SYSTEMATIC APPROACH TO LIVER FUNCTION TEST BY Dr. Navas Shareef. P.P (MBBS) THIS PRESENTATION IS MADE IN A SIMPLIFIED FORM SO THAT EVERYONE COULD UNDERSTAND ABOUT A LIVER FUNCTION TEST EASILY

1. APPROACH TO
ABNORMAL LFT
Dr.Navas Shareef .P .P

2. LIVER FUNCTION TEST
• Albumin
• Bilirubin:
• Total Bilirubin
• Direct Bilirubin (conjugated bilirubin)
• Serum aminotransferases
• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Alkaline Phosphatase
• Prothrombin time

4. THE APPROACH
Important questions to address:
•Acute vs. chronic (6 months, ?cirrhosis)
•Asymptomatic vs. symptomatic
?impaired function
•Recent insults to the liver?
EtOH, medications, pregnancy, hepatitis, herbs,
gallstones, hypotension, toxins

5. 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)

6. ALBUMIN
•Synthesized in the liver
•Production is controlled by multiple factors
including nutritional status, serum oncotic
pressure, cytokines, and hormones
•A serum albumin may be reflection of the
synthetic function of the liver.

7. ALBUMIN
• most important plasma protein made by the liver
• accounts for 65% of protein in serum
• half-life ~17-21 days
• useful indicator of liver function
• Other causes of decrease:
• sepsis or multiple organ failure
• acute liver failure
• dietary

8. 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

9. Direct Bilirubin
• conjugated
• water soluble
• polar
• seen in urine
• elevated with biliary
obstruction and
hepatocellular disease.
Indirect Bilirubin
•unconjugated
•lipid soluble
•non-polar
•not in urine
• Elevated with hemolysis,
hepatic disease

11. 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.

12. 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.

13. Bilirubin
production and
metabolism
UDP
Glucoronosyl
transferase
1g Hb=34mg Br

14. 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

15. 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

16. 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

17. 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

18. 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

19. ACUTE HEPATITIS (ALT>10XULN)
•Viral
•Ischaemic
•Toxins
•Autoimmune
•Acute Budd-Chiari
•Early phase of acute obstruction
•Metastatic liver-diffuse (extremely rare)

20. “HIT AND RUN” PATTERN OF LIVER ENZYMES
(AST 17H, ALT 47H):
ISCHEMIC, TOXIC, CBD STONE
AST
ALT

23. Elevated AST &
ALT, <4X normal
Hx & physical; stop
hepatotoxic meds
LFTs, PT, albumin,
CBC, Hep A/B/C, Fe,
TIBC, Ferritin
Positive serologyNegative serologyNegative serology,
asymptomatic
Serologies:
HAV IgM
HBsAg
HBcIgM
HCV Ab or
RNA

24. Stop EtOH & meds; wt
loss; glucose control
Repeat LFTs
Observation
Ultrasound, ANA, smooth
muscle Ab, ceruloplasmin,
antitrypsin, gliadin &
endomysial Ab
NEGATIVE SEROLOGY- ASYMPTOMATIC
Liver biopsy
Abnormal Normal
6 months
☺

25. Consider ultrasound, ANA,
smooth muscle Ab,
AMA,ceruloplasmin,
antitrypsin
Liver biopsy
NEGATIVE SEROLOGY- CLINICAL
SIGNS/SYMPTOMS OF LIVER DISEASE
Abnormal

26. • ANA(antinuclear antibody)
 sle, autoimmune hepatitis etc…
• ASMA (anti smooth muscle antibody)
autoimmune hepatitis….
• AMA (anti mitochondrial antibody)
primary biliary cirrhosis….

27. 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

28. ALKALINE PHOSPHATASE
•increases seen with cell injury or obstruction
slight to moderate (1-2x) – usually
hepatocellular
large increases (3-10x) – obstruction or
cholestasis

29. ALKALINE PHOSPHATASE

30. 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

32. 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.

33. 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)

34. 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

35. 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.

36. 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

37. 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

39. SUMMARY

40. 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

41. CASE 1 – 65 Y/O WOMAN
examination
•spider naevi
•mild splenomegaly
•otherwise normal

42. 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

43. 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

44. Answer:
•primary biliary cirrhosis
•just beginning to decompensate  consider for
LT
CASE 1 – 65 Y/O WOMAN

45. 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

46. 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

47. 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 mg/dl - normal albumin, PT
• WBC 28,000 - GGT 150 U/L (nl <45)
• how would you proceed?

48. REFERENCES
• Harrison's Principles of Internal Medicine, 19Ed
• American Family Physician journal
• BMJ post graduate medical journal
etc.

49. THANK YOU