Liver 1

Small Group
2022
Liver Tidbits

Understand the liver architecture

(don’t skip the histology lecture!)
Understand the portal venous system.
Is there a portal artery????
What does the liver actually do?
The liver synthesizes important stuff:
• Albumin
the big protein in the blood that carries
hormones and proteins around (the
“bus”) and contributes to oncotic pressure
• Coagulation Factors
factors that are part of the coagulation
pathway
• Glycogen
carbohydrates are stored as glycogen
• Urea
toxic ammonia (byproduct of protein
metabolism) is converted to nontoxic urea
to be safely eliminated in urine
• Lipoproteins
the major components of the fat
transportation system
Liver jobs
• Bile salts
fatty substances produced to help
dissolve and digest dietary fats and
oils. Secreted through the
gallbladder.
• Phospholipids
used to make cell membranes
• Cholesterol
essential substance to make
hormones, etc. Found in every cell
of the body.
• Transport proteins
proteins that carry toxic metals like
iron (on transferrin) and copper (on
ceruloplasmin)
The liver stores important stuff:
Liver jobs
• Carbohydrates (as glycogen)
• Vitamins (B12, A, D, E, K)
• Lipids
• Minerals like iron and copper
The liver detoxifies:
• Some examples are bilirubin, alcohol, ammonia, xenobiotics (drugs, food additives,
environmental pollutants)
The liver secretes and concentrates bile:
• Remember: Bile ≠ Bilirubin ≠ Bile Salts
The liver extracts and processes:
• Nutrients and lipids absorbed in the intestines come here for processing
The liver filters and removes:
• The portal venous blood is cleared here
Bile ≠ Bilirubin ≠ Bile Salts
What is bile?
It is the greenish alkaline fluid that is secreted by the liver, stored in the gallbladder,
and discharged into the duodenum. It aids in the digestion of lipids and is one
mechanism of excreting conjugated bilirubin, the waste product of old hemoglobin.
Bile is made up of bile salts, bilirubin, fats, salts and water.

What is bilirubin?
Bilirubin is the waste product of hemoglobin in red blood cell turnover. It is found in
the blood in 2 forms: unconjugated and conjugated. See the next slide.

What are bile salts?

Bile salts are specialized salts made by the liver to emulsify fats in the duodenum
and prepare them for digestion. They are necessary for absorption of fat-soluble
vitamins A, D, E and K. They are reabsorbed in the portal system and recycled.
Excretion of Bilirubin Involves Multiple Steps

Formation
Transport
ABCC2
Uptake
Storage
Conjugation
Secretion
Biliary Transport
Intestinal Transport
Elimination

7
What kind of elevated bilirubin will this patient have,
unconjugated or conjugated?
Disease/process Type of Bilirubinuria? Would the “transaminases”
hyperbilirubinemia (AST, ALT) be elevated?

Hemolysis unconjugated none Usually normal, unless the

(examples: SLE, sickle dz, cause of the hemolysis also
some drugs, some infxns) affects the liver

Acute hepatic necrosis conjugated ++++, because lots of conjugated Elevated. The damaged cells
(example: hepatitis, drug bilirubin is leaked in the leak their enzymes (the
toxicity) bloodstream which is then LFTs) directly into the blood.
excreted in urine

Cholestasis conjugated + Usually there is some

(example: gallstones elevation, depending on the
blocking the duct) amount of dysfunction

Cirrhosis conjugated + The cells may be so

depleted that there are
very few to make enzymes.
 32 yo sustains multiple injuries and blood loss in a motor vehicle
accident. He undergoes a prolonged surgery and multiple blood
transfusions. Unfortunately, the episodes of hypovolemia cause him
to develop ATN (acute tubular necrosis) with a creatinine of 4.5 which
indicates acute kidney failure. Jaundice develops on the second post-
operative day. His labs on this same day demonstrate a bilirubin of
Case 1 25 mg/dL (normal = 0.1-1.5 mg/dL) and marked bilirubinuria.

