Clover toxicity is caused by ingestion of alsike clover (Trifolium hybridum) or red clover (Trifolium pratense), resulting in signs of photosensitivity and liver failure.
Synonym(s)
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Dew poisoning
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Trifoliosis
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Big liver disease
Epidemiology
Risk Factors
Consumption of pasture or hay containing alsike or red clover
Geography and Seasonality
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Found mainly in Canada and the northwestern United States
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Most cases occur from April to November
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Associated with a wet spring
Clinical Presentation
Disease Forms/Subtypes
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Photosensitization
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Chronic hepatic disease
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Chronic wasting and failure to thrive
History, Chief Complaint
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Owners may observe a necrotizing dermatitis primarily affecting white skin, weakness, weight loss, anorexia, ataxia, and behavior changes.
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History of consumption of alsike or red clover hay or pasture.
Physical Exam Findings
Icterus, photosensitivity dermatitis, ulceration of mucous membranes, hepatic encephalopathy, weight loss
Etiology and Pathophysiology
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Alsike or red clover ingestion resulting in bile duct proliferation and perilobular (periportal) fibrosis.
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Photosensitization is the result of systemic accumulation of the chlorophyll metabolite phylloerythrin that is not removed by the diseased liver. Phylloerythrin is a photodynamic agent that absorbs ultraviolent radiation, particularly in unpigmented skin, leading to skin necrosis.
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Signs develop 2 to 4 weeks after ingestion.
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The exact toxin(s) are not known, although fungal infection of the clover with Cymodothea trifolii increases the risk of liver disease.
Clover disease, the severe clinical manifestation of phytoestrogen poisoning, and rarely seen today, includes dystocia, prolapse of the uterus or vagin*, severe infertility, and death. The more common and less severe field expression of phytoestrogen poisoning is a significant decrease in fertility rate. It may be temporary with normal reproductive efficiency returning soon after the ewes are moved to clover-free pasture. In ewes exposed to a low level intake of estrogens over a long period, e.g., in excess of two grazing seasons, a process of irreversible “defeminization” may occur. This is a state of permanent subfertility. The estrous cycle is normal, but an abnormally large number of ewes fail to conceive. In affected flocks, there may also be a high incidence of maternal dystocia caused by uterine inertia, or failure of the cervix or vagin* to dilate. Affected ewes show little evidence of impending parturition and many full-term fetuses are born dead.
Clover Fern family (after Italian Count Luigi Ferdinando Marsigli (1658–1730), Latinized as Marsilius). 3 genera (Marsilea, leaves with 4 pinnae, Pilularia, leaves filiform or thread-like, and Regnellidium, leaves with 2 pinnae)/ca. 75 species. (Figure 4.38)
FIGURE 4.38. POLYPODIOPSIDA—SALVINIALES. Marsileaceae. A–I. Marsilea sp., clover-fern. A. Plant showing rhizome bearing roots and leaves. B,C. Close-ups showing leaves with 4, distal pinnae. D. Young leaf showing coiled circinate vernation. E. Sporocarp, sagittal-section, with thick wall and internal microsporangia and megasporangia. F. Sporocarp close-up, showing microsporangia (containing numerous microspores) and megasporangia (each containing one meagspore). G. Female gametophyte, with distal acrolamellae and apical sperm lake. H. Sperm cells, close-up, embedded within acrolamellae. I. Herbarium specimen of Marsilea quadrifolia, bearing sporocarps from rhizome. J,K. Pilularia americana, pillwort. J. Plant in habitat. K. Soil removed, showing subterranean sporocarps.
