- Hepatocellular injury patterns are seen with elevated AST and ALT and are often caused by drugs, alcohol, viral hepatitis, steatohepatitis, autoimmune conditions, and genetic disorders. Cholestatic patterns feature elevated alkaline phosphatase and can be from intrahepatic causes like primary biliary cirrhosis or extrahepatic causes like gallstones, cholangiocarcinoma, or chronic pancreatitis. Isolated hyperbilirubinemia may indicate hemolysis, liver disease, or genetic conditions affecting bilirubin metabolism.

1. APPROACH TO LIVER FUNCTION
TEST
Dr.ABHINAV KUMAR
Dept. of Gastroenterology

2. Liver Function Test
• Albumin
• Bilirubin:
– Total Bilirubin
– Direct Bilirubin (conjugated bilirubin)
• Serum aminotransferases
– Aspartate aminotransferase (AST)
– Alanine aminotransferase (ALT)
• Alkaline Phosphatase
• Prothrombin time

3. 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.

4. Bilirubin
• Used to determine liver’s ability to clear endogenous/exogenous
substances from the circulation
• Indirect (unconjugated) bilirubin
– Elevated with hemolysis, hepatic disease
• Direct (conjugated) bilirubin
– Elevated with biliary obstruction and hepatocellular disease.
• Jaundice usually develops with a bilirubin ≥ 3 mg/dL

5. Aminotransferases
• Hepatic enzymes that are usually intracellular, but are released from
hepatocytes with hepatocellular injury.
• Includes aspartate aminotransferase (AST) and alanine
aminotransferase (ALT)
• AST/ALT ratio
– Normal is 0.8
– In alcoholic hepatitis, is usually > 2

6. Alkaline Phosphatase
• A group of enzymes that catalyze the hydrolysis of a large number of
organic phosphate esters.
• In liver, believed to play an active role in down-regulating the
secretory activities of the intrahepatic biliary epithelium
• Found in:
• Liver
• Bone
• intestine
• First trimester placenta
• Kidney
– Gamma-glutamyl transpeptidase (GGT):
• Liver origin: Elevated GGT
• Bone origin: Normal GGT

7. Prothrombin Time (PT)
• Liver is in charge of the synthesis of many clotting factors :
– Factor I (fibrinogen)
– Factor II (prothrombin)
– Factor V
– Factor VII
– Factor IX
– Factor X
– Factors XII and XIII
• Elevated PT may be reflection of decreased synthetic activity of liver.

8. Assessing the patient with abnormal Liver
Function Tests
• Most of the time, the cause of elevated LFTs can be illicited without
invasive testing (biopsy)
• If no cause of abnormality is found, most frequently the cause is
alcohol liver disease, steatosis, or steatohepatitis
• 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

9. Hepatocellular Injury
• Medications:
– History: Need to assess temporal relationship with drug, see if
patient improves once medication removed
– NSAIDs, antibiotics, statins, anti-tuberculosis medications, anti-
epileptic drugs, acetaminophen
• Frequently cause isolated elevated aminotransferases
– Acetaminophen overdose
• Toxicity is likely to occur with single ingestions greater than
250 mg/kg or those greater than 12 g over a 24-hour period
• AST/ALT elevations is first sign of liver damage (usually 24-
hours after ingestion)
• Alcohol Use:
– Frequently have AST:ALT ratio ≥ 2:1
– History: Need accurate assessment of alcohol intake, including
CAGE questions.

