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228 Cards in this Set
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Definition necrosis?
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The death of a cell or cell group, due to loss of membrane integrity and leakage of cellular contents - due to various etiologies.
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What are the main etiologies of necrosis?
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1. Hypoxia
2. Physical injury 3. Chemical injury |
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How is the timeline development of necrosis?
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Initially we see nothing, but over a few hours we man see disruption of cell membranes and intracellular organelles - detected quickly in EM than LM
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What is released to blood in necrosis?
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- K+
- Enzymes Both can be measured in peripheral blood |
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What is the pathogenesis of necrosis?
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1. Some etiological factor is introduced on cells
2. The plasma membrane barrier function is lost 3. Ca2+ and Na+ pass into cell & swell it 4. K+ and enzymes are released 5. Inlammatory cells (neutrophils) are attracted! |
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You have spoken about the enzymes.
Where are they from and what do they do? |
They come from the lysosomes. And when the cell dies, the lysosomes rupture & cause self-digestion of the cells, in autolysis
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Definition autolysis?
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Digesting oneself with own enzymes - so digesting the necrotic tissue
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Definition heterolysis?
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This is digestion of someone else - like neutrophils digesting dead cells with enzymes
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What changes can we see in the LM?
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1. Cytoplasmic changes
2. Nuclear changes |
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What are the cytoplasmic changes in necrosis?
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- Increased eosinophilia, mostly due to loss of glycogen particles
- Myelin figures |
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What is myelin figures?
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This is some concentrically layered, fingerprint-like material derived from intracellular membranes and organelles - from autolysis
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What are the 3 successive nuclear changes seen in necrosis?
Why do they occur? |
1. Karyolysis
2. Pyknosis 3. Karyorrhexis All due to breakdown of DNA and chromatin |
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What is karyolysis?
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Fading of the basophilia of chromatin - due to DNAase activity
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What is pyknosis?
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Nuclear DNA shrink into basophilic mass of chromatin
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What is karyorrhexis?
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Fragmentation of the pyknotic nucleus - before it in 1-2 days the nucleus disappears completely
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What are the known types of necrosis?
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1. Colliquatiev / liquefative
2. Coagulative 3. Casseous 4. Hemorrhagic 5. Fat necrosis 6. Fibrinoid necrosis |
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Definition liquefative necrosis?
Where and why does it occur? |
Necrosis with a liquid consistency - occur in 2 instances:
1. Bacterial and sometimes fungal infections - since inflammatory cells are requited and enzymes of the leukocytes digest (liquefy) the tissue 2. In CNS - in hypoxic death - for some reason the neurons are completely digested, soft and liquefied. Eventually, it's removed by phagocytes |
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What type of necrosis is an abscess?
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Liquefative
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What happen to location of ischemic injury in brain after hypoxia?
What is another name for the softening? |
1. Softening (liquefaction) & necrosis of neurons
2. Organisation of infarct begins & macrophages appear to eat the myelin 3. What remains is a 'pseudocyst' with scarring and shrinkage around the scarred area Another name for the softening is 'brain malacia' |
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What are the cerebral macrophages called?
What are they called after they have eaten the myelin? |
Glial cells
And they become 'foam cells' |
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What is a pseudocyst?
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A pathological cavity without its own lining!
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What is the major cause of cerebromalacia?
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1. Obstruction of arteries (2x vertebral & 2x int. carotid)
2. Acute hypoglycmia 3. Carbon monoxide 4. Barbiturate poisoning The neurons are more susceptible to hypoxia than the supporting cells! (and also hypoglycemia.. Have a very little glycogen storage, something like 20microgram) |
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What is a coagulative necrosis and which organs is it typical for?
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This is a necrosis of cells of typical solid organs like kidneys, heart and spleen.
It is typical for infarcts (areas of ischemc necrosis) and it keep the architecture for several days - since it seems like both the proteins and the enzymes are inactivated - so lysis does not occur |
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What is the most common cause of coagulative necrosis?
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Loss of blood supply
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How does coagulative necrosis look in LM?
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Often V-shaped infarct, paler than other tissue, with infiltration of leukocytes that digest the dead cells.
Cells are dead, higher eosinophilia but the outer lining is often retained. Nucleuses show all the nuclear changes of karyolysis, pyknosis and karyorrhexis |
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How is healing of coagulative necrosis?
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1. Necrotic part of organ (e.g. heart) is infiltrated by granulation tissue (fibroblasts + endothelial cells)
2. Fibroblasts produce collagen & elastin 3. Produce a scar, with poor function |
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What is caseous necrosis?
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This is a type of necrosis with a 'cheese-like' appearance, associated with Mycobacterium tuberculosis - usually lung is affected
The architecture is completely destroyed, outlines cannot be recognized. The area is enclosed in a granuloma |
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How is the granuloma in a TB infection?
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1. Central caseous necrosis (maybe due to the attempts of killing the bacteria in a central foci?)
2. Around we find multiple epitheloid cells (modified macrophages) and giant cells (fused macrophages) 3. Outermost we find lymphocytes and a rim of fibrous tissue |
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How is the pathogenesis of development of the tuberculous follicle?
