This chapter covers several important pathological processes that used to be classified as ‘tissue degenerations’. They are unified by the fact that they all involve abnormal accumulations of pigments or other substances that build up as a result of a variety of different pathological processes. These materials can be classified as endogenous if they are produced In the body, or exogenous if they are derived from outside.
13.1. Abnormal endogenous accumulations
You should:
• state the main characteristics and pathological significance of fatty change, lipofuscin, haemosiderin and amyloid
• distinguish metastatic from dystrophic calcification
• recognise abnormal melanin accumulation
• understand the term hyaline
• discuss the principles of the inherited storage disorders.
Haemosiderin
Haemosiderin is a golden yellow to brown pigment found in lysosomes within the cell cytoplasm. It is composed of aggregates of partially degraded ferritin, which is protein-covered ferric oxide and phosphate. It can be visualised using the Prussian blue reaction, when haemosiderin appears dark blue.
Haemosiderin represents iron deposition and accumulates in tissues in two main circumstances. First, if there is haemorrhage into a tissue the haemoglobin is broken down and haemosiderin is deposited in macrophages locally. This process occurs in many chronic inflammatory conditions; the extravasated red blood cells are broken down and haemosiderin is produced from the iron they contain. The identification of haemosiderin in a tissue sample can be a clue to previous haemorrhage or inflammation.
Second, an excess of circulating iron can result in systemic haemosiderin accumulation. For example, primary haemochromatosis is an inherited disease in which there is excessive absorption and widespread deposition of haemosiderin in the tissues, especially the liver, pancreas, heart and skin. The iron is toxic to the tissues and leads to fibrosis of the liver (cirrhosis), fibrosis of the pancreas (leading to diabetes mellitus), and heart failure.
Other causes of systemic iron deposition include increased absorption of iron from the intestine, haemolytic anaemia and recurrent blood transfusions. The presence of iron in the tissues is termed haemosiderosis, which is not be confused with the disease haemochromatosis as described previously.
Melanin
Melanin is the brown/black pigment normally present in the cytoplasm of cells in the basal layer of the epidermis, called melanocytes. Melanin is derived from tyrosine, stored in melanosomes and distributed to the other epidermal cells. The function of melanin is to block harmful UV rays from reaching the epidermal nuclei. It may accumulate in excessive quantities in benign or malignant melanocytic neoplasms and its presence is a useful diagnostic feature for such lesions. In inflammatory skin lesions, where the epidermis is damaged, melanin may be released from injured basal cells and taken up by dermal macrophages. This gives rise to post-inflammatory pigmentation of the skin. Melanin can be identified in tissue sections by the use of the Masson–Fontana stain.
Excessive melanin pigmentation of the skin is a feature of certain diseases, e.g. Addison’s disease and neurofibromatosis.
Lipofuscin
This is the yellow/brown ‘wear-and-tear’ pigment seen in atrophic tissues (see atrophy, Ch. 3). It also accumulates in ageing cells of the liver, myocardium and elsewhere. Lipofuscin does not seem to damage cells and does not cause clinical problems.
Calcification
Calcification is the deposition of calcium salts within tissues, often causing them to become chalky, hard or brittle. There are two main types of calcification:
• dystrophic
• metastatic.
Dystrophic calcification
This type of calcification occurs within diseased tissues. The plasma calcium and phosphate levels are normal. The exact mechanism by which dystrophic calcification occurs is not known. Examples include calcification within areas of necrosis, foci of old tuberculosis, atheromatous plaques, and in neoplasms. The calcification can often be identified on radiographs.
Metastatic calcification
Metastatic calcification occurs in normal tissues as a consequence of raised plasma calcium concentrations (hypercalcaemia). Common causes of hypercalcaemia include widespread metastatic cancer in the bones, hyperparathyroidism and multiple myeloma. Metastatic calcification does not often cause clinical problems, although occasionally renal failure can follow calcification of the kidneys.
Hyaline
Hyaline simply means ‘glassy’ and is used as a descriptive term by pathologists for a variety of materials that have a uniform pink (eosinophilic) appearance under the microscope. Deposits of protein in renal tubules and Mallory bodies in the liver can be described as exhibiting a hyaline appearance. In longstanding diabetes and hypertension, accumulation of proteins in the walls of arterioles causes them to become hyalinised.
Amyloidosis
The term amyloid means ‘starch-like’ and as such is misleading because amyloid is not a carbohydrate. Amyloid is a descriptive term used for a group of proteinaceous substances that may be deposited in tissues and organs to give characteristic naked eye, microscopic and ultrastructural appearances.
What is amyloid?
Amyloid is an abnormal protein characterised by a β-pleated sheet configuration deposited in the extracellular matrix. Many different proteins can produce amyloid, and the type of protein found in the amyloid deposits depends on the underlying disease. For example, in patients with multiple myeloma (a neoplastic proliferation of antibody-producing plasma cells), the amyloid is composed of antibody fragments. The β-pleated sheets form long, non-branching fibrils with a diameter of about 8nm; they can be observed under the electron microscope. Once the β-pleated sheets have formed, the body’s intra- and extracellular proteolytic enzyme systems find it almost impossible to digest; therefore, it accumulates inexorably.
Almost all types of amyloid also contain a second substance, a glycoprotein known as the P component (or P protein). The P component is a doughnut-shaped pentamer.
When amyloid is deposited in large amounts, the tissue becomes pale, smooth and waxy in texture. Histologically, amyloid stains pink with Congo red dye; the pink colour turns apple green under polarised light, a property unique to amyloid.
Where does amyloid accumulate?
Amyloid can accumulate within any tissue or organ. The disease may affect just one tissue or organ, i.e. localised amyloidosis, or several, i.e. systemic amyloidosis. It always accumulates outside cells and has a predilection for basement membranes and interstitial connective tissues.
Where there is abundant amyloid deposition, cells become ‘strangled’ and organ failure occurs. There is also evidence that some types of amyloid have a direct toxic effect on cells. For example, β-amyloid in the brain damages neurones, possibly by free radical production.
When does amyloid accumulation occur?
It is thought that defective proteolysis of the precursor protein results in amyloid production. The two most common examples of systemic amyloidosis are:
• AL amyloid: Patients with multiple myeloma typically have excessive amounts of circulating intact and fragmented immunoglobulin light chains. Defective proteolysis of these light chains gives an amyloid protein called AL amyloid.
• AA amyloid
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