The liver is an amazing organ. It performs hundreds of essential functions including metabolism (of fats, proteins and carbohydrates), detoxification, synthesis of plasma proteins (albumin, globulins and coagulation proteins), storage of glycogen and gluconeogenesis (the generation of glucose from non-carbohydrate substrates), immunological functions and the synthesis of many essential compounds. The liver is at particular risk of the effects of poisons because it is one of the first organs exposed to ingested substances and is the major metabolising organ of the body.
Liver damage from poisoning can occur through various mechanisms. Some substances contain hepatotoxic substances or compounds that are metabolised to hepatotoxic chemicals. In some cases the mechanism of liver toxicosis is unknown. In the second article looking at poisons by organ system we discuss some poisons that affect the liver.
Unknown mechanism of liver damage
Xylitol has been much in the news lately and is well recognised as causing liver failure, although the mechanism of liver damage remains unknown. It may be due to prolonged adenosine triphosphate (ATP) depletion from xylitol metabolism resulting in cellular necrosis or production of reactive oxygen species that damage cell membranes and macromolecules (Dunayer and Gwaltney-Brant, 2006). In addition to liver damage, xylitol also causes hypoglycaemia as it is a potent stimulator of insulin release in dogs and this causes a decrease in blood glucose. A dose of 0.05 g/kg (50 mg/kg) xylitol can cause hypoglycaemia in dogs and more than 0.5 g/kg (500 mg/kg) can cause liver failure (Dunayer, 2006), although this may be idiosyncratic rather that a dose-related effect (Dunayer, 2006) since not all dogs that ingest more than 0.5 g/kg develop liver failure (Piscitelli et al, 2010). It is important to note that liver failure can occur in the absence of, or lack of diagnosis of, hypoglycaemia.
Xylitol is a sugar substitute (Figure 1) most commonly encountered as a sweetener in a wide variety of foods, particularly chewing gums. It is also found in many chewable medicines, and some ice cream and peanut butters. It is important when presented with a dog with hypoglycaemia and/or liver failure to determine if it may have been exposed to a potential source of xylitol. Xylitol-induced hypoglycaemia and liver damage is seen in dogs but not cats (or indeed humans) and the reasons for these species differences in the response to xylitol are unknown.
Figure 1. Xylitol is a well-recognised cause of liver failure in dogs.
Xylitol-induced hypoglycaemia can occur within an hour (Dunayer, 2006), but may be several hours after ingestion of chewing gum (up to 12 hours in some cases). This delay seen with xylitol-containing chewing gums is likely due to the formulation and because dogs generally do not chew the gum and swallow it whole (Murphy and Coleman, 2012). In some cases, particularly those with subsequent liver damage, hypoglycaemia can be delayed 24–48 hours (Dunayer and Gwaltney-Brant, 2006). Signs of liver damage occur 2–72 hours after ingestion (Dunayer and Gwaltney-Brant, 2006; Murphy and Coleman, 2012; Schmid and Hovda, 2016), but liver enzymes generally start to rise within 4–24 hours (Xia et al, 2009; Murphy and Coleman, 2012).
Clinical features of hypoglycaemia include tachycardia, ataxia, lethargy, weakness, coma, convulsions, hemiparesis, hypokalaemia, hypomagnesaemia and hypophosphataemia. Vomiting is common after ingestion of xylitol (Dunayer, 2006).
There are numerous reports of xylitol-induced liver failure in dogs (Foss, 2004; Dunayer and Gwaltney-Brant, 2006; Todd and Powell, 2007; Schmid and Hovda, 2016). There is raised alanine aminotransferase (ALT) and aspartate aminotransferase (AST), with a less marked rise in alkaline phosphatase (ALP), and elevated bilirubin. More rarely there is prolonged clotting time, thrombocytopenia and hyperphosphataemia.
If ingestion of xylitol was within an hour, the dog has not vomited already and is asymptomatic, emesis can be induced. Emesis is generally not recommended in dogs with clinical signs of hypoglycaemia, as there is a risk of aspiration if the dog has hypoglycaemic-induced central nervous system depression.
