Liver Function Tests

Question 1

Explain how billirubin is metabolized and excreted both in a normal person and in a person with high levels of billirubin.

Answer 1

Billirubin is a breakdown product of heme. In the body, 85% of heme comes from the metabolism of old RBCs, but the remainder comes from recycling of myoglobin and enzymes that contain heme (cytochromes, catalases). The metabolism of heme to billirubin takes place in either macrophages or hepatocytes. Once billirubin is produced in these cells, it is secreted into the blood where it binds to albumin. Albumin carries it to the liver where the billirubin is actively uptaken into the hepatocyte and albumin is released back into the bloodstream. Once inside the liver cell, billirubin undergoes conjugation where it is made into glucuronide - billirubin by the enzyme UDP-glucuronide transferase. In a normal healthy person who does not have high levels of billirubin, conjugated billirubin is secreted from the liver in the bile and goes to the gallbladder. Once in the gallbladder, it is secreted as bile into the small intestine. In the GI tract, it is acted upon by bacteria in the colon which turn it into urobilogen. Urobilogen can be excreted in the feces (gives feces its brown color) or it can be absorbed into the blood and secreted in the urine. This is all normal.

When a person has high levels of billirubin in their blood, their liver is processing more billirubin than a normal person. As such, high levels of conjugated billirubin can accumulate in the liver and some of this can be secreted into the blood instead of the bile. Once in the blood, the conjugated billirubin is excreted in the urine, giving the urine a very dark yellow color. Additionally, when high billirubin is present in the blood, it’s possible that the person may not be able to uptake it all into the liver and you can see unconjugated billirubin in the blood. This cannot be excreted so it circulates and causes jaundice.

Question 2

What are the risk factors for liver disease?

Answer 2

Question 3

What liver pathology is seen here?

Answer 3

Cirrhosis that leads to obstruction of biliary secretion from liver so there is green nodules on liver due to build up of bile in liver

Question 4

What liver pathology is seen here?

Answer 4

Fatty liver (alcoholism, diabetes, metabolic syndrome, obesity)

Question 5

What liver pathology is seen here?

Answer 5

Ascites

Question 6

What are the 3 classifications of jaundice?

Answer 6

• Pre-hepatic / hemolytic –> drug induced, hemolytic anemia, etc –> results in build up of billirubin in blood that is unconjugated b/c liver can’t conjugate fast enogh
• Hepatocellular –> damge to liver from toxins, infections, etc –> results in build up of both conjugated and unconjugated billirubin
• Post-hepatic –> liver function is fine but there is an issue getting bile from liver to gallbladder (cirrhosis, tumor, gallstones) –> results in build up of conjugated billirubin

Question 7

If unconjugated billirubin is found in the serum, it is most likely due to […]

Answer 7

Hemolytic disorder

Question 8

If conjugated billirubin is found in the serum, it is most likely due to […]

Answer 8

Liver and/or billiary tract disease

Question 9

If a person has unconjugated billirubin in serum, will you find billirubin in their urine?

Answer 9

No - can’t be excreted

Question 10

Billirubin found in the urine implies […]

Answer 10

That the billirubin is conjugated and the presence of hepatobilliary disease

Question 11

What are the possible causes of unconjugated hyperbillirubinemia?

Answer 11

Question 12

• What is different about seeing unconjugated hyperbillirubinemia in a newborn vs. an adult?
• What are the causes of this in a newborn?
• What is the treatment if it is found to be pathologic?
• What is the biggest consequence of untreated hyperbillirubinemia in a newborn?

Answer 12

• It is sometimes not pathologic in newborn b/c their hepatobiliary system is immature so in some infants it clears on its own as the liver develops more
• See slide for rest of questions

Question 13

Why do we measure blood ammonia in relation to liver function?

Answer 13

Question 14

There are several liver enzymes that can be tested for tin the serum. What does increased enzyme activity tell you?

Answer 14

Only tells you about liver dysfunction, not liver function

Question 15

Let’s say a person has jaundice and you need to distinguish between the causes of jaundice. What 3 enzymes can be measured in serum to check for liver dysfunction that indicates hepatocellular damage?

Answer 15

AST

• Non-specific to liver, also in RBCs so can be high with hemolytic jaundice also
• Extramitochondrial and mitochondrial

ALT

• Found primarily in liver, if this is high it indicates liver damage
• Strictly extramitochondrial

LDH

• Cytosolic enzyme, has several isozymes throughout body so it has poor diagnostic sensitivity and specificity for liver disease

Question 16

• Let’s say that a person has elevated levels of AST and ALT. How do you distinguish between elevation that signals liver disease and elevation that may not be due to liver disease?
• What does the ratio of AST:ALT tell you?

