Lecture 16 - Liver Pathology 1 Flashcards
What are the various cell types in the liver?
- Hepatocytes
- Kupffer cells
- Hepatic stellate cells (HSC)
- Pit cells (NK cells of the liver)
- Cholangiocytes
- Endothelial cells
What are the NK cells of the liver?
Pit cells
What are the resident macrophages of the liver?
Where are these located?
Kupffer cells
Attached to the luminal wall of the endothelium
What are the stem cells of the liver?
Where are these located?
Hepatic stellate cells (HSC)
In the Space of Disse, surrounding the endothelium
What are the various categories of liver function?
Metabolic
Catabolic
Synthetic
Storage
Excretory
Describe glucose metabolism in the liver
- Glucose formation: (glycogenolysis, gluconeogenesis)
* Glycogenesis & storage thereof
Describe lipid metabolism in the liver
- TG synthesis
- Lipoprotein synthesis
- Uptake of FAs
List the various compounds that are synthesised in the liver
- Albumin
- Clotting factors
- Complement
- Cholesterol
List some examples of catabolic function in the liver
- Ammonia conversion to urea
- Break down of foreign toxic substances
- Break down of endogenous toxic substances
- Activation of drugs
Describe the excretory function of the liver
Bile formation, containing:
• many toxic break down products for excretion
Which compounds are stored in the liver?
- Glycogen
- Fat soluble vitamins (A, D, E & K)
- Cu, Fe
- Fatty acids
Describe the cellular architecture of the liver
Two models:
• Lobular
• Acinar
Liver lobule:
• Hepatocytes, forming plates
• Sinusoids (lined by fenestrated endothelium, Kupffer cells)
• Central vein
• Portal tract (HPV, H. artery, bile duct)
• Spaces of Disse (collagen forming reticulin framework, HSCs)
• Bile canaliculi (in between abutting hepatocytes)
What are liver cell plates?
Single cell thick layer of hepatocytes surrounding the sinusoids
What does the portal tract consist of?
Hepatic portal vein
Hepatic artery x2
Bile duct
Surrounded by some collagen
How much blood is delivered to the liver per minute?
1.5 L per minute
1L: hepatic portal veins
500 mL: hepatic arteries
Describe the functional unit of the liver
Acinus
Zone 1:
• Closest to the branches of the hepatic artery
•Rich oxygen supply
Zone 2
Zone 3:
• Furthest from the hepatic artery, near central vein
• Prone to anoxia
• Poor oxygen supply
Describe the old and the new lobule
Old - Lobule
• ‘Imaginary lobule’
• Three portal tracts make up to corners
• Not related to function
1950’s - acinus
• Funcitonal unit
• 3 zones, defined based on their oxygen supply from the terminal hepatic artery
Which part of the acinus will start to die off first when there is decreased blood flow?
Zone 3, furthest from the hepatic artery
What is special about the internal structure of hepatocytes?
- Much ER (Endoplasmic reticulum)
* Many mitochondria
Compare the function of sER and rER
- rER: protein synthesis
* sER: detoxification
Describe the location of the bile canaliculus
In between abutting hepatocytes
What happens upon injection of a drug such as Phenobarbital into liver hepatocytes
- Proliferation of sER in hepatocytes
* Increased demand for drug detoxification
Compare the molecules present in hepatocytes in Zones 1 and 3, and the ramifications of this
Zone 1:
• High glutathione
Zone 3:
• High CYPs
• High ADH (alcohol dehydrogenase)
→ Zone 3 more prone to alcohol damage, since it have more enzymes that break it down into acetaldehyde, which is the toxic species
What type of injury are zone 3 hepatocytes prone to?
- Toxic
- Anoxic
- Alcoholic
Describe liver regeneration
Liver has great capacity for regeneration
There will be regeneration with up to 2/3rds of the liver are resected
Due to:
• Stable cell population in the liver
• Cells can re-enter the cell cycle
How is microcirculation of the liver controlled?
Contraction of HSCs
What is the Reticulin framework?
Collagen fibres in the spaces of Disse
Normally very organised, but structure is lost in liver injury
What is the function of Kupffer cells?
Describe:
• How they become activated
• Molecules they produce when activated
• Effect of various molecules produced
Resident macrophages in the liver
Adhere to the luminal surface of the endothelial cells of the sinusoids
Function:
• Phagocytosis of particulate matter in the blood
Activation:
1. Resting
→ Experience cytokine / endotoxin
- Primed Kupffer cells
• Hypertrophy
• Extension of processes - Activated Kupffer cell:
- Phagocytosis
- Eicosanoid production → inflammation
- Cytokine production → inflammation
- GF production → HSC proliferation and differentiation
- Protease production → breakdown of ECM
Which inflammatory mediators do Kupffer cells produce?
