Liver Function, Diseases and Diagnostic Tests-Part I and II

What is the largest internal organ in the human body?

The liver

How much does the liver weigh?

Between 1.4 to 1.6 kg (3.2-3.7 lb)

Where is the liver located in the body?

In the upper right quadrant of the body

How many main lobes does the liver have?

2 lobes, right and left

How does the size of the right lobe compare to the left lobe?

It is 6 times larger

How many total lobes does the liver have?

4, with each main lobe having 2 smaller lobes

How many independent segments are there in the liver?

8

Why are the boundaries of liver segments important?

For transplants and cancer removal

What central role does the liver play in the body?

Metabolism (biotransformation)

How does the liver contribute to metabolism?

It processes and transforms substrates like carbohydrates, fats, and proteins for energy

What is an example of the liver’s detoxification function?

It detoxifies substances like alcohol and conjugates bilirubin for clearance

What is xenobiotic metabolism, and what is its significance?

It is the livers ability to render drugs, alcohol, and chemicals non-toxic through metabolism and then excretion through the kidney

What macronutrients does the liver metabolize?

proteins, carbohydrates, and lipids.

Which hormones and vitamins does the liver metabolize?

thyroid hormone, cortisol, and vitamin D

How does the liver contribute to digestion?

It produces bile

What are some substances stored in the liver?

1. Glycogen

2. Iron (ferritin)

3. Copper

4. Fat-soluble vitamins A, D, E, and K

How long can the liver store iron in males?

Up to 3 years

What are some proteins synthesized by the liver?

1. Albumin

2. Transthyretin

3. Immunoglobins

4. Ceruloplasmin

5. α1-antitrypsin

6. α-fetoprotein

7. Coagulation proteins.

What is the function of bile acids synthesized by the liver?

They allow for the absorption of dietary fats and fat-soluble vitamins

Which growth-related factor does the liver synthesize?

Insulin-like growth I (IGF-1)

What role does the liver play in the renin-angiotensin-aldosterone system (RAAS)?

It makes angiotensinogen, which is a key component of RAAS

How does the liver regulate iron entry into circulation?

It makes hepcidin, which regulates iron entry into the bloodstream

What blood-related hormones does the liver produce?

Thrombopoietin and erythropoietin, which are involved in hematopoiesis.

What immunologic role does the liver have?

It contains Kupffer cells (macrophages) and secretes liver-derived IgA, contributing to immune defense and clearance of pathogens

What is one of the main functions of the liver?

To eliminate waste products such as bilirubin

Why is bilirubin important for heme excretion?

It serves as a way to excrete unwanted heme from the body.

Where is bilirubin mainly produced from?

From the breakdown of old RBCs (senescent RBCs).

How much bilirubin is formed daily?

About 200-400 mg

What percentage of bilirubin comes from old RBCs?

80% is produced from HGB released from old RBCs

What are other sources of bilirubin production besides RBCs?

The other 20% comes from myoglobin and heme-containing enzymes like (P450)

Name examples of heme-containing proteins.

1. HGB (4 heme groups)

2. Myoglobin (1 heme group)

3. P450

Where does the degradation of RBCs occur?

In the RES, which includes the liver (90%), spleen, and BM

What is the function of the reticuloendothelial system (RES)?

It acts as a housekeeping system, like vacuum cleaners, and clearing old RBCs, and other cellular debris

What is the first step in bilirubin formation?

The porphyrin ring from HGB is converted into biliverdin (green bilirubin) by the enzyme heme oxygenase

What enzyme converts biliverdin into bilirubin?

Biliverdin reductase

What are the three major phases of bilirubin metabolism?

1. Pre-hepatic

2. Hepatic

3. Post-hepatic

What happens during the prehepatic phase?

Bilirubin is produced from the breakdown of old RBCs before transported to the liver

How is bilirubin transported in the blood?

With it being lipophilic (fat-soluble), bilirubin binds to albumin for transport in the blood

What occurs during the hepatic phase?

The liver process bilirubin by conjugating it with glucuronic acid, making it water soluble for excretion

What happens during the post-hepatic phase?

Conjugated bilirubin is excreted into the intestines via bile and further metabolized by gut bacteria into urobilinogen

What is the fate of urobilinogen in the intestines?

