How to approach an abnormal LFT

1. Abnormal LFTs

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

5. 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

6. Biliary Tract

7. 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

8. 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

9. 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.

11. 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
 Bilirubin can be elevated with both combinations.

12. 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.

13. 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)

14. 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

15. 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

16. 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.

17.  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.
Hepatocellular Injury

18. 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
 In some cases, ultimately liver transplant

19. Wilson’s Disease – Kayser-Fleisher
Rings

20. 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.

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

22. 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.

23. 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.

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

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

26. 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

27. Cholangiogram of Primary Sclerosing
Cholangitis

28. 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

29. 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

30. Isolated Hyperbilirubinemia
 Unconjugated (indirect) hyperbilirubinemia
 Overproduction of bilirubin
 Hemolysis
 Dubin-Johnson Syndrome and Rotor Syndrome
 Decrease in uptake, conjugation, or excretion of
bilirubin
 Increased unconjugated (indirect) bilirubin
 Liver Disease

31. 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

32. 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

33. 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

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

35. Scenario # 1
 A 43-year old woman who has consumed a pint of
80-proof whiskey daily for 18 years presents with
right upper quadrant pain. The pain began
approximately a week ago and has been
transiently relieved by her taking two extra-
strength acetaminophen tablets every 4 hours for
the past 4 days. She has had some nausea and
vomiting but no fever. There is no history of
jaundice or cholelithiasis. The patient used
intravenous drugs and shared needles during her
late teen years.

36. Scenario # 1
 Physical Exam
 Enlarged tender liver that percusses to 17 cm in
the right midclavicular line and a tattoo on the
right buttock
 Labs:
 Bilirubin: 2 mg/dL AST: 3800
Alk. Phos: 198
PT: normal

37. Scenario #1
 The most likely diagnosis is:
(A) Alcoholic hepatitis
(B) Acute cholecystitis
(C) Acetaminophen hepatotoxicity
(D) Acute viral hepatitis B
(E) Acute viral hepatitis C

38. Scenario # 2
 A 54-year old asymptomatic man volunteers to
donate blood and is found to have elevated
aminotransferase levels. He has no known
medical problems and no history of hepatitis. He
drinks no alcohol, takes no medications, and has
not seen a physician in more than 10 years. He is
active, works as a truck driver, and has noted no
change in his physical condition. He has no
family history of liver disease.

39. Scenario # 2
 Physical Exam:
 Obesity – Ht: 5’ 10”, 115 kg
 Labs:
 AST: 45 ALT: 85 Alk. Phos: 90
 Hepatitis serologies (A, B, C): negative
 ESR: normal ANA: negative
 Smooth muscle antibody: negatie
 Total chol: 260 LDL; 225 Triglycerides: 830
 Liver biopsy:
 Large-droplet steatosis without significant inflammatory reaction
and no fibrosis. Ultrasonography shows a mildly enlarged fatty
liver.

40. Scenario # 2
 The appropriate management of this patient
would be:
(A) Interferon therapy for presumed chronic non-B, non-C
hepatitis
(B) Alcohol rehabilitation and counseling
(C) Weight loss and therapy for hyperlipidemia
(D) Endoscopic retrograde cholangiopancreatography
(ERCP) to evaluate the biliary tree
(E) Corticosteroid therapy

41. Scenario # 3
 A 43-year old woman complains of itching that
keeps her awake at night. Physical examination
is normal except for the liver, which is felt 7 cm
below the right costal margin.
 CBC is normal
 Creatinine: 0.8 mg/dL, Bilirubin: 0.6 mg/dL
 ALT: 78 U/L, Albumin: 4.2 g/dL
 Alkaline Phosphatase: 450 U/L
 Cholangiogram: normal

42. Scenario # 3
 Which test would be most accurate in
diagnosing her underlying disorder?
(A) Serum protein electrophoresis
(B) Anti-Smooth Muscle Antibody
(C) Antimitochondrial antibody
(D) Technetium-99m liver-spleen scan
(E) Endoscopic retrograde
cholangiopancreatography (ERCP)