Carcinogen

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https://en.wikipedia.org/wiki/Carcinogen 

 

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise in both natural and synthetic substances. Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

Cancer is any disease in which normal cells are damaged and do not undergo programmed cell death as fast as they divide via mitosis. Carcinogens may increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors. Usually, severe DNA damage leads to programmed cell death, but if the programmed cell death pathway is damaged, then the cell cannot prevent itself from becoming a cancer cell.

There are many natural carcinogens. Aflatoxin B₁, which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally occurring microbial carcinogen. Certain viruses such as hepatitis B and human papilloma virus have been found to cause cancer in humans. The first one shown to cause cancer in animals is Rous sarcoma virus, discovered in 1910 by Peyton Rous. Other infectious organisms which cause cancer in humans include some bacteria (e.g. Helicobacter pylori) and helminths (e.g. Opisthorchis viverrini  and Clonorchis sinensis).

Dioxins and dioxin-like compounds, benzene, kepone, EDB, and asbestos have all been classified as carcinogenic. As far back as the 1930s, Industrial smoke and tobacco smoke were identified as sources of dozens of carcinogens, including benzo[a]pyrene, tobacco-specific nitrosamines such as nitrosonornicotine, and reactive aldehydes such as formaldehyde, which is also a hazard in embalming and making plastics. Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.

Co-carcinogens are chemicals that do not necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer.

After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation. The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. However, in some cases, these reactions can also convert a less toxic carcinogen into a more toxic carcinogen.

DNA is nucleophilic; therefore, soluble carbon electrophiles are carcinogenic, because DNA attacks them. For example, some alkenes are toxicated by human enzymes to produce an electrophilic epoxide. DNA attacks the epoxide, and is bound permanently to it. This is the mechanism behind the carcinogenicity of benzo[a]pyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.

IUPAC definition.

 

Carcinogenicity: Ability or tendency to produce cancer. Note: In general, polymers are not known as carcinogens or mutagens, however, residual monomers or additives can cause genetic mutations.

Radiation

CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation (alpha, beta, gamma, or neutron and the radioactive strength), its consequent capacity to cause ionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. Carcinogenicity of radiation depends on the type of radiation, type of exposure, and penetration. For example, alpha radiation has low penetration and is not a hazard outside the body, but emitters are carcinogenic when inhaled or ingested. For example, Thorotrast, a (incidentally radioactive) suspension previously used as a contrast medium in x-ray diagnostics, is a potent human carcinogen known because of its retention within various organs and persistent emission of alpha particles. Low-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.

Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum including radio waves, microwaves, infrared radiation and visible light are thought not to be, because they have insufficient energy to break chemical bonds. Evidence for carcinogenic effects of non-ionizing radiation is generally inconclusive, though there are some documented cases of radar technicians with prolonged high exposure experiencing significantly higher cancer incidence.

Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses. For most people, ultraviolet radiations from sunlight is the most common cause of skin cancer. In Australia, where people with pale skin are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.

Substances or foods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic. In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can produce secondary radiation through nuclear transmutation.

In prepared food

Chemicals used in processed and cured meat such as some brands of bacon, sausages and ham may produce carcinogens. For example, nitrites used as food preservatives in cured meat such as bacon have also been noted as being carcinogenic with demographic links, but not causation, to colon cancer. Cooking food at high temperatures, for example grilling or barbecuing meats, may also lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzo[a]pyrene). Charring of food looks like coking and tobacco pyrolysis, and produces carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by human enzymes into epoxides, which attach permanently to DNA. Pre-cooking meats in a microwave oven for 2–3 minutes before grilling shortens the time on the hot pan, and removes heterocyclic amine (HCA) precursors, which can help minimize the formation of these carcinogens.

Reports from the Food Standards Agency have found that the known animal carcinogen acrylamide is generated in fried or overheated carbohydrate foods (such as french fries and potato chips). Studies are underway at the FDA and Europe regulatory agencies to assess its potential risk to humans.

In cigarettes

There is a strong association of smoking with lung cancer; the lifetime risk of developing lung cancer increases significantly in smokers. A large number of known carcinogens are found in cigarette smoke. Potent carcinogens found in cigarette smoke include polycyclic aromatic hydrocarbons (PAH, such as benzo[a]pyrene), Benzene, and Nitrosamine.

Mechanisms of carcinogenicity

Carcinogens can be classified as genotoxic or nongenotoxic. Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-nitroso-N-methylurea (NMU) or non-chemical agents such as ultraviolet light and ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.

Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic compounds.

Classification

Approximate equivalences
between classification schemes

IARC	GHS	NTP	ACGIH	EU
Group 1	Cat. 1A	Known	A1	Cat. 1
Group 2A	Cat. 1B	Reasonably suspected	A2	Cat. 2
Group 2B
	Cat. 2		A3	Cat. 3
Group 3
			A4
Group 4			A5

International Agency for Research on Cancer

The International Agency for Research on Cancer (IARC) is an intergovernmental agency established in 1965, which forms part of the World Health Organization of the United Nations. It is based in Lyon, France. Since 1971 it has published a series of Monographs on the Evaluation of Carcinogenic Risks to Humans that have been highly influential in the classification of possible carcinogens.

• Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
• Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
• Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
• Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
• Group 4: the agent (mixture) is probably not carcinogenic to humans.

Globally Harmonized System

The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) is a United Nations initiative to attempt to harmonize the different systems of assessing chemical risk which currently exist (as of March 2009) around the world. It classifies carcinogens into two categories, of which the first may be divided again into subcategories if so desired by the competent regulatory authority:

• Category 1: known or presumed to have carcinogenic potential for humans
  • Category 1A: the assessment is based primarily on human evidence
  • Category 1B: the assessment is based primarily on animal evidence
• Category 2: suspected human carcinogens

U.S. National Toxicology Program

The National Toxicology Program of the U.S. Department of Health and Human Services is mandated to produce a biennial Report on Carcinogens. As of June 2011, the latest edition was the 12th report (2011). It classifies carcinogens into two groups:

• Known to be a human carcinogen
• Reasonably anticipated being a human carcinogen

American Conference of Governmental Industrial Hygienists

The American Conference of Governmental Industrial Hygienists (ACGIH) is a private organization best known for its publication of threshold limit values (TLVs) for occupational exposure and monographs on workplace chemical hazards. It assesses carcinogenicity as part of a wider assessment of the occupational hazards of chemicals.

• Group A1: Confirmed human carcinogen
• Group A2: Suspected human carcinogen
• Group A3: Confirmed animal carcinogen with unknown relevance to humans
• Group A4: Not classifiable as a human carcinogen
• Group A5: Not suspected as a human carcinogen

European Union

The European Union classification of carcinogens is contained in the Dangerous Substances Directive and the Dangerous Preparations Directive. It consists of three categories:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances which should be regarded as if they are carcinogenic to humans.
• Category 3: Substances which cause concern for humans, owing to possible carcinogenic effects but in respect of which the available information is not adequate for making a satisfactory assessment.

This assessment scheme is being phased out in favor of the GHS scheme (see above), to which it is very close in category definitions.

Safe Work Australia

Under a previous name, the NOHSC, in 1999 Safe Work Australia published the Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(1999)]. Section 4.76 of this document outlines the criteria for classifying carcinogens as approved by the Australian government. This classification consists of three categories:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances that should be regarded as if they were carcinogenic to humans.
• Category 3: Substances that have possible carcinogenic effects in humans but about which there is insufficient information to make an assessment.

Common carcinogens

Occupational carcinogens

Occupational carcinogens are agents that pose a risk of cancer in several specific work-locations:

Carcinogen	Associated cancer sites or types	Occupational uses or sources
Arsenic and its compounds	Lung Skin Hemangiosarcoma	Smelting byproduct Component of: Alloys Electrical and semiconductor devices Medications (e.g. melarsoprol) Herbicides Fungicides Animal dips Drinking water from contaminated aquifers.
Asbestos	Lungs Asbestosis Gastrointestinal tract Pleural Mesothelioma Peritoneal Mesothelioma	Not in widespread use, but found in: Constructions Roofing papers Floor tiles Fire-resistant textiles Friction linings (brake pads) (only outside Europe) Replacement friction linings for automobiles still may contain asbestos
Benzene	Leukemia Hodgkin's lymphoma	Light fuel oil Former use as solvent commodity chemical
Beryllium and its compounds	Lung	Lightweight alloys Aerospace applications Nuclear reactors
Cadmium and its compounds	Prostate	Yellow pigments Phosphors Solders Batteries Metal paintings and coatings
Hexavalent chromium(VI) compounds	Lung	Paints Pigments Preservatives
Nitrosamines	Lung Esophogus Liver	cigarette smoke nitrite-treated foods (cured meats)
Ethylene oxide	Leukemia	commodity chemical Sterilant for hospital equipment
Nickel	Nose Lung	Nickel plating Ferrous alloys Ceramics Batteries Stainless-steel welding byproduct
Radon and its decay products	Lung	Uranium decay Quarries and mines Cellars and poorly ventilated places
Vinyl chloride	Hemangiosarcoma Liver	Production of polyvinyl chloride
Shift work that involves circadian disruption	Breast
Involuntary smoking (Passive smoking)	Lung
Radium-226, Radium-224, Plutonium-238, Plutonium-239 and other alpha particle emitters with high atomic weight	Bone (they are bone seekers) Liver	Nuclear fuel processing Radium dial manufacturing

Others

• Gasoline (contains aromatics)
• Lead and its compounds
• Alkylating antineoplastic agents (e.g. mechlorethamine)
• Styrene
• Other alkylating agents (e.g. dimethyl sulfate)
• Ultraviolet radiation from the sun and UV lamps
• Alcohol (causing head and neck cancers)
• Other ionizing radiation (X-rays, gamma rays, etc.)

Major carcinogens implicated in the four most common cancers worldwide

In this section, the carcinogens implicated as the main causative agents of the four most common cancers worldwide are briefly described. These four cancers are lung, breast, colon, and stomach cancers. Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths.

