Plant poisoning clinical toxicology pharm

Mushrooms and mycotoxin poisoning.

1. PLANT POISONING MUSHROOMS, MYCOTOXINS

2. INTRODUCTION Some plants can be poisonous if you eat them. Others can hurt you if you get them on your skin. For small plants, all parts of the plants are poisonous. For others, only certain parts of the plant are harmful. The danger can range from mild irritation to severe illness or death. A few commonly grown plants are highly poisonous. Few plant poisonings have specific antidotes.

3. MUSHROOMS “Mushroom” refers to the reproductive portion of a fungus that grows up from an underground mycelium, i.e., a mass of filaments or hyphae constituting the vegetative portion of the fungus. Of the numerous species of mushrooms, less than 5% are poisonous, while many are edible and are very popular in Western and Chinese cuisine. All toxic mushrooms belong to two divisions: * Basidiomycetes and Ascomycetes*

4. The important parts of a poisonous mushroom include: -The pileus (cap), -stipe (stem or stalk), -lamellae (gills), -volva, -veil, -annulus (ring), -and spores. Pileus refers to the broad, cap-like structure from the undersurface of which hangs the gills or lamellae . The latter radiate out like the spokes of a wheel. Spores are located on the lamellae and are microscopic reproductive structures produced in the millions and range in color from white to black, with shades of pink, brown, and purple in between. The stipe is the stalk or stem supporting the pileus . The annulus (“ring of death”) is a ring-like structure surrounding the stipe below its junction with the pileus. The veil is a membrane that completely or partially covers the lamellae. Volva (“death cup”) represents the remnant of the veil found around the base of the stipe in some species.

5. Depending on the nature of toxin present, mushrooms can be classified into several groups. Examples include: ■ Amanita species comprising A. phalloides, A. virosa , A. bisporigera , A. hygroscopica , A. suballiacea , A. tenuifolia, A. verna, and A. ocreata ■ Galerina species comprising G. autumnalis , G. marginata, G. sulcipes , and G. venenata . ■ Lepiota species comprising L. castanea , L. helveola , L. chlorophyllum , L. josserandii , L. subincarnata , and L. brunneoincarnata .

6. TOXINS: Amatoxins, phallotoxins, and virotoxins are all cyclopeptides. Nine amatoxins have been identified: alpha, beta, gamma, and epsilon amanitins , amanullin , amanullinic acid, proamanullin and amanin . MODE OF ACTION: Of all the toxins, phalloidin appears to be the most rapid-acting, while amanitin causes more delayed manifestations. Phalloidin interrupts actin polymerization and impairs cell membrane function, but has limited absorption and therefore toxicity. Phalloidin binds to the actin F (filamentous polymer) of the plasma membranes and hence increases the permeability of the plasma membranes of hepatocytes. Amatoxins are more potent and can cause substantial hepatic, renal, and CNS damage.

7. LATENT PERIOD: There is often a latent period of 6 to 24 hours following ingestion. The toxins are not destroyed by cooking. CLINICAL FEATURES: 1. Phase I: Abdominal pain, nausea, vomiting, diarrhoea fever, tachycardia, hypoglycaemia , hypotension and electrolyte imbalance, lasting for about a day. The diarrhoea is often severe, watery, and cholera-like (up to 2 to 4 litres /day). Metabolic acidosis may occur. 2. Phase II: The phase of remission, during which the patient may be considered to have recovered and may even be sent home, only to return moribund soon thereafter. 3. Phase III: Two to three days after ingestion of the toxic mushroom, the third devastating phase unfolds leading to hepatic, renal, and (occasionally) pancreatic failure. Hepatotoxicity manifests in the form of elevations of AST, ALT, and bilirubin levels, hypoglycaemia , jaundice, encephalopathy with convulsions, coma, and death in 7 to 10 days (after ingestion). Hypoglycaemia is a grave marker signifying poor prognosis. Cardiovascular collapse usually accompanies severe hepatic failure at the terminal stage. Adult respiratory distress syndrome (ARDS) may develop in the later stages of cyclopeptide mushroom poisoning, in conjunction with severe hepatic impairment and coagulopathies. Polyneuropathy, developing several days after mushroom ingestion, has been reported in some patients. Manifestations included the following: loss of strength in the lower extremities, absence of deep tendon reflexes, and alteration of pain and temperature

