“Goldberger, I need you to go down South and investigate an outbreak” demanded the Surgeon General.
“Yes Sir!”, replied Dr Joseph Goldberger, “Errr, what outbreak am I investigating Sir?”
“The leprosy-like skin infection outbreak that no one has ever been able to discover a cause for of course, it’s affecting millions of people down there.”
“Yes Sir!” replied Dr Goldberger again, whilst probably thinking with a sinking heart “OMG, this sounds like a nightmare…”
But when you work for an organisation such as the US Public Health Service in 1915 and your boss tells you to do something you pack your bags and off you go. So he did…
The outbreak in question was of a skin disorder (a bit like leprosy) which was affecting vast areas of the Southern United States of America, and appeared to be spreading. Between 1906 and 1940 there were over 3 million cases, and 100,000 deaths, due to a disease called pellagra in the Southern USA.
The condition was first described in 1735 by Gaspar Casal, a Catalan Physician, who noted cases of severe dermatitis occurring on exposed areas of skin.
It was also endemic in Northern Italy where it causes 100s of thousands of cases in the 1880s and where it was called “pell agra” meaning “holly-like skin” because of the severe dermatitis that led to very rough and painful skin lesions.
The Italians noted that the disease was more common in the Lombard region and was associated with eating corn (maize) and so the main theory was that corn carried a toxic substance or germ that caused the disease. The other main theory was that a vector e.g. mosquito, associated with areas where corn was grown was transmitting a germ that caused the disease.
And these were still the main theories about the cause of pellagra when Dr Goldberger was dispatched to the Southern US to investigate what was going on.
What are the symptoms of pellagra?
There are four main symptoms of pellagra, known as the 4Ds:
- Dermatitis – symmetrical, photosensitive, pigmented dermatitis in the areas of skin exposed to sun e.g. hands, arms, face and neck
- Dementia – also insomnia, anxiety, disorientation, delusions and encephalopathy
If you start to apply the processes of outbreak investigation you can see why pellagra was thought to be an infectious disease:
- Establish case definition – the 4Ds, consistent across cases
- Confirm cases are real – go down to the South and see the cases for yourself
- Confirm outbreak and determine extent – count the numbers, see they are associated in time, place and person and spreading
It definitely looks like an outbreak…
The outbreak investigation
The next step in the outbreak investigation:
- Examine descriptive epidemiological features of the cases
So, this is where Dr Goldberger gets clever. He observed where cases were occurring and then looked for “closed systems” he could investigate further because he could control the variables in these systems.
In particular, Dr Goldberger noted that there were lots of cases in orphanages and mental institutions. Now this could still fit with an infectious cause circulating through the unsanitary conditions as we often see with infections like infectious gastroenteritis in refugee camps. But Goldberger was smarter than that, he realised that the cases in the orphanage were age dependent; younger children did not get pellagra. The only difference he could find between the younger children and the older children was diet. The older children had the same corn or maize heavy diet that adults in the mental institution got, whereas younger children had things like milk and eggs.
So, what next for the outbreak investigation:
- Generate hypotheses – Dr Goldberger concluded that it wasn’t the corn causing the disease but the lack of other sources of protein in the diet which was the problem
- Test hypotheses – this was relatively easy, with public funding Dr Goldberger changed the diet of the children and adults and gave them fresh animal and leguminous (e.g. peas and beans) protein
With the change in diet, the cases of pellagra got better, and since they were still being given corn as well this proved that corn wasn’t the cause, but rather it happened to be associated with other dietary insufficiencies.
Dr Goldberger also experimented on 11 prisoners and showed that giving only a corn-based diet caused pellagra (unethical perhaps… I don’t know what the prisoners got out of it!).
However Dr Goldberger (a Northerner) didn’t get the opportunity to find the exact cause as his theory that pellagra was associated with poverty and poor diet in the South meant his conclusions were unpopular with Southern politicians and he was sent packing back North… oh well….
So, what does cause pellagra if it’s not an infection?
The answer to the cause of pellagra wasn’t discovered until 1937 when an American biochemist called Conrad Elvehjem showed that giving niacin, also called Vitamin B3, to dogs cured them of pellagra.
So, pellagra is not an infection, despite how it presents and spreads, but rather is caused by a lack of niacin (Vitamin B3).
Niacin (nicotinic acid and nicotinamide) is absorbed from the gut and used by the body in the synthesis of carbohydrates, fatty acids and proteins. It is an essential vitamin. It is also possible for the body to produce niacin from tryptophan (also absorbed from the gut) but the process is very inefficient with 60 parts of tryptophan forming 1 part of niacin.
We require a dietary source of niacin which is present in yeast, meat, grains, legumes and seeds. It is present in corn BUT not in a form we can absorb from our guts! Corn has to be processed before the niacin becomes bioavailable, in a process known as nixtamalization (it is washed and cooked in an alkali solution to free the niacin from the hemicellulose in the corn cell wall).
The reason that pellagra was so common in Italy and the Southern USA was that the diet in these regions was almost entirely corn dependant, but the corn wasn’t being processed with alkali. However, the Native Americans and the Native Central Americans also ate a lot of corn but they knew that corn had to be processed first and they didn’t have a problem with pellagra… they used a lime-water solution to prepare corn before cooking it e.g. when making tortillas. ECIC (aka my wife) says that it is also “well known” that the Native Central Americans grew holistically using companion planting with the “Three Sisters” of corn, squash and beans… so they would have had another source of dietary niacin, not just from tortillas!
Nowadays, flour is enriched with niacin, and we have more varied diets, and so pellagra is uncommon in developed countries, although dietary pellagra is still common in resource poor areas. The most common causes of pellagra in the UK are:
- In alcoholics who don’t eat properly
- Anorexia nervosa
- As a complication of bariatric surgery where malabsorption occurs
- Secondary to drugs preventing tryptophan conversion to niacin (e.g. Isoniazid, Pyrazinamide, Chloramphenicol, Ethionamide, Phenobarbital, Azathioprine) – some of these are antibiotics so there is some microbiology in this blog… honest!
- Carcinoid syndrome where tryptophan is converted to other compounds e.g. serotonin, rather than niacin
- Hartnup’s disease where tryptophan cannot be absorbed from the gut due to a congenital problem
I think there are lots of lessons to learn from the story of pellagra:
- Keep an open mind when investigating outbreaks, what may appear obvious or be the conventional “wisdom of the day”, may actually not be the case after all, OR sometimes weird things do happen, 2+2 really can = 5!
- Politics can get in the way of good research, if Goldberger was able to continue his research, he probably would have found the cause of pellagra much faster
- If we listened and learnt from Native peoples rather than trying to exterminate or assimilate them the World would be a better place
- Poverty is still associated with preventable diseases
- Eat your peas and beans… they are good for you!