Lung cancer

Lung cancer (pulmonary carcinoma) is the most common cancer in the world, both in terms of cases (1.6 million cases; 12.7% of total cancer cases) and deaths (1.4 million deaths; 18.2% of total cancer deaths). Lung cancer is largely caused by tobacco smoke. Risk estimates for lung cancer in the United States indicate that tobacco smoke is responsible for 90% of lung cancers. Other factors are implicated in lung cancer, and these factors can interact synergistically with smoking so that total attributable risk adds up to more than 100%. These factors include occupational exposure to carcinogens (about 9-15%), radon (10%) and outdoor air pollution (1-2%). Tobacco smoke is a complex mixture of more than 5,300 identified chemicals. The most important carcinogens in tobacco smoke have been determined by a “Margin of Exposure” approach. Using this approach, the most important tumorigenic compounds in tobacco smoke were, in order of importance, acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, cadmium, acetaldehyde, ethylene oxide, and isoprene. Most of these compounds cause DNA damage by forming DNA adducts or by inducing other alterations in DNA. DNA damages are subject to error-prone DNA repair or can cause replication errors. Such errors in repair or replication can result in mutations in tumor suppressor genes or oncogenes leading to cancer.

Breast cancer

Breast cancer is the second most common cancer [(1.4 million cases, 10.9%), but ranks 5th as cause of death (458,000, 6.1%)]. Increased risk of breast cancer is associated with persistently elevated blood levels of estrogen. Estrogen appears to contribute to breast carcinogenesis by three processes; (1) the metabolism of estrogen to genotoxic, mutagenic carcinogens, (2) the stimulation of tissue growth, and (3) the repression of phase II detoxification enzymes that metabolize ROS leading to increased oxidative DNA damage. The major estrogen in humans, estradiol, can be metabolized to quinone derivatives that form adducts with DNA. These derivatives can cause dupurination, the removal of bases from the phosphodiester backbone of DNA, followed by inaccurate repair or replication of the apurinic site leading to mutation and eventually cancer. This genotoxic mechanism may interact in synergy with estrogen receptor-mediated, persistent cell proliferation to ultimately cause breast cancer. Genetic background, dietary practices and environmental factors also likely contribute to the incidence of DNA damage and breast cancer risk.

Colon cancer

Colorectal cancer is the third most common cancer [1.2 million cases (9.4%), 608,000 deaths (8.0%)]. Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States. In addition, substantial evidence implicates bile acids as an important factor in colon cancer. Twelve studies (summarized in Bernstein et al.) indicate that the bile acids deoxycholic acid (DCA) and/or lithocholic acid (LCA) induce production of DNA-damaging reactive oxygen species and/or reactive nitrogen species in human or animal colon cells. Furthermore, 14 studies showed that DCA and LCA induce DNA damage in colon cells. Also 27 studies reported that bile acids cause programmed cell death (apoptosis). Increased apoptosis can result in selective survival of cells that are resistant to induction of apoptosis. Colon cells with reduced ability to undergo apoptosis in response to DNA damage would tend to accumulate mutations, and such cells may give rise to colon cancer. Epidemiologic studies have found that fecal bile acid concentrations are increased in populations with a high incidence of colon cancer. Dietary increases in total fat or saturated fat result in elevated DCA and LCA in feces and elevated exposure of the colon epithelium to these bile acids. When the bile acid DCA was added to the standard diet of wild-type mice invasive colon cancer was induced in 56% of the mice after 8 to 10 months. Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging carcinogens in colon cancer.

Stomach cancer

Stomach cancer is the fourth most common cancer [990,000 cases (7.8%), 738,000 deaths (9.7%)]. Helicobacter pylori infection is the main causative factor in stomach cancer. Chronic gastritis (inflammation) caused by H. pylori is often long-standing if not treated. Infection of gastric epithelial cells with H. pylori results in increased production of reactive oxygen species (ROS). ROS cause oxidative DNA damage including the major base alteration 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG resulting from ROS is increased in chronic gastritis. The altered DNA base can cause errors during DNA replication that have mutagenic and carcinogenic potential. Thus H. pylori-induced ROS appear to be the major carcinogens in stomach cancer because they cause oxidative DNA damage leading to carcinogenic mutations. Diet is thought to be a contributing factor in stomach cancer - in Japan where very salty pickled foods are popular, the incidence of stomach cancer is high. Preserved meat such as bacon, sausages, and ham increases the risk while a diet high in fresh fruit and vegetables may reduce the risk. The risk also increases with age.

Pulmonary alveolus

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Pulmonary_alveolus 

 

Pulmonary alveolus
The alveoli
Details
System	Respiratory system
Location	Lung
Identifiers
Latin	alveolus pulmonis
MeSH	D011650
TH	H3.05.02.0.00026

A pulmonary alveolus (plural: alveoli, from Latin alveolus, "little cavity") is a hollow cup-shaped cavity found in the lung parenchyma where gas exchange takes place. Lung alveoli are found in the acini at the beginning of the respiratory zone. They are located sparsely on the respiratory bronchioles, line the walls of the alveolar ducts, and are more numerous in the blind-ended alveolar sacs. The acini are the basic units of respiration, with gas exchange taking place in all the alveoli present.^[1] The alveolar membrane is the gas exchange surface, surrounded by a network of capillaries. Across the membrane oxygen is diffused into the capillaries and carbon dioxide released from the capillaries into the alveoli to be breathed out.

