Hepatobiliary Tract and Pancreatic Enzymes

Question 1

What is bilirubin?

Answer 1

yellow breakdown product of normal heme catabolism

Question 2

Steps of bilirubin metabolism: Initial steps

Answer 2

1. Old RBCs are phagocytized by macrophages of reticuloendothelial system (RES)
   In the spleen (mainly), liver and lymph nodes

Question 3

Metabolism of bilirubin: Inside macrophages

Answer 3

1st - heme is converted to biliverdin by the enzyme heme oxygenase (HMOX)
2nd - biliverdin is converted to bilirubin by biliverdin reductase (BVR)

Question 4

Metabolism of bilirubin: Transport to the liver

Answer 4

Unconjugated bilirubin (indirect bilirubin) is bound to albumin and is transported through the plasma into the liver

Question 5

Metabolism of bilirubin: Inside the liver

Answer 5

Hepatocytes detach bilirubin from albumin to bring it inside the cell (uptake occurs via facilitated diffusion)
Bilirubin then conjugates with glucuronic acid to make conjugated bilirubin (direct bilirubin) → more water soluble

Conjugated bilirubin is excreted from the liver in the form of bile into the biliary system

Question 6

Metabolism of bilirubin: Intestine

Answer 6

Once bile bilirubin(conjugated) is secreted into the intestine, intestinal bacteria convert to urobilinogens

Some urobilinogen is absorbed by intestinal cells and enters the portal blood

Some reabsorbed urobilinogen re-enters the bile

Question 7

Metabolism of bilirubin: Reabsorbed and transported to the kidney

Answer 7

Some reabsorbed urobilinogen is transported by blood to the kidneys and is excreted in urine
Urobilin → product of oxidation of urobilinogen → responsible for the yellow color of urine

Question 8

Metabolism of bilirubin: Urobilinogen in the digestive tract

Answer 8

Remaining urobilinogen travels down the digestive tract and is converted to stercobilinogen
Oxidized to stercobilin, which is excreted and is responsible for the brown color of feces

Question 9

Unconjugated or indirect bilirubin

Answer 9

Albumin-bound that is insoluble

Makes up most of the bilirubin in the blood

Question 10

Conjugated or direct bilirubin

post-hepatic

Answer 10

Water soluble form

Less common in the plasma but can occur from leaks in the hepatocytes.

Question 11

What are some possible causes of elevated serum bilirubin concentrations?

Answer 11

1. Overproduction of bilirubin
2. Impaired uptake, conjugation, or excretion of bilirubin
3. Backward leakage of bilirubin from damaged hepatocytes or bile ducts

Question 12

Reasons for increase in serum unconjugated bilirubin

Answer 12

Increased production (hemolysis)
Impaired uptake
Impaired conjugation

Question 13

Reasons for increase in serum conjugated bilirubin

Answer 13

Decreased excretion into bile ductules
Backward leakage (obstruction or blockage)

Question 14

Unconjugated bilirubin lab value

Answer 14

Concentration is concentrated from total and direct bilirubin

Question 15

Lab findings in prehepatic jaundice

Answer 15

Serum: Increased unconjugated bilirubin

Urine: No bilirubin present
Urobilinogen > 2 units (high)
Brown discolorations

Stool: Increased fecal urobilinogen

Question 16

Prehepatic (hemolytic) jaundice

Answer 16

Due to overproduction of bilirubin resulting from hemolytic processes that produce high levels of unconjugated bilirubin.

