Pernicious Anemia
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Pernicious anemia is a disease where not enough
red blood cell Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
s are produced due to a deficiency of vitamin B12. Those affected often have a gradual onset. The most common initial symptoms are feeling tired and weak. Other symptoms may include
shortness of breath Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...
, feeling faint, a smooth red tongue, pale skin, chest pain,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
and
vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...
, loss of appetite, heartburn, numbness in the hands and feet, difficulty walking, memory loss, muscle weakness, poor
reflexes In biology, a reflex, or reflex action, is an involuntary, unplanned sequence or action and nearly instantaneous response to a Stimulus (physiology), stimulus. Reflexes are found with varying levels of complexity in organisms with a nervous s ...
, blurred vision, clumsiness, depression, and confusion. Without treatment, some of these problems may become permanent. Pernicious anemia refers to a type of
vitamin B12 deficiency Vitamins are organic molecules (or a set of closely related molecules called vitamers) that are essential to an organism in small quantities for proper metabolic function. Essential nutrients cannot be synthesized in the organism in suff ...
anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
that results from lack of intrinsic factor. Lack of intrinsic factor is most commonly due to an
autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
attack on the cells that create it in the
stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...
. It can also occur following the surgical removal of all or part of the stomach or
small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...
; from an inherited disorder or illnesses that damage the stomach lining. When suspected, diagnosis is made by
blood test A blood test is a medical laboratory, laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose ...
s initially a
complete blood count A complete blood count (CBC), also known as a full blood count (FBC) or full haemogram (FHG), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blo ...
, and occasionally, bone marrow tests. Blood tests may show fewer but larger red blood cells, low numbers of young red blood cells, low levels of vitamin B12, and
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
to intrinsic factor. Diagnosis is not always straightforward and can be challenging. Because pernicious anemia is due to a lack of intrinsic factor, it is not preventable. Pernicious anemia can be treated with injections of vitamin B12. If the symptoms are serious, frequent injections are typically recommended initially. There are not enough studies that pills are effective in improving or eliminating symptoms. Often, treatment may be needed for life. Pernicious anemia is the most common cause of clinically evident vitamin B12 deficiency worldwide. Pernicious anemia due to autoimmune problems occurs in about one per 1000 people in the US. Among those over the age of 60, about 2% have the condition. It more commonly affects people of northern European descent. Women are more commonly affected than men. With proper treatment, most people live normal lives. Due to a higher risk of
stomach cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the Gastric mucosa, lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a numb ...
, those with pernicious anemia should be checked regularly for this. The first clear description was by Thomas Addison in 1849. The term "pernicious" means "deadly", and this term came into use because, before the availability of treatment, the disease was often fatal.


