Did you know that anemia was first named as a clinical entity in 1807?

By William Aird

Anemia was recognized as a clinical entity in the early 1800s. Yet the routine use of the microscope and methods to quantitate red blood cell counts, hemoglobin concentration, and the hematocrit did not see the light of day until late 1800s. So how was anemia defined between the early and late decades of the 19th century? You guessed it: history and physical exam!

The story begins in the 17th century with the early use of the microscope to discover the red blood cell, initially termed “red globule”, in a variety of species:

  • In 1658, the Dutch naturalist, Jan Swammerdam (1637-1680), was the first person to observe erythrocytes under the microscope, describing them as oval particles in frog blood.1
  • In 1661, Marcello Malpighi (1628-1694) an Italian physician and biologist, observed red blood cells when examining fresh preparations of frog lungs.2
  • In 1674, Antoni van Leeuwenhoek (1632-1723), a Dutch draper, provided the first detailed description of human red blood cells (his own).3

Between the 1600s and the mid-1800s there was virtually no progress in characterizing or understanding blood cells – in fact, the microscope became all but obsolete throughout the biosciences during this period, contributing in so small way to the virtual stagnation of medicine as a discipline. Why was there such little progress at a time when microscopes were available?

  • First, there was widespread skepticism about the validity of microscopic studies. Could one really believe what one was seeing through a microscope lens, one step removed from the naked senses? Surely, it was argued, the presence of artifacts was obscuring the field and rendering any conclusions meaningless. Nothing it seemed could rival the accuracy and confidence of the naked eye in studying the surrounding world.
  • Second, medicine remained firmly rooted in humoralism during this time. The finding that blood contains particles (red cells) did not fit neatly into the humoral scheme, and while acknowledged from time to time did not figure into disease nosology, diagnosis or treatment.
  • Third, the use of microscopy to study unstained blood, while perhaps unleveraged during this period, provides limited information. Significant advances would depend on the development of new technologies to study red blood cells.

In the 1860s and 1870s, the tide began to turn as physicians became more comfortable using the microscope to examine blood in their patients. Over a short span of just 8 years (1877-1885), a, number of techniques appeared which revolutionized the field of hematology:

  • Hemocytometer for counting red blood cells – 18774
  • Hemoglobin measurement – 18785
  • Staining of peripheral smears – 18796
  • Device for measuring hematocrit – 18897

Yet, well before these inventions, the medical field recognized anemia as a bona fide clinical entity.8 The first uses of the term anemia in the English literature appeared in 1807 with the publication of a paper titled Concise Observations on Anæmia. According to the author, Professor Halle from the School of Medicine at Paris, the characteristic symptoms included “the universal loss of colour and yellow tinge of the skin, swelling, impossibility of walking without suffocation, palpitations, and habitual sweats”.9

Postmortem examination revealed that “all of the vessels, both arteries and veins, were destitute of coloured blood, and contained only a small quantity of serous blood”.10 Citing a 1761 French publication, Hall writes that Joseph Lieutaud is “the only (other) person who has described this kind of disease”. Hall concludes: “According to these phenomena and the physical state, to which we do not doubt but they correspond, we think it proper to give to this disease the name of anaemia, (deficiency of blood) imagined by Lieutaud”.11 The naming of a condition or disorder is an important turning point in the history of disease. It signals a readiness for pursuing the disorder as an entity in its own right, something with diagnostic, therapeutic and prognostic potential.

In 1839, an author, responding to a request for a prize essay on anemia which seems to have gone unanswered for several years, wrote in the The Boston Medical and Surgical Journal (the precursor to the New England Journal of Medicine): “Anaemia is the opposite of plethora, and may be defined, ‘A deficiency of blood in the whole body, not proceeding from natural or artificial hemorrhage, giving rise to a waxy, bloodless state of the countenance and surface, emaciation, feeble quick pulse, and greater languor and debility'”.12