*Know what kinds of conditions can cause this. Slide 14

Question 17

Hepatocellular jaundice

Answer 17

Results from injury or disease of the parenchymal cells of the liver and can be caused by (things that can caused by damage to liver cells):
Viral hepatitis
Cirrhosis
Infectious mononucleosis
Reactions to hepatotoxic medications

Question 18

Lab findings in hepatocellular jaundice

Answer 18

Serum: Increased total bilirubin, increased conjugated bilirubin, increased unconjugated bilirubin

Urine: Decreased urobilinogen
Increased conjugated bilirubin
Dark color

Stool: Pale color, decreased fecal urobilinogen

Question 19

Posthepatic of obstructive janudice

Answer 19

Usually the result of obstruction of the common bile duct or hepatic ducts due to gallstones or due to neoplasms (of the bile duct, gallbladder, or pancreas)

Question 20

Lab findings in posthepatic/ obstructive jaundice

Answer 20

Serum: Increased total bilirubin, increased conjugated bilirubin, normal unconjugated

Urine: Decreased or no urobilinogen, presence of conjugated bilirubin
Dark color

Stool: Pale color, decreased fecal urobilinogen

Question 21

Neonatal jaundice

Answer 21

Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during their first week. This is a common condition called physiological jaundice

Question 22

Contributing factors of neonatal jaundice

Answer 22

1. Low glucronyltransferase activity in hepatocytes
   Before birth, glucuronyltransferase is actively down-regulated, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus. After birth, it takes some time for this enzyme to gain function, leading to physiological jaundice.
2. Shorter life span of fetal RBCs
   RBC lifespan is approximately 80 to 90 days in a full term infant, compared to 100 to 120 days in adults
3. Lower conversion of bilirubin into urobilinogen in the intestines
   Due to intestinal flora not being established yet; results in relatively high absorption of bilirubin back into the circulation

Question 23

Pathological neonatal jaundice

Answer 23

Extreme jaundice can cause permanent brain damage from kernicterus (bilirubin encephalopathy)

Question 24

Pathological neonatal jaundice critical lab values

Answer 24

Bilirubin > 15 mg/dL

Question 25

Treatment for neonatal jaundice

Answer 25

Phototherapy | Plasma exchange transfusion

Question 26

Dubin-johnson syndrome

Answer 26

Rare autosomal disorder that is associated with a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile.

Question 27

Dubin-johnson syndrome lab findings

Answer 27

Increase in conjugated bilirubin without elevation of ALT or AST Patient typically does not have symptoms and does not require treatment.

Question 28

Rotor syndrome

Answer 28

Rare, relatively benign autosomal recessive bilirubin disorder. Defect in hepatic storage of conjugated bilirubin, which leaks into the plasma, resulting in hyperbilirubinemia

Question 29

Rotor syndrome lab findings

Answer 29

Characterized by chronic conjugated and unconjugated hyperbilirubinemia without evidence of hemolysis

Question 30

Gilbert's syndrome

Answer 30

Relatively common. Reduced activity of the enzyme glucuronyltransferase, which conjugates bilirubin (~30% of normal activity). Normally no serious consequences but can have mild jaundice.

Question 31

Gilbert's syndrome labs

Answer 31

Produces mildly elevated levels of unconjugated bilirubin (<3 mg/dL)

Question 32

Crigler-Najjar syndrome

Answer 32

Very rare inherited disorder affecting the metabolism of bilirubin. Minimal (Type II) to absent (Type I) activity of the enzyme glucuronyltransferase, which conjugates bilirubin. Typically have jaundice and very high levels of unconjugated bilirubin which can lead to kernicterus.

Question 33

Crigler-najjar syndrome lab findings

Answer 33

Unconjugated hyperbilirubinemia in the presence of normal liver function test findings is characteristic

Question 34

Elevated indirect bilirubin ddx

Answer 34

``` Neonatal jaundice Hemolytic anemias Trauma in the presence of a large hematoma (hemolysis) Hemorrhagic pulmonary infarcts Crigler-Najjar syndrome Gilbert’s syndrome ```

Question 35

Elevated conjugated (direct) bilirubin ddx

Answer 35

Choledocholithiasis (gallstone in the common bile duct) Dubin-Johnson syndrome Cancer of the head of the pancreas

Question 36

Bilirubin interfering factors

Answer 36

``` 1. Patient diet and medications: High fat meal may cause decreased bilirubin by interfering with the chemical reactions. Certain foods (carrots, yams) and drugs (pyridium-urine) can increase the yellow hue in the serum and falsely increase bilirubin levels. Prolonged fasting and anorexia raise the bilirubin level Nicotinic acid (hyperlipidemia tx) increases unconjugated bilirubin. ``` 2. Specimen care: Light: 1-hr exposure of the specimen to sunlight or high-intensity artificial light at room temperature will decrease the bilirubin content Air bubbles and shaking of the specimen may cause decreased levels