Alveoli are particular to mammalian lungs. Different structures are involved in gas exchange in other vertebrates.

Structure

Diagrammatic view of lung showing magnified inner structures including alveolar sacs at 10) and lobules at 9).

The alveoli are located in the alveolar sacs of the lungs in the pulmonary lobules of the respiratory zone, representing the smallest functional units in the respiratory tract. They are also present in the respiratory bronchioles as scattered outpockets, extending from their lumens. The respiratory bronchioles lead into alveolar ducts which are deeply lined with alveoli. Each respiratory bronchiole gives rise to between two and eleven alveolar ducts. Each duct opens into five or six alveolar sacs into which clusters of alveoli open. New alveoli continue to form until the age of eight years.

Alveolar sacs and capillaries.

A typical pair of human lungs contain about 300 million alveoli, producing 70 m² (750 sq ft) of surface area. Each alveolus is wrapped in a fine mesh of capillaries covering about 70% of its area. The diameter of an alveolus is between 200 and 500 µm.

Microanatomy

Blood circulation around alveoli

The alveoli consist of an epithelial layer of simple squamous epithelium, and an extracellular matrix surrounded by capillaries. The epithelial lining is part of the alveolar membrane, also known as the respiratory membrane, that allows the exchange of gases. The membrane has several layers – a layer of lining fluid that contains surfactant, the epithelial layer and its basement membrane; a thin interstitial space between the epithelial lining and the capillary membrane; a capillary basement membrane that often fuses with the alveolar basement membrane, and the capillary endothelial membrane. The whole membrane however is only between 0.2 µm at its thinnest part and 0.6 µm at its thickest.

In the alveolar walls there are interconnecting air passages between the alveoli known as the pores of Kohn. The alveoli contain some collagen fibers and elastic fibers. The elastic fibres allow the alveoli to stretch when they fill with air during inhalation. They then spring back during exhalation in order to expel the carbon dioxide-rich air.

A histologic slide of a human alveolar sac

There are three major types of alveolar cell. Two types are pneumocytes known as type I and type II cells found in the alveolar wall, and a large phagocytic cell known as an alveolar macrophage that moves about in the lumens of the alveoli, and in the connective tissue between them. Type I cells are squamous, thin and flat and form the structure of the alveoli. Type II cells release pulmonary surfactant to lower surface tension. Type II cells can also differentiate to replace damaged type I cells.

Function

Type I cells

The cross section of an alveolus with capillaries is shown. Part of the cross section is magnified to show diffusion of oxygen gas and carbon dioxide through type I cells and capillary cells.

 

Gas exchange in the alveolus.

Type I cells are thin and flat epithelial lining cells, that form the structure of the alveoli. They are squamous (giving more surface area to each cell) and their long cytoplasmic extensions line more than 95% of the alveolar surface.

Type I cells are involved in the process of gas exchange between the alveoli and blood. These cells are extremely thin sometimes only 25 nm – the electron microscope was needed to prove that all alveoli are lined with epithelium. This thin lining enables a fast diffusion of gas exchange between the air in the alveoli and the blood in the surrounding capillaries. 

The nucleus of a type I cell occupies a large area of free cytoplasm and its organelles are clustered around it reducing the thickness of the cell. This also keeps the thickness of the blood-air barrier reduced to a minimum.

The cytoplasm in the thin portion contains pinocytotic vesicles which may play a role in the removal of small particulate contaminants from the outer surface. In addition to desmosomes, all type I alveolar cells have occluding junctions that prevent the leakage of tissue fluid into the alveolar air space.

The relatively low solubility (and hence rate of diffusion) of oxygen, necessitates the large internal surface area (about 80 square m [96 square yards]) and very thin walls of the alveoli. Weaving between the capillaries and helping to support them is an extracellular matrix, a meshlike fabric of elastic and collagenous fibres. The collagen fibres, being more rigid, give the wall firmness, while the elastic fibres permit expansion and contraction of the walls during breathing.

Type I pneumocytes are unable to replicate and are susceptible to toxic insults. In the event of damage, type II cells can proliferate and differentiate into type I cells to compensate.

Type II cells

An annotated diagram of the alveolus

Type II cells are the most numerous cells in the alveoli, yet do not cover as much surface area as the squamous type I cells. Type II cells in the alveolar wall contain secretory granular organelles known as lamellar bodies that fuse with the cell membranes and secrete pulmonary surfactant. This surfactant is a film of fatty substances, a group of phospholipids that reduce alveolar surface tension. The phospholipids are stored in the lamellar bodies. Without this coating, the alveoli would collapse. The surfactant is continuously released by exocytosis. Reinflation of the alveoli following exhalation is made easier by the surfactant, which reduces surface tension in the thin fluid coating of the alveoli. The fluid coating is produced by the body in order to facilitate the transfer of gases between blood and alveolar air, and the type II cells are typically found at the blood-air barrier. 

Type II cells start to develop at about 26 weeks of gestation, secreting small amounts of surfactant. However, adequate amounts of surfactant are not secreted until about 35 weeks of gestation – this is the main reason for increased rates of infant respiratory distress syndrome, which drastically reduces at ages above 35 weeks gestation.

