A/6-11 CELL INJURY, ACCUMULATIONS, PIGMENTS, CALCIFICATION (Leiel) Flashcards

1
Q

What separates reversible cell injury from irreversible cell injury?

A

“point of no return” = irreversible cell injury.

The points of no return:

  1. Ca++ influx
  2. Profound disturbance in membrane function
  3. Inability to reverse mitochondrial dysfunction
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2
Q

The 2 main morphologic changes in the reversible cell injury include:

A
  1. cellular swelling / hydronic degeneration
  2. Fatty changes (steatosis)
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3
Q

What are the 5 reasons for fat accumulation?

A
  1. Starvation
  2. Hypoxia
  3. Toxins, alcohol
  4. Protein malnutrition
  5. Obesity
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4
Q

The microscopical changes of reversible cell injury include:

A
  1. Plasma membrane alteration such as blebbing and loosening of intercellular attachments
  2. Mitochondrial swelling, appearance of phospholipid-rich amorphous densities
  3. Dilation of ER with ditachment of ribosomes and dissociation of polysomes
  4. Nuclear alterations with clumping of chromatin
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5
Q

Examples of fat accumulation diseases

A
  1. Hepatic steatosis (fatty liver)
  2. Nutmeg liver (hepar muscolutum adiposum)
  3. Tiger heart (degeneration adipose insularis myocardii)
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6
Q

What is Atherosclerosis?

A

a chronic inflammatory response of the vascular wall to a variety of insults including endothelial injury, accumulation of lipids in smooth muscle cells and macrophages and thrombosis

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7
Q

What makes atherosclesrosis?

A

It is an intimal plaque

(lipid/necrotic core, fibrous cap, shoulder) So

Plaque = lipid core + fibrous cap + 2 shoulder

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8
Q

What are the 3 groups that the risk factors of atherosclerosis are divided into?

A
  1. Major constitutional risk factors
    • Age, Gender, Genetics
  2. Major modifiable factors
    • Hyperlipidemia/hypercholesterolemia (LDL, HDL, Lipoprotein A), Hypertension, Cigarette smoking, Diabetes mellitus
  3. Additional risk factors
    • Inflammation, Hyperhomocystinemia, Obesity, Lack of exercise, Stressful life, Competitive personality
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9
Q

What is the pathogenesis of atherosclerosis?

A

Chronic endothelial injury →

Accumulation of lipoproteins in the vessel wall →

Monocyte adhesion to the vessel wall →

Platelet adhesion and activation →

Production of growth factor ⇒

Lipid accumulation

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10
Q

What are the possible morphologies of atherosclerosis?

A
  1. Fatty streaks
  2. Primary plaques (lipid/necrotic core, fibrous cap, shoulder)
  3. Complicated plaque: (rupture, thrombi incorporation, hemorrhage, atheroembolism, aneurysm, calcification)
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11
Q

Prevention of atherosclerosis

A
  • Primary prevention:
    • prevent the disease or lead to its regression
    • stop smoking, control of hypertension, exercise, lowering LDL and increasing HDL
  • Secondary prevention:
    • prevent MI or stroke
    • Usage of statins, aspirin, b-blockers, surgical intervention like coronary bypass.
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12
Q

What is Amyloidosis?

A

A condition associated with a number of inherited and inflammatory disorders in which extracellular deposits of fibrillar proteins are responsible for the tissue damage and functional compromise.

The abnormal fibrils are the result of aggregation of misfolded proteins.

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13
Q

Protein accumulation might occur in the following cases:

A
  1. Excess of protein in presented to the cell.
  2. Increased protein synthesis
  3. Cell injury.
  4. Abnormal folding of proteins
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14
Q

Describe the pathogenesis of Amyloidosis

A

misfolded proteins → aggregate to form fibrillar protein → 4-6 fibrils crossed in β-pleated configuration ⇒ amyloid.

