A radioactive tracer, radiotracer, or radioactive label is a chemical compound in which one or more atoms have been replaced by a radionuclide so by virtue of its radioactive decay
it can be used to explore the mechanism of chemical reactions by
tracing the path that the radioisotope follows from reactants to
products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling. In biological contexts, use of radioisotope tracers are sometimes called radioisotope feeding experiments.
Isotopes of a chemical element differ only in the mass number. For example, the isotopes of hydrogen can be written as 1H, 2H and 3H, with the mass number superscripted to the left. When the atomic nucleus of an isotope is unstable, compounds containing this isotope are radioactive. Tritium is an example of a radioactive isotope.
The principle behind the use of radioactive tracers is that an atom in a chemical compound
is replaced by another atom, of the same chemical element. The
substituting atom, however, is a radioactive isotope. This process is
often called radioactive labeling. The power of the technique is due to
the fact that radioactive decay is much more energetic than chemical
reactions. Therefore, the radioactive isotope can be present in low
concentration and its presence detected by sensitive radiation detectors such as Geiger counters and scintillation counters. George de Hevesy won the 1943 Nobel Prize for Chemistry "for his work on the use of isotopes as tracers in the study of chemical processes".
There are two main ways in which radioactive tracers are used
When a labeled chemical compound undergoes chemical reactions
one or more of the products will contain the radioactive label. Analysis
of what happens to the radioactive isotope provides detailed
information on the mechanism of the chemical reaction.
A radioactive compound is introduced into a living organism and the
radio-isotope provides a means to construct an image showing the way in
which that compound and its reaction products are distributed around the
organism.
Production
The commonly used radioisotopes have short half lives and so do not occur in nature in large amounts. They are produced by nuclear reactions.
One of the most important processes is absorption of a neutron by an
atomic nucleus, in which the mass number of the element concerned
increases by 1 for each neutron absorbed. For example,
In this case the atomic mass increases, but the element is unchanged.
In other cases the product nucleus is unstable and decays, typically
emitting protons, electrons (beta particle) or alpha particles. When a nucleus loses a proton the atomic number decreases by 1. For example,
Neutron irradiation is performed in a nuclear reactor.
The other main method used to synthesize radioisotopes is proton
bombardment. The proton are accelerated to high energy either in a cyclotron or a linear accelerator.
Tracer isotopes
Hydrogen
Tritium (hydrogen-3) is produced by neutron irradiation of 6Li:
Tritium has a half-life4500±8 days (approximately 12.32 years) and it decays by beta decay. The electrons
produced have an average energy of 5.7 keV. Because the emitted
electrons have relatively low energy, the detection efficiency by
scintillation counting is rather low. However, hydrogen atoms are
present in all organic compounds, so tritium is frequently used as a
tracer in biochemical studies.
14C decays by beta decay,
with a half-life of 5730 years. It is continuously produced in the
upper atmosphere of the earth, so it occurs at a trace level in the
environment. However, it is not practical to use naturally-occurring 14C for tracer studies. Instead it is made by neutron irradiation of the isotope 13C which occurs naturally in carbon at about the 1.1% level. 14C has been used extensively to trace the progress of organic molecules through metabolic pathways.
Nitrogen
13N decays by positron emission with a half-life of 9.97 min. It is produced by the nuclear reaction
15O decays by positron emission with a half-life of 122 sec. It is used in positron emission tomography.
Fluorine
18F decays predominately by β emission, with a half-life of 109.8 min. It is made by proton bombardment of 18O in a cyclotron or linear particle accelerator. It is an important isotope in the radiopharmaceutical industry. For example, it is used to make labeled fluorodeoxyglucose (FDG) for application in PET scans.
It decays by beta decay with a half-life of 14.29 days. It is commonly used to study protein phosphorylation by kinases in biochemistry.
33P is made in relatively low yield by neutron bombardment of 31P. It is also a beta-emitter, with a half-life of 25.4 days. Though more expensive than 32P, the emitted electrons are less energetic, permitting better resolution in, for example, DNA sequencing.
Both isotopes are useful for labeling nucleotides and other species that contain a phosphate group.
It decays by beta-decay with a half-life of 87.51 days. It is used to label the sulfur-containing amino-acidsmethionine and cysteine. When a sulfur atom replaces an oxygen atom in a phosphate group on a nucleotide a thiophosphate is produced, so 35S can also be used to trace a phosphate group.
99mTc is a very versatile radioisotope, and is the most commonly used radioisotope tracer in medicine. It is easy to produce in a technetium-99m generator, by decay of 99Mo.
99Mo → 99mTc + e− + ν e
The molybdenum isotope has a half-life of approximately 66 hours
(2.75 days), so the generator has a useful life of about two weeks. Most
commercial 99mTc generators use column chromatography, in which 99Mo in the form of molybdate, MoO42− is adsorbed onto acid alumina (Al2O3). When the 99Mo decays it forms pertechnetate TcO4−,
which because of its single charge is less tightly bound to the
alumina. Pulling normal saline solution through the column of
immobilized 99Mo elutes the soluble 99mTc, resulting in a saline solution containing the 99mTc as the dissolved sodium salt of the pertechnetate. The pertechnetate is treated with a reducing agent such as Sn2+ and a ligand. Different ligands form coordination complexes which give the technetium enhanced affinity for particular sites in the human body.
99mTc decays by gamma emission, with a half-life: 6.01
hours. The short half-life ensures that the body-concentration of the
radioisotope falls effectively to zero in a few days.
123I is produced by proton irradiation of 124Xe. The caesium isotope produced is unstable and decays to 123I. The isotope is usually supplied as the iodide and hypoiodate in dilute sodium hydroxide solution, at high isotopic purity. 123I has also been produced at Oak Ridge National Laboratories by proton bombardment of 123Te.
