Autoimmunity is the failure of an organism to recognize its own constituent parts (down to the sub-molecular levels) as "self", which results in an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Prominent examples include Coeliac disease, diabetes mellitus type 1 (IDDM), systemic lupus erythematosus (SLE), Sjögren's syndrome, multiple sclerosis (MS), Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, and rheumatoid arthritis (RA). See List of autoimmune diseases.
The misconception that an individual's immune system is totally incapable of recognising "self" antigens is not new. Paul Ehrlich, at the beginning of the twentieth century, proposed the concept of horror autotoxicus, wherein a 'normal' body does not mount an immune response against its own tissues. Any autoimmune response thus was perceived to be abnormal and postulated to be connected with human disease. Now, it is accepted that autoimmune responses are vital to the development and functioning of vertebrate immune systems, and central to the development of immunological tolerance to self-antigens. The latter concept has been termed natural autoimmunity. Autoimmunity should not be confused with alloimmunity.
Contents
[hide]
* 1 Low-level autoimmunity
* 2 Immunological tolerance
* 3 Genetic Factors
* 4 Sex
* 5 Environmental Factors
* 6 Pathogenesis of autoimmunity
* 7 Classification
* 8 Diagnosis
* 9 Treatments
* 10 See also
* 11 References
* 12 External links
[edit] Low-level autoimmunity
While a high level of autoimmunity is unhealthy, a low level of autoimmunity may actually be beneficial. First, low-level autoimmunity might aid in the recognition of neoplastic cells by CD8+ T cells, and thus reduce the incidence of cancer.
Second, autoimmunity is likely to have a role in allowing a rapid immune response in the early stages of an infection when the availability of foreign antigens limits the response (i.e. when there are few pathogens present). In their study Stefanova et al. (2002) injected an anti-MHC Class II antibody into mice expressing a single type of MHC Class II molecule (H-2b) to temporarily prevent CD4+ T cell-MHC interaction. Naive CD4+ T cells (those which have not encountered any antigens before) recovered from these mice 36 hours post anti-MHC administration showed decreased responsiveness to the antigen pigeon cytochrome C peptide, as determined by Zap-70 phosphorylation, proliferation and Interleukin-2 production. Thus Stefanova et al. (2002) demonstrated that self-MHC recognition (which, if too strong may contribute to autoimmune disease) maintains the responsiveness of CD4+ T cells when foreign antigens are absent.[1] This idea of autoimmunity is conceptually similar to play-fighting. The play-fighting of young cubs (TCR and self-MHC) may result in a few scratches or scars (low-level-autoimmunity), but is beneficial in the long-term as it primes the young cub for proper fights in the future.
[edit] Immunological tolerance
Pioneering work by Noel Rose and Witebsky in New York, and Roitt and Doniach at University College London provided clear evidence that autoimmune diseases are a result of loss of tolerance. An essential prerequisite for the pathogenesis of autoimmune diseases is indeed the breakage of immunological tolerance, which is the ability of an individual to differentiate 'self' from 'non-self'. This breakage leads to the immune system mounting an effective and specific immune response against self determinants. The exact genesis of immunological tolerance is still elusive, but several theories have been proposed since the mid-twentieth century to explain its origin.
Three hypotheses have gained widespread attention among immunologists:
* Clonal Deletion theory, proposed by Burnet, according to which self-reactive lymphoid cells are destroyed during the development of the immune system in an individual. For their work Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize in Physiology or Medicine "for discovery of acquired immunological tolerance".
* Clonal Anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.[2]
* Idiotype Network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.[3]
In addition, two other theories are under intense investigation:
* the so-called "Clonal Ignorance" theory, according to which, host immune responses are directed to ignore self-antigens.[4]
* the "Suppressor population" or "Regulatory T cell" theories, wherein regulatory T-lymphocytes (commonly CD4+FoxP3+ cells, among others) function to prevent, downregulate, or limit autoaggressive immune responses.
Tolerance can also be differentiated into 'Central' and 'Peripheral' tolerance, on whether or not the above checking mechanisms operate in the central lymphoid organs (Thymus and Bone Marrow) or the peripheral lymphoid organs (lymph node, spleen etc., where self-reactive B-cells may be destroyed). It must be emphasised that these theories are not mutually exclusive, and evidence has been mounting suggesting that all of these mechanisms may actively contribute to vertebrate immunological tolerance.
[edit] Genetic Factors
Certain individuals are genetically susceptible to developing autoimmune diseases. This susceptibility is associated with multiple genes plus other risk factors. Genetically predisposed individuals do not always develop autoimmune diseases.
Three main sets of genes are suspected in many autoimmune diseases. These genes are related to:
* immunoglobulins,
* T-cell receptors, and
* the major histocompatibility complexes (MHC).
The first two, which are involved in the recognition of antigens, are inherently variable and susceptible to recombination. These variations enable the immune system to respond to a very wide variety of invaders, but may also give create lymphocytes which are capable of self-reactivity.
Scientists such as H. McDevitt, G. Nepom, J. Bell and J. Todd have also provided strong evidence that certain MHC class II allotypes are strongly correlated with specific autoimmune diseases:
* HLA DR2 is strongly positively correlated with Systemic Lupus Erythematosus and multiple sclerosis, and negatively correlated with DM Type 1.
* HLA DR3 is correlated strongly with Sjögren's syndrome, myasthenia gravis, SLE and DM Type 1.
* HLA DR4 is correlated with the genesis of rheumatoid arthritis, Type 1 diabetes mellitus and pemphigus vulgaris.
Fewer correlations exist with MHC class I molecules. The most notable and consistent is the association between HLA B27 and ankylosing spondylitis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease.
The contributions of genes outside the MHC complex remain the subject of research, in animal models of disease (Linda Wicker's extensive genetic studies of diabetes in the NOD mouse), and in patients (Brian Kotzin's linkage analysis of susceptibility to SLE).
[edit] Sex
Sex also seems to have a major role in the development of autoimmunity; most of the known autoimmune diseases tend to show a female preponderance, the most important exceptions being ankylosing spondylitis which has a male preponderance, and Crohn's disease, which has a roughly equal prevalence in males and females. The reasons for this are unclear. Apart from inherent genetic susceptibility, several animal models suggest a role for sex steroids.
It has also been suggested that the slight exchange of cells between mothers and their children during pregnancy may induce autoimmunity.[5] This would tip the gender balance in the direction of the female.
Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced X chromosome inactivation.[6]
[edit] Environmental Factors
An interesting inverse relationship exists between infectious diseases and autoimmune diseases. In areas where multiple infectious diseases are endemic, autoimmune diseases are quite rarely seen. The reverse, to some extent, seems to hold true. The hygiene hypothesis attributes these correlations to the immune manipulating strategies of pathogens. Whilst such an observation has been variously termed as spurious and ineffective, according to some studies, parasite infection is associated with reduced activity of autoimmune disease.[7][8][9]
The putative mechanism is that the parasite attenuates the host immune response in order to protect itself. This may provide a serendipitous benefit to a host that also suffers from autoimmune disease. The details of parasite immune modulation are not yet known, but may include secretion of anti-inflammatory agents or interference with the host immune signaling.
A paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases. For example, Klebsiella pneumoniae and coxsackievirus B have been strongly correlated with ankylosing spondylitis and DM Type 1, respectively. This has been explained by the tendency of the infecting organism to produce super-antigens which are capable of polyclonal activation of B-lymphocytes, and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below).
Certain chemical agents and drugs can also be associated with the genesis of autoimmune conditions, or conditions which simulate autoimmune diseases. The most striking of these is the drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the symptoms in a patient.
Overexposure to pesticides and toxins may also induce autoimmunity.
[edit] Pathogenesis of autoimmunity
Several mechanisms are thought to be operative in the pathogenesis of autoimmune diseases, against a backdrop of genetic predisposition and environmental modulation. It is beyond the scope of this article to discuss each of these mechanisms exhaustively, but a summary of some of the important mechanisms have been described:
* T-Cell Bypass - A normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities. This requirement of a T-cell can be by-passed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the β-subunit of T-cell receptors in a non-specific fashion.
* Molecular Mimicry - An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens and amplify the immune response. The most striking form of molecular mimicry is observed in Group A beta-haemolytic streptococci, which shares antigens with human myocardium, and is responsible for the cardiac manifestations of Rheumatic Fever.
* Idiotype Cross-Reaction - Idiotypes are antigenic epitopes found in the antigen-binding portion (Fab) of the immunoglobulin molecule. Plotz and Oldstone presented evidence that autoimmunity can arise as a result of a cross-reaction between the idiotype on an antiviral antibody and a host cell receptor for the virus in question. In this case, the host-cell receptor is envisioned as an internal image of the virus, and the anti-idiotype antibodies can react with the host cells.
* Cytokine Dysregulation - Cytokines have been recently divided into two groups according to the population of cells whose functions they promote: Helper T-cells type 1 or type 2. The second category of cytokines, which include IL-4, IL-10 and TGF-β(to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses.
* Dendritic cell apoptosis - immune system cells called dendritic cells present antigens to active lymphocytes. Dendritic cells that are defective in apoptosis can lead to inappropriate systemic lymphocyte activation and consequent decline in self-tolerance.[10]
The roles of specialized immunoregulatory cell types, such as regulatory T cells, NKT cells, γδ T-cells in the pathogenesis of autoimmune disease are under investigation.
[edit] Classification
Autoimmune diseases can be broadly divided into systemic and organ-specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.
* Systemic syndromes include SLE, Sjögren's syndrome, Scleroderma, Rheumatoid Arthritis and polymyositis.
* Local syndromes may be endocrinologic (DM Type 1, Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus vulgaris), haematologic (autoimmune haemolytic anaemia), neural (multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.
[edit] Diagnosis
Diagnosis of autoimmune disorders largely rests on accurate history and physical examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein). In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens.
[edit] Treatments
Current treatments for autoimmune disease are usually immunosuppressive, anti-inflammatory, or palliative.[4] Non-immune therapies, such as hormone replacement in Hashimoto's thyroiditis or DM Type 1 treat outcomes of the autoaggressive response. Dietary manipulation limits the severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS. More specific immunomodulatory therapies, such as the TNFα antagonists etanercept, have been shown to be useful in treating RA. These immunotherapies may be associated with increased risk of adverse effects, such as susceptibility to infection.
Jumat, 26 Oktober 2007
neurotransmitter
eurotransmitters are chemicals that are used to relay, amplify and modulate signals between a neuron and another cell. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:
* It is synthesized endogenously, that is, within the presynaptic neuron;
* It is available in sufficient quantity in the presynaptic neuron to exert an effect on the postsynaptic neuron;
* Externally administered, it must mimic the endogenously-released substance; and
* A biochemical mechanism for inactivation must be present.
However, there are other materials, such as the zinc ion, that are neither synthesized nor catabolized (i.e., degraded; see Anabolism) and are considered neurotransmitters by some. Thus, the old definitions are being revised.
Contents
[hide]
* 1 Types of neurotransmitters
* 2 Effects
* 3 Mechanism of action
* 4 Post-synaptic effect
* 5 Specifications
* 6 Common neurotransmitters
* 7 See also
* 8 References
* 9 External links
[edit] Types of neurotransmitters
There are many different ways to classify neurotransmitters. Often, dividing them into amino acids, peptides, and monoamines is sufficient for many purposes.
Some more precise divisions are as follows:
* Around 10 "small-molecule neurotransmitters" are known:
o acetylcholine
o monoamines (epinephrine E, norepinephrine NE, dopamine DA, serotonin 5-HT, and melatonin)
o 3 or 4 amino acids, depending on exact definition used: (primarily glutamic acid, GABA, aspartic acid & glycine)
o Purines, (Adenosine, ATP, GTP and their derivatives)
o Fatty acids are also receiving attention as the potential endogenous cannabinoid.[citation needed]
* Over 50 neuroactive peptides (vasopressin, somatostatin, neurotensin, etc.) have been found, among them hormones such as LH or insulin that have specific local actions in addition to their long-range signalling properties.
* Single ions, such as synaptically-released zinc, are also considered neurotransmitters by some.[citation needed]
The major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and GABA.
[edit] Effects
Some examples of neurotransmitter action:
* Acetylcholine - voluntary movement of the muscles
* Norepinephrine - wakefulness or arousal
* Dopamine - voluntary movement and motivation, "wanting"
* Serotonin - memory, emotions, wakefulness, sleep and temperature regulation
* GABA (gamma aminobutyric acid) - inhibition of motor neurons
* Glycine - spinal reflexes and motor behaviour
* Neuromodulators - sensory transmission-especially pain
It is important to appreciate that it is the receptor that dictates the neurotransmitter's effect.
[edit] Mechanism of action
Within the cells, small-molecule neurotransmitters are usually packaged in vesicles. When an action potential reaches the cell body, the rapid depolarization causes calcium ion (Ca2) channels to open. Calcium then stimulates the transport of vesicles to the synaptic membrane and their release at synaptic boutons - a form of exocytosis. These neurotransmitters are released in quanta, whereby a single quantum consists of a vesicle containing possibly thousands of neurotransmitters[1].
The neurotransmitters then diffuse across the synaptic cleft to bind to densely and geometrically arranged receptors. The receptors are broadly classified into ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated ion channels that open or close through neurotransmitter binding. Metabotropic receptors, which can have a diverse range of effects on a cell, transduct the signal by secondary messenger systems, or G-proteins.
Neuroactive peptides are made in the neuron's soma and are transported through the axon to the synapse. They are usually packaged into dense-core vesicles and are released through a similar, but metabolically distinct, form of exocytosis used for small-molecule synaptic vesicles.
[edit] Post-synaptic effect
A neurotransmitter's effect is determined by its receptor. For example, GABA can act on both rapid or slow inhibitory receptors (the GABA-A and GABA-B receptor respectively). Many other neurotransmitters, however, may have excitatory or inhibitory actions depending on which receptor they bind to.
Neurotransmitters may cause either excitatory or inhibitory post-synaptic potentials. That is, they may help the initiation of a nerve impulse in the receiving neuron, or they may discourage such an impulse by modifying the local membrane voltage potential. In the central nervous system, combined input from several synapses is usually required to trigger an action potential. Glutamate is the most prominent of excitatory transmitters; GABA and glycine are well-known inhibitory neurotransmitters.
Many neurotransmitters are removed from the synaptic cleft by neurotransmitter transporters in a process called reuptake (or often simply 'uptake'). Without reuptake, the molecules might continue to stimulate or inhibit the firing of the postsynaptic neuron. Another mechanism for removal of a neurotransmitter is digestion by an enzyme. For example, at cholinergic synapses (where acetylcholine is the neurotransmitter), the enzyme acetylcholinesterase breaks down the acetylcholine. Neuroactive peptides are often removed from the cleft by diffusion, and eventually broken down by proteases.
[edit] Specifications
While some neurotransmitters (glutamate, GABA, glycine) are used very generally throughout the central nervous system, others can have more specific effects, such as on the autonomic nervous system, by both pathways in the sympathetic nervous system and the parasympathetic nervous system, and the action of others are regulated by distinct classes of nerve clusters which can be arranged in familiar pathways around the brain. For example, Serotonin is released specifically by cells in the brainstem, in an area called the raphe nuclei, but travels around the brain along the medial forebrain bundle activating the cortex, hippocampus, thalamus, hypothalamus and cerebellum. Also, it is released in the Caudal serotonin nuclei, so as to have effect on the spinal cord. In the peripherial nervous system (such as in the gut wall) serotonin regulates vascular tone. Dopamine classically modulates two systems: the brain's reward mechanism, and movement control.
Neurotransmitters that have these types of specific actions are often targeted by drugs.
* Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer.
* Prozac is a selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin.
* AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.
Some neurotransmitter/neuromodulators like zinc not only can modulate the sensitivity of a receptor to other neurotransmitters (allosteric modulation) but can even penetrate specific, gated channels in post-synaptic neurons, thus entering the post-synaptic cells. This "translocation" is another mechanism by which synaptic transmitters can affect postsynaptic cells.
Diseases may affect specific neurotransmitter pathways. For example, Parkinson's disease is at least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
[edit] Common neurotransmitters
Category ↓ Name ↓ Abbreviation ↓ Metabotropic ↓ Ionotropic ↓
Small: Amino acids Aspartate - -
Neuropeptides N-Acetylaspartylglutamate NAAG Metabotropic glutamate receptors; selective agonist of mGluR3 -
Small: Amino acids Glutamate (glutamic acid) Glu Metabotropic glutamate receptor NMDA receptor, Kainate receptor, AMPA receptor
Small: Amino acids Gamma-aminobutyric acid GABA GABAB receptor GABAA receptor, GABAC receptor
Small: Amino acids Glycine Gly - Glycine receptor
Small: Acetylcholine Acetylcholine Ach Muscarinic acetylcholine receptor Nicotinic acetylcholine receptor
Small: Monoamine (Phe/Tyr) Dopamine DA Dopamine receptor -
Small: Monoamine (Phe/Tyr) Norepinephrine (noradrenaline) NE - -
Small: Monoamine (Phe/Tyr) Epinephrine (adrenaline) Epi - -
Small: Monoamine (Phe/Tyr) Octopamine - -
Small: Monoamine (Phe/Tyr) Tyramine -
Small: Monoamine (Trp) Serotonin (5-hydroxytryptamine) 5-HT Serotonin receptor, all but 5-HT3 5-HT3
Small: Monoamine (Trp) Melatonin Mel Melatonin receptor -
Small: Monoamine (His) Histamine H Histamine receptor -
PP: Gastrins Gastrin - -
PP: Gastrins Cholecystokinin CCK Cholecystokinin receptor -
PP: Neurohypophyseals Vasopressin Vasopressin receptor -
PP: Neurohypophyseals Oxytocin Oxytocin receptor -
PP: Neurohypophyseals Neurophysin I - -
PP: Neurohypophyseals Neurophysin II - -
PP: Neuropeptide Y Neuropeptide Y NY Neuropeptide Y receptor -
PP: Neuropeptide Y Pancreatic polypeptide PP - -
PP: Neuropeptide Y Peptide YY PYY - -
PP: Opioids Corticotropin (adrenocorticotropic hormone) ACTH Corticotropin receptor -
PP: Opioids Dynorphin - -
PP: Opioids Endorphin - -
PP: Opioids Enkephaline - -
PP: Secretins Secretin Secretin receptor -
PP: Secretins Motilin Motilin receptor -
PP: Secretins Glucagon Glucagon receptor -
PP: Secretins Vasoactive intestinal peptide VIP Vasoactive intestinal peptide receptor -
PP: Secretins Growth hormone-releasing factor GRF - -
PP: Somtostatins Somatostatin Somatostatin receptor -
SS: Tachykinins Neurokinin A - -
SS: Tachykinins Neurokinin B - -
SS: Tachykinins Substance P - -
PP: Other Bombesin - -
PP: Other Gastrin releasing peptide GRP - -
Gas Nitric oxide NO - -
Gas Carbon monoxide CO - -
Other Anandamide AEA Cannabinoid receptor -
Other Adenosine triphosphate ATP P2Y12 P2X receptor
[edit] See also
* Neuropsychopharmacology
* Nervous system
[edit] References
1. ^ J. Del Castillo and B. Katz, "The effect of magnesium on the activity of motor nerve endings", 124:553-559
[edit] External links
Wikimedia Commons has media related to:
Neurotransmitter
* Molecular Expressions Photo Gallery: The Neurotransmitter Collection
* Brain Neurotransmitters
* Endogenous Neuroactive Extracellular Signal Transducers
* MeSH Neurotransmitter
[hide]
v • d • e
Cell physiology: cell signaling
Key concepts Ligand - Cell signaling networks - Signal transduction - Apoptosis - Second messenger system (Ca2+ signaling, Lipid signaling)
Processes Paracrine - Autocrine - Juxtacrine - Neurotransmitters - Endocrine (Neuroendocrine)
Types of proteins Receptor (Transmembrane, Intracellular) - Transcription factor (General, Preinitiation complex, TFIID, TFIIH) - Adaptor protein
Retrieved from "http://en.wikipedia.org/wiki/Neurotransmitter"
Categories: All articles with unsourced statements | Articles with unsourced statements since February 2007 | Articles with unsourced statements since March 2007 | Neurotransmitters | Neurochemistry | Molecular neuroscience
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* It is synthesized endogenously, that is, within the presynaptic neuron;
* It is available in sufficient quantity in the presynaptic neuron to exert an effect on the postsynaptic neuron;
* Externally administered, it must mimic the endogenously-released substance; and
* A biochemical mechanism for inactivation must be present.
