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Basics ⬇

Outline

BASICS

Overview!!navigator!!

  • Many toxins can cause liver disease (i.e. toxic hepatopathy) in horses, with plant toxins being the most common
  • The pathophysiology of the hepatic disease will vary depending upon the specific toxin. PAs are known to inhibit mitosis and to cause progressive fibrosis. Some plant hepatotoxins such as those produced by alsike clover and panicum as well as mycotoxins and iron toxicosis may cause mostly periportal inflammation/apoptosis, vacuolization, biliary proliferation, and fibrosis
  • Drug-associated hepatopathy in the horse can occur with the coadministration of rifampin (rifampicin) and doxycycline in nursing foals being treated for Rhodococcus equi
  • Regardless of the initial site and mechanism of disease, prolonged injury and activation of hepatic stellate cells will often result in hepatic fibrosis. Proliferation of hepatocytes, beginning in the periportal region and moving in towards perivenous zones, will occur in many toxic hepatopathies as an attempt to repair the injury. Once severe hepatic fibrosis and/or prolonged attempts of proliferative repair are established microscopic examination of the liver may be of little help in identifying the initial type of injury or specific toxin
  • Treatment is primarily aimed at removing the source of the toxin and providing supportive care

Signalment!!navigator!!

Any age, breed, or sex.

Signs!!navigator!!

  • Mostly those of hepatoencephalopathy—head pressing, circling, blindness, maniacal behavior or depression, and excessive yawning
  • Photosensitization may occur on white-haired parts of the body or mucous membranes. A more generalized dermatitis may occur in association with liver disease. This more generalized disease may be caused by the adverse dermatologic effects of elevated serum bile acids, nutrient deficiencies caused by intestinal malabsorption, or from immune-mediated dermatitis. Uveitis may also occur from immune mechanisms
  • Icterus and discolored urine may be noted
  • Colic may occur because of gastric impaction, changes in liver size, or generalized discomfort
  • Weight loss occurs in many but not all cases of chronic poisoning

Causes and Risk Factors!!navigator!!

Numerous, but the most common include the following.

PA-Containing Plants

  • Senecio spp. (i.e. groundsel and ragwort), Amsinckia intermedia (i.e. fiddleneck), Cynoglossum officinale (hound's tongue), Heliotropium europaeum (heliotrope), and Echium plantagineum (Patterson's curse) are common in parts of North America
  • Usually ingested when mixed in “first cutting” alfalfa hay
  • Plants tend to be bitter with low palatability, but in drought conditions with sparse grasses may also be ingested in the pasture
  • Estimated that horses must ingest 2% or more of body weight to develop hepatic failure

Alsike Clover

  • One of the most common pasture-associated hepatopathies (northeastern USA and Canada)
  • Increased incidence of disease in wet seasons when clover grows well
  • Also causes disease when a large amount of clover is present in hay
  • Unknown if the toxic principle is the plant itself or mycotoxin produced by fungus living on the plant

Panicum

  • Panicum coloratum (kleingrass), Panicum virgatum (switchgrass), Panicum dichotomiflorum (fall Panicum)
  • Ingestion of pasture or hay can lead to disease, environmental variables may play a role—several cases of toxicity in horses fed fall Panicum hay in the late fall/early winter which was harvested in the same year
  • The toxic principle is thought to be saponin

Iron

  • Generally a result of overzealous oral iron administration or chronic ingestion of very high iron contaminated water
  • In newborn foals, even small amounts of iron given orally before colostrum may be fatal
  • In adult horses, very large amounts of iron given orally are necessary to produce toxicity

Mycotoxins

  • Fusarium moniliformis in horses fed contaminated grains
  • Most horses with Fusarium spp. poisoning have clinical signs associated with leukoencephalomalacia rather than hepatic failure
  • Horses have variable response to aflatoxins, ranging from no/minimal disease to death
  • A horse with presumptive microcystin-associated liver failure has been described

Drug Induced

  • Rare in the horse
  • Severe toxic hepatopathy reported in nursing foals treated for R. equi with rifampin and doxycycline; recommended to use caution with this combination of antibiotics in foals
  • No current reports of NSAID hepatopathy in horses
  • Imidocarb use in donkeys linked to severe hepatic disease, but not in horses
  • Age, species, genetic profiles affect hepatic metabolism and body elimination—generally, donkeys (especially miniatures) have increased hepatic metabolism, newborn foals have decreased hepatic metabolism

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

  • Primary hyperammonemia seen in adult horses with intestinal disease, Morgan foals, and foals with portosystemic shunts and in horses with encephalitis, central nervous system trauma, and selected metabolic disorders (e.g. severe acidosis)
  • Disorders leading to primary hyperammonemia generally involve only a mild increase in hepatic enzymes and do not have abnormalities in liver function tests (e.g. direct bilirubin, bile acids)

CBC/Biochemistry/Urinalysis!!navigator!!