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1-2 days
- TB inside neutrophils 1. week - TB goes intracellularly in macrophages 2. weeks - Conversion to epitheloid and giant Langhans cells - Killing of bacteria starts 3. weeks - Visible at naked eye, caseation centrally |
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What is the caseation an effect of?
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1. Type IV HSR
2. Bacterial activity and CD8+ T-cells with perforins 3. Ischemia |
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In potential healing of caseous necrosis - it often leads to?
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Calcification - stone hard.
Seen on X-rays |
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Why has incidence of tuberculosis decreased after 2nd world war?
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1. Better nutrition and hygiene
2. BCG immunization 3. Chemotherapy |
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BCG means?
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Bacillus Calmette–Guérin
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What is a hemorrhagic necrosis?
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Usually a coagulative necrosis of solid organ with invasion of blood from surrounding tissue
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In which organs is hemorrhagic necrosis typical?
What is the cause, usually? |
Well-vascularized tissues like:
- Lung Pulmonary embolism (of DVT) obstructs pulm. artery and cause infarct with bleeding - Small bowel Obstruction of superior mesenteric artery |
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What is fat necrosis?
What is the causes? |
Focal areas of fat destruction, usually from the work of activated lipases on triglycerides.
The causes are: 1. Trauma 2. Activation of pancreatic enzymes (most common) |
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What is the action of activated lipases on triglycerides?
What is this process also called? |
1. Triglycerides are released from fat
2. Lipase attack it (usually pancreatic, leaked out from acini in e.g. acute pancreatitis) 3. Fatty acids combine with calcium 4. Create insoluble SOAPS - which looks like chalky white areas Process is called 'saponification' |
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How does fat necrosis look in LM?
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Necrotic fat cels with basophilic calcium deposits - surrounded by inflammatory reaction
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Fat necrosis is also called?
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Balzers necrosis
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How can pancreatic lipases be activated?
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1. Acute pancreatitis
2. Obstruction of hepato-pancreatic ampulla by stones (gall or calcium) and bile flows into pancreatic duct and activates enzymes --> Self digestion Has a yellow discoloration! |
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What is fibrinoid necrosis?
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A form of necrosis - where in some immunological mediated diseases - antibody-antigen complexes are deposited in arterial walls.
These complexes, together with fibrin that have leaked out of vessels - produce a bright eosinophilic appearance - called 'fibrinoid' (looking like fibrin - when stained with H&E) |
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2 examples of fibrinoid necrosis?
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- Polyarteritis nodosa
- Rheumatic fever |
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In cardiomyocyte death - what can we detect in serology?
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- Creatine kinase enzyme
- Troponin contractile protein |
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In hepatic bile duct epithelial death - what may we detect in serology?
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Alkaline phosphatase
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In hepatocyte damage - what may we see in serology?
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Transaminases:
ALT AST |
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What is gangrene?
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A complication of necrosis - when there is bacterial infection involved - which release proteolytic enzymes.
These enzymes degrade necrotic tissue, releasing foul-smelling gases and tissue become green or black - due to the Hb breakdown. |
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3 types of gangrene?
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1. Dry
2. Wet 3. Gaseous |
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Dry gangrene
- What is it? - How does it look? - Who is affected more commonly? - What is treatment? |
- It is necrosis of lower extremities, due to arterial occlusion.
- It becomes black - Diabetics (with gradual arterial occlusion of extremities) and patients with atherosclerosis of lower extremities are typically affected (diabetes accelerates atherosclerosis) - Treatment is amputation |
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How does gangrene become black?
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1. RBCs are hemolyzed
2. Hemoglobin is released 3. Bacterias produce 'hydrogen sulphide' - which act on hemoglobin 4. It becomes iron sulphide - which has a black color |
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Wet gangrene
- Cause? |
Cause - 2 theories:
1. Usually a bacterial infection superimposing a coagulative necrosis (loss of blood supply + bacteria) --> Then bacteria have a liquefative action and attract leukocytes - leading to wet gangrene. 2. Venous congestion of edema associated. |
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Examples of wet gangrene?
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- Cholecystitis
- Acute appendicitis - Strangulation of viscera (2) |
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What is gas gangrene?
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Necrotic tissue is infected by anaerobic gas-forming bacteria - which produce small bubbles causing tissue swelling
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Which bacterias commonly cause gas gangrene?
Why is it not a problem anymore? |
Gram positive clostridia:
- Clostridia Perfringens - found in soil and enter wound and proliferate there Not problem anymore since we have ATB - but during 1st WW it was a common and dangerous complication of war wound. |
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How may one develop gangrene of bowel?
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1. Thrombembolism or embolism
2. Strangulated hernia 3. Intussusception (invagination) 4. Volvulus (twist) |
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Definition atrophy?
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Reduced size of cell or organ - from a normally developed one - due to loss of cell substance
Cells have lower function, but they are not dead |
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Difference atrophy and hypoplasia?
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Hypoplasia organ was never normally developed - if it was congenital it was smaller
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What is simple atrophy?
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Only cells ecome smaller - but number stays the same
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Numerical atrophy and example?
