You will note immediately that I have done two things in the title, 1) to use the word ‘one’ rather than ‘a’ or ‘the’. I make no pretence that this article is a definitive history of this condition and 2) I have used the UK spelling of anaemia throughout, knowing that for those of you in the USA you will want it to say anemia and those of you in other countries might want me to call it Addision-Biermers, auto-immune gastritis, B12 malabsorption or B12 deficiency. What I am not talking about is dietary B12 deficiency but rather the often misdiagnosed and under-treated condition brought about by an auto-immune condition which inhibits the ability of the body to absorb B12 through the traditional digestion route and which leads to cobalamin (B12) deficiency, atrophy of the stomach lining and megaloblastic anaemia (ie your red blood cells are the wrong shape to carry oxygen around your body efficiently).
Firstly, I have to introduce you to some important names that will come up in our story below:
- James Combe, Edinburgh (1796–1883)
- Thomas Addison, London (1793–1860)
- Michael Anton Biermer, Zurich (1827–1892)
- James Samuel Risien Russell, British Guyana/Scotland (1863 -1939)
- Richard Clarke Cabot, Massachusetts (1869-1939)
- George Whipple, New Hampshire (1878 – 1976)
- George Minot, Massachusetts (1885-1950)
- William P Murphy, Wisconsin (1892-1987)
- William Osler, Montreal (1849-1919)
- William Bosworth Castle, Massachusetts (1897-1990)
- Edwin Cohn, New York (1892-1953)
- Dorothy Hodgkin, England (1910-1994)
- Robert F Schilling, Wisconsin (1919-2014)
Secondly, I need to remind you that medicine in the 19th century, when PA was first named or discovered, call it what you will, was very different than it is today. As was the way people communicated with each other. There was no internet to research symptoms or to find information. There was no health care service of any kind and other than a few laws for the poor, you largely survived or died depending on your status in society and the hand you were dealt regarding your diseases and job.
Thirdly, I need to mention that I am neither a medical professional nor a scientist. I have explained the technical terms in words that mean something to me and from what I have learned on my own journey. There may be other important contributors along the road who I have not mentioned, not out of malice, but because there is a limit to the length any article should be! So on to the history:
The period of discovery for Pernicious Anaemia takes us to the French Revolution, the reign of Queen Victoria, the Industrial Revolution and times of great political and social change. It was an age of exploration, scientific discovery, and invention with significant developments in all areas, including chemistry, biology, and medicine. It was also an era of institutions and asylums, poor housing and poor nutrition for many. Women who were prone to fatigue and ‘the sighs’ were labelled hysterical in any situation that made people uncomfortable in a patriarchal society. Female hysteria was a common diagnosis. The symptoms were listed as chest pain, shortness of breath, difficulty swallowing, yawning, cold extremities, tears and laughter, delirium, laziness, irritability, confusion, etc.
It was also a time of Jane Austen’s world of the doctor, surgeon and apothecary with clear distinctions between their roles. The doctor, a gentleman of the old school, socially acceptable and who was paid clandestinely so as not to insult his status; the surgeon, whose job it was to remove growths and perform amputations without anaesthesia or antiseptic; and the apothecary, the chemist, druggist and forerunner of the pharmacist, mixing up their potions and considered the lowest ‘rung’ on the medical ladder. All these ‘professionals’ would often have no qualifications or formal training and learned on the job with a basic apprenticeship.
Thank goodness for the inquisitive minds of people in those times and the thirst for knowledge through dissection of bodies, trial and error of chemistry and a willingness to share and discuss their findings. This was a time of radical thinkers and great leaps forward in science.
Let’s start with James Combe in 1824, because he first reported a case of a man with severe pallor, diarrhoea, and typical features of severe anaemia. Despite treatment with iron, spa water and a nourishing diet, the patient died. Combe, being a surgeon, performed an autopsy with his friend Dr Kellie and found the stomach was thin, showing no vessels and was transparent (atrophic gastritis). He didn’t call it Pernicious Anaemia, but published a paper about his findings and referring to various continental doctors’ findings in this area so he is often credited with being the first to discover the condition.
Some years later, Thomas Addison, having studied medicine in Edinburgh, became a physician at Guys hospital in London. In 1849 he was researching anaemia and discovered an adrenal hormone disease which became known as Addison’s disease. But during this research he also described a type of megaloblastic anaemia, which later became known as Addison-Biermer’s disease or Pernicious Anaemia. If we were to make a film about the history of PA, Thomas Addison’s life would be the drama in the early part of the film, as he suffered from clinical depression and committed suicide by jumping off the house he was living in at the time. There used to be a marble bust of him at Guy’s Hospital. I hope it is still there.
