Hepatic disease is common in large animals. Increases in serum hepatic enzymes and total bile acid concentration may indicate hepatic dysfunction, insult, disease, or failure. Although liver disease is especially common in horses and foals, progression to liver failure is not.
Diseases that frequently result in hepatic failure in horses include Theiler disease, Tyzzer disease (foals), pyrrolizidine alkaloid toxicosis, hepatic lipidosis, suppurative cholangitis or cholangiohepatitis, cholelithiasis, and chronic active hepatitis. Obstructive disorders (biliary stones, right dorsal colon displacement, neoplasia, duodenal ulceration and stricture, hepatic torsion, portal vein thrombosis), aflatoxicosis, leukoencephalomalacia, pancreatic disease, kleingrass or alsike clover poisoning, portal caval shunts, hepatic abscess, and perinatal herpesvirus 1 infections sporadically result in hepatic failure. Less frequently, hepatic failure is associated with endotoxemia, steroid administration, inhalant anesthesia, systemic granulomatous disease, drug-induced amyloidosis, hyperammonemia in Morgan foals, parasite damage, iron toxicity, or after neonatal isoerythrolysis.
In ruminants, hepatobiliary disease is associated with hepatic lipidosis, hepatic abscesses, endotoxemia, pyrrolizidine alkaloid and other plant toxicoses, certain clostridial diseases, liver flukes, mycotoxicosis, and mineral toxicosis (copper, iron, zinc) or deficiency (cobalt). Vitamin E or selenium deficiency (hepatosis dietetica), aflatoxicosis, ascarid migration, bacterial hepatitis, and ingestion of toxic substances (eg, coal tar, cyanamide, blue-green algae, plants, gossypol) are associated with hepatic injury in swine.
Although the exact incidence of hepatic disease in camelids (llamas, alpacas) is unknown, it appears to be common in North America. Hepatic lipidosis (secondary more often than primary) is reportedly the most common liver disease in llamas and alpacas, occurring in both crias and adults. Bacterial (Salmonella spp, Escherichia coli, Listeria spp, Clostridium spp) cholangiohepatitis, adenoviral hepatitis and pneumonia, fungal hepatitis (coccidioidomycosis), toxic hepatopathy (copper), halothane-induced hepatic necrosis, hepatic neoplasia (lymphosarcoma, hemangiosarcoma, adenoma), and liver fluke infestation have also been reported in camelids.
The liver can respond to insult in only a limited number of ways. Fat droplets in the liver may be an early and often reversible change. Biliary hyperplasia is also reversible if the insult is removed early. Necrosis of hepatocytes indicates more recent damage. The dead cells are removed by an inflammatory process and replaced with either new hepatocytes or fibrosis. Unless the dysfunction is acute and hepatocellular regeneration is evident, prognosis for animals with liver failure is usually unfavorable. Early hepatic fibrosis may be reversible with prompt recognition and intervention. Chronic disease with extensive loss of hepatic parenchyma and fibrosis, especially with portal bridging, warrants a poor prognosis.
Clinical signs of hepatic disease may not be evident until >60%–80% of the liver parenchyma is nonfunctional or when hepatic dysfunction is secondary to disease in another organ system. Clinical signs may vary with the course of the disease (acute or chronic), primary site of injury (hepatocellular, biliary), and specific cause. Onset of signs of hepatic encephalopathy and liver failure is often acute regardless of whether the hepatic disease process is acute or chronic. Clinical signs and severity of hepatic pathology reflect the degree of compromise of one or more of the liver’s vital functions, including blood glucose regulation; fat metabolism; production of clotting factors, albumin, fibrinogen, nonessential amino acids, and plasma proteins; bile formation and excretion; bilirubin and cholesterol metabolism; conversion of ammonia to urea; polypeptide and steroid hormone metabolism; synthesis of 25-hydroxycholecalciferol; and metabolism and/or detoxification of many drugs and toxins.
Icterus, weight loss, or abnormal behavior are common in horses with liver disease and hepatic failure. CNS signs are often the initial and predominant sign in horses with acute hepatic failure, whereas weight loss is a prominent sign in most but not all horses with chronic liver disease and failure. Photosensitization and, less commonly, bilateral pharyngeal paralysis, causing inspiratory stridor, diarrhea, or constipation, may be present. Affected cattle usually show inappetence, decreased milk production, and weight loss. Tenesmus and ascites are seen in cattle but are not common in affected horses. Weight loss may be the only sign associated with liver abscesses. Icterus, which is most pronounced when the biliary system is diseased, is also common in horses with acute liver failure. It is more variably present in horses with chronic liver failure or in ruminants. Fasting hyperbilirubinemia is a more common cause of icterus in horses and is not associated with hepatic disease. Occasionally, persistent hyperbilirubinemia (primarily indirect or unconjugated bilirubin) may be seen in healthy horses (especially Thoroughbreds) without evidence of hemolysis or hepatic disease. In ruminants, icterus is more commonly due to hemolysis and primarily involves increases in indirect bilirubin. Hyperbilirubinemia caused by obstructive biliary conditions is rare in goats and sheep.
