Accumulations: Injury by endogenous and exogenous substances

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AccumulationsInjury by endogenous and exogenous
substances

• Doç. Dr.
• A. Isin DOGAN EKICI

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Why are the substances accumulate?

• When injury is sublethal or sustained, cells and
  tissues tend to accumulate substances in abnormal
  quantities.
• One of the cellular manifestations of metabolic
  derangements in pathology is the accumulation of
  abnormal amounts of various substances.

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The substances accumulated may be either
endogenous or exogenous in origin.

• (1) a normal cellular material accumulated in
  excess, such as water, lipid, protein, and
  carbohydrates
• (2) an abnormal substance, either exogenous, such
  as a mineral, or a product of abnormal
  metabolism
• (3) a pigment or an infectious product.

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• 1. A normal endogenous substance is produced at a
  normal or increased rate, but the rate of
  metabolism is inadequate to remove it. An example
  of this type of process is fatty change in the
  liver due to intracellular accumulation of
  triglycerides.
• 2. A normal or abnormal endogenous substance
  accumulates because it cannot be metabolized or
  is deposited intracellularly in an amorphous or
  filamentous form. One important cause is a
  genetic enzymatic defect in a specific metabolic
  pathway, so that some particular metabolite
  cannot be used. The resulting diseases are
  referred to as storage disease.
• 3. 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.
  Accumulations of carbon particles and such
  non-metabolizable chemicals as asbestos particles
  are examples of this type of alteration.

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• Classification of accumulated materials
• A. Endogenous substances
• Lipids
• Glycogen and carbohydrates
• Protein and proteinaceous material
• Products of abnormal metabolism
• Endogenous pigments
• B. Exogenous substances
• Exogenous pigments
• Iatrogenic accumulations
• C. Pathologic calcification

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FATTY CHANGE

• (Fatty metamorphosis, fatty degeneration,
  steatosis)
• Accumulation of excess neutral fat in vacuoles
  within non-adipocytes
• one big fat vacuole, ? "macrovesicular
• many little fat vacuoles ? "microvesicular

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• Fatty change of injured cells occurs classically
  in the liver and the heart.
• There are at least six mechanisms by which the
  liver cell accumulates fat during disease, any or
  all of which may be operating in a given
  situation
• 1. Too much free fat coming to the liver
• 2. Too much fatty acid synthesis by the liver
• 3. Impaired fatty acid oxidation by the liver
• 4. Excess esterification of fatty acid to
  triglycerides by the liver
• 5. Too little apoprotein synthesis by the liver
• 6. Failure of lipoprotein secretion by the liver.

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• Fatty liver develops during heavy Alcoholism, and
  all six mechanisms are known to contribute here.
• Other causes of liver include,
• Kwashiorkor
• Reye's syndrome
• poisoning by phosphorus, carbon tetrachloride,
  outdated tetracycline
• pregnancy
• galactosemia
• ischemia
• hepatitis C virus.

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• Fatty change in the heart is seen in two classic
  situations
• 1) It most often reflects poor oxygenation (i.e.,
  chronic severe anemia).
• 2) The heart damaged by diphtheria exotoxin is
  uniformly fatty (Diphtheria blocks carnitine
  metabolism).

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• Accumulation of fat in phagocytic cells is a
  common subject in pathology.
• The fat is usually made up largely of cholesterol
  esters.
• Atherosclerosis, the 1 disease in the world,
• results when phagocytic cells in the intimal
  layers of large arteries become engorged with
  cholesterol and its esters.
• The phagocytes themselves tend to die off and
  leave the cholesterol to crystallize.
• One can recognize cholesterol (esters) in tissue
  sections by the "needle-shaped" clear spaces left
  behind when it is removed in processing.

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• Lipophages are scavenger macrophages.
• This is common wherever lipid-rich tissues (belly
  fat, brain, others) have been injured, or where
  alveoli cannot drain.
• The cytoplasm of these cells typically looks
  "foamy" (" cells")
• Masses" composed of foamy cells are called
  xanthomas ("xanthos" means yellow).
• These often (but not always) suggest some problem
  with blood lipids.

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• Fatty ingrowth ("stromal infiltration of
  fat", "lipomatosis") is totally different from
  fatty change.
• It is metaplasia of an organ's capillary
  pericytes into mature adipocytes.
• This is a common finding in lymph nodes, in the
  pancreas, and in the right ventricle and atria of
  the heart.
• Usually it has no effect on organ function.
• The most important appearance of fatty ingrowth
  in medical pathology is as a component of most
  muscular dystrophies.