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Less numbers of cells
- For example lipomatous atrophy - where parenchymal organ cells are replaced by fat |
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Parenchymal organs that may undergo lipomatous atrophy?
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- Thymus
- Skeletal muscle - Heart - Pancreas |
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8 causes of atrophy?
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1. Physiological
2. Inadequate nutrition 3. Vascular atrophy 4. Pressure atrophy 5. Radiation 6. Inactivation 7. Neurogenic causes 8. Endocrine causes |
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Mechanism behind atrophy?
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Combination of:
- Decreased protein synthesis - Increased protein degradation (ubiquitin-proteasome pathway) |
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Examples of physiological atrophy?
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1. Senile atrophy of skin, fat, muscles, organs, brain
2. Involution of organs 3. Brown atrophy |
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Which organs typically involute?
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- Thymus
- Female genitalia and breast |
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What is brown atrophy?
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Some organs get darker with age - like liver and heart - due to increased lipofuschin and shrinkage of cell
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In inadequate nutrition - what is atrophied?
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First subcutaneous fat
Later fat of all organs - and eventually proteins (except brain) |
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What is cachexia?
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A condition in malignancies with increased protein degradation - believed to occur through the ubiquitin-proteasome pathway.
(protein labelled by ubiquitin - thus recognized and transported to proteasomes for degradation) |
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What is vascular atrophy?
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When blood supply to an organ (e.g. kidney) have been decreased to a critical level - the cell adapt to the condition and reduce the metabolic demand - and thus atrophies
They have time to adapt and even develop collaterals - since it happens over years. Common cause is atherosclerosis. |
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If occlusion occur in a vascular atrophied area - what happens?
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Not necessarily anything, since over time of gradual occlusion, collaterals have occured.
But if sudden occlusion = necrosis |
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What is pressure atrophy?
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Long lasting increasing pressure leads to decreased vascular and nutritional supply to that area - leading to atrophy.
- Growing tumor pressing on surrounding structures - Aortic aneurysm causing tissue atrophy - even of bone! - Gall stone causing pressure atrophy of wall If sudden impact of pressure = necrosis |
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How is doses of radiation related to atrophy?
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High doses = necrosis
Low doses = atrophy |
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Example of radiation atrophy?
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Radiation of tumor from different angles:
- Necrosis of tumor - Atrophy of skin and glands |
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Atrophy due to inactivation?
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e.g. broken arm in plaster cast - atrophy of skin, bone and muscle
Recover by exercise (and swimming?) |
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Neurogenic atrophy?
Example? |
If tissue looses it's innervation
Example - Poliomyelitis - inflammation of grey matter of spinal cord due to virus |
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Endocrine causes of atrophy?
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Loss of endocrine stimulation, e.g. in hypofunction of hypophysis: General cachexia
= 'Simmons cachexia" |
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Definition amyloid?
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A waxy, proteinaceous substance deposited in various extracellular tissues in some disorders
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Which tissues are overall commonly affected by amyloidosis?
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- Around blood vessels
- Basement membranes - Interstitium |
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What does amyloid consist of?
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2 components:
1. Variable component (always >90% - AA / AL / EL) 2. Constant component = Amyloid P protein (SAP) |
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What is serum amyloid P protein? (SAP)
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A glycoprotein normally found in serum
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How is the configuration of the amyloid proteins - thus gives it the property of resistance to degradation?
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Usually proteins are in a alpha-helix folding - but in all amyloid proteins there are abnormal folding:
They have a b-pleated sheet configuration - which is resistant to degradation - and it's staining properties. |
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How to detect amyloid deposition with naked eye?
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Use Lugol's iodine solution:
You add iodine to amyloid (Called Virchow's 1) - which will turn amyloid DEEP BROWN, while normal tissue is YELLOW Work, since amyloid binds to iodine like starch does - therefore iodine is starch-like. |
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How to certainly detect amyloid in LM?
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Use congo red staining - which in polarized light (through horizontal and vertical filters) becomes APPLE GREEN
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How to specifically detect the constant compound amyloid protein P?
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Use immunostaining
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What are the 3 classes of amyloid?
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1. AL - Amyloid Light chain derived
2. AA - Amyloid A protein 3. EA - Endocrine amyloid?? Not sure, but Ryska spoke about it. |
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So the AL amyloid consist of?
And is associated with what disorders? |
1. 10% amyloid P protein
2. 90% light chains of immunoglobulins Associated with monoclonal plasma cell dyscrasias |
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And AA consist of?
And is associated with what disorders? |
10% amyloid P protein
90% serum AA protein - an acute phase reactant, produced in chronic inflammatory reactions |
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Examples of plasma cell dyscrasias leading to AL amyloidosis?
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- Multiple myeloma
- Monoclonal gammopathy - Waldenströms macroglobulinemia |
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Examples of chronic inflammations leading to AA amyloidosis?
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- Tuberculosis
- Osteomyelitis - Rheumatoid arthritis - Bronchiectasis - Familial mediterranean fever (inherited) |
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How does amyloid look in EM?
