Vitamin B12 deficiency

From Wikipedia, the free encyclopedia

Vitamin B12 deficiency
Other names	Hypocobalaminemia, cobalamin deficiency
Cyanocobalamin
Specialty	Neurology, hematology
Symptoms	Decreased ability to think, depression, irritability, abnormal sensations, changes in reflexes
Complications	Megaloblastic anemia
Causes	Poor absorption, decreased intake, increased requirements
Diagnostic method	Blood levels below 120–180 picomol/L (170–250 pg/mL) in adults
Prevention	Supplementation in those at high risk
Treatment	Supplementation by mouth or injection
Frequency	6% (<60 20="" old="" years="">60 years old)

Vitamin B₁₂ deficiency, also known as cobalamin deficiency, is the medical condition of low blood levels of vitamin B₁₂. In mild deficiency a person may feel tired and have a reduced number of red blood cells (anemia). In moderate deficiency there may be inflammation of the tongue and the beginning of neurological problems including abnormal sensations such as pins and needles, while severe deficiency may include reduced heart function and greater neurological problems.

 Neurological problems may include changes in reflexes, poor muscle function, memory problems, decreased taste, and in extreme cases psychosis. Sometimes temporary infertility may also occur. In young children symptoms include poor growth, poor development, and difficulties with movement. Without early treatment, some of the changes may be permanent.

Common causes include poor absorption from the stomach or intestines, deficient intake, and increased requirements. Decreased absorption may be due to pernicious anemia, surgical removal of the stomach, chronic inflammation of the pancreas, intestinal parasites, certain medications, and some genetic disorders. Medications that may decrease absorption include proton pump inhibitors and metformin. Decreased intake may occur in vegetarians or people who are malnourished. Increased requirements occur in people with HIV/AIDS, and in those with rapid red blood cell breakdown. Diagnosis is typically based on blood levels of vitamin B₁₂. Elevated methylmalonic acid levels may also indicate a deficiency. A type of anemia known as megaloblastic anemia is often but not always present.

Treatment consists of using vitamin B₁₂ by mouth or by injection; initially in high daily doses, followed by less frequent lower doses as the condition improves. If a reversible cause is found, that cause should be addressed if possible. If no reversible cause is found - or when found it cannot be eliminated - lifelong vitamin B₁₂ administration is usually recommended. Vitamin B₁₂ deficiency is preventable with supplements containing the vitamin: this is recommended in pregnant vegetarians and vegans, and not harmful in others. Risk of toxicity due to vitamin B₁₂ is low.

Vitamin B₁₂ deficiency in the US and the UK is estimated to occur in about 6 percent of those under the age of 60, and 20 percent of those over the age of 60. In Latin America, rates are estimated at 40 percent and they may be as high as 80 per cent in parts of Africa and Asia.

Signs and symptoms

Vitamin B₁₂ deficiency can lead to anemia and neurological disorders. A mild deficiency may not cause any discernible symptoms, but as the deficiency becomes more significant, symptoms of anemia may result, such as weakness, fatigue, light-headedness, rapid heartbeat, rapid breathing and pale color to the skin. It may also cause easy bruising or bleeding, including bleeding gums, gastrointestinal side effects including sore tongue, stomach upset, weight loss, and diarrhea or constipation. If the deficiency is not corrected, nerve cell damage can result. If this happens, vitamin B₁₂ deficiency may result in tingling or numbness to the fingers and toes, difficulty walking, mood changes, depression, memory loss, disorientation and, in severe cases, dementia.

The main type of vitamin B ₁₂ deficiency anemia is pernicious anemia. It is characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia). This is due to the inhibition of DNA synthesis (specifically purines and thymidine)
2. Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control. These are thought to be due to defective DNA synthesis inhibiting replication in a site with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia. There is an association with GAVE syndrome (commonly called watermelon stomach) and pernicious anemia.
3. Neurological symptoms: Sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation), subacute combined degeneration of spinal cord, seizures, or even symptoms of dementia and or other psychiatric symptoms may be present. Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.

The presence of peripheral sensory-motor symptoms or subacute combined degeneration of spinal cord strongly suggests the presence of a B₁₂ deficiency instead of folate deficiency. Methylmalonic acid, if not properly handled by B₁₂, remains in the myelin sheath, causing fragility. Dementia and depression have been associated with this deficiency as well, possibly from the under-production of methionine because of the inability to convert homocysteine into this product. Methionine is a necessary cofactor in the production of several neurotransmitters. 

