Cell

Question 1

Cell injury

(a) total recovery
(b) permanent impairment
(c) death

See diagram

Answer 1

Can result in

(a) total recovery
(b) permanent impairment
(c) death

Most cells are capable of significant reparative processes, and if they survive an insult, they generally repair it.
If the damage is not lethal but is very severe or persistent and beyond the capacity of the cell to regenerate, the cell may activate mechanisms that result in its own death.

Question 2

Cell death and cell changes

Answer 2

Cell death may result in replacement by:
• a cell of the same type
• a cell of another type (Hyperplasia, hypertrophy, atrophy, metaplasia)
• non-cellular structures

Cell changes includes:
• Hydropic change
• Fatty change
• Eosinophilic change
• Nuclear changes

Question 3

Hydropic change

Answer 3

Cellular damage that affects the membrane-bound ion pumps results in a loss of control of the normal cellular ionic milieu.

The unregulated diffusion of ions into the cells is accompanied by a passive osmotic influx of water. Consequently the cell swells as the cytoplasm becomes diluted. Histologically these damaged cells have a pale swollen appearance in haematoxylin and eosin-stained sections.

Question 4

Fatty change

microvesicular and macrovesicular steatosis

Answer 4

This is a characteristic change seen in liver cells as a response to cellular injury from a variety of causes. Under the microscope the cells contain many small vacuoles finely dispersed through the cytoplasm (microvesicular), or a single large vacuole (macrovesicular steatosis) that displaces the nucleus.

Specific fat stains such as Sudan black or Oil red O can be used.

Fatty change in the liver occurs as a result of damage to energy- generating mechanisms and to protein synthesis since fat is transported out of the cell by energy-dependent protein carrier mechanisms and damage to these results in passive fat accumulation. The most common cause is exposure of the hepatocytes to alcohol.

Question 5

Eosinophilic change

Answer 5

Haematoxylin stains acids such as deoxyribonucleic acid (DNA) and ribonucleic-acid (RNA), and eosin stains proteins.

Cellular damage often results in a diminution of cytoplasmic RNA, and thus the colour of such cells becomes slightly less purple and more pink (eosinophilic). Characteristic of cardiac myocytes in the early stages of ischaemia.

Eosinophilic change must be distinguished from oncocytosis, which also causes cells to have a profoundly eosinophilic and finely granular cytoplasm due to the accumulation of mitochondria within the cytoplasm e.g. endometrium, kidney neoplasia.

Question 6

Nuclear changes
(karyolysis)
(pyknosis)
(karyorhexis)
(clumping)

Answer 6

These may be subtle, such as

1) Disposition of chromatin around the periphery of the nucleus, often referred to as clumping
2) More extreme alterations such as condensation of the nucleus (pyknosis)
3) Fragmentation (karyorhexis)
4) Dilatation of the perinuclear cisternae of the endoplasmic reticulum (karyolysis).

A small circular structure, the nucleolus, becomes more apparent as the nucleus is activated; this is the centre for the production of mRNA.

AgNOR staining is particularly abnormal in malignant transformed cells.

Question 7

Accumulations: Amyloid

Answer 7

Extracellular proteins that accumulate and cause problems by simple bulk effect. It accumulates around vessels causing progressive vascular occlusion.

The common feature of all the conditions underlying amyloidosis is the production of large amounts of active proteins. These proteins are inactivated by transformation of their physical form into beta-pleated sheets which are inert (silk is a beta-pleated sheet, which is why silk sutures are not metabolised in the human body).

The human body has no enzymes for metabolising beta-pleated sheets, and amyloid, therefore, accumulates. The material is waxy in appearance and reacts with iodine to form a blue-black pigment similar to the product of reaction of starch and iodine (amyloid starch-like).

Question 8

Accumulations: Amyloid: Diseases

Answer 8

The types of disease associated with amyloid production are:

1) Chronic inflammatory processes such as tuberculosis
2) Rheumatoid disease
3) Chronic osteomyelitis
4) Tumours with a large production of protein, typically myeloma; and miscellaneous disease with protein production such as some inflammatory skin diseases
5) Some tumours of endocrine glands and neurodegenerative diseases such as Alzheimer’s disease.

Question 9

Accumulations: Pigment

Bruising, haematomas, jaundice

Answer 9

When blood escapes from vessels into tissue the haemoglobin

1) Gives skin a dark grey-black colour to the bruise.
2) As the haemoglobin is metabolised through biliverdin and bilirubin, it changes from green to yellow and is finally removed.

Such haematomas generally have no significance unless they are very bulky or if they become infected.

