1. Under some circumstances الظروف cells may accumulate abnormal amounts of various substances, which may be harmless or associated with varying degrees درجات of injury. The substance may be located in the cytoplasm, within organelles (typically lysosomes), or in the nucleus, It may be synthesized توليف by the affected cells may be produced elsewhere. ABNORMAL INTRACELLULAR ACCUMULATIONS

2. There are 3 main pathways of abnormal intracellular accumulations A normal substance is produced at a normal or an increased rate, but the metabolic rate is inadequate to remove it. Example of this type of process is fatty change in the liver. Abnormal metabolism, as in fatty change in the liver 1. ABNORMAL METABOLISM PATHWAYS OF ABNORMAL INTRACELLULAR ACCUMULATIONS

3. Mutations causing alterations in protein folding and transport, so that defective molecules accumulate intracellularly. 2. GENETIC OR ACQUIRED DEFECTS A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion. Example: Mutations that cause defective folding and transport may lead to accumulation of proteins (e.g., α1-antitrypsin deficiency).An inherited defect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases.

4. An abnormal exogenous 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. Example: Accumulations of carbon or silica particles are examples of this type of alteration. An inability to degrade phagocytized particles, as in carbon pigment accumulation. A deficiency of critical enzymes responsible for breaking down certain compounds, causing substrates to accumulate in lysosomes, as in lysosomal storage diseases. 3. DEFICIENCY OF CRITICAL ENZYMES

5. Fatty دهني change refers to any abnormal accumulation تراكم of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but it may also occur in heart, skeletal muscle, kidney, and other organs. Fatty Change (Steatosis) Steatosis تنكس دهني may be caused by toxins, protein malnutrition سوء التغذية, diabetes mellitus, obesity, and anoxia. Alcohol abuse تعاطي الكحول and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations.

6. Free fatty acids from adipose tissue or ingested food are normally transported into hepatocytes, where they are esterified تجمعت to triglycerides, converted تحويل into cholesterol or phospholipids, or oxidized to ketone bodies Egress (Exit) of the triglycerides from the hepatocytes requires يتطلب the formation of complexes with apoproteins to form lipoproteins, which are able to enter the circulation. Fatty Change (Steatosis)

7. Excess ( فائض ) accumulation ( تراكم ) of triglycerides may result from defects ( العيوب ) at any step from fatty acid entry to lipoprotein exit Hepatotoxins ذيفان الكبد (e.g., alcohol) alter mitochondrial and SER function and thus inhibit fatty acid oxidation; CCl4 and protein malnutrition سوء التغذية decrease the synthesis of apoproteins; Anoxia نقص الأكسجين inhibits كبح fatty acid oxidation; and Starvation الموت جوعا increases fatty acid mobilization from peripheral stores Fatty Change (Steatosis)

8. The significance ( أهمية ) of fatty change depends ( السبب ) on the cause and severity ( خطورة ) of the accumulation. When mild ( معتدل ) it may have no effect on cellular function. More severe fatty change may impair ( يضعف ) cellular function, but unless some vital intracellular process is irreversibly impaired (e.g., in CCl4 رابع كلوريد الكربون poisoning), fatty change is reversible. In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called Nonalcoholic steatohepatitis Fatty Change (Steatosis)

9. Normal liver Right: Fatty change in liver. Liver from an alcoholic shows large vacuoles (V) in the hepatocytes (H) with displacement of nucleus (N). Fatty Change

10. Cholesterol and cholesterol esters In atherosclerosis, cholesterol accumulates ( يتراكم ) in smooth muscle cells and macrophages (A type of white blood ) in the intima of arteries Other Lipids Accumulation

11. Atherosclerosis Normal Atherosclerosis

12. In hereditary hyperlipemia, cholesterol accumulates ( يتراكم ) in macrophages, usually under the skin, forming tumor-like structures known as xanthomas (accumulation of lipids in large foam cells within the skin)lipidsfoam cells Other Lipids Accumulation

13. Intracellular Accumulations of Proteins 1. Normal constituent – Proteins -Mostly intracellular( exception- Amyloid protein); Folding ( للطي ) is important for transport and function; Chaperones - help in the protein folding & transport ; Defects ( خلل ) in Protein folding - lead to neurodegenerative diseases (Alzheimer's; Huntington's, Parkinson's diseases) and Type II DM;

14. Intracellular Accumulations of Protiens Disorders due to defects in protein folding  1. α1-antitrypsin deficiency- Slow folding of protein (↑accumulation in ER -liver) ;  2. Cystic fibrosis - Cystic fibrosis (CF) is a genetic disorder that particularly affects the lungs and digestive systemlungs digestive system  3. Familial Hypercholesterolemia - is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL, "bad cholesterol"), in the blood and early cardiovascular disease.genetic disorderhigh cholesterol levelslow-density lipoproteincardiovascular disease

15. Intracellular Accumulation of Glycogen Glucose derived from glycogen breakdown is an important source of energy for the body. It provides energy for muscle contraction, and serves as the primary source of energy for the brain. Defective metabolism in Normal constituent of Glycogen leads to glycogen storage/accumulation Glycogen storage disease (GSD,) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types

16. Glycogen normally is present in the livers of people in the fed state, and is abundant if the patient with an IV line infusing glucose ("dextrose“) In hyperglycemia, it is common to see glycogen in hepatic nuclei pancreatic beta cells proximal tubular epithelial cells These accumulations are probably harmless. Glycogen also accumulates within the cells in genetic disorders, referred to as the glycogen storage diseases Intracellular Accumulation of Glycogen

18. Glycogen appears as clear vacuoles in the cytoplasm of cells 1. Von- Gierke's Disease (enlarged liver) 2. Pompe's Disease (The heart is unusually large; cyanosis and episodes of dyspnea) 3. McArdle’s Disease (excrete burgundy-colored urine after exercise) Diseases-

19. Extracellular Accumulations CalcificationHyaline changeAmyloid and amyloidosisGoutFibrinoid

20. Calcification “Deposition of calcium salts in vital or dying/dead tissues” Dystrophic and metastatic Dystrophic calcification is the deposition of calcium in dead tissues while metastatic calcification is deposition of calcium in normal tissues.

