Causes of Diseases: Etiology, Genetic, Infectious, Immune, Environmental and Iatrogenic Factors

Learning objectives

• Define etiology, cause, risk factor, predisposition, trigger, mediator and protective factor.
• Classify diseases as congenital, genetic, infectious, immune-mediated, nutritional, metabolic, physical, chemical, vascular, degenerative, neoplastic, behavioural, environmental or iatrogenic.
• Explain the infectious-disease agent–host–environment model and chain of infection.
• Distinguish association from causation and identify necessary, sufficient and contributing causes.
• Use a cause-and-context framework to analyse emergency presentations and choose prevention strategies.
• Recognise when the cause remains idiopathic, multifactorial or uncertain, and document that uncertainty safely.

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1. Meaning of etiology

Etiology is the cause or causes of a disease. A cause is a factor that contributes to the occurrence of a disease through a biologically or socially plausible pathway. Etiology may be:

Term	Meaning	Example
Primary cause	The initiating factor that starts the disease process.	Plasmodium infection initiating malaria.
Predisposition	An intrinsic or acquired susceptibility that makes disease more likely.	HbSS genotype predisposes to sickling complications.
Exposure	Contact with a potentially harmful agent or condition.	Needlestick exposure to infected blood or inhalation of silica.
Trigger/precipitant	The immediate event that converts susceptibility into clinical disease.	Exercise triggering bronchospasm in an asthmatic patient.
Risk factor	A characteristic associated with increased probability of disease.	Smoking increases lung-cancer risk; it does not prove causation in one individual.
Modifier	A factor that changes severity, duration or outcome after disease begins.	Delayed antibiotics worsening sepsis outcome.
Mediator	An intermediate biological or social step linking exposure to outcome.	Hypertension mediating part of the relationship between obesity and stroke.
Protective factor	A factor that reduces the probability or severity of disease.	Vaccination, mosquito nets or adequate folate before pregnancy.

2. Cause, association and causation

Two factors can occur together without one causing the other. A credible causal inference considers temporality, dose–response relationship, biological plausibility, consistency, reversibility after removing the exposure, and alternative explanations. In a patient, however, urgent treatment often begins before causation is proved.

Necessary and sufficient causes

• Necessary cause: must be present for a disease to occur in a defined setting. A specific pathogen may be necessary for a particular infection, although infection may not always produce clinical disease.
• Sufficient cause: a complete combination of factors capable of producing the outcome. Many diseases have several different sufficient pathways.
• Component cause: one part of a causal combination; it may be insufficient alone.
• Contributory cause: increases probability or severity but is neither necessary nor sufficient by itself.

Example: Myocardial infarction may follow plaque rupture, thrombosis, endothelial injury, high LDL exposure, smoking, hypertension and genetic susceptibility. No single factor explains every case.

3. The major etiological categories

The same disease may appear in several categories. Diabetes may be genetic, autoimmune, metabolic and environmental; liver cancer may be neoplastic but also infection-associated; chronic lung disease may be physical, chemical, behavioural and inflammatory at the same time.

3.1 Congenital and developmental causes

Congenital means present at birth, not necessarily inherited. Causes include chromosomal abnormalities, single-gene variants, multifactorial development, intrauterine infection, maternal disease, nutritional deficiency, medicines, alcohol, radiation, toxins and unknown developmental events.

Cause	Mechanism/example	Prevention or response
Chromosomal abnormality	Extra, missing or rearranged chromosome; may alter multiple organ systems.	Preconception counselling, prenatal screening and appropriate newborn assessment.
Teratogenic exposure	Drug, alcohol, infection, radiation or toxin interferes with organ development during a susceptible window.	Medication review, vaccination, infection prevention and antenatal care.
Maternal disease	Diabetes, phenylketonuria, thyroid disease or severe malnutrition changes fetal development.	Preconception optimisation and monitored pregnancy care.
Mechanical/vascular event	Amniotic-band disruption, placental insufficiency or vascular interruption.	Antenatal monitoring; treatment is often supportive or surgical after birth.
Unknown developmental cause	No cause identified despite assessment.	Document as unexplained, offer recurrence counselling when indicated.

