Degeneration and infiltration are retrogressive changes in cells and tissues characterised by abnormal structural changes and decreased functions. They are nonspecific responses of cells and tissues following a variety of injuries. Some of these processes may be reversible if the injury is mild. If the injury is severe and persistent, it may progress to the point where the involved cell dies. The distinction between the point where the cells would recover and the point where the process is irreversible and leads to cell death is arbitrary. In theory, the difference between the two processes is vague. Most literatures however define these two processes as:
 

1) Degeneration - the accumulation of metabolites or other substances in a cell damaged by preceding injury;
2) Infiltration - the overloading of previously normal cells by materials which are abnormal in either type of quantity.

1) Water overload
2) Metabolite overload which involves  excessive accumulation of normal  metabolic products, such as fat,  glycogen, or protein (hyaline or  proteinaceous); and
3) Storage loading, which involve overloading by non-degradable products such as pigments, minerals, and exogenous substances.

Hydropic degeneration (Acute cellular swelling, Cloudy Swelling) - occur because of marked mitochondrial damage, cessation of ATP production and failure of sodium pump leading to increased osmotic pressure within cells. The alteration is on selective permeability of cellular membranes leading to influx of water molecules.

Acute cell swelling or hydropic degeneration occurs due to failure of the injured cells to maintain electrolyte balance through the "Sodium-Potassium pump". As this mechanism is energy dependent, a fall in ATP in injured cells causes the efflux of Potassium ions. With the influx of Sodium ions, the increasing osmotic pressure in the cytoplasm attracts water molecules. As a result, swelling of the cells occurs, and is evident grossly as enlarged pale, and heavy organ. Microscopically, affected cells show vacuoles in the cytoplasm with no distinct borders. The cytoplasm is diluted, and dispersed. This type of degeneration is apt to be present in most types of injury. It is particularly severe in toxic and febrile conditions. The condition is best seen in organs with intense metabolic rates of metabolism such as the liver, kidneys, and brain. Acute cell swelling in epithelial surfaces is revealing and often bears evidence of injury characterised by blisters, wheals and flares, including ulcers.

II. METABOLITE OVERLOAD

1) FAT OVERLOAD: - An overload of fat occurs in parenchymal cells particularly liver cells, and in tubular epithelial cells of the kidney, and myocardial cells. This condition occurs in disease conditions that disturb the normal metabolism of fat. Normally, fatty acid is oxidised and combined to proteins to form lipoproteins that are released into the circulation. The following mechanisms result to the accumulation of lipids in cells:

1) Abnormally high levels of fat in the diet with a resultant overload in fat metabolism;
2) Interference in protein production impeding lipoprotein production;
3) Impairment in the conjugation process,
4) Interference in oxidation of fat, and
5) Interference in the release of lipoprotein from the cytoplasm of cells

Figure 4. Fat metabolism in liver cells. Interference in any of these processes led to an abnormal accumulation of lipids in cells.

Grossly, the affected organ (usually the liver) shows uniform paleness with a greasy cut surface. This type of degeneration is common in conditions where fat is abnormally utilised due to failure in carbohydrate utilisation as a source of energy (example in diabetes), or in the absence of carbohydrate as a source for energy (example in starvation).

a) Fatty change (Fatty degeneration, Fat phanerosis) - implies the presence multiple small droplets of fat within the cytoplasm of cells without nuclear displacement. Fat accumulates due to inability of the cell to metabolise fat. It is considered a primary degenerative change in cells. Microscopically, vacuoles with distinct borders appear in the cytoplasm of affected cells. These vacuoles make the cytoplasm to appear foamy, and may coalesce to form large globules. In routinely stained preparations, the material is lost but may be demonstrated using special stains in frozen sections.

b) Fatty infiltration (Steatosis) - characterised by the presence of a single globule of fat displacing the nuclei to one side; the fat globule being a "transport fat" derived from fat depots and carried in the blood stream. This change is similar to fatty degeneration.

2) PROTEIN OVERLOAD

a) Hyaline Change (Hyalinisation, Hyaline degeneration) - the term "hyaline" describes pink-staining homogenous glassy cytoplasmic droplets in cells. It is due to degeneration of cell protein. Included also is the accumulation of protein within cells following abnormal metabolism.

b) Fibrinoid  - a special type of protein accumulation so named due to its resemblance to coagulated fibrin, and found in degenerating blood vessel walls and connective tissue. It includes plasma proteins including fibrin, albumin and globulin particularly immunoglobulins and complement. Occur in association with necrosis of connective tissue and blood vessel walls (see later).

c) Amyloidosis - a special form of protein accumulation characterised by the deposition of proteinaceous material in basement membrane. Amyloid consists of fibrillar beta-pleated protein molecules similar in structure to immunoglobulins.

d) Mucopolysaccharidosis (myxoid or myxomatous degeneration, mucoid degeneration) - Mucopolysaccharides are conjugates of protein and carbohydrates normally found in secretions of epithelial cells. These substances are also found in the ground substance of connective tissues and cartilage. Excessive accumulation of these substances is currently called mucopolysaccharidosis. Mucoid degeneration refers to overproduction of mucinous secretion by cells. Myxomatous degeneration is described as the transformation of tissues into a jelly-like structure. The latter two terms are no longer in use.  In routinely stained sections, this material is amorphous similar in character to embryonic connective tissue which deposits in tissues in some disease conditions like hypothyroidism (myxedema). It always occurs in cachectic and wasting diseases at the later stage and commonly observed in omentum, coronary groove of the heart, and between skeletal muscles. Grossly, the organ affected assumes a gelatinous appearance and consistency.

