Idiopathy

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An idiopathy is any disease with unknown pathogenesis or apparently spontaneous origin.[1]
From Greek idios "one's own" and pathos "suffering", idiopathy means
approximately "a disease of its own kind". For some medical conditions, one or more causes are
somewhat understood, but in a certain percentage of people with the condition, the cause may
not be readily apparent or characterized. In these cases, the origin of the condition is said to be
idiopathic. With some other medical conditions, the root cause for a large percentage of all cases
have not been establishedfor example, focal segmental glomerulosclerosis or ankylosing
spondylitis; the majority of these cases are deemed idiopathic.[2] With other conditions, idiopathic
cases account for only a small percentage (for example, pulmonary fibrosis).[3]
Advances in medical science improve etiology (the study of causes of diseases) and nosology
(the classification of diseases); thus, regarding any particular condition or disease, as more root
causes are discovered, and as events that seemed spontaneous have their origins revealed, the
percentage of cases designated as idiopathic decreases.
The word essential is sometimes synonymous with idiopathic (as in essential proteinuria or
essential thrombocythemia), and the same is true of primary (as in primary biliary cirrhosis or
primary amenorrhea), with the latter term being used in such cases to contrast with secondary in
the sense of "secondary to [i.e., caused by] some other condition." Another, less common
synonym is agnogenic (agno-, "unknown" + -gen, "cause" + -ic). The word cryptogenic (crypto-,
"hidden" + -gen, "cause" + -ic) has a sense that is synonymous with idiopathic[4] and a sense that
is contradistinguished from it.
Some congenital conditions are idiopathic, and sometimes the word congenital is used
synonymously with idiopathic; but careful usage prefers to reserve the word congenital for
conditions to which the literal sense of the word applies (that is, those whose pathophysiology
has existed since the neonatal period).

See also[edit]
Look up idiopathy in Wiktionary, the free dictionary.

Cryptogenic disease

Diagnosis of exclusion

Idiosyncratic drug reaction

Functional disorder

References[edit]
1.

Jump up ^ "Oxford Reference". Concise Medical Dictionary (8 ed.). Retrieved 2014-01-18.

2.

Jump up ^ Daskalakis N, Winn M (2006). "Focal and segmental glomerulosclerosis". Cell Mol
Life Sci 63 (21): 250611. doi:10.1007/s00018-006-6171-y. PMID 16952054.

3.

Jump up ^ "Medical Encyclopedia: Idiopathic pulmonary fibrosis". MedlinePlus. Retrieved

2007-02-13.

4.

Jump up ^ Elsevier, Dorland's Illustrated Medical Dictionary, Elsevier.

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Categories:

Medical terminology

Nosology

Idiopathic diseases

Cancer
From Wikipedia, the free encyclopedia

Jump to: navigation, search

For other uses, see Cancer (disambiguation).

Cancer

A coronal CT scan showing a malignant mesothelioma

Legend: tumor , central pleural effusion, 1 & 3 lungs,
2 spine, 4 ribs, 5 aorta, 6 spleen, 7 & 8 kidneys, 9 liver.
Classification and external resources
Pronunciation

/knsr/

Synonyms

malignant tumor, malignant neoplasm

Specialty

Oncology

ICD-10

C00C97

ICD-9-CM

140239

DiseasesDB

28843

MedlinePlus

001289

MeSH

D009369
[edit on Wikidata]

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or
spread to other parts of the body.[1][2] Not all tumors are cancerous; benign tumors do not spread to
other parts of the body.[2] Possible signs and symptoms include a lump, abnormal bleeding,
prolonged cough, unexplained weight loss and a change in bowel movements.[3] While these
symptoms may indicate cancer, they may have other causes.[3] Over 100 cancers affect humans.[2]
Tobacco use is the cause of about 22% of cancer deaths.[1] Another 10% is due to obesity, poor
diet, lack of physical activity and drinking alcohol.[1][4] Other factors include certain infections,
exposure to ionizing radiation and environmental pollutants.[5] In the developing world nearly
20% of cancers are due to infections such as hepatitis B, hepatitis C and human papillomavirus
(HPV).[1] These factors act, at least partly, by changing the genes of a cell.[6] Typically many
genetic changes are required before cancer develops.[6] Approximately 510% of cancers are due
to inherited genetic defects from a person's parents.[7] Cancer can be detected by certain signs and
symptoms or screening tests.[1] It is then typically further investigated by medical imaging and
confirmed by biopsy.[8]
Many cancers can be prevented by not smoking, maintaining a healthy weight, not drinking too
much alcohol, eating plenty of vegetables, fruits and whole grains, vaccination against certain
infectious diseases, not eating too much processed and red meat, and avoiding too much sunlight
exposure.[9][10] Early detection through screening is useful for cervical and colorectal cancer.[11] The
benefits of screening in breast cancer are controversial.[11][12] Cancer is often treated with some
combination of radiation therapy, surgery, chemotherapy, and targeted therapy.[1][13] Pain and
symptom management are an important part of care. Palliative care is particularly important in
people with advanced disease.[1] The chance of survival depends on the type of cancer and extent
of disease at the start of treatment.[6] In children under 15 at diagnosis the five-year survival rate
in the developed world is on average 80%.[14] For cancer in the United States the average fiveyear survival rate is 66%.[15]
In 2012 about 14.1 million new cases of cancer occurred globally (not including skin cancer
other than melanoma).[6] It caused about 8.2 million deaths or 14.6% of human deaths.[6][16] The
most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and
stomach cancer. In females, the most common types are breast cancer, colorectal cancer, lung
cancer and cervical cancer.[6] If skin cancer other than melanoma were included in total new
cancers each year it would account for around 40% of cases.[17][18] In children, acute lymphoblastic
leukaemia and brain tumors are most common except in Africa where non-Hodgkin lymphoma
occurs more often.[14] In 2012, about 165,000 children under 15 years of age were diagnosed with
cancer. The risk of cancer increases significantly with age and many cancers occur more
commonly in developed countries.[6] Rates are increasing as more people live to an old age and as
lifestyle changes occur in the developing world.[19] The financial costs of cancer were estimated at
$1.16 trillion US dollars per year as of 2010.[20]

Contents
[hide]

1 Definitions

2 Signs and symptoms

o 2.1 Local symptoms
o 2.2 Systemic symptoms
o 2.3 Metastasis

3 Causes
o 3.1 Chemicals
o 3.2 Diet and exercise
o 3.3 Infection
o 3.4 Radiation
o 3.5 Heredity
o 3.6 Physical agents
o 3.7 Hormones

4 Pathophysiology
o 4.1 Genetics
o 4.2 Epigenetics
o 4.3 Metastasis

5 Diagnosis
o 5.1 Classification
o 5.2 Pathology

6 Prevention
o 6.1 Dietary
o 6.2 Medication

o 6.3 Vaccination

7 Screening
o 7.1 Recommendations

7.1.1 U.S. Preventive Services Task Force

7.1.2 Japan

o 7.2 Genetic testing

8 Management
o 8.1 Chemotherapy
o 8.2 Radiation
o 8.3 Surgery
o 8.4 Palliative care
o 8.5 Immunotherapy
o 8.6 Alternative medicine

9 Prognosis

10 Epidemiology

11 History

12 Culture
o 12.1 Economic effect

13 Research

14 Pregnancy

15 Other animals

16 Notes

17 Further reading

18 External links

Definitions
Cancers are a large family of diseases that involve abnormal cell growth with the potential to
invade or spread to other parts of the body.[1][2] They form a subset of neoplasms. A neoplasm or
tumor is a group of cells that have undergone unregulated growth and will often form a mass or
lump, but may be distributed diffusely.[21][22]
All tumor cells show the six hallmarks of cancer. These characteristics are required to produce a
malignant tumor. They include:[23]

Cell growth and division absent the proper signals

Continuous growth and division even given contrary signals

Avoidance of programmed cell death

Limitless number of cell divisions

Promoting blood vessel construction

Invasion of tissue and formation of metastases[24]

The progression from normal cells to cells that can form a detectable mass to outright cancer
involves multiple steps known as malignant progression.[24][25]

Signs and symptoms

Main article: Cancer signs and symptoms

Symptoms of cancer metastasis depend on the location of the tumor.

When cancer begins, it produces no symptoms. Signs and symptoms appear as the mass grows or
ulcerates. The findings that result depend on the cancer's type and location. Few symptoms are
specific. Many frequently occur in individuals who have other conditions. Cancer is a "great
imitator". Thus, it is common for people diagnosed with cancer to have been treated for other
diseases, which were hypothesized to be causing their symptoms.[26]

Local symptoms
Local symptoms may occur due to the mass of the tumor or its ulceration. For example, mass
effects from lung cancer can block the bronchus resulting in cough or pneumonia; esophageal
cancer can cause narrowing of the esophagus, making it difficult or painful to swallow; and
colorectal cancer may lead to narrowing or blockages in the bowel, affecting bowel habits.
Masses in breasts or testicles may produce observable lumps. Ulceration can cause bleeding that,
if it occurs in the lung, will lead to coughing up blood, in the bowels to anemia or rectal
bleeding, in the bladder to blood in the urine and in the uterus to vaginal bleeding. Although
localized pain may occur in advanced cancer, the initial swelling is usually painless. Some
cancers can cause a buildup of fluid within the chest or abdomen.[26]

Systemic symptoms
General symptoms occur due to effects that are not related to direct or metastatic spread. These
may include: unintentional weight loss, fever, excessive fatigue and changes to the skin.[27]
Hodgkin disease, leukemias and cancers of the liver or kidney can cause a persistent fever.[26]
Some cancers may cause specific groups of systemic symptoms, termed paraneoplastic
phenomena. Examples include the appearance of myasthenia gravis in thymoma and clubbing in
lung cancer.[26]

Metastasis
Main article: Metastasis
Cancer can spread from its original site by local spread, lymphatic spread to regional lymph
nodes or by haematogenous spread via the blood to distant sites, known as metastasis. When
cancer spreads by a haematogenous route, it usually spreads all over the body. However, cancer
'seeds' grow in certain selected site only ('soil') as hypothesized in the soil and seed hypothesis of
cancer metastasis. The symptoms of metastatic cancers depend on the tumor location and can
include enlarged lymph nodes (which can be felt or sometimes seen under the skin and are
typically hard), enlarged liver or enlarged spleen, which can be felt in the abdomen, pain or
fracture of affected bones and neurological symptoms.[26]

Causes
Main article: Causes of cancer
The majority of cancers, some 9095% of cases, are due to environmental factors. The remaining
510% are due to inherited genetics.[5] Environmental, as used by cancer researchers, means any
cause that is not inherited genetically, such as lifestyle, economic and behavioral factors and not
merely pollution.[28] Common environmental factors that contribute to cancer death include
tobacco (2530%), diet and obesity (3035%), infections (1520%), radiation (both ionizing and
non-ionizing, up to 10%), stress, lack of physical activity and environmental pollutants.[5]
It is not generally possible to prove what caused a particular cancer, because the various causes
do not have specific fingerprints. For example, if a person who uses tobacco heavily develops
lung cancer, then it was probably caused by the tobacco use, but since everyone has a small
chance of developing lung cancer as a result of air pollution or radiation, the cancer may have
developed for one of those reasons. Excepting the rare transmissions that occur with pregnancies
and occasional organ donors, cancer is generally not a transmissible disease.[29]

Chemicals
Further information: Alcohol and cancer and Smoking and cancer

The incidence of lung cancer is highly correlated with smoking.

Exposure to particular substances have been linked to specific types of cancer. These substances
are called carcinogens.
Tobacco smoke, for example, causes 90% of lung cancer.[30] It also causes cancer in the larynx,
head, neck, stomach, bladder, kidney, esophagus and pancreas.[31] Tobacco smoke contains over
fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.[32]
Tobacco is responsible about one in five cancer deaths worldwide[32] and about one in three in the
developed world[33] Lung cancer death rates in the United States have mirrored smoking patterns,
with increases in smoking followed by dramatic increases in lung cancer death rates and, more
recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death
rates in men since 1990.[34][35]
In Western Europe, 10% of cancers in males and 3% of cancers in females are attributed to
alcohol exposure, especially liver and digestive tract cancers.[36] Cancer from work-related
substance exposures may cause between 220% of cases,[37] causing at least 200,000 deaths.[38]
Cancers such as lung cancer and mesothelioma can come from inhaling tobacco smoke or
asbestos fibers, or leukemia from exposure to benzene.[38]

Diet and exercise

Main article: Diet and cancer
Diet, physical inactivity and obesity are related to up to 3035% of cancer deaths.[5][39] In the
United States excess body weight is associated with the development of many types of cancer
and is a factor in 1420% of cancer deaths.[39] A UK study including data on over 5 million
people showed higher body mass index to be related to at least 10 types of cancer and
responsible for around 12,000 cases each year in that country.[40] Physical inactivity is believed to
contribute to cancer risk, not only through its effect on body weight but also through negative
effects on the immune system and endocrine system.[39] More than half of the effect from diet is
due to overnutrition (eating too much), rather than from eating too few vegetables or other
healthful foods.

Some specific foods are linked to specific cancers. A high-salt diet is linked to gastric cancer.[41]
Aflatoxin B1, a frequent food contaminant, causes liver cancer.[41] Betel nut chewing can cause
oral cancer.[41] National differences in dietary practices may partly explain differences in cancer
incidence. For example, gastric cancer is more common in Japan due to its high-salt diet[42] while
colon cancer is more common in the United States. Immigrant cancer profiles develop mirror
that of their new country, often within one generation.[43]

Infection
Main article: Infectious causes of cancer
Worldwide approximately 18% of cancer deaths are related to infectious diseases.[5] This
proportion ranges from a high of 25% in Africa to less than 10% in the developed world.[5]
Viruses are the usual infectious agents that cause cancer but cancer bacteria and parasites may
also play a role.
Oncoviruses (viruses that can cause cancer) include human papillomavirus (cervical cancer),
EpsteinBarr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's
sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and
hepatitis C viruses (hepatocellular carcinoma) and human T-cell leukemia virus-1 (T-cell
leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter
pylori-induced gastric carcinoma.[44][45] Parasitic infections associated with cancer include
Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes,
Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[46]

Radiation
Main article: Radiation-induced cancer
Up to 10% of invasive cancers are related to radiation exposure, including both ionizing
radiation and non-ionizing ultraviolet radiation.[5] Additionally, the majority of non-invasive
cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation, mostly
from sunlight. Sources of ionizing radiation include medical imaging and radon gas.
Ionizing radiation is not a particularly strong mutagen.[47] Residential exposure to radon gas, for
example, has similar cancer risks as passive smoking.[47] Radiation is a more potent source of
cancer when combined with other cancer-causing agents, such as radon plus tobacco smoke.[47]
Radiation can cause cancer in most parts of the body, in all animals and at any age. Children and
adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation
exposure before birth has ten times the effect.[47]
Medical use of ionizing radiation is a small but growing source of radiation-induced cancers.
Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a
second form of cancer.[47] It is also used in some kinds of medical imaging.[48]

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin
malignancies.[49] Clear evidence establishes ultraviolet radiation, especially the non-ionizing
medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most
common forms of cancer in the world.[49]
Non-ionizing radio frequency radiation from mobile phones, electric power transmission and
other similar sources have been described as a possible carcinogen by the World Health
Organization's International Agency for Research on Cancer.[50] However, studies have not found
a consistent link between mobile phone radiation and cancer risk.[51]

Heredity
Main article: Cancer syndrome
The vast majority of cancers are non-hereditary ("sporadic"). Hereditary cancers are primarily
caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic
mutation that has a large effect on cancer risk and these cause less than 310% of cancer.[52] Some
of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a
more than 75% risk of breast cancer and ovarian cancer,[52] and hereditary nonpolyposis
colorectal cancer (HNPCC or Lynch syndrome), which is present in about 3% of people with
colorectal cancer,[53] among others.

Physical agents
Some substances cause cancer primarily through their physical, rather than chemical, effects.[54] A
prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers
that are a major cause of mesothelioma (cancer of the serous membrane) usually the serous
membrane surrounding the lungs.[54] Other substances in this category, including both naturally
occurring and synthetic asbestos-like fibers, such as wollastonite, attapulgite, glass wool and
rock wool, are believed to have similar effects.[54] Non-fibrous particulate materials that cause
cancer include powdered metallic cobalt and nickel and crystalline silica (quartz, cristobalite and
tridymite).[54] Usually, physical carcinogens must get inside the body (such as through inhalation)
and require years of exposure to produce cancer.[54]
Physical trauma resulting in cancer is relatively rare.[55] Claims that breaking bones resulted in
bone cancer, for example, have not been proven.[55] Similarly, physical trauma is not accepted as a
cause for cervical cancer, breast cancer or brain cancer.[55] One accepted source is frequent, longterm application of hot objects to the body. It is possible that repeated burns on the same part of
the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may
produce skin cancer, especially if carcinogenic chemicals are also present.[55] Frequent
consumption of scalding hot tea may produce esophageal cancer.[55] Generally, it is believed that
the cancer arises, or a pre-existing cancer is encouraged, during the process of healing, rather
than directly by the trauma.[55] However, repeated injuries to the same tissues might promote
excessive cell proliferation, which could then increase the odds of a cancerous mutation.

Chronic inflammation has been hypothesized to directly cause mutation.[55][56] Inflammation can
contribute to proliferation, survival, angiogenesis and migration of cancer cells by influencing
the tumor microenvironment.[57][58] Oncogenes build up an inflammatory pro-tumorigenic
microenvironment.[59]

Hormones
Some hormones play a role in the development of cancer by promoting cell proliferation.[60]
Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation,
differentiation and apoptosis, suggesting possible involvement in carcinogenesis.[61]
Hormones are important agents in sex-related cancers, such as cancer of the breast,
endometrium, prostate, ovary and testis and also of thyroid cancer and bone cancer.[60] For
example, the daughters of women who have breast cancer have significantly higher levels of
estrogen and progesterone than the daughters of women without breast cancer. These higher
hormone levels may explain their higher risk of breast cancer, even in the absence of a breastcancer gene.[60] Similarly, men of African ancestry have significantly higher levels of testosterone
than men of European ancestry and have a correspondingly higher level of prostate cancer.[60]
Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol
glucuronide, have the lowest levels of prostate cancer.[60]
Other factors are relevant: obese people have higher levels of some hormones associated with
cancer and a higher rate of those cancers.[60] Women who take hormone replacement therapy have
a higher risk of developing cancers associated with those hormones.[60] On the other hand, people
who exercise far more than average have lower levels of these hormones and lower risk of
cancer.[60] Osteosarcoma may be promoted by growth hormones.[60] Some treatments and
prevention approaches leverage this cause by artificially reducing hormone levels and thus
discouraging hormone-sensitive cancers.[60]

Pathophysiology
Main article: Carcinogenesis

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell
somewhat.

Genetics
Cancer is fundamentally a disease of tissue growth regulation. In order for a normal cell to
transform into a cancer cell, the genes that regulate cell growth and differentiation must be
altered.[62]
The affected genes are divided into two broad categories. Oncogenes are genes that promote cell
growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and
survival. Malignant transformation can occur through the formation of novel oncogenes, the
inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of
tumor suppressor genes. Typically, changes in multiple genes are required to transform a normal
cell into a cancer cell.[63]
Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an
entire chromosome can occur through errors in mitosis. More common are mutations, which are
changes in the nucleotide sequence of genomic DNA.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic

amplification occurs when a cell gains copies (often 20 or more) of a small chromosomal locus,
usually containing one or more oncogenes and adjacent genetic material. Translocation occurs
when two separate chromosomal regions become abnormally fused, often at a characteristic
location. A well-known example of this is the Philadelphia chromosome, or translocation of
chromosomes 9 and 22, which occurs in chronic myelogenous leukemia and results in production
of the BCR-abl fusion protein, an oncogenic tyrosine kinase.
Small-scale mutations include point mutations, deletions and insertions, which may occur in the
promoter region of a gene and affect its expression, or may occur in the gene's coding sequence
and alter the function or stability of its protein product. Disruption of a single gene may also
result from integration of genomic material from a DNA virus or retrovirus, leading to the
expression of viral oncogenes in the affected cell and its descendants.
Replication of the data contained within the DNA of living cells will probabilistically result in
some errors (mutations). Complex error correction and prevention is built into the process and
safeguards the cell against cancer. If significant error occurs, the damaged cell can self-destruct
through programmed cell death, termed apoptosis. If the error control processes fail, then the
mutations will survive and be passed along to daughter cells.
Some environments make errors more likely to arise and propagate. Such environments can
include the presence of disruptive substances called carcinogens, repeated physical injury, heat,
ionising radiation or hypoxia.[64]
The errors that cause cancer are self-amplifying and compounding, for example:

A mutation in the error-correcting machinery of a cell might cause that cell and its
children to accumulate errors more rapidly.

