| What are intracellular accumulations? | Cells may accumulate substances, may be harmless or cause cell injury, due to an abnormality in cell metabolism.
May be endogenous or exogenous substances. |
| What are the three main pathways of intracellular accumulations? | Inadequate removal and degradation of an endogenous substance (hepatic steatosis, cholestasis)
Excessive production of endogenous product (hemosiderosis, a1-antitrypsin deficiency, lysosomal disease glycogenosis...)
Abnormal exogenous substance accumulate (carbon, silica) |
| What is steatosis (fatty changes)? | Accumulation of TGs in parenchymal cells, most often in liver but may occur in heart, muscle, kidney or other organs
Causes: toxins, protein malnutrition, DM, Obesity (most common cause in industrial countries, hypoxia, infection. |
| How is the gross appearance of steatotic liver? | Size increase, soft consistency, yellow color, leaves a mark of fatty deposits on the blade |
| What are the microscopic appearances of liver steatosis? | Cytoplasm of hepatocytes have optically empty vacuoles (with paraffin embedding)
Steatosis appears in two forms (macrovauolar - push nucleus to the periphery, microvacuolar - central nucleus)
It is a reversible lesion resolved by cessation of agression |
| How do cells get cholesterol intracellular accumulations? | Usually cholesterol is controlled by membrane generation, but cells may get overloaded with lipids (cholesterol and TGs) by increased intake or decreased catabolism
Atherosclerosis is most important one |
| How to proteins accumulate intracellular? | Less common than fat accumulation, in kidney nephrotic syndrome causes heavy protein leakage of glomerular filter thus increased reabsorption (of albumin) giving pink hyaline cytoplasmic droplets in cells of proximal tubule
If it persists, proteinuria abates (decreases)
Another example is Igs accumulate in RER of plasma cells forming eosinophilic Russel bodies |
| How do glycogen accumulate intracellular? | Associated with abnormal glucose/ glycogen metabolism.
Most typical is poorly controlled DM with glycogen accumulation in renal tubule epithelium, cardiac myocytes, beta cells of langerhans
Glycogen could also accumulate in cells with genetic disorders called glycogenoses |
| How is intracellular pigment accumulation? | Exogenous (carbon) or endogenous (lipofuscin, melanin, Hb derivatives) accumulate.
Most commonly carbon going to tracheobronchial lymph nodes blackening the nodes and the pulmonary parenchyma (anthracosis) |
| Talk about lipofuscin pigment intracellular accumulation. | Brown-yellowish pigment accumulates with cell aging, complex of lipid and protein accumulate in a variety of tissues with aging or atrophy
not injurious but a marker of past free radical injury
Could cause brown atrophy |
| Talk about melanin pigment intracellular accumulation. | Could go to basal keratinocytes of skin or dermal macrophages causing black color to screen against UV) |
| How is cholestasis intracellular accumulation? | Visible accumulation of bile in liver tissue, turns liver green, accumulation in interhepatocyte canaliculi or interlobular bile ducts and sometimes seen in heptocytes
Caused by bile duct obstacles, toxic liver injury, viral liver injury |
| How is hemosiderin intracellular accumulation? | Hb derived pigment, golden yellow - brown, in tissues with excess iron (ferritin micelles...)
identified by Prussian blue histochemical rxn (Perls)
usually pathological, but small amounts in bone, spleen, liver may be normal.
Excessive accumulation - Hemosiderosis- is seen in hemochromatosis
rarely could be exogenous |
| What is localized hemosiderosis? | Related to gross bleeding , lysed RBCs, lysosomes of macrophages transform Hb to hemosiderin explaining variation in color of traumatized areas.
Like: cardiac lung siderosis, tatooed scars from hemorrhagic infarcts, evolution of thrombosis |
| What is generalized hemosiderosis? | Increase body iron in poly visceral overload, in macrophage and parenchymal cells.
Macroscopically visible by brown discoloration of viscera, hardness of viscera, screeching noise in cutting |
| What are the causes of generalized hemosiderosis? | Primitive or secondary
mechanisms involved : increased duodenal absorption of dietary iron, abnormal iron use, refractory anemia/ hemolysis, repeated blood transfusion |
| What is primitive generalized hemosiderosis/ hemochromatosis? | Inherited autosomal recessive transmission, iron accumulate in parenchyma causing destruction and fibrosis
Mostly affects liver, pancreas, heart and endocrine glands
From iron stock 30-50 g (10 times normal) |
| How is liver hemochromatosis? | Iron present in hepatocytes, kupffer cells, portal space macrophages.
