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Intracellular Accumulations

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Accumulations

Intracellular

Water

Fatty change

Cholesterol & esters

Protein

Glycogen

Pigments

Calcium

Extracellular

Amyloid

INTRACELLULAR  ACCUMULATION

↑ production of normal product but inadequate function

Normal / abnormal substance accumulate but defective mechanism of removal.

↑ Exogenous substance no removal mechanism.

Intracellular accumulations of endogenous or exogenous substances

-         Lipids:  fat may accumulate in the liver as fatty change

-         Proteins:  abnormal protein accumulation is often irreversible.

-         Glycogen:  glycogen storage diseases

-         Complex Lipids:  sphinglolipidoses and other lipid accumulations .

-         Complex carbohydrates:  mucopolysaccharidoses and other complex carbohydrate diseases.

Intracellular accumulations of endogenous or exogenous substances

-        Minerals:

-       iron, as hemosiderin, or

-       carbon, as anthracotic pigment

-       Calcium, as calcification

-        Pigments:

-       lipofuscin is a benign brown pigment of lipid origin that may accumulate with age, or

-       melanin from melanomas, or

-       bilirubin as in jaundice

Fatty Change

Hepatic lipid accumulation is characterized by intracellular accumulation of triglycerides, and due to the failure of metabolic removal.

Defects in fat metabolism are often induced by alcohol consumption, and also associated with diabetes, obesity, and toxins.

Fatty change is most often seen in the liver. Also seen in heart & pancreas, and is generally reversible.

FATTY CHANGE
– Microscopic features

Fat vacuoles coalesce and displace the nucleus to the periphery of the cell

vacuoles appear clear, with well-defined edges

lipid accumulations must be distinguished from accumulations of water or glycogen, using special preparation and stain – Oil Red-O.

Cholesterol & esters

Accumulates in macrophages (foam cells) & FB giant cells

Atherosclerosis

Hereditary & aquired hyperlipidemia →xanthoma

Protein accumulation

Kidney in nephrotic syndrome.

Plasma cells immunoglobulin.

Mallory bodies. eosinophilic intracytoplasmic hyaline body

Calcification

1.             Dystrophic calcification

Abnormal CaPO4 deposition in dead or dying tissue

Examples.

Arterial wall as

medial calcific sclerosis.

Atherosclerosis &

valvular heart disease.

In areas of tissue necrosis

Caseation ,

coaggulative or

fat necrosis.

Dead parasite & their ova.

Calcification

2.             Metastatic calcification

Abnormal calcium deposition in “normal” tissues secondary to hypercalcemia

(in soft tissues that are not the site of previous damage )

Calcification

Metastatic calcification

Ca deposition in normal tissue due to hypercalcemia.

Hyperparathyroidism ↑ PTH bone resorption.

Destruction of bone tissue & →bone resorption

prolonged immobilization,

metastatic bone tumor.

Chronic renal failure.

↑ Vitamin D

Common sites kidney, stomach, lungs

Morphology

With H&E stain : basophilic amorphous granular appearance

Von Kossa stain – black deposits

Amyloidosis

A medical condition resulting from aggregation of extracellularly deposited abnormal proteins called amyloid fibrils that cause damage to organs and tissues.

These fibrils are insoluble, linear, rigid and measures approximately 7.5 to 10µm in width

Amyloidosis

Types associated with different disease.

H&E stain hyaline acellular eosinophilic material

Congo red stains red in light &

green birefingence in polarized light.

Electron microscopy shows regular fibrillar structure

X-ray diffraction shows beta pleated sheet structure

Mechanism of formation

Amyloid fibrils arise from misfolded proteins. Alpha helix to beta pleated sheet

Proteins are deposited extracellularly

Proteins aggregate and form fibrils called amyloid fibrils.

Misfolded proteins may result from point mutations.

Deposited as localized vs systemic

localized; close to cells producing it.

Systemic; distant sites from these cells producing these abnormal proteins.

In 1854 Rudolph Virchow named it amyloid based on color after staining these proteins with iodine and sulfuric acid. Meaning cellulose or starch

Classification:

23 different human subtypes named based on A for amyloid followed the precursor protein e.g AL, AH.

Classificaton of amyloid

Localized

Larynx,lung ,bladder

Systemic Amyloidosis

Multiple myeloma associated

Reactive (secondary amyloidosis)

AA amyloid

Rheumatoid arthritis

IBD

Osteomylitis

Hodgkins disease & RCC

Hereditary amyloidosis

Further Clinical Manifestations

CNS/Neuro:

Neuropathy both autonomic and peripheral,

dementia.

Corneal deposits.

Cardiac:

Cardiomyopathy typically restrictive(right sided)

Pulmonary:

-Pleural effusions

-Parenchymal nodules

-Tracheal and bronchial infiltration causing hoarseness, airway obstruction and  dysphagia.

Renal: Proteinuria, nephrotic syndrome, renal failure leading to kidney transplant or dialysis.

