Mushroom poisoning caused by species of the genus Cortinarius Fries

Arch Toxicol (1983) 53:87-106 Ardalvu of

TOXICOLOGY �9 Springer-Verlag 1983

Review

Mushroom Poisoning Caused by Species of the Genus Cortinarius Fries

Trond Schumacher and Klaus H~iland

Botanical Institute, Box 1045, Blindern, Oslo 3 Botanical Garden and Museum, Trondheimsveien 23 B, Oslo 5, Norway

Abstract. Symptomatology, clinical characteristics and pathogenesis of mushroom poisoning caused by Cort inarius species are surveyed. The isolation of a bipyridilium - orellanine - from Cort inar ius ore l lanus is held to be responsible for the nephrotoxicity of this species as well as the closely related C. spec ios i ss imus . The present knowledge on the toxicity of structurally related and well-known bipyridines such as paraquat and diquat is brought up and found comparable to orellanine toxicity. Pharmacokinetic experiments on the nephrotoxic bipyridines suggest that haemoperfusion is a rational therapy of intoxicated persons, even several days after mushroom ingestion.

Key words: Cortinarius toxins - Poisonous Cort inar ius - Cort inar ius

ore l lanus - Cort inar ius spec ios i s s imus - Orellanine

Introduction

In the last decade toxic mushrooms have been given much attention, thus resulting in a considerable increase of knowledge. This has elicited several review articles (cf. Lampe 1979), and the first interdisciplinary textbooks on mushroom poisonings and toxic mushrooms have also appeared (Gulden and Schumacher 1977; Lincoff and Mitchell 1977; Rumack and Salzman 1978). There is, however, one specific and extremely severe type of poisoning due to some species of the genus Cort inar ius , which has been only briefly mentioned in these works, even though the toxicity of these mushrooms has been repeatedly demonstrated. Furthermore, recent chemical studies on the nature of the toxins in the deadly poisonous species of Cort inarius have made it possible to understand some aspects of their toxicity, also giving suggestions for a better therapy. In this paper the documentations of and the more important contributions to the toxicity of these species are given in an attempt to add to the present knowledge of this type of mushroom poisoning.

88 Trond Schumacher and Klaus H~iland

Acc identa l Po i son ings - His tory

In 1952 a remarkable epidemic appeared within certain families in a small area in the Konin province Poland. 102 persons (63 females and 39 males) were suddenly taken ill with symptoms such as an excessive thirst, a dryness and a burning pain in the mouth, gastric and abdominal pains, nausea, emesis, chills, and pains in the loins. Some of the victims also got headaches, constipation or diarrhoea and muscular pains. A group of 24 developed severe oliguria or even anuria and were brought to hospital, where the condition of an acute renal failure was ascertained. Sixteen persons soon developed critical uremic symptoms and 11 patients died 6-167 days after the onset of the disease. The possibility of a kind of infectious agent being responsible for the epidemic was ventilated, but was soon excluded. However, through some careful interviews of the patients and the bereaved families it turned out that the victims had eaten a medium-sized reddish-brown mushroom some days earlier, a mushroom which occurred in large numbers in the area that particular year. The time lag between ingestion of the mushroom and the onset of the disease was however exceptionally long, from 3-14 days, and far exceeded the period of latency for the various types of mushroom poisoning known at that time. Nevertheless, the fact that they all had eaten an unidentified mushroom the preceding days was indeed suspicious. Therefore, the mushroom was collected and tested experimentally on cats and rabbits, and the animals died 5-12 days after both oral and intraperitoneal administration. The histopathological findings from autopsy material of the kidneys were similar to those found in the human victims. In 1955 a Polish physician and hygienist, S. Grzymala, could present the results at a local conference on epidemiology and hygiene in Poznan.

A new type of mushroom poisoning with two remarkable characteristics had been observed: The mushroom had primarily nephrotoxic effects, and the time lag between ingestion of the mushroom and the initial symptoms was from 3 to 14 days.

In the years 1955 and 1957 some new cases of this type of poisoning were observed in Poland, and now the mushroom was identified as Cortinarius orellanus Fr. (Skirgiello and Nespiak 1957, 1958). In a first paper Grzymala reported on 136 cases of poisoning with 23 fatalities, the earliest was back in 1938 (Grzymala 1957), and several articles followed on clinics and new incidents of poisoning by C. orellanus in Poland (Grzymala 1958a, b, c; 1959a, b; 1964a; 1965a; Wysocki et al. 1958). In this period 144 cases of poisoning due to C. orellanus were reported, out of which 25 were fatal.

The toxicity and clinical characteristics of this new type of mushroom poisoning were soon quoted by contemporary European mycologists, a.o. by Heim (1963) and Moser (1969a, b; 1971). Heim (1963) referred it to what he called a 'paraphalloid syndrome' type, due to the delayed onset of symptoms and the serious course, thus resembling poisoning by Arnanita phalloides. Moser (1971) also referred to a case of poisoning in Germany, where two persons received serious renal failure after the ingestion of presumably Cortinarius speciosissimus, a species close to and in the same section (Orellanei) as C. orellanus. During the last ten years new incidents of poisoning due to

Mushroom Poisoning Caused by Species of the Genus Cortinarius Fries 89

C. orellanus and C. speciosissimus have been recorded from Europe; by C. orellanus from Switzerland (Favre et al. 1976; Leski et al. 1976), FRG (Velvart in Leski et al. 1976; F/irber and Feldmeier 1977), France (Marichal et al. 1977) and Czechoslovakia (Stredov~i et al. 1978), - by C. speciosissimus from France (Traverso 1973), Finland (Hulmi et al. 1974; Harmaja 1973; Kuhlb/ick in Heath et al. 1980), Sweden (Heath et al. 1980), Scotland (Short et al. 1980) and Norway (Fauchald and Westlie 1982; Hr and Schumacher 1982). Altogether 180 cases of poisoning have been attributed to these two mushrooms. In Norway C. speciosissimus possibly provoked renal failure and death among sheep in pasture too (Over~s et al. 1979).

