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
Angiogenesis in connective tissue response?
Break down BM of vessel, endothelial migration and proliferation, maturation and recruitment of supporting pericytes. VEGF key.
Fibrosis in connective tissue response?
Controlled by growth factors from platelets/inflammatory cells/injured epithelial/endothelial cells. Main function is to promote fibroblast production of ECM; some (myofibroblasts) have role in contractility.
Two congenital antibody deficiencies?
X-linked agammaglobulinaemia, AR agammaglobulinaemia
Acquired antibody deficiency?
Protein losing states e.g. nephrotic syndrome, enteropathy; rituximab is anti-CD20.
Types of neutrophil deficiency?
Congenital: neutropenia, failure of migration, failure of function (chronic granulomatous disease)
Aquired: marrow failure, chemo/radio, other drugs.
How does congenital complement deficiency present?
Recurrent pyogenic infection (streptococci, Hib in particular as need to opsonise to remove). C5-9 deficiency leads to recurrent meningococcal disease
What kind of pathogens does complement/Ab/neutrophil deficiency leave you vulnerable to?
EC e.g. most bacteria
What is SCID?
Genetic disorder, umbrella term, with B and T cells impaired. Get defective Ab response either directly from B cells or from TH cell defects. Get severe bacterial/viral/fungal disease; die within a year without HSCT.
Which two compounds are key for protection from mycobacteria (+ salmonella)?
IL-12 (induces TH1) and IFN-y (TH1 effector)
AIRE deficiency? APECED
Defect with central tolerance; can’t express usual range of peptides in thymus so don’t eliminate auto-reactive T cells. Get adrenal failure, chronic candidiasis, hypoparathyroidism.
Hyperacute rejection?
Occurs in minutes; relates to pre-formed antibodies in recipient (from previous sensitising event e.g. miscarriage, transfusion, E. coli mimicry) [pre-existing humoral immunity]. Complement and coagulation initiated, organ vessels blocked, get organ death.
Acute rejection?
Cell-mediated, from weeks to months. T cells infiltrate organ. Occurs because high levels of inflammation provides costimulation for T cells acting on donor Ag.
Chronic rejection?
Years. May be linked to ischaemic-reperfusion injury. Get endothelial damage and concentric arteriosclerosis, then fibrosis.
Direct allorecognition?
Donor APC to recipient LN; recipient T cell activated (by non self MHC) migrates to graft and attacks it. 10% T cells stimulates = large polyclonal response = acute rejection.
Indirect allorecognition?
Recipient APC processes peptides from dead donor cells; presents to T cell, activated. Oligoclonal. Activates macrophages; may cause fibrosis etc. leading to chronic rejection.
Criteria for GVHD?
Graft contains immunocompetent cells, host appears foreign to graft (has alloantigens), host unable to mount effective immune reaction to graft
Patients at high risk for GVHD?
- Transfusion of unirradiated blood products (neonates, immunosuppressed); prevented by irradation [leukodepletion]
- Solid organ transplant recipients (liver)
- Allogeneic HSCT! Most important
GVHD pathophysiology?
- Damaged host tissue; stimulate APCs; competent donor T cell against non-self MHC
- Donor T cell activates immune response
- Phagocytes propagate this and get tissue destruction
Acute GVHD basics?
Skin, liver, gut hit!
How can chronic GVHD develop?
70% from acute GVHD, 20% de novo, 10% after acute resolves. Can present in just about any way; may mimic SScl/SLE: get bronchiolitis obliterants in lung, oesophageal dysmotility, lichen planus-like skin/oral lesions.
Acute GVHD: derm?
Painful macules on PALMS AND SOLES. Get erythema, erythroderma, papules, bullae and vesicles.
Acute GVHD: hepatic?
Asymptomatic elevation in bilirubin/ALT/AST/ALP. Cholestatic picture.
Acute GVHD: GI?
Anorexia, diarrhoea, ileus, intestinal bleeding, pain.
Preventing GVHD?
Choose best donor, deplete T cells from donor, suppress donor T cells with ciclosporin etc.
Graft versus leukaemia?
Donor T cells eliminate residual malignant cells. Can lead to remission. Closely linked to GVHD. May actually be poorer survival in leukaemia patients who get identical twin HSCT and relapse, than those who get poorer match and GVHD; hard to tell which is better.
In summary, GVHD: good or bad?
Should try to prevent but may benefit in malignant disease!
How do most GVHD patients die?
Sepsis (opportunistic)
What is metaplasia?
Replacement of a fully differentiated tissue by another (usually in response to persistent injury) and reverts to original cell type if the source of injury is removed e.g. Barret’s oesophagus
What is dysplasia?
Characterised by architectural and cytological changes similar to those seen in malignancy, but less pronounced. Considered pre-cancerous.
Common chemical carcinogens?
Cigarette smoke, strong electrophiles e.g. vinyl chloride, aflatoxin, azo dyes and nitrosamines
What is initiation (re carcinogenesis)?
Interaction of carcinogen with DNA introduces permanent change (mutation) to the DNA which is then replicated. May be detrimental or may confer growth advantage . Does not in itself cause cancer.
What is promotion (re carcinogenesis)?
Promotion is a lengthy and reversible process, where multiple transient exposures to promoters confer advantage to cells THAT HAVE BEEN INITIATED BY ANOTHER COMPOUND without necessarily altering DNA. Removal or the promoter may result in stabilisation/reversal of increased risk.
What is progression (re carcinogenesis)?
Irreversible; change from premalignant to invasive cancer. Cells undergo multiple DNA changes (which are detectable on microscopy) to confer invasive and metastatic potential.
Treatment targets in carcinogenesis phases?
- Blocking agents prevent initiation
- Suppressing agents preferentially target promotion and progressoin stages
- Inhibiting angiogenesis and invasive can prevent metastasis
Cigarette smoking and cancer?
- Directly inflames bronchial mucosa causing malignant change
- Also absorbed and metabolised, then excretion/storage into bladder/biliary tree/breast causes further malignant change
