INTRACELLULAR ACCUMULATIONS and CALCIFICATION

Lecturer name: Dr. Maha ArafahLecture Date: 27-9-2011

(Foundation Block, Pathology)

Objectives Understand the pathological changes

leading to abnormal accumulations of pigments and other substances in cells.

List conditions and features of fatty change, haemosiderin, melanin and lipofuscin accumulations in cells.

Know the main types and causes of calcifications (dystrophic and metastatic).

Degeneration

Degeneration is used to describe pathological processes which result in deterioration (often with destruction) of tissues and organs.

Examples:1. Osteoarthritis : a degenerative joint disease in

which gradual destruction and deterioration of the bones and joint occurs.

2. Alzheimer's disease : a degenerative neurological disease where there is a progressive deterioration in brain function.

3. Solar elastosis: UV-induced degeneration of the connective tissue in skin.

Accumulation

Under some circumstances cells may accumulate abnormal amounts of various substances.

They may be harmless or associated with varying degrees of injury .

Cells may accumulate pigments or other substances as a result of a variety of different pathological or physiological processes.

Overview of Accumulation

May be found: in the cytoplasm within organelles (typically lysosomes) in the nucleus

The accumulations can be classified as endogenous or exogenous.

Came to the cell through: Synthesis by affected cells Produced elsewhere.

Pathways of Accumulation

α-1antitrypsin deficiency

Pathways of Accumulation

Fatty Change(Steatosis)

Fatty Change

Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells.

It is usually an early indicator of cell stress and reversible injury.

Site: liver, most common site which has a central role in

fat metabolism. it may also occur in heart: anaemia or starvation

(anorexia nervosa) Other sites: skeletal muscle, kidney and other

organs.

Causes of Fatty Change

Toxins (most importantly: Alcohol abuse)

diabetes mellitus Protein malnutrition (starvation) Obesity Anoxia

Hepatotoxins (e.g. alcohol) by disrupting mitochondria and SER ; anoxia

CCl4 and protein malnutrition

Starvation will increase this

•Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation.

The significance of fatty change

Depends on the cause and severity of the accumulation. Mild it may have no effect on cellular function. Severe fatty change may transiently impair

cellular function

The iron is toxic to the tissues and leads to fibrosis of the liver (cirrhosis) and pancreas (leading to diabetes mellitus).

Light microscopy of fatty change

Early: small fat vacuoles in the cytoplasm around the nucleus.

Later stages: the vacuoles coalesce to create cleared spaces that displace the nucleus to the cell periphery

Occasionally contiguous cells rupture (fatty cysts)

Is Fatty liver reversible?

Fatty change is reversible except if some vital intracellular

process is irreversibly impaired (e.g., in CCl4 poisoning),

Prognosis of Fatty liver

Mild: benign natural history (approximately 3% will develop cirrhosis

Moderate to sever: inflammation, degeneration in hepatocytes, +/- fibrosis (30% develop cirrhosis)

5 to 10 year survival:67% and 59%

Other form of accumulation

Cholesteryl esters These give atherosclerotic plaques their characteristic yellow color and contribute to the pathogenesis of the lesion This is called atherosclerosis

Pigments

Pigments are colored substances that are either: exogenous, coming from outside the

body, or endogenous, synthesized within the

body itself.

Exogenous pigment

Pigments and insoluble substances may enter the body from a variety of sources.

They may be toxic and produce inflammatory tissue reactions or they may be relatively inert.

Indian ink pigments produce effective tattoos because they are engulfed by dermal macrophages which become immobilized and permanently deposited.

Exogenous pigment

The most common is carbon When inhaled, it is phagocytosed by

alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.

Exogenous pigment

Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).

Exogenous pigmentCarbon in Lung

Heavy accumulations may induce emphysema or a fibroblastic reaction that can result in a serious lung disease ( coal workers' pneumoconiosis)

Endogenous pigments

Endogenous pigments include certain derivatives of hemoglobin, melanin, and lipofuscin.

Hemosiderin ( iron)

is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron.

Hemosiderin pigments is composed of aggregates of partially degraded ferritin, which is protein-covered ferric oxide and phosphate.

It can be seen by light and electron microscopy

Hemosiderin ( iron)

Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal.

