Pathology: General Pathology

General pathology explains how normal physiology is altered in disease. It provides the shared language and core mechanisms that apply across organ systems, from a mild skin burn to myocardial infarction to cancer. While organ-specific pathology focuses on where a disease occurs, general pathology focuses on how disease happens: how cells are injured, how tissues respond, how inflammation is triggered and resolved, how repair restores function or leaves scarring, and how neoplasia arises when growth control fails.

Understanding these principles is not academic trivia. Clinicians use them to interpret symptoms, lab results, and imaging findings. Scientists use them to design therapies that interrupt harmful pathways while preserving normal function.

Cellular Injury: When Adaptation Fails

Cells constantly adjust to their environment. When demands increase or conditions change, they attempt to adapt. Disease begins when stress exceeds the cell’s ability to cope, resulting in injury.

Cellular Adaptations to Stress

Before cells are irreversibly damaged, they often show predictable adaptive patterns:

• Hypertrophy: Increased cell size, common in cardiac muscle in response to hypertension.
• Hyperplasia: Increased cell number, such as endometrial proliferation under estrogen.
• Atrophy: Reduced cell size and function, seen in disuse or loss of innervation.
• Metaplasia: Replacement of one differentiated cell type with another better suited to stress, such as squamous metaplasia in chronic smokers’ bronchi.

Adaptation can be protective, but it may also create vulnerability. Metaplasia, for example, can reduce normal function and increase the risk of dysplasia.

Causes and Mechanisms of Injury

Common causes of cellular injury include ischemia, toxins, infections, immune reactions, genetic defects, and nutritional imbalances. Many converge on a few central mechanisms:

• ATP depletion due to impaired oxidative phosphorylation, especially in ischemia.
• Mitochondrial dysfunction, reducing energy production and promoting cell death pathways.
• Oxidative stress from reactive oxygen species, damaging lipids, proteins, and DNA.
• Loss of calcium homeostasis, activating enzymes that degrade membranes and cytoskeleton.
• Membrane damage, compromising ion gradients and cellular integrity.

A classic example is ischemic injury. Reduced blood flow limits oxygen and nutrients, impairing ATP generation. Ion pumps fail, cells swell, and if perfusion is not restored, irreversible damage follows.

Reversible vs Irreversible Injury

Reversible injury often features cellular swelling, fatty change in organs like the liver, and temporary functional impairment. Irreversible injury is marked by severe membrane damage and nuclear changes that reflect loss of genetic integrity.

In practice, this distinction matters because interventions like reperfusion therapy in heart attack aim to restore viability before the point of no return. Yet reperfusion itself can contribute to injury through oxidative stress and inflammation, illustrating that pathology often involves trade-offs.

Cell Death: Necrosis and Apoptosis

Two major patterns of cell death underpin many diseases:

• Necrosis: Uncontrolled cell death with membrane rupture and inflammation. It is typical of infarction and severe toxin injury.
• Apoptosis: Regulated cell death with minimal inflammation, important in development and in eliminating damaged or infected cells.

Apoptosis can be triggered intrinsically by DNA damage or ER stress, or extrinsically through death receptors. In cancer, defects in apoptosis allow abnormal cells to persist. In neurodegenerative disease, excessive apoptosis may contribute to tissue loss.

Inflammation: The Body’s Rapid Response System

Inflammation is a protective response to injury or infection, designed to eliminate the cause of damage and initiate repair. It is also a frequent source of symptoms and tissue injury when dysregulated.

Acute Inflammation

Acute inflammation develops rapidly and is characterized by vascular changes and recruitment of leukocytes, especially neutrophils.

Key vascular events include:

• Vasodilation, increasing blood flow and causing redness and warmth.
• Increased vascular permeability, leading to fluid exudation and swelling.
• Leukocyte recruitment, guided by adhesion molecules and chemotactic signals.

Clinically, acute inflammation underlies abscess formation, bacterial pneumonia, and acute appendicitis. Its hallmark is speed and intensity, often resolving completely if the trigger is removed.

Chronic Inflammation

Chronic inflammation persists over time and features macrophages, lymphocytes, and ongoing tissue destruction with attempts at healing. It may result from persistent infections, prolonged exposure to toxic agents, or autoimmune reactions.

