Refer to: Becker CE, Tong TG, Boerner U, et al: Diagnosis andtreatment of Amanita phalloides-type mushroom poison-ing-Use of thioctic acid. West J Med 125:100-109, Aug1976

Diagnosis and Treatment of AmanitaPhalloides-Type Mushroom PoisoningUse of Thioctic Acid

CHARLES E. BECKER, MD; THEODORE G. TONG, PharmD; UDO BOERNER, DSc;ROBERT L. ROE, MD; ROBERT A. T. SCOTT, MD, and MICHAEL B. MacQUARRIE, MD,San Francisco; and FREDERIC BARTTER, MD, Bethesda

The number of cases of mushroom poisoning is increasing as a result of theincreasing popularity of "wild" mushroom consumption. Amanitin and phal-loidin cytotoxins found in some Amanita and Galerina species produce themost severe and frequent life-threatening symptoms of Amanita phalloides-type poisoning. Delay in onset of symptoms, individual susceptibility variationand lack of rapid and reliable identification have contributed to the significantmorbidity and mortality of this type of poisoning.

A rapid chromatographic assay for identifying the potent cytotoxins andapparently successful management using thioctic acid of two cases of A. phal-loides-type mushroom poisoning are reported. All known cases of A. phal-loides-type mushroom poisoning treated with thioctic acid in the United Statesare summarized.

THE GATHERING AND EATING of wild mushroomsis a popular pastime in the United States, partlyowing to increased interest in "organic" foods andin the hallucinogenic substances found in certainspecies. Severe and life-threatening poisoningsfrom the ingestion of wild mushrooms have in-creased in frequency. Of the 2,000 or so speciesof mushrooms known to exist, fewer than 50 arepoisonous to man.' Many mushroom hunters be-

From the Medical Service (Drs. Becker, Tong, Roe, Scott andMacQuarrie), and the Toxicology Laboratory (Dr. Boerner), SanFrancisco General Hospital, and the 'Department of Medicine,SChool of Medicine (Drs. Becker and Roe), and the Division ofClinical Pharmacy, School of Pharmacy (Dr. Tong), University ofCalifornia, San Francisco, and the National Heart and Lung In-stitute, Bethesda, Maryland (Dr. Bartter).

Submitted December 4, 1975.Reprint requests to: Editorial Office, Room 4101, San Francisco

General Hospital, 1001 Potrero Avenue, San Francisco, CA 94110.

lieve that poisonous varieties can be identifiedeasily2'3 and many have the erroneous notion thatsome toxic species can be rendered harmless bycooking in a particular manner. As a result, evenexperienced mushroom seekers have been strickenwhen they harvested and ate poisonous varieties.From 1957 to 1964, 30 deaths from ingestion

of wild mushrooms were reported in the UnitedStates; 11 of these occurred in California.2 From1964 to 1974, 57 cases of mushroom poisoning,including eight deaths, occurred in Californiaalone (Table 1); 18 of the poisonings and fourof the deaths occurred in 1972.The principal toxins of the most poisonous

mushrooms are complex proteins containing

100 AUGUST 1976 * 125 * 2

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TABLE 2.-Diagnosis of Mushroom Poisoning

ToxicCause Constituents1'"0 Genus and Species Comments

Cellular Toxins AmanitinsPhalloidins

Amanita (Sp. phalloides,verna, virosa)

Found mostly in wooded areas, frequently duringlate summer and fall seasons. No obnoxious tasteor smell. Gastrointestinal symptoms occur 6 to24 hours after ingestion. A transient period of im-provement is followed by metabolic disturbancesand renal and hepatic impairment. Most fatalitiesoccur within several days. As little as one third ofa single cap can be fatal in a child. Mortality is40 to 90 percent. These species of Amanita ac-count for nearly 90 percent of all cases of severemushroom poisoning.

Amanitins Galerina (Sp. autumnalis,marginata, venenata)

These species are found in the western and mid-western United States on lawns, meadows, and de-caying wood. Symptoms are similar to those of A.phalloides-type poisoning. Despite absence of thephalloidin toxin, the mortality risk from ingestionof these species should be considered as significantas for A. phalloides due to presence of amanitin.

