LFTs and liver function assessment

General approach to abnormal LFTs:

Primary liver disorder vs secondary liver derangement?
Intrahepatic vs non-hepatic cause?
Is this a clinically significant derangement?
Acute vs chronic? If chronic, is it compensated or decompensated?

Bilirubin

Cause
- Pre-hepatic
  - Haemolysis
    - Rarely produces bili levels > 50-90micromol/L
- Hepatic
- Post-hepatic
Conjugated/unconjugated has limited value in clinical practice. Conjugated levels are highest in cholestatic disease and fulminant liver failure. Unconjugated hyperbilirubinaemia may reflect haemolysis, physiological neonatal jaundice or genetic defects (including Gilbert's).
Renal failure will reduce renal clearance of conjugated bili, which can have a significant effect on serum levels.

Albumin

Factors impacting levels: nutrition, hepatic synthesis, losses (nephrotic syndrome, protein-losing enteropathy)
Half-life of 17-26 days - usually chronic rather than acute dysfunction

INR

Vitamin K-dependent clotting factors are synthesised by the liver. Factors VII, IX and X often fall with significant disease.
Derangements can develop quickly, due to short half-life. Can even occur within hours (fatty liver of pregnancy).
Cholestasis can lead to vitamin K malabsorption and raise INR that way. If the INR fails to come down with vitamin K, that suggests hepatocellular dysfunction.

Transaminases

Best conceptualised as reflecting hepatocyte damage or injury - do not reflect functional capacity. Enter the circulation following hepatocellular lysis, or sometimes sublethal hepatocyte injury.
Aetiology
- NAFLD
  - Most common cause of transaminase derangements in Australia.
- Viral hepatitis
  - ALT levels usually higher than AST
- Alcoholic liver disease
  - AST usually more than double ALT (in the presence of cirrhosis, the diagnostic value of AST:ALT ratios is lost)
- Marked elevations (>1000 U/L) often reflect viral hepatitis, drug reactions, or acute exacerbations of chronic autoimmune hepatitis. Can also be seen with cholestasis, shock and cardiac failure.
- Hepatic mets
ALT (alanine aminotransferase)
- Liver-specific: elevation here is highly suggestive of liver disease
AST (aspartate aminotransferase)
- Enzyme found in liver, skeletal muscle, myocardium, kidney, pancreas, erythrocytes. Damage to any of these cell lines will result in derangements.
Persistent elevation requires investigation to exclude significant chronic liver disease.

ALP (alkaline phosphatase)

Enzyme localised to the biliary membrane of hepatocytes. Marker of biliary disease or a hepatic infiltrative disorder.
Also found in bone (Paget's disease, tumours involving bone, acromegaly, fractures), intestine, kidney, placenta, and can be elevated with damage to these organs. Also will be high during pregnancy and during periods of rapid growth (neonatal and adolescent periods). Can see a mild rise during infarction of heart, lung, GIT and kidneys.
75% of patients with cholestasis have ALP > 3x ULN
- It CAN be normal in cholestasis.
Mild elevations of ALP are often seen in hepatocellular injury.

GGT (gamma glutamyl transpeptidase)

Membrane-bound enzyme present in liver, pancreas, kidney, intestine and prostate
Levels increase with any liver disease. NO increase in a normal pregnancy or with bone disease.
Associated with ALP in cholestatic disease - an elevated GGT supports hepatic origin of an elevated ALP.
Heavy drinkers will often have an elevated GGT. Should normalise over 2-5 weeks of abstinence.
Also consider:
- Biliary disease
- Pancreatitis
- Obesity
- Hyperlipidaemia
- Anorexia nervosa
- Diabetes mellitus
- Hyperthyroidism
- Porphyria
- MI
- Drugs - barbiturates, tricyclic antidepressants, anticonvulsants

LDH (lactate dehydrogenase)

Glycolytic enzyme present in all cells
Will be elevated out of proportion to transaminases in ischaemic liver injury and secondary malignancy

AFP

Elevation > 1000 U/L is most often due to HCC

Jaundice

Pre-hepatic

- Gilbert's disease
  - Most common cause of unconjugated hyperbilirubinaemia
  - Mild hereditary deficiency of glucuronyl transferase - 5-7% of population
  - Disease exacerbated by fasting and febrile illness
  - If serum ALP and transaminases are normal, haemolysis is excluded, and hyperbilirubinaemia is unconjugated, requires no further investigation
- Bilirubin overproduction
  - Aetiology
    - Chronic haemolysis e.g. prosthetic heart valves
    - Hereditary spherocytosis
    - Acute intravascular haemolysis
      - Sickle cell crisis
      - Transfusion reaction
    - Acute extravascular haemolysis
      - Reabsorption of haematoma
    - Ineffective erythropoiesis (leads to destruction of RBCs in bone marrow)
      - Aetiology
        Pernicious anaemia
        
