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Pernicious anemia
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Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of megaloblastic anemia due to vitamin B12 deficiency, caused by impaired absorption of vitamin B-12 due to the absence of intrinsic factor in the setting of atrophic gastritis, and more specifically of loss of gastric parietal cells.
While the term 'pernicious anemia' is sometimes also incorrectly used to indicate megaloblastic anemia due to any cause of vitamin B12 deficiency, its proper usage refers to that caused by atrophic gastritis and parietal cell loss only.
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Pernicious anemia (also known as Biermer's anemia, Addison's anemia, or Addison-Biermer anemia) is a form of megaloblastic anemia due to vitamin B12 deficiency, caused by impaired absorption of vitamin B-12 due to the absence of intrinsic factor in the setting of atrophic gastritis, and more specifically of loss of gastric parietal cells.
While the term 'pernicious anemia' is sometimes also incorrectly used to indicate megaloblastic anemia due to any cause of vitamin B12 deficiency, its proper usage refers to that caused by atrophic gastritis and parietal cell loss only. It is the most common cause of adult vitamin B-12 deficiency.
Mechanisms and manifestations
Pathophysiology
Vitamin B-12 cannot be produced by the human body, and must therefore be obtained from diet. Normally, dietary vitamin B-12 can only be absorbed by the ileum when it is bound by the intrinsic factor produced by parietal cells of the gastric mucosa. In pernicious anemia, this process is impaired because of loss of parietal cells, resulting in insufficient absorption of the vitamin, which over a prolonged period of time ultimately leads to vitamin B-12 deficiency and thus megaloblastic anemia. This anemia is a result of the body's inability to produce DNA in sufficient quantities for blood cell synthesis, due to interruption of a biochemical pathway that is dependent on vitamin B-12 and/or folic acid as cofactors, which synthesizes thymine, a DNA component.
Presentation
The presentation of pernicious anemia resembles that of any other form of anemia, but is often accompanied by the manifestations of vitamin B12 deficiency (notably neurological abnormalities such as peripheral neuropathy), as well as by other manifestations of autoimmune atrophic gastritis.
Causes
Most commonly (in temperate climates), the cause for impaired binding of vitamin B12 by intrinsic factor is autoimmune atrophic gastritis, in which autoantibodies are directed against parietal cells (resulting in their loss) as well as against the intrinsic factor 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 non-autoimmune origin, such as that frequently occurring in elderly people affected with long-standing chronic gastritis of any cause (including Helicobacter pylori infection).
Note that forms of vitamin B-12 deficiency other than pernicious anemia must be considered in the differential diagnosis of megaloblastic anemia. 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, .
Symptoms
The symptoms of PA vary from patient to patient. Some patients might experience all of the symptoms listed below, whilst others may experience just one or two. Some patients are asymptomatic and experience no symptoms and yet can still PA. Similarly, the degree to which the symptoms are experienced will depend on a number of factors including how soon treatment was started.
Common physical symptoms
Fatigue
None of the above words adequately or accurately explains the feeling that is experienced by the majority of patients with Pernicious Anaemia. The physical tiredness is also often accompanied with mental fatigue and apathy. The most common description recognised by patients is that of “The Strange Tiredness” which is understood by most sufferers as being an adequate description of the experience. Sometimes the Strange Tiredness lasts for hours, sometimes days and often it’s the case that it never really fully goes away. It is also usual for the Strange Tiredness to be worse on some days than on others and it can be debilitating for the long-term sufferer. Patients and their families and friends often have to make lifestyle adjustments to be able to manage this experience. Many patients retire to their beds in an effort to manage their condition and the saying “at least ten, usually twelve and sometimes more” is sometimes used by sufferers to describe how many hours sleep they need. Feeling tired or exhausted can be a very negative experience as anyone who has played sport can tell you. But this Strange Tiredness is not a pleasant experience. It is an insidious, creeping, overpowering feeling that seems to sap any strength that the patient might have. It doesn’t often leave the sufferer being unable to do normal and everyday tasks but rather makes such tasks (however trivial) a real trial. Sufferers often cope with everyday work and domestic tasks, but most struggle to do so. Many patients wake up tired in the morning, despite sleeping heavily for over the usual 8 hours the patient. A great many patients report needing more than 10 hours each night.