3.2 Genetic causes

Genetic disease results from pathogenic variation in DNA or chromosome structure/function. It may be germline and heritable, de novo, mitochondrial, epigenetic or somatic (acquired in a cell clone). A genetic cause can produce disease by loss of function, gain of function, toxic protein, altered dosage, abnormal regulation or defective DNA repair.

Genetic pattern	Core idea	Examples
Single-gene/Mendelian	One gene has a major effect; inheritance may be autosomal dominant, autosomal recessive, X-linked or mitochondrial.	Sickle-cell disease, cystic fibrosis, haemophilia, familial hypercholesterolaemia.
Chromosomal	Numerical or structural chromosome abnormality.	Trisomy 21, Turner syndrome, translocation-associated disease.
Multifactorial/polygenic	Many variants each contribute small effects, interacting with environment.	Hypertension, type 2 diabetes, asthma, coronary disease.
Somatic/acquired	Mutation arises in a body-cell clone and is not usually inherited.	Driver mutations in cancer; mosaic disorders.
Mitochondrial	Defective oxidative phosphorylation with variable tissue involvement and maternal inheritance.	Selected encephalomyopathies and myopathies.

Penetrance is whether a genotype produces a phenotype; expressivity is how strongly it is expressed. Age, sex, modifier genes, epigenetics and environment can alter both. A negative family history does not exclude a de novo variant or recessive disease.

3.3 Infectious causes

Infectious diseases are caused by organisms or infectious particles that enter, survive, replicate or exert toxins in a host. Major agents include bacteria, viruses, fungi, protozoa, helminths, ectoparasites, prions and some biologically active toxins.

Agent group	Ways it causes damage	Examples
Bacteria	Invasion, toxins, enzymes, immune activation, biofilm and tissue destruction.	Tuberculosis, bacterial pneumonia, cholera, sepsis.
Viruses	Direct cytolysis, altered cell function, persistent infection, oncogenesis or immune-mediated injury.	Influenza, HIV, hepatitis B, HPV.
Fungi	Invasion, toxins or hypersensitivity; opportunistic disease when immunity is impaired.	Candidiasis, cryptococcosis, invasive aspergillosis.
Protozoa/helminths	Invasion, blood loss, obstruction, nutrient theft, immune injury or chronic inflammation.	Malaria, schistosomiasis, hookworm.
Prions	Misfolded proteins induce abnormal protein aggregation and neurodegeneration.	Creutzfeldt–Jakob disease.

3.4 Agent–host–environment model

In infectious disease, disease occurs through interaction between an agent, a susceptible host and an environment that permits exposure. The agent’s infectious dose, virulence and route interact with host immunity, age, genetics, nutrition and comorbidities.

1. Agent: pathogen or toxin with a source, reservoir, survival properties and route of exit.
2. Reservoir: person, animal or environment in which the agent normally lives and multiplies.
3. Portal of exit: respiratory secretions, blood, faeces, urine, skin, genital secretions or vector.
4. Mode of transmission: direct contact, droplets, airborne spread, vehicle-borne, food/water, fomites, blood exposure or vector.
5. Portal of entry: respiratory tract, gastrointestinal tract, mucosa, broken skin, placenta or injection.
6. Susceptible host: person lacking sufficient immunity or barriers.

Prevention works by breaking any link: vaccination changes susceptibility, hand hygiene reduces transmission, safe water removes the vehicle, ventilation reduces airborne concentration and treatment reduces the reservoir.

3.5 Immune-mediated causes

Immune mechanism	What goes wrong	Examples
Hypersensitivity	Excessive or misdirected immune response damages otherwise harmless targets.	Anaphylaxis, asthma, drug eruptions, immune-complex disease.
Autoimmunity	Loss of tolerance causes immune attack against self-antigens.	Type 1 diabetes, systemic lupus, rheumatoid arthritis, autoimmune thyroid disease.
Immunodeficiency	Absent or defective immune components increase infection, malignancy or autoimmunity.	HIV-associated immunodeficiency, congenital antibody deficiency, neutropenia.
Alloimmunity	Response to genetically different cells from another person.	Transplant rejection, haemolytic disease of the newborn.
Chronic inflammation	Persistent immune activation produces fibrosis, remodelling and tissue destruction.	Chronic hepatitis, inflammatory bowel disease, silicosis-associated inflammation.

