RETROGRESSION (DEGENERATIONS)

Degenerations are defined as the light microscopic changes of reversible cell injury by a variety of agents
while cell death or necrosis is a state of irreversible cell disorganisation when the cell is incapable of
performing any function. There may be instances when cellular changes progress from degeneration
(reversible cell injury) to necrosis (irreversible cell injury). For example, if the injurious agent is removed
following acute injury or the cell is able to withstand the assault of the stress, the cell injury is reversible
with complete restoration of structural and functional integrity; such changes are termed degenerations.
On the other hand, if the cell is exposed to severe and persistent injury, the changes that result are irre -
versible i.e. cell death or necrosis occurs. The precise 'point of no return', however, can not be accurately
identified.
Based on type of injury, degenerations can be classified into 2 broad groups: those with primary
changes in the cell, and those with interstitial accumulations compressing cells secondarily.
Some of these degenerative changes.
CELLULAR SWELLING
This is the commonest and earliest form of cell injury. Other synonyms of cellular swelling used in the
past are cloudy swelling (for gross appearance of the affected organ) and albuminous degeneration
(considered to be deranged protein metabolism).
Classification of Degenerations.
I. PRIMARY CHANGES IN THE CELLS:
1. Intracellular accumulation of water e.g..
(a) Cloudy swelling
(b) Hydropic and vacuolar change
2. Intracellular accumulation of fat e.g. Fatty change
3. Intracellular accumulation of carbohydrates e.g.
(a) Glycogenosis
(b) Mucinous change or mucoid degeneration
4. Intracellular accumulation of proteins e.g.
(a) Colloid droplets in proximal tubular epithelial cells in proteinuria
(b) Russell bodies in plasma cells
II. INTERSTITIAL ACCUMULATION COMPRESSING CELLS:
1. Amyloid
2. Hyaline change
3. Mucinous change;
4. Fatty infiltration
Cloudy swelling results from impaired regulation of cellular volume, especially for sodium. This
regulation is operative at 3 levels: at the plasma membrane itself, at the sodium pump on the plasma
membrane, and at the supply of ATP. Injurious agent may interfere with these regulatory mechanisms and
result in accumulation of sodium in the cell which, in turn, leads to inflow of water to maintain iso-
osmotic conditions and hence cellular swelling occurs.
Grossly the affected organ such as kidney, liver or heart muscle is enlarged due to swelling. The cut
surface bulges outwards and is slightly opaque.
Microscopically it is characterised by 2 features:
The cells are swollen and the microvasculature compressed. The cellular swelling is due to increased
influx of sodium and extracellular water into the cell and escape of potassium.
The cytoplasm is granular. This is due to swelling of endoplasmic reticulum and increase in the number
and size of lyosomes and mitochondria.
VACUOLAR AND HYDROPIC CHANGE
Vacuolar and hydropic degenerations have gross appearance like that of cloudy swelling. But the
cytoplasm, rather than granular, is vacuolated. The vacuoles, represent distended endoplasmic reticulum
or mitochondria, or may be large pinocytic vacuoles.
Hydropic change occurs when water transfer is most active, especially in the renal tubular cells, e.g.
following intraveous administration of hypertonic glucose, or in hypokalaemia.

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HYALINE CHANGE
The word 'hyaline' means glassy (hyalos = glass). Hyaline is a descriptive histological term for glassy,
homogeneous, eosinophilic appearance of material in haematoxylin and eosin stained sections and does
not refer to any specific substance. Hyaline change is associated with heterogeneous pathologic
conditions and may be intracellular or extracellular.
Intracellular Hyaline.
1. Hyaline droplets in the proximal tubular epithelial cells in cases of excessive reabsorption of plasma
proteins.
2. Hyaline degeneration of voluntary muscle, also called Zenker's degeneration, occur in rectum
abdominalis muscle in typhoid fever. The muscle loses its fibrillar staining and becomes glassy and
hayline.
3. Mallorys hyalin representing aggregates of intermediate filaments in the hepatocytes in alcoholic liver
cell injury.
4. Nuclear or cytoplasmic hyaline inclusions in some viral infections.
5. Russell's bodies representing excessive immunoglobulins in the rough endoplasmic reticulum of the
plasma cells.
6. Corpora amylacea are rounded masses of concentric hyaline laminae seen in the prostate in the elderly,
in the brain and in the spinal cord in old age, and in old infarcts of the lung.
Extracellular Hyaline. A few examples of extracellular hyaline change are:
1. Hyaline degeneration in leiomyomas of the uterus.
2. Hyalinised old scar of fibrocollagenous tissue.
3. Hyaline arterioloscelerosis is renal vessels in hypertension and diabetes mellitus.
4. Hyalinised glomeruli in chronic glomeruhnephritis.
Though fibrin and amyloid have hyaline appearance, they have distinctive features and staining
reactions and can be distinguished from nonspecific hyalin material.