125I is frequently used in radioimmunoassays because of its relatively long half-life (59 days) and ability to be detected with high sensitivity by gamma counters.
129I is present in the environment as a result of the testing of nuclear weapons in the atmosphere. It was also produced in the Chernobyl and Fukushima disasters. 129I decays with a half-life of 15.7 million years, with low-energy beta and gamma
emissions. It is not used as a tracer, though its presence in living
organisms, including human beings, can be characterized by measurement
of the gamma rays.
Many other isotopes have been used in specialized radiopharmacological studies. The most widely used is 67Ga for gallium scans. 67Ga is used because, like 99mTc, it is a gamma-ray emitter and various ligands can be attached to the Ga3+ ion, forming a coordination complex which may have selective affinity for particular sites in the human body.
An extensive list of radioactive tracers used in hydraulic fracturing can be found below.
In metabolism research, tritium and 14C-labeled glucose are commonly used in glucose clamps to measure rates of glucose uptake, fatty acid synthesis, and other metabolic processes. While radioactive tracers are sometimes still used in human studies, stable isotope tracers such as 13C are more commonly used in current human clamp studies. Radioactive tracers are also used to study lipoprotein metabolism in humans and experimental animals.
In medicine, tracers are applied in a number of tests, such as 99mTc in autoradiography and nuclear medicine, including single-photon emission computed tomography (SPECT), positron emission tomography (PET) and scintigraphy. The urea breath test for helicobacter pylori commonly used a dose of 14C
labeled urea to detect h. pylori infection. If the labeled urea was
metabolized by h. pylori in the stomach, the patient's breath would
contain labeled carbon dioxide. In recent years, the use of substances
enriched in the non-radioactive isotope 13C has become the preferred method, avoiding patient exposure to radioactivity.
An alcoholic beverage (also called an adult beverage, alcoholic drink, strong drink, or simply a drink) is a drink that contains ethanol, a type of alcohol that acts as a drug and is produced by fermentation of grains, fruits, or other sources of sugar. The consumption of alcoholic drinks, often referred to as "drinking", plays an important social role in many cultures. Most countries have laws regulating the production, sale, and consumption of alcoholic beverages, and the temperance movement advocates against the consumption of alcoholic beverages. Regulations may require the labeling of the percentage alcohol content (as ABV or proof) and the use of a warning label. Some countriesban such activities entirely, but alcoholic drinks are legal in most parts of the world. The global alcoholic drink industry exceeded $1 trillion in 2018.
According to the World Health Organization, alcohol is the highest risk-group carcinogen, and no quantity of its consumption can be considered safe. According to the Centers for Disease Control and Prevention
dietary guidelines on alcohol, it is not recommended to start consuming
alcohol for any reason; for those who drink, "drinking less is better
for health than drinking more", and growing research indicates that even
moderate drinking has no positive health benefits overall.
A systemic metanalysis of 107 cohort studies concluded low daily
alcohol intake gives neither harm nor benefit; however, increased
consumption, even at relatively low levels of daily intake (>2
beverages for women and >3 beverages for men), does increase health
and mortality risks.
Alcohol is one of the most widely used recreational drugs in the world, and about 33% of all humans currently drink alcohol. In 2015, among Americans, 86% of adults had consumed alcohol at some point, with 70% drinking it in the last year and 56% in the last month. Alcoholic drinks are typically divided into three classes—beers, wines, and spirits—and typically their alcohol content is between 3% and 50%.
Discovery of late Stone Age jugs suggest that intentionally fermented drinks existed at least as early as the Neolithic period (c. 10,000 BC).
Several other animals are affected by alcohol similarly to humans and,
once they consume it, will consume it again if given the opportunity,
though humans are the only species known to produce alcoholic drinks
intentionally.
Fermented drinks
Wine (left) and beer (right) are served in different glasses.
Beer is a beverage fermented from grainmash. It is typically made from barley or a blend of several grains and flavored with hops.
Most beer is naturally carbonated as part of the fermentation process.
If the fermented mash is distilled, then the drink becomes a spirit. Beer is the most consumed alcoholic beverage in the world.
Fermented tea (also known as post-fermented tea or dark tea) is a class of tea that has undergone microbial fermentation,
from several months to many years. The tea leaves and the liquor made
from them become darker with oxidation. Thus, the various kinds of
fermented teas produced across China are also referred to as dark tea, not be confused with black tea. The most famous fermented tea is kombucha which is often homebrewed, pu-erh, produced in Yunnan Province, and the Anhua dark tea produced in Anhua County of Hunan Province. The majority of kombucha on the market are under 0.5% ABV.
Fermented water is an ethanol-based water solution with approximately 15-17% ABV without sweet reserve. Fermented water is exclusivelyfermented with white sugar, yeast,
and water. Fermented water is clarified after the fermentation to
produce a colorless or off-white liquid with no discernible taste other
than that of ethanol.
Fermented sugar water
Fermented sugar water is fermented water with added refined sugar.
Mead (/miːd/)
is an alcoholic drink made by fermenting honey with water, sometimes
with various fruits, spices, grains, or hops. The alcoholic content of
mead may range from as low as 3% ABV to more than 20%. The defining
characteristic of mead is that the majority of the drink's fermentable
sugar is derived from honey. Mead can also be referred to as
"honeywine."
Wine is a fermented beverage most commonly produced from grapes. Wine involves a longer fermentation process than beer and often a long aging process (months or years), resulting in an alcohol content of 9%–16% ABV.
