1. Clinical Biochemistry of Liver Disease
Liver Function Tests
&
Clinical Biochemistry of Liver Disease
Mohamad Nusier MD. PhD.

2. Illustrative case History
75 yr old female presented to her GP
C/O dyspepsia and “back “ pain
Background hx:
Breast Ca – Rx with mastectomy, Tamoxifen
Variegate Porphyria
Type 2 Diabetes mellitus
Subclinical Hypothyroidism
GP requested Liver Function Tests (Liver Profile)

3. Albumin 43 (34-48) g/L
Total Bilirubin 7 (0 – 21) umol/L
Alkaline Phosphatase 67 ( ) IU/L
GGT 93 (5 – 36) IU/L
Alanaine transaminase (ALT) 40 (6 – 31) IU/L

4. In view of abnormal LFTs the GP ordered further investigations
Anti Smooth Muscle Abs (ASMA) - negative
Anti Mitochondrial Abs (AMA) - negative
Alpha-1 Antitrypsin 1.5 (0.9 – 2.0) g/L
Caeuroloplasmin (20 – 60) mg/dl
Transferrrin Saturation 34% (15 – 45) %
PT 14.8 (11.5 – 15.0) s
APTT s (25 – 35) s
APTT: activated partial thromboplastin time

5. GP requested imaging studies in view of negative blood tests
Ultrasound of abdomen and pelvis
Liver
Diffuse inhomogenous somewhat echogenic texture
No focal lesion
Bile ducts not dilated
CT scan of abdomen
Normal size
Subcapsular surface of the liver has a nodular outline
Liver texture has a diffuse slightly coarse appearance
Appearances consistent with Cirrhosis

6. Learning Point
The only indicator for the presence of underlying cirrhosis in this patient were her mildly abnormal LFTs
Pay attention to minor abnormalities!

7. What are the functions of the liver?
Key role in intermediary metabolism
e.g. gluconeogenesis, glycolysis, ketogeneis, lipid synthesis
Protein synthesis – including many plasma proteins and blood
clotting factors
Bile secretion and role in digestion
Primary site of xenobiotic detoxification -drug and toxin metabolism
Ureagenesis - ? Role in acid-base balance

8. What are Liver Function Tests (LFTs)
Total Bilirubin
Conjugated vs. Unconjugated
Alkaline Phosphatase (ALP)
-Reference range varies with age – higher in childhood
and adolescence
Isoenzymes e.g. bone, liver, intestine, malignancy
Bile flow
Gamma-glutamyl transferase (GGT)
-Sensitive indicator of liver disorder
-Cholestasis
-Induced by many drugs and toxins e.g. C2H5OH,
pheytoin, barbiturates, ? statins

9. Transaminases
-Alanine aminotransferase (ALT)
-Aspartate aminotransferase (AST)
-ALT is more liver specific
-AST is also found in cardiac and skeletal muscle
-Hepatocellular integrity
Albumin
- Plasma transport protein
Assesses Protein synthesis in liver
Prothrombin time
Extrinsic pathway of coagulation
Reflects protein synthetic function

10. What role do LFTs in clinical management ?
Detecting the presence of liver disease
Indicating the broad diagnostic category of the liver disease
Monitoring treatment

11. Specialised Liver-related tests
Viral Hepatitis Screen – A, B, C etc.
Autoimmune Heptitis screen – AMA (antimitochondrial antibody), ASMA (Antismooth muscle antibodies)
Serum protein electrophoresis
α1- antitrypsin
α fetoprotein (AFP)
Transferrin Saturation, Ferritin, HFE Genotyping (hereditary hemochromatosis)
Ceruloplasmin, Plasma, Urine Copper
Ultrasound scan, CT, MRI
Biopsy

12. Clinical History C2H5OH Hx
Family Hx – Hemochromatosis, Wilson Disease,
Drug Hx – What medication is the patient taking?
Travel Hx – Recent travel, Blood transfusions

13. Bilirubin production and metabolism
UDP
Glucoronosyl
transferase

14. Hyperbilirubinaemia
Jaundice evident with Bilirubin levels μmol/L
Normally 95% of plasma bilirubin is unconjugated
Conjugated – Hepatic/posthepatic
(Bilirubinuria)
Hepatocellular diseases
Cholestatic diseases
Dubin-Johnson**
Rotor’s syndrome**
Unconjugated - prehepatic
*(No bilirubinuria)
Hemolysis
Resolving hematoma
Gilbert’s Syndrome
Crigler-Najjar syndrome
*Except in Nephrotic syndrome
**Benign congenital conjugated hyperbilirubinemia