INTRACELLULAR ACCUMULATIONS
Intracellular accumulation of substances in abnormal amounts can occur within the cytoplasm or nucleus
of the cell. This phenomenon was previously referred to as infiltration, implying thereby that something
unusual has infiltrated the cell from outside which is not always the case. Intracellular accumulation of
mild degree causes reversible cell injury while more severe damage results in irreversible cell injury.
Such abnormal intracellular accumulations can be divided into 3 groups:
I. Accumulation of constituents of normal cell metabolism produced in excess e.g. accumulations of lipids
(fatty change), proteins and carbohydrates.
II. Accumulation of abnormal substances produced as a result of abnormal metabolism due to lack of
some enzymes e.g. storage diseases or inborn errors of metabolism.
III. Accumulation of 'pigments e.g. endogenous pigments under special circumstances, and exogenous
pigments due to lack of enzymatic mechanisms to degrade the substances or transport them to other sites.
INTRACELLULAR ACCUMULATION OF PROTEINS
Pathologic accumulation of proteins in the cytoplasm of cells may occur in the following conditions.
1. In proteinuria, there is excessive renal tubular reabsorption of proteins by the proximal tubular
epithelial cells which show pink hyaline droplets in their cytoplasm. The change is reversible so that with
control of proteinuria the protein droplets disappear.
2. The cytoplasm of actively functioning plasma cells shows pink hyaline inclusions called Russell's
bodies representing synthesised immunoglobulins.
AMYLOIDOSIS
Amyloidosis is the term used for group of diseases characterised by extracellular deposition of fibrillar
proteinaceous substance called amyloid. First described by Rokitansky in 1842, the substance was
subsequently named by Virchow as 'amyloid' under the mistaken belief that the material was starch-like
(amylon=starch) because the cut surface of an organ containing amyloid stained brown with iodine and
turned violet on addition of dilute sulfuric acid. Though tremendous strides have been made as regards the
nature and origin of this substance since then, the term amyloid is still retained. However, more recently,
an alternative term P-fibrillosis, has been proposed based on P-pleated sheet configuration of fibrillar pro-
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teins as described below.
NATURE AND ETIOLOGY OF AMYLOIDOSIS
By light microscopy with H &: E staining, amyloid appears as extracellular, homogeneous, structureless
and eosinophilic hyaline material. However, ultrastructural examination and chemical analysis reveal the
complex nature of amyloid. Based on these studies, the homogeneous appearing amyloid under light
microscope is in fact composed of 2 main types of complex proteins.
1. Fibril proteins comprising about 90% of amyloid.
2. P-component constituting the remaining 10% of amyloid.
CLASSIFICATION OF AMYLOIDOSIS:
1. Primary systemic (generalised amyloidosis)
2. Secondary (reactive) systemic generalised amyloidosis
3. Heredofamilia amyloidisis
4. Localised amyloidosis

