1. Intracellular accumulations
Lecture 6
Intracellular accumulations
Aging/Senescence
Associate Professor
Dr. Alexey Podcheko
Spring 2015

2. Intended Learning Outcomes
To know 4 mechanisms of intracellular accumulations
To know mechanisms of intracellular lipid accumulation
To know examples of diseases associated with cholesterol accumulation in the tissues
To know examples of diseases associated with protein intra/extracellular accumulations
To know examples of diseases associated with excessive accumulation of Hemosiderin, Ca, Melanin
To know diseases associated with premature senescence

3. Intracellular Accumulations
As a result of metabolic derangements cells can accumulate abnormal amounts of various substances
There are two categories of substances:
Normal cellular constituents (lipids, proteins, carbohydrates)
Abnormal substances (deposits of salts, products of infectious agents, abnormal metabolites)

4. First main mechanisms of intracellular accumulation (out of 4)
1. Normal endogenous substance is produced at normal or increased rate, but the rate of metabolism is inadequate to remove it (hepatic steatosis, protein droplets in the plasma cells of patients with multiple myeloma)
plasma cells, including forms with multiple nuclei, prominent nucleoli, and cytoplasmic droplets containing Ig.

5. Second main mechanisms of intracellular accumulation
2. Product of the mutated gene accumulates in the cell due to defects in the protein folding/transport or cell unable degrade abnormal protein (mutated alpha1-antytrypsin in the liver cells, degenerative disorders of CNS)

6. Third main mechanisms of intracellular accumulation
3. A normal endogenous substance accumulates due to inherited defects in enzymes that are required for metabolism of the substance
Lysosomal storage diseases examples:
Tay-Sachs disease aka Hexosaminidase A deficiency – gangliosides accumulate in the nerve cells of the brain
Gaucher's disease aka   lysosomal gluco-cerebrosidase  deficiency - accumulation of glucocerebroside in white blood cells, macrophages, oligodendrocytes and Schwann cells
These enlarged, pale neurons are in a brain of the child with Tay-Sachs disease

7. Forth main mechanisms of intracellular accumulation
4. Exogenous abnormal substance accumulated because cell does not have enzymes to degrade substance or transport system to carry away the substance (carbon, silica, asbestos)
Here is anthracotic pigment in macrophages in a hilar lymph node. Anthracosis is nothing more than accumulation of carbon pigment from breathing dirty air. Smokers have the most pronounced anthracosis. The anthracotic pigment looks bad, but it causes no major organ dysfunction.

8. Intracellular Accumulation of Lipids
Types of Lipids accumulating in the cells:
Triglycerides (fatty change in liver cells)
Cholesterol/cholesterol esters (atherosclerosis, xanthomas)
Phospholipids (myelin figures), complex lipids (Lipid storage disorders – sphingolipid, glucocerebroside accumulation)
Moving along, let speak about sub cellular features of injury
One of the manifestations of metabolic derangements in cells is the intracellular accumulation of abnormal amounts of various substances.
Let start from the lipids: consumption of alcohol can induce fatty changes in the liver
Consumption of lipids in excess can lead to cholesterol deposition in blood vessels
And complex lipids are accumulating during genetic diseases such as Tay-Sachs disease( has been traced to a defect in the HEXA gene, the gene that encodes an enzyme called hexosaminidase A.Enzymes are proteins that break down substances in the body. Hexosaminidase A breaks down a group of fatty acids called the gangliosides. In Tay-Sachs disease, however, the defective HEXA genes do not function correctly, leading to low levels of hexosaminidase A. Without proper amounts of this enzyme, gangliosides accumulate in the brain and destroy nerve cells.)
Niemann–Pick disease
a missense mutation causes complete deficiency of sphingomyelinase. Sphingomyelin is a component of cell membrane including the organellar membrane and so the enzyme deficiency blocks degradation of lipid, resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte lineage. Affected cells become enlarged, sometimes up to 90 micrometres in diameter, secondary to the distention of lysosomes with sphingomyelin and cholesterol. Histology demonstrates lipid laden macrophages in the marrow, as well as "sea-blue histiocytes" on pathology. Numerous small vacuoles of relatively uniform size are created, imparting a foamy appearance to the cytoplasm.