Despite Addison’s early findings, it wasn’t until 1871 when a more accurate description was made, this time by Michael Biermer, a German physician, who wrote about a disorder he called ‘progressive pernicious anaemia’ or as he would have said ‘progressiver, perniciöser anaemie’. He called it pernicious because of the insidious nature of the disease and because it was untreatable at that time. He acknowledged the work of Thomas Addison and later it became also known as ‘Addison-Biermer’s disease’.
A brief mention here of James Russell, a Guyanese-British physician, neurologist, professor of medicine, and professor of medical jurisprudence who wrote a paper on and coined the term sub-scute combined degeneration of the spinal cord ( SACD). The most common cause of this condition is a deficiency of vitamin B12. This may be due to a dietary deficiency, malabsorption due to lack of intrinsic factor or parietal cells or inhalation of nitrous oxide. Severe B12 deficiency results in the myelin sheath wasting away and is a potential complication of Pernicious Anaemia. It commonly presents with sensory deficits, paraesthesia, weakness, ataxia (lack of coordination) and gait disturbance.
In 1907 along came Richard Clarke Cabot with his report on 1200 patients with Pernicious Anaemia. An American physician who advanced clinical haematology and was an innovator in teaching methods and a pioneer in social work, he noted that for these patients their average survival was between one and three years. PA was a fatal disease, and the treatment was unsuccessful and arbitrary.
Things started improving in the 1920s, when the importance of the role of the liver in the blood making process was discovered by George Whipple. Whipple was an American physician, pathologist and biomedical researcher, who joined the pathology department of John Hopkins School of Medicine in 1905. He took some time off from this role to travel and study abroad and this included some time in Europe where he studied anaemia in rabbits. He became interested in the liver, blood and anaemia and was a prolific publisher of papers in this area. Whipple published a series of papers in 1925 wherein he demonstrated that raw liver fed to anaemic dogs was the most effective diet for reversing anaemia and boosting the production of red blood cells. This inspired George Minot and William Murphy to treat Pernicious Anaemia with raw liver despite the original finding being in relation to iron and not B12. Minot was a medical researcher and professor of medicine at Harvard where he was a member of their Pernicious Anaemia Committee.
Murphy was a physician, but his research into war injury work led him to bleed dogs to make them anaemic. He then fed the dogs various substances to see if they improved. He found that ingesting large amounts of liver seemed to lead to improvement more quickly than other foods. Minot and Whipple then set about to work out why this was and showed that iron in the liver was responsible for curing anaemia from bleeding. Meanwhile liver had been tried on people with Pernicious Anaemia and results were seen there as well. The active ingredient in this case, found serendipitously, was not iron, but rather a water-soluble extract containing a new substance.
From this extract, chemists were eventually able to isolate cobalamin, the most chemically complex (and some say most beautiful) of all vitamins. We now know that water-soluble extract as vitamin B12, but more of that later. For now I want to sidetrack slightly to the day-to-day impact of these discoveries.
Before these discoveries, people died of Pernicious Anaemia. Mary Todd Lincoln, wife of Abraham Lincoln probably died of Pernicious Anaemia in 1888. She was institutionalised in a private asylum, tried to commit suicide, she suffered from eyesight problems, falls and damage to her spinal cord, weakness, fatigue, fevers, headaches, gait problems, rapid heartbeat, mouth soreness, swelling, irritability, delusions, and hallucinations. She died aged 63 attributed to heart failure.
In the late 1920s and early 1930s, doctors started treating people diagnosed with Pernicious Anaemia with raw liver, often liquidised and eaten in large quantities. The disease was no longer fatal if treated. In yet another published paper by a William, this time William Thomas Wilkins, he refers to the efficacy of treatment of PA with raw liver. He mentions that periods of hospitalisation and stomach tube feedings seemed to result in difficulties in getting the patient to continue with their treatment (I wonder why!) so he tasked Clara Schroeder of Ohio, a woman ‘gifted in the culinary art’, to prepare an edible liver cocktail. Apparently, this dish proved acceptable and even enjoyable for some.
