HEPATIC ABSCESSES

T.G. Nagaraja

Definition and Etiology

Hepatic abscesses occur sporadically in most animals but are most common in ruminants, particularly cattle fed high-grain diets. Hepatic abscesses occur at all ages and in all types of cattle, including dairy cows, but have the greatest economic impact in feedlot cattle, in which the incidence ranges from 1% to 2% to as high as 90% to 95%, but averages 20% to 30% in most feedlots.136 Because hepatic abscesses are generally a direct result of feeding practices, diet is an important factor influencing the prevalence. The prevalence of liver abscesses in dairy cows has not been documented, other than the anecdotal observations of liver abscesses “being not uncommon” in slaughtered heifers and cows. Most of the cows slaughtered are culled animals with low productivity, often related to disease, removed as a routine strategy to improve herd productivity.

Hepatic abscesses are generally polymicrobial infections, and in most cases the organisms are anaerobes. In the bovine, Fusobacterium necrophorum (formerly Sphaerophorus necrophorus), a gram-negative, pleomorphically rod-shaped anaerobe, is the primary etiologic agent. The organism also is implicated as the primary pathogen in necrotic laryngitis (calf diphtheria), foot rot, and foot abscesses in cattle.137,138 F. necrophorum is a normal inhabitant of the rumen, and its role in ruminal fermentation is mainly to utilize lactic acid and degrade protein. The organism is in higher concentration in grain-fed than forage-fed cattle, possibly because of the increased availability of lactic acid from starch fermentation. Several virulence factors have been implicated in the pathogenesis of F. necrophorum infections.138 These include leukotoxin, endotoxic lipopolysaccharide (LPS), hemolysin, hemagglutinin, capsule, adhesins or pili, platelet aggregation factor, dermonecrotic toxin, and extracellular enzymes (e.g., proteases, deoxyribonucleases).139 Leukotoxin is believed to be the major virulence factor. The leukotoxin is cytotoxic to polymorphonuclear neutrophil leukocytes (PMNs), macrophages, hepatocytes, and ruminal epithelial cells. Because of leukotoxin, the organism is able to survive, proliferate, and establish itself, to set up infection of the ruminal wall and liver. There are two subspecies of F. necrophorum, subsp. necrophorum (formerly biotype A) and subsp. funduliforme (formerly biotype B). These two subspecies differ in cell morphology, colony characteristics, growth patterns in broth, and most importantly, in virulence factors. Subspecies necrophorum is more virulent (produces more leukotoxin) and thus more frequently encountered in liver abscesses than subsp. funduliforme, which tends to occur more often in mixed infections.140,141

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In most situations, Arcanobacterium pyogenes (formerly Actinomyces, Corynebacterium), a gram-positive rod shaped organism, is the second most frequent pathogen isolated from liver abscesses. The ruminal wall appears to be the niche for A. pyogenes, an aerobe, because the wall provides an aerobic microenvironment in an otherwise anaerobic environment of the rumen.142 The organism may also act in synergy with F. necrophorum to cause liver abscesses.143

Pathogenesis

Abscesses in the liver result from entry and establishment of F. necrophorum either alone or with other bacteria. The routes by which the bacteria can gain access to the liver include: the portal vein, hepatic artery, umbilical vein (in newborn with omphalophlebitis), bile duct system, and direct extension. Entry through the hepatic artery (after an episode of septicemia) or the bile ducts (usually from obstruction, infection ascending from duodenum, or migration of flukes) is a rare occurrence. The direct extension of infection from adjacent tissues and organs, usually of traumatic origin, such as direct puncture of the liver by a foreign body lodged in the reticulum, is more likely to occur in dairy cows. Traumatic reticuloperitonitis caused by metallic objects lodged in the reticulum and perforating through the reticular wall, rarely involving the ruminal wall, is often a predisposing factor for liver abscesses in dairy cows. However, in both dairy cows and feedlot cattle, the most common route of entry of bacteria into the liver is the portal vein.

