Pernicious anemia is one of many types of the larger family of
megaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
s. It is caused by loss of gastric parietal cells, and subsequent inability to absorb vitamin B
12.
Usually seated in an
atrophic gastritisAtrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
, the
autoimmuneAutoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
destruction of
gastricThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
parietal cellParietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s leads to a lack of
intrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
. Since the absorption from the gut of normal dietary amounts of
vitamin B12Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
is dependent on intrinsic factor, the loss of intrinsic factor leads to
vitamin B12 deficiencyVitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
. While the term 'pernicious anemia' is sometimes also incorrectly used to indicate
megaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
due to
any cause of
vitamin B12 deficiencyVitamin B12 deficiency or hypocobalaminemia is a low blood level of vitamin B12, it can cause permanent damage to nervous tissue as a long term effect. Vitamin B12 was discovered from its relationship to the disease pernicious anemia, which is an autoimmune disease that destroys parietal cells in...
, its proper usage refers to that caused by atrophic gastritis, parietal cell loss, and lack of intrinsic factor only.
The loss of ability to absorb vitamin B
12 is the most common cause of adult vitamin B
12 deficiency. Such a loss may be due to pernicious anemia (with loss of intrinsic factor) or to a number of other conditions that decrease production of gastric acid, which also plays a part in absorption of vitamin B
12 from foods.
Historically, pernicious anemia (PA) was detected only after it became "clinical" (caused an overt disease state) and the anemia was well established, i.e., liver stores of B
12 had been depleted. The "pernicious" aspect of the disease - prior to the discovery of treatment - was its invariably fatal prognosis, similar to leukemia at that time. However, in the time since elucidation of the cause of the disease, modern tests that specifically target B
12 absorption can be used to diagnose the disease before it becomes clinically apparent. In such cases, the disease may be diagnosed and treated without the patient ever becoming ill.
Replacement of vitamin stores does not correct the defect in absorption from loss of intrinsic factor. Since the defect defines the disease, a person without the ability to absorb vitamin B
12 in this way will have pernicious anemia for the remainder of his or her life. However, unless the patient has sustained permanent peripheral nerve damage before treatment, regular B
12 replacement will keep pernicious anemia in check, with no anemia and no further symptoms.
Although initial treatment of the disease usually involves injections of B
12 to rapidly replace body stores, a number of studies have shown that long-term vitamin replacement treatment may be maintained with high-dose oral B
12 supplements, since sufficient B
12 is absorbed from these by a normal intestine, even without any intrinsic factor. In this regard, nasal and sublingual forms of B
12 have not been found to have any special value over simple swallowed tablets.
Signs and symptoms
Pernicious anemia presents insidiously, and many of the signs and symptoms are due to anemia itself, where anemia is present. While it may consist of the triad of paraesthesias, sore tongue and weakness, this is not the chief symptom complex. The patient may complain of fatigue, depression, forgetfulness, difficulty concentrating, low-grade fevers, nausea and gastrointestinal symptoms (heartburn), weight loss. Because PA may affect the spinal cord, the patient may also complain of impaired urination, loss of sensation in the feet, unsteady gait, weakness, and clumsiness. Anemia may cause tachycardia (rapid heartbeat) and cardiac murmurs, along with a waxy pallor. In severe cases, the anemia may cause evidence of congestive heart failure.
Long-term complications may include gastric cancer and
carcinoidCarcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
s.
Many signs and symptoms are attributed to pernicious anemia:
- Fatigue, low blood pressure, rapid heart rate, high blood pressure, pallor
Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....
, depressionDepression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
, muscle weaknessMuscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
, and shortness of breath (known as 'the sighs')
- Difficulty in proprioception
Proprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...
- Mild cognitive impairment, including difficulty concentrating and sluggish responses, colloquially referred to as brain fog
Cognitive dysfunction is defined as unusually poor mental function, associated with confusion, forgetfulness and difficulty concentrating...
- Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
- Frequent diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- Paresthesia
Paresthesia , spelled "paraesthesia" in British English, is a sensation of tingling, burning, pricking, or numbness of a person's skin with no apparent long-term physical effect. It is more generally known as the feeling of "pins and needles" or of a limb "falling asleep"...
s, such as pins and needlesPins and Needles is a musical revue with a book by Arthur Arent, Marc Blitzstein, Emmanuel Eisenberg, Charles Friedman, David Gregory, Joseph Schrank, Arnold B. Horwitt, John Latouche, and Harold Rome and music and lyrics by Rome...
sensations or numbness in fingers or toes, due to B12 deficiency affecting nerve function
- Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
due to impaired formation of blood cells
- Glossitis
Glossitis is inflammation of the tongue. It causes the tongue to swell and change color. Finger-like projections on the surface of the tongue may be lost, causing the tongue to appear smooth....