Hepatic encephalopathy is associated with behavioral changes in horses, ruminants, and swine. The severity of hepatic encephalopathy often reflects the degree of hepatic failure but does not differentiate between acute or chronic liver failure. Signs of hepatic encephalopathy range from nonspecific depression and lethargy to head pressing, circling, aimless walking, dysphagia, ataxia, dysmetria, persistent yawning, pica, increased friendliness, aggressiveness, stupor, seizures, or coma. Pharyngeal or laryngeal collapse with loud, stertorous inspiratory noises and dyspnea occurs in some cases of hepatic failure, especially in ponies. The pathogenesis of hepatic encephalopathy is unknown, but proposed theories include ammonia as a neurotoxin, alterations in monoamine neurotransmission (serotonin, tryptophan) or catecholamine neurotransmitters, imbalance between aromatic and short branch chain amino acids resulting in increased inhibitory neurotransmitters (γ-aminobutyric acid, l-glutamate), neuroinhibition due to increased cerebral levels of endogenous benzodiazepine-like substances, increased permeability of the blood-brain barrier, and impaired CNS energy metabolism. Although the signs can be dramatic, hepatic encephalopathy is potentially reversible if the underlying hepatic disease can be resolved.
Photosensitization, which may be seen secondary to acute or chronic liver failure, must be differentiated from primary photosensitization (see Photosensitization Photosensitization read more ). Hepatogenous photosensitization develops when compromised hepatic function results in phylloerythrin, a photodynamic metabolite of chlorophyll, entering the skin. Phylloerythrin in the skin reacts with ultraviolet light and releases energy, causing inflammation and skin damage. Signs of photosensitization are varied but include uneasiness, pain, pruritus, mild to severe dermatitis with erythema, extensive subcutaneous edema, skin ulceration, sloughing of skin and ophthalmia with lacrimation, photophobia, and corneal cloudiness. Dermatitis and edema are particularly evident on nonpigmented, light-colored or hairless areas of the body and areas exposed to sun. Mucocutaneous junctions and patches of white hair are the most common sites of photosensitization in cattle. Occasionally, the underside of the tongue may be affected. Blindness, pyoderma, loss of condition, and occasionally death are possible sequelae. Pruritus may result from photosensitization or from deposition of bile salts in the skin secondary to alterations in hepatic excretion.
Diarrhea or constipation may be seen in animals with hepatic disease. Diarrhea is more commonly seen in cattle than in horses with chronic liver disease or in animals with chronic fascioliasis and hepatotoxic plant poisonings. Ponies and horses with hyperlipemia and hepatic failure may develop diarrhea, laminitis, and ventral edema. Some animals with liver disease have alternating diarrhea and constipation. Horses with liver failure and hepatic encephalopathy frequently develop colonic impaction due to decreased water intake. Constipation is characteristic of Lantana poisoning in goats and other ruminants.
Recurrent colic, intermittent fever, icterus, weight loss, and hepatic encephalopathy may be seen in horses with choleliths that obstruct the common bile duct. Infectious or inflammatory hepatic disease or failure of the liver to prevent endotoxin from gaining access to the systemic circulation may also result in intermittent fever and colic. Abdominal pain, due to pressure on the liver capsule from parenchymal swelling, often is seen in animals with acute diffuse hepatitis or trauma to the capsule itself. Affected animals stand with an arched back, are reluctant to move, or show signs of colic. In ruminants, pain may be localized to the liver by palpation over the anterior ventrolateral aspect of the abdomen or the last few ribs on the right side. Tenesmus followed by rectal prolapse is seen in some ruminants with liver disease. It may be associated with diarrhea, hepatic encephalopathy, or edema of the bowel from portal hypertension.
Hypoalbuminemia is not as frequently associated with liver disease in horses as previously thought. Due to the long half-life (~19–20 days in horses, ~16 days in cows) and liver reserve for albumin production, hypoalbuminemia is usually a very late event in the disease process. Serum total protein concentrations may be normal or increased because of an increase in β-globulins in horses with liver disease. Hypoalbuminemia and hypoproteinemia most commonly develop in chronic liver disease, and they are common findings in llamas with liver disease. Generalized ascites or dependent edema may result. Ascites is related to portal hypertension caused by venous blockage and increased hydrostatic pressure and to protein leakage into the peritoneal cavity. The abdominal fluid present with liver disease usually is a modified transudate. Hypoalbuminemia can aggravate the ascites, but if it is seen alone, it more likely will cause intermandibular, brisket, or ventral edema. Ascites is difficult to appreciate in horses and adult cattle unless it is extensive. Ascites is a common finding in calves with liver cirrhosis.