Enzyme Toxins Monomethyl-hydrazine(Gyromitrin)

Gyromita (Sp. esculenta)Helvella (Sp. esculenta,

underwoodii)

These species (except underwoodii) are not con-fined to any particular habitat or geographicregion. These mushrooms produce symptoms simi-lar to intoxication by amanitin but less severe,appearing 6 to 12 hours or more after ingestion.Symptoms are primarily gastrointestinal. Hemol-ysis and central nervous system effects are asso-ciated with these mushrooms. Certain people areresistant to their effects. Cooking may attenuatetoxicity. Estimated mortality is 2 to 4 percent.

Muscarine Inocybe (Sp. napipes)Clitocybe (Sp. rivulosa,

trunicola, cerussata,olearia, dealbata)

Toxins produce "muscarinic" effects, e.g. saliva-tion, lacrimation, nausea, bronchospasm, abdomi-nal pain, vomiting, diarrhea, headache and miosiswithin 15 to 30 minutes after ingestion. Brady-cardia, hypotension and shock may also occur.Death is infrequent. Treatment is primarily sup-portive and symptomatic. Atropine is a specificantidote for muscarine intoxication. There appearto be species differences because only some havecaused death.

IsoxazoleDerivatives:MuscimolMuscazoneIbotenic AcidPantherinTricholomic

Acid

Amanita (Sp. muscaria,

pantherina, cokeri, crenulata,solitaria)

Commonly fouind in wooded areas, especiallyconifer forests of western United States in springand fall. These mushrooms are also known as "flymushroom" or "fly agaric." These species havebeen associated with the toxin muscarine, but infact contain toxicologically insignificant quantitiesof it. They produce symptoms resembling the cen-tral nervous system effects of excessive atropineand display anticholinergic and mild hallucinogenicproperties. Symptoms occur within 1/4-2 hoursafter ingestion and frequently resemble alcoholintoxication. Severity and duration of symptomsvary with individual. Muscle spasms can occurafter ingestion of large quantities. Prognosis forrecovery is good. Avoid use of sedatives; atropineis contraindicated in treatment. Death is rare.

PsilocybinPsilocin

Psilocybe (Sp. cubensis,

eaerulescens, silvatica)Panaeolus (Sp. foenisecii

Psychotropic "LSD-like" manifestations begin about30 to 60 minutes after ingestion and may continuefor several hours. Recovery is spontaneous andusually within a day. Treatment is symptomatic.

102 AUGUST 1 976

NeurologicToxins

125 * 2

MUSHROOM POISONING

TABLE 2.-Diagnosis of Mushroom Poisoning (Continued)

ToxicCause Constituents'"" Genus and Species Comments

Gastrointestinal Not Yet *Boletus (Sp. satanas, eastwoodii) Irritating constituents have not been identified.Irritants Identified Clitocybe (Sp. nuda, illudens) Probably many toxins are involved. Mild to severe

Chlorophyllum (Sp. molybdites) nausea, vomiting, diarrhea, abdominal cramps, andRussula (Sp. emetica) other gastrointestinal symptoms occur 1/2 to 2Tricholoma (Sp. venenatum, hours after ingestion and may persist for several

pardinum) hours. The incidence and severity of gastrointesti-Catharellus (Sp. floccosus) nal symptoms are greater with raw mushrooms.Hebeloma (Sp. crystuliniforme) Treatment is supportive, and symptoms usuallyLactarius (Sp. torminosus, terminate spontaneously within a short time. Rare

glaucescens) fatalities have been reported.Naematoloma (Sp. fasciculare)Rhodophyllus (Sp. sinuatus)

Disulfiram-like Monomethyl- Coprinus (Sp. atramentarius) Disulfiram reaction-like symptoms of flushing,Constituents hydrazine palpitation, hyperventilation and tachycardia occur

only if alcohol is consumed in combination withthese mushrooms. These effects may take place upto 48 hours between ingestion of mushroom andalcohol and last for a short time. Gastrointestinalsymptoms of nausea, vomiting, and diarrhea havealso occurred. The severity of symptoms is greatestafter ingestion of raw mushrooms. Treatment issupportive and alcoholic beverages should beavoided.

