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gulf war syndrome



  1. Definition of disease
  2. Etiologic factors
  3. Pathogenesis
  4. Risk factors
  5. Host defenses
  6. Ischemic cell dysfunction
  7. Cell aging
  8. Oncogenesis
  9. Cell death – necrosis and apoptosis
  10. Clinical assessment of cell injury and dysfunction
  11. Healing


Disease is the inability to maintain homeostasis and/or full function

Homeostasis represents the functional and structural equilibrium of cells order to maintain the normal function of entire human organism; requires functional cooperation of widely distributed cells.

Diseases classification:

etiologic classification: traumatic disease, infectious diseases, immune diseases, metabolic diseases.

semiologic classification: acute diseases, chronic disease

anatomic classification: heart diseases, cerebral diseases, hepatic diseases, lung diseases, kidney diseases etc.

ontogenic classification: hereditary diseases, congenital disease, acquired diseases.


Etiologic factors are the initiating agents in cell injury and dysfunction.

Etiologic factors classification

A. Concerning to pathogenesis:

determinant etiologic factors : physical, chemical, biological agents;

secondary factors: malnutrition, cold, concomitant chronic diseases, iatrogenic factors.

B. Concerning the origin:

- endogenous factors: hypoxia/ischemia – may lead to myocardial infarction, stroke etc ; chemically reactive molecules (free radicals, oxidants) – may lead to cells injury, immune effectors proteins and cells lead to immune inflammation, growth factor stimulation or removal – may lead to neovascularisation, neoplasia or wound repair disorders ; atherosclerosis lead to myocardial infarction, stroke, peripheral arterial disease ; diabetes mellitus lead to diabetic neuropathy, diabetic retinopathy, diabetic nephropathy

- exogenous factors: physical, chemical, biological, stressing factors.

Fig 1. Free radicals action

Fig.2. Mechanism of intracellular dysfunction (calcium dysregulation).


Pathogenesis refers to mechanisms of diseases from etiology to complications

Mechanisms of disease

lethal cytotoxicity in critical cell populations with loss of cell function and associate inflammation;

reversible injury to critical cell populations with decreased cells functions.

disruption of cell-cell communication without direct injury.

Classification of pathogenetic mechanisms according to the level of disturbances:

molecular pathogenetic mechanism;

cellular pahogenetic mechanism;

organ pathogenetic mechanism;

systemic pathogenetic mechanism;

integrative pathogenetic mechanism (neuro-endocrine integrative mechanism) (fig.3).

Fig.3. Neuroendocrine integrative pathogenetic mechanism.


Risk factors represent the conditions who refers to transition to healthy organism to disease.

Classification of risk factors

Intrinsic risk factors:

inherited risk factors – increase the risk for certain diseases like multiple sclerosis in Nordic populations, Behcet disease in Turkish population, sickle anemia in African and Afro-American population.

constitutional diseases – increase of sympathetic activity increase the risk for arterial hypertension.

Extrinsic risk factors:

ambient risk factors – physical conditions (temperature, pressure, ionizing radiations), biological risk factors (bacterial, viral, worms infections, fungal infections);

geographical risk factors – areas with increase of risk for malaria and another tropical diseases

psychical risk factors – stress.

nutritional risk factors – lipids excesses lead to increase the risk for atherosclerosis, inadequate calcium ingestion lead to increase the risk for tetanus.

iatrogenic risk factors - inadequate drug therapy, inadequate surgical interventions.


The host defense mechanisms consist in:

physical and chemical barriers – are a non-specific mechanism of defenses and consist in:

  1. physical presence of structural barriers - skin, mucous membrane, epiglottis, sphincters, normal secretor and excretory flow
  2. biochemical processes – gastric acidity, endogenous microbial flora
  3. physical removal pathogens – lachrymal secretion, peristalsis, cough, urine flow

inflammatory response – circulating phagocytes, complement, inflammatory mediators

reticuloendothelial system – tissue phagocytes: liver – Kupffer cells, lung – alveolar macrophages, brain – microglial cells, spleen, lymph nodes


immune response

Interference with any of these mechanisms can increase the host susceptibility to disease.


Ischemia represents an inadequate tissue blood supply. Loss of normal blood flow and oxygenation in certain tissues lead to reversible and irreversible cell dysfunctions. The basis modifications which may lead to reversible or irreversible cells dysfunction is the ischemic cascade.