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Interlacing fibrils
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What pathological effects does amyloid deposition have?
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1. Pressure on adjacent cells --> Atrophy
2. Blood vessel deposition - Narrowing --> Local ischemia - Increased permeability --> Transudation of protein |
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Definition primary amyloidosis?
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Amyloidosis associated with plasma cell dyscrasias - commonest is multiple myeloma.
Can be both systemic and localized |
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Characteristics of multiple myeloma?
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Tumor originating from bone marrow - produces abnormal immunoglobulines (or higher ratio of light chain than heavy chain?)
Producing Bence-Jones proteinuria (abnormal light chains of Ig's) - which is unable to be uptaken by kidneys due to its abnormal folding or structure |
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What is secondary amyloidosis?
What do we also call it? What are the 2 theories for the amyloid deposition? Since normal elevated SAP would not lead to deposition, as it is seen in all chronic inflammations! |
Called this since it is 'secondary' to chronic inflammatory condition. (most cases) - so we call it reactive systemic amyloidosis
2 theories: There is a defect in enzymes that degrades serum amyloid proteins (SAP) - and this cause an excess of this - (amyloid associated protein) - leading to systemic deposition. 2. The acute phase proteins (SAP produced in liver have a genetical abnormalities - that makes it unable to be degraded by macrophages. |
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Most common causes of secondary amyloidosis?
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Tuberculosis
Osteomyelitis Bronchiectasis Hodgkin's lymphoma |
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Definition systemic amyloidosis?
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Distribution of amyloid systemically:
- Kidneys, spleen, bone marrow, liver, lymph nodes etc. Caused by either primary or secondary amyloidosis |
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Definition localized amyloidosis?
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Deposition in only ONE organ:
- Heart - Lung - Urinary bladder - Brian etc |
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Name 2 specific localized amyloidoses?
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1. Endocrine amyloidosis
2. Amyloidosis of aging |
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What is endocrine amyloidosis?
Examples? |
A endocrine tumor which produce microscopic deposits of amyloid
- Medullary carcinoma of thyroid gland with amyloid derived from calcitonin (polypeptide hormone) - Tumors of islets of Langerhans in pancreas - Type II diabetes islets of Langerhans |
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What is amyloidosis of old age?
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A amyloid deposition related to pre-albumin - may be deposited in heart, brain and joints.
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How is amyloid connected with Alzheimers?
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Amyloid deposition in brain is one of the theories!
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Grossly - with the iodine test - how is amyloid deposition seen in kidneys?
How is it seen in LM? What effect does it have on the kidney? |
Grossly: Brown spots
LM: Deposits around: - Glomerular capillaries - BM of atrophic tubules - Blood vessel walls Effect: - Proteinuria --> Nephrotic syndrome --> Renal failure ! Another effect may be that podocytes are very sensitive to hyperglycemia - this is toxic for them and they may be injured ! Arthung meine freunde |
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What is effect of amyloid deposition in GIT?
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Due to amyloid in capillary walls, which leads to increased permeability, patient has diarrhea and protein loss.
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Where is amyloid deposition in heart - and how does it lead to cardiac failure?
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Deposition
- Around cardiac muscle fibers - Capillary BMs Cardiac failure 1. Heart enlarged with thick walls 2. Amyloid makes the muscle stiff - which prevent cardiac filling 3. This cause restrictive ardiomyopathy 4. And also the blood supply to muscle fibers is bad |
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What is the most commonly affected organ in amyloidosis?
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Kidney
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What amyloid is deposited in Alzheimers disease?
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A beta folded amyloid
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Where is amyloid deposition in liver?
How heavy may the liver grow? |
In space of Disse - may grow up to 9kg
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What is senile cardiac amyloidosis?
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A local amyloidosis of old age, caused by normal transthyretin (transport molecule of thyroid hormone)
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Definition steatosis?
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Abnormal accumulation of fat in an abnormal location - may occur in almost all organs but most commonly liver
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How can you stain for steatosis?
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H&E -
Sudan III & IV |
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What is usually the cause of steatosis?
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1. Cell poisions
- Alcohol - Drugs - Hepatotoxins (chloroform) 2. Clinical disorders - Hypoxia due to o Anemia o Cardiac failure o Respiratory diseases |
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How does steatosis in heart look and when do it occur?
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Only occur in severe anemic patients - with tiger heart appearance of inner right atrium
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Why is the fat actually accumulated?
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Due to the damage of the cells - there are reduced cellular enzymatic activity - and cells are unable to metabolize the fat and thus it is stored.
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How may steatosis of heart lead to cardiac failure?
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It cause weakness of the muscle fibers - so in 2 cases:
1. Too rapid or large transfusions - heart is dilated due to its weakness and failure is result. 2. Sudden exertion - rise in BP and temporary left sided cardiac failure develop due to it's weakness. |
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So what typical organs does steatosis occur?
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Liver
Heart Kidney |
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In liver - if hypoxia or damage is persistent - steatosis leads to?
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Cirrhosis
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What are the most common disorders of lipid metabolism?