Liver abscesses are secondary to the primary foci of infection in the ruminal wall. Evidence to support this is the high correlation between ruminal wall lesions (rumenitis) and liver abscesses, thus the term rumenitis—liver abscess complex (Fig. 33-3). It is well accepted that ruminal lesions resulting from acidosis are the predisposing factors for hepatic abscesses. Acid-induced rumenitis and damage of the protective surface usually are associated with a sudden change to high-energy diets and other dietary indiscretions, such as a change in feeding patterns, letting cattle become overly hungry, feeding unpalatable diets, and feeding very little roughage.144 The ruminal damage often is aggravated by foreign objects in the feed, sharp feed particles, or hair.143 The ruminal wall that is damaged from acidity or penetration of foreign objects becomes susceptible to invasion and colonization by F. necrophorum. Once colonization has occurred, F. necrophorum can gain entry into the blood or cause ruminal wall abscesses and subsequently shed bacterial emboli to the portal circulation. Bacteria from the portal circulation are filtered by the liver, leading to infection and abscess formation.

image

Fig. 33-3 Pathogenesis of liver abscesses in cattle fed high-grain diets.

Modified from Nagaraja TJ, Chengappa MM: J Anim Sci 76:287, 1998.

Undoubtedly, the virulence factors of F. necrophorum play a critical role in the penetration and colonization of the ruminal epithelium and entry and establishment of infection in the liver. The protease activity, dermonecrotic activity, and cytotoxic effect of leukotoxin on ruminal cells may aid in penetration and colonization of the ruminal wall. F. necrophorum, being an anaerobe, must overcome both high oxygen concentrations and phagocytic mechanisms to survive, proliferate, and initiate abscess formation. The leukotoxin may protect it from phagocytosis. Also, the release of cytolytic products such as lysosomal enzymes and oxygen metabolites, resulting from destruction of phagocytes, has a detrimental effect on the liver parenchyma. Synergism with facultative bacteria, intravascular coagulation induced by endotoxic LPS and platelet aggregation factor; formation of fibrin-encapsulated abscesses, and impairment of oxygen transport by damaged erythrocytes (action of hemolysin) all may contribute to the establishment of an anaerobic microenvironment conducive to the growth of anaerobic bacteria within the ruminal wall and liver.

Pathology

Abscesses found in the liver at slaughter or necropsy often are well encapsulated, possessing thick, fibrotic walls. Histologically, a typical abscess is pyogranulomatous, with a necrotic center, encapsulated, and often surrounded by an inflammatory zone.141 Hepatic abscesses are pus filled, have capsules that vary in thickness, and range in size from a minute pinpoint to over 15 cm (6 inches) in diameter. The number of abscesses in the liver can vary from one to hundreds, and sizes range from less than 1 cm (0.4 inch) to greater than 15 cm in diameter, often encircled by a hyperemic zone. The larger abscesses may be the result of small abscesses coalescing early in development. The distribution of abscesses in the liver shows no consistent pattern, with superficial and deep abscesses distributed almost evenly. Often, small abscesses are scattered throughout the organ, whereas large abscesses are located close to the portal entry.

Clinical Signs and Diagnosis

Liver abscesses are detected only at the time of slaughter. Cattle, even those that carry hundreds of small abscesses or several large abscesses, seldom show any clinical signs. Occasionally, the rupture of a superficial abscess or erosion and perforation of the caudal vena cava could lead to extensive spread and massive infection of other organs and eventual death. Generally, hematology and liver function tests have not proved to be good indicators of liver abscesses.145 In animals in which abscesses were induced by experimental inoculation of F. necrophorum, hepatic dysfunction was documented by elevated serum protein, bilirubin, and enzymes, such as GGT and SDH concentrations.146

Ultrasonography is a useful technique in the diagnosis of various hepatic diseases in cattle because of the location and tissue consistency of the liver.147 The technique has been shown to be useful for monitoring the onset and progression of experimentally induced abscesses where the site of injection is known.146 The development of abscesses in feedlot calves has been recorded by ultrsonographic examination at regular intervals from weaning to slaughter.145 However, its application to the diagnosis in feedlot cattle is limited because the ultrasonographic scanning cannot visualize the whole liver, particularly the left side facing the internal organs, and parts of lobes are covered by other organs (e.g., lungs, kidneys).

