Dr.Navas Shareef .P .P
Liver Function Test
• Albumin
• Bilirubin:
• Total Bilirubin
• Direct Bilirubin (conjugated bilirubin)
• Serum aminotransferases
• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Alkaline Phosphatase
• Prothrombin time
The Approach
Important questions to address:
• Acute vs. chronic (6 months, ?cirrhosis)
Recent insults to the liver?
EtOH, medications, pregnancy, hepatitis, herbs,
gallstones, hypotension, toxins
• Asymptomatic vs. symptomatic
?impaired function
The Approach
• Hepatic vs cholestatic
• Magnitude of enzyme alteration (ALT >10x vs
minor abnormalities)
• Rate of change
• Nature of the course of the abnormality (mild
fluctuation vs progressive increase)
Albumin
• most important plasma protein made by the liver
• accounts for 65% of protein in serum
• half-life ~
17-21 days
• Production is controlled by multiple factors including
nutritional status, serum oncotic pressure, cytokines, and
hormones
• useful indicator of liver function
• Other causes of decrease:
sepsis or multiple organ failure
acute liver failure
dietary
Bilirubin
• Used to determine liver’s ability to clear
endogenous/exogenous substances from the circulation
• derived mainly from hemoglobin (95%)
• continuous production (300 mg daily)
• normal values of “total” bilirubin = 0.1-1.0 mg/dL
• Jaundice usually develops with a bilirubin ≥ 3 mg/dL
Direct Bilirubin
Indirect Bilirubin
• conjugated
• unconjugated
• lipid soluble
• non-polar
• not in urine
• Elevated with hemolysis,
hepatic disease
•
•
•
•
water soluble
polar
seen in urine
elevated with biliary
obstruction and
hepatocellular disease.
Unconjugated hyperbilirubinemia
• Indirect bilirubin fraction >85% of total bilirubin
occurs with increased bilirubin production or in
defects of hepatic uptake or conjugation, which in
turn may be inherited or acquired
• Gilbert’s syndrome( 3-7% population ):benign
disorder characterized by mild unconjugated
hyperbilirubinaemia,which is often exacerbated by
fasting & infections. It does not require any specific
treatment and the patient should be reassured.
CONJUGATED
HYPERBILIRUBINEMIA
• Direct bilirubin >15% of total bilirubin
• inherited or acquired defects in hepatic excretion.
• Bilirubin levels have prognostic significance in alcoholic
hepatitis, primary biliary cirrhosis, and in acute liver
failure.
• As conjugated bilirubin is excreted in urine, bilirubin
levels rarely exceed 6mg/dl in the absence of renal
failure or haemolysis.
Bilirubin production
and metabolism
1g Hb=34mg Br
UDP
Glucoronosyl
transferase
hepatic clearance reflects:
1. delivery to hepatocyte  hemolysis
2. uptake by hepatocyte  shunts, drugs (i.e., sulfa)
3. transport within hepatocyte  drugs, genetics
4. molecular alterations within hepatocyte  genetics
5. secretion into bile  cell damage, genetics
6. passage down bile ducts  obstruction
Aminotransferases
• Hepatic enzymes that are usually intracellular, but
are released from hepatocytes with hepatocellular
injury.
• Catalyze -amino group transfers
aspartate or alanine  ketoglutarate
• AST/ALT ratio
Normal is 0.8
In alcoholic hepatitis, is usually > 2
Aminotransferases
aspartate aminotransferase (AST)
• in cytosol and mitochondria
• liver > heart > skeletal muscle > kidneys > brain
> pancreas > lungs > WBCs > RBCs
• half-life 17hrs
alanine aminotransferase (ALT)
• in cytosol
• predominantly liver
• more sensitive and specific than AST
• Half-life 47hrs
Aminotransferases
• elevated in nearly all liver diseases (ALT > AST)
• marked  is usually hepatocellular disease
• levels may/may not reflect extent of damage
• do not correlate with eventual outcome
• usually <500 in obstructive jaundice
Exception: acute phase of biliary obstruction by the
passage of a gallstone into the common bile duct. In this,
the aminotransferases can briefly be in the 1000–2000
IU/L range. However, levels decrease quickly, and the
LFT rapidly evolve into typical of cholestasis
• usually parallel each other
• AST > ALT with EtOH, fulminant, and pregnancy
Aminotransferases
• acute hepatocellular disorders
ALT is higher than or equal to the AST.
