Consumption of the vegetables khesari (Lathyrus sativus), found in India, China, Ethiopia, and Nepal, can cause a devastating disease known as neurolathyrism.53 Khesari is a readily accessible food source in developing countries because it needs no irrigation, fertilizers, or pesticides, and its seeds are high in protein.54 Consumption of bread or other products produced from this crop can result in toxicity.
A neurotoxic amino acid, P-N-oxalyamino-L-alanine (BOAA), has been implicated in animal studies as the possible toxin responsible for neurolathyrism. In a primate model, oral consumption of BOAA alone caused a syndrome similar to neurolathyrism. BOAA in vitro inhibits the high-affinity uptake of glutamate transport by isolated synaptosomes, and it may inhibit mitchondrial complex I of the motor cortex and lumbar spinal cord.55 Intrathecal administration of BOAA to rats demonstrated interference with the transport of aspartic and glutamic acid in spinal nerves.56 The neuropathologic changes include loss of fibers in the pyramidal tracts of the spinal cord and pallor of the fasciculi gracilis.16
Males are more likely than females to be affected after consuming khesari,57 and the incidence is highest in the third and fourth decades of life. The syndrome appears after daily consumption of khesari for at least 2 or 3 months. Lathyrism usually occurs during famine conditions when the hearty crop becomes a majority of the diet. Initial symptoms are aching of the waist and rigidity of the calf muscles, known as lodakas in India. As symptoms progress, partial or total loss of control over the lower limbs occurs.53 Some patients have exaggerated knee and ankle reflexes and ankle clonus. Sensory loss is usually absent.16 The neurologic changes are permanent but nonprogressive, and motor weakness of the upper extremities is rare. No specific therapy has been identified.
Naturally occurring cardiac glycosides are found in many plants. The two most common oleanders, Nerium oleander and Thevetia peruviana, are native to the Mediterranean region and most tropical and subtropical regions around the world, and they are found worldwide as ornamental plants. The flowers of N. oleander are white, pink, and dark red, and its fruit is a pair of long narrow pods (Fig. 10-9). Thevetia peruviana has yellow flowers and green fruit. Other plants containing cardiac glycosides are shown in Box 10-3.
Oleander contains the cardiac glycosides oleandrin, neriine, oleandroside, nerioside, and digitoxigenin.58,59 Toxicity from oleander has been reported with the consumption of leaves and from the use of oleander twigs as skewers to cook meat.60 The toxicity of oleander poisoning is indistinguishable from
Box 10-3 Plants That Contain Cardiac Glycosides
I. Figwort family (Scrophulariaceae) A. Foxglove (Digitalis purpurea)
II. Lily family (Lillaceae)
A. Sea onion (Urginea maritima)
B. Lily of the valley (Convallaria majalis)
III. Dogbane family (Apocynaceae)
A. Yellow oleander (Thevetia peruviana)
B. Oleander (Nerium oleander)
C. Wintersweet (Carissa spectabilis)
D. Bushman's poison (Carissa acokanthera)
E. Sea mango (Cerbera manghas)
F. Frangipani (Plumeria rubra)
IV. Milkweed family (Asclepiadaceae)
A. Balloon cotton (Asclepias fruticosa)
B. Redheaded cottonbush (Asclepias curassavica)
C. King's crown (Calotropis procera)
D. Rubber vine (Cryptostegia grandiflora)
acute digoxin toxicity. Cardiac glycosides inhibit the Na-ATPase pump in cardiac cells. Cardiac intracellular sodium and calcium rise; intracellular potassium falls. The slope of phase 4 in the action potential is increased, resulting in increased automatic-ity of cardiac cells. Cardiac glycosides also enhance vagal tone and prolong phase 3 of the cardiac action potential in the atrioventricular node and the His-Purkinje conduction system.61
Accidental poisoning has occurred from chewing oleander flowers or leaves, eating meat cooked over burning oleander branches, and consuming liquids stirred with oleander stems. The ingestion of one oleander leaf is reported to be fatal.59 The clinical presentation is very similar to acute digoxin poisoning, with nausea and vomiting the initial symptoms. Cardiac toxicity is manifested by many different dysrhythmias. Bradydysrhyth-mias, including sinus arrest, sinus bradycardia, and atrioventricular nodal blockade, may be seen. Tachydysrhythmias can include atrial tachycardia with block, junctional tachycardia, ventricular tachycardia, and fibrillation. Laboratory abnormalities include profound hyperkalemia.