Each of those symptoms can occur either alone or along with others. The neurological complex, defined as myelosis funicularis, consists of the following symptoms:

1. Impaired perception of deep touch, pressure and vibration, loss of sense of touch, very annoying and persistent paresthesias
2. Ataxia of dorsal column type
3. Decrease or loss of deep muscle-tendon reflexes
4. Pathological reflexes — Babinski, Rossolimo and others, also severe paresis

Vitamin B₁₂ deficiency can cause severe and irreversible damage, especially to the brain and nervous system. These symptoms of neuronal damage may not reverse after correction of blood abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. Elderly people are at a even higher risk of this type of damage. In babies a number of neurological symptoms can be evident due to malnutrition or pernicious anemia in the mother. These include poor growth, apathy, having no desire for food, and developmental regression. While most symptoms resolve with supplementation some developmental and cognitive problems may persist.

Only a small subset of dementia cases have been found to be reversible with vitamin B12 therapy. Tinnitus may be associated with vitamin B₁₂ deficiency.

Causes

• Inadequate dietary intake of vitamin B₁₂. Vitamin B₁₂ occurs in animal products (eggs, meat, milk, fish) and in some edible algae. B₁₂ isolated from bacterial cultures is also added to many fortified foods, and available as a dietary supplement. Vegans, and to a lesser degree vegetarians, may also be at risk for B₁₂ deficiency due to inadequate dietary intake of B₁₂, if they do not supplement. Children are at a higher risk for B₁₂ deficiency due to inadequate dietary intake, as they have fewer vitamin stores and a relatively larger vitamin need per calorie of food intake.
• Selective impaired absorption of vitamin B₁₂ due to intrinsic factor deficiency. This may be caused by the loss of gastric parietal cells in chronic atrophic gastritis (in which case, the resulting megaloblastic anemia takes the name of "pernicious anemia"), or may result from wide surgical resection of stomach (for any reason), or from rare hereditary causes of impaired synthesis of intrinsic factor. B₁₂ deficiency is more common in the elderly because gastric intrinsic factor, necessary for absorption of the vitamin, is deficient, due to atrophic gastritis.
• Impaired absorption of vitamin B₁₂ in the setting of a more generalized malabsorption or maldigestion syndrome. This includes any form due to structural damage or wide surgical resection of the terminal ileum (the principal site of vitamin B₁₂ absorption).
• Forms of achlorhydria (including that artificially induced by drugs such as proton pump inhibitors and histamine 2 receptor antagonists) can cause B₁₂ malabsorption from foods, since acid is needed to split B₁₂ from food proteins and salivary binding proteins. This process is thought to be the most common cause of low B₁₂ in the elderly, who often have some degree of achlorhydria without being formally low in intrinsic factor. This process does not affect absorption of small amounts of B₁₂ in supplements such as multivitamins, since it is not bound to proteins, as is the B₁₂ in foods.
• Surgical removal of the small bowel (for example in Crohn's disease) such that the patient presents with short bowel syndrome and is unable to absorb vitamin B₁₂. This can be treated with regular injections of vitamin B₁₂.
• Long-term use of ranitidine hydrochloride may contribute to deficiency of vitamin B₁₂.
• Untreated celiac disease may also cause impaired absorption of this vitamin, probably due to damage to the small bowel mucosa. In some people, vitamin B₁₂ deficiency may persist despite treatment with a gluten-free diet and require supplementation.
• Some bariatric surgical procedures, especially those that involve removal of part of the stomach, such as Roux-en-Y gastric bypass surgery. (Procedures such as the adjustable gastric band type do not appear to affect B₁₂ metabolism significantly).
• Bacterial overgrowth within portions of the small intestine, such as may occur in blind loop syndrome, (a condition due to a loop forming in the intestine) may result in increased consumption of intestinal vitamin B₁₂ by these bacteria.
• The diabetes medication metformin may interfere with B₁₂ dietary absorption.
• A genetic disorder, transcobalamin II deficiency can be a cause.
• Alcoholism - if a "diet" of excessive alcohol intake is substituted for a diet adequate in sources of B₁₂.
• Nitrous oxide exposure, and recreational use.
• Infection with the Diphyllobothrium latum tapeworm
• Chronic exposure to toxigenic molds and mycotoxins found in water damaged buildings.
• Increased needs by the body due to AIDS, or hemolysis the breakdown of red blood cells.