Shortness of breath
This is one of the most misunderstood of all the symptoms. There are some sufferers who begin to breathe heavily when performing any physical activity such as walking up stairs, general household cleaning, lifting and brisk walking, but only very rarely is there any gasping for air. However, it is the need to take deep breaths when not performing any activity that causes the most concern. Sufferers often refer to this need to take in ‘lumps’ of air as ‘The Sighs.’ Often it may seem that the patient is struggling to breath, but he or she will simply be trying to satisfy the need to take in a deep breath. This can often be accompanied by the need to yawn, sometimes almost continually. One of the strangest aspects of The Sighs is that they don’t occur every day. Patients often talk of good & bad days. On good days the patient might not feel the need to ‘sigh’. On bad days he or she might need to ‘sigh’ for most of the day or for just a short period.
Swollen tongue (Glossitis)
This is often quoted as being one of the most common symptoms of P.A. However, only a small percentage of sufferers of Pernicious Anaemia experienced a swollen, smooth and ‘beefy’ red tongue. Perhaps the figure is as low as 10%. Those who do have a swollen tongue often complain that their tongue bleeds and becomes tender.
Feeling bloated or full
This is often accompanied by a physical swelling of the stomach. The patient will feel ‘full’.
Brittle, easily damaged nails
The nails on both hands and feet become brittle and split or break very easily. Many patients never have to trim or cut their nails as they break off whenever they become anything other than short.
Pins and needles sensation (Paraesthesia/Parasthesia)
This can be the first sign of damage to the peripheral nerves. The pins & needles can be experienced anywhere on the body but it mainly affects the tips of fingers and feet. Many patients report that these pins & needles disappear completely after they receive their prescribed treatment. Rather strangely in some cases the pins and needles disappear within hours of the first injection of Hydroxocobalamin being administered.
Sock and glove feeling.
This refers to a numb sensation in the patient’s fingers and feet – it feels as if you are wearing socks and gloves. Again this can be seen as damage to the peripheral nerves but patients often report that this sensation disappears once treatment is started.
Unaccountable sudden Diarrhea.
Again this is a often experienced but not often talked about and can be attributed to Irritable Bowel Syndrome—however this is not always the case.
Less common symptoms
- Unsteadiness or unusual gait due to central nervous system damage (demyelination).
- Vertigo.
- Burning feet/legs. This occurs mainly in middle-age and is usually worst at night. It is directly linked to B12 deficiency and usually disappears once treatment is started. It is known to doctors as Brierson-Goplan syndrome.
Common mental symptoms
As well as physical symptoms, sufferers of P.A. also experience changes to their mental ability. These cognitive symptoms are often more difficult to explain and deal with than the physical symptoms. It seems to be the case that these mental challenges are often not recognised or acknowledged by some medical professionals. As with the physical symptoms, the degree and effect of these symptoms will vary between different patients.
Brain fog
This is by far the most common complaint by sufferers of P.A. Patients find it difficult to define exactly what they experience on a ‘foggy’, but there is a general feeling of lack of focus and a lack of clarity in everything they experience. It’s as if the patient is experiencing being in a thick fog, with all of the senses failing to respond as quickly as they usually do.
The degree to which this occurs is directly proportional to whether the patient is experiencing a good or bad day. On a bad day it is possible that the patient will forget the names of even their closest relatives, be unable to recall even the most common proper nouns, repeatedly ask the same question, forget a conversation from even the shortest time before, make mistakes in their work — even the most fundamental mistakes and feel ‘not with it’. The patient will often seek peace and tranquillity in order to give full concentration to the task he or she is dealing with. The most common way in which the patient can explain what it feels like to be in a fog can be summarised by the following statements:
- “I just want the world to go away”.
- “I just want to be left alone”.
- “I don’t want to be forced into conversation”.
Patients also state that leisure activities such as reading, watching television or going to the cinema can be enjoyed during a ’fog’, but the next day the chapter of the book that was read, or the outcome of a t.v. programme and the plot of a film will be forgotten. The chapter of the book would have to be re-read and the television programme or film would have to be seen again.
‘Fogs’ can last a few hours, a day, or a few days. Patients are aware that they are experiencing a ‘fog’ but are unable to do anything about it. It’s simply a case of ‘riding it out’ Most patients wake up either the next day or in a few days time and experience a clarity and focus to their thinking which had been absent during the fog.
Irritability, impatience and mood swings
This is another very common condition amongst sufferers of Pernicious Anaemia and is probably has the greatest impact on personal relationships.
