Adaptive cell responses

The cell adapts to increased physiological demands or to pathological stimuli through growth alterations. These changes may take the form of hypertrophy, hyperplasia, atrophy, metaplasia, and dysplasia. If the pathological stimulus persists, the cell may undergo apoptosis (programmed cell death) or cell death.

Hyperplasia

Hyperplasia is an increase in the number of cells in an organ or tissue. It may be physiologic or pathological.

Physiologic hyperplasia occurs in response to:

• Hormonal stimulation (e.g. uterine hyperplasia in pregnancy)
• Compensation (e.g. hepatic regeneration after partial hepatectomy)

Pathological hyperplasia results from continued hormonal stimulation and can lead to conditions such as endometrial and prostatic hyperplasia. However, this type of hyperplasia regresses once the hormonal stimulation ceases.

The mechanism of hyperplasia is an increase in the number of cells due to increased transcription of growth-promoting genes activated by growth factors and hormones.

Hypertrophy

Hypertrophy is an increase in the size of cells, leading to an increase in the size of an organ. It may accompany hyperplasia.

Typically:

• Cells capable of regeneration (e.g. liver) respond to injury with both hypertrophy and hyperplasia.
• Non-dividing cells (e.g. myocardium) respond mainly by hypertrophy.

Hypertrophy may be physiologic or pathological.

Physiologic hypertrophy is seen in:

• Skeletal muscle after weight training
• Uterus in pregnancy (which shows both hypertrophy and hyperplasia)

Pathological hypertrophy is seen in the left ventricle in response to long-standing hypertension.

The mechanism of hypertrophy includes:

• Increased transcription of genes coding for cellular proteins
• Activation of transcription factors such as c-fos and c-jun
• Increased growth factors such as IGF -1
• Changes in contractile proteins to beta myosin
• Increased number of cytoplasmic organelles
• Increased DNA content

Some embryonic genes may be re-expressed, e.g. ANP in the heart.

Atrophy

Atrophy is a decrease in the size and weight of a tissue or organ due to loss of cell substance and organelles.

Physiologic atrophy is seen during embryonic development, for example:

• Degeneration of the notochord
• Degeneration of the mullerian ducts (in males)

It is also seen in the uterus following pregnancy and childbirth, as the uterus reverts back to its previous size.

Pathological atrophy can follow various causes that impair growth and development, and it can lead to cell death if persistent. Causes include:

• Decreased use or workload (e.g. muscle atrophy following prolonged immobilization in a cast)
• Inadequate nutrition (e.g. marasmus)
• Loss of hormonal stimulation (e.g. atrophy of uterine endometrium and breasts in menopause due to lack of estrogen)
• Loss of innervation (e.g. LMN palsy)
• Inadequate blood supply (e.g. peripheral vascular disease)
• Sustained pressure (e.g. atrophy of the renal cortex and medulla in long-standing hydronephrosis)

Ageing is normally accompanied by atrophy, especially in the brain, muscles, and heart.

Atrophic cells:

• Have fewer organelles (e.g. mitochondria and endoplasmic reticulum)
• Show increased protein degradation by cathepsins and acid hydrolases in lysosomes
• Use the ubiquitin-proteasome pathway
• Show an increase in autophagy

Cellular components contained in autophagic vacuoles are lysed by lysosomal enzymes.

“Brown atrophy” is a normal part of ageing and is seen in organs such as the heart and liver. It results from deposition of yellow-brown lipofuscin and lipochrome pigments due to autophagy and lipid peroxidation of membranes.

Metaplasia

Metaplasia is a reversible change in which one type of adult differentiated cell is replaced by another type of adult differentiated cell. It develops as an adaptation to local stress, and the metaplastic epithelium can better withstand that stress.

Examples include:

• Glandular metaplasia of the distal esophagus in GERD (Barrett’s esophagus)
• Intestinal metaplasia in pyloric and antral gastric epithelium
• Squamous metaplasia of glandular bronchial epithelium in cigarette smoking

Vitamin A deficiency can cause squamous metaplasia of the respiratory tract.

Long-standing metaplasia can predispose to malignancy.

The mechanism of metaplasia is reprogramming of stem cells in response to cytokines, growth factors, and hormones induced by local irritants such as acidity or cigarette smoke. In many cases, reversal is possible once exposure to the irritant is stopped.

Dysplasia

Dysplasia is a pre-neoplastic lesion characterised by disorderly cell growth. Some cells show a lack of maturation, and there is irregularity in cell shape and size.

Cytological features of atypia include:

• Enlarged nuclei with prominent nucleoli
• Increased nuclear to cytoplasm ratio
• Hyperchromasia
• Coarse or vesicular chromatin
• Loss of architecture

Nuclear features of dysplasia can be differentiated from neoplastic cells by the presence of normal mitotic spindles in dysplasia.

Dysplasia may be reversible if the initiating factor is removed.

Examples include:

• Squamous dysplasia of the cervix in response to HPV 16 and smoking
• Squamous dysplasia of the bronchus
• Squamous dysplasia of the skin due to UV light exposure