Liver Function

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Biochemistry teamwork 438 - Gastrointestinal & Nutrition Block
Objectives:

Understand the major metabolic functions of the liver and causes of liver dysfunction.

Discuss markers of liver function tests such as liver enzymes, bilirubin, albumin and
prothrombin time that can diagnose hepatic injury and assess hepatic function.

And…..

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 the Liver

Major Metabolic Functions

Examples of dysfunction

Hepatocellular Cholestasis
Detoxification Production (obstruction of bile
Synthetic Storage disease
& excretion flow)

Triglycerides Bilirubin Vitamins Bile salts Steatosis

Hepatitis
(fatty liver)
➢ A. ➢ Helps in digestion.
➢ D.
Cholesterol Cholesterol ➢ E.
➢ K.
➢ B12. Cirrhosis Jaundice
Drug
Lipoproteins
metabolites

Plasma Liver cancer Genetic Disorders

proteins Urea cycle

➢ Albumin. ➢ Hemochromatosis
Ammonia → urea
➢ Globulins. (iron storage).
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 Liver Function Tests (LFTs)
★ Noninvasive methods for screening of liver dysfunction.
Help in identifying general Assess severity & allow
1 types of disorder
2 prediction of outcome 3 Disease & treatment follow up

Classification
Markers of hepatic injury Markers of liver dysfunction
Mild or severe / acute or chronic

Hepatocellular Cholestasis Serum bilirubin

Or biliary obstruction total (direct & indirect) & conjugated

Alanine aminotransferase Alkaline phosphatase

Urine
(ALT) (ALP) 1 bile salts and urobilinogen
➔ Infiltrative disease.2

Protein
Aspartate aminotransferase γ-glutamyltransferase ◆ Total.
◆ Serum albumin .
(AST) (GGT) 3 ◆ Albumin/globulin ratio.
★ Synthetic function

Bilirubin Prothrombin Time

➔ Impaired conjugation .. ★ Synthetic function

Bile acids
1. Related to the bones but was found in the membrane in hepatocytes
2. Infiltrative disease in which the liver is invaded or replaced by non-hepatic substance such as neoplasm.
3. important for detection of alcohol/ drug abuse 4
 Liver Function Tests (LFTs)

Normal values don’t always Asymptomatic people may

indicate have abnormal
absence of disease Limitations results
Liver has a very large reserve capacity Diagnosis should be based on
clinical examination1

Bilirubin
A byproduct of RBC breakdown Serum levels Jaundice
1- Abnormal RBCs
Normal 0.2 – 0.8 mg/dL 2- Antibodies
The yellowish pigment in jaundice
Pre-hepatic 3- Drugs & toxins
Unconjugated 0.2 – 0.7 mg/dL (Hemolytic) 4- Hemoglobinopathies (thalessemia)
(indirect) 5- Gilbert’s syndrome 2
6- Crigler-Najjar syndrome 2
High levels are observed in : Conjugated 0.1 – 0.4 mg/dL 1- Viral hepatitis
1 (direct) Hepatic
Gallstones 2- toxic hepatitis
(Hepatocellular)
3- intrahepatic cholestasis
2 > 1 mg/dL
acute & chronic hepatitis Latent jaundice
less than 2 mg/dL 1- Extrahepatic cholestasis
2- gallstones
Post-hepatic 3- tumors of the bile duct
Jaundice > 2 mg/dL 4- carcinoma of the apex of pancreas
1. Remember that these tests aren’t sensitive nor specific for liver disease
2. Varying degrees of deficiency of bilirubin UDP-glucuronosyltransferase result in Crigler-Najjar I and II and Gilbert syndrome, with Crigler- Najjar I being the most severe.
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Explanation
1- Rupture of RBCs lead to release of heme

2- Heme is converted to biliverdin catalyzed by microsomal

heme oxygenase which is reduced to bilirubin

3- bilirubin is complexed with albumin and released at

entrance to the liver (unconjugated bilirubin).

4- Bilirubin is conjugated with UPD-glucuronic acid.

5- Conjugated bilirubin is secreted into bile and then

into the intestine.

6- Bacteria utilize glucuronic acid so it remove it from

bilirubin converting it into urobilinogen.

★ Fate of urobilinogen:
7- Some enter the portal circulation where:
8- Returns back to the liver.
9- filtered by the kidney as urobilin

10- majority is excreted with feces as stercobilin

(gives the feces its characteristic color)

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 Markers for liver dysfunction
Marker Urobilinogen Bile salts Serum albumin Serum globulin Prothrombin time

Most are metabolised Normally not found 3.5 - 5 g/dL (measured from the 2.5-4.5 g/dL
in the large intestine, in urine serum)
Normal
but a fraction is
levels
excreted in the urine:
less than 4 mg/day

Obstruction of biliary -The most abundant protein - α and β globulins are mainly - Synthesized by the liver
passages → leakage synthesized by the liver synthesized in the liver - Half life = 6 hours →
of bile salts into the -Synthesis depends on the - They constitute indicates present
Features
circulation → extent of functioning liver cell immunoglobulins (antibodies) function of the liver (an
excretion in urine mass early marker)
- Longer half life: 20 days

Excreted in urine Low in all chronic liver diseases High serum γ-globulins in It is prolonged only when
chronic hepatitis & cirrhosis: the liver loses more than
In ➔ IgG: autoimmune 80% of its reserve
disease hepatitis capacity
➔ IgA: alcoholic liver
disease

Measured from urine Albumin to globulin (A/G) ratio: - Vit. K also causes
- Normally: 1.2/1 - 1.5 /1 (1.2-1.5 albumin molecules for every 1 prolonged PT
Notes
globulin) - Vit K intake does not
- Hypoalbuminemia: globulin levels increase as a compensation affect PT in liver disease

