Outline of Lecture
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
