Evaluation of
Abnormal Liver Tests
Timothy R. Morgan
Outline
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What are Liver Tests?
Where in the liver do the “Liver Tests” come from?
Normal values
Tests of “liver function” vs. “liver injury”
Three questions!
Hepatocellular vs. Obstructive
Common causes of hepatocellular and obstructive
Work-up algorithm
Evaluation of severity of liver disease
Liver Tests
• Bilirubin, total, direct
<1.2 / <0.3 mg/dL
• Albumin
3.5 – 4.8 g/dL
• Aspartate aminotransferase (AST)
10 – 32 IU/mL
• Alanine aminotransferase (ALT)
3 – 30 IU/mL
• Alkaline phosphatase
30 – 115 IU/mL
• Gamma glutamyltransferase
2 – 65 U/mL
Normal Liver: H&E Stain
Hepatocyte
AST
ALT
Albumin
INR
Bilirubin
Cerulo
α-1 AT
THV
Bile
Ducts
Alk
Phos
GGT
Bilirubin
Portal
Vein
Portal
Portal
Bile
Duct
Liver Blood Tests
Markers of Cell Injury
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AST
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ALT
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ASpartate aminoTransferase
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ALanine aminoTransferase
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Also known as Serum GlutamicOxaloacetic Transaminase (SGOT)
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Also known as Serum Glutamic-Pyruvic
Transaminase (SGPT)
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AST found in heart, skeletal muscle,
brain, gastric mucosa, kidney,
pancreas, spleen, lung, and red blood
cells
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ALT found predominantly in liver, very
small amounts in kidney and muscle
.
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90% of AST in blood is released from
liver.
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Almost all ALT in blood is released
from the liver
Both are key enzymes in converting amino acids into high energy
molecules for gluconeogenesis
Both are intra-cellular enzymes – when their levels increase in the
blood, it means that cells are dying
Marker of injury, not function !
Liver Blood Tests
Markers of Cholestasis
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Alkaline Phosphatase
– Found in liver, bone, gut, and
placenta
– Source of alk phos confirmed by
elevations in Gamma Glutamyl
Transferase (GGT)
– Predominantly on the canalicular
membrane of the hepatocyte
– Alk phos enzyme is induced by
elevated levels of bile acids, which
can occur either from bile duct
obstruction or hepatocyte
injury/dysfunction
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Total Bilirubin
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Comprised of both Conjugated (direct)
and Unconjugated (indirect) bilirubin
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Bilirubin is produced during the
breakdown of hemoglobin
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Conjugation occurs in the hepatocyte
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Bilirubin rises due to over production
(i.e.. hemolysis), under secretion (i.e..
biliary obstruction, liver injury, shunt),
or impaired metabolism (i.e.. Gilbert’s
syndrome)
Often referred to as “cholestatic enzymes”
Reflect issues surrounding hepatic secretory function
Liver Blood Tests
Markers of Impaired Synthetic Function
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• INR
Albumin
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Blood protein that is made in the liver
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Half life of endogenous albumin is 1421 days (compared to T½ of infused
albumin, which is ~8 hours)
Reflects clotting cascade function of the
extrinsic clotting pathway (factors II, V, VII,
X)
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All extrinsic factors made by the liver
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Factors II, V, VII are also Vitamin K
dependent
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Rise in INR reflects deficient production of
at least one of the cofactors (in absence of
vitamin K deficiency)
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Factor VII has the shortest half life of all the
cofactors (3 hrs), and is a reasonable
measure of immediate liver function
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Production is inhibited by physiologic
stress (surgery, infection, acute
disease)
Production is inhibited in advanced
stages of chronic liver disease
These are true “liver function” tests
Liver Function vs.
Liver Injury
Liver Function
• Bilirubin, total, direct
• Albumin
• INR
Liver Injury
• AST
• ALT
• (GGT)
• (alk phos)
Three Questions!!
• What is the cause of the liver test
abnormalities?
• How “bad” is the liver injury?
• What are we going to do about it?
What is the cause of liver injury?
