MAID2.15-2.18 Flashcards
Histology of NASH and ASH?
Identical!
What AST/ALT ratio indicates advanced fibrosis?
> 0.8; better to exclude (<0.8) than include
Key cell in hepatic fibrosis?
Hepatic stellate cells (in SoD) becoming hepatic myofibroblasts. HSCs maintain ECM turnover; when activates become HM and produce heaps of collagen and TIMPS (replaces parenchyma) and become more contractile (disrupts flow): get portal HTN.
Regeneration in acute liver injury?
Inflammation, then regen involving hepatocytes, stem cells, bone marrow derived precursors, driven by cytokines inc. TGFa and hepatocyte growth factor
Pathology of chronic liver injury?
- Progressive fibrosis interferes with blood flow and liver funciton
- Continued injury causes abnormal liver cell regeneration and nodule formation
Combined = cirrhosis
Three types of response to liver injury?
- Resolution (matrix cleared)
- Organ failure (massive necrosis)
- Chronic inflammation and fibrosis (persistent injury)
Two ways infection can cause tissue damage?
Direct result of infectious agent; otherwise get ‘bystander’ phenomenon (where immune response damages cells)
How can ATP depletion lead to cell death?
Failure of Na+/K+ pump (ATP drive) means cells swell and die, or failure of active Ca2+ removal can activate enzymes that destroy cell
What type of injury is free radical production particularly important to?
Ischaemic-reperfusion injury
Features and aims of acute inflammation?
Rubor, tumour, dolor, calor; aim is to deliver cells and mediators to site of inflammation, for removal and repair. Vasculature therefore paramount
Increased vascular permeability in inflammation?
Mediated by histamine, interleukins. Occurs predominantely in venules. Causes endothelial cell contraction.
What happens when endothelium is directly damaged?
Get leakage of protein rich exudate until vessel occluded or repaired. Get oedema in surrounding tissues, viscous blood and reduced flow. This facilitates extravasation of leukocytes.
Endothelial cells and extravasation?
Histamine etc. causes selectin expression, TNFa causes ICAM/VCAM synthesis. Deficiency in these proteins (‘leukocyte adhesion deficiencies’) causes susceptibility to bacterial infection.
Phagocytosis?
Must be opsonised by complement, Ig, CHO then phago by PMNs/macrophages.
Role of fibrin in acute inflammation?
Forms network for cell migration
4 sequelae of acute inflammation?
- Complete resolution (minimal tissue damage, loss of labile cells)
- Abscess formation
- Healing by fibrosis and scar formation.
- Chronic inflammation
Key cells in chronic inflammation?
Monocytes and macrophages; PMNs dominate in acute.
“Healing” process?
When cellular injury results in necrosis get healing, which involves two distinct processes.
1. Regeneration (replacement of injured cells by proliferation of surviving cells of the same type)
2. CT tissue response with granulation tissue; may or may not lead to fibrosis.
Proportion of each depends on nature of injury and tissue e.g. skin has near complete restoration, CNS just forms CT. As a rule, better at proliferating = better at regenerating (more labile).
Healing in different kinds of liver injury?
Liver very good with acute injury; either dies completely or REGENERATES almost completely normally. With chronic injury, get less regeneration and more CT response. Combination of regenerative nodules and fibrosis = cirrhosis.
Regeneration process (proliferation of parenchymal cells in response to injury)?
Governed by growth factors causing transcription of protooncogenes and TS genes (via MAPK/cAMP/JAKSTAT). Can be autocrine (skin, liver), paracrine or endocrine. Key growth factors are EGF, TGF-a, IGF, HGF (hepatocyte). EGFR (TK) therefore key. Must inhibit response when complete.
Connective tissue response (as opposed to regeneration?)
Damage to epithelial cells AND matrix; means must restore structure as well as mass. Four processes are angiogenesis, proliferation of fibroblasts/myofibroblasts, ECM deposition (collagen), matrix remodelling.
Two processes involved in formation of GT?
Angiogenesis and fibroblast proliferation