8. USUAL FATAL DOSE: ■ About 2 to 3 mushrooms (A. phalloides). ■ Concentrations of 5 to 15 mg of amatoxins per gram of dried mushroom have been found, which is equivalent to one Amanita cap. According to some investigators, 0.1 mg/kg of amatoxin may be a lethal dose for human adults. ■ About 15 to 20 Galerina caps could kill a healthy adult, as will about 30 Lepiotas . DIAGNOSIS: The Meixner test, a simple colorimetric spot test for the detection of amatoxin, unfortunately, gives false positive reactions. Therefore, the test has limited clinical utility. Melzer’s test can be done to detect an amyloid reaction in cyclopeptide containing Amanitas. Hepatic and renal function tests. Serum electrolytes, urea, creatinine, and glucose levels. Detection of toxins in gastric aspirate, serum, urine, stool, and liver and kidney biopsies, using HPLC, TLC, or RIA. Monitor coagulation parameters (INR or PT), especially the clotting factors synthesized by the liver, i.e. fibrinogen, and prothrombin. Elevated AST, ALT, LDH, and serum bilirubin are the earliest and best indicators of liver damage, while glucose, fibrinogen, and prothrombin time are the best indicators of established hepatocellular failure.

9. SEVERITY CLASSIFICATION Grade 1: GI upset, no indications of liver or kidney failure. Symptomatic treatment only. Grade 2: All signs of intoxication, with a mild to moderate rise in transaminases (less than 500 units/L). Symptomatic treatment only. Grade 3: Severe hepatic damage with a great increase in transaminases (> 500 units/L), plus an impaired plasma clotting function (e.g. a prolonged prothrombin time). Sub-divided into two groups based on bilirubin values: a. Grade 3a: Bilirubin rise is mild or absent. b. Grade 3b: Bilirubin rise is steep and continuous (> 5 mg/ dL). These patients are at risk and should be transferred to a facility where liver transplant is possible. Grade 4: Steep rise in transaminases, accompanied by a steep decline in clotting function, a steep rise in bilirubin, and the onset of kidney dysfunction. These patients have a poor prognosis, and many die despite intensive care.

10. TREATMENT: 1. Stabilization: Restoration of fluid and electrolyte balance IV glucose Monitor coagulation(prothrombin and fibrinogen) frequently. Correction of hypokalemia 2. Decontamination: Activated charcoal Emesis and catharsis Hemoperfusion is said to be beneficial if performed within 24 hours of ingestion. Charcoal plasma perfusion (CPP) and continuous venovenous hemofiltration(CVVH) have been tried successfully in a few cases. 3. Antidotes Benzylpenicillin Thioctic acid Silybinin Cimetidine N-acetylcysteine Aucubin

11. 4. Treatment of Acute renal failure: General principles- – Hospital admission. – Invasive monitoring to detect complications before they become clinically evident. – Placement of CVP monitor, arterial line, urinary catheter, and nasogastric tube. – Endotracheal intubation if the patient is comatose. – Continuous pulse oximetry. – Mechanical ventilation, if there is evidence of hypercapnia or hypoxia. – Prevention of hypoglycemia by continuous infusion of 5 or 10% dextrose. – If hypoglycemia develops, infuse 50% dextrose. – Treatment of hypotension with crystalloid or colloid solutions, or drugs such as dopamine, noradrenaline, etc. – Treatment of renal failure with dialysis or arteriovenous ultrafiltration. – Prevention of gastroduodenal bleeding with regular doses of H2 antagonists or omeprazole. b. Treatment of hepatic encephalopathy – Lactulose –Dietary protein withdrawal –Metronidazole or neomycin

