Liver Dysfunction & Bilirubin Metabolism Flashcards
What are the functions of the liver?
Key role in iontemediary metabolism
Synthetic function
Detoxification & Excretion
Storage function
Production of bile salts
What metabolic processes is the liver involved in?
Gluconeogenesis
Glycolysis
Ketogenesis
What synthetic functions does the liver have?
Plasma proteins
Coagulation factors
Cholesterol
Triglycerides
Lipoporoteins
What detox and excretion processes is the liver involved in?
Urea cycle (Ammonia to urea)
Bilirubin
Cholesterol
Drug metabolites
Which substances does the liver store?
Vitamins A, D, E and K and B12
What is the function of production of bile salts?
Helps with digestion
What is cholestasis?
Bile cannot flow from the liver to the duodenum
What is jaundice?
Yellow or greenish pigmentation of the skin and whites of the eyes due to high levels of bilirubin
What is hepatitis?
Inflammation of the liver tissue
What is cirrhosis?
Liver does not function properly due to long-term damage characterised by the replacement of normal liver tissue by scar tissue
What is steatosis?
Abmormal retention of lipids within a cell
What is hemochromatosis?
Iron storage overload
What are liver function tests?
Noninvasive methods of screening for liver dysfunction
What are the functions of liver function tests?
Help in identifying general types of liver disease
Assess severity and allow prediction of outcome
Help in monitoring the treatment of the disease
What are the two broad categories of liver tests?
Tests to assess hepatic function
Tests to detect hepatic injury
What is Group I of LFTs?
Markers of liver dysfunction
What are the markers of liver dysfunction?
Serum bilirubin
Urine
Total protein, serum albumin, and albumin/globulin ratio
Prothrombin time
What do you measure within serum bilirubin?
Total and conjugated
What do measure within the urine test of Group I LFTs?
Bile salts and urobilinogen
What are Group II LFTs?
Markers of hepatocellular injury
What are the markers of hepatocellular injury?
ALT & AST
What are Group III LFTs?
Markers of cholestasis
What are the markers of cholestasis?
ALP
GGT
What are the limitations of LFTs?
Why?
- Normal LFT values do not always indicate the absence of liver disease
Because the liver has a very large reserve capacity - Asymptomatic people may have abnormal LFT results
What is serum albumin?
The most abundant protein in mammals
Where is serum albumin synthesised?
The liver
What gene encodes serum albumin?
ALB gene
Where is serum albumin dissolved?
In the blood stream
What is the function of serum albumin?
Primarily a carrier protein for unconjugated bilirubin, steroids, fatty acids and thyroid hormones
Also plays a key role in stabilising extracellular fluid volume by contributing to the osmotic pressure of the plasma
What are the normal levels of serum albumin?
3.5 to 5.5 g/L
What does the synthesis of serum albumin depend on?
The extent of functioning liver cell mass
What is the half life of serum albumin?
20 days
In which pathology does the serum albumin levels always decrease?
Chronic liver diseases
What is the difference between globulins and albumins?
Globar proteins with higher molecular weights than albumins
Insoluble in pure water but dissolve in dilute salt solutions
Where are α & β globulins synthesised?
By the liver
What are the normal serum levels of globulins?
16 to 30 g/L
Which globulins are known as antibodies?
Active γ globulins
High serum levels of IgG are observed in which pathologies?
Autoimmune hepatitis
High serum levels of IgA are observed in which pathologies?
Alcoholic liver disease
What is prothrombin?
A market of liver function
Where is prothrombin synthesised?
In the liver
What is prothrombin converted into and when?
Thrombin during coagulation
What is the half-life of prothrombin?
6 hours
What is prothrombin time?
A blood test that measures how long it taken blood to clot
What is the reference range for PT?
12 to 16 seconds
When is PT prolonged?
When liver loses more than 80% of its reserve capacity
What are other causes of prolonged PT?
Vitamin K deficiency, however, intake of vitamin K has no effect in the case of liver disease
Where is ALT found?
Plasma and in various body tissues but most common in the liver
What is the function of ALT?
