Lili of the valley

Lily-of-the-valley

What does lily-of-the-valley look like?

Lily-of-the-valley is a sweet and understated perennial which thrives on woodland floors.

Leaves: oval in shape, with an untoothed leaf edge. They are basal and grow in pairs.

Flowers: white in colour and bell-shaped. They grow in a one-sided spike which droops to one side.

Fruits/seeds: bright red berries, which are poisonous.

Not to be confused with: wild garlic (Allium ursinum) when the plants are not in flower as their leaves are similar. However, the leaves of wild garlic grow straight from the plant base whereas lily-of-the-valley has two or three leaves on one stem. When in flower the plants are easily distinguishable from each other – wild garlic flowers are star-shaped, while the lily-of-the-valley’s flowers are bell-shaped. Another good identification feature of wild garlic is the smell – which is unmistakably garlicky.

Solomon’s-seal (Polygonatum multiflorum) is another plant lily-of-the-valley might be confused with. Though Solomon’s seal also displays white flowers, they are longer in shape. Also, its oval, green, untoothed leaves grow alternately up the stem unlike lily-of-the-valley’s which grow at the base of the plant, in pairs.

May lily (Maianthemum bifolium) has leaves which may look similar to those of lily-of-the-valley but they grow halfway up the stem.

How Poisonous Is Lily of the Valley?

We don’t want to spoil anything from this season of Breaking Bad for those who haven’t seen it. But for the floss readers curious about lily of the valley, a plant that played a part in Sunday’s season finale, we’re happy to talk botany. Read on at your own risk.

So, what is lily of the valley?

Known by the scientific name Convallaria majalis, the lily of the valley is an herbaceous (the leaves and stems die at the end of the growing season and there’s no persistent woody stem) perennial found in temperate areas of the Northern Hemisphere. The plant forms large colonies by spreading underground stems and appears above ground with upright stems called pips. The lily blooms in the late spring and has white, bell-shaped, sweet-smelling flowers and small orange-red berries.

The plant pops up in Christian legend several times. As the story goes, lily of the valley was formed from the tears of Mary as she wept at the crucifixion of Jesus, and grew from the blood shed by Saint Leonard of Noblac during his fight with a dragon. The lily of the valley was also used as the floral emblem of Yugoslavia and is the national flower of Finland

Is it really poisonous?

You bet.

Toxicity is the plant’s defense against animals eating its seeds. All parts of the plant—the stems, the leaves, the flowers and the berries—are extremely poisonous and close to 40 different cardiac glycosides have been found in the plant so far.

Glycosides are chemical compounds where a sugar is bound to a non-carbohydrate molecule. By increasing calcium stores in and around cells, cardiac glycosides increase the force with which the heart contracts and the volume of blood it can pump. This is not necessarily a bad thing, and these compounds have been used in medicine since the ancient Roman Empire to treat arrhythmia and congestive heart failure (today, the drugs Lanoxin, Digitek, and Lanoxicaps are made from a purified cardiac glycoside extracted from the foxglove plant). In quantities over the recommended safe dosage, though, cardiac glycosides can wreak havoc on your gastrointestinal, circulatory and nervous systems (more on that later).

That doesn’t sound good. Could it be growing in my yard?

Possibly. The plant is widespread in the wild across Asia, continental Europe, England and the Appalachia region of the eastern United States. It’s also a popular garden plant because of its sweet-smelling flowers and ground-covering ability, so it wouldn’t be shocking to find it in a garden outside of its native range. Like, say, Albuquerque.

So I definitely shouldn’t be eating it, then?

Not unless blurry vision, diarrhea, vomiting and nausea, disorientation, drowsiness, headaches, red skin rashes, excessive salivation, sudden alterations in your cardiac rhythm and possible death sound like your idea of fun.

Oh. Let’s say that, er, a friend of a friend ate some. What’s next?

Get to a hospital, where treatment will include ingestion of activated charcoal, breathing support, IV fluids, an electrocardiogram and a temporary pacemaker, depending on the nature and severity of the symptoms. They might also recommend not hanging out with people who make and/or sell meth.

