for Gilbert syndrome

  • Tumor markers: HCG, AFP

  • Fibrosis scores: Hepascore, APRI

  • Imaging: US, CT, MRI (Feriscan)

APPROACH TO LFT INTERPRETATION

1) Pattern recognition: isolated vs combined abnormalities; hepatocellular pattern (AST/ALT) vs cholestatic pattern (ALP/GGT/bilirubin) vs mixed; magnitude and trajectory over time
2) Clinical history
3) Previous results: acute vs chronic, severity
4) Other tests: coagulation profile, ammonia, autoimmune markers, etc.

CASE STUDIES AND ILLUSTRATIVE SCENARIOS

Case 1 — 24-year-old female, acute illness, frozen berries context

  • Data (plasma):

    • Total Protein: 72, 75, 76 g/L (reference 60-80)

    • Albumin: 41, 42, 42 g/L (35-50)

    • Bilirubin: 19, 20, 18 µmol/L (<20)

    • ALP: 132, 132, 130 U/L (35-135)

    • ALT: 5030, 1750, 499 U/L (<40)

  • Interpretation: massive hepatocellular injury pattern (ALT massively elevated); cholestatic markers not markedly elevated; context suggests acute viral hepatitis; note indicates Hepatitis A as likely etiology

Case 2 — 20-year-old female, routine screen

  • Data: 2018/2016/2011 values

    • Total Protein: 75, 69, 71 g/L

    • Albumin: 49, 45, 48 g/L

    • Bilirubin: 28, 26, 31 µmol/L (<20)

    • ALP: 68, 55, 66 U/L

    • ALT: 33, 19, 31 U/L (<40)

  • Pattern: isolated hyperbilirubinaemia with normal/low transaminases

  • Conclusion: Gilbert’s syndrome (benign inherited unconjugated hyperbilirubinaemia)

  • Gilbert’s syndrome details:

    • Prevalence: 3-5 ext{%}

    • UGT1A1 gene: repeats >7

    • Decreased UDP-glucuronosyl transferase activity

    • Typically mild unconjugated bilirubin elevation; bilirubin may be normal; often <35 µmol/L (may be up to 70)

    • Increases with fasting, alcohol, illness; no bilirubinuria; other LFTs normal

Case 3 — 35-year-old male, high activity pattern

  • History: 4 days strenuous exercise, intense personality

  • Data (example from Case 3 table): Bili, ALP, GGT, ALT, ALB, TP across dates; notable ALT elevations are modest relative to Case 1 and may reflect muscle injury rather than hepatic injury

  • Pathophysiology: rhabdomyolysis can cause spillover of muscle enzymes (including ALT/AST) and mimic hepatocellular injury; CK and myoglobin are key markers (not provided here) and CK elevations peak around days 3-5

  • Conclusion: Consider rhabdomyolysis in differential diagnosis when ALT elevations accompany elevated CK; differentiate from primary liver injury based on pattern and additional muscle injury markers

Case 4 — 24-year-old female, codeine addiction with paracetamol overdose

  • Data (plasma):

    • Total Protein: 72 g/L (60-80)

    • Albumin: 41 g/L (35-50)

    • Bilirubin: 20 µmol/L (<20)

    • ALP: 132 U/L (35-135)

    • ALT: 6000 U/L (<40)

  • Paracetamol level: 70 mg/L (high)

  • Management and physiology:

    • Paracetamol (acetaminophen) overdose causes hepatotoxic metabolite NAPQI via CYP450 pathways

    • In overdose, conjugation saturates, more CYP450 metabolism -> NAPQI accumulation -> hepatocellular damage

    • Risk factors: alcohol use, anticonvulsants (enzyme induction), fasting, HIV, chronic liver disease

    • Time course: days 1-2 may be asymptomatic; days 3-4 may develop fulminant liver failure

    • Prognostic markers: very high ALT/AST (e.g., >1000-15000), raised INR

    • Paracetamol level guides risk; treatment includes activated charcoal if ingestion <1-2 hours; N-acetylcysteine (NAC) infusion started immediately if >8 hours post-ingestion or per nomogram if <8 hours

    • New Australian/NZ paracetamol nomogram referenced for dosing decisions

Case 5 — 40-year-old female with jaundice and abdominal pain

  • Data (plasma):

    • Total Protein: 69 g/L (60-80)

    • Albumin: 34 g/L (35-50)

    • Bilirubin: 167 µmol/L (<20)

    • ALP: 584 U/L (35-135)

