Hepatic/Biliary Flashcards
fWhat is physiological jaundice of the newborn?
occurs if the liver is immature and doesn’t have enough conjugating enzymes.
This results in high blood levels of unconjugated bilirubin, which can cross the blood brain barrier and deposit in the brain cells, causing encephalopathy (kernicterus).
Where is jaundice easily seen?
Sclera of the eyes
(sclera ictus)
At what level of bilirubin is jaundice recognized?
> 2.5 mg/dL
What is jaundice and how does it occur?
Jaundice is the yellow discoloration of body tissues due to high levels of bilirubin
Jaundice results from defect in normal metabolism or excretion of bilirubin
Explain how conjugated (direct) bilirubin is formed and the pathway to excretion in the bowel
In the liver, unconjugated bilirubin is conjugated with glucuronide molecule resulting in conjugated (direct) bilirubin. This is then excreted from the liver and into the intrahepatic canaliculi, which lead to the hepatic ducts, the common bile duct, and the bowel
What is the Bilirubin test used for? What are the normal and critical ranges?
Used to evaluate liver function
Part of the evaluation of adult patients with hemolytic anemias and newborns with jaundice
Normal range
Adult: Total 0.3-1.0 mg/dL
Indirect 0.2-0.8 mg/dL
Direct 0.1-0.3 mg/dL
Newborn: Total 1.0-12.0 mg/dL
Critical values: Adult > 12 mg/dL, Newborn > 15 mg/dL
Jaundice caused by hepatocellular dysfunction results in?
elevated indirect bilirubin and usually cannot be repaired surgically
Jaundice from extrahepatic dysfunction (gallstones, tumor blocking bile ducts) results in?
elevated direct bilirubin and usually can be repaired surgically
What is conjugated hyperbilirubinemia and what causes it?
Defect in metabolism that occurs after addition of glucuronide.
Caused by Obstruction of bile duct by a gallstone.
What is total bilirubin?
Total bilirubin = direct + indirect
Indirect is 70-85% of the total.
When is direct hyperbilirubinemia diagnosed?
With jaundice, when more than 50% is direct, it is considered direct hyperbilirubinemia from gallstones, tumor, inflammation, scarring, or obstruction of extrahepatic ducts.
When is Indirect hyperbilirubinemia diagnosed?
Indirect hyperbilirubinemia is diagnosed when less than 15-20% of the total is direct and is caused by accelerated RBC hemolysis, hepatitis, or drugs.
What does bilirubin in the urine suggest?
Direct bilirubin is water soluble and can be excreted in the urine
Bilirubin in the urine suggests disease affecting metabolism after conjugation or defects in excretion (gallstones)
Interfering factors of bilirubin?
Blood hemolysis and lipemia can produce inaccurate results
Drugs can cause increased blood level of total bilirubin – antibiotics, ascorbic acid, codeine, epinephrine, methotrexate, morphine, oral contraceptives, salicylates, steroids, sulfonamides, and vitamin A.
Drugs causing increased urine bilirubin levels include antibiotics, barbiturates, diuretics, oral contraceptives, steroids, sulfonamides, phenazopyridine
Drugs causing decreased blood levels of total bilirubin include barbiturates, caffeine, penicillin, and high dose salicylates
Drugs causing false negative results in the urine include vitamin C and indomethacin
Drugs causing false positive results in the urine include pyridium-like drugs that color the urine yellow or orange.
What can cause increased blood levels of indirect bilirubin?
Erythroblastosis fetalis, transfusion reaction, sickle cell anemia, hemolytic anemia, hemolytic jaundice, pernicious anemia, large volume blood transfusion, resolution of large hematoma – RBC destruction occurs, so large amounts of heme are available for catabolism into bilirubin, which exceeds the liver’s capability to conjugate bilirubin, so indirect bilirubin levels rise
Hepatitis, cirrhosis, sepsis, neonatal hyperbilirubinemia – diseased, injured, or immature liver cannot conjugate the bilirubin presented to it
Crigler-Najjar syndrome, Gilbert syndrome – congenital enzyme deficiencies interrupt conjugation of bilirubin
What causes increased blood levels of direct bilirubin?
Gallstones, extrahepatic duct obstruction (tumor, inflammation, gallstone, scarring, surgical trauma) – blockage of bile ducts
Extensive liver metastasis – intrahepatic ducts or hepatic ducts become obstructed
Cholestasis from drugs – some drugs inhibit excretion of bile from hepatocyte into the bile canaliculi
Dubin-Johnson syndrome, Rotor syndrome – congenital defects in enzyme quantity inhibit metabolism and excretion of bilirubin
What causes increased urine levels of bilirubin?