9. Steatosis (Fatty change)
Steatosis – abnormal accumulation of triglycerides within parenchymal cells
Target organs: liver, heart muscle, kidney
Causes: toxins, alcohol, lack of proteins, Diabetes, hypoxia
Name the three most common causes of fatty liver: Ans: diabetes, obesity, alcoholism (toxic)
diabetes, obesity, alcoholism (toxic) are the most common causes of fatty liver

10. Normal metabolism of triglycerides in hepatocytes
Step#1: Free fatty acids (FFA) transported into hepatocyte by fatty acids binding proteins or FFA synthesize from acetate in the hepatocytes
Step#2: Esterification into triglycerides or conversion into cholesterol/phospholipids or oxidization into ketone bodies.
Step#3: Triglycerides associate with apoproteins and form lipoproteins and released from the cells

11. Mechanisms of abnormal accumulation of triglycerides in the hepatocytes induced by alcohol
Shunting of normal substrates away from catabolism toward lipid biosynthesis due to excessive generation of NADH by alcohol dehydrogenase and acetaldehyde dehydrogenase
Impaired assembly and secretion of lipoproteins
Increased peripheral catabolism of fat- more fatty acids enter into hepatocytes
Acetaldehyde induces lipid peroxidation of lipoproteins – disruption of membranes and cytoskeleton
P450 activation produces excess of free radicals
Impairment of methionine metabolism leads to reduced level of glutathione – reduced detoxification activity of liver cells
Increase production of proinflammatory cytokines by hepatocytes and sinusoidal epithelial cells (TNF-a, IL-6, TGF-alpha and endothelins)

12. Hepatic Steatosis
fatty change of the liver. In most cells the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole

13. High fat diet induced hepatic steatosis
Oil red O staining

14. High fat diet induced intramyocardial lipid accumulation
Tigered effect of lipid accumulation
Oil red O staining

15. An autopsy of a 24-year-old medical student who died in the car accident revealed an enlarged (1800 g) liver with a yellow cut surface. The microscopic appearance of this liver is shown in the figure. Before death, the man's total serum cholesterol and triglyceride levels were normal, but he had a slightly decreased serum albumin concentration. Which of the following activities most likely
led to these findings?
(A) Injecting heroin
(B) Playing basketball
(C) Drinking beer
(D) Smoking cigarettes
(E) Ingesting aspirin

16. Intracellular accumulation of Cholesterol and Cholesterol Esters
Most of the cells do not deposit cholesterol but use it immediately
Pathologic cholesterol accumulations manifest by appearance of intracellular vacuoles
Diseases associated with cholesterol accumulation:
Atherosclerosis - cholesterol accumulation in the smooth muscle cells and macrophages
Morphological features:
Foam cells
Atheromas
Cholesterol Clefts- crystals of cholesterol
The cholesterol clefts of lipid, along with a few scattered foam cells and a couple of lymphocytes, are seen at high magnification in this atheromatous plaque.

17. Diseases associated with cholesterol accumulation
2. Xanthomas: Tumor like clusters of foamy cells in the subepithelial connective tissue of the skin and tendons
Morphological features: similar to atherosclerosis (foam cells+clefts)

18. Diseases associated with cholesterol accumulation
3. Cholesterolosis (strawberry gallbladder ): Focal accumulation of cholesterol-laiden macrophages in the lamina propria of the gallbladder

19. Diseases associated with cholesterol accumulation
4. Neimann-Pick Disease, Type C : Lysosomal storage autosomal recessive disease caused by mutation affecting an enzyme involved in cholesterol trafficking and accumulation of cholesterol in multiple organs
Features:
1. mutations in NPC1 and NPC2 genes (transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell)
2. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in 
lysosomes
Features:
mutations in NPC1 and NPC2 genes (transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell)
The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes

20. Intracellular accumulations of proteins
Usually appear as rounded eosinophilic droplets, vacuoles or aggregates
Sometimes deposited in extracellular spaces
Pathology associated with protein accumulation:
1. Reabsorbtion droplets in proximal renal tubules –Lipid Nephrosis( aka Minimal Change Disease)
Features:
Pink hyaline droplets within the cytoplasm of tubular cells
Minimal-Change Disease
This relatively benign disorder is the most frequent cause of nephrotic syndrome in children, but it is less common in adults. It is characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes) in glomeruli that appear virtually normal by light microscopy. The peak incidence is between 2 and 6 years of age. The disease sometimes follows a respiratory infection or routine prophylactic immunization. Its most characteristic feature is its usually dramatic response to corticosteroid therapy.[33]
Normal proximal tubules

21. Intracellular accumulations of proteins
Pathology associated with protein accumulation:
2. Russel Bodies – accumulation of immunoglobulins in plasma cells
Features:
ER is highly distended and looks like pink aggregate within the cell
Russel bodies (Myeloma)