In 1842, a case series titled Cases of anemia was published in the Lancet, illustrating the continued reliance on the history and physical exam to diagnose anemia.13 In each case, the author provides the patient’s full name, age, and occupation, and presents a detailed history. For example: “She has generally enjoyed good health until about two years ago, when she states that she suffered from giddiness and pain in the forehead; she was not able to walk up and down the stairs; she had palpitation of the heart, and pain on both sides of the chest… she says that her countenance was then very sallow”. The author then provides details about the physical exam. For example: “She is a sallow complexion and melancholic temperament,14 with black hair and eyes; the mucous membranes of the mouth and lips are extremely pale”. Conspicuously absent in all these cases is any consideration of microscopic findings or other lab values. But that did not deter the author from claiming confidence in his findings: “The general aspect of the disease [anemia]”, he concludes, “is so characteristic that it can never be mistaken by the least practiced eye”. He then lists these general aspects:

  • Pallor – especially marked in the mucous membrane of the lips, mouth, tongue, in the conjunctiva, and the hands and fingers
  • Extreme languor and coldness of the extremities arising from the deficient quantity and impoverished quality of the blood
  • Severe throbbing headache
  • Palpitations
  • Systolic murmur

What should we make of these lofty claims concerning diagnostic acumen? As the table below shows, modern-day evaluation of the sensitively and specificity of physical exam shows relatively high specificity, but poor sensitivity. Unless these 19th century had a far better eye than today’s physicians (not out of the realm of possibility), they were probably diagnosing a lot of cases correctly but also missing many diagnoses of anemia.

FindingSensitivity for anemia (%)Specificity for anemia (%)
Pallor at any site22-7766-92
Facial pallor4688
Nailbed pallor41-6066-93
Palmar pallor58-6474-96
Palmar crease pallor899
Conjunctival pallor31-6282-97
Tongue pallor4887
From Evidence-based Physical Diagnosis, 2021.

The next major advance in the pre-microscope/pre-lab era was Thomas Addison’s (1793-1860) famous description in 1880 of a distinct type of anemia, the clinical entity now known as pernicious anemia.15 By this time, light microscopes were just beginning to come into fashion, especially in Europe. However, Addison, like his predecessors, relied on history and physical exam alone. He writes about the pale countenance of his patients, their blanched, smooth, and waxy appearance, their seemingly bloodless lips gums and tongue, their exertion- and emotion-induced breathlessness and palpitations, their slight edema and their inability to rise from bed. Addison’s report was one of the last to define anemia on the basis of clinical exam alone, as it happened to coincide with the rediscovery of the centuries-old microscope and the invention of new lab-based techniques that would usher the field of hematology into the modern era.

But back to the natural senses. Can you imagine making a diagnosis of anemia without access to lab tests? Are there any causes you would feel comfortable diagnosing and treating by history and physical examination, alone? How about a 30-year-old woman with menorrhagia, who complains of fatigue, has shortness of breath, is losing her hair, eats 5 pounds of ice per day and on physical exam appears pale with a smooth glossy tongue, angular cheilitis and chipped fingernails? Would you be comfortable making a diagnosis? I would! She almost certainly has iron deficiency anemia and if for whatever reason I did not have access to labs, I would not hesitate to treat her with a trial of oral iron.

What about a patient of African descent who comes to your office complaining of excruciating bone pain in the back and lower extremities. He tells you that these pain episodes are recurrent. He has avoided physicians his own life, including during a 7-hour period in which he had prolonged unwanted penile erection 2 years earlier. Physical exam shows scleral icterus and retinal exam reveals “abnormal vessels”. Again, you have no access to a lab facility. Are you comfortable making a provisional diagnosis? I think most of us would put sickle cell disease at the top of the list.

As a final example, consider the 82-year-old man who had a mitral valve replacement 6 weeks ago and returns to the hospital with shortness of breath on exertion, fatigue and urine that suddenly changed to a red color the previous day. Physical exam shows new scleral icterus. Your diagnosis? Almost certainly valve hemolysis.

I am not suggesting we forgo lab testing to diagnose anemia. I only wish to point out that physicians working before the era of lab medicine (prior to 1880) had no choice but to rely on their powers of observation, and there were surely times when the history and physical examination yielded a high pretest probability of one or another condition. It is a humbling reminder that lab tests serve to supplement the clinical exam, not replace it.