*These species have been the most frequently associated with gastrointestinal irritants.

cyclic heptapeptides (phalloidins) and cyclicoctapeptides (amanitins).4 Phalloidin appears todisrupt hepatic cell membranes and to change thestructure of the hepatic endoplasmic reticulumadversely. The role of phalloidin in the produc-tion of symptoms and pathologic changes in theliver of a poisoned patient is unclear becausesome species now known to contain this cyclo-peptide and no amanitin have been consumedwithout causing the undue effects. The toxicity ofamanitin has been compared in vitro with that ofphalloidin and found to be 10 to 20 times greater.The amanitin is believed to be the major toxinresponsible for the symptoms and pathology fol-lowing the ingestion of Amanita phalloides-typemushrooms. This is best demonstrated by thetoxicity of some species of the Galerina mush-rooms that contain only amanitin. It has beenshown that amanitin inhibits the enzyme ribo-nucleic acid polymerase II and interferes with thesynthesis of messenger ribonucleic acid.5,6 Histo-chemical examination of hepatic cells after ex-posure to amanitin shows the presence of abnor-mal concentrations of lipids and carbohydrates inthe cell nuclei.78 Amanitin is also a direct-actingnephrotoxin that produces necrosis of the distaland proximal convoluted tubules.9Mushrooms containing phalloidin and amanitin

belong to the genera Amanita and Galerina, al-

though not all species of these genera containthese toxins (Table 2). In Europe, A. phallqidesis the most frequent cause of mushroom poison-ing; nearly 90 percent of all such deaths are at-tributed to A. phalloides, the "death cap."

In the United States, Amanita verna (the "de-stroying angel"), Amanita virosa and A. phal-loides are the common causes of mushroom poi-soning and death (90 percent). Recent deaths inCalifornia have been attributed to A. phalloides.Cases of severe mushroom poisoning by Galerinamarginata, autumnalis and venenata have oc-curred in this country but are infrequent.2 Poison-ing by the very toxic Amanita and Galerinaspecies will be referred to as A. phalloides-typepoisoning in this article.

There appears to be considerable variability inindividual susceptibility to the toxins of poisonousmushrooms.2 For instance, several members ofthe family of one of our patients (Case 1) ate themeal containing the offending mushrooms, butonly one other family member experienced anyill effects. Whether or not there is a quantity-con-sumed association to development of symptomsis unclear. Severity of symptoms has been thoughtto depend on the season and the state of matura-tion of the mushrooms when picked and eaten,the location where they were picked, and theamount ingested.2 There is no evidence to vali-

THE WESTERN JOURNAL OF MEDICINE 103

MUSHROOM POISONING

date this impression. Approximately 75 percentof the cases in California occurred in the fall,probably coincident to the season when thesepoisonous mushrooms are most abundant andeasily harvested.

During the past three years, we have managedfive patients; two are reported here. We consultedin three other cases of severe A. phalloides-typemushroom poisoning. The results of our expen-ence in identifying and treating A. phalloides-typemushroom poisoning are presented.

Diagnosis of Mushroom PoisoningThe time between ingestion and onset of symp-

toms and the type of systemic involvement (forexample, neurologic versus gastrointestinal) canbe helpful indexes for characterizing the type ofmushroom poisoning. Mushroom poisoning canbe divided into cases in which symptoms appearwithin several minutes to six hours after ingestionand those in which symptoms develop much later(Table 2).

TABLE 3.-Cases of Mushroom Poisonings Treated with Thioctic Acid (TA) in the United StatesCaseNo.Age Dose of TA Method of(year) and Duration Identification*Sex Year State of Treatment Mushroom (Result) Hospital Courset

1 .. 328 1973 California

2.. 87& 1974 California

3 .. 33 a 1974 California

4 .. 23 8 1974 California

300 mg X 6 days

100 mgX I daythen 300 mgX 6 days

100 mgX Idaythen 300 mgX 6 days

100 mg X I daythen 300 mgX 1 day

Amanita TLC (+) Refer to Case No. 1 described inphalloides mycologist text

A. phalloides

A. phalloides

TLC (+) Refer to Case No. 2 described inmycologist text

TLC (+) Admitted 12/30. Nausea, diarrhea,mycologist and vomiting beginning 12 to 16

hours after ingestion. Severe dehy-dration on admission. SGOT 728and 850 and SGPT 1,018 and 2,320units per ml. Treated with TA,glucose, and supportive measures.SGOT and SGPT returned to nor-mal levels during treatment. Dis-charged 1/17.

