Cellular Accumulations

Lecture 5

What are intracellular accumulations?

accumulations of a substance within the cell

What are extracellular accumulations?

occur outside the cell in the interstitium

What are causes of cellular accumulations?

• metabolic abnormalities that result in excessive production (fatty change)

• genetic abnormalities whcih lead to excessive storage or inability to break down or release a substance (lysosomal storage disease)

• indigestible substance where the cell lacks machinery to break down matieral or transport out of cell (carbon)

What is steatosis?

an accumulation of lipids within parenchymal cells

What are causes of hepatic (liver) lipidosis?

• increased mobilization of free fatty acids

• abnormal hepatocellular metabolism of lipids

• impaired release of lipoproteins

Describe the gross appearance of a liver affected by lipidosis

swollen with rounded edges, often yellow or brown, with an accentuated centrolobular pattern, and greasy to the touch

frequently float in formalin rather than sink

Describe the histological appearance of a liver affected by lipidosis

heptocytes have one or more colorless punctate cytoplasmic vacuoles whcih can displace the nucleus and result in degeneration and necrosis if severe

Why are lipid vacuoles from a liver affected by lipidosis colorless and punctate?

lipid vacuoles are colorless and punctate because the lipid has leached from the cell in the process of processing (alcohol in slide prep dissolves lipid but leaves clear space)

The presence of lipid in lipidosis can be confirmed with what histochemical stains?

• sudan black

• Oil-Red-O

Glycogen is stored where in homeostasis?

in the liver and skeletal muscle

With accumulation of glycogen, we often see accumulation with what conditions?

• storage disease

• canine hyperadrenocorticism

• diabetes mellitus

Describe the gross appearance of a liver affected by glycogen accumulation.

enlarged with rounded edges, is pale and often light brown and can be mottled in appearance

Describe the histological appearance of a liver affected by glycogen accumulation.

hepatocytes are enlarged, swollen with intracytoplasmic fine lacy vacuolation

How can pathologists differentiate between glycogen accumulation and cell swelling?

PAS with diastase stain

What does PAS with diastase stain do to carbohydrates and glycogen to help pathologists differentiate between glycogen accumulation and cell swelling?

PAS turns carbohydrates pink

diastase dissolves glycogen

How do you interpret a slide stained with PAS and treated with diastase?

In the PAS slide we expect to see PAS positive cytoplasm which confirms carbohydrate accumulation

If the pink is not present in the diastase treated slide, then that confirms glycogen

What can cause protein accumulation?

increased resorption, storage, or production

Proteins often stain what color in H&E stained tissue sections?

pink to orange

What are the rhomboid inclusions seen in the renal and hepatocyte epithelial cells in dogs?

crystalline protein inclusions

Viral inclusions can be intranuclear or cytoplasmic depending on what?

the viral agent

What are some viruses that produce exclusively intranuclear inclusions?

• herpes

• adenoviruses

• parvoviruses

What are some viruses that produce cytoplasmic inclusions?

• pox viruses

• rabies

What is an example of a virus that produces both intranuclear and intracytoplasmic inclusions?

canine distemper virus

Lead poisoning produces what type of inclusions?

intranuclear inclusions that are a mix of lead and proteins which are pale and eosinophilic but stain with acid fast stains

What is amyloidosis?

protein misfolding disorder converting them into insoluble non functional aggregates

Amyloid deposits are frequently found where?

blood vessels, basement membranes (particularly in liver and kidney), spleen

Amyloidosis is what type of accumulation?

extracellular

What are the five mechanisms of amyloidosis?

• propagation of misfolded proteins which serve as template for self replication

• accumulation of misfiled precursor peptides with failure to degrade them

• genetic mutations which promote protein misfolding

• protein overproduction because of abnormality or proliferation in synthesizing cells

• loss of chaperoning molecules or other essential components of the protein assembly process

Which type of amyloid is secreted in B cell proliferative disorders like plasma cell tumors and multiple myeloma?

AL amyloid

Which type of amyloid is synthesized from SAA which is secreted by the liver during inflammation?

AA amyloid

Hereditary amyloidosis can be seen in which breed of dog and cat?

• Shar Pei dog

• Abyssinian cats

Which amyloid is seen in dogs with cognitive dysfunction and Alzheimer’s disease?

beta amyloid

Grossly, amyloid can do what?

enlarge an organ and appear as a yellow, waxy, nodular, diffuse, or amorphous deposits

When stained with iodine, amyloid will appear what color?

black

How do we diagnose amyloidosis?

iodine stain of fresh tissue

congo red stain or apple green birefringent under polarized light for formalin fixed tissue

Amyloid stains what color with congo red?

red

Gout is common in which species?

birds and reptiles

Gout is what type of accumulation?

extracellular

What is gout?

the deposition of sodium urate crystals extracellularly in tissue

What are the two forms of gout?

visceral and articular

Where are deposits for articular gout?

chalky white deposits are found within and overlying joints

Where are deposits for visceral gout?

chalky white deposits found on the surface of viscera

What causes gout?

• dehydration

• renal failure

• excess protein intake

Cholesterol crystals appear as what on histology?

needle shaped clefts

True or false: Cholesterol crystals dissolve in histologic processing.