The ischemic cascade is a series of biochemical reactions that taken place in aerobic tissues after seconds to minutes of ischemia. This is typically secondary to stroke injury, or myocardial infarction. Most ischemic cells die do so due to the activation of chemical produced during and after ischemia. The ischemic cascade usually goes on for to three hours but can last for days, even after normal blood flow returns. The ischemic cascade can be generally characterized as follows:

1. Lack of oxygen causes the cells normal processes for making ATP for energy to fail. The increased amount of AMP (from un-recycled ATP) stimulates anaerobic glycolysis (AMP stimulate phosphofructokinase), glycogen is depleted, lactic acid (the end product of glycolisis) and phosphorus (from the ATP and other energy rich phosphates) accumulates, and cells pH drops precipitously, denaturing the proteins.

2. ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions, including calcium, to flow into the cell. The ion pumps can no longer transport calcium into the cell, and intracellular calcium levels get too high.

3. In the neurons, the presence of calcium, triggers the release the excitatory amino acid neurotransmitter glutamate ; glutamate stimulates the AMPA receptors and calcium permeable NMDA receptors, which open to allow more calcium into cells. Calcium can also cause the release of more glutamate. This process is called excitotoxicity.

4. Excess calcium entry causes the generation of harmful chemicals like free radicals, and calcium dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases

5. As the cell’s membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell.

6. The caspase-dependent apoptosis cascade is initiated, causing cells to “commit suicide”

7. If the cell dies through necrosis, it releases toxic chemicals into the environment around it.

8. If and when the tissue is reperfused, a number of factors lead to reperfusion injury.

9. An inflammatory response is mounted, and phagocyte cells engulf damaged but still viable tissue.

Consequently results:

- reversible cell dysfunction – by reperfusion which may lead finally to greater injury of the tissue ( the free radicals, especially toxic oxygen radicals are some important mediators of reperfusion injury). Further, when blood flow is restored to damaged cells, the newly-available calcium will pour through the damaged cell membranes and into mitochondria, killing cells even faster. Later, the neutrophyls, which fight disease using free radicals, accumulate at the sites of tissue injury. Of course, if blood is not restored, the tissues will die anyway.

- irreversible cell dysfunction – by membrane injury, enzyme escape, calcium intracellular influx, lysososme breakdown; all of these dysfunctions lead finally to autodigestion ; after mitochondrial damage occurs the cell dysfunction is considered irreversible (if the oxidative phosphorilation is restored, the dysfunction becomes reversible) ; consequently to irreversible dysfunction eosinophylia occurs.


A lot of cells functions decrease with aging:

- decrease of mitochondrial oxidative phosphorilation

- decrease of intracellular proteins and receptors synthesis

- decrease of reparations of chromosomal modifications.

An important aging disease is atherosclerosis which leads to decrease of blood flow and tissue hypoxia and ultimately to cell distruction.

Fig. 4. Intracellular aging processes.

Aging theories

Injury factors theory (endogenous/exogenous) – the aging process may occur after prolonged and repetitive exposure to exogenous factors like ionizing radiations or after decreases of defensive endogenous mechanisms like antioxidative mechanisms.

Inheritance theory – the aging process is consequently to malfunction of cells, which is a genetic condition. By genetic conditions may result DNA replications errors and cells multiplication dysfunctions (this theory is not value for neurons and muscle cells which are not multiply).


Neoplasia results from disturbances of responsiveness to cells normal growth controls. The occurrences of tumoral tissues are the result of disturbances of two types of genes:

the genes who support the cellular growth – pro-oncogenes genes (growth promoting genes)

the genes who controls tumor suppression – anti-oncogenes genes (cancer suppression genes).

Oncogenesis theories

  1. Genetic predisposition theory – concern to existence of genetic predisposition for tumors development
  2. Hereditary inheritance theory – sustains the hereditary transmission of some tumors like retinoblastoma, neurofibromatosis type I (von Recklinghausen disease), Wilms tumor (renal tumor in children) ; in these tumors is considered a decrease of anti-oncogenes genes activity
  3. Text Box:  Viral theory – some viruses may be carriers of oncogenic genes ; after functional transformation these viruses may induce in infected cells the occurrence of oncogenes signals ; a lot of viruses is considered to be implicated in tumors occurrence: retroviruses, hepatitis B virus, hepatitis C virus, herpes simplex type 2 virus, Epstein-Barr virus, papillomaviruses, etc.
  4. Toxically effect of chemical substances theory – the toxically substances may react with DNA, RNA and cellular protein; the result is the occurrence of pro-oncogenes signals who disturbed the activity of pro-oncogenes and also anti-oncogenes genes.
  5. The radiation effect theory – a proved relationship between the ultraviolet rays, X rays, and radionuclide exist; these factors have the ability to damage DNA ; even the therapeutically doses may be implicated in neoplasm occurrences.