(swollen red tongue) due to B12 deficiency
- May present with hyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
or hypothyroidismHypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
- Personality or memory changes
A complication of severe chronic PA is
subacute combined degeneration of spinal cordSubacute combined degeneration of spinal cord, also known as Lichtheim's disease, refers to degeneration of the posterior and lateral columns of the spinal cord as a result of vitamin B12 deficiency , vitamin E deficiency or Friedrich's ataxia...
, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response.
Causes
Most commonly (in temperate climates), the cause for impaired binding of vitamin B
12 by intrinsic factor is autoimmune
atrophic gastritisAtrophic gastritis is a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells and their eventual replacement by intestinal and fibrous tissues...
, in which
autoantibodiesAn autoantibody is an antibody manufactured by the immune system that is directed against one or more of the individual's own proteins. It is derived from the Greek "auto" which means "self", "anti" which means "against" and "body"...
are directed against
parietal cellParietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s (resulting in their loss), as well as against the
intrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
itself (rendering it unable to bind vitamin B
12).
Less frequently, loss of parietal cells may simply be part of a widespread atrophic gastritis of nonautoimmune origin, such as that frequently occurring in elderly people affected with long-standing chronic
gastritisGastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic...
of any cause (including
Helicobacter pyloriHelicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
infection).
Forms of vitamin B
12 deficiency other than pernicious anemia must be considered in the
differential diagnosisA differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
of
megaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
. For example, a B
12 deficient state which causes megaloblastic anemia and which may be mistaken for classical pernicious anemia may be caused by infection with the tapeworm
Diphyllobothrium latum, possibly due to the parasite's competition for vitamin B
12.
A similar disorder involving impaired B
12 absorption can also occur following gastric removal (
gastrectomyA gastrectomy is a partial or full surgical removal of the stomach.-Indications:Gastrectomies are performed to treat cancer and perforations of the stomach wall....
) or gastric bypass surgery, especially the
Roux-en-YRoux-en-Y may refer to:*A type of gastric bypass operation*Roux-en-Y anastomosis...
bypass. In this procedure, the stomach is separated into two sections, one a very small pouch for holding small amounts of food, and the other, the remainder of the stomach which becomes nonfunctional. Therefore, the mucosal cells are no longer available; nor is the required
intrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
. This results in inadequate GI absorption of B
12, and may result in a syndrome indistinguishable from pernicious anemia. Gastric bypass or gastrectomy patients must take B
12 as in treatment of pernicious anemia: either oral megadoses, or B
12 by injection.
Pathophysiology
Vitamin B
12 cannot be produced by the human body, and must be obtained from the diet. Normally, dietary vitamin B
12 is absorbed by the body in the small bowel only when it is bound by the
intrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
(IF) produced by
parietal cellParietal cells, or oxyntic cells, are the stomach epithelium cells that secrete gastric acid and intrinsic factor.Acetylcholine and gastrin . The histamine receptors act by increasing intracellular cAMP, whereas the muscarinic and gastrin receptors increase intracellular Ca2+ levels...
s of the
gastricThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
mucosa. Pernicious anemia is thought to occur when the body's immune system mistakenly targets the intrinsic factor, with a loss of parietal cells. Insufficient IF results in insufficient absorption of the vitamin. Although the normal body stores three to five years' worth of vitamin B
12 in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to vitamin B
12 depletion and the resulting anemia. Inhibition of DNA synthesis in red blood cells results in the formation of large, fragile megaloblastic erythrocytes.
Diagnosis
The insidious nature of the disease, and the fact that there is no single definitive test for pernicious anemia, may mean that a diagnosis is delayed. Pernicious anemia is suspected when the patient's blood smear shows large, fragile, immature erythrocytes (megaloblasts). The
Schilling testThe Schilling test is a medical investigation used for patients with vitamin B deficiency. The purpose of the test is to determine whether the patient has pernicious anemia.It is named for Robert F. Schilling.-Process:The Schilling test has multiple stages...
is no longer widely available, and the other main diagnostic signpost of low levels of serum B
12 cannot be relied upon, as sufferers can have high levels of serum B
12 and still have pernicious anemia. Blood and urine tests for
methylmalonic acidMethylmalonic acid is a dicarboxylic acid that is a C-methylated derivative of malonate.The coenzyme A linked form of methylmalonic acid, methylmalonyl-CoA, is converted into succinyl-CoA by methylmalonyl-CoA mutase, in a reaction that requires vitamin B12 as a cofactor...
may indicate a B
12 deficiency, even though serum B
12 is within the normally-acceptable range. Serum B
12 is not necessarily an indicator of efficient use by the body, in the muscles, for example.
A diagnosis of pernicious anemia first requires demonstration of
megaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
(through a full blood count), which evaluates the
mean corpuscular volumeThe mean corpuscular volume, or "mean cell volume" , is a measure of the average red blood cell size that is reported as part of a standard complete blood count....