Distilled beverages (also called liquors or spirit drinks) are alcoholic drinks produced by distilling (i.e., concentrating by distillation) ethanol produced by means of fermenting grain, fruit, or vegetables. Unsweetened, distilled, alcoholic drinks that have an alcohol content of at least 20% ABV are called spirits. For the most common distilled drinks, such as whiskey and vodka, the alcohol content is around 40%. The term hard liquor is used in North America to distinguish distilled drinks from undistilled ones (implicitly weaker). Vodka, gin, baijiu, shōchū, soju, tequila, whiskey, brandy and rum are examples of distilled drinks. Distilling concentrates the alcohol and eliminates some of the congeners. Freeze distillation concentrates ethanol along with methanol and fusel alcohols (fermentation by-products partially removed by distillation) in applejack.
Fortified wine is wine, such as port or sherry, to which a distilled beverage (usually brandy) has been added. Fortified wine is distinguished from spirits made from wine in that spirits are produced by means of distillation,
while fortified wine is wine that has had a spirit added to it. Many
different styles of fortified wine have been developed, including port, sherry, madeira, marsala, commandaria, and the aromatized wine vermouth.
Rectified spirit,
also called "neutral grain spirit", is alcohol which has been purified
by means of "rectification" (i.e. repeated distillation). The term neutral
refers to the spirit's lack of flavor that would have been present if
the mash ingredients had been distilled to a lower level of alcoholic
purity. Rectified spirit also lacks any flavoring added to it after
distillation (as is done, for example, with gin). Other kinds of spirits, such as whiskey, are distilled to a lower alcohol percentage to preserve the flavor of the mash.
Rectified spirit is a clear, colorless, flammable liquid that may contain as much as 95% ABV. It is often used for medicinal purposes. It may be a grain spirit or it may be made from other plants. It is used in mixed drinks, liqueurs, and tinctures, and also as a household solvent.
In the alcoholic drinks industry, congeners are substances produced during fermentation. These substances include small amounts of chemicals such as occasionally desired other alcohols, like propanol and 3-methyl-1-butanol, but also compounds that are never desired such as acetone, acetaldehyde and glycols.
Congeners are responsible for most of the taste and aroma of distilled
alcoholic drinks, and contribute to the taste of non-distilled drinks. It has been suggested that these substances contribute to the symptoms of a hangover. Tannins
are congeners found in wine in the presence of phenolic compounds. Wine
tannins add bitterness, have a drying sensation, taste herbaceous, and
are often described as astringent. Wine tannins adds balance, complexity, structure and makes a wine last longer, so they play an important role in the aging of wine.
Alcohol
consumption per person in 2016. Consumption of alcohol is measured in
liters of pure alcohol per person aged 15 or older.
The average number of people who drink as of 2016 was 39% for males and 25% for females (2.4 billion people in total). Females on average drink 0.7 drinks per day while males drink 1.7 drinks per day. The rates of drinking varies significantly in different areas of the world.
Age-standardised prevalence of current drinking for females (A) and males (B) in 2016, in 195 locations
Average standard drinks (10 g of pure ethanol per serving) consumed
per day, age-standardised, for females (A) and males (B) in 2016, in 195
locations
An apéritif is any alcoholic beverage usually served before a meal to stimulate the appetite, while a digestif is any alcoholic beverage served after a meal for the stated purpose of improving digestion. Fortified wine, liqueurs, and dry champagne are common apéritifs. Because apéritifs are served before dining, they are usually dry rather than sweet. One example is Cinzano, a brand of vermouth. Digestifs include brandy, fortified wines and herb-infused spirits (Drambuie).
Caloric content
The USDA uses a figure of 6.93 kilocalories (29.0 kJ) per gram of alcohol (5.47 kcal or 22.9 kJ per ml) for calculating food energy. For distilled spirits, a standard serving in the United States is 44 ml (1.5 US fl oz), which at 40% ethanol (80 proof),
would be 14 grams and 98 calories. For other than distilled spirits,
many alcoholic drinks contain carbohydrates, which adds to the calories
per serving.
Alcoholic drinks are considered empty calorie
foods because other than food energy they contribute no essential
nutrients. According to the U.S. Department of Agriculture, based on NHANES 2013–2014 surveys, women in the US ages 20 and up consume on average 6.8 grams/day and men consume on average 15.5 grams/day.
Alcohol is known to potentiate the insulin response of the human body to glucose,
which, in essence, "instructs" the body to convert consumed
carbohydrates into fat and to suppress carbohydrate and fat oxidation. Ethanol is directly processed in the liver to acetyl CoA,
the same intermediate product as in glucose metabolism. Because ethanol
is mostly metabolized and consumed by the liver, chronic excessive use
can lead to fatty liver. This leads to a chronic inflammation of the liver and eventually alcoholic liver disease.
Flavoring
Reduction
of red wine for a sauce by cooking it on a stovetop. It is called a
reduction because the heat boils off some of the water and most of the
more volatile alcohol, leaving a more concentrated, wine-flavoured
sauce.
Pure ethanol tastes bitter to humans; some people also describe it as sweet. However, ethanol is also a moderately good solvent
for many fatty substances and essential oils. This facilitates the use
of flavoring and coloring compounds in alcoholic drinks as a taste mask,
especially in distilled drinks.
Some flavors may be naturally present in the beverage's raw material.
Beer and wine may also be flavored before fermentation, and spirits may
be flavored before, during, or after distillation. Sometimes flavor is
obtained by allowing the beverage to stand for months or years in oak
barrels, usually made of American or French oak. A few brands of spirits
may also have fruit or herbs inserted into the bottle at the time of
bottling.