A third species of Cortinarius, C. splendens, has recently been held responsible for human poisoning in France (Chapuis 1980; Gerault 1981), giving the same symptomatology as for C. orellanus/speciosissimus-poisoning. If this is correct, this type of mushroom poisoning is not restricted to members of the generic section Orellanei, but also includes a representative of the section Phlegmacium.

Cortinarius venenosus is a Japanese species, which has brought about three fatal poisonings (Kawamura 1970). It was also found to be lethal to rabbits. From the description and illustrations provided (Kawamura 1970), this is probably not a true member of the genus Cortinarius, but rather a representative of the genus Galerina, which a.o. embraces deadly poisonous amatoxin- containing species (Tyler et al. 1963).

The experiences gathered on the clinical picture of C. orellanus/speciosissimus-poisoning makes it very reasonable to suggest that these mushrooms might have been responsible for some cases of renal failure of unknown origin. In literature, Myler et al. (1964) describes an incident of mushroom poisoning from North America, referred to the ingestion of an Amanita phaUoides-like mushroom, which is rather suggestive of Cortinarius poisoning. The clinical picture described, of an acute, oliguric, renal failure with progressive uremic symptoms without a hepato-biliar affection is almost diagnostic of this type of mushroom poisoning (see symptomatology section below). Lampe (1979) also gave attention to this 'atypical' incident of a severe mushroom poisoning, but presumably referred it to the case when only small amounts of an amatoxin-containing mushroom had been ingested. The Cortinarius species of North America are not known very well, but according to McKenny and Stuntz (1971) C. orellanus is known from the continent.

Experimental Studies on the Toxicity of Cortinarius Species

Grzymala (1957; 1959b; 1961a; 1962; 1964b; 1965b) was the first to demonstrate experimentally the toxicity of C. orellanus and its isolated toxin - orellanine - on test animals. Experiments were carried out with cats, rabbits, guinea pigs, mice, and dogs with comparable results in toxicity and histo-pathological changes on sections. The kidneys were the severely-injured organ held responsible for the lethality. Macroscopically they were enlarged with capsular bleedings, and a microscopic examination revealed a picture of 'toxic nephrosis'

90 Trond Schumacher and Klaus Hr

(tubular nephrosis) and interstitial nephritis, with a massive infiltration of lymphocytes in the renal parenchyma. Minor changes of hyperemia, hemor- rhagias, edemas, patchy cell degenerations, and invasion of inflammatory cells were detected in most organ systems; the liver in some animals also with foci of necrotic cells. According to Grzymala (1965b) the visible changes started in the liver and the adrenal glands, while kidney injuries were detectable after 2 -5 days. Damage and death were dose-related, and fresh, dried, stored, or boiled mushroom material gave the same toxicity. Material collected in different periods and different places gave no significant differences in toxicity.

Meanwhile, Pouchet (1960), Coulet et al. (1961) and Andraud et al. (1965) had demonstrated the toxicity of C. orellanus from France with comparable results. Later experiments carried out by Oddoux et al. (1966), Viallier et al. (1965; 1968), Testa (1970), Antkowiak and Gessner (1975), Gamper (1977) and K/irnsteiner and Moser (1981) have all confirmed the toxicity of C. orellanus or its toxin in isolation (see chemistry section below). Viallier et al. (1968) also demonstrated that the closely-related C. speciosissimus and C. orellanoides had toxic effects similar to C. orellanus. Animal experiments on the nephrotoxicity of C. speciosissimus were also carried out by Luft (in Moser 1971), Traverso (1973), Hulmi et al. (1974) and Nieminen (1976b).

Several studies of the toxicity of C. speciosissimus in rats were carried out by Nieminen and collaborators (Mrttrnen et al. 1975; Nieminen et al. 1975; Nieminen and Pyy 1976a, 1976b). They could demonstrate both an individual variation and marked sex differences in the renal damage caused by the mushroom. The toxicity of different specimens of C. speciosissimus also varied greatly. In male rats the first signs of renal damage were peritubular, cellular infiltrates occurring in the outer medullary zone, observed 2 days after the administration of the mushroom. After 4 days loci of inflammation were also visible in the inner cortex, and a subsequent necrotic damage of the tubular epithelial cells within the regions of inflammatory loci was observed. Both tubuli and collecting ducts were partly dilated, the epithelial cells of which were flat and atrophic. The changes in the outer cortex were less marked, but some of the proximal and distal convoluted tubuli were dilated and necrotic. Changes in the glomeruli were not observed. After a weak scar formation was observed and the number of inflammatory cells was noticeable reduced, however, a few small inflammatory foci in which scar formation had not yet begun, appeared in the inner cortex. In female rats the main or only lesions seen were interstitial infiltration and necrotic changes of the inner cortex, which appeared earlier (1-2 days) and were more severe than those observed in the males. Inflammatory foci in the medulla were occasionally found. The fully-developed histo-pathological picture was that of a tubulo-interstitial nephritis, comparable to the lesions found in C. orellanus-injuried kidneys. The kidney was the only affected organ by C. speciosissimus in rats.