• c/c viral hepatitis and NAFLD
AST:ALT ratio is typically <1 (but as cirrhosis develops,
this ratio rises to >1)
• alcoholic liver disease
AST:ALT ratio >2:1 .
The AST in alcoholic liver disease is rarely >300 IU/L,
and the ALT is often normal.
A low level of ALT in the serum is due to an alcohol
induced deficiency of pyridoxal phosphate
Acute hepatitis (ALT>10xULN)
• Viral
• Ischaemic
• Toxins
• Autoimmune
• Acute Budd-Chiari
• Early phase of acute obstruction
• Metastatic liver-diffuse (extremely rare)
“Hit and Run” pattern of liver enzymes
(AST 17h, ALT 47h):
ischemic, toxic, CBD stone
AST
ALT
Elevated AST & ALT,
<4X normal
Hx & physical; stop
hepatotoxic meds
LFTs, PT, albumin, CBC,
Hep A/B/C, Fe, TIBC,
Ferritin
Negative serology,
asymptomatic
Negative serology
Serologies:
HAV IgM
HBsAg
HBcIgM
HCV Ab or
RNA
Positive serology
Negative Serology- Asymptomatic
Stop EtOH & meds; wt
loss; glucose control
6 months
Abnormal
Repeat LFTs
Ultrasound, ANA, smooth
muscle Ab, ceruloplasmin,
antitrypsin, gliadin &
endomysial Ab
Liver biopsy
Normal
Observation
☺
Negative Serology- Clinical Signs/Symptoms of Liver
Disease
Consider ultrasound, ANA,
smooth muscle Ab,
AMA,ceruloplasmin, antitrypsin
Abnormal
Liver biopsy
• ANA(antinuclear antibody)
 sle, autoimmune hepatitis etc…
• ASMA (anti smooth muscle antibody)
autoimmune hepatitis….
• AMA (anti mitochondrial antibody)
primary biliary cirrhosis….
Alkaline Phosphatase
• enzymes that catalyze hydrolysis of large number of organic
phosphate esters.
• ALP mainly comes from surface of bile duct epithelial cells.
Cholestasis enhances synthesis and release of ALP
• Since half life is 1week ; ALP rise late in bile obstruction and
decrease slowly after resolution
• Found in:
• Liver
• Bone
• intestine
• 3rd trimester placenta
• Kidney
Alkaline Phosphatase
• increases seen with cell injury or obstruction
slight to moderate (1-2x) – usually
hepatocellular
large increases (3-10x) – obstruction or
cholestasis
Alkaline Phosphatase
GAMMA-GLUTAMYL TRANSPEPTIDASE
(GGT)
• GGT – to confirm hepatic source of ALP
• elevated ALP of Liver origin: Elevated GGT
elevated ALP of Bone origin: Normal GGT
• Normal levels=0-45 IU/L
• Non specific as Causes of elevations include
liver disease
» pancreatic disease
alcohol
» renal disease
cardiac disease
» obesity
radiotherapy
» diabetes
drugs – GGT is “inducible”
• phenobarbital
anticoagulants
• dilantin
oral contraceptives
• acetaminophen
tricyclic antidepressants
• Usually normal in pregnancy
Prothrombin Time (PT)
• Liver is in charge of the synthesis of many clotting
factors :
• Factor I (fibrinogen) , II (prothrombin) ,V
,VII , IX , X , XII and XIII
• PT measures the rate of conversion of prothrombin
to thrombin (requiring factors II, V, VII, and X) and
thus reflects a vital synthetic function of the liver
• Elevated PT may be reflection of decreased synthetic
activity of liver.