When I talk about PA I regularly mention the popular TV series and films called Downton Abbey set in the 1920s and early 1930s. In the TV series, the screenwriter, Lord Julian Fellowes, gives Dicky Merton a diagnosis of Pernicious Anaemia but in the next episode that is changed to iron deficiency anaemia. At the time the series was set, PA would have been fatal whereas iron deficiency was not. It was suspected by me that the blossoming love story between Lord Merton and Isobel Crawley would have had a less happy ending if the writer had stuck with PA. Interestingly, at least to me who reacted audibly to the final scene in the second film, Fellowes then wrote into the story that Lady Cora (who we had been teased throughout the film as having some sinister stomach issues probably cancer) “only had Pernicious Anaemia” and could expect to live a “normal life”. This prompted me to write to Lord Fellowes and point out that in the early 1930s, Lady Cora’s life would have been very miserable with fatigue, neuropathy, ‘the sighs’, gastric problems, increased risk of gastric cancer, psychosis, and mental health issues (known back then for women as hysteria). Lord Fellowes kindly explained that as I suspected with the character Merton, the point of giving him the more serious ‘Pernicious Anaemia’ was a key part in the story of Isobel being courted in series six. Fellowes explained to me that it was to force Isobel to confront her own feelings for Merton through her sorrow at his diagnosis. He said, “I didn’t want it to dominate their life together so eventually identified something which was much less difficult to manage”. Turning to Lady Cora, Fellowes explained that though the intention was for the audience to think that she had cancer, in the end he had wanted to give her diverticulitis. He acknowledged that this got changed in the final filming to Pernicious Anaemia although he doesn’t recall why. He explained that he worked with doctors by describing the kind of conditions he wanted his characters to have, and they would send back suggestions of diseases at the time which would play to the overall narrative of the story. We had interesting correspondence about illnesses in the 1920s and 1930s especially related to injuries in the first world war and childbirth (Sybil dies of eclampsia and Matthew Crawley has spinal damage misdiagnosed in a field hospital). I’m grateful to Lord Fellowes for taking the time to explain the writing process and acknowledging a learning curve about Pernicious Anaemia. I wonder if this should be my specialist subject in Mastermind.
Even if treatable in the 1920s, Pernicious Anaemia was still a serious condition and in 1924 the Detroit iron magnate Thomas Henry Simpson died of PA. His wife, Catherine MacDonald Simpson, sought to create an institute devoted to its study and a cure and donated money to the University of Michigan with which was built The Thomas H. Simpson Memorial Institute.
Back to Whipple Minot and Murphy, whose importance in this story should not be underestimated, although I applaud them only for their contribution to science in relation to Pernicious Anaemia. They all seem to have been less than perfect in some other areas of the views they held at the time! In 1926, Minot and William Parry Murphy amazed the medical world when they eradicated anaemia in 45 Pernicious Anaemia patients by feeding them a half-pound of beef liver daily. Now, what is important here is that these patients were exhibiting symptoms of anaemia and that is how they were diagnosed. Advanced blood tests such as Serum B12, Active B12, MMA and Homocysteine were not known. The first example of an immunoassay targeting vitamin B12 in human serum appeared in 1982! They were basing their diagnosis on symptoms and treating people accordingly. Something which we all have to fight for today.
Whipple Minot and Murphy, despite their names sounding like a Dickensian firm of lawyers, went on to share the 1934 Nobel Prize for their pioneering work on Pernicious Anaemia. The award for the Nobel Prize for Physiology and Medicine was for the discovery of the ‘anti-pernicious anaemia factor’ from their experiments with liver in the diet. The ‘extrinsic factor’ is now known as vitamin B12 (cobalamin) and provides an effective therapy for Pernicious Anaemia.
This seems a timely space to mention yet another William, William Bosworth Castle, who in the late 1930s discovered and described gastric intrinsic factor. Intrinsic factor was necessary to facilitate the absorption of an ‘extrinsic factor’ from the diet. The absence of IF causes Pernicious Anaemia. Castle’s discovery reflected the focus at the time of the importance of nutritional factors in relation to disease and the idea that many disorders could be treated or even cured by administration of a missing substance. Castle’s observations nearly a century ago are remarkable in their ingenuity and sadly something that the B12 deficiency and PA community of patients and advocates see as missing today from the diagnosis and treatment.
Some more people called William, in this case William Osler, a Canadian, and his colleague William Gardner, also contributed to the publication of papers about Pernicious Anaemia, in particular relating to observations on gastric atrophy, neuropathy and red cell changes in the blood and bone marrow.
Now, it is clearly not easy to eat uncooked liver and in 1928 a chemist and protein scientist called Edwin Cohn at Harvard, prepared an extract that was 50 to 100 times stronger than that obtained from raw liver and this became the standard treatment for Pernicious Anaemia until the 1950s. Remember that at this time the active ingredient in the raw liver (cobalamin) was as yet unknown.