Hypertrophic rust-colored micronodular cirrhosis.
Commonly causes hepatocellular carcinoma, with massive iron overload. |
| Talk about organs other than liver involved in hemochromatosis. | Myocardium (leads to subendocardial fibrosis can be cause of heart failure)
Endocrine Glands (Involved in hormonal insufficiency- ant pituitary decreasing GnRH..)
Skin and Mucosa (special hyperpigmentation, due to presence of hemosiderin in histiocytes of dermis and sweat glands/ epidermal melanosis following pituitary insufficiency) |
| What is secondary generalized hemosiderosis? | Pure hemosiderosis without sclerosis
Iron accumulates in phagocytes in liver/lymph nodes/skin, parenchyma are affected. |
| What is pathological calcification? | Increase in Ca, iron, Mg and other minerals all together.
Occur in 2 ways, dystrophic calcification, Metastatic calcification |
| What is dystrophic calcification? | Normal Ca deposition but deposit in injured tissues, usually in advanced atherosclerosis, but can be found incidentally with insignificant past cell injury, and may cause organ dysfunction (of damaged heart valves -->compromised valve motion, like aortic stenosis)
Starts from extracellular accumulation due to injury, usually calcium and phosphate |
| What is metastatic calcification? | Associated with hypercalcemia, by increased PTH, destruction of turnover mechanisms, tumors, immobilization, vitamin D intoxication and sarcoidosis, and renal failure in which phosphate retention leads to secondary hyperPTH |
| How is the morphology of pathological intracellular calcification? | Fine white granules, felt as gritty deposits
Dystrophic is common in caseous necrosis TB and could become radiopaque stone.
Basophilic deposits.
In lungs could cause respiratory deficits and massive deposits in kidney can lead to renal damage. |
| What are lysosomal overloaded diseases? | Genetic abnormality in a protein important for lysosomal function, causes accumulation of metabolite, may affect glycogenesis, sphingolipids (GM1 and GM2) and mucopolysaccharides
Dx by biopsy and stains |
| What is amyoidosis? | Intercellular deposit, extracellular fibrillar proteins accumulate and causes tissue damage.
Same morphology with all various protein types causing amyloidosis (30 different proteins)
Formed of interwind beta pleated sheath, 95% fibrils and 5% glycoproteins. |
| What are the three most common forms of amyloid? | AL (light amyloid) : Ig light chain as a whole or amino terminal or both.
AA (amyloid-associatated) : composed of protein derived from proteolysis of a larger precursor protein called serum amyloid-associated (SAA) synthesized in the liver.
beta amyloid (Abeta) derived from proteolysis of much larger glycoprotein called amyloid precursor protein |
| What are the classifications of amyloidosis? | Amyloidosis results from abnormal folding of proteins causing beta pleated sheath and with the inability to get degraded causes their accumulation extracellularily.
Primary amyloidosis, Reactive systemic amyloidosis and other forms of amyloidosis are present |
| What is primary amyloidosis of plasma cell proliferation? | AL type, systemic distribution, most common form of amyloidosis.
clonal proliferation of plasma cells forming Igs
Occurs with pt of multiple myeloma (15%) tumor, but most are not associated with the tumor. |
| What is reactive systemic amyloidosis? | AA type, systemic distribution, previously called secondary amyloidosis (secondary to inflammation)
Causes: TB, bronchiectasis and chronic osteomyelitis and Abx treatment, RA, Ankylosing spondylitis, IBD (Crohn and ulcerative colitis) |
| What are other forms of amyloidosis? | Heredofamilial (familial med fever)
Hemodialysis associated (deposits form beta2-microglobulin)
Localized amyloidosis (nodular deposits in lung, larynx, bladder, tongue, eye...)
Endocrine amyloid (medullary carcinoma thyroid, islet tumors of pancreas, pheochromocytoma...)
Aging amyloid (systemic in elderly) |
| How does amyloidosis appear macroscopically? | accumulates in large amounts, organ enlarged, gray tissue, waxy firm consistency |
| How is the histology of amyloidosis? | always extracellular, between cells close to basement membrane.
Plasma cell proliferation is associated with perivascular and vascular deposits
H&E stain amorphous eosinophilic extracellular substance.