(System: there are precursor proteins for each of the 23 amyloid types. When those proteins are misfolded, they accumulate and lead to amyloidosis)

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15
Q

What is used to identify amyloid structure in a tissue (histology?*)?

A

Congo staining (red dye) binds to the fibrils and if we use a polarization light it gives a green color.

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16
Q

The most important amyloid types are:

A
  1. AL = amyloid light chain protein
    • ​​The precursor of it are complete immunoglobulin light chains
  2. AA = amyloid associated fibril
    • Its precursor is SAA (serum amyloid associated protein)
  3. Aβ amyloid
    • Its precursor is APP (amyloid precursore protein)
  4. Transthyretin
    • A serum protein that binds thyroxine and retinol.
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17
Q

Classification of amyloidosis

A
  1. Immune dyscrasia associated amyloidosis
    • ​​Systemic amyloidosis, AL type, primary.
  2. Reactive systemic amyloidosis
    • ​​Systemic amyloidosis, AA type, secondary
  3. Familial amyloidosis
    • ​​AA type
  4. Localized amyloidosis (or: plasma cytoma)
    • ​​Neoplastic disease in one organ only
  5. Endocrine amyloidosis
    • APUD-OMAS
  6. Amyloid of aging
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18
Q

General macroscopic morphology of amyloidosis

A
  • It may or may not be apparent in macroscopic examination.
  • Often small amounts are not recognized until the surface of the organ is cut and painted with iodine and sulfuric acid (brown staining).
  • When accumulated in larger amount: enlarged organ, graish color, waxy, firm.
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19
Q

General microscopic morphology of amyloidosis

A
  • the deposit is extralcellular and begins between the cells.
  • As it accumulates it presses the cells and leads eventually to pressure atrophy.
  • We use congo red dye which under light gives a red/pinkish color and under the polarized light show greenish color.
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20
Q

Organ morphology of amyloidosis*

A
  • Kidney: deposits are usually found in the glomeruli, tubular cells, interstiatial peritubular tissue.
  • Liver: Disses space and then progresses to the parenchyma and sinuses.
  • Spleen: nodular or trabecular
  • Heart: subendocardial elevations
  • The GI is frequently involved in the systemic cases, thus, biopsy of the gingiva, intestine and rectum is good for diagnosis.
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21
Q

Clinical correlation (symptoms and outcome)

A

Symptoms:

  • Difficult to recognize.
  • Non-specific complains: weakness, fatigue, weight loss, then by: kidney disease, heart abnormality, enlarged liver and spleen. Proteinuria and the resultant kidney failure
  • Conduction disturbances Make biopsy and congo red staining

Outcomes

  • Death 1-3 years after diagnosis because the amyloid cannot be removed.
  • The primary is the most frequent.
  • The occurance of the secondary depends on the treatment of the inflammation.
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22
Q

Give examples for Exogeneous pigments

A
  • Carbon
  • silicium
  • tattoo
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23
Q

Describe what happens to the lung in urban life.

A

Carbon is inhaled → phagocytosed by alveolar macrophages → transported through the lymphatics to a regional tracheobronchial lymph node ⇒ aggregation of it blackens the lymph node and the parenchyma ⇒ !!!anthracosis!!! <3 ™

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24
Q

Describe the pathogenesis of coal workers pneumoconiosis

A

Pneumoconiosis describes a non-neoplastic lung reaction to inhalation of mineral dusts.

Substances are inhales like SiOH which is dangerous.