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Treatment

Both F. necrophorum and A. pyogenes are susceptible to penicillins and macrolides. However, antibiotic treatment is seldom practical in cattle because complete recovery is difficult to attain. Cattle with sequelae (e.g., CVCT syndrome), for economic reasons, are generally culled for slaughter.

Prevention

According to the U.S. Feed Additive Compendium, five antibiotics (bacitracin methylene disalicylate, chlortetracycline, oxytetracycline, tylosin, and virginiamycin) are approved for prevention of liver abscesses in feedlot cattle.148 These antibiotics vary in their inhibitory effect on F. necrophorum and A. pyogenes and their effectiveness in preventing liver abscesses. Tylosin, a macrolide, is the most effective antibiotic and the most commonly used feed additive (6 to 8 g/ton, or 60 to 90 mg/head/day) in the feedlot. Studies show that tylosin feeding reduces abscess incidence about 40% to 70%. A vaccine combination of F. necrophorum leukotoxoid and A. pyogenes bacterin given to feedlot cattle has been shown to reduce the prevalence and severity of liver abscesses.149 In addition to inclusion of antimicrobial compounds in the feed or vaccination, prudent bunk management to minimize ruminal acidosis is well accepted as a key factor for effective control of liver abscesses.

SEQUELAE

Septic cardiac and pulmonary emboli are also associated with liver abscesses in feedlot and dairy cattle. Occasionally, sudden death has been reported in cattle secondary to rupture of liver abscesses, with septic embolization in the right side of the heart. Generally, the condition starts as phlebitis caused by the extension of liver abscesses involving caudal vena cava. The phlebitis leads to thrombus formation anywhere between the liver and right atrium, but most often at the point of entry of caudal vena cava into the diaphragm. The clinical syndrome and the extent of lesions observed depend on the degree of thrombosis and type of organisms involved. The syndrome can range from death caused by rupture of caudal vena cava to various degrees of pulmonary embolism, pneumonia, infarction, endocarditis, hemoptysis, and epistaxis. Collectively, these lesions are categorized under caudal vena cava thrombosis (CVCT) syndrome.150,151

ECONOMIC IMPORTANCE

Liver abscesses are a major economic liability to the producer, the packer, and ultimately the consumer of beef. Abscesses are the leading cause of liver condemnation in the United States. The National Beef Quality Audit indicated that liver condemnations ranked as one of the top-10 concerns of packers.152 The greatest economic impact of hepatic abscesses is not from the condemnation of liver but from the reduced animal performance. Cattle with abscessed livers have reduced feed intake, reduced weight gain, decreased feed efficiency, and decreased carcass dressing percentage. These effects are evident only in cattle with the most severe abscesses (one or more large abscesses or multiple small abscesses).153

HEPATIC ABSCESSES IN HORSES

Hepatic abscesses occur sporadically in horses and are generally part of the intraabdominal abscess complex. In studies that have evaluated horses with intraabdominal abscesses, 12% (3/25)154 and 53% (8/15)155 of horses had abscesses in the liver. Hepatic abscesses in horses are usually associated with septic portal vein thrombosis but may also develop as an extension of the inflammatory process involving the intestinal tract, or as sequelae to abdominal surgery.156 A variety of bacterial species, particularly anaerobes, have been cultured from the pus. The most frequently isolated bacteria include Streptococcus equi, Escherichia coli, Bacteroides fragilis, Corynebacterium pseudotuberculosis, Fusobacterium necrophorum, and Peptostreptococcus species.155-157

Clinically, horses with hepatic abscesses cannot be differentiated from other intraabdominal abscesses. Generally, horses have a history of fever, loss of appetite, signs of colic, depression, and weight loss. Clinicopathologic changes are typical of chronic bacterial infection and include leukocytosis, thrombocytosis, hypoalbulinemia and decreased A/G ratio.154-156 The prognosis is generally poor because of failure to respond to antimicrobial treatment. Percutaneous or surgical drainage has been shown to be effective, with high survival rate in humans with hepatic abscesses.