10. Hepatocellular Injury
• Hepatitis A:
– Acute infection
– History: travel, recent outbreak, MSM; nausea, vomiting, jaundice
– Labs: Hepatitis A IgM, frequent elevated bilirubin
• Hepatitis B:
– Can be acute or chronic
– History: See if patient from Asia, Subsaharan Africa; Sexual history,
Drug use
– Labs: Hepatitis B surface antigen, surface antibody, core antibody
• Hepatitis C:
– History: IV drug abuse, blood transfusion prior to 1992, Sexual history,
Tattoos
– Labs: Hepatitis C antibody (Hepatitis C viral load if HIV positive or
immunocompromised)
• HIV:
– Often causes isolated elevated aminotransferases
– History: Sexual History, IV drug use
– Labs: HIV Antibody test (ELISA with reflex Western Blot)

11. Hepatocellular Injury
• Hereditary Hemochromatosis
– History: Family history of liver disease? Diabetes? Heart Failure?
Bronze skin?
– Labs:
• Serum iron, TIBC
– Calculate iron saturation = serum iron/TIBC
– If iron saturation > 45%, check ferritin
• Ferritin
– If > 400 ng/mL in men, or > 300 ng/mL in women, then
need to check liver biopsy or genetic testing
• Liver biopsy
– Homozygous hereditary hemochromatosis if iron index >
1.9
– If under age 40, and positive genetic testing, no biopsy
needed.
• Genetic Testing

12. Hepatocellular Injury
• Hepatic steatosis/Non-alcoholic steatohepatitis (NASH)
– Increase in AST/ALT are usually less than 4-fold.
– Ratio of AST/ALT is usually < 1
– History: Female, obesity, diabetes
– Labs:
• Labs to rule out other causes of hepatitis
• Abdominal Ultrasound: look for fatty infiltration of liver

13. Hepatocellular Injury
• Autoimmune Hepatitis
– History: Young to middle-aged female
– Labs:
• Serum protein electrophoresis (SPEP) – if polyclonal increase
in gamma globulin
• Anti-nucleur antibody: Positive
• Anti-smooth-muscle antibody (SMA)
• Liver biopsy: should be performed if the above are negative,
but autoimmune hepatitis still suspected.

14. Hepatocellular Injury
• Alpha-1-antitrypsin deficiency
– History: Family history, emphysema, young age
– Labs:
• Alpha-1-antitrypsin level/phenotype
– Treatment:
• Intravenous alpha-1 antiprotease helps with lung disease, but
liver transplant is ultimately only treatment for liver disease.

15. Hepatocellular Injury
• Wilson’s Disease
– A genetic disorder of biliary copper excretion
– History: Age (usually age 5 – 25, but up to age 40), family history
of liver disease; neuropsychiatric disease
– Evaluation:
• Serum ceruloplasmin: Low
• Opthalmologist: Exam for Kayser-Fleisher rings
• 24-hour urine copper
• Liver biopsy: Evaluate liver copper levels
– Treatment:
• Copper chelating agents
• Zinc

16. Wilson’s Disease – Kayser-Fleisher Rings

17. Hepatocellular Injury
• Shock Liver (ischemic hepatitis)
– Etiology: Shock, severe hypotension
– Severely elevated AST/ALT (50 times normal)
– Treatment: Re-establish good blood pressure/perfusion.
– Prognosis: Usually patients recover, but can progress to
fulminant liver failure requiring transplant.

18. Hepatocellular Injury
• Non-Hepatic Causes
• Usually only mild increase in AST/ALT
– Muscle disorders
– Hypothyroidism/Hyperthyroidism
– Celiac Disease
– Adrenal Insufficiency
– Anorexia nervosa

19. Hepatocellular Injury
• What if work-up is negative and AST/ALT remain elevated?
– Observe:
• Patients with two-fold or less increase in AST/ALT and no
hyperbilirubinemia
– Liver Biopsy
• Patients with > two-fold increase in AST/ALT, or abnormalities
of other liver function tests.

20. Cholestatic Pattern
• Predominantly elevated alkaline phosphatase
– 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.