In order to see whether the toxicity of C. speciosissimus would change under the influence of certain drugs, Nieminen and collaborators studied the concomitant effects of furosemid, phenobarbital, phenyl-butazone, and cyclophosphamide in C. speciosissimus-intoxicated rats (Nieminen et al. 1976a, 1976b; Nieminen 1976a). Administration of furosemid (potent, fast-acting


diuretic), or a pretreatment with phenobarbital (capacity-enhancing on liver metabolism) potentiated the cortical, tubular damage of the rat kidneys induced by the mushroom, while phenylbutazone (strong protein-binding agent) had no effect on the results. Cyclophosphamide (an immuno-suppressive), given at the same time as the mushroom, very effectively prevented the renal inflammatory reactions induced by the mushroom, and the only lesions observed were some dilated collecting ducts in the outer medullary zone of the kidney, the epithelia of which were either in regenerative mitosis or were atrophic.

M6tt6nen et al. (1975) also reported Cortinarius gentilis to be nephrotoxic in rats. However, the experiments were carried out on six individuals, out of which five got no signs of renal damage, while the sixth developed slightly-dilated convoluted tubuli and a mild peritubular inflammation, but no changes in the interstitium or glomeruli. Supported by the chromatographic evaluation of the chemical constituents of C. gentilis (Hr 1980), there is in fact little evidence as to the toxicity of this species, and new experiments must be undertaken to show whether C. gentilis is toxic or not. Based on toxicological studies on mice Viallier and collaborators concluded that Cortinarius cinnamomeus, C. malicorius, C. phoeniceus and C. sanguineus were also slightly nephrotoxic, however, not in a way comparable to C. orellanus and C. speciosissimus (Viallier et al. 1968). According to Gerault (1981) Cortinarius splendens gave nephrotoxic effects in rats, comparable to those described for C. orellanus and C. speciosissimus.

Literary Statements of Toxic Cortinarius Species

Quite a few species of Cortinarius have been suspected as being poisonous (Moser 1969a; 1978; Nespiak et al. 1973; Gerault 1976; Cetto 1978; Azema 1981; Flammer 1982). The assumptions are partly based on a chemo-chromatographic screening of the pertinent species, and partly on the fact of close infrageneric relationship to the proved toxic ones. A recent survey of the various species is given by Kubi6ka (1980), with the addition of three species, viz. Cortinarius atrovirens, C. majusculus and C. vitellinus, by subsequent authors (Azema 1981; Flammer 1982). It should be emphasized, though, that the presumed toxicity of all these species has never been demonstrated, neither accidentally nor experimentally.

Chemistry

The first attempts to isolate toxic components from C. orellanus were made by Grzymala (1961b; 1962; Grzymala and Fiksinski 1960). He succeeded in isolating a slightly acidic, pale yellowish-brown crude substance - orellanine - amounting to 1% of dried mushroom, which on test animals produced the same toxic effects as the mushroom. LDs0 (mice) is calculated to 8.3mg/kg (Antkowiak and Gessner 1978). A purification of the crude extract was carried out by Antkowiak and Gessner (1975). In its pure form orellanine is a colourless

92 Trond Schumacher and Klaus H0iland

r Orel lanine

Fig. 1. Chemical structures of orellanine and orelline

OH OH

Ore l l i ne

substance, which resists heating to 150 ~ C, then decomposes to yield a non-toxic substance for which the name orelline is proposed (Antkowiak and Gessner 1978; 1979). Orelline has also been detected in crude extracts from the mushroom (Antkowiak and Gessner 1979). With the aid of gel filtration and chromatography Antkowiak and Gessner (1975) separated three fractions of orellanine, Or b Or n and Oqn, which were products of decomposition. Or I and Or n were found to be physiologically active, causing kidney - and liver damage and cutaneous lesions after parenteral administration in mice, while oral application gave no pathological changes.

The chemical structures of orellanine and orelline have recently been elucidated (Antkowiak and Gessner 1978; 1979). Both are bipyridines, -orellanine a 2,2'-bipyridine-3,3' ,4,4'-tetrol- 1, l'-dioxide-, -orelline a 2,2'-bipyridine-3,3',4,4'-tetrol - , and they appear in two tautomeric configurations (Fig. 1).

Gamper (1977) and Kfirnsteiner and Moser (1981) isolated both a slow and a fast acting toxin from C. orellanus, however, without giving any details on their pathological effects. The slow acting toxin exhibited almost similar chemical properties as orellanine (cf. Antkowiak and Gessner 1975; 1978), and is probably identical to, or a slightly decomposed product of orellanine. In their work Ktirnsteiner and Moser (1981) have disputed the structure of orellanine, although their own results seem to support the conclusions made by Antkowiak and Gessner (1978; 1979). Their isolated slow-acting toxin has the chemical characteristics of an aromatic compound, with indications of a nitrogen-het- erocyclic ring system, and with phenolic and strong reducing properties. Even solubility characteristics are similar in orellanine and the slow-acting toxin, although the latter is said to be more easily dissolved in water than orellanine. In


Table 1. Applied procedures in some recent chromatographic investigations of chemical constituents of Cortinarius species

Authors Wash-Liquid Substrate

Gruber ( 1 9 6 9 ) Isoamylalcohol : pyridine: Paper water (30 : 20 : 15)

