Iournal o/lnternal Medicine 1989; 226: 1 4

Editorial In defence of the anecdotal

There has been a tendency during the last decades to speak disparagingly about anecdotal publications. We are only allowed to produce large collections of facts either regarding cohorts of patients or extensive analytical results. Both may be computerized and even very small numerical differences may become statistically significant if the numbers are great enough. This tendency is. of course, a reaction against the common statements regarding ‘clinical experience tells us ’, often founded upon very minimal facts. The history of medicine contains numerous such observations that have led the medical pro- fession’s astray. Sometimes the observation may be correct and reliable but the conclusions erroneous. One hundred years ago it was generally believed that tabes dorsalis was caused by inhibited sweating of the feet. This was at a time when we assumed that a number of disease factors had to get out of the body, and the logical therapy was abundant enemas or repeated bloodletting. If we return to the sweaty feet, the observation was correct as tabetic patients do not sweat, but we know now that this is caused by damage to the sympathetic innervation of the sweat glands. The causality was reversed. This type of reasoning may be found in many previous clinical publications and it is also quite probable that a number of our dogmas regarding causality will be similarly criticized by authors in the future.

Personally, I have always been very interested in the anecdotal because I want to be a doctor for individual sick patients. Also. scientically, obser- vations of individual patients may tell us new things that are otherwise hidden. There is a German expression - I think I made it up myself - ‘Ein Fall is kein Fall’. It is certainly correct that we may be misled by conclusions and observations regarding one patient. If we make the same unusual findings in two or preferably three patients with the same disease, it is probably worthwhile to discuss a biological connection. The feet of the tabetic is an excellent example of this. The observation in itself is true and it may help us to resolve some of the many mysteries of that disease.

Abbreviations: ACTH = adrenocorticotrophic hormone, PBG =

porphobilinogen.

Not infrequently, contacts with a patient, who teaches you some important lessons for the rest of your life, may be purely accidental. In 1932 a doctor, who was responsible for one of the wards in the department of internal medicine in Uppsala. suffered a slight traffic accident and had to be absent for some days. The professor and head of department asked me to take over the ward. I was then a student. Among the patients there was a woman born in 1882 in Sorsele in northern Sweden. In June 1932 she developed very severe abdominal colics with marked constipation and vomiting. She also had considerable hypertension, was subfebrile and tachycardic. With a severe hallucinosis she was very depressed. It was noted that her urine was dark red or brown.

I went to the laboratory of medical chemistry. At this time the head was an old and famous professor, Carl Thore Morner. He was a great botanist and also a collector of rare urinary calculi, what he called his Harn-Edelsteine (his jewels). When I said that I thought I had found a patient with acute porphyria. he became very interested and put the precious Gitter-Spektroskop at my disposal. There was no question about the fact that the urine contained a substance that gave the complicated and character- istic alkaline spectrum of porphyrin. This was an example of the dictum ‘from the bedside to the benchside ’ - in real life !

This started my life-long interest in the porphyrias [ 11. Further work showed that these urines contained a chromogen giving a very strong red colour with the so-called urobilinogen reaction of Ehrlich. Later Bo Vahlquist and I gave the chromogen the name porphobilinogen (PBG) because it was found that this colourless substance could be transformed into both porphyrins and an uncharacteristic red pigment, which we called porphobilin.

Later Westall and Rimington were able to deter- mine the structure of this PBG. Several years later, Shemin and his group proved that PBG was one link in the synthesis of haem. It was therefore clear that the study of this single patient and her PBG had started the search for the complete synthetic pathway of haemoglobin.

Much later, Bogorad and his group established the

1

1 I M B 226

2 EDITORIAL

fact that PGB was also the starting-point of chloro- phyll synthesis. It is perhaps somewhat surprising that studies on the urine of an old lady should help to clarify the formation of both the fundamental pigments of life : haemoglobin in animals and chlorophyll in plants. This history seems to me to be clearly anecdotal.

I certainly maintain that a very large part of my investigative interest has been started by some individual patient(s) whose name(s) I still remember. The patient with acute porphyria, who was men- tioned above, belongs to a family whose name became a byword for the diagnosis acute porphyria. It resulted in a large number of normal-sized pedigrees and a very large one started with a couple who married in Arjeplog in the north of Sweden in 1671. It now contains several hundred carriers of the trait. Dr Haeger-Aronsen was my collaborator in the porphyrin field for many years. She had a great deal of correspondence with members of this family. After some years we learned that certain names were connected with porphyria. It was also clear that new cases from Norrbotten, almost without exception, could be fitted into the family.

One day Dr Haeger-Aronsen received a letter from a new patient’s mother. It started with the words: ‘I have a confession to make’ and gave us information that her husband was not the father of the porphyric child. The biological father was a well known porphyric, who belonged to the family!

Such anecdotes make it diffult to accept new mutations off-hand and I have always wondered if the large number of patients with porphyria in our country might depend upon the same mutation arising many hundred years ago. That this is true in the northernmost part of Sweden seems indubitable

There has been much discussion, however, on whether external factors influence the phylogenetic picture. We know that lead is common in exactly the same locality where we found the clustering of porphyrics. This is an idea that would have appealed to Lamarck. Academically, it is of course regarded as heresy, but the very marked penetration of the trait in the group ‘from northern Sweden might perhaps be partly explained in this way?