Gallstones, extrahepatic duct obstruction (tumor, inflammation, gallstone, scarring, surgical trauma), extensive liver metastasis, cholestasis from drugs, Dubin-Johnson syndrome, Rotor syndrome – defects in bilirubin metabolism and excretion inhibit intestinal excretion of bilirubin.
Above are associated with direct hyperbilirubinemia, which is water soluble and is excreted.
What is Aspartate Aminotransferase (AST) used to evaluate and what are the normal ranges?
Used in evaluation of patients with suspected hepatocellular disease
Normal: 0-35 units/L
Where are high levels of AST found in the body?
Found in high concentration within highly metabolic tissue, such as heart muscle, liver cells, skeletal muscle cells, and lesser in the kidneys, pancreas, and RBCs.
When cells of a tissure containing high levels of AST are injured, what happens?
When cells of these tissues are injured, the cells lyse and AST is released and picked up in the blood, and the level rises
Amount of elevation is directly related to the number of cells affected by the disease or injury
AST is cleared from the blood in a few days
What is the time period for the rise and fall of AST after an injury?
Levels become elevated 8 hours after cell injury, peak at 24-36 hours, and return to normal in 3-7 days.
If injury is chronic, levels will remain elevated.
What common type of disease will cause elevations in AST
Diseases affecting hepatocytes will cause elevations
In acute hepatitis, levels can rise 20 times the normal value
In acute extrahepatic obstruction, levels quickly rise to 10 times the norm and swiftly fall
In cirrhosis, the level depends on the amount of active inflammation
When is the AST/ALT ratio usually > 1?
usually greater than 1 with alcoholic cirrhosis, liver congestion, and metastatic tumors of the liver.
The ratio is less accurate if AST > 10 times normal
When is the AST/ALT ratio < 1?
A ratio < 1 is seen with acute hepatitis, viral hepatitis, or infectious mononucleosis
AST interfering factors?
Pregnancy may decrease AST
Exercise may increase levels
Levels may be falsely decreased with pyridoxine deficiency (beriberi, pregnancy), severe chronic liver disease, uremia, or diabetic ketoacidosis
Drugs may increase levels – antihypertensives, coumadin, digitalis, erythromycin, hepatotoxic meds, isoniazid, oral contraceptives, opiates, salicylates, statins
What causes increased levels of AST?
Liver diseases (hepatitis, hepatic cirrhosis, drug induced liver injury, hepatic metastasis, hepatic necrosis (early stages only), hepatic surgery, infectious mononucleosis with hepatitis, hepatic infiltrative process (tumor) – liver cell injury causes cell death and lysis, releasing AST
Skeletal muscle diseases (trauma, recent noncardiac surgery, multiple traumas, severe deep burns, progressive muscular dystrophy, recent convulsions, heat stroke, primary muscle diseases (myopathy, myositis)) – cause muscle cell injury with cell death and lysis and release of AST
Other diseases (acute hemolytic anemia, acute pancreatitis) – cell injury leading to cell death and lysis and release of AST
What causes decreased levels of AST?
Acute renal disease
Beriberi
DKA
Pregnancy
Chronic renal dialysis
What is Alanine Aminotransferase (ALT) used for and what are the normal ranges?
Used in evaluation of patients with suspected hepatocellular disease as well as monitoring of improvement or worsening of these diseases
Normal: 4-36 international units/L
What will an abnormal ALT point to in jaundiced patients?
In jaundiced patients an abnormal ALT will point to the liver rather than RBC hemolysis as the source
Where is ALT found in the body?
Enzyme mainly found in the liver with lesser quantities in the heart muscle, skeletal muscle cells, and kidneys
Most ALT elevations are caused by?
Most ALT elevations are caused by liver dysfunction, so ALT is not only sensitive but also specific for liver disease.
Injury or disease in the liver will cause a release of ALT into the bloodstream.
In viral hepatitis the AST/ALT ratio is?
in viral hepatitis AST/ALT < 1
In hepatocellular disease (other than viral) AST/ALT is?
ALT/AST ratio is > 1
ALT interfering factors
Previous IM injections may cause elevated levels
Numerous drugs can cause increased ALT levels including acetaminophen, salicylates, codeine, contraceptives….
Causes of significant increases in ALT
Significantly increased levels – hepatitis, hepatic necrosis, hepatic ischemia
Causes of moderately increased levels of ALT
Moderately increased levels – cirrhosis, cholestasis, hepatic tumor, hepatotoxic drugs, obstructive jaundice, severe burns, and trauma to skeletal muscle
Causes of mildly increased levels of ALT
Mildly increased levels – myositis, pancreatitis, myocardial infarction, infectious mononucleosis, and shock
What is Alkaline phosphatase (ALP) used to detect? What are the normal values?
Used to detect and monitor diseases of the liver or bone
Normal: 30-120 units/L
Do children have increased or decreased levels of ALP?
Children have increased levels because their bones are growing.