Reversible transfer of an amino group from L-alanine to α-ketoglutarate
Which transferase is liver-specific enzyme?
ALT more than AST
What is the normal range of ALT?
10 to 55
What do high elevations of ALT indicate?
Acute hepatitis
What do moderate elevations of ALT indicate?
Alcoholic hepatitis
What do minor elevations of ALT indicate?
Cirrhosis, hepatitis C, non-alcoholic steatohepatitis
In what cases might ALT levels be elevated but there the individuals are healthy?
In obese but otherwise healthy individuals
What is the function of AST?
Reversible transfer of an amino group from aspartate to α - Ketoglutarate
What is the normal range of AST?
10 to 40
Where is AST found?
In the liver, skeletal muscle, myocardium, kidney, pancreas and RBCs
What is AST?
A marker of hepatocellular damage
In what cases are there high levels of AST?
Chronic hepatitis, cirrhosis and liver cancer
What is ALP?
A homodimeric protein enzyme, containing two zinc atoms crucial to its catalytic function
What is the optimal environment for ALP?
Optimally active in alkaline pH environments
What is ALP’s function under alkaline environments?
To dephosphorylate compounds
Is ALP a specific or non-specific marker of liver disease?
Non-specific
Where is ALP produced?
In bone osteoblasts
What other structures is ALP present on?
Hepatocyte membranę
What is the normal range of ALP?
45 to 115
When is moderate elevation of ALP seen?
Infective hepatitis, alcoholic hepatitis, and hepatocellular carcinoma
When is high elevation of ALP seen?
Obstructive jaundice and interhepatic cholestasis
When is very high elevation of ALP seen?
Bone disease
What is GGT?
Transferase that catalyses the transfer of gamma-glutamyl functional groups from molecules like glutathione to an acceptor that may be an amino acid or peptide
What is the function of GGT?
Key role in gamma-glutamyl cycle
What is gamma-glutamyl cycle?
A pathway for the synthesis and degradation of glutathione as well as the drug and xenobiotic detox
Where is GGT found?
Microsomal enzyme in hepatocytes and epithelium of small bile ducts and pancreas, kidney and intestines
What is the normal range of GGT?
15 to 85
When is moderate elevation of GGT seen?
Infective hepatitis and prostate cancers
In which cases is GGT increased despite normal liver functions?
In alcoholics, highly sensitive to detecting alcohol abuse
What is bilirubin?
A yellow bile pigment
What is bilirubin responsible for?
The yellow colour in urine and the brown colour of faeces
Yellow colour of bruises
Yellow colour in jaundice
What is the average life span of healthy RBCs?
120 days
What happens to senescent RBCs?
They undergo erythrophagocytosis by macrophages in the spleen and liver
What happens to global chains when RBCs are broken down?
Break down into amino acids
What happens to the heme when RBCs are broken down?
Heme oxygenate converts heme to biliverdin
Biliverdin reductase converts biliverdin to bilirubin
What is the function of biliverdin reductase?
Catalyses the conversion of biliverdin to bilirubin by transferring two hydrogen ions to the centrally located C10 carbon of bilirubin
What is the linear structure of Bilirubin?
Two dipyrroles joined by a central methene bridge
Why is bilirubin insoluble even though it has multiple polar groups?
Because of the internal hydrogen bonding, all polar groups are engaged and central methene bridge becomes buried
Why is the conjugation of bilirubin crucial?
It increases its aqueous solubility on preparation for its transport to bile
What does albumin function as in regards to bilirubin?
Carrier protein for transporting unconjugated bilirubin through the bloodstream to the liver in order for bilirubin to be conjugated
What is unconjugated bilirubin joined with to form conjugated bilirubin?
Glucuronic acid
What catalysed the conjugation of bilirubin with glucuronic acid?
Glucuronyl transferase
What is the first step of bilirubin conjugation?
Formation of bilirubin monoglucuronide, sufficient soluble for transport
In which cases in bilirubin monoglucuronide the predominant form of conjugated bilirubin?
In fetal and early neonatal life
What happens if you add another glucuronic acid to bilirubin monoglucuronide?
