Liver disease in the horse: diagnostic aids and differential diagnosis

July 1, 2007

By Michelle Henry Barton, DVM, PhD, Dipl. ACVIM

Article

Excessive use of corticosteroids has been reported to induce liver disease in the horse.

The most common clinical signs of hepatic insufficiency in horses are weight loss, hepatic encephalopathy, icterus and colic.

Because of the lack of specificity in clinical signs, liver-disease identification relies heavily on serum biochemical analysis. Although increases in sorbitol dehydro genase (SDH), gamma-glutamyl transpeptidase (GGT) activity and serum bile-acids concentration (SBA) are highly specific for liver disease in the horse, they are not specific for the type of disease.

Figure 1: Hepatic ultrasonography can provide helpful information on the size of the liver. In this patient, the liver appears rounded and swollen and actually is fractured (arrow) from excessive deposition of fat.

Therefore, to further identify the cause of liver disease, diagnostic imaging and histopathology often are necessary. This second article will review liver ultrasonography, biopsy and differential diagnosis.

Figure 2: Ultrasonography can help detect abnormal architecture. Here, a neoplasic lesion generated a focal hypoechoic lesion (arrows) that was distinct from the surrounding parenchyma.

Diagnostic imaging of the liver

Transabdominal ultrasonography is useful for obtaining information on the general size of the liver (Figure 1); changes in the hepatic parenchyma, including abscesses, cysts and neoplastic masses (Figure 2); and detecting dilated bile ducts (Figure 3) or obstruction with choleliths (Figure 4).

Figure 3: Biliary ducts (arrow) normally are not visible, but are in this horse with biliary obstruction. A short segment of a portal vein, characterized by short, hyperechoic parallel lines is visible (arrowhead).

Ultrasonography should be used to assess both the right and left sides of the liver, though the liver is most reliably imaged on the right side from approximately the 9th to the 14th inter costal spaces. The edges of the liver should appear crisply sharp.

Figure 4: This patient has obstructive cholelithiasis that is characterized by the presence of a hyperechoic focus (arrow) that generates an acoustic shadow within a dilated bile duct (arrowhead).

The architecture of the normal equine liver should be relatively uniform and appear less echogenic than the spleen. The walls of portal veins are more echogenic than hepatic veins and often are seen as short, white parallel lines in the parenchyma (Figure 3).

The biliary ducts are not normally seen in healthy horses, and the common bile duct cannot be imaged transabdominally in adult horses.

Lack of notable size or architectural ultrasonographic changes in the liver do not rule out the possibility of significant disease. If the liver is small or there are focal ultrasonographic changes, ultrasonography is useful for guiding biopsy instruments into the liver.

Liver biopsy

A liver biopsy often provides the most specific information for an etio logic diagnosis. The procedure is performed in the standing horse at the right 12th to 14th intercostal space, at the intersection of a line drawn from the tuber coxae to a point midway between the elbow and the point of the shoulder. Sedation may be needed.

Although a liver biopsy can be obtained solely by using the previously mentioned anatomical landmarks, an ultrasound-guided biopsy often significantly increases the chances of obtaining a useful sample.

The skin overlying the area to be sampled should be clipped, aseptically prepared and a local-acting anesthetic injected subcutaneously. A stab incision is then made with a No. 15 scalpel blade. A Tru-Cut (Baxter-Travenol, St. Louis) biopsy instrument is inserted and directed craniad and ventrad through the diaphragm into the liver.

Semi-automatic biospy instruments and automatic biopsy guns are helpful for a quick and accurate liver biopsy.

Samples should immediately be placed in formalin for histopathologic evaluation and in transport media for culture.

Precautions to consider prior to performing the procedure include the risk of hemorr hage, pneumothorax and peritonitis from bile leakage and colon or abscess puncture, and spread from infectious hepatitis.

These complications may be reduced by performing a hemostasis profile to assess the risk of hemorrhage and by using ultrasonography to guide needle placement. Although subclinical coagulopathy has been reported frequently in horses with liver disease, clinically significant or fatal hemorrhage after a liver biopsy are rare.

Differential diagnosis

The wide variety of clinical signs with hepatic disease, coupled with the fact that the majority of the hepatic parenchyma must be affected before function is lost, make the clinical distinction between acute and chronic liver disease challenging. The onset of signs may be sudden, even with chronic disease. A history of progressive weight loss or "failure to thrive" may indicate chronicity.