The Marsileaceae consist of rooted, aquatic herbs with emergent leaves, the blade (if present) sometimes floating. The stems are elongate, slender, creeping rhizomes, often bearing hairs, with aerenchyma and a solenostelic anatomy. The leaves are circinate, simple, or palmate with 2 or 4 sessile leaflets, veins dichotomous, often fusing apically. Sporocarps (interpreted as modified pinnate leaves or pinnae) are reniform with a stalk arising from the petiole base or leaf axil, each sporocarp bearing two halves, each of these with several rows of internal sori. Sori consist of a column of megasporangia and microsporangia that lacks an annulus (therefore indehiscent) and that are enveloped by a hood-like indusium. At germination (in water) the sporocarp releases an elongate, gelatinous structure, the sorophore, with several pairs of sori attached. Each megasporangium bears a single, trilete megaspore. After imbibing water, the megaspore releases a gelatinous mass, called acrolamellae. The acrolamellae, with apical longitudinal folds and basal horizontal folds, contains a central, liquid filled region called the sperm lake, into which the sperm migrate. The megasporangial wall breaks away and the endosporic, female gametophyte forms a single archegonium at the megaspore apex, rupturing the apex of the spore wall and protruding into the sperm lake. Microsporangia produce several trilete microspores, each microspore forming an endosporic, male gametophyte that bears and releases (by breakdown of sporangial and spore walls) numerous coiled, multiflagellate sperm cells, some of which enter the opening of the acrolamellae into the sperm lake region, which leads to the archegonium. Chromosome numbers: x = 10 (Pilularia) or 20 (Marsilea).
Distribution of the Marsileaceae is subcosmopolitan. Economic importance of family members includes use of Marsilea species as food (sporocarps or leaves) and cultivated ornamentals (especially Marsilea spp. & Regnellidium diphyllum). See Kramer (1990c) for general information, Pryer (1999) for a study of phylogenetic relationships, and Schneider and Pryer (2002) for studies of spore morphology in the family.
The Marsileaceae are distinctive in being rhizomatous, aquatic ferns, the leaves lacking blade tissue or palmate with two or four, sessile leaflets, sori developing within seed-like, dessication-resistant sporocarps, which, upon imbibing water, each release an elongate, gelatinous sorophore bearing the sori and sporangia, the spores heterosporous.
Both alsike clover and red clover are members of the Leguminosae family, subfamily Faboideae. They are hardy and palatable plants. They thrive in cool climates and are tolerant of wet, acidic, alkaline, saline, clay, and peaty soils. Because of these positive characteristics, these two species of plants have been used in pasture mixes throughout the United States and Canada. Depending on the specific cultivar of the plant, soil, and weather conditions, the plants can act as either short-lived perennials or can live for many years. Both types of clover can be grown alone or in combination with other grasses such as orchardgrass, timothy, and fescue, or small grains.
Alsike clover has stems that can be either erect or hanging down, often growing up to 36 inches tall (Color Plate 46). The leaves are palmately trifoliate in appearance. The leaflets are oval, 1 inch long, and finely serrated along the edges. The flowers are pink to white in globose heads up to 1 inch in diameter and located on short peduncles.
Red clover has erect stems that can grow up to 36 inches tall as well (Color Plate 47). The leaves are palmately trifoliate in appearance. The leaflets are oval to obovate, 1 to 2½ inches long, hairy, and commonly have an inverted V-shaped “water mark” on their upper surface. The stipules are large and broad at the base. The flowers are rose-purple or dark purple-red, located in dense globose heads approximately 1 inch long.
Egyptian or berseem clover (Trifolium alexandrinum): Berseem clover falls into two groups:
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Single cut (var. alexandrinum Boiss.): Unbranched or slightly branched Fahl group of cultivars, which have later maturity.
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Multicut (var. serotinum Zoh and Lern): Branches from the base. This includes the Mescawi group of varieties such as Bigbee and Multicut.
Berseem is adapted to neutral to alkaline soils and has tolerance to salinity. Winter growth rate is better than that of other annual legumes, and berseem lasts longer into the spring, but it will not tolerate severe winters and requires irrigation.
High yields of up to 22tonnesha-1 are possible. When making hay, conditioning helps to dry forage cut with a high moisture content. Several cuts are possible after autumn sowing. High growing points restrict grazing potential. A quick grazing rotation is required with resting periods for regrowth, rather than set stocking or prolonged grazing.
Trifoliums
Trifoliums make up the largest group of cool season annuals. Varieties with the best resistance to local diseases and insects should be used.
Crimson (Trifolium incarnatum)
Crimson clover can be grazed in winter and cut for silage or hay in the spring. The Caprera variety of crimson clover is characterized by high levels of soft seed, which restricts regeneration potential. It is quick to establish, and grows erectly with some autumn and early winter growth, but its highest production is in early spring. Deep rooting extends the spring growing period. Sow early with wheat or oats for grazing. Seed production is cheaper than for sub-clover.
Persian (shaftal) (Trifolium resupinatum)
Persian clover has rapid regrowth after grazing, high tolerance to waterlogging, and moderate tolerance to salinity. It is sometimes called shaftal or giant shaftal, but shaftal is really T. clusii (annual strawberry clover).