The occurrence of cancer is linked by multiple gene mutations (fig).

The pathophysiological consequences of neoplasia occurrence:

the tissue histology alteration leads to functional disturbances

the tumor growth may be dangerous for the neighborhood tissues

the competition effect with the normal cells for blood supply and nutrients (the neoplasic cells have the increased metabolism)

the angiogenesis potential of tumors lead to occurrence of own vascularisation and increase the hemorrhagic risk.


After functional irreversible alteration of cell cellular death may result. Two forms of cellular death exist: necrosis and apoptosis.


Mechanism: ischemia/hypoxia, toxins, severe infections etc. Results progressive degradation of cell structure by enzymatic intracellular systems which are activated as a result of intracellular protein degradations; the particle which results from these processes are removed by phagocytes.

Apoptosis = programmed cell death

Mechanisms: physiological process (development and atrophy), certain infections, certain toxins, immune-mediated. Results activation of nuclear enzymes (by increase of intracellular calcium) and consequently lead to DNA fragmentation.

Pathological increased apoptosis – can occur through the local formation of apoptotically effective mediators, the expression of their receptors, or the receptor-independent stimulation of signaling cascade. These events can be caused by ischemia (myocardial infarction, stroke), radiation or inflammation (infections, autoimmune inflammation). Apoptosis can accompanies the neuronal degeneration (Parkinson’s disease, Alzheimer’s disease, multiple sclerosis), toxic, ischemic, and inflammatory death of liver cells (liver failure), or B cells of the pancreatic islets (type 1 diabetes mellitus), or erythropoietic cells (aplastic anemia), or lymphocytes (immunodeficiency, HIV infection).

Pathological reduced apoptosis – lead to the excess of the affected cells. Among the causes are disorders of endocrine or paracrine regulation and viral infections. Absent apoptosis of virus infected cells can result in persisitent infections. Cells that escape apoptosis can develop into tumor cells. Insufficient apoptosis of immunocompetent cells is a cause of autoimmune diseases. Lack of apoptosis in pregnancy can result in abnormal embryonic or fetal development.

Pathophysiological consequences of necrosis and apoptosis: phagocytosis by neighbors, and inflammation.


clinical observation

identification of homeostasis alteration

adaptation mechanisms evaluation

etiologic and risk factors identification

pathogenetic mechanism evaluation

biological status examination (clinical assessment, paraclinical assessment – blood constituents and another biological products assessment)

enzyme release assessment for cell destruction – heart (myoglobin, CK, troponin, ALT, LDH), liver (AST, ALT, LDH, alkaline phosphatase), pancreas (amylase, lipase), muscle (CK, LDH, aldolasa, AST, ALT).

The relationship between cell dysfunction and disease syndrome is related in fig. 5.

Fig. 5. The relationship between the cell’s dysfunctions and disease syndrome.

    1. HEALING

Healing represents the processes by which the body restores his normal functions. This process require the general response or/and local response.

Healing by general mechanism:

The response of organisms to serious injury consists in following phases:

the early phase, termed ebb phase is dominated by cardiovascular instability, alteration of circulation blood volume, impairment of oxygen transport, and heightened autonomic activity; the shock occurrence is possible in this phase

the second phase – termed flow phase consist in hyperdinamic circulatory changes, fever, glucose intolerance, and muscle wasting

the final phase – termed anabolic phase – may persist for month and consist in mechanisms of restoration of normal functions until patient fully recovers.

Every type of mechanism of injury may lead to clinical characteristically evolution until return to healthy status.

Local healing

Local healing is the replacement of destroyed or lost tissue by viable tissue. It is achieved in two ways:

Repair – the destroyed cells are replacement with connective tissue with different structural and functional characteristics (ex. wound healing)

Regeneration – the destroyed cells are replacement with the same type of cells with identical structure and functions (epithelial cells regeneration, sanguine cells regeneration).