Dogs that have ingested a potentially toxic dose of xylitol should be admitted for monitoring. The following parameters should be obtained as baseline and monitored: blood glucose every 1–2 hours for at least 12 hours (Dunayer, 2006), potassium and phosphorus concentrations every 4–6 hours and corrected if necessary (Piscitelli et al, 2010), total bilirubin, liver enzymes, platelets, erythrocyte count and clotting parameters every 24 hours for at least 72 hours (Dunayer, 2006). As regular sampling is required in these patients it may be beneficial to use a sampling line. If this is not an option, it may be more practical to use an insulin syringe to blood sample and EMLA cream (containing lidocaine and prilocaine) to minimise stress to the patient.
It is also important to monitor the dog's mentation and cardiovascular status, as these are likely to change in animals with low blood glucose concentrations.
An antiemetic may be required to control vomiting. In dogs without clinical features of hypoglycaemia frequent small meals or oral sugar may be given for 8–12 hours (Dunayer, 2004). Dogs that have ingested more than >0.5 g/kg (500 mg/kg) should be started on intravenous dextrose therapy with monitoring of the blood glucose ever 2–4 hours (Dunayer, 2006). Dextrose therapy can be stopped after 24 hours if the blood glucose remains normal (Piscitelli et al, 2010).
Dogs that have ingested a potentially hepatotoxic dose should also be started on liver protectants, although their efficacy in xylitol-induced liver damage has not been evaluated. S-adenosyl-L-methionine (SAMe, 20 mg/kg orally), silymarin (50 mg/kg orally) or acetylcysteine can be considered (Piscitelli et al, 2010). For acetylcysteine the paracetamol treatment regimen can be used (oral or IV 140 mg/kg then 70 mg/kg orally every 6 hours for 36 hours or more).
Supportive fluid therapy may be required, particularly if the dog is not eating or drinking or requires rehydration following vomiting. Electrolyte supplementation may be required, and this can be given orally or intravenously, depending on the clinical condition of the dog and severity of biochemical changes. If feeding is ineffective or the dog is symptomatic then the hypoglycaemia should be corrected with an intravenous dextrose infusion.
The management of dogs in xylitol-induced liver failure is supportive. Plasma transfusions and vitamin K1 may be required in animals with coagulopathy.
Blue green algae
Cyanobacteria (blue-green algae) are a group of bacteria found in fresh, brackish and marine water bodies. Although they often have a blue-green colour they can also be red, brown and black. Blue-green algae occur in both freshwater and marine environments and are either floating (planktonic) or bottom-dwelling (benthic) (Gunn et al, 1992; Faassen et al, 2012). Under certain environmental conditions blue-green algae can quickly form extensive and often visible growths or blooms. These most commonly occur in warm weather and affect the colour, odour and taste of the water (Wood, 2016). If there is a strong wind or if the water is disturbed, cells can lose their ability to regulate their own buoyancy and may sink to the bottom or float to the top and cause surface scums (Figure 2). Not all blooms are toxic; analysis of blooms in Europe and North America found that 40% were toxic (Tyagi et al, 1999).
Figure 2. A pond with an algae bloom. Some blue-green algae (cyanobacteria) produce compounds that are toxic to the liver.
Dogs are commonly affected by cyanotoxins and have been reported to die after licking (including grooming) or eating algal material or swimming in affected water (Codd et al, 1992; Hamill, 2001; Hoff et al, 2007; Faassen et al, 2012; van Overbeeke, 2012; Backer et al, 2013). Cyanobacterial scum may also be ingested after washing up on the shore (Lürling and Faassen, 2013).
Mechanism of toxicity
Some cyanobacteria contain or produce a variety of toxic substances (cyanotoxins) and many produce more than one type of toxin (Tyagi et al, 1999).
Hepatotoxic compounds are the most commonly encountered in poisoning with cyanobacteria (Carmichael, 1992; Tyagi et al, 1999). These hepatotoxins are typically cyclic peptides which affect cellular proteins, and disrupt normal cytoskeletal structure (Falconer and Yeung, 1992; Dawson, 1998), leading to hepatic necrosis and failure. Hepatic haemorrhage also occurs. Fatalities resulting from exposure to this type of toxin normally occur as a result of hepatic necrosis, haemorrhage and hypovolaemic shock (McDermott et al, 1998). The most common compounds are nodularins, produced by species of Nodularia, and microcystins produced by Microcystis species. The compounds are released from the cyanobacteria on cell death.