Bone marrow: Bleeding abnormalities

Muscle: Hypertrophy of muscles, macroglossia

Skin: Nodules, plaques, easy bruising

GI:

Organomegaly (Hepatomegaly,splenomegaly),

gastroparesis, abnormal bowel movement usually constipation, malabsorption

Liver amyloid

Diagnosis

Unexplained medical disorder and you suspect amyloidosis: e.g

heart failure,

proteinuria,

hepatic dysfunction

Ultimately, you need Tissue biopsy:

Abd fat pad,

rectal,

salivary gland,

endomyocardium.

Bone marrow biopsy

Treatment

Treatment of this medical disorder is limited and research is still in progress.

Treatment differs depending on subtype.

AL and AH

-High dose mephalan plus dexamethasone/prednisone

-In selected candidates autologous stem cell transplant is an option.

- The goal with treatment is to get rid of clonal plasma cells that lead to immunoglobulin protein

AA: Treat the infection or chronic inflammatory condition causing apo serum A protein elevation.

Familial Mediterranean fever: Colchicine

Other conditions are treated conservatively or require organ transplant

Prognosis is poor with this medical disorder.

TAKE HOME MESSAGE

Can affect any organ system

Hematoxylin and Eosin (HE) and Congo stain only tells you these are amyloid fibrils

Need to immunostain to determine subtype

Different subtypes are treated differently.

A lot still have to be known about the therapy as prognosis is poor for this disease.

Amyloid

Congo red-stained amyloid shows light green birefringence when subjected to polarized light.

Pigments

Endogenous

Hb derived iron,bilirubin

Non Hb derived melanin, lipofusion

Exogenous

Anthracosis ,black pigment in smoking

Tatooing

Hemoglobin derived pigments

Excess iron accumulaton

Total body iron 2-4gm

Functional pool

Hb,

myoglobin,

cytochrome,

catalase

Storage pool

Macrophages of RES as Fe3+,ferritin,hemosidern

Stain Purssian blue reaction (PEARLs)

Iron overload

Localized ↑ iron in tissue

Hematoma

Chronic venous congestion lung ,heart

Systemic ↑ iron

Hemosiderosis Fe in RES without damage

Hemolytic disease

Multiple blood transfusions

I/V Fe administration

Idiopathic hemochromatosis

Lack of regulation of iron absorbtion & defects in monocyte macrophage system.

Deposited in liver, pancrease & RES.

→ fibrosis leading to secondary DM, liver cirrhosis & cancer.

Haemosiderin

derived from hemoglobin

golden yellow, granular or crystalline pigment

storage form of iron

forms in response to local or systemic excess of iron ®ferritin forms hemosiderin granules

Haemosiderin

local excess:  from gross or minute hemorrhage (eg. bruise)

systemic excess:  from increased absorption of dietary iron, impaired use of iron, hemolytic anemia, transfusions

Hemosiderin

Chronic passive congestion with hemosiderosis and edema in a lung

Hemosiderin

Chronic passive congestion with hemosiderin in alveolar macrophages

Hemosiderin/Melanin/etc.

Bilirubin

Bile pigment (bilirubin)

Derived from heme of Hb from destroyed RBC in RES

Conjugated in hepatocytes with glucuronic acid & excreted as bile.

Hyperbilirubinemia

jaundice

Hemolysis,

Hepatitis,

obstruction to outflow of bile.

Bilirubin

Bilirubin (bile) casts in hepatic canaliculi in chronic liver disease

Non –Hemoglobin derived

lipofusion

Brown pigment in cytoplasm is oxidized lipid derived from digested membrane organelle

Part of aging process & atrophy in which lipid peroxidation occurs.

Harmless to cells

↑ amount in brown atrophic organ

Lipofuscin

“Wear & tear” pigment

derived through lipid peroxidation of polyunsaturated lipids of subcellular membranes

accumulates in tissues undergoing slow, regressive changes – common in liver and heart of aging patients or patients with severe malnutrition and cancer cachexia

appears as a yellow-brown, finely granular, intracytoplasmic (or perinuclear) pigment

Lipofuscin/ceroid
(Latin: fuscus=brown, “brown lipid”)

Brown discoloration of intestinal muscle due to vitamin E deficiency and smooth muscle lipofuscinosis

Endogenous pigments

Melanin

Brown pigment synthesized in melanocytes.protects nuclei of basal epidermal cells from UV light.

Nevi- benign

Melanoma -malignant e.g. eye, rectum

Melanin (Greek, melas=black)

NEVI

Many, many adjectives and classifications.

The MAIN things to differentiate from melanomas

Junctional (more pigmented, more closely associated with melanoma)

Intradermal

Compound (both)

Melanin (Greek, melas=black)

Melanin in melanoma tumor cells

Exogenous pigments

Tattoos

Anthracosis

TATTOO, MICROSCOPIC

ANTHRACOSIS

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