Since the early 1940s I have been very interested in macroglobulinaemia [3]. By chance, we had three male patients in the department of medicine in Uppsala in the same year. They all had rather special clinical symptoms and their serum protein pattern

P I .

was characterized by a high content of macro- molecules. This was the foundation of macro- globulinaemia. Over the years, application of the clinical picture seen in these three patients made it possible to discover a large number of sufferers from macroglobulinaemia. It was a new disease both cytologically and clinically, and with a characteristic molecular pattern.

In principle the same was also true for other new disease pictures. We had three proband cases which I followed for a long time because they suffered from purpura hyperglobulinaemica. Three young girls with chronic liver disease were described and this initiated studies of chronic active liver disease all over the world. It was later a subject of much discussion, and I have often been asked about my 6rst publication on this topic. It occurs in the Verhandlungen der deutschen Gesellschajt jijr Gastro- enterologie in 1950 in Kissingen [4]. This publication is rather diflicult to 6nd but is always quoted, whereas several of my publications which are easy to locate are systematically ‘forgotten ’ by later authors.

An interesting example of a discovery that was purely anecdotal is the following. In 1953 I made the rounds with a friend, who was head of a department of medicine in another hospital. He showed me a lady who had a very peculiar flush, mainly in the face but also on the trunk and extremities. The flush was accompanied by strong hyperperistalsis. I said to my friend. Dr Ljungberg, ‘This is exactly the type of flush that we recently saw in a young boy with pulmonary stenosis.’ My host answered ‘This lady has something entirely different. She is suffering from a malignant carcinoid tumour with metastases.’ If I had looked at my watch, I might have dated the discovery of the carcinoid syndrome exactly to the minute, because the boy also had malignant carcinoid tumours. Edvard Ljungberg and I wrote a preliminary paper in 1953 [5] and in 1954, together with Bengt Pernow I wrote about the influence of hydroxytryptamine in the Lancet [6]. This was the start of a great many publications on this subject and I was stimulated to think about active substances produced by malignant turnours. Such paraneoplasia has been a favourite theme for my research through the years.

In a monograph that I wrote on this subject, I tried to collect as many anecdotal observations as possible regarding paraneoplastic phenomena that were re- versible after removal of the tumour. It is my h belief that one well-observed patient with well-

EDITORIAL 3

described symptoms disappearing after removal of the tumour is just as valuable and convincing as many other more intricate ‘proofs’ of a truly paraneoplastic condition [ 71.

In later years, we have a number of studies regarding so-called paraneoplastic symptoms, i.e. phenomena that are explained by production in the tumour cell of specific substances causing character- istic and uncommon symptoms. These should be reversible after removal of the tumour. Two anecdotal observations are fundamental in this respect. In 1948, Fuller Albright in Boston published obser- vations on a patient with renal carcinoma who had an unexplained hypercalcaemia [8]. There were no signs of parathyroid disease at the post-mortem and only one skeletal metastasis was found. Albright advanced the idea that the cancer cells in this patient may have produced a factor that caused increase of calcium in the plasma. He even sent bits of the tumour to Collip, who was a great expert at that time on parathormone. No hormone-like activity could be demonstrated in extracts from the cancer. Some years later, P l ip ton and Gellhorn followed this line and proved that removal of an ovarian malignant tumour in one patient was followed by normo- calcaemia [9]. With development of metastases hypercalcaemia recurred. To my mind this is a key observation of decisive quality.

Similar observations have followed rapidly. Grant Liddle was the first to prove that Cushing’s disease may be caused by the production of ACTH (adreno- corticotrophic hormone) in a patient with a malig- nant tumour. This was regarded as a unique finding at that time, but we now know that such paraneo- plastic hyperadrenocorticism is more common than ‘ primary ’ Cushing’s disease [lo].

There are many instances of diseases that have been discovered in one single patient and therefore are known by that patient’s name. The Hageman factor is an excellent example of this, because Oscar Ratnoff studied in great detail the symptoms of a man who did not suffer from any evident disease. In 19 5 5, Ratnoff published a paper about the disturbances of blood coagulation in this patient, whose blood was routinely evaluated preoperatively. This factor, now called factor XII. is obviously very important in many biological situations. Curiously, this man died from thrombosis [ 1 1 , 121.

There are also factors, e.g. the Stewart-Prower. that were discovered and described in detail from the study of a coagulation defect. The patient Stewart

was the offspring of a relationship between an aunt and a nephew and the inheritance is recessive.

There are other examples of detailed description of a new disease from the study of one single patient. In 1944, Paul Owren investigated the coagulation defect in a woman who suffered from severe bleed- ings. In 1947, he published continued studies on this patient in a large monograph and the disease has been called Owren’s disease. The missing factor is now called factor V. This is a magnificent, purely anecdotal study, which has enriched our knowledge regarding blood coagulation in a decisive way

For many years haemophilia was regarded as a homogenous disease, and its manner of inheritance was well defined. In 1947 Pavlovsky made the simple experiment of mixing blood from different haemophiliac patients in order to see if reciprocal improvement in coagulation could be found. One patient was found to have clinically and genetically classical haemophila but his blood corrected the coagulation defects in other classical haemophiliacs [ 141. This observation was further evaluated by Aggeler who gave us an advanced understanding of the defect. The condition was further analysed in one patient, whose name was Christmas. This name was used for many years. In the nomenclature the disease is now called haemophilia B and the missing factor is numbered IX.

