INTRACELLULAR ACCUMULATIONS and CALCIFICATION (Foundation Block, Pathology) Lecturer name: Dr. Maha Arafah Lecture Date: -9-2012

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

Starvation will increase this Hepatotoxins and anoxia (e.g. alcohol) by disrupting mitochondria and SER = Inhibit fatty acid oxidation Defects in any of the steps of uptake, catabolism, or secretion can lead to lipid accumulation. CCl4 and protein malnutrition

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: carbon Aggregates 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

Hemosiderin The 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: increased absorption of dietary iron impaired utilization of iron hemolytic anemias 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

Endogenous Pigments Melanin

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

Endogenous Pigments Lipofuscin

Lipofuscin Brown atrophy "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: Osteoarthritis : a degenerative joint disease in which gradual destruction and deterioration of the bones and joint occurs. Alzheimer's disease : a degenerative neurological disease where there is a progressive deterioration in brain function. 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 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: 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 calcification Main causes of hypercalcemia: increased secretion of parathyroid hormone destruction of bone due to the effects of accelerated turnover (e.g., Paget disease), immobilization, or tumors (multiple myeloma, leukemia, or diffuse skeletal metastases) vitamin D-related disorders including vitamin D intoxication and sarcoidosis 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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