Answer 16

• Normal range in serum is 10-20 Units/Liter
• 20 U/L - 300 U/L is not specific to liver disease
• > 1000 U/L indicates extensive liver damage due to drugs, virus, toxins
• See image

Question 17

Let’s say a person has jaundice and you need to distinguish between the causes of jaundice. What 3 enzymes can be measured in serum to check for liver dysfunction that indicates cholestasis or post-hepatic jaundice?

Answer 17

AlkPhos (ALP)

• Has isozymes in other parts of body, but is found near biliary cannaliculi in liver
• If elevated, and you don’t suspect other possible sources of elevation, it’s good indication of issue with biliary tract

Gamma glutamyl transpeptidase (GGT)

• Helps in DiffDx when ALP is elevated but you may suspect another cause of elevated ALP (bone disease)

5’-nucleotidase (5’-NT)

• Also found near bile cannalicular membrane, but not widely used clinically

Question 18

In the image below, which liver enzymes would you expect to be elevated in the following types of jaundice?

Answer 18

Question 19

Serum albumin is made exclusively by the liver. Is it a good measure of liver function?

Answer 19

It has a long half life (3 weeks) so if it is not normal it cannot detect acute disturbances to liver function. However, hypoalbuminemia is common in chronic liver disease like cirrhosis and reflects severe damage. However, you can also see hypoalbuminemia in other disorders. Important to measure other things too.

Question 20

What does increased globulins in blood tell you?

Answer 20

Question 21

Since albumin levels can’t detect acute liver damage, what other thing can you measure in the serum that can?

Answer 21

If you have cholestasis and can’t get bile into GI tract, you can’t absorb fat so you can’t absorb vitK which can lead to decreased clotting factors since many of these require vitK

Question 22

What other tests, aside from serum enzymes, albumin, globulin, and clotting factors, can be ordered to assess liver function?

Answer 22

Serology to look for virus

• Hep A,B,C,D,E
• Autoimmune Hep

Liver Biopsy

• Look at histological differences

Imaging

• Ultrasound, CT, MRI

Question 23

Compare the utility of LFTs with their limitations.

Answer 23

Question 24

Answer 24

Question 25

How is alcohol excreted?

Answer 25

Lungs, sweat, urine. Amount of excretion via these routes depends on how much is present in blood (i.e. at high blood alcohol see it excreted in breath, but not usually at low levels)

Question 26

What are the various ways in which alcohol is metabolized by the body?

Answer 26

Mostly liver, remainder occurs in brain, pancreas and stomach Mechanisms of metabolism: * 80% via: * Ethanol --(alcohol dehydrogenase)--\> Acetaldehyde --(aldehyde dehydrogenase)--\>acetate * Remainder via: * Ethanol --(catalase)--\>acetaldehyde --(aldehyde dehyrogenase)--\> acetate * Ethanol --(CytP4502E1)--\>acetaldehyde --(aldehyde dehyrogenase)--\> acetate

Question 27

What is antabuse?

Answer 27

Antabuse uses drugs to treat alcoholism. These drugs cause a buildup of acetaldehyde in the blood from the rapid conversion of ethanol to aldehyde and slow conversion of aldehyde to acetate. This causes the person to feel terrible and not get any of the rewarding effects of drinking the alcohol.

Question 28

What is the Microsomal ethanol oxidizing system?

Answer 28

* Rxn: Ethanol --(CytP4502E1)--\> acetaldehyde --(aldehyde dehydrogenase)--\> acetate * Inducible by chronic alcohol consumption

Question 29

All mechanisms of detoxifying alcohol result in a [...] NADH:NAD+ ratio.

Answer 29

High --\> the reactions result in the oxidation of the substrate so NAD+ is reduced to NADH as a result

Question 30

What compounds are produced as a result of alcohol metabolism?

Answer 30

ROS

Question 31

Why is GGT viewed as a possible marker for chronic alcohol abuse?

Answer 31

It is an inducible enzyme that is increased in the presence of chronic alcohol use (remember this detects cholestatic liver disease)

Question 32

Acetaldehyde is [short/long] lived in the body and is [...] reactive. It causes acute [....] like effects.

Answer 32

Short highly chemically Antabuse

Question 33

What are the direct toxic effects of too much ethanol in the body?

Answer 33

Ethanol, if present in high enough quantities such that it cannot be detoxified quick enough, is able to integrate itself into biological membranes leading to increased membrane fluidity. This is particularly dangerous for the blood brain barrier, which needs to be kept as a very tight barrier.

Question 34

What are the metabolic consequences of alcohol detoxification resulting in a high NADH:NAD+ ratio?

