Cell injury, Accumulations, Pigments, Calcification A6-A11 Flashcards
A/6. The morphology and mechanisms of reversible cell injury, examples.
What are the points of irreversible cell injury?
What are the gross morphology changes of reversible injury?
What are the cellular changes of reversible injury?
The points of irreverisble injury are:
- Ca++ increase
- Extreme membrane damage
- Irreversible mitochondrial damage
The main reversible gross morphology changes:
1) Cell Swelling / Hydropic Degeneration / Vacuolar Degeneration / parenchymatous degeneration / cloudy swelling.
- Due to hypoxia, and failure of Na+/H2O pump, and failure of osmotic regulation and H2O influx.
- Cells and organelles all become swollen.
2) Parenchymal Degeneration
* related to septic toxin poisoning.
3) Fatty change, steatosis.
- from starvation and increased fat mobilization
- from hypoxia preventing fatty acid oxidation
- from alcohol NADH increase
- protein malnutrition, preventing liver Apoprotein synthesis and causing fat accumulation
- obesity and excess diet adipose
The main cellular changes of reversible injury
- cell swelling
- some membrane blebbing
- mitochondria swelling
- dilation of ER and dissociation of ribosomes
- nuclear change, pyknosis
A/6. The morphology and mechanisms of reversible cell injury, examples.
Examples of reversible injury (organ examples)
- Fatty Liver, Hepatic statosis, usually from alcohol or severe obesity (non-alcoholic fatt liver disease). Hepatocyte accumulates fat vacuoles that displace the nuclei.
- Nutmeg Liver, Degeneratio Adiposa Insularis Hepatis. From right sided heart failure and blood congestion in the liver, pooling from the central vein outward. The central regions are hypoxic and have fat accumulation while the periportal regions are maintained.
- Tiger heart: Degeneratio Adiposa Insularis Myocardia. General cardiac hypoxia inhibits beta-oxidation, causing strips of adipose accumulation in the subendocardium.
- Subendocardial layer first,
- Subendocardium is supplied by the smallest arteries
- It contracts more than the other regions, performs the most work.
- It is under the greatest pressure during contraction (intramural, intramuscular pressure.
4) Degeneratio Adiposa Diffusa Myocardia. Fatty change throughout the myocardial layers, due to septic infection.
A/7. Pathomorphology and complications of atherosclerosis.
list risk factors
Non-modifyable risk factors
- Age above 40 years
- Males and post-menopausal women
- Genetics: Diabetes, Hyperlipidemias, Obesity
Major Modifiable risk factors
- Hyperlipidemia, dyslipoproteinemia
- High Lipoprotein A levels
- Hypertension
- Smoking
- Diabetes
Additional risk factors
- Inflammation (low grade CRP levels)
- High Homocsteine levels
- Metabolic syndrome
- Obesity
- Sedentary life
- Stress
A/7. Pathomorphology and complications of atherosclerosis
List the types of plaques and general plaque progression
The first two stages are reversible:
- Fatty streak
- Stable atherosclerotic plaque, with fibrous cap, collagen, fibroblasts, and an in tact epithelium
Then a various types of complicated plaques may develope, and are irreversible.
- Calcified plaque
- Vulnerable plaque with thin cap, thin shoulders, and thick core
- Aneurysm at or near the plaque site due to weakened vessel wall.
- Eroded Plaque, endothelium is denuded, exposing fibrous cap, fibrogenic
- Fissured/Ruptured plaque, exposing core, may caue fat embolism, or thromboembolism
- Internally hemorrhaged plaque
- Healed ruptured plaque, layered
- Occlusive/Stenotic plaque
A/7. Pathomorphology and complications of atherosclerosis
Complications caused by atherosclerosis
Heart and Aorta:
- Coronary heart disease –> Ischemic heart disease
- Coronary stenosis, occlusion, myocardial infarct.
- Hypertension, leading to hypertrophy, ischemia, and heart failure
- Aortic aneurysm, rupture.
Brain:
- Chronic low grade ischemia and confusion, mental impairment
- Thromboemoblisms generate transient ischemic attacks, stroke-like symptoms as small vessels are occluded.