Anemia may be seen in animals with liver dysfunction due to parasitic diseases, chronic copper toxicity (in ruminants), some plant poisonings, or chronic inflammatory disease. Anemia in acute fasciolosis results from severe hemorrhage into the peritoneal cavity as the larvae penetrate the liver capsule. Trauma and feeding activity of adult flukes within the bile ducts cause anemia and hypoproteinemia in animals with chronic fasciolosis. Chronic inflammatory disease (eg, hepatic abscesses, neoplasia) may cause anemia without accompanying hypoproteinemia.
Clinical signs of severe or terminal hepatic failure include coagulopathies and hemorrhage due to decreased production of clotting factors by the liver and possibly increased utilization in septic or inflammatory processes. A prolonged prothrombin time is usually seen first because factor VII has the shortest plasma half-life. Horses may develop a terminal hemolytic crisis caused by increased RBC fragility. This has not been reported in ruminants.
Fecal color rarely changes in adult herbivores with liver disease. In young ruminants and monogastric animals, cholestasis may result in lighter color feces being passed because of loss of stercobilin, a metabolite of bilirubin.
Liver disease should always be considered when nonspecific clinical signs, such as depression, weight loss, intermittent fever, and recurrent colic, are present without an apparent cause. Differentiation between acute and chronic hepatitis or failure based on the duration of clinical signs before presentation may be misleading, because the disease process is often advanced before clinical signs are evident. Early vague signs of depression and decreased appetite may be overlooked. Liver biopsy to determine the type of pathology, degree of hepatic fibrosis present, and the regenerative capabilities of the liver parenchyma is necessary to develop a treatment plan and give an accurate prognosis.
Laboratory tests often detect liver disease or dysfunction before hepatic failure occurs. Routine biochemical tests such as serum enzyme concentrations are sensitive indicators of liver disease, but they do not assess hepatic function. Dynamic biochemical tests that assess hepatic clearance provide quantitative information regarding hepatic function. Tests of hepatic function are useful diagnostic and prognostic tools and provide a guide for the modification of drug-dosing regimens.
Serum concentrations of liver-specific enzymes are generally higher in acute liver disease than in chronic liver disease. They may be within normal limits in the later stages of subacute or chronic hepatic disease. The magnitude of increases in hepatic enzymes (especially γ-glutamyl transpeptidase) should not be used to determine prognosis. Hepatic enzymes are used to determine the presence of disease but not necessarily the degree of hepatic dysfunction. Careful interpretation of laboratory values in conjunction with clinical findings is essential.
Sequential measurements of serum γ-glutamyl transpeptidase or transferase (GGT), sorbitol dehydrogenase (SDH; also called iditol dehydrogenase [IDH]), AST, bilirubin, and bile acids are commonly used to assess hepatic dysfunction and disease in large animals. Serum GGT, bilirubin and total bile acid concentrations, and sulfobromophthalein (BSP®) clearance are not sensitive indicators of liver disease in young calves. Although GGT is primarily associated with microsomal membranes in the biliary epithelium, it is also present in the canalicular surfaces of the hepatocytes, pancreas, kidneys, and udder. Because of urinary and milk excretion of GGT and the rarity of pancreatitis in large animals, increased serum GGT concentrations most commonly indicate bile duct or liver disease. Some consider GGT to be the single test of highest sensitivity for liver disease in adult large animals. Increase of GGT is most pronounced with obstructive biliary disease. In acute hepatic disease in horses, GGT may continue to increase for 7–14 days despite clinical improvement and return toward normal of other laboratory tests. Reportedly, serum GGT concentrations become increased within a few days of liver damage and remain increased until the terminal phase. Chronic hepatic fibrosis is the only liver disease in which an abnormal increase in GGT might not be seen. Neonatal foals have higher GGT concentrations due to GGT present in colostrum and milk. Younger adult horses, especially those in active training, may show a nonspecific increase in GGT that is not associated with liver disease or other increases in liver enzymes or serum bile acid concentration. GGT is of little value in diagnosing liver disease in neonatal calves or lambs, because it is present in colostrum and milk. GGT activity may also be increased with colonic displacement or administration of drugs (eg, corticosteroids, rifampin, benzimidazoles, anthelmintics). Some liver-derived enzymes are higher in young calves (GGT, alkaline phosphatase [AP], glutamate dehydrogenase, lactate dehydrogenase) and foals (AP, GGT, SDH, AST), because they are transiently increased or come from sources other than the liver. Serum levels of hepatic enzymes also vary in goats with age, breed, and sex. Reference ranges must be appropriate for the species and age group being evaluated.