There are two subspecies of Persian clover:
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Trifolium resupinatum var. majus has an erect habit, thick hollow stems, large leaflets, low hard seededness (1–2%), and late flowering and maturity. Varieties include Maral, Leeton, Laser, and Lightning.
2.
Trifolium resupinatum var. resupinatum has a more prostrate habit, thinner stems, and smaller leaflets. It flowers earlier than majus with more hard seededness and higher seed yields. Varieties include Kyambro and Nitro Prolific. Persian clover is palatable and nutritious providing up to five grazings and a hay cut, yielding up to 16tonnesDM per year. Regrowth is rapid after grazing. The plant’s erect habit allows it to grow and compete effectively with annual ryegrass and small-grain cereals. Mixtures with sub-clover can extend the growing season after sub-clover seed is set.
Arrowleaf clover (Trifolium vesiculosum)
Arrowleaf originated in the Mediterranean region and is characterized by rapid spring growth and is one of the latest maturing of the annual clovers. Establishment is slow due to delicate and drought-susceptible seedlings and grazing must be delayed to allow establishment. Arrowleaf will regenerate from seed, but is best used as a one-season annual. Arrowleaf responds well to rotational grazing (every 2–3 weeks), but when not grazed efficiently, it will become rank and be rejected by stock and associated grasses will be shaded. High level of hard seed affects regeneration and seed should be scarified before sowing new stands.
Rose clover (Trifolium hirtum)
Rose clover is useful when a balance between cold tolerance and winter production is required. It will reseed naturally but does not tolerate poor drainage and is sensitive to heavy grazing. Rose clover is used in mixtures with medics and sub-clover.
Alsike clover (Trifolium hybridium) is one of about 300 Trifolium species that have been associated with several different disease entities. Some of these diseases have been reproduced experimentally, and several toxins have been identified. For example, several phytoestrogen isoflavones and cyanogenic glycosides have been isolated and identified from Trifolium spp. The clover phytoestrogens are generally of littletoxicological importance since their concentrations and bioactivities are low. However, undersome growing and harvest conditions thischanges, and there are risks of estrogen-related reproductive disorders when animals are fedcontaminated hay or silage. Other toxins, including slaframine, a slobber-producing mycotoxin, have been identified. In addition to these poisonings there continue to occur as yet undefined conditions that result in liver disease when horses are fed alsike clover. Several toxins have been suspected, but none have been definitively proven. Toxicity is likely related to environmental conditions and possibly associated with mycotoxin production or some otherwise altered plant metabolite. Horses are the only species known to be susceptible to this toxicity, and epidemiologic studies positively link disease with exposure.
Exposure periods of weeks to months are generally required before horses develop hepatotoxicity. Several syndromes have been identified. The first, called “dew poisoning,” is characterized by photosensitivity with associated dermal edema, necrosis and sloughing, and possibly excessive salivation, and colic and diarrhea, depression, or excitation. The other is severe liver disease or recurrent bouts of liver disease that are seen clinically as icterus, weight loss, mental depression, anorexia, incoordination, dark discolored urine, and an enlarged, firm liver. Histologically, the liver has extensive biliary fibrosis with marked biliary epithelial proliferation. Hepatocellular necrosis is less common and often patchy. Early feeding trials suggested Alsike clover as the cause of liver disease, but numbers of animals and lack of complete post-mortem examinations in those studies imply that this conclusion is not definitive.
Although consumption of subterranean clover(Trifolium repens) and other phytoestrogen-rich forage or feed has caused lower conception rates in several animal species, the implicated plant species are not consumed in the human diet. Soy foods, on the other hand, are consumed in large quantities in China, Japan, and Korea and have not been associated with fertility problems or other adverse effects. In North America, soy infant formula has been used for more than 30 years; formula contains primarily the glycosides genistin and daidzin. A retrospective cohort study of adults aged 20 to 34 fed soy milk or cow milk as infants in a controlled feeding study found no significant differences between groups in pubertal maturation, reproductive history, menstrual history, hormonal disorders, height, weight, or current health. Women fed soy as infants reported slightly longer duration of menstrual bleeding and greater discomfort with menstruation (38).