Inhaled particles → impacted in the alveolar dust bifurcation → macrophages accumulate and phagocytose → reactive particles (like SiOH) kill the macrophages → leakage of lysosomal enzymes. through the macrophage system the active substances activate interleukins, TNF etc.

consequences: in the lung the macrophages produces necrosis → the necrosis is replaced by fibrosis → the alveoli and capillary are destroyed → the resistance of the lung increases → cor pulmonale chronicum: the work of the right heart side is increased (-> Heart failure**)

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25
Q

What are the three possibilities of lung findings in coal workers’ pneumoconiosis:

A
  • Asympthomatic anthracosis: the accumulation of the pigment without a cellular reaction
  • CWP (simple coal workers’ pneumoconiosis): accumulation of macrophages occur with little to no pulmonary dysfunction
  • CWP (complicated) or PMF (progressive massive fibrosis): fibrosis is extensive and lung function is compromised
26
Q

Morphology of coal workers’ pneumoconiosis

A
  • pulmonary anthracosis: inhaled carbon pigment is engulfed by alveolar and interstitial macrophages which accumulates in the lymphatic system including lymph node
  • CWP (simple): is characterized by coal macules and coal nodules; centrilobular emphysema might develop. upper lobe and upper part of the lower lobes.
  • PMF: coalescence of the coal nodules which seems as intensely blackened large scars (microscopically: dense collagen and a pigment).
27
Q

Clinical course of coal workers’ pneumoconiosis

A
  • CWP usually produces little decrement in lung function.
  • PWF developes it leads to an increased pulmonary dysfunction, pulmonary hypertension and cor pulmonale.
28
Q

Endogeneous pigments:

A
  1. Lipofuscin
  2. Melanin
  3. Hemosiderin
29
Q

Local Hemosiderosis

A

any transient bleeding.

Edema and hemorrhage → blue and brown as the Hg is broken down producing hemosiderin → hemosiderin is taken up by macrophages and the tissue’s color is restored.

“induratio bronea nulmonis” or “heart failure cells” are signs of:

  1. Mitral stenosis
  2. Left sided heart failure
30
Q

Systemic Hemosiderosis

A

The hemosiderin is everywhere. most cases caused by general hemolysis.

Systemic we can observe:

  • Autoimmune hemolytic anemia there is a breakdown of RBCs
  • Toxic effect

All the organs become brown.

Repeated blood transfusions.

31
Q

If the iron gets out (becomes free) its toxic effect leads to cell necrosis and fibrosis, How is it prevented?

A

In all cases of hemosiderosis the iron is packed with apoferritin and stored in macrophages.

32
Q

What is Hemocromatosis?

A

A genetic disorder which is characterized by accumulation of iron within the body.

33
Q

What is the underlying cause of Hemocromatosis

A

In the most common cases, it is an autosomal recessive disease which involves a mutation in the HFE gene, located on chromosome 6.

The coded protein is called hepcidin, a hormone produced in the liver and is responsible for regulation of iron levels by:

  • inhibit its absorption
  • decreases its deliberation from the intestine and macrophages into the plasma.
34
Q

Pathogenesis of Hemocromatosis

A

When HFE gene is mutated → hepcidin deacreases → iron increases

Increased level of iron leads to:

  • lipid peroxidation
  • stimulation of collagen formation
  • DNA damage

Iron overload → hemosiderin → taken up by macrophages until saturation → upon saturation: released

35
Q

Morphology of Hemocromatosis

A
  1. Deposition of hemosiderin in the liver, pancreas, heart, pituitary, adrenal, thyroid and PT, joints, skin
  2. Cirrhosis of the liver
  3. Pancreatic fibrosis
36
Q

Clinical features of Hemocromatosis

A

Usually appear in the 5th - 6th decade of life

  1. Cirrhosis → hepatomegaly. (increased risk for hepatocellular carcinoma due to DNA damage.)
  2. abdominal pain
  3. Skin pigmentation
  4. Diabetis mellitus: due to destruction of pancreatic islets
  5. Cardiac dysfunction
  6. Atypical arthritis
37
Q

What is melanin? (what is it’s precursor?)

A

Brown-black pigment produced from thyrosine in melanocytes.

Thyrosine -thyrosinase enzyme-> dehydroxphenil alanine ⇒ melanin

The melanocytes are located in the basal layers of the epidermis.