3) CARBOHYDRATE OVERLOAD

a) Glycogen degeneration - Glycogen degeneration involves the presence of abnormally large amount of glycogen in the cytoplasm of the cells. Glycogen is normally present in the cytoplasm of the cells (particularly in liver cells). However, excessive accumulation occurs in some disease processes  characterised by prolonged hyperglycaemia such as diabetes mellitus.

The microscopic changes are similar to acute cell swelling where clear vacuoles are present in the cells. This is because in routinely prepared sections, glycogen that is water-soluble is lost in the preparation. Special stains in frozen sections could show the abnormal accumulation of this substance in affected cells.

 III. STORAGE LOADING

1) LIPIDOSIS - Lipidosis refers the accumulation of lipid degradation products in the cytoplasm of cells. The degradation products are usually stored in lysosome bound vacuoles. These materials are usually products of peroxidation of fat and may be lipofuscins, ceroid, or cholesterol. Chronic fatty change may progress to lipidosis, with the lipid particles accumulating in the cytoplasm of cells converted into complex, non-degradable products. Microscopically, the stored materials are distinct particles in the cytoplasm of cells, assume a brown colour in routinely stained sections.

2) CALCIFICATION - calcification refers to a pathological deposition of calcium salts in cells and tissues. It is different from normal and heterotrophic bone formation. Forms include the following:

(a) Dystrophic calcification - when calcium salts are deposited in degenerate and necrotic cells and tissues.

(b) Metastatic calcification - because of excess ionised calcium in the blood. Tissue injury is not required for calcium to be deposited in tissues. This condition occurs in cases of excessive mobilisation of calcium from skeleton as in hypervitaminosis D, and hyperparathyroidism.

In both processes, the organ or tissues affected have a gritty texture on cut surface. Microscopically, the deposited calcium salts are intensely basophilic and breaks into fragments. Also included under this category are those deposits in tissues following uraemia (urine salts), and urate crystals following a defect in purine metabolism (gout).

3) PIGMENTATION - pigments of either exogenous or endogenous origin may accumulate within cells. They are usually innocuous but provide clues to the existence and nature of underlying disorder. Two forms of pigmentation occur based on the origin of the pigment:

(a) Exogenous pigmentation - following injection, inhalation, or absorption from the gut of some colored foreign materials. Exogenous pigments include the following groups of materials:

a.1) Metals - silver, bismuth, gold,   lead, and iron.
a.2) Coarse Materials - dust, carbon,   silica, and asbestos.
a.3) Colored substances - carotene,   tetracycline.
a.4) Fungi - monilia, aspergilli

(b) Endogenous pigmentation - due to altered metabolism of breakdown products of haemoglobin, melanin and fat. Endogenous forms of pigments include the following:

b.1. Haemoglobin derivatives

(1) Haematins - iron-negative pigments that occur following the action of acids to haemoglobin (artefacts), parasites in blood (e.g., malaria), or following trauma to tissues. Their presence in tissues has little significance, except perhaps an indication of poor techniques and solutions used in tissue fixation.

(2) Haemosiderin - iron-positive pigment chemically known as ferritin (the storage form of iron), seen in cases of trauma, excessive haemorrhage or haemolysis. These pigments occur abundantly in the cytoplasm of cells of the reticulo-endothelial system such as in the spleen, Kupffer cells in the liver, and bone marrow. The appearance of abnormal amount of this pigment usually suggests excessive formation because of haemolysis.

(3) Haematoidin or Bilirubin - following excessive haemorrhage or haemolysis, and failure of the liver to conjugate bilirubin into bile, and/or secrete bile. This pigment occurs in association with jaundice.

(4) Porphyrins - Porphyrin pigments may accumulate in tissues in rare disease conditions (example congenital porphyria) characterised by a defect in haemoglobin formation. Apart from this, it is a normal component in the formation of haemoglobin. However, it occurs in some disease conditions following ingestion of toxic plants (for porphyrin is formed following breakdown of the chlorophyll in plants). This pigment is photoreactive, i.e. it causes activation of some processes (production of toxic oxygen free radicals) that cause peroxidation of lipid membranes. The resultant condition is called photosensitisation.

b.2  Melanin pigmentation - granular protein containing pigment produced by melanocytes. Increased production occurs in association with tumours of the melanocytes (melanoma), excessive irradiation, and effects of sunlight.

b.3  Lipid derived pigment (Lipofuscins) - these pigments represent partially degraded lysosome-bound indigestible residues of autophagic vacuoles in cells. They are also known in many names as "Wear and Tear Pigment, Pigment of Brown Atrophy, Ceroid, or Lipochrome".