SDH, arginase, ornithine carbamoyltransferase (OCT), AST, isoenzyme 5 lactate dehydrogenase (LDH-5), glutamate dehydrogenase (GLDH), and AP are also used to assess hepatic dysfunction and disease. Arginase, SDH, and OCT are liver-specific enzymes in horses, most ruminants, and swine. SDH is most predictive for active hepatocellular disease, with marked increases in enzyme activity after hepatocellular damage. Mild increases in SDH can also occur with obstructive GI lesions, endotoxemia, anoxia from shock, acute anemia, hyperthermia, and anesthesia. Because of their short half-lives, SDH and LDH-5 are useful in assessing resolution or progression of liver insult. Both enzymes usually return to near-normal values 4 days after liver insult, and neither is usually increased in chronic liver disease. Rarely, in severe cases of hepatic failure, SDH may return to normal in spite of a fatal outcome. Arginase and GLDH are considered specific for acute liver disease, because both have high tissue concentrations in the liver and short half-lives in the blood. AST is highly sensitive for liver disease but lacks specificity, because high concentrations come from both liver and skeletal muscle. Other AST sources include cardiac muscle, erythrocytes, intestinal cells, and the kidneys. When CK is simultaneously measured to exclude muscle disease and the serum is not hemolyzed, increases in AST and LDH-5 are caused by hepatocellular disease. AST may remain increased 10–14 days or longer after an acute, transient insult to the liver. AST values are often normal in chronic hepatic disease. SDH and AST may be markedly increased with intrahepatic cholestasis and mildly increased with extrahepatic cholestasis. Increases in AP and GGT are associated with irritation or destruction of biliary epithelium and biliary obstruction. AP comes from the placenta, bone, macrophages, intestinal epithelium, and liver. AP is increased in very young calves and foals, probably because of the placental or bone source. In young calves, AP concentrations up to 1,000 IU/L at birth and 500 IU/L at several weeks of age are considered normal. AP concentrations of 152–2,835 IU/L are reported in foals (<12 hr old), and AP activity may remain high compared with adult levels for 1–2 mo. In calves (<6 wk old), none of the common tests (bilirubin, GGT, GLDH, AP, LDH, AST, or alanine transaminase) for liver damage or function are clinically useful for detection of hepatic disease when used alone. AST and GLDH are the most sensitive of the enzymes for hepatic injury, but AST also increases with muscle damage. AST concentrations in foals may be high compared with values of adults for many months. This increase is also likely related to muscle development. Transient and mild increases in SDH activity may be noted in some foals <2 mo old.
Serum concentration of bile acids is highly specific for liver dysfunction but does not define the type of insult or disease present. Serum bile acid concentrations increase with hepatocellular damage, cholestasis, or shunts from the portal system to the vena cava. Increases are highest with biliary obstruction and portosystemic shunts. Serum bile acid concentrations rise early in liver disease and often remain high through the later stages.
Total bile acid concentration remains increased in horses with chronic liver disease. In horses, there is no diurnal variation, no postprandial rise, and no significant hour-to-hour variation in bile acid concentrations. Serum total bile acid concentration in most healthy horses is <10 μmol/L. Concentrations of serum or plasma bile acids >20 μmol/L have a high sensitivity and positive predictive value for determining liver disease in horses but not in ruminants. Although bile acid concentrations >30 μmol/L can be an early predictor of liver failure, caution must be used in interpretation of mild increases, because bile acid concentrations up to 20 μmol/L may be seen in horses with anorexia. Prolonged, but not short-term (<14 hr), fasting may cause increased serum bile acid concentrations in horses.
Interpretation of total bile acid concentrations is difficult in foals <1 wk old. Compared with those in healthy adult horses, serum bile acid concentrations in healthy foals are considerably greater during the first 6 wk of life. When measuring serum bile acid concentrations in sick foals, it is particularly important to have healthy, age-matched controls or age-dependent clinical pathology values for reference.
In dairy cattle, serum bile acid measurement is of little value in recognizing fatty liver or liver disease or failure because of significant hour-to-hour variations. In recently freshened cows, serum total bile acid concentrations are significantly higher than in cows in mid-lactation or in 6-mo-old heifers.
Total bile acid concentration may be the best single test for hepatic disease in young calves. In calves, concentrations >35 μmol/L may indicate liver disease, bile obstruction, or a portosystemic shunt.
Reported reference intervals for serum concentration of bile acids are 1.1–22.9 μmol/L for llamas >1 yr old and 1.8–49.8 μmol/L for llamas <1 yr old. Bile acid concentrations in individual llamas may vary with feeding or sampling time of day, remaining within the reference interval.
Evaluation of serum bilirubin (direct and indirect) concentration is useful to determine hepatic dysfunction in horses and ruminants. Increases in bilirubin result from hemolysis, hepatocellular disease, cholestasis, or physiologic causes. Anorexia in horses causes a physiologic increase in total serum bilirubin to usually <6–8 mg/dL and rarely as high as 10.5–12 mg/dL, accumulating at a rate of ~1 mg/dL for each day of anorexia. The indirect bilirubin increases 2- to 3-fold, while the direct bilirubin remains within the reference range. In foals, indirect more than direct bilirubin may be increased with prematurity, neonatal isoerythrolysis, septicemia, or a portocaval shunt. Enteritis, umbilical infection, intestinal obstruction, and certain drugs (corticosteroids, heparin, halothane) may also cause hyperbilirubinemia. Mild, transient physiologic hyperbilirubinemia and icterus may be seen in newborn foals and calves. Although the mechanism(s) is not fully known, proposed causes include prebirth “loading of hepatocytes,” naturally high RBC destruction at or around birth, inefficiency in bilirubin excretion, or lower hepatocellular ligandin concentrations in neonatal foals than in adult horses. In healthy calves <72 hr old, total bilirubin may be as high as 1.5 mg/dL and up to 0.8 mg/dL in 1-wk-old calves. Direct bilirubin is usually <0.3 mg/dL in young calves. In healthy foals (<2 days old), total bilirubin concentrations may range from 0.9–4.5 mg/dL, with most being unconjugated bilirubin (0.8–3.8 mg/dL). Prematurity or illness (without liver disease) may increase unconjugated bilirubin fraction in young foals. Bilirubin concentrations in healthy foals should be within adult reference ranges by the time they are 2 wk old. Normal values for total bilirubin in goats are 0–0.1 mg/dL.
