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Author(s): Rebecca W. Van Dyke, M.D., 2012
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M2 GI Sequence
Liver Tests: Use and Interpretation
Rebecca W. Van Dyke, MD
Winter 2012
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Learning Objectives
• A. General: Understand the laboratory tests that are used in the clinical approach to liver disease and the pattern of abnormalities that occur in specific forms of liver injury.
– 1. When do we suspect a patient has liver disease? What tests can be used to accept or deny the presence of liver disease?
– 2. Can we define the type of liver disease the patient has by analyzing the results of the liver tests?– 3. How much functional liver tissue is present in a patient?
• • B. Specific:
– 1. Be able to interpret panels of biochemical liver tests in terms of general type of liver disease, chronicity and severity.
– 2. Be able to construct a differential diagnosis for different patterns of liver test results.– 3. Be able to identify potential problems in interpreting liver tests.
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Industry Relationship DisclosuresIndustry Supported Research and
Outside Relationships
• None
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How Do We Tell Someone Has Liver Disease?
Clues that may lead to a suspicion of liver disease:
AnorexiaFatigue
Nonspecific NauseaVomitingMental confusion
Jaundice (“yellow eyes”) More specific Dark urine (“coca-cola” urine) (late findings) Abdominal swelling; ascites
Peripheral edema; leg swelling
Unfortunately none of these are specific markers of liver disease and for many patients these are very late findings.
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Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/diseaseliver cell injurybile flow/cholestasis
2. Quantitate degree of liver function/dysfunctionquantitative liver tests
3. Diagnose general type of liver diseasepattern of liver test abnormalities
4. Diagnosis of specific liver diseasedisease-specific tests such as serology forviral hepatitis
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Tests of Liver Cell Injury/Death
Transaminases
Alanine amino transferase (ALT)
Aspartate amino transfersase (AST)
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Transaminases are enzymes that catalyze the transfer of-amino groups from amino acids to -keto acids.These enzymes are important in gluconeogenesis.
ALT (alanine aminotransferase)
alanine pyruvic acid + +ketoglutarate glutamate
AST (aspartate aminotransferase)
aspartate oxaloacetic acid + +ketoglutarate glutamate
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Transaminases:
AST(SGOT) ALT(SGPT)
Many tissues Liver only
Cytosol/mitochondria Cytosol
Normal blood levels: 20-70 IU/liter (depending on method)
Some AST/ALT release occurs normally
Require pyridoxal 5’-phosphate as an essential cofactor
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Multi-channel Automated Analysis of Enzymes in Blood
Patient serum
Substrate
ALT +
substrate
Colored product
lamp
Photodetector
Absorbance converted to enzyme activity
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ASTALT
Release of AST/ALT from Liver Cells during Acute Hepatocellular Injury
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Transaminases
Why do we used these enzymes to indicate liver damage?
1. Convenient to measure
2. Present in liver cells in large amounts
3. Direct release of enzymes into blood throughfenestrated endothelium allows rapid“quantitative” assessment of ongoinghepatocyte necrosis
4. Blood level roughly proportional to the numberof hepatocytes that died recently (hours-days)
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2000
100
200
500Serum Enzyme Level (IU/ml)
Cirrhosis (little ongoing
injury)
Mild chronic hepatitis C
(asymptomatic)
Acute viral hepatitis A
(clinically mild)
AST
ALT
Patterns: AST and ALT in Various Liver Diseases
Acute viral hepatitis A
(clinically severe)
3000
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Ischemic infarction: how high would AST/ALT go?
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Transaminases
Special considerations:
1. AST is also present in other tissues (muscle, brain, kidney, intestine). ALT is more specific for liver.
2. Even very mild liver abnormalities can cause slightly elevated AST/ALT
- for example, mild fatty liver.
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Fatty Liver: Most Common Cause of Mildly Increased AST/ALT
(~1.5-3x upper limit of normal)
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TransaminasesProblems with using transaminases to assess liver injury:
1. Only assess injury over the past 1-2 days as enzymes are cleared efficiently from blood by RES
2. May not accurately assess hepatocyte death from apoptosis
3. Magnitude of elevation does not necessarily correlate with extent of liver function or dysfunction at the present time or in the future.