Other cyanobacteria produce rapidly-acting neurotoxic compounds.
Gastrointestinal effects are often the primary presenting sign after cyanobacteria exposure.
Dogs are most commonly exposed to hepatotoxic cyanotoxins, and liver enzymes usually increase within 24 hours of exposure (Harding et al, 1995). Death can occur within a few hours (from neurotoxic cyanobacteria) to a few days after exposure to hepatotoxic cyanobacteria (Tyagi et al, 1999).
Initial signs of hepatotoxic cyanotoxin ingestion are non-specific with vomiting, diarrhoea, anorexia and lethargy. This is followed by weakness, pale mucous membranes, evidence of haemorrhage, hypotension or hypovolaemic shock and jaundice. Nephritis and liver failure may develop with coagulopathy, hypofibrinogenaemia, hypoproteinaemia, marked elevation of liver enzymes, bile acids, creatinine and urea. Anuria and decreased renal perfusion are also present in some cases (Simola et al, 2012). Death is due to hypovolaemic shock with hepatic haemorrhage or hepatic insufficiency.
Diagnosis of cyanobacteria poisoning is usually based on clinical signs and history of swimming in or drinking from an affected water body. Identification of cyanobacteria species cannot be performed by eye or by the general appearance of the bloom, and confirmation of exposure is not routine in most cases. Suspected blue-green algae exposure may be a reportable incident and animals, and dogs in particular, often act as a sign of water body safety (van Over-beeke, 2012; Backer et al, 2013). In the UK blue-green algae incidents should be reported to the Environment Agency which has a 24-hour Incident Hotline (telephone 0800 80 70 60, website https://www.gov.uk/government/organisations/environment-agency). If identification is required, then contact the local or government authority for advice. Samples should be refrigerated not frozen.
Treatment of cyanobacteria exposure is aggressive and supportive, as there are no specific antidotes for this type of poisoning. As it is not possible to confirm exposure within a clinically relevant time frame, all exposures are initially considered toxic and the animal should be decontaminated. In addition, it will not be possible immediately to determine whether a dog has been exposed to a hepatotoxin or a neurotoxin and there is the possibility that both types of toxin could be involved.
Emesis can be induced, but only if ingestion was very recent (<1 hour) and the dog is asymptomatic. Adsorbents (activated charcoal) should be given if practical, depending on the clinical condition of the dog. For suspected or confirmed hepatotoxic cyanotoxins the use of colestyramine (1–2 g/dog orally every 12 hours for 7 days or discharge) instead of activated charcoal has been advocated and was used in a dog that survived microcystin toxicity (Rankin et al, 2013). The rationale for colestyramine is based on studies showing binding of microcystin to colestyramine. In a rat study the degree of liver damage was less in those receiving colestyramine after microcystin administration compared with controls (Dahlem et al, 1989).
Thorough dermal decontamination is essential to prevent or reduce exposure from material on the coat. In critically ill animals, the dog should be stabilised first and then washed and collared. Care should be taken to protect staff during decontamination procedures as there is a risk of dermatitis (Bautista and Puschner, 2016).
All exposed animals should be observed for at least 6 hours post-exposure to assess for possible exposure to a neurotoxic cyanotoxin. Any further treatment of a symptomatic animal should be aimed at monitoring and management of potential liver toxicity.
In symptomatic animals it is essential to monitor liver function, clotting parameters, renal function and vital signs. Other treatment is mainly supportive with intravenous fluids and an antiemetic if required, to ensure hydration. Gut protectants and nutritional supplements have also been used.