Horses with hepatic disease and failure most often have significant increases in both indirect and direct bilirubin. With liver damage in horses or ruminants, most of the retained bilirubin is indirect (unconjugated), and the direct-to-total ratio usually is <0.3 (more than two-thirds is indirect). Acute liver failure caused by hepatic necrosis results in increases in both indirect and direct bilirubin fractions. In horses with acute liver failure, the increase in bilirubin is primarily because of an increase in the indirect fraction. Hepatocellular disease should be considered when the indirect bilirubin fraction is >25% of the total bilirubin value. Direct-reacting bilirubin rarely exceeds 25%–35% of the total bilirubin in horses. Increases of this magnitude suggest predominant biliary disease or obstruction. With bile blockage or intrahepatic cholestasis, the direct-to-total ratio may be >0.3 in horses or 0.5 in cows. Increases in direct bilirubin may be seen in septic foals with intestinal ileus and minimal evidence of hepatocellular dysfunction.
In chronic liver disease, bilirubin concentrations are often within normal limits. Adult cattle and calves may have severe liver disease without any increase in serum bilirubin. In cattle, goats, and sheep, circulating bilirubin concentrations increase only modestly with severe, generalized hepatic disease. The most dramatic increases in serum or plasma bilirubin concentrations are due to hemolytic crises rather than to liver dysfunction. In the absence of hemolysis, total serum bilirubin concentrations >2 mg/dL indicate impaired hepatic function in ruminants.
Urobilinogen may be detected by dipstick analysis in healthy horses. Increased concentrations of urobilinogen in urine without hemolysis are suggestive of a hepatic dysfunction, portosystemic shunting, or increased production by intestinal bacteria. Urobilinogen in the urine indicates the presence of a patent bile duct. Absence of urobilinogen may indicate complete biliary blockage, liver disease, or failure to excrete bilirubin into the intestine, reduce it by intestinal bacteria, or absorb it from the ileum. The correlation between urobilinogen and hepatocellular disease in animals is poor. Urobilinogen is unstable in urine; thus, analysis must be done within 1–2 hr, or the amount will be decreased or undetectable.
Serum albumin and protein concentrations are variable in horses and cattle with hepatic disease. Hypoproteinemia is not common in horses with acute liver disease. Serum albumin is most likely to be reduced in chronic liver disease due to decreased functional hepatic parenchyma. In one study of 84 horses, 13% were hypoalbuminemic. Albumin concentrations were below minimum reference values in 18% of horses with chronic liver disease and 6% with acute liver disease. Globulin concentrations were increased in 64% of the horses. Hyperproteinemia due to hyperglobulinemia (polyclonal gammopathy or increase in β-globulins) may develop in horses with severe acute or chronic liver disease. Total plasma protein concentration is often normal, but the albumin to globulin ratio may be decreased.
Plasma fibrinogen concentration may not be a sensitive test in horses with hepatic insufficiency. Low fibrinogen concentrations may result from parenchymal insufficiency or disseminated intravascular coagulopathy. A high fibrinogen concentration is associated with an inflammatory response in horses with cholangiohepatitis.
Abnormalities in prothrombin time (PT) are often the first detected because factor VII, a liver-synthesized vitamin K–dependent factor, has the shortest half-life. Serum PT may be rapidly prolonged with hepatic failure and is one of the first function tests to return to normal with recovery from acute hepatic disease. A normal PT determination, however, does not exclude coagulopathy due to vitamin K deficiency. Prolonged activated partial thromboplastin time (APTT) or other indications of coagulopathy may be noted in animals with severe hepatic disease. Because a number of factors may influence PT or APTT values in horses, the ratio of clotting time of the horse with suspected hepatic disease to that of a healthy horse’s value should be >1.3 for the test to be interpreted as abnormal.