However, there are other materials, such as the zinc ion, that are neither synthesized nor catabolized (i.e., degraded; see Anabolism) and are considered neurotransmitters by some. Thus, the old definitions are being revised.
Contents
[hide]
* 1 Types of neurotransmitters
* 2 Effects
* 3 Mechanism of action
* 4 Post-synaptic effect
* 5 Specifications
* 6 Common neurotransmitters
* 7 See also
* 8 References
* 9 External links
[edit] Types of neurotransmitters
There are many different ways to classify neurotransmitters. Often, dividing them into amino acids, peptides, and monoamines is sufficient for many purposes.
Some more precise divisions are as follows:
* Around 10 "small-molecule neurotransmitters" are known:
o acetylcholine
o monoamines (epinephrine E, norepinephrine NE, dopamine DA, serotonin 5-HT, and melatonin)
o 3 or 4 amino acids, depending on exact definition used: (primarily glutamic acid, GABA, aspartic acid & glycine)
o Purines, (Adenosine, ATP, GTP and their derivatives)
o Fatty acids are also receiving attention as the potential endogenous cannabinoid.[citation needed]
* Over 50 neuroactive peptides (vasopressin, somatostatin, neurotensin, etc.) have been found, among them hormones such as LH or insulin that have specific local actions in addition to their long-range signalling properties.
* Single ions, such as synaptically-released zinc, are also considered neurotransmitters by some.[citation needed]
The major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and GABA.
[edit] Effects
Some examples of neurotransmitter action:
* Acetylcholine - voluntary movement of the muscles
* Norepinephrine - wakefulness or arousal
* Dopamine - voluntary movement and motivation, "wanting"
* Serotonin - memory, emotions, wakefulness, sleep and temperature regulation
* GABA (gamma aminobutyric acid) - inhibition of motor neurons
* Glycine - spinal reflexes and motor behaviour
* Neuromodulators - sensory transmission-especially pain
It is important to appreciate that it is the receptor that dictates the neurotransmitter's effect.
[edit] Mechanism of action
Within the cells, small-molecule neurotransmitters are usually packaged in vesicles. When an action potential reaches the cell body, the rapid depolarization causes calcium ion (Ca2) channels to open. Calcium then stimulates the transport of vesicles to the synaptic membrane and their release at synaptic boutons - a form of exocytosis. These neurotransmitters are released in quanta, whereby a single quantum consists of a vesicle containing possibly thousands of neurotransmitters[1].
The neurotransmitters then diffuse across the synaptic cleft to bind to densely and geometrically arranged receptors. The receptors are broadly classified into ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated ion channels that open or close through neurotransmitter binding. Metabotropic receptors, which can have a diverse range of effects on a cell, transduct the signal by secondary messenger systems, or G-proteins.
Neuroactive peptides are made in the neuron's soma and are transported through the axon to the synapse. They are usually packaged into dense-core vesicles and are released through a similar, but metabolically distinct, form of exocytosis used for small-molecule synaptic vesicles.
[edit] Post-synaptic effect
A neurotransmitter's effect is determined by its receptor. For example, GABA can act on both rapid or slow inhibitory receptors (the GABA-A and GABA-B receptor respectively). Many other neurotransmitters, however, may have excitatory or inhibitory actions depending on which receptor they bind to.
Neurotransmitters may cause either excitatory or inhibitory post-synaptic potentials. That is, they may help the initiation of a nerve impulse in the receiving neuron, or they may discourage such an impulse by modifying the local membrane voltage potential. In the central nervous system, combined input from several synapses is usually required to trigger an action potential. Glutamate is the most prominent of excitatory transmitters; GABA and glycine are well-known inhibitory neurotransmitters.
Many neurotransmitters are removed from the synaptic cleft by neurotransmitter transporters in a process called reuptake (or often simply 'uptake'). Without reuptake, the molecules might continue to stimulate or inhibit the firing of the postsynaptic neuron. Another mechanism for removal of a neurotransmitter is digestion by an enzyme. For example, at cholinergic synapses (where acetylcholine is the neurotransmitter), the enzyme acetylcholinesterase breaks down the acetylcholine. Neuroactive peptides are often removed from the cleft by diffusion, and eventually broken down by proteases.
[edit] Specifications
While some neurotransmitters (glutamate, GABA, glycine) are used very generally throughout the central nervous system, others can have more specific effects, such as on the autonomic nervous system, by both pathways in the sympathetic nervous system and the parasympathetic nervous system, and the action of others are regulated by distinct classes of nerve clusters which can be arranged in familiar pathways around the brain. For example, Serotonin is released specifically by cells in the brainstem, in an area called the raphe nuclei, but travels around the brain along the medial forebrain bundle activating the cortex, hippocampus, thalamus, hypothalamus and cerebellum. Also, it is released in the Caudal serotonin nuclei, so as to have effect on the spinal cord. In the peripherial nervous system (such as in the gut wall) serotonin regulates vascular tone. Dopamine classically modulates two systems: the brain's reward mechanism, and movement control.
Neurotransmitters that have these types of specific actions are often targeted by drugs.
* Cocaine, for example, blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer.
* Prozac is a selective serotonin reuptake inhibitor (SSRI), hence potentiating the effect of naturally released serotonin.
* AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.
Some neurotransmitter/neuromodulators like zinc not only can modulate the sensitivity of a receptor to other neurotransmitters (allosteric modulation) but can even penetrate specific, gated channels in post-synaptic neurons, thus entering the post-synaptic cells. This "translocation" is another mechanism by which synaptic transmitters can affect postsynaptic cells.
Diseases may affect specific neurotransmitter pathways. For example, Parkinson's disease is at least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.
[edit] Common neurotransmitters
Category ↓ Name ↓ Abbreviation ↓ Metabotropic ↓ Ionotropic ↓
Small: Amino acids Aspartate - -
Neuropeptides N-Acetylaspartylglutamate NAAG Metabotropic glutamate receptors; selective agonist of mGluR3 -
Small: Amino acids Glutamate (glutamic acid) Glu Metabotropic glutamate receptor NMDA receptor, Kainate receptor, AMPA receptor
Small: Amino acids Gamma-aminobutyric acid GABA GABAB receptor GABAA receptor, GABAC receptor
Small: Amino acids Glycine Gly - Glycine receptor
Small: Acetylcholine Acetylcholine Ach Muscarinic acetylcholine receptor Nicotinic acetylcholine receptor
Small: Monoamine (Phe/Tyr) Dopamine DA Dopamine receptor -
Small: Monoamine (Phe/Tyr) Norepinephrine (noradrenaline) NE - -
Small: Monoamine (Phe/Tyr) Epinephrine (adrenaline) Epi - -
Small: Monoamine (Phe/Tyr) Octopamine - -
Small: Monoamine (Phe/Tyr) Tyramine -
Small: Monoamine (Trp) Serotonin (5-hydroxytryptamine) 5-HT Serotonin receptor, all but 5-HT3 5-HT3
Small: Monoamine (Trp) Melatonin Mel Melatonin receptor -
Small: Monoamine (His) Histamine H Histamine receptor -
PP: Gastrins Gastrin - -
PP: Gastrins Cholecystokinin CCK Cholecystokinin receptor -
PP: Neurohypophyseals Vasopressin Vasopressin receptor -
PP: Neurohypophyseals Oxytocin Oxytocin receptor -
PP: Neurohypophyseals Neurophysin I - -
PP: Neurohypophyseals Neurophysin II - -
PP: Neuropeptide Y Neuropeptide Y NY Neuropeptide Y receptor -
PP: Neuropeptide Y Pancreatic polypeptide PP - -
PP: Neuropeptide Y Peptide YY PYY - -
PP: Opioids Corticotropin (adrenocorticotropic hormone) ACTH Corticotropin receptor -
PP: Opioids Dynorphin - -
PP: Opioids Endorphin - -
PP: Opioids Enkephaline - -
PP: Secretins Secretin Secretin receptor -
PP: Secretins Motilin Motilin receptor -
PP: Secretins Glucagon Glucagon receptor -
PP: Secretins Vasoactive intestinal peptide VIP Vasoactive intestinal peptide receptor -
PP: Secretins Growth hormone-releasing factor GRF - -
PP: Somtostatins Somatostatin Somatostatin receptor -
SS: Tachykinins Neurokinin A - -
SS: Tachykinins Neurokinin B - -
SS: Tachykinins Substance P - -
PP: Other Bombesin - -
PP: Other Gastrin releasing peptide GRP - -
Gas Nitric oxide NO - -
Gas Carbon monoxide CO - -
Other Anandamide AEA Cannabinoid receptor -
Other Adenosine triphosphate ATP P2Y12 P2X receptor
[edit] See also
* Neuropsychopharmacology
* Nervous system
[edit] References
1. ^ J. Del Castillo and B. Katz, "The effect of magnesium on the activity of motor nerve endings", 124:553-559
[edit] External links
Wikimedia Commons has media related to:
Neurotransmitter
* Molecular Expressions Photo Gallery: The Neurotransmitter Collection
* Brain Neurotransmitters
* Endogenous Neuroactive Extracellular Signal Transducers
* MeSH Neurotransmitter
[hide]
v • d • e
Cell physiology: cell signaling
Key concepts Ligand - Cell signaling networks - Signal transduction - Apoptosis - Second messenger system (Ca2+ signaling, Lipid signaling)
Processes Paracrine - Autocrine - Juxtacrine - Neurotransmitters - Endocrine (Neuroendocrine)
Types of proteins Receptor (Transmembrane, Intracellular) - Transcription factor (General, Preinitiation complex, TFIID, TFIIH) - Adaptor protein
Retrieved from "http://en.wikipedia.org/wiki/Neurotransmitter"
Categories: All articles with unsourced statements | Articles with unsourced statements since February 2007 | Articles with unsourced statements since March 2007 | Neurotransmitters | Neurochemistry | Molecular neuroscience
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edema
DEFINITION — Edema means swelling in the small spaces that surround the body tissues and organs. Edema can occur nearly anywhere in the body. The location of the edema will depend, in part, on the underlying cause. Some of the most common sites are:
* Lungs (also called pulmonary edema)
* Abdomen (also called ascites)
* Extremities such as the lower legs (also called peripheral edema)
Pulmonary edema can be life-threatening. In comparison, ascites and peripheral edema can produce some discomfort and cosmetic concerns, but are generally not serious although the underlying cause of edema may be.
SYMPTOMS — Symptoms of edema depend upon the cause, but may include:
* Swelling or puffiness of the skin, causing it to appear stretched and shiny. This is typically seen in the lower legs (called peripheral edema) or lower back (called sacral edema, frequently seen in those who have been in bed for long periods). Swelling is often worst after sitting or standing for a period of time (due to gravity), and may be worst at the end of the day. Pushing on the swollen area for a few seconds will leave a dimple in the skin.
* Increased size of the abdomen (with ascites)
* Shortness of breath or difficulty breathing (with pulmonary edema)
CAUSES — In most cases, the process of edema formation begins when fluid leaks from the body's smallest blood vessels, called capillaries, into the surrounding tissues. The leakage can occur because of changes in pressure in the capillaries, weakening of the capillary wall from disease, or other factors.
Usually, the leakage itself is not enough to cause noticeable edema. However, when the body senses that fluid is being lost from the capillaries, it signals the kidneys to hold on to sodium and water. This results in an increase in the volume of fluid circulating in the blood vessels, which, in turn, leads to additional leakage of fluid from the capillaries. It is typically at this point that edema can be seen.
CONDITIONS ASSOCIATED WITH EDEMA — A number of different problems can cause edema. Some of the most common are unrelated to any specific disease. For example, damage to the veins in the legs (venous insufficiency) can cause abnormal pooling or clotting of blood in these vessels, leading to edema. Pregnancy, drug effects, and problems with drainage in the lymphatic system can also cause peripheral edema. Diseases commonly associated with edema include kidney disease, heart failure, and cirrhosis of the liver.
Venous insufficiency — A common cause of peripheral edema in clinical practice is venous insufficiency, one cause of which is a syndrome that may occur after an episode of venous blood clots (called deep vein thrombosis). In this case, the edema is usually limited to the lower extremities (feet or ankles) and may affect only one side (the left or right); other conditions that cause edema usually cause swelling of both extremities.
Pregnancy — Pregnant women retain a significant amount of sodium and water. Some of this excess fluid is required by the fetus and placenta. Edema of the hands, feet, and face is commonly seen.
Premenstrual syndrome — Edema that appears in a cyclic pattern (usually once per month) may occur due to premenstrual syndrome (PMS). Diuretics are of no benefit for edema related to PMS. (See "Patient information: Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD)").
Drugs — Edema can be a side effect of a wide variety of medications.
Kidney disease — The edema of kidney disease causes swelling in the legs and around the eyes. It is caused by an increase in pressure in the blood vessels; this occurs when the kidneys excrete an insufficient amount of sodium and fluid. The extra fluid increases pressure on the blood vessel walls, which allows fluids to move from inside the blood vessel to the space around the vessel. Low levels of protein (albumin) in the blood may also contribute to the movement of fluid from the capillaries.
Heart failure — In heart failure, also called congestive heart failure, the heart is weakened and its pumping action is impaired. It can affect the right heart chambers, which receive blood from the body and pump it to the lungs to be filled with oxygen; or it can affect the left heart chambers, which pump oxygenated blood to the rest of the body. (See "Patient information: Heart failure causes, symptoms, and diagnosis").
Heart failure develops as a result of other conditions that damage the heart. These include heart attacks due to coronary heart disease, diseases of the heart valves, and hypertension (high blood pressure).
In right heart failure, pressure builds in the right chambers because they fail to pump blood efficiently. The pressure is reflected back to the blood vessels in the body that lead to the right chambers, frequently causing peripheral edema and, sometimes, ascites. The patient therefore notices swelling in the legs and abdomen, as well as other symptoms.
In left heart failure, pressure builds in the left chambers because they are failing to pump blood efficiently. The increased pressure affects the large blood vessels that connect the left side of the heart with the lungs. This causes edema in the lungs, or pulmonary edema, causing shortness of breath.
Cirrhosis — With cirrhosis, congestion in the liver leads to an increase in pressure within the blood vessels in the liver and subsequently, in the blood vessels leading into the liver, causing ascites. The patient may have pronounced swelling in the abdomen, as well as edema in the feet or, if the patient is lying down most of the day, swelling in the lower back (also called sacral edema). (See "Patient information: Cirrhosis").
DIAGNOSING THE CAUSE — A healthcare provider may use a number of different tools to determine the most likely cause for edema. For example, close examination of the legs and veins in the neck provide valuable clues. By listening to the lungs through a stethoscope or viewing the lungs on x-ray, providers can detect the presence of fluid, which indicates pulmonary edema. Blood and urine tests give information about possible kidney or liver disease.
TREATMENT — Treatment of edema is directed at the underlying cause; this may be done by removing the excess fluid with diuretics, elevating the legs, or using compression stockings.
Pulmonary edema is life-threatening and requires immediate treatment. Fluid in the lungs interferes with the transfer of oxygen from the lungs to the bloodstream. Pulmonary edema is treated according to its cause, and commonly requires supplemental oxygen, mechanical ventilation (a respirator forces air into the lungs), and several medications.
Other forms of edema can be treated more slowly since they are of less danger to the patient. Slow removal is recommended for patients with cirrhosis (liver disease) since rapidly changing fluid levels can cause serious illness.
Diuretics — Diuretics cause the kidneys to increase their excretion of water and sodium, reducing fluid volume throughout the body. Diuretics must be used carefully as fluid removal decreases the blood volume. In some patients, this can result in a decrease in blood pressure.
There are several types of diuretics, and not all types are used to treat edema; the two primary types used for edema are loop diuretics (eg, furosemide (Lasix®) and potassium sparing diuretics (spironolactone)).
Although diuretics are beneficial in many types of edema, they are not appropriate in every case. In particular, diuretics are generally not recommended for venous insufficiency or for edema caused by pregnancy, where fluid retention is generally normal.
Side effects — Side effects of loop and potassium sparing diuretics are uncommon when taken at the recommended doses. Many patients must empty their bladder more frequently for several hours after taking their diuretic. Although some symptoms may result from the loss of sodium and potassium, most patients tolerate diuretics very well.
Body positioning — Leg, ankle, and foot edema can be improved by elevating the legs above heart level for 30 minutes three or four times per day. Leg elevation alone may be sufficient therapy for patients with mild venous insufficiency, but is usually not adequate for more severe cases. In addition, it may not be practical for those who work to elevate their legs several times per day.
