Lecture 8 - Reversible Cell Injury and Accumulations II

What is one of the manifestations of metabolic derangements in cells?

Accumulation of abnormal amounts of substances

What are the 2 categories of substances that accumulate intracellularly?

Normal cellular constituents (water, lipids, proteins, carbohydrates)

Abnormal substances

What are the sources of abnormal substances that can accumulate intracellularly?

Exogenous: mineral, products of infectious agents, products of pathologic processes elsewhere

Endogenous: product of abnormal synthesis or metabolism

Intracellular accumulations may accumulate...

In the cytoplasm (more common) or nucleus

May accumulate transiently or permanently

What are possible consequences of accumulations?

Harmless (incidental)

Varying degrees of injury (toxic)

What makes intracellular accumulation reversible?

If the overload can be controlled/stopped

Many processes result in abnormal intracellular accumulations that can often be categorized into what 4 types of abnormalities?

Abnormal metabolism

Defect in protein folding or transport

Lack of enzyme

Ingestion of indigestible materials

How does abnormal metabolism cause intracellular accumulations?

A normal endogenous substance is produced at a normal or increased rate but the rate of metabolism is inadequate to remove it

What are examples of abnormal metabolism that causes intracellular accumulations?

Hepatic lipidosis

Renal tubular proteinosis

Steroid hepatopathy

How does a defect in protein folding or transport cause intracellular accumulations?

An abnormal endogenous substance (usually from a genetic defect) causes improper folding, transport, and degradation, resulting in accumulation

Usually congenital and in young animals

What are examples of protein defects that cause intracellular accumulations?

Mutated alpha1-antitrypsin in liver

Degenerative CNS diseases (Alzheimer's)

How does the lack of an enzyme cause intracellular accumulations?

A normal endogenous substance accumulates because of defects in enzymes required to metabolize the substance

Defects are usually inherited

The substance will generally accumulate in lysosomes (this is where enzymes are usually housed)

What are examples of the lack of an enzyme causing intracellular accumulations?

Lysosomal storage diseases

How does the ingestion of indigestible materials cause intracellular accumulations?

An abnormal endogenous substance is deposited and accumulates because either...

The cell doesn't have the enzymatic machinery needed to break it down or...

The ability to transport the substance to another site

What is an example of ingestion of indigestible materials causing intracellular materials?

Pneumoconiosis (accumulation of inhaled materials in macrophages of the lungs)

What is lipidosis/steatosis/fatty change?

Accumulation of triglycerides and other lipid metabolites (fats and cholesterol) within parenchymal cells

Where is lipidosis most commonly seen?

Liver (hepatic lipidosis), the main organ involved in lipid metabolism

Can be seen in heart, kidneys, and skeletal muscle typically as a result of altered liver function

What is seen grossly in hepatic lipidosis?

Increase in weight/size

Slightly swollen with rounded edges

Diffusely pale and yellow-tinged

May feel greasy and be more friable

May float in formalin (lipid and H2O don't mix)

What is seen on histopathology in hepatic lipidosis?

Hepatocytes enlarged/distended by one to a few clear, punctate cytoplasmic vacuoles

Initially small/microvacuoles that will coalesce and enlarge over time

Extent of vacuolation depends on severity

Large vacuoles may displace the nucleus and make the cell look like an adipocyte

The underlying pathogenesis of hepatic lipidosis centers on...

The biochemical pathways of free fatty acid formation and metabolism in the liver

What is the function of FFAs? Where are they obtained from?

Derived from triglycerides and provide a large component of basal energy needs

Obtained from diet, chylomicrons in the blood, or adipose cells in body fat stores

What are the 5 mechanisms that may contribute to hepatic lipidosis?

