Intra- cellular accumulation: hyaline, mucin; Extra-cellular accumulation:

amyloidosis,

(Changes in reversible cell injury includes hyaline change and mucoid changes where
intracellular hyaline and mucine accumulations are seen respectively) (Refer Harshmohan
book)

Hyaline Change The word ‘hyaline’ means glassy (hyalos = glass). Hyaline
is a descriptive histologic term for glassy, homogeneous, eosinophilic
appearance of material in haematoxylin and eosin-stained sections and
does not refer to any specific substance. Though fibrin and amyloid have
hyaline appearance, they have distinctive features and staining reactions
and can be distinguished from non-specific hyaline material. Hyaline
change is associated with heterogeneous pathologic conditions. It may be
intracellular or extracellular.

INTRACELLULAR HYALINE.

Intracellular hyaline is mainly seen in epithelial cells. A few examples

are as follows:

1. Hyaline droplets in the proximal tubular epithelial cells in cases

of excessive reabsorption of plasma proteins.

2. Hyaline degeneration of rectus abdominalis muscle called Zenker’s

degeneration, occurring in typhoid fever. The muscle loses its fibrillar
staining and becomes glassy and hyaline.

3. Mallory’s hyaline represents aggregates of intermediate filaments

in the hepatocytes in alcoholic liver cell injury.

4. Nuclear or cytoplasmic hyaline inclusions seen in some viral

infections.

5. Russell’s bodies representing excessive immunoglobulins in the

rough endoplasmic reticulum of the plasma cells (Fig. 3.12).

EXTRACELLULAR HYALINE. Extracellular hyaline is seen in connective

tissues. A few examples of extracellular hyaline change are as under:

1. Hyaline degeneration in leiomyomas of the uterus (Fig. 3.13).

2. Hyalinised old scar of fibrocollagenous tissues.

3. Hyaline arteriolosclerosis in renal vessels in hypertension and

diabetes mellitus.

4. Hyalinised glomeruli in chronic glomerulonephritis.

5. 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.

Mucoid Change

Mucus secreted by mucous glands is a combination of proteins complexed

with mucopolysaccharides. Mucin, a glycoprotein, is its chief constituent.
Mucin is normally produced by epithelial cells of mucous membranes and
mucous glands, as well as by some connective tissues like in the umbilical
cord. By convention, connective tissue mucin is termed myxoid (mucus like).
Both types of mucin are stained by alcian blue. However, epithelial mucin
stains positively with periodic acid-Schiff (PAS), while connective
tissue mucin is PAS negative but is stained positively with colloidal
iron.

EPITHELIAL MUCIN.

Following are some examples of functional excess of epithelial mucin:

1. Catarrhal inflammation of mucous membrane (e.g. of respiratory tract,

alimentary tract, uterus).

2. Obstruction of duct leading to mucocele in the oral cavity and

gallbladder.

3. Cystic fibrosis of the pancreas.

4. Mucin-secreting tumours (e.g. of ovary, stomach, large bowel etc) (Fig.

3.14) .

CONNECTIVE TISSUE MUCIN. A few examples of disturbances of connective

tissue mucin are as under:
1. Mucoid or myxoid degeneration in some tumours e.g. myxomas,
neurofibromas, fibroadenoma, soft tissue sarcomas etc (Fig. 3.15) .

2. Dissecting aneurysm of the aorta due to Erdheim’s medial

degeneration and Marfan’s syndrome.

3. Myxomatous change in the dermis in myxoedema.

4. Myxoid change in the synovium in ganglion on the wrist

 AMYLOIDOSIS

Definition: Amyloidosis refers s to the extracellular deposition of fibrillary misfolded

proteins in various organs.

Figure 9: Misfolded protein and Amyloid

Pathogenesis: It is associated with miss-folding of proteins, which are deposited as

fibrils in extracellular tissues and interfere with normal function of tissues and organs;
it is either due to normal protein that is produced in excess amount or mutant proteins
that are prone to misfolding.

HOLOGYMADE EASYFigure10: Formation of fibril and deposition intravascular

Classification of Amyloidosis: According to the type of fibril amyloidosis is

categorized into the following subtypes

1-AL (Amyloid Light Chain Protein): Define as fibrils from light chains produced
by plasma cells, and are made up of complete immunoglobulin light chains,
amino-terminal fragments of light chains, or both of them. It is associated with
proliferation of plasma cells in multiple myeloma or any monoclonal proliferation of
B lymphocyte.

2-AA (Amyloid-Associated Proteins): Fibrils derived from a serum precursor called

SAA (serum amyloid-associated protein) that is synthesized in the liver during
inflammation; thus, long-standing inflammation leads to elevated SAA levels, and
ultimately the AA form of amyloid deposits.

Table 2: Showed type of Amyloid fibril and its clinical association

Clinical types Associated condition Amyloid

Fibril

Primary or Multiple myeloma AL

Secondary

Secondary Chronic inflammatory AA

disease,

Rheumatoid arthritis

,TB, skin, and lung

abscesses

Cancer, Hodgkin's
Secondary disease AA

3-Other Rare Types of Amyloidosis:

 ATTR (Amyloid Transthyretin Protein): Transthyretin protein is a product

of a mutation in the liver, occurs as familial or none familial type, and may
 alter its structure, making the protein resistant to proteolysis, this leads to the
formation of aggregates that deposit as amyloid.

