Accumulations: Injury by endogenous and exogenous substances

1. Accumulations:Injury by endogenous and exogenous substances Doç. Dr. A. Işın DOĞAN EKİCİ

2. Why are the substances accumulate? • When injury is sublethal or sustained, cells and tissues tend to accumulate substances in abnormal quantities. • One of the cellular manifestations of metabolic derangements in pathology is the accumulation of abnormal amounts of various substances.

3. The substances accumulated may be either endogenous or exogenous in origin. • (1) a normal cellular material accumulated in excess, such as water, lipid, protein, and carbohydrates; • (2) an abnormal substance, either exogenous, such as a mineral, or a product of abnormal metabolism; • (3) a pigment or an infectious product.

5. 1. A normalendogenous substance is produced at a normal or increased rate, but the rate of metabolism is inadequate to remove it. An example of this type of process is fatty change in the liver due to intracellular accumulation of triglycerides. • 2.A normal or abnormalendogenous substance accumulates because it cannot be metabolized or is deposited intracellularly in an amorphous or filamentous form. One important cause is a genetic enzymatic defect in a specific metabolic pathway, so that some particular metabolite cannot be used. The resulting diseases are referred to as storage disease. • 3.An abnormalexogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. Accumulations of carbon particles and such non-metabolizable chemicals as asbestos particles are examples of this type of alteration.

6. Classification of accumulated materials: A. Endogenous substances: • Lipids • Glycogen and carbohydrates • Protein and proteinaceous material • Products of abnormal metabolism • Endogenous pigments B. Exogenous substances: • Exogenous pigments • Iatrogenic accumulations C. Pathologic calcification

7. FATTY CHANGE (Fatty metamorphosis, fatty degeneration, steatosis) • Accumulation of excess neutral fat in vacuoles within non-adipocytes • one big fat vacuole,  "macrovesicular“ • many little fat vacuoles "microvesicular“

9. Fatty change of injured cellsoccurs classically in the liver and the heart. • There are at least six mechanisms by which the liver cell accumulates fat during disease, any or all of which may be operating in a given situation: • 1. Too much free fat coming to the liver • 2. Too much fatty acid synthesis by the liver • 3. Impaired fatty acid oxidation by the liver • 4. Excess esterification of fatty acid to triglycerides by the liver • 5. Too little apoprotein synthesis by the liver • 6. Failure of lipoprotein secretion by the liver.

10. Fatty liver develops during heavy Alcoholism, and all six mechanisms are known to contribute here. • Other causes of liver include, • Kwashiorkor • Reye's syndrome • poisoning by phosphorus, carbon tetrachloride, outdated tetracycline • pregnancy • galactosemia • ischemia • hepatitis C virus.

13. Fatty change in the heart is seen in two classic situations: 1) It most often reflects poor oxygenation (i.e., chronic severe anemia). 2) The heart damaged by diphtheria exotoxin is uniformly fatty (Diphtheria blocks carnitine metabolism).

14. Accumulation of fat in phagocytic cells is a common subject in pathology. • The fat is usually made up largely of cholesterol esters. • Atherosclerosis, the #1 disease in the world, • results when phagocytic cells in the intimal layers of large arteries become engorged with cholesterol and its esters. • The phagocytes themselves tend to die off and leave the cholesterol to crystallize. • One can recognize cholesterol (esters) in tissue sections by the "needle-shaped" clear spaces left behind when it is removed in processing.

18. Lipophages are scavenger macrophages. • This is common wherever lipid-rich tissues (belly fat, brain, others) have been injured, or where alveoli cannot drain. • The cytoplasm of these cells typically looks "foamy" (" cells") • “Masses" composed of foamy cells are calledxanthomas("xanthos" means yellow). • These often (but not always) suggest some problem with blood lipids.

20. Fatty ingrowth("stromal infiltration of fat", "lipomatosis") is totally different from fatty change. • It is metaplasia of an organ's capillary pericytes into mature adipocytes. • This is a common finding in lymph nodes, in the pancreas, and in the rightventricle and atria of the heart. • Usually it has no effect on organ function. • The most important appearance of fatty ingrowth in medical pathology is as a component of most muscular dystrophies.

22. COMPLEX LIPIDS & CARBOHYDRATES • These typically result from inborn errors of metabolism. • Typically the substance is stored in lysosomes. • Eventually enough accumulates to compromise organ function. • ...in what disease: • Gaucher's : glucocerebroside • Tay-Sachs‘ : ganglioside • Niemann-Pick's : sphingomyelin • Hunter's, Hurler's : mucopolysaccharide • Fabry's :ceramide trihexose.

23. Gaucher's disease is common, and produces huge,pink-staining, glucocerebroside-ladenmacrophagesin the bone marrow and elsewhere. • In gout, uric acid accumulates as nodules in the tissues. • These are called "tophi" (singular "tophus").

24. Many inherited disorders of metabolism can lead to accumulation of storage products in cells, as seen here with Gaucher's disease involving spleen. The large pale cells contain an accumulated storage product from lack of an enzyme.

25. GLYCOGEN ACCUMULATION • Glycogen ordinarily is present in the livers of people in the fed state, and is abundant if the patient has an i.v. line infusing glucose ("dextrose", "D5", etc.). • Inhyperglycemia, it is common to see glycogen in hepatic cells, pancreatic beta cells, and (if control is really poor) in the renal proximal tubular epithelial cells. • These accumulations are probably harmless. • The various glycogen storage diseases result frominborn errors of metabolism.