Liver enzymes should be measured to establish a baseline when the animal is admitted even if they have no signs. If abnormal or the animal is symptomatic the liver enzymes should be measured again at 24 and 48 hours. If liver enzymes are normal after 48 hours it is unlikely the animal is at risk of hepatotoxicity. If liver enzymes are raised monitoring should continue until signs start to resolve. Liver enzymes may be elevated for several weeks. Liver protectants such as acetylcysteine and/or SAMe could be considered. The efficacy of these drugs in dogs with hepatotoxicosis from cyanotoxins has not been investigated but liver protectants were used with other interventions in two dogs that survived hepatotoxic cyanotoxin exposure (Rankin et al, 2013; Sebbag et al, 2013).
If there is evidence of haemorrhage a clotting profile should be checked and vitamin K given if coagulopathy is present. Blood transfusions and correction of electrolyte imbalance is recommended in these cases (Stewart et al, 2008).
Mushroom toxins — amatoxins
Several fungi contain cyclopetides but the most common are Amanita species including Amanita phalloides (death cap) (but not Amanita muscaria which is also known as fly agaric).
Mechanisms of toxicity
Fungi containing amatoxins are by far the most toxic and poisoning is characterised by hepatorenal failure. Amatoxins are primarily hepatotoxins and rapidly penetrate liver cells where they bind reversibly to RNA polymerase II, and completely inhibit the transcription of DNA into messenger RNA (mRNA) (Vetter, 1998). This prevents protein synthesis and results in cell death and tissue necrosis. Amatoxins undergo enterohepatic circulation, increasing exposure to the toxins (Busi et al, 1979). There is also severe hypoglycaemia due to impaired break down of liver glycogen.
One cap of Amanita phalloides (Figure 3) can contain sufficient quantities of amatoxins to be lethal to a human, dog or cat (Puschner and Wegenast, 2012).
Figure 3. Amanita phalloides (commonly known as death cap) contains hepatotoxic compounds.
The clinical picture of poisoning with amatoxin-containing fungi occurs in several phases. There are no signs for the first 6–12 hours, followed by a gastrointestinal phase, starting from 6–24 hours and lasting 12–24 hours. There is lethargy with abdominal tenderness, vomiting, watery diarrhoea (may contain blood and mucus threads) with dehydration and collapse. Severe hypoglycaemia occurs.
This is followed by a second latent phase from around 24–48 hours and lasting 12–24 hours during which time liver enzymes rise and prothrombin time becomes prolonged. The terminal phase occurs from 48–96 hours postingestion with watery, bloody diarrhoea, jaundice, hepatic and renal failure, coagulopathy, encephalopathy, convulsions and coma. Death usually occurs within 5 to 16 days but has been reported within 24 hours in dogs (Cole, 1993; Puschner et al, 2007).
Mixed ingestions with other fungus species may confuse this picture and this should be borne in mind when handling cases of possible mushroom poisoning.
Management of amatoxin poisoning is symptomatic and supportive. The aim is to reduce absorption and enhance elimination of toxins with aggressive supportive therapy and antidotal treatment, if possible.
Repeat-dose activated charcoal should be given for 24 hours after ingestion. Charcoal administration after 24 hours may be of limited benefit. In symptomatic cases the blood pressure, fluid balance, glucose, electrolytes, blood pH, renal and liver function and clotting parameters should be monitored.
Diarrhoea should not be treated as large amounts of amatoxins are excreted in the faeces (Jaeger et al, 1993). If vomiting is persistent antiemetics may be given and animals should be aggressively rehydrated with intravenous fluids. Adequate hydration is important to maintain renal function. Human data suggest impaired renal function due to dehydration should respond to aggressive fluid replacement (Piqueras, 1989), but a large ingestion may result in direct renal toxicity (Constantino et al, 1978). Any electrolyte imbalances and hypoglycaemia should be corrected. Vitamin K or fresh frozen plasma should be given to correct clotting abnormalities. Blood transfusions may be required in dogs with severe clotting abnormalities or bleeding.
Several antidotes have been used for amatoxin poisoning. Silibinin blocks uptake of amatoxins (Abenavoli et al, 2010), and in humans a 20-year review of amatoxin poisoning supported the use of silibinin alone or in combination with other antidotes (Enjabert et al, 2002). Acetylcysteine is an antioxidant and free radical scavenger and has been shown to have a positive effect in humans with amatoxin poisoning (Enjabert et al, 2002; Butera et al, 2004). It should be given in combination with silibinin. Benzylpenicillin (penicillin G) was used for many years in the treatment of amatoxin poisoning in humans but it has been found to have little efficacy (Enjabert et al, 2002), and it is no longer recommended.