Testa (1970) Cyclohexane : ethylacetate (3 : 1) Silica-gel Antkowiak and Isopropanol : conc. HC1 : water Paper Gessner (1975) (85 : 22 : 18) Schumacher and Hexane : ethylacetate (3 : 1) Silica-gel H0iland (1978) H0iland (1980) Silica-gel Ethylformiate : formic acid :

toluene (50 : 15 : 35), saturated with water

K/irnsteiner and N-butanol : acetic acid : water Silica-gel Moser (1981) (3 : 1 : 1) and some other polar and cellulose

wash liquids

U V light both Antkowiak and Gessner (1975) and Kiirnsteiner and Moser (1981) observed a delayed bright turquoise-blue fluorescence of their toxin, a phenomenon rather characteristic when dealing with 2,2'-bipyridines, where U V irradiation produces photochemical degradation products, among others mono- pyridone, which is intense blue fluorescent when present even in negligible amounts (Calderbank and Slade 1976). The formation of a grey-blue product seen in an acidic solution of the toxin and FeCI3 (Kiirnsteiner and Moser 1981), is also observed in Fe3+-bipyridine-complexes (Heslop and Robinson 1963). In addition to the chemical evidence of a 2,2'-bipyridine structure of orellanine, the toxic effects of orellanine and welt-known bipyridines, such as for instance paraquat (a 4,4'-bipyridine) and diquat (a 2,2'-bipyridine), are comparable (see pathogenesis section below).

For the t ime being there has been no serious investigations of the toxins of other toxic Cortinarius species. Judged f rom toxicity studies, clinical features and chromatographic evaluation of extracts of C. speciosissimus there seems to be little doubt that this species contains orellanine too (Gruber 1969; Schumacher and H0iland 1978; H0iland 1980). This seems also to be the case in Cortinarius fluorescens, a South-American species with a chromatogram similar to that of C. orellanus and C. speciosissimus (Gruber 1969).

In literature there has been a lot of confusion concerning the substance groups and their possible toxicity in C. orellanus, C. speciosissimus and the other close Cortinarius species. The toxic components of the tested species have been variably attr ibuted to the presence of some blue to blue-green fluorescent spots during U V irradiation on chromatograms, however, without a standard- ization of the applied evaluation procedures. Thus, the results are not always comparable . In Table 1 the chromatographic procedures used in some contemporary studies are given. All chromatograms gave some blue to blue-green fluorescent fractions in U V irradiation. Especially the works of

94 Trond Schumacher and Klaus Hoiland

Gruber (1969), Antkowiak and Gessner (1975) and Kiirnsteiner and Moser (1981) show great similarities. They all used highly polar washing liquids and the developed chromatograms all exhibited two main bluish fluorescent spots. According to Antkowiak and Gessner (1975) orellanine is present in the upper of these, while orelline is represented in the lower. This upper fluorescent substance group was incubated in mice and gave delayed toxic effects and death to the animals (Antkowiak and Gessner 1975; Kiirnsteiner and Moser 1981). Testa (1970), when using a slightly polar eluation liquid, obtained 10 different fractions on chromatograms of C. orellanus. He suggested that they all represented toxic fractions of orellanine and indicated a polypeptide structure of the components. Four of his fractions, which gave a distinct fluorescence in UV light, were named grzymaline, benzonine a and b, and cortinarine. Later investigations could not verify Testa's results (Antkowiak and Gessner 1975; Gamper 1977), and it is accepted today that the substance groups isolated by Testa, which are present in many Cortinarius species (Schumacher and H~iland 1978; H~iland 1980), are not constituents of oreUanine (Antkowiak and Gessner 1975; K~rnsteiner and Moser 1981). The chromatograms of C. orellanus and C. speciosissimus published by H~iland (1980) also contained some fluorescent spots in addition to those of Gruber (1969), Antkowiak and Gessner (1975) and Kfirnsteiner and Moser (1981).

Based on the chemical characteristics of orellanine, there seems to be two simple methods to detect orellanine from Cortinarius species:

1. The Fe3+-orellanine reaction could be useful for both mycologists and medical personnel for demonstrating whether an unknown Cortinarius contains orellanine or not. A piece of fresh or dried mushroom is crushed and mixed with five parts of water, left to stand for 10 min at room temperature, and filtrated. The filtrate is mixed with an equal amount of 3% FeCI 3 �9 6 H20 in 0.5 N HC1. The solution turns dark grey-blue, like diluted ink, if the unknown Cortinarius species contains orellanine.

2. From the chromatographic behaviour of orellanine, a simplified procedure of detecting orellanine is as follows: A small piece of dried fungus is crushed and extracted in 50% ethanol, allowed to stand for 15 min at room temperature, and then the extract is applied to a silica gel plate (Merck 60) and chromatographically developed by a washing liquid of n-butanol:acetic acid : water (3 : 1 : 1). After drying, the plate is sprayed with 2% FeCI 3 in 0.5 N HCI. Orellanine then appears as a grey-blue tail-like halo from the application point and up to R~ 0.25-0.5.