The so-called coagulation cascade includes other steps that have been described after the study of single cases.

The porphyrias have yielded fundamental know- ledge regarding the structure of the red pigment in haemoglobin. One single patient may be regarded as the portal figure in these studies. A German patient called Petri was clinically studied in great detail by different doctors. In 19 15. Hans Fischer in Munich published his first studies on the urinary and faecal porphyrins from this patient [15. 161. Fischer con- tinued, together with a large number of collaborators, and the work resulted in the exact chemical structure of the faecal porphyrin with four carboxyl groups and detailed studies of the uroporphyrin with eight carboxyl groups. Very laborious studies involving the synthesis of a large number of porphyrins with different structures resulted in the synthesis of a protoporphyrin M. This is the carrier of the red colour in haemoglobin. Fischer received the Nobel prize in chemistry in 1930.

The continued studies were all based on work with

~ 3 1 .

1-2

4 EDITORIAL

the uro- and coproporphyrin from the patient Petri. For many years Herr Petri ‘worked’ in Fischer’s laboratory and his production of the precious por- phyrins could therefore be saved for science. For sometime another biochemist engaged Petri to come to his laboratory. Fischer always maintained that Petri came back to Munich because of the superior quality of the Bavarian beer. After Petri’s death the presence of porphyrins in different organs was described carefully in a special monograph on this post-mortem. It may well be said that Petri was an anecdotal figure.

Observations on single patients that have had fundamental value for the development of the medi- cal sciences are of course numerous, but profound analysis is rarely published. Even simple unsophis- ticated observations might be rewarding in a period when too many young investigators in clinical medicine believe that expensive machinery is necessary for making discovery.

J A N W A L D E N S T R ~ M Lund-Malmii, Sweden

References 1 Waldenstrom J. Studien iiber Porphyrie. Acta Med &and

2 Waldenstrom J. Geography and genetics of the porphyrias. 1937: Sqppl. 82: 1-254.

Acta Dermatovener 1982: Suppl. 100: 43-6.

3 Waldenstrom J. Incipient myelomatosis or ‘essential’ fibrino- genopenia-a new syndrome? Acta Med Scand 1944: 11 7: 216-47.

4 Waldenstrom J. Leber, Blutproteine und Nahrungseiweiss. Ver- handlungen der GesellschaR fur Verdauungs- und Stoff- wechselkrankheiten. XV. Tagung Bad Kissingen Sept. 1950.

5 Waldenstrom J. Ljungberg E. Carcinoidtumorer och vaso- motorik. Lrikartidn 1953; 5 0 : 690-2.

6 Waldenstrom J, Pernow B. Paroxysmal flushing and other symptoms caused by 5-hydroxy-tryptamine and histamine in patients with malignant tumours. Lancet 1954: U: 951-3.

7 Waldenstrom J. Paraneoplasia. Biological Signals in the Diagnosis ojCancer. New York: Wiley and Sons, 1978.

8 Albright F. Reifemkin EC. Parathyroid Glands and Metabolic Bone Disease. Baltimore: Williams and Wikins. 1948.

9 Plimpton CH. Gellhorn A. Hypercalcemia in malignant disease without evidence of bone destruction. Am / Med 19 56 : 2 1 : 750-9.

10 Liddle GW. Givens JR. Nicholson WE et a/ . The ectopic ACTH syndrome. Cancer Res 1965: 25: 1057-61.

1 1 Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of a clot-promoting fraction of plasma. / Clin Invest 1955: 34: 602-1 3.

12 Ratnoff OD, Busse RJ. Sheon RP. The demise of John Hageman. N Engl / Med 1968: 279: 760-1.

1 3 Owren PA. The coagulation of blood: investigation on a new clotting factor. Acta Med &and 1947: 128 (Suppl. 194).

14 Pavlovsky A. Contribution to the pathogenesis of hemophilia.

1 5 Fischer H. Uber das Urinporphyrin. Hoppe-St‘ykr Zschr Physiol

16 Fischer H: h e r das Kotporphyrin. Hoppe-St‘yler Zschr Physiol

pp. 1 1 3-19.

B l d 1947: 2: 185-91.

Chem 1915: 95: 34.

Chem 1915: 96: 148.

Erratum We wish to apologise for the typesetting errors that appeared in the title and list of authors of a paper published in the March 1989 issue of the Iournal oflnternal Medicine ( 2 2 5 : 3. pp. 185-90). These should have read : Platelet sodium and potassium ATPase activity and noradrenaline efflux rate in relation to autonomic and peripheral nerve function in insulin-dependent diabetic patients

B. krgstrom, I. Mattiasson, I. RosCn. B. Lilja & G. Sundkvist