INTRACELLULAR ACCUMULATIONS and CALCIFICATION

Lecturer name: Dr. Maha ArafahLecture Date: -9-2012

(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).

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

Storage Diseases

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).

Fatty Change(Steatosis)

Fatty Change Fatty change is: 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

Steatosis may be caused by:1. Toxins (most importantly: Alcohol

abuse)2. diabetes mellitus 3. Protein malnutrition (starvation)4. Obesity5. Anoxia

Hepatotoxins and anoxia (e.g. alcohol) by disrupting mitochondria and SER = Inhibit fatty acid oxidation

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

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

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: carbon

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: carbonAggregates of the

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

Heavy accumulations may induce fibrosis ( coal workers' pneumoconiosis)

Endogenous Pigments

Hemosidren Melanin 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

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

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

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

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

MelaninEndogenous Pigments

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: Nevus

LipofuscinEndogenous Pigments

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

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.

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 calcificationDystrophic 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:

Encountered in areas of necrosis of any type. E.g. a tuberculous lymph node is

essentially converted to radio-opaque lesion due to calcification

E.g. 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.

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 of hypercalcemia:

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 and sarcoidosis

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

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