Wine is important in cuisine not just for its value as an accompanying beverage, but as a flavor agent, primarily in stocks and braising, since its acidity lends balance to rich savory or sweet dishes. Wine sauce is an example of a culinary sauce that uses wine as a primary ingredient. Natural wines may exhibit a broad range of alcohol content, from below 9% to above 16% ABV, with most wines being in the 12.5–14.5% range. Fortified wines (usually with brandy) may contain 20% alcohol or more.
typically 30%-40% (range is from 15% to, in some rare cases, up to 98%)
The concentration of alcohol in a beverage is usually stated as the percentage of alcohol by volume (ABV, the number of milliliters (ml) of pure ethanol in 100 ml of beverage) or as proof. In the United States, proof is twice the percentage of alcohol by volume at 60 degrees Fahrenheit (e.g. 80 proof = 40% ABV). Degrees proof
were formerly used in the United Kingdom, where 100 degrees proof was
equivalent to 57.1% ABV. Historically, this was the most dilute spirit
that would sustain the combustion of gunpowder.
Ordinary distillation
cannot produce alcohol of more than 95.6% by weight, which is about
97.2% ABV (194.4 proof) because at that point alcohol is an azeotrope with water. A spirit which contains a very high level of alcohol and does not contain any added flavoring is commonly called a neutral spirit. Generally, any distilled alcoholic beverage of 170 US proof or higher is considered to be a neutral spirit.
Most yeasts
cannot reproduce when the concentration of alcohol is higher than about
18%, so that is the practical limit for the strength of fermented
drinks such as wine, beer, and sake. However, some strains of yeast have been developed that can reproduce in solutions of up to 25% ABV.
Shot sizes vary significantly from country to country. In the United Kingdom, serving size in licensed premises is regulated under the Weights and Measures Act (1985). A single serving size of spirits (gin, whisky, rum, and vodka) are sold in 25 ml or 35 ml quantities or multiples thereof. Beer is typically served in pints
(568 ml), but is also served in half-pints or third-pints. In Israel, a
single serving size of spirits is about twice as much, 50 or 60 mL.
The shape of a glass can have a significant effect on how much one pours. A Cornell University
study of students and bartenders' pouring showed both groups pour more
into short, wide glasses than into tall, slender glasses.
Aiming to pour one shot of alcohol (1.5 ounces or 44.3 ml), students on
average poured 45.5 ml & 59.6 ml (30% more) respectively into the
tall and short glasses. The bartenders scored similarly, on average
pouring 20.5% more into the short glasses. More experienced bartenders
were more accurate, pouring 10.3% less alcohol than less experienced
bartenders. Practice reduced the tendency of both groups to over pour
for tall, slender glasses but not for short, wide glasses. These
misperceptions are attributed to two perceptual biases: (1) Estimating
that tall, slender glasses have more volume than shorter, wider glasses;
and (2) Over focusing on the height of the liquid and disregarding the
width.
A "standard drink" of hard liquor does not necessarily reflect a typical serving size, such as seen here.
There is no single standard, but a standard drink of 10g alcohol, which is used in the WHO AUDIT (Alcohol Use Disorders Identification Test)'s questionnaire form example, have been adopted by more countries than any other amount. 10 grams is equivalent to 12.7 millilitres.
A standard drink is a notional drink that contains a specified amount of pure alcohol.
The standard drink is used in many countries to quantify alcohol
intake. It is usually expressed as a measure of beer, wine, or spirits.
One standard drink always contains the same amount of alcohol regardless
of serving size or the type of alcoholic beverage. The standard drink
varies significantly from country to country. For example, it is 7.62 ml
(6 grams) of alcohol in Austria, but in Japan it is 25 ml
(19.75 grams).
In the United Kingdom, there is a system of units of alcohol which serves as a guideline for alcohol consumption. A single unit of alcohol
is defined as 10 ml. The number of units present in a typical drink is
sometimes printed on bottles. The system is intended as an aid to people
who are regulating the amount of alcohol they drink; it is not used to
determine serving sizes.
In the United States, the standard drink contains 0.6 US fluid
ounces (18 ml) of alcohol. This is approximately the amount of alcohol
in a 12-US-fluid-ounce (350 ml) glass of beer, a 5-US-fluid-ounce
(150 ml) glass of wine, or a 1.5-US-fluid-ounce (44 ml) glass of a 40% ABV (80 US proof) spirit.
Alcohol laws regulate the manufacture, packaging, labelling,
distribution, sale, consumption, blood alcohol content of motor vehicle
drivers, open containers, and transportation of alcoholic drinks. Such
laws generally seek to reduce the adverse health and social impacts of
alcohol consumption. In particular, alcohol laws set the legal drinking age,
which usually varies between 15 and 21 years old, sometimes depending
upon the type of alcoholic drink (e.g., beer vs wine vs hard liquor or
distillates). Some countries do not have a legal drinking or purchasing
age, but most countries set the minimum age at 18 years.
Some countries, such as the U.S., have the drinking age higher
than the legal age of majority (18), at age 21 in all 50 states. Such
laws may take the form of permitting distribution only to licensed
stores, monopoly stores, or pubs
and they are often combined with taxation, which serves to reduce the
demand for alcohol (by raising its price) and it is a form of revenue
for governments. These laws also often limit the hours or days (e.g., "blue laws") on which alcohol may be sold or served, as can also be seen in the "last call"
ritual in US and Canadian bars, where bartenders and servers ask
patrons to place their last orders for alcohol, due to serving hour
cutoff laws. In some countries, alcohol cannot be sold to a person who
is already intoxicated. Alcohol laws in many countries prohibit drunk driving.
In some jurisdictions, alcoholic drinks are totally prohibited for reasons of religion (e.g., Islamic countries with sharia law) or for reasons of local option, public health, and morals (e.g., Prohibition in the United States from 1920 to 1933). In jurisdictions which enforce sharia law, the consumption of alcoholic drinks is an illegal offense, although such laws may exempt non-Muslims.
10,000–5000 BC: Discovery of late Stone Age jugs suggests that intentionally fermented drinks existed at least as early as the Neolithic period.
