Clinical Biochem 4 Flashcards
What are the 3 categories of Liver function tests (LFTs)
- Liver function
- Liver injury
- Non-specific markers
What does liver function measure? What are common tests for this?
- Measures the ability of livers to produce proteins (albumin, clotting proteins) (synthetic ability)
- liver usually has enormous synthetic reserve
Common tests of synthetic function:
- albumin
- Prothrobin time/ international normalized ratio (INR)
What does liver injury test measure?
Measure the health of hepatocytes.
What are common tests for hepatocellular injury? what about for cholestasis (slowing or stalling of bile) ?
Hepatocellular injury
- Aspartate aminotransferase (AST)
- Alanine aminotransferase (ALT)
Cholestasis
- Alkaline phosphate ALP
- Gamma-glutamyl transpeptidase (GGT)
What are non-specific markers tests? give examples
Tests that overlap cholestatic disease and heptocellular injuries
eg. - Lactate dehydrogenase test
- bilirubin test
Albumin
Reference range?
Role?
Low levels + non-hepatic causes?
Reference range?
- 35-50g/L
Role?
- Regulates plasma fluid
- binds/transport hormones, anions, drugs and fatty acids
Low levels + causes?
- <20g/L result in fluid imbalance like edema, ascites, pulmonary edema
Caused by
- malnutrition/malabsorption
- GI/kidney albumin loss
- inc. fluid volum (dilution)
- pregnancy
- burns, trauma, inflammation
What are limitations for using albumin as a measure of liver function? (2)
- liver has a larger capacity of albumin than needed for normal functioning
- Albumin has a long plasma half life and therefore serum albumin changes lag behind reduced liver production
What is the prothrombin time/INR used for?
measures the speed of the coagulation cascade allowing to assess the livers production of vitamin K dependant clotting proteins
- therefore, increased INR suggests impaired hepatic synthetic capacity
What specifically does prothrombin time measure? What are normal times
Time it takes for plasma to clot after addition of a tissue factor
(10-13 seconds)
What specifically is the international normalised ratio (INR)? Normal value?
What does a high value indicate?
- The PT, but normalized to the lab in which the measurement is done (should be the same no matter the PT)
Normal: 0.8-1.2
Increase in INR or PT
- indicate a decrease in livers production of clotting factors
What are some non-hepatic causes of increased INR/PT? How do you rule out non-hepatic causes?
VitK deficiencies from
- anticoagulants
- other drugs
- Malnutrition (lack of vit K)
- Fat malabsorption (reduction in vit K absorption)
**administer VitK
Explain cholestatic disease? what does it interfere with?
- condition in which substances normally excreted into bile is remained in the systemic circulation
- interferes with metabolism/secretion of bilirubin somewhere in the tract
- implies obstruction to biliruibin synthesis or secretion
What are symptoms of cholestatic disease?
- Jaundice (yellowing skin, white eyes) (high bilirubin)
- Pruritis (itching) from high bile salts
- Xanthomas (lipid deposition)
- Malabsorption of fat-soluble vitamins (ADEK)
- anorexia
- lipid deposits in skin
Explain the ALP alklaine phosphatase test for cholestatic? why is it used?
- Enzyme that transports metabolites across cell membranes
- Cholestasis enhances ALP synthesis and release
- Accumulation of bile salts increases
Describe assessment of ALP for a cholestatic disorder
4x normal
3x normal or less
- Use GGT test to confirm OR
- use electrophoresis to fractionate ALP isozyme
Describe GGT gamma glutamyl transpeptidase. What is it used for?
Billary excretory enzyme
Useful to determine if ALP has a hepatic origin
What values of ALP and GGT indicate:
- non-hepatic origin
- non Liver disease
Non-hepatic origin
- Abnormal high ALP + normal GGT
- high GGT + normal ALP
- high GGT + high ALP = usually liver cause
What does the hepatocellular injury involve?
- involve inflamed or damaged hepatocytes (not the biliary tract as opposed to cholestatic disease)
Where is ALT highest activity found
highest activity in the liver
Where is AST highest activity
highest activity in the heart
What does an increase AST without an increase in ALT suggest?