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1. Lysosomal storage diseases: (lipidoses)
- Gaucher's disease - Tay-Sach disease - Niemann-Pick disease - Fabry's disease - Wolman's disease 2. Hypercholesterolemia |
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What is Gaucher disease?
(Iphone 3G = 3 types) What 3 types are there? |
A disease with buildup of glucocerebrosides (kerasin) (product of fat metabolism) in tissues, the most common lipidosis
3 types: 1. Chronic form - most common 2. Infantile form 3. Juvenile form |
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Chronic form of gaucher disease?
Lead to? |
Lead to hepatosplenomegaly, bone abnormalities and maybe neurological problems
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Infantile form of gaucher disease - lead to?
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Death within 1 year - splenomegaly and neurological problems
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Juvenile form of Gaucher - detection and progression?
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Discovered in childhood - hepatosplenomegaly and slowly worsening neurological symptoms.
Kids surviving may live for many years |
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What can we see in spleen in Gaucher disease?
How may Gaucher be treated? |
Gaucher cells - lipid accumulated in macrophages - large cells with large pale cytoplasm
Treated by recombinant enzyme therapy |
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What is a glucocerebroside btw?
And what is another name for it? |
A product of fat metabolism
It is one of the cerebrosides - which is a glycosphingolipid - which is a part of cell membrane of muscle and neuronal cells Another name for glucocerebrosides is kerasin |
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Main symptoms of Gaucher disease?
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Hepatosplenomegaly
Brown pigmentation of skin |
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What is Tay-Sach disease?
"Small boy named Tay, he was a GANG member and got HEXED in the BRAIN - survived but got RETARDED and BLIND. To make him feel better he got a CHERRY lollipop - and then he died" |
A disease of accumulation of gangliosides in neuronal cells of CNS and PNS
Leading to gangliosidosis |
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What is symptoms of gangliosidosis?
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Motor skill retardation
Retardation Blindness Cherry macula of eye Died at age 4 |
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What are gangliosides?
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Also some lipid present on surface of cell membranes
A product of fat metabolism |
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What is Niemann-Pick disease?
"Nieman Picked his nose with his "SPHINGER" and got FAT and FOAMY |
A disorder of accumulation of sphingomyelin or cholesterol in tissues, due to defect in sphingomyelinase, leading to:
- Hepatosplenomegaly - Foamy cells in CNS, due to progressive dysfunction of nervous system |
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What is Fabry's disease?
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A buildup of glycolipids in tissues, leading to:
- Skin growths - Pain in the extremities - Poor vision -Kidney and heart failure X-linked so only affect boys |
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What is Wolman's disease?
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Accumulation of cholesterol esters and TAG's due to lipase deficiency
Lead to: - Adrenal calcification - Hepatosplenomegaly |
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Metabolic disorders of cholesterol?
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1. Familial hypercholesterolemia
---> 2. Xanthelasma palpebrarum |
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What is familial hypercholesterolemia?
What signs on skin does this produce? |
Autosomal Dominant condition with increased levels of 'bad' cholesterol (LDL) in blood - due to a mutation in LDL uptake receptor of liver (75% of them are there) - which remove most of the cholesterol.
Elevated serum cholesterol greatly increase risk of atherosclerosis and coronary artery disease Produce so-called xanthomas - cholesterol deposits along tendon sheats. Typical is the 'famous' xanthelasma palpebrarum' - deposits on the upper eyelid. |
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How does lipid metabolism disorders contribute to atherosclerosis?
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First lesion in atherosclerosis is accumulation of lipophages in tunica intima
--> Called 'fatty streaks' - develop into ath. plaque |
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What happens if bile contains a lot of lipids?
Why is this called 'strawberry gallbladder"? |
It accumulate in gallbladder mucosa - where lipophages rest.
Thus gallbladder mucosa becomes yellow and fat - so-called "strawberry gallbladder" (loads of small yellow spots on inner mucosa) |
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How does foamy cells of CNS develop - from the so-called lipophages?
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In CNS there are 2 types of lipophages:
1. Migroglia = neutrophils 2. Macroglia = macrophages Sometimes they may fuse = Giant cells If there is a local breakdown of myelin sheats, cell membranes etc - this is phagocytosed by the lipophages - and foamy cells develop |
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How may lipid metabolism disorder develop into a myopathy?
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When free Fatty Acid transport fail - carnithine dysfunction...
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What is the most common disorder of carbohydrate metabolism?
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Diabetes mellitus
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What fasting glycemia must be present to be diagnosed with DM?
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Over 11 mmol/L I think.
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How many categories and what main types of DM do we have?
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10 categories - but:
Type I - absolute insulin lack Type II - relative insulin lack These two are the only primary forms - the rest are secondary to some disease |
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Etiology of type I DM?
How many %? |
Progressive autoimmune destruction of beta cells of Langerhans, due to failure of self-tolerance of CD8+ T-cells
With acute onset and peak around 13 years. 10% |
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Etiology type II DM?
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Dult onset,
Combination of insulin resistance of tissues (receptors are worn out) and failure of compensatory response by beta cells. 90% |
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Name the most important other types of diabetes?