A further mutation in an oncogene might cause the cell to reproduce more rapidly and
more frequently than its normal counterparts.

A further mutation may cause loss of a tumor suppressor gene, disrupting the apoptosis
signalling pathway and immortalizing the cell.

A further mutation in signaling machinery of the cell might send error-causing signals to
nearby cells.

The transformation of a normal cell into cancer is akin to a chain reaction caused by initial
errors, which compound into more severe errors, each progressively allowing the cell to escape
more controls that limit normal tissue growth. This rebellion-like scenario is an undesirable
survival of the fittest, where the driving forces of evolution work against the body's design and
enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal
evolution, drives progression towards more invasive stages.[65] Clonal evolution leads to intratumour heterogeneity (cancer cells with heterogeneous mutations) that complicates designing
effective treatment strategies.

Characteristic abilities developed by cancers are divided into categories, specifically evasion of
apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained
angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism
and evasion of immune destruction.[24][25]

Epigenetics
Main article: Cancer epigenetics

The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis
The classical view of cancer is a set of diseases that are driven by progressive genetic
abnormalities that include mutations in tumor-suppressor genes and oncogenes and chromosomal
abnormalities. Later epigenetic alterations' role was identified.[66]
Epigenetic alterations refer to functionally relevant modifications to the genome that do not
change the nucleotide sequence. Examples of such modifications are changes in DNA
methylation (hypermethylation and hypomethylation), histone modification[67] and changes in
chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or
HMGA1).[68] Each of these alterations regulates gene expression without altering the underlying
DNA sequence. These changes may remain through cell divisions, last for multiple generations
and can be considered to be epimutations (equivalent to mutations).
Epigenetic alterations occur frequently in cancers. As an example, one study listed protein
coding genes that were frequently altered in their methylation in association with colon cancer.
These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated
genes, 10 were hypermethylated in 100% of colon cancers and many others were
hypermethylated in more than 50% of colon cancers.[69]
While epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes,
causing reduced expression of DNA repair proteins, may be of particular importance. Such

alterations are thought to occur early in progression to cancer and to be a likely cause of the
genetic instability characteristic of cancers.[70][71][72][73]
Reduced expression of DNA repair genes disrupts DNA repair. This is shown in the figure at the
4th level from the top. (In the figure, red wording indicates the central role of DNA damage and
defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damage
remains in cells at a higher than usual level (5th level) and cause increased frequencies of
mutation and/or epimutation (6th level). Mutation rates increase substantially in cells defective in
DNA mismatch repair[74][75] or in homologous recombinational repair (HRR).[76] Chromosomal
rearrangements and aneuploidy also increase in HRR defective cells.[77]
Higher levels of DNA damage cause increased mutation (right side of figure) and increased
epimutation. During repair of DNA double strand breaks, or repair of other DNA damage,
incompletely cleared repair sites can cause epigenetic gene silencing.[78][79]
Deficient expression of DNA repair proteins due to an inherited mutation can increase cancer
risks. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA
repair-deficiency disorder) have increased cancer risk, with some defects ensuring a 100%
lifetime chance of cancer (e.g. p53 mutations).[80] Germ line DNA repair mutations are noted on
the figure's left side. However, such germline mutations (which cause highly penetrant cancer
syndromes) are the cause of only about 1 percent of cancers.[81]
In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA
repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence
expression of DNA repair genes. This is indicated in the figure at the 3rd level. Many studies of
heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression
of DNA repair enzymes, some through epigenetic mechanisms. DNA repair inhibition is
proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition,
frequent epigenetic alterations of the DNA sequences code for small RNAs called microRNAs
(or miRNAs). MiRNAs do not code for proteins, but can "target" protein-coding genes and
reduce their expression.
Cancers usually arise from an assemblage of mutations and epimutations that confer a selective
advantage leading to clonal expansion (see Field defects in progression to cancer). Mutations,
however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the
breast or colon can have about 60 to 70 protein-altering mutations, of which about three or four
may be "driver" mutations and the remaining ones may be "passenger" mutations.[82]

Metastasis
Main article: Metastasis
Metastasis is the spread of cancer to other locations in the body. The dispersed tumors are called
metastatic tumors, while the original is called the primary tumor. Almost all cancers can
metastasize.[83] Most cancer deaths are due to cancer that has metastasized.[84]

Metastasis is common in the late stages of cancer and it can occur via the blood or the lymphatic
system or both. The typical steps in metastasis are local invasion, intravasation into the blood or
lymph, circulation through the body, extravasation into the new tissue, proliferation and
angiogenesis. Different types of cancers tend to metastasize to particular organs, but overall the
most common places for metastases to occur are the lungs, liver, brain and the bones.[83]

Diagnosis

Chest x-ray showing lung cancer in the left lung

Most cancers are initially recognized either because of the appearance of signs or symptoms or
through screening. Neither of these lead to a definitive diagnosis, which requires the examination
of a tissue sample by a pathologist. People with suspected cancer are investigated with medical
tests. These commonly include blood tests, X-rays, CT scans and endoscopy.
People may become extremely anxious and depressed post-diagnosis. The risk of suicide in
people with cancer is approximately double the normal risk.[85]

Classification
Further information: List of cancer types and List of oncology-related terms
Cancers are classified by the type of cell that the tumor cells resemble and is therefore presumed
to be the origin of the tumor. These types include:

Carcinoma: Cancers derived from epithelial cells. This group includes many of the most
common cancers and include nearly all those in the breast, prostate, lung, pancreas and
colon.

Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage, fat, nerve), each of
which develops from cells originating in mesenchymal cells outside the bone marrow.

Lymphoma and leukemia: These two classes arise from hematopoietic (blood-forming)
cells that leave the marrow and tend to mature in the lymph nodes and blood,
respectively.[86]

Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the
testicle or the ovary (seminoma and dysgerminoma, respectively).

Blastoma: Cancers derived from immature "precursor" cells or embryonic tissue.

Cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin
or Greek word for the organ or tissue of origin as the root. For example, cancers of the liver
parenchyma arising from malignant epithelial cells is called hepatocarcinoma, while a
malignancy arising from primitive liver precursor cells is called a hepatoblastoma and a cancer
arising from fat cells is called a liposarcoma. For some common cancers, the English organ name
is used. For example, the most common type of breast cancer is called ductal carcinoma of the
breast. Here, the adjective ductal refers to the appearance of the cancer under the microscope,
which suggests that it has originated in the milk ducts.
Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as
the root. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the
common name of this frequently occurring benign tumor in the uterus is fibroid). Confusingly,
some types of cancer use the -noma suffix, examples including melanoma and seminoma.
Some types of cancer are named for the size and shape of the cells under a microscope, such as
giant cell carcinoma, spindle cell carcinoma and small-cell carcinoma.

Pathology
The tissue diagnosis from the biopsy indicates the type of cell that is proliferating, its histological
grade, genetic abnormalities and other features. Together, this information is useful to evaluate
the prognosis of the patient and to choose the best treatment. Cytogenetics and
immunohistochemistry are other types of tissue tests. These tests may provide information about
molecular changes (such as mutations, fusion genes and numerical chromosome changes) and
may thus also indicate the prognosis and best treatment.

An invasive ductal carcinoma of the breast (pale area at the center) surrounded by spikes
of whitish scar tissue and yellow fatty tissue


An invasive colorectal carcinoma (top center) in a colectomy specimen

A squamous-cell carcinoma (the whitish tumor) near the bronchi in a lung specimen

A large invasive ductal carcinoma in a mastectomy specimen

Prevention
Main article: Cancer prevention
Cancer prevention is defined as active measures to decrease cancer risk.[87] The vast majority of
cancer cases are due to environmental risk factors. Many of these environmental factors are
controllable lifestyle choices. Thus, cancer is generally preventable.[88] Between 70% and 90% of
common cancers are due to environmental factors and therefore potentially preventable.[89]
Greater than 30% of cancer deaths could be prevented by avoiding risk factors including:
tobacco, excess weight/obesity, insufficient diet, physical inactivity, alcohol, sexually
transmitted infections and air pollution.[90] Not all environmental causes are controllable, such as
naturally occurring background radiation and cancers caused through hereditary genetic
disorders and thus are not preventable via personal behavior.

Dietary
Main article: Diet and cancer

While many dietary recommendations have been proposed to reduce cancer risks, the evidence to
support them is not definitive.[9][91] The primary dietary factors that increase risk are obesity and
alcohol consumption. Diets low in fruits and vegetables and high in red meat have been
implicated but reviews and meta-analyses do not come to a consistent conclusion.[92][93] A 2014
meta-analysis find no relationship between fruits and vegetables and cancer.[94] Coffee is
associated with a reduced risk of liver cancer.[95] Studies have linked excess consumption of red
or processed meat to an increased risk of breast cancer, colon cancer and pancreatic cancer, a
phenomenon that could be due to the presence of carcinogens in meats cooked at high
temperatures.[96][97] In 2015 the IARC reported that eating processed meat (e.g., bacon, ham, hot
dogs, sausages) and, to a lesser degree, red meat was linked to some cancers.[98][99]
Dietary recommendations for cancer prevention typically include an emphasis on vegetables,
fruit, whole grains and fish and an avoidance of processed and red meat (beef, pork, lamb),
animal fats and refined carbohydrates.[9][91]

Medication
Medications can be used to prevent cancer in a few circumstances.[100] In the general population,
NSAIDs reduce the risk of colorectal cancer, however due to cardiovascular and gastrointestinal
side effects they cause overall harm when used for prevention.[101] Aspirin has been found to
reduce the risk of death from cancer by about 7%.[102] COX-2 inhibitors may decrease the rate of
polyp formation in people with familial adenomatous polyposis, however it is associated with the
same adverse effects as NSAIDs.[103] Daily use of tamoxifen or raloxifene reduce the risk of breast
cancer in high-risk women.[104] The benefit versus harm for 5-alpha-reductase inhibitor such as
finasteride is not clear.[105]
Vitamins are not effective at preventing cancer,[106] although low blood levels of vitamin D are
correlated with increased cancer risk.[107][108] Whether this relationship is causal and vitamin D
supplementation is protective is not determined.[109] Beta-carotene supplementation increases lung
cancer rates in those who are high risk.[110] Folic acid supplementation is not effective in
preventing colon cancer and may increase colon polyps.[111] It is unclear if selenium
supplementation has an effect.[112]

Vaccination
Vaccines have been developed that prevent infection by some carcinogenic viruses.[113] Human
papillomavirus vaccine (Gardasil and Cervarix) decrease the risk of developing cervical cancer.
[113]
The hepatitis B vaccine prevents infection with hepatitis B virus and thus decreases the risk of
liver cancer.[113] The administration of human papillomavirus and hepatitis B vaccinations is
recommended when resources allow.[114]

Screening
Main article: Cancer screening

Unlike diagnostic efforts prompted by symptoms and medical signs, cancer screening involves
efforts to detect cancer after it has formed, but before any noticeable symptoms appear.[115] This
may involve physical examination, blood or urine tests or medical imaging.[115]
Cancer screening is not available for many types of cancers. Even when tests are available, they
may not be recommended for everyone. Universal screening or mass screening involves
screening everyone.[116] Selective screening identifies people who are at higher risk, such as
people with a family history.[116] Several factors are considered to determine whether the benefits
of screening outweigh the risks and the costs of screening.[115] These factors include:

Possible harms from the screening test: for example, X-ray images involve exposure to
potentially harmful ionizing radiation

The likelihood of the test correctly identifying cancer

The likelihood that cancer is present: Screening is not normally useful for rare cancers.

Possible harms from follow-up procedures

Whether suitable treatment is available

Whether early detection improves treatment outcomes

Whether the cancer will ever need treatment

Whether the test is acceptable to the people: If a screening test is too burdensome (for
example, extremely painful), then people will refuse to participate.[116]

Cost

Recommendations
U.S. Preventive Services Task Force
The U.S. Preventive Services Task Force (USPSTF) issues recommendations for various cancers:

Strongly recommends cervical cancer screening in women who are sexually active and
have a cervix at least until the age of 65.[117]

Recommend that Americans be screened for colorectal cancer via fecal occult blood
testing, sigmoidoscopy, or colonoscopy starting at age 50 until age 75.[118]

Evidence is insufficient to recommend for or against screening for skin cancer,[119] oral
cancer,[120] lung cancer,[121] or prostate cancer in men under 75.[122]

Routine screening is not recommended for bladder cancer,[123] testicular cancer,[124] ovarian
cancer,[125] pancreatic cancer,[126] or prostate cancer.[127]

Recommends mammography for breast cancer screening every two years from ages 50
74. Do not recommend either breast self-examination or clinical breast examination.[128] (A
2011 Cochrane review came to slightly different conclusions with respect to breast cancer
screening stating that routine mammography may do more harm than good.[129])

Japan
Screens for gastric cancer using photofluorography due to the high incidence there.[19]

Genetic testing
See also: Cancer syndrome
Gene
BRCA1, BRCA2
HNPCC, MLH1, MSH2, MSH6, PMS1,
PMS2

Cancer types
Breast, ovarian, pancreatic
Colon, uterine, small bowel, stomach, urinary
tract

Genetic testing for individuals at high-risk of certain cancers is recommended by unofficial

groups.[114][130] Carriers of these mutations may then undergo enhanced surveillance,
chemoprevention, or preventative surgery to reduce their subsequent risk.[130]

Management
Main articles: Management of cancer and oncology
Many treatment options for cancer exist. The primary ones include surgery, chemotherapy,
radiation therapy, hormonal therapy, targeted therapy and palliative care. Which treatments are
used depends on the type, location and grade of the cancer as well as the patient's health and
preferences. The treatment intent may or may not be curative.

Chemotherapy
Chemotherapy is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs
(chemotherapeutic agents) as part of a standardized regimen. The term encompasses a variety of
drugs, which are divided into broad categories such as alkylating agents and antimetabolites.[131]
Traditional chemotherapeutic agents act by killing cells that divide rapidly, a critical property of
most cancer cells.
Targeted therapy is a form of chemotherapy that targets specific molecular differences between
cancer and normal cells. The first targeted therapies blocked the estrogen receptor molecule,
inhibiting the growth of breast cancer. Another common example is the class of Bcr-Abl
inhibitors, which are used to treat chronic myelogenous leukemia (CML).[132] Currently, targeted

therapies exist for breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and
other cancers.[133]
The efficacy of chemotherapy depends on the type of cancer and the stage. In combination with
surgery, chemotherapy has proven useful in cancer types including breast cancer, colorectal
cancer, pancreatic cancer, osteogenic sarcoma, testicular cancer, ovarian cancer and certain lung
cancers.[134] Chemotherapy is curative for some cancers, such as some leukemias,[135][136] ineffective
in some brain tumors,[137] and needless in others, such as most non-melanoma skin cancers.[138] The
effectiveness of chemotherapy is often limited by its toxicity to other tissues in the body. Even
when chemotherapy does not provide a permanent cure, it may be useful to reduce symptoms
such as pain or to reduce the size of an inoperable tumor in the hope that surgery will become
possible in the future.

Radiation
Radiation therapy involves the use of ionizing radiation in an attempt to either cure or improve
symptoms. It works by damaging the DNA of cancerous tissue, killing it. To spare normal tissues
(such as skin or organs, which radiation must pass through to treat the tumor), shaped radiation
beams are aimed from multiple exposure angles to intersect at the tumor, providing a much larger
dose there than in the surrounding, healthy tissue. As with chemotherapy, cancers vary in their
response to radiation therapy.[139][140][141]
Radiation therapy is used in about half of cases. The radiation can be either from internal sources
(brachytherapy) or external sources. The radiation is most commonly low energy x-rays for
treating skin cancers, while higher energy x-rays are used for cancers within the body.[142]
Radiation is typically used in addition to surgery and or chemotherapy. For certain types of
cancer, such as early head and neck cancer, it may be used alone.[143] For painful bone metastasis,
it has been found to be effective in about 70% of patients.[143]

Surgery
Surgery is the primary method of treatment for most isolated, solid cancers and may play a role
in palliation and prolongation of survival. It is typically an important part of definitive diagnosis
and staging of tumors, as biopsies are usually required. In localized cancer, surgery typically
attempts to remove the entire mass along with, in certain cases, the lymph nodes in the area. For
some types of cancer this is sufficient to eliminate the cancer.[134]

Palliative care
Palliative care refers to treatment that attempts to help the patient feel better and may be
combined with an attempt to treat the cancer. Palliative care includes action to reduce physical,
emotional, spiritual and psycho-social distress. Unlike treatment that is aimed at directly killing
cancer cells, the primary goal of palliative care is to improve quality of life.