• History
– Alcohol use, medications, IVDU, past
abnormal liver tests, past jaundice, family
history,
• PE
– Itching, jaundice, liver size/firmness, spleen
– Spider angioma, ascites, encephalopathy
• Lab Tests
– Liver panel, comprehensive metabolic panel
– CBC with diff
– INR
Hepatocellular vs. Obstructive
Hepatocellular
AST and ALT
alkaline phosphatase
and bilirubin
“Obstructive”
alkaline phosphatase,
bilirubin and GGT
AST and ALT
Common Causes of Hepatocellular Injury
(AST and ALT)
Viral hepatitis (A, B, C)
HBsAg, anti-HCV, PCR
Alcohol
History, blood alcohol
Drugs/medications
history, stopping drug
Fatty Liver
BMI, FBS, TG, DM
Autoimmune
ANA, SMA
Hemochromatosis
Iron/TIBC/Ferritin, HFE
Wilson disease
Ceruloplasmin
Alpha-1 antitrypsin deficiency
level, phenotype
CHF, ischemic
history, time
Hepatocellular Injury
Raised ALT and AST
History
Age, gender
Travel,
Medications
Alcohol, IVD
Transfusions
HCV Ab
HBsAg
HCV-PCR
Physical Examination
chronic liver disease
(firm liver, spleen palp)
weight
ANA Iron/TIBC Ceruloplasmin Alpha-1 AT
SMA Ferritin
level
HFE gene
phenotype
Liver Biopsy
“Obstructive”
Bilirubin and Alkaline Phosphatase
• Choledocholethiasis (Common bile duct stones)
• Cancer with obstruction of CBD (pancreatic,
cholangiocarcinoma, gallbladder)
• Cancer metastatic to liver (e.g., colon, pancreas)
• Mass in liver (granulomas, abscess)
• Drug injury (cholestasis)
• Primary biliary cirrhosis
• Sclerosing cholangitis
• Third trimester of pregnancy
Diagnostic Tests for Obstructive
• Ultrasound of liver, gallbladder pancreas,
bile ducts
• CT, MRI
• Endoscopic retrograde
cholangiopancreatography,
• Endoscopic ultrasound
• Antimitochondrial antibody (AMA)
• Liver biopsy
“Obstruction”
Alkaline Phosphatase, Bilirubin, GGT
History
Age, gender
Jaundice
Medications
Weight loss, itching
AMA
AMA +
Liver Biopsy
Physical Examination
chronic liver disease
(firm liver, spleen palp)
weight
US, CT, MRI
Dilated Bile Ducts
ERCP / EUS
Mass or
Non-dilated Ducts
Liver Biopsy
How Bad is the Liver Disease?
• History
– Ascites, variceal bleeding, encephalopathy
• Physical Examination
– Firm liver, splenomegaly
– Spider angiomas, palmar erythema
– Ascites, hepatic encephalopathy
• Laboratory tests
– Albumin, bilirubin (direct), INR
– Platelet, WBC
• Liver Biopsy
HCV - Natural History
Stages of Fibrosis In Chronic Hepatitis
Periportal
Portal
Septal
1
2
3
4
Cirrhosis
What are we going to do
about the liver disease?
• Depends on cause of liver disease,
severity of liver disease and patient’s
wishes
Case 1
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23 yo Asian male college student.