A β 2M (Amyloid β 2 – Microglobulin): β 2-microglubuline is a

component of MHC class I molecules, this type of amyloidosis is associated
with long-term hemodialysis. There are other types of abnormal proteins
depsited in the body like A β (amyloid beta protein), associated with
Alzhemer disease, and deposited in the wall of the cerebral blood vessels.

Clinical Classification of Amyloidosis: Amyloid may be systemic (generalized),

involving several organs, or localized when deposits are limited to a single organ such
as the heart, kidney...etc., clinically the systemic type is classified to primary and
secondary:

 Primary Amyloidosis: It is of the AL type, in some cases, there is a readily

identifiable monoclonal plasma cell proliferation .

 Secondary Amyloidosis: Usually reactive and made of AA protein and it is

secondary to chronic inflammatory conditions . E.g. tuberculosis,
bronchiectasis, and chronic osteomyelitis and some malignant disease, e.g.
renalcell carcinoma and Hodgkin's lymphoma.

 Familial (Hereditary) Amyloidosis : It is associated with familial

Mediterranean fever , which is due to mutation of pyrogens, results in
persistent inflammation and fever .

 Endocrine Amyloid: It occur s in patient suffering from endocrine tumour s

e.g., medullary carcinoma, islet tumours of the pancreas, pheochromocytomas,
and undifferentiated carcinomas of the stomach, as well as in patients with
type II diabetes mellitus.

Amyloid of Aging (Senile Cardiac Amyloidosis ) : It is seen in elderly per

sons usually causing restrictive cardiomyopathy and arrhythmias.

Clinical Course of Amyloidosis: Most of the patients have no apparent clinical

manifestations, only presenting with nonspecific complaints such as weakness, fatigue,
and weight loss, later on it may present with organomagally, e.g., hepatomegaly,
splenomegaly, macroglossia, cardiac abnormalities, and renal involvement, giving rise
to nephritic syndrome and renal failure. Hepato-splenomegaly rarely causes
significant clinical dysfunction, cardiac amyloidosis may manifest as conduction
disturbances (cardiac arrhythmias) or as restrictive cardiomyopathy.
 Figure 11: Clinical presentation of amyloidosis

Microscopic Findings: On histological examination, the amyloid deposition is

always extracellular between cells. The histological diagnosis of amyloid is based
almost entirely on its staining characteristics. The most commonly used stain is
Congo red, which stains the amyloid deposits in pink or red color, under polarized
light the Congo red stain amyloid shows so called apple green birefringence.
Confirmation can be obtained by electron microscopy and immunohistochemistry.

Organic Changes in Amyliodosis

Kidney: The kidney may be abnormally large, pale, grey, and firm; in long-standing
cases, kidney may be reduced in size. Microscopically, the amyloid deposits is found
principally in the glomeruli, but also present in the interstitial peritubular tissue as
well as in the walls of the blood vessels, the glomeruli first develops focal deposits
within the mesangial matrix, diffuse or nodular thickenings of the basement
membranes of the capillary loops, with progression, the deposition encroaches on the
capillary lumen and eventually leads to total obliteration of the vascular tuft. The
interstitial peritubular deposits frequently are associated with the appearance of
amorphous pink casts within the tubular lumens, presumably of a proteinaceous
nature. Amyloid deposits may develop in the walls of blood vessels of all sizes, often
causing marked vascular narrowing.

Spleen: Amyloidosis of the spleen often causes moderate or even marked

enlargement. For obscure reasons, either of the following two patterns may develop:

 the deposits may be limited to the splenic follicles, producing tapioca-like

granules on gross examination (“sago spleen”),
  the amyloidosis may principally involve the splenic sinuses, eventually
extending to the splenic pulp, with formation of large

sheet-like deposits (“lardaceous spleen”).

In both patterns, the spleen is firm in consistency; the presence of blood in splenic
sinuses imparts a reddish color to the waxy friable deposits.

Liver: Amyloidosis of the liver may cause massive enlargement, in such advanced
cases the liver is extremely pale, grayish, and waxy on both the external surface and
the cut section. Histological analysis shows that amyloid deposits firstly appears in
the space and then Progressively enlarge to encroach on the adjacent hepatic
parenchyma and sinusoids, the trapped liver cells undergo compression atrophy and
are eventually replaced by sheets of amyloid; remarkably, normal liver function may
be preserved even in the setting of severe involvement.

Heart: Amyloid deposits may cause minimal to moderate cardiac enlargement, the
most characteristic gross findings are grey-pink, drop-like subendocardial elevations,
particularly in the atria. On histological examination, deposits typically are found
throughout the myocardium, beginning between myocardial fibers and eventually
causing pressure atrophy.

Other Organs: The adrenals, thyroid, and pituitary are common sites of involvement,
usually without apparent disturbance of function, the gastrointestinal tract is also a
favored site for deposition, amyloid may be found in various forms, and sometimes
producing masses that must be distinguished from neoplasm, nodular depositions in
the tongue may produce macroglossia. On the basis of the frequent involvement of
the gastrointestinal tract, gingival, intestinal, and rectal biopsies serve in the diagnosis
of suspected cases. Deposition of β 2-microglobulin amyloid in patients receiving
long-term dialysis occur s most commonly in the carpal ligaments of the wrist.