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GIS + MSS + HNS + HIS + ERS Practicals > Chemical Pathology 1: LFT > Flashcards

Chemical Pathology 1: LFT Flashcards

1
Q

Reference range

A

Based on findings obtained from reference population (representative sample / reference population)

Parametric method: Mean +/- 2 SD
Non-parametric method: 2.5-97.5 percentiles

—> 5% of normal subjects will have test results outside reference intervals
—> Deviation from reference interval does not mean presence of disease (always interpreted in clinical context)

There might be overlapping in Healthy reference range and Diseased reference range
—> High cutoff: High specificity, Low sensitivity (many false negative)
—> Low cutoff: Low specificity, High sensitivity (many false positive)

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2
Q

***Routine Liver Function Test

A
  1. Total protein
  2. Albumin
  3. Globulin (A:G ratio)
    - Immunoglobulin
    - α1-antitrypsin
    - Haptoglobin
    - Ceruloplasmin
    - Transferrin
    - Fibrinogen
    - Complements (C3, C4) etc.
  4. Bilirubin
    - Total
    - Conjugated (direct)
    - Unconjugated (indirect)
  5. Parenchymal enzymes
    - Alanine aminotransferase (ALT / SGPT)
    - Aspartate aminotransferase (AST / SGOT)
  6. Ductal enzymes
    - Alkaline phosphatase (ALP)
    - γ-Glutamyl transpeptidase (GGT)
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3
Q

***Tests for different liver “Functions”

A
  1. Albumin: Synthetic function
  2. Bilirubin: Excretory function
  3. Aminotransferase (ALT, AST): Hepatocellular injury
  4. Ductal enzymes: Biliary tract disease

Ductal enzymes induction: Alcohol, Drug

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4
Q

Total proteins

A

Total proteins = Albumin + Globulin

Normal A/G ratio >1

Reflect
1. Nutrition status
2. Immune status
3. Liver synthetic function
4. Kidney function

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5
Q

Albumin

A
  • Synthesised exclusive by liver
  • reflects ***Synthetic function
  • t1/2: ~3 weeks

Decreased in:
1. Chronic liver disease / liver failure
2. Malnutrition
3. Increased loss (e.g. nephrotic syndrome, burns, protein-losing enteropathy)
4. Hyper-catabolic states (e.g. trauma, sepsis)
5. Inflammation (∴ called Negative acute phase reactant)

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6
Q

Coagulation proteins

A

Factors I (fibrinogen), II, V, VII, XI, X
- Synthesised by liver
- ***very short plasma t1/2
—> ∴ sensitive markers for assessing acute hepatocellullar dysfunction —> deterioration / improvement

Prothrombin time / INR: depends on factors II, V, VII, X, fibrinogen
- Prolonged PT (not enough factors):
—> Hepatocellular disease
—> Vitamin K deficiency (e.g. obstructive jaundice) (vit K needed for activating factors II, VII, IX, X)

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7
Q

Evaluation of protein synthesis

A

t1/2
Albumin: 21 days
Transferrin: 6 days
Pre-albumin: 2 days
Factor VII: 6-8 hours (short)

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8
Q

Bilirubin

A

Produced from metabolism of Heme

Sources:
- 85%: haemoglobin in mature RBC (destroyed in reticuloendothelial cells of liver, spleen, BM)
- 15%: other heme-containing proteins (e.g. cytochromes, myoglobins)

Different moieties in blood:
1. Unconjugated / Indirect bilirubin
- 80-90% total bilirubin in blood
- water insoluble
- bind tightly to albumin

  1. Conjugated / Direct bilirubin
    - directly reacts with diazosulfanilic acid —> azobilirubin without addition of alcohol
  2. δ-Bilirubin
    - Conjugated bilirubin
    - covalently bound to albumin
    - not routinely measured, requires special assay
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9
Q

***Metabolism of Bilirubin

A

Haemoglobin
—> **Heme (+ Globin)
—(oxidation by Heme oxygenase)—> Porphyrin break open
—> **Biliverdin + Free Fe
—(Biliverdin reductase)—> **Bilirubin (transported in blood in association with serum albumin)
—> **Liver conjugates Free Bilirubin (water-insoluble)
—> **Conjugated bilirubin (Bilirubin-glucuronide, water-soluble)
—> excreted into bile (gallbladder to gut)
—> Conjugated bilirubin
—> Deconjugated by bacteria in intestine
—> **Urobilinogen by bacteria in intestine