About 10-20% of urobilinogen is absorbed, recirculated to the liver, and reexcreted, while the rest is eliminated.

What percentage of bilirubin is excreted in feces?

Approximately 80-90% of bilirubin is excreted via feces.

What gives feces their characteristic brown color?

Urobilinogen is reduced to brown stercobilin, which gives feces their characteristic color.

What is stercobilinogen, and how is it related to stercobilin?

It is an intermediate product that can be further oxidized to stercobilin, contributing to fecal pigmentation.

What pigment is responsible for the yellow color of urine?

Urobilin, also known as urochrome, is responsible for the yellow color of urine.

What happens to bilirubin when it reaches the liver?

Albumin is removed in the sinusoidal space, and bilirubin binds to ligandin, a carrier protein that transports it to hepatocytes.

What enzyme is responsible for conjugating bilirubin in the liver?

Uridyl diphosphate (UDP)-glucuronyl transferase binds two glucuronic acid molecules to bilirubin.

How many distinct forms of bilirubin exist in serum?

4

What is the unconjugated form of bilirubin called?

α-bilirubin.

Why is α-bilirubin clinically significant?

It is lipophilic and can cross the blood-brain barrier potentially causing kernicterus (brain damage due to bilirubin accumulation).

What are the conjugated forms of bilirubin?

β-bilirubin, γ-bilirubin, and δ-bilirubin.

What is β-bilirubin?

The mono-conjugated form of bilirubin with one glucuronic acid molecules

What is γ-bilirubin?

The di-conjugated form of bilirubin with two guluronic acid molecules

What is δ-bilirubin, and how is it different?

Also called biliprotein, is irreversibility bound to a protein, such as albumin, and is covalently linked

Which bilirubin fractions are water-soluble?

β-, γ-, and δ-bilirubin and correspond to the direct bilirubin fraction.

Which bilirubin fraction is water-insoluble?

α-bilirubin and is part of the indirect bilirubin fraction.

How can unconjugated bilirubin (α-bilirubin) be solubilized?

By using alcohols

Why is it important to distinguish bilirubin sub-forms in serum?

For lab determination and diagnosing liver function disorders

What is jaundice?

hyperbilirubinemia

What is jaundice characterized by?

Yellow discoloration of the skin, sclera (eyes, and mucous membrane

How many categories of jaundice exist?

prehepatic, hepatic, and post-hepatic jaundice.

What causes prehepatic jaundice?

Increased bilirubin before it reaches the liver

What happens to bilirubin levels in prehepatic jaundice?

Unconjugated bilirubin increases due to the failure to reach the liver for conjugation

Give examples of conditions that cause prehepatic jaundice.

• Hemolytic disease of the newborn (excessive RBC breakdown)

• Congestive heart failure (impaired circulation)

What causes hepatic jaundice?

Liver dysfunction, which prevents proper bilirubin conjugation or clearance

What are the two major defects in hepatic jaundice?

• Conjugation defect – Liver is unable to conjugate bilirubin (↑UB).

• Transport defect – Liver fails to clear bilirubin properly (↑CB).

Give an example of a condition causing hepatic jaundice.

Inherited hyperbilirubinemias, where the liver cannot process bilirubin effectively.

What is the primary cause of post-hepatic jaundice?

The obstruction of bile flow from the liver to the intestine

What conditions can cause post-hepatic jaundice?

• Gallstones (stone formation in bile ducts)

• Cancer (blocking bile flow)

What happens to bilirubin levels in post-hepatic jaundice?

Conjugated bilirubin and alkaline phosphate increase, urobilinogen is absent is absent in urine

Why is urobilinogen absent in urine in post-hepatic jaundice?

Since bile flow is blocked, bilirubin cannot reach the intestine to be converted into urobilinogen

What is Gilbert Syndrome?

It is the least serious of the inherited unconjugated hyperbilirubinemias, and is a mild benign, condition.

How common is Gilbert Syndrome? 1

It is the most common cause of mild jaundice

What is the main cause of Gilbert Syndrome?

It is caused by a reduced production of the enzyme UDP-glucuronyl transferase (UDPGT) due to a promoter mutation.