Paracetamol (also known as acetaminophen or APAP in some countries) is a very widely and readily available non-narcotic analgesic (Figure 4). It is used therapeutically in dogs but not in cats or ferrets.
Figure 4. Paracetamol is commonly available in the home and can cause methaemoglobinaemia and liver damage in cats and dogs.
Mechanisms of toxicity
Paracetamol is metabolised in the liver by several pathways: glucuronidation, sulphation and oxidation. The products of glucuronide and sulphate pathways are nontoxic and are excreted in bile and urine. In most species the oxidation pathway is minor while glucuronidation is the major pathway of paracetamol metabolism. The oxidation pathway produces a highly reactive compound called N-acetyl-p-benzoquinoneimine (NAPQI), which is conjugated with glutathione, then further metabolised to non-toxic metabolites. At low dosing this is an effective and efficient detoxification pathway but at higher paracetamol doses when the glucuronidation and sulphation routes are saturated the oxidation pathway increases in activity. This results in increased production of NAPQI, and subsequent glutathione depletion in the liver. NAPQI then binds with cellular molecules and proteins causing cell death in the liver.
Cats and ferrets have a restricted ability to conjugate with glucuronic acid (Court, 2001) as they have low levels of glucuronyl transferase, the enzyme that catalyses the final step of the glucuronidation pathway. These species therefore have a limited ability to metabolise paracetamol to non-toxic metabolites and are at particular risk of paracetamol poisoning.
Other paracetamol metabolites result in methaemoglobinaemia and Heinz body formation (as outlined in the previous article in this series on poisons affecting the blood) (Bates, 2019).
The most widely used antidote in paracetamol poisoning is acetylcysteine; it can reduce the toxic effects of the drug by a variety of mechanisms. First, it is a precursor of glutathione and is metabolised to form a substrate for glutathione synthesis in erythrocytes and the liver. Second, acetylcysteine acts directly on the reactive metabolite NAPQI to form an acetylcysteine conjugate which can be excreted (although this reaction is slow). Third, it is oxidised in the liver to form sulphate thereby increasing the capacity of the sulphation pathway.
The initial signs of paracetamol poisoning are progressive cyanosis and dyspnoea. Mucous membranes appear brown in colour, and weakness and lethargy may be observed due to methaemoglobinaemia. There may also be paw and facial oedema.
Liver enzymes increase from 24–36 hours after ingestion (Richardson, 2000), and decreased packed cell volume (PCV), methaemoglobinaemia (characterised by chocolate coloured blood) and Heinz body formation may be evident. From 2–7 days there may be haemoglobinuria, intravascular haemolysis, jaundice, and other evidence of liver damage may be seen in animals that survive the initial stages of paracetamol poisoning.
The aim of treatment for an animal with paracetamol poisoning is to ensure adequate oxygenation and prevent further metabolism of paracetamol to toxic metabolites with the use of antidotes, and to prevent damage to the liver and erythrocytes. Any animal with signs consistent with paracetamol toxicosis should be treated irrespective of the time since ingestion or the dose ingested.
If ingestion was recent (within 1–2 hours) an emetic and activated charcoal can be considered, depending on the animal's clinical condition. Activated charcoal is known to bind to paracetamol (Bainbridge et al, 1977; Wilson and Humm, 2013).
Antidotal therapy should be started in any animal with signs of poisoning or that has ingested a potentially toxic dose. Acetylcysteine is the antidote of choice and can be given by intravenous infusion or orally; however, it has a sulphurous smell and taste which can cause hypersalivation, so it needs to be diluted to improve palatability if administered orally. SAMe and ascorbic acid can be given in combination with acetylcysteine.
Other treatment is essentially supportive with monitoring for signs of hypoxia, methaemoglobinaemia, liver damage, anaemia, haemolysis and renal impairment. Oxygen will be required in animals with cyanosis, and whole blood transfusions may be required in animals with evidence of severe haemolysis, significant decrease in packed cell volume (PCV), or severe anaemia.
