Biochemical functions of the Liver

Prof. KG Gomathi

2/7/21

www.gmu.ac.ae COLLEGE OF MEDICINE

Learning Objectives

 Describe liver functions of metabolism, detoxification, and excretion.

 Explain the formation of bile and its role in the excretion of cholesterol
and bilirubin.
 

Readings:
Barrett KE, Barman SM, Boitano S, Reckelhoff JF. Transport & Metabolic
Functions of the Liver in Ganong's Medical Physiology Examination &
Board Review New York, NY: McGraw-Hill; available available in the gmu
e-library from http://accessmedicine.mhmedical.com
 Liver Has A Central Role In Metabolism

Due to its
• Anatomic placement

 Since the liver receives venous blood from the intestine all of
products of digestion, ingested drugs and other xenobiotics
reach it first are further metabolized before entering the
systemic circulation.

• Biochemical functions

 Hepatocytes have an immensely broad range of synthetic and

metabolic functions
 Liver has very high functional reserve

Normal liver functions continue with even just 25% of functional liver

Therefore mild disease may cause no symptoms and is detected only

by biochemical changes in the blood.

Severe liver disease will show up as jaundice, easy bruising and

profuse bleeding, ascites and hepatic encephalopathy
 Overview of biochemical functions of the liver

Markers of impairment in
Function
plasma
Heme catabolism bilirubin
Carbohydrate metabolism ↓glucose
Protein synthesis ↓albumin

prolonged prothrombin time

Protein catabolism ↑ammonia

↓urea
Lipid metabolism ↑cholesterol
↑triglycerides

Drug metabolism biological half-time of a drug

Bile acid metabolism ↑bile acids

 Biochemical Functions of liver
I. Metabolic Functions

1. Protein Metabolism
-Synthesis and Degradation of Proteins except Immunoglobulins
-Synthesis of Acute Phase Proteins
- Amino acid Metabolism
- Detoxification of ammonia and Urea Biosynthesis

    2. Carbohydrate Metabolism

- Glycogenesis
- Gluconeogenesis
- Glycogenolysis
   3. Lipid Metabolism
- Lipogenesis (Simple & Complex)
- Lipolysis
- Ketogenesis
- Bile Salt Synthesis

  II. Storage Functions

Iron, Glycogen, Vitamins (A, D, E, B12) .
 
III. Excretion and Detoxification –drugs and other chemicals
 
  IV. Protective Functions (Kupffer Cells)
 1. Ammonia metabolism and urea synthesis

• Catabolism of amino acids generates ammonia (NH3) and ammonium ions

(NH4+).

• Ammonia is toxic, particularly to the central nervous system (CNS).

• Impaired clearance of ammonia causes brain damage

• The urea cycle is the major route by which ammonia is converted into urea and
excreted.

• Liver failure results in hyperammonemia and hepatic encephalopathy

• Defects in any of the enzymes of the urea cycle lead to hyperammonemia

(inborn error of metabolism)
Five Steps In Urea Biosynthesis
Urea cycle disorders (Inborn errors of metabolism)

• Characterized by hyperammonemia, encephalopathy, and respiratory alkalosis.

• result in the accumulation of ammonia and glutamine.

• Clinical symptoms common to all urea cycle disorders include vomiting, avoidance
of high-protein foods, intermittent ataxia, irritability, lethargy, and severe mental
retardation.

• Infants initially appear normal, then exhibit progressive lethargy, hypothermia, and
apnea due to high plasma ammonia levels.

• Low-protein diet ingested as frequent small meals can result in significant

improvement and minimization of brain damage
Clinical conditions in which blood ammonia measurement is useful:

• Hepatic failure,
o Severe liver disease is the most common cause of disturbed ammonia
metabolism.
o Monitoring of blood ammonia may be used to determine prognosis

• Reye’s syndrome
o Acute metabolic disorder of the liver with severe fatty infiltration
o Blood ammonia concentration correlates with both the severity of disease
and prognosis.

• Inherited deficiencies of urea cycle

o Testing should be considered for any neonate with unexplained nausea,
vomiting, or neurological deterioration associated with feeding.
 2. Plasma proteins in liver disease

• Most plasma proteins are synthesized in the liver

• Albumin is the most abundant protein in blood and is synthesized

exclusively by the liver

• Low plasma total protein and albumin concentration occur commonly

in liver disease.
• Decreased albumin in plasma decreases oncotic pressure—causes
edema

• A good index of hepatocyte synthetic function is the production of the

coagulation factors II, VII, IX, and X. Functional concentration of
coagulation factors is assessed by measuring the prothrombin time
.
BILE FORMATION

• Bile contains bile acids, phosphatidylcholine, conjugated bilirubin, cholesterol,

and xenobiotics which are actively secreted into the bile canaliculi

Functions of the gallbladder

• Bile flows into the gallbladder when the sphincter of Oddi is closed (ie, the
period in between meals).
• In the gallbladder, the bile is concentrated by absorption of water.