Mechanism

The total amount of vitamin B₁₂ stored in the body is between two and five milligrams in adults. Approximately 50% is stored in the liver, but approximately 0.1% is lost each day, due to secretions into the gut—not all of the vitamin in the gut is reabsorbed. While bile is the main vehicle for B₁₂ excretion, most of this is recycled via enterohepatic circulation. Due to the extreme efficiency of this mechanism, the liver can store three to five years worth of vitamin B₁₂ under normal conditions and functioning. However, the rate at which B₁₂ levels may change when dietary intake is low depends on the balance between several variables.

Metabolic

Vitamin B₁₂ deficiency causes particular changes to the metabolism of two clinically relevant substances in humans:

1. Homocysteine (homocysteine to methionine, catalysed by methionine synthase) leading to hyperhomocysteinemia
2. Methylmalonic acid (methylmalonyl-CoA to succinyl-CoA, of which methylmalonyl-CoA is made from methylmalonic acid in a preceding reaction)

Methionine is activated to S-adenosyl methionine, which aids in purine and thymidine synthesis, myelin production, protein/neurotransmitters/fatty acid/phospholipid production and DNA methylation. 5-Methyl tetrahydrofolate provides a methyl group, which is released to the reaction with homocysteine, resulting in methionine. This reaction requires cobalamin as a cofactor. The creation of 5-methyl tetrahydrofolate is an irreversible reaction. If B₁₂ is absent, the forward reaction of homocysteine to methionine does not occur, homocysteine concentrations increase, and the replenishment of tetrahydrofolate stops. Because B₁₂ and folate are involved in the metabolism of homocysteine, hyperhomocysteinuria is a non-specific marker of deficiency. Methylmalonic acid is used as a more specific test of B₁₂ deficiency.

Pathomorphology

A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord and to pyramidal tracts in lateral cords. The pathophysiologic state of the spinal cord is called subacute combined degeneration of spinal cord.

In the brain itself, changes are less severe: They occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, and also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. Abnormalities might be observed in MRI.

Diagnosis

MRI image of the brain in vitamin B₁₂ deficiency, axial view showing the "precontrast FLAIR image": note the abnormal lesions (circled) in the periventricular area suggesting white matter pathology.

 

MRI image of the cervical spinal cord in vitamin B₁₂ deficiency showing subacute combined degeneration. (A) The midsagittal T2 weighted image shows linear hyperintensity in the posterior portion of the cervical tract of the spinal cord (black arrows). (B) Axial T2 weighted images reveal the selective involvement of the posterior columns.

 

Diagnosis is typically based on vitamin B₁₂ blood levels below 120–180 picomol/L (170–250 pg/mL) in adults. Elevated methylmalonic acid levels (values >0.4 micromol/L) may also indicate a deficiency.

Serum homocysteine and methylmalonic acid levels are considered more reliable indicators of B₁₂ deficiency than the concentration of B₁₂ in blood. The levels of these substances are high in B₁₂ deficiency and can be helpful if the diagnosis is unclear.

Routine monitoring of methylmalonic acid levels in urine is an option for people who may not be getting enough dietary B₁₂, as a rise in methylmalonic acid levels may be an early indication of deficiency.

If nervous system damage is suspected, B₁₂ analysis in cerebrospinal fluid is possible, though such an invasive test should be considered only if blood testing is inconclusive.

The Schilling test was a radio-isotope method, now outdated, of testing for low vitamin B₁₂.

Effect of folic acid

The National Institutes of Health (NIH) has found that "Large amounts of folic acid can mask the damaging effects of vitamin B₁₂ deficiency by correcting the megaloblastic anemia caused by vitamin B₁₂ deficiency without correcting the neurological damage that also occurs", there are also indications that "high serum folate levels might not only mask vitamin B₁₂ deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B₁₂ deficiency". Due to the fact that in the United States legislation has required enriched flour to contain folic acid to reduce cases of fetal neural-tube defects, consumers may be ingesting more than they realize. To counter the masking effect of B₁₂ deficiency the NIH recommends "folic acid intake from fortified food and supplements should not exceed 1,000 μg daily in healthy adults." Most importantly, B₁₂ deficiency needs to be treated with B₁₂ repletion. Limiting folic acid will not counter the irrevocable neurological damage that is caused by untreated B₁₂ deficiency.

Treatment

Hydroxocobalamin injection is a clear red liquid solution.