12. c. Treatment of cerebral oedema— – ICP monitoring. – Osmotic diuretics such as mannitol (1 gm/kg, as rapid IV infusion of 20% solution). This is repeated whenever ICP rises above 30 mmHg for 5 minutes or more. Plasma osmolarity must not exceed 320 mOsm . – Barbiturates such as IV thiopentone (3 to 5 mg/ kg) infused slowly over 15 minutes until signs of raised ICP resolve, or a maximum of 500 mg has been administered. – Proper positioning of the patient, i.e. head upright (with the head no higher than 30° from the horizontal). – Corticosteroids may not help in relieving cerebral oedema due to acute liver failure. d. Treatment of infection— Some investigators are of the opinion that prophylactic antibiotic therapy is vital to the treatment of acute liver failure. In any case, aggressive daily microbiologic surveillance is essential. e. Treatment of coagulopathy—Fresh frozen plasma is necessary if there is evidence of serious or persistent bleeding. f. Liver transplantation—Orthotopic liver transplantation (OLT) is indicated in the following circumstances: – Grade II encephalopathy and beyond. – Prolonged prothrombin time (greater than two times normal), despite administration of fresh-frozen plasma. – Serum bilirubin greater than 25 mg%. – Azotaemia . – Evidence of acidosis, hypoglycaemia , GI haemorrhage and hypofibrinogenaemia

13. Preventive Principles Never eat wild mushrooms obtained by foraging in the countryside unless the identity can be confirmed by an experienced mycologist. Distinguishing edible from toxic mushrooms is extremely difficult, regardless of what some foragers may claim. Even edible mushrooms can become toxic if allowed to go stale. Therefore, only fresh specimens should be eaten. Most toxic mushrooms resemble edible mushrooms at some stage of their growth. Even careful examination may not help in conclusively identifying a mushroom as non-toxic. Some tests such as Meixner test or Melzer’s test may be of help Susceptibility to the toxicity of a poisonous mushroom varies from individual to individual, some demonstrating evidence of severe poisoning, while others do not. There are a number of myths associated with mushrooms bandied about as facts by self-professed “experts”, which must be disregarded. Some species of mushroom may be edible in a particular geographical area, while in another location they may be toxic (“Jekyll & Hyde mushrooms”). Some mushrooms are toxic only if they are consumed along with alcohol. Mushrooms must always be well cooked, and never eaten raw. As a general rule, it must be remembered that the following kinds of mushrooms are potentially toxic: pure white mushrooms, little brown mushrooms, large brown mushrooms, and red or pink-pored boletes.

14. MYCOTOXINS There are several other fungi that elaborate various kinds of toxins (mycotoxins) that produce mild to moderate illness in humans The most important of these mycotoxins include aflatoxins, ergot alkaloids, and trichothecenes Aflatoxins Aflatoxins are naturally occurring bis-furanocoumarin compounds produced by the fungus Aspergillus flavus (and related species: A. parasiticus), and occur as contaminants of several nuts, grains, and seeds, such as peanuts, cottonseed, rye, barley, corn, etc. They are composed of highly substituted coumarin compounds that contain a fused dihydrofurofuran configuration. The aflatoxins are highly fluorescent. The “B” refers to blue, the “G” signifies green fluorescence, while “M” aflatoxins are fungal metabolites present in milk, and “T” compounds are found in tobacco. Most of them are associated with various types of liver damage. Consumption of dietary aflatoxins varies from 10 to 200 ng/kg/day, though the recommended maximum daily intake should be less than 50 ng/kg/day. Aflatoxins are usually encountered in the context of chronic exposure, via food intake or secondary to the handling of foodstuffs. Aflatoxins have been incriminated in the pathogenesis of the following conditions: ■ Hepatitis, fatty liver, cirrhosis ■ Hepatocellular carcinoma ■ Hepatic failure ■ Reye’s syndrome ■ Kwashiorkor