        Severe IDA
        
        Sideroblastic anaemia
        
        Folate deficiency
        
        Lead poisoning
  - Diagnosis
    - Blood film
    - Haptoglobin (will be low)
    - LDH (will be high)
- Impaired delivery to liver
  - Usually the result of portosystemic shunting (cirrhosis and CCF)

Hepatic

Post-hepatic

- Intra-hepatic cholestasis
  - Idiosyncratic drug reaction (augmentin, flucloxacillin, etc - see table below)
  - Viral hepatitis, especially hepatitis A, can occasionally do it
- Extra-hepatic obstructive jaundice
  - Usually stones or jaundice

Differentiating hepatocellular and obstructive:

Post-surgical/ICU jaundice

Increased bilirubin production
- Destruction of transfused cells
- RBCs damaged by cell saver
- Reabsorption of haematomas
- Other causes of haemolysis - see above
Liver ischaemia
- Check for presence of hypotension in perioperative period
- Transaminases rise rapidly to 1,000-10,000 with hyperbilirubinaemia and fall within 24-48 hours if normal perfusion is restored
Systemic infections causing cholestasis
Drug toxicity - often antibiotics, consider anaesthetic agents
TPN
- TPN can cause:
  - Fatty liver
  - Cholestasis
  - Portal inflammation
  - Gallstone formation
  - Occasionally steatohepatitis and cirrhosis
- Usually arises 1-4 weeks after initiation and resolves on discontinuation
  - Especially transaminase levels go up within 1 week, with ALP and GGT rising later. Increases in bilirubin can occur but are unusual
- Usually, it's multifactorial. Transaminase rise due to glucose intolerance. Cholestasis due to abnormal lipid metabolism.
- Small adjustments to TPN composition can fix this.

Further screening

Standard screen:

hepatitis A, B and C serology

EBV

CMV

HIV

antinuclear antibody (ANA)

smooth muscle antibody

antimitochondrial antibody

iron studies

TSH

cholesterol

Viral hepatitis

Paracetamol level
Liver biopsy - only if patient is not getting better or getting worse, and significant illness

The well patient with abnormal LFTs

Most commonly NAFLD, alcohol or drugs
First consider causes based on clinical context
History
- Hepatitis
  - Overseas travel/migration - Southeast Asia
  - Exposure to blood products/injection/tattooing
  - Sexual history
  - Exposure to others with liver disease
- Cholestatic factors
Examination
- Signs of chronic liver disease as above

Immunocompromised patient with jaundice

HIV
- Biliary pain and fever - AIDS cholangiopathy
Mycobacterium avium-intracellulare
Drugs
CMV
Bacillary peliosis hepatis
Lymphoma
Mycobacterium tuberculosis
Kaposi's sarcoma
Hepatitis B or C
Cryptococcal infection

Jaundice in patients with transplanted organs

Hepatic graft versus host disease
Veno-occlusive disease - common in first few weeks after BM transplant
Viral hepatitis
Drug-induced liver disease - cyclosporin

References:

'Abnormal liver function tests results' chapter in Clinical Gastroenterology 3e (Talley).

Assessment of liver function

Routine screening tests
- LFTs
  - Useful starting point
- Albumin
  - Synthesised exclusively in the liver - good general measure of hepatic synthetic function
  - Decreased synthesis in chronic malnutrition, acute injury/infection/inflammation
- PT/INR
  - Prolonged PT is a sign of advanced chronic liver disease
- Thrombocytopaenia
  - Provides insight into severity of portal HTN in patients with liver disease
Specific diagnostic tests
- Liver screen - see above
- Tumour markers (AFP/CEA)
- Tests based on liver's ability to clear exogenously administered substances are not very useful because they don't detect subclinical disease
  - Aminopyrine breath test (based on cytochrome P450 clearance of radiolabelled aminopyrine)
  - Antipyrene test
- Technetium-99m-galactosyl human serum albumin scintigraphy and Tc-99m-mebrofenin hepatobiliary scintigraphy are potentially useful to identify patients at risk for post-resectional liver failure who might benefit from liver-augmenting techniques
Quantitative tests
- Child-Pugh reflects peri-operative mortality after partial hepatectomy