- Arachidonic acid metabolites (eicosanoids)
- Cytokines
- GFs
Describe the effect of the following molecules that activated Kupffer cells release:
• TNF
• PDGF
• ED-1 (Endothelin 1)
• MCP-1 (monocyte chemotactic protein-1)
• TGF-beta
- HSC proliferation
• TNF
• PDGF - Contraction of HSCs
• ED-1 (Endothelin 1) - Fibrogenesis by activated HSCs
• TGF-beta - Chemotaxis
• PDGF
• MCP-1 (monocyte chemotactic protein-1)
Describe the change in phenotype of HSCs
1. Quiescent: • Compact shape • Lipid vacuoles containing vitamin A • Not proliferating • Cells in contact with basement membrane
- Initiation of activation
• Cytokine receptor expression
• Matrix disruption via collagenase secretion - Perpetuation of activation
• Proliferation (PDGF)
• Collagen synthesis (TGF-B)
• Basement membrane replaced with type I collagen
Compare collagen production in quiescent and activated HSCs
Quiescent:
• Types III & IV
Activated
• Type I
Which receptors are activated HSCs expressing?
- PDGF-receptor
* ED-1 receptor
What are the changes in actin in activated HSCs?
- ED-1 signalling
- Microfilaments (actin) arrange to form processes and cell contraction
→ Portal hypertension
What is end stage liver disease?
Cirrhosis
+/- HCC: Hepatocellular carcinoma
Define cirrhosis
Liver replacement by nodules
Nodules:
• Hepatocytes separated by anastomosing sheets of fibrous tissue (septa)
Loss of normal lobular architecture
What happens to portal tracts and central veins in cirrhosis?
Irregularly spaced
Imbedded in fibrous septa
What are the various classifications of cirrhosis?
Macronodular
• Nodules more than 3mm
Micronodular
• Nodules less than 3 mm
Mixed
Which malignancy is seen as a result of cirrhosis?
HCC: Hepatocellular carcinoma
What are the various clinical consequences of cirrhosis?
Portal hypertension
Hepatocellular failure
Hyperestrinism
HCC: Hepatocellular carcinoma
What is hyperestrinism?
What can it lead to?
Males are unable to break down oestrogen
Normally both sexes secrete these hormones
Males break them down, and females don’t
Increased oestrogen levels
Leads to:
• Testicular atrophy
• Gynaecomastia (growth of breasts)
• Altered hair distribution
Describe the sequelae of portal hypertension
Splenomegaly
• Because all the blood from the liver (as well as the gut) is going through the spleen
Oesophageal varices
Ascites
What is hypersplenism?
- Increased function of the spleen (due to splenomegaly)
* Increased break down of RBCs → anaemia
What are some consequences of Hypersplenism?
- Anaemia
- Leukopaenia
- Thrombocytopaenia (reduced platelets)
Describe oesophageal varices
- Portal hypertension in the liver, blood can’t go through, and thus must find an alternate route
- Blood goes through oesophageal veins
- Varices form: increase in size of the veins to cope with increase in blood flow
What are ascites?
- Liver starts pouring out lymph
* Collection of hepatic lymph into peritoneal cavity
What is caput medusae?
Opening up of veins around the umbilicus due to portal hypertension
Why do males develop testicular atrophy?
Secondary to hepatocellular failure
Hepatocytes stop breaking down oestrogen
Describe the processes that can no longer occur in hepatocellular failure
What are the clinical consequences of this?
- Inability to excrete bilirubin → jaundice
- Reduced albumin synthesis → peripheral oedema and ascites
- Decrease synthesis of clotting factors → haemorrhagic tendency
- Deficient ammonia metabolism → hepatic encephalopathy and coma
- Renal failure
What does an inability to excrete bilirubin lead to?
Jaundice
What does reduced albumin synthesis lead to?
Decreased oncotic pressure
→ Peripheral oedema & ascites
What does decreased synthesis of clotting factors lead to?
Haemorrhagic tendency
Describe deficiency in ammonia metabolism
What does it lead to?
Normally:
• Ammonia enters liver in portal vein
• Ammonia converted to urea by hepatocytes
• Urea leaves liver via hepatic vein
• Urea filtered from blood at kidneys and excreted
Cirrhosis: • Ammonia arriving at the liver is not converted to urea • Ammonia leaves liver in veins • Ammonia goes to brain → Hepatic encephalopathy → Coma
Is HCC often seen in cirrhosis?