Peripheral Vascular disease
- Low blood flow causing chronic ischemia, infections, poor wound healing, and gangrene or amputations
A/7. Pathomorphology and complications of atherosclerosis
prevention and treatment of atherosclerosis
Primary prevention:
- Lifestyle management before it develops.
- Diet
- Exercise
- Don’t smoke
- Manage blood pressure
- Manage blood lipids
Secondary prevention:
- Blood pressure management
- Lipid management
- Anti-coagulant prophylaxis
A/8. Amyloidosis
Amyloidosis is a category of pathologies caused by overlapping beta-pleated sheets from proteins.
Amyloid deposits are extracellular, trap cells nutrient restriction and atrophy, and can also induce inflammation.
Many proteins can cause amyloidosis, but the 3 most common are:
- AL protein amyloidosis: Amyloid light chain protein, made by plasma cells, and composed of immunoglobulin light chains or portions of the light chains. Seen in multiple myeloma.
- AA fibril amyloidosis: Amyloid associated fibril: A fragment derived from the Serum Amyloid A protein of the liver acute phase response. Thus, it is seen in chronic inflammatory disorders.
- A-beta amyloidosis: Alzheimer’s. Abeta is derived from APP protein.
- Transthyretin: A serum protein that transports thyroxine and retinol. Genetic mutations to this gene cause it to aggregate and form amyloid deposits. Causes familial amyloid polyneuropathies, and systemic amyloidosis.
- Beta-2 microglobulin: found in amyloidosis of long-term hemodialysis patients. Depositions of this serum protein accumulate due to inefficient filtration through dialysis machines, and patients kidney failure. Deposits in the joints, synovial membrane, and tendons.
A/8. Amyloidosis
What are the more general causes of protein accumulation disorders?
Causes of protein accumulation:
- Excessive protein exposure: as in Nephrosis. Excessive protein in the blood and glomerular leakage –> excessive tubular resorption of proteins, and tubular protein deposition, damage, decreased function.
- Excessive protein synthesis: Plasma cell immunoglobulin synthesis in the context of any neoplasms, inducing Russel body formation in the RER. Or Light chain amyloidosis in multiple myeloma
- Cell injury: Alcohol toxicity can cause cytoskeletal protein accumulation, forming mallory bodies. Which look like dark eosinophilic twisted ropes inside of hepatocytes.
- Misfolding of proteins: alpha-1 antitrypsin misfolding. causes accumulation and dysfunction of the protein. Causes excessive trypsin activation, and chronic destruction of the lung tissue, emphysema.
- Amyloidosis disorders: Amyloid light chain, serum amyloid a associated, amyloid beta, TTR, transthyretin misfolding, beta2 microglobulin, found in amyloidosis of long-term hemodialysis.
A/8. Amyloidosis
Nephrosis syndrome
Glomerulonephritis: In Glomerulonephritis, glomeruli lose protein and due to
endocytosis, there is protein accumulation in the tubular structure. Terms to distinguish:
1. Nephritis is an inflammation of the kidneys and may involve glomeruli, tubules or
interstitial tissue surrounding the glomeruli and tubules.
2. Glomerulonephritis is inflammation of the glomeruli.
3. Interstitial nephritis or tubule‐interstitial nephritis is inflammation of the spaces
between the renal tubules.
4. Nephrosis syndrome is a degenerative disease of the renal tubules. Nephrosis can be caused by kidney disease and excessive protein filtration and subsequent re-absorption by the tubules, or may be caused as a result of a different disorder.
A/8. Amyloidosis
What are the clinical forms of amyloidosis
Clinical forms of amyloidosis:
- a) Immune dyscresias (primary) ‐ Dyscresia means abnormal mixture. This comes from AL amyloid.
- Associated with multiple myeloma, light chain precipitation in different organs. These proteins are also secreted into the urine (Bence‐Jones protein).
- b) Reactive systemic amyloidosis (secondary) – Come from AA amyloid. In this case, the patient has chronic inflammation. I.e. auto‐immune diseases.
- c) Familial amyloidosis – hereditary (Mediterranean fever) – caused by mutation of the anti-inflammatory protein pyrin. Pyrin inhibits activation and proliferation of PMN immune cells. Causes chronic inflammation and AA amyloid deposition.