(MCV), as well the
mean corpuscular hemoglobin concentrationThe mean corpuscular hemoglobin concentration, or MCHC, is a measure of the concentration of hemoglobin in a given volume of packed red blood cells. It is reported as part of a standard complete blood count....
(MCHC). Pernicious anemia is identified with a high MCV and a normal MCHC (that is, it is a macrocytic,
normochromicNormochromic is a form of anemia in which the concentration of hemoglobin in the red blood cells is within the standard range. However, there are insufficient numbers of red blood cells. This includes: aplastic, posthemorrhagic, and hemolytic anemias and anemia of chronic disease.synonymous with...
anemia). Ovalocytes are also typically seen on the blood smear, and a
pathognomonicPathognomonic is a term, often used in medicine, that means characteristic for a particular disease. A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doubt...
feature of megaloblastic anemias (which include pernicious anemia and others) is hypersegmented neutrophils.
Pernicious anemia can also be diagnosed by evaluating its direct cause, vitamin B
12 deficiency, by measuring B
12 levels in serum. A
Schilling testThe Schilling test is a medical investigation used for patients with vitamin B deficiency. The purpose of the test is to determine whether the patient has pernicious anemia.It is named for Robert F. Schilling.-Process:The Schilling test has multiple stages...
can then be used to distinguish pernicious anemia from other causes of vitamin B
12 deficiency (notably
malabsorptionMalabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...
).
The diagnosis of atrophic gastritis Type A should be confirmed by gastroscopy and stepwise biopsy. Approximately 90% of individuals with PA have antibodies for parietal cells; however, only 50% of all individuals in the general population with these antibodies have pernicious anemia.
Treatment
The treatment of pernicious anemia varies from country to country and from area to area. There is no permanent cure for pernicious anemia, although repletion of vitamin B
12 should be expected to result in a cessation of anemia-related symptoms, a halt in neurological deterioration, and (in cases where neurological problems not advanced) neurological recovery and a complete and permanent remission of all symptoms, so long as B
12 is supplemented. Repletion of B
12 can be accomplished in a variety of ways.
The most accessible and inexpensive method of repletion is through dietary supplementation, in the form of oral or sublingual B
12 tablets. B
12 supplements are widely available at supermarkets, health food stores, and drug stores, though quality and cost may vary. In some countries, the cobalamin preparation may be available only via prescription. Doctors can prescribe cobalamin tablets that contain doses higher than what is commercially available.
A 2003 study found that oral and sublingual B
12 were absorbed equally well in a group of patients with very low B
12. In this study, 22% of the subjects that agreed to undergo the test (5 of 23), had abnormal Schilling tests, but showed no difference in treatment levels from the other subjects. When oral tablets are used to treat PA, higher-than-normal doses may be needed. The efficacy of using high dose B
12 tablets to treat ordinary PA (i.e. anemia due to atrophic gastritis) is well established. Oral supplementation allows B
12 to be absorbed in places other than the terminal ileum (where B
12 absorption usually takes place). A 2006 study found that oral B
12 repletion has the potential to be as effective as injections.
However, if oral and sublingual repletion of B
12 is inadequate, the patient may require B
12 injectionsAn injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
, which are usually given once a month, bypassing the need for gastrointestinal absorption altogether. Eventually, the patient may be able to do this at home. Cobalamin (one of the forms of B
12) is usually injected into the patient's muscle (intramuscular or IM) using
cyanocobalaminCyanocobalamin is an especially common vitamer of the vitamin B12 family. It is the most famous vitamer of the family, because it is, in chemical terms, the most air-stable...
(the United States, Canada and most European countries) or
hydroxocobalaminHydroxocobalamin is a natural form, or vitamer, of vitamin B12, a basic member of the cobalamin family of compounds. Hydroxocobalamin is the form of vitamin B12 produced by many bacteria which are used to produce the vitamin commercially. Like other forms of vitamin B12, hydroxocobalamin has an...
(Australia and the U.K.). The injections will typically need to be given for the remainder of the patient's life. The frequency of injections varies by country and health care practitioner, and may be as infrequent as once every three months in some countries. The most common complaint by members of the Pernicious Anaemia Society is that patients have different needs, with some patients needing more frequent injections than others. Some medical professionals believe that subcutaneous injections are more effective than intramuscular injections, but the evidence for this is currently unclear.
There are other methods of administering B
12, including nasal sprays and behind-the-ear patches. One small study from 1997, with six participants, found that intranasal delivery of B
12 led to increases in plasma cobalamin as high as eight times a given patient's baseline measurement. Further investigation of these delivery methods is needed.