Maternal grandmother died of liver disease
No alcohol use, no IVDU
Not on any medicines, no prior history of
liver disease
• PE
– Liver palpable, slightly firm
Case 1 Lab tests
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AST
ALT
Alkaline phosphatase
Total bilirubin
Direct bilirubin
Albumin
Total protein
84 IU/mL
129 IU/mL
114 IU/mL
1.0 IU/mL
0.2 IU/mL
4.0 g/dL
7.6 g/dL
Case 1
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HBsAg
Hepatitis C antibody
Iron/TIBC/Ferritin
ANA
Alpha-1 antitrypsin
Ceruloplasmin
positive
negative
98/278/351
negative
159 (normal)
33 (normal)
Case 3
• 32 yo man was at health fair and had
blood tests showing elevated ALT and
AST
• No prior liver disease, no medications, no
family history of liver disease, no IVDU
• Drinks 2-3 beers on weekend days
• PE: normal
Case 3 Lab tests
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AST
ALT
Alkaline phosphatase
Bilirubin T/D
Albumin
61 IU/mL
88 IU/mL
78 IU/mL
0.8 / 0.1 mg/dL
4.3 mg/dL
Case 3 differential Diagnosis
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Viral hepatitis
Drugs
Alcohol
Hemochromatosis
Wilson disease
Alpha-1 antitrypsin deficiency
Autoimmune disease
Case 3: Test Results
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HBsAg
HCV antibody
ANA
Alpha-1 antitrypsin
Ceruloplasmin
Iron/TIBC/Ferritin
HFE gene
negative
negative
negative
normal
normal
289/305/1740
double mutation of
C282Y
Hemochromatosis
(Prussian Blue Stain
Case 4
• 23 yo female office assistant seen in ER
for severe headache. Elevated ALT
• No personal or family history of liver
disease, no IVDU, no abdominal pain
• 3-4 drinks/day on weekends
• OCP
• PE: ?? Palpable spleen, otherwise normal
Case 4 Lab results
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AST
ALT
Alkaline phosphatase
Bilirubin T/D
Albumin
Total protein
91 IU/mL
133 IU/mL
145 IU/mL
1.2 / 0.4 IU/mL
3.6 IU/mL
7.6 IU/mL
Case 4: Differential Diagnosis
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Alcohol
Viral hepatitis
Medications
Autoimmune
Hemochromatosis
Wilson
Alpha-1 antitrypsin deficiency
Case 4 Test Results
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HBsAg
Hepatitis C antibody
Iron/TIBC/Ferritin
Ceruloplasmin
Alpha-1 antitrypsin
ANA
Smooth muscle antibody
negative
negative
68/389/154
66
normal
1:320
1:64
Autoimmune Hepatitis
Mieli-Vergani, G. & Vergani, D. (2011) Autoimmune hepatitis
Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.69
Case 5
• 48 yo female with mildly abnormal liver
tests for past few years
• Medications for Maxide and simvastatin,
estrogen
• Alcohol 1 drink/day, no IVDU, or surgery,
• Mother had hypertension, father had
diabetes and MI
• PE: BMI 31
Case 5 Labs
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AST
ALT
Alkaline phosphatase
Bilirubin T/D
Albumin
Total protein
Triglycerides
Glucose
53 IU/mL
69 IU/mL
154 IU/mL
0.8 / 0.2
4.1 g/dL
7.7 g/dL
413
108 mg/dL
Case 5 Differential Diagnosis
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Viral hepatitis
Alcohol
Fatty liver
Autoimmune
Hemochromatosis
Alpha-1 antitrypsin
Wilson
Medications
Case 5 Test Results
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HBsAg
Hep C antibody and PCR
Iron/TIBC/Ferritin
ANA and SMA
Ceruloplasmin
Alpha-1 antitrypsin
Glucose
Insulin
negative
negative
126/349/233
negative
normal
normal
105 mg/dL
elevated (2x)
Steatosis
THV
THV: terminal hepatic venule
Case 6
• 45 yo asymptomatic woman.
• No history of alcohol use or IVDU.
• No prescription meds. Occasionally takes
acetaminophen, ibuprofen, and various
alternative meds.
• Normal physical examination
Case 6 (lab tests)
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Total Bilirubin
Direct Bilirubin
Alkaline phosphatase
AST
ALT
Albumin
Total protein
1.2 mg/dl
0.3 mg/dl
437 IU/mL
45 IU/mL
60 IU/mL
4.4 g/dL
7.8 g/dL
Case 6 Differential Diagnosis
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Choledocholethiasis
Drugs
Primary biliary cirrhosis
Metastatic disease to liver
Granulomas in liver
• Ultrasound of liver and bile ducts
• Antimitochondrial antibody
Primary Biliary Cirrhosis
(Florid Duct Stage)
Case 7
• 66 yo man with 20 lb weight loss who says
his eyes turned yellow yesterday.
