ChemPath 4s: Liver CPC Flashcards
What does this show?
- hepatocytes arranged in a trabecula with sinusoids between them;
- the portal triad then consists of an artery, vein and bile duct
What is the space of Disse?
The ‘Space of Disse’ –
the spaces between the hepatocytes and the endothelium (discontinuous organisation) of the sinusoids meaning that the blood comes into contact with the all the liver enzymes
Label this image. Which zone (1-3) is the most oxygenated?
Portal tract → zone 1 (periportal) → 2 → 3 (centrilobular) → central vein
zone 1 has most oxygenated blood, zone 3 has least
Which zone (1-3) can be damaged by substances that are directly damaging
- Zone 1 (periportal)
- Directly hepatoxic substances
Which zone (1-3) can be damaged by substances that require bioactivation
- Zone 3 (centrilobular)
- Metabolised hepatotoxic substances (zone 3 = most metabolically active cells in the liver)
Which zone (1-3) can be damaged by hypoxia?
- Zone 3 (centrilobular)
- Hypoxic damage (blood lost quite a lot of oxygen by the time it passes through zones 1 and 2)
Damage to which zone can make ALP rise more due to close proximity to the bile ducts?
Zone 1 (periportal)
What are the Causes of a high bilirubin?
- Pre-hepatic (unconjugated)
- Haemolysis (Ix: FBC and blood film)
- Hepatic (Ix: repeat LFTs)
- Post-Hepatic (i.e. obstructive jaundice)
When does bilirubin conjugate?
once it has passed through the liver
How is Fractions of Bilirubin / ‘Split Bilirubin measured?
o This is done using the van den Bergh reaction
What does a DIRECT van den Bergh reaction measure?
conjugated bilirubin
How do you measure the uncongugated bilirubin?
Add methanol to van den Bergh reaction
which
→ complete reaction to allow you to measure total bilirubin
→ difference between two values gives the unconjugated bilirubin (i.e. an INDIRECT reaction)
Describe Paediatric Jaundice. What type of hyperbilirubinaemia is considered normal in children?
- This is usually NORMAL → usually caused by liver immaturity
- it should be an UNCONJUGATED hyperbilirubinaemia (because the liver cannot conjugate the bilirubin fast enough)
What should be done if high UNCONJUGATED bilirubin levels do not resolve in a child?
- other causes should be considered such as:
- hypothyroidism
- other causes of haemolysis
- perform a Coombs’ test (autoimmune haemolytic anaemia)
- measure unconjugated bilirubin levels
What does Phototherapy do?
- Converts bilirubin into lumirubin + photo-bilirubin
- These are isomers that do NOT need conjugation for excretion
What is the genetics behind Gilbert’s syndrome?
- Gilbert’s syndrome is autosomal recessive
- 50% carry the gene
- → 6% (1 in 20) have Gilbert’s
Is Gilbert’s syndrome malignant? is a biopsy needed for diagnosis?
- This is an entirely benign condition
- no need for a liver biopsy – identify from history
When might jaundice in Gilbert’s syndrome worsen?
periods of physiological stress e.g. fasting, , illness, dehydration, overexertion, menses
When might jaundice in Gilbert’s syndrome worsen?
periods of physiological stress e.g. fasting, , illness, dehydration, overexertion, menses
What can reduce bilirubin levels in Gilbert’s syndrome?
Phenobarbital
Outline the pathophysiology of Gilbert’s syndrome
UDP glucuronyl transferase activity is reduced to 30%
Unconjugated bilirubin is tightly albumin bound and does NOT enter the urine
So, they do NOT have bilirubinuria
Urobilinogen is ALWAYS present in the urine of normal people – this comes from the enterohepatic circulation
The bilirubin that you make will go through the biliary tree and into the bowel, where bacteria will convert bilirubin to stercobilinogen and urobilinogen – this is then reabsorbed into the circulation and you excrete it
So, the presence of urobilinogen in the urine tells you that the enterohepatic circulation is intact
Negative urobilinogen is suggestive of biliary obstruction
Which marker is most representative of liver function
• Prothrombin time is the most representative marker of liver function
What is the normal PT time?
normal PT is about 12-14 seconds
any higher, and its telling you that the liver is failing to make clotting factors
Is albumin a good marker of liver function?
Albumin is also a good marker (because it is representative of the liver’s synthetic function) but PT is better
What do AST and ALT tell you?
ALT and AST are enzymes that tell you that there is damage rather than telling you how your liver is actually functioning
Do NOT truly test the liver’s synthetic function
How is function of the liver assessed?