16. Gilbert’s Syndrome Present in 5% of the population Males > females
Genetic origin
– insertion of TA in promoter region of UGT-1A gene
Exacerbated by fasting and illness
Confirm unconjugated hyperbilirubinemia
Rule out hemolysis CBC, Reticulocyte count
Rule out underlying liver disease

17. Causes of neonatal jaundice
Unconjugated bilirubin level > 300μmol/L may be associated
with Kernicterus (brain damage due to uptake of unconjugated bilirubin)

18. Patterns of LFTs Hepatocellular Predominant elevation in AST/ALT ratio
Both enzymes require pyridoxal-5'-phosphate (vitamin B6) in order to carry out this reaction, although the effect of pyridoxal-5'-phosphate deficiency is greater on ALT activity than on that of AST. This has clinical relevance in patients with alcoholic liver disease, in whom B6 deficiency may decrease ALT serum activity and contribute to the increase in the AST/ALT ratio that is observed in these patients
Cholestatic
Predominant elevation in ALP with GGT ± Bilirubin
Mixed
Elevation in both AST/ALT, and ALP/GGT ± Bilirubin

19. Marked elevations in ALT/AST > X5
Causes of a Hepatocellular Pattern of LFTs
Marked elevations in ALT/AST > X5
(patient likely to be symptomatic)
Viral hepatitis
Ischaemic hepatitis
Autoimmune hepatitis
Drug/toxins e.g. alcoholic hepatitis

20. Causes of a Hepatocellular Pattern of LFTs
Mild/Moderate elevations in ALT/AST < X5
(patient may be asymptomatic)
Chronic Hepatitis
ALD (Adrenoleukodystrophy), Beta Oxidation of fatty acids disorder
NAFLD/NASH (Nonalcoholic fatty liver disease /Non-alcoholic steatohepatitis):
associated with obesity, T2DM, Hyerlipidemia
Metabolic liver disease:
Hereditary hemochromatosis, Wilson Disease, Alpha-1 antitrypsin deficiency
Drugs
Autoimmune Liver Disease

21. Approach to an asymptomatic patient with elevated ALT/AST
Elevated AST/ALT
Repeat test
? Muscle
problem
Still Elevated
Normal
Check CK
Elevated
Normal
Likely Liver Aetiology
Drug Hx etc
Viral serology
AI hepatitis screen
Fe/TIBC/Ferritin/HFE genotyping
Caeuruloplasmin if < 40 yr
A1AT
Celiac screen
Ultrasound scan
MRI/CT Bx

22. Causes of a Cholestatic Pattern of LFTs
Elevated ALP and GGT ± Bilirubin, relative to transaminases
Extrahepatic
(Bilirubin elevated)
Cholelithiasis (CBD)
Malignancy
Primary sclerosing cholangitis
Intrahepatic
(Bilirubin not elevated)
Medications
TPN (Total Parenteral Nutrition)
Sepsis
Postoperative
PBC (Primary Biliary Cirrhosis)
Alcoholic hepatitis
Liver metastasis
Pregnancy-related
CCF (Congestive Cardiac Failure)
CBD: common bile duct;
GGT is useful in differentiating Liver as a cause of elevated ALP

23. An approach to the patient with isolated elevation in ALP
Elevated ALP
Normal
What is GGT?
Elevated
bone, placenta,
Intestine etc.
US/CT/MRI
No abnormality
Biliary dilation
Focal mass
Medications
Consider other
causes
PBC
-AMA
Primary biliary cirrhosis (PBC)
Anti-mitochondrial antibodies (AMA
Specialized investigations

24. Other LFTs Serum ammonia
used for investigation of hepatic encephalopathy
-lacks sensitivity and specificity
-useful for investigation of urea cycle disorders
Serum LDH
-included in LFTs
-5 isoenzymes – heart, erythrocytes, skel mus, liver, others
-not specific for liver? role in ischemia-related abnormal LFTs
-useful in monitoring certain malignancies e.g. B-cell lymphoma
- “not really a LFT”

25. Reference Ranges for LFTs Biochemistry Department, St James’s Hopsital
Albumin
35-50 g/L
Bilirubin
<17 mmol/L
ALP*
IU/L*
AST
7-40 IU/L
ALT
7-35 IU/L
GGT
10-55 IU/L
* NB: Reference Range is age related

26. Hepatic necrosis observed within 36-72 hours
Paracetamol Overdose
Hepatic necrosis observed within hours
Accumulation of breakdown product NAPQI
NAPQI (N-acetyl-p-benzoquinone imine)

27. Early diagnosis and treatment of paracetamol OD is essential
Ideally before 12 hours post ingestion
N-acetylcysteine (Parvolex) is an effective agent