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Aristolochia clematitis, birthwort

Aristolochia clematitis, birthwort

Aristolochia clematitis, birthwort

Summary

One of the best examples of the problems arising from the belief that the look of a plant determined its use medicinally. May have been responsible for many thousands of deaths since, at least, Roman times. Its poisonous component, aristolochic acid, continues to kill as a result of upper urinary tract cancers resulting from its use in Chinese medicine.

Quite possibly, in terms of accidental poisoning, the most harmful plant of all those featured on this website. 

Though this page features the clematitis species from the Aristolochia genus, aristolochic acid is present throughout the genus

 

 

 

 

 

Family

Aristolochiaceae

Meaning of the Name

Aristolochia
From the Greek ‘aristos’, ‘best’ and ‘lochia’, ‘childbirth’.

clematitis
‘like a clematis’.

Common Names and Synonyms

birthwort

How Poisonous, How Harmful?

Quite possibly one of the most poisonous plants and, almost certainly, the most harmful. 

Contains aristolochic acid which has been shown to cause complete kidney failure. Recent work has shown that only very small amounts of aristolochic acid, if ingested regularly, can result in end stage renal disease and urinary tract cancer.

In 2001, the FDA issued a warning to consumers to immediately stop taking herbal medicines containing aristolochic acid.

How the Extent of Aristolochia Poisoning Came to be Known

Aristolochia clematitis, birthwort

Though no statistics are available, the use of birthwort during labour based purely on the appearance of the flower may have been responsible for many deaths in childbirth or soon after. Even today, death in childbirth is all too common but we will never know how many deaths in the past were due to the use of plants from the Aristolochia genus.

I am grateful to Professor Arthur Grollman for drawing my attention to the work he and others have done investigating the effects of aristolochic acid poisoning.

Prof Grollman provided me with information on a number of papers and articles that are available online. I have provided links to them at the appropriate points in this fascinating story.

While best known, in folklore, for the use which gives it its common name, species from the Aristolochia genus have been, and continue to be, used to treat a wide range of conditions, especially in traditional Chinese medicine. In Europe it was thought to have anti-inflammatory effects on gout and rheumatism. John Gerard gives many conditions which can be treated both by taking it internally and as a poultice for treating 'rottenness and corruption' and cleaning out ulcers before filling them with new flesh. In the USA, Aristolochia serpentaria, Virginia snake-root, was used to treat snake bite. And its uses in traditional Chinese medicine include pain relief, respiratory diseases, asthma and, notably, as a diuretic.

But, since 1956, evidence has mounted that, far from bringing relief from disease and suffering, plants in the Aristolochia genus have caused many deaths and, were it not for advanced medical procedures like kidney dialysis and transplantation, would have caused many more.

The story of how that evidence has been amassed is a mixture of diligent scientific research, the successful application of new discoveries related to DNA, a chance discovery in a Zagreb library and a nod of acknowledgement in a clinic waiting room.

Aristolochia clematitis

Just after the end of World War II, family doctors in north-west Bulgaria noted a high incidence of kidney disease but only in some areas. In 1956, a study of 664 patients was published noting that the disease formed clusters in villages, families and, sometimes, single households. Following publication, other disease clusters were reported in what was Yugoslavia and parts of Romania. As more was discovered about the disease, it was noted that there was also a raised incidence of urinary tract cancer.

Following two international conferences in the mid-1960s, the condition was designated as Balkan endemic nephropathy (BEN). Work continued to try and determine the cause with the greatest mystery being the discrete nature of the clusters. The disease occurred only in villages and small towns; it did not affect cities. Afflicted villages were separated by no more than a couple of kilometres from disease free villages and, though often found to affect members of the same family, it was shown that it was not hereditary.

Another puzzle was that it appeared that the disease required at least fifteen years residence in an afflicted area before symptoms emerged. It was never found in children.

Some environmental factor was assumed to be at work and a number of theories were researched. The one receiving the most attention was that a mycotoxin formed by both Aspergillus and Penicillium fungi contaminated local food. But there were enough conflicting theories that many of the affected population subscribed to some malign supernatural action as being the cause.

Aristolochia clematitis

A Serbian microbiologist, called Ivic, theorized that seeds of the plant could be contaminating the wheat used to bake bread, in the home. It is said that he was aware of reports of poisoning in horses that had grazed Aristolochia clematitis. He examined fields in afflicted areas and found birthwort growing, in small quantities, amongst the wheat and local people confirmed that they made no attempt to remove any seeds before using the contaminated wheat.

After conducting trials with rats and rabbits which showed that Aristolchia seeds caused both kidney damage and cancer, Ivic published full details of his careful research in 1969. For reasons which are, today, unknowable, his work was largely ignored and efforts continued to focus on the mycotoxin theory or some other environmental factor.

In 1991, scientists from the US Geological Survey published what became known as ‘the lignite theory’. This proposed that chemicals from coal deposits found in the afflicted areas leach into the water supply. These chemicals are known carcinogens and their proven presence in small, but higher, concentrations in wells of afflicted villages as against unafflicted settlements gave credence to this theory. The low concentrations found in the water supply seemed to fit the slow development of kidney disease seen in BEN.