Answer 34

* Other important metabolic reactions require NAD+ in order to function. * If there is insufficient NAD+, then pyruvate that is produced at the end of glycolysis will be preferentially converted to lactate to try and restore levels of NAD+ (pyruvate --\> lactate consumes NADH and regenerates NAD+). This will prevent the pyruvate from being used in TCA and ETC, resulting in decreased cellular metabolism when in a fed state. * Additionally, when in a fasted state, gluconeogenesis will be inhibited as well because pyruvate is needed as a substrate so the body will be unable to make new glucose when fasted. * Fatty acid oxidation will also be inhibited because one of the steps in oxidizing the acetyl-coA to fatty-acyl coA requries NAD+. * NADH is used directly by the ETC to synthesize ATP. High NADH signals to the body that it's in a high energy state, and slows glycolysis and, FA oxidation, and TCA cycle.

Question 35

What are the consequences of a build up of acetaldehyde from alcohol metabolism?

Answer 35

Question 36

What are the consequences of a build up of acetate from alcohol metabolism?

Answer 36

Acetate can be converted to acetyl-coA which is used to generate fatty acids leading to a fatty liver. The liver can attempt to deal with this excess fat by storing the fat in VLDL which is then secreted into the blood. This can result in increased peripheral vascular damage in the form of atherosclerosis due to hypertriglyceridemia. Additionally, if acetate is converted to acetyl-coA, then high acetyl-coA will shut off the TCA. As noted, some of this will be shuttled to fatty acid synthesis, but some will also be used to make ketone bodies leading to acidosis and ketosis.

Question 37

Why would you see hypoglycemia in a person who abuses alcohol?

Answer 37

They are likely to be malnourished. Since they're not taking in enough glucose because they likely get most of their calories from alcohol, they also are likely to have depleted glycogen stores. This puts them in a position to rely heavily on gluconeogenesis for new glucose to feed the brain. However, gluconeogenesis will be inhibited because of insufficient NAD+ that is needed to convert TCA precursors to pyruvate and the fact that any pyruvate that is made will be converted to lactate. Thus, they are at risk for hypoglycemia.

Question 38

How does high NADH:NAD+ relate to ROS?

Answer 38

High NADH:NAD+ also makes the cells more susceptible to damage from ROS because there is not enough NAD+ to oxidize the ROS

Question 39

Why are patients who abuse alcohol likely to present with acidosis?

Answer 39

Build up of lactic acid and ketoacids

Question 40

What is alcoholic liver disease?

Answer 40

Liver injury attributed to alcohol abuse

Question 41

What is the threshold at which a person is at risk for damaging their liver from alcohol consumption?

Answer 41

About 4 drinks/day for men and 2 drinks/day for women for a sustained period of time (I think he said 12 months). Exceeding threshold amounts in some liver injury in all persons but less than 50% will develop serious liver disease.

Question 42

True or false: damge to the liver from alcohol consumption is always irreversible.

Answer 42

False - there is a point at which, once crossed, abstinance from alcohol use no longer allows for return to baseline. However, before this threshold is crossed, it is possible for the liver to recover.

Question 43

Why does cirrhosis lead to portal HTN?

Answer 43

Damage from alcohol --\> fibrosis --\> nodule formation and disruption of normal liver sinusoid architecture leading to narrowed / blocked sinusoids --\> blood can't flow through sinusoids normally --\> increased resistance to flow --\> portal HTN

Question 44

Why does portal HTN lead to varices and GI bleeding?

Answer 44

Blood can't flow in portal system due to high resistance to flow --\> is rerouted through the systemic circulation via anastamoses between portal system and systemic veins --\> this distends systemic veins and increases pressure in these veins which can lead to visibly distended veins (particularly on front abdominal wall) --\> high pressure distended veins can lead to increased potential for ruture and GI bleeding

Question 45

Where is it most common to see varices?

Answer 45

Esophagus, rectum, stomach, abdominal wall (places where there are anastamoses)

Question 46

Why does ascites develop with liver damage?

Answer 46

Ascites is when lymph fluid leaks across hepatic sinusoids and leads to swelling of the abdomen. Thsi happens during cirrhosis because the sinusoids have increased pressure which pushes lymph fluid out into abdomen.

Question 47

What is hepatic encephalopathy?

Answer 47

Question 48

Other than diseases of the liver, what else might be observed or might develop in patients who abuse alcohol?

Answer 48

Hepatocellular carcinoma Esophageal Cancer Acute and/or chronic pancreatitis (--\> diabetes) Stroke Cardiac disease Fetal Alcohol syndrome

Question 49

What do each of these lab tests tell you about this patient and their chronic alcoholism?

Answer 49

Question 50

What vitamin deficiencies would you expect in a person who is a chronic alcoholic?

Answer 50