Compression stockings — Leg edema can also be prevented and treated with the use of compression stockings. Many types are available, including knee-high, thigh-high, and pantyhose. Knee-high stockings are sufficient for most patients; thigh-high stockings are less desirable because they tend to provide too much pressure behind the knees, reducing blood flow in the veins and causing discomfort.
Compression stockings that have varying degrees of pressure are best; the greatest pressure is applied at the ankle. The pressure should gradually decrease up to the knee. The white "antiembolism" stockings commonly given to patients in the hospital do not apply enough pressure at the ankle and are not adequate treatment for venous insufficiency.
Proper measurement and fitting of the stockings are important for the patient's comfort and safety. The following tips may also be helpful:
* Washing new compression stockings before wearing will reduce some of the initial stiffness and difficulty in putting them on.
* The stockings should be put on as early as possible in the morning when edema is minimal.
* Patients should lean against a firm back support (not on the bed) while putting on the stockings.
* Knee-high stockings can be put on by turning the leg portion of the stocking inside-out down to the heel. With the stocking stretched, the foot is slipped in while pulling the stocking firmly onto the foot by its folded edge. As the stocking is pulled on by the edge, it will turn right-side out and can be gently worked up the leg. Some manufacturers recommend wearing rubber gloves to slide the stocking up the leg rather than grasping and pulling the edge of the stocking.
* Heavy compression stockings may go on more easily if a light silk hose is worn under the compression garment, or if talcum powder is first applied to the foot and leg. Some patients do not have the strength or mobility to pull on compression stockings. Stockings are now available with a zippered back or velcro attachment.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of informati
* Lungs (also called pulmonary edema)
* Abdomen (also called ascites)
* Extremities such as the lower legs (also called peripheral edema)
Pulmonary edema can be life-threatening. In comparison, ascites and peripheral edema can produce some discomfort and cosmetic concerns, but are generally not serious although the underlying cause of edema may be.
SYMPTOMS — Symptoms of edema depend upon the cause, but may include:
* Swelling or puffiness of the skin, causing it to appear stretched and shiny. This is typically seen in the lower legs (called peripheral edema) or lower back (called sacral edema, frequently seen in those who have been in bed for long periods). Swelling is often worst after sitting or standing for a period of time (due to gravity), and may be worst at the end of the day. Pushing on the swollen area for a few seconds will leave a dimple in the skin.
* Increased size of the abdomen (with ascites)
* Shortness of breath or difficulty breathing (with pulmonary edema)
CAUSES — In most cases, the process of edema formation begins when fluid leaks from the body's smallest blood vessels, called capillaries, into the surrounding tissues. The leakage can occur because of changes in pressure in the capillaries, weakening of the capillary wall from disease, or other factors.
Usually, the leakage itself is not enough to cause noticeable edema. However, when the body senses that fluid is being lost from the capillaries, it signals the kidneys to hold on to sodium and water. This results in an increase in the volume of fluid circulating in the blood vessels, which, in turn, leads to additional leakage of fluid from the capillaries. It is typically at this point that edema can be seen.
CONDITIONS ASSOCIATED WITH EDEMA — A number of different problems can cause edema. Some of the most common are unrelated to any specific disease. For example, damage to the veins in the legs (venous insufficiency) can cause abnormal pooling or clotting of blood in these vessels, leading to edema. Pregnancy, drug effects, and problems with drainage in the lymphatic system can also cause peripheral edema. Diseases commonly associated with edema include kidney disease, heart failure, and cirrhosis of the liver.
Venous insufficiency — A common cause of peripheral edema in clinical practice is venous insufficiency, one cause of which is a syndrome that may occur after an episode of venous blood clots (called deep vein thrombosis). In this case, the edema is usually limited to the lower extremities (feet or ankles) and may affect only one side (the left or right); other conditions that cause edema usually cause swelling of both extremities.
Pregnancy — Pregnant women retain a significant amount of sodium and water. Some of this excess fluid is required by the fetus and placenta. Edema of the hands, feet, and face is commonly seen.
Premenstrual syndrome — Edema that appears in a cyclic pattern (usually once per month) may occur due to premenstrual syndrome (PMS). Diuretics are of no benefit for edema related to PMS. (See "Patient information: Premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD)").
Drugs — Edema can be a side effect of a wide variety of medications.
Kidney disease — The edema of kidney disease causes swelling in the legs and around the eyes. It is caused by an increase in pressure in the blood vessels; this occurs when the kidneys excrete an insufficient amount of sodium and fluid. The extra fluid increases pressure on the blood vessel walls, which allows fluids to move from inside the blood vessel to the space around the vessel. Low levels of protein (albumin) in the blood may also contribute to the movement of fluid from the capillaries.
Heart failure — In heart failure, also called congestive heart failure, the heart is weakened and its pumping action is impaired. It can affect the right heart chambers, which receive blood from the body and pump it to the lungs to be filled with oxygen; or it can affect the left heart chambers, which pump oxygenated blood to the rest of the body. (See "Patient information: Heart failure causes, symptoms, and diagnosis").
Heart failure develops as a result of other conditions that damage the heart. These include heart attacks due to coronary heart disease, diseases of the heart valves, and hypertension (high blood pressure).
In right heart failure, pressure builds in the right chambers because they fail to pump blood efficiently. The pressure is reflected back to the blood vessels in the body that lead to the right chambers, frequently causing peripheral edema and, sometimes, ascites. The patient therefore notices swelling in the legs and abdomen, as well as other symptoms.
In left heart failure, pressure builds in the left chambers because they are failing to pump blood efficiently. The increased pressure affects the large blood vessels that connect the left side of the heart with the lungs. This causes edema in the lungs, or pulmonary edema, causing shortness of breath.
Cirrhosis — With cirrhosis, congestion in the liver leads to an increase in pressure within the blood vessels in the liver and subsequently, in the blood vessels leading into the liver, causing ascites. The patient may have pronounced swelling in the abdomen, as well as edema in the feet or, if the patient is lying down most of the day, swelling in the lower back (also called sacral edema). (See "Patient information: Cirrhosis").
DIAGNOSING THE CAUSE — A healthcare provider may use a number of different tools to determine the most likely cause for edema. For example, close examination of the legs and veins in the neck provide valuable clues. By listening to the lungs through a stethoscope or viewing the lungs on x-ray, providers can detect the presence of fluid, which indicates pulmonary edema. Blood and urine tests give information about possible kidney or liver disease.
TREATMENT — Treatment of edema is directed at the underlying cause; this may be done by removing the excess fluid with diuretics, elevating the legs, or using compression stockings.
Pulmonary edema is life-threatening and requires immediate treatment. Fluid in the lungs interferes with the transfer of oxygen from the lungs to the bloodstream. Pulmonary edema is treated according to its cause, and commonly requires supplemental oxygen, mechanical ventilation (a respirator forces air into the lungs), and several medications.
Other forms of edema can be treated more slowly since they are of less danger to the patient. Slow removal is recommended for patients with cirrhosis (liver disease) since rapidly changing fluid levels can cause serious illness.
Diuretics — Diuretics cause the kidneys to increase their excretion of water and sodium, reducing fluid volume throughout the body. Diuretics must be used carefully as fluid removal decreases the blood volume. In some patients, this can result in a decrease in blood pressure.
There are several types of diuretics, and not all types are used to treat edema; the two primary types used for edema are loop diuretics (eg, furosemide (Lasix®) and potassium sparing diuretics (spironolactone)).
Although diuretics are beneficial in many types of edema, they are not appropriate in every case. In particular, diuretics are generally not recommended for venous insufficiency or for edema caused by pregnancy, where fluid retention is generally normal.
Side effects — Side effects of loop and potassium sparing diuretics are uncommon when taken at the recommended doses. Many patients must empty their bladder more frequently for several hours after taking their diuretic. Although some symptoms may result from the loss of sodium and potassium, most patients tolerate diuretics very well.
Body positioning — Leg, ankle, and foot edema can be improved by elevating the legs above heart level for 30 minutes three or four times per day. Leg elevation alone may be sufficient therapy for patients with mild venous insufficiency, but is usually not adequate for more severe cases. In addition, it may not be practical for those who work to elevate their legs several times per day.
Compression stockings — Leg edema can also be prevented and treated with the use of compression stockings. Many types are available, including knee-high, thigh-high, and pantyhose. Knee-high stockings are sufficient for most patients; thigh-high stockings are less desirable because they tend to provide too much pressure behind the knees, reducing blood flow in the veins and causing discomfort.
Compression stockings that have varying degrees of pressure are best; the greatest pressure is applied at the ankle. The pressure should gradually decrease up to the knee. The white "antiembolism" stockings commonly given to patients in the hospital do not apply enough pressure at the ankle and are not adequate treatment for venous insufficiency.
Proper measurement and fitting of the stockings are important for the patient's comfort and safety. The following tips may also be helpful:
* Washing new compression stockings before wearing will reduce some of the initial stiffness and difficulty in putting them on.
* The stockings should be put on as early as possible in the morning when edema is minimal.
* Patients should lean against a firm back support (not on the bed) while putting on the stockings.
* Knee-high stockings can be put on by turning the leg portion of the stocking inside-out down to the heel. With the stocking stretched, the foot is slipped in while pulling the stocking firmly onto the foot by its folded edge. As the stocking is pulled on by the edge, it will turn right-side out and can be gently worked up the leg. Some manufacturers recommend wearing rubber gloves to slide the stocking up the leg rather than grasping and pulling the edge of the stocking.
* Heavy compression stockings may go on more easily if a light silk hose is worn under the compression garment, or if talcum powder is first applied to the foot and leg. Some patients do not have the strength or mobility to pull on compression stockings. Stockings are now available with a zippered back or velcro attachment.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of informati
lung cancer
Lung cancer
From Wikipedia, the free encyclopedia
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Lung cancer
Classification & external resources
Cross section of a human lung. The white area in the upper lobe is cancer; the black areas indicate the patient was a smoker.
ICD-10 C33.-C34.
ICD-9 162
DiseasesDB 7616
MedlinePlus 007194
eMedicine med/1333 med/1336 emerg/335 radio/807 radio/405 radio/406
MeSH D002283
Lung cancer, or carcinoma of the lung, is a disease where epithelial (internal lining) tissue in the lung grows out of control. This leads to metastasis, invasion of adjacent tissue and infiltration beyond the lungs. Lung cancer, the most common cause of cancer-related death in men and the second most common in women,[1][2] is responsible for 1.3 million deaths worldwide annually.[3] The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss.[4]
The main types of lung cancer are small cell lung carcinoma and non-small cell lung carcinoma. This distinction is important because the treatment varies; non-small cell lung carcinoma (NSCLC) is sometimes treated with surgery, while small cell lung carcinoma (SCLC) usually responds better to chemotherapy.[5]
The most common cause of lung cancer is exposure to tobacco smoke.[6] The occurrence of lung cancer in non-smokers, who account for fewer than 10% of cases, appears to be due to a combination of genetic factors.[7][8] Radon gas,[9] asbestos,[10] and air pollution[11][12][13] may also contribute to lung cancer.
Lung cancer may be seen on chest x-ray and computed tomography (CT scan). The diagnosis is confirmed with a biopsy. This is usually performed via bronchoscopy or CT-guided biopsy.
Treatment and prognosis depend upon the histological type of cancer, the stage (degree of spread), and the patient's performance status. Possible treatments include surgery, chemotherapy, and radiotherapy. With treatment, the five-year survival rate is 14%.[4]
Contents
[hide]
* 1 Classification
o 1.1 Non-small cell lung carcinoma (NSCLC)
o 1.2 Small cell lung carcinoma (SCLC)
o 1.3 Metastatic cancers
o 1.4 Staging
* 2 Signs and symptoms
* 3 Causes
o 3.1 Smoking
o 3.2 Radon gas
o 3.3 Asbestos
o 3.4 Viruses
* 4 Pathophysiology
* 5 Diagnosis
* 6 Prevention
* 7 Screening
* 8 Treatment
o 8.1 Surgery
o 8.2 Chemotherapy
+ 8.2.1 Adjuvant chemotherapy for non-small cell lung carcinoma
o 8.3 Radiotherapy
o 8.4 Interventional radiology
o 8.5 Targeted therapy
* 9 Prognosis
* 10 Epidemiology
* 11 History
o 11.1 Treatment
* 12 References
* 13 External links
Classification
Frequency of histological types of lung cancer[14]
Histological type Frequency (%)
Non-small cell lung carcinoma 80.4
Small cell lung carcinoma 16.8
Carcinoid[15] 0.8
Sarcoma[16] 0.1
Unspecified lung cancer 1.9
The vast majority of lung cancers are carcinomas—malignancies that arise from epithelial cells. There are two main types of lung carcinoma, categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small cell (80.4%) and small-cell (16.8%) lung carcinoma.[14] This classification, based on histological criteria, has important implications for clinical management and prognosis of the disease.
Non-small cell lung carcinoma (NSCLC)
The non-small cell lung carcinomas are grouped together because their prognosis and management are similar. There are three main sub-types: squamous cell lung carcinoma, adenocarcinoma and large cell lung carcinoma.
Sub-types of non-small cell lung cancer[14]
Histological sub-type Frequency of all lung cancers (%)
Squamous cell lung carcinoma 31.1
Adenocarcinoma Adenocarcinoma (not otherwise specified) 23.2
Bronchioloalveolar carcinoma 3.0
Adenosquamous carcinoma 1.2
Papillary adenocarcinoma 0.7
Mucoepidermoid carcinoma[17] 0.1
Adenoid cystic carcinoma[18] 0.04
Other specified adenocarcinoma 1.1
Large cell carcinoma 10.7
Giant cell and spindle cell carcinoma 0.4
Other/unspecified non-small cell lung carcinoma 8.9
Accounting for 31.1% of lung cancers,[14] squamous cell lung carcinoma usually starts near a central bronchus. Cavitation and necrosis within the center of the cancer is a common finding. Well-differentiated squamous cell lung cancers often grow more slowly than other cancer types.[5]
Adenocarcinoma accounts for 29.4% of lung cancers.[14] It usually originates in peripheral lung tissue. Most cases of adenocarcinoma are associated with smoking. However, among people who have never smoked ("never-smokers"), adenocarcinoma is the most common form of lung cancer.[19] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different responses to treatment.[20]
Accounting for 10.7% of lung cancers,[14] large cell lung carcinoma is a fast-growing form that develops near the surface of the lung.[21] It is often poorly differentiated and tends to metastasize early.[5]
Small cell lung carcinoma (SCLC)
Small cell lung carcinoma (SCLC, also called "oat cell carcinoma") is less common. It tends to arise in the larger breathing tubes and grows rapidly, becoming quite large.[22] The "oat" cell contains dense neurosecretory granules (vesicles containing neuroendocrine hormones) which give this an endocrine/paraneoplastic syndrome association.[23] While initially more sensitive to chemotherapy, it ultimately carries a worse prognosis and is often metastatic at presentation. This type of lung cancer is strongly associated with smoking.[24]
Small cell lung carcinoma (microscopic view of a core needle biopsy)
Small cell lung carcinoma (microscopic view of a core needle biopsy)
Metastatic cancers
The lung is a common place for metastasis from tumors in other parts of the body. These cancers are identified by the site of origin, thus a breast cancer metastasis to the lung is still known as breast cancer. They often have a characteristic round appearance on chest x-ray.[25]
Primary lung cancers themselves most commonly metastasize to the adrenal glands, liver, brain, and bone.[5]
Staging
See also: Non-small cell lung carcinoma staging
Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is an important factor affecting the prognosis and potential treatment of lung cancer.
Non-small cell lung carcinoma is staged from IA ("one A", best prognosis) to IV ("four", worst prognosis).[26] Small cell lung carcinoma is classified as limited stage if it is confined to one half of the chest and within the scope of a single radiotherapy field. Otherwise it is extensive stage.[22]
Signs and symptoms
Symptoms that suggest lung cancer include:[27]
* dyspnea (shortness of breath)
* hemoptysis (coughing up blood)
* chronic coughing or change in regular coughing pattern
* wheezing
* chest pain or pain in the abdomen
* cachexia (weight loss), fatigue and loss of appetite
* dysphonia (hoarse voice)
* clubbing of the fingernails (uncommon)
* dysphagia (difficulty swallowing).
If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia.
Many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding from the cancer into the airway. This blood may subsequently be coughed up.
Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease.[28] In lung cancer, these phenomena may include Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia or syndrome of inappropriate antidiuretic hormone (SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors,[29] may invade the local part of the sympathetic nervous system, leading to changed sweating patterns and eye muscle problems (a combination known as Horner's syndrome), as well as muscle weakness in the hands due to invasion of the brachial plexus.
Many of the symptoms of lung cancer (bone pain, fever, weight loss) are nonspecific; in the elderly, these may be attributed to comorbid illness.[5] In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of metastasis include the bone, such as the spine (causing back pain and occasionally spinal cord compression), the liver and the brain. About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest x-rays.[4]
Causes
The main causes of lung cancer (and cancer in general) include carcinogens (such as those in tobacco smoke), ionizing radiation, and viral infection. This exposure causes cumulative changes to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium). As more tissue becomes damaged, eventually a cancer develops.[5]
Smoking
The incidence of lung cancer is highly correlated with smoking. Source: NIH.
The incidence of lung cancer is highly correlated with smoking. Source: NIH.
Smoking, particularly of cigarettes, is by far the main contributor to lung cancer. In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 85% in women).[30] Among male smokers, the lifetime risk of developing lung cancer is 17.2%. Among female smokers, the risk is 11.6%. This risk is significantly lower in non-smokers: 1.3% in men and 1.4% in women.[31] Cigarette smoke contains over 60 known carcinogens[32] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. The length of time a person smokes as well as the amount smoked increases the person's chance of developing lung cancer. If a person stops smoking, this chance steadily decreases as damage to the lungs is repaired and contaminant particles are gradually removed. Across the developed world, almost 90% of lung cancer deaths are caused by smoking.[33] In addition, there is evidence that lung cancer in never-smokers has a better prognosis than in smokers,[34] and that patients who smoke at the time of diagnosis have shorter survival than those who have quit.[35]
Passive smoking—the inhalation of smoke from another's smoking—is a cause of lung cancer in non-smokers. Studies from the U.S.,[36] Europe,[37] the UK,[38] and Australia[39] have consistently shown a significant increase in relative risk among those exposed to passive smoke. Recent investigation of sidestream smoke suggests it is more dangerous than direct smoke inhalation.[40]
Radon gas
Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer after smoking.[9]
Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK (which has granite as substrata), radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. The United States Environmental Protection Agency (EPA) estimates that one in 15 homes in the U.S. has radon levels above the recommended guideline of 4 picoCuries per liter (pCi/L).[41] Iowa has the highest average radon concentration in the United States; studies performed there have demonstrated a 50% increased lung cancer risk with prolonged radon exposure above the EPA's action level of 4 pCi/L.[42][43]
Asbestos
Asbestos can cause a variety of lung diseases, including lung cancer. There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer.[10] In the UK, asbestos accounts for 2–3% of male lung cancer deaths.[44] Asbestos can also cause cancer of the pleura, called mesothelioma (which is different from lung cancer).