People at all stages of cancer treatment typically receive some kind of palliative care. In some
cases, medical specialty professional organizations recommend that patients and physicians
respond to cancer only with palliative care.[144] This applies to patients who:[145]
1. display low performance status, implying limited ability to care for themselves[144]
2. received no benefit from prior evidence-based treatments[144]
3. are not eligible to participate in any appropriate clinical trial[144]
4. no strong evidence implies that treatment would be effective[144]
Palliative care may be confused with hospice and therefore only indicated when people approach
end of life. Like hospice care, palliative care attempts to help the patient cope with their
immediate needs and to increase comfort. Unlike hospice care, palliative care does not require
people to stop treatment aimed.
Multiple national medical guidelines recommend early palliative care for patients whose cancer
has produced distressing symptoms or who need help coping with their illness. In patients first
diagnosed with metastatic disease, palliative care may be immediately indicated. Palliative care
is indicated for patients with a prognosis of less than 12 months of life even given aggressive
treatment.[146][147][148]

Immunotherapy
Main article: Cancer immunotherapy
A variety of therapies using immunotherapy, stimulating or helping the immune system to fight
cancer, have come into use since 1997. Approaches include antibodies, checkpoint therapy and
adoptive cell transfer.[149]

Alternative medicine
Complementary and alternative cancer treatments are a diverse group of therapies, practices and
products that are not part of conventional medicine.[150] "Complementary medicine" refers to
methods and substances used along with conventional medicine, while "alternative medicine"
refers to compounds used instead of conventional medicine.[151] Most complementary and
alternative medicines for cancer have not been studied or tested using conventional techniques
such as clinical trials. Some alternative treatments have been investigated and shown to be
ineffective but still continue to be marketed and promoted. Cancer researcher Andrew J. Vickers
stated, "The label 'unproven' is inappropriate for such therapies; it is time to assert that many
alternative cancer therapies have been 'disproven'."[152]

Prognosis
See also: List of cancer mortality rates in the United States and Cancer survivor

Survival rates vary by cancer type and by the stage at which it is diagnosed, ranging from
majority survival to complete mortality five years after diagnosis. Once a cancer has
metastasized, prognosis normally becomes much worse.About half of patients receiving
treatment for invasive cancer (excluding carcinoma in situ and non-melanoma skin cancers) die
from that cancer or its treatment.[19]
Survival is worse in the developing world,[19] partly because the types of cancer that are most
common there are harder to treat than those associated with developed countries.[153]
Those who survive cancer develop a second primary cancer at about twice the rate of those never
diagnosed.[154] The increased risk is believed to be primarily due to the same risk factors that
produced the first cancer, partly due to treatment of the first cancer and to better compliance with
screening.[154]
Predicting short- or long-term survival depends on many factors. The most important are the
cancer type and the patient's age and overall health. Those who are frail with other health
problems have lower survival rates than otherwise healthy people. Centenarians are unlikely to
survive for five years even if treatment is successful. People who report a higher quality of life
tend to survive longer.[155] People with lower quality of life may be affected by depression and
other complications and/or disease progression that both impairs quality and quantity of life.
Additionally, patients with worse prognoses may be depressed or report poorer quality of life
because they perceive that their condition is likely to be fatal.
Cancer patients have an increased risk of blood clots in veins. The use of heparin appears to
improve survival and decrease the risk of blood clots.[156]

Epidemiology
Main article: Epidemiology of cancer
See also: List of countries by cancer rate

Death rate adjusted for age for malignant cancer per 100,000 inhabitants in 2004[157]
no data
180205
55
205230
5580
230255
80105
255280
105130
280305
130155
305
155180

In 2008, approximately 12.7 million cancers were diagnosed (excluding non-melanoma skin
cancers and other non-invasive cancers)[19] and in 2010 nearly 7.98 million people died.[158]
Cancers account for approximately 13% of deaths. The most common are lung cancer (1.4
million deaths), stomach cancer (740,000), liver cancer (700,000), colorectal cancer (610,000)
and breast cancer (460,000).[159] This makes invasive cancer the leading cause of death in the
developed world and the second leading in the developing world.[19] Over half of cases occur in
the developing world.[19]
Deaths from cancer were 5.8 million in 1990.[158] Deaths have been increasing primarily due to
longer lifespans and lifestyle changes in the developing world.[19] The most significant risk factor
for developing cancer is age.[160] Although it is possible for cancer to strike at any age, most
patients with invasive cancer are over 65.[160] According to cancer researcher Robert A. Weinberg,
"If we lived long enough, sooner or later we all would get cancer."[161] Some of the association
between aging and cancer is attributed to immunosenescence,[162] errors accumulated in DNA
over a lifetime[163] and age-related changes in the endocrine system.[164] Aging's effect on cancer is
complicated by factors such as DNA damage and inflammation promoting it and factors such as
vascular aging and endocrine changes inhibiting it.[165]
Some slow-growing cancers are particularly common, but often are not fatal. Autopsy studies in
Europe and Asia showed that up to 36% of people have undiagnosed and apparently harmless
thyroid cancer at the time of their deaths and that 80% of men develop prostate cancer by age 80.
[166][167]
As these cancers do not cause the patient's death, identifying them would have represented
overdiagnosis rather than useful medical care.
The three most common childhood cancers are leukemia (34%), brain tumors (23%) and
lymphomas (12%).[168] In the United States cancer affects about 1 in 285 children.[169] Rates of
childhood cancer increased by 0.6% per year between 1975 and 2002 in the United States[170] and
by 1.1% per year between 1978 and 1997 in Europe.[168] Death from childhood cancer decreased
by half since 1975 in the United States.[169]

History
Main article: History of cancer

Engraving with two views of a Dutch woman who had a tumor removed from her neck in 1689
Cancer has existed for all of human history.[171] The earliest written record regarding cancer is
from circa 1600 BC in the Egyptian Edwin Smith Papyrus and describes breast cancer.[171]
Hippocrates (ca. 460 BC ca. 370 BC) described several kinds of cancer, referring to them with

the Greek word karkinos (crab or crayfish).[171] This name comes from the appearance of
the cut surface of a solid malignant tumor, with "the veins stretched on all sides as the animal the
crab has its feet, whence it derives its name".[172] Galen stated that "cancer of the breast is so
called because of the fancied resemblance to a crab given by the lateral prolongations of the
tumor and the adjacent distended veins".[173]:738 Celsus (ca. 25 BC 50 AD) translated karkinos
into the Latin cancer, also meaning crab and recommended surgery as treatment.[171] Galen (2nd
century AD) disagreed with the use of surgery and recommended purgatives instead.[171] These
recommendations largely stood for 1000 years.[171]
In the 15th, 16th and 17th centuries, it became acceptable for doctors to dissect bodies to
discover the cause of death.[174] The German professor Wilhelm Fabry believed that breast cancer
was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a
follower of Descartes, believed that all disease was the outcome of chemical processes and that
acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer
was a poison that slowly spreads and concluded that it was contagious.[175]
The physician John Hill described tobacco snuff as the cause of nose cancer in 1761.[174] This was
followed by the report in 1775 by British surgeon Percivall Pott that chimney sweeps' carcinoma,
a cancer of the scrotum, was a common disease among chimney sweeps.[176] With the widespread
use of the microscope in the 18th century, it was discovered that the 'cancer poison' spread from
the primary tumor through the lymph nodes to other sites ("metastasis"). This view of the disease
was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874.[177]

Culture
Though many diseases (such as heart failure) may have a worse prognosis than most cases of
cancer, cancer is the subject of widespread fear and taboos. The euphemism "after a long illness"
is still commonly used (2012), reflecting an apparent stigma.[178] This deep belief that cancer is
necessarily a difficult and usually deadly disease is reflected in the systems chosen by society to
compile cancer statistics: the most common form of cancernon-melanoma skin cancers,
accounting for about one-third of cancer cases worldwide, but very few deaths[179][180]are
excluded from cancer statistics specifically because they are easily treated and almost always
cured, often in a single, short, outpatient procedure.[181]
Cancer is regarded as a disease that must be "fought" to end the "civil insurrection"; a War on
Cancer was declared in the US. Military metaphors are particularly common in descriptions of
cancer's human effects and they emphasize both the state of the patient's health and the need to
take immediate, decisive actions himself, rather than to delay, to ignore, or to rely entirely on
others. The military metaphors also help rationalize radical, destructive treatments.[182][183]
In the 1970s, a relatively popular alternative cancer treatment in the US was a specialized form
of talk therapy, based on the idea that cancer was caused by a bad attitude.[184] People with a
"cancer personality"depressed, repressed, self-loathing and afraid to express their emotions
were believed to have manifested cancer through subconscious desire. Some psychotherapists
said that treatment to change the patient's outlook on life would cure the cancer.[184] Among other
effects, this belief allowed society to blame the victim for having caused the cancer (by

"wanting" it) or having prevented its cure (by not becoming a sufficiently happy, fearless and
loving person).[185] It also increased patients' anxiety, as they incorrectly believed that natural
emotions of sadness, anger or fear shorten their lives.[185] The idea was ridiculed by Susan Sontag,
who published Illness as Metaphor while recovering from treatment for breast cancer in 1978.[184]
Although the original idea is now generally regarded as nonsense, the idea partly persists in a
reduced form with a widespread, but incorrect, belief that deliberately cultivating a habit of
positive thinking will increase survival.[185] This notion is particularly strong in breast cancer
culture.[185]
One idea about why people with cancer are blamed or stigmatized, called the just-world
hypothesis, is that blaming cancer on the patient's actions or attitudes allows the blamers to
regain a sense of control. This is based upon the blamers' belief that the world is fundamentally
just and so any dangerous illness, like cancer, must be a type of punishment for bad choices,
because in a just world, bad things would not happen to good people.[186]

Economic effect
In 2007, the overall costs of cancer in the USincluding treatment and indirect mortality
expenses (such as lost productivity in the workplace) was estimated to be $226.8 billion. In
2009, 32% of Hispanics and 10% of children 17 years old or younger lacked health insurance;
"uninsured patients and those from ethnic minorities are substantially more likely to be
diagnosed with cancer at a later stage, when treatment can be more extensive and more
costly."[187]

Research
Main article: Cancer research

University of Florida Cancer Hospital

Because cancer is a class of diseases,[188][189] it is unlikely that there will ever be a single "cure for
cancer" any more than there will be a single treatment for all infectious diseases.[190] Angiogenesis
inhibitors were once incorrectly thought to have potential as a "silver bullet" treatment applicable
to many types of cancer.[191] Angiogenesis inhibitors and other cancer therapeutics are used in
combination to reduce cancer morbidity and mortality.[192]
Experimental cancer treatments are studied in clinical trials to compare the proposed treatment to
the best existing treatment. Treatments that succeeded in one cancer type can be tested against

other types.[193] Diagnostic tests are under development to better target the right therapies to the
right patients, based on their individual biology.[194]
Cancer research focuses on the following issues:

Agents (e.g. viruses) and events (e.g. mutations) that cause or facilitate genetic changes
in cells destined to become cancer.

The precise nature of the genetic damage and the genes that are affected by it.

The consequences of those genetic changes on the biology of the cell, both in generating
the defining properties of a cancer cell and in facilitating additional genetic events that
lead to further progression of the cancer.

The improved understanding of molecular biology and cellular biology due to cancer research
has led to new treatments for cancer since US President Richard Nixon declared the "War on
Cancer" in 1971. Since then, the country has spent over $200 billion on cancer research,
including resources from public and private sectors.[195] The cancer death rate (adjusting for size
and age of the population) declined by five percent between 1950 and 2005.[196]
Competition for financial resources appears to have suppressed the creativity, cooperation, risktaking and original thinking required to make fundamental discoveries, unduly favoring low-risk
research into small incremental advancements over riskier, more innovative research. Other
consequences of competition appear to be many studies with dramatic claims whose results
cannot be replicated and perverse incentives that encourage grantee institutions to grow without
making sufficient investments in their own faculty and facilities.[197][198][199]

Pregnancy
Cancer affects approximately 1 in 1,000 pregnant women. The most common cancers found
during pregnancy are the same as the most common cancers found in non-pregnant women
during childbearing ages: breast cancer, cervical cancer, leukemia, lymphoma, melanoma,
ovarian cancer and colorectal cancer.[200]
Diagnosing a new cancer in a pregnant woman is difficult, in part because any symptoms are
commonly assumed to be a normal discomfort associated with pregnancy. As a result, cancer is
typically discovered at a somewhat later stage than average. Some imaging procedures, such as
MRIs (magnetic resonance imaging), CT scans, ultrasounds and mammograms with fetal
shielding are considered safe during pregnancy; some others, such as PET scans, are not.[200]
Treatment is generally the same as for non-pregnant women. However, radiation and radioactive
drugs are normally avoided during pregnancy, especially if the fetal dose might exceed 100 cGy.
In some cases, some or all treatments are postponed until after birth if the cancer is diagnosed
late in the pregnancy. Early deliveries are often used to advance the start of treatment. Surgery is
generally safe, but pelvic surgeries during the first trimester may cause miscarriage. Some

treatments, especially certain chemotherapy drugs given during the first trimester, increase the
risk of birth defects and pregnancy loss (spontaneous abortions and stillbirths).[200]
Elective abortions are not required and, for the most common forms and stages of cancer, do not
improve the mother's survival. In a few instances, such as advanced uterine cancer, the
pregnancy cannot be continued and in others, the patient may end the pregnancy so that she can
begin aggressive chemotherapy.[200]
Some treatments can interfere with the mother's ability to give birth vaginally or to breastfeed.[200]
Cervical cancer may require birth by Caesarean section. Radiation to the breast reduces the
ability of that breast to produce milk and increases the risk of mastitis. Also, when chemotherapy
is given after birth, many of the drugs appear in breast milk, which could harm the baby.[200]

Other animals
Veterinary oncology, concentrating mainly on cats and dogs, is a growing specialty in wealthy
countries and the major forms of human treatment such as surgery and radiotherapy may be
offered. The most common types of cancer differ, but the cancer burden seems at least as high in
pets as in humans. Animals, typically rodents, are often used in cancer research and studies of
natural cancers in larger animals may benefit research into human cancer.[201]
In non-humans, a few types of transmissible cancer have been described, wherein the cancer
spreads between animals by transmission of the tumor cells themselves. This phenomenon is
seen in dogs with Sticker's sarcoma, also known as canine transmissible venereal tumor.[202]

Notes
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^ Jump up to: a b c d e f g h "Cancer Fact sheet N297". World Health Organization. February 2014.
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2.

^ Jump up to: a b c d "Defining Cancer". National Cancer Institute. Retrieved 10 June 2014.

3.

^ Jump up to: a b "Cancer - Signs and symptoms". NHS Choices. Retrieved 10 June 2014.

4.

Jump up ^ "Obesity and Cancer Risk". National Cancer Institute. January 3, 2012. Retrieved 4
July 2015.

5.

^ Jump up to: a b c d e f g Anand P, Kunnumakkara AB, Kunnumakara AB, Sundaram C, Harikumar

KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (September 2008). "Cancer is a preventable disease that
requires major lifestyle changes". Pharm. Res. 25 (9): 2097116. doi:10.1007/s11095-008-9661-9.
PMC 2515569. PMID 18626751.

6.

^ Jump up to: a b c d e f g World Cancer Report 2014. World Health Organization. 2014. pp. Chapter
1.1. ISBN 9283204298.

7.

Jump up ^ "Heredity and Cancer". American Cancer Society. Retrieved July 22, 2013.

8.

Jump up ^ "How is cancer diagnosed?". American Cancer Society. 2013-01-29. Retrieved 10

June 2014.

9.

^ Jump up to: a b c Kushi LH, Doyle C, McCullough M, et al. (2012). "American Cancer Society
Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with
healthy food choices and physical activity". CA Cancer J Clin 62 (1): 3067. doi:10.3322/caac.20140.
PMID 22237782.

10.

Jump up ^ Parkin, DM; Boyd, L; Walker, LC (6 December 2011). "16. The fraction of cancer
attributable to lifestyle and environmental factors in the UK in 2010.". British Journal of Cancer. 105
Suppl 2: S7781. doi:10.1038/bjc.2011.489. PMC 3252065. PMID 22158327.

11.

^ Jump up to: a b World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 4.7.
ISBN 9283204298.

12.

Jump up ^ Gtzsche PC, Jrgensen KJ (4 Jun 2013). "Screening for breast cancer with
mammography.". The Cochrane database of systematic reviews 6: CD001877.
doi:10.1002/14651858.CD001877.pub5. PMID 23737396.

13.

Jump up ^ "Targeted Cancer Therapies". NCI. 2014-04-25. Retrieved 11 June 2014.

14.

^ Jump up to: a b World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 1.3.
ISBN 9283204298.

15.

Jump up ^ "SEER Stat Fact Sheets: All Cancer Sites". National Cancer Institute. Retrieved 18
June 2014.

16.

Jump up ^ "The top 10 causes of death Fact sheet N310". WHO. May 2014. Retrieved 10 June
2014.

17.

Jump up ^ Dubas, LE; Ingraffea, A (Feb 2013). "Nonmelanoma skin cancer.". Facial plastic
surgery clinics of North America 21 (1): 4353. doi:10.1016/j.fsc.2012.10.003. PMID 23369588.

18.

Jump up ^ Cakir, B; Adamson, P; Cingi, C (Nov 2012). "Epidemiology and economic burden of
nonmelanoma skin cancer.". Facial plastic surgery clinics of North America 20 (4): 41922.
doi:10.1016/j.fsc.2012.07.004. PMID 23084294.

19.

^ Jump up to: a b c d e f g h Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (February
2011). "Global cancer statistics". CA: a cancer journal for clinicians 61 (2): 6990.
doi:10.3322/caac.20107. PMID 21296855.

20.

Jump up ^ World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 6.7.
ISBN 9283204298.

21.

Jump up ^ "Cancer Glossary". cancer.org. American Cancer Society. Retrieved September 11,
2013.

22.

Jump up ^ "What is cancer?". cancer.gov. National Cancer Institute. Retrieved September 11,
2013.

23.

Jump up ^ Hanahan, D; Weinberg, RA (7 January 2000). "The hallmarks of cancer.". Cell 100
(1): 5770. doi:10.1016/s0092-8674(00)81683-9. PMID 10647931.

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References

Holland, James F. (2009). Holland-Frei cancer medicine. (8th ed.). New York: McGrawHill Medical. ISBN 978-1-60795-014-1.

Further reading

Kleinsmith, Lewis J. (2006). Principles of cancer biology. Pearson Benjamin Cummings.

ISBN 978-0-8053-4003-7.

Mukherjee, Siddhartha (16 November 2010). The Emperor of All Maladies: A Biography
of Cancer. Simon & Schuster. ISBN 978-1-4391-0795-9. Retrieved August 7, 2013.

Pazdur, Richard; et al. (May 2009). Cancer Management: A Multidisciplinary Approach.

Cmp United Business Media. ISBN 978-1-891483-62-2. (online at cancernetwork.com)

Tannock, Ian (2005). The basic science of oncology. McGraw-Hill Professional.

ISBN 978-0-07-138774-3.

Manfred Schwab (2008). Encyclopedia of Cancer (4 Volume Set). Berlin: Springer.

ISBN 3-540-36847-7.

External links
Wikimedia Commons has media related to Cancer.
Wikisource has the text of the 1911 Encyclopdia Britannica article Cancer.

Cancer at DMOZ
[hide]

Overview of tumors, cancer and oncology (C00D48, 140239)

Causes of cancer
From Wikipedia, the free encyclopedia

Jump to: navigation, search

For the cellular mechanisms of cancer development, see Carcinogenesis.

Most cancers are related to environmental, lifestyle, or behavioral exposures.[1] The term
"environmental", as used by cancer researchers, refers to everything outside the body that
interacts with humans.[2] In this sense, the environment is not limited to the biophysical
environment (e.g. exposure to factors such as air pollution or sunlight, encountered outdoors or
indoors, at home or in the workplace), but also includes lifestyle, economic and behavioral
factors.[3] Common environmental factors that contribute to cancer death include cringe tobacco
(according to one estimate, accounting for 2530% of deaths), diet and obesity[contradictory] (3035%),
infections (1520%), radiation (both ionizing and non-ionizing, up to 10%), stress,[contradictory] lack of
physical activity, and environmental pollutants.[4]
It is nearly impossible to prove what caused a cancer in any individual, because most cancers
have multiple possible causes. For example, if a person who uses tobacco heavily develops lung
cancer, then it was probably caused by the tobacco use, but since everyone has a small chance of
developing lung cancer as a result of air pollution or radiation, then there is a small chance that
the cancer developed because of air pollution or radiation. Cancer is generally not contagious in
humans, though it can be caused by oncoviruses and cancer bacteria.
It should be noted that aging has been repeatedly and consistently regarded as an important
aspect to consider when evaluating the risk factors for the development of particular cancers;
aging is considered a risk factor and this is explained by the observation that many molecular and
cellular changes are involved in the development of cancer, so it is very likely that these changes
accumulate during the aging process (that is, molecular and cellular changes collectively leading
to cancer accumulate throughout the years), eventually manifesting themselves as cancer.[5] Over
30% of cancers are potentially avoidable by reducing key risk factors, of which much the
significant is tobacco use, which is the cause of about 22% of cancer deaths.[5] Another 10% is
due to obesity, a poor diet, lack of physical activity, and drinking alcohol.[5] Other factors include
certain infections, exposure to ionizing radiation, and environmental pollutants.[4] In the
developing world nearly 20% of cancers are due to infections such as hepatitis B, hepatitis C,
and human papillomavirus.[5] These factors act, at least partly, by changing the genes of a cell.[6]
Typically many such genetic changes are required before cancer develops.[6] Approximately 5
10% of cancers are due to genetic defects inherited from a person's parents.[7]

Contents
[hide]

1 Chemicals

2 Diet and exercise

3 Infection

4 Radiation

5 Heredity

6 Physical agents

7 Hormones

8 Other

9 References

Chemicals[edit]
Further information: Alcohol and cancer and Smoking and cancer

The incidence of lung cancer is highly correlated with smoking.

