Natural product, unnatural practice

Vitamin C is essential to human health, but our understanding of its role has been perverted by practitioners of 'alternative' medicine.

The 18th-century discovery that oral citrus juice can protect seafarers against the vicious disease of scurvy is well documented1. The identity of the responsible compound is established, as is its molecular structure. It can be synthesised in the laboratory, and its name is ascorbic acid or Vitamin C. It is essential for the maintenance of collagen structure. Humans are unable to synthetise it themselves, and must obtain it from their food. The daily requirement (RDI) in our diet to prevent scurvy is about 40 mg.

But there are those who are giving huge doses of this substance by intravenous injection to treat cancer, infections, and a great variety of other conditions. The doses can be up to a thousand times more than the recommended daily intake. The differences of opinion between these 'alternative' practitioners and those who practise evidence-based medicine can be full of rancour. They are the stuff of sensational press reporting.

Such an episode was the TV 3 documentary Living Proof: Vitamin C, Miracle cure? aired on 18 August 2010 and still available on-line.

I would like to examine in more detail the history of Vitamin C discovery and use, the origins of the 'alternative' practices, their dangers, and the danger of the acceptance of unproven material as 'fact'.

The discovery of vitamin C

Some 61 million years ago our anthropoid ancestors experienced a genetic mutation which took away their (and our) ability to synthesise Vitamin C2. Guinea pigs have also lost this capacity (14 million years ago) as have some varieties of fruit bats. The loss of ability to manufacture this substance was offset by the extensive dietary sources in plants. Thus, when human beings began their 'Out of Africa' migrations, this genetic change did not offer any hindrance. Humans went on to inhabit deserts, Pacific islands and Arctic wastes, as well as forests. The genetic change did not offer any selective pressure, and is described as 'neutral'. However, human need for dietary Vitamin C became distressingly clear with the advent of long sea voyages by Europeans.

The toll of the deficiency state, scurvy, was huge. The potential rewards of exploration were equally large, and drove the seafaring. Competition at sea for those rewards led to the formation of naval forces, the competency of which was severely compromised by this scourge.

When Cartier and his men were forced to winter over in Canada in 1535 scurvy became a major problem. The local native Americans recognised the condition and showed Cartier how a tea made from white cedar needles was curative1 (an early example of how effective medical practice can be based on experience, rather than formal experiment!).

The effect of citrus juice on scurvy was becoming apparent by the early 17th Century when James Lancaster of the East India Company wrote _Lemons help to prevent scurvy_1 and citrus juice became part of the standard rations on the company's ships.

In 1740, James Lind, a Royal Naval surgeon, performed an early controlled clinical trial. He took 12 scurvy sufferers and divided them into six groups of two. He treated one pair with citrus, and the other five pairs each with a different alternative treatment. Only the citrus two were healed. This was conclusive evidence for the efficacy of citrus, but the Royal Navy Victualling Board did not react. No doubt, cost was a factor.

Reinforcement of the work by Lind and the experience of others occurred with the outstanding record of no loss of life from scurvy during Cook's first voyage. He introduced two dietary factors: citrus juice and wort, a fermented malt drink. Cook was not clear which factor was responsible, but clearly scurvy was preventable.

In 1795 the Royal Navy made citrus juice a standard part of rations. Brown1 ascribes much of the British naval success in the Napoleonic War to this change, with the ensuing good health of the crews.

The active principle in citrus juice was identified in 1927 by a Hungarian chemist, Szent-Gyorgyi, working in Cambridge. The chemical was synthesised by another chemist, Haworth, working in Manchester in 1933.

Subsequently, the paleogenetics have been determined2, and the site of the genetic change which has rendered us susceptible to scurvy has been found.

A daily intake of Vitamin C necessary to prevent scurvy has been determined.

This story is an excellent example of the human ability to observe, remember, and compare, and to reason from the results. It also includes less laudable features of our natures, such as the driving force of the profit motive in trade, and controlling costs in public enterprises to the exclusion of the public good.

However, something else has happened. Over the last 60 years a vociferous body of opinion has emerged, which claims that Vitamin C is also a cure for cancer (among other things) and that practitioners of evidence-based medicine are deliberately withholding an effective treatment from cancer sufferers.

How can this be?

