Presumptive chronic pyrrolizidine alkaloid poisoning in 2 pygmy goats due to ingestion of tansy ragwort (Jacobaea vulgaris) in southwestern British Columbia

Abstract

Two pygmy goats from a herd of 3 animals in British Columbia died within 24 hours of exhibiting lethargy. Histopathology revealed liver failure and tansy ragwort (Jacobaea vulgaris) was discovered in the goats’ pasture. Goats are typically resistant to the toxic effects of tansy ragwort. This is the first report of presumed tansy ragwort toxicity in goats in North America.

A pigmy goat on a small farm in the Fraser Valley was first noted to be lethargic the morning of March 3rd, 2015, and died that afternoon. The goat belonged to a herd of 3 animals and had year-round access to pasture, hay, and corn, oats, and barley (COB).

Case description

A 5-year-old female pygmy goat was submitted for postmortem examination to the British Columbia Animal Health Centre (AHC) on March 4, 2015. On postmortem examination, the animal was in excellent body condition. The rumen contained rich green feed material and there were normal formed feces in the colon. Segments of jejunum were dilated with watery contents. There was scattered petechial and ecchymotic hemorrhage throughout the epicardium. The liver was diffusely tan/gray with scattered capsular petechia, and the gallbladder wall was markedly edematous.

Histopathology of the liver revealed moderate generalized vacuolation of centro-acinar and mid-zonal hepatocytes, with hepatocellular megalocytosis, megalokaryosis, and occasional binucleation (Figure 1). Necrotic hepatocytes were individually scattered and Kupffer cells frequently contained a green-brown granular pigment. In the renal cortices, the tubular epithelial cells were hypereosinophilic with loss of cellular detail. There was extensive pericardial hemorrhage.

Figure 1.

Goat 1 — liver. Hepatocellular vacuolation, binucleated hepatocytes, megalokaryosis, and megalocytosis are evident. Hepatocellular changes have disrupted hepatic cord structure. Bridging portal fibrosis and bile ductule hyperplasia are absent. Arrowheads indicate hepatocytes with intense eosinophilic cytoplasm and loss of nuclear basophilia indicative of cell degeneration. Hematoxylin and eosin (H&E) stain. Bar = 50 μm.

The wall of the gallbladder was edematous, with bacilli colonizing its mucosal surface. Culture for the bacilli yielded heavy growth of Clostridium perfringens and toxin typing was positive for type A. Toxin exposure from the clostridia or an exogenous source was suspected and liver tissue was sent to Michigan State University Diagnostic Center for Population & Animal Health for toxicology. None of the compounds screened for by gas chromatography mass spectrometry (GC/MS) were present. The GC/MS test screens for over 100 000 organic molecules, including pesticides, herbicides, pharmaceuticals, industrial chemicals, and natural toxins. It does not screen for dehydropyrrolizidine alkaloid metabolites.

On July 9th, 2015 a 3-year-old female pygmy goat from the same group was presented to the Animal health Centre (AHC) with a 24-hour history of lethargy followed by sudden death. On postmortem examination, the animal was in good body condition, with congestion of the oral mucous membranes and a mild increase in pericardial fluid with moderate petechiation of the epicardial surface of the heart. The spleen was shrunken. The liver was pale with tan brown mottling in the caudate and right lateral lobes. The gallbladder was distended with bile and the bile duct was patent. There was increased watery fluid in the abomasum, small intestine, and cecum, and moderate edema of the abomasal rugae. Fecal pellets were soft and incompletely formed.

Culture of the gastrointestinal tract failed to isolate clostridia; however, heavy growth of non-hemolytic Escherichia coli was cultured from the bladder. Although postmortem examination found no evidence of parasitic disease, routine fecal floatation indicated a heavy load of strongyles.

Histopathology of the liver demonstrated moderate generalized macro- and micro-vesicular hepatocellular cytoplasmic vacuolation suggestive of lipid. Moderate bile ductule hyperplasia often extended into adjacent sinusoids. There was mild to moderate portal and septate fibrosis, and a mild, mainly lymphocytic, increase in portal inflammatory cells (Figures 2, 3). Hepatocytes displayed moderate megalocytosis, megalokaryosis, and occasional binucleation with sporadic hepatocyte degeneration (Figures 2, 3). Pigment-laden Kupffer cells were scattered in the portal tracts. There was mild to moderate multifocal hyaline and coagulative changes in the skeletal myofibers and confirmed submucosal edema of the abomasum. In the brain, moderate status spongiosus affected the cerebral and cerebellar white matter.

