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= Portal inflammation = Inflammation of the portal triad area contained to that area. We can see a demarcation where inflammation ends, and hepatocytes begin. May occur alongside interface inflammation.

= Lobular inflammation = Inflammatory infiltrate throughout the lobule

= Interface inflammation = If there is spillage of inflammation from the portal triad area across the limiting plate (can’t draw a straight-ish line to demarcate the infiltrate from hepatocytes, then we have interface inflammation.

Ballooning
The hepatocyte swells due to defective osmotic regulation at the cell membrane. Causes include oxidative damage, intracellular deposits and insulin. A reduction in available ATP result in an increase in intracellular Ca2+ and an influx of volume. Cytoskeletal elements start becoming rope-like. If hyaline filaments are visible with cytokeratin condensation, then we have Mallory-Denk bodies. The cell membrane will eventually rupture

Steatosis
Injury can lead to fatty metamorphosis of the hepatocytes. The liver is responsible for the formation of lipids, and so these can easily accumulate in the cells. There are two types:

·       Macro-vesicular steatosis – 1 vacuole per hepatocyte, with marginalised nucleus. Large, clear droplets of fat.

·       Micro-vesicular steatosis – multiple vacuoles per hepatocyte, with central nucleus. Small, fine droplets of fat. Less common, and generally only seen in patches combined with macrovesicular steatosis.

Wall tension is proportionate to radius, so the larger vacuoles are at higher risk of bursting – releasing toxic contents.

A common cause is alcoholic diseases – EtOH is converted to aldehyde creating an excess of NADH, which is used for lipid synthesis, resulting in lipid accumulation.

Cholestasis
If the excretion of bile from the hepatocytes into the bile canaliculi is interrupted, or the bile ducts further down are blocked, then there will be back-up of bile. This can occur in the hepatocytes (hepatocellular cholestasis) or in the canalicular spaces (canalicular cholestasis).

The interruption of flow can be

·       Obstructive: stones, tumour compression

·       Non-obstructive:  toxic effects on NTCP reducing bile uptake from blood or on BSEP reducing bile secretion into the canaliculi

The consequence of cholestasis is visible bile accumulation in hepatocytes or canicular spaces, accompanied by ballooning, Mallory bodies, copper retention. If the cause is obstructive, we may have portal oedema and proliferation of bile ducts.

Apoptosis
Hepatocyte apoptosis is programmed death with hepatocyte shrinkage, nuclear chromatin condensation (pyknosis) and fragmentation (karyorrhexis) and cellular fragmentation into acidophilic apoptotic bodies. It is a physiological process that is essential for cell renewal and occurs when cells age (telomere length reduced).

There are two pathways:

·       Extrinsic: FAS ligand and TNFa activate pro-caspases → caspases → death receptor. Perforin from CD8 T-cells then allows granzyme B to enter the cytoplasm and initiate proteolysis.

·       Intrinsic: misfolding of proteins in ER → caspase 3 release and autophagy → mitochondrial damage and DNA fragmentation

Necrosis
Necrosis may be triggered by any damage that results in reduced ability of the hepatocytes to produce ATP. The loss of energy results in failure of the Ca2+ pumps and increase in intracellular Ca2+ concentration. The osmotic gradient changes and there is an influx of fluid, resulting in ballooning and membrane rupture. Rupture of the membrane results in release of cytoplasm components, and hence inflammation and activation of the extrinsic apoptosis pathway.

Ca2+ concentration increase also affects mitochondrial permeability and this activates the intrinsic apoptosis pathway.

Thus, we have a combination of necrosis and apoptosis (necroapotosis). Zone 3 of the portal lobule, with the lowest pO2, is most vulnerable.

Parenchymal extinction lesions
If there is widespread parenchymal loss, we may have confluent necrosis – zonal loss of hepatocytes. It may begin as a zone around the central vein, with the resulting space filled by cellular debris, macrophages, remnants of reticular network.

In bridging necrosis, the zone around the central vein may link central veins to portal triads or bridge adjacent portal triads.

Parenchymal extinction is defined as a focal loss of contiguous hepatocytes. Even in hepatitis, vascular insult from inflammation or thrombosis may be a major contributor to parenchymal loss.