The alternatives

In 1954 and again in 1959, WJ McCormick advanced what he explicitly described as a hypothesis3. This was that cancer spread was caused by a degeneration of the basement membranes of epithelial tissues due to a deficiency of Vitamin C.

In 1966, Irwin Stone wrote a brief proposal that scurvy was indeed a genetic disease and an in-born error of metabolism4. He went on to extrapolate findings about the Vitamin C synthesis rate in rats (which have retained this ability), to a 70 kg human, on a per kilogram basis, and said that the resultant 1.8 to 4.0 g of ascorbic acid per day was the real human requirement. He compared this to the then-accepted figure of 70 mg. He said there was room for investigation of the effect of Vitamin C in large doses on infectious diseases, cardiovascular disease, collagen diseases, cancer and the ageing process.

In 1969 a general surgeon working in Scotland, Ewan Cameron, put forward the theory that the invasive nature of cancers was due to the loss of integrity of basement membranes. He postulated that this was due to an abnormality in the hyaluronidase enzyme system, and that Vitamin C was involved.

In 1970, a world famous scientist, Linus Pauling, published a paper, _Evolution and the Need for Ascorbic Acid_5. He was an authority on the electronic structure of atoms and molecules, and had worked in the field of quantum mechanics. His laboratory work involved x-ray diffraction technology. He was a peace activist who incurred the wrath of the US State Department, which withdrew his passport 1952-1954. He was awarded the Nobel Prize in Chemistry in 1954, and the Nobel Peace Prize in 1963. He had impeccable credentials.

However, as Sam Harris says, when debating the validity of evidence and arguments, credentials just offer a rough indication of what a person is likely to know, or should know6. In his 1970 paper Pauling argued that Vitamin C is so abundant in plant foods that the loss of synthetic activity implied the need for huge amounts of an essential foodstuff. He calculated the total amount of Vitamin C in a variety of foods, if that food on its own were to provide a daily 2500-Calorie energy intake. He assumed that the huge difference between these results and the then-recommended daily intake of 70 mg, indicated a large deficiency in the human diet. He did not comment that the ability to absorb ingested Vitamin C might be limited. The association of his name with the ensuing arguments can lend weight to unproven contentions.

Cameron read this paper and realised he and Pauling had things in common. He wrote to Pauling and thus began a productive association. In 1976 Cameron and Pauling published a joint paper, _Supplemental ascorbate in the supportive treatment of cancer_7. In their summary they wrote:

"The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer."

What did they do?

They treated 100 cancer patients with intravenous Vitamin C at a dose of 10 g a day for about 10 days, and then the same dose by mouth each day. Each patient's state was agreed, by at least two physicians, to be at that stage when continuing any conventional treatment would offer no further benefit. Some were chosen from a larger group by random selection but there was no formal randomisation process. By this definition, these patients may already have responded to conventional treatment and could have been in remission after treatment.

The control patients (n=1000) were treated by the same physicians at the same hospital, without Vitamin C, over the previous 10 years. They were selected by a random search of the hospital records. There were 10 controls for each treated patient, matched for sex, age (+/- 5 years), and tumour type. The definition of the date of untreatability was by a variety of indications, including the finding of inoperability at laparotomy, the abandonment of any definitive anti-cancer treatment, or the date of admission to hospital for terminal care.

There were other criteria for setting the date of presentation, but these are not described in the paper. It is clear that the dates of presentation for the controls would have included terminally ill patients with little life expectancy, while the treated group could have included patients much earlier in the course of their disease, with a much longer life expectancy. There are good reasons for the longer survival of the treated patients other than Vitamin C treatment. The two groups were not comparable, and the results, despite the large numbers and small P-values, do not demonstrate any effect of Vitamin C. One could be forgiven for thinking that terms such as random selection and random search are deliberately misleading.

As Pooh-Bah said: Merely corroborative detail, intended to give artistic verisimilitude to an otherwise bald and unconvincing narrative8.

In 1979 Cameron and Pauling, together with Brian Leibovitz of the Oregon Medical School, published _Ascorbic acid and cancer: a review_9. In the abstract they point out that the paper describes factors which cause resistance to tumour growth and spread. The paper describes the role of Vitamin C in many of these mechanisms. They suggest that the antioxidant properties of Vitamin C might contribute to any anti-cancer effect.

In their summary they state:

"No properly designed prospective clinical trial has as yet been carried out to assess the value of supplemental [my emphasis] ascorbate in general cancer management."