Function of the liver is measured by:
- Albumin
- Clotting factors (PT, PTTK)
- Bilirubin
Where is alkaline phosphatase (ALP) show? What is it usually used as a marker of (when in the presence of raised GGT)?
- ALP is particularly concentrated in the liver, bile duct and bone tissues.
- ALP is often raised in liver pathology due to increased synthesis in response to cholestasis.
- As a result, ALP is a useful indirect marker of cholestasis.
What does a raised ALP and GGT show?
- raised GGT can be suggestive of biliary epithelial damage and bile flow obstruction.
- It can also be raised in response to alcohol and drugs such as phenytoin.
- A markedly raised ALP with a raised GGT is highly suggestive of cholestasis.
What does an isolated raised ALP show? (no raised GGT)
A raised ALP in the absence of a raised GGT should raise your suspicion of non-hepatobiliary pathology. Alkaline phosphatase is also present in bone and therefore anything that leads to increased bone breakdown can elevate ALP.
- Bony metastases or primary bone tumours (e.g. sarcoma)
- Vitamin D deficiency
- Recent bone fractures
- Renal osteodystrophy
What does an isolated raised bilirubin indicate? (ALT and AST are normal)
An isolated rise in bilirubin is suggestive of a pre-hepatic cause of jaundice.
Causes of an isolated rise in bilirubin include:
- Gilbert’s syndrome: the most common cause.
- Haemolysis: check a blood film, full blood count, reticulocyte count, haptoglobin and LDH levels to confirm.
What does this clinical picture show?
- These LFTs suggest a hepatic cause of jaundice (high bilirubin)
- The AST and ALT are very high → suggest hepatocyte damage
- The ALP is marginal (it is usually highest in times of biliary obstruction)
What are the causes of abnormal LFTs?
- Pre-hepatic – Gilberts, haemolysis
- Hepatic – viral hepatitis, alcoholic hepatitis, cirrhosis
- Post-hepatic – gallstones, pancreatic
How do you distinguish alcoholic hepatitis from other forms of hepatitis based on ALT and AST alone?
- ALT > AST = other forms of hepatitis
- AST > ALT = alcoholic hepatitis
What are the causes of hepatitis?
- Viral causes – check viral titres
- Autoimmune
- Alcoholic
What are the Features of hepatitis?
- fever,
- jaundice,
- raised ALT/AST
= LIVER TRIANGLE
How is Hep A transmitted?
- fAEco-oral transmission route – food or men-on-men sex
- Contaminated water is often the major source
- E.G. Recent shellfish consumption (improper washing)
What are the acute symptoms of Hep A?
- asymptomatic,
- or – nausea, D+V, fever, jaundice, RUQ pain
Describe the course of Hep A infection
Onset = 2-6 weeks; symptoms last = ~8weeks
Often infectious whilst asymptomatic
After viral titres start to drop, you get a rise in IgM antibodies and you become unwell with jaundice
If you survive the initial few weeks, you will produce IgG antibodies and from that point onwards you are cured and immune
What is the Tx of Hep A?
- Treatment supportive (alcohol avoided) –
- vaccine called Havrix exists that contains some antigens of hepatitis A
What kind of virus is Hep B?
DNA virus
What % of Hep B infections become chronic?
only 5-10% go chronic
What are the routes of transmission of Hep B infection?
Routes of infection:
- Sex (more commonly through unprotected sex than HCV)
- Vertically (mother → child)
- Blood products
What is the clinical presentation of Hep b/
- Normally acute presentation (can be acute ± chronic
- Hepatitis symptoms–fever, jaundice, N+V ,RUQ pain)
- But a chronic infection follows in~10% of people
What are the 2 main antigens that are measured to identify Hep B infection?
main antigens measured (cannot measure core Ag):
- HBsAg
- HBeAg (highly infectious) - goes down after start fighting
Can anti-HBc be measured? What does this show?
- Anti-HBc also tells you that they have been exposed to hepatitis B inthe past,
- but we don’t have the capability to measure HBc antigen
What does the Hep B vaccine contain?
- The vaccine contains HBsAg (so, if you have been vaccinated you will have anti-HBs)
- However, you will NOT have HBeAg or anti-HBe
Which antigen is never cleared in chronic Hep B patients?
- Chronic carriers (bottom image) never clear the HBsAg
- however infectivity decreases with time
What is the Tx of Hep B?
- Acute–supportive
- Chronic– anti-viral therapy
What kind of virus is Hep C?
RNA virus
What % of Hep C infections become chronic?
60-80% go chronic
What might Hep B and Hep C viruses be associated with?