 

B₁₂ can be supplemented by pill or injection and appears to be equally effective in those with low levels due to deficient absorption of B₁₂.

When large doses are given by mouth its absorption does not rely on the presence of intrinsic factor or an intact ileum. Generally 1 to 2 mg daily is required as a large dose. Even pernicious anemia can be treated entirely by the oral route. These supplements carry such large doses of the vitamin that 1% to 5% of high oral doses of free crystalline B₁₂ is absorbed along the entire intestine by passive diffusion.

Epidemiology

Vitamin B₁₂ deficiency is quite common and widespread. In the US and UK, as around 6 percent of people have the deficiency, and this rises to around 20 percent in those over the age of sixty. In less developed countries the rates are higher. For example across Latin America 40 percent, in some parts of Africa 70 percent, and in some parts of India 70 and 80 percent.

History

Adapted from:

• 1849 - Thomas Addison first described a case of pernicious anemia.
• 1877 - William Osler and William Gardner first described a case of neuropathy in this condition.
• 1878 - Hayem first described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles", now called macrocytes.

• 1880 - Paul Ehrlich first identified megaloblasts in the bone marrow in this condition.
• 1887 - Ludwig Lichtheim first described a case of myopathy in this condition.
• 1926 - George Minot shared the 1934 Nobel Prize with William Murphy and George Whipple, for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B₁₂.
• 1929 - William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition.

Other animals

Ruminants, such as cows and sheep, absorb B₁₂ synthesized by their gut bacteria. Sufficient amounts of cobalt need to be consumed for this B₁₂ synthesis to occur.

In the early 20th century during the development for farming of the North Island Volcanic Plateau of New Zealand, cattle suffered from what was termed "bush sickness". It was discovered that the volcanic soils lacked the cobalt salts essential for synthesis of the vitamin by their gut bacteria.

The "coast disease" of sheep in the coastal sand dunes of South Australia in the 1930s was found to originate in nutritional deficiencies of the trace elements, cobalt and copper. The cobalt deficiency was overcome by the development of "cobalt bullets", dense pellets of cobalt oxide mixed with clay given orally for lodging in the animal's rumen.

Leukemia

From Wikipedia, the free encyclopedia

Leukemia
Other names	Leukaemia
A Wright's stainled bone marrow aspirate smear from a person with precursor B-cell acute lymphoblastic leukemia.
Pronunciation	/luːˈkiːmiːə/
Specialty	Hematology and oncology
Symptoms	Bleeding, bruising, feeling tired, fever, increased risk of infections
Usual onset	All ages
Causes	Inherited and environmental factors
Risk factors	Smoking, family history, ionizing radiation, some chemicals, prior chemotherapy, Down syndrome.
Diagnostic method	Blood tests, bone marrow biopsy
Treatment	Chemotherapy, radiation therapy, targeted therapy, bone marrow transplant, supportive care
Prognosis	Five-year survival rate 57% (USA)
Frequency	2.3 million (2015)
Deaths	353,500 (2015)

Leukemia, also spelled leukaemia, is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, feeling tired, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.

The exact cause of leukemia is unknown. A combination of genetic factors and environmental (non-inherited) factors are believed to play a role. Risk factors include smoking, ionizing radiation, some chemicals (such as benzene), prior chemotherapy, and Down syndrome. People with a family history of leukemia are also at higher risk. There are four main types of leukemia—acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)—as well as a number of less common types. Leukemias and lymphomas both belong to a broader group of tumors that affect the blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and lymphoid tissues.

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. The average five-year survival rate is 57% in the United States. In children under 15, the five-year survival rate is greater than 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.

In 2015, leukemia was present in 2.3 million people and caused 353,500 deaths. In 2012 it 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, about 90% of all leukemias are diagnosed in adults, with AML and CLL being most common in adults. It occurs more commonly in the developed world.

Classification

Four major kinds of leukemia

Cell type	Acute	Chronic
Lymphocytic leukemia (or "lymphoblastic")	Acute lymphoblastic leukemia (ALL)	Chronic lymphocytic leukemia (CLL)
Myelogenous leukemia ("myeloid" or "nonlymphocytic")	Acute myelogenous leukemia (AML or myeloblastic)	Chronic myelogenous leukemia (CML)

General classification

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. 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. 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.