Including their 1976 article of course! This article cites 358 references.

When Cameron retired at the age of 65, he accepted Pauling's offer of a post as medical director and senior research professor at the Linus Pauling Institute. In 1991, Gladys Block from the National Cancer Institute, USA, published a paper entitled _Vitamin C and Cancer Prevention: the Epidemiological Evidence_10. She wrote that the epidemiological evidence for a protective effect of vitamin C against some cancers is strong.

"It is likely that ascorbic acid, carotenoids and other factors in fruit and vegetables act jointly. Increased consumption of fruit and vegetables should be encouraged."

This paper had nothing to do with the treatment of cancer.

Back to science

Criticism of papers supporting the use of very high dose oral or intravenous Vitamin C in the treatment of cancer has led to important further work. In 2004, Padayatty and others showed that oral Vitamin C quickly reached a maximum plasma level despite increasing doses11. Intravenous doses achieved very high plasma levels, of the sort said to inhibit tumour cell growth in vitro. This paper made the point that studies where the ascorbate was given in high dose by mouth should be re'evaluated.

Hoffer and others (including Padayatty) published in 2008 an account of the tumour response to high dose intravenous Vitamin C in 24 patients with cancer12. Despite high serum levels of Vitamin C, no patient had an objective anti'cancer response. They wrote:

"The likelihood of an objective anti'cancer response to IV ascorbic acid alone is slight in unselected patients with multiply treated advanced cancer."

The question of the safety of Vitamin C is often taken for granted by those who advocate its use in cancer treatment. However, in 2005 Massey et al showed that oral Vitamin C intake of 1000 mg twice a day increased urinary oxalate excretion in both stone formers and those without a history of stones13. Increased urinary oxalate is a risk factor for kidney stone formation14. Wong and others reported a case of acute oxalate nephropathy after a massive intravenous dose of Vitamin C15.

In 2010, Padayatty and others published an account of the experience of adverse effects of intravenous use of Vitamin C by alternative medicine practitioners16. They agreed that in those with depressed renal function, to an unspecified degree, or with glucose'6'phosphate dehydrogenase deficiency, there is a risk of adverse effects. In other situations, high dose Vitamin C seems remarkably safe. However, one should look at the way they gained the information on which they based their conclusion.

They distributed questionnaires to attendees at conferences of complementary and alternative medicine practitioners. In 2006, 106 of 300 (35 percent) answered. In 2008, 93 of 250 (37 percent) answered. Of these 93, 22 had responded in 2006. The conclusion from this small responding number is of course strongly biased by the unwillingness of any practitioner who had had adverse effects from this use of Vitamin C to go on record, particularly in the US!

This paper quotes the annual sales of Vitamin C in the US in 2007 to be worth $884 million.

For critically ill patients on artificial respiration, immobility increases urine calcium excretion17. Intravenous Vitamin C would accentuate the danger of acute renal stone formation under these circumstances.

In January, 2013, James Watson published in Open Biology a paper summarising established data about the sequence of events when cells become cancerous18. The biology is complicated. However, one point he makes is:

"In light of the recent data strongly hinting that much of late'stage cancer's untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes, than prevents, cancer."

Recent events in NZ

In 2008, the New Zealand Family Physician (now called the Journal of Primary Health Care) published a large paper on this subject19. The authors all had close associations with the Centre for Advanced Medicine Ltd, itself a subsidiary of Master Projects Pte Ltd, of Singapore. The Singapore company has subsidiaries in the fields of osteopathy, acupuncture, and iridology.

Among the authors, one was a literature reviewer for Feedback Research Ltd Auckland, and another was chief scientific adviser for the same company. Feedback Research Ltd states on its website:

"Our primary ongoing project is supporting the work of the doctors, nurses and team at the Centre for Advanced Medicine."

Feedback Research Ltd is a subsidiary of Master Projects Pte Ltd.

The paper recommends investigating the role of Vitamin C in disease intervention at doses higher than previously considered relevant, and rehearses many of the arguments outlined above. For example, that the daily intake in the diet is a measure of need among wild animals.

There is also a section on palliation for terminal cancer patients by the use of intravenous Vitamin C, and reference to scavenging free radicals and carcinogens without evidence of any cancer response. There is a reference to haemodialysis patients, whose anaemia does not respond to erythropoietin, responding to Vitamin C. There is no comment about the possibility of iron deficiency anaemia responding to Vitamin C by increased iron absorption, an established response. There are 112 references cited, but many of them are from the same authors.