Question 37

Bilirubin levels in which there is detectable jaundice

Answer 37

> 2.5 to 3 mg/dL in adults | > 5 mg/dL in newborn

Question 38

Alkaline phosphatase (ALP)

Answer 38

An enzyme originating mainly in the bone, liver, biliary tract epithelium, and placenta, with some activity in the kidney and intestines. It is used as an index of liver and bone disease when correlated with other clinical findings.

Question 39

ALP: Liver disease

Answer 39

When excretion of this enzyme is impaired as a result of obstruction in the biliary tract During rapid regeneration of biliary tract after injury (contents of cells spill out during cell division).

Question 40

ALP: bone disease

Answer 40

The enzyme level rises in proportion to new bone cell production resulting from osteoblastic activity and the deposit of calcium in the bones

Question 41

ALP is the most sensitive test to indicate

Answer 41

Tumor metastasis to the liver | Also concerning of possible bone metastasis.

Question 42

Sources of ALP from bone origin:

Answer 42

Pathologic new bone growth occurs with osteoblastic metastatic tumors (e.g. breast, prostate) Paget’s disease (excessive breakdown and formation of bone, followed by disorganized bone remodeling) Healing fractures RA Hyperparathyroidism Normal growing bones

Question 43

ALP 1

Answer 43

Isoenzyme of liver origin

Question 44

ALP 2

Answer 44

Isoenzyme of bone origin

Question 45

ALP 3

Answer 45

Isoenzyme elevated in intestinal pathology

Question 46

ALP and 5'-nucleotidase

Answer 46

If both are elevated the most likely source is liver

Question 47

ALP and GGT

Answer 47

If both are elevated once again the likely source is the liver

Question 48

Bone disease with elevated ALP ddx

Answer 48

Paget’s disease (levels 10 to 25x normal) Metastatic bone tumor Osteogenic sarcoma Osteomalacia

Question 49

Possible causes of decreased ALP

Answer 49

``` Congenital hypophosphatemia Malnutrition, scurvy (vitamin C deficiency) Hypothyroidism Pernicious anemia Celiac sprue ```

Question 50

ALP interfering factors

Answer 50

1. Patient population: Young children, those experiencing rapid growth, pregnant women, postmenopausal women have physiologically high levels of ALP. 2. Diet: Recent ingestion of a meal (esp. fatty meal) may cause elevation, so a fasting patient is preferred Overnight fasting for isoenzymes. 3. Specimen care: Testing should be done the same day and sample should be refrigerated (as ALP levels increase at room temp) ALP levels decrease if blood is anticoagulated (i.e. with warfarin) 4. Medications (examples slide 46)

Question 51

Aminotransferases

Answer 51

Enzymes that catalyze the reversible transfer of an amino group between an amino acid and an alpha-keto acid. Needed to synthesize liver proteins. Includes alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

Question 52

Alanine aminotransferase (ALT)

Answer 52

An enzyme with high concentrations found in the liver and relatively low concentrations found in the heart, muscle, and kidney (it is pretty much liver-specific). Used to identify hepatocellular diseases of the liver.

Question 53

Significantly elevated ALT ddx

Answer 53

Hepatitis Hepatic necrosis or ischemia Viral, infectious, or toxic hepatitis (30 to 50x normal)

Question 54

Moderately elevated ALT ddx

Answer 54

``` Cirrhosis Cholestasis Hepatic tumor Hepatotoxic drugs Obstructive jaundice Severe burns Trauma to striated muscle ```

Question 55

Mildly increased ALT ddx

Answer 55

Pancreatitis Myocardial infarction (with liver damage) Infectious mononucleosis Shock (Injury or disease affecting the liver, heart, or skeletal muscles will cause a release of this enzyme into the bloodstream.)