Type II cells are also capable of cellular division, giving rise to more type I and II alveolar cells when the lung tissue is damaged.

MUC1, a human gene associated with type II pneumocytes, has been identified as a marker in lung cancer.

Macrophages

The alveolar macrophages reside on the internal lumenal surfaces of the alveoli, the alveolar ducts, and the bronchioles. They are mobile scavengers that serve to engulf foreign particles in the lungs, such as dust, bacteria, carbon particles, and blood cells from injuries. They are also called dust cells.

Clinical significance

Diseases

Surfactant

Insufficient surfactant in the alveoli is one of the causes that can contribute to atelectasis (collapse of part or all of the lung). Without pulmonary surfactant, atelectasis is a certainty. Insufficient surfactant in the lungs of preterm infants causes infant respiratory distress syndrome (IRDS). Impaired surfactant regulation can cause an accumulation of surfactant proteins to build up in the alveoli in a condition called pulmonary alveolar proteinosis. This results in impaired gas exchange.

Inflammation

Pneumonia is an inflammatory condition of the lung parenchyma, which can be caused by both viruses and bacteria. Cytokines and fluids are released into the alveolar cavity, interstitium, or both, in response to infection, causing the effective surface area of gas exchange to be reduced. In severe cases where cellular respiration cannot be maintained, supplemental oxygen may be required.

• Diffuse alveolar damage can be a cause of acute respiratory distress syndrome(ARDS) a severe inflammatory disease of the lung.
• In asthma, the bronchioles, or the "bottle-necks" into the sac are restricted, causing the amount of air flow into the lungs to be greatly reduced. It can be triggered by irritants in the air, photochemical smog for example, as well as substances that a person is allergic to.
• Chronic bronchitis occurs when an abundance of mucus is produced by the lungs. The production of this substance occurs naturally when the lung tissue is exposed to irritants. In chronic bronchitis, the air passages into the alveoli, the respiratory bronchioles, become clogged with mucus. This causes increased coughing in order to remove the mucus, and is often a result of extended periods of exposure to cigarette smoke.
• Hypersensitivity pneumonitis

Structural

Almost any type of lung tumor or lung cancer can compress the alveoli and reduce gas exchange capacity. In some cases the tumor will fill the alveoli.

• Cavitary pneumonia is a process in which the alveoli are destroyed and produce a cavity. As the alveoli are destroyed, the surface area for gas exchange to occur becomes reduced. Further changes in blood flow can lead to decline in lung function.
• Emphysema is another disease of the lungs, whereby the elastin in the walls of the alveoli is broken down by an imbalance between the production of neutrophil elastase (elevated by cigarette smoke) and alpha-1 antitrypsin (the activity varies due to genetics or reaction of a critical methionine residue with toxins including cigarette smoke). The resulting loss of elasticity in the lungs leads to prolonged times for exhalation, which occurs through passive recoil of the expanded lung. This leads to a smaller volume of gas exchanged per breath.
• Pulmonary alveolar microlithiasis is a rare lung disorder of small stone formation in the alveoli.

Fluid

A pulmonary contusion is a bruise of the lung tissue caused by trauma. Damaged capillaries can cause blood and other fluids to accumulate in the tissue of the lung, impairing gas exchange.

Pulmonary edema is the buildup of fluid in the parenchyma and alveoli usually caused by left ventricular heart failure, or by damage to the lung or its vasculature.

Anaphylaxis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Anaphylaxis 

 

Anaphylaxis
Other names	Anaphylactoid, anaphylactic shock
Angioedema of the face such that the boy cannot open his eyes. This reaction was caused by an allergen exposure.
Specialty	Allergy and immunology
Symptoms	Itchy rash, throat swelling, shortness of breath, lightheadedness
Usual onset	Over minutes to hours
Causes	Insect bites, foods, medications
Diagnostic method	Based on symptoms
Differential diagnosis	Allergic reaction, angioedema, asthma exacerbation, carcinoid syndrome
Treatment	Epinephrine, intravenous fluids
Frequency	0.05–2%

Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. It typically causes more than one of the following: an itchy rash, throat or tongue swelling, shortness of breath, vomiting, lightheadedness, and low blood pressure. These symptoms typically come on over minutes to hours.

Common causes include insect bites and stings, foods, and medications. Other causes include latex exposure and exercise. Additionally, cases may occur without an obvious reason. The mechanism involves the release of mediators from certain types of white blood cells triggered by either immunologic or non-immunologic mechanisms. Diagnosis is based on the presenting symptoms and signs after exposure to a potential allergen.

The primary treatment of anaphylaxis is epinephrine injection into a muscle, intravenous fluids, and positioning the person flat. Additional doses of epinephrine may be required. Other measures, such as antihistamines and steroids, are complementary. Carrying an epinephrine autoinjector and identification regarding the condition is recommended in people with a history of anaphylaxis.

Worldwide, 0.05–2% of the population is estimated to experience anaphylaxis at some point in life. Rates appear to be increasing. It occurs most often in young people and females. Of people who go to a hospital with anaphylaxis in the United States about 99.7% survive. The term comes from the Ancient Greek: ἀνά, romanized: ana, lit. 'against', and the Ancient Greek: φύλαξις, romanized: phylaxis, lit. 'protection'.