While labelled as an original scientific paper this article is a review of papers which support the authors' contentions. I have devised a measurement which serves to outline the tenor of this process. It is called The May Poll and is a count of the number of times the word may is used. There are 17 such episodes in this paper. We can be more exacting, with the May Poll Index, which relates the number of uses of the word may to the number of pages of writing. In this case 17 / 4.3 (= 3.95). Compare this with any scientific writing!

The last line of the abstract appears to acknowledge that there are no thorough investigations in the clinical setting of the role of high'dose Vitamin C. There are 53 varieties of oral vitamin C preparations currently on the NZ market: a lot of business.

The Centre for Advanced Medicine in Remuera uses an intravenous preparation manufactured in the US by McGuff Pharmaceuticals. The package insert suggests a maximum dose of 2 g daily. CAM recommends up to 50 g IV three times a day.

The NZ Herald published a leader, Opinions of the Ignorant Can't Beat Research on 20 October, 2012. Here are some excerpts.

"Enthusiastic amateurs are entitled to disagree with experts, but they must produce convincing evidence to back their claims.

"When people claim something unexpected, and contrary to expert opinion on a subject, the burden of proof falls on them.

"[Experts' views] deserve to be given more value than views motivated by the unpleasant consequences of a scientific consensus or the failure of a conventional practice to offer a satisfactory outcome."

The leader was commenting on the views of Patrick Stokes, of Melbourne's Deakin University Department of Philosophy, recently published as an opinion piece in the Herald (9 October, 2012, in the Business Section, You're not entitled to your opinion).

They are views which all press publications should respect.

The Vitamin C saga illustrates the dangers of the perversion of normal physiology in terms of the gross distortion of baseline needs. It is based on the adage that if a little is helpful, more must be better. A whole lot more must be a whole lot better. There is nothing natural about these practices.

This story also illustrates the need for fundamental science education to prevent unscrupulous exploitation of those in need. I can respect a right to a belief, but I reserve respect for those beliefs which stand up to scientific examination.

References.

1. Brown, S. Scurvy. How a surgeon, a mariner and a gentleman solved the greatest medical mystery of the age of sail. Viking, Australia.2003. ISBN 0 670 04120 3.
2. Drouin G, Godin, J'R, Page B. Curr Genom.2011. 12: 371'8.
3. McCormick W J. ( 1959). . Arch Pediatr. 1959; 76: 168'71.
4. Stone I. Perspect Biol Med. 1966; 10: 133'4.
5. Pauling L. Proc Natl Acad Sci USA. 1970; 67: 1643'8.
6. Harris S. (2012) Google Sam Harris. The Blog. 2012; November 11.
7. Cameron E, Pauling L. Proc Natl Acad Sci. USA. 1976; 73: 3685'9.
8. Gilbert W S. (1836'1911.) The Mikado.
9. Cameron E, Pauling L, Leibovitz B. Cancer Res. 1979; 39: 663'81.
10. Block G. Am J Clin Nutr. 1991; 53: Suppl. 1, 270s'82s.
11. Paddayatty S J, He Sun, Yaohui Wang, et al. and intravenous. Ann Int Med. 2004; 140: 533'7.
12. Hoffner L J, Levine S, Assouline D, Paddayatty S J, et al. trial of Ann Oncol. 2008; 19: (11) 1967'74.
13. Massey L K, Liebman M, Kynast'Gales S A.. J Nutr. 2005; 135: 1673'7.
14. Wallace M, Mason K, Gray J. . N Z Med J. 1981; 94: 87'9.
15. Wong K, Thomson C, Bailley R R. Aust N Z J Med. 1994; 24: (4) 410'1.
16. Padayatty S J, Sun H, Chen Q, et al.. PLOS One 2010. 5; (7) e11414.
17. Stewart A F, Adler M, Byers C et al. . N Engl J Med. 1982; 306: (19) 1136'40.
18. Watson J. Open Biology. 2013; 3: 120144; doi: 10.1098/rsob.120144. (Google: 'Open Biology'.)
19. Ge M, O'Reilly A, Baillie N, et al. . NZFP. 2008; 35: (5), 312'8.