Toxic Principle At least 38 cardenolides have been isolated from Convallaria majalis. Also present are various saponins. All parts of the plant are poisonous, with the greatest concentration of cardenolides being in the roots. The attractive red berries are the commonest source of poisoning in children. The cardenolides have a digitalis-like activity, causing cardiac conduction disturbances. Description Convallaria majalis is a popular perennial garden plant originating from Europe, and North America. It grows in dense colonies from a slender underground rhizome. Leaves are basal, broadly elliptic to oblong, sheathing, glabrous, and dull green. Inflorescences are terminal one-sided racemes, with 5-18 white flowers, each with 6 fused, recurved petals. Some cultivars have, pale pink flowers, and variegated leaves The flowers are strongly perfumed. Fruits are red berries with numerous seeds.
Gastrointestinal Vomiting and diarrhea
Treatment Depending on how long it has been since the plant was eaten, induction of vomiting, gastric lavage, or administration of activated charcoal is indicated. Cathartics may also be used to help eliminate the plant rapidly from the digestive system. Serum potassium levels should be closely monitored and appropriate intravenous fluid therapy initiated as necessary. Phenytoin, as an anti-arrhythmic drug effective against supraventricular and ventricular arrhythmias can be used as necessary. Since the effects of the Convallaria cardenolides a very similar to those of digitalis, the use of commercially available digitalis antibody (Digibind – Burroughs Wellcome) may be a beneficial in counteracting the effects on the cardenolides.
Cardiovascular system As with digitalis poisoning, clinical signs can vary from vomiting and diarrhea, to cardiac arrhythmias and death.4 Postmortem findings are usually not specific and a diagnosis is often made by finding the plant parts in the digestive system.
Diagnosis At post mortem, the berries and leaves may be found in the stomach.
Special Notes Lily of the valley is a common garden plant prized for its perfumed white flowers, and is an attractive groundcover. It can also be grown as a potted plant. The attractive, sweet-tasting, red berries are an attraction to children and not infrequently cause poisoning when ingested. Relatively few cases of animal poisoning from lily of the valley have been reported.

Author Spotlight

The beautiful flower graces my yard with its presence during the spring, and you might even find it in yours. Its large, upright stems are called pipes, and from them hang sweet-smelling, bell-shaped, white or sometimes pink flowers, and its berries are orange-red. Don’t be fooled by its beauty; all parts of this plant are extremely poisonous.

lily of the valley, flickr

Lily of the valley is also known by many other names: May lily, Our Lady’s Tears, Mary’s Tears, convall-lily, lily constancy, ladder-to-heaven, Jacob’s ladder,and male lily.

In Christian legend, this flower is linked with Easter and the crucifixion of Christ. As Jesus was being crucified, Mary’s tears are rumored to have formed into these beautiful flowers. Another way they are said to have formed is from the tears of Eve when she was kicked out of the Garden of Eden. This flower is also seen as a symbol of the second coming of Christ.

German legend links this flower to Easter and spring. The blooming of this dainty-looking flower brings to mind the feast of Ostara, the virgin goddess of spring.

lily of the valley,

The national flower of Finland, lily of the valley is quite common across North America, Northern Asia, and Northern Europe.

This extremely picturesque flower, the symbol of purity and humility, is highly poisonous. If it is ingested, chances are you could die a painful death. Every part of this beautiful plant is poisonous; even the water it has been kept in is poisonous. On a toxicity scale of 1 to 6, this plant earns a 6.

lily of the valley, flickr

The reaction to the poison is immediate. Symptoms would include the following:
hot flashes
tense irritability
patches of red skin
headache
hallucinations
cold, clammy skin
dilated pupils
vomiting
stomach pains
nausea
excessive salivation
slow heartbeat
coma
death from heart failure

lily of the valley, flickr

Is there any hope for survival if this flower is ingested? Well, yeah, but since the poison acts so fast, help needs to be obtained very quickly. Pumping of the stomach, or gastric lavage, is recommended, as are doses of cardiac depressants to bring the rhythm of the heart under control.

girl writing, etc.usf.edu

This is a method of poisoning that I have yet to run across in any fiction story, but it is a good way for your character to poison his or her victim. The flower could be ground up into a powder and added to a cup of tea or coffee before being served to the intended victim. If you criminal character is a cook, he could also grind add into a powder then cook it into whatever dish was being prepared. Spaghetti sauce would be an appropriate food in which to add it The victim could be told it was a new spice. Also, this way it can be ensured that the victim ingests enough of the poison for him to die.

lily of the valley,

Whether or not the victim succumbs to the ingested poison and whether or not the murderer is caught is all up to you.