Particular substances have been linked to specific types of cancer. Tobacco smoking is associated
with many forms of cancer,[8] and causes 80% of lung cancer.[9] Daily long-term vaping with a
high voltage (5.0 V) electronic cigarette may generate formaldehyde-forming chemicals at a
greater level than smoking, which was determined to be a lifetime cancer risk of approximately 5
to 15 times greater than smoking.[10]
Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an
example of a chemical carcinogen that is not a mutagen.[11] In Western Europe 10% of cancers in
males and 3% of cancers in females are attributed to alcohol.[12]
Decades of research has demonstrated the link between tobacco use and cancer in the lung,
larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas.[13] Tobacco smoke contains
over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.[14]
Tobacco is responsible for about one in three of all cancer deaths in the developed world,[8] and
about one in five worldwide.[14] Lung cancer death rates in the United States have mirrored
smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death
rates and, more recently, decreases in smoking rates since the 1950s followed by decreases in
lung cancer death rates in men since 1990.[15][16] However, the numbers of smokers worldwide is
still rising, leading to what some organizations have described as the tobacco epidemic.[17]

Cancer related to one's occupation is believed to represent between 220% of all cases.[18] Every
year, at least 200,000 people die worldwide from cancer related to their workplace.[19] Most
cancer deaths caused by occupational risk factors occur in the developed world.[19] It is estimated
that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S.
are attributable to occupation.[20] Millions of workers run the risk of developing cancers such as
lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia
from exposure to benzene at their workplaces.[19]

Diet and exercise[edit]

Diet, physical inactivity, and obesity are related to approximately 3035% of cancer deaths.[4][21]
In the United States excess body weight is associated with the development of many types of
cancer and is a factor in 1420% of all cancer deaths.[21] Physical inactivity is believed to
contribute to cancer risk not only through its effect on body weight but also through negative
effects on immune system and endocrine system.[21] More than half of the effect from diet is due
to overnutrition rather than from eating too little healthy foods.
Diets that are low in vegetables, fruits and whole grains, and high in processed or red meats are
linked with a number of cancers.[21] A high-salt diet is linked to gastric cancer, aflatoxin B1, a
frequent food contaminate, with liver cancer, and Betel nut chewing with oral cancer.[22] This may
partly explain differences in cancer incidence in different countries. For example, gastric cancer
is more common in Japan due to its high-salt diet[23] and colon cancer is more common in the
United States. Immigrants develop the risk of their new country, often within one generation,
suggesting a substantial link between diet and cancer.[24]

Infection[edit]
Main article: Infectious causes of cancer
Worldwide approximately 18% of cancer deaths are related to infectious diseases.[4] This
proportion varies in different regions of the world from a high of 25% in Africa to less than 10%
in the developed world.[4] Viruses are the usual infectious agents that cause cancer but bacteria
and parasites may also have an effect.
A virus that can cause cancer is called an oncovirus. These include human papillomavirus
(cervical carcinoma), EpsteinBarr virus (B-cell lymphoproliferative disease and nasopharyngeal
carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas),
hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seen in
Helicobacter pylori-induced gastric carcinoma.[25] Parasitic infections strongly associated with
cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver
flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[26]

Radiation[edit]

Main article: Radiation-induced cancer

Up to 10% of invasive cancers are related to radiation exposure, including both ionizing
radiation and non-ionizing ultraviolet radiation.[4] Additionally, the vast majority of non-invasive
cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation.
Sources of ionizing radiation include medical imaging, and radon gas. Radiation can cause
cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid
tumors usually take 1015 years, and can take up to 40 years, to become clinically manifest, and
radiation-induced leukemias typically require 210 years to appear.[27] Some people, such as those
with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average
to developing cancer from radiation exposure.[27] Children and adolescents are twice as likely to
develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the
effect.[27] Ionizing radiation is not a particularly strong mutagen.[27] Residential exposure to radon
gas, for example, has similar cancer risks as passive smoking.[27] Low-dose exposures, such as
living near a nuclear power plant, are generally believed to have no or very little effect on cancer
development.[27] Radiation is a more potent source of cancer when it is combined with other
cancer-causing agents, such as radon gas exposure plus smoking tobacco.[27]
Unlike chemical or physical triggers for cancer, ionizing radiation hits molecules within cells
randomly. If it happens to strike a chromosome, it can break the chromosome, result in an
abnormal number of chromosomes, inactivate one or more genes in the part of the chromosome
that it hit, delete parts of the DNA sequence, cause chromosome translocations, or cause other
types of chromosome abnormalities.[27] Major damage normally results in the cell dying, but
smaller damage may leave a stable, partly functional cell that may be capable of proliferating and
developing into cancer, especially if tumor suppressor genes were damaged by the radiation.[27]
Three independent stages appear to be involved in the creation of cancer with ionizing radiation:
morphological changes to the cell, acquiring cellular immortality (losing normal, life-limiting
cell regulatory processes), and adaptations that favor formation of a tumor.[27] Even if the
radiation particle does not strike the DNA directly, it triggers responses from cells that indirectly
increase the likelihood of mutations.[27]
Medical use of ionizing radiation is a growing source of radiation-induced cancers. Ionizing
radiation may be used to treat other cancers, but this may, in some cases, induce a second form of
cancer.[27] It is also used in some kinds of medical imaging. It is estimated that 0.4% of cancers in
2007 in the United States are due to CTs performed in the past and that this may increase to as
high as 1.52% with rates of CT usage during this same time period.[28]
Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin
malignancies.[29] Clear evidence establishes ultraviolet radiation, especially the non-ionizing
medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most
common forms of cancer in the world.[29]
Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and
other similar sources have been described as a possible carcinogen by the World Health

Organization's International Agency for Research on Cancer.[30] However, studies have not found
a consistent link between cell phone radiation and cancer risk.[31]

Heredity[edit]
Main article: Cancer syndrome
The vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers are
primarily caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a
genetic mutation which has a large effect on cancer risk and these cause less than 310% of all
cancer.[32] Some of these syndromes include: certain inherited mutations in the genes BRCA1 and
BRCA2 with a more than 75% risk of breast cancer and ovarian cancer,[32] and hereditary
nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of
people with colorectal cancer,[33] among others.

Physical agents[edit]
Some substances cause cancer primarily through their physical, rather than chemical, effects on
cells.[34] A prominent example of this is prolonged exposure to asbestos, naturally occurring
mineral fibers which are a major cause of mesothelioma, which is a cancer of the serous
membrane, usually the serous membrane surrounding the lungs.[34] Other substances in this
category, including both naturally occurring and synthetic asbestos-like fibers such as
wollastonite, attapulgite, glass wool, and rock wool, are believed to have similar effects.[34] Nonfibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and
crystalline silica (quartz, cristobalite, and tridymite).[34] Usually, physical carcinogens must get
inside the body (such as through inhaling tiny pieces) and require years of exposure to develop
cancer.[34]
Physical trauma resulting in cancer is relatively rare.[35] Claims that breaking bones resulted in
bone cancer, for example, have never been proven.[35] Similarly, physical trauma is not accepted
as a cause for cervical cancer, breast cancer, or brain cancer.[35] One accepted source is frequent,
long-term application of hot objects to the body. It is possible that repeated burns on the same
part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers),
may produce skin cancer, especially if carcinogenic chemicals are also present.[35] Frequently
drinking scalding hot tea may produce esophageal cancer.[35] Generally, it is believed that the
cancer arises, or a pre-existing cancer is encouraged, during the process of repairing the trauma,
rather than the cancer being caused directly by the trauma.[35] However, repeated injuries to the
same tissues might promote excessive cell proliferation, which could then increase the odds of a
cancerous mutation. There is no evidence that inflammation itself causes cancer,[35] yet
inflammation can contribute to proliferation, survival and migration of cancer cells by
influencing the microenvironment around tumors.[36]

Hormones[edit]

Some hormones play a role in the development of cancer by promoting cell proliferation.[37]
Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation,
differentiation and apoptosis, suggesting possible involvement in carcinogenesis.[38]
Hormones are important agents in sex-related cancers such as cancer of the breast, endometrium,
prostate, ovary, and testis, and also of thyroid cancer and bone cancer.[37] For example, the
daughters of women who have breast cancer have significantly higher levels of estrogen and
progesterone than the daughters of women without breast cancer. These higher hormone levels
may explain why these women have higher risk of breast cancer, even in the absence of a breastcancer gene.[37] Similarly, men of African ancestry have significantly higher levels of testosterone
than men of European ancestry, and have a correspondingly much higher level of prostate cancer.
[37]
Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol
glucuronide, have the lowest levels of prostate cancer.[37]
Other factors are also relevant: obese people have higher levels of some hormones associated
with cancer and a higher rate of those cancers.[37] Women who take hormone replacement therapy
have a higher risk of developing cancers associated with those hormones.[37] On the other hand,
people who exercise far more than average have lower levels of these hormones, and lower risk
of cancer.[37] Osteosarcoma may be promoted by growth hormones.[37] Some treatments and
prevention approaches leverage this cause by artificially reducing hormone levels, and thus
discouraging hormone-sensitive cancers.[37]

Other[edit]
Excepting the rare transmissions that occur with pregnancies and only a marginal few organ
donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft
rejection caused by MHC incompatibility.[39] In humans and other vertebrates, the immune system
uses MHC antigens to differentiate between "self" and "non-self" cells because these antigens are
different from person to person. When non-self antigens are encountered, the immune system
reacts against the appropriate cell. Such reactions may protect against tumor cell engraftment by
eliminating implanted cells. In the United States, approximately 3,500 pregnant women have a
malignancy annually, and transplacental transmission of acute leukemia, lymphoma, melanoma
and carcinoma from mother to fetus has been observed.[39] The development of donor-derived
tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated
tumors seems to be malignant melanoma, that was undetected at the time of organ harvest.[40] Job
stress does not appear to be a significant factor at least in lung, colorectal, breast and prostate
cancers.[41]

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Arthritis
From Wikipedia, the free encyclopedia

Jump to: navigation, search

Not to be confused with Arteritis.

Arthritis

Hands affected by rheumatoid arthritis, an autoimmune form

of arthritis
Classification and external resources
Specialty

Rheumatology

ICD-10

M00-M25

ICD-9-CM

710 -719

DiseasesDB

15237

MedlinePlus

001243

eMedicine

topic list

MeSH

D001168
[edit on Wikidata]

Arthritis (from Greek arthro-, joint + -itis, inflammation; plural: arthritides) is a form of joint
disorder that involves inflammation in one or more joints.[1][2] There are over 100 different forms
of arthritis.[3][4] The most common form of arthritis is osteoarthritis (degenerative joint disease), a
result of trauma to the joint, infection of the joint, or age. Other arthritis forms are rheumatoid
arthritis, psoriatic arthritis, and related autoimmune diseases. Septic arthritis is caused by joint
infection.
The major complaint by individuals who have arthritis is joint pain. Pain is often constant, and
may be localized to the joint affected. The pain from arthritis is from inflammation around the
joint, damage to the joint from disease, daily wear and tear of the joint, muscle strains caused by
forceful movements against stiff and painful joints, and from fatigue.

Contents
[hide]

1 Classification

2 Prevalence

3 Signs and symptoms

o 3.1 Disability

4 Diagnosis

o 4.1 Osteoarthritis
o 4.2 Rheumatoid arthritis
o 4.3 Lupus
o 4.4 Gout
o 4.5 Comparison of Types
o 4.6 Other

5 Treatment
o 5.1 Physical therapy
o 5.2 Medications
o 5.3 Surgery
o 5.4 Alternative medicine

6 Epidemiology

7 History

8 See also

9 References

10 External links

Classification[edit]
There are several diseases where joint pain is primary, and is considered the main feature.
Generally when a person has "arthritis" it means that they have one of these diseases, which
include:

Osteoarthritis

Rheumatoid arthritis

Gout and pseudo-gout

Septic arthritis

Ankylosing spondylitis

Juvenile idiopathic arthritis

Still's disease

Joint pain can also be a symptom of other diseases. In this case, the arthritis is considered to be
secondary to the main disease; these include:

Psoriasis (Psoriatic arthritis)

Reactive arthritis

Ehlers-Danlos Syndrome

Haemochromatosis

Hepatitis

Lyme disease

Sjogren's disease

Hashimoto's Thyroiditis

Celiac disease[5]

Non-celiac gluten sensitivity[6][7][8]

Inflammatory bowel disease (including Crohn's disease and ulcerative colitis)

Henoch-Schnlein purpura

Hyperimmunoglobulinemia D with recurrent fever

Sarcoidosis

Whipple's disease

TNF receptor associated periodic syndrome

Granulomatosis with polyangiitis (and many other vasculitis syndromes)

Familial Mediterranean fever

Systemic lupus erythematosus

An undifferentiated arthritis is an arthritis that does not fit into well-known clinical disease
categories, possibly being an early stage of a definite rheumatic disease.[9]

Prevalence[edit]
Disability due to musculoskeletal disorders increased by 45% from 1990 to 2010. Of these,
osteoarthritis is the fastest increasing major health condition.[10] Among the many reports on the
increased prevalence of musculoskeletal conditions, data from Africa are lacking and
underestimated. A systematic review assessed the prevalence of arthritis and included twenty
population-based and seven hospital-based studies.[11] The majority of studies, twelve, were from
South Africa. Nine studies were well-conducted, eleven studies were of moderate quality, and
seven studies were conducted poorly. The results of the systematic review were as follows:

Rheumatoid arthritis: 0.1% in Algeria (urban setting); 0.6% in Democratic Republic of

Congo (urban setting); 2.5% and 0.07% in urban and rural settings in South Africa
respectively; 0.3% in Egypt (rural setting), 0.4% in Lesotho (rural setting)

Osteoarthritis: 55.1% in South Africa (urban setting); ranged from 29.5 to 82.7% in South
Africans aged 65 years and older
o Knee osteoarthritis has the highest prevalence from all types sites of osteoarthritis,
with 33.1% in rural South Africa

Ankylosing spondylitis: 0.1% in South Africa (rural setting)

Psoriatic arthritis: 4.4% in South Africa (urban setting)

Gout: 0.7% in South Africa (urban setting)

Juvenile idiopathic arthritis: 0.3% in Egypt (urban setting)

Signs and symptoms[edit]

Extra-articular features of joint disease[12]

Cutaneous nodules
Cutaneous vasculitis lesions
Lymphadenopathy
Oedema
Ocular inflammation
Urethritis
Tenosynovitis (tendon sheath effusions)
Bursitis (swollen bursa)
Diarrhea
Orogenital ulceration
Pain, which can vary in severity, is a common symptom in virtually all types of arthritis. Other
symptoms include swelling, joint stiffness and aching around the joint(s). Arthritic disorders like
lupus and rheumatoid arthritis can affect other organs in the body, leading to a variety of
symptoms.[13] Symptoms may include:

Inability to use the hand or walk

Stiffness, which may be worse in the morning, or after use

Malaise and fatigue

Weight loss

Poor sleep

Muscle aches and pains

Tenderness

Difficulty moving the joint

It is common in advanced arthritis for significant secondary changes to occur. For example,
arthritic symptoms might make it difficult for a person to move around and/or exercise, which
can lead to secondary effects, such as:

Muscle weakness

Loss of flexibility

Decreased aerobic fitness

These changes, in addition to the primary symptoms, can have a huge impact on quality of life.

Disability[edit]
Arthritis is the most common cause of disability in the USA. More than 20 million individuals
with arthritis have severe limitations in function on a daily basis.[14] Absenteeism and frequent

visits to the physician are common in individuals who have arthritis. Arthritis can make it very
difficult for individuals to be physically active and some become home bound.
It is estimated that the total cost of arthritis cases is close to $100 billion of which almost 50% is
from lost earnings. Each year, arthritis results in nearly 1 million hospitalizations and close to 45
million outpatient visits to health care centers.[15]
Decreased mobility, in combination with the above symptoms, can make it difficult for an
individual to remain physically active, contributing to an increased risk of obesity, high
cholesterol or vulnerability to heart disease.[16] People with arthritis are also at increased risk of
depression, which may be a response to numerous factors, including fear of worsening
symptoms.[17]

Diagnosis[edit]
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adding citations to reliable sources. Unsourced material may be challenged and
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Diagnosis is made by clinical examination from an appropriate health professional, and may be
supported by other tests such as radiology and blood tests, depending on the type of suspected
arthritis.[18] All arthritides potentially feature pain. Pain patterns may differ depending on the
arthritides and the location. Rheumatoid arthritis is generally worse in the morning and
associated with stiffness; in the early stages, patients often have no symptoms after a morning
shower. Osteoarthritis, on the other hand, tends to be worse after exercise. In the aged and
children, pain might not be the main presenting feature; the aged patient simply moves less, the
infantile patient refuses to use the affected limb.[citation needed]
Elements of the history of the disorder guide diagnosis. Important features are speed and time of
onset, pattern of joint involvement, symmetry of symptoms, early morning stiffness, tenderness,
gelling or locking with inactivity, aggravating and relieving factors, and other systemic
symptoms. Physical examination may confirm the diagnosis, or may indicate systemic disease.
Radiographs are often used to follow progression or help assess severity.
Blood tests and X-rays of the affected joints often are performed to make the diagnosis.
Screening blood tests are indicated if certain arthritides are suspected. These might include:
rheumatoid factor, antinuclear factor (ANF), extractable nuclear antigen, and specific antibodies.

Osteoarthritis[edit]
Main article: Osteoarthritis
Osteoarthritis is the most common form of arthritis.[19] It can affect both the larger and the smaller
joints of the body, including the hands, wrists, feet, back, hip, and knee. The disease is essentially
one acquired from daily wear and tear of the joint; however, osteoarthritis can also occur as a

result of injury. In recent years, some joint or limb deformities, such as knock-knee or acetabular
overcoverage or dysplasia, have also been considered as a predisposing factor for knee or hip
osteoarthritis. Osteoarthritis begins in the cartilage and eventually causes the two opposing bones
to erode into each other. The condition starts with minor pain during physical activity, but soon
the pain can be continuous and even occur while in a state of rest. The pain can be debilitating
and prevent one from doing some activities. Osteoarthritis typically affects the weight-bearing
joints, such as the back, knee and hip. Unlike rheumatoid arthritis, osteoarthritis is most
commonly a disease of the elderly. More than 30 percent of women have some degree of
osteoarthritis by age 65. Risk factors for osteoarthritis include prior joint trauma, obesity, and a
sedentary lifestyle.