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COMPLEX LIPIDS CARBOHYDRATES

• These typically result from inborn errors of
  metabolism.
• Typically the substance is stored in lysosomes.
• Eventually enough accumulates to compromise organ
  function.
• ...in what disease
• Gaucher's glucocerebroside
• Tay-Sachs ganglioside
• Niemann-Pick's sphingomyelin
• Hunter's, Hurler's mucopolysaccharide
• Fabry's ceramide trihexose.

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• Gaucher's disease is common, and produces huge,
  pink-staining, glucocerebroside-laden macrophages
  in the bone marrow and elsewhere.
• In gout, uric acid accumulates as nodules in the
  tissues.
• These are called "tophi" (singular "tophus").

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Many inherited disorders of metabolism can lead
to accumulation of storage products in cells, as
seen here with Gaucher's disease involving
spleen. The large pale cells contain an
accumulated storage product from lack of an
enzyme.
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GLYCOGEN ACCUMULATION

• Glycogen ordinarily is present in the livers of
  people in the fed state, and is abundant if the
  patient has an i.v. line infusing glucose
  ("dextrose", "D5", etc.).
• In hyperglycemia, it is common to see glycogen in
  hepatic cells, pancreatic beta cells, and (if
  control is really poor) in the renal proximal
  tubular epithelial cells.
• These accumulations are probably harmless.
• The various glycogen storage diseases result from
  inborn errors of metabolism.

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Glycogen Storage Diseases
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Myxoid Change

• Increased gelatinous edematous ground
  substance
• Hypotyroidism (Generalized myxedema)
• Hypertyroidism (localized myxedema especially in
  pretibial region)

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• Myxomatous degeneration ("myxoid degeneration")
• If there is associated damage to the connective
  tissue fibers,examples
• "cystic medial necrosis" of the aorta
• Barlow's floppy mitral valve (affects about 5 of
  population)
• Myxoid change of the intima
• narrows the renal arteries in scleroderma and
  Balkan nephropathy,
• eventually causing kidney failure.
• Accumulation of epithelial mucin,
• large pools,
• mucin producing cancers.

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Signet ring cell carcinoma
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Protein Proteinaceous material

• Hyaline The term hyaline is widely used as a
  descriptive histologic term rather than a
  specific marker for cell injury.
• It usually refers to an alteration within cells
  or in the extra-cellular space, which describes
  any substance that stains a homogeneous pink on
  routine HE stains. It is composed of globular or
  filamentous proteins.
• Extracellular accumulation hyaline is more common
  than intra-cellular occurrence.

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HYALINE

• Epithelial hyaline
• Eosinophilic droplets in the proximal tubular
  epithelial cells
• when patient are losing lots of protein trough
  their glomeruli, you can detect hyaline casts in
  their urine!
• Mallory's alcoholic hyaline
• in liver cells
• usually reflects weeks of heavy drinking (in
  "alcoholic hepatitis").

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• Alpha-1 protease inhibitor ("antitrypsin")
  globules
• look like multi-sized cherries within hepatocytes
  
• Giant mitochondria
• a feature of alcoholic liver disease .
• Mesenchymal hyaline
• Keloids / hypertrophic scars and other abnormal
  fibrous proliferations.
• Excess basement membrane and other proteins
• small arteries in high blood pressure and
  diabetes.
• Russell bodies
• round accumulations of monoclonal immunoglobulin
  that are inside the plasma cells.

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Examples for intracellular protein accumulations

• Protein droplet accumulation Eosinophilic
  droplets in the proximal convoluted tubular
  epithelium of the kidney in severe proteinuria.
• Mallory body (Mallory alcoholic hyaline)
  Intracellular amorphous eosinophilic protein
  aggregates in the hepatocytes (associated with
  alcoholic liver disease and with a variety of
  liver diseases, e.g., hepatocellular carcinoma,
  hepatolenticuler degeneration, cytoskeletal
  damaging chemicals).
• Neurofibrillary tangles Filamentous inclusions
  consisted of neurofilaments and protein, and
  classically found in the brain of Alzheimer
  patients.
• Massive globular deposits Huge amount of protein
  aggregates in the hepatocytes of a-1-antitrypsin
  deficiency patients.
• Russell bodies Round accumulations of
  monoclonal immunoglobulin inside the plasma cells

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Examples for extracellular protein accumulations

• Hyalinization of collagen in keloids /
  hypertrophic scars and other abnormal fibrous
  proliferations.
• Hyalinization of mesenchymal tumors Leiomyoma
  uteri, Fibroma.
• Hyalinization of blood vessels Excess basement
  membrane and other proteins "hyalinize" the small
  arteries in high blood pressure and diabetes.