Serum concentration of urea may be decreased in both acute and chronic liver failure. Hypoglycemia is common in foals with hepatic failure. Blood glucose concentrations in adult horses with hepatic dysfunction are frequently normal or increased. Hypoglycemia, while less common in adult horses and ruminants with hepatic dysfunction, is more likely in chronic liver disease. Plasma triglyceride concentrations are markedly increased in ponies, miniature horses, donkeys, and adult horses with hepatic lipidosis. The magnitude of increase in serum triglycerides may correlate with prognosis in horses. Alterations in triglycerides, very-low-density lipoproteins, and esterified cholesterol levels are more common in ruminants than in horses with hepatic insufficiency. Neonatal foals have higher blood cholesterol and triglyceride concentrations than adult horses.
Plasma ammonia concentrations may be increased with hepatic insufficiency but do not correlate well with severity of hepatic encephalopathy except during portocaval shunts. Increased concentrations of blood ammonia and signs of hepatic encephalopathy without hepatic failure are reported in Morgan weanlings with hyperornithinemia, hyperammonemia, and normocitrullinuria syndrome and in adult horses with primary or idiopathic hyperammonemia. Ingestion of urea or ammonium salts is more likely to cause increases of blood ammonia and encephalopathy in cattle than in horses.
PCV and serum iron concentrations are often high in horses with severe liver disease. An increased PCV may persist in the face of fluid therapy and normal hydration status until the underlying liver disease is resolved. Secondary erythrocytosis (with or without increased erythropoietin concentration) has been noted in some horses with hepatic neoplasia. Increased serum iron concentration is commonly seen in horses with either hepatic and/or hemolytic disease.
Sulfobromophthalein (BSP®) or indocyanine green dyes can be used to assess hepatobiliary transport. The BSP half-life is prolonged when >50% of hepatic function is lost. The normal clearance half-life of BSP is <3.7 min in horses, 2.13 ± 0.19 min in goats, and ≤4 min in sheep. BSP clearance is longer in calves (5–15 min) than in adult cattle (≤5 min). Although dye excretion tests are usually prolonged with hepatic dysfunction, they may still be within the normal range. Hyperbilirubinemia, decreased hepatic blood flow, and significant cholestasis may falsely prolong BSP clearance, and hypoalbuminemia may falsely shorten it. BSP clearance in goats is most often prolonged with generalized hepatic lipidosis secondary to pregnancy toxemia. Determination of BSP clearance time, rather than half-life, reportedly is more useful in detection of liver disease. BSP clearance time in healthy fed and 3-day fasted horses is 10 mL/min/kg and 6 mL/min/kg, respectively. These tests, however, are of limited use in clinical practice because of the lack of commercially available pharmaceutical-grade BSP. Expense, procedural limitations, and equipment requirements for quantitation of indocyanine green clearance have limited its use as a diagnostic test.
Biliary patency and hepatocyte function, structure, and blood flow may be evaluated by hepatobiliary scintigraphy. Radionucleotide liver scans and biliary scans can detect alterations in blood flow or hepatic masses and biliary obstruction (atresia, cholangitis, cholelithiasis), respectively. Scintigraphy has been used in pigs, foals, and lambs to differentiate biliary obstruction from other causes of hyperbilirubinemia.
Ultrasonography can be used to evaluate liver size, appearance (shape, texture), and location in horses and ruminants for diagnosis of hepatomegaly, hepatolithiasis, biliary dilatation, cholelithiasis, or focal lesions. Tumors, cysts, abscesses, and granulomas may be seen. Diffuse diseases are harder to detect than focal processes, because the former cause less distortion of normal hepatic architecture. Diagnosis of diffuse liver disease should be substantiated by biopsy and histopathology. Ultrasound can be used to guide collection of liver biopsy specimens and to perform cholecystocentesis and aspiration of abscesses, masses, or bile samples (fluke eggs, bile acids, culture). It is also an accurate, noninvasive way to monitor the progression or resolution of disease. In horses, the liver should be imaged from both the right and left sides of the animal.
Percutaneous liver biopsy is the definitive way to diagnose hepatic disease. Histologic evaluation of the liver provides valuable information regarding cause and severity of the disease process. Most cases of liver disease are diffuse, so the sample will be representative of the disease. Samples can be obtained blindly, but ultrasonographic guidance decreases the risk of complications (peritonitis due to bile leakage or intestinal puncture, hemorrhage, or pneumothorax). Liver biopsies can also be obtained during laparoscopy, which offers the additional advantage of being able to visualize the surface of the liver and other abdominal organs for evidence of disease.
Samples should be placed in media for bacterial culture and sensitivity and in formalin for histologic evaluation. Coagulation profiles (prothrombin time, partial thromboplastin time, fibrinogen, fibrin degradation products, and optional platelet count) may be performed before liver biopsy to reduce the risk of hemorrhage. Liver biopsy may not be advised in an animal with clinical or clinicopathologic evidence of a coagulopathy or a hepatic abscess, because hemorrhage or contamination of the peritoneal cavity may result.
Contrast abdominal radiography in foals may help diagnose gastroduodenal obstructions and secondary cholangiohepatitis. Portosystemic shunts in foals or young calves can be identified with mesenteric portovenography by injecting radiopaque contrast solution into a jejunal mesenteric vein, followed by fluoroscopy or sequential survey radiographs to monitor the hepatic blood flow.