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3. Secondary forms like:
- Endocrine diseases - Metabolic diseases - Drug therapy - Pancreatic inflammation 4. Gestational diabetes |
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What endocrine diseases may lead to diabetes?
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- Growth hormone excess (acromegaly)
- Cushing syndrome - Pheochromocytoma |
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What metabolic diseases may lead to diabetes?
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Hemochromatosis
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What drugs may lead to diabetes?
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Glucocorticoids
Thiazide diuretics |
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What pancreatic inflammations may lead to diabetes?
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- Chronic pancreatitis
- Mumps - Cystic fibrosis |
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What is the function of insnulin on adipose tissue?
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- Increased glucose uptake
- Increased lipogenesis - Decreased lipolysis Saving mode |
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What is the function of insulin on striated muscle?
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- Increased glucose uptake
- Increased glycogen synthesis - Increased protein synthesis Saving mode |
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What is the function of insulin on liver?
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- Increased glycogen synthesis
- Increased lipogenesis - Decreased gluconeogenesis |
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What is gestational diabetes?
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Glucosuria during pregnancy and birth of overweight babies - return to normal after pregnancy.
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What is the primary function of insulin?
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Speed up uptake of glucose to cells of the body - mainly:
- Skeletal muscle (glycogen or oxidized to ATP) - Adipose tissue (lipid storage) |
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Why does insulin only stimulate skeletal muscles and adipose tissues for glucose uptake?
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Since the rest of the cells (brain, heart etc) are insulin-independent - since they cannot be sure that insulin is always there!
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What 3 mechanisms are regulating normal glucose homeostasis?
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1. Glucose production of liver
2. Glucose uptake and utilization of peripheral tissues 3. Counterregulatory mechanisms of insulin |
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What is the underlying etiology of type I diabetes?
Genetical & environmental |
Multifactoral.
1. Genetical familial incidence = 80% , most likely due to some MHC II antigens (thus CD8+ attack them) 2. Environmental factors - Coxsackie virus B, which may have lead to molecular mimickry |
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What etiological factors plays a role in DM II?
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Genetic:
- Maybe some 'diabetogenic genes' - shown high prevalence in twins Environmental - Obesity, sedentary lifestyle... |
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2 metabolic factors in DMII is :
- Insulin resistance - Beta cell dysfunction How can tissue become insulin resistant? |
Here OBESITY plays a role, since DM risk increases with visceral obesity - via:
1. Excess free FA's - Products of FA metabolism are potent inhibitors of insulin signalling (direct) - Excess FA's in macrophages and beta cells lead to inflammation - which cause release of cytokines which impede insulin secretion (indirect) 2. Adipokines - These are hormones secreted by adipose tissues, which promote peripheral insulin resistance |
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2 metabolic factors in DMII is :
- Insulin resistance - Beta cell dysfunction How can beta cells become dysfunctional? |
1. Inability to adapt to the long term demands of peripheral insulin resistance and increased insulin secretion..
They get exhausted! |
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What are the 3 main results of insulin lack?
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1. Hyperglycemia
2. Increased lipolysis 3. Increased gluconeogenesis from AA's |
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Prolonged hyperglycemia in DM leads to?
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1. Glucosuria --> Osmotic diuresis (loss of K+/Na+) and water --> Hypovolemia and thirst --> Polydipsia
2. Increased plasma osmolarity --> Thirst --> Polydipsia |
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Increased fat catabolism in DM leads to?
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Excess acetyl Co-A production
--> Converted to ketone bodies Patient enters ketoacidosis Acid is attempted secreted with Na+ and K+, which leads to further electrolyte depletion |
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Increased gluconeogenesis in DM leads to?
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Loss of weight - even despite polyphagia!
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What changes are seen in the pancreatic tissue in diabetes? (both usually have same changes)
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!! Usually no change is seen in islets !! - but sometimes:
1. Reduction in size and numbers (if onset quick of type I - although studies are doubtful) 2. Increase in size and numbers of islets - In children of diabetic mother 3. Amyloid deposition 4. Insulitis |
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How come there is increased pancreas islets in baby of diabetic mother?
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1. Mother has diabetes - baby is exposed to high levels of glucose
2. Islets of babies undergoes compensatory hypertrophy to adapt to higher levels 3. When umbilical cord is cut - baby suddenly has extreme production of insulin to normal glucose levels 4. And baby go into a severe hypoglycemia But this doesnt happen now in the modern world - since mother is treated. |
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How come there is amyloid deposition in islets in type II diabetes - and what type of amyloid?
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Because beta-cells secrete 'islet-amyloid protein' (AE = endocrine amyloid) - along with insulin.
This is deposited in islets - reflecting the prolonged activity of beta cells. |
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What is insulitis?
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Necrosis of beta cells and lymphocytic infiltration - as an autoimmune process!
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Some changes occur in vessels after 10-15 years of DM… If patient disiplined takes insulin, it goes slowly - and opposite - if not: may take 5 years before they die of acute MI.
What are the changes? |
1. Diabetic macrovascular disease
2. Arteriolosclerosis 3. Diabetic microangiopathy And it's the combination of these 3 which results in poor perfusion and ischemia of target tissue! |
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What is diabetic macroangopathy?