Biliary secretion
• Release of cholecystokinin (CCK) in response to nutrients causes gallbladder
contraction.

• CCK, also activates vagal afferents to trigger relaxation of the sphincter of Oddi
to permit bile outflow 
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 3. Bilirubin metabolism

• Bilirubin is the catabolic product of heme.

• Bilirubin is derived from the breakdown of hemoglobin

• from senescent red blood cells in the spleen, bone marrow, and
liver (reticulo-endothelial system).

• Bilirubin produced in the reticuloendothelial cells is transported in

plasma bound to albumin to the liver

• Bilirubin (total and direct) are used to classify jaundice and

diagnose hepatitis
 Role of liver in Bilirubin metabolism

• The hepatic uptake of bilirubin is mediated by a membrane carrier

• Solubility of bilirubin is increased by conjugating it with glucuronic

acid.

• Formation of bilirubin diglucuronide is catalyzed by the Uridine

diphosphate (UDP)-glucuronyl transferase.

• Conjugated bilirubin is secreted by the hepatocyte into the biliary

canaliculi.

• Obstruction in the bile duct causes increase in conjugated bilirubin

in serum

.
• Conjugated bilirubin in the gut is
catabolized by bacteria to form
Stercobilinogen which is colorless.

• Stercobilinogen forms stercobilin which is

colored;

• Most Stercobilin is responsible for the

brown color of feces.
 LFT In Jaundice

• Jaundice is the commonest presentation of liver dysfunction

• Yellow discoloration of sclera and skin due to deposition of bile pigment

(Bilirubin)

• Clinically evident when bilirubin > 2.3 mg%

• On the basis of structural and functional abnormalities, jaundice is

classified into three types:
- Pre-hepatic
- Hepatic
- Post-hepatic
Bile salts Nil + +++
Inherited defects of bilirubin metabolism

1. Crigler-Najjar Syndrome, Type I

• unconjugated hyperbilirubinemia,
• lack of UGT1A1 activity in hepatic tissue.
• Neither UGT1A1 activity nor the serum bilirubin concentration responds to
administration of phenobarbital 
• autosomal recessive pattern of inheritance. The majority of patients (type IA)
exhibit defects in the glucuronide conjugation.

2. Crigler-Najjar Syndrome, Type II

• Unconjugated hyperbilirubinemia but bilirubin concentrations are lower
• UGT1A1 in liver is usually present at reduced levels (typically ≤10% of
normal)
• responds to enzyme inducers such as phenobarbital

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Gilbert Syndrome (GS)

• common, with many series placing its prevalence at ≥8% by mild

unconjugated hyperbilirubinemia,
• normal values for standard hepatic biochemical tests

Dubin-Johnson Syndrome (DJS)

• conjugated hyperbilirubinemia 
• selective defect in excretion of bilirubin conjugates 

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 4. Role of liver in Drug metabolism

• Most drugs are metabolized in the liver.

• Hepatic metabolism increases hydrophilicity of drugs and their ability to be

excreted through the kidneys or in bile.

• It also inactivates most drugs

• Some drugs inactive (prodrugs) are converted to their active forms as a

result of liver processing.

.
• Phase I reaction- addition of the OH group to increase solubility
(catalyzed by cytochrome P-450 oxidases).

• Phase II reaction- conjugation by glucuronidation or sulfation,

• There are 12 cytochrome P-450 gene families, of which three,

designated CYP1, CYP2 and CYP3, are responsible for most of the
phase I drug metabolism.

• Six enzymes, CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 and

CYP2E1, are responsible for approximately 90% of drug metabolism.

• CYP3A4 is one of the most important cytochrome P-450 enzymes

Ethanol metabolism

• Excess intake of ethyl alcohol remains the most common cause of

liver disease

• Ethanol causes excessive fat deposition in the liver (alcoholic

steatosis) leading to hepatitis and cirrhosis

• Ethanol is oxidized in the liver, mainly by alcohol dehydrogenase

(ADH), to form acetaldehyde which is toxic

• Shift in the NADH/NAD+ ratio inhibits β-oxidation of fatty acids and

promotes triglyceride synthesis: excess of triglycerides is deposited in
the liver and secreted into plasma as VLDL