Mushroom toxin — gyromitrins
Another group of toxic compounds present in some mushrooms is gyromitrins, most commonly encountered in Gyromitra esculenta, but other species also contain these toxic compounds.
Mechanisms of toxicity
In the stomach, gyromitrins are rapidly hydrolysed to N-methyl-N-formylhydrazine (MFH), some of which is then hydrolysed more slowly to the major toxin mono-methylhydrazine (MMH). The mechanism of toxicity is not entirely clear. Monomethylhydrazine can bind to pyridoxine (vitamin B6) which is a co-factor in various enzyme systems and in amino acid metabolism and MMH is also oxidised in the liver to unstable compounds which decompose to produce liver damage (Michelot and Toth, 1991).
Poisoning with these fungi is rarely reported in animals (Puschner and Wegenast, 2012), but death occurred in a dog from ingestion of less than one G. esculenta cap (Bernard, 1979).
Gyromitrin poisoning is characterised by gastrointestinal and hepatorenal signs. In the gastrointestinal phase (onset 2 to 24 hours after ingestion) there is abdominal tenderness, vomiting, diarrhoea, lethargy and pyrexia. The hepatorenal phase (onset 36 to 48 hours after ingestion) is characterised by hepatotoxicity and jaundice, tremor and muscle fasciculations, haemolysis, renal failure, severe convulsions, coma and respiratory arrest.
Gastric lavage or an emetic can be considered if ingestion is recent, depending on the animal's clinical condition. Activated charcoal can be given but treatment is symptomatic and supportive. The renal and liver function and blood glucose should be monitored. Convulsions should be treated conventionally with diazepam initially and phenobarbital if necessary.
Pyridoxine is the specific treatment for convulsions or coma in humans with gyromitrin poisoning, but it does not protect against renal or hepatic effects. The dosage of pyridoxine in dogs is 75–150 mg/kg intravenously (IV) (Puschner and Wegenast, 2012), as a 5–10% solution in 5% dextrose over 30–60 minutes.
Another natural source of compounds metabolised to hepatotoxins are cycads, an ancient group of plants commonly mistaken for ferns or palms (they are related to neither) that can be grown as house plants. All cycads have two types of cones (borne on different plants), one pollenbearing and the other seed-bearing. There are several genera classified as cycads. Cycas species are widely cultivated as ornamentals and the most commonly encountered is Cycas revoluta (sago palm, false sago palm or Japanese sago palm, Figure 5).
Figure 5. Cycas revoluta (sago palm but unrelated to palms) can cause severe liver damage in dogs.
All parts of the plant are toxic, particularly the seed kernels (also called nuts). Many cases in dogs involve the seeds even though they are reported to have an acrid and unpalatable flavour (Senior et al, 1985). As few as 1–2 seeds can cause poisoning and death in a medium sized dog (Milewski and Khan, 2006).
Mechanisms of toxicity
There are several toxins present in cycads. The azoxyglycosides cycasin, macrozamin and neocycasin are metabolised by β-glucosidase (which is produced by intestinal bacteria) to methylazoxymethanol (MAM). This compound and its derivatives are responsible for the hepatic and gastrointestinal effects of cycads (through alkylation of DNA and RNA). Neurotoxic effects seen with cycad toxicosis may be due to an amino acid, β-methylamino-L-alanine (BMAA). The main mode of action is via excitotoxic mechanisms, as studies have demonstrated increased generation of reactive oxygen species and calcium influx with disruption of mitochondrial activity and neuronal death. A third toxin, an unidentified high molecular weight compound, is also thought to be neurotoxic. Concentrations of the toxins vary with the species, the season and in individual plants.
There is very little information on cycad poisoning in cats but it is expected that they will exhibit the same signs of poisoning as dogs. In dogs, effects have been reported from 15 minutes to 3 days with a duration of 4 hours to 9 days. Laboratory parameters change 24–48 hours after ingestion (Albretsen et al, 1998).