Additionally, the diseases are subdivided according to which kind of blood cell is affected. This divides leukemias into lymphoblastic or lymphocytic leukemias and myeloid or myelogenous leukemias:

• 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.
• In myeloid or myelogenous leukemias, the cancerous change takes place in a type of marrow cell that normally goes on to form red blood cells, some other types of white cells, and platelets.

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.

Specific types

• Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in young children. It also affects adults, especially those 65 and older. Standard treatments involve chemotherapy and radiotherapy. The survival rates vary by age: 85% in children and 50% in adults. Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.
• 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 75%. It is incurable, but there are many effective treatments. One subtype is B-cell prolymphocytic leukemia, a more aggressive disease.
• Acute myelogenous leukemia (AML) occurs more commonly in adults than in children, and more commonly in men than women. It is treated with chemotherapy. The five-year survival rate is 40%, except for APL (Acute Promyelocytic Leukemia), which has a survival rate greater than 90%. Subtypes of AML include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia.
• 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.
• Large granular lymphocytic leukemia may involve either T-cells or NK cells; like hairy cell leukemia, which involves solely B cells, it is a rare and indolent (not aggressive) leukemia.
• 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.
• Clonal eosinophilias (also called clonal hypereosinophilias) are a group of blood disorders characterized by the growth of eosinophils in the bone marrow, blood, and/or other tissues. They may be pre-cancerous or cancerous. Clonal eosinophilias involve a "clone" of eosinophils, i.e., a group of genetically identical eosinophils that all grew from the same mutated ancestor cell. These disorders may evolve into chronic eosinophilic leukemia or may be associated with various forms of myeloid neoplasms, lymphoid neoplasms, myelofibrosis, or the myelodysplastic syndrome.

Pre-leukemia

• 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.

Signs and symptoms

Common symptoms of chronic or acute leukemia

 

The most common symptoms in children are easy bruising, pale skin, fever, and an enlarged spleen or liver.

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 feeling sick, having fevers, chills, night sweats, feeling fatigued and other 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 afflicted 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 which 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

There is no single known cause for any of the different types of leukemias. The few known causes, which are not generally factors within the control of the average person, account for relatively few cases. The cause for most cases of leukemia is unknown. 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, a few viruses such as human T-lymphotropic virus, and some chemicals, 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.

Viruses have also been linked to some forms of leukemia. For example, human T-lymphotropic virus (HTLV-1) causes adult T-cell leukemia.

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.

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

The increase in white blood cells in leukemia.

 

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.

Treatment

Most forms of leukemia are treated with pharmaceutical medication, typically combined into a multi-drug chemotherapy regimen. Some are also treated with radiation therapy. In some cases, a bone marrow transplant is effective.

Acute lymphoblastic

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 the 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.
• Alternatively, allogeneic bone marrow transplantation may be appropriate for high-risk or relapsed people.

Chronic lymphocytic

Decision to treat

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:

• Falling hemoglobin or platelet count
• Progression to a later stage of disease
• Painful, disease-related overgrowth of lymph nodes or spleen
• An increase in the rate of lymphocyte production

Treatment approach

For most people with CLL, it is incurable by present treatments, so treatment is directed towards suppressing the disease for many years, rather than totally and permanently eliminating it. The primary chemotherapeutic plan is combination chemotherapy with chlorambucil or cyclophosphamide, plus a corticosteroid such as prednisone or prednisolone. The use of a corticosteroid has the additional benefit of suppressing some related autoimmune diseases, such as immunohemolytic anemia or immune-mediated thrombocytopenia. In resistant cases, single-agent treatments with nucleoside drugs such as fludarabine, pentostatin, or cladribine may be successful. Younger and healthier people may choose allogeneic or autologous bone marrow transplantation in the hope of a permanent cure.

Acute myelogenous

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 chemotherapy with additional drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.

Chronic myelogenous

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.

Hairy cell

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.

T-cell prolymphocytic

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.

Juvenile myelomonocytic

Treatment for juvenile myelomonocytic leukemia can include splenectomy, chemotherapy, and bone marrow transplantation.

Prognosis

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 61% 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.

Race is a risk factor in the United States. Hispanics, especially those under the age of 20, are at the highest risk for leukemia, while whites, Native Americans, Asian Americans, and Alaska Natives are at higher risk than African Americans.

More men than women are diagnosed with leukemia and die from the disease. Around 30 percent more men than women have leukemia.

UK

Overall, leukaemia 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. This, however, led 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".

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 leukaemia 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.