1. Excessive FFAs delivered by gut or adipose tissue

2. Decreased oxidation or use of fatty acids due to mitochondrial injury or hypoxia

3. Impaired synthesis of apoprotein (toxins, aflatoxin)

4. Impaired combination of triglycerides and protein to form lipoproteins (uncommon)

5. Impaired release of lipoproteins from hepatocytes (uncommon)

Hepatic lipidosis most commonly arises from...

Conditions that cause increased mobilization of body fat stores

Increased demands over a short period of time

Who is at higher risk for developing hepatic lipidosis?

Obese animals, they have more fat stores to mobilize

Diabetes mellitus

What are common events that can cause hepatic lipidosis in vet med?

Late pregnancy in ruminants, particularly those with multiple (pregnancy toxemia)

Early lactation in dairy cows (ketosis/milk fever)

Anorexia in toy breed puppies

Anorexia in obese cats

What is fatty change in the liver?

Lipidosis often related to altered lipid metabolism

Fatty vacuolation within cell cytoplasm

What is fatty infiltration?

Infiltration of mature adipocytes into non-adipose tissues

Normal lipid metabolism

What are causes of fatty infiltration?

Increased levels of lipid stores causes increased numbers of adipocytes (hyperplasia) that may develop within skeletal muscle, heart, and other tissues

In some instances of tissue atrophy, the cells that are lost may be replaced by adipocytes

What species may atherosclerosis be seen in?

Experimental in pig, rabbit, chicken

Birds (parrots), aged pigs, dogs with hypothyroidism and diabetes mellitus (typically have hypercholesterolemia)

What is atherosclerosis?

Accumulation of cholesterol and cholesterol esters in the cytoplasm of smooth muscle cells and macrophages in arterial walls that leads to luminal thinning

What does atherosclerosis look like grossly?

Vessels are thickened, tortuous, firm, yellow-white and may be gritty (mineralized)

Seen in the heart, mesentery, kidneys

What does atherosclerosis look like on histopathology?

Cells have a foamy appearance (from cholesterol) and cholesterol clefts

What is the function of the glomerulus in regards to protein?

Filter out unwanted material, keep proteins in

The little protein that does get through it reabsorbed by the proximal tubules

What is renal tubular proteinosis?

There is damage to the glomerulus that cases increase protein entering the proximal tubules, which increases protein reabsorption in the tubular epithelial cells and causes cytoplasmic protein accumulation

Indicates elevated protein being lost by glomerulus, proteinuria

What is seen on histopathology in renal tubular proteinosis?

Hyaline (bright pink and glassy) droplets within the epithelial cell cytoplasm

How is renal tubular proteinosis reversed?

Protein absorbed by vesicles that fuse with lysosomes (phagolysosomes) and then degraded

What are Mott cells?

Plasma cells that have accumulation of protein (antibody) within the cytoplasm

Causes a bright pink, glassy (hyaline) globules called Russel bodies in the cytoplasm

Manifestation of cellular ingestion of the ER

When are Mott cells seen?

Some chronic inflammatory diseases like plasma cell stomatitis in cats, plasma cell pododermatitis in cats, and IBD

What is glycogen? Where is it found?

Readily available energy source stored in the cytoplasm of healthy cells, usually liver and skeletal muscle

Stores become depleted during times of starvation or sickness

Excessive accumulation of glycogen is generally due to...

Abnormal glucose or glycogen metabolism

What is glucocorticoid (steroid) hepatopathy?

Excess amount of glucocorticoid and steroid hormones increases glycogen production and storage in the liver

What are the 2 types of glucocorticoid/steroid elevations?

Endogenous and exogenous

What are exogenous elevations of glucocorticoids?

Prolonged or high-dose corticosteroid or sex steroid hormone administration

Iatrogenic (done by us)

Prednisone, dexamethasone

What are endogenous elevations of glucocorticoids?

Hyperadrenocorticism (Cushing's) from...

Increased cortisol from adrenal cortex (from functional pituitary tumor or adrenal cortical tumor)

Increased sec steroid levels (functional gonadal neoplasm)

What is seen grossly in glucocorticoid steroid hepatopathy?