Believe it or not, this poisonous flower does have its medicinal uses. Just like foxglove, it is used for heart problems, but if too much is ingested, the recipient won’t have any more cardiac issues to worry about. With what you now know about this flower, would you risk taking it ? And how would your character put this knowledge to use?

Recommended Articles:
Arsenic, the King of Poisons
Cyanide, the Classic Poison
Monkshood, the Killer Plant
Flying Death
Death by Honey

Foraging fun: False lily of the valley

False lily of the valley (Maianthemum dilatatum) is one of those plants you see in the Pacific Northwest all the time in shady, forested riversides. Most of us never know that it’s a crisp and lightly peppery edible wild plant. I love using these as a lettuce wrap, they look and taste gorgeous.

Not to be confused with actual lily of the valley (Convallaria_majalis) which is deadly poisonous, but isn’t a native BC plant.

Where do I look?

  • Near rivers in shady forests, sitka spruce forests near the sea especially.

When do I look?

  • Spring when the leaves are tender

Key Features?

  • heart shaped leaves with long stalks, growing in groups
  • small white flowers (parts in 4 unlike most lilys)
  • small green berries turn mottled brown, then reddish
  • low elevation, wet, shady, forested areas

Know these look alikes first…

  • Lily of the valley which doesn’t grow naturally in the Pacific Northwest but can be found in cultivated gardens.
  • Corn lily (Veratrum viride) is a poisonous native BC plant that grows more like a corn stalk and is much larger with multiple leaves growing from the stalk. Still a good one to know. Higher elevations, open stream areas.

Chef’s tips on food uses

  • Lovely in salads
  • Use as a lettuce wrap (I usually fry up some ground pork with ginger and hoisin as the filling)

Come on one of our wild foraging walks with a wildcraft guide this Spring to learn about more spectacular native edibles of BC. April 30 to May (Fall is wild mushroom season) – More info here

Rapid Detection of the Active Cardiac Glycoside Convallatoxin of Lily of the Valley Using LOCI Digoxin Assay

Abstract

Objectives:

To explore the luminescent oxygen channeling technology–based digoxin immunoassay (LOCI digoxin assay) for rapid detection of lily of the valley extract and convallatoxin. The potential in vitro binding of convallatoxin with Digibind was also evaluated.

Methods:

Aliquots of a drug-free serum pool and a digoxin serum pool were supplemented with lily of the valley extract or convallatoxin, and then apparent digoxin concentrations were measured using the LOCI digoxin assay. Mice were administered lily of the valley extract or 50 μg of convallatoxin, and digoxin concentrations in serum specimens were measured 1 and 2 hours after gavage. Aliquots of a serum pool supplemented with convallatoxin or lily of the valley extract were further supplemented with various concentrations of Digibind and free apparent digoxin concentrations were measured.

Results:

Apparent digoxin concentrations were observed when aliquots of a drug-free serum pool were supplemented with convallatoxin or lily of the valley extract, and also with convallatoxin or herbal extract. Bidirectional interference of convallatoxin and lily of the valley extract with serum digoxin measurement using the LOCI assay was also observed. Digibind was capable of binding convallatoxin in vitro.

Conclusions:

LOCI digoxin assay can be used for rapid detection of convallatoxin, and Digibind can bind convallatoxin in vitro.

The lily family is composed of 280 to 300 genera made up of 4,000 to 4,600 different species. Ninety genera representing approximately 525 species are found in North America. Lilies are popular decorative plants and are also found in floral arrangements. The Convallaria genus, commonly called “lily of the valley,” is well known as a toxic member of the lily family, although various genera of lily family plants can cause toxicity.1 Lily of the valley (Convallaria majalis) takes its name from convallis (valley), leiron (lily), and majalis (May). Lily of the valley is a perennial herb that is 10 to 30 cm in height and has white flowers during April to June and red berries during July. Lily of the valley grows in the cooler climate of North America and also in Europe and certain parts of Asia. The entire plant is toxic, containing saponins responsible for digestive disorders and cardiac glycosides causing digitalis-like toxicity. The principle toxic cardiac glycoside found in lily of the valley is convallatoxin. There are several reports of lily of the valley poisoning. An 87-year-old woman suffering from advanced dementia was admitted to the hospital for ingestion of two sprigs of lily of the valley offered to her by the family. Fortunately the patient survived and was eventually discharged from the hospital.2 Symptoms of digitalis-like toxicity in a family after accidental ingestion of lily of the valley plant has also been reported.3 Moxley et al4 reported the case of a 1-year-old mixed-breed dog after ingestion of lily of the valley plant; postmortem examination revealed leaf fragments of lily of the valley plant in the intestine.