38
Q

What are the melanin alterations?

A
  1. Ephelis
  2. Melasma
  3. Vitiligo: no melanin
    • hereditary (albinism)
    • autoimmine disease
  4. Melanocyte nevus:
39
Q

What is the pathogenesis of the common nevus?

A

the melanocytes are normally found in the basal layer of the epidermis.

From the dermoepithelial junction, the cells migrate into the underlying dermis and also upward to superficial layers.

  • Dermis: the cells are smaller and more mature, producing little or no pigment, grow in cords
  • Upward: cells are bigger and less mature, produce melanin and grow in nests
40
Q

Morphology and Clinical features of nevus

A
  • the nevi are round cells that initially grow along the junction and are called junctional nevi.
  • They then grow to the underlying dermis (compound nevi) and upward to form dermal nevi. The later 2 are more elevated than the 1st one.

Clinical feature

  • The nevi are brown, uniformly pigmented, small solid elevations of the skin with well defined borders.
  • transformation of the nevus leads to melanoma
41
Q

What is Pathologic calcification and its forms?

A

Abnormal deposition of calcium salts together with small amounts of iron, magnesium and other minerals.

Occurs in 2 forms:

  1. Dystrophic (normocalcemic) calcification
  2. Metastatic (hypercalcemic) calcification
42
Q

Dystrophic (normocalcemic) pathogenesis

A

Can be either an intracellular or an extracellular process, in both, the ultimate result is the formation of Ca-phosphate.

Extracellular: there is a membrane bound vesicle. Ca is located inside this vesicle. An enzyme called “membrane-bound phosphatase” generates phosphate ions. The phosphate binds the Ca and the final result is the formation of crystals. More and more of this crystals are generated, a process called propagation

Intracellular: the process is initiated in the mitochondria of dead or dying cells that have lost their ability to regulate intracellular calcium

43
Q

Dystrophic (normocalcemic) morphology

A
  • Grossly seen as white granules or clumps, often felt as gritty deposits. Sometimes a tuberculous lymph node is converted to radio-opaque stone.
  • Histologically: the calcification appears as an intracellular of extracellular basophilic deposits. In time, heterotopic bone may be formed in the site of calcification.
44
Q

Dystrophic (normocalcemic) Diseases

A
  1. Calcifing aortic stenosis
  2. Artificial valves
  3. Atherosclerosis
  4. Neoplasma
  5. Infectious disease
45
Q

Metastatic (hypercalcemic) calcification

A

The serum calcium levels is increased.

Due to the following circumstances:

  • Neoplastic disease that destroys the bone.
  • Increased secretion of parathyroid hormone.
  • Vitamin D related disorders
  • Renal failure
46
Q

Morphology and clinical features of metastatic (hypercalcemic) calcification

A

Can occur everywhere but principally effects the lung, vasculature, kidneys and gastric mucosa.

The calcium deposits resembles those described in the dystrophic type.

Extensive calcification in the lung and in the kidney will cause respiratory deficits and renal damage, respectively.

47
Q

Gallstone (cholelithiasis) Risk factors

A
  • Age
  • Gender
  • Ethnic and geographic
  • Heredity
  • Decreased gallbladder motility
48
Q

There are 2 main types of gallstone:

A
  • Cholesterol stones - Contain crystalline cholesterol monohydrate.
  • Pigment stones
49
Q

Cholesterol stones Pathogenesis

A

Excess cholesterol is eliminated from the body through the bile, either as free cholesterol or as bile salts.

When its concentration exceeds the solubilizing capacity of the bile it remains dispersed and nucleates into solid monohydrate crystals.

50
Q

What are the 4 conditions occurring simultaneously during the formation of cholesterol stones?

