METABOLIC DISORDERS

GROUP MEMBERS
 REJOICE SANDRA SJEPSA2111
 JOB OGECHA SJOBRO2111
 NYAMIAKA GERALD SKEBNY2111
 MIRIAM FAITH JEPTOO SJEPMI2111
 KEPHA ATUTI SKEPATI1821
 KIBET STACY SKIBJE2112
 EDDAH JEROP SJERKI2113
 FRANKLINE KIPCHUMBA SFRAKI2111
 KELVIN KIPLIMO SKELKI2115
 DYLAN JUMA
 GODWIN CHERUIYOT
categories of disorders

• Lipid metabolism disorders

• protein metabolism disorders
• carbohydrate metabolism disoders
• intracellular accumulations
INTRACELLULAR ACCUMULATIONS

• This is accumulation of abnormal amounts of

various substances due to manifestations of
metabolic derangements in the cell.
• It occurs due to accumulation of normal
cellular substance such as water, lipid,
carbohydrates, protein & abnormal exogenous
and endogenous substances into the tissues.
intacellular accumulations
• Exogenous abnormal substances include minerals or
product of infectious agents.
• Endogenous substances include synthetic & metabolic
products.
• It maybe reversible or permanent.
• Maybe harmless but occasionally harmful.
• The substance maybe located in cytoplasm, nucleus or
within organelles (typically lysosomes).
• Intracellular accumulations can be produced by the
affected cell or produced elsewhere in the body but
stored in the cell.
causes

Abnormal metabolism; Production of a normal

endogenous substance at normal or increased
rate, but the rate of metabolism is inadequate
to remove it.
Mutations causing alterations in protein
folding and transport, so that defective
molecules accumulate intracellularly.
causes

A deficiency of critical enzymes responsible

for breaking down certain compounds, causing
substrates to accumulate in lysosomes, as in
lysosomal storage diseases.
An inability to degrade phagocytosed
particles. Accumulations of carbon or silica
particles are examples of this type of
alteration.
LIPID METABOLISM DISORDER

Lipid accumulation
• is abnormal lipid accumulation in cell.
• It maybe of fatty acid (steatosis) or
cholesterol.
1.STEATOSIS (FATTY CHANGE)

 Fatty change refers to any abnormal accumulation of

triglycerides within parenchymal cells.
 It is most often seen in the liver, since this is the
major organ involved in fat metabolism, but it may
also occur in heart, skeletal muscle, kidney, and other
organs.
 Steatosis may be caused by toxins, protein
malnutrition, diabetes mellitus, obesity, and anoxia.
Alcohol abuse and diabetes associated with obesity
are the most common causes of fatty change in the
liver (fatty liver) in industrialized nations.
continuation
 Free fatty acids from adipose tissue or ingested food are normally
transported into hepatocytes, where they are esterified to triglycerides,
converted into cholesterol or phospholipids, or oxidized to ketone bodies .
Some fatty acids are synthesized from acetate within the hepatocytes as
well.
 Egress of the triglycerides from the hepatocytes requires the formation of
complexes with apoproteins to form lipoproteins, which are able to enter
the circulation .
 Excess accumulation of triglycerides may result from defects at any step
from fatty acid entry to lipoprotein exit, thus accounting for the occurrence
of fatty liver after diverse hepatic insults.
 Hepatotoxins (e.g., alcohol) alter mitochondrial and SER function and thus
inhibit fatty acid oxidation; CCl4 and protein malnutrition decrease the
synthesis of apoproteins; anoxia inhibits fatty acid oxidation; and starvation
increases fatty acid mobilization from peripheral stores
Causes of lipid accumulation in liver

Excessive entry of free fatty acids in the liver s.a

starvation in cancer patients. Starvation increases
mobilization of fatty acids from peripheral
stores.
Inhibition of catabolism in liver s.a in
alcoholism( alcohol is a hepatotoxin that leads to
increased synthesis & reduced breakdown of
lipids) & hypoxia (inhibits fatty acid oxidation)
Decreased synthesis of apoproteins s.a protein
malnutrition.
2. Cholesterol & cholesteral esters
metabolism
 Cellular cholesterol metabolism is tightly regulated to
ensure normal cell membrane synthesis without significant
intracellular accumulation.
 However, phagocytic cells may become overloaded with
lipid (triglycerides, cholesterol, and cholesteryl esters) in
several different pathologic processes.
 Macrophages in contact with the lipid debris of necrotic
cells or abnormal (e.g., oxidized) forms of lipoproteins
may become stuffed with phagocytosed lipid. These
macrophages may be filled with minute, membrane-bound
vacuoles of lipid, imparting a foamy appearance to their
cytoplasm (foam cells).
Atherosclerosis