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Hyaline-like material

• It is not true hyaline, but it looks like
  hyaline!
• Amyloid is another extracellular accumulation
  that always has a hyaline appearance.
• Fibrin can be intensely eosinophilic and appear
  "hyaline".
• Fibrinoid is a special "material" seen in the
  walls of blood vessels that are dead but still
  contain flowing blood. (This condition could be
  seen in malignant hypertension or vasculitis).

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• The centers of rheumatoid nodules may be filled
  with "fibrinoid",
• and it is also characteristically seen in the
  myocardium in rheumatic fever.
• Radiation injury to vessels appears as
  hyaline-fibrinoid in vessel walls.
• Spironolactone bodies are an other fibrinoid
  material that are found in the mineralocorticoid-p
  roducing cells of the adrenal gland in people
  treated with this drug.
• In chronic kidney disease, entire glomeruli may
  "hyalinize".

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Products of Abnormal metabolism

• SODIUM URATE (Gout disease)
• A cellular reaction to uric acid crystal
  deposition causes gout. Gout is the subject of
  the errors of the purine metabolism.
• Primary gout Primary gout is related to
  under-excretion or over-production of uric acid
  (inborn errors of purine metabolism),
• Secondary gout It is related to increased cell
  turnover or widespread cell destruction increase
  uric acid production

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• -Myeloproliferative diseases or their treatment
  lymphoma, leukemia
• -Chemicals and drugs alcohol ingestion, lead
  poisoning, thiazide diuretics, acetoacetic acid,
• -Renal disorders renal failure, renal tubular
  disorders,
• -Skin diseases hyperproliferative skin disorders
  (psoriasis),
• -Dietary disorders obesity, excess intake of
  anchovies, sardines, kidney, liver, and meat
  extracts,
• -Hormonal disorders hypoparathyroidism,
• -Others Lesch-Nyhan syndrome, Paget disease,
  hyperlipidemia, glycogen storage diseases (von
  Gierke).

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Pathogenesis of Gout

• Purine metabolism disorder uric acid/urate to
  accumulate in blood and tissues
• monosodium salts of uric acid precipitate,
  forming crystals
• Any condition predisposing to acidosis also
  precipitates urate crystals.
• Urate initially precipitates in the form of
  needle like crystals.
• The resulting crystals stimulate phagocytosis by
  neutrophils and initiation of the inflammatory
  cascade.

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• deposition of urate crystalsformation of
  characteristic tophi and (singular tophus)
• firm, nodular, subcutaneous deposits of urate
  crystals surrounded by foreign-body giant cells
  and fibrosis.
• The physical characteristics of urate crystals
  allow them to be recognized by polarizing
  microscopy.

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• Urate deposition tends to in relatively avascular
  tissues
• cartilage,
• epiphyseal bone
• periarticular tissues
• Kidney involvement leads to severe renal damage

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Complications of gout

• -Repeated acute attacks, or uric acid buildup,
  destroy the cartilage and underlying bones, which
  may become fused.
• -One fourth of gout patients develop uric acid
  kidney stones.
• -Tophi in medulla and pyramids (chronic urate
  nephropathy) cause acute and chronic kidney
  problems.
• -Patients with hyperuricemia tend to develop high
  blood pressure

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AMYLOID (Amyloidosis)

• The term amyloid denotes a variety of fibrillary
  proteins deposited in interstitial tissues in
  certain pathologic conditions.
• Amyloid is often deposited in vascular walls
  (BM), finally, the surrounding cells undergo
  pressure atrophy.

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• When iodine is added to fresh tissue containing
  amyloid, a brown color is produced.
• In histologic sections, amyloid stains as
  follows
• (a) With Congo red stain, amyloid appears red,
  with apple-green birefringence when viewed under
  polarized light.
• (b) With hematoxylin and eosin (HE), it stains
  homogeneous pink.
• (c) With crystal violet, amyloid shows
  metachromasia, appearing pink.
• (d) With thioflavin T, amyloid presents
  fluorescence,
• (e) Amyloid may also be stained
  immunohistochemically using antibodies specific
  to the various subtypes of fibrils.

