Dr. Maha Arafah Assistant Professor Department of Pathology King Khalid University Hospital and King Saud University Monday Oct 11, :00 to 12:00 am

 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).

 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.

 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.

1. Normal or increased rate of production of a normal substance, but metabolic rate is inadequate to remove it (e.g. fatty change in liver)

2. A normal or an abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport, or secretion. e.g. In α-1antitrypsin deficiency, α1at accumulates in the liver causing cirrhosis)

3. An inherited defect in an enzyme may result in failure to degrade a metabolite. The resulting disorders are called storage diseases.

4. An abnormal exogenous substance is deposited and accumulates because the cell has neither the enzymatic machinery to degrade the substance nor the ability to transport it to other sites. (e.g. Accumulations of carbon or silica particles)

 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).

(Steatosis)

 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.

 Toxins (most importantly: Alcohol abuse)  diabetes mellitus  Protein malnutrition (starvation)  Obesity  Anoxia

 common cause of this is: Excessive alcohol consumption Other causes: starvation, obesity,CCl 4 etc.  In the liver, fatty accumulation occurs when cell damage compromises the ability of the hepatocyte to bind fat to protein and transport it through the cell.

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.

 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  In the severe form, fatty change may precede cell death, and may be an early lesion in a serious liver disease called nonalcoholic steatohepatitis

 Most common site: the liver and the heart.  With increasing accumulation, the organ enlarges and becomes progressively yellow, soft, and greasy.

 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)

 Fatty change is reversible except if some vital intracellular process is irreversibly impaired (e.g., in CCl4 poisoning),

 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%

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

Atherosclerosis: Smooth muscle cells and macrophages are filled with lipid vacuoles composed of cholesterol and cholesteryl esters

 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).

 Pigments are colored substances that are either:  exogenous, coming from outside the body, or  endogenous, synthesized within the body itself.

 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.

 The most common is carbon  When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.

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

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

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

 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

 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.

 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

The iron ions of hemoglobin accumulate as golden-yellow hemosiderin. The iron can be identified in tissue by the Prussian blue histochemical reaction

 is systemic overload of iron, hemosiderin is deposited in many organs and tissues  It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs.  With progressive accumulation, parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected

 Hemosiderosis occurs in the setting of: 1.increased absorption of dietary iron 2.impaired utilization of iron 3.hemolytic anemias 4.transfusions (the transfused red cells constitute an exogenous load of iron)..

 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 is the brown/black pigment which is normally present in the cytoplasm of cells at the basal cell layer of the epidermis, called melanocytes.  Melanin is derived from tyrosine, stored in melanosomes and distributed to the other epidermal cells.  The function of melanin is to block harmful UV rays from the epidermal nuclei.

 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, where the epidermis is damaged, melanin may be released from injured basal cells and taken up by dermal macrophages. This gives rise to post-inflammatory pigmentation of the skin.

 Melanin can be identified in tissue sections by the use of the Masson- Fontana stain.

 "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.  Consists of complexes of lipid and protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids of subcellular membranes.  It is not injurious to the cell but is important as a marker of past free-radical injury.  The brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.

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

 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).

 Define calcification  Types of calcification  Causes, feature and effect of dystrophic calcification  Causes, feature and effect of metastatic 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:

 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 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

 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

 Initiation (or nucleation)  Propagation (intracellular or extracellular) The ultimate end product is the formation of crystalline calcium phosphate

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

 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.

 Extensive calcifications in the lungs may produce remarkable respiratory deficits  Massive deposits in the kidney (nephrocalcinosis) can cause renal damage.

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 Depositions of lipids:  Fatty change: accumulation of free triglycerides in cells, resulting from excessive intake or defective transport (often because of defects in synthesis of transport proteins)  May be a manifestation of reversible cell injury

 Cholesterol deposition: result of defective catabolism and excessive intake;  occur in macrophages and smooth muscle cells of vessel walls in atherosclerosis

 Deposition of pigments: typically indigestible pigments, such as  carbon,  lipofuscin (breakdown product of lipid peroxidation),  iron (usually due to overload, as in hemosiderosis)

 Dystrophic calcification: deposition of calcium at sites of cell injury and necrosis  Metastatic calcification: deposition of calcium in normal tissues, caused by hypercalcemia (usually a consequence of parathyroid hormone excess)

Thank you

 Degeneration is used to describe pathological processes which result in deterioration (often with destruction) of tissues and organs.  Examples:  Osteoarthritis is a degenerative joint disease in which gradual destruction and deterioration of the bones and joint occurs.  Alzheimer's disease is a degenerative neurological disease where there is a progressive deterioration in brain function.  UV-induced degeneration of the connective tissue in skin solar elastosis.