Transcript Document

Approach to
Abnormal Liver Tests
Anne Larson, MD
Hepatology
University of Washington
Anne Larson MD
Case 1 – 65 y/o woman
comes to you to establish care
complaints
fatigue
pruritis
dry eyes
past history
hysterectomy for fibroids 10 years ago
no alcohol, tobacco or drug use
Anne Larson MD
Case 1 – 65 y/o woman
exam
spider angiomata
mild splenomegaly
otherwise normal
Anne Larson MD
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
Anne Larson MD
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
Anne Larson MD
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
Anne Larson MD
Case 3
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?
Anne Larson MD
Approach to Abnormal Liver Tests
If patient is asymptomatic
The First Step:
repeat the tests to confirm the results
make sure to stop all alcohol use
Anne Larson MD
The Diagnosis
No single test is sufficient
No single battery of tests is sufficient
Anne Larson MD
The Diagnosis
Most liver disease can be diagnosed by:
taking a meticulous history
recognizing the pattern of enzyme elevations
rationally selecting a few “second-line” tests
and imaging studies
Anne Larson MD
Types of Liver Tests
grouped by the liver function they assess
measures of hepatobiliary cell injury
measures of transport efficiency of organic
compounds
measures of hepatic synthetic function
Anne Larson MD
Tests Reflecting Cell Injury
Aminotransferases (ALT & AST)
Alkaline Phosphatases
Transpeptidases
5’-Nucleotidase
Anne Larson MD
Tests Reflecting Cell Injury
Aminotransferases
Catalyze -amino group transfers
aspartate or alanine  ketoglutarate
indicators of liver cell (hepatocyte) injury
sensitive but not specific
most useful marker of cell inflammation or necrosis
represent a “leak” from damaged cells
Anne Larson MD
Tests Reflecting Cell Injury
Aminotransferases - cont
aspartate aminotransferase (AST)
in cytosol and mitochondria
liver > heart > skeletal muscle > kidneys > brain >
pancreas > lungs > WBCs > RBCs
alanine aminotransferase (ALT)
in cytosol
predominantly liver
more sensitive and specific than AST
Anne Larson MD
Tests Reflecting Cell Injury
Aminotransferases – cont.
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
usually parallel each other
AST > ALT with EtOH, fulminant, and pregnancy
Anne Larson MD
Tests Reflecting Cell Injury
Alkaline Phosphatase
catalyzes organic phosphate esters
the enzyme is bound to hepatic canalicular membrane
elevation may be due to induction of enzyme
synthesis rather than inability of liver to secrete it
into the bile
increases seen with cell injury or obstruction
slight to moderate (1-2x) – usually hepatocellular
large increases (3-10x) – obstruction or cholestasis
Anne Larson MD
Tests Reflecting Cell Injury
Alkaline Phosphatase – cont.
isolated elevations
infiltrative disease – tumor, abscess, granuloma, amyloid
Non-liver causes of elevations:
bone disease
chronic renal failure
renal cancer
pregnancy
sepsis (esp. GNRs)
Hodgkin's disease
hypothyroidism
congenital hypophosphatasia
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diabetes
intestinal disease
genetic (pseudoelevation)
osteitis deformans
multiple bone fractures
intraabdominal infections
pernicious anemia
zinc deficiency
Anne Larson MD
Tests Reflecting Cell Injury
-glutamyl transpeptidase (GGT)
catalyzes transfer of -glutamyl groups
high concentrations in bile ductule epithelial cells
useful to exclude “bone” source for Alk Phos
correlates with alk phos levels in liver disease
sensitive but not specific
 in renal failure, MI, pancreatitis, diabetes
Anne Larson MD
Tests Reflecting Cell Injury
GGT – cont.
Causes of elevations:
liver disease
alcohol
cardiac disease
radiotherapy
drugs – GGT is “inducible”
phenobarbital
dilantin
acetaminophen
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pancreatic disease
renal disease
obesity
diabetes
anticoagulants
oral contraceptives
tricyclic antidepressants
Anne Larson MD
Tests Reflecting Cell Injury
5’-Nucleotidase (5NT)
hydrolyzes 5’ phosphates from nucleotides
associated with canalicular and sinusoidal membranes
physiologic function unknown
only hepatobiliary tissue can release 5’-NT
specific for hepatic disease
highest in cholestatic conditions
Anne Larson MD
Tests Measuring Transport Efficiency
Hepatic clearance reflects:
1. delivery to hepatocyte (blood flow)
2. uptake by hepatocyte
Anne Larson MD
Tests Measuring Transport Efficiency
Hemoglobin
(1)
Alb
Heme
B-Alb (2)
Other Tissue
Cytochromes, etc.
Anne Larson MD
Tests Measuring Transport Efficiency
Hepatic clearance reflects:
1. delivery to hepatocyte (blood flow)
2. uptake by hepatocyte
3. transport within hepatocyte
4. molecular alterations within hepatocyte
Anne Larson MD
Tests Measuring Transport Efficiency
Hemoglobin
(1)
Heme
B-Alb (2)
Alb
B (3)

Conjugated (4)


Other Tissue
Cytochromes, etc.
Anne Larson MD
Tests Measuring Transport Efficiency
Hepatic clearance reflects:
1. delivery to hepatocyte (blood flow)
2. uptake by hepatocyte
3. transport within hepatocyte
4. molecular alterations within hepatocyte
5. secretion by hepatocyte into bile
6. passage down bile ducts into duodenum
Anne Larson MD
Tests Measuring Transport Efficiency
Hemoglobin
(1)
Other Tissue
Cytochromes, etc.
Heme
B-Alb (2)
Alb
B (3)