Signs and symptoms

Pernicious anemia often presents slowly, and can cause harm insidiously and unnoticeably. Untreated, it can lead to neurological complications, and in serious cases, death. The onset may be vague and slow and the condition can be confused with other conditions, and there may be few to many symptoms without anemia. Pernicious anemia may be present without a person experiencing symptoms at first, over time, feeling tired and weak,
lightheadedness Lightheadedness is a common and typically unpleasant sensation of dizziness or a feeling that one may faint. The sensation of lightheadedness can be short-lived, prolonged, or, rarely, recurring. In addition to dizziness, the individual may fee ...
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
, headaches,
rapid Rapid(s) or RAPID may refer to: Hydrological features * Rapids, sections of a river with turbulent water flow * Rapid Creek (Iowa River tributary), Iowa, United States * Rapid Creek (South Dakota), United States, namesake of Rapid City Sport ...
or irregular heartbeat, breathlessness, glossitis (a sore red tongue), poor ability to exercise, low blood pressure, cold hands and feet, pale or
yellow Yellow is the color between green and orange on the spectrum of light. It is evoked by light with a dominant wavelength of roughly 575585 nm. It is a primary color in subtractive color systems, used in painting or color printing. In t ...
skin, easy bruising and bleeding, low-grade
fever Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
s, tremor, cold sensitivity,
chest pain Chest pain is pain or discomfort in the chest, typically the front of the chest. It may be described as sharp, dull, pressure, heaviness or squeezing. Associated symptoms may include pain in the shoulder, arm, upper abdomen, or jaw, along with n ...
,
upset stomach Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...
, loss of appetite, heartburn, weight loss,
diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
,
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...
, severe
joint pain Arthralgia () literally means 'joint pain'. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication Medication (also called medicament, medicine, pharmaceutic ...
, feeling abnormal sensations including tingling or numbness to the fingers and toes (''pins and needles''), and tinnitus, may occur. Anemia may present with a number of further common symptoms, including hair thinning and loss, early greying of the hair, mouth ulcers, bleeding gums,
angular cheilitis Angular cheilitis (AC) is inflammation of one or both corners of the mouth. Often the corners are red with skin breakdown and crusting. It can also be itchy or painful. The condition can last for days to years. Angular cheilitis is a type of ch ...
, a look of exhaustion with pale and dehydrated or cracked lips and dark circles around the eyes, as well as brittle nails. In more severe or prolonged cases of pernicious anemia, nerve cell damage may occur. This is may result in sense loss, difficulty in
proprioception Proprioception ( ) is the sense of self-movement, force, and body position. Proprioception is mediated by proprioceptors, a type of sensory receptor, located within muscles, tendons, and joints. Most animals possess multiple subtypes of propri ...
,
neuropathic pain Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuo ...
, difficulty walking, poor balance, loss of sensation in the feet,
muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includ ...
, blurred vision (either due to
retinopathy Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically in ...
or
optic neuropathy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...
), impaired urination, fertility problems, decreased sense of taste and smell, decreased level of consciousness, changes in reflexes, memory loss, mood swings, depression,
irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...
, cognitive impairment, confusion, anxiety, clumsiness, psychosis, and, in more severe cases, dementia. Anemia may also lead to cardiac murmurs and/or altered blood pressure ( low or high). The deficiency may also present with thyroid disorders. In severe cases, the anemia may cause congestive heart failure. A complication of severe chronic PA is
subacute combined degeneration of spinal cord Subacute combined degeneration of spinal cord, also known as myelosis funiculus, or funicular myelosis, also Lichtheim's disease, and Putnam-Dana syndrome, refers to degeneration of the posterior and lateral columns of the spinal cord as a resul ...
, which leads to distal sensory loss (posterior column), absent ankle reflex, increased knee reflex response, and extensor plantar response. Other than anemia, hematological symptoms may include
cytopenia Cytopenia is a reduction in the number of mature blood cells. It can have many causes, and commonly occurs in people with cancer being treated with radiation therapy or chemotherapy. Types * Anemia – a reduction of the red blood cells in the bo ...
s, intramedullary
hemolysis Hemolysis or haemolysis (), also known by #Nomenclature, several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may ...
, and pseudothrombotic microangiopathy. Vitamin B12 deficiency, which is reversible, is occasionally confused with
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
, which is an irreversible condition presenting with some of the same hematological symptoms, including hypercellular bone marrow with blastic differentiation and hypersegmented neutrophils. Pernicious anemia can cause
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
and may lead to
bone fracture A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a ''c ...
s. Pernicious anemia can contribute to a delay in physical growth in children, and may also be a cause for delay in puberty for adolescents.