Immune responses can be both protective and pathogenic. In tuberculosis, host immunity contains organisms but granulomatous inflammation also damages tissue. In sepsis, the host response may cause more organ injury than direct microbial invasion.

3.6 Nutritional causes

Nutritional disease results from deficiency, excess, imbalance or impaired utilisation. Causes include food insecurity, malabsorption, chronic illness, restrictive diets, alcoholism, increased physiological needs and poverty. Nutritional problems may coexist with infection and worsen immunity, healing and drug pharmacokinetics.

Pattern	Examples	Important consequences
Protein–energy deficiency	Wasting, oedematous malnutrition, inadequate intake or severe illness.	Immunodeficiency, poor wound healing, muscle weakness and altered drug binding.
Iron deficiency	Blood loss, low intake, pregnancy or malabsorption.	Microcytic anaemia, fatigue, impaired development.
Vitamin deficiency	Folate/B12 deficiency, vitamin A/D/C deficiency.	Neural injury, anaemia, bone disease, visual impairment or poor collagen formation.
Electrolyte/water imbalance	Vomiting, diarrhoea, renal failure, endocrine disease or inappropriate fluid intake.	Arrhythmia, seizures, coma, weakness or shock.
Excess/over-nutrition	Obesity, excess alcohol, high sodium or toxic vitamin doses.	Diabetes, hypertension, fatty liver, vascular disease or toxicity.

3.7 Physical causes

• Mechanical trauma: blunt or penetrating injury, crush, acceleration/deceleration, blast and repetitive strain.
• Temperature: burns, scalds, hypothermia, frostbite, heat exhaustion and heat stroke.
• Radiation: ultraviolet, ionising radiation and therapeutic exposure can cause DNA injury, burns, cataracts and cancer.
• Electricity: arrhythmia, respiratory arrest, deep burns and muscle damage may occur despite small skin lesions.
• Pressure: barotrauma, decompression illness, altitude hypoxia and compartment syndrome.
• Noise/vibration: sensorineural hearing loss and occupational injury.
• Motion/force: falls, sports injuries and repetitive occupational microtrauma.

Physical injury often has a dose–time relationship: intensity, duration, surface area and tissue susceptibility determine damage. Emergency assessment must look beyond the visible lesion.

3.8 Chemical and toxic causes

Chemical injury may be deliberate or accidental, occupational, environmental, medication-related or iatrogenic. Toxicity depends on dose, route, duration, metabolism, interactions, age, pregnancy, genetics and organ reserve.

Toxic category	Examples	Characteristic concern
Corrosives	Acids, alkalis and industrial cleaners.	Oropharyngeal, oesophageal, gastric, ocular or skin burns.
Systemic poisons	Organophosphates, cyanide, carbon monoxide, methanol, ethylene glycol.	Rapid neurological, respiratory, metabolic or cardiovascular collapse.
Hepatotoxins	Paracetamol overdose, alcohol, aflatoxin, some herbal products.	Hepatocellular injury and acute liver failure.
Nephrotoxins	Heavy metals, some medicines, solvents and plant toxins.	Acute kidney injury, electrolyte abnormalities and hypertension.
Occupational/environmental	Silica, asbestos, pesticides, lead, mercury, air pollution.	Chronic lung, neurological, renal, reproductive or malignant disease.
Drug-related	Overdose, adverse drug reaction, interaction or medication error.	Recognise dose, timing, formulation and antidote early.

In poisoning, identify the substance, amount, time, route and co-exposures; stabilise airway and circulation; check glucose and temperature; and use a poison centre or toxicology protocol. Do not induce vomiting or give an unproven antidote.

3.9 Metabolic and endocrine causes

Metabolic disease results from abnormal synthesis, storage, transport or utilisation of energy and structural molecules. Endocrine disease results from excess, deficiency, resistance or abnormal action of hormones.