7000–5600 BC: Examination and analysis of ancient pottery jars from the neolithic village of Jiahu in the Henan
province of northern China revealed residue left behind by the
alcoholic drinks they had once contained. According to a study published
in the Proceedings of the National Academy of Sciences,
chemical analysis of the residue confirmed that a fermented drink made
of grape and hawthorn fruit wine, honey mead and rice beer was being
produced in 7000–5600 BC (McGovern et al., 2005; McGovern 2009). The results of this analysis were published in December 2004.
9th–10th centuries AD: Medieval Muslim chemists such as Jābir ibn Ḥayyān (Latin: Geber, ninth century) and Abū Bakr al-Rāzī (Latin: Rhazes, c. 865–925)
experimented extensively with the distillation of various substances.
The distillation of wine is attested in Arabic works attributed to al-Kindī (c. 801–873 CE) and to al-Fārābī (c. 872–950), and in the 28th book of al-Zahrāwī's (Latin: Abulcasis, 936–1013) Kitāb al-Taṣrīf (later translated into Latin as Liber servatoris).
12th century: The process of distillation spread from the Middle East to Italy, where distilled alcoholic drinks were recorded in the mid-12th century. In China, archaeological evidence indicates that the true distillation of alcohol began during the 12th century Jin or Southern Song dynasties. A still has been found at an archaeological site in Qinglong, Hebei, dating to the 12th century.
14th century: In India, the true distillation of alcohol was introduced from the Middle East, and was in wide use in the Delhi Sultanate by the 14th century. By the early 14th century, distilled alcoholic drinks had spread throughout the European continent.
Treatment may involve some combination of chemotherapy, radiation therapy, targeted therapy, and bone marrow transplant, in addition to supportive care and palliative care as needed. Certain types of leukemia may be managed with watchful waiting.
The success of treatment depends on the type of leukemia and the age of
the person. Outcomes have improved in the developed world. Five-year survival rate is 65% in the United States.
In children under 15 in first-world countries, the five-year survival
rate is greater than 60% or even 90%, depending on the type of leukemia. In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.
In 2015, leukemia was present in 2.3 million people worldwide and caused 353,500 deaths.In 2012, it had newly developed in 352,000 people.
It is the most common type of cancer in children, with three-quarters
of leukemia cases in children being the acute lymphoblastic type. However, over 90% of all leukemias are diagnosed in adults, with CLL and AML being most common in adults. It occurs more commonly in the developed world.
Clinically and pathologically, leukemia is subdivided into a variety of large groups. The first division is between its acute and chronic forms:
Acute leukemia
is characterized by a rapid increase in the number of immature blood
cells. The crowding that results from such cells makes the bone marrow
unable to produce healthy blood cells resulting in low hemoglobin and low platelets. Immediate treatment is required in acute leukemia because of the rapid progression and accumulation of the malignant cells,
which then spill over into the bloodstream and spread to other organs
of the body. Acute forms of leukemia are the most common forms of leukemia in children.
Chronic leukemia is characterized by the excessive buildup of relatively mature, but still abnormal, white blood cells (or, more rarely, red blood cells).
Typically taking months or years to progress, the cells are produced at
a much higher rate than normal, resulting in many abnormal white blood
cells. Whereas acute leukemia must be treated immediately, chronic forms
are sometimes monitored for some time before treatment to ensure
maximum effectiveness of therapy. Chronic leukemia mostly occurs in
older people but can occur in any age group.
In lymphoblastic or lymphocytic leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form lymphocytes, which are infection-fighting immune system cells. Most lymphocytic leukemias involve a specific subtype of lymphocyte, the B cell.
Combining these two classifications provides a total of four main
categories. Within each of these main categories, there are typically
several subcategories. Finally, some rarer types are usually considered
to be outside of this classification scheme.
Chronic lymphocytic leukemia
(CLL) most often affects adults over the age of 55. It sometimes occurs
in younger adults, but it almost never affects children. Two-thirds of
affected people are men. The five-year survival rate is 85%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease.
Chronic myelogenous leukemia (CML) occurs mainly in adults; a very small number of children also develop this disease. It is treated with imatinib (Gleevec in United States, Glivec in Europe) or other drugs. The five-year survival rate is 90%. One subtype is chronic myelomonocytic leukemia.
Hairy cell leukemia
(HCL) is sometimes considered a subset of chronic lymphocytic leukemia,
but does not fit neatly into this category. About 80% of affected
people are adult men. No cases in children have been reported. HCL is
incurable but easily treatable. Survival is 96% to 100% at ten years.
T-cell prolymphocytic leukemia (T-PLL) is a very rare and aggressive leukemia affecting adults; somewhat more men than women are diagnosed with this disease. Despite its overall rarity, it is the most common type of mature T cell leukemia; nearly all other leukemias involve B cells. It is difficult to treat, and the median survival is measured in months.
Adult T-cell leukemia is caused by human T-lymphotropic virus (HTLV), a virus similar to HIV.
Like HIV, HTLV infects CD4+ T-cells and replicates within them;
however, unlike HIV, it does not destroy them. Instead, HTLV
"immortalizes" the infected T-cells, giving them the ability to
proliferate abnormally. Human T-cell lymphotropic virus types I and II
(HTLV-I/II) are endemic in certain areas of the world.
Transient myeloproliferative disease, also termed transient leukemia, involves the abnormal proliferation of a clone of non-cancerous megakaryoblasts. The disease is restricted to individuals with Down syndrome
or genetic changes similar to those in Down syndrome, develops in a
baby during pregnancy or shortly after birth, and resolves within 3
months or, in ~10% of cases, progresses to acute megakaryoblastic leukemia. Transient myeloid leukemia is a pre-leukemic condition.
