CHEMICAL PATHOLOGY OF LIVER DISEASES Flashcards
(36 cards)
What are the zones of the liver acinus?
Which zone is most involved in drug metabolism and most susceptible to drug-induced damage?
Based on the differential blood flow to the acinus, it is divided into 3 functional zones
* periportal highest oxygen content: this zone is least susceptible to ischaemic attack
* mediolobular intermediate
* centrilobular lowest oxygen content, most susceptible to ischaemic damage.
This zone is most involved in drug metabolism, most susceptible to drug-induced damage
What are the metabolic functions of the liver?
Glycolysis, the Krebs cycle, gluconeogenesis, glycogen synthesis and glycogenolysis, lipogenesis, ketogenesis, amino acid synthesis and degradation, and protein synthesis all take place in the hepatocytes.
Hepatocytes also metabolise and detoxify endogenous (haem) and exogenous products (drugs), which are then excreted via the biliary tree
What are the sources of bilirubin?
- Haemoglobin : The breakdown of RBC releases haemoglobin
- It is also released from and an ineffective erythropoiesis
- Other haem containing proteins e.g. myoglobin and cytochrome P450
About 70 to 80% of daily bilirubin production is derived from the breakdown of senescent (old) red blood cells, while the remainder is derived from ineffective erythropoiesis and the breakdown of other haem-containing proteins.
How is Bilirubin formed and metabolized?
Why is bilirubin neurotoxic?
Globin and Haem are formed from breaking down of haemoglobin
Globin (a protein) is broken down to its constituent amino acids.
Haem (a 4 ring structure containing Fe at its centre) is broken down (via biliverdin) to carbon monoxide, iron and bilirubin.
The bilirubin at this stage is termed unconjugated bilirubin.
Unconjugated bilirubin is hydrophobic in nature strongly bind to albumin in it hydrophobic site
Some drugs displace it from its albumin binding site e.g salicylate or any of the sulphonamides.
It is highly neurotoxic causing kernicterus when deposited in the cell membranes of basal ganglia
How is Unconjugated Bilirubin metabolized?
Unconjugated Bilirubin Uptake by the Liver
The unconjugated bilirubin - albumin complex is carried in the plasma to the hepatic sinusoids.
Within the hepatocyte the unconjugated bilirubin is bound to ligandin
How is Conjugated Bilirubin formed and then metabolized?
What is the rate limiting step of this process?
Conjugation of Bilirubin by the Liver
- The bilirubin is then conjugated with glucuronic acid by UDP-glucuronyl transferase (UDPGT I) to bilirubin monoglucuronide (BMG) and by UDPGT II to bilirubin diglucuronide (BDG).
- Conjugated bilirubin is more water soluble
- Conjugated bilirubin is transported out of the liver cells into the bile canaliculi
This is a rate -limiting step in bilirubin metabolism - Bilirubin along with bile flows through the canaliculi, into the bile ducts, and finally into the duodenum
What happens to bilirubin in the GIT?
What then happens to urobilinogen?
Clinical correlate of urobilinogen?
In the GIT, bacterial flora convert conjugated bilirubin to urobilinogen.
Most of the urobilinogen (colourless) is further converted by colon bacteria to urobilin and stercobilin (brown).
About 20% of urobilinogen in the small intestine is reabsorbed into the portal circulation and re-excreted back to the intestine (enterohepatic circulation).
Some urobilinogen appears in normal urine but becomes excess if re-uptake is defective as a result of liver damage or an increased bilirubin production
What are the primary bile acids?
What are the secondary bile acids?
How are bile acids conjugated & metabolized?
The primary bile acids are chenodeoxycholic acid and cholic acid, they are metabolic products of cholesterol from the liver.
The primary bile acids are made more soluble by conjugation with glycine or taurine.
Conjugated bile acids are transported out of the liver cells into the bile canaliculi
In the GIT, bacterial enzymes deconjugate and α dehydroxylate the primary bile acids and convert them to the secondary bile acids lithocholic acid and deoxycholic acid.
Most of the bile acids in the GIT are reabsorbed into the portal circulation (75% in the ileum and 10% in the colon), taken up by the liver again and re-excreted (enterohepatic circulation).
Normally a small amount escapes into the systemic circulation.
Any form of obstruction of biliary tree causes reflux of bile acid in the system
What is Normal serum total bilirubin?
<17 μmol/l
Does normal urine contain bilirubin and why?
Normal urine contains no bilirubin, since unconjugated bilirubin is albumin-bound and not filtered.
Increased amounts of unconjugated bilirubin are found in plasma in:
. Increased bilirubin production
. Decreased uptake or conjugation of bilirubin
. in generalised hepatocellular dysfunction
. in specific rare inherited syndromes (Gilbert’s and Criggler-Najjar syndromes).