Although no single blood test is specific for distinguishing acute from chronic hepatic disease, the presence of hyperglobulinemia and/or hypoalbuminemia may suggest chronicity. Histopathologically, the hallmark evidence of chronicity is the presence of fibrosis. For the purpose of discussion of specific hepatic disorders, diseases have been classified as either acute or chronic, based on the known etiology of the disease and by the frequency of occurrence (Table 1). For this discussion, a brief review of the most common differential diagnoses follows.

Table 1: Differential list for liver disease in horses

Theiler's disease

Although it remains one of the most common causes of acute hepatic failure in horses, the exact cause of Theiler's disease remains unclear. The onset of clinical signs of hepatic failure is acute, often rapidly progressing over several days. Most horses are anorectic and icteric; hepatic encephalopathy is reported in the majority of cases. The disease typically occurs sporadically.

Frequently, horses with Theiler's disease have received an equine-origin biological four to 10 weeks prior to the onset of hepatic failure; hence the name "serum-associated hepatitis."

Some reports suggest that lactating broodmares given tetanus antitoxin after parturition are particularly prone to Theiler's disease.

Recent inoculation with an equine-origin biological, coupled with an abrupt onset of clinical signs and laboratory evidence of hepatic insufficiency, are strongly suggestive of Theiler's disease. No single laboratory test is diagnostic; however, disproportionately increased SDH activity is supportive evidence of acute hepatic necrosis.

The histopathologic findings of widespread centrilobular-to-midzonal hepatocellular necrosis with hemorrhage offer the strongest diagnostic evidence of Theiler's disease.

Hyperlipidemia and hepatic lipidosis

Ponies, miniature horses and donkeys are most susceptible to hyperlipemia. Fat mobilization from adipose stores usually is first triggered by a stress, inability to maintain energy homeostasis or a negative energy balance, as may occur during late gestation, lactation, starvation or secondary to anorexia induced by some other primary disease, such as entero colitis, endotoxemia, parasitism, pituitary adenoma, azotemia and neonatal septicemia.

If fat mobilization exceeds the liver's ability to use it as an energy source or the liver's ability to repackage the fat and return it to the periphery, hepatic lipidosis ensues, disrupting normal hepatic function.

The onset of clinical signs of hyper lipemia often is acute and includes icterus, anorexia, weakness, severe depression, ataxia, muscular weakness, recumbency, diarrhea, mild colic, fever and dependent edema. In severe cases, clinical signs of hepatic failure may prevail, and sudden death due to hepatic rupture may occur.

Hyperlipemia should be considered in the differential diagnosis for ponies or miniature horses with clinical signs of severe depression, anorexia and icterus. The normal triglyceride level in horses and ponies should be less than 50 mg/dl, but may be four-times higher in healthy donkeys and pregnant pony mares. A definitive diagnosis of hepatic lipidosis is confirmed by the concurrent demonstration of increased blood concentrations of triglyceride (Figure 5), laboratory evidence of hepatic disease and ultrasonographic or histopathologic findings of fatty infiltration in the liver.

Figure 5: Opalescent appearance of plasma with excessive triglycerides in a pony with hyperlipidemia.

Toxic hepatopathy

There are numerous chemicals, drugs, mycotoxins and plant toxins that are hepatotoxic, but these rarely cause acute hepatic failure in horses. Clinical signs and routine laboratory diagnostics will not distinguish between these toxins, so diagnosis largely relies on exclusion of other causes, history of exposure and, in some cases, documentation of the toxin in the blood or liver.

Plants that have been reported to cause hepatic necrosis in horses in North America include: Kleingrass (Panicum), Lantana, Lechuguilla, Whitebrush, Sneezeweed (Helenium spp.), Lupine, bluegreen algae and ryegrass. Ingestion of pyrrolizidine alkaloid-containing plants is a common cause of chronic liver disease in horses and is discussed separately below.

Horses rarely are exposed to hepato toxic chemicals in sufficient amounts to induce hepatic failure. Potential hepatotoxic chemicals include arsenic, carbon tetrachloride, chlorinated hydrocarbons, carbon disulphide, pentachlorophenols, phenol, phosphorus, polybrominated biphenyl and paraquat. All of these cause centrilobular necrosis, except phosphorus, which causes primarily periportal changes.