  1. Unabsorbed
    —> Urobilinogen —> **Stercobilinogen -(oxidation)-> **Stercobilin (excreted as faeces)
  2. Reabsorbed —> Liver —> **Blood circulation
    —> Urobilinogen -(kidneys)-> **    Urobilinogen -(oxidation)-> ***Urobilin (1% of total Urobilinogen excreted in urine)
  3. 10% Reabsorbed —> Liver
    —> Re-excreted in bile
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10
Q

Jaundice / Icterus

A
  • ↑ Bilirubin level (>30-40 μmol/L) —> Yellowing of skin and sclera

Causes:
1. Pre-hepatic: Unconjugated hyperbilirubinemia
2. Hepatic: Conjugated hyperbilirubinemia (intrahepatic cholestasis)
3. Post-hepatic: Conjugated hyperbilirubinemia

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11
Q

Bile salt vs Bilirubin

A

Bile salt:
- Synthesised by Liver from Cholesterol / by Bacteria in gut
- Pruritis if accumulate in skin

Bilirubin:
- Breakdown product by Liver from RBC
- Yellow pigment —> Jaundice / Brown colour in faeces

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12
Q

***Unconjugated hyperbilirubinemia

A

↑ Unconjugated bilirubin —> ***NO Bilirubinuria

  1. ↑ Bilirubin production
    - ***Haemolysis
  2. ↓ Hepatic conjugation
    - **Gilbert’s syndrome, **Crigler-Najjar syndrome
    —> Defects in UDP-GT gene
  3. Neonates
    - physiological jaundice
    - breast milk jaundice
    - congenital hypothyroidism
  4. Mild chronic hepatitis
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13
Q

***Conjugated hyperbilirubinemia

A

↑ Conjugated bilirubin —> ***Bilirubinuria —> Dark urine

  1. Heptocellular diseases
    - Hepatitis
    - Cirrhosis
  2. Bile duct obstruction
  3. Intra / Extra-hepatic cholestatic diseases
  4. Autoimmune cholestatic diseases (primary biliary cirrhosis, primary sclerosing cholangitis)
  5. Drugs (chlorpromazine, ofloxacin, cyclosporine)
  6. Total parenteral nutrition
  7. Inherited defects in excretion (Dubin-Johnson syndrome, Rotor syndrome)
  8. Neonates
    - biliary atresia
    - inborn errors of metabolism
    - α1-antitrypsin deficiency
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14
Q

Biliary tract obstruction

A

↓ Conjugated bilirubin delivery to gut
1. ↓ Urobilinogen reabsorbed back to liver (via enterohepatic circulation)
—> ↓ Urobilinogen but ↑ Conjugated bilirubin in urine
—> Tea colour urine (Dark urine)

  1. ↓ Stercobilinogen
    —> Clay-colour stool
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15
Q

Urine bilirubin

A
  • only Conjugated bilirubin / Urobilin is excreted in urine
  • Dipstick tests
  • ↑ blood level of Conjugated bilirubin —> excreted by kidneys —> ***tea-colour urine

False Positive:
- ***Phenothiazines

False Negative:
- Ascorbic acid (vit C)
- **Rifampicin
- Aged sample (conjugated bilirubin hydrolysed —> unconjugated bilirubin at room temperature)
- **exposure to UV light (bilirubin —> biliverdin)

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16
Q

Urinary Urobilinogen

A
  • Normally <1% of total Urobilinogen excreted in urine
  • very sensitive but non-specific test for liver damage / haemolytic disease

Increased:
Early hepatitis, Mild liver cell damage, Mild toxic hepatic injury
—> ↑ Conjugated bilirubin in gut
—> ↑ Urobilinogen

Decreased / Absent:
Obstructive Jaundice
—> ↑ Conjugated bilirubin in blood but ↓ Conjugated bilirubin into gut
—> ↓ Urobilinogen