Rheumatoid arthritis[edit]
Main article: Rheumatoid arthritis
Rheumatoid arthritis (RA) is a disorder in which the body's own immune system starts to attack
body tissues. The attack is not only directed at the joint but to many other parts of the body. In
rheumatoid arthritis, most damage occurs to the joint lining and cartilage which eventually
results in erosion of two opposing bones. RA often affects joints in the fingers, wrists, knees and
elbows, is symmetrical (appears on both sides of the body), and can lead to severe deformity in a
few years if not treated. RA occurs mostly in people aged 20 and above. In children, the disorder
can present with a skin rash, fever, pain, disability, and limitations in daily activities. With earlier
diagnosis and aggressive treatment, many individuals can lead a better quality of life than if
going undiagnosed for long after RA's onset. The drugs to treat RA range from corticosteroids to
monoclonal antibodies given intravenously. Treatments also include analgesics such as NSAIDs
and disease-modifying antirheumatic drugs (DMARDs), while in rare cases, surgery may be
required to replace joints, but there is no cure for the disease.[20]
Treatment with DMARDs is designed to initiate an adaptive immune response, in part by CD4+
T helper (Th) cells, specifically Th17 cells.[21] Th17 cells are present in higher quantities at the
site of bone destruction in joints and produce inflammatory cytokines associated with
inflammation, such as interleukin-17 (IL-17).[22]
Bone erosion is a central feature of rheumatoid arthritis. Bone continuously undergoes
remodeling by actions of bone resorbing osteoclasts and bone forming osteoblasts. One of the
main triggers of bone erosion in the joints in rheumatoid arthritis is inflammation of the
synovium, caused in part by the production of pro-inflammatory cytokines and receptor activator
of nuclear factor kappa B ligand (RANKL), a cell surface protein present in Th17 cells and
osteoblasts.[22] Osteoclast activity can be directly induced by osteoblasts through the
RANK/RANKL mechanism.[23]

Lupus[edit]
Main article: Lupus erythematosus

Lupus is a common collagen vascular disorder that can be present with severe arthritis. Other
features of lupus include a skin rash, extreme photosensitivity, hair loss, kidney problems, lung
fibrosis and constant joint pain.[24]

Gout[edit]
Main article: Gout
Gout is caused by deposition of uric acid crystals in the joint, causing inflammation. There is
also an uncommon form of gouty arthritis caused by the formation of rhomboid crystals of
calcium pyrophosphate known as pseudogout. In the early stages, the gouty arthritis usually
occurs in one joint, but with time, it can occur in many joints and be quite crippling. The joints in
gout can often become swollen and lose function. Gouty arthritis can become particularly painful
and potentially debilitating when gout cannot successfully be treated.[25] When uric acid levels
and gout symptoms cannot be controlled with standard gout medicines that decrease the
production of uric acid (e.g., allopurinol, febuxostat) or increase uric acid elimination from the
body through the kidneys (e.g., probenecid), this can be referred to as refractory chronic gout or
RCG.[26]

Comparison of Types[edit]
Comparison of some major forms of arthritis[27]
Osteoarthritis
Rheumatoid arthritis
Gouty arthritis
[28]
Speed of onset Months
Weeks-months
Hours for an attack[29]
Hands (proximal
Weight-bearing joints
interphalangeal and
Main
(such as knees, hips,
Great toe, ankles, knees
metacarpophalangeal
locations vertebral column) and
and elbows
joint) wrists, ankles,
hands
knees and hips
May occur, though often
mild compared to
Inflammation
Yes
Yes
inflammation in
rheumatoid arthritis

Radiologic
changes

Narrowed joint
space

Osteophytes

Local
osteosclerosis

Subchondral cysts

Laboratory None

Narrowed joint
space

"Punched out" bone

erosions

Bone erosions

Anemia, elevated ESR

Crystal in joints

and C-reactive protein

(CRP), rheumatoid factor,
anti-citrullinated protein
antibody

findings

Other
features

No systemic signs

Bouchard's and
Heberden's nodes

Extra-articular
features are
common
Ulnar deviation,
swan neck- and
Boutonniere
deformity of the
hand

Tophi

Nephrolithiasis

Other[edit]
Infectious arthritis is another severe form of arthritis. It presents with sudden onset of chills,
fever and joint pain. The condition is caused by bacteria elsewhere in the body. Infectious
arthritis must be rapidly diagnosed and treated promptly to prevent irreversible joint damage.[30]
Psoriasis can develop into psoriatic arthritis. With psoriatic arthritis, most individuals develop the
skin problem first and then the arthritis. The typical features are of continuous joint pains,
stiffness and swelling. The disease does recur with periods of remission but there is no cure for
the disorder. A small percentage develop a severe painful and destructive form of arthritis which
destroys the small joints in the hands and can lead to permanent disability and loss of hand
function.[31]

Treatment[edit]
There is no known cure for either rheumatoid or osteoarthritis. Treatment options vary depending
on the type of arthritis and include physical therapy, lifestyle changes (including exercise and
weight control), orthopedic bracing, and medications. Joint replacement surgery may be required
in eroding forms of arthritis. Medications can help reduce inflammation in the joint which
decreases pain. Moreover, by decreasing inflammation, the joint damage may be slowed.

Physical therapy[edit]
In general, studies have shown that physical exercise of the affected joint can have noticeable
improvement in terms of long-term pain relief. Furthermore, exercise of the arthritic joint is
encouraged to maintain the health of the particular joint and the overall body of the person.[32]
Individuals with arthritis can benefit from both physical and occupational therapy. In arthritis the
joints become stiff and the range of movement can be limited. Physical therapy has been shown

to significantly improve function, decrease pain, and delay need for surgical intervention in
advanced cases.[33] Exercise prescribed by a physical therapist has been shown to be more
effective than medications in treating osteoarthritis of the knee. Exercise often focuses on
improving muscle strength, endurance and flexibility. In some cases, exercises may be designed
to train balance. Occupational therapy can provide assistance with activities as well as
equipment.

Medications[edit]
There are several types of medications that are used for the treatment of arthritis. Treatment
typically begins with medications that have the fewest side effects with further medications being
added if insufficiently effective.[34]
Depending on the type of arthritis, the medications that are given may be different. For example,
the first-line treatment for osteoarthritis is acetaminophen (paracetamol) while for inflammatory
arthritis it involves non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen. Opioids and
NSAIDs are less well tolerated.[35]
Rheumatoid arthritis (RA) is autoimmune so in addition to using pain medications and antiinflammatory drugs, this type uses another category of drug called disease modifying antirheumatic drugs (DMARDS). An example of this type of drug is Methotrexate. These types of
drugs act on the immune system and slow down the progression of RA.

Surgery[edit]
A number of rheumasurgical interventions have been incorporated in the treatment of arthritis
since the 1950s. Arthroscopic surgery for osteoarthritis of the knee provides no additional benefit
to optimized physical and medical therapy.[36]

Alternative medicine[edit]
A Cochrane review in 2000 concluded that transcutaneous electrical nerve stimulation (TENS)
for knee osteoarthritis was more effective in pain control than placebo.[37]
Low level laser therapy may be considered for relief of pain and stiffness associated with
arthritis.[38] Evidence of benefit is tentative.[39][40]
Pulsed electromagnetic field therapy has been shown to effectively treat pain associated with
arthritic conditions.[41] The FDA has not approved PEMF for the treatment of arthritis. In Canada,
PEMF devices are legally licensed by Health Canada for the treatment of pain associated with
arthritic conditions.

Epidemiology[edit]

Arthritis is predominantly a disease of the elderly, but children can also be affected by the
disease. More than 70% of individuals in North America affected by arthritis are over the age of
65.[citation needed] Arthritis is more common in women than men at all ages and affects all races, ethnic
groups and cultures. In the United States a CDC survey based on data from 20072009 showed
22.2% (49.9 million) of adults aged 18 years had self-reported doctor-diagnosed arthritis, and
9.4% (21.1 million or 42.4% of those with arthritis) had arthritis-attributable activity limitation
(AAAL). With an aging population, this number is expected to increase.[42]

History[edit]
While evidence of primary ankle osteoarthritis has been discovered in dinosaurs,[43] the first
known traces of human arthritis date back as far as 4500 BC. In early reports, arthritis was
frequently referred to as the most common ailment of prehistoric peoples.[44] It was noted in
skeletal remains of Native Americans found in Tennessee and parts of what is now Olathe,
Kansas. Evidence of arthritis has been found throughout history, from tzi, a mummy (circa
3000 BC) found along the border of modern Italy and Austria, to the Egyptian mummies circa
2590 BC.[45]
In 1715, William Musgrave published the second edition of his most important medical work,
De arthritide symptomatica, which concerned arthritis and its effects.[46]

See also[edit]

Arthritis Care (charity in the UK)

Arthritis Foundation (US not-for-profit)

Knee arthritis

Osteoimmunology

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External links[edit]

Arthritis at DMOZ

American College of Rheumatology US professional society of rheumatologists

Arthritis Foundation US national not-for-profit organization for arthritis

Arthritis Research UK (UK medical research charity)

Arthritis Australia (Australian national not-for-profit organization for arthritis)

National Institute of Arthritis and Musculoskeletal and Skin Diseases - US National

Institute of Arthritis and Musculoskeletal and Skin Diseases

Fibromyalgia
From Wikipedia, the free encyclopedia

Jump to: navigation, search

Fibromyalgia

The location of the nine paired tender points that constitute

the 1990 American College of Rheumatology criteria for

fibromyalgia.
Classification and external resources
Pronunciation

/fabromald/[1]

Synonyms

fibromyalgia syndrome (FMS)

Specialty

Rheumatology

ICD-10

M79.7 Fibromyalgia

ICD-9-CM

729.1 Myalgia and myositis,

unspecified

MedlinePlus

000427

eMedicine

med/790 med/2934 ped/777 pmr/47

Patient UK

Fibromyalgia

MeSH

D005356
[edit on Wikidata]

Fibromyalgia (FM) is a medical condition characterised by chronic widespread pain and a

heightened pain response to pressure.[2] Other symptoms include feeling tired to a degree that
normal activities are affected, sleep problems, and troubles with memory.[3] Some people also
report restless legs syndrome, bowel or bladder problems, numbness and tingling, and sensitivity
to noise, lights or temperature.[4] Fibromyalgia is frequently associated with depression, anxiety,
and posttraumatic stress disorder. Other types of chronic pain are also frequently present.[3]
The cause of fibromyalgia is unknown but believed to involve a combination of genetic and
environmental factors with half the risk attributed to each.[3][4] The condition runs in families and
many genes are believed to be involved.[5] Environmental factors may include psychological
stress, trauma, and certain infections.[3] The pain appears to result from processes in the central
nervous system and the condition is referred to as a "central sensitization syndrome".[2][3]
Fibromyalgia is recognized as a disorder by the US National Institutes of Health and the

American College of Rheumatology.[4][6] There is no specific diagnostic test.[4] Diagnosis involves

first ruling out other potential causes and verifying that a set number of symptoms are present.[3][4]
The treatment of fibromyalgia can be difficult. Recommendations often include getting enough
sleep, exercising regularly, and eating a healthy diet.[4] Cognitive behavioral therapy may also be
helpful.[3] The medications duloxetine, milnacipran, or pregabalin may be used. Use of opioid
pain medication is poorly supported by evidence. Dietary supplements also lack evidence to
support their use. While fibromyalgia can last a long time, it does not result in death or tissue
damage.[4]
Fibromyalgia is estimated to affect 28% of the population. Females are affected about two times
as often as males. Rates appear similar in different areas of the world and among different
cultures. Fibromyalgia was first defined in 1990 with updated criteria in 2011.[3] There is
controversy about the classification, diagnosis, and treatment of fibromyalgia.[7][8] While some
feel the diagnosis of fibromyalgia may negatively affect a person, other research finds it to be
beneficial.[3] The term "fibromyalgia" is from New Latin, fibro-, meaning "fibrous tissues", Greek
myo-, "muscle", and Greek algos, "pain"; thus the term literally means "muscle and
connective tissue pain".[9]

Contents
[hide]

1 Classification

2 Signs and symptoms

3 Cause
o 3.1 Genetics
o 3.2 Lifestyle
o 3.3 Sleep disturbances
o 3.4 Psychological factors
o 3.5 Non-celiac gluten sensitivity

4 Pathophysiology
o 4.1 Dopamine dysfunction
o 4.2 Serotonin metabolism

o 4.3 Poly-modal sensitivity

o 4.4 Neuroendocrine disruption
o 4.5 Sympathetic hyperactivity
o 4.6 Cerebrospinal fluid
o 4.7 Brain imaging studies

5 Diagnosis
o 5.1 2010 provisional criteria
o 5.2 Differential diagnosis

6 Management
o 6.1 Medications

6.1.1 Antidepressants

6.1.2 Anti-seizure medication

6.1.3 Opioids

6.1.4 Others

o 6.2 Psychological therapies

o 6.3 Exercise

7 Prognosis

8 Epidemiology

9 History

10 Society and culture

o 10.1 Economics
o 10.2 Controversies

11 Research

12 Notes

13 References

14 External links

Classification[edit]
Fibromyalgia is classed as a disorder of pain processing due to abnormalities in how pain signals
are processed in the central nervous system.[10] The American College of Rheumatology classify
fibromyalgia as being a functional somatic syndrome.[7] The expert committee of the European
League Against Rheumatism classify fibromyalgia as a neurobiological disorder and as a result
exclusively give pharmacotherapy their highest level of support.[7] The International
Classification of Diseases (ICD-10) lists fibromyalgia as a diagnosable disease under "Diseases
of the musculoskeletal system and connective tissue," under the code M79-7, and states that
fibromyalgia syndrome should be classified as a functional somatic syndrome rather than a
mental disorder. Although mental disorders and some physical disorders commonly are comorbid with fibromyalgia especially anxiety, depression, irritable bowel syndrome, and chronic
fatigue syndrome the ICD states that these should be diagnosed separately.[7]
Differences in psychological and autonomic nervous system profiles among affected individuals
may indicate the existence of fibromyalgia subtypes. A 2007 review divides individuals with
fibromyalgia into four groups as well as "mixed types":[11]
1. "extreme sensitivity to pain but no associated psychiatric conditions" (may respond to
medications that block the 5-HT3 receptor)
2. "fibromyalgia and comorbid, pain-related depression" (may respond to antidepressants)
3. "depression with concomitant fibromyalgia syndrome" (may respond to antidepressants)
4. "fibromyalgia due to somatization" (may respond to psychotherapy)

Signs and symptoms[edit]

The defining symptoms of fibromyalgia are chronic widespread pain, fatigue, sleep disturbance,
and heightened pain in response to tactile pressure (allodynia).[12] Other symptoms may include
tingling of the skin (paresthesias),[12] prolonged muscle spasms, weakness in the limbs, nerve
pain, muscle twitching, palpitations,[13] and functional bowel disturbances.[14][15]
Many people experience cognitive dysfunction[12][16] (known as "fibrofog"), which may be
characterized by impaired concentration,[17] problems with short[17][18] and long-term memory,
short-term memory consolidation,[18] impaired speed of performance,[17][18] inability to multi-task,
cognitive overload,[17][18] and diminished attention span. Fibromyalgia is often associated with
anxiety and depressive symptoms.[18]
Other symptoms often attributed to fibromyalgia that may be due to a comorbid disorder include
myofascial pain syndrome, also referred to as chronic myofascial pain, diffuse non-dermatomal
paresthesias, functional bowel disturbances and irritable bowel syndrome, genitourinary
symptoms and interstitial cystitis, dermatological disorders, headaches, myoclonic twitches, and
symptomatic hypoglycemia. Although fibromyalgia is classified based on the presence of chronic
widespread pain, pain may also be localized in areas such as the shoulders, neck, low back, hips,
or other areas. Many sufferers also experience varying degrees of myofascial pain and have high
rates of comorbid temporomandibular joint dysfunction. 2030% of people with rheumatoid
arthritis and systemic lupus erythematosus may also have fibromyalgia.[19]

Cause[edit]
The cause of fibromyalgia is unknown. However, several hypotheses have been developed
including "central sensitization".[12] This theory proposes that people with fibromyalgia have a
lower threshold for pain because of increased reactivity of pain-sensitive nerve cells in the spinal
cord or brain.[2] Neuropathic pain and major depressive disorder often co-occur with fibromyalgia
the reason for this comorbidity appears to be due to shared genetic abnormalities, which leads
to impairments in monoaminergic, glutamatergic, neurotrophic, opioid and proinflammatory
cytokine signaling. In these vulnerable individuals psychological stress or illness can cause
abnormalities in inflammatory and stress pathways which regulate mood and pain. Eventually a
sensitisation and kindling effect occurs in certain neurons leading to the establishment of
fibromyalgia and sometimes a mood disorder.[20] The evidence suggests that the pain in

fibromyalgia results primarily from pain processing pathways functioning abnormally. In simple
terms it can be described as the volume of the neurons being set too high and this hyperexcitability of pain processing pathways and under-activity of inhibitory pain pathways in the
brain results in the affected individual experiencing pain. Some neurochemical abnormalities that
occur in fibromyalgia also regulate mood, sleep and energy, thus explaining why mood, sleep
and fatigue problems are commonly co-morbid with fibromyalgia.[10]

Genetics[edit]
A mode of inheritance is currently unknown, but it is most probably polygenic.[5] Research has
also demonstrated that fibromyalgia is potentially associated with polymorphisms of genes in the
serotoninergic,[21] dopaminergic[22] and catecholaminergic systems.[23] However, these
polymorphisms are not specific for fibromyalgia and are associated with a variety of allied
disorders (e.g. chronic fatigue syndrome,[24] irritable bowel syndrome[25]) and with depression.[26]
Individuals with the 5-HT2A receptor 102T/C polymorphism have been found to be at increased
risk of developing fibromyalgia.[27]

Lifestyle[edit]
Stress may be an important precipitating factor in the development of fibromyalgia.[28]
Fibromyalgia is frequently comorbid with stress-related disorders such as chronic fatigue
syndrome, posttraumatic stress disorder, irritable bowel syndrome and depression.[29] A
systematic review found significant association between fibromyalgia and physical and sexual
abuse in both childhood and adulthood, although the quality of studies was poor.[30] Poor lifestyles
including being a smoker, obesity and lack of physical activity may increase the risk of an
individual developing fibromyalgia.[31]
Two studies that employed single-voxel magnetic resonance spectroscopy (1H-MRS) reported
metabolic abnormalities within the hippocampal complex in people with fibromyalgia. As the
hippocampus plays crucial roles in maintenance of cognitive functions, sleep regulation, and pain
perception, it was suggested that metabolic dysfunction of the hippocampus may be implicated in
the appearance of these symptoms.[32][33]
Some authors have proposed that, because exposure to stressful conditions can alter the function
of the hypothalamic-pituitary-adrenal (HPA) axis, the development of fibromyalgia may stem
from stress-induced disruption of the HPA axis.[34]

Sleep disturbances[edit]
In 1975, Moldofsky and colleagues reported the presence of anomalous alpha wave activity
(typically associated with arousal states) measured by electroencephalogram (EEG) during nonrapid eye movement sleep of "fibrositis syndrome".[15] By disrupting stage IV sleep consistently
in young, healthy subjects, the researchers reproduced a significant increase in muscle tenderness
similar to that experienced in "neurasthenic musculoskeletal pain syndrome" but which resolved
when the subjects were able to resume their normal sleep patterns.[35]

Psychological factors[edit]
There is strong evidence that major depression is associated with fibromyalgia (1999),[36]
although the nature of the association is debated.[37] A comprehensive review into the relationship
between fibromyalgia and major depressive disorder (MDD) found substantial similarities in
neuroendocrine abnormalities, psychological characteristics, physical symptoms and treatments
between fibromyalgia and MDD, but currently available findings do not support the assumption
that MDD and fibromyalgia refer to the same underlying construct or can be seen as subsidiaries
of one disease concept.[38] Indeed, the sensation of pain has at least two dimensions: a sensory
dimension which processes the magnitude and location of the pain, and an affective-motivational
dimension which processes the unpleasantness. Accordingly, a study that employed functional
magnetic resonance imaging to evaluate brain responses to experimental pain among people with
fibromyalgia found that depressive symptoms were associated with the magnitude of clinically
induced pain response specifically in areas of the brain that participate in affective pain
processing, but not in areas involved in sensory processing which indicates that the amplification
of the sensory dimension of pain in fibromyalgia occurs independently of mood or emotional
processes.[39] Fibromyalgia has also been linked with bipolar disorder, particularly the hypomania
component.[40]

Non-celiac gluten sensitivity[edit]

Non-celiac gluten sensitivity (NCGS) may be an underlying cause of fibromyalgia symptoms but
further research is needed.[41][42]

Pathophysiology[edit]
The brains of people with fibromyalgia show functional and structural differences from those of
people without fibromyalgia, but it is unclear whether the brain anomalies cause fibromyalgia
symptoms, or are the product of an unknown underlying common cause. Some research suggests
that these brain anomalies may be the result of childhood stress, or prolonged or severe stress.[29]