Granulomatous inflammation is a distinctive form, where activated macrophages aggregate into granulomas, often in response to organisms or foreign material that resist eradication. This pattern is diagnostically important because it narrows the differential diagnosis and guides further testing.

Systemic Effects of Inflammation

Inflammation is not confined to the local tissue. Systemic cytokine effects can cause fever, increased acute-phase proteins, leukocytosis, and changes in metabolism. These responses can be lifesaving, but in severe cases they contribute to sepsis and multi-organ dysfunction.

Repair: Regeneration, Scarring, and Functional Consequences

Once injury occurs, the body attempts to restore integrity. Repair ranges from perfect regeneration to imperfect healing with fibrosis.

Regeneration vs Fibrosis

• Regeneration replaces lost cells with the same type, restoring normal architecture. It is most effective in tissues with proliferative capacity, such as epithelium.
• Fibrosis forms scar tissue when regeneration is limited or the extracellular matrix framework is damaged. Fibrosis restores strength but may impair function.

A practical example is liver injury. With mild, limited damage and preserved architecture, the liver can regenerate effectively. With repeated injury and chronic inflammation, fibrosis accumulates and can progress to cirrhosis, fundamentally altering blood flow and organ function.

Wound Healing: Key Steps

Wound healing involves overlapping phases:

1. Hemostasis: clot formation to stop bleeding.
2. Inflammation: removal of debris and pathogens.
3. Proliferation: granulation tissue formation, angiogenesis, fibroblast activity.
4. Remodeling: collagen reorganization, scar maturation, tensile strength increases.

Complications reflect failures or excesses of these processes. Insufficient healing may lead to wound dehiscence or ulceration; excessive collagen can cause hypertrophic scars or keloids.

Neoplasia Principles: When Growth Control Breaks

Neoplasia refers to new, abnormal growth driven by genetic and epigenetic alterations. The central concept is autonomy: neoplastic cells proliferate in ways that are poorly regulated by the normal constraints that maintain tissue organization.

Benign vs Malignant Tumors

• Benign tumors tend to grow slowly, remain localized, and resemble the tissue of origin.
• Malignant tumors invade surrounding tissues and can metastasize to distant sites.

The clinical stakes are determined not only by histologic appearance but by behavior. A small malignant tumor can be more dangerous than a large benign mass if it spreads or compromises critical structures.

Hallmarks of Malignant Behavior

Malignancies commonly show:

• Uncontrolled proliferation due to disrupted cell-cycle regulation.
• Evasion of apoptosis, allowing survival despite damage.
• Angiogenesis, supplying nutrients to expanding tumor tissue.
• Invasion and metastasis, enabling dissemination through lymphatics or blood.
• Genomic instability, accelerating evolution of aggressive clones.

These principles align with modern cancer therapy. Many treatments target proliferative signaling, tumor angiogenesis, or immune evasion. Even without naming specific drugs, the logic of therapy is rooted in general pathology: interrupt the mechanisms that make malignant growth possible.

Dysplasia and Carcinogenesis

Between normal tissue and cancer lies a continuum. Dysplasia reflects disordered growth and maturation, often arising in the setting of chronic irritation or inflammation. Not all dysplasia progresses to cancer, but it signals increased risk and justifies surveillance or intervention.

Carcinogenesis is a multistep process. Mutations accumulate over time, and selection favors clones that grow faster, resist death, and invade. This evolutionary view helps explain why early detection improves outcomes and why cancers can become resistant to therapy.

Why General Pathology Matters in Everyday Medicine

General pathology connects clinical findings to underlying mechanisms:

• Chest pain and elevated cardiac enzymes reflect ischemic injury and necrosis.
• Swelling and redness around a wound reflect acute inflammation and vascular leakage.
• Chronic cough with tissue remodeling reflects chronic inflammation and repair.
• A persistent mass raises questions of neoplasia, invasion, and potential metastasis.

By focusing on cellular injury, inflammation, repair, and neoplasia, general pathology provides a framework that stays useful regardless of the organ system involved. It trains the clinician and scientist alike to ask the same essential questions: what injured the tissue, how did the body respond, what healed or failed to heal, and what might happen next.