Enlarged, pale liver that may be mottled

Not friable or greasy like in hepatic lipidosis, more firm

What is seen on histopathology in glucocorticoid steroid hepatopathy?

Markedly enlarged hepatocytes by clear space in cytoplasm

More feathery and indistinct vacuoles

Typically no displacement of nucleus

What are characteristics of hepatic lipid accumulation?

Abnormal lipid metabolism

Clear, punctate vacuoles that can be micro vesicular (numerous small punctate) or macrovesicular (few large punctate)

Possibly displaced nucleus

What are characteristics of hepatic glycogen accumulation?

Abnormal glucose and glycogen metabolism

Small, fuzzy to foamy vacuoles

No displaced nucleus

What are characteristics of lysosomal storage diseases?

Characterized by accumulation of material in lysosomes

Material can be variety and combination of proteins, carbohydrates, lipids

Absence of specific enzymes required for breakdown of the material

What may cause lysosomal storage diseases?

Most are genetic inherited

Can be induced by toxins targeting the specific enzyme

What cell types are most affected by lysosomal storage diseases?

All cell types are vulnerable but long-lived post-mitotic cells tend to be most affected like neurons and muscle

How might we see lysosomal storage diseases clinically?

Young animal with progressive neuromuscular impairment

What is seen on histopathology in lysosomal storage diseases?

Cells distended by accumulated material in the cytoplasm (often represents crowded engorged lysosomes)

Accumulation of macrophages engulfing material that cannot be metabolized

Tissues are unhappy so may see inflammation, degeneration, atrophy, loss of cells

What is alpha-mannosidosis?

In cats

Deficiency in alpha-mannosidase blocks catabolism of mannose

Accumulation of material within lysosomes of neurons and other cells which causes neurologic disease

What is globoid cell leukodystrophy?

Deficiency in galactocerebrosidase (component of myelin that helps break it down/recycle) leads to material accumulation in oligodendrocytes, Schwann cells, and macrophages

Destruction of myelin producing cells and myelin that is incorrectly produced

Macrophages come to clean up the mess but also accumulate material

What are rhomboid crystalline protein inclusions?

AKA crystalloids or brick inclusions

Incidental finding, non-infectious

Large, eosinophilic, rhomboidal inclusions found in nuclei of hepatocytes and renal tubular epithelial cells

Found in older dogs

What are lead inclusion bodies?

May see in renal tubular epithelial cells in cases of lead toxicity/poisoning

Inclusion represents lead and protein

Non-infectious

Smudgy, pale, amphiphilic irregular

What stain best highlights lead inclusion bodies?

Acid-fast staining

What are characteristics of viral inclusion bodies?

May be in nucleus, cytoplasm, or both

Typically represents accumulation of viral proteins, virions, or viral particles that may be mixed with other proteins

The presence or absence of viral inclusion bodies depends on...

Where in the timeline of infection you are

More often seen early in infection

Disappear as infected cells are lysed and cleared, or as reparative processes replace the lesion

In general, DNA viruses have __ inclusions

Intranuclear

In general, RNA viruses have __ inclusions

Intracytoplasmic

What are characteristics of canine parvovirus and its inclusions?

DNA virus that targets rapidly dividing cells

Intranuclear pink inclusion that displaces chromatin to outer edge, forming a circle around inclusion

Found in crypt enterocytes and bone marrow cells

What are characteristics of rabies virus and its inclusions?

Caused by a rhabdovirus, which is an RNA virus with neurotropic nature

Pink/red/brown inclusion bodies (Negri bodies) that are intracytoplasmic

What are characteristics of canine distemper virus and its inclusions?

Morbillivirus, a large RNA virus that can cause disease in lungs (pneumonia), GI (enteritis), and brain (encephalitis)

Pink intranuclear and intracytoplasmic inclusions