Chlorophyllum TLC (-)molybdites mycologist

Admitted 8/26. Abdominal pain,nausea, diarrhea, vomiting, andfever 2 hours after ingestion.SGOT 25, SGPT 20, LDH 210,CPK 70 units per ml, bilirubin(total) 1.0 mg per 100 ml. Treatedwith TA, glucose, and supportivemeasures. Discharged 8/29.

5 .. 409 1974 New York

6 ..508 1974 New York

100 mgX1I daythen 300 mgX 4 days

100 mgX Idaythen 300 mgX 2 days

Galerinaautunmalis

G. autumnalis

TLC (+) Admitted 10/30. Severe nausea,mycologist vomiting, diarrhea, and abdominal

cramps 10 hours after ingestion.BUN 23, serum creatinine 1.2, bili-rubin (total) 2.4 mg per 100 ml,SGOT 100, LDH 224 units perml, urine glucose +1, acetone+ 1. Treated with TA, glucose, andsupportive measures on day 2 oftreatment. Course otherwise un-complicated. Discharged 11/8.

TLC (+) Admitted 10/30. Nausea, vomiting,mycologist diarrhea, and abdominal cramps

12 hours after ingestion. BUN 45,serum creatinine 1.8, bilirubin(total) 1.2 mg per 100 ml, SGOT33, SGPT 36. Treated with TA,glucose and supportive measures.Course uncomplicated. Discharged11/4.

104 AUGUST 1976 * 125 * 2

MUSHROOM POISONING

TABLE 3.-Cases of Mushroom Poisonings Treated with Thioctic Acid (TA) in the United States (Continued)CaseNo.Age Dose of TA Method of

(year) and Duration Identification*Sex Year State of Treatment Mushroom (Result) Hospital Courset

7 .. 719 1974 Washington

8 .. 588 1972 Ohio

9 .. 249 1972 Ohio

10 14 mo 8 1972 Ohio

11 .. 52 9 1972 California

100 mgXlI daythen 300 mgX 5 days

300 mgX 13 days

300 mgX5 days

300 mg X 1 day

300 mg X 1 day

12 .. 35a 1970 Pennsylvania 300 mgX6 days

G. autumnalis TLC (+) Admitted 11/21. Nausea, vomiting,mycologist profuse diarrhea, tachycardia, and

slight abdominal pain 12 to 16hours after ingestion. Treated withTA, glucose, and supportive meas-ures. Course uncomplicated andlaboratory indexes were withinnormal limits. Discharged 12/1.

Amanita virosa mycologist Admitted 10/2. Severe hypoten-sion, vomiting, and diarrhea 6hours after ingestion. BUN 51,serum creatinine 4.5 mg per 100ml, SGOT 900, SGPT 1,750, LDH1,920 units per ml, Hct 58%.Complicated course requiring he-modialysis; biopsy revealed acutetubular necrosis, liver functiontests returned to normal values atcompletion of a 13 day course ofTA, glucose, and supportive meas-ures. Maculopapular rash and ery-thema multiforme of unknownetiology developed at completionof TA treatment. Discharged10/21.

A. virosa mycologist Admitted 10/3. Nausea, vomiting,and diarrhea of 1½2 day durationbeginning about 6 hours after in-gestion. Treated with TA, glucose,and supportive measures. Courseuncomplicated. Discharged 10/12.

A. phalloides mycologist Admitted 10/3. No symptoms. He-patic and renal functions normalthroughout. Treated with TA, glu-cose, and supportive measures.Course uneventful. Discharged10/8.