A preliminary screening of material of Cortinarius orellanus, C. speciosissimus, C. gentilis, C. cinnamomeus, C. malicorius, C. phoeniceus and C. sanguineus according to the above procedures has been performed by the present authors. Cortinarius orellanus and C. speciosissimus gave positive reactions on orellanine, while the other species did not. Cortinarius orellanoides and C. splendens have not been tested yet, neither have the many presumptively toxic species listed by Kubi6ka (1980), Azema (1981) and Flammer (1982). A full scale screening of all Cortinarius species for orellanine should be performed. Among the presumptively toxic species of the genus, the isolation of potentially toxic antraquinone-derivatives in some of them (Steglich et al. 1969; Steglich and


Topfer-Petersen 1973) has been cited in support for a possible toxicity in these species. Such an interconnection has, however, never been demonstrated. The chemical support for additional toxic substance groups, besides orellanine, which might give some similar or quite different types of mushroom poisoning in man, is at present rather poor. Thus, in the following sections the discussion is restricted to the only documented type of mushroom poisoning caused by Cortinarius species, namely the extremely serious type of poisoning caused by the orellanine-containing representatives of the genus.

Symptomatology and Clinical Characteristics

The clinical features of C. orellanus poisoning are well-documented through the works of Grzymala (1958a, b, c; 1959a, b; 1964a; 1965a, b, c). The hallmarks for this type of mushroom poisoning are the long latent period of 2-17 days between the ingestion of the mushroom and the onset of symptoms, and the clinical characteristics of an acute, renal failure.

In a material of 135 intoxicated persons, Grzymala (1965b) demonstrated a connection in symptomatology and severity of the poisoning on the one hand and the latent period before the onset of symptoms on the other hand. A short latent period before the initial symptoms appear is indiciative of a more severe poisoning and serious clinical course than a long incubation. Grzymala described three clinical groups and courses. The mildest type, seen in 19 persons, was characterized by a delayed onset, 10-17 days after ingestion, with thirst and a burning dryness in the mouth, followed by a temporary increase in urine output and a rapid recovery within days. A more serious poisoning was observed in 76 cases, with a latent period of 3 -4 days and initial symptoms such as nausea, emesis, headache, chills, and constipation, in addition to the symptoms above. Oliguria, loin pain and demonstration of protein, blood, cells, and other urine precipitates soon occurred, however, without serious dysfunction of the kidneys apparent in blood tests. The reconvalescent period was from 3 -4 weeks, usually without the need of hospitalization. The most serious group, represented by 40 out of 135, developed an acute, renal failure and uremic symptoms from 3-20 days after mushroom ingestion. The first symptoms appeared after 2 -3 days and were similar to the second group above. One half of the intoxicated persons in this group died from 4-16 days after the mushroom meal, while the other half recovered after from 2 months to 21/2 years, some also ended up with persistent symptoms of chronic renal failure. In another paper Grzymala (1959b) also gave a summary of the various symptoms and complaints of 132 intoxicated persons. The more important, which were observed in more than one-third of the patients, are given in Table 2.

Later case reports on poisonings due to both C. orellanus and C. speciosissimus have confirmed the clinical characteristics as outlined by Grzymala (Hulmi et al. 1974; Marichal et al. 1977; Ffirber and Feldmeier 1977; Short et al. 1980; Fauchald and Westlie 1982). Due to the new possibilities of a more adequate treatment, however, the advanced uremic symptoms are no longer a part of the clinical picture. From the many documentations of


Table 2. Subjective complaints in poisoning by Cortinarius orellanus (from Grzymala 1959b).

Symptoms Number of total (132)

Excessive thirst 130 Nausea 107 Dryness and burning in mouth 97 Vomiting 93 Headache 87 Chills 77 Loin pain 75 Abdominal pain 75 Tinnitus 49

Less frequent symptoms were constipation, diarrhoea, skin rashes, muscular pains, hyperhidrosis, edema, dyspnea, and somnolens.

poisonings by these two fungi in recent years, it seems possible to recognize a typical, serious intoxication as follows: The symptoms appear from 2 -6 days after ingestion of the mushroom. The onset is sudden with nausea and emesis accompanied by gastric and abdominal pains. The gastric complaints may get better or persist, but after a short period a burning thirst, anorexia, muscular and pronounced bilateral loin pains develop, usually accompanied by headaches, night sweat and chills. The patient commonly thinks he has got an epidemic, communicable disease, for instance influenza, and usually stays in bed for days before enervation and complaints force him to the physician and hospital. In poisonings due to C. speciosissimus, most cases have not been admitted to hospital before 8-14 days after mushroom ingestion, and then the clinical picture is that of an acute, oliguric renal failure. Cases of non-oliguric renal insufficiency have also been observed, and seem to have a better prognosis (Grzymala 1959b; 1965a; Short et al. 1980; Fauchald and Westlie 1982).

When renal biopsy has been performed, the histo-pathological findings have been those of a tubulo-interstitial nephritis with focal tubular damage, interstitial edema, and patchy infiltration of lymphocytes, plasma cells, and some polymorphs, with a subsequent development of fibrotic tissue (F~irber and Feldmeier 1977; Marichal et al. 1977; Short et al. 1980), a picture coalescent with that described from test animals. However, in some cases a slight glomerular affection with a diffuse, proliferative glomerulitis, and mesangial cell reactions has also been observed (Marichal et al. 1977; Short et al. 1980). These findings coincide with those described in autopsy material (Grzymala 1959b). Immu- nofluorescence studies of renal tissue have mostly been negative, but in some cases deposition of complement (C3) and IgA in glomeruli, and IgG, IgA and fibrin in tubular casts have been demonstrated (Marichal et al. 1977; Short et al. 1980).