Dopamine dysfunction[edit]
The "dopamine hypothesis of fibromyalgia" proposes that the central abnormality responsible for
symptoms associated with fibromyalgia is a disruption of normal dopamine-related
neurotransmission.[43][unreliable medical source?] Insufficient dopamine in a part of the body is termed
hypodopaminergia. Dopamine is a catecholamine neurotransmitter with roles in pain perception
and natural analgesia. There is also strong evidence for a role of dopamine in restless leg
syndrome,[44] which is a condition found frequently in people with fibromyalgia.[45] Some people
with fibromyalgia responded to pramipexole, a dopamine agonist that selectively stimulates
dopamine D2/D3 receptors and is used to treat both Parkinson's disease and restless leg
syndrome.[46]

Serotonin metabolism[edit]

In 1975, researchers hypothesized that serotonin, a neurotransmitter that regulates sleep patterns,
mood, concentration and pain, could be involved in the pathophysiology of fibromyalgiaassociated symptoms.[15] In 1992, decreased serotonin metabolites in people's blood samples[47]
and cerebrospinal fluid were reported.[48] However, selective serotonin reuptake inhibitors
(SSRIs) have met with limited success in alleviating the symptoms of the disorder, while drugs
with activity as mixed serotonin-norepinephrine reuptake inhibitors (SNRIs) have been more
successful.[49] However, the relevance of dysregulated serotonin metabolism to pathophysiology is
a matter of debate.[50] Complicating the analysis, one of the more effective types of medication for
the treatment of the disorder (i.e. serotonin 5-HT3 antagonists) actually blocks some effects of
serotonin.[51]

Poly-modal sensitivity[edit]
Results from studies examining responses to experimental stimulation suggest that people with
fibromyalgia may have heightened sensitivity of the nociceptive system, which senses pressure,
heat, cold, electrical and chemical stimulation.[52] Experiments examining pain regulatory systems
have shown that people with fibromyalgia display an exaggerated wind-up in response to
repetitive stimulation[53] and an absence of exercise-induced analgesic response.[54]

Neuroendocrine disruption[edit]
Levels of hormones under the direct or indirect control of growth hormone (GH), including
insulin-like growth factor 1 (IGF-1), cortisol, leptin and neuropeptide Y may be abnormal in
people with fibromyalgia.[55] Several authors have demonstrated low growth hormone levels or
low IGF-I levels in patients with fibromyalgia compared with controls. Moreover, people with
fibromyalgia have an abnormal sleep pattern involving stages 3 and 4 of non-REM sleep during
which growth hormone is predominantly secreted.[56] Further support for a causal role for growth
hormone deficiency comes from observations that such deficiency in adults has been associated
with many of the symptoms described by people with fibromyalgia. Growth hormone is
important in maintaining muscle homeostasis, and it has been suggested that low levels may be
responsible for delayed healing of muscle microtrauma in fibromyalgia.[57] Low (IGF-1) levels in
some people with fibromyalgia have led to the theory that these people may actually have a
different, treatable syndrome, adult growth hormone deficiency.[58] However, there remains some
disagreement about the role of HGH in fibromyalgia.[59]
People with fibromyalgia may have alterations of normal neuroendocrine function, characterized
by mild hypocortisolemia,[60] hyperreactivity of pituitary adrenocorticotropin hormone release in
response to challenge, and glucocorticoid feedback resistance.[61]
Other abnormalities include reduced responsivity of thyrotropin and thyroid hormones to
thyroid-releasing hormone,[62] a mild elevation of prolactin levels with disinhibition of prolactin
release in response to challenge[63] and hyposecretion of adrenal androgens.[64]
These changes might result from chronic stress, which, after being perceived and processed by
the central nervous system, activates hypothalamic corticotrophin-releasing hormone neurons.
Chronic overactivity of these neurons could disrupt normal function of the pituitary-adrenal axis

and cause an increased stimulation of hypothalamic somatostatin secretion, which, in turn, could
inhibit the secretion of other hormones.[65]

Sympathetic hyperactivity[edit]
Functional analysis of the autonomic system in people with fibromyalgia has demonstrated
disturbed activity characterized by hyperactivity of the sympathetic nervous system at baseline[66]
with reduced sympathoadrenal reactivity in response to a variety of stressors including physical
exertion and mental stress.[67][68] People with fibromyalgia demonstrate lower heart rate variability,
an index of sympathetic/parasympathetic balance, indicating sustained sympathetic hyperactivity,
especially at night.[69] In addition, plasma levels of neuropeptide Y, which is co-localized with
norepinephrine in the sympathetic nervous system, have been reported as low in people with
fibromyalgia,[55] while circulating levels of epinephrine and norepinephrine have been variously
reported as low, normal and high.[70][71] Administration of interleukin-6, a cytokine capable of
stimulating the release of hypothalamic corticotropin-releasing hormone which in turn stimulates
activity within the sympathetic nervous system, results in a dramatic increase in circulating
norepinephrine levels and a significantly greater increase in heart rate over baseline in people
with fibromyalgia as compared to healthy controls.[72]

Cerebrospinal fluid[edit]
One of the most reproduced laboratory finding in people with fibromyalgia is an elevation in
cerebrospinal fluid levels of substance P, a putative nociceptive neurotransmitter.[73][74]
Metabolites for the monoamine neurotransmitters serotonin, norepinephrine, and dopamine all
of which play a role in natural analgesia have been shown to be lower,[48] while concentrations
of endogenous opioids (i.e., endorphins and enkephalins) appear to be higher.[75] The mean
concentration of nerve growth factor, a substance known to participate in structural and
functional plasticity of nociceptive pathways within the dorsal root ganglia and spinal cord, is
elevated.[76] There is also evidence for increased excitatory amino acid release within
cerebrospinal fluid, with a correlation demonstrated between levels for metabolites of glutamate
and nitric oxide and clinical indices of pain.[77]

Brain imaging studies[edit]

Evidence of abnormal brain involvement in fibromyalgia has been provided via functional
neuroimaging. The first findings reported were decreased blood flow within the thalamus and
elements of the basal ganglia and mid-brain (i.e., pontine nucleus).[78][79] Differential activation in
response to painful stimulation has also been demonstrated.[80][81] Brain centers showing
hyperactivation in response to noxious stimulation include such pain-related brain centers as the
primary and secondary somatosensory cortices, anterior cingulate cortex, and insular cortex.
People also exhibit neural activation in brain regions associated with pain perception in response
to nonpainful stimuli in such areas as the prefrontal, supplemental motor, insular, and cingulate
cortices.
Evidence of hippocampal disruption indicated by reduced brain metabolite ratios has been
demonstrated by studies using single-voxel magnetic resonance spectroscopy (1H-MRS).[32][33] A

significant negative correlation was demonstrated between abnormal metabolite ratios and a
validated index of the clinical severity (i.e. the Fibromyalgia Impact Questionnaire).[82]
Correlations between clinical pain severity and concentrations of the excitatory amino acid
neurotransmitter glutamate within the insular cortex have also been demonstrated using 1HMRS.[83]
An acceleration of normal age-related brain atrophy has been demonstrated using voxel-based
morphometry (VBM) with areas of reduced gray matter located in the cingulate cortex, insula
and parahippocampal gyrus. Grey matter loss appears to increase 9.5 times the normal rate with
each year.[84] Studies utilizing positron emission tomography have demonstrated reduced
dopamine synthesis in the brainstem and elements of the limbic cortex.[85]
A significant negative correlation between pain severity and dopamine synthesis was
demonstrated within the insular cortex. A subsequent study demonstrated gross disruption of
dopaminergic reactivity in response to a tonic pain stimulus within the basal ganglia with a
significant positive correlation between the defining feature of the disorder (i.e. tender point
index) and dopamine D2 receptor binding potential specifically in the right putamen.[86]
Finally, reduced availability of mu-opioid receptors in the ventral striatum/nucleus accumbens
and cingulate cortex has been demonstrated, with a significant negative correlation between
affective pain levels and receptor availability in the nucleus accumbens.[87]

Diagnosis[edit]

The location of the nine paired tender points that comprise the 1990 American College of
Rheumatology criteria for fibromyalgia.
There is no single test that can fully diagnose fibromyalgia and there is debate over what should
be considered essential diagnostic criteria and whether an objective diagnosis is possible. In most

cases, people with fibromyalgia symptoms may also have laboratory test results that appear
normal and many of their symptoms may mimic those of other rheumatic conditions such as
arthritis or osteoporosis. The most widely accepted set of classification criteria for research
purposes was elaborated in 1990 by the Multicenter Criteria Committee of the American College
of Rheumatology. These criteria, which are known informally as "the ACR 1990", define
fibromyalgia according to the presence of the following criteria:

A history of widespread pain lasting more than three months affecting all four
quadrants of the body, i.e., both sides, and above and below the waist.

Tender points there are 18 designated possible tender points (although a person with the
disorder may feel pain in other areas as well). Diagnosis is no longer based on the
number of tender points.[88][89]

The ACR criteria for classification of patients were originally established as inclusion criteria for
research purposes and were not intended for clinical diagnosis but have now become the de facto
diagnostic criteria in the clinical setting. It should be noted that the number of tender points that
may be active at any one time may vary with time and circumstance. A controversial study done
by a legal team looking to prove their client's disability based primarily on tender points and
their widespread presence in non-litigious communities prompted the lead author of the ACR
criteria to question now the useful validity of tender points in diagnosis.[90] Use of control points
has been used to cast doubt on whether a person has fibromyalgia, and to claim the person is
malingering; however, no research has been done for the use of control points to diagnose
fibromyalgia, and such diagnostic tests have been advised against, and people complaining of
pain all over should still have fibromyalgia considered as a diagnosis.[7]

2010 provisional criteria[edit]

Widespread Pain Index (WPI) Areas

In 2010, the American College of Rheumatology approved provisional revised diagnostic criteria
for fibromyalgia that eliminated the 1990 criteria's reliance on tender point testing.[91] The revised
criteria use a widespread pain index (WPI) and symptom severity scale (SS) in place of tender
point testing under the 1990 criteria. The WPI counts up to 19 general body areas[a] in which the
person has experienced pain in the preceding two weeks. The SS rates the severity of the person's
fatigue, unrefreshed waking, cognitive symptoms, and general somatic symptoms,[b] each on a
scale from 0 to 3, for a composite score ranging from 0 to 12. The revised criteria for diagnosis
are:

WPI 7 and SS 5 OR WPI 36 and SS 9,

Symptoms have been present at a similar level for at least three months, and

No other diagnosable disorder otherwise explains the pain.[91]:607

Differential diagnosis[edit]
Two patients initially diagnosed with fibromyalgia were subsequently shown to have myotonia
congenita.[92] Both patients had been seen by rheumatologists and diagnosed with fibromyalgia.
The diagnoses were revised when electromyographic studies revealed myotonic discharges in
some of the muscles. Genetic analysis of the skeletal muscle chloride channel which is the
underlying cause of myotonia congenita revealed that both patients had mutations in this gene.
Over 130 mutations in this gene have been described and the phenotype is very variable which
may account for the difficulty in the initial diagnosis.[93][94]

Management[edit]
As with many other medically unexplained syndromes, there is no universally accepted treatment
or cure for fibromyalgia, and treatment typically consists of symptom management.
Developments in the understanding of the pathophysiology of the disorder have led to
improvements in treatment, which include prescription medication, behavioural intervention and
exercise. Indeed, integrated treatment plans that incorporate medication, patient education,
aerobic exercise and cognitive-behavioural therapy have been shown to be effective in
alleviating pain and other fibromyalgia-related symptoms.[95]
The Association of the Scientific Medical Societies in Germany,[96] the European League Against
Rheumatism[97] and the Canadian Pain Society[98] currently publish guidelines for the diagnosis
and management of FMS.

Medications[edit]

Health Canada and the US Food and Drug Administration (FDA) have approved pregabalin[99]
and duloxetine, for the management of fibromyalgia. The FDA also approves milnacipran, but
the European Medicines Agency refused marketing authority.[100]
Antidepressants[edit]
Antidepressants are "associated with improvements in pain, depression, fatigue, sleep
disturbances, and health-related quality of life in people with FMS."[101] The goal of
antidepressants should be symptom reduction and if used long term, their effects should be
evaluated against side effects. A small number of people benefit significantly from the SNRIs
duloxetine and milnacipran and the tricyclic antidepressants (such as amitriptyline) however
many people experience more adverse effects than benefits.[102][103] While amitriptyline has been
used as a first line treatment, the quality of evidence to support this use is poor.[104]
It can take up to three months to derive benefit from the antidepressant amitriptyline and up to
six months to gain maximal response from duloxetine, milnacipran, and pregabalin. Some
medications have the potential to cause withdrawal symptoms when stopping so gradual
discontinuation may be warranted particularly for antidepressants and pregabalin.[7]
Anti-seizure medication[edit]
The anti-convulsant drugs gabapentin[105] and pregabalin[106] may be used. Gabapentin is of a
significant benefit in about 30% of people who take it. However, it is commonly associated with
adverse effects.[105] A Cochrane review of pregabalin use in chronic pain concluded: "A minority
of patients will have substantial benefit with pregabalin, and more will have moderate benefit.
Many will have no or trivial benefit, or will discontinue because of adverse events."[107] A metaanalysis of four trials of pregabalin in fibromyalgia found that, for people who did respond to
pregabalin, there was a reduction in their time off work of greater than 1 day per week.[108]
Opioids[edit]
The Association of the Scientific Medical Societies in Germany makes no recommendation
either for or against the use of weak opioids because of the limited amount of scientific research
addressing their use in the treatment of FM. They strongly advise against using strong opioids.[96]
The European League Against Rheumatism recommends the weak opioid tramadol but not
strong opioids.[97] The Canadian Pain Society says that opioids, starting with a weak opioid like
tramadol, can be tried but only for people with moderate to severe pain that is not well-controlled
by non-opioid pain-killers. They discourage the use of strong opioids, and only recommend
using them while they continue to provide improved pain and functioning. Healthcare providers
must monitor people on opioids for ongoing effectiveness, side effects and possible unwanted
drug behaviours.[98]
The combination of tramadol and paracetemol has demonstrated efficacy, safety and tolerability
(for up to two years in the management of other pain conditions) without the development of
tolerance. It is as effective as a combination of codeine (another mild opioid) and paracetamol
but produces less sleepiness and constipation.[109]

A large study of US people with fibromyalgia found that between 2005 and 2007 37.4% were
prescribed short-acting opioids and 8.3% were prescribed long-acting opioids,[110] with around
10% of those prescribed short-acting opioids using tramadol;[111] and a 2011 Canadian study of
457 people with FM found 32% used opioids and two thirds of those used strong opioids.[98]
Others[edit]
A 2007 review of three randomized placebo controlled studies concluded that a period of nine
months of growth hormone was required to reduce fibromyalgia symptoms and normalize IGF-1.
[112]
A 2014 also found some evidence support its use.[113] Sodium oxybate increases growth
hormone production levels through increased slow-wave sleep patterns. However, this
medication was not approved by the FDA for the indication for use in people with fibromyalgia
due to the concern for abuse.[114]
The muscle relaxants cyclobenzaprine and tizanidine are sometimes used off-label to treat
fibromyalgia.[115] The use of NSAIDs is not recommended as first line therapy.[116]
Dopamine agonists (e.g. pramipexole and ropinirole) resulted in some improvement in a minority
of people,[46] but numerous side effects, including the onset of impulse control disorders like
compulsive gambling and shopping, have led to concern about this approach.[117]
Preliminary clinical data have demonstrated that low-dose naltrexone (LDN) may provide
symptomatic improvement in fibromyalgia.[118]

Psychological therapies[edit]
Cognitive behavioural therapy (CBT) and related psychological and behavioural therapies have a
small to moderate effect in reducing symptoms of fibromyalgia.[119][120] The greatest benefit occurs
when CBT is used along with exercise.[95][121]
A meta-analysis of 1,119 subjects found "strong evidence that multicomponent treatment has
beneficial short-term effects on key symptoms of FMS." [122] A 2010 systematic review of 14
studies reported that CBT improves self-efficacy or coping with pain and reduces the number of
physician visits at post-treatment, but has no significant effect on pain, fatigue, sleep or health
related quality of life at post-treatment or followup. Depressed mood was also improved but this
could not be distinguished from some risks of bias.[123]

Exercise[edit]
Exercise improves fitness and sleep and may reduce pain and fatigue in some people with
fibromyalgia.[124][125] In particular, there is strong evidence that cardiovascular exercise is effective
for some people.[126] Long-term aquatic-based exercise has been proven beneficial as it combines
cardiovascular exercise with resistance training.[127]
In children, fibromyalgia is often treated with an intense physical and occupational therapy
program for amplified musculoskeletal pain syndromes. These programs also employ counseling,

art therapy, and music therapy. These programs are evidence-based and report long term total
pain resolution rates as high as 88%.[128]

Prognosis[edit]
Although in itself neither degenerative nor fatal, the chronic pain of fibromyalgia is pervasive
and persistent. Most people with fibromyalgia report that their symptoms do not improve over
time. An evaluation of 332 consecutive new people with fibromyalgia found that disease-related
factors such as pain and psychological factors such as work status, helplessness, education, and
coping ability had an independent and significant relationship to FM symptom severity and
function.[129]

Epidemiology[edit]
Fibromyalgia is estimated to affect 28% of the population,[3][130] with a female to male incidence
ratio that is somewhere between 7:1 and 9:1.[12][131]
Fibromyalgia may not be diagnosed in up to 75% of affected people.[10]

History[edit]
Chronic widespread pain had already been described in the literature in the 19th century but the
term fibromyalgia was not used until 1976 when Dr P.K. Hench used it to describe these
symptoms.[7] Many names, including "muscular rheumatism", "fibrositis", "psychogenic
rheumatism", and "neurasthenia" were applied historically to symptoms resembling those of
fibromyalgia.[132] The term fibromyalgia was coined by researcher Mohammed Yunus as a
synonym for fibrositis and was first used in a scientific publication in 1981.[133] Fibromyalgia is
from the Latin fibra (fiber)[134] and the Greek words myo (muscle)[135] and algos (pain).[136]
Historical perspectives on the development of the fibromyalgia concept note the "central
importance" of a 1977 paper by Smythe and Moldofsky on fibrositis.[137][138] The first clinical,
controlled study of the characteristics of fibromyalgia syndrome was published in 1981,[139]
providing support for symptom associations. In 1984, an interconnection between fibromyalgia
syndrome and other similar conditions was proposed,[140] and in 1986, trials of the first proposed
medications for fibromyalgia were published.[140]
A 1987 article in the Journal of the American Medical Association used the term "fibromyalgia
syndrome" while saying it was a "controversial condition".[141] The American College of
Rheumatology (ACR) published its first classification criteria for fibromyalgia in 1990,[142]
although these are not strictly diagnostic criteria.[11]

Society and culture[edit]

See also: Living With Fibromyalgia

Economics[edit]
People with fibromyalgia generally have higher health care costs and utilization rates. A study of
almost 20,000 Humana members enrolled in Medicare Advantage and commercial plans
compared costs and medical utilizations and found that people with fibromyalgia used twice as
much pain-related medication as those without fibromyalgia. Furthermore, the use of
medications and medical necessities increased markedly across many measures once diagnosis
was made.[143]

Controversies[edit]
Being a disorder defined relatively recently and still not completely understood, fibromyalgia
continues to be a diagnosis that sometimes is disputed. Dr. Frederick Wolfe, lead author of the
1990 paper that first defined the diagnostic guidelines for fibromyalgia, stated in 2008, that he
believed it "clearly" not to be a disease but instead a physical response to depression and stress,
[144]
and in 2013 that its causes "are controversial in a sense" and "there are many factors that
produce these symptoms some are psychological and some are physical and it does exist on a
continuum".[145]
Some members of the medical community do not consider fibromyalgia a disease because of a
lack of abnormalities on physical examination and the absence of objective diagnostic tests.[137][146]
Yunus objects to the psychological characterization of FM. He argues that data indicating it is not
psychological has been ignored or manipulated.[147]
Neurologists and pain specialists tend to view fibromyalgia as a pathology due to dysfunction of
muscles and connective tissue as well as functional abnormalities in the central nervous system.
Rheumatologists define the syndrome in the context of "central sensitization" heightened brain
response to normal stimuli in the absence of disorders of the muscles, joints, or connective
tissues. On the other hand, psychiatrists often view fibromyalgia as a type of affective disorder,
whereas specialists in psychosomatic medicine tend to view fibromyalgia as being a somatic
symptom disorder. However, there is extensive research evidence to support the view that the
central symptom of fibromyalgia, namely pain, has a neurogenic origin. These controversies
don't engage healthcare specialists alone; some patients object to fibromyalgia being described in
purely somatic terms.[7][10]
The validity of fibromyalgia as a unique clinical entity is a matter of contention because "no
discrete boundary separates syndromes such as FMS, chronic fatigue syndrome, irritable bowel
syndrome, or chronic muscular headaches".[126][148] Because of this symptomatic overlap, some
researchers have proposed that fibromyalgia and other analogous syndromes be classified
together as functional somatic syndromes for some purposes.[149]

Research[edit]
Investigational medications include cannabinoids and the 5-HT3 receptor antagonist tropisetron.
[150]
A controlled study of guaifenesin failed to demonstrate any benefits from this treatment.[151][152]

Notes[edit]
1.