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• On electron microscopy, amyloid appears as
  nonbranching fibrils 70-100 angstroms wide. These
  fibrils are usually crisscross but may be
  parallel.
• On x-ray diffraction, amyloid exhibits a pleated
  beta-sheet structure that renders the protein
  very resistant to enzymatic degradation,
  contributing to its accumulation in tissues.

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Chemical Composition of Amyloid

• A. Amyloid of Immunoglobulin Origin
• In AL amyloid, the protein is composed of
  fragments of the light chains of immunoglobulin
  molecules. AL is produced by neoplastic plasma
  cells (myeloma) and B lymphocytes (B cell
  lymphomas).
• Amyloid light chains resemble the free light
  chains (Bence Jones proteins) or light chain
  fragments that is produced by the neoplastic
  plasma cells or B lymphocytes.
• B. Amyloid of Other Origin
• (1) serum amyloid-associated protein, an acute
  phase protein produced by the liver during any
  inflammatory process
• (2) prealbumin
• (3) other peptide fragments.

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Classification of Amyloidosis

• Systemic Amyloidosis
• 1.1. Primary pattern of distribution AL amyloid
  is found in the heart, gastrointestinal tract,
  tongue, skin, and nerves (primary amyloidosis and
  neoplasms of B lymphocytes (plasma cell myeloma
  and B cell malignant lymphomas)). In rheumatoid
  arthritis, a non-immunoglobulin amyloid (AA) is
  deposited in this primary pattern.
• 1.2. Secondary pattern of distribution AA
  amyloid derived from plasma a1-globulins is found
  in the liver, spleen, kidney, adrenals,
  gastrointestinal tract, gingivae and skin.
• chronic inflammatory diseases such as
  tuberculosis, leprosy, rheumatoid arthritis,
  chronic osteomyelitis, bronchiectasis, chronic
  pyelonephritis, and inflammatory bowel disease
  (reactive systemic amyloidosis, secondary
  amyloidosis).

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• 2.Localized Amyloidosis
• may take the form of nodular, tumor-like masses
  that occur rarely in the larynx, tongue, bladder,
  lung, or skin.
• associated with localized plasma cell neoplasms.
• In Alzheimer's disease, deposits of a special
  form of amyloid occur in the extra-cellular brain
  substance (plaques).

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The thioflavin stain viewed with fluorescence
microscopy highlights the neuritic plaques of
Alzheimer's disease with amyloid deposition which
fluoresces bright green, as shown here.
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• 3.Amyloid in Neoplasms
• endocrine neoplasms, eg, medullary carcinoma of
  the thyroid, some of odontogenic tumors. The
  amyloid protein is AE, usually derived from
  precursor molecules of certain peptide hormones
  (eg, calcitonin).
• 4.Heredofamilial Amyloidosis
• amyloid type is AF or AA.
• classified as neuropathic, nephropathic, or
  cardiac, depending on the site of maximal
  involvement.
• Familial Mediterranean Fever (FMF) (autosomal
  recessive,fever and inflammation of joints and
  serosal membranes, and amyloidosis with secondary
  pattern of distribution.)
• 5.Senile Amyloidosis
• Small amounts of amyloid (AS type) are frequently
  found in the heart, pancreas, and spleen in the
  elderly.
• In the late stages of type II diabetes mellitus,
  amyloidosis occurs in the abnormal pancreatic
  islets.

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Medullary carcinoma of Thyroid
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• Neuritic plaques with Alzheimer's disease are
  seen here.
• They have an amyloid core as seen here with Congo
  red stain.
• Small peripheral cerebral arteries may also be
  involved

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Accumulation ofEndogenous pigments

• MELANIN
• HEMOSIDERIN
• HEMATIN HEMOZIN
• BILIRUBIN
• COPPER
• LIPOFUSCIN

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• Melanin
• From Greek "melos", black.
• This is the principal pigment of human skin.
• It is a complex largely polymerized
  5,6-dihydroxyindole and other tyrosine
  metabolites.
• Melanins are widely distributed in the animal
  kingdom, and the melanin in octopus ink is much
  like ours.
• Neuromelanin in the brain is much like skin
  melanin.
• Races from near the equator are protected from
  skin cancer and hypervitaminosis D by dark
  pigmentation.