27. Glycogen Storage Diseases

28. Myxoid Change • Increased gelatinous & edematous ground substance; • Hypotyroidism (Generalized myxedema) • Hypertyroidism (localized myxedema; especially in pretibial region)

29. Myxomatous degeneration ("myxoid degeneration") • If there is associated damage to the connective tissue fibers,examples: • "cystic medial necrosis" of the aorta • Barlow's floppy mitral valve (affects about 5% of population) • Myxoid change of the intima • narrows the renal arteries in scleroderma and Balkan nephropathy, • eventually causing kidney failure. • Accumulation ofepithelial mucin, • large pools, • mucin producing cancers.

30. Signet ring cell carcinoma

31. Protein&Proteinaceous material Hyaline:The term “hyaline” is widely used as a descriptive histologic term rather than a specific marker for cell injury. It usually refers to an alteration within cells or in the extra-cellular space, which describesany substance that stains a homogeneous pink on routine H&E stains. It is composed of globular or filamentous proteins. Extracellular accumulation hyaline is more common than intra-cellular occurrence.

32. HYALINE Epithelial hyaline: • Eosinophilic droplets in the proximal tubular epithelial cells • when patient are losing lots of protein trough their glomeruli, you can detect hyaline casts in their urine! • Mallory's alcoholic hyaline • in liver cells • usually reflects weeks of heavy drinking (in "alcoholic hepatitis").

33. Alpha-1 protease inhibitor("antitrypsin") globules • look like multi-sized cherries within hepatocytes • Giant mitochondria • a feature of alcoholic liver disease . Mesenchymal hyaline: • Keloids / hypertrophic scars and other abnormal fibrous proliferations. • Excess basement membrane and other proteins • small arteries in high blood pressure and diabetes. • Russell bodies • round accumulations of monoclonal immunoglobulin that are inside the plasma cells.

34. Examples for intracellularprotein accumulations: • Protein droplet accumulation: Eosinophilic droplets in the proximal convoluted tubular epithelium of the kidney in severe proteinuria. • Mallory body (Mallory alcoholic hyaline): Intracellular amorphous eosinophilic protein aggregates in the hepatocytes (associated with alcoholic liver disease and with a variety of liver diseases, e.g., hepatocellular carcinoma, hepatolenticuler degeneration, cytoskeletal damaging chemicals). • Neurofibrillary tangles: Filamentous inclusions consisted of neurofilaments and protein, and classically found in the brain of Alzheimer patients. • Massive globular deposits: Huge amount of protein aggregates in the hepatocytes of a-1-antitrypsin deficiency patients. • Russell bodies: Round accumulations of monoclonal immunoglobulin inside the plasma cells

36. Examples for extracellularprotein accumulations: • Hyalinization of collagen: in keloids / hypertrophic scars and other abnormal fibrous proliferations. • Hyalinization of mesenchymal tumors: Leiomyoma uteri, Fibroma. • Hyalinization of blood vessels: Excess basement membrane and other proteins "hyalinize" the small arteries in high blood pressure and diabetes.

38. Hyaline-like material • It is not true hyaline, but it looks like hyaline! • Amyloidis another extracellular accumulation that always has a hyaline appearance. • Fibrincan be intensely eosinophilic and appear "hyaline". • Fibrinoid is a special "material" seen in the walls of blood vessels that are dead but still contain flowing blood. (This condition could be seen in malignant hypertension or vasculitis).

39. The centers of rheumatoid nodules may be filled with"fibrinoid", • and it is also characteristically seen in the myocardium in rheumatic fever. • Radiation injury to vessels appears as hyaline-fibrinoid in vessel walls. • Spironolactone bodies are an other fibrinoid material that are found in the mineralocorticoid-producing cells of the adrenal gland in people treated with this drug. • In chronic kidney disease, entire glomeruli may "hyalinize".

42. Products of Abnormal metabolism SODIUM URATE (Gout disease) • A cellular reaction to uric acid crystal deposition causes gout. Gout is the subject of the errors of the purine metabolism. • Primary gout: Primary gout is related to under-excretion or over-production of uric acid (inborn errors of purine metabolism), • Secondary gout: It is related to increased cell turnover or widespread cell destruction increase uric acid production;

43. -Myeloproliferative diseases or their treatment: lymphoma, leukemia • -Chemicals and drugs: alcohol ingestion, lead poisoning, thiazide diuretics, acetoacetic acid, • -Renal disorders: renal failure, renal tubular disorders, • -Skin diseases: hyperproliferative skin disorders (psoriasis), • -Dietary disorders: obesity, excess intake of anchovies, sardines, kidney, liver, and meat extracts, • -Hormonal disorders: hypoparathyroidism, • -Others: Lesch-Nyhan syndrome, Paget disease, hyperlipidemia, glycogen storage diseases (von Gierke).

44. Pathogenesis of Gout • Purine metabolism disorder = uric acid/urate to accumulate in blood and tissues • monosodium salts of uric acid precipitate, forming crystals • Any condition predisposing to acidosis also precipitates urate crystals. • Urate initially precipitates in the form of needlelike crystals. • The resulting crystals stimulate phagocytosis by neutrophils and initiation of the inflammatory cascade.

45. deposition of urate crystals=formation of characteristic tophi and (singular tophus); • firm, nodular, subcutaneous deposits of urate crystals surrounded by foreign-body giant cells and fibrosis. • The physical characteristics of urate crystals allow them to be recognized by polarizing microscopy.

46. Urate deposition tends to in relatively avascular tissues; • cartilage, • epiphyseal bone • periarticular tissues • Kidney involvement leads to severe renal damage

47. Complications of gout • -Repeated acute attacks, or uric acid buildup, destroy the cartilage and underlying bones, which may become fused. • -One fourth of gout patients develop uric acid kidney stones. • -Tophi in medulla and pyramids (chronic urate nephropathy) cause acute and chronic kidney problems. • -Patients with hyperuricemia tend to develop high blood pressure