Jump up ^ Shoulder girdle (left & right), upper arm (left & right), lower arm (left &
right), hip/buttock/trochanter (left & right), upper leg (left & right), lower leg (left & right), jaw
(left & right), chest, abdomen, back (upper & lower), and neck. [91]:607

2.

Jump up ^ Somatic symptoms include, but are not limited to: muscle pain, irritable
bowel syndrome, fatigue or tiredness, problems thinking or remembering, muscle weakness,
headache, pain or cramps in the abdomen, numbness or tingling, dizziness, insomnia, depression,
constipation, pain in the upper abdomen, nausea, nervousness, chest pain, blurred vision, fever,
diarrhea, dry mouth, itching, wheezing, Raynaud's phenomenon, hives or welts, ringing in the
ears, vomiting, heartburn, oral ulcers, loss of or changes in taste, seizures, dry eyes, shortness of
breath, loss of appetite, rash, sun sensitivity, hearing difficulties, easy bruising, hair loss, frequent
or painful urination, and bladder spasms.[91]:607

References[edit]
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3.

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11.

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Fibromyalgia at DMOZ

Arthritis Types Fibromyalgia by the CDC

Questions and Answers About Fibromyalgia by the National Institute of Arthritis and
Musculoskeletal and Skin Diseases

National Institute of Arthritis and Musculoskeletal and Skin Diseases - US National

Institute of Arthritis and Musculoskeletal and Skin Diseases

Irritable bowel syndrome

From Wikipedia, the free encyclopedia

Jump to: navigation, search

This article is about a functional disorder. For bowel inflammation, see Inflammatory bowel
disease.

Irritable bowel syndrome

Classification and external resources
Synonyms

spastic colon, nervous colon, mucous colitis,

spastic bowel[1]

Specialty

Gastroenterology

ICD-10

K58

ICD-9-CM

564.1

DiseasesDB

30638

MedlinePlus 000246
eMedicine

med/1190

Patient UK

Irritable bowel syndrome

MeSH

D043183
[edit on Wikidata]

Irritable bowel syndrome (IBS) is a group of symptomsincluding abdominal pain and

changes in the pattern of bowel movements without any evidence of underlying damage.[1] These
symptoms occur over a long time, often years.[2] It has been classified into four main types
depending on if diarrhea is common, constipation is common, both are common, or neither
occurs very often (IBS-D, IBS-C, IBS-M, or IBS-U respectively).[1] IBS negatively affects
quality of life and may result in missed school or work.[3] Disorders such as anxiety, major
depression, and chronic fatigue syndrome, are common among people with IBS.[1][4]
The causes of IBS are not clear.[2] Theories include gutbrain axis problems, small intestinal
bacterial overgrowth, genetic factors, food sensitivity, and gut motility problems.[2] Onset may be
triggered by an intestinal infection,[5] or stressful life event.[6] IBS is a functional gastrointestinal
disorder.[1] Diagnosis is based on signs and symptoms in the absence of worrisome features.[7]
Worrisome features include onset at greater than 50 years of age, weight loss, blood in the stool,
or a family history of inflammatory bowel disease.[7] Other conditions that may present similarly

include celiac disease, microscopic colitis, inflammatory bowel disease, bile acid malabsorption,
and colon cancer.[7]
There is no cure for IBS.[8] Treatment is carried out to improve symptoms.[8] This may including
dietary changes, medication, probiotics, and counselling.[8] Dietary measures include increasing
soluble fiber intake, a gluten free diet, or a diet low in fermentable oligosaccharides,
disaccharides, monosaccharides, and polyols (FODMAP).[7][9] The medication loperamide may be
used to help with diarrhea while laxatives may be used to help with constipation.[7]
Antidepressants may improve overall symptoms and pain.[7] Patient education and a good doctor
patient relationships are an important part of care.[7][10]
About 10 to 15% of people in the developed world are believed to be affected by IBS.[1][11] It is
more common in South America and less common in Southeast Asia.[7] It is twice as common in
women as men and typically occurs before age 45.[1] The condition appears to become less
common with age.[7] IBS does not affect life expectancy or lead to other serious diseases.[12] The
first description of the condition was in 1820 while the current term "irritable bowel syndrome"
came into use in 1944.[13]

Contents
[hide]

1 Classification

2 Signs and symptoms

3 Cause
o 3.1 Post-infectious
o 3.2 Stress
o 3.3 Bacteria
o 3.4 Fungus
o 3.5 Protozoa

4 Mechanism

5 Diagnosis
o 5.1 Differential diagnosis
o 5.2 Investigations

o 5.3 Misdiagnosis
o 5.4 Comorbidities

6 Management
o 6.1 Diet

6.1.1 FODMAPs diet

6.1.2 Fiber

o 6.2 Medication

6.2.1 Laxatives

6.2.2 Antispasmodics

6.2.3 Discontinuation of proton pump inhibitors

6.2.4 Tricyclic antidepressants

6.2.5 Serotonin agonists

6.2.6 Serotonin antagonists

6.2.7 Other agents

6.2.8 SIBO therapy

o 6.3 Psychological therapies

o 6.4 Stress relief

6.4.1 Probiotics

6.4.2 Herbal remedies

6.4.3 Yoga

6.4.4 Acupuncture

7 Epidemiology

o 7.1 Gender

8 History

9 Economics
o 9.1 United States

10 Research

11 References

12 External links

Classification[edit]
IBS can be classified as either diarrhea-predominant (IBS-D), constipation-predominant (IBS-C),
or with alternating stool pattern (IBS-A) or pain-predominant.[14] In some individuals, IBS may
have an acute onset and develop after an infectious illness characterized by two or more of:
fever, vomiting, diarrhea, or positive stool culture. This postinfective syndrome has consequently
been termed "postinfectious IBS" (IBS-PI).

Signs and symptoms[edit]

The primary symptoms of IBS are abdominal pain or discomfort in association with frequent
diarrhea or constipation and a change in bowel habits.[15] Symptoms usually are experienced as
acute attacks that subside within one day, but recurrent attacks are likely.[16] There may also be
urgency for bowel movements, a feeling of incomplete evacuation (tenesmus), bloating, or
abdominal distension.[17] In some cases, the symptoms are relieved by bowel movements.[10]
People with IBS, more commonly than others, have gastroesophageal reflux, symptoms relating
to the genitourinary system, chronic fatigue syndrome, fibromyalgia, headache, backache, and
psychiatric symptoms such as depression and anxiety.[4][17] About a third of men and women who
have IBS also report sexual dysfunction typically in the form of a reduction in libido.[18]

Cause[edit]
While the causes of IBS are still unknown, it is believed that the entire gutbrain axis is affected.
[19][20]

The risk of developing IBS increases six-fold after acute gastrointestinal infection. Postinfection,
further risk factors are young age, prolonged fever, anxiety, and depression.[21] Psychological
factors, such as depression or anxiety, have not been shown to cause or influence the onset of
IBS, but may play a role in the persistence and perceived severity of symptoms.[22] Nevertheless,
they may worsen IBS symptoms and the patient quality of life.[22] Antibiotic use also appears to

increase the risk of developing IBS.[23] Research has found that genetic defects in innate immunity
and epithelial homeostasis increase the risk of developing both post-infectious as well as other
forms of IBS.[24]

Post-infectious[edit]
Approximately 10 percent of IBS cases are triggered by an acute gastroenteritis infection.
Genetic defects relating to the innate immune system and epithelial barrier as well as high stress
and anxiety levels appear from evidence to increase the risk of developing post-infectious IBS.
Post-infectious IBS usually manifests itself as the diarrhea predominant subtype. Evidence has
demonstrated that the release of high levels of proinflammatory cytokines during acute enteric
infection causes increased gut permeability leading to translocation of the commensal bacteria
across the epithelial barrier resulting in significant damage to local tissues which is likely to
result in chronic gut abnormalities in sensitive individuals. However, increased gut permeability
is strongly associated with IBS regardless of whether IBS was initiated by an infection or not.[24]

Stress[edit]
Publications suggesting the role of brain-gut "axis" appeared in the 1990s[25] and childhood
physical and psychological abuse is often associated with the development of IBS.[26]
Given the high levels of anxiety seen in IBS patients and the overlap with conditions such as
fibromyalgia and chronic fatigue syndrome, a potential model of IBS involves a disruption of the
stress system. The stress response in the body involves the HPA axis and the sympathetic nervous
system, both of which have been shown to operate abnormally in IBS patients. Psychiatric illness
or anxiety precedes IBS symptoms in two-thirds of patients, and psychological traits predispose
previously healthy people to developing IBS after gastroenteritis.[27][28]

Bacteria[edit]
Small intestinal bacterial overgrowth occurs with greater frequency in patients who have been
diagnosed with IBS compared to healthy controls. SIBO is most common in diarrhea
predominate IBS but also occurs in constipation predominant IBS more frequently than healthy
controls. Symptoms of SIBO include bloating, abdominal pain, diarrhea or constipation among
others. IBS may be the result of the immune system interacting abnormally with gut microbiota
resulting in an abnormal cytokine signalling profile.[29]

Fungus[edit]
There is growing evidence that alterations of gut microbiota (dysbiosis) is associated with the
intestinal manifestations of IBS, but also with the psychiatric morbidity that coexists in up to
80% of patients with IBS.[30] The role of the gut mycobiota, and especially of the abnormal
proliferation of the yeast Candida albicans in some patients with IBS, is under investigation.[31]

Protozoa[edit]

Prevalence of protozoal infections in industrialized countries (United States and Canada) in the
21st century[32][33]
Protozoal infections can cause symptoms that mirror specific IBS subtypes,[34] e.g., infection by
certain substypes of blastocystis hominis (blastocystosis) has a significant (possibly causal)
relationship with IBS-D;[35][36] certain protozoal infections also occur more frequently in IBS
patients.[37][38] Dientamoeba fragilis has also been considered a possible organism to study, though
it is also found in people without IBS.[39]

Mechanism[edit]
There is evidence that abnormalities occur in the gut flora of individuals who have IBS, such as
reduced diversity, a decreased abundance of bacteria belonging to the phylum Bacteroidetes, and
an increased abundance of those belonging to the phylum Firmicutes.[40] The changes in gut flora
are most profound in individuals who have diarrhoea predominant IBS. Antibodies against
common components (namely flagellin) of the commensal gut flora are a common occurrence in
IBS affected individuals.[41] Chronic low-grade inflammation commonly occurs in IBS affected
individuals with abnormalities found including increased enterochromaffin cells, intraepithelial
lymphocytes, and mast cells resulting in chronic immune mediated inflammation of the gut
mucosa.[19][42]
Genetic, environmental, and psychological factors seem to be important in the development of
IBS. Studies have shown that IBS has a genetic component even though there is a predominant
influence of environmental factors.[43] IBS has been reported in greater quantities in
multigenerational families with IBS than in the regular population.[44]

Diagnosis[edit]

No specific laboratory or imaging test can be performed to diagnose irritable bowel syndrome.
Diagnosis involves excluding conditions that produce IBS-like symptoms, and then following a
procedure to categorize the patient's symptoms. Ruling out parasitic infections, lactose
intolerance, small intestinal bacterial overgrowth, and celiac disease is recommended for all
patients before a diagnosis of irritable bowel syndrome is made. In patients over 50 years old,
they are recommended to undergo a screening colonoscopy.[45] IBS sufferers are at increased risk
of being given inappropriate surgeries such as appendectomy, cholecystectomy, and
hysterectomy due to their IBS symptoms being misdiagnosed as other medical conditions.[46]

Differential diagnosis[edit]
Colon cancer, inflammatory bowel disease, thyroid disorders, and giardiasis can all feature
abnormal defecation and abdominal pain. Less common causes of this symptom profile are
carcinoid syndrome, microscopic colitis, bacterial overgrowth, and eosinophilic gastroenteritis;
IBS is, however, a common presentation, and testing for these conditions would yield low
numbers of positive results, so it is considered difficult to justify the expense.[47]
Some people, managed for years for IBS, may have non-celiac gluten sensitivity (NCGS).[48]
Gastrointestinal symptoms of IBS are clinically indistinguishable from those of NCGS, but the
presence of any of the following non-intestinal manifestations suggest a possible NCGS:
headache or migraine, "foggy mind", chronic fatigue,[49] fibromyalgia,[50][51][52] joint and muscle
pain,[49][50][53] leg or arm numbness,[49][50][53] tingling of the extremities,[49][53] dermatitis (eczema or skin
rash),[49][53] atopic disorders,[49] allergy to one or more inhalants, foods or metals[49][50] (such as mites,
graminaceae, parietaria, cat or dog hair, shellfish, or nickel[50]), depression,[49][50][53] anxiety,[50]
anemia,[49][53] iron-deficiency anemia, folate deficiency, asthma, rhinitis, eating disorders,[50]
neuropsychiatric disorders (such as schizophrenia,[53][54] autism,[50][53][54] peripheral neuropathy,[53][54]
ataxia,[54] attention deficit hyperactivity disorder[49]) or autoimmune diseases.[49] An improvement
with a gluten-free diet of immune-mediated symptoms, including autoimmune diseases, once
reasonably ruled out coeliac disease and wheat allergy, is another way to realize a differential
diagnosis.[49]
Because many causes of diarrhea give IBS-like symptoms, the American Gastroenterological
Association published a set of guidelines for tests to be performed to rule out other causes for
these symptoms. These include gastrointestinal infections, lactose intolerance, and coeliac
disease. Research has suggested these guidelines are not always followed.[45] Once other causes
have been excluded, the diagnosis of IBS is performed using a diagnostic algorithm. Well-known
algorithms include the Manning criteria, the obsolete Rome I and II criteria, and the Kruis
criteria, and studies have compared their reliability.[55] The more recent Rome III process was
published in 2006. Physicians may choose to use one of these guidelines or may simply choose
to rely on their own anecdotal experience with past patients. The algorithm may include
additional tests to guard against misdiagnosis of other diseases as IBS. Such "red flag" symptoms
may include weight loss, gastrointestinal bleeding, anemia, or nocturnal symptoms. However,
red flag conditions may not always contribute to accuracy in diagnosis; for instance, as many as
31% of IBS patients have blood in their stool, many possibly from hemorrhoidal bleeding.[55]

The diagnostic algorithm identifies a name that can be applied to the patient's condition based on
the combination of the patient's symptoms of diarrhea, abdominal pain, and constipation. For
example, the statement "50% of returning travelers had developed functional diarrhea while 25%
had developed IBS" would mean half the travelers had diarrhea while a quarter had diarrhea with
abdominal pain. While some researchers believe this categorization system will help physicians
understand IBS, others have questioned the value of the system and suggested all IBS patients
have the same underlying disease but with different symptoms.[56]

Investigations[edit]
Investigations are performed to exclude other conditions:

Stool microscopy and culture (to exclude infectious conditions)

Blood tests: Full blood examination, liver function tests, erythrocyte sedimentation rate,
and serological testing for coeliac disease

Abdominal ultrasound (to exclude gallstones and other biliary tract diseases)

Endoscopy and biopsies (to exclude peptic ulcer disease, coeliac disease, inflammatory
bowel disease, and malignancies)

Hydrogen breath testing (to exclude fructose and lactose malabsorption)

Misdiagnosis[edit]
Some common examples of misdiagnosis include infectious diseases, coeliac disease,[57]
Helicobacter pylori,[58][59] parasites (non-protozoal).[34][60][61]
Coeliac disease in particular is often misdiagnosed as IBS. The American College of
Gastroenterology recommends all patients with symptoms of IBS be tested for coeliac disease.[62]
Bile acid malabsorption is also sometimes missed in patients with diarrhea-predominant IBS.
SeHCAT tests suggest around 30% of D-IBS patients have this condition, and most respond to
bile acid sequestrants.[63]
Chronic use of certain sedative-hypnotic drugs, especially the benzodiazepines, may cause
irritable bowel-like symptoms that can lead to a misdiagnosis of irritable bowel syndrome.[64]

Comorbidities[edit]
Several medical conditions, or comorbidities, appear with greater frequency in patients
diagnosed with IBS.

Neurological/Psychiatric: A study of 97,593 individuals with IBS identified comorbidities

such as headache, fibromyalgia, and depression.[65] IBS occurs in 51% of chronic fatigue
syndrome patients and 49% of fibromyalgia patients, and psychiatric disorders occur in
94% of IBS patients.[4]

Inflammatory bowel disease: IBS may be a type of low-grade inflammatory bowel

disease.[66] Researchers have suggested IBS and IBD are interrelated diseases,[67] noting
that patients with IBD experience IBS-like symptoms when their IBD is in remission.[68][69]
A three-year study found that patients diagnosed with IBS were 16.3 times more likely to
be diagnosed with IBD during the study period.[70] Serum markers associated with
inflammation have also been found in patients with IBS.

