1. Mini Review

2. Necrosis v. Apoptosis Decreased ATP production Increased mitochondrial permeability Leakage of Ca++ Ca-activated hydrolases degrade lipid, protein, RNA, DNA Denatured nucleic acid and protein may be large or small After initial “blebbing” of ER or plasma membranes, membranes burst ATP depletion initiates necrosis Inflammation elicited Bax/Bak channels open Increased mitochondrial permeability Leakage of CytC CytC/Apaf-1-activated caspases cascade to activate DNase Condensed nucleosomal DNA is cut into 200 bp fragments After initial “blebbing,” condensed apoptotic bodies form ATP required for apoptotic enzyme activity No inflammation

4. http://www.imgenex.com/emarketing/Autophagy_landingpage/Autophagy_pathway.jpg

5. Pigments and accumulations

6. Normal cellular constituent vs. abnormal substance Transient vs. permanent Harmless vs. toxic Cytoplasm vs. nucleus Cell produced vs. produced other place in body Intracellular Accumulations

8. Metabolic Functions of Liver

9. Lipids Triglycerides Cholesterol http://health-7.com/imgs/15/939.jpg http://academic.brooklyn.cuny.edu/biology/bio4fv/page/cholesterol.JPG

10. Fatty Change Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver in which deranged lipoprotein transport from injury (most often alcoholism) leads to accumulation of lipid in the cytoplasm of hepatocytes.

13. http://www.ijp-online.com/articles/2012/44/3/images/Indian%20J%20Pharmacol_2012_44_3_299_96297_f1.jpg

14. Cholesterol Athersclerosis Xanthomas Cholesterolosis Niemann-Pick disease, type C

15. http://www.lab.anhb.uwa.edu.au/mb140/c orepages/vascular/Images/aty10he.jpg

17. http://dermatology-s10.cdlib.org/123/case_presentations/xanthoma/1.jpg Xanthoma http://www.ajronline.org/content/188/5/1380/F19.large.jpg

19. Proteins Pink in H&E staining Proteins may accumulate as aggregates in vacuoles or in extracellular spaces Protein droplets may stain brightly in proximal tubules Secretory granules budded from ER may stain brightly as Russell bodies Misfolded proteins aggregate, such as  1 - antitrypsin in hepatocytes

20. Russell Body http://www.atlasbloodcells.es/imagenes_atl as/thumbm_11263233826_4.jpg http://imagebank.hematology.org/Content%5C10939%5C10939_ full.JPG

21. Hyaline Histologic appearance of pale, glassy,diffuse pink in H&E staining Eosine binds free amino groups –N-ends, Lys, Arg –May indicate protein breakdown or influx of plasma proteins Accumulation of staining, not itself a pigment http://library.med.utah.edu/WebPath/jpeg4/LIVER015.jpg

22. Amyloid Amyl = starch Misfolded proteins in B-pleated sheet formation that resist digestion and accumulate as inclusions Amyloid accumulations in glomeruli stain brown with iodine, similar to the iodine reaction with glycogen Amyloid and glycogen stain pink under white light with Congo red, but polarized light bounces off amyloid and looks green

23. http://www.pathology.vcu.edu/education/PathLab/pages/renalpath/rpsr/images /amyloid_sr/image03.jpg http://gsm.utmck.edu/research/HICP/images/apple_green.gif http://www.anaspec.com/images/b-amyloid%201-40.gif

24. Glycogen Glycogen is a readily available energy source stored in the cytoplasm of healthy cells. Excessive intracellular deposits of glycogen are seen in patients with an abnormality in either glucose or glycogen metabolism. Glycogen dissolves in aqueous fixatives; for its localization, tissues are best fixed in absolute alcohol.