Soybeans are quite high in oxalates, containing 0.67 to 3.5 grams oxalates per 100 grams of dry weight. Commercial soy foods contain between 16 and 638 mg oxalates per serving, comparable to peanut butter, refried beans, and lentils (39). The oxalate content of soy foods may be of concern in patients who are avoiding oxalates because of nephrolithiasis (most kidney stones are composed of calcium oxalate). Some women with vulvodynia also choose to minimize dietary oxalates, which may aggravate symptoms.
There is much misinformation on the Internet about the putative adverse effects of soy on the thyroid. Genestin does inactivate thyroid peroxidase, and soy consumption may be linked to thyroid dysfunction if iodine is deficient. Iodine deficiency is a serious problem in many developing countries, but it is rare in North America due to iodine fortification of table salt. Soy supplementation does not appear to affect thyroid function in most iodine-replete women (40). It is possible, however, that soy interferes with the absorption of thyroid medication. In one case, a 45-year-old woman with hypothyroidism who required high doses of levothyroxine was able to reduce her dose by separating ingestion of a soy drink from ingestion of levothyroxine (41).
Although consumption of soy or other beans is probably benign, the safety of concentrated extracts or high doses of purified isoflavones has not been established. This is an issue because pure genistein or isoflavone mixtures are available at heath food stores.
The main cool-season annual legumes include Persian clover, berseem clover, crimson clover, arrowleaf clover, and subterranean clover. They can be grown alone or along with grasses. Annual legumes produce high-quality feed with a high digestibility and protein content. Clovers can be used to balance the protein deficiencies in maize, sorghum, cereal, and other forages. They can be grazed and conserved as hay or silage. Bloat can occur during grazing and should be controlled. Careful drying is required for silage production as the legumes have a low WSC content. They need to be dried efficiently to concentrate the WSC and ensure suitable silage fermentation. The legumes fix nitrogen, which contributes to the production of associated grasses following crops or pasture.
Management options include not planting soybeans next to clover fields. Also, pesticide applications may be useful for vector control. Alternatively, the use of tolerant soybean varieties is important for disease control. A major QTL, Rsdv1, for resistance has been reported between SSR markers Sat_217 and Sat_211 on chromosome 5 (Yamash*ta, Takeuchi, Ohnishi, Sasaki, & Tazawa, 2013). Also, coat protein-mediated transgenic resistance has been reported (Tougou et al., 2007). No reports suggest these strategies have been adopted in commercial production.
Virions of SBMV, GCFV, LTSV, SNMV, SCMoV, TRoSV, VTMoV and CMMV encapsidate minor amounts of heterogeneous subgenomic (sg) or putative sgRNAs. VTMoV virions contain two discrete sgRNAs, RNA-1a (0.63 × 106Da) and RNA-1b (0.25 × 106Da), besides the genomic RNA (Fig. 2). CfMV virions encapsidate a discrete 0.5 × 106Da RNA and several intermediate-sized putative sgRNAs. Included among the heterogeneous population of SBMV and TRoSV sgRNAs are the autonomized coat protein cistrons. The sgRNAs of SBMV, RYMV and LTSV possess VpG at their 5′ ends followed by the same sequence motifs as their respective genomic RNAs. LTSV, RYMV, SCMoV, SNMV and VTMoV virions encapsidate discrete, viroid-like satellite (sat) RNAs, in addition to the genomic and subgenomic RNAs. These satRNAs exist in linear and circular forms (Fig. 2). Complete sequences are known for satRNAs of LTSV (322nt), RYMV (220nt), SCMoV (322nt and 380nt), SNMV (377nt) and VTMoV (366nt). The satRNAs of SNMV and VTMoV exhibit a high degree of sequence hom*ology and are different from those of SCMoV or LTSV. At 220nt, RYMV satRNA represents the smallest known, naturally occurring virioid-like RNA. A region comprising 19% of the sequence of RYMV satRNA shows about 93% hom*ology to the satRNA of a Canadian LTSV isolate. The sobemoviral satRNAs contain a conserved hammerhead structure which is involved in self-cleavage (ribozyme).
Figure 2. Polyacrylamide gel electrophoresis and electron microscopy of the virion RNAs of velvet tobacco mottle sobemovirus. (Reproduced with permission from Velvet Tobacco Mottle Virus, AAB Descriptions of Plant Viruses no. 317, 1986; courtesy of Dr J. W. Randles.)
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