Pathological aspects of repair process:

nutritional deficiency – proteins, C vitamin etc


diabetes mellitus



glucocorticoid therapy

inadequate blood flow (atherosclerosis, venous insufficiency)

continue immune stimulation (collagen diseases)

For the wound healing the factors who contributed the healing is ilustrated in fig. 6.

An important phenomenon of healing is neuroplasticity.

Neuroplasticity refers to the ability of the nervous system to adaptation to external and internal stimuli. After the various neurological diseases (stroke, cerebral tumors, cerebral trauma), the functional rehabilitation is based by neuroplasticity. By neuroplasticity the adjaent neurons (by morphologic and functional modifications) take the functions of injured neurons.

The efficiency of rehabilitation process depends on: patient age, the site and the size of lesion, the associative pathology, and specific rehabilitation therapy.

Figure 6. The cycle of injury and inflammation in the wound.


Following major tissue injury and dysfunctions systemic responses occur which are independent of the type or site of the injury or dysfunctions itself. Such responses arise, for example, following severe traumatic lesions, severe infections, extensive burns, massive hemorrhage, and major surgery. They can be considered in their temporal relationship to the time of injury.

Early reactions (first 48 h)

a.      Vascular

Selective arterial constriction increase peripheral resistance and tends to compensate for diminished cardiac output. The main vessels involved are those of the skin and splanchnic circulation, whilst blood flow to the heart, brain and skeletal muscle is maintained at normal levels. When vasoconstriction fails to maintain normal blood pressure, the clinical picture of shock develops. Underperfusion of tissues leads to accumulation of acid metabolites and vessels cease to respond to normal constrictor stimuli. Progressive and irreversible arteriolar dilatation occurs and blood is ‘sequestrated’ in the greatly enlarged capillary reservoir. Intractable hypotension results and this constitutes a possible lethal condition.

Main types of shock:



loss of plasma (extensive burns)

loss of fluids and electrolytes (severe diarrhoea)


myocardial infarction

major pulmonary embolism

following cardiac surgery

myocarditis and other causes of acute cardiac failure




neurogenic (spinal injuries)


Hypovolemia – a fall in cardiac output resulting from reduced blood volume

Cardiogenic – a fall in output resulting from inadequate heart function (‘pump failure’)

Vascular mechanism

pooling of blood in a large peripheral vessels due to loss of vasomotor tone

pooling the blood in capillaries resulting from persistent venular constriction

increased vascular permeability

slowing of blood flow resulting from sludge of red blood cells

disseminated intravascular coagulation (DIC)

B. Metabolic reactions

  1. hyperglycemia
  2. fall in body temperature
  3. decreased oxygen consumption
  4. alteration of intracellular oxidative mechanisms

Irreversible shock

  1. Oxygen consumption markedly reduced
  2. Diminished heat production
  3. Increasing hypoxia
  4. Metabolic acidosis
  5. Hypotension
  6. Hypoglycemia

C. Hormonal reactions

Increased production of:

catecholamines T increase cardiac output, constrict arterioles, increase gluconeogenesis

corticosteroids T retention of Na+, excretion of K+, catabolism of proteins

aldosterone T K+ deficiency

ADH T water retention

growth hormone T mobilization of adipose tissue

thyroxine T protein synthesis

Late reactions

A.     Metabolic reactions

Catabolic phase

rise in oxygen consumption

rise in body temperature

catabolism of protein increased

increased mobilization of fatty acids

increased gluconeogenesis

Anabolic phase

positive nitrogen balance restored

electrolyte equilibrium regained

B.     Hematologic reactions

increased formation of platelets

increased fibrinogen production

decreased plasminogen

neutrophyl leucocytosis



C.     Immunological reactions

reactive changes in lymphoid tissues

production of IgM antibodies directed at various components of the injured tissues.

Clinical consequences of shock

Heart - cardiac failure by subendocardial hemorrhage

Brain – anoxic or hypoxic encephalopathy

Pituitary – necrosis following hypovolemia giving rise to: a. acute insufficiency – Sheehan’s syndrome b. chronic insufficiency – Simmond’s disease

Lungs – pulmonary edema, pulmonary thrombembolism, atelectasis

Adrenals – acute insufficiency ; massive hemorrhage – Waterhouse-Friderichsen syndrome

Gastrointestinal tract – acute ulceration of the stomach and duodenum – Curling’s ulcers ; hemorrhagic entheropathy – resulting from hypoxia

Liver – acute failure by acute necrosis

Kydney – acute failure by acute tubular necrosis and microthrombosis.

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