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• Most people make mostly eumelanin,
• redheads make mostly pheomelanin (pheomelanin
  doesn't protect from sunlight but actually
  generates more free radical when light-exposed).
• Actually most mammals (including most people)
  make both
• Dark-skinned and most light-skinned make equal
  amounts of tyrosinase (the rate-limiter), but it
  works much better in dark-skinned people
• the amount of tyrosinase in red-heads is
  controversial.
• Albinos cannot make melanin, and usually have
  genetic defects of tyrosine metabolism.

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• Causes of hyperpigmentation
• UV
• Freckle (ephelis)
• More estrogen
• Pregnancy (melesma)
• Liver diseases
• Addisons disease
• Hemochromatosis
• Peutz-Jeghers syndrome
• Neurofibromatosis

• Causes of hypopigmentation
• Vitiligo (loss of melanocytes)
• Albinism
• Hypopituitarism
• Autoimmune thyroiditis
• Pernicious anemia

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• Melanin is characteristically seen in melanocytes
  and their tumors (nevus pigmentosus, malignant
  melanoma)
• Diseases with increased cause hyperpigmentation.
• Sun-tanning is physiologic (and does not keep out
  cancer-causing rays).
• Ferric ion blocks breakdown of melanin, which
  explains the dark pigmentation in the skin of
  hemochromatosis patients and over
  dermatofibromas.
• Melanin in the urine indicates extensive
  malignant melanoma.

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Hemosiderin

• The stainable form of iron is hemosiderin, a
  complex mixture of proteins and ferric ions.
• It is faintly visible as shiny golden granules in
  unstained tissue sections.
• The best way to visualize hemosiderin is using
  acid ferrocyanide, which forms a striking blue
  complex with stainable ferric ion ("Prussian
  blue").
• In hepatocytes, hemosiderin tends to locate near
  the bile canaliculi.

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• Note that ferrous iron in heme groups
  (hemoglobin, myoglobin, cytochromes) does not
  stain.
• Neither does the ferric iron stored as ferritin,
  since the apoferritin protein shields the iron
  atoms.
• Normally there is some stainable hemosiderin in
  marrow, spleen, liver.
• Localized accumulations of iron ("local
  hemosiderosis") reflect longstanding congestion
  (lungs, leg veins), repeated minor injury
  (shrapnel fragments, sports, etc.).

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• Generalized hemosiderosis has several causes
• Many red cell transfusions without blood loss
• Too much iron being absorbed from the intestines
• longstanding hemolysis
• heavy drinking
• hemochromatosis gene (chromosome 6)
• no transferrin in serum (liver becomes loaded,
  marrow empty)
• Problems in using the iron
• ineffective erythropoiesis (thalassemia, others)
• sideroblastic anemia
• interleukin 1 effect (blocks uptake of iron by
  normoblasts, "anemia of chronic disease")

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• Gross excess of ferrous iron in the diet
• iron supplements
• vitamin C abuse (extreme)
• certain foreign wines (iron is added)
• Bantu beer (brewed in old steel oil drums).
• Excess hemosiderin eventually causes organ injury
  by generating free oxygen radicals.
• This leads to organ failure, which is called
  "hemochromatosis".
• In a few cases, the disease has been detected by
  sufferers' tripping airport metal detectors.

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• Hemozoin
• This is a ferric iron pigment that looks like
  hemosiderin when unstained, but which does not
  exhibit the Prussian Blue reaction because the
  iron is sequestered by protein.
• It consists of polymerized heme with each iron
  atom joined to a carboxyl group on the next
  porphyrin unit.
• It is seen in RE cells in malaria the plasmodia
  protect themselves from free iron-heme complex by
  converting it into this substance.
• Hematin
• Sometimes deposited in RE cells in other cases of
  heavy hemolysis,
• is ferriprotoporphyrin IX hydroxide.

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Bilirubin

• This is the non-iron-containing, yellow-orange
  pigment that results from breakdown of porphyrin
  rings (mostly hemoglobin).
• Bilirubin by itself is insoluble in water and is
  carried on albumin to the liver, where
  hepatocytes conjugate it with glucuronic acid and
  pour it into the bile.
• Elevated levels of bilirubin in the blood mean
  jaundice (icterus).