either cardiac or muscle disease
High sensitivity (SNOUT) for AST/ALT
Negative results are likely to be true negatives (low false negative rates)
- Small % of people WITH hepatocellular disease will test normal AST/ALT
Low specificity SPIN for AST/ALT
Positive results are likely to be false positive
(high specificity would = low false positive)
- Large % of people WITHOUT hepatocellular disease will test positive
Explain mild, moderate, and marked elevation in ALT/AST concentration
Mild: <5 times upper reference range limit
- mild + elevation of other liver markers/repeated elevations
Moderate: 5-10 times the upper reference range limit
Marked: 10+ times the upper range limit
- moderate-marked = acute hepatic injury causing high aminotransferases
What are some limitations for using AST/ALT as a measure of liver injury
- peak/trough
- causes of false elevation
- 10-15% variation of aminotransferases (low at 8 am, high at 4pm)
- Other causes of false elevation
○ Muscular origin + high creatine kinase
○ Drugs
○ Exercise - Aminotransferases fall with dialysis
- Levels can also be normal even with liver damage
- Other causes of false elevation
Explain the variation of aminotransferase in liver diseases
- elevation of ALT/AST can help indicate the cause for hepatocellular injury, but not the prognosis of the disease
ex. lower aminotransferase for liver cirrhosis, (a chronic disease, poor prognosis) vs. aschemic or toxic liver injury which can be acute with full recovery
What are the 4 evaluations of liver injury markers
- magnitude of aminotransferase alteration
- Consider patient specific factors (age, meds, conditions, timing of test)
- Compare values to recent values (asses rate of change)
- Assess trends/patterns (inc. or dec)
Lactate dehydrogenoase LDH
Reference range?
Where is found?
What is it used to diagnose?
Causes of high LDH?
Reference range?
- 100-210 IU/L
Where is found?
- found in most tissue (not just liver)
What is it used to diagnose?
- ischemia (inadequate supply of blood esp heart)
- Liver Cancer
Causes of high LDH?
- Hepatitis, billiary obstruction, metastatic liver disease, ischemia, cirrhosis exacerbation
- affected by fewer medications than aminotransferases
ADH to LDH
What does more than 1.5 ratio differentiate?
less than 1.5 ratio?
1.5+: differentiates between viral hepatitis and acute ischemic hepatitis
<1.5: occurs during acetaminophen toxicity
What can you compare to indicate where in the liver the injury lies?
Comparing conjugated vs unconjugated bilirubin levels.
Conjugated: Water soluble (direct)
- always has hepatic cause
Unconjugated: not water soluble, sent to liver (indirect)
- not always hepatic cause
is bilirubin a sensative indicator for hepatic dysfunction/prognosis?
No
What are potential diseases from high bilirubin (hyperbilirubinemia) (2)
Jaundice
- yellow skin/sclera
Kernicterus in infants
- lethargy, seizure, death
What are 2 causes of hyperbilirubinemia
- increased bilirubin production (extrahepatic)
- inc breakdown of hemoglobin (RBCs) - Impaired uptake (processing) of unconjugated biliruibin by the liver (intrahepatic)
What does unconjugated hyperbilirubinemia + high aminotransferases indicate?
likely hepatobiliary disease (liver disease)
What does unconjugated hyperbilirubinemia and normal aminotransferases indicate? cause?
No liver disease but possibly:
- extra bilirubin production (eg. hemolysis)
- neonatal jaundice
- Gilbert’s syndrome
What are possible causes of conjugated hyperbilirubinemia? when is it defined?
Causes
- obstruction of biliary tract
- damaged hepatocytes or bile ducts
***Always reflect hepatobiliary disease
Defined when direct (conjugated) bilirubin is greater than 50% of total bilirubin
- bilirubin still in normal range
- bilirubin still very low in serum
Differentiate between conjugated and unconjugated bilirubin in cholestatic disease vs. hepatocellular injury
Cholestatic disease
- high conjugated hyperbilirubinemia
-light coloured stool
- in conjuction with elevation in ALP and GGT
Hepatocellular
- mixed conjugated and unconjugated bilirubin
- in conjunction with AST and ALT
What is the child-pugh scoring for?
Used for chronic liver disease prognosis
What are the primary determinants of hepatic clearance for dose adjustment? (2)
- Intrinsic clearance
- Hepatic blood flow
What is the initial screening used for dose adjustment for abnormal hepatic synthetic function?
- INR
- Albumin
What does a good hepatic function and hepatic disease indicate in NON prodrugs
- bioavailability
Good hepatic function:
- low bioavailability of drug –> inc dose
Hepatic disease
- high bioavailability of drug –> dec dose
What does a good hepatic function and hepatic disease indicate in PRODRUGS (activated by liver)
Good hepatic function:
- high activity of drug –> decrease dose
Hepatic disease
- low activity of drug –> inc dose
What do drugs that are highly extracted indicate? What should you do with liver dysfunction?
- High first pass metabolism
- lots of drug taken up by liver (high bioav)
- **decrease dose to maintain cmax values
What do drugs that have low extraction indicate? What should you do with liver dysfunction?
- Low first pass metabolism
- less drug is taken up by liver (less bioav)
- **need to adjust dose
What consideration should you have for cholestatic disease?
- avoid drugs that cause/worsen cholestasis
What consideration should you have for cirrhosis disease?
likely have impaired renal function (overestimated CrCl is common)