Initial treatment of animals with signs of hepatic disease or insufficiency is often supportive and started before the underlying cause and extent of hepatic damage is known. History, clinical signs, and laboratory data may give some clue as to the nature of the hepatic disease process, but liver biopsy is usually required to make a definitive diagnosis and to determine the degree of hepatic injury. Specific therapies for hepatic disease depend on cause, presence of liver failure, chronicity, degree of hepatic fibrosis or biliary obstruction, and species affected. Increases in hepatic enzymes without hepatic disease may not require specific therapy for the liver but rather for the primary disease.
Therapy is most successful when intervention is early, hepatic fibrosis is minimal, and evidence of regeneration in the liver exists. Horses with severe or bridging fibrosis respond poorly because of inadequate potential for liver regeneration. The goals for treatment of large animals with hepatic disease or insufficiency are to control hepatic encephalopathy, to treat the underlying disease process, to provide supportive care to allow time for liver regeneration, and most importantly, to prevent injury to the animal and those working with the animal. Animals with hepatic encephalopathy often show aggressive and unpredictable behavior that can result in injury to self or handlers.
Horses with hepatic encephalopathy may be aggressive or demonstrate repetitive behaviors that make restraint difficult. To ensure safety of the animal and handlers, sedation is required. Because most sedatives and tranquilizers are metabolized by the liver, their elimination half-life may be prolonged in animals with hepatic failure; therefore, dosages should be minimized initially until it is determined how the animal responds to lower dosages. Xylazine or detomidine given in small doses to effect can be used to control horses exhibiting abnormal behavior. Diazepam should be avoided in animals with hepatic encephalopathy, because it may enhance the effect of γ-aminobutyric acid on inhibitory neurons and worsen neurologic signs. Acepromazine should also be avoided, because it may lower the seizure threshold.
Dehydration, acid-base and electrolyte imbalances, and hypoglycemia should be corrected with appropriate IV fluids. Initially, a balanced polyionic solution is administered for rehydration. Potassium supplementation is added (10–40 mEq/L, depending on infusion rate) if the animal is hypokalemic or hypophagic. If IV infusion is not possible in ruminants, rehydration may be attempted by oral administration of fluids if rumen motility is normal. Rarely, some horses with hepatic disease have polycythemia, making evaluation of hydration status by PCV difficult. Severe acidosis may be present. Because rapid correction of the acidosis may exacerbate neurologic signs, acidosis should be corrected gradually by IV administration of fluids with a high concentration of electrolytes. If this fails or if blood pH is <7.1 (bicarbonate <14 mEq/L), bicarbonate may be administered cautiously. Supplemental vitamins are optional. Adequate fresh water should be available if the animal can swallow normally.
Factors that may contribute to the hepatic encephalopathy should be eliminated. Glucose as a 5%–10% solution is given to correct hypoglycemia if present. In addition, glucose supplementation helps decrease blood ammonia concentrations and reduces catabolic gluconeogenesis, protein catabolism, and need for hepatic gluconeogenesis. Unless the animal is hyperglycemic, a continuous IV infusion of glucose (5% at 2 mL/kg/hr or 10% at 1 mL/kg/hr) should be given, even to animals that are not hypoglycemic. The infusion rate should be adjusted so that euglycemia is maintained. Induction of moderate to severe hyperglycemia, rapid changes in glucose level, and glucosuria should be avoided. IV glucose should be used in combination with balanced electrolyte fluids and not as the sole fluid source.
Therapies directed toward decreasing either ammonia production in or absorption from the bowel include administration of mineral oil, neomycin, lactulose, and metronidazole. Administration of mineral oil decreases absorption and facilitates removal of ammonia. Passing a nasogastric tube in an animal with hepatic encephalopathy must be done cautiously, because nasal bleeding caused by decreased clotting factors may be difficult to control. Oral administration of neomycin (10–30 mg/kg, bid-qid for 1–2 days) has been used to decrease ammonia-producing bacteria in the intestine. Lactulose (0.2 mL/kg, bid; 0.3 mL/kg, PO, qid; or 90–120 mL/450 kg, tid-qid) is metabolized to organic acids by bacteria in the ileum and colon. Reduction in colonic pH reportedly fosters an increased bacterial assimilation of ammonia, decreased ammonia production, ammonia trapping in the bowel, intestinal microflora changes, and osmotic catharsis. Reportedly, oral administration of vinegar (acetic acid) has the same effect on colonic pH and ammonia concentration in the gut. Metronidazole (10–15 mg/kg, PO, bid-qid) decreases ammonia-producing organisms in horses but should not be used in food animals. If the animal can swallow, oral drugs can be mixed with corn syrup or molasses and given via dose syringe to avoid trauma and the risk of inducing hemorrhage during passage of a nasogastric tube. Neomycin, lactulose, and metronidazole may all potentially induce mild to severe diarrhea (salmonellosis) because of disruption of GI flora. Use of the drugs in combination is more likely to induce diarrhea than any one of the drugs given alone. Because metronidazole is metabolized by the liver, caution must be used when administering the drug to horses with hepatic failure. Neurologic signs due to metronidazole toxicosis may mimic hepatoencephalopathy.