Viruses
Viruses are known to cause lung cancer in animals[45][46] and recent evidence suggests similar potential in humans. Implicated viruses include human papillomavirus,[47] JC virus,[48] simian virus 40 (SV40), BK virus and cytomegalovirus.[49] These viruses may affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division.
Pathophysiology
Main article: Carcinogenesis
Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.[50] Oncogenes are genes that are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.[51] Mutations in the K-ras proto-oncogene are responsible for 20–30% of non-small cell lung cancers.[52] Chromosomal damage can lead to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q and 17p are particularly common in small cell lung carcinoma. The TP53 tumor suppressor gene, located on chromosome 17p, is often affected.[53]
Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for interleukin-1,[54] cytochrome P450,[55] apoptosis promoters such as caspase-8,[56] and DNA repair molecules such as XRCC1.[57] People with these polymorphisms are more likely to develop lung cancer after exposure to carcinogens.
Diagnosis
Chest x-ray showing a cancerous tumor in the left lung
Chest x-ray showing a cancerous tumor in the left lung
Performing a chest x-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion. If there are no x-ray findings but the suspicion is high (such as a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the necessary information. Bronchoscopy or CT-guided biopsy is often used to identify the tumor type.[4]
CT scan showing a cancerous tumor in the left lung
CT scan showing a cancerous tumor in the left lung
The differential diagnosis for patients who present with abnormalities on chest x-ray includes lung cancer, as well as nonmalignant diseases. These include infectious causes such as tuberculosis or pneumonia, or inflammatory conditions such as sarcoidosis. These diseases can result in mediastinal lymphadenopathy or lung nodules, and sometimes mimic lung cancers.[5]
Prevention
See also: Smoking ban and List of smoking bans
Prevention is the most cost-effective means of fighting lung cancer. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the prevention of lung cancer, and smoking cessation is an important preventative tool in this process.[58]
Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries, with California taking a lead in banning smoking in public establishments in 1998. Ireland played a similar role in Europe in 2004, followed by Italy and Norway in 2005, Scotland as well as several others in 2006, and England in 2007. New Zealand has also banned smoking in public places as of 2004.
The state of Bhutan has had a complete smoking ban since 2005.[59] In many countries, pressure groups are campaigning for similar bans. Arguments cited against such bans are criminalisation of smoking, increased risk of smuggling and the risk that such a ban cannot be enforced.[60]
Screening
Main article: Lung cancer screening
Screening refers to the use of medical tests to detect disease in asymptomatic people. Possible screening tests for lung cancer include chest x-ray or computed tomography (CT) of the chest. So far, screening programs for lung cancer have not demonstrated any clear benefit. Randomized controlled trials are underway in this area to see if decreased long-term mortality can be directly observed from CT screening.[61]
Treatment
Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the patient's performance status. Common treatments include surgery, chemotherapy, and radiation therapy.[4]
Surgery
Main article: Lung cancer surgery
If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.
Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.
Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[62] Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed.
Procedures include wedge resection (removal of part of a lobe), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed.[63] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[64]
Chemotherapy
Small cell lung carcinoma is treated primarily with chemotherapy, as surgery has no demonstrable influence on survival. Primary chemotherapy is also given in metastatic non-small cell lung carcinoma.
The combination regimen depends on the tumor type. Non-small cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide or vinorelbine.[65] In small cell lung carcinoma, cisplatin and etoposide are most commonly used.[66] Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan and irinotecan are also used.[67][68]
Adjuvant chemotherapy for non-small cell lung carcinoma
Adjuvant chemotherapy refers to the use of chemotherapy after surgery to improve the outcome. During surgery, samples are taken from the lymph nodes. If these samples contain cancer, then the patient has stage II or III disease. In this situation, adjuvant chemotherapy may improve survival by up to 15%.[69][70] Standard practice is to offer platinum-based chemotherapy (including either cisplatin or carboplatin).[71]
Adjuvant chemotherapy for patients with stage IB cancer is controversial as clinical trials have not clearly demonstrated a survival benefit.[72][73] Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small cell lung carcinoma have been inconclusive.[74]
Radiotherapy
Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients with non-small cell lung carcinoma who are not eligible for surgery. This form of high intensity radiotherapy is called radical radiotherapy. A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), where a high dose of radiotherapy is given in a short time period.[75] For small cell lung carcinoma cases that are potentially curable, in addition to chemotherapy, chest radiation is often recommended.[76] The use of adjuvant thoracic radiotherapy following curative intent surgery for non-small cell lung carcinoma is not well established and controversial. Benefits, if any, may only be limited to those in whom the tumor has spread to the mediastinal lymph nodes.[77][78]
For both non-small cell lung carcinoma and small cell lung carcinoma patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy). Unlike other treatments, it is possible to deliver palliative radiotherapy without confirming the histological diagnosis of lung cancer.
Patients with limited stage small cell lung carcinoma are usually given prophylactic cranial irradiation (PCI). This is a type of radiotherapy to the brain, used to reduce the risk of metastasis.[79] More recently, PCI has also been shown to be beneficial in those with extensive small cell lung cancer. In patients whose cancer has improved following a course of chemotherapy, PCI has been shown to reduce the cumulative risk of brain metastases within one year from 40.4% to 14.6%.[80]
Interventional radiology
Radiofrequency ablation is more frequently used for this condition as it is nontoxic and causes little pain. It is especially effective when combined with chemotherapy as it catches the cells deeper inside a tumor—the ones difficult to reach with chemotherapy due to reduced blood supply to the center of the tumor. It is done by inserting a small heat probe into the tumor to kill the tumor cells.[81]
Targeted therapy
In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGF-R) which is expressed in many cases of non-small cell lung carcinoma. It was not shown to increase survival, although females, Asians, non-smokers and those with bronchioloalveolar carcinoma appear to derive the most benefit from gefitinib.[20]
Erlotinib (Tarceva), another tyrosine kinase inhibitor, has been shown to increase survival in lung cancer patients[82] and has recently been approved by the FDA for second-line treatment of advanced non-small cell lung carcinoma. Similar to gefitinib, it appeared to work best in females, Asians, non-smokers and those with bronchioloalveolar carcinoma.[83]
The angiogenesis inhibitor bevacizumab (in combination with paclitaxel and carboplatin) improves the survival of patients with advanced non-small cell lung carcinoma.[84] However this increases the risk of lung bleeding, particularly in patients with squamous cell carcinoma.
Advances in cytotoxic drugs,[85] pharmacogenetics[86] and targeted drug design[87] show promise. A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 inhibitors,[88] the apoptosis promoter exisulind,[89] proteasome inhibitors,[90] bexarotene[91] and vaccines.[92] Future areas of research include ras proto-oncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition, and tumor suppressor gene replacement.[93]
Prognosis
Main articles: Non-small cell lung carcinoma staging and Manchester score
Prognosis depends on the cell type (histology), stage (degree of spread), and the patient's performance status. Overall 5 year survival rates vary from 8.9% in developing countries to 15% in the United States.[94]
For non-small cell lung carcinoma, prognosis is poor. Following complete surgical resection of stage IA disease, five-year survival is 67%. With stage IB disease, five-year survival is 57%.[95] The 5-year survival rate of patients with stage IV NSCLC is about 1%.[6]
For small cell lung carcinoma, prognosis is also poor. The overall five-year survival for patients with SCLC is about 5%.[4] Patients with extensive-stage SCLC have an average five-year survival rate of less than 1%. The median survival time for limited-stage disease is 20 months, with a five-year survival rate of 20%.[6]
Epidemiology
Lung cancer distribution in the United States
Lung cancer distribution in the United States
Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality with 1.35 million new cases per year and 1.18 million deaths, with the highest rates in Europe and North America.[94] The population segment most likely to develop lung cancer is over-fifties who have a history of smoking. Lung cancer is the second most commonly occurring form of cancer in most western countries, and it is the leading cancer-related cause of death. Although the rate of men dying from lung cancer is declining in western countries, it is actually increasing for women due to the increased takeup of smoking by this group. Among lifetime non-smokers, men have higher age-standardized lung cancer death rates than women.
Not all cases of lung cancer are due to smoking, but the role of passive smoking is increasingly being recognized as a risk factor for lung cancer, leading to policy interventions to decrease undesired exposure of non-smokers to others' tobacco smoke. Emissions from automobiles, factories and power plants also pose potential risks.[11][13][96]
Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the U.S. have the highest mortality among women. Lung cancer incidence is currently less common in developing countries.[97] With increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China[98] and India.[99]
History
Lung cancer was extremely rare before the advent of cigarette smoking. Malignant lung tumors made up only 1% of all cancers seen at autopsy in 1878, but had risen to 10–15% by the early 1900s.[100] Case reports in the medical literature numbered only 374 worldwide in 1912.[101] A review of autopsies showed that that the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.[102] In Germany, in 1929 physician Fritz Lickint recognized the link between smoking and lung cancer.[100] This led to an aggressive anti-smoking campaign.[103] The British Doctors Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking.[104] As a result, in 1964 the Surgeon General of the United States recommended that smokers should stop smoking.[105]
The connection with radon gas was first recognized among miners in the Ore Mountains near Schneeberg, Saxony. Silver has been mined there since 1470. However these mines are rich in uranium, with accompanying radium and radon gas. Miners developed a disproportionate amount of lung disease, eventually recognized as lung cancer in the 1870s. An estimated 75% of former miners died from lung cancer. Despite this discovery, mining continued into the 1950s due to the USSR's need for uranium.[106]
Treatment
The first successful pneumonectomy for lung cancer was carried out in 1933.[107] Initially, pneumonectomy was the surgical treatment of choice.[108] However with improvements in cancer staging and surgical techniques, lobectomy with lymph node dissection has now become the treatment of choice.[109][110]
Palliative radiotherapy has been used since the 1940s.[108] Radical radiotherapy, initially used in the 1950s, was an attempt to use larger radiation doses in patients with relatively early stage lung cancer, but who were otherwise unfit for surgery.[111] In 1997, continuous hyperfractionated accelerated radiotherapy (CHART) was seen as an improvement over conventional radical radiotherapy.[75]
With small cell lung carcinoma, initial attempts in the 1960s at surgical resection[112] and radical radiotherapy[113] were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.[114]
From Wikipedia, the free encyclopedia
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Lung cancer
Classification & external resources
Cross section of a human lung. The white area in the upper lobe is cancer; the black areas indicate the patient was a smoker.
ICD-10 C33.-C34.
ICD-9 162
DiseasesDB 7616
MedlinePlus 007194
eMedicine med/1333 med/1336 emerg/335 radio/807 radio/405 radio/406
MeSH D002283
Lung cancer, or carcinoma of the lung, is a disease where epithelial (internal lining) tissue in the lung grows out of control. This leads to metastasis, invasion of adjacent tissue and infiltration beyond the lungs. Lung cancer, the most common cause of cancer-related death in men and the second most common in women,[1][2] is responsible for 1.3 million deaths worldwide annually.[3] The most common symptoms are shortness of breath, coughing (including coughing up blood), and weight loss.[4]
The main types of lung cancer are small cell lung carcinoma and non-small cell lung carcinoma. This distinction is important because the treatment varies; non-small cell lung carcinoma (NSCLC) is sometimes treated with surgery, while small cell lung carcinoma (SCLC) usually responds better to chemotherapy.[5]
The most common cause of lung cancer is exposure to tobacco smoke.[6] The occurrence of lung cancer in non-smokers, who account for fewer than 10% of cases, appears to be due to a combination of genetic factors.[7][8] Radon gas,[9] asbestos,[10] and air pollution[11][12][13] may also contribute to lung cancer.
Lung cancer may be seen on chest x-ray and computed tomography (CT scan). The diagnosis is confirmed with a biopsy. This is usually performed via bronchoscopy or CT-guided biopsy.
Treatment and prognosis depend upon the histological type of cancer, the stage (degree of spread), and the patient's performance status. Possible treatments include surgery, chemotherapy, and radiotherapy. With treatment, the five-year survival rate is 14%.[4]
Contents
[hide]
* 1 Classification
o 1.1 Non-small cell lung carcinoma (NSCLC)
o 1.2 Small cell lung carcinoma (SCLC)
o 1.3 Metastatic cancers
o 1.4 Staging
* 2 Signs and symptoms
* 3 Causes
o 3.1 Smoking
o 3.2 Radon gas
o 3.3 Asbestos
o 3.4 Viruses
* 4 Pathophysiology
* 5 Diagnosis
* 6 Prevention
* 7 Screening
* 8 Treatment
o 8.1 Surgery
o 8.2 Chemotherapy
+ 8.2.1 Adjuvant chemotherapy for non-small cell lung carcinoma
o 8.3 Radiotherapy
o 8.4 Interventional radiology
o 8.5 Targeted therapy
* 9 Prognosis
* 10 Epidemiology
* 11 History
o 11.1 Treatment
* 12 References
* 13 External links
Classification
Frequency of histological types of lung cancer[14]
Histological type Frequency (%)
Non-small cell lung carcinoma 80.4
Small cell lung carcinoma 16.8
Carcinoid[15] 0.8
Sarcoma[16] 0.1
Unspecified lung cancer 1.9
The vast majority of lung cancers are carcinomas—malignancies that arise from epithelial cells. There are two main types of lung carcinoma, categorized by the size and appearance of the malignant cells seen by a histopathologist under a microscope: non-small cell (80.4%) and small-cell (16.8%) lung carcinoma.[14] This classification, based on histological criteria, has important implications for clinical management and prognosis of the disease.
Non-small cell lung carcinoma (NSCLC)
The non-small cell lung carcinomas are grouped together because their prognosis and management are similar. There are three main sub-types: squamous cell lung carcinoma, adenocarcinoma and large cell lung carcinoma.
Sub-types of non-small cell lung cancer[14]
Histological sub-type Frequency of all lung cancers (%)
Squamous cell lung carcinoma 31.1
Adenocarcinoma Adenocarcinoma (not otherwise specified) 23.2
Bronchioloalveolar carcinoma 3.0
Adenosquamous carcinoma 1.2
Papillary adenocarcinoma 0.7
Mucoepidermoid carcinoma[17] 0.1
Adenoid cystic carcinoma[18] 0.04
Other specified adenocarcinoma 1.1
Large cell carcinoma 10.7
Giant cell and spindle cell carcinoma 0.4
Other/unspecified non-small cell lung carcinoma 8.9
Accounting for 31.1% of lung cancers,[14] squamous cell lung carcinoma usually starts near a central bronchus. Cavitation and necrosis within the center of the cancer is a common finding. Well-differentiated squamous cell lung cancers often grow more slowly than other cancer types.[5]
Adenocarcinoma accounts for 29.4% of lung cancers.[14] It usually originates in peripheral lung tissue. Most cases of adenocarcinoma are associated with smoking. However, among people who have never smoked ("never-smokers"), adenocarcinoma is the most common form of lung cancer.[19] A subtype of adenocarcinoma, the bronchioloalveolar carcinoma, is more common in female never-smokers, and may have different responses to treatment.[20]
Accounting for 10.7% of lung cancers,[14] large cell lung carcinoma is a fast-growing form that develops near the surface of the lung.[21] It is often poorly differentiated and tends to metastasize early.[5]
Small cell lung carcinoma (SCLC)
Small cell lung carcinoma (SCLC, also called "oat cell carcinoma") is less common. It tends to arise in the larger breathing tubes and grows rapidly, becoming quite large.[22] The "oat" cell contains dense neurosecretory granules (vesicles containing neuroendocrine hormones) which give this an endocrine/paraneoplastic syndrome association.[23] While initially more sensitive to chemotherapy, it ultimately carries a worse prognosis and is often metastatic at presentation. This type of lung cancer is strongly associated with smoking.[24]
Small cell lung carcinoma (microscopic view of a core needle biopsy)
Small cell lung carcinoma (microscopic view of a core needle biopsy)
Metastatic cancers
The lung is a common place for metastasis from tumors in other parts of the body. These cancers are identified by the site of origin, thus a breast cancer metastasis to the lung is still known as breast cancer. They often have a characteristic round appearance on chest x-ray.[25]
Primary lung cancers themselves most commonly metastasize to the adrenal glands, liver, brain, and bone.[5]
Staging
See also: Non-small cell lung carcinoma staging
Lung cancer staging is an assessment of the degree of spread of the cancer from its original source. It is an important factor affecting the prognosis and potential treatment of lung cancer.
Non-small cell lung carcinoma is staged from IA ("one A", best prognosis) to IV ("four", worst prognosis).[26] Small cell lung carcinoma is classified as limited stage if it is confined to one half of the chest and within the scope of a single radiotherapy field. Otherwise it is extensive stage.[22]
Signs and symptoms
Symptoms that suggest lung cancer include:[27]
* dyspnea (shortness of breath)
* hemoptysis (coughing up blood)
* chronic coughing or change in regular coughing pattern
* wheezing
* chest pain or pain in the abdomen
* cachexia (weight loss), fatigue and loss of appetite
* dysphonia (hoarse voice)
* clubbing of the fingernails (uncommon)
* dysphagia (difficulty swallowing).
If the cancer grows in the airway, it may obstruct airflow, causing breathing difficulties. This can lead to accumulation of secretions behind the blockage, predisposing the patient to pneumonia.
Many lung cancers have a rich blood supply. The surface of the cancer may be fragile, leading to bleeding from the cancer into the airway. This blood may subsequently be coughed up.
Depending on the type of tumor, so-called paraneoplastic phenomena may initially attract attention to the disease.[28] In lung cancer, these phenomena may include Lambert-Eaton myasthenic syndrome (muscle weakness due to auto-antibodies), hypercalcemia or syndrome of inappropriate antidiuretic hormone (SIADH). Tumors in the top (apex) of the lung, known as Pancoast tumors,[29] may invade the local part of the sympathetic nervous system, leading to changed sweating patterns and eye muscle problems (a combination known as Horner's syndrome), as well as muscle weakness in the hands due to invasion of the brachial plexus.