Figure 2.

Goat 2 — liver. Macro- and micro-vesicular cytoplasmic vacuolation of hepatocytes is widespread. Bridging portal fibrosis (arrow), bile ductule hyperplasia (small arrowhead) and hepatocellular cytoplasmic vacuolation, both micro-vesicular (open arrowhead) and macrovesicular (closed arrowhead) are shown. H&E stain. Bar = 100 μm.

Figure 3.

Goat 2 — liver. Hepatocellular vacuolation is evident. Hepatocellular changes have disrupted hepatic cord structure. Arrowheads indicate binucleated hepatocytes, megalokaryosis, and megalocytosis. H&E stain. Bar = 50 μm.

The remaining goat was given away and lost to follow-up.

Clinical course, postmortem findings, and histopathology results pointed to toxin exposure and moderate hepatic lipidosis contributing to liver failure in both goats. Examination of the goats’ pasture discovered large numbers of tansy ragwort (Jacobaea vulgaris) in the flowering stage distributed throughout (Figure 4). The Centre for Forest Biology at the University of Victoria confirmed the plant as J. vulgaris (personal communication, Patrick von Aderkas, Centre for Forest Biology, 2016). The pasture was otherwise of mediocre quality and heavily browsed. The goats also had access to hay year-round, which was made from an adjacent pasture of similar quality. On visual inspection, the hay was mostly thin-stem, cut late after going to seed. The hay was likely of similar composition to the goats’ pasture; however, it was not specifically analyzed for the presence of tansy ragwort.

Figure 4.

Concentration of Jacobaea vulgaris in the pasture where the goats were browsing in July, 2015. The plant is in its flowering stage.

Discussion

Tansy ragwort (Jacobaea vulgaris, formerly Senecio jacobaea), a biennial plant native to Europe, is now naturalized throughout Ontario, the Maritime provinces, and southwestern British Columbia. Members of the genus Jacobaea produce several secondary plant compounds guarding them against herbivores and insects. Toxicity varies considerably among species. Tansy ragwort’s toxicity to livestock is due mainly to pyrrolizidine alkaloids (PAs), specifically dehydropyrrolizidine alkaloids with a 1–2 unsaturation. Tansy ragwort causes agricultural revenue losses worldwide; in fact, pasture management for ragwort species is required by law in Australia, Ireland, and the UK (1,2). More than 26 animal species, including humans, are susceptible (1).

Pyrrolizidine alkaloids (PA) are hepatotoxic, carcinogenic, fetotoxic, and teratogenic (1). Absorbed from the small intestine, they reach the liver via the portal circulation. Their toxicity is due to a product of metabolism; hepatic microsomal enzymes dehydrogenate PA to pyrrole derivatives, which are thought to alkylate DNA and other macromolecules in the hepatocytes, inhibiting mitosis and cell division (1).

Histologically, PA toxicity leads to hepatocellular karyomegaly, cytomegaly, and in some cases vacuolar changes. The hepatocytes eventually reach a critical mass and cell death, hepatic fibrosis, and secondary biliary hyperplasia result (1,3). Toxic hepatocellular injury often leads to micro- and macrovesicular cytoplasmic vacuolation (lipidosis) due to interference with the complex pathway of hepatocellular lipid metabolism; throughput of lipid in the hepatocyte is diminished and leads to accumulation within the cytoplasm (4).

Postmortem examination typically reveals an enlarged firm liver, ascites, and patchy gastroenteritis, and usually indicates a chronic exposure with slow hepatic degeneration, although acute hepatic necrosis can occur at very high doses (1,5).

Pale livers with extensive hepatocellular degeneration, vacuolation, and megalocytosis, and megalokaryosis in both animals were consistent with other pathology reports of PA toxicity in goats (6–8). Although fibrosis and bile duct proliferation are commonly reported in the literature, histopathology in this case revealed these findings only in the second goat (1,6). The second goat could have been more resistant to PA toxicity, or shown greater aversion to the ragwort, causing a prolonged exposure to a lower dose. Alternatively, it is possible this was a subacute event, with chronic changes from a previous exposure.