An important, almost consistent clinical feature of C. orellanus/speciosissimus poisoning, which makes an exclusion of the other serious, well-known types of mushroom poisoning possible, is the lack of clinical evidence of a liver


engagement. In poisonings due to C. speciosissimus, hepatocellular damage has never been demonstrated while in C. orellanus just a few cases have been observed (Grzymala 1959b, 1965a; Marichal et al. 1977; Favre et al. 1976). This has been regarded as a possible difference between C. orellanus- and C. speciosissimus poisonings (Short et al. 1980; Jensen 1981). When Grzymala concluded that there were signs of a hepato-biliar engagement in C. orellanus poisonings, this was mainly based on postmortem examinations, where in some cases liver enlargement, fatty degeneration and some necrotic patches in liver cells were observed. Clinically, only three intoxicated persons were recorded with subicterus (out of 135), although a hyperbilirubinemia was never demonstrated (Grzymala 1959b; 1965a). According to Grzymala, however, the initial emesis and abdominal pains were signs of a hepato-biliar affection, which is not necessarily the whole truth. As apparent from the clinical casuistics reported, the liver affection, when present, is mild and transient during the first declining days and passes at a subclinical level (F/irber and Feldmeier 1977; Marichal et al. 1977). The records of C. orellanus poisonings from Switzerland (Favre et al. 1976; Leski et al. 1976) are not typical for this type of mushroom poisoning. The clinical pictures of a relatively short incubation period (4 -9 h), an initial enteritis, and a demonstration of severe hepatocellular damage with subsequent acute renal failure (cf. Favre et al. 1976) are more indicative of the amatoxin-type of mushroom poisoning, as seen after the ingestion of some Amanita, Lepiota or Galerina species. Judged from the clinical picture and the shortage of a proper identification of the ingested mushrooms, we assume that C. orellanus was not responsible for these poisonings. The disability of demonstrating a liver engagement in C. orellanus/speciosissimus poisoning is typical. Whether a subclinical, mild liver affection is a consistent feature during the first declining days, before hospitalization, remains to be cleared up.

Pathogenesis

Little is known about the pathogenetic mechanisms involved in Cortinarius orellanus/speciosissimus-poisoning. Andraud et al. (1965) observed that extracts of Cortinarius orellanus diminished the number of sulfhydrilic groups in renal and hepatic tissue, an effect they attributed to a presumably lactonic property of the toxin.

K/irnsteiner and Moser (1981) refers to some preliminary studies where an isolated toxin from C. orellanus is said to inhibit DNA-dependent RNA polymerase B from rat liver and RNA from Escherichia coli.

Based on the histo-pathological findings and the concomitant drug-mediated effects in the kidneys of Cortinarius speciosissimus-intoxicated rats, Nieminen and collaborators also made some suggestions and conclusions both with regard to the primary sites of actions of the 'toxins' and the possible mechanisms involved. An attempt to make a coherent account of the results of their experiments is found in Nieminen (1976b). The fact that the only visible lesions of the kidneys in cyclophosphamide - treated male rats were epithelial cell


injuries and dilatation of collecting ducts of the medullary zone, was cited in support of the epithelial cells of medullary collecting ducts being the primary site of action of the Cortinarius toxins (Nieminen 1976b). In male rats, the mushroom-induced damage of tubular epithelial cells of inner cortex, which was effectively prevented by cyclophosphamide, was maintained as a probable secondary change, induced by the inflammatory loci in the outer medullary zone (Nieminen et al. 1975). However, because this cortical necrosis was the only lesions observed in female rats, the idea that it still had to be a direct effect of the toxins was heightened (Nieminen and Pyy 1976). Supported by experiments on phenobarbital-treated, C. speciosissimus-intoxicated rats, Nieminen (1976b) suggested that the two different types of damage observed - in medulla and cortex respectively - were caused by different toxins with different metabolic properties. This was so as phenobarbital effectively increased the renal tubular damage of cortex in the female rat, while it had no effect on the inflammatory response in the outer medullary zone, which was observed in the male rat. The toxin responsible for the delayed cortical damage was assumed to be a product of liver metabolism. However, the possibility of a kind of interaction between phenobarbital and Cortinarius toxins at the level of the renal tubular cells was also ventilated (Nieminen 1976b).

The marked sex differences, but also the great individual variation in susceptibility to the toxins, were referred to some kind of a genetic variation (Nieminen 1976b).

Since the concomitant administration of furosemid increased the renal damage induced by C. speciosissimus, it was concluded that despite the long timelag before visible lesions of the kidneys appear, Cortinarius toxins must reach the kidney in high concentration within a few hours after the oral administration of the mushroom (Nieminen et al. 1976b).

So far, the experiments carried out on the toxic Cortinarius species do not throw much light on the pathogenetic mechanisms behind the mushroom-induced lesions. However, the recent isolation and structure elucidation of orellanine lays the foundation of new assumptions in this matter.

As evident from toxicological studies of other cationic bipyridines, the 2,2'-bipyridyl-structure of orellanine have some definite toxicological implica- tions. Cationic bipyridines - such as the well-known paraquat (4,4'-bipyridyl) and diquat (2,2'-bipyridyl) - are toxic both in plants and animals. Paraquat and diquat destroy the photosynthetic apparatus of green plants and are therefore commonly made use of as herbicides (Calderbank and Slade 1976). After accidental ingestion they have proved to be highly toxic also in man. Their mammalian toxicity has been intensively studied during the past few years, and it now seems well established that these bipyridines impair renal function and have the kidney as the main or most important target organ. Both paraquat and diquat produce renal failure in mice, rats, dogs, monkeys, and man, and histologic evidence of an acute tubular necrosis (tubulo-interstitial nephritis) has also been observed (Conning et al. 1969; Davies et al. 1977; Lock and Ishmael 1979; Lock 1979; Purser and Rose 1979).