Lily of the valley extract is used in herbal medicine despite known toxicity of the plant. Herbalists in the 16th century recommended blossoms of lily of the valley soaked in wine for strengthening the memory, soothing inflamed eyes, and to ease symptoms of gout.5 Lily of the valley extract is a component of many herbal preparations used as a tonic for the heart. Convallatoxin, the major cardiac glycoside present in lily of the valley, has digitalis-like properties by inhibition of sodium potassium adenosine triphosphatase, thereby causing a positive inotropic effect.6

Convallatoxin is structurally similar to digoxin Figure 1. Therefore, the possibility of rapid detection of convallatoxin in serum was studied using luminescent oxygen channeling technology–based digoxin assay (LOCI digoxin assay). Because a person taking digoxin may also take lily of the valley extract for its cardiotonic effect, the effect of lily of the valley extract on serum digoxin measurement using the LOCI digoxin assay was also studied. We further explored the possibility of neutralizing convallatoxin and cardiac glycosides of lily of the valley herbal preparation by using Digibind, the fab fragment of the polyclonal antidigoxin antibody.

Figure 1

A, Structure of digoxin. B, Structure of convallatoxin. (Adapted from http://pubchem.ncbi.nlm.nih.gov.)

Figure 1

A, Structure of digoxin. B, Structure of convallatoxin. (Adapted from http://pubchem.ncbi.nlm.nih.gov.)

Materials and Methods

Convallatoxin was purchased from the Sigma Chemical Company (St. Louis, MO). Lily of the valley herbal extract (Wise Woman Herbals, Creswell, OR) was obtained from a local herbal store in Houston, TX. LOCI is the digoxin assay used at Memorial Hermann Hospital, an 850-bed tertiary care hospital and level 1 trauma center located in the Texas Medical Center, Houston. LOCI digoxin assay kits were purchased from Siemens Diagnostics (Deerfield, IL) and assays were run on a Vista 1500 auto analyzer (Siemens Diagnostics) following the manufacturer’s protocol. Centrifree Micropartition System filtration devices with a molecular weight cutoff of 30,000 Da were obtained from Amicon (Danvers, MA). The LOCI digoxin assay uses a specific mouse monoclonal antibody against digoxin and requires no sample pretreatment before assessment. The analytic measurement range of this assay is from 0.06 to 5.0 ng/mL of serum digoxin concentration. Standard solutions of convallatoxin were made in absolute ethanol, followed by further dilution with ethanol to prepare working standards.

Aliquots of digoxin-free serum pools were supplemented with either convallatoxin (10 ng/mL-2.5 μg/mL) or liquid extract of lily of the valley (5–20 μL/mL). Microliter quantities of convallatoxin ethanol working solution or lily of the valley extract were added to dry test tubes followed by evaporation of the solvent under a gentle stream of nitrogen and reconstitution with an aliquot of drug-free serum. The apparent digoxin concentrations were then measured using the LOCI digoxin assay. Each measurement was performed in triplicate and results are expressed as the mean and 1 standard deviation.

Digoxin serum pools were prepared by combining deidentified serum specimens from patients receiving digoxin that were submitted for therapeutic drug monitoring. The specimens were used after performing and reporting all results to the ordering clinicians, and after holding these specimens for 1 week as required by our laboratory protocol and guidelines of the University of Texas-Houston Institutional Review Board. Aliquots of the digoxin pool were supplemented with various amounts of pure convallatoxin or lily of the valley extract, with digoxin concentrations measured before and after supplementation.

To investigate whether convallatoxin or components of lily of the valley extract can be detected in vivo using the LOCI digoxin assay, BALB/c mice (Jackson Laboratories, Bar Harbor, ME) were orally gavaged with 50 μL of either 50 μg of convallatoxin (dissolved in saline containing 10% ethyl alcohol) or lily of the valley extract diluted 1:1 in normal saline. The vehicle control contained only normal saline with 10% alcohol. Three mice were used per group. Blood was drawn 1 and 2 hours after gavage and apparent digoxin concentrations were measured using the LOCI digoxin assay. No duplicate measurements of individual mice were possible because of limited specimen volume. Animal experiments were performed according to approved guidelines provided by the University of Texas Houston Health Science Center’s committee on animal welfare.