22. Intracellular accumulations of proteins
Pathology associated with protein accumulation:
3. Alcoholic Hyaline – accumulation of keratin intermediate filaments in the hepatocytes during alcoholic hepatitis
Features:
Favorite USMLE picture of alcoholic hepatitis – fatty changes+ pink condensed ropy material inside of the cells
Mallory bodies: Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments such as cytokeratin 8 and 18, in complex with other proteins such as ubiquitin. Mallory bodies are visible as eosinophilic cytoplasmic clumps in hepatocytes. These inclusions are a characteristic but not specific feature of alcoholic liver disease, since they also present in NAFLD, PBC, Wilson disease, chronic cholestatic syndromes, and hepatocellular tumors.
Mallory bodies

23. Extracellular accumulations of proteins
Amyloid
Hyaline arteriolosclerosis
Hyaline membrane disease of the newborn
Congo red stain is diagnostic stain for amyloidosis
Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings. Because amyloid deposition appears insidiously and sometimes mysteriously, its clinical recognition ultimately depends on morphologic identification of this distinctive substance in appropriate biopsy specimens. With the light microscope and hematoxylin and eosin stains, amyloid appears as an amorphous, eosinophilic, hyaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells. To differentiate amyloid from other hyaline deposits (e.g., collagen, fibrin), a variety of histochemical techniques, described later, are used. Perhaps most widely used is the Congo red stain, which under ordinary light imparts a pink or red color to tissue deposits, but far more striking and specific is the green birefringence of the stained amyloid when observed by polarizing microscopy ( Fig ).

24. Amyloidosis group of diseases characterized by deposition of amyloid
Amyloid is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide variety of clinical settings.
Main Features:
No distinct chemical structure
Congo red stain provide apple-green birefringence in the polarized light due to beta-sheet conformation of fibrills proteins
More than 20 biochemically distinct forms, most frequently tested ALight (plasma cell tumors), serumAA (chronic inflammation), ABeta (Alzheimer )

25. Hyaline arteriolosclerosis
Hyaline is any deposition of protein in the extracellular space that gives a homogeneous, glassy pink appearance on H&E staining
Hyaline arteriolosclerosis is the deposition of proteins in the arterioles
Mechanism:
plasma protein leakage across the endothelium due to increased hydrostatic pressure and
increased production of cell matrix by smooth muscle cells in vessel wall
Dysfunction of endothelial cells induced by hyperglycemia

26. Note the eosinophilic thick hyaline membranes lining the dilated alveoli.
Hyaline arteriolosclerosis is a small vessel arteriosclerosis that is commonly found in diabetics and hypertensive patients.

27. Hyaline membrane disease of newborn
Alternating atelectasis and dilation of alveoli
Deficiency of pulmonary surfactant due to mutations or insufficient level of glucocorticoids
Hyaline composed of fibrin mixed with cell debris

28. Other Cellular Alterations During Injury
Exogenous pigments
Anthracotic pigmentation of lungs
Tattoos

29. Other Cellular Alterations During Injury
Pigments are colored substances which accumulate under special circumstances, can be endogenous and exogenous
Endogenous pigments
1. Lipofuscin
2. Melanin
3. Hemosiderin

30. LIPOFUCIN Wear and tear pigment
Product of lipid peroxidation and aging
Perinuclear yellow-brown pigment
Preferred locations: Liver and Heart
Pathology: Excessive accumulation of Lipofuscin in the heart is associated with atrophy of heart- brown atrophy
The yellow-brown granular pigment seen in the hepatocytes here is lipochrome (lipofuscin) which accumulates over time in cells (particularly liver and heart) as a result of "wear and tear" with aging. It is of no major consequence, but illustrates the end result of the process of autophagocytosis in which intracellular debris is sequestered and turned into these residual bodies of lipochrome.