A. phalloides mycologist Admitted 11/5. Nausea, vomiting,diarrhea, and abdominal crampsdeveloped 12 hours after ingestion."Improved" on fourth day butthen became progressively disori-ented and obtundated. TA begunon day 7 after ingestion at "timeof cerebral death." Died on 11/14.

A. verna mycologist Admitted 11/15. Severe abdominalpain, nausea, vomiting, and diar-rhea developed 9 hours after inges-tion. Treated for 5 days with glu-cose and supportive measures.Liver function decreased: SGOT2,000+ units per ml and bilirubin(total) 7.6 mg per 190 ml. Con-dition complicated by hepatomeg-aly, ascites, and intermittent coma.TA started on day 8 after inges-tion. Liver function tests returnedto normal values by sixth day ofTA. Liver biopsy showed necrosiswith repair. Discharged 12/2.

*TLC = thin layer chromatography.iSGOT = serum glutamic oxaloacetic transaminase; SGPT = ser um glutamic pyruvate transaminase; LDH= lactic dehydrogenase;CPK=creatine phosphokinase; BUN=blood urea nitrogen, and Hct=hematocrit.

THE WESTERN JOURNAL OF MEDICINE 105

MUSHROOM POISONING

Most nonlethal poisonous mushrooms producesymptoms soon after ingestion, whereas A. phal-loides-type mushrooms produce life-threateningreactions 6 to 24 hours after ingestion. However,since a mixture of wild mushrooms is often in-gested; early onset of symptoms does not excludethe possibility of more serious poisoning. Poison-ing with immediate onset of symptoms is furtherdistinguishable by the type of symptoms; that is,gastrointestinal disturbance, parasympathetic stim-ulation and hallucinations. Such poisoning israrely serious, and recovery usually occurs within24 hours (Table 2).Symptoms of the more toxic A. phalloides-type

mushrooms characteristically occur in three stages.( 1 ) The first stage occurs abruptly, 6 to 24 hoursafter ingestion: abdominal pain, nausea, vomiting,diarrhea (occasionally bloody) and hematuria.These are frequently accompanied by fever, tach-ycardia, hyperglycemia, hypotension, dehydrationand electrolyte imbalance. (2) During the next24 to 48 hours (two to three days after ingestion),there appears to be remission of symptoms in theface of progressive deterioration of hepatic andrenal function. (3) During the subsequent 24 to48 hours (three to four day, after ingestion),hepatocellular damage and renal impairmentprogressively worsen, and jaundice, hypoglycemia,oliguria, delirium and confusion develop. Myocar-diopathy and coagulopathy may be present, andconvulsions, coma and death may occur. Themortality rate varies from 40 to 90 percent.,"1Death from A. phalloides-type poisoning is usu-ally the result of hepatic or renal failure orboth. 11-13

Because of the delayed onset of symptoms inA. phalloides-type poisoning, patients frequentlyfail to associate their symptoms with the ingestionof wild mushrooms. Therefore, a careful historyof the patient's activities before onset of symp-toms is imperative. Failure to suspect mushroompoisoning, to identify the more toxic A. phal-loides-type mushrooms and to implement earlytreatment contribute to the high morbidity andmortality associated with the ingestion of A. phal-loides-type mushrooms.

Morphologic and ToxicologicIdentification of Mushrooms

In a suspected case of mushroom poisoning,identification of the species by morphologic char-acteristics is a formidable task because the ap-pearance of the mushroom may be distorted by

handling and cooking. Attempts to identify themretrospectively by collecting mushrooms from thearea where the ingested ones were harvested isunreliable because poisonous species frequentlygrow in immediate proximity to nontoxic ones.Examination of fungus spores in the gastric con-tents may also be inconclusive. If poisoning byA. phalloides-type mushrooms is suspected, gas-tric contents, mushroom samples, and stool speci-mens, if available, should be assayed to verifythe presence of the amanitin and phalloidin toxins.To confirm the diagnosis of mushroom poison-

ing, we modified a thin-layer chromatographicassay that can rapidly detect the presence ofamanitin and phalloidin. (This assay is done inthe Toxicology Laboratory at San Francisco Gen-eral Hospital.) Vomitus, intestinal aspirate, stoolor uneaten specimens are dehydrated in a roto-vacuum evaporator. Fat is removed by refluxingwith benzene in a Soxhlet apparatus. The defattedmaterial is then extracted with methanol. Thisextract, containing the toxic cyclopeptides, istaken to dryness in vacuo and the residue is dis-solved in 2 ml of anhydrous methanol. Aliquotsof this extract are then spotted on commerciallyavailable 0.25 mm silica G-60 thin-layer chroma-tography plates.