Damage to the bone marrow, by way of displacing the normal bone
marrow cells with higher numbers of immature white blood cells, results
in a lack of blood platelets, which are important in the blood clotting process. This means people with leukemia may easily become bruised, bleed excessively, or develop pinprick bleeds (petechiae).
White blood cells, which are involved in fighting pathogens,
may be suppressed or dysfunctional. This could cause the person's
immune system to be unable to fight off a simple infection or to start
attacking other body cells. Because leukemia prevents the immune system
from working normally, some people experience frequent infection, ranging from infected tonsils, sores in the mouth, or diarrhea to life-threatening pneumonia or opportunistic infections.
Finally, the red blood cell deficiency leads to anemia, which may cause dyspnea and pallor.
Some people experience other symptoms, such as fevers, chills, night sweats, weakness in the limbs, feeling fatigued and other common flu-like symptoms. Some people experience nausea or a feeling of fullness due to an enlarged liver and spleen; this can result in unintentional weight loss. Blasts affected by the disease may come together and become swollen in the liver or in the lymph nodes causing pain and leading to nausea.
If the leukemic cells invade the central nervous system, then neurological symptoms (notably headaches) can occur. Uncommon neurological symptoms like migraines, seizures, or coma
can occur as a result of brain stem pressure. All symptoms associated
with leukemia can be attributed to other diseases. Consequently,
leukemia is always diagnosed through medical tests.
The word leukemia, which means 'white blood', is derived
from the characteristic high white blood cell count that presents in
most affected people before treatment. The high number of white blood
cells is apparent when a blood sample is viewed under a microscope,
with the extra white blood cells frequently being immature or
dysfunctional. The excessive number of cells can also interfere with the
level of other cells, causing further harmful imbalance in the blood
count.
Some people diagnosed with leukemia do not have high white blood
cell counts visible during a regular blood count. This less-common
condition is called aleukemia. The bone marrow still contains
cancerous white blood cells that disrupt the normal production of blood
cells, but they remain in the marrow instead of entering the
bloodstream, where they would be visible in a blood test. For a person
with aleukemia, the white blood cell counts in the bloodstream can be
normal or low. Aleukemia can occur in any of the four major types of
leukemia, and is particularly common in hairy cell leukemia.
Causes
Studies in 2009 and 2010 have shown a positive correlation between exposure to formaldehyde and the development of leukemia, particularly myeloid leukemia. The different leukemias likely have different causes.
Leukemia, like other cancers, results from mutations in the DNA. Certain mutations can trigger leukemia by activating oncogenes or deactivating tumor suppressor genes,
and thereby disrupting the regulation of cell death, differentiation or
division. These mutations may occur spontaneously or as a result of
exposure to radiation or carcinogenic substances.
Among adults, the known causes are natural and artificial ionizing radiation and petrochemicals, notably benzene and alkylating chemotherapy agents for previous malignancies. Use of tobacco is associated with a small increase in the risk of developing acute myeloid leukemia in adults. Cohort and case-control studies have linked exposure to some petrochemicals and hair dyes
to the development of some forms of leukemia. Diet has very limited or
no effect, although eating more vegetables may confer a small protective
benefit.
A few cases of maternal-fetal transmission (a baby acquires leukemia because its mother had leukemia during the pregnancy) have been reported. Children born to mothers who use fertility drugs to induce ovulation are more than twice as likely to develop leukemia during their childhoods than other children.
In a recent systematic review and meta-analysis of any type of leukemia in neonates using phototherapy, typically to treat neonatal jaundice,
a statistically significant association was detected between using
phototherapy and myeloid leukemia. However, it is still questionable
whether phototherapy is genuinely the cause of cancer or simply a result
of the same underlying factors that gave rise to cancer.
Radiation
Large doses of Sr-90 emission from nuclear reactor accidents, nicknamed bone seeker increases the risk of bone cancer and leukemia in animals and is presumed to do so in people.
Genetic conditions
Some
people have a genetic predisposition towards developing leukemia. This
predisposition is demonstrated by family histories and twin studies.
The affected people may have a single gene or multiple genes in common.
In some cases, families tend to develop the same kinds of leukemia as
other members; in other families, affected people may develop different
forms of leukemia or related blood cancers.
In addition to these genetic issues, people with chromosomal
abnormalities or certain other genetic conditions have a greater risk of
leukemia. For example, people with Down syndrome have a significantly increased risk of developing forms of acute leukemia (especially acute myeloid leukemia), and Fanconi anemia is a risk factor for developing acute myeloid leukemia. Mutation in SPRED1 gene has been associated with a predisposition to childhood leukemia.
Chronic myelogenous leukemia is associated with a genetic abnormality called the Philadelphia translocation;
95% of people with CML carry the Philadelphia mutation, although this
is not exclusive to CML and can be observed in people with other types
of leukemia.
Non-ionizing radiation
Whether or not non-ionizing radiation causes leukemia has been studied for several decades. The International Agency for Research on Cancer expert working group undertook a detailed review of all data on static and extremely low frequency
electromagnetic energy, which occurs naturally and in association with
the generation, transmission, and use of electrical power. They concluded that there is limited evidence that high levels of ELF magnetic (but not electric) fields might cause some cases of childhood leukemia. No evidence for a relationship to leukemia or another form of malignancy in adults has been demonstrated. Since exposure to such levels of ELFs is relatively uncommon, the World Health Organization
concludes that ELF exposure, if later proven to be causative, would
account for just 100 to 2400 cases worldwide each year, representing 0.2
to 4.9% of the total incidence of childhood leukemia for that year
(about 0.03 to 0.9% of all leukemias).
Diagnosis is usually based on repeated complete blood counts and a bone marrow examination
following observations of the symptoms. Sometimes, blood tests may not
show that a person has leukemia, especially in the early stages of the
disease or during remission. A lymph node biopsy can be performed to diagnose certain types of leukemia in certain situations.