AST and ALT = rate of destruction of hepatocytes
Liver function = number of functional hepatocytes left
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Not all liver abnormalities cause liver cell death: simple liver cyst with
normal liver tests
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Transaminases and Alcoholic Liver Disease: A Twist
Pyridoxal 5’-phosphate (P5P) deficiency:
AST and ALT require P5P (vit. B-6) as an enzymatic cofactor
Alcoholics are often deficient in P5P as their major calorie source is alcohol
P5P deficiency results in lower synthesis of AST/ALT (less in hepatocytes) and very low enzymatic activity (ALT worse than AST)
Less AST/ALT released into blood and it isn’t measured by lab assays
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Transaminases and Alcoholic Liver Disease
Further: Mitochondrial AST and alcohol Alcohol shifts mAST from mitochondria to plasma
membrane where it readily enters blood – thus AST easier to remove from hepatocytes.
Therefore: AST>>ALT is released into bloodfrom damaged hepatocytes
AND
both AST/ALT enzymatic activities in bloodare lower than expected from the extent of liverdamage/dysfunction.
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AST/ALT and Pyridoxal 5’ Phosphate
P5’P
Numerous active enzymes with P5’P Few inactive enzymes without P5’PPoorly measured by lab assays
AST is Affected Less than ALT so AST>ALT
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Release of AST/ALT from Liver Cells After Alcohol Exposure
ASTALT
Alcohol increases mitochondrial AST on liver cell plasma membrane where it readily enters blood. Thus AST>>ALT in blood.
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1000
100
200
650Serum Enzyme Level (IU/ml)
Alcoholic hepatitis
Mild chronic hepatitis C
Acute viral hepatitis A
AST
ALT
Patterns: AST versus ALT
Ratio 2.4 Ratio 0.8Ratio 0.65
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Tests of Cholestasis/Reduced Bile Flow
Enzymes released as a Accumulation in liver/blood consequence of decreased of substances normally bile flow excreted in bile
Alkaline phosphatase Bilirubinor
5’-nucleotidase Bile saltsLeucine aminopeptidase-glutamyl transpeptidase
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Alkaline Phosphatase: Location at Canalicular (Apical) Membrane
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Alkaline phosphatase Origin of enzyme and mechanism of increase in cholestatic liver disease:
1. Apical membrane of hepatocyte and bile duct cells 2. Very sensitive to any changes in bile flow, obstruction of large or small bile ducts. 3. Amplified by bile acid retention 4. Easily released into blood as it is a GPI-anchored protein solubilized from membrane by detergents (bile acids) Easily measured spectrophotometrically Purpose: ? Detoxifies lipopolysaccharide (LPS) from bacteria
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Bile Acids (Bile Salts) such asTaurocholate
stimulate productionof alkaline phosphatasemolecules.
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Normal (A) and(B) BlebbedHepatocytes
Bile acid-induced injury
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Alkaline Phosphatase 5’ Nucleotidase GGTP
GPI-Anchored Proteins
Release of GPI-Anchored Proteins From Liver During Cholestasis
Hepatocyte
Blood
Bile canaliculus
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1000
100
200
500Serum Enzyme Level (IU/ml)
Hepato- cellular disease
Mild early partial
bile duct obstruction
Acute bile duct
obstruction
Alkaline Phosphatase in Various Liver Diseases
Long-standing bile duct
obstruction
1500
Degree of elevation of AP is highly variable depending on duration and extent of cholestasis and other unknown factors.
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Alkaline Phosphatase
Interpretation of elevated levels:1. Cholestasis (especially in extrahepatic
obstruction2. Infiltrative diseases (granulomas)3. Neoplastic disease infiltrating liver
Sensitive test as will go up if only some small ducts are obstructed and/or if there is only partial obstruction of major ducts.
Disadvantages:Not completely specific because of isoenzymes
in other organs (bone, intestine, placenta)Ex: bone disease, intestinal obstruction, pregnancy.