Enter our next Nobel Prize winning scientist in the person of Dorothy Hodgkin, a biochemist influential in defining the structure of penicillin and insulin. In the history of PA she made a significant discovery in 1948 when she encountered vitamin B12. Vitamin B12 was discovered by Karl Folkers, a scientist at the company Merck. Hodgkin discovered that vitamin B12 contained cobalt, and she realised the structure could be determined by X-ray crystallography analysis. The large size of the molecule, and the fact that the atoms were largely unaccounted for —aside from cobalt— posed a challenge in structure analysis that had not been previously explored. Her discovery was described by experts at the time as significant as “breaking the sound barrier”. Dorothy was awarded the Nobel Prize for the structure of vitamin B12 in 1955.
This discovery of the active ingredient in liver now known as cobalamin (vitamin B12) led to the treatment of giving a few micrograms of this substance to people with Pernicious Anaemia to prevent the relapse in the disease. It is still the treatment today for people with Pernicious Anaemia regardless of whether or not they have megaloblastic anaemia.
A further important advance was made in the early 1960s by D Doniach, M Roitt and K Taylor with the recognition that Pernicious Anaemia is an autoimmune disease and has an association with thyroid disease.
Along came Robert F Schilling, who studied at the University of Wisconsin and spent most of his career working on urine radioactivity testing for vitamin B12 deficiency. The Schilling test was named after him in 1953. This test was to assess the absorption of vitamin B12. In stage two of the test, the addition of intrinsic factor could confirm the diagnosis of Pernicious Anaemia if the test result was abnormal. The Schilling test is now considered obsolete with reliance on blood tests taking its place. Part of the reason for this test no longer being used is that cobalt radioisotopes required are no longer available and also partly because injectable B12 and large dose oral B12 are relatively inexpensive. Unfortunately for PA patients the accuracy of the B12 serum blood test and Intrinsic Factor/intrinsic factor anti-body test are not as accurate as would benefit the patient and there is an unwillingness in the healthcare profession to prescribe sufficient B12 to deal with symptoms despite its relative lack of expense and ease of self-administration.
Fast-forward to 2005 when Martyn Hooper, diagnosed with Pernicious Anaemia, founded the Pernicious Anaemia Society. The original aim of the Society was simply to provide an easy-to-understand explanation of the condition to newly diagnosed patients. It quickly became obvious to Martyn that there were serious issues with the way Pernicious Anaemia and B12 deficiency generally were diagnosed and treated and the Society became a registered charity in July 2006. Martyn went on to write three books about Pernicious Anaemia and tirelessly campaigned for improvements, greater understanding, better research and education in the health care profession until his retirement in March 2023.
There are others of course since then, who have been vocal and outspoken about B12 deficiency and the need for better diagnosis and treatment and I don’t mention them by name here as there are many who are active and knowledgeable on the subject. History will look back kindly on these people too as they are making a difference in many people’s lives.
This brings us up to date and into 2023 and the problems we are facing in the future. The publication of the draft NICE guidelines on vitamin B12 deficiency in over 16s at present looks inadequate to meet the needs of people with malabsorption issues, especially PA. There is a lack of education about nutrition in the training of GPs and medical specialists, patients are done a disservice by the lack of awareness, persistence of myths and the lottery of finding the right specialism for Pernicious Anaemia in the medical profession. The rise of plant based diets and the change in food production raises the potential for long term consequences of B12 deficiency for future generations; research shows the importance of B12 in other conditions like Parkinson’s, MS and dementia but is underfunded; use of drugs for conditions like diabetes and acid reflux as well as nitrous oxide which deplete B12 are pushed by the pharmaceutical industry without sufficient education about the importance of B12 to the human body. I could go on, but it is depressing, and I want to finish on a positive note.
I wrote this article because history helps us understand the present and prepare for the future. It encourages us to look at society, systems, ideologies, governments, cultures, and technology and how these were all built upon and how they changed the world. History helps us explain patterns and should shape our future decisions and actions.
As a patient with Pernicious Anaemia and as the newly appointed Chief Executive Officer of the Pernicious Anaemia Society, I am of course frustrated by what appears to have been so few big changes in the science and in the day-to-day medical knowledge of the diagnosis and treatment of this condition in recent years when so many giant leaps were taken initially. I am however heartened by the outstanding ongoing contribution from people in the research community, patient advocacy groups and by patients themselves who are speaking up about their symptoms and treatment to raise awareness and campaign for better understanding and treatment.