The ability of Digibind to bind convallatoxin or components of lily of the valley herbal extract was also explored in vitro. For this purpose, one drug-free serum pool was supplemented with convallatoxin (2.5 μg/mL) and another drug-free serum pool was supplemented with lily of the valley extract (10 μL of the extract/mL of serum). Digibind was then added to aliquots of these supplemented pools. After incubation at 37°C for 20 minutes, the free apparent digoxin concentration was measured in the protein-free ultrafiltrate prepared by centrifuging each specimen using the Centrifree Micropartition System filter for 30 minutes at ×1,500g.

Statistical analyses were performed using the two-tailed Student t test. A statistically significant difference was considered at 95% confidence interval or higher (P < .05).

Results

Significant apparent digoxin concentrations using the LOCI digoxin assay were observed when aliquots of drug-free serum pool were supplemented with either convallatoxin or liquid extract of lily of the valley, indicating that the LOCI digoxin assay can be used for rapid detection of convallatoxin as well as digoxin-like immunoreactive components of lily of the valley herbal extract. For example, when an aliquot of drug-free serum pool was supplemented with 100 ng/mL of convallatoxin, the mean observed apparent digoxin level was 0.88 ng/mL, and with a higher amount of convallatoxin (1 μg/mL) the observed mean value was 4.25 ng/mL. When another aliquot of the drug-free serum pool was supplemented with lily of the valley extract to achieve a final concentration of 20 μL/mL, the observed mean apparent digoxin concentration was 1.99 ng/mL Table 1. Based on the observed apparent digoxin concentration, convallatoxin concentration in the serum can be calculated using a polynomial equation: y=89.9×2−524x+617.3where y represents concentration of convallatoxin in ng/mL and x represents observed apparent digoxin concentration observed by the LOCI digoxin assay (ng/mL). Using this equation, concentration of convallatoxin can be calculated in the lily of the valley extract. With 5 μL/mL of lily of the valley extract, the observed apparent digoxin concentration was 0.83 ng/mL, which represented convallatoxin concentration of approximately 154 ng/mL. Table 1

Effect of Supplementing Aliquots of Drug-Free Serum Pool With Convallatoxin or Lily of the Valley Extract on LOCI Digoxin Assaya

Table 1

Effect of Supplementing Aliquots of Drug-Free Serum Pool With Convallatoxin or Lily of the Valley Extract on LOCI Digoxin Assaya

To investigate if convallatoxin can also be detected in vivo, mice were fed 50 μg/mL of convallatoxin. The observed apparent digoxin concentration 1 hour after feeding was 0.72 ng/mL (mouse 6) and 2 hours after feeding was 0.40 ng/mL Table 2. Similar results were observed when mice were fed 50 μL of lily of the valley extract, indicating that the LOCI digoxin assay can be used to detect the presence of convallatoxin in serum in vivo after exposure to lily of the valley.

Table 2

In Vivo Apparent Digoxin Levels as Measured With the LOCI Digoxin Assay After Feeding Mice Convallatoxin or Lily of the Valley Extracta

Table 2

In Vivo Apparent Digoxin Levels as Measured With the LOCI Digoxin Assay After Feeding Mice Convallatoxin or Lily of the Valley Extracta

Because cross-reactivity of a substance should be tested in the presence of the primary analyte,7 the effect of adding convallatoxin or lily of the valley extract to aliquots of a digoxin pool to test cross-reactivity of convallatoxin in the presence of the primary analyte digoxin was investigated. Bidirectional interference (negative interference with smaller amounts of convallatoxin and positive interference with higher amounts of convallatoxin) of convallatoxin with serum digoxin measurement using the LOCI digoxin assay was observed. Similar effects were also observed with lily of the valley extract. For example, mean digoxin concentration in the digoxin serum pool was 1.62 ng/mL. When an aliquot of this digoxin pool was further supplemented with 50 ng/mL of convallatoxin, the observed digoxin concentration was significantly reduced to 1.06 ng/mL. However, in the presence of 500 ng/mL of convallatoxin the observed digoxin concentration was 2.88 ng/mL, which was significantly greater than the original digoxin level of 1.62 ng/mL observed in the original digoxin pool. A similar bidirectional interference was observed when other aliquots of the same digoxin pool were supplemented with various amounts of lily of the valley extract Table 3.

