Transcript What are Liver Function Tests (LFTs)

Liver Function Tests
&
Clinical Biochemistry of Liver Disease
Mohamad Nusier MD. PhD.
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)
Albumin 43 (34-48) g/L
Total Bilirubin 7 (0 – 21) umol/L
Alkaline Phosphatase 67 (35 -104) IU/L
GGT 93 (5 – 36) IU/L
Alanaine transaminase (ALT) 40 (6 – 31) IU/L
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 26.2 (20 – 60) mg/dl
•Transferrrin Saturation 34% (15 – 45) %
•PT 14.8 (11.5 – 15.0) s
•APTT 30.4 s (25 – 35) s
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
Liver
-Normal size
-Subcapsular surface of the liver has a nodular outline
-Liver texture has a diffuse slightly coarse appearance
Appearances consistent with Cirrhosis
Learning Point
• The only indicator for the presence of
underlying cirrhosis in this patient were her
mildly abnormal LFTs
• Pay attention to minor abnormalities!
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
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
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
What role do LFTs in clinical management ?
Detecting the presence of liver disease
Indicating the broad diagnostic category of the liver disease
Monitoring treatment
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
Clinical History
C2H5OH Hx
Family Hx – Hemochromatosis, Wilson Disease,
Drug Hx – What medication is the patient taking?
Travel Hx – Recent travel, Blood transfusions
Bilirubin production and metabolism
UDP
Glucoronosyl
transferase
Hyperbilirubinaemia
•Jaundice evident with Bilirubin levels 35-70 μmol/L
•Normally 95% of plasma bilirubin is unconjugated
Unconjugated - prehepatic
*(No bilirubinuria)
Conjugated – Hepatic/posthepatic
(Bilirubinuria)
•Hemolysis
•Resolving hematoma
•Gilbert’s Syndrome
•Crigler-Najjar syndrome
•Hepatocellular diseases
•Cholestatic diseases
•Dubin-Johnson**
•Rotor’s syndrome**
*Except in Nephrotic syndrome
**Benign congenital conjugated hyperbilirubinemia
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
Causes of neonatal jaundice
Unconjugated bilirubin level > 300μmol/L may be associated
with Kernicterus (brain damage due to uptake of unconjugated bilirubin)
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
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
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
Approach to an asymptomatic patient with elevated ALT/AST
Elevated AST/ALT
? Muscle
problem
Repeat test
Normal
Still Elevated
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
Causes of a Cholestatic Pattern of LFTs
Elevated ALP and GGT ± Bilirubin, relative to transaminases
Intrahepatic
(Bilirubin not elevated)
Extrahepatic
(Bilirubin elevated)
•Medications
•TPN (Total Parenteral Nutrition)
•Sepsis
•Postoperative
•PBC (Primary Biliary Cirrhosis)
•Alcoholic hepatitis
•Liver metastasis
•Pregnancy-related
•CCF (Congestive Cardiac Failure)
•Cholelithiasis (CBD)
•Malignancy
•Primary sclerosing cholangitis
GGT is useful in differentiating Liver as a cause of elevated ALP
An approach to the patient with isolated elevation in ALP
Elevated ALP
Normal
What is GGT?
Elevated
bone, placenta,
Intestine etc.
US/CT/MRI
Biliary dilation
No abnormality
Focal mass
Medications
Primary biliary cirrhosis (PBC)
Anti-mitochondrial antibodies (AMA
PBC
-AMA
Consider other
causes
Specialized investigations
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”
Reference Ranges for LFTs
Biochemistry Department, St James’s Hopsital
Albumin
Bilirubin
35-50 g/L
ALP*
40-120 IU/L*
AST
ALT
7-40 IU/L
7-35 IU/L
GGT
10-55 IU/L
<17 mmol/L
* NB: Reference Range is age related
Paracetamol Overdose
•Hepatic necrosis observed within 36-72 hours
•Accumulation of breakdown product NAPQI
Early diagnosis and treatment of
paracetamol OD is essential
•Ideally before 12 hours post ingestion
•N-acetylcysteine (Parvolex) is an effective agent