• No prior liver disease, 1-2 drinks per day,
• Uncle had colon cancer, mother had
breast cancer
• PE: jaundice, mildly tender RUQ
Case 7 Lab Tests
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AST
ALT
Albumin
Bilirubin (T/D)
Alk phos
GGT
98 IU/mL
112 IU/mL
3.5 g/dL
10.3 / 5.5 mg/dL
1012 U/mL
833 U/mL
Case 7 Differential Dx
• Biliary tract obstruction
– Pancreatic cancer
– Cholangiocarcinoma
– Choledocholethiasis (CBD stone)
ERCP
Double-Duct Sign
Case 8
• 25 yo man with depression
• Uses multiple drugs: heroin, ecstasy,
methamphetamine, marijuana; most
recently several days prior to admission
• No significant alcohol use
• No regular medications
• PE: normal
Case 8 Lab Tests
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AST
ALT
Alk Phos
Bilirubin T/D
Albumin
T. Protein
INR
Creatinine
2150 IU/mL
2005 IU/mL
78 IU/mL
4.3/1.4 mg/dL
4.3 g/dL
6.9 g/dL
2.2
0.78 mg/dL
Case 8: Differential Diagnosis
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Acute viral hepatitis (A, B, C, E)
Drug toxicity (Acetaminophen)
Ischemic hepatitis
Autoimmune hepatitis
Wilson disease
Case 8: Lab Results
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HBsAg
HBcAb-IgM
Hepatitis A-IgM
Hepatitis C Ab
Hepatitis C PRC
ANA
Ceruloplasmin
Acetaminophen
Negative
Negative
Negative
Negative
Negative
Negative
22 (normal: 20 – 60)
87
Case 2
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67 yo man
No alcohol or tobacco, no IVDU
no family history of liver disease
lisinopril and simvastatin
• PE
– Unremarkable
Case 2 Lab Tests
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AST
ALT
Alkaline phosphatase
Bilirubin T/D
Albumin
35 IU/mL
78 IU/mL
106 IU/mL
1.0 / 0.2 mg/dL
3.9 mg/dL
Case 2 Differential Diagnosis
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Hepatitis B,
Hepatitis C
Hemochromatosis
Wilson, autoimmune, drugs
Alpha-1 antitrypsin deficiency
Case 2 Test results
• HBsAg
• Hepatitis C antibody
negative
negative
– Negative HCV-RNA
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Iron/TIBC/Ferritin
ANA
Ceruloplasmin
Alpha-1 antitrypsin
– Phenotype
189/402/255
negative
normal
39 (90-199)
S/Z
Alpha-1 antitrypsin
Liver Histology
Three Questions!!
• What is the cause of the liver test
abnormalities?
• How “bad” is the liver injury?
• What are we going to do about it?
Hepatocellular vs. Obstructive
Hepatocellular
AST and ALT
alkaline phosphatase
and bilirubin
“Obstructive”
alkaline phosphatase,
bilirubin and GGT
AST and ALT
Common Causes of Hepatocellular Injury
(AST and ALT)
Viral hepatitis (A, B, C)
HBsAg, anti-HCV, PCR
Alcohol
History, blood alcohol
Drugs/medications
history, stopping drug
Fatty Liver
BMI, FBS, TG, DM
Autoimmune
ANA, SMA
Hemochromatosis
Iron/TIBC/Ferritin, HFE
Wilson disease
Ceruloplasmin
Alpha-1 antitrypsin deficiency
level, phenotype
CHF, ischemic
history, time
Hepatocellular Injury
Raised ALT and AST
History
Age, gender
Travel,
Medications
Alcohol, IVD
Transfusions
Anti-HCV
HBsAg
HCV-PCR
Physical Examination
chronic liver disease
(firm liver, spleen palp)
weight
ANA Iron/TIBC Ceruloplasmin Alpha-1 AT
SMA Ferritin
level
HFE gene
phenotype
Liver Biopsy
“Obstructive”
Bilirubin and Alkaline Phosphatase
• Drug injury (cholestasis)
• Choledocholethiasis (Common bile duct stones)
• Cancer with obstruction of CBD (pancreatic,
cholangiocarcinoma, gallbladder)
• Cancer metastatic to liver (eg, colon, pancreas)
• Mass in liver (granulomas, abscess)
• Primary biliary cirrhosis
• Sclerosing cholangitis
• Women in third trimester
“Obstruction”
Alkaline Phosphatase, Bilirubin, GGT
History
Age, gender
Jaundice
Medications
Weight loss, itching
AMA
AMA +