Urine
1%
Conjugated (4)


Secreted
(5)
(6)
Feces
99%
Anne Larson MD
Tests Measuring Transport Efficiency
Hemoglobin
(1)
Other Tissue
Cytochromes, etc.
Heme
B-Alb (2)
Alb
B (3)

Urine
1%
Conjugated (4)


Secreted
(5)
(6)
Feces
99%
Anne Larson MD
Tests Measuring Transport Efficiency
Remember, 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
Anne Larson MD
Transport Efficiency
Bilirubin
derived mainly from hemoglobin (95%)
continuous production (300 mg daily)
normal liver reserve can rev up 2-3 times
normal values of “total” bilirubin = 0.1-1.0 mg/dL
conjugated plus unconjugated
direct plus indirect
jaundice evident with levels >3.0 mg/dL
Anne Larson MD
Tests Measuring Transport Efficiency
Types of Bilirubin
Direct Bilirubin
conjugated
water soluble
polar
seen in urine
Indirect Bilirubin
unconjugated
lipid soluble
non-polar
not in urine
Anne Larson MD
Tests Measuring Synthetic Function
Prothrombin Time (PT)
Albumin
Number Connection Tests / mental status
The liver is the only source of albumin and
the prothrombin group of clotting factors
Anne Larson MD
Tests Measuring Synthetic Function
Prothrombin Time (PT)
sick liver can’t make clotting factors
factors 2, 5, 7, 9, 10 (made only in the liver)
prolonged PT reflects failure of liver synthesis
Other causes of prolongation:
congenital deficiencies
consumptive coagulopathies (i.e., DIC)
drugs (i.e., warfarin)
vitamin K deficiency (i.e., dietary,  bile output)
Anne Larson MD
Tests Measuring Synthetic Function
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
Anne Larson MD
Tests Measuring Synthetic Function
Number Connection Test
liver is site of detoxification
failure leads to toxins in blood
toxins unknown
encephalopathy is sign of liver synthetic failure
Anne Larson MD
The Approach
Important questions to address:
acute vs. chronic (6 months, ?cirrhosis)
hepatocellular vs. cholestatic
asymptomatic vs. symptomatic
?impaired function
recent insults to the liver?
EtOH, medications, pregnancy, hepatitis, herbs,
gallstones, hypotension, toxins
Anne Larson MD
The Approach
Hepatocellular Injury
mainly  AST & ALT +/-  AP, GGT, bilirubin
 2 enzyme elevations  high likelihood of liver dz
guides:
Mild
(<3 x normal)
fatty liver, EtOH, chronic hepatitis
Moderate (2-10 x normal)
EtOH, chronic hepatitis, cirrhosis, neoplasm, gallstones
Severe (>10x normal; usually >1,000)
ischemic, viral, toxic (e.g., acetaminophen, herbs)
Anne Larson MD
The Approach
Cholestatic Liver Disease
mainly alkaline phosphatase & GGT +/- bilirubin
determine source of AP
determine fraction of bilirubin elevated
if all indirect, generally not liver
ultrasound and/or CT scan
to rule out obstructive disease, tumors, gallstones
Anne Larson MD
The Approach
Chronic Liver Disease
 6 months of abnormal liver tests
symptoms
asymptomatic – majority of cases
fatigue
arthralgias
pruritis
jaundice
Anne Larson MD
The Approach
Chronic Liver Disease – cont.
Common Causes – 95% of cases:
Hepatitis C - (+) HCV-Ab and HCV-PCR
Hepatitis B – (+) HBsAg and HBV-DNA
Alcoholic liver disease
Hemochromatosis – fasting Fe/TIBC >50%;
 ferritin
Autoimmune hepatitis – (+) ANA, (+) ASMA,  IgG
Anne Larson MD
The Approach
Chronic Liver Disease – cont.
Less Common Causes
Primary Biliary Cirrhosis (PBC) - (+) AMA;  IgM
Primary Sclerosing Cholangitis (PSC) – abnormal ERCP
Wilson’s Disease ( ceruloplasmin)
1-Antitrypsin Deficiency ( 1AT level)
Drugs (i.e., MTX, INH, amiodarone, methyldopa)
Anne Larson MD
The Approach
Chronic Liver Disease – cont.
signs of cirrhosis
spider angiomata
gynecomastia
portal hypertension (caput medusa)
palmar erythema (seen in 10-15% of normal population)
advanced end stage liver disease – refer pronto!
ascites
varices
encephalopathy
»  albumin
»  prothrombin time
Anne Larson MD
Case
screening labs reveal
platelets 90,000
bilirubin normal
AST/ALT normal
- alk phos 4x nl
- albumin 3.4 (nl >3.5)
- PT normal
what are the possible diagnoses?
what do you want to do next?
Anne Larson MD
Case 1
Further lab testing:
HAV (-) HBV (-) HCV (-)
ANA (-)
ASMA (-)
AMA (+) 1:1280
iron studies normal
ultrasound – splenomegaly, small liver, no bil dil
What Next?
Anne Larson MD
Case
Answer:
primary biliary cirrhosis
just beginning to decompensate  send for OLT
Anne Larson MD
Summary
No ideal study or battery to evaluate liver
abnormal liver tests are often the first
sign of liver disease
normal or minimally elevated tests don’t
exclude serious disease or cirrhosis
liver biopsy remains the gold standard to
detecting and determining cause of disease