31. Melanin Black-brown pigment Found in melanocytes and substantia nigra
This is the microscopic appearance of a malignant melanoma. Large polygonal cells (or spindle cells in some cases) have very pleomorphic nuclei which contain prominent nucleoli. The neoplasm is making brown melanin pigment. A Fontana-Masson stain for melanin may help to detect small amounts of cytoplasmic melanin.
malignant melanoma

32. Hemosiderin Golden-yellow-brown granules
Areas of hemorrhage or bruises
Systemic Iron overload (Hemosiderosis/Hemochromatosis)
Prussian Blue Stain to detect iron
Hemosiderosis – systemic overload of iron which leads to deposition of iron in various organs
Causes: 1. Increased dietary iron
2. Hemolytic anemias
3. Repeated blood transfusions

33. HEREDITARY HEMOCHROMATOSIS
Mutations of genes encoding HFE, transferrin receptor 2 (TfR2), or hepcidin
 I.    HEREDITARY HEMOCHROMATOSIS  Mutations of genes encoding HFE, transferrin receptor 2 (TfR2), or hepcidin  
The dark brown color of the liver, as well as the pancreas (bottom center) and lymph nodes (bottom right) on sectioning is due to extensive iron deposition in a middle-aged man with hereditary hemochromatosis (HHC).
HHC results from a mutation involving the hemochromatosis gene (HFE) that leads to increased iron absorption from the gut. The prevalence is between 1:200 and 1:500 persons in the U.S. About 1 in 10 persons of northern European ancestry carries the abnormal recessive HFE gene, and most of these are the C282Y mutation.

34. Prussian Blue Stain to detect iron
Prussian blue reaction is seen in this iron stain of the liver to demonstrate large amounts of hemosiderin that are present in hepatocytes and Kupffer cells.
Prussian blue reaction of the liver

35. Pathologic forms of Calcification
Dystrophic calcification: precipitation of Ca3(PO4)2 in dying or necrotic tissues (saponification)
Metastatic calcification: precipitation of Ca3(PO4)2 in normal tissues due to hypercalciemia

36. Dystrophic calcification examples
Fat Necrosis and saponification
Psammoma bodies –laminated calcification (papillary cancer of thyroid, ovaries serous cystadenocarcinoma , meningiomas)
Monckeberg’s medial calcific sclerosis
Atherosclerotic plaques
Oligodendrocytoma and craniopharyngioma associated with calcification of brain tissue

37. Psammoma bodies: Thyroid Papillary Carcinoma Psammomatous meningioma
Also may be found in:
Papillary renal cell carcinoma
Ovarian papillary serous cystadenocarcinoma
Endometrial adenocarcinomas
Peritoneal and Pleural Mesothelioma
Prolactinoma of the pituitary 

38. Metastatic calcification examples
Hyperparathyroidism (primary)
Parathyroid adenomas
Renal failure (due to accumulation of phosphates!)
Paraneoplastic syndrome
Vit D intoxication
Milk-alkali syndrome
Sarcoidosis
Paget Disease
Multiple Myeloma to the bone
Metastatic cancer to the bone
Which organs are calcified: lungs, intestine and blood vessels.
Causes:
1. Increased secretion of PTH
2. Destruction of bone tissue by tumors
3. Vit D overdose, increased sensitivity to Vit D
4. Renal failure with hyperPO4-emia

39. Metastatic Calcification (examples)
Here is so-called "metastatic calcification" in the lung of a patient with a very high serum calcium level (hypercalcemia).
Coronary artery with atherosclerosis (fibrous plaque). The atheromatous fibrous plaque is localized in the intima of the artery, beneath the endothelium, producing the thickening of the wall and, secondary, the narrowing of the lumen and the atrophy of the muscular layer by compression. The fibrous plaque contains collagen fibres(eosinophilic), precipitates of calcium (hematoxylinophilic) and rare lipid-laden cells. (H&E, ob. x4)
Lung
Coronary Artery

40. A 70-year-old man died suddenly
A 70-year-old man died suddenly. At autopsy, multiple tissue sites were sampled for microscopic analysis. Examination of the tissues showed noncrystalline amorphous deposits of calcium salts in gastric mucosa, renal interstitium, and
alveolar walls of lungs. Which of the following conditions would most likely explain these findings?
(A) Chronic hepatitis
(B) Disseminated tuberculosis
(C) Renal failure due to chronic glomerulonephritis
(D) Generalized atherosclerosis
(E) Normal aging process

41. Cellular Aging and Senescence
Result of progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage
Decreased cellular proliferation
Terminal growth arrest- senescence
Mechanisms of Senescence:
Incomplete replication of telomeres
Increased levels of cell cycle inhibitors (p16, p21)
Accumulation of genetic errors

42. Cellular Aging and Senescence

43. Cellular Aging and Senescence

44. Role of Telomeres in replicative senescence

45. SIRT1- Sirtuin1 – histone deacetylase
Consequences of caloric restriction on cell metabolism and survival pathways.
SIRT1- Sirtuin1 – histone deacetylase
Caloric restriction (CR) promotes cellular resistance to stress, inhibits apoptosis, promotes DNA repair and increases cellular production of antioxi-dants. CR lowers blood insulin-like growth factor-l (IGF-I) and insulin levels, increases Sirt1 leves and DNA repair