Liver Biopsy
Physical Examination
chronic liver disease
(firm liver, spleen palp)
weight
US, CT, MRI
Dilated Bile Ducts
ERCP
Mass or
Non-dilated Ducts
Liver Biopsy
“Liver Function” Tests
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Bilirubin, total, direct
Albumin, (total protein [globulin])
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Gamma glutamyltransferase
INR
Platelets
WBC, MCV, hemoglobin
“Liver Injury” Tests
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Bilirubin, total, direct
Albumin, (total protein [globulin])
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Alkaline phosphatase
Gamma glutamyltransferase
INR
Platelets
WBC, MCV, hemoglobin
• Albumin
– Made by liver
– Decreased due to low production (cirrhosis),
loss through kidney (nephrotic syndrome),
catabolism (burns, malnutrition) and
increased total body water (cirrhosis)
• Globulins (total protein – albumin)
– Elevated in multiple myeloma, autoimmune
liver disease, cirrhosis of many causes,
– If elevated, order SPEP, UPEP
• Alkaline phosphatase
– Found on bile canniculus and in bone
– Increased in bile duct obstruction, masses in
liver (mets, granuloma) and bone disease
• Gamma glutamyltransferase (GGTP)
– Specific to liver
– Increased in alcohol use, bile duct
obstruction, masses in liver
AST and ALT
• Aspartate aminotransferase (AST)
– Found in mitochondria and in cytosol
– Increased in many liver disease
– muscle injury (MI, rhabdomyolysis)
• Alanine aminotransferase (ALT)
– Found in cytosol
– “specific” to liver
– Elevated in many liver disease with
inflammation and liver cell death
Diagnostic Tests for Hepatocellular
• AST to ALT ratio
AST> ALT usually alcohol use
ALT>AST all other causes (viral hepatitis)
• HBsAg, Hep C antibody, HCV-PCR,
IgM Hepatitis A
• Antinuclear antibody (ANA), smooth muscle
antibody (SMA)
• Iron, TIBC, ferritin, HFE gene (hemochromatosis)
• Ceruloplasmin
• Alpha-1 antitrypsin level and phenotype
Case 2
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Asian
Family history of liver disease
?? Firm liver
Elevated ALT>AST
DDx
– Chronic viral hepatitis (B or C)
– Hemochromatosis
– Wilson, Alpha-1 antitrypsin,
Cirrhosis
(Liver Biopsy, Masson Trichrome Stain
Normal Values
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AST
10 – 32 U/L
ALT
3 – 30 U/L
Bilirubin T/D
<1.3 / <0.3
Alk Phosphatase 35 – 105 U/L
GGT
2 – 65 U/L
Albumin
3.5 - 4.5
Ceruloplasmin
40 – 80
Alpha-1 AT
89 – 199
ERCP
Double-Duct Sign
How Bad is the Liver Disease?
• Laboratory tests
– Usually normal until patient develops cirrhosis
– Platelet count
– Bilirubin (especially direct)
– Albumin
– INR
How Bad is the Liver Disease?
• Ultrasound and CT usually not helpful
• Liver spleen scan
– Redistribution to the bone marrow (more
important than spleen)
• Liver biopsy
– Fibrosis
– Inflammation
– Etiology
Autoimmune Hepatitis
Mieli-Vergani, G. & Vergani, D. (2011) Autoimmune hepatitis
Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2011.69
What is the cause of liver injury?
•
•
•
•
History, PE
Routine Lab tests
Hepatocellular vs. obstructive
“Special” lab tests
How Bad is the Liver Disease?
• History
– Ascites, variceal bleeding, encephalopathy,
• Physical Examination
– Firm liver, splenomegaly
– Spider angiomas, palmar erythema
– Ascites, hepatic encephalopathy
• Laboratory tests
– Albumin, bilirubin (direct), INR
– Platelet, WBC
• Liver Biopsy
HCV - Natural History
Stages of Fibrosis In Chronic Hepatitis
Periportal
Portal
Septal
1
2
3
4
Cirrhosis
What are we going to do
about the liver disease?
• Depends on cause of liver disease,
severity of liver disease and patient’s
wishes