What are the features of Hep C infection?
What are the features of Hep C infection?
How might Hep B and Hep C be distinguished in exam qs?
- HBV and HCV are similar but in SBAs look for clues in –
- source of infection - Hep B sex, vertically; Hep C blood products
- chronicity - Hep B fewer chronic than Hep C
How does Hep D infection occur?
- REQUIRES CO-INFECTION WITH HEPATITIS B – HDV needs HBV surface antigen to invade liver cells
How is Hep E transmitted?
- fAEco-oral transmission route – food or men-on-men sex
- food: Shellfish // Uncooked pork
What is the course of infection of Hep E infection?
Who suffers from increased risk of Hep E infection?
- Expectant mothers
- Immunocompromised patients(“E- mmunocompromised”)
What do the arrows show?
Ballooning degeneration ± Mallory-Denk bodies:
- There are lots of cells containing fat
- The arrows are pointing at balloon cells containing mallory hyalin
- Too much alcohol → fat deposits in the liver, however, these will go away if. they stop drinking alcohol
- If alcohol abuse persists, you may develop alcoholic hepatitis (neutrophils will infiltrate the liver)
- When hepatocytes get damaged by alcohol hepatitis, you see balloon cells containing mallory hyaline
- This may NOT be reversible
What does the darker stuff show?
The darker material on the left image shows bile which accumulates when Mallory hyaline blocks its flow
What does this image show?
staining collagen – this pattern is characteristic of alcohol abuse and cirrhosis
What are the DEFINING Histological Features of Alcoholic Hepatitis?
- Liver cell damage (ballooning ± Mallory-Denk bodies)
- Inflammation
- Fibrosis
What are the Associated histological features of Alcoholic Hepatitis?
- Fatty change
- Megamitochondria
Differential Diagnosis for Fatty Liver Disease
-
Non-alcoholic steatohepatitis (NASH)
- This looks exactly like alcoholic hepatitis
- It is the most common cause of liver disease in the Western world
- Alcoholichepatitis
- Malnourishment (Kwashiorkor)
What are the associated features of
What is nutmeg liver indicative of?
venous congestion (i.e. Budd-Chiari, congestive HF, etc.)
What is the Tx of hepatitis?
- Supportive
- Stop alcohol
- Nutrition
- Vitamins (esp. B1 and thiamine)
- Occasionally steroids (anti-inflammatory)
What might B1, B3 and B12 deficiencies cause?
- B1 (thiamine) → Beri-Beri;
- B3 (niacin) → pellagra;
- B12 (cobalamin) → B12 deficiency / SCDC
What happens if alcohol is stopped in hepatitis?
- If alcohol is stopped, the liver can regenerate.
- However, it will heal in a disorganised fashion which makes it difficult for the blood to flow through it leading to increased blood pressure (portal HTN)
What are the Features of chronic STABLE (alcoholic) liver disease
- Palmar erythema
- Spider naevi (>5)
- Gynaecomastia (failure of liver to break oestradiol down)
- Dupuytren’s contracture
What are the clinical features of portal hypertension?
Caput Medusae on umbilicus
What else may be found alongside portal HTN in a hepatitis picture?
Due to portal hypertension in reorganised liver
- Splenomegaly will be found as well
- May also discover scrotal oedema and shifting dullness (non-shifting is also normal due to FAT) from ascites
What are the Features of portal HTN? what is this caused by?
(usually caused by cirrhosis):
- Visible veins
- Ascites
- Splenomegaly
What is Liver failure is defined by?
- Failed clotting factor and albumin production
- Failed clearance of bilirubin
- Failed clearance of ammonia (leads to encephalopathy)
- Flapping tremor (asterixis) = manifestation of hepatic encephalopathy
Describe fatty liver changes
other than
- Alcoholic hepatitis
- Chronic stable liver disease
- Resultant portal hypertension
- Liver failure (asterixis)
What else can Alcohol Abuse cause?
Portosystemic Anastomoses:
- Oesophageal varices
- Umbilical vein recanalizing
- Rectal varices
- Spleno-renal shunt
What is found O/E in obstructive jaundice?
What is Courvoisier’s Law?
if the gallbladder is palpable in a jaundiced patient, the cause is unlikely to be gallstones (i.e. it is more likely to be pancreatic cancer) – will also be a PAINLESS jaundice
- If you have gallstones, it will make your gallbladder be small and fibrotic (i.e. non-palpable
What are the Ix for ?obstructive jaundice?
Where does pancreatic cancer metastasise to?
Pancreatic cancer typically metastasises to the liver because the portal vein transports blood from the cancer to the live