25. http://geneticpeople.com/wp-content/uploads/2011/03/1048885-1116574-1840.jpg

26. Pigments Exogenous Endogenous http://www.mda-sy.com/pathology/JPEG3/SKIN063.JPG Tattoo

27. Exogenous Pigments Lipofuscin Melanin Hemosiderin

28. Lipofuscin Fuscus = brown Inclusions of lipid peroxides, phosphates, proteins Not harmful Accumulates in liver, heart from normal “wear and tear” Sign of free radical damage Pigment accumulates near nucleus Indicative of age, oxidative damage Does not stain blue with Prussian blue or Perl’s iron

29. Lipofuscin

30. Melanin Melas = black Synthesized from tyrosine by tyrosinase Reaction confined to melanosome compartment of melanocytes in dermis Whole melanosome is transferred to keratinocytes in epidermis Blocks UV radiation Benign accumulations (freckles, moles) are called nevi (pl., singular: nevus or naevus = from birth; birthmark) Alternative name, lentigo, like a lentil or pea

32. http://ahdc.vet.cornell.edu/clinpath/modules/chem/images/iron%20metabolism.jpg Hemochromatosis Bilirubin

33. http://ahdc.vet.cornell.edu/clinpath/modules/chem/images/iron%20metabolism.jpg

35. Hemoglobin

36. Oxyhemoglobin Oxygen-bound hemoglobin, Hb or HbO2, is red Mucous membranes and nail beds look pink http://medsci.indiana.edu/a215/virtualscope/images/blood4_b.jpg Deoxyhemoglobin Reduced hemoglobin, HHb is dark purple-red Mucous membranes and nail beds look blue (cyan) http://easypediatrics.com/wp- content/uploads/2012/08/cyanosis.jpg

37. Hemolysis and Hemoglobinuria

38. Colors of bruising Initial hemorrhage of RBCs into tissue is cleared by macrophages, which process Hb  Oxyhemoglobin and Deoxyhemoglobin  Deoxyhemoglobin and Biliverdin  Biliverdin and Bilirubin  Bilirubin and Hemosiderin  Hemosiderin When iron is completely cleared, tissue resumes normal color Accumulation of hemosiderin is hemosiderosis Hemochromatosis is severe, chronic accumulation

39. Colors of bruising

40. Bilirubin Metabolism Bilirubin (B) B-L B +UDP-GU B-GU B-(GU)2 Ligandin (L) Glucuronyl Transferase (GT) Glucuronyl Transferase (GT) Sinusoid Hepatocyte Cannaliculus UDP-Gu = Uridine diphosphoglucuronic acid 80+% excreted, 20-% reabsorbed

41. Hepatic bile ducts

42. Jaundice, icterus Bilirubin build-up in tissues  Prehepatic or hemolytic: due to excessive hemolysis build-up of unconjugated bilirubin  Hepatic or hepatocellular: due to failure of at least 80% of liver function both conjugated and unconjugated bilirubin accumulates  Posthepatic or obstructive: due to failure of bile to drain into GI Conjugated bilirubin accumulates

44. Excessive accumulation of iron Accumulation of hemosiderin is hemosiderosis Hemosiderin is normally found in marrow, spleen, liver Hemosiderosis in tissues is secondary to:  iron intake oveload (enteral or parenteral), long-term hemodialysis or transfusions, blood disorders Hemochromatosis is severe, chronic accumulation in liver, pancreas, myocardium  Primary, genetic hemochromatosis most frequent in men of northern European descent Hemochromatosis results in oxidative damage and inflammation

45. Hemosiderosis, hemochromatosis

46. Pathologic Calcification Dystrophic Calcification Metastatic Calcification

47. Dystrophic calcification Associated with necrosis, aging or damaged heart valves Precipitated calcium salts look white Basophilic when stained with H&E Blue granular crystals

48. Calcified bicuspid http://ars.els-cdn.com/content/image/1-s2.0- S105488071100007X-gr2.jpg

50. Psammoma body Histologically, with the usual hematoxylin and eosin stain, calcium salts have a basophilic, amorphous granular, sometimes clumped appearance. On occasion single necrotic cells may constitute seed crystals that become encrusted by the mineral deposits. The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies because of their resemblance to grains of sand.

51. Metastatic calcification Associated with imbalances in phosphorous equilibrium or hypercalcemia  Hyperparathyroidism stimulates resorption of Ca from bone  Accelerated bone turnover due to immobility, metastatic cancer, leukemia, Paget disease  Vitamin-D intoxication, sarcoidosis  Renal failure Phosphate retention Hyperparathyroidism Principally affects acid secreting cellls  Gastric mucosa, kidneys, lungs, systemic arteries, pulmonary veins

52. Sarcoidosis

53. Cellular Aging