Approach to Abnormal Liver Tests Anne Larson, MD Hepatology University of Washington.

Approach to Abnormal Liver Tests

Anne Larson, MDHepatology

University of Washington

Anne Larson MD

Case 1 – 65 y/o woman

comes to you to establish care

complaintsfatiguepruritisdry eyes

past historyhysterectomy for fibroids 10 years agono alcohol, tobacco or drug use

Anne Larson MD


examspider angiomatamild splenomegalyotherwise normal

Anne Larson MD


screening labs revealplatelets 90,000 - alk phos 4x ulnbilirubin normal - albumin 3.3 (nl >3.5)AST/ALT normal - PT normal

what do you want to do next?be thinking about this

Anne Larson MD

Case 2 – 43 y/o female

complaining of4 days of prolonged, severe RUQ painfever, severe nausea, some vomitingworse after eating

Past History20 yr ago began periodic attacks

evening RUQ pain, fluctuating intensity, no feverslasting 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 scapulamarked tenderness in RUQ persisting days

told in the past she had gallstones

Anne Larson MD

Case 3

Examtemp 38.5°C pulse 100 uncomfortable/sweatingmarked tenderness in RUQ with splinting(+) Murphy's signicterusbilirubin 6 mg/dl - alk phos 3x nl (~400 U/L)ALT 100 mg/dl - normal albumin, PTWBC 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 resultsmake 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


Aminotransferases

Catalyze -amino group transfersaspartate or alanine ketoglutarate

indicators of liver cell (hepatocyte) injurysensitive but not specificmost useful marker of cell inflammation or necrosisrepresent a “leak” from damaged cells

Anne Larson MD


Aminotransferases - cont

aspartate aminotransferase (AST)in cytosol and mitochondrialiver > heart > skeletal muscle > kidneys > brain > pancreas > lungs > WBCs > RBCs

alanine aminotransferase (ALT)in cytosolpredominantly livermore sensitive and specific than AST

Anne Larson MD


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 otherAST > ALT with EtOH, fulminant, and pregnancy

Anne Larson MD


Alkaline Phosphatase

catalyzes organic phosphate estersthe 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 obstructionslight to moderate (1-2x) – usually hepatocellularlarge increases (3-10x) – obstruction or cholestasis

Anne Larson MD


Alkaline Phosphatase – cont.

isolated elevationsinfiltrative disease – tumor, abscess, granuloma, amyloid

Non-liver causes of elevations:bone disease » diabeteschronic renal failure » intestinal diseaserenal cancer » genetic (pseudoelevation)pregnancy » osteitis deformanssepsis (esp. GNRs) » multiple bone fracturesHodgkin's disease » intraabdominal infectionshypothyroidism » pernicious anemiacongenital hypophosphatasia » zinc deficiency

Anne Larson MD


-glutamyl transpeptidase (GGT)

catalyzes transfer of -glutamyl groupshigh concentrations in bile ductule epithelial cells

useful to exclude “bone” source for Alk Phoscorrelates with alk phos levels in liver disease

sensitive but not specific in renal failure, MI, pancreatitis, diabetes

Anne Larson MD


GGT – cont.

Causes of elevations:liver disease » pancreatic diseasealcohol » renal diseasecardiac disease » obesityradiotherapy » diabetesdrugs – GGT is “inducible”

phenobarbital anticoagulantsdilantin oral contraceptivesacetaminophen tricyclic antidepressants

Anne Larson MD


5’-Nucleotidase (5NT)

hydrolyzes 5’ phosphates from nucleotidesassociated 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


HemoglobinHemoglobin(1)(1)

HemeHeme

B-Alb (2)B-Alb (2)

Other TissueOther TissueCytochromes, etc.Cytochromes, etc.

AlbAlb

Anne Larson MD





3. transport within hepatocyte

4. molecular alterations within hepatocyte

Anne Larson MD



HemeHeme

B (3)B (3)

Conjugated (4)Conjugated (4)

B-Alb (2)B-Alb (2)


AlbAlb

Anne Larson MD





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



HemeHeme

B (3)B (3)


SecretedSecreted(5)(5)

B-Alb (2)B-Alb (2)

Other TissueOther TissueCytochromes, etcCytochromes, etc..

(6)(6) FecesFeces99%99%

UrineUrine1%1%

AlbAlb

Anne Larson MD



HemeHeme

B (3)B (3)


SecretedSecreted(5)(5)

B-Alb (2)B-Alb (2)


(6)(6) FecesFeces99%99%

UrineUrine1%1%

AlbAlb

Anne Larson MD


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

Bilirubinderived 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 unconjugateddirect plus indirect

jaundice evident with levels >3.0 mg/dL

Anne Larson MD


Types of Bilirubin

Direct Bilirubin Indirect Bilirubinconjugated unconjugated

water soluble lipid solublepolar non-polar

seen in urine not in urine

Anne Larson MD

Tests Measuring Synthetic Function

Prothrombin Time (PT)AlbuminNumber Connection Tests / mental status

The liver is the only source of albumin and the prothrombin group of clotting factors

Anne Larson MD


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 deficienciesconsumptive coagulopathies (i.e., DIC)drugs (i.e., warfarin)vitamin K deficiency (i.e., dietary, bile output)

Anne Larson MD


Albumin

most important plasma protein made by the liveraccounts for 65% of protein in serumhalf-life ~17-21 days

useful indicator of liver function

Other causes of decrease:sepsis or multiple organ failureacute liver failuredietary

Anne Larson MD


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 dzguides:

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 elevatedif all indirect, generally not liver

ultrasound and/or CT scanto rule out obstructive disease, tumors, gallstones

Anne Larson MD

The Approach

Chronic Liver Disease

6 months of abnormal liver tests

symptomsasymptomatic – majority of casesfatiguearthralgiaspruritisjaundice

Anne Larson MD

The Approach

Chronic Liver Disease – cont.

Common Causes – 95% of cases:

Hepatitis C - (+) HCV-Ab and HCV-PCRHepatitis B – (+) HBsAg and HBV-DNAAlcoholic liver diseaseHemochromatosis – fasting Fe/TIBC >50%; ferritinAutoimmune hepatitis – (+) ANA, (+) ASMA, IgG

Anne Larson MD

The Approach


Less Common Causes

Primary Biliary Cirrhosis (PBC) - (+) AMA; IgMPrimary Sclerosing Cholangitis (PSC) – abnormal ERCPWilson’s Disease ( ceruloplasmin)1-Antitrypsin Deficiency ( 1AT level)

Drugs (i.e., MTX, INH, amiodarone, methyldopa)

Anne Larson MD

The Approach


signs of cirrhosisspider angiomatagynecomastiaportal hypertension (caput medusa)palmar erythema (seen in 10-15% of normal population)

advanced end stage liver disease – refer pronto!ascites » albuminvarices » prothrombin timeencephalopathy

Anne Larson MD

Case

screening labs revealplatelets 90,000 - alk phos 4x nlbilirubin normal - albumin 3.4 (nl >3.5)AST/ALT normal - 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 (+) 1:1280iron studies normal

ultrasound – splenomegaly, small liver, no bil dil

What Next?

Anne Larson MD

Case

Answer:

primary biliary cirrhosisjust 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

Approach to Abnormal Liver Tests Anne Larson, MD Hepatology University of Washington.

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Transcript of Approach to Abnormal Liver Tests Anne Larson, MD Hepatology University of Washington.