Goeger et al (6) fed a 10% tansy ragwort ration to goats for 9 to 24 mo, and documented pathological findings. Chronic interstitial nephritis was noted. In this case, the first goat exhibited hypereosinophilia and loss of cellular detail of the renal tubular epithelial cells, but renal pathology was not detected in the second goat. Interstitial nephritis is rarely associated with clinical disease in ruminants although it can be a postmortem finding in goats (5). The renal pathology in this case was likely incidental. While the Goeger study (6) did not observe ascites or edema of the abomasum or mesentery, we observed edema of the gallbladder in the first goat herein, and edema of the abomasal rugae in the second. Abomasal edema was reported in a study of 5 Nubian goats that died of PA toxicity (9).

Clinical signs of acute PA toxicity include lethargy, weakness, and abdominal pain without loss of body condition. Death follows within a few days to weeks (5). Clinical signs of chronic PA toxicity reflect impaired hepatic perfusion due to fibrosis and decreased liver function, resulting in progressive weight loss, anorexia, lethargy, abdominal pain, and icterus. However, even in cases of chronic exposure, an acute hepatic insufficiency syndrome can present as sudden lethargy, anorexia, and ataxia, with rapid clinical deterioration and death (4,5). Hepatic encephalopathy is commonly a feature, as hepatic failure results in systemic accumulation of ammonia and other toxic metabolites, leading to neurotransmitter disturbances and cerebral edema (5). Histologically, status spongiosis is observed, particularly at points of confluence between the white and gray matter of the cerebral cortex, cerebellum, and brainstem (5). Moderate status spongiosis affected the cerebral and cerebellar white matter in the second goat. However, a veterinary examination and hematology were not performed antemortem and icterus was not observed. Consequently, hepatic encephalopathy cannot be definitively established.

Both the acute and progressive syndromes of chronic exposure were reported in 2006 in a herd of beef cows in Ontario exposed for 3 mo to J. vulgaris on pasture. Clinical signs of encephalopathy were not observed (4).

In clinical cases, toxicosis and hepatic insufficiency are suspected based on hematology. Hyperammonemia, bilirubinemia, and hypoalbuminemia are reliably seen, and bromsulphalein clearance rate is impaired. Serum gamma glutamyl transpeptidase (GGT) and glutamate dehydrogenase (GLDH) are also early indicators of hepatic injury in ruminants, but may return to normal levels in the later stages of disease (3,5). Liver biopsy and histopathology can be useful in estimating the degree of liver damage antemortem (3). However, a diagnosis of PA toxicosis is only confirmed with positive identification of pyrrole derivatives in the liver or blood, and in many cases only a presumptive diagnosis can be reached (5).

Differential diagnoses considered were blue-green algae, copper and iron toxicity, aflatoxins, various phytotoxins, and metabolic disease. Blue-green algae were unlikely as there was no body of water in the pasture and the goats drank municipal water. Non-fatal iron and copper toxicity cause acute hepatocellular necrosis, which may trigger portal fibrosis and biliary hyperplasia. However, megalocytosis and karyomegaly are not seen. At lower levels of chronic aflatoxin exposure, histological lesions can be similar to those caused by chronic PA toxicity, with megalocytosis, cell necrosis, bile ductule proliferation, and occasionally lipidosis. In the case of aflatoxin exposure, hepatocellular polyploidy is rare and megalocytosis is usually also seen in the renal proximal tubular epithelium. However, megalocytosis of the renal tubular epithelium was reported in a horse with PA toxicity (10). Hepatic lipidosis and secondary ketosis was ruled out due to the presence of megalocytosis, the good body condition of the goats, the absence of a chronic concomitant disease that would induce fat mobilization, and the observation that hepatocellular vacuolation is reported in goats experimentally fed PAs (6).

In the absence of toxin detection, the presence of multinucleated hepatocytes, the long-term opportunity for PA exposure, and the absence of opportunity for exposure to aflatoxins strongly influenced etiologic interpretation of PA toxicity in this case. In addition to tansy ragwort, other important plant genera responsible for liver disease in ruminants in North America include Crotolaria, Cynoglossum, Amsinckia, and Senecio (11). Tansy ragwort was the only candidate identified on pasture.