Due to a common ground structure and the fact that the toxicity of orellanine and these well-known bipyridines is fairly similar, it is supposed that orellanine is


handled by the human organism and exhibits its effects through similar (or even the same) mechanisms as other bipyridines. Therefore, a short summarize on the present knowledge on mammalian pharmacokinetics and pathogenetic mechanisms of paraquat and especially diquat (with an identical, chemical ground structure) seems beneficial.

What concerns the metabolism and nephro-pathophysiological effects of the bipyridines, quite a lot is known. Especially the studies carried out on dogs (Davies et al. 1977) and monkeys (Purser and Rose 1979) appear to be reasonable models also in man. Following oral administration of paraquat, there is a rapid, but incomplete absorption from the gut, most probably by means of an active, energy-dependent process. There is no evidence of a prolonged phase of absorption (Davies et al. 1977). Paraquat and diquat are stable and highly water soluble compounds, and they are not metabolized to any significant extent when administered to animals (Daniel and Gage 1966). According to Lock (1979), neither paraquat nor diquat is bound to plasma in the rat. A maximum plasma concentration is found from la/2-6-(10) h after ingestion (Davies et al. 1977; Purser and Rose 1979). Elimination occurs in the kidneys with little or no biliary excretion (Daniel and Gage 1966). In small (sul~lethal) doses paraquat and diquat are rapidly cleared (within hours) via the kidneys, also involving an active secretion by the strong base secretory mechanism in the renal tubuli and collecting ducts (Davies et al. 1977; Lock 1979; Lock and Ishmael 1979; Purser and Rose 1979). Following ingestion of high doses, a marked reduction in renal excretion is observed (after 12 h in the rat and the monkey) (Lock 1979; Purser and Rose 1979). In the dog and the monkey a severe tubular necrosis develops the subsequent days, thereby reducing the clearance of the substances manifold (Davies et al. 1977; Purser and Rose 1979). In experiments of paraquat on monkeys, Purser and Rose (1979) found significant plasma paraquat concen- trations several days after high dosing. According to Lock (1979) the reduction in renal excretory function induced by paraquat and diquat, is a result of fluid redistribution with a subsequent reduction in renal blood flow, a haemodynamic modification probably being a major factor in all types of acute tubular necrosis (Chapman and Legrain 1979).

At a cellular level, the herbicidal and mammalian actions of the cationic bipyridines have been attributed to their ability to take part in biochemical redox-reactions (Calderbank and Slade 1976; Davies et al. 1977). The cationic bipyridines are easily reduced to free radicals, and avidly re-oxidized by molecular oxygen with the concomitant production of superoxide radicals. These cyclic redox-reactions may be carried out by NADPH + H+-dependent enzymes in the cell too (Gage 1968), and the production of superoxide, which is cytotoxic - either directly, or by generating singlet oxygen - is thought to be an underlying mechanism responsible for the cell injuries (Davies et al. 1977). A more comprehensive mechanism proposed is the attack of singlet oxygen on unsaturated lipids of the cell membrane, thus producing lipid - free radicals with a consequent membrane damage (Bus et al. 1976). Another implication of the cyclic redox-reactions of bipyridines, which has been proposed as the cytotoxic mechanism, is that these reactions may cause a continuous intracellular NADPH + H+-oxidation, giving metabolic disturbances in the cell (Rose et al.


1976b; Smith and Rose 1977). Recent studies have demonstrated that paraquat and diquat, when once accumulated in the cell, will in fact produce a rapid decrease in NADPH + H+/NADP+-ratio (Witschi et al. 1977; Rose et al. 1980), a stimulation of the pentose phosphate pathway (NADPH + H+-regenerating cyclus) (Rose et al. 1976b; Lock and Ishmael 1979; Forman et al. 1980) and a deprivation of fatty acid synthesis (NADPH + H+-dependent) (Smith and Rose 1977; Lock and Ishmael 1979; Rose et al. 1980). The mechanism behind the gradually depletion of intracellular NADPH + H +, however, whether it is a result of NADPH + H + oxidation, NADPH + H + destruction, or an interfer- ence on (and maybe an occupation of) enzymes essential to the generation of NADPH + H + in the cell, has not yet been ascertained. What seems clear is that the bipyridines cause a shift in the redox state of the cells, and that inhibition of intracellular metabolic systems dependent upon NADPH + H + may be an important part of the toxic mechanism involved.

Paraquat was found to be actively accumulated by renal cortical slices in the mouse (Ecker et al. 1975); in rats paraquat and diquat only accumulated to a small extent (Rose et al. 1976a). Lock and Ishmael (1979) demonstrated an increase in the activity of the pentose phosphate pathway and an inhibition of fatty acid synthesis in renal cortical slices from rat, when mounted in paraquat- and diquat-solutions (in vitro studies), while preparation of slices 17 and 24 h after oral dosing could not demonstrate alterations in these cellular activities. This indicates that in vivo these bipyridines had not accumulated so as to alter the redox state of the cells after 24 h. Whether this occurs after days and can be demonstrated in other animals, including man, then being responsible for the delayed nephrotoxic effects of bipyridyls in man, remains to be seen.

Then, is it possible that the above characteristics of bipyridine toxicity are applicable to Cortinarius orellanus/speciosissimus poisoning?