15. MOA: Aflatoxins accumulate in the presence of liver disease, and the association with hepatic cancer is confounded by the occurrence of hepatitis B. The latter is not only a risk factor for liver cancer, but may also impair excretion of aflatoxins, causing further liver injury and DNA damage. Thus, it must be admitted that in these conditions it is not clear whether aflatoxin is a primary cause of the disease, is an incidental product that accumulates secondary to the disease process or is a contributing cause in association with other factors. INVESTIGATION/DIAGNOSIS: Aflatoxins can be detected in body fluids and tissues by RIA and ELISA. HPLC with fluorescence detection has also been used to detect and quantify aflatoxins in blood or tissue. Elevation of serum alkaline phosphatase is a good indicator of aflatoxin toxicity. In one study, there was a significant correlation between urinary levels of aflatoxins and the presence of hepatitis B surface antigen in serum, with the risk of an increased incidence of hepatocellular carcinoma. MANAGEMENT: Treatment is mostly supportive. In one experimental study involving ducklings which were given 5 micrograms of aflatoxin and 50 mg of turmeric for 14 days, increased weight gain was seen compared to controls. Almost complete reversal of fatty changes, granular degeneration, and necrosis was observed. Antioxidants such as vitamin A have been shown in vitro to inhibit aflatoxin-induced DNA adduct formation.

16. TRICHOTHECANS: These mycotoxins are produced by Fusarium roseum , F. moniliforme , F. nivale , and F. oxysporum . Other fungal genera that produce similar toxins include Myrothecium, Trichoderma, Cephalosporium , Verticimonosporium , and Stachybotrys . Over 100 trichothecenes have been identified. The most frequent natural contaminants are deoxynivalenol, diacetoxyscirpenol, HT-toxin, nivalenol, and T-2 toxin. Contamination of corn, sorghum, barley, or wheat with these toxins, is not uncommon leading to outbreaks of poisoning characterised by abdominal pain, throat irritation, vomiting, diarrhoea, vertigo, and headache. Trichothecene toxins are multi-toxins affecting many systems. Acute toxicity resembles the damage done by radiation, nitrogen mustard, or mitomycin C. Primary damage is to the GI tract, and lymphoid and haematopoietic systems. Symptoms include: Alimentary toxic aleukia, first identified in Siberia, has been associated, in humans, with the consumption of grain contaminated with T-2 toxin. The aleukia usually occurs in four stages: i . Hyperemia of the mucosa, accompanied by weakness, fever, nausea, and vomiting. In more severe cases, acute oesophagitis , gastritis, and gastroenteritis may occur. Seizures and circulatory failure may occur in rare instances. ii. The second stage is characterized by the development of leukopenia, granulopenia, and progressive lymphocytosis. iii. In the third stage, severe hemorrhagic diathesis, and necrotic pharyngitis and laryngitis can occur, resulting in death in some instances, by total occlusion of the larynx. Severe bone marrow suppression may also occur. iv. The fourth stage is characterized by recovery, though exposed individuals are susceptible to secondary infections. Visual disturbances and salivation have been reported in acute poisoning, as have conjunctivitis, rhinitis, pharyngitis, and epistaxis. Angina, tachycardia, and hypotension may occur. Conditions resembling septic shock, and poor perfusion of the GI system and other organs have also been reported. Treatment: Treatment involves the administration of activated charcoal, which may be beneficial in decontamination of the GI tract, and supportive measures for haemopoietic problems, GI damage, and skin damage.

17. Questions Write a note on mycotoxin poisoning. 2m Classify poisonous mushrooms. Write in detail about mushroom poisoning. 6m List out different poisonous mushrooms. 2m Write a note on mycotoxin poisoning. 10m Write about prevention and control of mycotoxin poisoning. 2m Give me a brief note on mushrooms. 5m Enumerate the clinical features and complications of fungal food poisoning. 5m Write the clinical symptoms of plant poisoning. Add a note on the treatment of plant poisoning. 10m List out mushroom species potentially toxic to human beings. 5m Treatment of mushroom poisoning. 5m