What are the THREE key features of cirrhosis
- Bridging fibrous septa (Portal tract –> portal tract and Portal tract –> central veins)
- Regenerative nodules of hepatocytes within fibrous septa
- Reorganisation of entire liver architecture, leading to reorganisation of the vascular architecture
What are the causes of liver cirrhosis?
- Viral hepatitis (Hep B, Hep C, EBV, CMV etc)
- Alcoholic liver disease
- Non-alcoholic steatohepatitis
- Biliary Diseases (primary & secondary biliary cirrhosis, primary sclerosing cholangitis, autoimmune conditions)
- Inherited metabolic conditions (haemochromotosis, wilson’s disease & alpha-1 antitrypsin deficiency)
- Idiopathic
What is the pathogenesis of liver cirrhosis?
Chronic insult/damage/injury to the liver causes a chronic inflammatory response (hepatocyte death also occurs). Kupffer cells, endothelial cells, lymphocytes, hepatocytes & biliary duct cells release inflammatory cytokines which stimulate Stellate cells in the Space of Disse to lay down collagen. This collagen causes the endothelial fenestrations to disappear/become ineffective so the hepatocytes are no longer able to secrete stuff like albumin, LDL and coagulants etc into the blood. New vascular channels form within the fibrous septa, shunting blood flow around the parenchyme. Meanwhile, hepatocyte regeneration continues forming ‘regeneration nodules’ within the fibrous septa.
What are the three main outcomes of liver cirrhosis?
- Portal Hypertension [Includes ascites, portal-caval anastomeses, splenomegaly, hepatic encephalopathy]
- Progressive liver failure
- Increased risk of hepatocellular carcinoma
How does alcoholism lead to steatohepatitis and steatosis?
STEATOSIS:
Alcohol is metabolised into acetylaldehyde and then acetate in two oxidated reactions that convert NAD+ to NADH. NAD+ is also used by the glycolysis and Krebs cycle, and so if this is used up by alcohol metabolism, then energy cannot be produced by normal pathways. Instead, the liver relies more on peripheral fat for metabolism, and so it builds up in the cells. It is characterised by peripherally displaced nuclei and macrovesicular accumulations of lipid within the hepatocytes. NO inflammation.
STEATOHEPATITIS:
metabolism of ethanol also uses P450 system, which is induced to be more active. As a result, more ROS are produced which damage cell proteins directly, intiating cell damage and immune response. It also causes an impaired antioxidant production (particularly glutathione) so that ROS are not buffered as well.
Acetylaldehyde (alcohol intermediate) can also peroxidise fat directly, as well as bind to protein, which also initiates an immune response.
This results in hepatocellular injury and an inflammatory response, characterised by swollen/necrotic hepatocytes (centrally placed nuclei), mallory bodies around nuclei and a neutrophilic infiltration, with the start of fibrosis between PT and CV, and PT-PT.
What are the microscopic features of steatohepatitis?
- Swollen/necrotic hepatocytes (due to inability to secrete protein/lipid the cell swells but nucleus remains central).
- Mallory bodies aroudn the nuclei - eosinophilic filaments etc around nuclei (not specific to alcoholic steatohepatitis)
- Neutrophilic infiltration
- Lysed cells or acidophilic bodies (apoptosed cells)
What are the microscopic features of alcoholic cirrhosis?
- Micronodular appearance.
- Collagen/fibrosis deposited dain pericellular/perisinusoidal spaces by Stellate cells and extend to portal tracts/central veins (chicken wire appearance)
- Fibrosis usually starts in ZONE 3 (around central vein) as poorest O2 supply.
Define Chronic Kidney Disease
- Evidence of kidney injury/damage (eg haematuria/proteinuria)
- Reduced eGFR/impaired renal function
- Structural renal abnormalities
Present for > 3 months
What are the causes of CKD (Aetiology)
- Diabetic Nephropathy (35%)
- Glomerulonephritis (25% - IgA)
- Hypertension (15%)
- Adult Polycystic Kidney Disease (6%)
- Reflux Nephropathy (2%)
- Analgesic Nephropathy (1%)
- Miscellaneous (Cancer, interstitial nephritis, etc 12%)
- Uncertain (6%)
What are the features of Nephrotic Syndrome?
- Proteinuria (frothy)
- Hypoalbuminaemia (lost in urine)
- Oedema (Decreased plasma oncotic pressure due to low albumin)
- Elevated cholesterol (increased synthetic function of liver due to low albumin)
What are the stages of CKD, and what is the eGFR?
Stage 1: >90ml/min (normal if no evidence of kidney damage) Stage 2: 60-90ml/min Stage 3: 30-60ml/min Stage 4: 15-30ml/min Stage 5: <15ml/min