Signs and symptoms

Signs and symptoms of anaphylaxis

Anaphylaxis typically presents many different symptoms over minutes or hours with an average onset of 5 to 30 minutes if exposure is intravenous and 2 hours if from eating food. The most common areas affected include: skin (80–90%), respiratory (70%), gastrointestinal (30–45%), heart and vasculature (10–45%), and central nervous system (10–15%) with usually two or more being involved.

Skin

Urticaria and flushing on the back of a person with anaphylaxis

Symptoms typically include generalized hives, itchiness, flushing, or swelling (angioedema) of the afflicted tissues. Those with angioedema may describe a burning sensation of the skin rather than itchiness. Swelling of the tongue or throat occurs in up to about 20% of cases. Other features may include a runny nose and swelling of the conjunctiva. The skin may also be blue tinged because of lack of oxygen.

Respiratory

Respiratory symptoms and signs that may be present include shortness of breath, wheezes, or stridor. The wheezing is typically caused by spasms of the bronchial muscles while stridor is related to upper airway obstruction secondary to swelling. Hoarseness, pain with swallowing, or a cough may also occur.

Cardiovascular

While a fast heart rate caused by low blood pressure is more common, a Bezold–Jarisch reflex has been described in 10% of people, where a slow heart rate is associated with low blood pressure. A drop in blood pressure or shock (either distributive or cardiogenic) may cause the feeling of lightheadedness or loss of consciousness. Rarely very low blood pressure may be the only sign of anaphylaxis.

Coronary artery spasm may occur with subsequent myocardial infarction, dysrhythmia, or cardiac arrest. Those with underlying coronary disease are at greater risk of cardiac effects from anaphylaxis. The coronary spasm is related to the presence of histamine-releasing cells in the heart.

Other

Gastrointestinal symptoms may include crampy abdominal pain, diarrhea, and vomiting. There may be confusion, a loss of bladder control or pelvic pain similar to that of uterine cramps. Dilation of blood vessels around the brain may cause headaches. A feeling of anxiety or of "impending doom" has also been described.

Causes

Anaphylaxis can occur in response to almost any foreign substance. Common triggers include venom from insect bites or stings, foods, and medication. Foods are the most common trigger in children and young adults while medications and insect bites and stings are more common in older adults. Less common causes include: physical factors, biological agents such as semen, latex, hormonal changes, food additives such as monosodium glutamate and food colors, and topical medications. Physical factors such as exercise (known as exercise-induced anaphylaxis) or temperature (either hot or cold) may also act as triggers through their direct effects on mast cells. Events caused by exercise are frequently associated with the ingestion of certain foods. During anesthesia, neuromuscular blocking agents, antibiotics, and latex are the most common causes. The cause remains unknown in 32–50% of cases, referred to as "idiopathic anaphylaxis." Six vaccines (MMR, varicella, influenza, hepatitis B, tetanus, meningococcal) are recognized as a cause for anaphylaxis, and HPV may cause anaphylaxis as well. Physical exercise is an uncommon cause of anaphylaxis; in about a third of such cases there is a co-factor like taking an NSAID or eating a specific food prior to exercising.

Food

Many foods can trigger anaphylaxis; this may occur upon the first known ingestion. Common triggering foods vary around the world. In Western cultures, ingestion of or exposure to peanuts, wheat, nuts, certain types of seafood like shellfish, milk, and eggs are the most prevalent causes. Sesame is common in the Middle East, while rice and chickpeas are frequently encountered as sources of anaphylaxis in Asia. Severe cases are usually caused by ingesting the allergen, but some people experience a severe reaction upon contact. Children can outgrow their allergies. By age 16, 80% of children with anaphylaxis to milk or eggs and 20% who experience isolated anaphylaxis to peanuts can tolerate these foods.

Medication

Any medication may potentially trigger anaphylaxis. The most common are β-lactam antibiotics (such as penicillin) followed by aspirin and NSAIDs. Other antibiotics are implicated less frequently. Anaphylactic reactions to NSAIDs are either agent specific or occur among those that are structurally similar meaning that those who are allergic to one NSAID can typically tolerate a different one or different group of NSAIDs. Other relatively common causes include chemotherapy, vaccines, protamine and herbal preparations. Some medications (vancomycin, morphine, x-ray contrast among others) cause anaphylaxis by directly triggering mast cell degranulation.

The frequency of a reaction to an agent partly depends on the frequency of its use and partly on its intrinsic properties. Anaphylaxis to penicillin or cephalosporins occurs only after it binds to proteins inside the body with some agents binding more easily than others. Anaphylaxis to penicillin occurs once in every 2,000 to 10,000 courses of treatment, with death occurring in fewer than one in every 50,000 courses of treatment. Anaphylaxis to aspirin and NSAIDs occurs in about one in every 50,000 persons. If someone has a reaction to penicillins, his or her risk of a reaction to cephalosporins is greater but still less than one in 1,000. The old radiocontrast agents caused reactions in 1% of cases, while the newer lower osmolar agents cause reactions in 0.04% of cases.