46. Diseases of Premature Aging
1. Hutchinson-Guilford progeria - the process of aging, including features such as male-pattern baldness, cataracts and coronary artery disease, life expectancy is less than 10 years
-Cause: mutation in the LMNA gene encoding nuclear protein lamin A ( abnormal protein accumulates in the nucleus and affect mitotic activity)

47. Diseases of Premature Aging
2. Werner syndrome (adult progeria) - early cataracts, hair loss, atrophy of the skin, osteoporosis, atherosclerosis, increased risk for the development of a variety cancers. Patients typically die in the fifth decade. from either cancer or cardiovascular disease. Life expectancy app. 50 years
Cause: loss of function of the Werner (WRN) gene, which codes for a protein with multiple DNA-dependent enzymatic activities, including ATPase, helicase, exonuclease and strand annealing

48. Diseases of Premature Aging
3. Cockayne syndrome - easily sunburns, premature aging, microcephaly, neurodevelopment delay, short stature (height <5th percentile), contractures, unsteady gait, spasticity, rounded back, deep set eyes, small slender straight nose, dental caries, retinopathy and/or cataracts, hearing loss, life expectancy app. 12 years
Cause: mutations in the genes that participate in transcription-coupled DNA repair, CSA and CSB, lead to cells accumulating DNA damage, causing defects in transcription and eventuating in cell death.
Age 12

49. Objectives Review: Name the three most common causes of fatty liver:
1. Diabetes
2. Obesity
3. Alcoholism

50. Objectives Review:
To know 2 morphological signs of alcoholic hepatitis
fatty changes
Alcoholic hyaline - pink condensed ropy material inside of the cells

51. Objectives Review:
Be able to name 2 diseases associated with hyaline changes
Hyaline arteriosclerosis (Essential Hypertension)
Hyaline membrane disease of the newborn- (Neonatal Respiratory Distress Syndrome )

52. Objectives Review:
To know main causes of anthracotic pigmentation of lungs
Smoking
Inhalation of carbon dust in big cities or occupational hazard

53. Objectives Review:
List at least one tissue where is possible to find deposition of Lipofuscin, Melanin and Hemosiderin
Lipofuscin – Liver, Heart
Melanin – Melanoma
Hemosiderin – Liver, Lymph nodes.

54. Objectives Review:
List 3 types of tumors morphologically associated with psammoma bodies
Papillary Thyroid Cancer
Papillary Ovarian Cancer
Meningioma
List at least one tissue where is possible to find deposition of lipofucin, melanine and hemosiderin
List 3 types of tumors morphologically associated with psammoma bodies
Name at least 2 disease associated with metastatic calcification

55. Objectives Review:
Name at least 2 diseases associated with metastatic calcification
1 hyperparathyroidism (parathyroid gland tumors, renal failure)
2 diffuse skeletal metastasis (multiple myeloma)
3 vitamin D intoxication
4 renal failure

56. Please, take your pen and answer on the following questions You have 80 seconds to answer each question

57. Q1: A 69-year-old woman has had transient ischemic attacks for the past 3 months. On physical examination, she has an audible bruit on auscultation of the neck. A right carotid endarterectomy is performed. The curetted atheromatous plaque has a grossly yellow-tan, firm appearance. Microscopically, which of the following materials can be found in abundance in the form of crystals that produce long, cleft-like spaces?
(A) Glycogen
(B) Lipofuscin
(C) Hemosiderin
(D) Immunoglobulin
(E) Cholesterol
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58. Q2. An experiment analyzes cells for enzyme activity associated with sustained cellular proliferation. Which of the following
cells is most likely to have the highest telomerase activity?
(A) Endothelial cells
(B) Germ cells
(C) Neurons
(D) Neutrophils
(E) Erythrocytes
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59. Q3: A 22-year-old woman has a congenital anemia that has required multiple transfusions of RBCs for many years. On physical examination, she now has no significant findings; however, liver function tests show reduced serum albumin and high level of iron. Which of the following findings would most likely appear in a liver biopsy specimen?
(A) Steatosis in hepatocytes
(B) Bilirubin in canaliculi
(C) Glycogen in hepatocytes
(D) Amyloid in portal triads
(E) Hemosiderin in hepatocytes
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