Treatment of acute oleander ingestion includes gastric decontamination, correction of hyperkalemia, and standard treatment of cardiac dysrhythmias. The advent of specific antibody fragments against digoxin poisoning has revolutionized the care of digoxin-poisoned patients refractory to supportive therapy. The antibody fragments (Fab fragments) bind to and inactivate digoxin, with the resulting complex filtered by the kidney. The use of Fab fragments for the treatment of oleander toxicity in humans is limited to anecdotal case reports;60 however, a study using high doses of digoxin Fab fragments for the treatment of oleander poisoning in a canine model was successful in reversing both dysrhythmias and hyperkalemia and prevented mortaility.62 A series from Sri Lanka demonstrated efficacy using multiple doses of activated charcoal in the management of T peruviana poisoning.63
Poison hemlock (Conium maculatum) is found in North and South America, Europe, and as an ornamental in Asia. It is also known by the common names poison fool's parsley, hemlock, spotted hemlock, and California or Nebraska fern.64 Poison hemlock grows to a height of 3 to 9 ft (Fig. 10-10). Younger plants have light green leaves that resemble those of a fern and have been mistaken for parsley. The large stems of maturing plants have purple spots. The fleshy white taproot has been mistaken for parsnips. Poison hemlock grows in groups along roadsides, in ditches, and in other uncultivated areas.
The toxins in poison hemlock are the piperidine alkaloids coniine and y-coniceine. The action of coniine is similar to that of nicotine. Animal studies demonstrate that coniine activity on isolated ileum and duodenum is blocked with atropine pretreatment. This implies that coniine stimulates parasympathetic ganglia and explains the observed nicotinic effects following exposure to this plant, which include salivation, mydriasis, and tachycardia, followed by bradycardia. These alkaloids also act as nondepolarizing antagonists at the neuromuscular junction, similar in action to tubocurare.65 Rhabdomyolysis and acute tubular necrosis have also been reported with poison hemlock ingestion.66
Symptoms are directly referable to the dual toxicity of the hemlock alkaloids. Salivation, urination, and defecation often precede the loss of tone in skeletal muscle. Death most frequently occurs due to respiratory arrest. There is no antidote; supportive care, including ventilator support and gastric decontamination, should be undertaken when the diagnosis of poison hemlock ingestion is suspected.
The syndrome of hepatic veno-occlusive disease is found throughout the world associated with consumption of local teas. The disorder has been described in the West Indies, Afghanistan, India, and Israel. The rise in popularity of alternative medicine and the use of herbal teas has led to cases in Europe and the United States.67,68
The agents responsible for herbal-based hepatic veno-occlusive disease are the pyrrolizidine alkaloids. They are found in Jamaican "bush teas," comfrey (Symphytum officinale), grain contaminated with pyrrolizidine-containing weeds,69 and in many other herbs used to prepare medicinal teas or dietary supplements. Approximately 3% of the world's flowering plants contain toxic pyrrolizidine alkaloids.70 The dose and duration of exposure required for toxicity are unclear, and no "safe" level of exposure has been established.71 Pyrrolizidine alkaloids are readily absorbed from the gastrointestinal tract and metabolized by the liver. The alkaloids undergo transformation to inactive or active metabolites by several metabolic pathways; they can be deactivated by N-oxidation or by hydrolysis of their ester bonds, or they can be activated by liver microsomal P450 enzymes that convert the alkaloid into a pyrrolic ester. Pyrrolic esters are potent oxidizers that can cause acute hepatotoxicity and cellular necrosis.72 Chronic hepatotoxicity is also seen with pyrrolizidine alkaloid ingestion, and pathologic findings in animal models of this disease include enlarged hepatocytes.
Veno-occlusive disease results from nonthrombotic occlusion of the small intrahepatic branches of the hepatic vein by loose connective tissue. Damage to the venous endothelium leads to a proliferative fibrotic response resulting in occlusion. Veno-occlusive disease is defined pathologically as a progressive and concentric nonthrombotic occlusion of the lumina of small intrahepatic veins (diameter less than 300 m) by loose connective tissue with necrosis of hepatocytes in centrilobu-lar areas.71 Since false-negative biopsy results can occur, veno-occlusive disease is primarily a clinical diagnosis.
The natural history of veno-occlusive disease includes acute and chronic forms. Acute veno-occlusive disease is characterized by ascites, abdominal pain, hepatomegaly, nausea, and vomiting. A cohort of 20 children with suspected pyrrolizidine poisoning in South Africa were examined. The prothrombin time was prolonged in 89% of patients, aspar-tate aminotransferase was elevated in all patients, and alanine aminotransferase was elevated in 84%. A spectrophotometry test was developed by the investigators that detected pyrrolizidine metabolites in the urine. Mortality in this series was 40%.73 Chronic veno-occlusive disease presents as cirrhosis with stigmata of liver disease.
Management of hepatic veno-occlusive disease is supportive. Sodium should be restricted and plasma expanders used to maintain oncotic pressure and limit ascites. Spironolactone is recommended for diuresis. Prostaglandin inhibitors are to be avoided to maintain renal blood flow in the presence of decreased intravascular volume.