For comparison, extracts prepared from A.phalloides mushroom and 5, 10 and 20 Mt1 ofalpha-amanitin and phalloidin (both as 0.1 per-cent solutions in methanol) are spotted as com-parison standards. The thin-layer chromato-graphic solvent system consists of a mixture of100 ml of glycol monobutylether, 85 ml concen-trated aqueous ammonia and 0.5 ml transcinna-maldehyde. The average time for the solvent frontto ascend 12 cm is approximately three hours.The plate while still moist is sprayed with 0.1percent fluorescamine in methanol. Fluorescaminereacts with the primary amino group of alpha-amanitin to form derivatives that fluoresce asbluish-white spots under ultraviolet light.

These are compared with the standards. Thesame chromatogram is then sprayed with 0.5 per-cent transcinnamaldehyde in methanol. The sol-vent is allowed to evaporate and the chroma-togram is exposed for 15 minutes to hydrogenchloride gas. The amanitin and phalloidin appearas bluish- to purplish-colored spots. The chroma-togram should be evaluated immediately becausethe color of the toxins fades rapidly. The solventsystem gives average relative distance (rf )values of 0.35 for alpha-amanitin, 0.31 for beta-

106 AUGUST 1976 * 125 * 2

MUSHROOM POISONING

amanitin, 0.50 for gamma-amanitin and 0.25 forphalloidin. Alpha-amanitin and phalloidin whenapplied as pure substances have a minimum de-tection limit of 50 jig and 80 to 100 /Ag respec-tively.

TreatmentEarly ModesNo specific treatment of A. phalloides-type

poisoning has been available in the past. Theonly treatment available has been supportive, in-cluding correction of fluid, metabolic and coagu-lation disturbances. Induction of emesis is notbeneficial, unless it is done soon after ingestion,because of the long interval between ingestionand the appearance of symptoms. Cathartics andactivated charcoal have been recommended,14 al-though there is no proof of their usefulness in thetreatment of A. phalloides-type poisoning. If used,they should be administered soon after ingestion.Numerous forms of therapy such as exchangetransfusion'3 and administration of large doses ofcorticosteroids15 or antiphalloidin antisera'6 havebeen used, but none has been shown to be moreeffective than supportive care. Hemodialysis hasbeen used successfully to treat renal failure,'2"16-'8but its effectiveness is not attributed simply to theremoval of amanitin and phalloidin. These toxinsappear to be poorly dialyzable when studied invitro; hemodialysis would not remove them effec-tively in the poisoning circumstance.

Studies with dogs given up to 0.044 mg of 14C.methyl alpha-amanitin per kg of body weight byintravenous injection showed that after five hours,the concentration in serum fell below detectionlimit, which is <0.3 percent of the toxin doseadministered. After six hours, 85 percent of theradioactivity associated with the toxin could beaccounted for in the urine.'9

Cytochrome C has protected mice given lethaldoses of amanitin from symptoms of poisoning.20Penicillin, phenylbutazone, chloramphenicol andsulfamethoxazole administered to animals poi-soned with amanitin resulted in improved survivalrates." It has been suggested that these com-pounds displace amanitin from plasma albuminbinding sites, thus enhancing renal excretion ofthe cyclopeptide toxin.

Thioctic AcidDuring the past ten years, the use of thioctic

acid (alpha lipoic acid) in the successful treat-ment of A. phalloides-type mushroom poisoning

has been reported enthusiastically in the Euro-pean literature.'5"18'22'23 Finestone and co-workersreported the first successful treatment of A. phal-loides-type mushroom poisoning with thioctic acidin the United States in 1968.'4'5 In their patient,eight days after ingestion of A. verna, 300 mg ofthioctic acid was infused intravenously over 24hours for three days. After 72 hours, the dosagewas tapered over six days and discontinued whenthe serum transaminase levels returned to normal.