There are still people, living in the afflicted areas, who blame the water for taking the lives of members of their community.

There have also been theories suggesting that BEN results from a viral infection.

Then, in 1992, two women, in a clinic waiting room in Belgium, nodded ‘Hello’ to each other.

Doctors at the clinic had noted a sudden increase in the number of women under 50 years of age who were suffering serious kidney failure. This is known as end stage renal disease (ESRD) because, unless there is dialysis or transplantation, death is inevitable. They had no indication of any connection between the women and were puzzled as to whether there might be a connection between the cases.

By chance, Dr. Jean-Louis Vanherweghem noticed two of his patients acknowledge each other. He enquired as to how they knew each other and discovered that they attended the same weight loss spa where traditional Chinese medicine (TCM) was given to them as part of a weight loss regime.

Aristolochia clematitis, birthwort

Further work found that all the young women attending the clinic had been using TCM for this purpose and that, of approximately 1800 in total, 105 had developed ESRD. Of these, several went on to develop upper urinary tract cancer.

It was found that the herbal substance in use, being sold as ‘Stephania’, contained Aristolochia fangchi instead of Stephania tetrandra. In Chinese, Aristolochia fangchi is known as ‘Guang Fang ji’ and Stephania tetrandra is ‘Han Fang ji’ and the two have some limited physical similarities. Defenders of TCM tried to blame other substances for the women’s conditions but, Dr. Vanherweghem and his colleagues undertook thorough research to shown that the ‘Stephania’ was the most likely candidate. In the way of scientists, they concluded that the kidney disease was ‘related’ to the use of TCM products containing aristolochic acid. That ‘relation’ was enough for the US FDA to issue a ‘Letter to Health Professionals’ on 31 May 2000 calling for an end to the use of aristolochic acid and implementing a ban on its importation.

Belgian scientists also found in one group of 39 women who had attended the weight loss spa that 18 developed urothelial carcinoma and they were able to show that the risk of developing cancer was linked to the cumulative dose of aristolochic acid.

Dr. Vanherweghem et al published their findings in The New England Journal of Medicine in June 2000 in a paper entitled ‘Urothelial Carcinoma Associated with the Use of a Chinese Herb (Aristolochia fangchi)’ that was read by Arthur Grollman.

Arthur Grollman is the Distinguished Professor of Pharmacological Sciences and Medicine, Stony Brook University, Stony Brook, NY, USA and has a long-term interest in problems arising from the use of herbal remedies, in part, because many people associate the term ‘natural’ with ‘safe’.

He was familiar with the condition known as Balkan endemic nephropathy and immediately began to make arrangements to travel to Croatia to see if there were some local herbal remedy, containing aristolochic acid, that might provide the long sought after answer to the riddle of what really causes BEN.

Aristolochia clematitis growing in Croatia

Aristolochia clematitis growing
amongst wheat in Croatia
(used with permission from Professor
Grollman)

He found no such remedy, but, in another intervention by chance, Grollman came across a paper, in German, in the University of Zagreb library dealing with the poisoning of horses. The next day, he visited the area with a farmer he had met having dialysis and saw Aristolochia growing amongst the wheat in the farmer's fields. Grollman began, with a team of colleagues, to investigate further. At this time the work focussed on surveys of affected people who confirmed that, in the afflicted areas, people were aware that small amounts of birthwort seeds were often present in the wheat they used to bake bread at home. In addition, seeds from Aristolochia clematitis, collected in the area, were studied to determine the aristolochic acid content.

Prof. Grollman was eager that as many people as possible in the affected areas of the Balkans should learn about the harm being caused by Aristolochia clematitis seeds and, therefore, in 2005, published his team’s work in a paper entitled ‘Endemic Nephropathy: the Case for Chronic Poisoning by Aristolochia’ in the Croatian Medical Journal. (Sorry, the link I had to this article no longer works.)

Further research, , such as ‘Aristolochic acid and the etiology of endemic (Balkan) nephropathy’ published in ‘Proceedings of the National Academy of Sciences of the United States of America’ in 2007, using DNA techniques not previously available, has shown that people with BEN have alterations to their DNA that can be shown to be uniquely the result of poisoning by aristolochic acid.

Aristolochia clematitis

It was also found that the incidence of BEN was declining and this decline could be linked to changes in lifestyle in the area with fewer families growing their own wheat and baking at home.

Many interesting questions remain, some of which may never be answered while others are the subject of continuing research.

The first is why the harmful effects of Aristolochia species were not noted earlier in human history? Aristolochia, birthwort, is mentioned in detail by John Gerard but he was only following earlier references from the likes of Dioscorides and other writers and none of these writers record any concerns about its use though they do where these arise with other plant remedies. 

This lack of concern over its use is not just related to ancient times. For example, there is no evidence of unusually high levels of kidney disease in the Balkans until after World War II but the domestic arrangements found to be essential to the occurrence of BEN had been in place for very much longer. One possibility, in addition to the general situation in the past that death happened and its cause was not capable of investigation, is that, prior to the second half of the 20th century, people simply did not live long enough for the very slow development of kidney failure which has, now, been shown to be the result of long-term exposure to low levels of aristolochic acid.