A
  1. Supersaturation of the bile with cholesterol
  2. Nucleation into monohydrate crystals
  3. Hypomobility of the gallbladder (stasis) which promotes nucleation
  4. Mucus hypersecretion to trap the crystals, enhancing their aggregation into stones
51
Q

Risk factors of cholesterol stones

A
  • Demography
  • Female sex hormones
  • Obesity, rapid weight reduction, treatment with hypocholesteremic agent ( increased biliary cholesterol secretion)
  • Hyperlipidemia syndroms
52
Q

Morphology of cholesterol stones

A

Arise exclusively in the gallbladder and consist of 50-100% cholesterol.

2 types:

  • pure cholesterol stones: pale yellow color
  • cholesterol stones containing calcium carbonate, phosphates, bilirubin: gray-white-black discoloration. Ovoid and firm. 80% are radiolucent, rest are radiopague due to the presence of sufficient amount of calcium carbonate.
53
Q

Pathogenesis of pigment stones

A

The presence of unconjugated bilirubin increases the likelihood for its formation. The precipitates are primarily insoluble calcium bilirubinate salts.

54
Q

Risk factors of pigment stones

A
  • Demography
  • Chronic hemolytic syndromes
  • Biliary infection
  • GI disorders
55
Q

Morphology of pigment stones

A

May arise anywhere in the biliary tree. Are classified according to color:

56
Q

Clinical featurs of pigment stones

A

70-80% of the patients remain asymptomatic throughout life. The rest become symptomatic with a rate that increases with time.

Symptomes:

  • excruciating pain
  • inflammation of the gallbladder
  • empyema, perforation, fistulae or inflammation of the biliary tree
  • obstructive cholestasis
  • pancreatities
  • occasionally, large stones might reach the intestine and make an obstruction (gallstone ileus)
57
Q

Urolithiasis definition

A

calculus formation at any level in the urinary collecting system

58
Q

Types of renal stones

A
  • 80%: stones composed of calcium oxalate and/or calcium oxalate mixed with calcium phosphate.
  • 10%: composed of magnesium, ammonium, phosphate (struvite)
  • 6-7%: uric acid
  • 1-2%: cystine

All of the types contain in advance an organic matrix of mucoprotein.

59
Q

Causes of renal stones

A

The most important cause is increased urine concentration of the stone’s constituent, in an amount that exceeds their solubility in the urine.

Also, the lack of substances that inhibit mineral precipitation may leads to the formation of kidney stones.

60
Q

צריך חפירה על כל אבן?

A
  • Calcium stones: 50% of the stones in this group are caused by hypercalcemia, which is due to excess absorption from the gut or due to a certain renal defect that leads to calcium reabsorption. In 10% of the cases there is hypercalcemia that leads to hypercalciuria 20% of the stones are the result of hyperuricosuria (excessive excresion of uric acid in the urine that provides a nidus for calcium deposition). Also, a high urine pH favors the formation of this stone type.
  • Struvite: due to renal infection. Persons with a persistently alkaline urine due to UTIs
  • Uric acid: 50% of this types are idiopathic. The rest might be the result of Gout or leukemias that lead to high uric acid levels in the urine (hyoeruricemia). Low pH favors the formation of this stone type
  • Cystine: associated with a genetically determined defect in the renal transport of certain amino acids. Is also favored by low pH.
61
Q

Morphology of renal stones

A
  • Unilateral in 80% of the cases.
  • Commonly found in the renal pelvis, calyces and bladder.
  • Small and either smooth or jagged.
  • Staghorn calculi: branching structures that are occasionally formed due to the accretion of salts
62
Q

Clinical features of renal stones

A
  • The presence of large stones (usually in the pelvis) may be asymptomatic and harmless.
  • The smaller stones may pass to the urether, leading to an intense pain (called urethral or renal colic) that radiates to the groin. Gross hematuria is observed.
  • If a stone obstructs the urine flow it might lead to an ulceration and bleeding.
  • The patient is exposed to bacterial infection.
  • A st​one can be diagnosed radiologically.