Many of the symptoms of lung cancer (bone pain, fever, weight loss) are nonspecific; in the elderly, these may be attributed to comorbid illness.[5] In many patients, the cancer has already spread beyond the original site by the time they have symptoms and seek medical attention. Common sites of metastasis include the bone, such as the spine (causing back pain and occasionally spinal cord compression), the liver and the brain. About 10% of people with lung cancer do not have symptoms at diagnosis; these cancers are incidentally found on routine chest x-rays.[4]
Causes
The main causes of lung cancer (and cancer in general) include carcinogens (such as those in tobacco smoke), ionizing radiation, and viral infection. This exposure causes cumulative changes to the DNA in the tissue lining the bronchi of the lungs (the bronchial epithelium). As more tissue becomes damaged, eventually a cancer develops.[5]
Smoking
The incidence of lung cancer is highly correlated with smoking. Source: NIH.
The incidence of lung cancer is highly correlated with smoking. Source: NIH.
Smoking, particularly of cigarettes, is by far the main contributor to lung cancer. In the United States, smoking is estimated to account for 87% of lung cancer cases (90% in men and 85% in women).[30] Among male smokers, the lifetime risk of developing lung cancer is 17.2%. Among female smokers, the risk is 11.6%. This risk is significantly lower in non-smokers: 1.3% in men and 1.4% in women.[31] Cigarette smoke contains over 60 known carcinogens[32] including radioisotopes from the radon decay sequence, nitrosamine, and benzopyrene. Additionally, nicotine appears to depress the immune response to malignant growths in exposed tissue. The length of time a person smokes as well as the amount smoked increases the person's chance of developing lung cancer. If a person stops smoking, this chance steadily decreases as damage to the lungs is repaired and contaminant particles are gradually removed. Across the developed world, almost 90% of lung cancer deaths are caused by smoking.[33] In addition, there is evidence that lung cancer in never-smokers has a better prognosis than in smokers,[34] and that patients who smoke at the time of diagnosis have shorter survival than those who have quit.[35]
Passive smoking—the inhalation of smoke from another's smoking—is a cause of lung cancer in non-smokers. Studies from the U.S.,[36] Europe,[37] the UK,[38] and Australia[39] have consistently shown a significant increase in relative risk among those exposed to passive smoke. Recent investigation of sidestream smoke suggests it is more dangerous than direct smoke inhalation.[40]
Radon gas
Radon is a colorless and odorless gas generated by the breakdown of radioactive radium, which in turn is the decay product of uranium, found in the earth's crust. The radiation decay products ionize genetic material, causing mutations that sometimes turn cancerous. Radon exposure is the second major cause of lung cancer after smoking.[9]
Radon gas levels vary by locality and the composition of the underlying soil and rocks. For example, in areas such as Cornwall in the UK (which has granite as substrata), radon gas is a major problem, and buildings have to be force-ventilated with fans to lower radon gas concentrations. The United States Environmental Protection Agency (EPA) estimates that one in 15 homes in the U.S. has radon levels above the recommended guideline of 4 picoCuries per liter (pCi/L).[41] Iowa has the highest average radon concentration in the United States; studies performed there have demonstrated a 50% increased lung cancer risk with prolonged radon exposure above the EPA's action level of 4 pCi/L.[42][43]
Asbestos
Asbestos can cause a variety of lung diseases, including lung cancer. There is a synergistic effect between tobacco smoking and asbestos in the formation of lung cancer.[10] In the UK, asbestos accounts for 2–3% of male lung cancer deaths.[44] Asbestos can also cause cancer of the pleura, called mesothelioma (which is different from lung cancer).
Viruses
Viruses are known to cause lung cancer in animals[45][46] and recent evidence suggests similar potential in humans. Implicated viruses include human papillomavirus,[47] JC virus,[48] simian virus 40 (SV40), BK virus and cytomegalovirus.[49] These viruses may affect the cell cycle and inhibit apoptosis, allowing uncontrolled cell division.
Pathophysiology
Main article: Carcinogenesis
Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.[50] Oncogenes are genes that are believed to make people more susceptible to cancer. Proto-oncogenes are believed to turn into oncogenes when exposed to particular carcinogens.[51] Mutations in the K-ras proto-oncogene are responsible for 20–30% of non-small cell lung cancers.[52] Chromosomal damage can lead to loss of heterozygosity. This can cause inactivation of tumor suppressor genes. Damage to chromosomes 3p, 5q, 13q and 17p are particularly common in small cell lung carcinoma. The TP53 tumor suppressor gene, located on chromosome 17p, is often affected.[53]
Several genetic polymorphisms are associated with lung cancer. These include polymorphisms in genes coding for interleukin-1,[54] cytochrome P450,[55] apoptosis promoters such as caspase-8,[56] and DNA repair molecules such as XRCC1.[57] People with these polymorphisms are more likely to develop lung cancer after exposure to carcinogens.
Diagnosis
Chest x-ray showing a cancerous tumor in the left lung
Chest x-ray showing a cancerous tumor in the left lung
Performing a chest x-ray is the first step if a patient reports symptoms that may be suggestive of lung cancer. This may reveal an obvious mass, widening of the mediastinum (suggestive of spread to lymph nodes there), atelectasis (collapse), consolidation (pneumonia), or pleural effusion. If there are no x-ray findings but the suspicion is high (such as a heavy smoker with blood-stained sputum), bronchoscopy and/or a CT scan may provide the necessary information. Bronchoscopy or CT-guided biopsy is often used to identify the tumor type.[4]
CT scan showing a cancerous tumor in the left lung
CT scan showing a cancerous tumor in the left lung
The differential diagnosis for patients who present with abnormalities on chest x-ray includes lung cancer, as well as nonmalignant diseases. These include infectious causes such as tuberculosis or pneumonia, or inflammatory conditions such as sarcoidosis. These diseases can result in mediastinal lymphadenopathy or lung nodules, and sometimes mimic lung cancers.[5]
Prevention
See also: Smoking ban and List of smoking bans
Prevention is the most cost-effective means of fighting lung cancer. While in most countries industrial and domestic carcinogens have been identified and banned, tobacco smoking is still widespread. Eliminating tobacco smoking is a primary goal in the prevention of lung cancer, and smoking cessation is an important preventative tool in this process.[58]
Policy interventions to decrease passive smoking in public areas such as restaurants and workplaces have become more common in many Western countries, with California taking a lead in banning smoking in public establishments in 1998. Ireland played a similar role in Europe in 2004, followed by Italy and Norway in 2005, Scotland as well as several others in 2006, and England in 2007. New Zealand has also banned smoking in public places as of 2004.
The state of Bhutan has had a complete smoking ban since 2005.[59] In many countries, pressure groups are campaigning for similar bans. Arguments cited against such bans are criminalisation of smoking, increased risk of smuggling and the risk that such a ban cannot be enforced.[60]
Screening
Main article: Lung cancer screening
Screening refers to the use of medical tests to detect disease in asymptomatic people. Possible screening tests for lung cancer include chest x-ray or computed tomography (CT) of the chest. So far, screening programs for lung cancer have not demonstrated any clear benefit. Randomized controlled trials are underway in this area to see if decreased long-term mortality can be directly observed from CT screening.[61]
Treatment
Treatment for lung cancer depends on the cancer's specific cell type, how far it has spread, and the patient's performance status. Common treatments include surgery, chemotherapy, and radiation therapy.[4]
Surgery
Main article: Lung cancer surgery
If investigations confirm lung cancer, CT scan and often positron emission tomography (PET) are used to determine whether the disease is localised and amenable to surgery or whether it has spread to the point where it cannot be cured surgically.
Blood tests and spirometry (lung function testing) are also necessary to assess whether the patient is well enough to be operated on. If spirometry reveals poor respiratory reserve (often due to chronic obstructive pulmonary disease), surgery may be contraindicated.
Surgery itself has an operative death rate of about 4.4%, depending on the patient's lung function and other risk factors.[62] Surgery is usually only an option in non-small cell lung carcinoma limited to one lung, up to stage IIIA. This is assessed with medical imaging (computed tomography, positron emission tomography). A sufficient pre-operative respiratory reserve must be present to allow adequate lung function after the tissue is removed.
Procedures include wedge resection (removal of part of a lobe), lobectomy (one lobe), bilobectomy (two lobes) or pneumonectomy (whole lung). In patients with adequate respiratory reserve, lobectomy is the preferred option, as this minimizes the chance of local recurrence. If the patient does not have enough functional lung for this, wedge resection may be performed.[63] Radioactive iodine brachytherapy at the margins of wedge excision may reduce recurrence to that of lobectomy.[64]
Chemotherapy
Small cell lung carcinoma is treated primarily with chemotherapy, as surgery has no demonstrable influence on survival. Primary chemotherapy is also given in metastatic non-small cell lung carcinoma.
The combination regimen depends on the tumor type. Non-small cell lung carcinoma is often treated with cisplatin or carboplatin, in combination with gemcitabine, paclitaxel, docetaxel, etoposide or vinorelbine.[65] In small cell lung carcinoma, cisplatin and etoposide are most commonly used.[66] Combinations with carboplatin, gemcitabine, paclitaxel, vinorelbine, topotecan and irinotecan are also used.[67][68]
Adjuvant chemotherapy for non-small cell lung carcinoma
Adjuvant chemotherapy refers to the use of chemotherapy after surgery to improve the outcome. During surgery, samples are taken from the lymph nodes. If these samples contain cancer, then the patient has stage II or III disease. In this situation, adjuvant chemotherapy may improve survival by up to 15%.[69][70] Standard practice is to offer platinum-based chemotherapy (including either cisplatin or carboplatin).[71]
Adjuvant chemotherapy for patients with stage IB cancer is controversial as clinical trials have not clearly demonstrated a survival benefit.[72][73] Trials of preoperative chemotherapy (neoadjuvant chemotherapy) in resectable non-small cell lung carcinoma have been inconclusive.[74]
Radiotherapy
Radiotherapy is often given together with chemotherapy, and may be used with curative intent in patients with non-small cell lung carcinoma who are not eligible for surgery. This form of high intensity radiotherapy is called radical radiotherapy. A refinement of this technique is continuous hyperfractionated accelerated radiotherapy (CHART), where a high dose of radiotherapy is given in a short time period.[75] For small cell lung carcinoma cases that are potentially curable, in addition to chemotherapy, chest radiation is often recommended.[76] The use of adjuvant thoracic radiotherapy following curative intent surgery for non-small cell lung carcinoma is not well established and controversial. Benefits, if any, may only be limited to those in whom the tumor has spread to the mediastinal lymph nodes.[77][78]
For both non-small cell lung carcinoma and small cell lung carcinoma patients, smaller doses of radiation to the chest may be used for symptom control (palliative radiotherapy). Unlike other treatments, it is possible to deliver palliative radiotherapy without confirming the histological diagnosis of lung cancer.
Patients with limited stage small cell lung carcinoma are usually given prophylactic cranial irradiation (PCI). This is a type of radiotherapy to the brain, used to reduce the risk of metastasis.[79] More recently, PCI has also been shown to be beneficial in those with extensive small cell lung cancer. In patients whose cancer has improved following a course of chemotherapy, PCI has been shown to reduce the cumulative risk of brain metastases within one year from 40.4% to 14.6%.[80]
Interventional radiology
Radiofrequency ablation is more frequently used for this condition as it is nontoxic and causes little pain. It is especially effective when combined with chemotherapy as it catches the cells deeper inside a tumor—the ones difficult to reach with chemotherapy due to reduced blood supply to the center of the tumor. It is done by inserting a small heat probe into the tumor to kill the tumor cells.[81]
Targeted therapy
In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGF-R) which is expressed in many cases of non-small cell lung carcinoma. It was not shown to increase survival, although females, Asians, non-smokers and those with bronchioloalveolar carcinoma appear to derive the most benefit from gefitinib.[20]
Erlotinib (Tarceva), another tyrosine kinase inhibitor, has been shown to increase survival in lung cancer patients[82] and has recently been approved by the FDA for second-line treatment of advanced non-small cell lung carcinoma. Similar to gefitinib, it appeared to work best in females, Asians, non-smokers and those with bronchioloalveolar carcinoma.[83]
The angiogenesis inhibitor bevacizumab (in combination with paclitaxel and carboplatin) improves the survival of patients with advanced non-small cell lung carcinoma.[84] However this increases the risk of lung bleeding, particularly in patients with squamous cell carcinoma.
Advances in cytotoxic drugs,[85] pharmacogenetics[86] and targeted drug design[87] show promise. A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 inhibitors,[88] the apoptosis promoter exisulind,[89] proteasome inhibitors,[90] bexarotene[91] and vaccines.[92] Future areas of research include ras proto-oncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition, and tumor suppressor gene replacement.[93]
Prognosis
Main articles: Non-small cell lung carcinoma staging and Manchester score
Prognosis depends on the cell type (histology), stage (degree of spread), and the patient's performance status. Overall 5 year survival rates vary from 8.9% in developing countries to 15% in the United States.[94]
For non-small cell lung carcinoma, prognosis is poor. Following complete surgical resection of stage IA disease, five-year survival is 67%. With stage IB disease, five-year survival is 57%.[95] The 5-year survival rate of patients with stage IV NSCLC is about 1%.[6]
For small cell lung carcinoma, prognosis is also poor. The overall five-year survival for patients with SCLC is about 5%.[4] Patients with extensive-stage SCLC have an average five-year survival rate of less than 1%. The median survival time for limited-stage disease is 20 months, with a five-year survival rate of 20%.[6]
Epidemiology
Lung cancer distribution in the United States
Lung cancer distribution in the United States
Worldwide, lung cancer is the most common cancer in terms of both incidence and mortality with 1.35 million new cases per year and 1.18 million deaths, with the highest rates in Europe and North America.[94] The population segment most likely to develop lung cancer is over-fifties who have a history of smoking. Lung cancer is the second most commonly occurring form of cancer in most western countries, and it is the leading cancer-related cause of death. Although the rate of men dying from lung cancer is declining in western countries, it is actually increasing for women due to the increased takeup of smoking by this group. Among lifetime non-smokers, men have higher age-standardized lung cancer death rates than women.
Not all cases of lung cancer are due to smoking, but the role of passive smoking is increasingly being recognized as a risk factor for lung cancer, leading to policy interventions to decrease undesired exposure of non-smokers to others' tobacco smoke. Emissions from automobiles, factories and power plants also pose potential risks.[11][13][96]
Eastern Europe has the highest lung cancer mortality among men, while northern Europe and the U.S. have the highest mortality among women. Lung cancer incidence is currently less common in developing countries.[97] With increased smoking in developing countries, the incidence is expected to increase in the next few years, notably in China[98] and India.[99]
History
Lung cancer was extremely rare before the advent of cigarette smoking. Malignant lung tumors made up only 1% of all cancers seen at autopsy in 1878, but had risen to 10–15% by the early 1900s.[100] Case reports in the medical literature numbered only 374 worldwide in 1912.[101] A review of autopsies showed that that the incidence of lung cancer had increased from 0.3% in 1852 to 5.66% in 1952.[102] In Germany, in 1929 physician Fritz Lickint recognized the link between smoking and lung cancer.[100] This led to an aggressive anti-smoking campaign.[103] The British Doctors Study, published in the 1950s, was the first solid epidemiological evidence of the link between lung cancer and smoking.[104] As a result, in 1964 the Surgeon General of the United States recommended that smokers should stop smoking.[105]
The connection with radon gas was first recognized among miners in the Ore Mountains near Schneeberg, Saxony. Silver has been mined there since 1470. However these mines are rich in uranium, with accompanying radium and radon gas. Miners developed a disproportionate amount of lung disease, eventually recognized as lung cancer in the 1870s. An estimated 75% of former miners died from lung cancer. Despite this discovery, mining continued into the 1950s due to the USSR's need for uranium.[106]
Treatment
The first successful pneumonectomy for lung cancer was carried out in 1933.[107] Initially, pneumonectomy was the surgical treatment of choice.[108] However with improvements in cancer staging and surgical techniques, lobectomy with lymph node dissection has now become the treatment of choice.[109][110]
Palliative radiotherapy has been used since the 1940s.[108] Radical radiotherapy, initially used in the 1950s, was an attempt to use larger radiation doses in patients with relatively early stage lung cancer, but who were otherwise unfit for surgery.[111] In 1997, continuous hyperfractionated accelerated radiotherapy (CHART) was seen as an improvement over conventional radical radiotherapy.[75]
With small cell lung carcinoma, initial attempts in the 1960s at surgical resection[112] and radical radiotherapy[113] were unsuccessful. In the 1970s, successful chemotherapy regimens were developed.[114]
G.I tract
Gut" redirects here. For other uses, see GUT.
Upper and Lower gastrointestinal tract
Upper and Lower gastrointestinal tract
The gastrointestinal tract (GI tract), also called the digestive tract, or the alimentary canal, is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. The major functions of the GI tract are ingestion, digestion, absorption, and excretion.
The GI tract differs substantially from animal to animal. For instance, some animals have multi-chambered stomachs, while some animals' stomachs contain a single chamber. In a normal human adult male, the GI tract is approximately 6.5 meters (20 feet) long and consists of the upper and lower GI tracts. The tract may also be divided into foregut, midgut, and hindgut, reflecting the embryological origin of each segment of the tract.
Contents
[hide]
* 1 Upper gastrointestinal tract
* 2 Lower gastrointestinal tract
* 3 Accessory organs
* 4 Embryology
* 5 Physiology
o 5.1 Specialization of organs
o 5.2 Immune function
* 6 Histology
o 6.1 Mucosa
o 6.2 Submucosa
o 6.3 Muscularis externa
o 6.4 Adventitia/Serosa
* 7 Human uses of animal gut
* 8 References
o 8.1 Notes
o 8.2 General references
* 9 See also
* 10 External links
[edit] Upper gastrointestinal tract
The upper GI tract consists of the mouth, pharynx, esophagus, and stomach.
* The mouth contains the buccal mucosa, which contains the openings of the salivary glands; the tongue; and the teeth.
* Behind the mouth lies the pharynx, which leads to a hollow muscular tube, the esophagus.
* Peristalsis takes place, which is the contraction of muscles to propel the food down the esophagus which extends through the chest and pierces the diaphragm to reach the stomach.
* The stomach, in turn, leads to the small intestine.
The upper GI tract roughly corresponds to the derivatives of the foregut, with the exception of the first part of the duodenum (see below for more details.)
[edit] Lower gastrointestinal tract
The lower GI tract comprises the intestines and anus.
* Bowel or intestine
o Small intestine, which has three parts:
+ Duodenum
+ Jejunum
+ Ileum
o Large intestine, which has three parts:
+ Cecum (the vermiform appendix is attached to the cecum).