Venom

Venom from stinging or biting insects such as Hymenoptera (ants, bees, and wasps) or Triatominae (kissing bugs) may cause anaphylaxis in susceptible people. Previous reactions, that are anything more than a local reaction around the site of the sting, are a risk factor for future anaphylaxis; however, half of fatalities have had no previous systemic reaction.

Risk factors

People with atopic diseases such as asthma, eczema, or allergic rhinitis are at high risk of anaphylaxis from food, latex, and radiocontrast agents but not from injectable medications or stings. One study in children found that 60% had a history of previous atopic diseases, and of children who die from anaphylaxis, more than 90% have asthma. Those with mastocytosis or of a higher socioeconomic status are at increased risk. The longer the time since the last exposure to the agent in question, the lower the risk.

Pathophysiology

Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems. It is due to the release of inflammatory mediators and cytokines from mast cells and basophils, typically due to an immunologic reaction but sometimes non-immunologic mechanism.

Immunologic

In the immunologic mechanism, immunoglobulin E (IgE) binds to the antigen (the foreign material that provokes the allergic reaction). Antigen-bound IgE then activates FcεRI receptors on mast cells and basophils. This leads to the release of inflammatory mediators such as histamine. These mediators subsequently increase the contraction of bronchial smooth muscles, trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart muscle depression. There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans.

Non-immunologic

Non-immunologic mechanisms involve substances that directly cause the degranulation of mast cells and basophils. These include agents such as contrast medium, opioids, temperature (hot or cold), and vibration. Sulfites may cause reactions by both immunologic and non-immunologic mechanisms.

Diagnosis

Anaphylaxis is diagnosed on the basis of a person's signs and symptoms. When any one of the following three occurs within minutes or hours of exposure to an allergen there is a high likelihood of anaphylaxis:

1. Involvement of the skin or mucosal tissue plus either respiratory difficulty or a low blood pressure causing symptoms
2. Two or more of the following symptoms after a likely contact with an allergen:

   a. Involvement of the skin or mucosa

   b. Respiratory difficulties

   c. Low blood pressure

   d. Gastrointestinal symptoms

3. Low blood pressure after exposure to a known allergen

Skin involvement may include: hives, itchiness or a swollen tongue among others. Respiratory difficulties may include: shortness of breath, stridor, or low oxygen levels among others. Low blood pressure is defined as a greater than 30% decrease from a person's usual blood pressure. In adults a systolic blood pressure of less than 90 mmHg is often used.

During an attack, blood tests for tryptase or histamine (released from mast cells) might be useful in diagnosing anaphylaxis due to insect stings or medications. However these tests are of limited use if the cause is food or if the person has a normal blood pressure, and they are not specific for the diagnosis.

Classification

There are three main classifications of anaphylaxis. Anaphylactic shock is associated with systemic vasodilation that causes low blood pressure which is by definition 30% lower than the person's baseline or below standard values. Biphasic anaphylaxis is the recurrence of symptoms within 1–72 hours with no further exposure to the allergen. Reports of incidence vary, with some studies claiming as many as 20% of cases. The recurrence typically occurs within 8 hours. It is managed in the same manner as anaphylaxis. Pseudoanaphylaxis or anaphylactoid reactions are a type of anaphylaxis that does not involve an allergic reaction but is due to direct mast cell degranulation. Non-immune anaphylaxis is the current term used by the World Allergy Organization with some recommending that the old terminology no longer be used.

Allergy testing

Skin allergy testing being carried out on the right arm

 

Patch test

Allergy testing may help in determining the trigger. Skin allergy testing is available for certain foods and venoms. Blood testing for specific IgE can be useful to confirm milk, egg, peanut, tree nut and fish allergies.

Skin testing is available to confirm penicillin allergies, but is not available for other medications. Non-immune forms of anaphylaxis can only be determined by history or exposure to the allergen in question, and not by skin or blood testing.

Differential diagnosis

It can sometimes be difficult to distinguish anaphylaxis from asthma, syncope, and panic attacks. Asthma however typically does not entail itching or gastrointestinal symptoms, syncope presents with pallor rather than a rash, and a panic attack may have flushing but does not have hives. Other conditions that may present similarly include: scrombroidosis and anisakiasis.

Post-mortem findings

In a person who died from anaphylaxis, autopsy may show an "empty heart" attributed to reduced venous return from vasodilation and redistribution of intravascular volume from the central to the peripheral compartment. Other signs are laryngeal edema, eosinophilia in lungs, heart and tissues, and evidence of myocardial hypoperfusion. Laboratory findings could detect increased levels of serum tryptase, increase in total and specific IgE serum levels.

Prevention

Avoidance of the trigger of anaphylaxis is recommended. In cases where this may not be possible, desensitization may be an option. Immunotherapy with Hymenoptera venoms is effective at desensitizing 80–90% of adults and 98% of children against allergies to bees, wasps, hornets, yellowjackets, and fire ants. Oral immunotherapy may be effective at desensitizing some people to certain food including milk, eggs, nuts and peanuts; however, adverse effects are common. For example, many people develop an itchy throat, cough, or lip swelling during immunotherapy. Desensitization is also possible for many medications, however it is advised that most people simply avoid the agent in question. In those who react to latex it may be important to avoid cross-reactive foods such as avocados, bananas, and potatoes among others.