Where? in the mononuclear phagocytes of the

bone marrow, spleen, and liver. Why?

there is extensive red cell breakdown.

Hemosiderin

Local excesses of iron, and consequently of hemosiderin, result from hemorrhage.

Bruise: The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and bilirubin (red bile) from the heme

HemosiderinThe iron ions of hemoglobin accumulate as golden-yellow hemosiderin.

The iron can be identified in tissue by the Prussian blue histochemical reaction

Hemosiderosis(systemic overload of iron)

is systemic overload of iron, hemosiderin is deposited in many organs and tissues

Site: liver, bone marrow, spleen, and lymph nodes

With progressive accumulation,

parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected

Hemosiderosis

Hemosiderosis occurs in the setting of:

1.increased absorption of dietary

iron 2.impaired utilization of iron3.hemolytic anemias4.transfusions (the transfused red

cells constitute an exogenous load of iron).

.

Effect of hemosiderosis

In most instances of systemic hemosiderosis, the iron pigment does not damage the parenchymal cells

However, more extensive accumulations of iron are seen in hereditary hemochromatosis with tissue injury including liver fibrosis, heart failure, and diabetes mellitus

Melanin

Melanin is the brown/black pigment which is normally present in the cytoplasm of cells at the basal cell layer of the epidermis, called melanocytes.

The function of melanin is to block

harmful UV rays from the epidermal nuclei.

Melanin: Causes of accumulation

Melanin may accumulate in excessive quantities in benign or malignant melanocytic neoplasms and its presence is a useful diagnostic feature melanocytic lesions.

In inflammatory skin lesions, post-inflammatory pigmentation of the skin.

Melanin

Lipofuscin

"wear-and-tear pigment" is an insoluble brownish-yellow granular intracellular material that seen in a variety of tissues (the heart, liver, and brain) as a function of age or atrophy.

Brown atrophy

Lipofuscin

By electron microscopy, the pigment appears as perinuclear electron-dense granules

PATHOLOGIC CALCIFICATION

Pathologic calcification

is a common process in a wide variety of disease states

it implies the abnormal deposition of calcium salts with smaller amounts of iron, magnesium, and other minerals.

It has 2 types:

Types of Pathologic calcification

Dystrophic calcification: When the deposition occurs in dead or

dying tissues it occurs with normal serum levels of

calcium

Metastatic calcification: The deposition of calcium salts in normal

tissues It almost always reflects some

derangement in calcium metabolism (hypercalcemia)

Dystrophic calcification:

Dystrophic calcification is encountered in areas of necrosis of any type.

It is certain in the atheromas of advanced atherosclerosis, associated with intimal injury in the aorta and large arteries

Although dystrophic calcification may be an incidental finding indicating insignificant past cell injury, it may also be a cause of organ dysfunction.

For example, Dystrophic calcification of the aortic valves is

an important cause of aortic stenosis in the elderly

Dystrophic calcification of the aortic valves

Morphology of Dystrophic calcification

calcium salts are grossly seen as fine white granules or clumps, often felt as gritty deposits.

Sometimes a tuberculous lymph node is essentially converted to radio-opaque stone.

Histologically, calcification appears as intracellular and/or extracellular basophilic deposits.

In time, heterotopic bone may be formed in the focus of calcification.

Dystrophic calcification in the wall of the stomach

Metastatic calcification

Metastatic calcification can occur in normal tissues whenever there is hypercalcemia.

Metastatic calcificationMain causes:

1. increased secretion of parathyroid hormone

2. destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (multiple myeloma, leukemia, or diffuse skeletal metastases)

3. vitamin D-related disorders including vitamin D intoxication

4. renal failure, in which phosphate retention leads to secondary hyperparathyroidism.

Morphology of Metastatic calcification

Metastatic calcification can occur widely throughout the body but principally affects the interstitial tissues of the vasculature, kidneys, lungs, and gastric mucosa.

The calcium deposits morphologically resemble those described in dystrophic calcification.

Effect of Metastatic calcification

Extensive calcifications in the lungs may produce remarkable respiratory deficits

Massive deposits in the kidney

(nephrocalcinosis) can cause renal damage.

Metastatic calcification" in the lung of a patient with a very high serum calcium

level

Summary

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