Orellanine - having the same chemical ground structure as other physiological active bipyridines - is supposed to have the same ability to take part in intracellular, cyclic redox reactions with the production of free radicals (Fig. 2). Although not investigated, orellanine is probably also capable to deplete the NADPH + H + level and thus cause irreversible alterations in cell metabolism with subsequent cell damage of its target cells, when once accumulated in sufficient amounts. Recent studies have shown that aqueous extracts of Cortinarius speciosissimus destroy the photosynthetic apparatus in Lemna minor (duck-weed) in the same way as paraquat and diquat, thus indicating that orellanine takes part in electron transport (redox-reactions) within plant cells (H0iland 1983). tNon-toxic Cortinariuslspecies had no effects on Lemna. The assumption that it is the ability of the cationic bipyridines to pick up electrons to form a radical which is responsible for their cytotoxic effects, is also supported by toxicity studies of orelline. This compound-isolated from Cortinarius orellanus-lacks positively-charged nitrogen atoms and cannot take part in redox reactions. Experiments have confirmed that orelline is harmless to test animals (Antkowiak and Gessner 1975).

In the light of what is known about the metabolism and excretion of the dipyridines from the body, the observed toxic effects of Cortinarius orellanus/speciosissimus are in great part understandable. Orellanine is soon taken care


Fig. 2a, b. Proposed intracellular, toxic mechanisms that may be involved in orellanine poisoning. Cyclic redox-reactions of orellanine may produce: (a) cytotoxic superoxide, and (b) NADPH + H+-depletion and consequent metabolic disturbances through the involvement of redox enzymes, which may require NADPH + H + for their own reduction, or may possibly be involved in NADPH + H+-generating cycles of the cell

•+•OH N + -O / OH Enz' ~ HO'~+N/O- ~ O - red, H O ~

Enz. N ~ ~ OH ox. -0 -/ OH 0

Ho. N.O-

of by the kidneys - a fact also supported by the interaction of furosemid and the mushroom toxin on the kidney (Nieminen et al. 1976b) - probably making use of the cationic secretory transport system of tubuli and collecting ducts. The potentiated renal damage caused by phenobarbital (Nieminen 1976a) is most likely a result of competition for the same transport system as used by orellanine, a system known to be important for the excretion of weak acids such as phenobarbital from the body. Consequently, at the level of the nephron the epithelial ceils of tubuli and collecting ducts are target cells especially exposed to injuries. The proposed intracellular toxic mechanism with NADPH + H+-de - pletion would - through the influence on vital cell processes - need hours and days to impoverish the cells to a degree of inevitable necrosis. This is in concordance with the delayed toxic effects observed in this type of mushroom poisoning. As the bipyridines (probably also including orellanine) following a severe intoxication, may circulate in the blood for days, an enhancement of the cell injuries by time is to be expected through a mechanism such as proposed above. Consequently, it is of utmost importance to try to eliminate the toxin (artificially) as soon as possible to avoid the progress of cell injuries.

The clinical history and histopathological findings suggest the role of toxic-ischemic renal lesions. However, the existence of renal alterations as a consequence of some immune reaction cannot be exluded either. The delayed massive cellular infiltration and edema of renal interstitial tissue, which was experimentally prevented by the concomitant use of an immunosuppressive (cyclophosphamide), leaving the animals with less severe renal damage, indicates the involvement of an immuno-allergic mechanism (cf. Nieminen et al. 1976a). Clinically, Marichal et al. (1977) and Short et al. (1980) got evidence of an activation of an immunological mechanism in the renal damage of some intoxicated persons, however, in most cases, this has not been observed.

102 Trond Schumacher and Klaus H~iland

Prognosis and Therapy

As pointed out by Grzymala (1959b; 1965a) there is a connection between the incubation period before onset of symptoms and the severity of poisoning. Generally, a short incubation period indicates more severe poisoning. The rather variable individual response to C. orellanus/speciosissirnus-poisoning makes an assessment of outcome difficult. A method to measure bipyridines in plasma has been developped by Draffan et al. (1976). The possibility to get an exact measurement of the orellanine-content in plasma would expect to give a good indication of the severity of poisoning, and also be a guide for a better treatment. However, such a method could also be used diagnostically, when it is reasonable to suggest a kind of mushroom being responsible for the nephrotoxic effects.

The clinical picture usually brings about a late hospitalization, which makes an effective therapy difficult. On the basis of informations on the pharmacokinetics of the bipyridines, treatment should concentrates on removing orellanine from the circulation by haemoperfusion (not by forced diuresis!), even though the mushroom has been ingested several days before. Heath et al. (1980) reported the successful treatment of two persons by haemoperfusion over resin filters started up 5 days after the ingestion of Cortinarius speciosissimus. Haemoperfusion cannot always prevent the development into a severe, chronic renal failure. In recent years quite a few persons have been permanently bound to haemodialysis or have received a renal transplant to restore renal function.

Whether the use of an immunosuppressive drug, such as for instance cyclophosphamide, would influence the renal damage in a positive direction in man if applied in the acute stage, has not been clinically tested.

As apparent from the present review of Cortinarius poisoning, there is a bad need for further investigations on the pathogenetic mechanisms and pharmacokinetics in orellanine-poisoning. A more rational therapy should not rest on assumptions and deduced knowledge only, but be supported by scientific evidence.

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Received November 8, 1982

Mushroom poisoning caused by species of the genus Cortinarius Fries

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