Intracellular Accumulations & Pigments Flashcards
Intracellular accumulations are?
• These are substances which accumulate in the cell due to increased production or defective removal by the cell.
• These accumulations could be
Source _____ or _______
Effect _____ or _______
Residency _____ or _______
Location _____ or _______
endogenous/exogenous
toxic/non-toxic
temporary/permanent
cytoplasm or nucleus
4 causes of intracellular accumulation
2 normal endogenous
- A normal endogenous substance produced at a normal or increased rate but the rate of metabolism is inadequate to remove it
E.g. is seen with fatty droplets in the liver. - A normal endogenous substance accumulates due to a defect in the enzyme required for its metabolism.
E.g. Lysosomal storage dx
4 causes of intracellular accumulation
1 abnormal endogenous
1 abnormal exogenous
- An abnormal endogenous substance accumulates e.g. the product of a mutated gene or misfolded proteins which cannot be degraded accumulate in the cell.
E.g. is neurodegenerative diseases - An abnormal exogenous substance accumulates in the cell because the cell lacks the ability to degrade it or transport it to other sites. E.g. is carbon particles in alveolar macrophages.
Steatosis;
Mostly seen in the ____because it is the major organ involved in fat metabolism. May also be present in the ____,____ &____.
Special stains used to identify fatty droplets microscopically are
Liver
Heart, muscle & kidney
Sudan black & oil Red-O
6Causes of steatosis
- Alcohol abuse
- diabetes
- Obesity
- Carbon tetrachloride (CCl4) and protein malnutrition cause reduced apoprotein synthesis which results in defective lipid transport
- Hypoxia impairs fatty acid oxidation
- Starvation causes mobilization of fat from peripheral stores
In steatosis, Alcohol alters mitochondrial and microsomal function leading to?
In DM?
increased synthesis and reduced breakdown of lipids.
elevated glucose provides more substrate for triglyceride synthesis.
Types of cholesterol accumulation
Explain strawberry gall bladder
Atherosclerosis in blood vessels
• Xanthomas in connective tissue and skin
• Cholesterolosis in the gall bladder
• Niemann-Pick disease type C
In cholesterolosis, surface appearance of mucosa of gall bladder resembles strawberry due to multiple collections of TGs and cholesterol esters
Protein accumulation
- In proteinuria, droplets in proximal renal tubules
- Immunoglobulins may accumulate in plasma cells within the ER producing inclusions called Russell bodies
- Alpha 1 antitrypsin deficiency (emphysema), the enzyme is deficient because its precursors are misfolded and have accumulated in the liver.
- Accumulation of cytoskeletal proteins: keratin intermediate filaments are seen in alcoholic hyaline which is characteristic of alcoholic liver disease. Neurofibrillary tangles found in Alzheimer disease are made up of neurofilaments
- Aggregation of abnormal proteins e.g. in amyloidosis.
Glycogen accumulation
• Seen in disorders of glucose or glycogen metabolism. E.g. in D.M, normal glucose uptake by cells is impaired. Seen in hepatocytes (stained by PAS/PASD)
• Also seen in genetic disorders of enzymes involved in glucose/glycogen metabolism. These are called glycogen storage d
Pigments could be ____ or ____
• Could be endogenous or exogenous
Endogenous pigments include
• lipofuscin (wear and tear pigment)
• Hemosiderin
• Homogentisic acid – deposited in the connective tissues, skin in patients with alkaptonuria. The pigmentation is known as ochronosis.
• Melanin
• Bilirubin
Exogenous pigments
Carbon/coal dust seen as anthracosis in lungs and may also cause coal workers pneumoconiosis.
Tattoo pigments are also absorbed by dermal macrophages.
A man has been diabetic with poorly controlled blood sugar for the past five years. Which of the following may be characteristic changes in his body organs as a result of the chronic illness?
A. Fatty liver
B. Atherosclerosis in blood vessels
C. Glycogen accumulation in hepatocytes
D. Carbon dust in the lungs
E. All of the above
A young lady walks into the clinic. She complains of black coloured urine. On examination, you notice black patches on her face. Which of the following may be implicated?
A. Melanin
B. Alkaptonuria/Homogentisic acid
C. Coal dust
D. Tatoo pigments in the urine
E. None of the abov
Pigments are
Pigments are coloured substances, some of which accumulate in the cell under special circumstances.
Pigments could be what or what or what
● They could be:
○ Normal e.g. melanin or abnormal e.g. tatoo
○ Endogenous i.e. synthesized by the body
or Exogenous i.e. derived from the external environment
I’m anthracosis seen in carbon or coal dust what happens
In anthracosis, the macrophages which ingest the inhaled carbon particles, also elaborate cytokines which encourage the formation of fibrosis in the lungs. This may result in difficulty in respiration.
About carbon (coal) dust
• Carbon (Coal dust) is the most common exogenous pigment.
• It is ubiquitous and is inhaled daily as an air pollutant
• When inhaled, it is ingested by the macrophages in
the alveoli which transport them via lymphatic channels to the regional lymph nodes
This pigments forms the dark coloured patches seen on the pleural surface of the lungs and lymph nodes in the tracheobronchial tree.