Other endogenous pigments include the bile pigments in obstructive jaundice. These can be seen in the skin and even more clearly in the sclera because they bind preferentially to elastin and this material occurs in greatest concentration in these tissues.

Question 10

Accumulations: Melanin

Answer 10

The commonest pigment in human skin is melanin, which is red/yellow (pheomelanin), or brown/black (eumelanin), but if it occurs in deep sites, as in blue naevi, can appear blue due to the Tyndall effect.

Melanin pigments are often markers of pigmented tumour pathology.
1) Widespread malignant melanoma the melanin production can be so great melanin appears in urine.
2 (Melanin production is under hormonal control, and ACTH-related to MSH (melanocyte stimulating hormone), can cause pigmentation

Melanosis coli is a heavy black pigmentation of the colon associated with anthracene laxative use and is unrelated to melanin–the pigment in melanosis coli is lipofuscin –and is itself inert. Melanin can be distinguished from haemosiderin and lipofuscin by its positive staining with the Masson Fontana method.

Question 11

Accumulations: Pigment: Haemosiderin

Answer 11

Haemosiderin is a granular light brown pigment composed of iron oxide and protein. It accumulates in tissues–particularly:

1) Liver
2) Pancreas
3) Skin
4) Gonads

Haemosiderin also accumulates in tissues where bleeding has occurred.

Haemosiderin can be distinguished from melanin and lipofuscin by its positive Prussian blue reaction when exposed to potassium ferrocyanide and hydrochloric acid.

Question 12

Accumulations: Pigment: Lipofuscin

Answer 12

Lipofuscin is a brown pigment that accumulates in ageing cells and is often called age pigment. It does not appear to cause any damage and is an incidental marker of ageing. It is mainly formed from old cellular membranes by the peroxidation of lipids. They are thought to be mainly of mitochondrial origin.

Lipofuscin shows neither the Prussian blue reaction nor is it stained with the Masson Fontana method.

Question 13

Accumulations: Pigment: Exogenous pigments

Answer 13

Exogenous pigments are introduced in tattooing and some have been toxic in various ways.

Commonly used in tattooing:

1) Mercuric chloride (a red pigment)
2) Potassium dichromate (a green pigment)

Question 14

Accumulations: Crystal diseases
Gout
Pseudogout
Thyroid

Answer 14

1) Gout in the case of sodium urate crystals
2) Pseudogout in the case of calcium pyrophosphate.

Calcium oxalate crystals are commonly found within the colloid of normal thyroid tissue and may be associated with a low functional state of the thyroid follicles.

Question 15

Effect of radiation: Bone marrow

Answer 15

The effect of radiation is to suspend renewal of all cell lines.

1) Granulocytes are reduced before erythrocytes (which survive much longer).
2) May cause complete recovery to aplastic anaemia and death.

In the long-term survivor there is an increased incidence of leukaemia.

Question 16

Effect of radiation: Skin
Hyperpigmentation
Thinning of the dermis
Telangiectasia

Answer 16

1) Irradiation of the epidermis results in cessation of mitosis with desquamation and hair loss. If enough stem cells survive, hair will regrow and any epidermal defects will regenerate.
2) Damage to melanocytes results in melanin deposition in the dermis, where it is ingested by phagocytic cells which remain in the skin and result in hyperpigmentation.
3) Destruction of dermal fibroblasts results in an inability to produce collagen and subsequently to thinning of the dermis.
4) Damage to small vessels in the skin is followed by thinning of their walls, with dilatation and tortuosity, and hence telangiectasia.

Larger vessels undergo endarteritis obliterans with time.

Question 17

Effect of radiation: Intestines

Answer 17

Diarrhoea
Malabsorption
Strictures

Irradiation of the surface epithelium of the small intestines results in its loss with consequent diarrhoea and malabsorption. Damage to the full thickness of the wall will result in stricture formation.

Question 18

Effect of radiation: Gonads

Answer 18

Germ cells are very radiosensitive, and even low dose exposure may cause sterility. Mutations may also occur in germ cells, which could result in a teratogenic effect.

Question 19

Effect of radiation: Lungs

Answer 19

Progressive pulmonary fibrosis usually occurs

Question 20

Effect of radiation: Kidneys

Answer 20

Irradiation of the kidney usually leads to a gradual loss of parenchyma, resulting in impaired renal function.

Damage to renal vessels results in intra-renal artery stenosis and the development of hypertension.

Question 21

Cell death: Necrosis

Answer 21

This is characterised by death of large numbers of cells in groups and the presence of an inflammatory reaction. Necrosis is the most familiar form of cell death and is associated with trauma, infection, ischaemia, toxic damage and immunological insults.