- d) Local amyloidosis – Nodular, tumor‐like deposits of amyloid on a single organ. Come from AL light chain. The organ develops a neoplasm; in the neoplasm, amyloid is acting away. This is distinct from the systemic form.
- e) Endocrine amyloidosis – On certain endocrine tumors. This occurs in those neoplasms which produce endocrine hormones and the hormones are therefore progenitors of the amyloid.
- f) Amyloidosis aging – This is transtyrtein related (TTR) deposition. Polyneuropathies from brain deposition and heart depositions
- g) Nephrotic syndrome
- h) Restrictive cardiomyopathy / arrhythmia
- *Clinical Symptoms of amyloidopathy:**
a) In the kidney: Proteinuria, kidney failure, and nephrotic syndrome
b) In the liver, generally no symptoms because of huge liver capacity.
i. Hepatosplenomegaly is present.
c) In the heart:
i. Restrictive cardiomyotony.
ii. Rigid wall and problems with relaxation of the left ventricle, so diastolic failure.
iii. The disease has a bad prognosis. Not more than 3‐5 year survival.
iv. It will be there during the person’s lifetime → cannot be removed; damaged organs need transplant.
A/8 Amyloidosis
How is it diagnosed?
Diagnosed by biopsy.
- It is Extracellular, Eosinophilic, Amorphous substance.
- Congo-red staining, or Polarized light causing apple-green coloration
- *Morphological characteristics of amyloid.
a) Pallor. As amyloid accumulates extracellularly, cells atrophy because the surrounding amyloid compresses it and takes away nutrition and oxygen.
b) Organs become bigger (‐megaly), heavier, pale, and waxy.
c) Mostly seen in parenchymal organs (Kidney, spleen, liver, heart**)
d) Also in the GI tract and tongue. A tongue biopsy or rectal biopsy can be used to detect.
e) In the kidney, found in glomeruli (it is located at the mesangium and basement membrane), and in tubular system and vessels.
f) In liver, located in the space of Disse and around hepatocytes. Normally, there is no liver failure but regeneration.
g) In the heart, they are located sometimes subendocardial but also between myocardial fibers causing reduced muscle distension capacity (no pump problems).
h) In the spleen, can be nodular/follicular or sinusoidal.
A/8 Amyloidosis
Hyaline accumulation disorders
Hyaline: the name of multiple different substances that are glassy and pink in haematoxylin and eosin stain.
- Pink Eosinophilic substance
- Stains bright magenta with periodic acid‐Schiff (PAS) stain.
- Acellular and proteinaceous material.
c) Diseases of hyaline accumulation:
* *i. Kidney:**
1. Hyaline arteriosclerosis, Nephrosclerosis (also known as arterial/arteriolar hyalinosis). It is a vascular lesion characterized by accumulation of serum proteins in the subendothelial space and often extending into the media. Is associated with:
- Diabetes mellitus. Causes a chemical injury on the cells. In diabetes mellitus, both afferent and efferent arterioles are affected.
- Hypertension. Hypertension causes a physical pressure‐type injury on the cells. In hypertension, usually the afferent arteriole is affected.
- Some drugs.
- Hyaline arteriosclerosis is a major cause of renal failure.
2. Hyalinic glomeruli. glomerular nephritis causes protein leakage through the filtration barrier.
- a. There is leakage of plasma protein and excess production of extracellular matrix, precipitation of hyalinic material onto the glomeruli basement membrane, sometimes called end‐stage kidney.
ii. Liver:
1. Mallory Hyaline. This is globular red hyaline material within hepatocytes. It is
also known as alcoholic hyaline (Mallory was an alcoholic. Mallory bodies are also the alcohol induced amyloidosis in the hepatocytes).
- *iii. Lung:**
- *1. Hyaline membrane disease.** Endothelial damage of the alveoli and plasma leaks and precipitates forming a membranous amorphous tissue.
a. Adult respiratory distress syndrome.
b. Infant respiratory distress syndrome.
A/9. Exogenous and endogenous pigments
Exogenous pigment accumulations
1. Anthracosis
- Inhaled carbon (main component of dust and dirt), is phagocytosed and carried to lymph nodes in the lung. Carbon is a neutral chemical and there is no pathology.