HEPATIC LIPIDOSIS

John Maas

Erwin G. Pearson

The conditions described next can cause hepatic lipidosis. Pathophysiology and prevention are similar for each and are described at the end of this section.

FAT COW SYNDROME, LIPID MOBILIZATION SYNDROME

Definition and Etiology

Fat cow syndrome is a multifactorial condition occurring in dairy cows after parturition. The syndrome is characterized by progressive depression and failure to respond to treatment of other predisposing diseases. It is associated with excessive mobilization of fat to the liver in well-conditioned or overconditioned cows. This mobilization of fat is induced by the negative energy balance and hormonal changes that occur during the periparturient period. This negative energy balance in most cases is aggravated by concurrent periparturient diseases that reduce feed intake and increase energy needs.158-161

Clinical Signs

The clinical condition occurs in the postparturient period. Most affected cows are either obese or very well conditioned, with a large amount of omental and subcutaneous fat. Presenting signs usually include depression, anorexia, weight loss, and weakness that can lead to recumbency. Most will have nonspecific signs, such as decreased rumen motility and decreased milk production. Other signs vary and are related to concurrent diseases. The concurrent diseases most frequently seen are metritis, retained fetal membranes, mastitis, parturient paresis, and displaced abomasum.158,159 It is important to look for these other diseases; even if mild, they could be significant in these cases and must be treated.

Clinical Pathology and Diagnostic Tests

Most laboratory tests are poor indicators of hepatic lipidosis and are of little value in determining the severity of the disease.162 Liver-derived enzymes are usually elevated above the level in the dry cow but are often within normal ranges. Some serum enzyme levels increase in the periparturient period in normal cows. Many cows with hepatic lipidosis have a leukopenia and a degenerative left shift, but this is not specific. As expected, serum free fatty acids (FFAs) will be increased, and triglycerides and cholesterol will be decreased. Most of the total cholesterol is in lipoproteins. Serum total bile acids are not significantly increased in most cows with fatty livers.163 The sulfobromophthalein dye excretion test may be useful prognostically, because those with a half-life longer than 9 minutes have a more guarded prognosis.164Table 33-9 provides common abnormal laboratory findings.

Table 33-9 Common Clinicopathologic Abnormalities in Fat Cow Syndrome

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Liver biopsy may confirm the fatty infiltration of the hepatocytes, but a moderate to high amount of fat (15% to 30% total fat on a wet-weight basis)* is present in the liver of all postparturient, high-producing dairy cows, even those that remain healthy.165,166 Fat is usually quantified by histologic methods, by measuring total hepatic fat on a wet weight basis, or by floating in copper sulfate solutions of various specific gravity (to estimate total fat on a wet-weight basis).167 A recent review advocated the use of tricacylglycerol analysis on a wet-weight basis to differentiate degrees of hepatic lipidosis.161 These workers categorized hepatic lipidosis as normal, mild, moderate, and severe by the triacylglycerol concentrations of less than 1%, 1% to 5%, 5% to 10%, and greater than 10%, respectively.161 At present, triacylglycerol analysis of hepatic tissue is not a routine procedure in veterinary diagnostic laboratories. Thus, total hepatic fat concentrations remain the “gold standard” for laboratory diagnosis. Clinically, little correlation exists between the amount of hepatic fat and signs of disease until the fat is more than 34% wet weight, at which point the liver tissue will float in distilled water with a specific gravity of 1.000.

Pathophysiology

See pp. 915 and 916.

Epidemiology

Fat cow syndrome occurs sporadically in dairy cows but more frequently in those with loose housing where the dry cows are managed with the lactating cows in one group. Cows often become overconditioned during late lactation and during the dry period. The overconditioning may be caused by a poor breeding program associated with cows spending prolonged time in the low lactation strings and having excessive weight gain. Morbidity as high as 90% occurred in the original reports.160 Mortality can exceed 25%, with even higher rates without intensive treatment and correction of concurrent diseases. Clinical disease in obese cows that enter the dry period can be minimized by carefully controlling their diets to meet National Research Council (NRC) requirements and preventing milk fever.

