Cells in Trouble - Adapt and survive or die!

Question 1

Define the 5 reversible cell adaptations which occur in response to a change in environment and give an example of each adaptation

Answer 1

1. Hypertrophy. An increase in cell size eg. myocardial hypertrophy in response to sustained high blood pressure.
2. Hyperplasia. An increase in cell number eg. endometrial hyperplasia due to prolonged stimulation of the endometrium by the hormone oestrogen.
3. Metaplasia. A change from one differentiated (mature) cell type to another mature cell type which is better able to withstand the adverse environment eg. intestinal metaplasia of the oesophagus (Barretts oesophagus).
4. Dysplasia. Disordered cell growth caused by a carcinogen eg. cervical dysplasia caused by human papilloma virus infection.
5. Atrophy. A reduction in cell size eg. if a muscle loses its nerve supply it will undergo denervation atrophy.

Question 2

What is the significance for the patient of intestinal metaplasia of the lower oesophagus?

Answer 2

The most important learning point about metaplasia is that if the influences which cause the metaplasia persist, this can initiate malignant transformation of the metaplastic epithelium (from metaplasia to dysplasia to neoplasia). In the oesophagus, where there is a long history of acid reflux from the stomach, this can cause intestinal metaplasia which over time can progress to dysplasia and this can then progress to adenocarcinoma (a malignant tumour showing glandular differentiation (gland formation)).

Question 3

What is the significance for the patient of squamous metaplasia of the bronchus?

Answer 3

Cigarette smoking causes squamous metaplasia of the bronchus (normally lined by pseudostratified columnar epithelium), which can progress to dysplasia, which can later progress to invasive squamous cell carcinoma of the bronchus.

Question 4

What is the significance for the patient of endometrial hyperplasia?

Answer 4

Prolonged stimulation of the endometrium (the womb lining) by the hormone oestrogen can cause an increase in cell number and gland number (hyperplasia). This increases the risk of the development of a gland-forming cancer of the endometrium (endometrial adenocarcinoma).

Question 5

What are the 3 possible outcomes for a cell which is irreversibly damaged?

Answer 5

1. Necrosis.
2. Apoptosis.
3. Necroptosis.

Question 6

What is necrosis?

Answer 6

Necrosis is an accidental/unregulated form of cell death where cell membranes are damaged causing lysosomal enzymes to be released and the cell contents to leak resulting in an inflammatory reaction. Necrosis is always pathological.

Question 7

List 6 pathological types of necrosis and an example of the diseases in which these occur.

Answer 7

1. Coagulative necrosis - myocardial ischaemia (necrosis due to lack of blood supply).
2. Liquefactive necrosis - stroke (ischaemic necrosis in the brain).
3. Gangrenous necrosis - peripheral vascular disease.
4. Caseous necrosis - tuberculosis.
5. Fat necrosis - pancreatitis.
6. Fibrinoid necrosis - vasculitis.

Question 8

What molecular features characterise necrosis?

Answer 8

In necrosis, mitochondria are damaged, depleting ATP and causing failure of energy-dependent functions. Influx of calcium activates enzymes eg. proteases. Free radicals accumulate and damage proteins, lipids and nucleic acids. Increased membrane permeability affects plasma membranes, lysosomal membranes and mitochondrial membranes. Intracellular proteins which leak out of necrotic cells can also appear in the serum eg. Troponin is released into the blood stream in the context of myocardial necrosis and can be measured to confirm a myocardial infarction (heart attack).

Question 9

What is apoptosis?

Answer 9

Apoptosis is programmed cell death and can be either physiological or pathological. It can be caused by protein or DNA damage. There is no loss of membrane integrity and no inflammatory reaction.

Question 10

What exposures/diseases are associated with apoptosis and disrupted apoptosis?

Answer 10

Radiation, hypoxia and cytotoxic drugs can damage DNA and if repair mechanisms fail apoptosis is induced to prevent malignancy.

p53 is a tumour suppressor gene which normally stops cells dividing if DNA is damaged and if the damage is too great apoptosis is triggered. p53 mutations predispose to cancer.

Misfolded proteins can accumulate in the endoplasmic reticulum (ER) causing ER stress and subsequent apoptosis.

Viral infections eg. HIV can cause apoptosis directly or by a host immune reaction (via cytotoxic T-cells).

T-cells can also cause apoptosis in tumours and in transplants during cellular rejection.

Apoptosis causes atrophy in the setting of duct obstruction eg. pancreas, salivary gland and kidney.

Question 11

List the two apoptosis pathways.

Answer 11

1. Intrinsic (mitochondrial) pathway.

2. Extrinsic (death receptor) pathway.

Question 12

Explain how the intrinsic apoptosis pathway works.

Answer 12

The intrinsic pathway is triggered by cell injury, DNA damage or decreased hormone stimulation. There is inactivation of a molecule called BCL-2 which is an anti-apoptotic molecule normally. This inactivation allows cytochrome C to leak from the inner mitochondrial matrix into the cytoplasm of the cell to activate caspases. Caspases are proteases which can breakdown cell proteins.

Question 13

Explain how the extrinsic apoptosis pathway works.

Answer 13

The extrinsic pathway can be activated by FAS ligand binding to the FAS death receptor on a target cell, activating caspases. This is the mechanism by which lymphocytes which respond to self can be eliminated. This pathway can also be triggered by Tumour Necrosis Factor (TNF) binding to the tumour necrosis factor receptor on a target cell. Some viruses and normal cells can produce a molecule called FLIP which can block apoptosis.

Question 14

Once a cell dies by apoptosis, what happens then?

Answer 14

Phosphatidylserine flips from the inner to the outer aspect of the cell membrane and this is recognised by macrophage receptors. Macrophages phagocytose the apoptotic bodies and the dead cells disappear within minutes. This is a very efficient process.

Question 15

List the 4 mechanisms which can cause abnormal accumulations to occur within cells and give one example of a disease associated with each mechanism.

Answer 15

1. Abnormal metabolism eg. fat accumulating in liver cells in alcoholic liver disease.
2. Lack of an enzyme eg. lysosomal storage diseases.
3. Defect in protein folding or transport eg. nephrotic syndrome causes excess protein loss through the kidneys and causes protein accumulation in kidney cells.
4. Ingestion of indigestible material eg. carbon accumulation in pneumoconiosis (a lung disease seen in coal miners).

Question 16

Describe the two forms of pathological calcification.

Answer 16

Dystrophic calcification occurs when calcium is deposited in tissue which is injured or dead and in this form calcium metabolism is normal.

Metastatic calcification is seen in association with hypercalcaemia. This may be caused by a parathyroid tumour or by production of parathyroid hormone related protein by other tumours. Paget’s disease of bone and multiple myeloma increase osteoclast activity causing hypercalcaemia. An excess of Vitamin D causes an increase in calcium and sarcoidosis is a disorder where granulomas form and these macrophages can activate a vitamin D precursor causing hypercalcemia. In renal failure, retention of phosphate can cause secondary hyperparathyroidism which can also raise blood calcium.