Congo red stain pink but green perifringence of stained amyloid.
subtyping by mass spectroscopy. |
| How does amyloidosis affect the heart? | Involved in senile systemic amyloidosis, enlarged and firm with no change on gross inspection.
Histologically starts as focal subendocardial accumulations and within myocardium between myofibrils, causing pressure atrophy of heart muscle.
In addition to EKG changes due to subendocardial deposits |
| How does amyloidosis affect the liver? | Inapparent grossly but may cause hepatomegaly.
Starts at space of disse then goes to hepatic parenchyma and sinusoids.
Could cause with time deformity, pressure atrophy, hepatocyte disappearance -->total replacement of a large part of the liver.
Vascular involvement and deposits in kupffer cells, usually preseved liver function |
| How does amyloidosis affect the kidneys? | Most common and serious complication of amyloidosis, normal usually but if severe they may shrink because of ischemia by vascular narrowing due to the deposits within arterial walls.
May deposit in glomeruli as subtle thickening of mesangium, causing distortion of glomerular vascular tuft and capillary narrrowing |
| How does amyloidosis affect the spleen? | May be inapparent or splenomegaly.
2 distinct patterns of accumulation: Splenic follicules (tapoica-like granules, sage spleen), and Splenic sinuses walls and connective tissue framework in red pulp
Could create lardaceous spleen if connected amyloidosis |
| What are effects of amyloidosis on various organs? | Tongue: Nodules causing macroglossia tumor forming.
Respiratory tract: Larynx down to smallest bronchioles
Brain: Alzheimer plaques , or autonomic NS for familial amyloidotic neuropathies. |
| What are lesions related to aging? | Related genes of aging are acrogeria and progeria, cellular aging causes organ aging.
Some organ systems get damaged due to aging by 2 mechanisms: determined genetic clock (Incomplete replication causing telomere shortening and clock gene involvement)
And external factors (repari stopped) |
| How does cell function get affected by aging? | Reduced cell function, irreversible oxidative damage accumulation (lipofuscin for example), reduced chromosome repair, decreased ability to multiply, acceleration of apoptosis... |
| How is the morphological aspect of organ aging? (lung, vessesls and heart) | Not all organs age at the same rate.
Production of elastase increasing with age, Organs rich in elastic fibers age the fastest.
The aging of many organs is characterized by atrophy.
Lung : destruction of alveolar elastic fibers.
Vessels : calcification and stiffening of the wall of elastic arteries, intimal thickning of aortic wall
Heart : decrease of myocardial cell, accumulation of lipofuchsine, and calcifications of aortic and mitral valves |
| How is morphological aspect of aging on osteoarticular, kidney and GI? | Osteoarticular system : almost inevitable beyond the age of 60;
bone mass is reduced (osteoporosis);
muscles atrophy and are partially replaced by fatty tissue;
joint cartilages deteriorate and are no longer repaired by chondrocytes, tendons
Ligaments stiffen under the effect of glycosylation.
Kidney : Glomerular anf interstitial fibrosis.
GI tract:
Progressive atrophy of mucosa
Decrease of the regeneration potential of epithelial cells
Decreased activity of glandular cells. |
| How does skin appear with aging? | the distribution of lesions is heterogeneous according to the different parts of the body;
thinning of the skin, especially by thinning of the dermis, the elastic fibers of which become scarce, and the collagen of which becomes rare and stiffens under the effect of glycosylation.
The basal layer flattens out by reduction of the elastic fibers of the papillary dermis.
Wrinkles appear with a decrease in the subcutaneous adipose tissue.
The skin becomes dry, and the secretions of the sebaceous and sweat glands decrease.
The hair follicles are less numerous and the melanocytes become scarce leading to the bleaching of hair and body hair.
In addition, there are lesions related to exposure to solar radiation: elastosis, actinic keratosis, Dubreuilh's melanosis. |
| How is CNS aging? | During normal aging the weight of the brain decreases slightly
The meninges thicken and are fibrous
The cortex atrophies and the ventricles are dilated.
The number of neurons in the cortex and the hippocampus decreases
Senile plaques can be seen in the hippocampus as well as neurofibrillary degeneration.
Changes in enzymes and neurotransmitters can have a physiological impact on functional networks
Alzheimer's disease is not linked to aging, but its frequency increases with age |