It becomes bilirubin diglucuronide, which is the fully conjugated form
What does conjugated bilirubin do?
Passes through the bile and reaches the intestines
What substances deconjugate bilirubin?
Intestinal bacteria
What happens to the free bilirubin in the small intestine?
Reduced to urobilinogen and then into stercobilinogen
What percentage of bilirubin is converted into stercobilinogen?
Over 80%
Where is stercobilin excreted?
In the faeces, gives the brown colour
What happens to the remainder urobilinogen?
Reabsorbed from the intestine and enters portal blood
Some of it returns to the liver and is re-excreted (enter-hepatic circulation)
What happens to the urobilinogen that does not return to the liver?
Passes through the kidney and is converted into urobilin that is excreted in the urine and gives it its yellow colour
What is the bilirubin that is conjugated with the glucuronic acid called?
Direct or conjugated bilirubin
What is the bilirubin that is not conjugated with glucuronic acid called?
Indirect or unconjugated bilirubin
What is all the bilirubin in the blood called?
Total bilirubin
What is the normal levels of the different kinds of bilirubin?
Total: 0.3 to 1mg/dl
Unconjugated: 0.2 to 0.7 mg/dl
Conjugated: 0.1 to 0.3 mg/dl
What happens if serum bilirubin > 1?
Hyperbilirubinemia
What happens if serum bilirubin > 2?
Jaundice
What is neonatal jaundice?
Jaundice in newborns, especially seen in premies
When does neonatal jaundice appear?
Appears after 24 hours, picks up after 4 to 5 days and then disappears after 14 days
What causes neonatal jaundice?
Bilirubin accumulates as glucurynol transferase is low at birth
Unconjugated bilirubin is increased in blood > albumin
Diffuses into basal ganglia and cause toxic encephalopathy
What is the treatment for neonatal jaundice?
Blue fluorescent ligt, convers bilirubin to more polar –> water soluble isomers –> which can be excreted unto bile without glucuronic acid
What are the causes for haemolytic jaundice?
Excessive hemolysis
Low haemoglobin levels
Increased levels of indirect bilirubin
Sickle cell anemia, thalassemia, malaria and haemolytic transfusion reaction
What causes hepatic jaundice?
Impaired uptake of bilirubin by hepatocytes
Impaired conjugation of bilirubin with hepatocytes
Impaired secretion of bilirubin by hepatocytes
What happens to the elevates of both direct and indirect bilirubin in hepatic jaundice?
Both increase
What happens to AST and ALT during hepatic jaundice?
Significant increase
What happens to aLP during hepatic jaundice?
Moderate increase
What can cause hepatic jaundice?
Hepatitis, cirrhosis, Crigler-Najjar syndrome, gilbert’s syndrome, dubin-johsnon syndrome, rotor syndrome, drug toxicity
What cause obstructive jaundice?
Impaired excretion of bilirubin due to obstruction in the bile flow from the liver to the ntestien
What happens to the levels of direct bilirubin in obstructive jaundice?
Increase
What happens to ALP levels in obstructive jaundice?
Significant increase
What happens to AST and ALT levels in obstructive jaundice?
Moderate increase
What can cause obstructive jaundice?
Gallstones, inflammation, carcinoma of head of pancreas
What is congenital hyperbilirubinemia?
Bilirubin is elevated in blood due to inherited defects in the bilirubin metabolic pathway
What is the Crigler-Najjar syndrome?
Low activity of glucuronyltransferase
What does Crigler-Najjar syndrome present like?
Severe hyperbilirubinemia in neonates
Complicated by kernicterus and early death
What is Gilbert’s syndrome?
Decreased production of glucuronyltransferase due to mutations
What population is Gilbert’;s syndrome more common in?
In men, 2 to 3% of men
How does Gilbert’s syndrome present?
Usually asymptomatic
LFT’s are normal
What is the Dubin-Johnson/Rotor syndrome?
Defect in transfer of conjugated bilirubin into biliary canaliculi
Conjugated hyperbilirubinemia