Atherosclerosis: smooth muscle cells &

macrophages are filled with lipid vacuoles
composed of cholesterol & cholesteryl esters
forming foam cells within intima layer of
vessels.
These give artherosclerotic plaques their
characteristic yellow color & contribute to the
pathogenesis of the lesion.
xanthomas

xanthomas: cluster of foam cells in sub-

epithelial connective tissues of skin & tendons
forming masses .
cholesterosis

focal accumulation of cholesterol laden

macrophages in lamina propia of gall bladder.
Neimann Pick disease Type C(NPC)

 This is a lysosomal storage disorder characterized by

cholesterol accumulation in multiple organs.
 NPC is an autosomal recessive lipidosis that is characterized by
lysosomal storage of cholesterol & glycosphingolipids.
 In normal mammalian cells, low density lipoprotein (LDL) is
bound & internalized by cell surface receptors & is hydrolyzed
in the endocytic compartment. The cholesterol that is released
is transported to the cell surface & endoplasmic reticulum.
 In NPC cells, LDL derived cholesterol accumulates in
lysosomes & endosomes. LDL cholesterol transport from
endocytic compartments to other cellular compartments is
delayed.
PROTEIN METABOLISM DISORDERs

Protein accumulation may occur because

excesses are presented to the cells or because the
cells synthesize excessive amounts.
Protein accumulation appears as rounded,
eosinophilic droplets, vacuoles or aggregates in
cytoplasm.
On electron microscopy they can be amorphous,
fibrillar or crystalline in appearance.
1. Nephrotic syndrome
In the kidney trace amounts of albumin filtered through
the glomerulus are normally reabsorbed by pinocytosis
in the proximal convoluted tubules.
However, in disorders with heavy protein leakage
across the glomerular filter (e.g., nephrotic syndrome),
there is a much larger reabsorption of the protein.
Pinocytic vesicles containing this protein fuse with
lysosomes, resulting in the histologic appearance of
pink, hyaline cytoplasmic droplets. The process is
reversible; if the proteinuria stops, the protein droplets
are metabolized and disappear.
2. Russell bodies

 Russell bodies are multiple round cytoplasmic hyaline

inclusions that are frequently seen in bone marrow aspirates
in myeloma.
 Proteins accumulated maybe normal secreted proteins that
are produced in excessive amounts as occurs in certain
plasma cells engaged in active synthesis of
immunoglobulins.
 Marked accumulation of newly synthesized
immunoglobulins may occur in the Rough Endoplasmic
Reticulum of some plasma cells, forming rounded,
eosinophilic Russell bodies.
3. Alpha 1 antitrypsin deficiency

 There is protein folding defect which leads to

build up of partially folded proteins which
aggregate in Endoplasmic Reticulum of liver
or also results in emphysema.
 The synthesized protein lacks the ability to
migrate from ER to golgi zone & thus
accumulates inside ER as hyaline globules.
4.Accumulation of cytoskeletal proteins

1.Mallory body or alcoholic hyaline

Refers to alteration within cells or in the extracellular space
that gives a homogenous, glassy, pink appearance in routine
histologic sections stained with H & E
Is an eosinophilic cytoplasmic inclusion in liver cells that is
highly characteristic of alcoholic liver disease. These
inclusions are composed predominantly of aggregated
intermediate filaments.
2.Neurofibrillary tangle
Is found in the brain in Alzheimer disease . Its an aggregated
protein inclusion that contains microtubule associated
proteins. a reflection of a disrupted neuronal cytoskeleton.
5. amyloidosis
Amyloid deposition
 In this condition a waxy substance composed
essentially of an abnormal protein is deposited in the
extracellular tissues, particularly around the supporting
fibres of blood vessels & basement membranes.
 Amyloid is resistant to degradation & removal by the
usual process so that the deposition progresses.
 Amyloid maybe suspected when the organs are pale &
enlarged, and have a firm waxy texture at post mortem
or microscopically using biopsy material in a living
being.
AmyloidsClassification