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Mechanisms of icterus

• Hemolytic jaundice
• Hepatocellular jaundice
• Obstructive jaundice

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• Copper pigment
• Deposited in the liver and/or basal ganglia in
  Wilson's disease.
• Homogentisic acid polymer ("alkapton")
• Patients with the hereditary arthritis syndrome
  "alkaptonuria" accumulate this substance,
• which breaks down into black pigment, in
  cartilages (nose, ears), joints, sweat.
• The accumulation itself is called "ochronosis".

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• Lipofuscin ("lipochrome)
• "fuscus" is Latin for brown
• This is another brown pigment
• un-digestible residue of subcellular membranes
  whose unsaturated lipids have been scrambled by
  free radicals.
• Lipofuscin is the "wear-and-tear pigment".
• It is considered harmless, and does not stain
  with lipid dyes.
• Lipofuscin's an important component of the cores
  of extracellular Alzheimer's lesions.

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• Yellow-brown granular pigment seen in the
  hepatocytes here is lipochrome (lipofuscin) which
  accumulates over time in cells (particularly
  liver and heart) as a result of "wear and tear"
  with aging.

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• Lipofuscins ....even in youth
• the interstitial cells of the testis
• the epithelial cells of the epididymis and
  seminal vesicles
• lipofuscin at the poles of the cardiac nuclei
  even in babies
• earwax pigment is a lipofuscin.
• Lipofuscin becomes more abundant during normal
  aging, or following atrophy.
• "Brown atrophy" is simply atrophy where the
  lipofuscin is visible grossly.

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Exogenous Pigments

• Carbon
• Carbon particles enter our bodies in smoke and
  soot or as the pigment in jailhouse tattoos.
• Carbon settles in macrophages, where it remains
  indefinitely.
• Carbon in the lungs and nearby lymph nodes is
  called "anthracosis".
• "Blue scars" result from wounds sustained in a
  coal mine. The dust becomes trapped in the fresh
  wound for life.
• Other mineral dusts include silica (colorless,
  very harmful) and iron oxide ("rusty lung", not
  very harmful).

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• Anthracotic pigment in macrophages in a hilar
  lymph node. Anthracosis is nothing more than
  accumulation of carbon pigment from breathing
  dirty air. Smokers have the most pronounced
  anthracosis. The anthracotic pigment looks bad,
  but it causes no major organ dysfunction

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• Asbestos fibers Asbestos fibers cause pulmonary
  and pleural inflammation and cancer.
• Tobacco pigment It is common in alveolar
  macrophages in heavy smokers. It is a fine,
  powdery mix of brown pigments, sometimes
  including iron.

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Asbest
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TATTOO

• The term tattoo describes the deliberate
  placement of permanent colors into the skin or
  the accidental entry of pigmented material.
• Accidental tattooing may occur after abrasion
  injuries.
• Traumatic tattoos are not uncommon however,
  decorative tattoos are the most common form.
• Complications resulting from decorative tattoos
  are relatively rare conside-ring the popularity
  of tattooing however, the introduction of
  foreign substances into the skin can result in a
  toxic or immunologic response.

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• HEAVY METALS
• Argyria It results from silver salts being
  permanently deposited in the skin, liver and
  kidney.
• Lead Lead poisoning may present lead salts
  deposits in the gingivae, bones, and brain.

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IATROGENIC ACCUMULATIONS

• Oral mineral oil Lipogranulomas in the spleen
  and celiac lymph nodes are thought to have
  several causes, including oral mineral oil.
• Lymphangiogram contrast medium This is oil which
  stays in lymph nodes for years.
• Tetracycline Once in the bloodstream,
  tetra-cycline can be incorporated into the
  calcification process of developing teeth, in
  which it affects either primary or secondary
  dentition after maternal or childhood ingestion,
  respecttively.
• Tetracyclines diffuse through dentin to the
  enamel interface, chelating calcium ions and
  incorporating into hydroxyapatite as a stable
  orthophosphate complex.
• Bright-yellow bandlike appearance that fluoresces
  under ultraviolet light, although upon exposure
  to sunlight, the color gradually changes to gray
  or red-brown.

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Tetracycline teeth
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CALCIFICATION

• Calcium salts (hydroxides, phosphate-hydroxides)
  are abnormally deposited.
• Regardless of cause, calcium salts stain dark
  blue on HE.
• If there is any doubt, special stains like the
  Von Kossa of Alizarin red demonstrate it is
  calcium.
• Pathologic calcification
• Dystrophic calcification
• Metastatic calcification
• Tumoral calcinosis