+ Colon (ascending colon, transverse colon, descending colon and sigmoid flexure)
+ Rectum
* Anus
[edit] Accessory organs
Accessory organs to the alimentary canal include the liver, gallbladder, and pancreas. The liver secretes bile into the small intestine via the biliary system, employing the gallbladder as a reservoir. Apart from storing and concentrating bile, the gallbladder has no other specific function. The pancreas secretes an isosmotic fluid containing bicarbonate and several enzymes, including trypsin, chymotrypsin, lipase, and pancreatic amylase, as well as nucleolytic enzymes (deoxyribonuclease and ribonuclease), into the small intestine. Both of these secretory organs aid in digestion.
[edit] Embryology
The gut is an endoderm-derived structure. At approximately the 16th day of human development, the embryo begins to fold ventrally (with the embryo's ventral surface becoming concave) in two directions: the sides of the embryo fold in on each other and the head and tail fold towards one another. The result is that a piece of the yolk sac, an endoderm-lined structure in contact with the ventral aspect of the embryo, begins to be pinched off to become the primitive gut. The yolk sac remains connected to the gut tube via the vitelline duct. Usually this structure regresses during development; in cases where it does not, it is known as Meckel's diverticulum.
During fetal life, the primitive gut can be divided into three segments: foregut, midgut, and hindgut. Although these terms are often used in reference to segments of the primitive gut, they are nevertheless used regularly to describe components of the definitive gut as well.
Each segment of the primitive gut gives rise to specific gut and gut-related structures in the adult. Components derived from the gut proper, including the stomach and colon, develop as swellings or dilatations of the primitive gut. In contrast, gut-related derivatives—that is, those structures that derive from the primitive gut but are not part of the gut proper—in general develop as outpouchings of the primitive gut. The blood vessels supplying these structures remain constant throughout development.[1]
Part Range in adult Gives rise to Arterial supply
foregut the pharynx, to the upper duodenum pharynx, esophagus, stomach, upper duodenum, respiratory tract (including the lungs), liver, gallbladder, and pancreas branches of the celiac artery
midgut lower duodenum, to the first half of the transverse colon lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, and first half of the transverse colon branches of the superior mesenteric artery
hindgut second half of the transverse colon, to the upper part of the anal canal remaining half of the transverse colon, descending colon, rectum, and upper part of the anal canal branches of the inferior mesenteric artery
[edit] Physiology
[edit] Specialization of organs
Four organs are subject to specialization in the kingdom Animalia.
* The first organ is the tongue which is only present in the phylum Chordata.
* The second organ is the esophagus. The crop is an enlargement of the esophagus in birds, insects and other invertebrates that is used to store food temporarily.
* The third organ is the stomach. In addition to a glandular stomach (proventriculus), birds have a muscular "stomach" called the ventriculus or "gizzard." The gizzard is used to mechanically grind up food.
* The fourth organ is the large intestine. An outpouching of the large intestine called the cecum is present in non-ruminant herbivores such as rabbits. It aids in digestion of plant material such as cellulose
[edit] Immune function
The gastrointestinal tract is also a prominent part of the immune system.[2] The low pH (ranging from 1 to 4) of the stomach is fatal for many microorganisms that enter it. Similarly, mucus (containing IgA antibodies) neutralizes many of these microorganisms. Other factors in the GI tract help with immune function as well, including enzymes in the saliva and bile. Enzymes such as Cyp3A4, along with the antiporter activities, are also instrumental in the intestine's role of detoxification of antigens and xenobiotics, such as drugs, involved in first pass metabolism. Health-enhancing intestinal bacteria serve to prevent the overgrowth of potentially harmful bacteria in the gut. Microorganisms are also kept at bay by an extensive immune system comprising the gut-associated lymphoid tissue (GALT).
[edit] Histology
The GI tract has a uniform general histology with some differences which reflect the specialization in functional anatomy.[3] The GI tract can be divided into 4 concentric layers:
* Mucosa
* Submucosa
* Muscularis externa (the external muscle layer)
* Adventitia or serosa
[edit] Mucosa
The mucosa is the innermost layer of the GI tract, surrounding the lumen, or space within the tube. This layer comes in direct contact with the food (or bolus), and is responsible for absorption and secretion, important processes in digestion.
The mucosa can be divided into:
* Epithelium
* Lamina propria
* Muscularis mucosae
The mucosae are highly specialized in each organ of the GI tract, facing a low pH in the stomach, absorbing a multitude of different substances in the small intestine, and also absorbing specific quantities of water in the large intestine. Reflecting the varying needs of these organs, the structure of the mucosa can consist of invaginations of secretory glands (e.g., gastric pits), or it can be folded in order to increase surface area (examples include villi and plicae circulares).
[edit] Submucosa
The submucosa consists of a dense irregular layer of connective tissue with large blood vessels, lymphatics and nerves branching into the mucosa and muscularis. It contains Meissner's plexus, an enteric nervous plexus, situated on the inner surface of the muscularis externa.
[edit] Muscularis externa
The muscularis externa consists of a circular inner muscular layer and a longitudinal outer muscular layer. The circular muscle layer prevents the food from going backwards and the longitudinal layer shortens the tract. The coordinated contractions of these layers is called peristalsis and propels the bolus, or balled-up food, through the GI tract. Between the two muscle layers are the myenteric or Auerbach's plexus.
[edit] Adventitia/Serosa
The adventitia consists of several layers of epithelia. When the adventitia is facing the mesentery or peritoneal fold, the adventitia is covered by a mesothelium supported by a thin connective tissue layer, together forming a serosa, or serous membrane.
[edit] Human uses of animal gut
* The use of animal gut strings by musicians can be traced back to the third dynasty of Egypt. In the recent past, strings were made out of lamb gut. With the advent of the modern era, musicians have tended to use strings made of silk, or synthetic materials such as nylon or steel. Some instrumentalists, however, still use gut strings in order to evoke the older tone quality. Although such strings were commonly referred to as "catgut" strings, cats were never used as a source for gut strings.
* Sheep gut was the original source for natural gut string used in racquets, such as for tennis. Today, synthetic strings are much more common, but the best strings are now made out of cow gut.
* Gut cord has also been used to produce strings for the snares which provide the snare drum's characteristic buzzing timbre. While the snare drum currently almost always uses metal wire rather than gut cord, the North African bendir frame drum still uses gut for this purpose.
* "Natural" sausage hulls (or casings) are made of animal gut, especially hog, beef, and lamb.
* Animal gut was used to make the cord lines in longcase clocks and for fusee movements in bracket clocks, but may be replaced by metal wire.
* The oldest condoms found were made from animal intestine.
Upper and Lower gastrointestinal tract
Upper and Lower gastrointestinal tract
The gastrointestinal tract (GI tract), also called the digestive tract, or the alimentary canal, is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. The major functions of the GI tract are ingestion, digestion, absorption, and excretion.
The GI tract differs substantially from animal to animal. For instance, some animals have multi-chambered stomachs, while some animals' stomachs contain a single chamber. In a normal human adult male, the GI tract is approximately 6.5 meters (20 feet) long and consists of the upper and lower GI tracts. The tract may also be divided into foregut, midgut, and hindgut, reflecting the embryological origin of each segment of the tract.
Contents
[hide]
* 1 Upper gastrointestinal tract
* 2 Lower gastrointestinal tract
* 3 Accessory organs
* 4 Embryology
* 5 Physiology
o 5.1 Specialization of organs
o 5.2 Immune function
* 6 Histology
o 6.1 Mucosa
o 6.2 Submucosa
o 6.3 Muscularis externa
o 6.4 Adventitia/Serosa
* 7 Human uses of animal gut
* 8 References
o 8.1 Notes
o 8.2 General references
* 9 See also
* 10 External links
[edit] Upper gastrointestinal tract
The upper GI tract consists of the mouth, pharynx, esophagus, and stomach.
* The mouth contains the buccal mucosa, which contains the openings of the salivary glands; the tongue; and the teeth.
* Behind the mouth lies the pharynx, which leads to a hollow muscular tube, the esophagus.
* Peristalsis takes place, which is the contraction of muscles to propel the food down the esophagus which extends through the chest and pierces the diaphragm to reach the stomach.
* The stomach, in turn, leads to the small intestine.
The upper GI tract roughly corresponds to the derivatives of the foregut, with the exception of the first part of the duodenum (see below for more details.)
[edit] Lower gastrointestinal tract
The lower GI tract comprises the intestines and anus.
* Bowel or intestine
o Small intestine, which has three parts:
+ Duodenum
+ Jejunum
+ Ileum
o Large intestine, which has three parts:
+ Cecum (the vermiform appendix is attached to the cecum).
+ Colon (ascending colon, transverse colon, descending colon and sigmoid flexure)
+ Rectum
* Anus
[edit] Accessory organs
Accessory organs to the alimentary canal include the liver, gallbladder, and pancreas. The liver secretes bile into the small intestine via the biliary system, employing the gallbladder as a reservoir. Apart from storing and concentrating bile, the gallbladder has no other specific function. The pancreas secretes an isosmotic fluid containing bicarbonate and several enzymes, including trypsin, chymotrypsin, lipase, and pancreatic amylase, as well as nucleolytic enzymes (deoxyribonuclease and ribonuclease), into the small intestine. Both of these secretory organs aid in digestion.
[edit] Embryology
The gut is an endoderm-derived structure. At approximately the 16th day of human development, the embryo begins to fold ventrally (with the embryo's ventral surface becoming concave) in two directions: the sides of the embryo fold in on each other and the head and tail fold towards one another. The result is that a piece of the yolk sac, an endoderm-lined structure in contact with the ventral aspect of the embryo, begins to be pinched off to become the primitive gut. The yolk sac remains connected to the gut tube via the vitelline duct. Usually this structure regresses during development; in cases where it does not, it is known as Meckel's diverticulum.
During fetal life, the primitive gut can be divided into three segments: foregut, midgut, and hindgut. Although these terms are often used in reference to segments of the primitive gut, they are nevertheless used regularly to describe components of the definitive gut as well.
Each segment of the primitive gut gives rise to specific gut and gut-related structures in the adult. Components derived from the gut proper, including the stomach and colon, develop as swellings or dilatations of the primitive gut. In contrast, gut-related derivatives—that is, those structures that derive from the primitive gut but are not part of the gut proper—in general develop as outpouchings of the primitive gut. The blood vessels supplying these structures remain constant throughout development.[1]
Part Range in adult Gives rise to Arterial supply
foregut the pharynx, to the upper duodenum pharynx, esophagus, stomach, upper duodenum, respiratory tract (including the lungs), liver, gallbladder, and pancreas branches of the celiac artery
midgut lower duodenum, to the first half of the transverse colon lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, and first half of the transverse colon branches of the superior mesenteric artery
hindgut second half of the transverse colon, to the upper part of the anal canal remaining half of the transverse colon, descending colon, rectum, and upper part of the anal canal branches of the inferior mesenteric artery
[edit] Physiology
[edit] Specialization of organs
Four organs are subject to specialization in the kingdom Animalia.
* The first organ is the tongue which is only present in the phylum Chordata.
* The second organ is the esophagus. The crop is an enlargement of the esophagus in birds, insects and other invertebrates that is used to store food temporarily.
* The third organ is the stomach. In addition to a glandular stomach (proventriculus), birds have a muscular "stomach" called the ventriculus or "gizzard." The gizzard is used to mechanically grind up food.
* The fourth organ is the large intestine. An outpouching of the large intestine called the cecum is present in non-ruminant herbivores such as rabbits. It aids in digestion of plant material such as cellulose
[edit] Immune function
The gastrointestinal tract is also a prominent part of the immune system.[2] The low pH (ranging from 1 to 4) of the stomach is fatal for many microorganisms that enter it. Similarly, mucus (containing IgA antibodies) neutralizes many of these microorganisms. Other factors in the GI tract help with immune function as well, including enzymes in the saliva and bile. Enzymes such as Cyp3A4, along with the antiporter activities, are also instrumental in the intestine's role of detoxification of antigens and xenobiotics, such as drugs, involved in first pass metabolism. Health-enhancing intestinal bacteria serve to prevent the overgrowth of potentially harmful bacteria in the gut. Microorganisms are also kept at bay by an extensive immune system comprising the gut-associated lymphoid tissue (GALT).
[edit] Histology
The GI tract has a uniform general histology with some differences which reflect the specialization in functional anatomy.[3] The GI tract can be divided into 4 concentric layers:
* Mucosa
* Submucosa
* Muscularis externa (the external muscle layer)
* Adventitia or serosa
[edit] Mucosa
The mucosa is the innermost layer of the GI tract, surrounding the lumen, or space within the tube. This layer comes in direct contact with the food (or bolus), and is responsible for absorption and secretion, important processes in digestion.
The mucosa can be divided into:
* Epithelium
* Lamina propria
* Muscularis mucosae
The mucosae are highly specialized in each organ of the GI tract, facing a low pH in the stomach, absorbing a multitude of different substances in the small intestine, and also absorbing specific quantities of water in the large intestine. Reflecting the varying needs of these organs, the structure of the mucosa can consist of invaginations of secretory glands (e.g., gastric pits), or it can be folded in order to increase surface area (examples include villi and plicae circulares).
[edit] Submucosa
The submucosa consists of a dense irregular layer of connective tissue with large blood vessels, lymphatics and nerves branching into the mucosa and muscularis. It contains Meissner's plexus, an enteric nervous plexus, situated on the inner surface of the muscularis externa.
[edit] Muscularis externa
The muscularis externa consists of a circular inner muscular layer and a longitudinal outer muscular layer. The circular muscle layer prevents the food from going backwards and the longitudinal layer shortens the tract. The coordinated contractions of these layers is called peristalsis and propels the bolus, or balled-up food, through the GI tract. Between the two muscle layers are the myenteric or Auerbach's plexus.
[edit] Adventitia/Serosa
The adventitia consists of several layers of epithelia. When the adventitia is facing the mesentery or peritoneal fold, the adventitia is covered by a mesothelium supported by a thin connective tissue layer, together forming a serosa, or serous membrane.
[edit] Human uses of animal gut
* The use of animal gut strings by musicians can be traced back to the third dynasty of Egypt. In the recent past, strings were made out of lamb gut. With the advent of the modern era, musicians have tended to use strings made of silk, or synthetic materials such as nylon or steel. Some instrumentalists, however, still use gut strings in order to evoke the older tone quality. Although such strings were commonly referred to as "catgut" strings, cats were never used as a source for gut strings.
* Sheep gut was the original source for natural gut string used in racquets, such as for tennis. Today, synthetic strings are much more common, but the best strings are now made out of cow gut.
* Gut cord has also been used to produce strings for the snares which provide the snare drum's characteristic buzzing timbre. While the snare drum currently almost always uses metal wire rather than gut cord, the North African bendir frame drum still uses gut for this purpose.
* "Natural" sausage hulls (or casings) are made of animal gut, especially hog, beef, and lamb.
* Animal gut was used to make the cord lines in longcase clocks and for fusee movements in bracket clocks, but may be replaced by metal wire.
* The oldest condoms found were made from animal intestine.
tbc
tuberculosis
Tuberculosis (abbreviated as TB for tubercle bacillus or Tuberculosis) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis most commonly attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, bones, joints and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti can also cause tuberculosis, but these species do not usually infect healthy adults.[1]
Over one-third of the world's population has been exposed to the TB bacterium, and new infections occur at a rate of one per second.[2] Not everyone infected develops the full-blown disease, so asymptomatic, latent TB infection is most common. However, one in ten latent infections will progress to active TB disease, which, if left untreated, kills more than half of its victims.
In 2004, mortality and morbidity statistics included 14.6 million chronic active TB cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries.[2] In addition, a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse or HIV/AIDS.
The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.[3] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.[4] TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems.[5] The World Health Organization declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis aiming to save 14 million lives between 2006 and 2015.[6]
Contents
[hide]
* 1 Other names
* 2 Symptoms
* 3 Bacterial species
o 3.1 Evolution
* 4 Transmission
* 5 Pathogenesis
* 6 Diagnosis
* 7 Progression
* 8 Treatment
* 9 Prevention
o 9.1 Vaccines
* 10 Epidemiology
* 11 History
o 11.1 Folklore
o 11.2 Study and treatment
* 12 Infection of other animals
* 13 See also
* 14 References
* 15 Further reading
* 16 External links
Other names
In the past, tuberculosis was called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names included phthisis (Greek for consumption) and phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king's evil, because it was believed that a king's touch would heal scrofula; and Pott's disease, or gibbus of the spine and joints.[7][8] Miliary tuberculosis – now commonly known as disseminated TB– occurs when the infection invades the circulatory system resulting in lesions which have the appearance of millet seeds on X-ray.[7][9]
Symptoms
Further information: Tuberculosis classification
When the disease becomes active, 75% of the cases are pulmonary TB. Symptoms include chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to fatigue very easily.[2]
In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB more common in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura, the central nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Although extrapulmonary TB is not contagious, it may co-exist with pulmonary TB, which is contagious.[10]
Bacterial species
Main article: Mycobacterium tuberculosis
Scanning electron micrograph of Mycobacterium tuberculosis
Scanning electron micrograph of Mycobacterium tuberculosis
The primary cause of TB , Mycobacterium tuberculosis (M. TB), is an aerobic bacterium that divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.[11] (For example, one of the fastest-growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolic acid content of its cell wall.[12] MTB is a small rod-like bacillus that can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in vitro.[13]
Using certain histological techniques on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).[12] The most common staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include an auramine-rhodamine stain and fluorescent microscopy.
The M. tuberculosis complex includes 3 other TB-causing mycobacteria: M. bovis, M. africanum and M. microti. The first two only very rarely cause disease in immunocompetent people. On the other hand, although M. microti is not usually pathogenic, it is possible that the prevalence of M. microti infections has been underestimated.[14]
Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium avium and M. kansasii. The last two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.[15]
Evolution
During its evolution, M. tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that M. tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain.[16]
Transmission
When people suffering from active pulmonary TB cough, sneeze, speak, kiss, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze, for instance, can release up to 40,000 droplets.[17] People with prolonged, frequent, or intense contact are at highest risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year.[2] Others at risk include people in areas where TB is common, people who inject illicit drugs (especially when sharing needles), residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.[18]
Transmission can only occur from people with active—not latent—TB. The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.[10] The chain of transmission can therefore be broken by isolating patients with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious.[19]
Pathogenesis
Mycobacterium tuberculosis (stained red) in sputum
Mycobacterium tuberculosis (stained red) in sputum
About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease. However, if untreated, the death rate for these active TB cases is more than 50%.[20]
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within alveolar macrophages.[21] The primary site of infection in the lungs is called the Ghon focus. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to the more distant tissues and organs where secondary TB lesions can develop in lung apices, peripheral lymph nodes, kidneys, brain, and bone.[22] All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.[23]
Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes (CD4+) secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected.[24] T lymphocytes (CD8+) can also directly kill infected cells.[21]
Importantly, bacteria are not always eliminated within the granuloma, but can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.[25]
If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. Patients with this disseminated TB have a fatality rate of approximately 20%, even with intensive treatment.[26]
In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis.[25] Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.[25]
Diagnosis
For more details on this topic, see Tuberculosis diagnosis.