Do you think this post-op day 2 hyperbilirubinemia is mostly

conjugated or unconjugated bilirubin?
Because he has bilirubinuria, we know he has elevated conjugated
bilirubin. If he also has ongoing hemolysis, he may also have elevated
unconjugated bilirubin, but a healthy liver is very efficient at converting
the unconjugated bilirubin to conjugated, even in a stressed state.
 What are some ways his MVA, surgeries, and transfusions lead to hyperbilirubinemia?
1. RBCs in transfusions have a shorter lifespan than native RBCs and are likely undergoing
increased breakdown.
2. Hematomas are being resorbed and the heme is undergoing breakdown.
3. The kidneys are not fully able to help excrete conjugated bilirubin.

If his liver is also affected, other mechanisms could include:

Case 1 The hypovolemic/hypotensive episodes that damaged the kidneys could have also
damaged the liver, causing it to be less efficient or even causing a fewer number of
functioning hepatocytes. In this situation livers often respond with cholestasis, which
causes hyperbilirubinemia. Drugs from the surgeries and interventions can cause/worsen
cholestasis. Physical trauma to liver or biliary tree during the MVA may worsen the
problem.

Why is there an increase in UCB (unconjugated bilirubin).

As the hematomas resolve, there will be an increased load of UCB. If the liver cannot keep
up due to overload of the uptake process – then the UCB could increase.
In the functioning hepatocytes, conjugation itself will not be decreased UNLESS the patient
has Gilbert’s (decreased enzyme that conjugates bilirubin with glucuronic acid).
 CC: 21 yo college student goes to student health because her friend tells her that she has
“yellow eyes”
HPI: She has been tired after staying up most of the night writing a term paper. She denies
N/V/F/C or myalgias. She noticed yellow sclera after her prom where she had stayed up
all night and again during a flu.
PMH: none
SHx: weekend pot and alcohol, no tobacco or other drugs. She travelled to Europe 3 mo
Case 2 ago, but no eating/drinking except in developed cities. Hep A and B vaccinated.
Meds: Oral contraceptives, rare NSAID
NKDA

PE: Appears healthy, VSS

Sclera: yellow tint bilaterally
Abd: NT, soft, no HSM

Labs:
Hct 36% (nl)
AST/ALT nl
Total bili = 3.5 (nl .1-1.5)
Conjugated bili = 0.4
 Is her elevated bilirubin predominantly unconjugated or conjugated? What are
the possible disease mechanisms of her type of hyperbilirubinemia?

She has unconjugated hyperbilirubinemia. The disease categories would be:

• A problem with overproduction of bilirubin, such as in hemolytic anemia (a
massive breakdown of red blood cells) or resolution of a large hematoma.
• A problem transporting the unconjugated bilirubin to the liver, such as in heart
failure.
• A problem with uptake of the unconjugated bilirubin by the hepatocytes, as

Case 2 can happen with some medications.

• A problem with the conjugation process itself within the hepatocyte, such as
with decreased UDP-glucuronosyltransferase enzyme (Gilbert’s) or absent UDP-
glucuronosyltransferase (Crigler-Najjar).
Infants born with Crigler-Nijjar do not survive unless they receive liver transplant (except there is
a very rare survivable form).

Of these disease possibilities, what is your best guess as to her diagnosis?

She does not have anemia, nor reports a large hematoma. She has no S/S of heart
failure. She has not taken any medications to interfere with uptake. She must
have Gilbert’s.
 Gilbert’s Syndrome is a common benign condition reported in 4 – 16% of the
general population. It is the result of a defect in the promotor of the gene that
makes the UDP-glucuronosyltransferase enzyme that is responsible for conjugating
bilirubin within the hepatocytes. This genetic defect leads to a decreased amount
of active enzyme. The deficiency of enzyme varies per patient, so the degree of
increased unconjugated bilirubin varies.

The unconjugated bilirubin rises in the presence of stressors like fever, sepsis,
Gilbert’s fasting (especially if avoiding fats) and staying up all night. Most patients report
Syndrome episodic icteric sclera or jaundice with no other symptoms, although more
extreme cases may have malaise or abdominal discomfort when their UCB is
elevated. The syndrome is often discovered by accident on incidental lab draws;
many people go throughout life not knowing they have it.

People with Gilbert’s have the same long-term outcomes as the general
population. No special treatment is necessary. People with Gilbert’s may even
have some benefit of the chronically increased UCB; Gilbert’s seems to be
associated with lower incidence of atherosclerotic heart disease and cancers.