What diabetic diseases does it lead to? |
Accelerated atherosclerosis of large and medium arteries.
1. Lead to acute MI (main cause of death) 2. Gangrene of the lower extremities 3. Renal arteries - although the microvascular changes are much more important here |
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What is diabetic arteriosclerosis?
What is it in association with? |
Hyaline thickening of small arteries - causing narrowing.
Associated also with hypertension - so diabetic with hypertension = bad combination! |
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What is diabetic microangiopathy?
What diabetic diseases does it lead to? |
Thickening of BM in small capillaries by type IV collagen
1. Decreased perfusion 2. Increased permeability to plasma proteins Leading to: - Diabetic nephropathy - Diabetic retinopathy - Diabetic neuropathy |
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How come patient with diabetes die suddenly without any pain - due to acute MI?
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Since if patient have also diabetic neuropathy - he does not feel the chest pain - and infarct can go on silently.
Often in autopsy we see huge post myocardial scar - without any documentation of this in his papers. |
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What is diabetic gangrene of lower extremities?
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Complication of the progressive vessel changes in diabetes.
Narrowing of vessels due to sclerosis and atherosclerosis (atheromas) - lead to hypoxia and ischemic injury to tissues. Starts in toes - one amputate - comes again more proximally - usually end up amputating whole leg. |
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How many people in CZ have diabetes?
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5% 'only' = 1/2 million people!!!
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What other complications has the narrowed blood vessels for the lower extremities?
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If there is any injury - it leads to severe inflammation, osteomyelitis and non-healing ulcers.
Called 'diabetic foot' - it is very annoying and dangerous also. |
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What is the second most common cause of death in diabetes?
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Renal injury - due to diabetic nephropathy
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What is diabetic nephropathy?
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A progressive renal failure due to the diabetic changes of:
1. Glomeruli 2. Vessels 3. Tubules 4. Renal pelvis |
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What diabetic changes occur in glomeruli?
What is it called? And what is the specific lesions called? |
Diabetic microangiopathy makes the glomeruli sclerotic - and the extra BM material shows as nodules between the glomerular loops - which looks like this old mirror your grandma used to look in
It is called 'nodular glomerulosclerosis' And the lesions are called 'Kimmelstiel-Wilson' lesion - IMPORTANT (steiner likes this) |
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The Kimmelstiel-Wilson lesion of glomeruli - what does it lead to?
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1. Thickening of the BM of course
2. Higher permeability of glomeruli => Patient loose plasma proteins to urine - leading to 'nephrotic syndrome' |
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What kidney changes are pathognomonic for diabetes?
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1. Nodular glomerulosclerosis
2. Hyaline arteriolosclerosis of BOTH efferent and afferent arterioles (do not happen in any other disease) |
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Which part of kidney is most sensitive to ischemic changes?
What happen to the tissue and what is the complications? |
The papillae - that is why in diabetic nephropathy - papillary necrosis is very common.
1. Necrotic infarction 2. If they are released from kidney - they may block urine outflow and cause hydronephrosis |
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What happens in the renal tubules in diabetes?
What are the cells there then called? |
High storage of glycogen and fat in proximal tubular cells - leading to so-called 'Armani cells'
I guess it is stored since there is so much glucosuria |
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How does Armani cells look?
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Pale vacuoles - look like an empty window in our slides
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Why cannot the cells store glucose as glucose?
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SInce it is very osmotically active - so it would cause explosive cells
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What happens to renal pelvis in diabetes?
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Bacteria grow much easier since :
1. They have loads of glucose 2. They have a severe immunodeficiency Therefore it leads to pyelonephritis |
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What is the last organ in diabetes which is significantly injured?
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The retina of the eye - so called 'diabetic retinopathy'
It is the most common cause of blindness in developed countries! |
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How is retinal changes corresponding to renal changes?
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They are the same - if no problem with retina - there is no problem with kidney:)
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What is the mechanism of diabetic retinopathy?
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1. Vascular injury & sclerosis
2. Vessels become fragile and rupture 3. Bleeding behind retina & scarring of these areas 4. Result in detachment of retina from surface 5. Result in loss of vision |
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Other manifestations of diabetic retinopathy than just loss of vision?
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1. White-ish discoloration of lens = Catarrhact
2. Increased intraocular pressure = glaucoma => Blindness too |
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How does diabetes affects nerves - and which nerves are affected?
What is this condition called? |
It is called diabetic nephropathy
Products of diabetic metabolism (either hyperglycemia or ketone bodies…) are toxic to neurons. This affect both motor and sensory nerves - but most sensory. Also vascular supply is lower. |
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How does diabetes cause immunosuppression?
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The machanism is unclear - although in both diabetes and hyperglycemia models, there is very diminished immune function - especially of neutrophils.
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What infections are typical in diabetes with immunosuppression?
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- Oral candidiasis
- Vulval candidiasis - Colpitis - Pyelonephritis Etc. |
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How can we stain glycogen in cells?
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PAS method => Purple
Best carmine => Red |
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What is a glycogenosis?