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 Markers for hepatocellular injury
Marker Aspartate aminotransferase (AST) Alanine aminotransferase (ALT)

Normal 8-20 U/L ● Male: 13-35

levels ● Female: 10 - 30

Marker for hepatocellular damage - More liver-specific than AST

- Appears in plasma many days before clinical signs appear
Features - Obese but otherwise normal individuals may have elevated
ALT levels

High serum levels are observed in: ➔ Minor elevations (50 - 100 U/L):
● Chronic hepatitis ◆ cirrhosis
● Cirrhosis ◆ hepatitis C
● Liver cancer ◆ non-alcoholic steatohepatitis (NASH)
In disease
➔ Moderate elevations (100 - 300 U/L):
◆ alcoholic hepatitis
➔ High serum levels (300 - 1000 U/L):
◆ acute hepatitis

Not very specific for liver disease; - If both AST + ALT were high → liver disease
could be used as a marker for - If AST levels were much higher than ALT → could indicate basal
Notes diseases in organs such as the heart, muscle damage since it’s also present in cardiac + skeletal
the brain, the kidney, skeletal muscles
muscles, bones

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 Markers of cholestasis
Marker Alkaline phosphatase (ALP) Ɣ Glutamyltransferase (GGT)

Normal 40 - 125 U/L 10 - 30 U/L

levels

- Non-specific marker of liver disease - Used for glutathione synthesis

- Produced by bone osteoblasts (for bone calcification) + - Highly sensitive for alcohol abuse; it is increased in
Features
placenta1 alcoholics despite normal liver function tests
- Present on hepatocyte membrane

➔ Minor elevations observed in: ➔ Moderate elevations observed in:

◆ infective hepatitis ◆ Infective hepatitis
◆ alcoholic hepatitis ◆ Prostate cancers
◆ hepatitis ➔ High in alcoholics
In ◆ hepatocellular carcinoma
disease ➔ High elevations observed in:
◆ Extrahepatic obstruction (obstructive jaundice)
◆ Intrahepatic cholestasis
➔ Very high levels observed in:
◆ Bone diseases2

1. Could be high in pregnancy Alcohol leads to liver damage and affects many
2. Elevated alone, without GGT indicates bones disease → parameters. However, since GGT is very sensitive to
Notes
ALP + GGT are always measured together to indicate liver alcohol, it becomes elevated earlier than other
obstruction enzymes

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Take Home Messages

LFTs help detect liver injury and function

LFTs do have some limitations

Done studying? Let’s

see if your memory is
still working!!
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 Summary
Serum levels:
Hepatic jaundice: viral hepatitis;
➔ Latent jaundice: > 1 mg/dL
toxic hepatitis; intrahepatic
➔ Jaundice: > 2 mg/dL
cholestasis
Bilirubin/ Jaundice

Prehepatic jaundice: abnormal Post-hepatic jaundice:

RBCs; antibodies; drugs & toxins; extrahepatic cholestasis;
Thalassemia; Gilbert’s syndrome; gallstones; tumors of bile duct;
Crigler-Najjar syndrome carcinoma of the pancreas

Marker Serum Serum Prothrombin

Bilirubin Bile salts AST ALT ALP GGT
albumin globulin time

Change Excreted in Prolonged

urine

Disease - Gallstones Biliary All chronic Chronic When the liver - Chronic - Minor: cirrhosis, - Minor: infective Moderate:
passage liver hepatitis & loses more hepatitis hepatitis C, hepatitis, alcoholic infective
- Acute & obstruction diseases cirrhosis: than 80% of its - Cirrhosis NASH hepatitis, hepatitis, hepatitis,
chronic reserve - Liver hepatocellular prostate
hepatitis - IgG: capacity cancer - Moderate: carcinoma cancer
autoimmun alcoholic - Moderate:
e hepatitis hepatitis extrahepatic High in
- IgA: obstruction, alcoholics
alcoholic - Severe: acute intrahepatic
liver hepatitis cholestasis
disease - Severe: bone
diseases
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 Quiz
MCQs : SAQs :
Q1: A patient presents with jaundice, abdominal pain, and nausea. Clinical Q1: Name 3 markers related to cholestasis:
laboratory results show increase in serum conjugated bilirubin, presence of urinary
bilirubin but absence of urine urobilinogen. What is the most likely cause of the Q2: list the causes of pre hepatic , hepatic
jaundice? & post hepatic jaundice .
a) Decreased hepatic conjugation b) Decreased hepatic uptake
c) Decreased secretion of bile into the intestine d) Increased hemolysis Q3: what do we observe when bilirubin
serum is elevated ?
Q2: In post hepatic jaundice, ALT levels rise markedly.
a) True b) False Q4: Name 3 markers observed in alcoholic
liver disease:
Q3: _________ is responsible for the yellow coloring in jaundice.
a) bilirubin b) urobilinogen c) urobilin d) stercobilin ★ MCQs Answer key:

1) C 2) B 3) A 4) A 5) B 6) B
Q4: Which of the following LFTs is more specific?
a) ALT b) Serum bilirubin c) alpha fetoprotein d) AST ★ SAQs Answer key:

1) Alkaline phosphatase (ALP) - γ-glutamyltransferase (GGT)

Q5: Which of the following is produced in the bones? - bilirubin
a) GGT b) ALP c) Prothrombin d) AST 2) Slide 5
3) Gallstones , acute & chronic hepatitis
4) Serum globulin, ALP, ALT, GGT

Q6: Which of the following markers indicate present liver function?

a) Serum albumin b) Prothrombin time c) GGT d) ALP
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