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Serum Bilirubin (Bile Acids)
Rationale:Liver is virtually the only mechanism for excretionCholestasis from any cause results in “back-up”
of these compounds in blood
Interpretation:Cholestasis: extrahepatic or intrahepatic
Disadvantages:Does not distinguish hepatocellular disease,
in which hepatocytes don’t make bile,from bile duct obstruction
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Bilirubin
An organic anion
The byproduct of heme breakdown
In mammals bilirubin must be conjugated toglucuronic acid and excreted in bile
Blood levels go up if any steps in production or hepatocyte excretion are altered. However obstruction at the level of bile ducts must be complete or virtually complete for bilirubin levels in blood to change
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Bile Canaliculus
Hepatocyte
MRP-2: Multispecific organic anion transporter
ATP
Conjugated bilirubin Glutathione S-conjugates other organic anions
Unconj Bilirubin
SER
Unconj BR
Conj BR
Conj BR
RBC breakdown in RES
Hepatic Bilirubin Transport
Blood
UDP-glucuronide
Unconj BR+
Conj BR
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Bile Canaliculus
Hepatocyte
Multispecific organic anion transporter
ATP
Conjugated bilirubin Glutathione S-conjugates other organic anions
Unconj Bilirubin
SER
Unconj BR
Conj BR
Conj BR
Gilbert's syndrome (mild) Crigler-Najjar syndrome (severe)
Dubin-Johnson syndrome Rotor's syndrome ?estrogen/cyclosporin
Hemolysis
Hepatic Bilirubin Transport and Mechanisms of Hyperbilirubinemia
Blood
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Unconj Bilirubin
SER
Unconj BR
Conj BR
Mechanism of Hyperbilirubinemia in Liver Disease
UDP-glucuronide
Unconj BR+
Conj BR
Overall Rate-Limiting Step
Conj BR
Albumin
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Interpretation of Elevated Serum Bilirubin
Conjugated hyperbilirubinemia:BR reached liver and was conjugated but not excreted in bile
1. Cholestasis/biliary obstruction (must be essentially complete)2. Hepatocellular damage (collateral damage to all liver functions)
bile formation impaired >> conjugation impaired3. Rare disorders of canalicular secretion of conjugated bilirubin
Unconjugated hyperbilirubinemia:BR didn't reach liver efficiently or wasn't conjugated
1. Massive overproduction - acute hemolysis2. Impaired conjugation
common: Gilbert's syndrome (mild)rare: Crigler-Najjar syndrome (severe)
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BRAlb
Alb BR
ER
BR
BR-Glu Bile
Hepatocyte
Blood
BR-Glu
BR-Glu
BR-Glu
Alb
Bili-albumin conjugate or "delta bilirubin"
Formation of Bilirubin-Albumin Conjugates
Further: Bilirubin Undergoes Non-Enzymatic Reaction with Albumin
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Why is Bili-Albumin of Clinical Interest?
• Not of interest during liver disease as this form of bilirubin is measured as conjugated bilirubin.
• However, after resolution of cholestasis/liver disease, bili-albumin is cleared like albumin– Albumin half-life: several weeks– Conj. bilirubin half-life: hours to days–
• Thus resolution of jaundice is often SLOW compared to improvement of other liver functions.
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Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/diseaseliver cell injurybile flow/cholestasis
2. Quantitate degree of liver function/dysfunctionquantitative liver tests
3. Diagnose general type of liver diseasepattern of liver test abnormalities
4. Diagnosis of specific liver diseasedisease-specific tests such as serology forviral hepatitis
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TESTS OF LIVER FUNCTION
AlbuminClotting factors
BilirubinBile Acids
14C-Aminopyrine
Blood Level
Production
Elimination
Metabolism
Blood Level
Metabolites 14CO2
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Albumin
• Rationale– Liver is the sole source
• Interpretation of Decreased Level– Decreased liver production
– Increased renal/GI loss (nephrotic syndrome; protein losing enteropathy in inflammatory bowel disease
– Protein malnutrition
• Disadvantages– Prolonged half-life
– No unique interpretation
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Prothrombin Time
• Rationale– Liver is sole source of vitamin K-dependent clotting
factors, including those critical for PT– Factor VII has very short half-life (hours)
• Interpretation of Increased PT– Hepatocyte protein synthesis impaired– Vitamin K deficiency/Coumadin therapy– Disseminated intravascular coagulopathy
• Advantages– Rapidly reflects changes in liver function
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Interpretation of Abnormal Albumin/Prothrombin Time
Liver markedly diseased - reserve function gone
Albumin: monitors slow changes in liver function(months to years)
reflects long-term liver dysfunction
Protime: monitors rapid changes in liver function(hours to days/weeks)
reflects either short or long-term liverdysfunction
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Other Clues to Globally Impaired Liver Function
Bilirubin: goes up with any disease that globally impairsliver function (OR blocks bile flow)
Glucose: hypoglycemia (late finding; indicates very poor liver function)