Mantoux tuberculin skin test
Mantoux tuberculin skin test
Tuberculosis can be a difficult disease to diagnose, due mainly to the difficulty in culturing this slow-growing organism in the laboratory. A complete medical evaluation for TB must include a medical history, a chest X-ray, and a physical examination. Tuberculosis radiology is used in the diagnosis of TB. It may also include a tuberculin skin test, a serological test, microbiological smears and cultures. The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression.[10]
Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to purified protein derivatives of M. tuberculosis. Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection and thus the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.[27] New TB tests are being developed that offer the hope of cheap, fast and more accurate TB testing. These use polymerase chain reaction detection of bacterial DNA and antibody assays to detect the release of interferon gamma in response to mycobacteria.[28] Rapid and inexpensive diagnosis will be particularly valuable in the developing world.
Progression
Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease—1 to 5% of cases—this occurs soon after infection. However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2 to 23% of these latent cases, often many years after infection.[29] The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.[20]
Other conditions that increase risk include drug injection, mainly due to the lifestyle of IV drug users; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; diabetes mellitus; silicosis; prolonged corticosteroid therapy and other immunosuppressive therapy; head and neck cancers; hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass or gastrectomy; chronic malabsorption syndromes; or low body weight.[10]
Twin studies in the 1950's showed that the course of TB infection was highly dependent on the genetics of the patient. At that time, it was rare that one identical twin would die and the other live.[30]
Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.[31]
Treatment
For more details on this topic, see Tuberculosis treatment.
Treatment for TB uses antibiotics to kill the bacteria. The two antibiotics most commonly used are rifampicin and isoniazid. However, instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 12 months) to entirely eliminate mycobacteria from the body.[10] Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance.[32] People with these latent infections are treated to prevent them from progressing to active TB disease later in life. However, treatment using Rifampin and Pyrazinamide is not risk-free. The Centers for Disease Control and Prevention (CDC) notified healthcare professionals of revised recommendations against the use of rifampin plus pyrazinamide for treatment of latent tuberculosis infection, due to high rates of hospitalization and death from liver injury associated with the combined use of these drugs.[33]
Drug resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance occurs in persons who are infected with a resistant strain of TB. A patient with fully-susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low quality medication.[32] Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug resistant TB (MDR-TB) is defined as resistance to the two most effective first line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.[4]
Prevention
TB prevention and control takes two parallel approaches. In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB. Unfortunately, no vaccine is available that provides reliable protection for adults. However, in tropical areas where the incidence of atypical mycobacteria is high, exposure to nontuberculous mycobacteria gives some protection against TB.[34]
Vaccines
Many countries use BCG vaccine as part of their TB control programs, especially for infants. This was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921.[35] However, mass vaccination with BCG did not start until after World War II.[36] The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.[37]
In South Africa, the country with the highest prevalence of TB, BCG is given to all children under the age of three.[38] However, the effectiveness of BCG is lower in areas where mycobacteria are less prevalent, therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:[10]
* Infants or children with negative skin-test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
* Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.
Several new vaccines to prevent TB infection are being developed. The first recombinant tuberculosis vaccine entered clinical trials in the United States in 2004, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).[39] A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans.[40] A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University,[41] and is based on a genetically modified vaccinia virus. Because of the limitations of current vaccines, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.[42][43]
Epidemiology
Annual number of new reported TB cases. Data from WHO.
Annual number of new reported TB cases. Data from WHO.[44]
World TB incidence. Cases per 100,000; Red = >300, orange = 200–300; yellow = 100–200; green 50–100 and grey <50. Data from WHO, 2006.
World TB incidence. Cases per 100,000; Red = >300, orange = 200–300; yellow = 100–200; green 50–100 and grey <50. Data from WHO, 2006.[44]
According to the World Health Organization (WHO), nearly 2 billion people—one–third of the world's population—have been exposed to the tuberculosis pathogen.[45] Annually, 8 million people become ill with tuberculosis, and 2 million people die from the disease worldwide.[46] In 2004, around 14.6 million people had active TB disease with 9 million new cases. The annual incidence rate varies from 356 per 100,000 in Africa to 41 per 100,000 in the Americas.[2] Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS.[47]
In 2004, the country with the highest incidence of TB was South Africa, with 718 cases per 100,000 people. India has the largest number of infections, with over 1.8 million cases.[44] In developed countries, tuberculosis is less common and is mainly an urban disease. In the United Kingdom, TB incidences range from 40 per 100,000 in London to less than 5 per 100,000 in the rural South West of England;[48] the national average is 13 per 100,000. The highest rates in Western Europe are in Portugal (42 per 100,000) and Spain (20 per 100,000). These rates compare with 113 per 100,000 in China and 64 per 100,000 in Brazil. In the United States, the overall tuberculosis case rate was 4.9 per 100,000 persons in 2004.[46]
The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults.[49] However, in countries where TB has gone from high to low incidence, such as America, TB is mainly a disease of older people.[50]
There are a number of known factors that make people more susceptible to TB infection: worldwide the most important of these is HIV. Co-infection with HIV is a particular problem in Sub-Saharan Africa, due to the high incidence of HIV in these countries.[44] Smoking more than 20 cigarettes a day also increases the risk of TB by two- to four-times.[51] Diabetes mellitus is also an important risk factor that is growing in importance in developing countries.[52]
History
Tubercular decay has been found in the spines of Egyptian mummies. Pictured: Egyptian mummy in the British Museum
Tubercular decay has been found in the spines of Egyptian mummies. Pictured: Egyptian mummy in the British Museum
Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 17,000 years before the present.[53] However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is currently unclear.[54] Skeletal remains show prehistoric humans (4000 BC) had TB, and tubercular decay has been found in the spines of mummies from 3000-2400 BC.[55] Phthisis is a Greek term for tuberculosis; around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal.[56] Genetic studies suggest that TB was present in South America for about 2,000 years.[57] In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BC to circa 100 AD).[58]
Folklore
Before the Industrial Revolution, tuberculosis may sometimes have been regarded as vampirism. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that this was caused by the original victim draining the life from the other family members. Furthermore, people who had TB exhibited symptoms similar to what people considered to be vampire traits. People with TB often have symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin and coughing blood, suggesting the idea that the only way for the afflicted to replenish this loss of blood was by sucking blood.[59] Another folk belief attributed it to being forced, nightly, to attend fairy revels, so that the victim wasted away owing to lack of rest; this belief was most common when a strong connection was seen between the fairies and the dead.[60] Similarly, but less commonly, it was attributed to the victims being "hagridden"—being transformed into horses by witches (hags) to travel to their nightly meetings, again resulting in a lack of rest.[60]
TB was romanticized in the nineteenth century. Many at the time believed TB produced feelings of euphoria referred to as "Spes phthisica" or "hope of the consumptive". It was believed that TB sufferers who were artists had bursts of creativity as the disease progressed. It was also believed that TB sufferers acquired a final burst of energy just before they died which made women more beautiful and men more creative.[61]
Study and treatment
Although it was established that the pulmonary form was associated with 'tubercles' by Dr Richard Morton in 1689,[62][63] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s and was not named 'tuberculosis' until 1839 by J. L. Schönlein.[64] During the years 1838–1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers into the cave in the hope of curing the disease with the constant temperature and purity of the cave air: they died within a year.[65] The first TB sanatorium opened in 1859 in Görbersdorf, Germany (today Sokołowsko, Poland) by Hermann Brehmer.[66]
In regard to this claim, The Times for January 15, 1859, page 5, column 5, carries an advertisement seeking funds for the Bournemouth Sanatorium for Consumption, referring to the balance sheet for the past year, and offering an annual report to prospective donors, implying that this sanatorium was in existence at least in 1858.
Dr. Robert Koch discovered the tuberculosis bacilli.
Dr. Robert Koch discovered the tuberculosis bacilli.
The bacillus causing tuberculosis, Mycobacterium tuberculosis, was identified and described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery.[67] Koch did not believe that bovine (cattle) and human tuberculosis were similar, which delayed the recognition of infected milk as a source of infection. Later, this source was eliminated by the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it 'tuberculin'. It was not effective, but was later adapted as a test for pre-symptomatic tuberculosis.[68]
The first genuine success in immunizing against tuberculosis was developed from attenuated bovine-strain tuberculosis by Albert Calmette and Camille Guerin in 1906. It was called 'BCG' (Bacillus of Calmette and Guerin). The BCG vaccine was first used on humans in 1921 in France,[35] but it wasn't until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany.[36]
Tuberculosis, or 'consumption' as it was commonly known, caused the most widespread public concern in the 19th and early 20th centuries as an endemic disease of the urban poor. In 1815, one in four deaths in England was of consumption; by 1918 one in six deaths in France were still caused by TB. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons; the sanatoria for the middle and upper classes offered excellent care and constant medical attention.[66] Whatever the purported benefits of the fresh air and labor in the sanatoria, even under the best conditions, 50% of those who entered were dead within five years (1916).[66]
Public health campaigns tried to halt the spread of TB
Public health campaigns tried to halt the spread of TB
The promotion of Christmas Seals began in Denmark during 1904 as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907–08 to help the National Tuberculosis Association (later called the American Lung Association).
In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.
In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease remained a significant threat to public health, such that when the Medical Research Council was formed in Britain in 1913 its initial focus was tuberculosis research.[69]
It was not until 1946 with the development of the antibiotic streptomycin that effective treatment and cure became possible. Prior to the introduction of this drug, the only treatment besides sanatoria were surgical interventions, including the pneumothorax technique—collapsing an infected lung to "rest" it and allow lesions to heal—a technique that was of little benefit and was largely discontinued by the 1950s.[70] The emergence of multidrug-resistant TB has again introduced surgery as part of the treatment for these infections. Here, surgical removal of chest cavities will reduce the number of bacteria in the lungs, as well as increasing the exposure of the remaining bacteria to drugs in the bloodstream, and is therefore thought to increase the effectiveness of the chemotherapy.[71]
Hope that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, tuberculosis cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases rose again, reaching 6,300 in 2000 and 7,600 cases in 2005.[72] Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence in the late 1980s.[73] The number of those failing to complete their course of drugs is high. NY had to cope with more than 20,000 "unnecessary" TB-patients with multidrug-resistant strains (resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.[74]
Infection of other animals
Main article: Mycobacterium bovis
Tuberculosis can be carried by mammals; domesticated species, such as cats and dogs, are generally free of tuberculosis, but wild animals may be carriers. In some places, regulations aiming to prevent the spread of TB restrict the ownership of novelty pets; for example, the U.S. state of California forbids the ownership of pet gerbils.[75]
Mycobacterium bovis causes TB in cattle. An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is underway. It has been found that herd infection is more likely in areas where infected vector species such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders.[76] Controlling the vectors through possum eradication and monitoring the level of disease in livestock herds through regular surveillance are seen as a "two-pronged" approach to ridding New Zealand of the disease.
In the Republic of Ireland and the United Kingdom, badgers have been identified as one vector species for the transmission of bovine tuberculosis. As a result, governments have come under pressure from some quarters, primarily dairy farmers, to mount an active campaign of eradication of badgers in certain areas with the purpose of reducing the incidence of bovine TB. The UK government has not committed itself on the issue, not least because it fears public opinion: badgers are a protected species. The effectiveness of culling on the incidence of TB in cattle is a contentious issue, with proponents and opponents citing their own studies to support their position.
Tuberculosis (abbreviated as TB for tubercle bacillus or Tuberculosis) is a common and deadly infectious disease caused by mycobacteria, mainly Mycobacterium tuberculosis. Tuberculosis most commonly attacks the lungs (as pulmonary TB) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, bones, joints and even the skin. Other mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti can also cause tuberculosis, but these species do not usually infect healthy adults.[1]
Over one-third of the world's population has been exposed to the TB bacterium, and new infections occur at a rate of one per second.[2] Not everyone infected develops the full-blown disease, so asymptomatic, latent TB infection is most common. However, one in ten latent infections will progress to active TB disease, which, if left untreated, kills more than half of its victims.
In 2004, mortality and morbidity statistics included 14.6 million chronic active TB cases, 8.9 million new cases, and 1.6 million deaths, mostly in developing countries.[2] In addition, a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse or HIV/AIDS.
The rise in HIV infections and the neglect of TB control programs have enabled a resurgence of tuberculosis.[3] The emergence of drug-resistant strains has also contributed to this new epidemic with, from 2000 to 2004, 20% of TB cases being resistant to standard treatments and 2% resistant to second-line drugs.[4] TB incidence varies widely, even in neighboring countries, apparently because of differences in health care systems.[5] The World Health Organization declared TB a global health emergency in 1993, and the Stop TB Partnership developed a Global Plan to Stop Tuberculosis aiming to save 14 million lives between 2006 and 2015.[6]
Contents
[hide]
* 1 Other names
* 2 Symptoms
* 3 Bacterial species
o 3.1 Evolution
* 4 Transmission
* 5 Pathogenesis
* 6 Diagnosis
* 7 Progression
* 8 Treatment
* 9 Prevention
o 9.1 Vaccines
* 10 Epidemiology
* 11 History
o 11.1 Folklore
o 11.2 Study and treatment
* 12 Infection of other animals
* 13 See also
* 14 References
* 15 Further reading
* 16 External links
Other names
In the past, tuberculosis was called consumption, because it seemed to consume people from within, with a bloody cough, fever, pallor, and long relentless wasting. Other names included phthisis (Greek for consumption) and phthisis pulmonalis; scrofula (in adults), affecting the lymphatic system and resulting in swollen neck glands; tabes mesenterica, TB of the abdomen and lupus vulgaris, TB of the skin; wasting disease; white plague, because sufferers appear markedly pale; king's evil, because it was believed that a king's touch would heal scrofula; and Pott's disease, or gibbus of the spine and joints.[7][8] Miliary tuberculosis – now commonly known as disseminated TB– occurs when the infection invades the circulatory system resulting in lesions which have the appearance of millet seeds on X-ray.[7][9]
Symptoms
Further information: Tuberculosis classification
When the disease becomes active, 75% of the cases are pulmonary TB. Symptoms include chest pain, coughing up blood, and a productive, prolonged cough for more than three weeks. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss, pallor, and often a tendency to fatigue very easily.[2]
In the other 25% of active cases, the infection moves from the lungs, causing other kinds of TB more common in immunosuppressed persons and young children. Extrapulmonary infection sites include the pleura, the central nervous system in meningitis, the lymphatic system in scrofula of the neck, the genitourinary system in urogenital tuberculosis, and bones and joints in Pott's disease of the spine. An especially serious form is disseminated TB, more commonly known as miliary tuberculosis. Although extrapulmonary TB is not contagious, it may co-exist with pulmonary TB, which is contagious.[10]
Bacterial species
Main article: Mycobacterium tuberculosis
Scanning electron micrograph of Mycobacterium tuberculosis
Scanning electron micrograph of Mycobacterium tuberculosis
The primary cause of TB , Mycobacterium tuberculosis (M. TB), is an aerobic bacterium that divides every 16 to 20 hours, an extremely slow rate compared with other bacteria, which usually divide in less than an hour.[11] (For example, one of the fastest-growing bacteria is a strain of E. coli that can divide roughly every 20 minutes.) Since MTB has a cell wall but lacks a phospholipid outer membrane, it is classified as a Gram-positive bacterium. However, if a Gram stain is performed, MTB either stains very weakly Gram-positive or does not retain dye due to the high lipid & mycolic acid content of its cell wall.[12] MTB is a small rod-like bacillus that can withstand weak disinfectants and survive in a dry state for weeks. In nature, the bacterium can grow only within the cells of a host organism, but M. tuberculosis can be cultured in vitro.[13]
Using certain histological techniques on expectorate samples from phlegm (also called sputum), scientists can identify MTB under a regular microscope. Since MTB retains certain stains after being treated with acidic solution, it is classified as an acid-fast bacillus (AFB).[12] The most common staining technique, the Ziehl-Neelsen stain, dyes AFBs a bright red that stands out clearly against a blue background. Other ways to visualize AFBs include an auramine-rhodamine stain and fluorescent microscopy.