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A glycogen storage disease - where due to an enzyme deficit - there is accumulation of glycogen in tissues - resulting in various diseases depending on which tissue
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There are 12 different glycogenoses. What are the 3 most important ones?
"Very Poor Metabolism" |
1. Von Gierke's
2. Pompe's 3. McArdle's |
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Which enzyme is deficient and what does it lead to in Von Gierke's disease?
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Glucose-6-phosphatase is deficient, so liver cannot transform glycogen --> Glucose
So there is a buildup of glycogen in liver |
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Which enzyme is deficient and what does it lead to in Pompe's disease?
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Deficient some lysosomal enzyme (lysosomal glucosidase)
Which can affect all tissues (Pompeii) - but more frequently cause deposits of heart (the PUMP) - in which glycogen buildups cause muscle weakness thus pump weakness |
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Which enzyme is deficient and what does it lead to in McArdle's disease?
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Muscle glyocgen phosphorylase - leads to muscle weakness too I think - due to increased deposition of gylcogen.
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What can we see in LM of these glycogenoses?
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Large, pale apple-like cells, full of glycogen!
Can stain them with PAS or Best Carmine to confirm. |
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Which cancer can also accumulation of glycogen occur?
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Kidney cancer.
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In which genital tissue is it normal with glyocgen?
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Endometrium.
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Definition degeneration?
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A change from a high functional tissue to a less functional tissue
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What is caseous degeneration?
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A necrosis in which tissue changes into a soft, cheese-like mass - typical for tuberculosis
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What is cerebroretinal degeneration?
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Degeneration of brain cell and macula retinae - like in Tay-Sach.
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What is colloid degeneration?
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Degeneration with conversion of the tissues into a gelatinous or gumlike material
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What is cystic degeneration?
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Degeneration with formation of cysts
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What is fatty degeneration?
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Deposits of fat globules in a tissue
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What is fibroid degeneration?
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Degeneration of a leiomyoma with subsequent fibrosis
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What is hepatolenticular degeneration?
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Seen in Wilson's disease - a disorder of copper metabolism characterized by:
- Cirrhosis - Basal ganglia degeneration of brain - Deposition of green pigment of corneal periphery |
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What is hyaline degeneration?
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Regressive change in cells in which cytoplasm takes on a homogenous, glassy appearance.
Also used loosely to describe histological appearance of tissues |
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What is hydropic degeneration?
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A degeneration where epithelial cells absorb much water
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What is lattice degeneration of retina?
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Bilateral, benign asymptomatic condition - where patches of fine grey or white liens intersect at irregular intervals in peripheral retina - making numerous round punched out areas of retinal holes or thinnings
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What is macular degeneration?
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A progressive worsening of the macula in the eye - responsible for the central vision.
Disorder lead to irreversible loss of central vision, and initially vision may be gray and distorted. |
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What is mucoid degeneration?
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Degeneration with deposits of myelin and lecithin in the cells
Lecithin = any group of phospholipid deposited in tissues Mucoid = looking like mucous |
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What is mucous degeneration?
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Degeneration with accumulation of mucus in epithelial tissues
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What is myofibrillar degeneration?
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Damage to selective cardiac cells - when surrounding interstitial cells, nerves and capillaries remain viable
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What is myxomatous degeneration?
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Same as mucous degeneration
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What is wallerian degeneration?
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Fatty degeneration of a nerve fiber that have been cut from it's nutritive source.
Macrophages eat the myelin and become foamy cells |
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What is calcaerous degeneration?
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Degeneration of tissue with deposit of calcaerous material (calcium)
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What is fibrinous degeneration?
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Necrosis with deposit of fibrin within the cells of the tissue
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What is ascending degeneration?
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wallerian degeneratino affecting centripetal nerve fibers - progressing towards brain or SC
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What is descending degeneration?
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WAllerian degeneration extending peripherally along nerve fibers
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What is gray degeneration?
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Degeneration of white substance of SC - in which loses its myelin and assumes a gray color
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What is striatonigral degeneration?
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Multiple system atrophy with nerve cell degeneration - mainly in region of SN and neostratum.
SImilar symptoms of parkinsonism |
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What is tapetoretinal degeneration?
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Degeneration of the pigmented layer of retina
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What is Zenker's degeneration?
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Hyaline degeneration and necrosis of striated muscle
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What is albuminoid degeneration?
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Cloudy swelling - early stage of degenerative change - looking swollen - and will revert to normal when cause is removed
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What is ballooning degeneratino?
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Swelling of cytoplasm in epidermal cells without vacuolization
- Enlarged or condensed nuclei and acantholysis. Typical for viral infections of skin, also called koilocytosis |
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What is feathery degeneration?
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Said of hepatocytes:
- Hydropic change in hepatocytes which have suffered from long-term exposure to cholestasis |
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What is fibrinoid degeneration?
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Deposition or replacement with eosinophilic fibrillar or granular substance looking like fibrin
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What is fibroid degeneration?
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Degeneration into fibrous tissue
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What is spongy degeneration?
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In LM it looks spongy.
Usually applied to tissue of CNS, caused by loss of myelin |