17
Q

Liver enzymes

A

AST, ALT, ALP, GGT

Activity of enzyme in blood is a balance between:
- Rate of release into ECF compartment (e.g. Blood)
- Rate of clearance / uptake from ECF

Enzymes in blood mainly derived from:
- Metabolic breakdown
- Turnover of cells and tissues

Most enzymes:
- enzyme concentration gradient between intracellular and extracellular >100
- if blood sample haemolysed —> false ↑ in enzyme
- Cell membrane integrity —> crucial role in retaining enzymes within the cell

18
Q

ALT (SGPT) + AST (SGOT)

A

Parenchymal enzymes
- in Hepatocytes
- Liver cell damage: leak into blood

AST:
- heart, liver, skeletal muscle, kidney, pancreas, spleen, lungs, RBC (↓ concentration)
- Cytoplasm (cAST) + Mitochondria (mAST)

ALT:
- liver + kidney (heart, skeletal muscle, RBC)
- Cytoplasm ONLY
- ***more specific to liver pathologies than AST
- only aminotransferase in LFT in some labs

ALT, AST level:
- ↑ 10-100x —> Hepatocellular injury
- ↑ <10x —> Cholestasis
- **ALT > AST in most type of disease
—> **except: **Alcoholic hepatitis, **HCC, ***Widespread hepatic necrosis (release of mAST e.g. acute toxic / ischaemic liver injuries)
- enzyme level (大至小):
1. Ischaemic/toxic liver injury
2. Acute viral hepatitis
3. Autoimmune hepatitis
4. Alcoholic liver disease
5. Chronic hepatitis (may even be within ref range)
6. Liver cirrhosis (may even be within ref range)

19
Q

ALP

A
  • Ductal enzyme (different isoforms)

Location:
- Bone, Liver, Intestine, Placenta

2 sites of origins:
1. Sinusoidal surface of hepatocytes
2. Microvilli of bile canaliculi, bile ducts

ALP level:
1. Cholestasis:
—> ↑ (↑ ALP production —> some released into blood)

  1. Hepatocellular damage:
    —> Normally / slightly ↑
  2. Space-occupying lesions of liver (e.g. HCC, metastasis, liver abscess —> partial biliary obstruction):
    —> Isolated ↑ in ALP (accompanied by ↑ GGT, normal bilirubin) (similar to enzyme inducing medications)
  3. Other diseases
    - pregnancy (placental origin, most heat-stable)
    - high levels in children (active bone growth)
    - diseases of bone associated with ↑ osteoblast activity (fracture, bony metastasis, osteodystrophy, Paget’s disease)
    - some malignancies (Regan’s ALP)

Interpretation:
- Differentiation of sources of ALP is important (Bone, Liver, Intestine, Placenta)
- **Concomittant ↑ GGT —> Hepatic origin (if no alcoholic / enzyme inducing drugs)
- **Heat-stability test —> provide rough guide to source of ALP (Placental > Liver > Bone)
- Specific immunoassay for bone-ALP (costly)
- ***Electrophoresis: separation of different isoenzymes

20
Q

GGT

A
  • Ductal enzyme

Location:
- Bile canaliculi

Interpretation:
- **More specific to liver than ALP —> ↑ in Cholestasis
- Differentiate tissue origin of ↑ ALP
- **Induced by alcohol and drugs (phenytoin, phenobarbital, rifampicin)

21
Q

***Patterns of LFT

A
  1. Hepatocellular pattern
    - ↑ ALT, AST predominantly
    - viral hepatitis, drugs (paracetamol), ischaemic injury (shock, hepatic congestion due to heart failure)
  2. Cholestatic pattern
    - ↑ ALP, GGT, Bilirubin
    - gallstones, cholangitis, cholangicarcinoma, carcinoma of pancreas head, liver metastasis, primary biliary cirrhosis, ***liver cirrhosis, drugs (phenytoin, phenobarbital, rifampicin)
  3. Mixed pattern
    - ↑ ALT, AST, ALP, GGT, Bilirubin
    - hepatic insult is prolonged, irrespective of underlying / primary etiology

Assessment of liver enzyme abnormalities:
1. Predominant pattern (Hepatocellular vs Cholestasis)
2. Magnitude + Time profile of enzyme alteration