Causes

Vitamin B12 cannot be produced by the human body, and must be obtained from the diet. When foods containing B12 are eaten, the vitamin is usually bound to protein and is released by proteases released by the pancreas into the small bowel. Following its release, most B12 is absorbed by the body in the small bowel (
ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may ...
) after binding to a protein known as intrinsic factor. Intrinsic factor is produced by
parietal cell Parietal cells (also known as oxyntic cells) are epithelial cells in the stomach that secrete hydrochloric acid (HCl) and intrinsic factor. These cells are located in the gastric glands found in the lining of the fundus and body regions o ...
s of the
gastric mucosa The gastric mucosa is the mucous membrane layer of the stomach, which contains the gastric pits, to which the gastric glands empty. In humans, it is about one mm thick, and its surface is smooth, soft, and velvety. It consists of simple secretor ...
(stomach lining) and the intrinsic factor-B12-complex is absorbed by enterocytes in the
ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may ...
's cubam receptors. PA is characterised by B12 deficiency caused by the absence of intrinsic factor. Other disorders that can disrupt the absorption of vitamin B12 in the small intestine include
celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spel ...
, surgical removal,
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
, and HIV. PA may be considered as an end stage of autoimmune
atrophic gastritis Atrophic gastritis is a process of chronic inflammation of the gastric mucosa of the stomach, leading to a loss of gastric gland, gastric glandular cells and their eventual replacement by Intestinal metaplasia, intestinal and fibrous tissues. As ...
, a disease characterised by stomach atrophy and the presence of
antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...
to parietal cells and intrinsic factor. Autoimmune atrophic gastritis, is localised to the body of the stomach, where parietal cells are located. Antibodies to intrinsic factor and parietal cells cause the destruction of the oxyntic gastric mucosa, in which the parietal cells are located, leading to the subsequent loss of intrinsic factor synthesis. Without intrinsic factor, the ileum can no longer absorb the B12. Atrophic gastritis is often a precursor to
gastric cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
. Although the exact role of ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, Flagellum#bacterial, flagellated, Bacterial cellular morphologies#Helical, helical bacterium. Mutants can have a rod or curved rod shape that exhibits l ...
'' infection in PA remains controversial, evidence indicates ''H. pylori'' is involved in the pathogenesis of the disease. A long-standing ''H. pylori'' infection may cause gastric autoimmunity by a mechanism known as molecular mimicry. Antibodies produced by the immune system can be cross-reactive and may bind to both ''H. pylori''
antigen In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
s and those found in the
gastric mucosa The gastric mucosa is the mucous membrane layer of the stomach, which contains the gastric pits, to which the gastric glands empty. In humans, it is about one mm thick, and its surface is smooth, soft, and velvety. It consists of simple secretor ...
. The antibodies are produced by activated
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s that recognise both pathogen and self-derived peptides. The
autoantigen In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
s believed to cause the autoreactivity are the alpha and beta subunits of the sodium-potassium pump. In a study, B12 deficiency caused by ''Helicobacter pylori'' was positively correlated with CagA positivity and gastric inflammatory activity, rather than gastric atrophy. Less commonly, ''H. pylori'' and Zollinger-Ellison syndrome may cause a form of nonautoimmune gastritis that can lead to pernicious anemia. Impaired B12 absorption can also occur following gastric removal ( gastrectomy) or gastric bypass surgery. In these surgeries, either the parts of the stomach that produce gastric secretions are removed or they are bypassed. This means intrinsic factor, as well as other factors required for B12 absorption, are not available. However, B12 deficiency after gastric surgery does not usually become a clinical issue. This is probably because the body stores many years' worth of B12 in the liver and gastric surgery patients are adequately supplemented with the vitamin. Although no specific PA susceptibility genes have been identified, a genetic factor likely is involved in the disease. Pernicious anemia is often found in conjunction with other autoimmune disorders, suggesting common autoimmune susceptibility genes may be a causative factor. In spite of that, previous family studies and case reports focusing on PA have suggested that there is a tendency of genetic heritance of PA in particular, and close relatives of the PA patients seem to have higher incidence of PA and associated PA conditions. Moreover, it was further indicated that the formation of antibodies to gastric cells was autosomal dominant gene determined, and the presence of antibodies to the gastric cells might not be necessarily related to the occurrence of atrophic gastritis related to PA.