True

Cholesterol crystals are a form of what accumulation?

extracellular

Cholesterol crystals form where?

at sites of necrosis

Cholesterol crystals typically elicit what?

granulomatous inflammation

Fibrosis is what type of accumulation?

extracellular

What is fibrosis?

collagen deposition, predominantly type I collagen in the interstitium or organs or tissues

Fibrosis is generally a result of what?

necrosis or inflammation and is a part of healing

Define neovascularization.

proliferation of small vessels due to response to injury or disease

What is fatty infiltration?

increase in the number of adipocytes in an organ or tissue

What type of accumulation is fatty infiltration?

extracellular

What can cause fatty infiltration?

can occur due to obesity or certain cardiomyopathies

What is pathologic calcification?

the deposition of calcium salts (phosphates and carbonates) in soft tissues which would not occur in healthy states

What are the two forms of calcification?

• dystrophic

• metastatic

Which type of calcification is a result of necrosis where intracellular calcium is released from sequestered places within the cell or into the extracellular space?

dystrophic

Which type of calcification targets specific sites first, generally the tunica intima and media of blood vessels, particularly in the lungs, pleural surface, kidneys, and stomach?

metastatic

Metastatic calcification is due to a calcium/phosphorus imbalance which occurs for numerous reasons including?

• vitamin D toxicosis

• hyperparathyroidism

• chronic kidney disease

• iatrogenic supplementation

• certain neoplasias (PTH-rp producing neoplasms, anal sac gland adenocarcinoma, lymphoma, other carcinomas)

Metastatic calcification results from?

hypercalcemia

What is melanin?

brown black intracellular (endogenous) pigment produced by melanocytes

A congenital lack of pigmentation is termed albinism and is due to what?

lack of tyrosinase

What disease conditions cause depigmentation?

• copper deficiency

• Chediak-Higashi syndrome

What causes hyperpigmentation?

chronic inflammatory states or neoplasia

Congenital melanosis is non pathological in what animals?

black faced sheep, cattle, chow chows, etc

Melanin is formed by?

oxidation of tyrosine which needs copper containing enzyme tyrosinase

What is a lipoprotein which accumulates in lysosomes in long lived post mitotic cells (neurons, cardiac myocytes) seen in greater quantities in aged animals?

lipofuscin

Lipofuscin stains how?

PAS positive

will react with lipid stains like sudan black and oil red o

Is lipofuscin an intracellular or extracellular pigment?

intracellular

Which endogenous pigment looks very similar to lipofuscin but has a different biochemical composition and is pathologic?

ceroid

What causes ceroid pigment?

• cachexia

• vitamin E deficiency (brown colored smooth muscle of the gut)

• lysosomal storage disease

What exogenous pigment can be confused with icterus, is a fat soluble pigment from plants, and is precursor to vitamin A which are antioxidants?

carotenoids

Which carotenoid is the precursor for vitamin A?

B-carotene

What is the term for accumulation of carbon in tissues?

anthracosis

Is carbon an endogenous or exogenous pigment?

exogenous

Grossly, anthracosis produces what?

a fine black grey stippling of the lung

Histologically, anthracosis is seen as accumulations of what?

fine black granular pigment often accompanied by refractive crystalline material within peribronchiolar macrophages

What are common sites to find anthracosis?

• skin secondary to tattooing

• lung from inhalation of smoke or dust

• tracheobronchial lymph nodes (draining macrophages from lung)

Is tetracycline an endogenous or exogenous pigment?

exogenous

What is tetracycline?

an antibiotic which binds to calcium phosphate in teeth and bones

If tetracycline is administered to young animals at the time of remineralization, it results in what?

permanent discoloration of teeth and bones

Initiallt staining due to tetracycline is what color?

yellow with exposure to light and oxidation turns brown

fluoresces bright yellow under UV light

Hemoglobin is what type of pigment?

hematogenous

Hemoglobin is the normal red pigment of what?

RBCs

The ferrous ion in hemoglobin is converted to ferric acid, resulting in brown colored blood termed what?

methemoglobin

What pigment forms the pink tinge to well perfused, well oxygenated tissues?

hemoglobin

What creates a blue cast to poorly perfused or hypoxic tissues (cyanosis)?

deoxygenated hemoglobin

What type of pigment is hemosiderin?

hematogenous

Whihc hemotogenous pigment is formed from aggregates of ferritin (iron bound to the ferritin protein)?

hemosiderin

What is the golden yellow to light brown granular refractive pigment which can be seen in the spleen, liver, heart failure cells, and bruises?

hemosiderin

When ferritin is bound with iron it forms what?

hemosiderin

What is the bright yellow brown to orange red crystalline hemotogenous pigment derived from hemosiderin that contains no iron and resembles bilirubin?

hematoiden

What hemotgenous pigment results from RBC degradation in macrophages (breakdown of heme component)?

bilirubin

Icterus is an accumulation of what pigment?

bilirubin

What is porphyria?

inherited metabolic defect in heem synthesis

Porphyria results in what?

deficinecy of urophyringoen III cosynthase which results in pink to red brown discoloration of dentin and bone

Porphyria fluoresces what color under UV light?

red

Does hyperbilirubinemia equal icterus?

No, you can have hyperbilirubinemia without icterus