• Inborn metabolic errors: enzyme or transporter defects cause toxic accumulation or deficient products.
• Acquired metabolic disease: diabetes, dyslipidaemia, fatty liver and metabolic syndrome arise from interacting genetic, nutritional and behavioural factors.
• Endocrine excess: thyrotoxicosis, Cushing syndrome, hyperparathyroidism.
• Endocrine deficiency: adrenal crisis, hypothyroidism, hypoparathyroidism.
• Hormone resistance: insulin resistance, nephrogenic diabetes insipidus or receptor defects.

3.10 Vascular and haemodynamic causes

Vascular disease may result from abnormal flow, vessel-wall injury, thrombosis, embolism, vasospasm, rupture or inadequate perfusion. Major mechanisms include:

• Ischaemia: insufficient blood flow causes oxygen and nutrient deprivation.
• Infarction: ischaemic necrosis of tissue due to interrupted blood supply.
• Congestion: impaired venous drainage causes oedema and chronic tissue injury.
• Thrombosis/embolism: intravascular clot or travelling material obstructs flow.
• Haemorrhage: blood escapes from vessels due to rupture, erosion or abnormal coagulation.
• Shock: systemic circulatory failure causes inadequate tissue perfusion; causes include hypovolaemia, pump failure, obstruction and distributive states.

3.11 Degenerative and ageing-related causes

Ageing, repeated injury, abnormal protein accumulation, mitochondrial dysfunction, impaired repair and vascular disease may produce progressive degeneration. Degenerative change is not automatically “normal ageing”; disease is diagnosed when structure or function exceeds expected age-related variation or causes impairment.

3.12 Neoplastic causes

Neoplasia results from accumulated genetic and epigenetic alterations that permit autonomous or dysregulated cellular proliferation. Causes include inherited susceptibility, tobacco, alcohol, radiation, oncogenic infections, occupational exposures, chronic inflammation, obesity and random replication errors. Cancer is therefore both a disease process and the result of interacting causes over time.

3.13 Behavioural and psychosocial causes

Behavioural exposures can be direct causes, mediators or risk markers. Tobacco, harmful alcohol use, unsafe sex, poor diet, inactivity, sleep deprivation, medication non-adherence and substance use affect disease through biological pathways. Psychosocial stress, violence, poverty, discrimination and insecure housing alter neuroendocrine, immune and behavioural responses and influence access to prevention and treatment.

These factors must be addressed without blame. A behaviour is one component of a causal system, not a moral diagnosis.

3.14 Iatrogenic and health-care-associated causes

Iatrogenic disease is caused unintentionally by medical investigation or treatment. Examples include adverse drug reactions, drug interactions, contrast reactions, radiation injury, catheter infection, procedure-related bleeding, pressure injuries, hospital-acquired infection and diagnostic delay.

• Verify patient identity, medicine, dose, route, timing, allergies and renal/hepatic function.
• Use aseptic technique and remove unnecessary lines and devices.
• Communicate abnormal results and safety-net patients after discharge.
• Report adverse events and near misses so systems improve rather than blaming individuals.

3.15 Idiopathic and cryptogenic disease

Idiopathic means that no cause has been identified despite appropriate evaluation. Cryptogenic often means a cause is suspected but not demonstrable. These labels should be used after reasonable assessment, not as a substitute for thinking. “Unknown cause” can later become “cause identified” when new tests or evidence emerge.

4. Multifactorial disease: the usual clinical reality

Many common diseases arise from the interaction of multiple component causes. A useful model is:

Disease	Possible interacting contributors	Prevention opportunities
Type 2 diabetes	Family susceptibility, adiposity, diet, inactivity, age, medications, sleep and socioeconomic context.	Healthy food access, physical activity, weight management, screening and early treatment.
Asthma exacerbation	Airway hyper-responsiveness, viral infection, allergens, smoke, poor adherence and psychosocial stress.	Controller therapy, trigger reduction, vaccination, inhaler education and action plans.
Stroke	Hypertension, atrial fibrillation, diabetes, smoking, dyslipidaemia, genetics and age.	Blood-pressure control, anticoagulation when indicated, smoking cessation and rapid TIA care.
Cervical cancer	Persistent high-risk HPV infection, immune status, smoking, screening access and treatment delays.	HPV vaccination, screening, treatment of precancer and timely cancer care.
Peptic ulcer disease	H. pylori, NSAID exposure, smoking, severe physiological stress and host susceptibility.	Eradication, safer analgesic prescribing, gastroprotection and smoking cessation.