 Amyloids are classified into 2 main types;

 Primary i.e without known cause
 Secondary i.e associated with chronic inflammatory
diseases s.a TB, osteomyelitis & rheumatoid arthritis.
 The amyloidosis can also be systemic or localised.
 Systemic amyloidosis is derived from abnormal
monoclonal proliferation of plasma cells & acute
reactant protein.
 Localised amyloidosis is derived from endocrine
polypeptides.s
Nature of amyloid

 Chemical – the fibrils are composed of one

major & 2 minor components.
 Protein- variable
 protein- constant. Normally found in serum
(serum amyloid protein)
 Carbohydrate- a glycosaminoglycan this gives
the iodine stain.
 Physical- the fibrils are organised uniquely
(beta pleated)
 pathogenesis of amyloid
 Almost any tissue in the body maybe affected by amyloid
deposition but most important changes occur in the kidney, GIT
& heart.
 In the kidneys, glomerular capillary permeability is altered
leading to gross proteinuria.
 GIT due to altered permeability of the capillaries, the patient
suffers from diarrhoea & protein loss. There may also be
malabsorption, nutritional deficiencies & electrolyte imbalance.
 Heart, amyloid deposition occurs around the cardiac muscle
fibres & the capillary basement membranes. Cardiac failure
develops mainly due to the mechanical effect of amyloid,
preventing proper muscular contraction & partly to malnutrition
of the muscle fibres caused by poor blood supply.
CARBOHYDRATE METABOLISM
DISORDERS
glycogen accumulation

 is Associated with abnormalities in the metabolism of

either glucose or glycogen.
 In poorly controlled diabetes mellitus, glycogen
accumulates in renal tubular epithelium, cardiac
myocytes & beta cells of the islets of langerhans.
 Glycogen accumulates within cells in a group of
closely related genetic disorders collectively referred to
as glycogen storage diseases or glycogenoses.
 In these diseases, enzymatic defects in the synthesis or
breakdown of glycogen result in massive stockpiling
with secondary injury & cell death.
PATHOLOGICAL CALCIFICATION
introduction
 Pathologic calcification is a common process in a wide variety of
disease states; it implies the abnormal deposition of calcium
salts, together with smaller amounts of iron, magnesium, and
other minerals.
 When the deposition occurs in dead or dying tissues, it is called
dystrophic calcification; it occurs in the absence of calcium
metabolic derangements (i.e., with normal serum levels of
calcium).
 In contrast, the deposition of calcium salts in normal tissues is
known as metastatic calcification and almost always reflects
some derangement in calcium metabolism (hypercalcemia).
 It should be noted that while hypercalcemia is not a prerequisite
for dystrophic calcification, it can exacerbate it.
 Dystrophic calcification
 Dystrophic calcification is encountered in areas of necrosis of
any type.
 It is virtually inevitable in the atheromas of advanced
atherosclerosis, associated with intimal injury in the aorta and
large arteries and characterized by accumulation of lipids.
 Although dystrophic calcification may be an incidental
finding indicating insignificant past cell injury, it may also be
a cause of organ dysfunction. For example, calcification can
develop in aging or damaged heart valves, resulting in
severely compromised valve motion. Dystrophic calcification
of the aortic valves is an important cause of aortic stenosis in
the elderly
Metastatic calcification
 Metastatic calcification can occur in normal tissues
whenever there is hypercalcemia (increase in the blood
calcium). The four major causes of hypercalcemia are as
follows;
 Parathyroid overactivity due to tumor & hyperplasia
secondary to metabolic acidosis; causes mobilisation of
calcium from bone leading to increased blood calcium.
 Vitamin D overdosage causing increased absorption of
calcium, hence increased blood calcium & deposition
occurs in the kidneys, arteries & lungs.
 renal failure, in which phosphate retention leads to
secondary hyperparathyroidism.
causes

 iv. destruction of bone due to the effects of

accelerated turnover (e.g., Paget disease),
immobilization, or tumors (increased bone
catabolism associated with multiple myeloma,
leukemia, or diffuse skeletal metastases