Pathophysiology

Although the healthy body stores three to five years' worth of B12 in the liver, the usually undetected autoimmune activity in one's gut over a prolonged period of time leads to B12 depletion and the resulting anemia; pernicious anemia refers to one of the hematologic manifestations of chronic auto-immune gastritis, in which the immune system targets the parietal cells of the stomach or intrinsic factor itself, leading to decreased absorption of vitamin B12. The body needs enough intrinsic factor to absorb and reabsorb vitamin B12 from the
bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...
, the lack of which reduces the time needed to develop a deficiency. B12 is required by enzymes for two reactions: the conversion of methylmalonyl-CoA to
succinyl-CoA Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A. Sources It is an important intermediate in the citric acid cycle, where it is synthesized from Alpha-Ketoglutaric acid, α-ketoglutarate ...
, and the conversion of homocysteine to
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...
. In the latter reaction, the
methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...
of levomefolic acid is transferred to homocysteine to produce tetrahydrofolate and methionine. This reaction is catalyzed by the enzyme methionine synthase with B12 as an essential cofactor. During B12 deficiency, this reaction cannot proceed, which leads to the accumulation of levomefolic acid. This accumulation depletes the other types of folate required for
purine Purine is a heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted puri ...
and thymidylate synthesis, which are required for the synthesis of DNA. Inhibition of
DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all life, living organisms, acting as the most essential part of heredity, biolog ...
in maturing red blood cells results in the formation of large, fragile megaloblastic
erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...
s. The neurological aspects of the disease are thought to arise from the accumulation of methylmalonyl- CoA due to the requirement of B12 as a cofactor to the enzyme methylmalonyl-CoA mutase.


Diagnosis

The insidious nature of PA may mean that diagnosis is delayed. Diagnosis is not always straightforward and can be challenging and can take up to several years to receive a diagnosis from the onset of symptoms and almost 60% of those affected are misdiagnosed or not initially diagnosed at all. PA may be suspected when a patient's
blood smear A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the i ...
shows large, fragile, immature erythrocytes, known as megaloblasts. A diagnosis of PA first requires demonstration of
megaloblastic anemia Megaloblastic anemia is a type of macrocytic anemia. An anemia is a red blood cell defect that can lead to an undersupply of oxygen. Megaloblastic anemia results from inhibition of DNA replication, DNA synthesis during red blood cell production. ...
by conducting a
full blood count A complete blood count (CBC), also known as a full blood count (FBC) or full haemogram (FHG), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blo ...
and blood smear, which evaluates the
mean corpuscular volume The mean corpuscular volume, or mean cell volume (MCV), is a measure of the average volume of a red blood corpuscle (or red blood cell). The measure is obtained by multiplying a volume of blood by the proportion of blood that is cellular (the hem ...
(MCV), as well the mean corpuscular hemoglobin concentration (MCHC). PA is identified with a high MCV ( macrocytic anemia) and a normal MCHC ( normochromic anemia). Ovalocytes are also typically seen on the blood smear, and a
pathognomonic Pathognomonic (synonym ''pathognomic'') 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 PA and others) is hypersegmented neutrophils. Neuropsychiatric symptoms can precede hematological signs and are often the presenting manifestation of the disease. Vitamin B12 serum levels are used to detect its deficiency, but do not distinguish its causes. Vitamin B12 levels can be falsely high or low and data for
sensitivity and specificity In medicine and statistics, sensitivity and specificity mathematically describe the accuracy of a test that reports the presence or absence of a medical condition. If individuals who have the condition are considered "positive" and those who do ...
vary widely. Normal serum levels may be found in cases of deficiency where myeloproliferative disorders,
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
, transcobalamin II, or
small intestinal bacterial overgrowth Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon (or large bowel), which is r ...
are present. Low levels of serum vitamin B12 may be caused by other factors than B12 deficiency, such as
folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. This may result in megaloblastic anemia in which red blood cells become abnormally large, and folate deficiency anemia is the term given ...
,
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
,
oral contraceptive Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. The introduction of the birth control pill ("the Pill") in 1960 revolutionized the options for contraception, ...
use, haptocorrin deficiency, and
myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, a ...
. High serum levels may caused by supplementing with vitamin B12, present of antibodies to intrinsic factor, or due to underlying condition. The presence of antibodies to gastric parietal cells and intrinsic factor is common in PA. Parietal cell antibodies are found in other autoimmune disorders and also in up to 10% of healthy individuals. However, around 85% of PA patients have parietal cell antibodies, which means they are a sensitive marker for the disease. Intrinsic factor antibodies are much less sensitive than parietal cell antibodies, but they are much more specific. They are found in about half of PA patients and are very rarely found in other disorders. These antibody tests can distinguish between PA and food-B12 malabsorption. A buildup of certain metabolites occurs in B12 deficiency due to its role in metabolic processes and cellular functions. Methylmalonic acid (MMA) can be measured in both the blood and urine, whereas homocysteine is only measured in the blood. An increase in both MMA and homocysteine distinguishes B12deficiency from folate deficiency because homocysteine alone increases in the latter. Elevated
gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. ...
levels can be found in around 80–90% of PA cases, but they may also be found in other forms of gastritis. Decreased pepsinogen I levels or a decreased pepsinogen I to pepsinogen II ratio may also be found, although these findings are less specific to PA and can be found in food-B12 malabsorption and other forms of gastritis. The diagnosis of atrophic gastritis type A should be confirmed by gastroscopy and stepwise biopsy. About 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.