What type of bilirubin is elevated in Gilbert Syndrome?

Unconjugated bilirubin (UB), due to a problem with bilirubin conjugation

What specific problems lead to Gilbert Syndrome?

• Defective conjugation due to reduced UDP-glucuronyl transferase activity.

• Impaired active transport of bilirubin by ligandin through the hepatocyte cell membrane to the microsome (where UDPGT is located).

Does Gilbert Syndrome require treatment?

No, treatment is not necessary since it is a mild and benign condition.

What is Crigler-Najjar Syndrome (C-N)?

A rare inherited condition characterized by unconjugated hyperbilirubinemia due to a deficiency in or absence of UDP-glucuronyl transferase (UDPGT).

What type of genetic inheritance does Crigler-Najjar Syndrome follow?

Autosomal recessive trait

What causes Crigler-Najjar Syndrome?

A decreased or absent UDP-glucuronyl transferase (UDPGT) enzyme, leading to impaired bilirubin conjugation.

How rare is Crigler-Najjar Syndrome?

It is the rarest

What are the two types of Crigler-Najjar Syndrome?

• C-N Type I – Severe form

• C-N Type II – Milder form

What are the characteristics of Crigler-Najjar Type I?

• It is the severe form.

• Leads to death or irreversible brain damage (Kernicterus) within the first year of life.

• Unconjugated bilirubin (UB) crosses the blood-brain barrier (BBB) because it is lipophilic and toxic.

What are the characteristics of Crigler-Najjar Type II?

• It is the milder form.

• Patients typically have no symptoms other than jaundice.

Why does Crigler-Najjar Type I lead to Kernicterus while Type II does not?

Type I has complete absence of UDPGT, leading to dangerously high unconjugated bilirubin levels, which can cross the BBB and cause neurotoxicity. In Type II, some UDPGT activity remains, preventing severe complications.

How common is Gilbert’s Syndrome? 2

It is common and affects about 5% of males, but it is rare in females.

What bilirubin levels are seen in Crigler-Najjar Syndrome?

25-50 mg/dL, which is significantly high.

What is Lucey-Driscoll Syndrome?

It is caused by a circulating inhibitor of the bilirubin conjugation enzyme UDP-glucuronyltransferase (UDP-GT), typically from the mother, leading to unconjugated hyperbilirubinemia in the newborn.

How does the circulating inhibitor affect bilirubin metabolism in Lucey-Driscoll Syndrome?

It prevents proper bilirubin conjugation, leading to unconjugated hyperbilirubinemia in the newborn.

What is Dubin-Johnson Syndrome (D-J)?

An inherited condition caused by a defect in the excretion, secretion, and or transport of conjugated bilirubin within hepatocytes (intracellular)

Is Dubin-Johnson Syndrome a serious condition?

No, it is a chronic and benign condition that typically does not cause severe harm. However it does produce an obstructive liver disease

What is the main cause of Dubin-Johnson Syndrome?

The deposition of lipofuscin, which blocks the transport of conjugated bilirubin into the bile canaliculi impairing its excretion

What is lipofuscin, and how does it relate to Dubin-Johnson Syndrome?

It is a black-brown pigmentation that accumulates in the liver cells, This accumulation results in impaired biliary excretion of conjugated bilirubin

How does lipofuscin deposition affect bilirubin metabolism in Dubin-Johnson Syndrome?

It blocks the transport of bilirubin from hepatocytes to bile canaliculi, leading to impaired excretion of conjugated bilirubin into bile.

What is the visible sign of Dubin-Johnson Syndrome?

The accumulation of black-brown lipofuscin pigmentation in the liver, which can be observed on liver biopsy.

What is the bottom-line issue in Dubin-Johnson Syndrome?

The defective removal of bilirubin from the hepatocyte and its impaired excretion into bile

What is Rotor Syndrome?

An inherited condition characterized by conjugated hyperbilirubinemia, which is caused by a defect in bilirubin transport within hepatocytes.

What is the genetic inheritance pattern of Rotor Syndrome?

Autosomal recessive trait.

What causes Rotor Syndrome?

A bilirubin transport defect, specifically impaired uptake of bilirubin into the cytosol of hepatocytes