What does the development of the malignancy depend on?
10-30% of heavy drinkers
Depends on cause of cirrhosis Higher in: • Hep B & C • Haemochromatosis • Alpha-1-antitrypsin deficiency
What is a critical factor influencing susceptibility to drug induced liver injury?
Genetic variability (of CYPs especially)
What is ABCD of drug toxicity?
A: augmented, on-target, predictable
B: bizarre, idiosyncratic
C: chronic, long term use
D: delayed
Which zone of the liver undergoes the most necrosis in toxic liver injury?
Why is this so?
Usually Zone 3
• CYPs in the highest concentration here
• Drug converted to a reactive metabolite in the highest concentrations in this zone
What is zonal necrosis?
Specific zones of the liver undergoing necrosis
Normally is zone 3
Which drugs when overused can cause zonal necrosis?
Paracetamol
How much alcohol is safe?
80 mg / day ??
Describe metabolism of ethanol
- CYPs in microsomes (sER)
- ADH in cytosol
- Catalase in peroxisomes
Converted to:
• Acetaldehyde
• NAPH also produced
What is the effect on fatty acid metabolism of ethanol?
- Increased lipolysis
- Increased delivery of FFA to liver)
- increased fatty acid synthesis in hepatocytes
- Decreased mitochondrial oxidation of FAs
- Increased production of TG
- Decreased release of lipoproteins from liver cells
Describe the alcoholic liver disease spectrum
- Steatosis
- Steatohepatitis
- Cirrhosis
Describe the histology of liver cells in severe steatosis
Liver cells are filled with fat, and there is not enough cell left for the liver to function properly
This does not normally progress to fibrosis
For fibrosis, you need to have necrosis and inflammation, so that HSC to lay down collagen
What is steatohepatitis?
Alcohol hepatitis
What are the histological characteristics of steatohepatitis?
- Zone 3 ballooning
- Zone 3 spotty necrosis
- Zone 3 inflammation
- Zone 3 activation of HSC
- Micronodular cirrhosis
- Obliteration of the central vein
Describe ballooning hepatocytes
What is the cause?
• Hepatocytes increase in size by 5-20 times
Cause:
• Acetaldehyde causes the cytoskeleton to collapse to form Mallory bodies in the cell
• Cell loses its shape
• Other proteins associate in the Mallory bodies
• Cell stops secreting proteins, as the cytoskeleton track is missing
• Increase in intracellular osmotic pressure
• Swelling of cell
What are some functions of the cell cytoskeleton?
- Gives cell shape
- Determines the location of the organelles within the cell
- Contractility of the cell
- Transport of proteins and fats around the cell
What are the proteins involved in the Mallory bodes?
Keratin
Ubiquitin
Hsp62 (Heat shock protein)
Proteasome
How do ballooning hepatocytes stain?
Very light, there is no cytoskeleton to be stained apart form the Mallory body aggregates
What happens to the central vein in steatohepatitis?
The central vein is obliterated
Because
• The structure is dependent on the liver plate cells surrounding it
• These cells give structure to the sinusoids as well as the veins.
- The wall of the sinusoids are the liver cell plates.
- If they disappear, this framework collapses and the lumen disappears
Describe the histology of micronodular cirrhosis
- Obliteration of central veins
- Complete disorganisation of vascular structure
- Blood has difficulty flowing through the liver
- Portal hypertension
Curvilinear fibrosis
• Surrounds and isolates nodules of regenerating liver
• Gives rise to micronodular cirrhosis
Hepatocytes are trying to regenerate and reform this liver mass
Nodules form
What are curvilinear fibrous septa?
Fibrous tissue bridging the portal tracts and central zones
What is Bilirubin?
Yellow break down product of haeme (from haemoglobin)
Excreted into bile & urine
Describe what is happening in spotty necrosis?
When is this seen?
Seen in steatohepatitis, in zone 3
• Clusters of neutrophils
What causes mallory body formation?
Acetaldehyde
Where is vitamin A stored in the liver?
HSCs
Characterise the endothelium lining the sinusoids in the liver
Sieve plates: fenestrated
Fenestrae allow only the movement of small compounds or plasma into the spaces of Disse (cells can’t move across)
How do abutting hepatocytes join together?
Attached together with studs like lego
NB bile canaliculi running between abutting hepatocytes