Since 1968, thioctic acid has been used experi-mentally in the United States in 11 other patientswith A. phalloides-type poisoning. A review ofthese cases shows that in nearly all there waschemical and clinical evidence of hepatocellulardamage; ten of the patients recovered withoutmajor sequelae (Table 3).The only side effect of thioctic acid to date has

been hypoglycemia. Whether the hypoglycemiawas a direct effect of the drug26'27 or a result ofsevere hepatic damage2 secondary to mushroompoisoning remains unclear. To date, the only pa-tient in the United States who did not respondfavorably to thioctic acid as far as we know re-ceived the drug late in the course,'8 since thepatients in all other reports survived when giventhe drug two to three days after ingestion (exceptthat of Finestone and co-workers25). This indi-cates that early administration may be necessaryfor the drug to produce its effect.

Results of studies of thioctic acid use in animalsin which toxic effects were induced with amanitinare varied. In two studies, administration of thi-octic acid failed to reverse the toxic effects20'26and in one'6 hypoglycemia occurred. The signifi-cance of the hypoglycemia observed in man andanimals and the reported lack of effectiveness ofthioctic acid in animals need to be studied further.The investigational drug protocol approved by

the Food and Drug Administration for the use ofthioctic acid states that it should be used only inknown or strongly suspected cases of ingestion ofA. phalloides, A. virosa or A. verna mushrooms.29Although they are not included in the protocol,G. autumnalis, marginata and venenata containamanitin, and thioctic acid is appropriate treat-ment (Table 3) in poisonings by these mush-rooms as well.

Initially, 25 mg of thioctic acid in a solution ofglucose and water may be infused intravenouslyfour times a day. On the second day, dependingon clinical status, the dose may be increased to75 mg four times a day. This may be continued

THE WESTERN JOURNAL OF MEDICINE 107

MUSHROOM POISONING

for 14 days using findings on daily liver enzymefunction tests as a guide. Measurement of serumglutamic oxaloacetic transaminase (SGOT), glu-tamic pyruvic transaminase (SGPT), lactic dehy-drogenase (LDH), creatinine, blood urea nitro-gen and glucose levels and urinalysis should becarried out at least once a day and more fre-quently if necessary. Because thioctic acid issensitive to light and heat, bottles and infusionlines containing the solution must be covered.

The mechanism of action of thioctic acid inpatients with A. phalloides-type poisoning is un-clear. Lipoic acid is a component of coenzymesnecessary to oxidize ketoacids such as pyruvate.It has been suggested that (1) thioctic acid mayproduce its protective effect at the level of theenzymes of the Krebs cycle29 or (2) that thedisulfide constituents of thioctic acid form a com-plex with the cyclopeptides to modify their tox-icity.20'29

Because of the high morbidity and mortality ofA. phalloides-type poisoning, it would seem im-possible to conduct a random double-blind clini-cal study of thioctic acid. While the cases repre-sented here and the three in which we consultedcannot offer unequivocal evidence that thiocticacid was useful, they do shoW that the agent issafe to administer and apparently contributed tothe recovery of these patients despite clinical andchemical evidence of severe liver impairment be-fore it was given (Table 3). However, the con-tribution of intense supportive care is difficult toassess.

Since the chromatographic assay method nowenables specific and definitive diagnosis of A.phalloides-type mushroom poisoning and sincethioctic acid lacks significant toxicity, we believethat the use of thioctic acid concomitantly withvigorous supportive treatment in such cases isjustified. Except for the occurrence of hypogly-cemia, this agent appears to be safe when usedproperly. Despite the much larger initial dosegiven in Case 1 and the reported use of this drugfor over 13 days in another (Table 3, Case No.8), no ill effects have been observed. In Case2, a seven day course of thioctic acid was ad-ministered according to the protocol, and the re-sponse was impressive.