5. Host factors that modify disease

Host factor	How it changes disease	Clinical examples
Age	Changes immunity, metabolism, organ reserve, drug handling and exposure patterns.	Sepsis in neonates, atypical MI in older adults.
Sex and pregnancy	Hormones, anatomy, immune responses and physiology alter susceptibility and treatment.	Pregnancy-related hypertension, autoimmune disease variation.
Genetics	Changes receptors, enzymes, immunity and structural proteins.	G6PD deficiency, pharmacogenomic reactions, sickle cell.
Nutrition	Modifies barrier function, immunity, healing and drug toxicity.	Malnutrition increasing infection and pressure-injury risk.
Immune status	Determines containment of infection and risk of autoimmunity or malignancy.	Opportunistic infection in advanced HIV or neutropenia.
Comorbidity	Reduces reserve and changes the presentation of a new disease.	Renal failure altering potassium and drug clearance.
Medication/substance use	May cause disease, mask symptoms or change test results.	Beta-blockers masking tachycardia; steroids increasing infection risk.
Previous exposure/immunity	Changes response to infection, allergens, drugs and vaccines.	Severe reaction after re-exposure to an allergen.

6. Environmental and social determinants

Diseases arise in people, not in isolated organs. Housing, water, sanitation, air quality, food security, occupation, education, transport, income, conflict, gender-based violence and access to health services alter both exposure and the ability to recover.

• Indoor smoke and poor ventilation increase respiratory disease and infection transmission.
• Unsafe water and sanitation increase enteric infection and parasitic disease.
• Occupational exposure can cause lung disease, hearing loss, poisoning, trauma or cancer.
• Distance and cost delay diagnosis and worsen emergency outcomes.
• Stigma can delay HIV, mental-health, sexual-health or cancer care.

Social determinants are not “background details”; they are causal conditions that should be included in history-taking and prevention planning.

7. Cause-specific clinical reasoning

Ask five questions for any new presentation

1. What was the baseline? Identify chronic disease, medications, pregnancy, immune status and organ reserve.
2. What changed and when? Time course separates many infectious, vascular, toxic, traumatic and degenerative causes.
3. What exposures occurred? Travel, food/water, contacts, occupation, drugs, toxins, trauma and sexual exposure.
4. What host factors matter? Age, genetics, comorbidities, vaccination, nutrition and prior immunity.
5. What dangerous causes must be treated before confirmation? Shock, hypoxia, hypoglycaemia, meningitis, anaphylaxis, poisoning, ectopic pregnancy, myocardial infarction and stroke.

8. Emergency examples: cause changes immediate treatment

9. Prevention follows the cause

Prevention level	Goal	Cause-focused examples
Primordial	Prevent emergence of risk factors.	Healthy urban design, clean air, food policies, tobacco control and safe workplaces.
Primary	Prevent disease before it occurs.	Vaccination, condoms, mosquito nets, folate, PPE, balanced nutrition.
Secondary	Detect disease early and stop progression.	Screening, contact tracing, blood-pressure checks, cervical screening, early HIV testing.
Tertiary	Reduce complications and disability.	Rehabilitation, chronic disease control, renal protection and pressure-ulcer prevention.
Quaternary	Prevent harm from unnecessary medical intervention.	Avoid antibiotics for viral illness, unnecessary imaging, polypharmacy and unsafe procedures.

10. Worked cases

Case 1: Fever, confusion and hypotension

Presentation: an older patient has fever, confusion, tachycardia and low blood pressure after dysuria.

Cause framework: likely infection, but the differential includes drug toxicity, adrenal crisis, myocardial infarction and haemorrhage. Host factors include age, diabetes, renal disease and recent antibiotics. Immediate priorities are airway/breathing/circulation, glucose, cultures where they do not delay antibiotics, lactate, fluids/vasopressors when indicated, source control and reassessment.