The M. tuberculosis complex includes 3 other TB-causing mycobacteria: M. bovis, M. africanum and M. microti. The first two only very rarely cause disease in immunocompetent people. On the other hand, although M. microti is not usually pathogenic, it is possible that the prevalence of M. microti infections has been underestimated.[14]
Other known pathogenic mycobacteria include Mycobacterium leprae, Mycobacterium avium and M. kansasii. The last two are part of the nontuberculous mycobacteria (NTM) group. Nontuberculous mycobacteria cause neither TB nor leprosy, but they do cause pulmonary diseases resembling TB.[15]
Evolution
During its evolution, M. tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that M. tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain.[16]
Transmission
When people suffering from active pulmonary TB cough, sneeze, speak, kiss, or spit, they expel infectious aerosol droplets 0.5 to 5 µm in diameter. A single sneeze, for instance, can release up to 40,000 droplets.[17] People with prolonged, frequent, or intense contact are at highest risk of becoming infected, with an estimated 22% infection rate. A person with active but untreated tuberculosis can infect 10–15 other people per year.[2] Others at risk include people in areas where TB is common, people who inject illicit drugs (especially when sharing needles), residents and employees of high-risk congregate settings, medically under-served and low-income populations, high-risk racial or ethnic minority populations, children exposed to adults in high-risk categories, patients immunocompromised by conditions such as HIV/AIDS, people who take immunosuppressant drugs, and health care workers serving these high-risk clients.[18]
Transmission can only occur from people with active—not latent—TB. The probability of transmission from one person to another depends upon the number of infectious droplets expelled by a carrier, the effectiveness of ventilation, the duration of exposure, and the virulence of the M. tuberculosis strain.[10] The chain of transmission can therefore be broken by isolating patients with active disease and starting effective anti-tuberculous therapy. After two weeks of such treatment, people with non-resistant active TB generally cease to be contagious.[19]
Pathogenesis
Mycobacterium tuberculosis (stained red) in sputum
Mycobacterium tuberculosis (stained red) in sputum
About 90% of those infected with Mycobacterium tuberculosis have asymptomatic, latent TB infection (sometimes called LTBI), with only a 10% lifetime chance that a latent infection will progress to TB disease. However, if untreated, the death rate for these active TB cases is more than 50%.[20]
TB infection begins when the mycobacteria reach the pulmonary alveoli, where they invade and replicate within alveolar macrophages.[21] The primary site of infection in the lungs is called the Ghon focus. Bacteria are picked up by dendritic cells, which do not allow replication, although these cells can transport the bacilli to local (mediastinal) lymph nodes. Further spread is through the bloodstream to the more distant tissues and organs where secondary TB lesions can develop in lung apices, peripheral lymph nodes, kidneys, brain, and bone.[22] All parts of the body can be affected by the disease, though it rarely affects the heart, skeletal muscles, pancreas and thyroid.[23]
Tuberculosis is classified as one of the granulomatous inflammatory conditions. Macrophages, T lymphocytes, B lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma, with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T lymphocytes (CD4+) secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected.[24] T lymphocytes (CD8+) can also directly kill infected cells.[21]
Importantly, bacteria are not always eliminated within the granuloma, but can become dormant, resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of cell death, also called necrosis, in the center of tubercles. To the naked eye this has the texture of soft white cheese and was termed caseous necrosis.[25]
If TB bacteria gain entry to the bloodstream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of TB disease is most common in infants and the elderly and is called miliary tuberculosis. Patients with this disseminated TB have a fatality rate of approximately 20%, even with intensive treatment.[26]
In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis.[25] Affected tissue is replaced by scarring and cavities filled with cheese-like white necrotic material. During active disease, some of these cavities are joined to the air passages bronchi and this material can be coughed up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotics kills bacteria and allows healing to take place. Upon cure, affected areas are eventually replaced by scar tissue.[25]
Diagnosis
For more details on this topic, see Tuberculosis diagnosis.
Mantoux tuberculin skin test
Mantoux tuberculin skin test
Tuberculosis can be a difficult disease to diagnose, due mainly to the difficulty in culturing this slow-growing organism in the laboratory. A complete medical evaluation for TB must include a medical history, a chest X-ray, and a physical examination. Tuberculosis radiology is used in the diagnosis of TB. It may also include a tuberculin skin test, a serological test, microbiological smears and cultures. The interpretation of the tuberculin skin test depends upon the person's risk factors for infection and progression to TB disease, such as exposure to other cases of TB or immunosuppression.[10]
Currently, latent infection is diagnosed in a non-immunized person by a tuberculin skin test, which yields a delayed hypersensitivity type response to purified protein derivatives of M. tuberculosis. Those immunized for TB or with past-cleared infection will respond with delayed hypersensitivity parallel to those currently in a state of infection and thus the test must be used with caution, particularly with regard to persons from countries where TB immunization is common.[27] New TB tests are being developed that offer the hope of cheap, fast and more accurate TB testing. These use polymerase chain reaction detection of bacterial DNA and antibody assays to detect the release of interferon gamma in response to mycobacteria.[28] Rapid and inexpensive diagnosis will be particularly valuable in the developing world.
Progression
Progression from TB infection to TB disease occurs when the TB bacilli overcome the immune system defenses and begin to multiply. In primary TB disease—1 to 5% of cases—this occurs soon after infection. However, in the majority of cases, a latent infection occurs that has no obvious symptoms. These dormant bacilli can produce tuberculosis in 2 to 23% of these latent cases, often many years after infection.[29] The risk of reactivation increases with immunosuppression, such as that caused by infection with HIV. In patients co-infected with M. tuberculosis and HIV, the risk of reactivation increases to 10% per year.[20]
Other conditions that increase risk include drug injection, mainly due to the lifestyle of IV drug users; recent TB infection or a history of inadequately treated TB; chest X-ray suggestive of previous TB, showing fibrotic lesions and nodules; diabetes mellitus; silicosis; prolonged corticosteroid therapy and other immunosuppressive therapy; head and neck cancers; hematologic and reticuloendothelial diseases, such as leukemia and Hodgkin's disease; end-stage kidney disease; intestinal bypass or gastrectomy; chronic malabsorption syndromes; or low body weight.[10]
Twin studies in the 1950's showed that the course of TB infection was highly dependent on the genetics of the patient. At that time, it was rare that one identical twin would die and the other live.[30]
Some drugs, including rheumatoid arthritis drugs that work by blocking tumor necrosis factor-alpha (an inflammation-causing cytokine), raise the risk of activating a latent infection due to the importance of this cytokine in the immune defense against TB.[31]
Treatment
For more details on this topic, see Tuberculosis treatment.
Treatment for TB uses antibiotics to kill the bacteria. The two antibiotics most commonly used are rifampicin and isoniazid. However, instead of the short course of antibiotics typically used to cure other bacterial infections, TB requires much longer periods of treatment (around 6 to 12 months) to entirely eliminate mycobacteria from the body.[10] Latent TB treatment usually uses a single antibiotic, while active TB disease is best treated with combinations of several antibiotics, to reduce the risk of the bacteria developing antibiotic resistance.[32] People with these latent infections are treated to prevent them from progressing to active TB disease later in life. However, treatment using Rifampin and Pyrazinamide is not risk-free. The Centers for Disease Control and Prevention (CDC) notified healthcare professionals of revised recommendations against the use of rifampin plus pyrazinamide for treatment of latent tuberculosis infection, due to high rates of hospitalization and death from liver injury associated with the combined use of these drugs.[33]
Drug resistant tuberculosis is transmitted in the same way as regular TB. Primary resistance occurs in persons who are infected with a resistant strain of TB. A patient with fully-susceptible TB develops secondary resistance (acquired resistance) during TB therapy because of inadequate treatment, not taking the prescribed regimen appropriately, or using low quality medication.[32] Drug-resistant TB is a public health issue in many developing countries, as treatment is longer and requires more expensive drugs. Multi-drug resistant TB (MDR-TB) is defined as resistance to the two most effective first line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB (XDR-TB) is also resistant to three or more of the six classes of second-line drugs.[4]
Prevention
TB prevention and control takes two parallel approaches. In the first, people with TB and their contacts are identified and then treated. Identification of infections often involves testing high-risk groups for TB. In the second approach, children are vaccinated to protect them from TB. Unfortunately, no vaccine is available that provides reliable protection for adults. However, in tropical areas where the incidence of atypical mycobacteria is high, exposure to nontuberculous mycobacteria gives some protection against TB.[34]
Vaccines
Many countries use BCG vaccine as part of their TB control programs, especially for infants. This was the first vaccine for TB and developed at the Pasteur Institute in France between 1905 and 1921.[35] However, mass vaccination with BCG did not start until after World War II.[36] The protective efficacy of BCG for preventing serious forms of TB (e.g. meningitis) in children is greater than 80%; its protective efficacy for preventing pulmonary TB in adolescents and adults is variable, ranging from 0 to 80%.[37]
In South Africa, the country with the highest prevalence of TB, BCG is given to all children under the age of three.[38] However, the effectiveness of BCG is lower in areas where mycobacteria are less prevalent, therefore BCG is not given to the entire population in these countries. In the USA, for example, BCG vaccine is not recommended except for people who meet specific criteria:[10]
* Infants or children with negative skin-test results who are continually exposed to untreated or ineffectively treated patients or will be continually exposed to multidrug-resistant TB.
* Healthcare workers considered on an individual basis in settings in which a high percentage of MDR-TB patients has been found, transmission of MDR-TB is likely, and TB control precautions have been implemented and were not successful.
Several new vaccines to prevent TB infection are being developed. The first recombinant tuberculosis vaccine entered clinical trials in the United States in 2004, sponsored by the National Institute of Allergy and Infectious Diseases (NIAID).[39] A 2005 study showed that a DNA TB vaccine given with conventional chemotherapy can accelerate the disappearance of bacteria as well as protect against re-infection in mice; it may take four to five years to be available in humans.[40] A very promising TB vaccine, MVA85A, is currently in phase II trials in South Africa by a group led by Oxford University,[41] and is based on a genetically modified vaccinia virus. Because of the limitations of current vaccines, researchers and policymakers are promoting new economic models of vaccine development including prizes, tax incentives and advance market commitments.[42][43]
Epidemiology
Annual number of new reported TB cases. Data from WHO.
Annual number of new reported TB cases. Data from WHO.[44]
World TB incidence. Cases per 100,000; Red = >300, orange = 200–300; yellow = 100–200; green 50–100 and grey <50. Data from WHO, 2006.
World TB incidence. Cases per 100,000; Red = >300, orange = 200–300; yellow = 100–200; green 50–100 and grey <50. Data from WHO, 2006.[44]
According to the World Health Organization (WHO), nearly 2 billion people—one–third of the world's population—have been exposed to the tuberculosis pathogen.[45] Annually, 8 million people become ill with tuberculosis, and 2 million people die from the disease worldwide.[46] In 2004, around 14.6 million people had active TB disease with 9 million new cases. The annual incidence rate varies from 356 per 100,000 in Africa to 41 per 100,000 in the Americas.[2] Tuberculosis is the world's greatest infectious killer of women of reproductive age and the leading cause of death among people with HIV/AIDS.[47]
In 2004, the country with the highest incidence of TB was South Africa, with 718 cases per 100,000 people. India has the largest number of infections, with over 1.8 million cases.[44] In developed countries, tuberculosis is less common and is mainly an urban disease. In the United Kingdom, TB incidences range from 40 per 100,000 in London to less than 5 per 100,000 in the rural South West of England;[48] the national average is 13 per 100,000. The highest rates in Western Europe are in Portugal (42 per 100,000) and Spain (20 per 100,000). These rates compare with 113 per 100,000 in China and 64 per 100,000 in Brazil. In the United States, the overall tuberculosis case rate was 4.9 per 100,000 persons in 2004.[46]
The incidence of TB varies with age. In Africa, TB primarily affects adolescents and young adults.[49] However, in countries where TB has gone from high to low incidence, such as America, TB is mainly a disease of older people.[50]
There are a number of known factors that make people more susceptible to TB infection: worldwide the most important of these is HIV. Co-infection with HIV is a particular problem in Sub-Saharan Africa, due to the high incidence of HIV in these countries.[44] Smoking more than 20 cigarettes a day also increases the risk of TB by two- to four-times.[51] Diabetes mellitus is also an important risk factor that is growing in importance in developing countries.[52]
History
Tubercular decay has been found in the spines of Egyptian mummies. Pictured: Egyptian mummy in the British Museum
Tubercular decay has been found in the spines of Egyptian mummies. Pictured: Egyptian mummy in the British Museum
Tuberculosis has been present in humans since antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of bison dated 17,000 years before the present.[53] However, whether tuberculosis originated in cattle and then transferred to humans, or diverged from a common ancestor, is currently unclear.[54] Skeletal remains show prehistoric humans (4000 BC) had TB, and tubercular decay has been found in the spines of mummies from 3000-2400 BC.[55] Phthisis is a Greek term for tuberculosis; around 460 BC, Hippocrates identified phthisis as the most widespread disease of the times involving coughing up blood and fever, which was almost always fatal.[56] Genetic studies suggest that TB was present in South America for about 2,000 years.[57] In South America, the earliest evidence of tuberculosis is associated with the Paracas-Caverna culture (circa 750 BC to circa 100 AD).[58]
Folklore
Before the Industrial Revolution, tuberculosis may sometimes have been regarded as vampirism. When one member of a family died from it, the other members that were infected would lose their health slowly. People believed that this was caused by the original victim draining the life from the other family members. Furthermore, people who had TB exhibited symptoms similar to what people considered to be vampire traits. People with TB often have symptoms such as red, swollen eyes (which also creates a sensitivity to bright light), pale skin and coughing blood, suggesting the idea that the only way for the afflicted to replenish this loss of blood was by sucking blood.[59] Another folk belief attributed it to being forced, nightly, to attend fairy revels, so that the victim wasted away owing to lack of rest; this belief was most common when a strong connection was seen between the fairies and the dead.[60] Similarly, but less commonly, it was attributed to the victims being "hagridden"—being transformed into horses by witches (hags) to travel to their nightly meetings, again resulting in a lack of rest.[60]
TB was romanticized in the nineteenth century. Many at the time believed TB produced feelings of euphoria referred to as "Spes phthisica" or "hope of the consumptive". It was believed that TB sufferers who were artists had bursts of creativity as the disease progressed. It was also believed that TB sufferers acquired a final burst of energy just before they died which made women more beautiful and men more creative.[61]
Study and treatment
Although it was established that the pulmonary form was associated with 'tubercles' by Dr Richard Morton in 1689,[62][63] due to the variety of its symptoms, TB was not identified as a single disease until the 1820s and was not named 'tuberculosis' until 1839 by J. L. Schönlein.[64] During the years 1838–1845, Dr. John Croghan, the owner of Mammoth Cave, brought a number of tuberculosis sufferers into the cave in the hope of curing the disease with the constant temperature and purity of the cave air: they died within a year.[65] The first TB sanatorium opened in 1859 in Görbersdorf, Germany (today Sokołowsko, Poland) by Hermann Brehmer.[66]
In regard to this claim, The Times for January 15, 1859, page 5, column 5, carries an advertisement seeking funds for the Bournemouth Sanatorium for Consumption, referring to the balance sheet for the past year, and offering an annual report to prospective donors, implying that this sanatorium was in existence at least in 1858.
Dr. Robert Koch discovered the tuberculosis bacilli.
Dr. Robert Koch discovered the tuberculosis bacilli.
The bacillus causing tuberculosis, Mycobacterium tuberculosis, was identified and described on March 24, 1882 by Robert Koch. He received the Nobel Prize in physiology or medicine in 1905 for this discovery.[67] Koch did not believe that bovine (cattle) and human tuberculosis were similar, which delayed the recognition of infected milk as a source of infection. Later, this source was eliminated by the pasteurization process. Koch announced a glycerine extract of the tubercle bacilli as a "remedy" for tuberculosis in 1890, calling it 'tuberculin'. It was not effective, but was later adapted as a test for pre-symptomatic tuberculosis.[68]
The first genuine success in immunizing against tuberculosis was developed from attenuated bovine-strain tuberculosis by Albert Calmette and Camille Guerin in 1906. It was called 'BCG' (Bacillus of Calmette and Guerin). The BCG vaccine was first used on humans in 1921 in France,[35] but it wasn't until after World War II that BCG received widespread acceptance in the USA, Great Britain, and Germany.[36]
Tuberculosis, or 'consumption' as it was commonly known, caused the most widespread public concern in the 19th and early 20th centuries as an endemic disease of the urban poor. In 1815, one in four deaths in England was of consumption; by 1918 one in six deaths in France were still caused by TB. After the establishment in the 1880s that the disease was contagious, TB was made a notifiable disease in Britain; there were campaigns to stop spitting in public places, and the infected poor were "encouraged" to enter sanatoria that resembled prisons; the sanatoria for the middle and upper classes offered excellent care and constant medical attention.[66] Whatever the purported benefits of the fresh air and labor in the sanatoria, even under the best conditions, 50% of those who entered were dead within five years (1916).[66]
Public health campaigns tried to halt the spread of TB
Public health campaigns tried to halt the spread of TB
The promotion of Christmas Seals began in Denmark during 1904 as a way to raise money for tuberculosis programs. It expanded to the United States and Canada in 1907–08 to help the National Tuberculosis Association (later called the American Lung Association).
In the United States, concern about the spread of tuberculosis played a role in the movement to prohibit public spitting except into spittoons.
In Europe, deaths from TB fell from 500 out of 100,000 in 1850 to 50 out of 100,000 by 1950. Improvements in public health were reducing tuberculosis even before the arrival of antibiotics, although the disease remained a significant threat to public health, such that when the Medical Research Council was formed in Britain in 1913 its initial focus was tuberculosis research.[69]
It was not until 1946 with the development of the antibiotic streptomycin that effective treatment and cure became possible. Prior to the introduction of this drug, the only treatment besides sanatoria were surgical interventions, including the pneumothorax technique—collapsing an infected lung to "rest" it and allow lesions to heal—a technique that was of little benefit and was largely discontinued by the 1950s.[70] The emergence of multidrug-resistant TB has again introduced surgery as part of the treatment for these infections. Here, surgical removal of chest cavities will reduce the number of bacteria in the lungs, as well as increasing the exposure of the remaining bacteria to drugs in the bloodstream, and is therefore thought to increase the effectiveness of the chemotherapy.[71]
Hope that the disease could be completely eliminated have been dashed since the rise of drug-resistant strains in the 1980s. For example, tuberculosis cases in Britain, numbering around 117,000 in 1913, had fallen to around 5,000 in 1987, but cases rose again, reaching 6,300 in 2000 and 7,600 cases in 2005.[72] Due to the elimination of public health facilities in New York and the emergence of HIV, there was a resurgence in the late 1980s.[73] The number of those failing to complete their course of drugs is high. NY had to cope with more than 20,000 "unnecessary" TB-patients with multidrug-resistant strains (resistant to, at least, both Rifampin and Isoniazid). The resurgence of tuberculosis resulted in the declaration of a global health emergency by the World Health Organization in 1993.[74]
Infection of other animals
Main article: Mycobacterium bovis
Tuberculosis can be carried by mammals; domesticated species, such as cats and dogs, are generally free of tuberculosis, but wild animals may be carriers. In some places, regulations aiming to prevent the spread of TB restrict the ownership of novelty pets; for example, the U.S. state of California forbids the ownership of pet gerbils.[75]
Mycobacterium bovis causes TB in cattle. An effort to eradicate bovine tuberculosis from the cattle and deer herds of New Zealand is underway. It has been found that herd infection is more likely in areas where infected vector species such as Australian brush-tailed possums come into contact with domestic livestock at farm/bush borders.[76] Controlling the vectors through possum eradication and monitoring the level of disease in livestock herds through regular surveillance are seen as a "two-pronged" approach to ridding New Zealand of the disease.
In the Republic of Ireland and the United Kingdom, badgers have been identified as one vector species for the transmission of bovine tuberculosis. As a result, governments have come under pressure from some quarters, primarily dairy farmers, to mount an active campaign of eradication of badgers in certain areas with the purpose of reducing the incidence of bovine TB. The UK government has not committed itself on the issue, not least because it fears public opinion: badgers are a protected species. The effectiveness of culling on the incidence of TB in cattle is a contentious issue, with proponents and opponents citing their own studies to support their position.
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