1. Primary Systemic Amyloidosis

Primary amyloidosis is often severe in the heart, bowel, skin, skeletal muscle, and less often in the
solid abdominal viscera.
2. Secondary (Reactive) Systemic Amyloidosis
The second form of systemic or generalised amyloidosis is reactive or secondary in which the fibril
proteins contain AA amyloid. Secondary or reactive amyloidosis occurs a.s a complication of chronic
infectious or non-infectious inflammatory conditions such as tuberculosis, bronchiectasis, chronic
osteomyelitis, chronic pyelonephritis, leprosy, autoimmune disorders (e.g. rheumatoid arthritis,
dermatomyositis and scleroderma), inflammatory bowel disease (ulcerative colitis and Crohn's disease)
and some tumours (e.g. renal cell carcinoma and Hodgkin's disease).
Secondary amyloidosis is typically distributed in solid abdominal viscera like the liver, spleen,
kidneys and adrenals.
3. Heredofamilial Amyloidosis
A few rare examples of genetically-determined amyloidosis having familial occurrence and seen in
certain geographic regions have been described. These are as under:
(i) Familial Mediterranean fever. This is an autosomal recessive disease and is seen in people of
Mediterranean region (e.g. Separdic Jews, Armenians, Arabs and Turks). The condition is characterised
by periodic attacks of fever and polyserositis i.e. inflammatory involvment of the pleura, peritoneum, and
synovium causing pain in the chest, abdomen and joints.
(ii) Hereditary neuropathic amyloidosis. This is an autosomal dominant disorder in which amyloid is
deposited in the peripheral and autonomic nerves resulting in muscular weakness, pain and paraesthesia.
4. Localised Amyloidosis
This form of amyloidosis is largely confined to a single organ. Localised amyloidosis includes the
following 3 varieties:
(i) Tumour-forming amyloidosis. About 10% cases of amyloidosis have one or more nodules of
amyloid, usually AL type, in an organ.
(ii) Endocrine amyloidosis. Some endocrine tumours are associated with microscopic deposits
of amyloid e.g. in medullary carcinoma of the thyroid, pheochromocytoma, carcinoma of the stomach and
islet cell tumour of the pancreas.
(iii) Senile amyloidosis. It includes 2 forms:
(a) Senile cardiac amyloidosis is seen in 50% of people above the age of 70 years. The deposits are seen
in the heart and aorta.
(b) Senile cerebral amyloidosis is deposition of amyloid material in the walls of cerebral blood vessels in
60% of people above the age of 70 years. Patients of Alzheimer's disease also develop amyloid in the
senile plaques.
STAINING CHARACTERISTICS OF AMYLOID
As already stated, amyloid by light microscopy with H &c E staining appears as extracellular,
homogeneous, structureless and eosinophilic hyaline material, especially in relation to blood vessels.
However, if the deposits are small, they are difficult to detect by routine H &C E stains. Besides, a few
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other hyaline deposits may also take pink colour. Therefore, special stains and techniques are employed to
distinguish and confirm amyloid deposits. These are as under:
1. CONGO RED AND POLARISED LIGHT.
All types of amyloid have affinity for Congo red stain.
2. FLUORESCENT STAINS. Fluorescent stains like thioflavin-S and T bind to amyloid and fluo-resce
yellow under ultraviolet light.
3. IMMUNOLOGICAL METHODS. More recently, indirect fluorescence method employing
fluorescein isothiocyanate (FITC) and immunoperoxidase methods are being used to distinguish different
types of amyloid fibril proteins.
PATHOLOGIC CHANGES IN AMYLOIDOSIS OF ORGANS
Although amyloidosis of different organs shows variation in morphologic pattern, some features are
applicable in general to most of the involved organs.
Macroscopically the affected organ is usually enlarged, pale and rubbery. Cut surface shows firm, waxy
and translucent parenchyma which takes positive staining with the iodine test.
Microscopicallyy the deposits of amyloid are found in the extracellular locations, initially in the walls of
small blood vessels producing microscopic changes and effects, while later the deposits are in large
amounts causing macroscopic changes and effects of pressure atrophy.
Based on these general features of' amyloidosis, the salient pathologic findings of' major organ
involvements are described below.
Amyloidosis of Kidneys
Amyloidosis of the kidneys is most common and most serious because of ill-effects on renal function.
The deposits in the kidneys are found in most cases of secondary amyloidosis and in about one third cases
of primary amyloidosis. Amyloidosis of the kidney accounts for about 20% < of deaths from amyloidosis.
Even small quantities of amyloid deposits in the glomeruli can cause ; proteinuria and nephrotic
syndrome.
Grossly the kidneys may be normal-sized, eniarged or terminally contracted due to ischaemic effect of
narrowing of vascular lumina. Cut surface is pale, waxy and translucent.
Microscopically, amyloid deposition occurs primarily in the glomeruli, though it may involve peritubular
interstitial tissue and the walls of arterioles as well.
In the glomeruli, the deposits initially appear on the basement membrane of the glomemlar capillaries,
but later extend to produce luminal narrowing and distortion of the glomerular capillary tuft. This results
in abnormal increase in permeability of the glomerular capillaries to macromolecules with consequent
proteinuria and nephrotic syndrome.
In the tubules, the amyloid deposits likewise begin close to the tubular epithelial basement membrane.
Subsequently, the deposits may extend further outwards into the intertubular connective tissue, and
inwards to produce degenerative changes in the tubular epithelial cells and amyloid casts in the tubular
lumina.
The vascular involvement affects chiefly the walls of small arterioles and venules, producing
narrowing of their lumina and consequent ischaemic effects.
Amyloidosis of Spleen
Amyloid deposition in the spleen, for some unknown reasons, may have one of the following two
patterns:
1. 'SAGO SPLEEN'. The splenomegaly is not marked and cut surface shows characteristic translucent,
pale and waxy nodules resembling sago grains and hence the name. Microscopically, the amyloid deposits
begin in the walls of the arterioles of the white pulp and may subsequently replace the follicles.
2. 'LARDACEOUS SPLEEN'. There is generally moderate to marked splenomegaly (weight up to 1
kg). Cut surface of the spleen shows map-like areas of amyloid (lardaceous-lard-like; lard means fat of
pigs). Microscopically, the deposits involve the walls of splenic sinuses and the small arteries and in the
connective tissue of the red pulp.
Amyloidosis of Liver
In about half the cases of systemic amyloidosis, liver involvement by amyloidosis is seen.
Grossly, the liver is often enlarged, pale, waxy and firm.
Histologically, the features are as under.
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 The amyloid initially appears in the space of Disse (the space between the hepatocytes and sinusoidal
endothelial cells).
Later, as it increases, it compresses the cords of hepatocytes so that eventually the liver cells are
shrunken and atrophic and replaced by amyloid. However, hepatic function remains normal even at an
advanced stage of the disease.
To a lesser extent, portal tracts and Kupffer cells are involved in amyloidosis.
Amyloidosis of Heart
Heart is involved in systemic amyloidosis quite commonly, more so in the primary than in secondary
systemic amyloidosis. It may also be involved in localised form of amyloidosis in very old patients.
Amyloidosis of the heart may produce arrythmias due to deposition in the conduction system.
Grossly, the heart is often normal in size. However, at times it may be enlarged and show tiny
nodular deposits of amyloid underneath the endocardium, subendocardially, and between the myocardial
fibres. Later, there may be pressure atrophy of the myocardial fibres.