Following diagnosis, blood chemistry tests can be used to
determine the degree of liver and kidney damage or the effects of
chemotherapy on the person. When concerns arise about other damages due
to leukemia, doctors may use an X-ray, MRI, or ultrasound.
These can potentially show leukemia's effects on such body parts as
bones (X-ray), the brain (MRI), or the kidneys, spleen, and liver
(ultrasound). CT scans can be used to check lymph nodes in the chest, though this is uncommon.
Despite the use of these methods to diagnose whether or not a
person has leukemia, many people have not been diagnosed because many of
the symptoms are vague, non-specific,
and can refer to other diseases. For this reason, the American Cancer
Society estimates that at least one-fifth of the people with leukemia
have not yet been diagnosed.
Management of ALL is directed towards control of bone marrow and
systemic (whole-body) disease. Additionally, treatment must prevent
leukemic cells from spreading to other sites, particularly the central nervous system (CNS) e.g. monthly lumbar punctures. In general, ALL treatment is divided into several phases:
Induction chemotherapy to bring about bone marrow remission. For adults, standard induction plans include prednisone, vincristine, and an anthracycline drug; other drug plans may include L-asparaginase or cyclophosphamide.
For children with low-risk ALL, standard therapy usually consists of
three drugs (prednisone, L-asparaginase, and vincristine) for the first
month of treatment.
Consolidation therapy or intensification therapy to
eliminate any remaining leukemia cells. There are many different
approaches to consolidation, but it is typically a high-dose, multi-drug
treatment that is undertaken for a few months. People with low- to
average-risk ALL receive therapy with antimetabolite drugs such as methotrexate and 6-mercaptopurine (6-MP). People who are high-risk receive higher drug doses of these drugs, plus additional drugs.
CNS prophylaxis (preventive therapy) to stop cancer from spreading to the brain and nervous system in high-risk people. Standard prophylaxis may include radiation of the head and/or drugs delivered directly into the spine.
Maintenance treatments with chemotherapeutic drugs to prevent
disease recurrence once remission has been achieved. Maintenance
therapy usually involves lower drug doses and may continue for up to
three years.
Hematologists
base CLL treatment on both the stage and symptoms of the individual
person. A large group of people with CLL have low-grade disease, which
does not benefit from treatment. Individuals with CLL-related
complications or more advanced disease often benefit from treatment. In
general, the indications for treatment are:
Many different anti-cancer drugs are effective for the treatment of
AML. Treatments vary somewhat according to the age of the person and
according to the specific subtype of AML. Overall, the strategy is to
control bone marrow and systemic (whole-body) disease, while offering
specific treatment for the central nervous system (CNS), if involved.
In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission and a lower risk of disease resistance. Consolidation and maintenance
treatments are intended to prevent disease recurrence. Consolidation
treatment often entails a repetition of induction chemotherapy or the
intensification of chemotherapy with additional drugs. By contrast,
maintenance treatment involves drug doses that are lower than those
administered during the induction phase.
There are many possible treatments for CML, but the standard of care for newly diagnosed people is imatinib (Gleevec) therapy. Compared to most anti-cancer drugs, it has relatively few side effects and can be taken orally at home. With this drug, more than 90% of people will be able to keep the disease in check for at least five years, so that CML becomes a chronic, manageable condition.
In a more advanced, uncontrolled state, when the person cannot
tolerate imatinib, or if the person wishes to attempt a permanent cure,
then an allogeneic bone marrow transplantation may be performed. This
procedure involves high-dose chemotherapy and radiation followed by
infusion of bone marrow from a compatible donor. Approximately 30% of
people die from this procedure.
Decision to treat
People with hairy cell leukemia who are symptom-free typically do not
receive immediate treatment. Treatment is generally considered necessary
when the person shows signs and symptoms such as low blood cell counts
(e.g., infection-fighting neutrophil count below 1.0 K/µL), frequent
infections, unexplained bruises, anemia, or fatigue that is significant
enough to disrupt the person's everyday life.
Typical treatment approach
People who need treatment usually receive either one week of cladribine, given daily by intravenous infusion or a simple injection under the skin, or six months of pentostatin, given every four weeks by intravenous infusion. In most cases, one round of treatment will produce a prolonged remission.
Other treatments include rituximab infusion or self-injection with Interferon-alpha. In limited cases, the person may benefit from splenectomy (removal of the spleen).
These treatments are not typically given as the first treatment because
their success rates are lower than cladribine or pentostatin.
Most people with T-cell prolymphocytic leukemia, a rare and
aggressive leukemia with a median survival of less than one year,
require immediate treatment.
T-cell prolymphocytic leukemia is difficult to treat, and it does not respond to most available chemotherapeutic drugs. Many different treatments have been attempted, with limited success in certain people: purine analogues (pentostatin, fludarabine, cladribine), chlorambucil, and various forms of combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone CHOP, cyclophosphamide, vincristine, prednisone [COP], vincristine, doxorubicin, prednisone, etoposide, cyclophosphamide, bleomycin VAPEC-B). Alemtuzumab (Campath), a monoclonal antibody that attacks white blood cells, has been used in treatment with greater success than previous options.
Some people who successfully respond to treatment also undergo stem cell transplantation to consolidate the response.
The
success of treatment depends on the type of leukemia and the age of the
person. Outcomes have improved in the developed world. The average five-year survival rate is 65% in the United States. In children under 15, the five-year survival rate is greater (60 to 85%), depending on the type of leukemia. In children with acute leukemia who are cancer-free after five years, the cancer is unlikely to return.
Outcomes depend on whether it is acute or chronic, the specific abnormal white blood cell type, the presence and severity of anemia or thrombocytopenia, the degree of tissue abnormality, the presence of metastasis and lymph node and bone marrow
infiltration, the availability of therapies and the skills of the
health care team. Treatment outcomes may be better when people are
treated at larger centers with greater experience.
