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01 June 2012

Mystery disease outbreak in Ethiopia solved: linked to weed toxin

Imagine this…

A mysterious disease terrorising your community, not infectious but spreading nonetheless, and killing your relatives and neighbours. All you want to do is pack your bags and flee. Worse, when your plight comes to the attention of the health authorities, they are stumped and its not going to be easy or quick to solve.

A recent example of this kind of illness is “nodding disease (South Sudan, Uganda, and Tanzania), which affects children 5-15 years old: they suffer epileptic seizures which causes their heads to nod, and they end up severely disabled and finally die. The USA’s Centre for Disease Control (CDC) is working to identify the cause: so far, the best guess is that it’s linked to the parasite that causes river blindness combined with an autoimmune reaction, and exposure to chemicals could predispose.

Other examples of non-communicable disease outbreaks

On Global Health, I found there are outbreaks going back to 1911 (epidemic dropsy) but more recent ones were in India,  Bangladesh, Nigeria, Brazil, China, Afghanistan and even the USA.

 What are the likely causes for these outbreaks? The body of research, as found on databases like Global Health, tells us that they could be contamination of food and water supply, exposure to chemicals or heavy metals in the environment, or even use of traditional medicine.

 Mystery liver disease in Ethiopia with a ‘happy’ ending

Can public health authorities in low-income countries solve & stop such outbreaks?   Yes. In 2005, in Ethiopia, a 4 year long outbreak of liver disease in Tseda Emba, a small village of the Tahtay Koraro district of Tigray, finally reached the attention of the Tigray Health Bureau (THB). Now, in 2012, the multidisciplinary and one-health approach they initiated has “solved” the mysterious illness, significantly reducing new cases. 

 The research work was the subject of an entire session at the recent World Congress Public Health (WCPH-2012) in Ethiopia, and is now published as 5 papers in the supplement to April 2012’s edition of Ethiopian Medical Journal (EMJ). [Abstracts to these papers will be available on Global Health]. It demonstrates the relevance of the one-health approach to public health in low-income countries and is a fascinating detective story…

Investigation of the outbreak

In 2005, THB’s first step was to arrange for clinical specialists from Addis Ababa university (AAU) to examine some 18 affected people & send samples of blood, urine food etc to CDC, Atlanta. With tests ruling out parasitic, bacterial and viral infections, and no help from the CDC Atlanta forthcoming, THB then contacted the Ethiopian Ministry of Health (MOH).  This led to 4 Ethiopian institutions running field studies on different sample households: the AAU Faculty of Medicine, WHO Ethiopia, EHNRI (Ethiopian Health and Nutrition Research Institute), the Drug Administration and Control Authority.  Team’ combinations included an epidemiologist, gastroenterologist, infectious disease specialist, pathologist, microbiologist, biochemist, nutritionist, public health, veterinarian and agriculturalist.  

 The infectious disease specialists eliminated viral hepatitis, the most common cause of liver disease worldwide. That gone, the symptoms of abdominal pain, rapidly filling ascites and hepatomegaly, suggested agents toxic to the liver such as  pesticides, phalloids (mushrooms), aflatoxins (from fungal growth on food crops) and alkaloids (from  certain common weeds and medicinal plants). The agriculturalists helped eliminate the possibility of pesticide poisoning…the villagers didn’t use any on their crops or in storage.  Aflatoxins were also eliminated.

Epidemiological study established that the outbreak affected 118 people and the fatality rate was 38%, with death occurring within 12 months from the onset of symptoms. Under-2 year old children were unaffected because they were breastfed, and all but 21 cases came from the same village. Users of a particular unprotected well were 3 times more likely to develop the liver disease. Clinical investigation & pathology established that it was toxic hepatitis (veno-occlusive liver disease, VOLD or VOD) caused by pyrrolizidine alkaloid (PA) poisoning.  (The damage is done by a metabolite of PA, pyrrole, and apparently its only detectable for 4 weeks).  PA originated from the Ageratum plant species found growing in the well. Well done to the biochemists and microbiologists!  

EHNRI contributes unique insight

There must have been a few light-bulb moments when the Health & Nutrition Institute teams reported back. Their understanding of human behaviour proved vital in their investigation of  drinking water sources, use of pesticides and fertilisers, grain storage, use of traditional medicinal plants, cereal flours and beverages.   They too found Ageratum plants were the source. In addition they discovered further aggravating factors:

1.     Villagers use these conveniently located Ageratum plants to wash their pots at the well and then use them as covers

2.     Women were greasing their baking pans with a mixture of melted polyethylene plastic bags, castor seeds (containing the toxin Ricin), and seeds from Argemone mexicana ( containing another toxic alkaloid, sanguinarine).

3.     A. mexicana seeds were also a brewing ingredient of Tela, the local alcoholic beverage!

Based on mouse studies, they linked the disease to consumption of both contaminated well water and of Tela. Mice all developed liver necrosis when fed for 2 weeks with the water or Tela (distilled first to remove alcohol) from the affected village, and pyrrole was present in the livers.  Samples from a control village had no effect.

Steps taken to reduce village outbreak

Use of the well was banned and a handpump erected which has resulted in reduced case numbers.  However, even the handpump water seems to be contaminated (its next to the well) and so an entirely new water source is needed.

Outbreaks of VOLD  in the world

Outbreaks of VOLD have occurred in India and Iran linked to the consumption of cereals contaminated with Crotalaria seeds and in Tajikstan (1992), there were 3906 cases from consumption of wheat contaminated with Heliotropum seeds/roots during a food shortage. Individual cases in Africa, Asia and even the USA are linked to consumption of herbal teas, traditional medicinal plants or honey from bees foraging on these plants. There are no antidotes: just symptom treatment. The WHO has reported that the lowest intake of PA to cause VOLD is 0.015 mg/kg body weight per day…for a 70kg adult, that’s 1mg per day.

New data from WCPH-2012

Two questions unanswered by the EMJ papers, were tackled in the WCPH-2012 session.  Ageratum species are common throughout Ethiopia … why is it causing a problem in this village and in 6 districts in Tigray (total =1000 cases since 2001)? Are domestic animals (goats, cattle) affected as some of the villagers claim?

In separate papers from Getachew Abebe and Danielle Buttke, we were told that:

1.     the Ageratum species in Tigray, Ageratum conyzoides which had not previously been linked to hepatotoxicity, has a higher level of PA, and it’s found ideal soil conditions…low in organic matter.

2.     Not just water but cereal grain is contaminated: 10% of millet grain harvested is contaminated with A. conyzoides seeds and Crotalaria is also contributing PA to cereal products. 

3.     Veterinarians find that domestic animals have liver damage typical of chronic PA exposure and that goats fed with Ageratum powder develop VOLD after 2 months. They have set up sentinel animals for a national study. 

 Final conclusion

The cause: Toxic alkaloid ingestion from unprotected well water contaminated though the growth therein of the plant Ageratum species, compounded by pot-washing & baking routines, and from Tela made with brewing additive A. mexicana seeds.  Elsewhere in Tigray, you also have to factor in Crotalaria species growing as a weed in cereal crops.

The solution:  reducing infestation with Ageratum conyzoides by improving the soil with nitrogen, training farmers to de-weed crops before harvest, using clean protected water supplies and domestic education to avoid brewing, washing & baking with poisonous plant materials. 

This is the first outbreak of VOLD in Ethiopia and the authorities are determined not to have another.  Though the mystery is apparently solved, the fact that people are still dying from it means that the villagers of Tseda Emba just want to move away…

 

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