Diagnosis
The insiduous nature of the disease, and the fact that there is no single definitive test for Pernicious Anaemia can often mean that a diagnosis is late. The Schilling Test is no longer available, and the other main diagnostic signpost of low levels of serum B12 cannot be relied upon as sufferers can have high levels of serum B12 and still have Pernicious Anaemia
A diagnosis of pernicious anemia first requires demonstration of megaloblastic anemia (through a full blood count) which evaluates the mean corpuscular volume (MCV), as well the mean corpuscular hemoglobin concentration (MCHC). Pernicious anemia is identified with a high MCV and a normal MCHC (that is, it is a macrocytic, normochromic anemia). . Ovalocytes are also typically seen on the blood smear, and a pathognomonic 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 test can then be used to distinguish pernicious anemia from other causes of vitamin B-12 deficiency (notably malabsorption).
A diagnosis of atrophic gastritis should be confirmed by gastroscopy with biopsies. Approximately 90% of individuals with pernicious anemia 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 Anaemia varies from country to country and from area to area. There is, as yet, no cure for Pernicious Anaemia and consequently treatment centres on replacing Vitamin B12. This is done in a variety of ways. Cobalamin (B12) is usually injected into the patient's muscle (IntraMuscular or I.M.) using Cyanocobalamin (The United States, Canada and most European countries) or Hydroxocobalamin (Australia and the U.K.). The injections will be for life and will be given every month in some countries and every three months in other countries. The single most common cause of complaint by members of the Pernicious Anaemia Society is that patients needs vary and some patients need more frequent injections than others .
In some countries the Cobalamin preparation is available over the counter from chemists, while in other countries it is only available via doctors prescription.
Patients who are needlephobic, or patients who are unable to receive injections for another reason can be prescribed Cyanocobalmin tablets in very high doses which means that some of the B12 is absorbed further on in the digestive process than where absorption usually takes place. The efficacy of using tablets to treat Pernicious Anaemia is unknown as only scant research into this has taken place.
Some patients are treated by Methylcobalamin Sub-Lingual tablets that are placed under the tongue where some B12 is absorbed via the membrane under the tongue.
Some doctors and medical professionals believe that Sub Cutaneous injections are more effective than I.M. injections.
There are other methods of administering B12 including behind the ear patches and nasal sprays but again the efficacy of these methods of treatment has not been subjected to any serious scientific investigation.
Being a manifestation of vitamin B-12 deficiency, pernicious anemia is treated by administering vitamin B-12 supplements. Oral tablets are sometimes used, though if this approach is used, much higher doses are given than normally required in order to overcome the impaired absorption that characterizes pernicious anemia.
If oral tablets are not desired, vitamin B-12 can also be administered via injection, which is usually given once a month, thus bypassing any intrinsic factor problems and the need for gastrointestinal absorption altogether. Often the patient can learn to do this at home with the same syringes and needles used for insulin treatment of diabetes.
History
Dr. Addison first described the disease, from which it acquired the common name of Addison's Anemia. In 1907 Richard Clarke Cabot 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 un-treated 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 Whipple suggested raw liver as a treatment. After verification of Whipple's results in 1926, pernicious anemia victims ate or drank at least 1/2 a pound of raw liver, or drank raw liver juice every day. This continued for several years until a concentrate of liver juice became available after 1928.
The first workable treatment for pernicious anemia began with the work of George Whipple who made the 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 liver 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 that it was contained in raw liver juice (in the process also showing that ironically 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 etiology the three men shared the 1934 Nobel Prize in Medicine.
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 reduced the cost
of treatment considerably.
The active ingredient in liver was 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 B-12. 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 sufferers
- Inez Milholland, American Suffragette
- Alexander Graham Bell, Scottish scientist and inventor who immigrated to Canada
- Sir Laurence Gomme public servant and folklorist
- Annie Oakley.
- Norman Warne, editor/publisher and fiancé of Beatrix Potter.
- Yoon Eun Hye, a South Korean actress
- Betsie ten Boom, sister to Corrie ten Boom, victim of the Holocaust, and in the book, The Hiding Place
- David Hilbert, German mathematician
- Sam Hughes, Canadian Minister of Militia and Defence
- Henry Sweet, English linguist and phoneticist
- Sir Stafford Cripps - British Politician and Chancellor of the Exchequer in the post-World War 2 Labour government.
- Suzanne Lenglen - French tennis player
External links
- , a UK-based charitable organisation
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