Increased amounts of conjugated bilirubin are found in the plasma (and urine) in:
Decreased excretion of bilirubin as seen in obstructive liver disease and in specific rare inherited syndromes (Rotor’s and Dubin-Johnson syndromes).
Increased amounts of urobilinogen are found in the urine in:
Normal urine contains some urobilinogen.
Increased amounts of urobilinogen are found in the urine in:
* Increased bilirubin production.
* Decreased re-uptake into liver due to hepatocellular dysfunction (but not if obstruction prevents bilirubin to reach GIT).
What are enzymes that reflect liver damage?
Aspartate aminotransaminase (AST) has widespread tissue distribution including liver, red blood cells, skeletal and cardiac muscle.
Alanine transaminase (ALT) is more liver-specific.
Lactate Dehydrogenase (LD or LDH) has widespread tissue distribution including liver, red blood cells, skeletal and cardiac muscle.
The LD5 isoenzyme is found in the liver and skeletal muscle only
How can Plasma Proteins be used in the diagnosis of liver diseases?
Albumin is decreased in chronic liver disease, but is insensitive as an index of liver function.
Clotting factors have short half-lives, e.g. factor VII t½ = 4h. The prothrombin time (INR) and partial thromboplastin time (PTT) may be prolonged in liver disease
Immunoglobulins show a generalised increase (polyclonal) in chronic liver disease, especially cirrhosis.
* In primary biliary cirrhosis IgM is characteristically increased.
* In alcoholic cirrhosis IgA is characteristically increased
* In autoimmune chronic active hepatitis IgG is particularly increased
What are Enzymes Reflecting Cholestasis?
Alkaline phosphatase (ALP) has widespread tissue distribution including liver, bone, placenta and GIT. It is released into plasma in cholestasis.
Gamma-glutamyl transferase (GGT) is more liver-specific. Serum level increased by cholestasis or chronic ingestion of alcohol, barbiturates, phenytoin and other drugs which induce the enzyme.
5’-nucleotidase (5’-NT): This enzyme is also elevated in cholestasis, especially when ALP is elevated.
What is jaundice?
Jaundice becomes clinically visible when serum bilirubin is___
This is the yellow appearance of skin and sclerae due to the presence of an excessive amount of bilirubin (jaundice becomes clinically visible when serum bilirubin is >40 μmol/l).
The liver has a large reserve capacity - jaundice only appears with severe impairment of liver function
What are the Prehepatic causes of Jaundice?
A. Prehepatic Jaundice (increased production of bilirubin)
Haemolytic Disorders
* Abnormal haemoglobins (e.g. sickle cell anaemia).
* RBC membrane defects (e.g. hereditary spherocytosis).
* Malaria.
Ineffective Erythropoiesis
* Megaloblastic anaemias.
What are the intrahepatic causes of jaundice?
B. Intrahepatic Jaundice (decreased handling of bilirubin by the liver)
- Decreased uptake of bilirubin
- Decreased conjugation of bilirubin
- Decreased excretion of bilirubin into bile canaliculi
Defect In Uptake / Conjugation Of Bilirubin
GILBERT’S SYNDROME
CRIGGLER-NAJJAR SYNDROMES :
Defect in Excretion of Bilirubin into Bile Canaliculi
DUBIN-JOHNSON and ROTOR’S SYNDROMES :
* Benign inherited disorders.
* Increased levels of conjugated bilirubin in serum and urine.
* Due to impaired excretion
What is acute viral hepatitis?
- This is a common infectious disease worldwide.
- Clinical severity varies from asymptomatic, through mild hepatitis, to severe fulminant hepatitis which can be fatal.
- It is responsible for the majority of chronic liver disease, which in turn may be associated with hepatocellular carcinoma.
- Causes are hepatitis A and B (commonest), Non-A, Non-B hepatitis (Hepatitis C, D and E viruses) EBV, CMV
What is Biochemical Features in Hepatitis?
Bilirubin
increased unconjugated bilirubin throughout, and increased conjugated bilirubin especially during obstructive phase.
Urine positive for bilirubin, and urobilinogen increased due to impaired re-uptake of urobilinogen by liver.
ALT and AST : Early rise in serum transaminases reflecting hepatocyte damage. Start to rise before onset of jaundice and it may be elevated without jaundice. In massive hepatic necrosis transaminases levels may suddenly decrease (grave prognostic sign)
ALP and GGT : Not greatly elevated early. Later marked increases as intrahepatic cholestasis develops due to swelling of cells
Causes of INTRAHEPATIC CHOLESTASIS
- Drugs
- Benign recurrent intrahepatic cholestasis. Precipitated by viral infections.
Plasma proteins in hepatits
Albumin only slightly decreased due to long half-life. It may be normal depending on the severity
Immunoglobulins: early increase in IgM, later IgG.
Decreased prothrombin index due to impaired synthesis of clotting factors. Not restored by vitamin K.
Transient mild rise in alpha-foetoprotein during regeneration phase
