Epidemic dropsy

Epidemic dropsy is a form of edema due to intoxication with Argemone mexicana (Mexican prickly poppy).

In Northern India, epidemic dropsy occurs as a food adulterant disease where use of mustard oil as cooking medium is common. When mustard oil is adulterated deliberately (as in most cases) or accidental contamination with argemone oil, proteinuria (specifically loss of albumin) occurs, with a resultant edema as would occur in nephrotic syndrome. Other symptoms are bilateral pitting edema of extremities headache, nausea, loose bowels, erythema and breathlessness. In severe cases fatalities are reported due to congestive heart failure.The toxic effects of argemone oil have been attributed to the presence of benzophenanthridine alkaloids, sanguinarine and dihydrosanguinarine. It has been reported that the sanguinarine alkaloid content in argemone oil varies from 0.44% to 0.50%.

Besides India, widespread epidemics have been reported from Mauritius,Fiji Islands, Northwest Cape districts of South Africa, Madagascar and also from Nepal. Apart from South African study where the epidemic occurred through contamination in wheat flour, all the epidemics occurred through the consumption of mustard oil contaminated with argemone oil.

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History

The earliest reference to argemone oil poisoning was made by Lyon (1889), who reported four cases of poisoning in Calcutta in 1877 from the use of this oil in food. Since then, Epidemic Dropsy has been reported from Bengal, Bihar, Orissa, Madhya Pradesh, Haryana, Assam, J&K, Uttar Pradesh, Gujarat, Delhi and Maharashtra, mainly due to consumption of food cooked in argemone oil mixed mustard oil or occasionally by body massage with contaminated oil.The epidemic in 1998 at New Delhi, India is the largest so far, in which over 60 persons lost their lives and more than 3000 victims were hospitalized (Das and Khanna, 1998). Even after that the epidemics occurred at alarming frequency in Gwalior (2000), Kannauj (2002) and Lucknow (2005) cities of India (Das et al, 2005).

Argemone mexicana Linn

Argemone mexicana (family Papaveraceae), a native of West Indies and naturalized in India, is known as “Shailkanta” in Bengal and “Bharbhanda” in Uttar Pradesh. It is also popularly known as “Pivladhatura” or “Satyanashi”, meaning devastating. The plant grows wildly in mustard and other fields. Its seeds are black in colour and are similar to the dark coloured mustards seeds (Brassica nigra) in shape and size. Adulteration of argemone seeds in light yellow colored mustard seeds (Brassica compestris) can easily be detected, but these seed are rather difficult to visualize when mixed with dark coloured mustard seeds. Argemone seeds yield approximately 35% oil. Argemone seeds find use as a substitute because of the easy availability, low cost and their complete miscibility with mustard oil (Das and Khanna, 1997).

Mechanism of toxicity

Several lines of evidence have been proposed to enumerate the mechanism of toxicity of argemone oil/alkaloid. It has been suggested that the impairment of hepatic phase I and phase II enzymes by argemone oil may decrease the rate of metabolism of the alkaloid, which in turn may be responsible for the slow elimination of the compound/metabolite through urine and faeces . The retention of sanguinarine in the GI tract, liver, lung, kidney, heart, and serum even after 96 hrs of exposure indicates these as the likely target sites of argemone oil toxicity. The inhibition of Na⁺-K⁺-ATPase activity of heart by sanguinarine is due to interaction with the cardiac glycoside receptor site of the enzyme,which may be responsible for producing degenerative changes in cardiac muscle fibers in the auricular wall of rats fed argemone oil and could be related to tachycardia and cardiac failure in Epidemic Dropsy patients. The decrease in glycogen levels following argemone oil intoxication could be due to enhanced glycogenolysis leading to the formation of glucose-1-phosphate, which enters the glycoltic pathway resulting in accumulation of pyruvate in the blood of experimental animals and dropsy patients. The enhancement of glycogenolysis can further be supported by the interference of sanguinarine in the uptake of glucose through blocking of sodium pump via Na⁺-K⁺-ATPase and thereby inhibiting the active transport of glucose across intestinal barrier. It is well established that increased pyruvate concentration in blood uncouples oxidative phosphorylation, and this may be responsible for thickening of interalveolar septa and disorganized alveolar spaces in lungs of argemone oil-fed rats and the breathlessness as has been observed in human victims.

The other facet of argemone oil toxicity,In vitro studies have shown that the toxicity of argemone oil is due to the production of reactive oxygen species (ROS) and which in turn may cause enhancement in lipid peroxidation (LPO) in various hepatic subcellular fractions including microsomes and mitochondria of rats. The damage in hepatic microsomal membrane causes loss of cytochrome P-450 and its dependent membrane bound enzymes responsible for xenobiotic metabolism thereby leading in a delay of sanguinarine excretion. The toxicity of sanguinarine has also been shown to be dependent on the reactivity of iminium bond with nucleophilic sites like thiol groups, present at the active sites of the enzymes and thus suggesting the electrophilic nature of the alkaloid. Recent studiese in the blood of dropsy patients has revealed that there is extensive ROS production in the argemone oil intoxication leading to depletion of total antioxidants in the body and especially lipid soluble antioxidants such as vitamin E and A (tocopherol and retinol)are highly depleted in dropsy patients. There is an extensive damage to the anti-oxidant defense system (anti-oxidant enzymes and anti-oxidants) of the blood.

References

• Das M, Khanna SK. Clinicoepidemiological, toxicological, and safety evaluation studies on argemone oil. Crit Rev Toxicol 1997;27:273-97. PMID 9189656
• Das M, Ansari KM, Dhawan A, Shukla Y, Khanna SK. Correlation of DNA damage in epidemic dropsy patients to carcinogenic potential of argemone oil and isolated sanguinarine alkaloid in mice.Int J Cancer. 2005 Dec 10;117(5):709-17. PMID 15981203
• Lyon IB. Textbook of medical jurisprudence for India, 1st edition. 1889;214.
• Das M, Babu K, Reddy NP, Srivastava LM.Oxidative damage of plasma proteins and lipids in epidemic dropsy patients: alterations in antioxidant status.Biochim Biophys Acta. 2005;1722(2):209-17. PMID 15715957
• Das M, Khanna SK. Epidemic dropsy.Natl Med J India. 1998;11(5):207-8. PMID 10997165
• Sharma BD, Malhotra S, Bhatia V, Rathee M. Epidemic dropsy in India. Postgrad Med J 1999;75:657-61. PMID 10621875
• Seifen E, Adams RJ, Riemer RK. Sanguinarine: a positive inotropic alkaloid which inhibits cardiac Na+,K+-ATPase. Eur J Pharmacol. 1979;60(4):373-7. PMID 230984
• Siddiqui A, Sayeed I, Zafar KS, Islam F. Argemone oil augmented oxidative stress in discrete areas of rat brain.2002; Nov;69(5):734-40. [1]