History
The British physician
Thomas AddisonThomas Addison was a renowned 19th-century English physician and scientist. He is traditionally regarded as one of the "great men" of Guy's Hospital in London....
first described the disease in 1849, from which it acquired the common name of Addison's anemia. In 1907,
Richard Clarke CabotRichard Clarke Cabot was an American physician who advanced clinical hematology, was an innovator in teaching methods, and was a pioneer in social work.-Family History:...
reported on a series of 1200 patients with PA. Their average survival was between one and three years.
Dr. William Bosworth Castle performed an experiment whereby he ingested raw hamburger meat and regurgitated it after an hour, and subsequently fed it to a group of ten patients. A control group were fed untreated raw hamburger meat. The former group showed a disease response whereas the latter group did not. This was not a sustainable practice, but it demonstrated the existence of an 'intrinsic factor' from gastric juice.
Pernicious anemia was a fatal disease before about the year 1920, when
George WhippleGeorge Hoyt Whipple was an American physician, pathologist, biomedical researcher, and medical school educator and administrator...
suggested raw
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
as a treatment. The first workable treatment for pernicious anemia began when Whipple made a discovery in the course of experiments in which he bled dogs to make them anemic, then fed them various foods to see which would make them recover most rapidly (Whipple was looking for treatments for anemia from bleeding, not pernicious anemia). Whipple discovered that ingesting large amounts of
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
seemed to cure anemia from blood loss, and tried liver ingestion as a treatment for pernicious anemia, reporting improvement there also, in a paper in 1920. George Minot and William Murphy then set about to partly isolate the curative property in liver and showed in 1926 that it was contained in raw liver juice (in the process also showing that it was the iron in liver tissue, not the soluble factor in liver juice, which cured the anemia from bleeding in dogs; thus, the discovery of the liver juice factor as a treatment for pernicious anemia had been by coincidence). For the discovery of the cure of a previously fatal disease of unknown
etiologyEtiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
, the three men shared the 1934
Nobel Prize in MedicineThe Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
.
After Minot and Murphy's verification of Whipple's results in 1926, pernicious anemia victims ate or drank at least one-half pound of raw liver, or drank raw liver juice, every day. This continued for several years, until a concentrate of liver juice became available. In 1928, chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural food (liver). The extract could even be injected into muscle, which meant that patients no longer needed to eat large amounts of liver or juice. This also reduced the cost of treatment considerably.
The active ingredient in liver remained unknown until 1948, when it was isolated by two chemists, Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin, which the discoverers named
vitamin B12Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins...
. The new vitamin in liver juice was eventually completely purified and characterized in the 1950s, and other methods of producing it from bacteria were developed. It could be injected into muscle with even less irritation, making it possible to treat pernicious anemia with even more ease.
Pernicious anemia was eventually treated with either vitamin B
12 injections, or else large oral doses of vitamin B
12, typically between 1 and 4 mg (1000 to 4000 mcg) daily.
Notable cases
- Alexander Graham Bell
Alexander Graham Bell was an eminent scientist, inventor, engineer and innovator who is credited with inventing the first practical telephone....
- Scottish-Canadian scientist and inventor
- Annie Oakley
Annie Oakley , born Phoebe Ann Mosey, was an American sharpshooter and exhibition shooter. Oakley's amazing talent and timely rise to fame led to a starring role in Buffalo Bill's Wild West show, which propelled her to become the first American female superstar.Oakley's most famous trick is perhaps...
- Gunnar Nordström
Gunnar Nordström was a Finnish theoretical physicist best remembered for his theory of gravitation, which was an early competitor of general relativity...
Notable Finnish theoretical physicist. Possibly caused by handling of radioactive material and baths in a Finnish saunaThe Finnish sauna is a substantial part of Finnish culture. There are five million inhabitants and over two million saunas in Finland - an average of one per household. For Finnish people the sauna is a place to relax in with friends and family, and a place for physical and mental relaxation as...
where water containing radioactive material was used in the belief that it was healthy.
- Norman Warne
Norman Dalziel Warne was the third son of publisher Frederick Warne, and joined his father's firm Frederick Warne & Co. as editor. In 1900 the company rejected Beatrix Potter's The Tale of Peter Rabbit, but eventually reconsidered and published the book in October 1902 to great success...
- editor/publisher and fiancé of Beatrix PotterHelen Beatrix Potter was an English author, illustrator, natural scientist and conservationist best known for her imaginative children’s books featuring animals such as those in The Tale of Peter Rabbit which celebrated the British landscape and country life.Born into a privileged Unitarian...
.
- Yoon Eun Hye
Yoon Eun-hye is a South Korean actress, singer, entertainer and model. She debuted as a member of girl group Baby V.O.X, staying with the group from 1999 to 2005...
- a South Korean actress
- Inez Milholland
Inez Milholland Boissevain was a suffragist, labor lawyer, World War I correspondent, and public speaker who greatly influenced the women's movement in America.-Biography:...
- American suffragist
External links