Epidemiology
Deaths due to leukemia per million persons in 2012
0-7
8-13
14–22
23–29
30–34
35–39
40–46
47–64
65–85
86–132
In 2010, globally, approximately 281,500 people died of leukemia. In 2000, approximately 256,000 children and adults around the world developed a form of leukemia, and 209,000 died from it.
This represents about 3% of the almost seven million deaths due to
cancer that year, and about 0.35% of all deaths from any cause. Of the sixteen separate sites the body compared, leukemia was the 12th most common class of neoplastic disease and the 11th most common cause of cancer-related death. Leukemia occurs more commonly in the developed world.
United States
About
245,000 people in the United States are affected with some form of
leukemia, including those that have achieved remission or cure. Rates
from 1975 to 2011 have increased by 0.7% per year among children. Approximately 44,270 new cases of leukemia were diagnosed in the year 2008 in the US.
This represents 2.9% of all cancers (excluding simple basal cell and
squamous cell skin cancers) in the United States, and 30.4% of all blood cancers.
Among children with some form of cancer, about a third have a type of leukemia, most commonly acute lymphoblastic leukemia.
A type of leukemia is the second most common form of cancer in infants
(under the age of 12 months) and the most common form of cancer in older
children.
Boys are somewhat more likely to develop leukemia than girls, and white
American children are almost twice as likely to develop leukemia than
black American children.
Only about 3% cancer diagnoses among adults are for leukemias, but
because cancer is much more common among adults, more than 90% of all
leukemias are diagnosed in adults.
More men than women are diagnosed with leukemia and die from the disease. Around 30 percent more men than women have leukemia.
Australia
In Australia, leukemia is the eleventh most common cancer.
In 2014–2018, Australians diagnosed with leukaemia had a 64% chance
(65% for males and 64% for females) of surviving for five years compared
to the rest of the Australian population–there was a 21% increase in
survival rates between 1989–1993.
UK
Overall, leukemia
is the eleventh most common cancer in the UK (around 8,600 people were
diagnosed with the disease in 2011), and it is the ninth most common
cause of cancer death (around 4,800 people died in 2012).
History
Rudolf Virchow
Leukemia was first described by anatomist and surgeon Alfred-Armand-Louis-Marie Velpeau in 1827. A more complete description was given by pathologist Rudolf Virchow in 1845. Around ten years after Virchow's findings, pathologist Franz Ernst Christian Neumann
found that the bone marrow of a deceased person with leukemia was
colored "dirty green-yellow" as opposed to the normal red. This finding
allowed Neumann to conclude that a bone marrow problem was responsible
for the abnormal blood of people with leukemia.
By 1900, leukemia was viewed as a family of diseases as opposed to a single disease. By 1947, Boston pathologist Sidney Farber believed from past experiments that aminopterin,
a folic acid mimic, could potentially cure leukemia in children. The
majority of the children with ALL who were tested showed signs of
improvement in their bone marrow, but none of them were actually cured.
Nevertheless, this result did lead to further experiments.
In 1962, researchers Emil J. Freireich, Jr. and Emil Frei III
used combination chemotherapy to attempt to cure leukemia. The tests
were successful with some people surviving long after the tests.
Etymology
Observing an abnormally large number of white blood cells in a blood sample from a person, Virchow called the condition Leukämie in German, which he formed from the two Greek words leukos (λευκός), meaning 'white', and haima (αἷμα), meaning 'blood'. It was formerly also called leucemia.
Society and culture
According to Susan Sontag,
leukemia was often romanticized in 20th-century fiction, portrayed as a
joy-ending, clean disease whose fair, innocent and gentle victims die
young or at the wrong time. As such, it was the cultural successor to tuberculosis, which held this cultural position until it was discovered to be an infectious disease. The 1970 romance novel Love Story is an example of this romanticization of leukemia.
In the United States, around $5.4 billion is spent on treatment a year.
Research directions
Significant
research into the causes, prevalence, diagnosis, treatment, and
prognosis of leukemia is being performed. Hundreds of clinical trials are being planned or conducted at any given time.
Studies may focus on effective means of treatment, better ways of
treating the disease, improving the quality of life for people, or
appropriate care in remission or after cures.
In general, there are two types of leukemia research: clinical or translational research and basic research.
Clinical/translational research focuses on studying the disease in a
defined and generally immediately applicable way, such as testing a new
drug in people. By contrast, basic science research studies the disease
process at a distance, such as seeing whether a suspected carcinogen
can cause leukemic changes in isolated cells in the laboratory or how
the DNA changes inside leukemia cells as the disease progresses. The
results from basic research studies are generally less immediately
useful to people with the disease.
Treatment through gene therapy is currently being pursued. One such approach used genetically modified T cells, known as chimeric antigen receptor T cells
(CAR-T cells), to attack cancer cells. In 2011, a year after treatment,
two of the three people with advanced chronic lymphocytic leukemia were
reported to be cancer-free
and in 2013, three of five subjects who had acute lymphocytic leukemia
were reported to be in remission for five months to two years. Subsequent studies with a variety of CAR-T types continue to be promising. As of 2018, two CAR-T therapies have been approved by the Food and Drug Administration. CAR-T treatment has significant side effects, and loss of the antigen targeted by the CAR-T cells is a common mechanism for relapse. The stem cells that cause different types of leukemia are also being researched.
Pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.
How it is handled depends primarily on the type of leukemia. Nearly all
leukemias appearing in pregnant women are acute leukemias. Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester. Chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with Interferon-alpha hormones.
Treatment for chronic lymphocytic leukemias, which are rare in pregnant
women, can often be postponed until after the end of the pregnancy.