Other Reading

This article from 'The Scientist' magazine provides a detailed summary for the general reader of the work done on BEN.

A 'Letter to the Editor' of the Swiss Medical Weekly entitled  'Herbal Remedies: Renal Tragedies' looks at a number of substances in addition to Aristolochia.

Balkan Nephropathy: Evolution of Our Knowledge is a review presented at the World Kidney Forum and published, in 2008, by the American Journal of Kidney Diseases.

Paracelsus is usually credited with being the first person to say that the “poison is in the dose” and the two situations illustrate that perfectly. The very low levels of aristolochic acid in the bread in the afflicted areas of the Balkans mean that, typically, it takes fifteen to twenty years for BEN to appear whereas, in Belgium, the higher doses present in the ‘Stephania’ being used to assist weight loss produced ESRD in a very much shorter time.

Aristolochia clematitis

Since both methods of dosing have been shown to produce the same results the term Balkan endemic nephropathy has been superseded by the name aristolochic acid nephropathy (AAN).

An important puzzle results from the incident in Belgium. Though around 1800 women were found to have taken ‘Stephania’ for weight loss, only 105 suffered ESRD. Investigations are focussing on whether there is some genetic pre-disposition built into the DNA of sufferers.

There are also open questions over the effects of aristolochic acid in Chinese medicines. Is the use of Aristolochia fangchi in place of Stephania tetrandra the result of error based on the confusion of their Chinese names? Or, does the substitution simply mean that TCM manufacturers and practitioners believe the two herbs to be interchangeable? If the latter is true, then could there be widespread exposure to aristolochic acid amongst users of TCM both in China and worldwide? 

In Taiwan, following the results of the Belgian studies, use of extracts from plants in the Aristolochia genus was outlawed in 2003. In October 2010, the journal Occupational and Environmental Medicine published a paper entitled 'Occupational kidney disease among Chinese herbalists exposed to herbs containing aristolochic acids'. This retrospective case-controlled study found that Chinese herbalists were more likely to develop urothelial carcinoma than the general population. Though women are more likely to suffer these cancers, male herbalists were found to be affected. The authors believe that the 'cottage industry' style of much of the herbalism industry (herbalists working from home and preparing medications in the kitchen or at the dining table) could contribute to increased exposure to aristolochic acid, though, as they point out, it is to be expected that herbalists would self-medicate with herbal preparations.

The authors note that there is a trend towards importing complete preparations from China rather than herbalists making their own and express concern that stricter enforcement of the ban on aristolochic acid may be necessary. Whilst noting the inherent limitations of a retrospective study, the authors believe that urothelial carcinoma should be recognised as an occupational disease for herbalists and that they should have regular health assessments made available to them.

Prof Grollman’s work is continuing and could, in time, lead to the conclusion that the true answer to the often-asked question ‘Which plant has accidentally poisoned the most people?’ is Aristolochia. 

Other Incidents

In February 2010, the Old Bailey, in London, was told that a woman who took Chinese herbal medicine for five years for her complexion suffered cancer and kidney failure. The pills, described as 'safe and natural and without side effects' were found to contain aristolochic acid. Click here to read a report of this incident in 'The Independent' newspaper.

Folklore and Facts

The womb shaped flower

The womb shaped flower

Given that extracts from plants in the Aristolochia genus have proven effects on the human body there is quite a bit of work going on to see if those effects can be beneficial. In August 2011, results of a laboratory study suggested that some components could be useful in treating a certain type of drug-resistant TB.

Aristolochia clematitis provides an important example of the Doctrine of Signatures* and the harm it may have caused. The small yellow flower, which appears early in the summer, has a bulb at one end with a tube and a trumpet shaped opening. This was taken to be a representation of a womb and birth canal leading to the plant being given to women in labour. 'Aristolochia' means 'best birth', an indication of the extent of this use.

Pliny says that eating the plant with beef immediately after conception will lead to a male child.

It is not a common plant in the UK and does not appear on the HTA list. It is, though, still found growing in Berkshire in the grounds of a ruined 12th century nunnery. It is not known if the nuns provided midwifery services or grew the plants for their own use.

A south American variety of Aristolochia is said to have been used in the same way as tobacco in areas where tobacco did not grow.

*The Doctrine of Signatures is the name given, in the 16th century, to a belief going back to, at least, Roman times. The belief is that the shape of a plant or its native environment gives an indication of its medicinal effects. This notion seems ridiculous to us but it is actually more rational that it appears. Every society has a creation belief and the arrogance of the human race means all these beliefs share the view that the universe, and everything in it, was created to benefit mankind. The 'creator' in whatever form a particular belief adopts, left signs to help the human race find its way around.

The question of how these erroneous beliefs survived for so long gets into the territory of placebo effect, the principle of post hoc ergo proptor hoc and regression to the mean which I won't pursue further here.

Amazingly, there are still some 'alternative therapists' today who maintain that the Doctrine of Signatures is a valid principle. Whilst I can forgive our ancestors for doing their best to understand a complex world, I have less tolerance for the snake oil salesmen who continue to push this scientifically discredited view of medicine.