Where is ALP present?
Highest concentration found in liver, biliary tract epithelium, and bone as well as the intestinal mucosa and placenta.
Present in Kupffer cells in the liver and line the biliary collecting system.
When is the function of ALP increased?
Its function is increased in alkaline (pH of 9-10) environment
What is the most sensitive test to indicate tumor metastasis to the liver
ALP
Where is ALP excreted?
into the bile
Can isoenzymes of ALP distinguish between liver (ALP1) and bone (ALP2) diseases
Yes
New bone growth is associated with increased or decreased ALP levels?
increased
Intefering factors of ALP
Recent ingestion of a meal can raise level
Age – young children with rapid bone growth have increased levels, especially during growth spurt
Drugs may increase levels – antibiotics, colchicine, indomethacin, methotrexate
Drugs may decrease levels – cyanides, nitrofurantoin, oxalates
Causes of increased levels of ALP
Primary cirrhosis, intrahepatic or extrahepatic biliary obstruction, primary or metastatic liver tumor – any obstruction of bile flow will cause elevations in ALP
Metastatic tumor to bone, healing fracture, hyperparathyroidism, osteomalacia, Paget disease, rheumatoid arthritis, rickets – ALP comes from the bone.
Intestinal ischemia or infarction, myocardial infarction, or sarcoidosis
Causes of decreased levels of ALP?
Hypophosphatemia – insufficient phosphate to make ALP
Hypophosphatasia, malnutrition, milk alkali syndrome, pernicious anemia, scurvy
What is Gamma Glutamyl Transferase (GGT) an indicator of? What are the normals values?
Sensitive indicator of hepatobiliary disease
Indicator of heavy and chronic alcohol use
Used to test liver cell dysfunction
Normal range: Male 8-38 units/L, Female > 45: 5-27 units/L
What is the function of GGT in the body?
GGT participates in the transfer of amino acids and peptides across the cell membrane
What is the most sensitive liver enzyme for detecting biliary obstruction, cholangitis, or cholecystitis
GGT
Where is GGT found in the body?
Highest concentrations found in the liver and biliary tract with lesser amounts in the kidney, spleen, heart, intestine, brain, and prostate (this is why men have higher levels than women).
GGT elevation parallels what other enzyme?
Elevation parallels ALP but is more sensitive
GGT is not elevated in bone diseases as is ALP
A normal GGT with an elevated ALP implies??
Skeletal disease
An elevated GGT and elevated ALP implies???
Hepatobiliary disease
Is GGT elevated in childhood or pregnancy?
GGT not elevated in childhood or pregnancy like ALP
Interfering factors of GGT?
Values may decrease in late pregnancy
Drugs that cause increased levels are alcohol, phenobarbital, and phenytoin
Drugs that cause decreased levels include oral contraceptives
Causes of increased levels of GGT?
Liver diseases (hepatitis, cirrhosis, hepatic necrosis, hepatic tumor or metastasis, hepatotoxic drugs, cholestasis, jaundice) – liver and biliary cells lyse and release GGT
- *MI**
- *Alcohol ingestion**
Pancreatic diseases (pancreatitis, pancreatic cancer) – pancreas cells contain GGT
Epstein-Barr virus (infectious mononucleosis), cytomegalovirus, and Reye syndrome
What is the 5’-Nucelotidase measurement used for? What are the normal values?
Used to support the diagnosis of hepatobiliary obstructive disease by confirming that an elevated ALP is the result of liver pathology rather than pathology of another tissue origin
Normal: 0.0-1.6 units at 37o C
What organ is 5’-nuceliotidase specific to?
Enzyme is specific to the liver. It is elevated in patients with liver diseases, especially those with cholestasis.
Explain the metabolic pathway involved to make unconjugated (indirect) bilirubin
Bilirubin metabolism begins with RBC breakdown in the spleen with release of Hgb, which is broken down to heme and globin molecules.
Heme is catabolized to form biliverdin, which is transformed to bilirubin.
If 5’-nucelotidase is elevated along with ALP it indicates?
the pathology is in the liver
If 5’-nucleotidase is normal with an elevated ALP it indicates?
the source is outside the liver (bone, kidney, spleen)
Interfering factors of 5’-nucleotidase
hepatotoxic agents
Causes of increased levels of 5’-nucleotidase
Bile duct obstruction, cholestasis – most specific for conditions that cause intrahepatic or extrahepatic biliary obstruction
Hepatitis, cirrhosis, hepatic necrosis, hepatic ischemia, hepatic tumor, hepatotoxic drugs
What is the Total Protein, Albumin, Globulin, Protein electrophoresis test used for?