Differential diagnosis

Forms of vitamin B12 deficiency other than PA must be considered in the
differential diagnosis In healthcare, a differential diagnosis (DDx) is a method of analysis that distinguishes a particular disease or condition from others that present with similar clinical features. Differential diagnostic procedures are used by clinicians to di ...
of megaloblastic anemia. For example, a B12-deficient state which causes megaloblastic anemia and which may be mistaken for classical PA may be caused by infection with the tapeworm '' Diphyllobothrium latum'', possibly due to the parasite's competition with host for vitamin B12. The classic test for PA, the Schilling test, is no longer widely used, as more efficient methods are available. This historic test consisted, in its first step, of taking an oral dose of
radiolabel A radioactive tracer, radiotracer, or radioactive label is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide (a radioactive atom). By virtue of its radioactive decay, it can be used to exp ...
led vitamin B12, followed by quantitation of the vitamin in the patient's urine over a 24-hour period via measurement of the
radioactivity Radioactive decay (also known as nuclear decay, radioactivity, radioactive disintegration, or nuclear disintegration) is the process by which an unstable atomic nucleus loses energy by radiation. A material containing unstable nuclei is conside ...
. A second step of the test repeats the regimen and procedure of the first step, with the addition of oral intrinsic factor. A patient with PA presents lower than normal amounts of intrinsic factor; hence, addition of intrinsic factor in the second step results in an increase in vitamin B12 absorption (over the baseline established in the first). The Schilling test distinguished PA from other forms of B12 deficiency, specifically, from Imerslund–Gräsbeck syndrome, a B12-deficiency caused by mutations in ''CUBN'' that codes for cubilin the cobalamin receptor. Vitamin B12 deficiency is also prevalent in patients having
Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...
, so it should be differentiated.


Treatment

Pernicious anemia is usually easily treated by providing the necessary level of vitamin B12 supplementation. Pernicious anemia can be treated with intramuscular injections of vitamin B12. Initially in high daily doses, followed by less frequent lower doses, as the condition improves. Activity may need to be limited during the course of treatment. As long as the body is saturated with vitamin B12 expected to result in cessation of anemia-related symptoms and there are no other symptoms, unless there are irreversible neurological complications. There are not enough studies on whether pills are as effective in improving or eliminating symptoms as parenteral treatment.
Folate Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
supplementation may affect the course and treatment of pernicious anemia if vitamin B12 not replaced. In some severe cases of anemia, a
blood transfusion Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used ...
may be needed to resolve haematological effects. Treatment is lifelong. The treatment of PA varies by country and area. Opinions vary over the efficacy of administration (parenteral/oral), the amount and time interval of the doses, or the forms of vitamin B12 (e.g. cyanocobalamin/hydroxocobalamin). More comprehensive studies are still needed in order to validate the feasibility of a particular therapeutic method for PA in clinical practices.


Prognosis

A person with well-treated PA can live a healthy life. Failure to diagnose and treat in time, however, may result in permanent neurological damage, excessive fatigue, depression, memory loss, and other complications. In severe cases, the neurological complications of pernicious anemia can lead to death – hence the name, " pernicious", meaning deadly. There is an increased risk of
gastric cancer Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
in those with pernicious anemia linked to the common feature of atrophic gastritis.