21. Cholestatic Pattern - Intrahepatic
• Drugs:
– Anabolic steroids, contraceptives, antibiotics
• Total parenteral nutrition (TPN)
• Cirrhosis:
– Viral hepatitis (Hepatitis B, C)
– Alcohol hepatitis

22. Cholestatic Pattern - Intrahepatic
• Primary Biliary Cirrhosis
– Autoimmune disease
– Predominately in women, usually ages 35-65
– May have history of other autoimmune disease
– Symptoms: Pruritis, fatigue, hyperpigmentation, musculoskeletal
complaints
– Labs:
• RUQ Ultrasound
• Anti-mitochondrial antibody
• Liver biopsy to verify diagnosis

23. Cholestatic Pattern – Both Intrahepatic and
Extrahepatic
• Primary Sclerosing Cholangitis
– chronic progressive disorder of unknown etiology that is
characterized by inflammation, fibrosis, and stricturing of medium
size and large ducts in the intrahepatic and extrahepatic biliary
tree
– ~ 90% have inflammatory bowel disease, especially ulcerative
colitis
– Symptoms: Pruritus, fatigue, RUQ pain
– Diagnosis:
• Ultrasound
• Cholangiogram: multifocal stricturing and dilation of
intrahepatic and/or extrahepatic bile ducts
– Prognosis:
• Poor; average life expectancy after diagnosis is ~12 years
• 10-15% risk of developing cholangiocarcinoma
• Liver transplant is ultimate only treatment

24. Cholangiogram of Primary Sclerosing
Cholangitis

25. Cholestatic Pattern - Extrahepatic
• Choledocholithiasis (gall stones!)
– History:
• The 3 F’s
• RUQ colicky abdominal pain
– Diagnosis/Treatment: Ultrasound, ERCP (to remove stones)
• Malignancy
– Cholangiocarcinoma
– Pancreatic
– Metastatic cancer
– Diagnosis: Ultrasound, MRCP
– Treatment: ERCP, biliary stent

26. Cholestatic Pattern - Extrahepatic
• Chronic Pancreatitis
– History: Recurrent pancreatitis
– Symptoms: Abdominal pain, frequently referred to back
• HIV Cholangiopathy
– Usually seen in AIDS patients with CD4 count well below 100/mm3
– Usually caused by: Cryptosporidium. Microsporidium, CMV
– Symptoms: RUQ pain, Diarrhea, Occassional fever, Occassional
jaundice
– Diagnosis:
• ERCP
• Cholangiography – shows multifocal strictures of extrahepatic
biliary tree

27. Isolated Hyperbilirubinemia
• indirect hyperbilirubinemia
– Overproduction of bilirubin
• Hemolysis
– Decrease in uptake, conjugation, or excretion of bilirubin
• Increased unconjugated (indirect) bilirubin
• Liver Disease

28. Isolated Unconjugated Hyperbilirubinemia
• Drugs
– Probenecid, Rifampicin
• Gilbert’s Disease
– Autosomal recessive disorder
– 3 to 7 % of population
– Most common in white males
– Jaundice, increased unconjugated bilirubin (always < 6)
– Occurs when patient under stress/infection
• Crigler-Najjar type II
– Caused by gene mutation
– Reduced activity of Bilirubin UDP glucuronosyl

29. SUMMARY
• Hepatocellular Injury –
mostly ↑ AST/ALT
– Drugs
– Alcohol hepatitis
– Hepatitis A
– Hepatitis B
– Hepatitis C
– Steatohepatitis (NASH)
– Autoimmune hepatitis
– Wilson’s Disease
– Hereditary
Hemochromatosis
– Alpha-1 antitrypsin
deficiency

30. SUMMARY
• EXTRAHEPATIC
– Gall stones
– Primary Sclerosing
Cholangitis
– Malignancy
– Chronic pancreatitis
– HIV cholangiopathy
Cholestatic Pattern
• INTRAHEPATIC
– Drugs
– Hepatitis A, B, C
– Alcoholic hepatitis
– TPN
– Primary Sclerosing
Cholangitis
– Primary Biliary Cirrhosis

31. SUMMARY
• Isolated elevated indirect (unconjugated) bilirubin
– Hemolysis
– Drugs
– Gilbert’s Disease
– Crigler-Najjar type II