Water hemlock (Cicuta maculata) is found throughout North America. Water hemlock belongs to the family Umbelliferae and is related to European water hemlock (Cicuta virosa) and English hemlock or water dropwort (Oenanthe crocata).74 Water hemlock is a perennial herb that grows from 3 to 7 ft with clustered, short, and thickened tuberous roots and hairless, purple striped, or mottled stems.75 They have small, white, heavily scented flowers. Water hemlock roots are chambered (Fig. 10-11). A cut stem reveals yellow oily sap that smells like raw parsnip.76
The poison isolated from water hemlock is called cicu-toxin. Cicutoxin is found in all parts of the plant, with the root containing the highest concentration.77 Cicutoxin is an unsaturated aliphatic alcohol that acts primarily as a neuro-toxin. Virol A is a component of C. virosa that has been found to inhibit GABA receptors in an animal model.78 Poisoning can occur from ingestion or dermal exposure.
A lethal dose of water hemlock can be contained in one rootstalk (rhizome).79 Children have died from using the hollow stems as whistles or peashooters.80 Onset of symptoms can occur within 15 minutes of exposure and initially includes nausea, vomiting, and abdominal pain. Early vomiting may be protective if undigested plant is expelled, but vomiting should not be induced due to the risk of aspiration during convulsions. Severe poisonings result in diaphoresis, salivation, bronchorrhea, and respiratory insufficiency. Death usually follows the development of intractable seizures. Rhabdomyolysis, renal failure, and severe metabolic acidosis may also be seen.81 An examination of cicuta poisonings reported from 1900 to 1975 revealed 30% mortality.82
Treatment is supportive; there is no specific antidote. Mechanical ventilation should be used when necessary. Convulsions should be treated with large doses of benzodi-azepines or barbiturates. Adequate urine flow should be maintained to reduce the incidence of renal failure in the setting of rhabdomyolysis.
Plant dermatitis is one of the most common mechanisms by which plants cause human disease. The number of plants that cause dermatitis is legion, and they are found throughout the world. Dermal exposure to some plants can be life threat-ening.83 There are four main mechanisms by which plants cause human dermatitis: immediate hypersensitivity, irritant or mechanical dermatitis, phytophotodermatitis, and delayed hypersensitivity.
Urticariogenic plants cause immediate contact dermatitis. Some plants have stinging hairs that introduce irritating plant toxins through mechanical breaks in the skin (e.g., stinging trees of Australia and stinging nettle). Others cause a hypersen-sitivity response through direct contact alone (e.g., strawberry, castor bean, and chrysanthemum). Contact with these plants causes hives, pruritus, and sometimes anaphylaxis and shock.84 Treatment of simple urticaria involves use of cold compresses and antihistamines. Systemic reactions may require more intensive therapy.
Many plants cause an irritant contact dermatitis. Simple mechanical irritation through spines or prickly hairs is one method by which plants cause human disease. The thorns of a flowering plant or spines of a cactus can penetrate the skin and cause fungal (Sporothrix), bacterial (Staphylococcus aureus), and other disease.84 Chemical irritants are produced by some plants and can cause dermatitis. The manchineel tree, Dieffenbachia, and Philodendron are examples of plants that exert their toxicity through chemical irritation. Acute clinical findings include erythema, edema, and papular and vesicular reactions. In severe cases, bullae, pustules, and ulcerations may occur. Treatment of mechanical and chemical irritants revolves around removal of the irritating stimulus. This may include manual removal of thorns or copious irrigation of the skin to remove chemical irritants.
Phytophotodermatitis occurs when the skin is exposed to both a plant toxin and ultraviolet radiation. Celery, citrus, Queen Anne's lace, and the common fig can cause a dermatitis characterized by a painful, vesicular, erythematous rash that lasts for 1 or 2 weeks. Healing skin may show hyperpig-mentation. Phytophotodermatitis is differentiated from allergic contact dermatitis by its presence only in sun-exposed areas and the finding of hyperpigmentation during healing.84
Allergic contact dermatitis results from cell-mediated immunity and is often referred to as a delayed hypersensitivity reaction. Poison ivy, poison oak, mango, and cashew can cause allergic contact dermatitis. The reaction only occurs in those previously exposed and sensitized to the plant. Exposed areas will show erythema, vesiculation, weeping, and pruritus. The lesions heal over several weeks and usually leave no residual scarring or pigmentation. Treatment of phytophotodermatitis and allergic contact dermatitis is similar. In mild cases, antihist-amines and topical corticosteroids may provide symptomatic relief. More severe cases warrant the use of oral corticosteroids.84
Tropical plants contain a variety of components that can be toxic to humans and animals. New species and toxins are constantly being discovered and described in all areas of the world. Their effects are still unknown in human exposures. Some varieties, such as water hemlock and ackee, can cause life-threatening toxicity when ingested. More commonly, gastroenteritis is the hallmark of most plant exposures but can lead to weakness and dehydration in severe cases. The more common and better understood toxicities existing among plant species found in tropical and subtropical environments have been presented in this chapter. Most victims of these poisonings survive if administered aggressive support with airway protection and fluid rehydration.
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