    • ALT: 48 U/L (<40)

  • Pattern: cholestatic picture with high bilirubin and ALP; ALT not markedly elevated

  • Conclusion: likely biliary obstruction; notes suggest common bile duct stone

Case 5 – Summary points

  • Key teaching: isolated bilirubin elevation with very high bilirubin and ALP suggests cholestasis/obstruction; transaminases may be normal or only mildly elevated

HEPATITIS VIRUSES (SUMMARY)

  • Hepatitis A: faecal-oral via contaminated food or water; usually self-limiting but can be severe

  • Hepatitis B: transmitted via infected blood/body fluids (IV drug use, sex, vertical transmission); risk of chronic infection higher if infection occurs at younger age; potential progression to cirrhosis and HCC

  • Hepatitis C: transmitted via infected blood/body fluids (IV drug use, vertical transmission); most acute cases are asymptomatic; high rate of chronic infection

  • Hepatitis D: defective virus; requires HBV to replicate; co-infection/superinfection with HBV

  • Hepatitis E: faecal-oral transmission; typically self-limiting; higher risk in pregnant women; less common in Australia except travel

MAFLD / NAFLD REVISION

  • MAFLD stands for Metabolic Associated Fatty Liver Disease; renamed from NAFLD in 2020 to emphasize metabolic dysregulation rather than nonalcoholic status alone

  • Diagnostic criteria require:
    1) Type 2 diabetes, or
    2) Overweight or obesity (BMI thresholds), or
    3) Evidence of hepatic steatosis (>5%) on imaging or histology, plus
    4) At least two metabolic risk abnormalities

  • Metabolic risk abnormalities include:

    • Waist circumference: ≥102/88 ext{ cm} in Caucasian men/women (or ≥90/80 ext{ cm} in Asian populations)

    • Blood pressure: ≥130/85 ext{ mmHg} or treatment for hypertension

    • Triglycerides: ≥150 ext{ mg/dL} (or treatment)

    • HDL-cholesterol: <40 ext{ mg/dL} in men or <50 ext{ mg/dL} in women (or treatment)

    • Prediabetes: fasting glucose 100-125 mg/dL (5.6-6.9 mmol/L) or two-hour post-load glucose 140-199 mg/dL (7.8-11.0 mmol/L) or HbA1c 39-47 mmol/mol (5.7-6.4%)

    • HOMA-IR ≥ 2.5

    • hs-CRP > 2 mg/L

  • Purpose: identify metabolic dysregulation and assess risk of advanced fibrosis

KEY POINTS FOR LFT INTERPRETATION

  • Pattern recognition is central: isolated abnormality vs combination; hepatocellular vs cholestatic vs mixed

  • Severity matters: magnitude and trajectory; mild abnormalities are common and may normalize

  • Additional markers help determine etiology and complications (clotting, ammonia, autoimmune tests, fibrosis scores)

  • Abnormal LFTs do not always indicate liver disease; normal LFTs do not guarantee absence of liver disease

ADDITIONAL RESOURCES AND CONTEXT

  • The content references a clinical podcast about LFT interpretation with Dr Chanika Ariyawansa; useful for practical understanding of non-hepatic causes, pattern recognition, and LFT nuances

  • Overall goal: integrate anatomy, biochemistry, and clinical patterns to interpret LFTs and guide management

SUMMARY OF SYMBOLIC AND NUMERIC ELEMENTS USED IN THIS NOTES

  • ALT half-life: t_{1/2} ext{(ALT)} = 47 ext{ hours}

  • AST half-life: t_{1/2} ext{(AST)} = 17 ext{ hours}

  • Gilbert’s syndrome: UGT1A1 ext{ gene repeats } > 7

  • MAFLD criteria: BMI thresholds ext{BMI} \ge 25 ext{ kg/m}^2; waist circumference and metabolic risk abnormalities as listed

  • Paracetamol management: NAC therapy; time-sensitive charcoal and nomogram reference

  • Case-typical values are shown in the case summaries using the following patterns:

    • Case 1: ALT massively elevated (hepatocellular pattern)

    • Case 2: isolated unconjugated bilirubin elevation (Gilbert’s syndrome)

    • Case 3: possible rhabdomyolysis-associated enzyme elevations; consider non-hepatic source

    • Case 4: paracetamol overdose with ALT ~6000 U/L; high risk of fulminant liver failure

    • Case 5: cholestatic picture with very high bilirubin and ALP; biliary obstruction (stone in common bile duct)