Case 2: Acute wheeze after a new medicine

Presentation: wheeze, urticaria and hypotension minutes after an injection.

Cause framework: likely IgE-mediated or non-IgE anaphylaxis. The exposure is the new medicine; the host may have previous atopy or no known risk factor. Treat immediately with IM adrenaline, airway/oxygen support and fluids. Do not wait for serum tryptase or a definitive allergy label.

Case 3: Anaemia in a young adult

Presentation: fatigue, pallor and microcytosis.

Cause framework: iron deficiency may result from blood loss, low intake, malabsorption or increased need; thalassaemia trait, chronic inflammation and lead exposure are alternatives. Treating iron without finding the cause may delay diagnosis of gastrointestinal bleeding, pregnancy-related loss or malignancy.

Case 4: Drug-induced liver injury

Presentation: jaundice and high ALT after a new herbal medicine.

Cause framework: suspect an iatrogenic/chemical cause, but exclude viral hepatitis, biliary obstruction, autoimmune disease and ischaemic injury. Stop non-essential suspected agents, assess INR/glucose/mental state, review acetaminophen exposure and refer urgently if acute liver failure is possible.

11. Common mistakes in explaining disease causes

Mistake	Why it is unsafe	Better wording
“The patient got disease because of poor lifestyle.”	Blames the patient and ignores genetics, environment and access.	“Several genetic, metabolic, behavioural and social factors contribute; identify modifiable factors without blame.”
“The culture is positive, so it is the cause.”	Colonisation and contamination can mimic infection.	“Interpret the organism with symptoms, site, specimen quality and host response.”
“No family history means not genetic.”	De novo, recessive, reduced-penetrance and unrecognised disease are possible.	“Assess phenotype and inheritance pattern; refer for genetic evaluation when indicated.”
“It is idiopathic, so nothing can be done.”	Unknown cause does not mean untreatable or imaginary.	“Cause remains unidentified; treat the syndrome, monitor and reassess as evidence evolves.”
“The drug caused it because it was taken before symptoms.”	Temporal sequence alone does not prove causation.	“Assess timing, known adverse-effect pattern, alternatives, dechallenge and rechallenge risk.”
“The exposure explains every symptom.”	Patients may have two simultaneous problems.	“Test whether the exposure accounts for severity, pattern and objective findings.”

12. Examination-ready summary

• Etiology is the study of the causes of disease.
• Causes may be intrinsic or extrinsic, congenital or acquired, single or multifactorial.
• Major categories include genetic, infectious, immune, nutritional, metabolic, endocrine, physical, chemical, vascular, degenerative, neoplastic, behavioural, environmental and iatrogenic causes.
• Risk factors increase probability; they are not necessarily sufficient or necessary causes.
• Infectious disease reflects agent–host–environment interaction and a chain of transmission.
• Genetic susceptibility and environmental exposure commonly interact.
• Immune responses can protect against disease or cause tissue injury.
• Social determinants influence exposure, susceptibility, access to treatment and outcome.
• “Idiopathic” means cause not identified after assessment; it is not a diagnosis of exclusion without thought.
• In emergencies, stabilize life threats while investigating cause; early treatment need not wait for a final label.

13. Quick self-test

1. Distinguish a cause, risk factor, trigger and modifier using myocardial infarction as an example.
2. Why can an infectious organism be present without causing disease?
3. List the six links in the chain of infection and one intervention that breaks each link.
4. Explain why congenital does not mean hereditary.
5. Give three examples of immune-mediated disease and identify whether the immune response is excessive, misdirected or deficient.
6. Why is a positive culture not automatically proof of invasive infection?
7. Which prevention level is vaccination? Which is rehabilitation after stroke?

Sources and further reading

• WHO: Noncommunicable diseases and interacting genetic, physiological, environmental and behavioural factors
• CDC Principles of Epidemiology: agent–host–environment and chain of infection
• CDC infection-control overview
• NCBI Bookshelf: Genes and Disease
• NCBI Bookshelf: Infectious agents and how they cause disease
• WHO ICD-11 classification framework
• Pathology: the clinical description of human disease