Table 3

Effect of Supplementing Aliquots of Digoxin Pool With Convallatoxin or Lily of the Valley Extract on Serum Digoxin Measurement Using the LOCI Digoxin Assaya

Table 3

Effect of Supplementing Aliquots of Digoxin Pool With Convallatoxin or Lily of the Valley Extract on Serum Digoxin Measurement Using the LOCI Digoxin Assaya

The possibility of binding convallatoxin and digoxin-like immunoreactive substances present in lily of the valley extract using Digibind, the fab fragment of polyclonal antidigoxin antibody, was also studied. For this purpose, one drug-free serum pool was supplemented with 1 μg/mL of convallatoxin and another aliquot with 10 μL/mL of lily of the valley extract. Aliquots of each pool were further supplemented with various concentrations of Digibind representing in vivo concentrations observed in patients overdosed with digoxin and being treated with Digibind. After incubation, both total and free digoxin levels were determined using the LOCI digoxin assay. Digibind was capable of binding convallatoxin, as evidenced by significantly lower free digoxin level (including none detected level) in the presence of Digibind. For example, the total and free apparent digoxin levels in the drug-free serum pool supplemented with 1 μg/mL of convallatoxin were 4.55 ng/mL and 3.48 ng/mL, respectively. In the presence of 5 μg/mL of Digibind, the free apparent digoxin concentration was reduced to 1.66 ng/mL, indicating that Digibind is capable of binding free (non–protein bound) convallatoxin in serum. No apparent free digoxin level was observed in the presence of higher quantities of Digibind. Similar results were observed when another drug-free serum pool was supplemented with lily of the valley extract followed by further addition of Digibind Table 4. The total digoxin measurements were affected by the presence of Digibind, but free digoxin measurements were not affected by Digibind because of the higher molecular weight (molecular weight of Digibind: approximately 46,200 Da where the cutoff of the filtration device was 30,000 Da). Digibind was absent in the protein-free ultrafiltrate. Elimination of Digibind interference in serum digoxin measurement by using free digoxin determination has been reported.8

Table 4

Effect of Digibind on Apparent Total and Free Digoxin Concentration in Aliquots of Serum Pool Supplemented With Convallatoxin and Digibind or Lily of the Valley Extract and Digibind

Table 4

Effect of Digibind on Apparent Total and Free Digoxin Concentration in Aliquots of Serum Pool Supplemented With Convallatoxin and Digibind or Lily of the Valley Extract and Digibind

Discussion

Accidental poisoning by lily of the valley in both animals and humans has been reported. In addition, it is possible that a person taking digoxin may also take lily of the valley herbal supplement due to increased and widespread use of herbal remedies. Therefore, a rapid diagnosis of poisoning with lily of the valley could be highly useful. The data presented here indicate that the LOCI digoxin assay can indirectly indicate the presence of convallatoxin in the serum measured as digoxin equivalent. In addition, convallatoxin can also be detected in vivo after mice are fed convallatoxin. However, confirmation with a specific method such as liquid chromatography–mass spectrometry should be used to measure digoxin and confirm the presence of convallatoxin if suspected. Because convallatoxin has significant cross-reactivity with antidigoxin antibody used in the LOCI digoxin assay, it is possible that it may also cross-react with antidigoxin antibody used in other commercially available digoxin assays. Further studies are needed to investigate if LOCI digoxin assay is unique in its cross-reaction with convallatoxin or if other digoxin assays have similar capabilities.

Digoxin is a cardiac glycoside with a narrow therapeutic range. Therefore, it is important to accurately measure serum digoxin level. Immunoassays are widely used for digoxin measurement in clinical laboratories but digoxin assays also suffer from various interferences. Jones and Morris9 analyzed digoxin values in 36 plasma samples by sending aliquots to two different laboratories using different digoxin immunoassays. They observed clinically significant discordance in 39% of their samples and commented that interference of digoxin-like immunoreactive substances may explain only some of the discordance. Various other endogenous and exogenous factors are known to interfere with serum digoxin measurements using immunoassays.10 Our results indicate that the LOCI digoxin assay is unsuitable for therapeutic drug monitoring of digoxin due to significant interferences of convallatoxin. According to the 2013 College of American Pathologists survey (first quarter), of 3,069 participating laboratories performing digoxin immunoassays, 493 are using LOCI digoxin assay on the Vista 1500 analyzer.