21. Dystrophic Calcification “Deposition of calcium salts in dead or dying tissues” Principally in areas of coagulative, liquefactive, caseous and/or fat necrosis that persist for rather long periods of time. Represents evidence of previous cell injury Normal levels of serum calcium (around 10 mg/100 ml) and in the absence of derangement in calcium metabolism

22. Can cause organ dysfunction (heart valves, Atherosclerosis) Dystrophic Calcification

23. Metastatic Calcification Deposition of calcium salts in vital tissues in association with a defect in calcium metabolism that is characterized by hypercalcemia Usual causes: (1) Hyperparathyroidism, either primary or secondary (2) Vitamin-D intoxication (تسمم) (3) Deficiency (ناقص) of magnesium (4) Hypercalcemia of malignancy (خبث)

24. Metastatic Calcification Principally in interstitial tissue of blood vessels, kidneys, lungs and gastric mucosa Fundamental abnormality: Pathologic entry of large amounts of ionic calcium into cell organelles, chiefly the mitochondria

25. Hyaline Change “A homogeneous, glassy, pink appearance in tissues or cells stained with H&E” Widely used descriptive histologic term rather than a specific marker for cell injury Connective tissue hyaline Epithelial hyaline Kerato-hyaline

26. Amyloid and Amyloidosis Deposition of amyloid protein fibrils in tissue Immune system dysfunction Abnormal processing of components of immunoglobulins, insulin, growth hormone and an acute-phase reactant of inflammation called the serum amyloid associated protein (SAA)

27. Detection of Amyloid Small amounts: Virtually undetectable Large amounts: Organ enlargement and a yellowish to greyish discoloration Rubbery consistency ( متسق) Painting the cut surface organs with iodine: A brownish to yellow-red color

28. Detection of Amyloid

29. Histologically Amyloid Homogeneous, eosinophilic material that stains reddish pink with the Congo red stain.

30. Gout “Deposition of uric acid and urate crystals in tissues subsequent to defective purine metabolism” The condition occurs primarily in humans and in birds. In birds, articular and visceral forms of gout are recognized

31. Articular Gout Uric acid and urate crystals are deposited in joint spaces Affected joints are enlarged, and white, chalky (طباشير) masses (“tophil”) may be observed when opened. The condition may result in severe pain

32. Articular Gout

33. Visceral Gout Uric and urate crystals are deposited over the serous surfaces within the body cavity (pleural, pericardium, etc.) Serous membranes line and enclose several body cavities, known as serous cavities Deposits are also found in the renal tubules Grossly, serous membranes are encrusted ( مرصع) by a thin grayish layer having a metallic sheen (لمعان)

34. Visceral Gout

35. Fibrinoid Fibrinoid: There is accumulation of proteinaceous material) in the tissue matrix resembles fibrin It is typically seen in a focus of tissue injury (especially in vessel walls or in connective tissue) It is most often located in the intima and media of vessel walls

36. Pigments Colored substances; can be normal constituent  melanin or abnormal  hemosiderin; can be exogenous  Carbon, Tattoo (وشم ) or endogenous  Bilirubin, Hemosiderin; Intracellular Accumulations

37. Carbon particles enter our bodies in smoke and soot Carbon settles in macrophages, where it remains indefinitely. Carbon in the lungs and nearby lymph nodes is called "anthracosis” Carbon: causes coal worker’s pneumoconiosis (سحار)(CWP) Heavy deposits could be associated with lung fibrosis and emphysema Tattoo  Pigmentation of the skin (dermal pigment laden macrophages without inflammatory response) Exogenous Pigments

38. Endogenous 1. Melanin (normal black pigment) 2. Hemosiderin : Hemoglobin - derived, golden yellow-to-brown pigment; Complications -Liver  Fibrosis, Cirrhosis; Heart  Failure (Cardiomyopathy), Pancreas- Diabetes mellitus 3. Bilirubin ; Major pigment of bile; Non iron hemoglobin derived pigment in patients with Jaundice

39. Iron is normally carried by transferrins In cells, it is stored in association with apoferritin, to form ferritin micelles ( المذيلات ) Ferritin is a constituent of most cell types When there is excess of iron, ferritin forms hemosiderin granules Hemosiderin granules are easily seen with the light microscope Lack of stainable iron of course indicates systemic iron deficiency Under normal conditions, small amounts of hemosiderin can be seen in the mononuclear phagocytes of –Bone marrow; Spleen; Liver Hemosiderin

40. Prussian Blue stain H&E

41. Bilirubin

42. Composed of polymers of lipids, phospholipids and protein Derived from lipid peroxidation of polyunsaturated lipids of subcellular membranes Lipofuscin is normally present in: –Interstitial cells of the testis, –Epithelial cells of the epididymis and seminal vesicles –Cardiac nuclei –Earwax pigment Lipofuscin becomes more abundant during –normal aging – severe malnutrition –cancer cachexia "Brown atrophy" is simply atrophy where the lipofuscin is visible grossly By age 90, the heart may contain 30% lipofuscin by weight. Lipofuscin (* "lipochrome"; "fuscus" is Latin for brown)