Coal worker’s pneumoconiosis is a disease condition where
there is a fibroblastic reaction to the large amounts of coal dust inhaled by workers in this profession.
Now endogenous
Lipofuscins are
● Granules composed of lipid-protein complexes.
● Found in ageing or debilitating diseases and are the end
products of oxygen radical mediated membrane damage
which are not eliminated by intracellular lipid peroxidation.
● They subsequently persist in the lysosomes as collections of
indigestible material.
● Not injurious to the cell
Morphology of lipofuscin
● Yellow-brown, finely granular cytoplasmic (perinuclear) pigment.
● No gross features
Characteristics of melanin
● Non-haemoglobin derived brown-black pigment.
● Normally seen in the skin, hair etc
● Synthesized in the melanocytes and dendritic cells by the
action of tyrosinase on tyrosine to form
dihydroxyphenylalanine (DHPA).
Disorders of melanin pigmentation can cause _______& ______
● generalised and localised hyperpigmentation/hypopigmentation
Diseases of generalised hyperpigmentation is
● Addison’s disease: hyperpigmentation of sun exposed areas
● Chloasma: seen in pregnancy/oral contraceptive pills.
Oestrogen induced hyperpigmentation of the face, nipples,
genitalia.
● Chronic arsenic poisoining: classic raindrop pigmentation of
the skin.
Disease of focal hyperpigmentation is
● Neurofibromatosis: Cafe-au-lait spots
● Peutz-Jeghers syndrome: Peri-oral
● Melanosis coli: mucosa of the colon
● Melanotic tumours: skin
● Lentigo: skin
● Dermatopathic lymphadenopathy: Lymph nodes draining skin lesions
General hypopigmentation is also known as?
Diseases include
Albinism
● Genetic defect in tyrosinase
● Oculocutaneous cases have almost no pigment in the skin
and hair and complain of severe photophobia.
● Chronic sun exposure may lead to skin cancer
Focal hypopigmentation
● Leucoderma: localised loss of skin pigmentation. Autoimmune condition.
● Vitiligo: More common, may be familial
● Acquired focal hypopigmentation: healing of wounds,
leprosy, lupus etc.
In alkaptonuria
● Autosomal recessive disorder
● Deficiency of oxidase enzyme which is required to break
down homogentisic acid.
● Homogentisic acid therefore accumulates in the tissues
and is excreted in the urine.
● Urine turns black if allowed to stand for a few hours in the
air (oxidation of homogentisic acid).
● The black pigment is called ochronosis and is deposited both inter and intracellularly. E.g. Joints, ligaments, skin tissue.
In bilirubin
● Pigment also derived from haemoglobin but is non-iron containing, found in bile.
● Excess bilirubin (hyperbilirubinaemia) causes jaundice ● Aetiology
○ Increased production (excessive RBC destruction)
○ Defective conjugation (liver disease/injury)
○ Defective transport (intra/extrahepatic bile ducts)
● Accumulates as yellow pigment in the fluids and tissues of the body e.g. hepatocytes, skin, sclera.
● In infants, high levels of unconjugated bilirubin may cause brain injury (kernicterus)
In Haemosiderin
Iron in tissues can be stored either as
○ Ferettin (Fe complexed to apoferritin)
○ Haemosiderin (formed by aggregates of ferritin)
● Excessive storage of haemosiderin occurs when there is increased breakdown of red blood cells or systemic iron overload.
● Can be localised or generalised
Localised Haemosiderosis
● When there is haemorrhage into the tissue, the red blood cells are lysed releasing their haemoglobin which is then taken up by macrophages, degraded and stored as haemosiderin. Examples are
○ Haemosiderin laden macrophages at sites of endometriotic deposits
○ Haemosiderin laden alveolar macrophages (heart failure cells) in the lungs in left ventricular failure
Generalised haemosiderosis
Causes are broadly categorised into:
● Increased breakdown of haemoglobin e.g. chronic hemolytic anaemia, excessive blood transfusion
● Excessive intestinal absorption of iron
● Excessive iron intake e.g. multivitamins, alcohol brewed in
certain vessels.
In Increased Haemolysis
● In various forms of chronic haemolytic anaemia, there is iron overload resulting from excessive haemoglobin breakdown.
● Treatment with blood transfusions or parenteral iron only worsens the condition
In Excessive absorption of iron
● Excessive absorption even with normal intake is known as idiopathic or hereditary haemochromatosis.
● It is an autosomal dominant disease
● Characterised by:
○ Pigmented liver cirrhosis
○ Skin pigmentation
○ Pancreatic damage resulting in diabetes (‘bronze
diabetes’)
In Excessive iron intake
● First observed in the Bantu tribe of South Africa.
● Consumption of alcohol brewed in ungalvanised iron
vessels.
● Later found in other communities without similar history of
alcohol brewing/consumption.
● A gene called ferroportin has been identified as the
predisposing factor to this overload.
Histology of hemosiderin
● Intracytoplasmic coarse, golden-brown, granular pigment
● Visualised with Prussian blue/Perl’s stain
Free radicals cause cellular injury bt 2 things
Peroxidation of lipids
Oxidation of DNA & proteins