Different patterns of necrosis are recognised and given specific names such as coagulative necrosis and liquefactive necrosis.

Question 22

Cell death: Necrosis: Coagulative and liquefactive necrosis

Answer 22

Coagulative necrosis is the common event in most tissues, including myocardium, whilst liquefactive necrosis predominates in the brain.

If there is no infection then the tissue can become mummified, and this is described as dry gangrene; if infection supervenes then anaerobic bacteria can cause wet gangrene.

Question 23

Cell death: Necrosis: caseous necrosis

Answer 23

In tuberculous foci of infection a particular type of necrosis occurs with a mixture of cell membranes and bacterial debris with a ‘cheesy’ appearance known as caseous necrosis. This frequently undergoes subsequent calcification.

Question 24

Cell death: Necrosis: Fat necrosis

Answer 24

The term fat necrosis refers to a specific clinical entity around the pancreas when lipases have been released and autolysis occurs.

In the breast, commonly following trauma, a rather specific and histologically startling form of fat necrosis occurs. This probably results from an inflammatory reaction to fat escaping from ruptured fat cells and can suggest carcinoma both clinically and mammographically although the diagnosis is usually obvious histologically.

Question 25

Apoptosis: Apoptotic bodies

Answer 25

The morphological hallmark of apoptosis is the apoptotic body which is eosinophilic and may contain some karryorhectic nuclear debris. It is a result of shrinkage of the cell cytoplasm and nuclear disruption. These apoptotic bodies are taken up by surrounding cells and digested.

The early stages in apoptosis are characterised by surface blebbing and margination of chromatin followed by cell shrinkage and breakup into smaller apoptotic bodies.

Epidermal apoptotic bodies are large and pink because of their high content of cytoskeletal
structures.

Epithelial cells are often extruded from the epithelium into the underlying connective tissue stroma where they are taken up by macrophages.

Apoptotic bodies in particular situations attracted specific names:
• Civatte or colloid bodies in lichen planus;
• Kamino bodies in melanocytic lesions;
• Councilman bodies in acute viral hepatitis; and
• tingible bodies (found in macrophages) in
lymphomas.

Question 26

Apoptosis process

Answer 26

The first recognised metabolic step is the production of endonucleases which cut the DNA into short double-stranded fragments; this is an irreversible step.

Calcium influx into the cell is an energy-dependent process in apoptosis in distinction to the passive entry in necrosis, but it is an early step and this indicates that it is an important mechanism in cell death generally.

Inhibiting RNA and protein synthesis inhibits apoptosis, confirming the observation that it is a dynamic process and is energy dependent.

Question 27

Skin healing process

Answer 27

Time course of events in the healing of skin:

• minutes: blood clot forms; surface dehydrates to form scab;
• 24 hours: first phases of inflammation (neutrophils at the margins; edges of epidermis thicken and begin to migrate because of increased mitosis);
• 3 days: granulation tissue becoming covered by epidermis; vertical collagen fibres at edges; macrophages replace neutrophils
• 5 days: collagen fibrils begin to bridge wound; new vessels abundant; single-layered epidermis begins to become multilayered;
• Week 2: collagen and vessels being remodelled; fibroblasts still active and proliferating; vessels reduced in number; and
• Week 4–5: wound strengthens; inflammatory infiltrate gone; collagen continues to remodel; adnexae do not regenerate.

The above account is typical for mucosal and skin healing, but other tissues have other specific features that modify this account. The most distinct difference is with bone.

Question 28

Bone healing

Answer 28

• Blood vessels within the bone and the periosteum are damaged and blood leaks out. This rapidly clots to form a haematoma.
• As in other tissues the haematoma forms a framework along which various cell types can migrate.
• The clot then organises over the next week, with inflammatory cells modifying the structure and fibroblasts secreting collagen.
• The inflammatory cells and the platelets release various growth factors: transforming growth factor beta (TGFb); platelet-derived growth factor (PDGF); fibroblast growth factor (FGF).
• The osteoblasts normally resident in the periosteum become activated and begin to produce woven bone which is constantly being modified by mechanical forces exerted on it. These are translated into tiny electrical currents, and many experiments have been undertaken to study the effects of electrical current on fracture healing.
• The mesenchymal cells in the surrounding soft tissues also become activated and begin to secrete cartilage (fibrocartilage and hyaline cartilage) around the fracture site.
• By the second and third week the mass of healing tissue reaches its maximum girth but is still too weak for weight bearing.
• As woven bone approaches the new cartilage this undergoes enchondral ossification and bridges the deficit with new bone.
• Remodeling may continue for many weeks, but eventually the repair may be indistinguishable from the original bone or it may be even stronger than previously.