Dogs typically develop gastrointestinal and hepatic effects after ingestion of cycads. Vomiting, haematemesis, diarrhoea (may be bloody), dehydration, abdominal discomfort and depression occur. There is hepatocellular necrosis with jaundice and secondary cholestasis, and in severe cases coagulopathy and ascites. Disseminated intravascular coagulation (DIC) has been reported (Holmgren and Hultén, 2009), and neurological effects with weakness, ataxia, coma and convulsions can occur.
Laboratory findings include hypoproteinaemia, raised liver enzymes, increased prothrombin time, hyper- or hypoglycaemia, hypocholesterolaemia, leucocytosis, thrombocytopenia, proteinuria, glycosuria, bilirubinuria and azotaemia.
Ingestion of cycad plant material can cause serious poisoning and treatment is recommended following ingestion of any quantity. Gastrointestinal decontamination with an emetic should be considered if ingestion was recent, vomiting has not occurred and the animal is stable. Repeated dose activated charcoal is recommended (Ferguson et al, 2011), as the main toxin undergoes enterohepatic circulation (Fatourechi et al, 2013). Laxatives and/or enemas may also be helpful to reduce transit time through the gut as intestinal bacteria are responsible for the conversion of substances in the plant to the main toxic compound (Fatourechi et al, 2013).
Treatment is supportive with attention to replacing fluid loss and protecting the liver and the gastrointestinal tract. Rehydration is usually required, and an antiemetic should be given if necessary. Gastroprotectants such as sucralfate and omeprazole may reduce gastrointestinal effects. A hepatic protectant such as SAMe (20 mg/kg orally daily) can be given (although there are no studies on the effectiveness of such therapies in cycad toxicosis). Liver enzymes should be monitored daily for at least 3 days in symptomatic animals. Other parameters to monitor include haematology (white blood cells, platelets), electrolytes, cholesterol, protein, renal function and clotting parameters. Animals that have had no signs within the first 24 hours and have normal blood results are unlikely to be at risk of poisoning. Vitamin K1 may reverse hypoprothrombinaemia. It is not indicated for coagulopathy that results from decreased hepatic production of clotting factors but may be of benefit in animals with deceased absorption of vitamin K due to cholestasis (Fatourechi et al, 2013). Blood or plasma transfusions may be required in severe cases. A well-balanced, low-protein diet should also be given.
Treatment should continue until clinical signs resolve or for as long as the liver function is abnormal. Hepatic fibrosis, acquired portosystemic shunts and cancer (liver, renal and gastrointestinal tract) can occur as long-term consequences of cycad exposure, although the incidence in dogs is unknown (Fatourechi et al, 2013).
Prognosis in dogs treated soon after ingestion is good, but if the animal is showing signs then prognosis is guarded (Albretsen et al, 1998). Those with serious complications of acute liver insult (e.g. cholestasis, DIC, sepsis) are more likely to have a poor outcome (Ferguson et al, 2011).
Poisoning can result in adverse effects on the liver through a variety of mechanisms, particularly through disruption of the normal functioning of the cell via damage to cellular molecules including DNA and RNA. This leads to the death of liver cells and hepatic necrosis. The liver is at high risk of damage by toxic metabolites because it is the main site of metabolism in the body and the first organ (after the gut) to receive ingested poisons. Xylitol and paracetamol are common and readily available substances that are toxic to the liver. Other hepatotoxic compounds are produced by some mushrooms, algae and plants such as cycads. When considering possible causes of hepatotoxicity, availability, including medicines and foodstuffs in the home, and seasonal availability, will also need to be considered.
- A number of drugs and chemicals can affect the normal functioning of the liver.
- Disruption of normal cellular functions causes cell death and hepatic necrosis.
- Xylitol and paracetamol are commonly encountered substances which can cause liver toxicity in dogs.
- Some blue-green algae (cyanobacteria) and mushrooms produce compounds that damage the liver.
- Acute ingestion of some plants, particularly cycads, can cause liver failure in dogs.
- When discussing with owners possible sources of substances causing liver damage in pets it is important to discuss medicines, plants and foodstuffs available in the home and seasonal risks such as blue-green algae and mushrooms.