Question 56

ALT interfering factors

Answer 56

1. Medications: Salicylates (ASA) may alter ALT levels (either increased or decreased) Drugs that increase levels - acetaminophen, allopurinol, codeine, indomethacin, INH (isoniazid), methotrexate, methyldopa, nitrofurantoin, OCPs, propranolol, tetracyclines and verapamil. Heparin causes increased ALT. 2. Patient population: Obesity causes increases in ALT. 3. Specimen care: Hemolyzed blood causes increases in ALT

Question 57

Aspartate aminotransferase (AST)

Answer 57

An enzyme present in tissues of high metabolic activity Found in high concentration in heart muscle, liver cells, skeletal muscle cells, and to a lesser degree in the kidneys, brain, pancreas, spleen (RBCs) and lungs (not liver-specific). Amount of AST in the blood is directly related to the number of damaged cells and the amount of time that passes between injury to the tissue and the test.

Question 58

AST and AMI

Answer 58

In AMI, the AST level rises within 6 to 10 hours after an MI, peaks at 12 to 48 hours, and returns to normal in 3 to 4 days assuming further cardiac injury does not occur. If there is a second rise in AST levels then it could indicate extension from initial injury.

Question 59

Significantly elevated AST ddx

Answer 59

Acute myocardial infarction (AMI) (4 to 10x normal value) ``` Liver disease (10 to 100x normal) Acute and chronic hepatitis Active cirrhosis (drug or alcohol induced) Alcoholic hepatitis Infectious mononucleosis Hepatic necrosis and metastasis Reye’s syndrome (potentially fatal syndrome that has numerous detrimental effects on many organs, especially the brain and liver; associated with aspirin use in children) Primary or metastatic carcinoma ``` **Notice that it is MUCH more elevated in liver disease!

Question 60

Decreased AST ddx

Answer 60

Chronic renal dialysis Acute renal disease Vitamin B₆ deficiency (B6 is a required cofactor for AST activity)

Question 61

AST interfering factors

Answer 61

1. Patient population: Slight decreases occur in pregnancy, when there is abnormal metabolism of pyridoxine (vitamin B₆). 2. Alcohol/medications: Alcohol ingestion affects results Hepatotoxic medications 3. Concurrent pathologies: False decreases occur in DKA, azotemia, and severe liver disease. Gross hemolysis can cause falsely elevated level.

Question 62

AST vs ALT level comparison: AMI

Answer 62

AST level is always increased in AMI, but ALT does not always increase in AMI unless there is liver damage.

Question 63

AST vs ALT: Acute Liver

Answer 63

Usually ALT>AST, while in chronic liver conditions, AST>ALT. acute toxic or viral hepatitis: ALT >>> AST hepatic necrosis or ischemia: ALT>AST extrahepatic biliary obstruction: ALT>AST

Question 64

AST vs ALT: Chronic liver

Answer 64

Intrahepatic biliary obstruction: AST>ALT | alcoholic liver disease: AST > ALT

Question 65

Gamma Glutamyl transpeptidase (GGT)

Answer 65

Present mainly in the liver, biliary tract, kidney, and pancreas. Used to determine hepatobiliary dysfunction/liver cell dysfunction and to detect alcohol-induced liver disease Very sensitive to the amount of alcohol consumed by chronic alcoholics.

Question 66

Increased levels of GGT ddx

Answer 66

Liver disease (hepatitis, cirrhosis, hepatic necrosis, hepatic tumor or metastasis, hepatotoxic drugs, cholestasis, jaundice) Myocardial infarction (may occur 4 days after AMI, probably implies liver damage from cardiac insufficiency) Alcohol ingestion Pancreatic diseases (pancreatitis, cancer) Carcinoma of the prostate EBV, CMV and Reye’s syndrome (may be associated with subclinical hepatitis that can occur with these infections)

Question 67

GGT interfering factors

Answer 67

1. Patient population: may be decreased late in pregnancy 2. Drugs: Alcohol, phenytoin, and phenobarbital cause increased levels. Clofibrate (hyperlipidemia treatment) and OCPs may cause decreased levels