Epidemiology

PA is estimated to affect 0.1% of the general population and 1.9% of those over 60, accounting for 20–50% of B12 deficiency in adults. A review of literature shows that the prevalence of PA is higher in Northern Europe, especially in Scandinavian countries, and among people of African descent, and that increased awareness of the disease and better diagnostic tools might play a role in apparently higher rates of incidence.


History

A case of anemia with a first recognition of associated
atrophic gastritis Atrophic gastritis is a process of chronic inflammation of the gastric mucosa of the stomach, leading to a loss of gastric gland, gastric glandular cells and their eventual replacement by Intestinal metaplasia, intestinal and fibrous tissues. As ...
a feature of pernicious anemia, was first described in 1824 by James Combe. This was fully investigated in 1849, by British physician Thomas Addison, from which it acquired the common name of ''Addison's anemia''. In 1871, the first accurate description of the disease in continental Europe was made by Michael Anton Biermer, a
German German(s) may refer to: * Germany, the country of the Germans and German things **Germania (Roman era) * Germans, citizens of Germany, people of German ancestry, or native speakers of the German language ** For citizenship in Germany, see also Ge ...
physician who noted the insidious course of the condition. Because it was untreatable and fatal at the time, he first referred to it as "pernicious" anemia. Russell coined the term
subacute combined degeneration of spinal cord Subacute combined degeneration of spinal cord, also known as myelosis funiculus, or funicular myelosis, also Lichtheim's disease, and Putnam-Dana syndrome, refers to degeneration of the posterior and lateral columns of the spinal cord as a resul ...
. In 1907, Richard Clarke Cabot reported on a series of 1,200 patients with PA; their average survival was between one and three years. Pernicious anemia was a fatal disease before about the year 1920; until the importance of the
liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
in
hematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
was recognized, the treatment of pernicious anemia was unsuccessful and arbitrary. It may have motivated George Whipple, who had a keen interest in
liver diseases Hepato-biliary diseases include liver diseases and biliary diseases. Their study is known as hepatology. Liver diseases Viral hepatitis * Acute hepatitis A * Acute hepatitis B * Acute hepatitis C * Acute hepatitis D – this is a superinfecti ...
, to investigate the liver's role in hematopoiesis. Whipple began evaluating the effects of treatments for anemia caused by chronic blood loss. Whipple, Huber, and Robchett studied the effects on
hemoglobin Hemoglobin (haemoglobin, Hb or Hgb) is a protein containing iron that facilitates the transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole exception of the fish family Channichthyidae. Hemoglobin ...
and blood regeneration of a variety of treatments, among which only raw liver showed real promise. Serendipity is said to have played a role in this discovery. Whipple observed that blood regeneration was poor in dogs fed cooked liver after chronic blood loss. Had it not been that a lazy laboratory technician gave the dogs raw liver, the much more dramatic response might not have been discovered then. Around 1926, George Minot and William P. Murphy, who learned of Whipple's discovery, sought raw liver as a treatment for pernicious anemia. They later suggested a high-protein diet with high amounts of raw liver. This caused a rapid improvement in symptoms and a simultaneous rise in
red blood cell Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...
counts.
Fruit In botany, a fruit is the seed-bearing structure in flowering plants (angiosperms) that is formed from the ovary after flowering. Fruits are the means by which angiosperms disseminate their seeds. Edible fruits in particular have long propaga ...
and
iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
were also part of the diet, and it appears that at this point, Minot and Murphy were not quite sure that the liver was a very important factor. It was thought that iron in liver tissue, not liver juice-soluble factor, cured hemorrhagic anemia in dogs. Thus, the discovery of liver juice as a treatment for pernicious anemia had been by coincidence. However, Minot, Murphy, and Whipple received the joint Nobel Prize for discovering a cure for a previously fatal disease of unknown cause in 1934, becoming the first Americans to be awarded the
Nobel Prize in Physiology and Medicine The Nobel Prize in Physiology or Medicine () is awarded yearly by the Nobel Assembly at the Karolinska Institute, Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single ...