Used to diagnose, evaluate, and monitor disease course in patients with cancer (lymphoma, myeloma), intestinal/renal protein wasting states, immune disorders, liver dysfunction, impaired nutrition, and chronic edematous states
Normal range for Total protein, albumin, and globulin
Total Protein 6.4-8.3 g/dL
Albumin 3.5-5 g/dL
Globulin 2.3-3.4 g/dL
What makes up the total protein measurement?
consists of prealbumin, albumin, and globulins
Where is albumin formed and what is its function?
Albumin is formed in the liver and makes up 60% of the total protein.
Albumin maintains colloidal osmotic pressure and transports drugs, hormones, and enzymes.
What is albumin a measure of?
It is a measure of hepatic function. When diseased, the hepatocyte cannot synthesize albumin so the level greatly decreases.
Albumin half life is 12-18 days, so impaired hepatic albumin synthesis may not be recognized initially
What are globulins?
Key building blocks of antibodies; very small role in maintaining osmotic pressure
What are Alpha1 globulins?
Alpha1 globulins are mostly alpha1 antitrypsin but also includes some transporting proteins like thyroid and cortisol binding globulin
What are Alpha2 globulins?
Alpha2 globulins include serum haptoglobins (bind hemoglobin during hemolysis), ceruloplasmin (carrier for copper), prothrombin, and cholinesterase (enzyme used in catabolism of acetylcholine)
What are Beta1 globulins?
Beta1 globulins include lipoproteins, transferrin, plasminogen, and complement proteins
What are Beta 2 globulins?
Beta2 globulins include fibrinogen
What are Gamma globulins?
Gamma globulins are the immune globulins (antibodies)
What is the normal albumin / globulin ratio?
Normally, the albumin/globulin ratio is > 1.0
What happens to albumin in collagen vascular diseases?
In collagen vascular diseases like lupus, the capillary permeability is increased, so albumin, which is much smaller than globulin, is lost into the extravascular space.
What happens to protein levels in chronic liver disease?
Chronic liver disease has low albumin, high globulin, and normal total protein because the liver cannot produce albumin, but globulin is adequately made in the reticuloendothelial system.
What is the role of electrophoresis?
Electrophoresis separates the components of protein
What are the Interfering factors for Total Protein, Albumin, Globulin, Protein electrophoresis
Prolonged tourniquet can increase both fractions of total proteins
Sampling blood proximal to an IV can cause inaccurately low protein levels
Drugs that increase protein levels are anabolic steroids, androgens, corticosteroids, growth hormone, insulin
Drugs that decrease protein levels include ammonium ions, estrogens, hepatotoxic drugs, and oral contraceptives
What causes increased albumin levels?
Increased albumin levels caused by dehydration which causes decreased intravascular volume
What causes decreased albumin levels?
Malnutrition – lack of amino acids
Pregnancy – albumin decreases
Liver disease (hepatitis, metastatic tumor, cirrhosis, hepatocellular necrosis)
Protein losing enteropathies ( malabsorption syndromes – Crohns disease, sprue, Whipple disease) – proteins lost from intestines due to inadequate absorption
Protein losing nephropathies (nephrotic syndrome, nephrosis) – albumin (lipoid nephrosis) or all proteins (glomerulonephritis) lost through the kidneys
- *Third space losses** (ascites, severe burns) – albumin lost in serum that weeps from open burns or accumulates in peritoneum
- *Overhydration**
Increased capillary permeability (collagen vascular diseases such as lupus) – albumin seeps into tissues and causes edema, or in the kidneys causes proteinuria
Inflammatory disease – inflammation, necrosis, infarction, or burns increase acute phase reactant proteins, mainly globulins, so albumin decreases
What causes increased Alpha1 globulins?
Inflammatory disease – alpha1 antitrypsin is an acute phase reactant protein that increases with inflammation, necrosis, infarction, malignancy, or burns
What causes decreased Alpha1 globulins?
Genetic causes
What causes increased Beta globulin levels?
Hypercholesterolemia – beta lipoprotein is a beta globulin and is increased
Iron deficiency anemia – transferrin is a beta globulin and is increased
What causes decreased Beta globulin levels?
Malnutrition – transferrin is a beta globulin and is decreased in malnutrition
What causes increased Gamma globulin levels?
Multiple myeloma, Waldenstrom macroglobulinemia – cancers with production of gamma globulin from neoplastic plasma cells or lymphocytes
Chronic inflammatory disease (rheumatoid arthritis, lupus) – autoantibodies cause a gamma globulin spike
Malignancy (Hodgkin’s disease, lymphoma, leukemia) – elevated gamma globulins
Hyperimmunization – increase in IgA
Cirrhosis
Acute and chronic infection – antibody response with increase in immunoglobulins
What causes decreased gamma globulin levels?
Genetic immune disorders
Secondary immune deficiency – steroid use, nephrotic syndrome, severe gram negative infection, lymphoma, and leukemia have deficient levels of immunoglobulins