Management

Anaphylaxis is a medical emergency that may require resuscitation measures such as airway management, supplemental oxygen, large volumes of intravenous fluids, and close monitoring. Passive leg raise may also be helpful in the emergency management.

Administration of epinephrine is the treatment of choice with antihistamines and steroids (for example, dexamethasone) often used as adjuncts. A period of in-hospital observation for between 2 and 24 hours is recommended for people once they have returned to normal due to concerns of biphasic anaphylaxis.

Epinephrine

An old version of an EpiPen auto-injector

Epinephrine (adrenaline) is the primary treatment for anaphylaxis with no absolute contraindication to its use. It is recommended that an epinephrine solution be given intramuscularly into the mid anterolateral thigh as soon as the diagnosis is suspected. The injection may be repeated every 5 to 15 minutes if there is insufficient response. A second dose is needed in 16–35% of episodes with more than two doses rarely required. The intramuscular route is preferred over subcutaneous administration because the latter may have delayed absorption. Minor adverse effects from epinephrine include tremors, anxiety, headaches, and palpitations.

People on β-blockers may be resistant to the effects of epinephrine. In this situation if epinephrine is not effective intravenous glucagon can be administered which has a mechanism of action independent of β-receptors.

If necessary, it can also be given intravenously using a dilute epinephrine solution. Intravenous epinephrine, however, has been associated both with dysrhythmia and myocardial infarction. Epinephrine autoinjectors used for self-administration typically come in two doses, one for adults or children who weigh more than 25 kg and one for children who weigh 10 to 25 kg.

Adjuncts

Antihistamines (both H1 and H2), while commonly used and assumed effective based on theoretical reasoning, are poorly supported by evidence. A 2007 Cochrane review did not find any good-quality studies upon which to base recommendations and they are not believed to have an effect on airway edema or spasm. Corticosteroids are unlikely to make a difference in the current episode of anaphylaxis, but may be used in the hope of decreasing the risk of biphasic anaphylaxis. Their prophylactic effectiveness in these situations is uncertain. Nebulized salbutamol may be effective for bronchospasm that does not resolve with epinephrine. Methylene blue has been used in those not responsive to other measures due to its presumed effect of relaxing smooth muscle.

Preparedness

People prone to anaphylaxis are advised to have an "allergy action plan." Parents are advised to inform schools of their children's allergies and what to do in case of an anaphylactic emergency. The action plan usually includes use of epinephrine autoinjectors, the recommendation to wear a medical alert bracelet, and counseling on avoidance of triggers. Immunotherapy is available for certain triggers to prevent future episodes of anaphylaxis. A multi-year course of subcutaneous desensitization has been found effective against stinging insects, while oral desensitization is effective for many foods.

Prognosis

In those in whom the cause is known and prompt treatment is available, the prognosis is good. Even if the cause is unknown, if appropriate preventative medication is available, the prognosis is generally good. If death occurs, it is usually due to either respiratory (typically asphyxia) or cardiovascular causes (shock), with 0.7–20% of cases causing death. There have been cases of death occurring within minutes. Outcomes in those with exercise-induced anaphylaxis are typically good, with fewer and less severe episodes as people get older.

Epidemiology

The number of people who get anaphylaxis is 4–100 per 100,000 persons per year, with a lifetime risk of 0.05–2%. About 30% of people get more than one attack. Exercise-induced anaphylaxis affects about 1 in 2000 young people.

Rates appear to be increasing: with the numbers in the 1980s being approximately 20 per 100,000 per year, while in the 1990s it was 50 per 100,000 per year. The increase appears to be primarily for food-induced anaphylaxis. The risk is greatest in young people and females.

Anaphylaxis leads to as many as 500–1,000 deaths per year (2.7 per million) in the United States, 20 deaths per year in the United Kingdom (0.33 per million), and 15 deaths per year in Australia (0.64 per million). Another estimate from the United States puts the death rate at 0.7 per million. Mortality rates have decreased between the 1970s and 2000s. In Australia, death from food-induced anaphylaxis occur primarily in women while deaths due to insect bites primarily occur in males. Death from anaphylaxis is most commonly triggered by medications.

History

The term aphylaxis was coined by Charles Richet in 1902 and later changed to anaphylaxis due to its nicer quality of speech. In his experiments, Richet injected a dog with sea anemone (Actinia) toxin in an attempt to protect it. Although the dog had previously tolerated the toxin, on re-exposure, three weeks later with the same dose, it developed fatal anaphylaxis. Thus instead of inducing tolerance (prophylaxis), when lethal responses resulted from previously tolerated doses, he coined the word a (without) phylaxis (protection). He was subsequently awarded the Nobel Prize in Physiology or Medicine for his work on anaphylaxis in 1913. The phenomenon itself, however, has been described since ancient times. The term comes from the Greek words ἀνά, ana, meaning "against", and φύλαξις, phylaxis, meaning "protection".

Research

There are ongoing efforts to develop sublingual epinephrine to treat anaphylaxis. Subcutaneous injection of the anti-IgE antibody omalizumab is being studied as a method of preventing recurrence, but it is not yet recommended.