. It is not easy to eat uncooked liver, and extracts were developed as a concentrate of liver juice for
intramuscular injection Intramuscular injection, often abbreviated IM, is the medical injection, injection of a substance into a muscle. In medicine, it is one of several methods for parenteral, parenteral administration of medications. Intramuscular injection may be ...
. In 1928, chemist Edwin Cohn prepared an extract that was 50 to 100 times stronger than obtained from raw liver. This became part of the standard management of pernicious anemia until the 1950s. The active ingredient in the liver remained unknown until 1948. The anti-pernicious anemia factor was only isolated from the liver by Smith, Rex, and others. The substance was
cobalamin Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. One of eight B vitamins, it serves as a vital cofactor (biochemistry), cofactor in DNA synthesis and both fatty acid metabolism, fatty acid and amino a ...
, which the discoverers called "vitamin B12". They showed that giving a few micrograms could prevent relapse in the disease.
Dorothy Hodgkin Dorothy Mary Crowfoot Hodgkin (née Crowfoot; 12 May 1910 – 29 July 1994) was a Nobel Prize-winning English chemist who advanced the technique of X-ray crystallography to determine the structure of biomolecules, which became essential for ...
and co-workers went on to use
X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...
to elucidate the structure of cobalamin for which she, too, was awarded a
Nobel Prize The Nobel Prizes ( ; ; ) are awards administered by the Nobel Foundation and granted in accordance with the principle of "for the greatest benefit to humankind". The prizes were first awarded in 1901, marking the fifth anniversary of Alfred N ...
. Understanding of the pathogenesis of pernicious anaemia increased over subsequent decades. It had long been known that the disease was associated with defects in the gastrointestinal tract: patients had chronic gastritis and lack of acid secretion (
achlorhydria Achlorhydria and hypochlorhydria are states where the production of hydrochloric acid in gastric secretions of the stomach is absent or low, respectively. Achlorhydria is commonly a complication of some other disease, such as chronic '' Helicobac ...
). It is known that transport of physiological amounts of vitamin B12 depends on the combined actions of gastric, ileal and pancreatic components. The gastric moiety was discovered and named ' intrinsic factor' by
William Castle William Castle (born William Schloss Jr.; April 24, 1914 – May 31, 1977) was an American film director, producer, screenwriter, and actor. He is known for the horror film, horror and thriller film, thriller B movie, B-movies he directed durin ...
in 1930. A further important advance was made in the early 1960s by Doniach with the recognition that pernicious anemia is an
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
. Pernicious anemia is eventually treated with only injections of B12; injections are typically 1 mg every other day, or twice weekly. A medical author takes the view that
Mary Todd Lincoln Mary Ann Todd Lincoln (Birth name, née Todd; December 13, 1818July 16, 1882) was First Lady of the United States from 1861 until the assassination of her husband, President Abraham Lincoln, in 1865. Mary Todd was born into a large and wealthy ...
, the wife of American President
Abraham Lincoln Abraham Lincoln (February 12, 1809 – April 15, 1865) was the 16th president of the United States, serving from 1861 until Assassination of Abraham Lincoln, his assassination in 1865. He led the United States through the American Civil War ...
, had pernicious anemia for decades and died from it in 1882.


Research


Permeation enhancers

Treatment using oral drugs is an easier option in management but the bioavailability of vitamin B12 is low. This is due to low absorption in the intestine, and breakdown by enzyme activity. Research continues to focus on the use of permeation enhancers or permeation absorbers in combination with the treatment. One of the better performing enhancers studied is ''salcoprozate sodium'' (SNAC). SNAC is able to form a noncovalent complex with cobalamin while preserving its chemical integrity and protect vitamin B12 from gastric acidity. This complex is much more lipophilic than the water-soluble vitamin B12, so is able to pass through cellular membranes with greater ease. Molecular dynamics are used in experiments to gain an understanding of the molecular interactions involved in the different molecules used and the degree of ease achieved in absorption across the gastric epithelium.


References


External links

{{DEFAULTSORT:Pernicious Anemia Hematopathology Nutritional anemias Wikipedia medicine articles ready to translate Wikipedia neurology articles ready to translate