2. Coal Miner’s Pneumoconiosis – Silicosis / Silicon Oxide:
- Inhaled Silicon. Macrophages take it up and it forms SiOH which kills the macrophage, and remains in the lung being toxic. This causes continual damage and many fibrotic lesions in the lung.
- Increases pulmonary resistance, Cor pulmonaris, RH failure.
- Inhaled Iron can also cause this.
ii. Tattoos. The only concern here is that the tattoo can cover the early stage of melanoma.
A/9. Exogenous and endogenous pigments
Endogenous pigments: Lipofuscin and Hemosiderin, Hemochromatosis.
Lipofuscin:
- Brown, perinuclear, granular deposits, resulting from remnants of lysosomal lipid-degradation. Contains mostly lipids, but also sugars and metals.
- Found in heart, liver, kidney, adrenals, and nerve cells.
- Associated with aging and accumulated free radial/oxidative injury -> lipid peroxidation.
- brown atrophy of the heart: Aging and chronic inflammation of cancer will cause a great deal of lipofuscin accumulation in the heart, making it small, shortened with wavy coronary arteries, sharp edges, apex pointing downward, and atrophic. This is a secondary consequence of some other disease.
Hemosiderin:
- An accumulation of Ferrin Mycelles inside of a macrophage.
- Many Apoferritin molecules surrounding a single Iron Atom.
- Accumulates after macrophages degrade Heme.
- Forms brown-yellow pigment
- Stains dark blue with Prussian Blue stain.
Local Hemosiderosis:
- Bruises - yellow/brown color
- Brown induration of the lung: occurs when increased pulmonary pressure and stasis causes small bleeding and leakage of RBCs into the alveoli. These are then phagocytosed by local macrophages, forming hemosiderin making the lung brown.
- Mitral Stenosis: causes a diatolic failure, insufficient blood can pass from the left atria into the LV. Retrograde pressure and pulmonary stasis.
- Left Sided Heart Failure: Backwards Left Heart failure, causing pulmonary stasis.
Systemic Hemosiderosis: All organs are affected due to Systemic Hemolysis.
- Intravascular hemolysis: due to some acquired hemolytic disorder, folate deficiency or infection with hemolytic microbe.
Hemochromatosis: Systemic iron accumulation due to Hepsidin deficiency. Hepsidin negatively regulates iron absorption in the GI, preventing excess.
- Uninhibited iron absorption goes on for 30 or 40 years in affected MEN, then symptoms appear. Women are generally protected until very late post-menopause, due to monthly iron loss.
- Accumulates throughout body, causing progressive multi-organ failure.
- Liver cirrhosis, failure, drastically increased risk of hepatocellular carcinoma. Pancreatitis, Intestinal fibrosis and malabsorption syndrome, hypertension and eventual heart failure.
A/9. Exogenous and endogenous pigments
Melanin, Alkapton
Melanin: Black/brown pigment made by melanocytes in the basal layer of skin epithelium, and then transfered to epithelial cells. Made from tyrosine by Tyrosinase.
Melanin is stained by:
- S100 or Melan-A immunohistochemistry
- Hydrogen peroxide bleaching.
Melanin accumulations or disorders:
- Ephilis: freckles
- Melasma: A really really big freckle, a large skin discoloration that usually appears during pregnancy due to the increased hormone expression and then disappears
- Vitiligo: the absense of melanocytes. Local vitiligo is caused by an autoimmune reaction against melanocytes. Most notable in black people. Albinism is systemic vitiligo, due to Tryosinase deficiency.
- Melanocyte Nevi. Accumulations of melanocytes in the epidermis and dermis, a mole. The deeper the nevus penetrates into the dermal tissue, the mor likely it is to progress to a malignant melanoma.
- Epidermal nevus
- Compound nevus - in both epidermis and dermis
- Dermal nevus - into the dermal layer.
- Malignant melanoma.
- Malignant Melanoma. Very dangerous, highly metastatic cancer originating from melanocytes.
Alkaptonuria
- Enzyme deficiency for the metabolism of Phenylalanine and Tyrosine. Alkapton accumlates and binds collagen. Black deposits form in the joints, and turns urine black.
- Causes osteoarthritis.