Pattern may be blurred esp. in prolonged / chronic disease
- prolonged obstruction —> significant liver cell destruction (also ↑ ALT, AST)
- acute hepatitis may develop cholestatic pattern (∵ intrahepatic cholestasis)
- hepatocellular enzymes may paradoxically ↓ in very advanced / end-stage liver failure

22
Q

Limitations of LFT

A
  1. Lack sensitivity
    - LFT may be normal in certain liver diseases e.g. early cirrhosis, non-cirrhotic portal fibrosis (rare), congenital hepatic fibrosis (very rare) etc.
  2. Lack specificity
    - Albumin may ↓ in other chronic disease, acute inflammatory conditions (negative acute phase reactant), proteinuria, other protein-losing condition
    - AST/ALT may ↑ in muscle diseases
    - Bilirubin may ↑ in haemolysis
23
Q

Case 1:
High Total bilirubin
High Conjugated bilirubin
High ALP
Normal ALT
Normal Total protein
Normal Albumin

A
  • Hyperbilirubinemia (Conjugated bilirubin)
  • Elevated ALP but normal ALT —> Ductal pattern

Probably obstruction e.g. Cholangitis

  • Check if GGT also raised —> Hepatic origin
  • Ultrasound —> look for biliary problem
24
Q

Case 2:
High GGT
High ALP
Normal AST
Normal Total protein
Normal Albumin
Normal Total bilirubin

A

High ALP + High GGT —> Hepatic origin
- need to confirm if alcohol-induced / drug-induced
- if not —> Hepatic origin

Confirm with heat stability index / electrophoresis

Bilirubin normal —> Space-occupying lesion causing partial biliary obstruction
—> normal ∵ liver has high capacity, not normally affected by small lesions

25
Q

Case 3:
High ALT
High GGT
High ALP
High Total bilirubin
Low Albumin
Normal Total protein

History:
Chronic Hep B
Spider naevi
Palmar erythema
Palpable liver and nodular

A

Chronic liver disease

Assessing severity:
- Albumin to test synthetic function
- Clotting factors: PT should be prolonged

Acute confusion and hepatic tremor
—> Ammonia toxicity —> Hepatic encephalopathy —> test NH3 in blood

26
Q

Case 4:
High ALP
Normal GGT
Normal ALT
Normal Total bilirubin

History:
Low back pain
Gross haematuria
Urinary urgency on/off

A

GGT normal —> NOT hepatic origin
Gross haematuria, urinary urgency —> urinary tract problem
High ALP —> may be bone origin

Considering low back pain
—> may be Tumour metastasis to bone (e.g. prostate cancer)

Confirming clinical suspicion:
- Heat stability index
- Imaging

27
Q

Case 5:
Increasing + High Total Bilirubin
Decreasing but still high ALT
High GGT throughout
Increasing + High ALP
Decreasing + Low Albumin
Normal total protein

History:
Fever
Rigor
Poor appetite
Right upper quadrant pain
2 week holiday in Vietnam

A

Enzymes go first before Total bilirubin (ALT peak before Total bilirubin)
Mixed pattern

Likely diagnosis:
Acute hepatitis with cholestatic element (Intrahepatic cholestasis)

Further test:
Serology —> Hepatitis A, B, D

28
Q

Case 6:
High Total bilirubin
High ALT
High GGT
High ALP
Low Albumin
Normal Total protein

History:
Chronic heavy drinker
Slightly yellow sclera
Enlarged, hard, non-tender liver

A

Markedly increased GGT (>100 fold) than ALT increase
—> additional increase in GGT due to induction by alcohol
—> pattern of alcoholism

Helpful additional parameters:
- AST (normally ALT > AST except in alcoholic hepatitis: AST > ALT)

29
Q

Case 7:
Increasing + High Total bilirubin
Normal Conjugated bilirubin
Normal ALT
Normal GGT
Normal ALP

History:
Good past health
Routine medical checkup

A

Probably benign

Normal ALT —> Hepatocyte ok
Normal GGT, ALP —> Biliary tract ok

Isolated increase in Total Bilirubin but normal Conjugated bilirubin
—> imply increase in Unconjugated bilirubin
—> probably genetic disease due to good past health
—> Gilbert’s syndrome (decreased UGT activity —> mild liver disorder)

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