Reports of CasesCase 1. A 32-year-old man had been well un-

til March 2, 1973 when nausea, vomiting, feverand severe diarrhea developed 12 hours after he

had eaten four large wild mushrooms picked inFresno County, California. The family physicianadministered atropine and prochlorperazine, butthe nausea and vomiting persisted. The patientwas admitted to a local hospital with severe dehy-dration and oliguria. Laboratory data includedSGOT, 2,580; SGPT, 4,420 units per ml; totalbilirubin, 1.9 (direct, 1.3 and indirect, 0.6);blood urea nitrogen, 41, and creatinine, 1.9 mgper 100 ml.

The patient was transferred to the Universityof California Moffitt Hospital in San Francisco,where symptoms of severe hepatic injury con-tinued, although renal function returned towardnormal values. Because of strong suspicion thatthe mushrooms ingested by the patient were A.phalloides-type (subsequently confirmed by chro-matographic detection of alpha- and gamma-amanitins and phalloidin at the Toxicology Lab-oratory of San Francisco General Hospital) in-formed consent was obtained from the patient toadminister thioctic acid.A total of 300 mg per 24 hours in 10 percent

glucose in H20 were infused intravenously on daythree after ingestion. The patient's condition im-proved and there was resolution of symptoms.By the sixth day of thioctic acid administration,the following values were noted: total bilirubin,0.8 mg per 100 ml; direct bilirubin, 0.3 mg per100 ml; SGOT, 40 units, and SGPT, 250 units perml. Thioctic acid therapy was terminated and thepatient was discharged.

Case 2. An 87-year-old man had been in goodhealth until December 16, 1974 when severenausea, vomiting, profuse diarrhea, and cramp-ing pain of the arms, lower abdomen and legsdeveloped suddenly; he was admitted to a localhospital. The patient 22 hours before had eatenapproximately a half cup of mushrooms collectedin Santa Clara County. There was no excessivesalivation, lacrimation, photophobia or diplopiabut the patient was confused and disoriented. Hebecame progressively oliguric and was transferredto the University of California Moffitt Hospital inSan Francisco.On admission, the patient was alert and

oriented, but anorectic, nauseated and vomitingoccasionally. Prothrombin time was 15.4 seconds(control 11.4) and partial thromboplastin timewas 43.7 seconds (control 28.6). The serumcreatinine level was 4.4, glucose level was 208and blood urea nitrogen value was 43 mg per 100ml. Cooked and uncooked specimens of mush-

108 AUGUST 1976 * 125 * 2

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rooms collected by the patient were obtained forchromatographic analysis (also done at San Fran-cisco General Hospital's Toxicology Laboratory)and found to contain amanitin and phalloidin.

Treatment with thioctic acid, 25 mg every sixhours infused intravenously in 10 percent glucosein H20 or saline solution, and neomycin, 1 gramper day given orally, was started on day threeafter ingestion. After 24 hours, the dosage ofthioctic acid was increased to 75 mg every sixhours. On day two of thioctic acid therapy, levelsof blood urea nitrogen decreased to 39 andcreatinine to 2.1 mg per 100 ml. The followingclinical values were noted: SGOT, 2,160; SGPT,1,350; LDH, 4,640; alkaline phosphatase, 65 unitsper ml, bilirubin, 2.3 mg per 100 ml, andprothrombin time, 18.4 seconds (control 11.3).On day seven of thioctic acid therapy, administra-tion of the drug was discontinued because liverfunction tests had returned to normal values.On December 23, blood urea nitrogen and

serum creatinine levels were 73 and 14.8 mg per100 ml, respectively; hemodialysis was begun. OnDecember 30, findings on liver function tests hadreturned to within normal limits except for slighthypoalbuminemia and an elevated alkaline phos-phatase level. Dialysis was carried out on threesubsequent occasions (January 2, 6 and 10). OnJanuary 23, 1975, renal function was stable, withblood urea nitrogen levels varying between 100and 110 and serum creatinine levels between 7and 8 mg per 100 ml, and except for a persist-ently elevated alkaline phosphatase level, findingson liver function tests had returned to the normalrange and gastrointestinal bleeding, atrial fibrilla-tion, and pericardial and pleural effusions hadsuccessfully resolved; the patient was discharged.

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