There is no established lethal dose for PA in livestock, although general parameters have been established (1). Ruminants are more resistant to the hepatotoxic effects of PA’s than are monogastrics. Sheep may be the most resistant ruminants, needing to consume 100% of their body weight over a few months to produce chronic toxicity. Goats are more resistant than cattle (1,6).

Species and individual variation in susceptibility are thought to be due to differences in ruminal microflora, which degrade PA and decrease the amount entering hepatic portal circulation (1). Plants on pasture (or PA levels in contaminated fodder) are rarely abundant enough to cause acute toxicity, and PA poisoning in ruminants is almost always due to chronic exposure (1).

The goats in this case were 3- and 5-years-old, and had been maintained on the same pasture for their entire lives. Tansy ragwort may not have existed on the pasture at this density for the goats’ entire lifespans, and could have been a more recent intruder. The weed is a skilled invader of unmanaged pastures and invasion risk is high if plants are identified within 50 m (2).

The density of tansy ragwort in the pasture was high (Figure 4). Due to frequent mowing, the density of tansy ragwort in the hay may have been less than on the pasture (2). If the poor pasture quality encouraged ragwort consumption and contamination of the hay was as high as 20%, the goats could have consumed 0.2 kg of tansy ragwort each day, or 100% of their body weight over 3 mo. This estimate is consistent with a study by Goeger et al (6), in which 120% of body weight fed over 5 mo was sufficient to cause chronic toxicity in goats, whereas 5% to 20% was well-tolerated (1). Similarly, Knight and Walter (11) report the chronic lethal dose in goats to be 1.2 to 4.4 kg/kg of body weight. A potential peracute toxicity in the first goat would require an unusually high rate of tansy ragwort consumption. Dosages for peracute toxicity in goats are not known because the time-dose relationship and individual differences are variable (1).

Treatment for PA toxicosis is symptomatic and often unsuccessful. Identifying other affected animals and preventing further exposure should be the primary focus and pasture management can be an effective tool for limiting exposure. Except under drought conditions, cattle and horses will typically not graze ragwort species, and ingestion of quantities sufficient to cause disease usually only occurs if the plants have been baled or ensiled in feed (12,13). Sheep and goats, on the other hand, will willingly browse ragworts, although they do not appear to relish it (6,14).

Pasture management to control ragwort aims to reduce the number of plants and prevent existing plants from going to seed. This can be achieved by mechanical, chemical, or biological means. Intensive mowing before flowering reduces seed production. Proper pasture management also helps prevent spread, as ragwort tends to establish where soil is exposed and forage is in poor condition (15).

Application of nitrogen in high quantities (100 kg/hectare/y) can reduce the occurrence of common ragwort by 80% (16). Herbicides have been tested with variable success; 2,4-D is effective at the seedling and young rosette stage, and dicamba when the plants are more advanced. However, clovers are also vulnerable to these herbicides (16,17). Biological control using the cinnabar moth (Tyria jacobaeae) and the flea beetle (Longitarus jacobaeae) has been very effective (2), but implementation of these biological agents in British Columbia has not yielded dramatic results (16).

Pyrrolizidine alkaloid toxicosis in livestock is a public health concern. These alkaloids are excreted in the milk, and neonates and small children are at greater risk because they are more physiologically susceptible to intoxication and because milk constitutes a large part of their diet (1). The goats in this case served as pets and posed no risk to human health.

The pathology in this case was typical of subacute to chronic PA exposure despite the short course of observed clinical disease, good body condition, and absence of icterus. The hepatocyte karyomegaly in both goats, and the bile ductule hyperplasia and septate fibrosis in the second goat, ruled out an acute exposure event. Indeed, acute onset of hepatic insufficiency and rapid clinical deterioration is a syndrome of chronic tansy ragwort toxicity reported in the literature (5). Because septate fibrosis and bile ductule hyperplasia were not observed in the first goat, subacute exposure cannot be ruled out. Nevertheless, it seems unlikely that these goats would have voluntarily eaten enough tansy ragwort over 3 to 6 d to elicit a subacute toxicity (1,5).

Poisoning from J. vulgaris is unusual in goats, and to our knowledge this is the first report of this occurrence in North America. Although goats willingly browse ragwort species, they are highly resistant to its toxic effects and overt disease is uncommon.