Examples of intrinsically hepatotoxic drugs that cause zonal centri lobular necrosis include carbon disulfide and carbon tetrachloride. Idiosyncratic hepatotoxicity has been reported following administration of erythromycin, rifampin, tetracycline, halothane, phenothiazines, dantrolene, diazepam, sulfonamides, phenobarbital, phenytoin and aspirin. Excessive use of potent corticosteroids (triamcinolone) has been reported to induce liver disease in the horse.

Chronic megalocytic hepatopathy

Megalocytic hepatopathy occurs worldwide and is the most common cause of chronic liver failure in horses in certain parts of the United States. It is caused by the ingestion of pyrrolizidine alkaloid-containing plants. The development of clinical signs of liver disease is usually delayed for weeks to months after consumption. The onset of obvious hepatic failure, characterized by hepatic encephalopathy and photosensitization, is usually abrupt and occurs late in the disease. There are numerous species of pyrrolizidine alkaloid-containing plants in the United States. Senecio spp. and Amsinckia are primarily found in western states and Crotolariaspp. (Figure 6) and Heliotropium primarily in the Southeast.

Figure 6: Crotalaria, a pyrrolizadine alkaloid-containing plant.

Pyrrolizidine alkaloids are quite stable and intoxication may occur after ingestion of contaminated hay, pellets or grain. Ingested pyrrolizidine alkaloids are metabolized by hepatic microsomal enzymes to toxic pyrrole derivatives that impair cellular replication and protein synthesis, resulting in the formation of large hepatocytes (i.e. megalocytes). When the megalocytes die, fibrosis ensues. When fibrosis becomes extensive, failure is inevitable.

A presumptive diagnosis of megalocytic hepatopathy can be made from history of exposure to pyrrolizidine alkaloids, clinical signs and laboratory evidence of hepatic disease. Because fibrosis occurs periportally, GGT activity is persistently increased. The histopathologic findings of megalocytosis, biliary hyperplasia and fibrosis are essentially pathognomonic.

Cholelithiasis and cholangiohepatitis

Cholelithiasis occurs most commonly in adult, middle-aged horses. The most frequently reported clinical signs include icterus, abdominal pain, fever, depression and weight loss. Clinical signs often are intermittent unless the common bile duct is occluded, whereupon persistent abdominal pain prevails.

In horses, choleliths mostly consist of calcium bilirubinate (Figure 7) and are associated with cholangitis, which accounts for the presence of fever. Choleliths that obstruct bile flow cause increased biliary pressure, which likely is the reason for abdominal discomfort. If biliary pressure is not resolved, pressure-induced periportal hepatocellular necrosis with subsequent fibrosis ensues.

Figure 7: A large cholelith surgically removed from the common bile duct of a horse.

Cholelithiasis should be considered in the differential diagnosis in horses with a history of fever, icterus and abdominal pain, especially if accompanied by signs of hepatic disease. Hematology often reveals leukocytosis due to mature neutrophilia, especially if cholangitis is present. The most common abnormal laboratory findings that suggest cholestatic liver disease include markedly increased GGT (greater than 15 times normal) and markedly increased serum bile-acids concentration.

Hepatic ultrasonography often is helpful in securing a diagnosis by the presence of visibly dilated bile ducts and/or hyperechoic foci within the bile ducts that may cast acoustic shadows (Figures 3 and 4).

Determination of obstruction of the common bile duct in horses is difficult, as the common bile duct cannot be seen by transabdominal ultrasonography; thus choledocholiths often are detected only via palpation during exploratory celiotomy.

Obtaining a liver biopsy is useful for diagnostic, therapeutic and prognostic purposes. The histopathologic findings of periportal fibrosis, biliary stasis and hyperplasia and cholangitis are not pathognomonic for cholelithiasis; however, a liver biopsy may help rule out other causes of biliary stasis. Concentric fibrosis around intrahepatic bile ducts is evidence of occlusion of the common bile duct.

Michelle Henry Barton, DVM, PhD, Dipl. ACVIM is the Josiah Meigs Distinguished Teaching Professor at the University of Georgia's College of Veterinary Medicine, where she is a large-animal internist in academic practice. She received her DVM from the University of Illinois in 1985, her PhD in physiology at the University of Georgia in 1990 and became an ACVIM diplomate in 1990.