BUN: low BUN is a late and poorly specific finding in liver dysfunction due to poor urea synthesis
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Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/diseaseliver cell injurybile flow/cholestasis
2. Quantitate degree of liver function/dysfunctionquantitative liver tests
3. Diagnose general type of liver diseasepattern of liver test abnormalities
4. Diagnosis of specific liver diseasedisease-specific tests such as serology forviral hepatitis
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Interpretation of Liver Tests
A. Consider nonhepatic causes of abnormal liver tests
B. Examine the pattern of liver test abnormalities to categorize liver disease:
1. cholestatic versus hepatocellular
2. acute versus chronic
3. decompensated versus mild functional function impairment
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Patterns of Abnormal Liver Tests
Hepatocellular Cholestasis
Major: AST/ALT Alkaline Phosphatase
Minor: Bilirubin BilirubinPT/albumin AST/ALT
PT (Vit K deficiency)
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20
1
2
10
Fold Increase
AST or ALT PTBilirubinAlkaline Phosphatase
Hepatocellular disease
Cholestatic disease
Patterns: Acute Liver Disease
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Clues to Acute vs Chronic Liver Disease
Abnormalities of PT versus albumin
Known duration of abnormal liver tests
History of exposure to potential causative agents
Clinical signs of consequences of long-standing liver disease
Tempo of subsequent changes in AST/ALT, bilirubin, PTchronic tends to change slowlyacute tends to change quickly
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20
1
2
10
Fold Increase
AST or ALT PTBilirubinAlkaline Phosphatase
Patterns: Chronic Liver Disease with Impaired Liver Function
Albumin
-2
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Clues to Severity of Liver Dysfunction
Prothrombin time
Albumin
(Bilirubin, glucose)
(Clinical signs of consequences of severe liver dysfunction such as hepatic encephalopathy)
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Clues to severityof liver damageand, potentially, toseverity of liverdysfunction may come from thetemporal sequenceof changes in readily available livertests.
For example, rapidfall in AST/ALTin severe hepatitismay not be a goodsign.
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Purpose of Liver Tests
1. Screen for clues to the presence of liver injury/diseaseliver cell injurybile flow/cholestasis
2. Quantitate degree of liver function/dysfunctionquantitative liver tests
3. Diagnose general type of liver diseasepattern of liver test abnormalities
4. Diagnosis of specific liver diseasedisease-specific tests such as serology forviral hepatitis
These are discussed in future lectures
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Summary
• Use biochemical tests to assess– Presence of liver disease– General type of liver disease– Sense of severity of liver dysfunction– Sense of acute versus chronic disease
• Use liver tests with other data to work through differential diagnosis– See algorithms in syllabus and textbook
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Approach to the Patient with Jaundice (Bilirubin)
History, PE Lab tests: AP, AST/ALT, Alb. PT
Abnormal findings suggesting liver disease
Suspect intrahepatic cholestasis or hepatocellular disease
Suspect extrahepatic cholestasis
Noninvasive imaging of the biliary tree: ultrasound or CT (may go to direct duct visualization in some cases)
Specific diagnostic tests hepatitis screen AMA, ANA, SMA Ceruloplasmin Fe/TIBC, ferritin Stop drugs Consider liver biopsy Consider CT to r/o structural disease Medical management/ observation
Normal ducts
Dilated ducts
Normal ducts, still suspect extrahepatic cholestasis
Relief of biliary obstruction: surgical endoscopic percutaneous
Direct duct visualization (ERCP or PTC)
Obstruction visualized
No obstruction visualized
Normal liver tests
Fractionate bilirubin
Unconjugated hyperbilirubinemia
Conjugated hyperbilirubinemia
Hemolysis Gilbert’s syndrome Crigler-Najjar syndrome
Dubin-Johnson syndrome Rotor syndrome
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Approach to Patient with Increased Alkaline Phosphatase
Exclude pregnancy, physiologic causes
Obtain additional biochemical markers of cholestasis (GGTP, 5'-NT, or AP isoenzymes, serum bilirubin)
Nonhepatic cause of AP Hepatic cause of AP
Consider: bone disease (eg, Paget's disease, hyperparathyroidism, bone metastasis) ectopic AP secretion
Large (> 3-fold) elevation of AP
Modest (< 3-fold) elevation of AP
Consider: hepatocellular injury (eg, viral and alcoholic hepatitis)
Abdominal ultrasound or CT scan
Dilated ducts Non-dilated ducts
Consider: choledocholithiasis, cancer of the pancreas, cholangiocarcinoma, biliary stricture, pancreatitis
Focal hepatic defectsNormal or diffusely abnormal liver
Consider: primary or metastatic cancer of the liver, pyogenic/amebic abscess
Liver biopsy and consider: primary biliary cirrhosis, granulomas
Modified from: Kelley Textbook of Internal Medicine, 3rd edition, 1997, pp 663.
Alkaline phosphatase (AP)
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A variety of cases are provided in your syllabus to allow practice in analyzing liver tests.