Until the nature of the underlying hepatic disease is known, treatment with broad-spectrum antimicrobials is warranted if infectious hepatitis is suspected. A trimethoprim-sulfa combination is a good empiric choice because of its activity against gram-negative bacteria and its high concentration in bile. Penicillin in combination with an aminoglycoside has a broad spectrum of action and may be of benefit if a Streptococcus sp or an anaerobic or gram-negative coliform is suspected. Enrofloxacin has also been recommended. First- and second-generation cephalosporins have been used in foals and in other species. Ceftiofur sodium also has an enterohepatic cycle, with ~15% of active drug recycled through the liver and excreted out the biliary tree. Ceftiofur has a broader spectrum than most early generation cephalosporins and has proved useful to treat acute or recurrent ascending bacterial cholangiohepatitis. Metronidazole may be administered when anaerobic infection is suspected in horses. Specific antimicrobial therapy based on culture and sensitivity of a liver biopsy is ideal.
Pain may be controlled with appropriate doses of an NSAID (eg, flunixin meglumine, 1.1 mg/kg, IV, bid, or phenylbutazone 4.4 mg/kg, IV or PO, bid). Vitamin K1 (up to 1 mg/kg, SC; 40–50 mg/450 kg, SC) and plasma transfusions (1–2 L/100 kg) may be given when coagulopathies develop or hypoalbuminemia is present. In some horses with acute hepatic disease and failure, antioxidant (dimethyl sulfoxide, acetylcysteine, vitamin E, S-adenosylmethionine [SAMe]), and anti-inflammatory (flunixin meglumine, phenylbutazone) therapy may be useful. Mannitol has been recommended for treatment of suspected brain edema in fulminant hepatoencephalopathy. Horses with hepatic disease should be protected from sunlight.
Dietary management is essential for management of animals with hepatic encephalopathy or acute or chronic hepatopathy. Affected animals should be fed carefully, because dysphagia may be a problem. Relatively small amounts should be fed frequently, although this recommendation may prove impractical in the longterm for many clients. The diet should meet energy needs with readily digestible carbohydrates, provide adequate but not excessive protein, have a high ratio of branched-chain amino acids to aromatic amino acids, and be moderate to high in starch to decrease need for hepatic glucose synthesis. Fat and salt should not be added to the diet. Feeds used successfully in horses include grass or oat hay, corn, and sorghum. Small amounts of molasses may be added to improve palatability and add energy. Linseed meal and soybean meal have an excellent branched-chain to aromatic amino acid ratio and may be used as a protein supplement in small quantities. Beet pulp may be substituted for oat or grass hay. Beet pulp may be soaked first to allow full expansion before being fed. Choke may be a problem in some animals eating beet pulp.
The feeding of alfalfa hay, alfalfa-containing feeds, or other legume hays to horses with hepatic disease is controversial. Although alfalfa hay has a better branched-chain to aromatic amino acid ratio than grass hay, it may have too high a protein content. Feeding grass hay is preferred for animals with hyperammonemia or signs of hepatic encephalopathy. A mixed grass/alfalfa hay can be fed to horses without central neurologic signs if weight loss is a problem and the added protein is tolerated. Grazing grass pastures is allowable as long as signs of hepatic encephalopathy are controlled and exposure to sunlight is avoided.
Other feeds high in branched-chain amino acids include sorghum, bran, or milo. Parenteral or enteral supplement with branched-chain amino acids helps restore the normal ratio of branched-chain to aromatic amino acids. Supplementation with vitamins A, D, E, and K might be indicated, because these fat-soluble vitamins are not stored effectively or readily available from a diseased liver. Vitamin K1 may be indicated in animals with a coagulopathy. Large amounts of fat should not be fed to meet energy requirements; excessive fat may lead to a fatty liver.
Transfaunation (see Ruminal Fluid Transfer: Ruminal Fluid Transfer: Esophageal obstruction due to a foreign body (see Esophageal Obstruction in Large Animals) leads to severe discomfort and acute free-gas bloat. Physical removal of the object may be hampered... read more ) with rumen fluid from a healthy cow may help reestablish normal ruminal flora and enhance the appetite of affected cattle. Animals that will not eat voluntarily must be force fed. A gruel may be given by nasogastric tube in horses and swine or by orogastric tube or rumen fistula in ruminants. In ruminants, forced feeding of alfalfa meal (15% protein) and dried brewer’s grain or beet pulp with potassium chloride and normal rumen fluid has been recommended. Alfalfa hay and alfalfa-containing feeds may be better tolerated by cattle than by horses with hepatic disease. IV polyionic fluids with 5% dextrose, potassium chloride, and B vitamins may also be needed in animals not consuming adequate amounts.