Bidirectional (positive/negative) interference of convallatoxin in LOCI digoxin assay is interesting. As Valdes and Jortani11 pointed out, such bidirectional interference is most likely caused by complex kinetic characteristics of the immunoreaction. Under equilibrium conditions, most cross-reactivity results in a positive interference, but the demand for immunoassay results to be automated and available faster precludes such equilibrium chemistry, making bidirectional interference a possibility in the automated assays governed by nonequilibrium chemistry. In addition, a wash step might have contributed to negative interference by washing off bound interfering substance if present in low concentration during such a step. This opens up additional bound antibody sites available for label binding, thereby contributing to altered signal causing negative interference. In the presence of more interfering substances, such a wash off is not feasible, thus contributing to positive interference.

Digibind is useful in reversing life-threatening digitalis toxicity. However, Digibind is also capable of reversing various cardiac toxins such as oleandrin and bufalin (other herbal medicines) that have structural similarity to digoxin.12 Camphausen et al13 described a 7-year-old boy who presented to the hospital 6 hours after ingestion of oleander and was successfully treated with Digibind. Bandara et al14 reviewed toxicity of oleander and usefulness of digoxin-specific fab fragment as useful therapy for oleander poisoning. Our results indicate that Digibind is also capable of binding convallatoxin in vitro.

In conclusion, this represents the first report of rapid detection of convallatoxin indirectly as digoxin-like immunoreactivity using the LOCI digoxin assay as well as in vitro binding of Digibind with convallatoxin. We further demonstrated that the LOCI digoxin assay is unsuitable for therapeutic drug monitoring of digoxin in a patient receiving digoxin and also self-medicated with an herbal supplement containing lily of the valley extract.

1. Fitzgerald KT . Lily toxicity in the cat. Top Companion Anim Med. 2010;25:213–217. 2. Alexandre J Foucault A Coutance G et al. . Digitalis intoxication induced by an acute accidental poisoning of lily of the valley. Circulation. 2012;125:1053–1055. 3. Edgerton PH . Symptoms of digitalis like toxicity in a family after accidental ingestion of lily of the valley plant. J Emerg Nurs. 1989;15:220–223. 4. Moxley RA Schneider NR Steinegger DH et al. . Apparent toxicosis associated with lily of the valley (Convallaria majalis) ingestion in a dog. J Am Vet Med Assoc. 1989;195:485–487. 5. Haass LF . Convallari majalis (lily of the valley) (also known as our lady’s tears, ladder to heaven). J Neurol Neurosurg Psychiatry. 1995;59:367. 6. Choi DH Kang DG Cui X et al. . The positive inotropic effect of the aqueous extract of Convallaria keiskei in beating rabbit atria. Life Sci. 2006;79:1178–1185. 7. Miller JJ Valdes R . Methods for calculating cross reactivity in immunoassays. J Clin Immunoassay. 1992;15:97–100. 8. Rainey P . Digibind and free digoxin. Clin Chem. 1999;45:719–721. 9. Jones TE Morris RG . Discordant results from “real-world” patient samples assayed for digoxin. Ann Pharmacother. 2008;42:1797–1803. 10. Dasgupta A . Therapeutic drug monitoring of digoxin: impact on endogenous and exogenous digoxin-like immunoreactive substances. Toxicol Rev. 2006;25:273–281. 11. Valdes R Jortani SA . Unexpected suppression of immunoassay results by cross-reactivity: now a demonstrated cause of concern. Clin Chem. 2002;48:405–406. 12. Dasgupta A Emerson L . Neutralization of cardiac toxins oleandrin, oleandrigenin, bufalin and cinobufotalin by Digibind: monitoring the effect by measuring free digitoxin concentration. Life Sci. 1998;63:781–788. 13. Camphausen C Haas NA Mattke AC . Successful treatment of oleander intoxication (cardiac glycoside) with digoxin specific fab antibody fragment in a 7 year old child: case report and review of literature. Z Kardiol. 2005;94:817–823. 14. Bandara V Weinstein SA White J et al. . A review of the natural history, toxicology, diagnosis, and clinical management of Nerium oleander (common oleander) and Thevetia peruviana (yellow oleander) poisoning. Toxicon. 2010;56:273–281. Copyright© by the American Society for Clinical Pathology

Leave a Reply

Your email address will not be published. Required fields are marked *