Prothrombin Time (PT)
Other causes of prolongation:
congenital deficiencies
consumptive coagulopathies (i.e., DIC)
drugs (i.e., warfarin)
vitamin K deficiency (i.e., dietary,  bile
output)
prolonged prothrombin time
due to hepatocellular
disease?
due to chronic cholestasis
with fat malabsorption?
administration of vitamin K
administration of vitamin K
PT remains high
PT comes to normal
Assessing the patient with abnormal Liver Function Tests
Certain patterns exist with LFTs
•Hepatocellular Injury: Very high AST,
ALT with mild/moderately elevated
alkaline phosphatase.
•Cholestatis: mild/moderately elevated
AST/ALT with very high alkaline
phosphatase
•Bilirubin can be elevated with both
combinations.
Cholestatic Pattern
• Predominantly elevated alkaline phosphatase
Determine source of AP
Need to check GGT to see if bone or liver in origin
• Blood types O and B: can have elevated serum alkaline
phosphatase after eating a fatty meal due to an influx of
intestinal alkaline phosphatase
• Need to determine if the cholestasis is intrahepatic or
extrahepatic in origin.
• determine fraction of bilirubin elevated
• if all indirect, generally not liver
• ultrasound and/or CT scan
• to rule out obstructive disease, tumors, gallstones
Cholestatic Pattern
• INTRAHEPATIC
• Drugs
• Hepatitis A, B, C
• Alcoholic hepatitis
• TPN
• Primary Sclerosing
Cholangitis
• Primary Biliary
Cirrhosis
• EXTRAHEPATIC
• Gall stones
• Primary Sclerosing
Cholangitis
• Malignancy
• Chronic pancreatitis
• HIV cholangiopathy
summary
Case 1 – 65 y/o woman
complaints
•fatigue
•pruritus
•dry eyes
past history
•hysterectomy for fibroids 10 years ago
•no alcohol, tobacco or drug use
Case 1 – 65 y/o woman
examination
•spider naevi
•mild splenomegaly
•otherwise normal
Case 1 – 65 y/o woman
screening labs reveal
• platelets 90,000
• bilirubin normal
• AST/ALT normal
• Alk phos 4x uln
• Albumin 3.3 (nl >3.5)
• PT normal
what do you want to do next?
• be thinking about this
Case 1 – 65 y/o woman
• Further lab testing:
• HAV (-) HBV (-) HCV (-)
• ANA (-)
• ASMA (-)
• AMA (+) 1:1280
• iron studies normal
• ultrasound – splenomegaly, small liver, no bil dil
Case 1 – 65 y/o woman
Answer:
• primary biliary cirrhosis
• just beginning to decompensate  consider for
LT
Case 2 – 43 y/o female
complaining of
• 4 days of prolonged, severe RUQ pain
• fever, severe nausea, some vomiting
• worse after eating
Past History
• 20 yr ago began periodic attacks
• evening RUQ pain, fluctuating intensity, no
fevers
• lasting 1-4 hours with residual RUQ
tenderness
Case 2 – 43 y/o female
Past History (cont)
• during last 8 years, continued episodes
• pain more intense and prolonged, accompanied
by penetrating pain to back below scapula
• marked tenderness in RUQ persisting days
• told in the past she had gallstones
Case 2 – 43 y/o female
• Exam
• temp 38.5°C pulse 100 uncomfortable/sweating
• marked tenderness in RUQ with splinting
• (+) Murphy's sign
• icterus
• bilirubin 6 mg/dl
- alk phos 3x nl (~400 U/L)
• ALT 100 IU/L
- normal albumin, PT
• WBC 28,000
- GGT 150 U/L (nl <45)
• how would you proceed?
REFERENCES
• Harrison's Principles of Internal Medicine, 19Ed
• American Family Physician journal
• BMJ post graduate medical journal
etc.