  • CBC abnormalities most often involve neutrophilia and sometimes erythrocytosis
  • Liver enzymes, both hepatocellular (i.e. AST, SDH, glutamate dehydrogenase) and biliary (i.e. GGT, ALP), are markedly elevated in acute toxic hepatopathy, although AST and ALP are not liver specific. SDH has a short half-life and repeated measurements can be used to determine progression of disease. In chronic toxicities (e.g. PA poisoning), enzymes may not be markedly elevated, although GGT remains elevated in most cases, even with chronic fibrosis
  • Serum bile acids will be elevated in most cases if there is moderate loss of liver function
    • In horses with chronic liver disease values >25 mmol/L are indicative of a poor prognosis
  • Blood urea nitrogen and fibrinogen generally are abnormally low
  • Albumin, because of its long half-life, may remain normal or slightly low
  • Both conjugated and unconjugated bilirubin levels are increased with liver failure. In most cases, the greatest increase involves unconjugated bilirubin. With severe cholestasis, the conjugated bilirubin concentration may be ≥25% of the total bilirubin
  • Urine may be discolored (dark brown to orange) and, when shaken, the foam may appear green
  • Urine dipstick examination usually is positive for bilirubin

Other Laboratory Tests!!navigator!!

  • Prothrombin and partial thromboplastin times are prolonged, but platelet numbers and function remain normal so clinically significant bleeding is unusual
  • Blood ammonia may be high or normal
  • Urinary and/or hepatic concentrations of specific toxins may be found
  • Serum ferritin and measurement of hepatic iron may help to confirm the diagnosis of iron hepatopathy. Serum iron is frequently and secondarily elevated with a variety of liver diseases in the horse

Imaging!!navigator!!

Ultrasonography is the procedure of choice.

Other Diagnostic Procedures!!navigator!!

Liver biopsy is most commonly performed for microscopic diagnosis of either hepatocellular necrosis (e.g. acute iron poisoning), periportal or diffuse fibrosis from chronic toxicosis, and/or megalocytosis (e.g. PAs). Specific etiologies or etiopathogeneses are rarely found in cases of chronic hepatopathy, but the liver biopsy does allow for refining of the differential diagnosis list, treatment plan, or prognosis.

Treatment ⬆ ⬇

TREATMENT

  • In some cases, such as with hepatoencephalopathy, horses may need hospitalization to control abnormal behavior and supply supportive therapy (see chapter Icterus (prehepatic, hepatic, posthepatic))
  • Avoid activity, sunlight, and high-protein feeds but feed moderate amounts of protein to help prevent muscle catabolism and muscle aminogenesis

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

  • Detomidine (5–10 μg/kg IV) may be required to control maniacal behavior and propofol (2 mg/kg IV) can be used to control seizure/maniacal behavior in foals; it is important to avoid oversedation
  • Long-term sedation can be provided with pregabalin (3 mg/kg every 12 h PO) or gabapentin (5–12 mg/kg every 12 h PO)
  • For horses with hepatic failure, anorexia, and neurologic signs, IV fluids should be used—acetated Ringer's solution supplemented with 20–40 mEq KCl/L and dextrose (50 g/L)
  • In cases of hepatoencephalopathy, neomycin (10–20 mg/kg every 8 h PO for 1–3 days) to decrease ammonia produced by gastrointestinal bacteria. Lactulose (0.3–0.5 mL/kg every 8 h PO) can be administered concurrently to further decrease the chance of hyperammonemia and also soften stool in order to prevent constipation. Prebiotics or probiotics can also be given
  • Pentoxifylline (8.4 mg/kg BID) can be used for anti-inflammatory/antifibrosis treatment
  • S-adenosylmethionine (10 mg/kg daily), vitamin E (5 IU/kg daily PO), and milk thistle extract supplements can be used for antioxidant therapy
  • Colchicine (0.03 mg/kg daily PO) may be administered in hopes of decreasing fibrosis

Contraindications/Possible Interactions!!navigator!!

Colchicine should not be used to treat PA toxicosis as both colchicine and PA pyrroles inhibit mitosis.

Follow-up ⬆ ⬇

FOLLOW-UP

  • Prevent toxin exposure to all horses in the future
  • Feed a moderate-protein/high-energy feed, protect from sunlight
  • Avoid stress
  • Monitor serum enzymes and bile acids for progression of hepatic disease
  • Prognosis depends on toxin, degree of fibrosis, and progression of disease
  • All cases with moderate to extreme fibrosis have a guarded to poor prognosis for life >1 year

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Abbreviations!!navigator!!

  • ALP = alkaline phosphatase
  • AST = aspartate aminotransferase
  • GGT = γ-glutamyltransferase
  • NSAID = nonsteroidal anti-inflammatory drug
  • PA = pyrrolizidine alkaloid
  • SDH = sorbitol dehydrogenase

Suggested Reading ⬆ ⬇

Caloni F, Cortinovis C. Effects of fusariotoxins in the equine species. Vet J 2010;186:157–161.

Divers TJ. The equine liver in health and disease. Proc Am Assoc Equine Pract 2015;61:66–103.

Durham AE, Newton JR, Smith KC, et al. Retrospective analysis of historical, clinical, ultrasonographic, serum biochemical and haematological data in prognostic evaluation of equine liver disease. Equine Vet J 2003;35:542–547.

Smith MR, Stevens KB, Durham AE, Marr CM. Equine hepatic disease: the effect of patient- and case-specific variables on risk and prognosis. Equine Vet J 2003;35:549–552.

Author(s) ⬆

Authors: Thomas J. Divers and Nikhita P. De Bernardis

Consulting Editors: Henry Stämpfli and Olimpo Oliver-Espinosa