Abdominal surgery: IBS patients were at increased risk of having unnecessary gall
bladder removal surgery not due to an increased risk of gallstones, but rather to
abdominal pain, awareness of having gallstones, and inappropriate surgical indications.[71]
These patients also are 87% more likely to undergo abdominal and pelvic surgery and
three times more likely to undergo gallbladder surgery.[72] Also, IBS patients were twice as
likely to undergo hysterectomy.[73]

Endometriosis: One study reported a statistically significant link between migraine

headaches, IBS, and endometriosis.[74]

Other chronic disorders: Interstitial cystitis may be associated with other chronic pain
syndromes, such as irritable bowel syndrome and fibromyalgia. The connection between
these syndromes is unknown.[75]

Management[edit]
A number of treatments have been found to be effective including: fiber, talk therapy,
antispasmodic and antidepressant medication, and peppermint oil.[76][77][78]

Diet[edit]
Studies have shown that up to 70% of IBS patients benefited from eating a low FODMAP diet.
Symptoms most likely to improve from such a diet include urgency, flatulence, bloating,
abdominal pain, and altered stool output. One national guideline advises a low FODMAP diet for
managing IBS when other dietary and lifestyle measures have been unsuccessful.[79] This diet
restricts various carbohydrates which are poorly absorbed in the small intestine, as well as
fructose and lactose, which are similarly poorly absorbed in those with intolerances to them.
Reduction of fructose and fructan has been shown to reduce IBS symptoms in a dose-dependent
manner in patients with fructose malabsorption and IBS.[80]
Some IBS patients believe they have some form of dietary intolerance; however, tests attempting
to predict food sensitivity in IBS have proven disappointing. A small study reported that an IgG
antibody test was somewhat effective in determining food sensitivity in IBS patients, with

patients on the elimination diet experiencing 10% greater symptom-reduction than those on a
sham diet.[81] However, more research is necessary before IgG testing can be recommended.[82]
FODMAPs diet[edit]
A diet restricted in fermentable oligo- di- and monosaccharides and polyols (FODMAPs) now
has an evidence base sufficiently strong to recommend its widespread application in conditions
such as IBS and IBD.[83] They also state the restriction of FODMAPs globally, rather than
individually, controls the symptoms of functional gut disorders (e.g., IBS), and the majority of
IBD patients respond just as well. It is more successful than restricting only fructose and
fructans, which are also FODMAPs, as is recommended for those with fructose malabsorption.
Longer-term compliance with the diet was high.
Fiber[edit]
Some evidence suggests soluble fiber supplementation (e.g., psyllium/ispagula husk) is effective.
[9]
It acts as a bulking agent, and for many IBS-D patients, allows for a more consistent stool. For
IBS-C patients, it seems to allow for a softer, moister, more easily passable stool.
However, insoluble fiber (e.g., bran) has not been found to be effective for IBS.[84][85] In some
people, insoluble fiber supplementation may aggravate symptoms.[86][87]
Fiber might be beneficial in those who have a predominance of constipation. In people who have
IBS-C, soluble fiber can reduce overall symptoms, but will not reduce pain. The research
supporting dietary fiber contains conflicting, small studies complicated by the heterogeneity of
types of fiber and doses used.[88]
One meta-analysis found only soluble fiber improved global symptoms of irritable bowel, but
neither type of fiber reduced pain.[88] An updated meta-analysis by the same authors also found
soluble fiber reduced symptoms, while insoluble fiber worsened symptoms in some cases.[89]
Positive studies have used 1030 grams per day of psyllium.[90][91] One study specifically
examined the effect of dose, and found 20 g of ispaghula husk were better than 10 g and
equivalent to 30 g per day.[92]

Medication[edit]
Medications may consist of stool softeners and laxatives in IBS-C and antidiarrheals (e.g.,
opiate, opioid, or opioid analogs such as loperamide, codeine, diphenoxylate) in IBS-D for mild
symptoms and stronger opiates such as morphine and oxycodone for severe cases.[93][94][95]
Drugs affecting serotonin (5-HT) in the intestines can help reduce symptoms.[96] On the other
hand, many IBS-D patients report that SSRI type medications exacerbate spasms and diarrhea.
This is thought to be due to the large number of serotonin receptors in the gut. 5HT3 antagonists
such as ondansetron are effective in postinfectious IBS and diarrhoea-dominant IBS due to their
blockade of serotonin on 5HT3 receptors in the gut; the reason for their benefit is believed to be
that excessive serotonin in the gut is thought to play a role in the pathogenesis of some subtypes

of IBS. Certain atypical antipsychotic medications, such as clozapine and olanzapine, may also
provide relief due to serotonergic properties these agents possess, acting on the same receptors as
other medications in this specific category.[97] Benefits may include reduced diarrhoea, reduced
abdominal cramps, and improved general well-being. Any nausea present may also respond to
5HT3 antagonists owing to their antiemetic properties.[98] Serotonin stimulates the gut motility
and so agonists can help constipation-predominate irritable bowel, while antagonists can help
diarrhea-predominant irritable bowel. Selective serotonin reuptake inhibitors, SSRIs, frequently
prescribed for panic and/or anxiety disorder and depression, affect serotonin in the gut, as well as
the brain. The bowels are highly dependent on serotonin for neural communication. "Selective
serotonin reuptake inhibitor antidepressants seem to promote global well-being in some patients
with irritable bowel syndrome and, possibly, some improvement in abdominal pain and bowel
symptoms, but this effect appears to be independent of improved depression. Further research is
required."[99]
Mast cells and the compound that they secrete are central to the pathophysiology and implicated
in the treatment of IBS;[19] some of the secreted mast cell mediators (and associated receptors)
which have been implicated in symptoms of IBS or specific subtypes include: histamine (HRH1,
HRH2, HRH3), tryptase and chymase (PAR2), serotonin (5-HT3), PGD2 (DP1).[19] Histamine
also causes epithelial secretion of chloride ions and water (associated with secretory diarrhea) by
signaling through a receptor or ligand-gated ion channel that has not been identified as of 2015.[19]
A 2015 review noted that both H1-antihistamines and mast cell stabilizers have shown efficacy
in reducing pain associated with visceral hypersensitivity in IBS;[19] other lower quality studies
have also suggested the benefit of these agents for IBS.[19] In a related review on idiopathic mast
cell activation syndromes (including IBS), a combined treatment approach using
antileukotrienes, H1/H2-antihistamines, and a mast cell stabilizer are suggested.[100]
Laxatives[edit]
For patients who do not adequately respond to dietary fiber, osmotic laxatives such as
polyethylene glycol, sorbitol, and lactulose can help avoid "cathartic colon" which has been
associated with stimulant laxatives.[101] Among the osmotic laxatives, doses of 1726 g/d of
polyethylene glycol have been well studied. Lubiprostone (Amitiza) is a gastrointestinal agent
used for the treatment of idiopathic chronic constipation and constipation-predominant IBS. It is
well tolerated in adults, including elderly patients. As of July 20, 2006, lubiprostone had not been
studied in pediatric patients. Lubiprostone is a bicyclic fatty acid (prostaglandin E1 derivative)
that acts by specifically activating ClC-2 chloride channels on the apical aspect of
gastrointestinal epithelial cells, producing a chloride-rich fluid secretion. These secretions soften
the stool, increase motility, and promote spontaneous bowel movements. Unlike many laxative
products, lubiprostone does not show signs of tolerance, dependency, or altered serum electrolyte
concentration.
Antispasmodics[edit]
The use of antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine) may
help patients, especially those with cramps or diarrhea. A meta-analysis by the Cochrane

Collaboration concludes if seven patients are treated with antispasmodics, one patient will
benefit.[93] Antispasmodics can be divided in two groups: neurotropics and musculotropics.

Neurotropics for example, phenobarbitals such as Donnatal or atropine act at the

nerve fibre of the parasympathicus, but also affect other nerves, causing side effects in
many patients.

Musculotropics, such as mebeverine, act directly at the smooth muscle of the

gastrointestinal tract, relieving spasm without affecting normal gut motility.[citation needed] Since
this action is not mediated by the autonomic nervous system, the usual anticholinergic
side effects are absent.[citation needed]

Discontinuation of proton pump inhibitors[edit]

Proton pump inhibitors (PPIs) used to suppress stomach acid production may cause bacterial
overgrowth leading to IBS symptoms. Discontinuation of PPIs in selected individuals has been
recommended as it may lead to an improvement or resolution of IBS symptoms.[102]
Tricyclic antidepressants[edit]
Strong evidence indicates low doses of tricyclic antidepressants can be effective for IBS.
However, the evidence is less robust as to the effectiveness of other antidepressant classes such
as SSRIs.[85][87]
Serotonin agonists[edit]

Tegaserod (Zelnorm), a selective 5-HT4 agonist for IBS-C, is available for relieving IBS
constipation in women and chronic idiopathic constipation in men and women. On March
30, 2007, the FDA requested Novartis Pharmaceuticals to voluntarily discontinue
marketing of tegaserod based on the recently identified finding of an increased risk of
serious cardiovascular adverse events (heart problems) associated with use of the drug.
Novartis agreed to voluntarily suspend marketing of the drug in the United States and in
many other countries. On July 27, 2007, the FDA approved a limited-treatment IND
program for tegaserod in the US to allow restricted access to the medication for patients
in need if no comparable alternative drug or therapy is available to treat the disease. The
FDA had issued two previous warnings about the serious consequences of tegaserod. In
2005, it was rejected as an IBS medication by the European Union. Tegaserod, marketed
as Zelnorm in the United States, was the only agent approved to treat the multiple
symptoms of IBS (in women only), including constipation, abdominal pain, and bloating.

Selective serotonin reuptake inhibitor antidepressants (SSRIs), because of their

serotonergic effect, would seem to help IBS, especially patients who are constipation
predominant. Initial crossover studies[103] and randomized controlled trials[104][105][106] support
this role.

Serotonin antagonists[edit]

Alosetron, a selective 5-HT3 antagonist for IBS-D and cilansetron (also a selective 5-HT3
antagonist) were trialed for IBS. Due to severe adverse effects, namely ischemic colitis and
severe constipation, they are not available or recommended.[87]
Other agents[edit]
Magnesium aluminum silicates and alverine citrate drugs can be effective for IBS.[87]
Evidence is conflicting about the benefit of antidepressants in IBS. Some meta-analyses have
found a benefit, while others have not.[107] A meta-analysis of randomized controlled trials of
mainly TCAs found three patients have to be treated with TCAs for one patient to improve.[108] A
separate randomized controlled trial found TCAs are best for patients with IBS-D.[109]
Rifaximin can be used as an effective treatment for abdominal bloating and flatulence,[110][111]
giving more credibility to the potential role of bacterial overgrowth in some patients with IBS.[112]
Domperidone, a dopamine receptor blocker and a parasympathomimetic, has been shown to
reduce bloating and abdominal pain as a result of an accelerated colon transit time and reduced
faecal load, that is, a relief from 'hidden constipation'; defecation was similarly improved.[113]
The use of opioids is controversial due to the potential risk of tolerance, physical dependence,
and addiction, but can be the only relief for some diarrhea-predominant cases when other
treatment has been ineffective.[114]
SIBO therapy[edit]
Statistically significant reduction in IBS symptoms occurs following antibiotic therapy for small
intestinal bacterial overgrowth.[115] However, recent research has shown that the lactulose
hydrogen breath test does not actually measure SIBO, and that SIBO is unlikely to be the cause
of IBS.[116]

Psychological therapies[edit]
The mind-body or brain-gut interactions has been proposed for IBS, and is gaining increasing
research attention.[85] Hypnosis can improve mental well-being, and cognitive behavioural therapy
can provide psychological coping strategies for dealing with distressing symptoms, as well as
help suppress thoughts and behaviours that increase the symptoms of IBS,[85][87] although the
evidence base for effectiveness of psychotherapy and hypnosis is weak and such therapies are in
general not recommended.[46] However, in treatment resistant cases where pharmacological
therapies over a period of at least 12 months have failed to give relief, NICE clinical guidelines
recommend that consideration should be given to psychological treatment strategies such as
cognitive behavioural therapy [CBT], hypnotherapy and/or psychological therapy.[117]

Stress relief[edit]

Reducing stress may reduce the frequency and severity of IBS symptoms. Techniques that may
be helpful include:

Relaxation techniques such as meditation

Physical activities such as yoga or tai chi

Regular exercise such as swimming, walking, or running[118]

Probiotics[edit]
Probiotics can be beneficial in the treatment of IBS; taking 10 billion to 100 billion beneficial
bacteria per day is recommended for beneficial results. However, further research is needed on
individual strains of beneficial bacteria for more refined recommendations.[85][119] Probiotics have
positive effects such as enhancing the intestinal mucosal barrier, providing a physical barrier,
bacteriocin production (resulting in reduced numbers of pathogenic and gas-producing bacteria),
reducing intestinal permeability and bacterial translocation, and regulating the immune system
both locally and systemically among other beneficial effects.[46] Probiotics may also have positive
effects on the gut-brain axis by their positive effects countering the effects of stress on gut
immunity and gut function.[120]
A number of probiotics have been found to be effective, including Lactobacillus plantarum,[46]
and Bifidobacteria infantis;[121] but one review found only Bifidobacteria infantis showed
efficacy.[122] B. infantis may have effects beyond the gut via it causing a reduction of
proinflammatory cytokine activity and elevation of blood tryptophan levels, which may cause an
improvement in symptoms of depression.[123] Some yogurt is made using probiotics that may help
ease symptoms of IBS.[124] A probiotic yeast called Saccharomyces boulardii has some evidence
of effectiveness in the treatment of irritable bowel syndrome.[125]
Certain probiotics have different effects on certain symptoms of IBS. For example,
Bifidobacterium breve, B. longum, and Lactobacillus acidophilus have been found to alleviate
abdominal pain. B. breve, B. infantis, L. casei, or L. plantarum species alleviated distension
symptoms. B. breve, B. infantis, L. casei, L. plantarum, B. longum, L. acidophilus, L. bulgaricus,
and Streptococcus salivarius ssp. thermophilus have all been found to affect flatulence levels.
Most clinical studies show probiotics do not improve straining, sense of incomplete evacuation,
stool consistency, fecal urgency, or stool frequency, although a few clinical studies did find some
benefit of probiotic therapy. The evidence is conflicting for whether probiotics improve overall
quality of life scores.[126]
Probiotics may exert their beneficial effects on IBS symptoms via preserving the gut microbiota,
normalisation of cytokine blood levels, improving the intestinal transit time, decreasing small
intestine permeability, and by treating small intestinal bacterial overgrowth of fermenting
bacteria.[126]
Herbal remedies[edit]

Peppermint oil appears useful.[127] Safety during pregnancy has not been established, however,
and caution is required not to chew or break the enteric coating; otherwise, gastroesophageal
reflux may occur as a result of lower esophageal sphincter relaxation. Occasionally, nausea and
perianal burning occur as side effects.[85] Iberogast, a multi-herbal extract, was found to be
superior in efficacy to placebo.[128] Commiphora mukul and Plantago ovata[129]
Only limited evidence exists for the effectiveness of other herbal remedies for IBS. As with all
herbs, it is wise to be aware of possible drug interactions and adverse effects.[85]
Yoga[edit]
Yoga may be effective for some IBS patients, especially poses which exercise the lower
abdomen.[87]
Acupuncture[edit]
A meta-analysis found no benefits of acupuncture relative to placebo for IBS symptom severity
or IBS-related quality of life.[130] Acupuncture might be beneficial for some patients with IBS, but
current evidence does not support its use.[85]

Epidemiology[edit]

Percentage of population with IBS reported in various studies in different countries

The prevalence of IBS varies by country and by age range examined. The bar graph at right
shows the percentage of the population reporting symptoms of IBS in studies from various
geographic regions (see table below for references). The following table contains a list of studies
performed in different countries that measured the prevalence of IBS and IBS-like symptoms:
[hide]Percentage of population reporting symptoms of IBS in various studies from various
geographic areas
Country Prevalence Author/year
Notes
[131]
Canada
6%
Boivin, 2001
Study measured prevalence of GI abdominal
Japan
10%[132]
Quigley, 2006
pain/cramping
[133]
United
8.2%
Ehlin, 2003 Prevalence increased substantially 19702004
Kingdom

10.5%[134]

Wilson, 2004

14.1%[135]

Hungin, 2005 Most undiagnosed

15%[131]

Boivin, 2001 Estimate

Pakistan

14%[136]

Jafri, 2007

Pakistan

34%[137]

Mexico
City

35%[138]

Brazil

43%[132]

Mexico

46%[132]

United
States
United
States

Much more common in 1630 age range. Of IBS

patients, 56% male, 44% female
Jafri, 2005
College students
n=324. Also measured functional diarrhea and
Schmulson,
functional vomiting. High rates attributed to "stress of
2006
living in a populated city."
Study measured prevalence of GI abdominal
Quigley, 2006
pain/cramping
Study measured prevalence of GI abdominal
Quigley, 2006
pain/cramping

Gender[edit]
Women are around two to three times more likely to be diagnosed with IBS and four to five
times more likely to seek specialty care for it than men.[139] These differences likely reflect a
combination of both biological (sex) and social (gender) factors. People diagnosed with IBS are
usually younger than 45 years old.[1] Studies of female patients with IBS show symptom severity
often fluctuates with the menstrual cycle, suggesting hormonal differences may play a role.[140]
Endorsement of gender-related traits has been associated with quality of life and psychological
adjustment in IBS.[141] Gender differences in healthcare-seeking may also play a role.[142] Gender
differences in trait anxiety may contribute to lower pain thresholds in women, putting them at
greater risk for a number of chronic pain disorders.[143] Finally, sexual trauma is a major risk
factor for IBS, with as many as 33% of all patients reporting such abuse. Because women are at
higher risk of sexual abuse than men, gender-related risk of abuse may contribute to the higher
prevalence of IBS in women.[144]

History[edit]
One of the first references to the concept of an "irritable bowel" appeared in the Rocky Mountain
Medical Journal in 1950.[145] The term was used to categorize patients who developed symptoms
of diarrhea, abdominal pain, and constipation, but where no well-recognized infective cause
could be found. Early theories suggested the irritable bowel was caused by a psychosomatic or
mental disorder.

Economics[edit]

The examples and perspective in this section may not represent a worldwide
view of the subject. Please improve this article and discuss the issue on the talk
page. (July 2011)

United States[edit]
The aggregate cost of irritable bowel syndrome in the United States has been estimated at $1.7
10 billion in direct medical costs, with an additional $20 billion in indirect costs, for a total of
$21.730 billion.[3] A study by a managed care company comparing medical costs of IBS patients
to non-IBS controls identified a 49% annual increase in medical costs associated with a diagnosis
of IBS.[146] IBS patients incurred average annual direct costs of $5,049 and $406 in out-of-pocket
expenses in 2007.[147] A study of workers with IBS found that they reported a 34.6% loss in
productivity, corresponding to 13.8 hours lost per 40 hour week.[148] A study of employer-related
health costs from a Fortune 100 company conducted with data from the 1990s found IBS patients
incurred US $4527 in claims costs vs. $3276 for controls.[149] A study on Medicaid costs
conducted in 2003 by the University of Georgia's College of Pharmacy and Novartis found IBS
was associated in an increase of $962 in Medicaid costs in California, and $2191 in North
Carolina. IBS patients had higher costs for physician visits, outpatients visits, and prescription
drugs. The study suggested the costs associated with IBS were comparable to those found in
asthma patients.[150]

Research[edit]
Individuals with IBS have been found to have decreased diversity and numbers of bacteroidetes
microbiota. Preliminary research into the effectiveness of fecal microbiota transplant in the
treatment of IBS has been very favourable with a 'cure' rate of between 36 percent and 60 percent
with remission of core IBS symptoms persisting at 9 and 19 months follow up.[151][152] Treatment
with probiotic strains of bacteria has shown to be effective, though not all strains of
microorganisms confer the same benefit and adverse side effects have been documented in a
minority of cases.[153]
There is increasing evidence for the effectiveness of mesalazine, an aminosalicylate[disambiguation needed]
drug, in the treatment of IBS.[154] Mesalazine is a drug with anti-inflammatory properties that has
been reported to significantly reduce immune mediated inflammation in the gut of IBS affected
individuals with mesalazine therapy resulting in improved IBS symptoms as well as feelings of
general wellness in IBS affected people. It has also been observed that mesalazine therapy helps
to normalise the gut flora which is often abnormal in people who have IBS. The therapeutic
benefits of mesalazine may be the result of improvements to the epithelial barrier function.[155]
An IgG-mediated food intolerance diet led to a 24% greater deterioration in symptoms compared
to those on the elimination diet and food elimination based on IgG antibodies may be effective in
reducing IBS symptoms and is worthy of further biomedical research.[81] The main problem with
this study was that the differences in symptoms were only observed in exclusion diets is limited,
treatment based on "abnormally" high IgG antibodies cannot be recommended.[156]

Differences in visceral sensitivity and intestinal physiology have been noted in IBS. Mucosal
barrier reinforcement in response to oral 5-HTP was absent in IBS compared to controls.[157]
IBS/IBD individuals are less often HLA DQ2/8 positive than in upper functional gastrointestinal
disease and healthy populations.[158]
A questionnaire in 2006 designed to identify patients' perceptions about IBS, their preferences on
the type of information they need, and educational media and expectations from health care
providers revealed misperceptions about IBS developing into other conditions, including colitis,
malnutrition, and cancer. The survey found IBS patients were most interested in learning about
foods to avoid (60%), causes of IBS (55%), medications (58%), coping strategies (56%), and
psychological factors related to IBS (55%). The respondents indicated they wanted their
physicians to be available by phone or e-mail following a visit (80%), have the ability to listen
(80%), and provide hope (73%) and support (63%).[159]

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External links[edit]

Irritable bowel syndrome at DMOZ

UNC Center for Functional GI & Motility Disorders