Necropsy Findings

Generalized obesity is noted unless the animal has been ill for more than 1 to 2 weeks. Changes in the liver are most striking; it is enlarged, with swollen and rounded edges, is pale yellow in color, and may float in water. Histologically, there is fatty infiltration of the hepatocytes, especially in the centrilobular and intermediate areas. However, these liver tissues are not much different from those of healthy, high-producing dairy cows in early lactation. The pathologist must make an extra effort to find lesions of other periparturient diseases, even if mild.

Treatment and Prognosis

Prognosis must be guarded unless the concurrent diseases can be treated successfully and the liver fat mobilized. It is most important to treat the primary disease. Reducing the negative energy balance and treating the hepatic lipidosis as described on p. 916 must be tackled vigorously. Prevention is based on preventing overconditioning during the late lactation period and the dry period and treating periparturient diseases in a timely manner. General prevention of hepatic lipidosis is covered in more detail on p. 917.

PROTEIN-ENERGY MALNUTRITION/PREGNANCY TOXEMIA OF BEEF COWS

Etiology

Protein-energy malnutrition (PEM) and pregnancy toxemia of beef cows are conditions of pregnant beef cattle on marginal diets, usually occurring in the winter and manifested by weight loss, weakness, depression, and sometimes inability to rise. The condition is the result of the negative energy balance caused by decreased quality and quantity of feed when caloric requirements are increased by fetal development and cold weather. Growing, pregnant heifers are especially susceptible because energy requirements for growth are superimposed on the other caloric requirements. A number of other factors, such as unpalatable feed, snow cover, and diseases, may reduce caloric intake (see Chapter 9). Fatty infiltration of hepatocytes occurs transiently in early PEM, and at necropsy the liver is smaller than normal.

Clinical Signs and Differential Diagnosis

Animals are usually thin and have a long hair coat. In some cases they are down and unable to rise but are still alert. The body temperature may be normal or subnormal. Occasionally, the cows also develop diarrhea. Most animals die 7 to 14 days after becoming recumbent.168 Differential diagnosis includes Johne’s disease, lymphosarcoma, parasitism, chronic pulmonary disease, other deficiencies, and debilitating diseases.

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Clinical Pathology and Diagnostic Tests

Diagnosis is usually based on demonstrating decreased caloric intake and ruling out other chronic diseases that could cause debility. Laboratory tests support but do not rule out the disease. Total serum calcium may be decreased. Packed cell volume also may be decreased, and serum insulin levels may be reduced. A ketonuria is not typical in PEM.

Necropsy Findings

Muscle mass usually is decreased. Serous (brown) atrophy of fat is often present, especially in the coronary groove, bone marrow, and perirenal areas. Lesions of concurrent disease also may be found if PEM is acute, and a fatty yellow liver may be noted.

Treatment and Prognosis

Treatment is often unrewarding. Efforts to reverse an advanced catabolic state may fail. A 454-kg cow requires 13 Mcal of metabolizable energy daily, or approximately 6.5 L of 50% glucose solution by continuous drip. Alfalfa pellet gruels are helpful if force-fed, and approximately 11 kg/day of alfalfa is recommended. Propylene glycol (150 to 200 mL) orally twice daily can be helpful as a glucose precursor. Treatments include IV fluids, improving the energy balance as described later, and treating any concurrent disease. Prevention and control by nutrition are discussed on p. 917.

PREGNANCY TOXEMIA IN EWES AND DOES

Definition and Etiology

Pregnancy toxemia, also known as ketosis or twin-lamb disease, is a condition occurring in ewes and does during the last 2 to 4 weeks of gestation. It is characterized by anorexia, weakness, and depression. The condition is caused by a negative energy balance resulting from increased energy demands of rapid fetal growth in late gestation and insufficient intake.

Clinical Signs

Animals with pregnancy toxemia are usually separated from the rest of the flock or herd. They have a poor appetite, and many appear blind. They eventually become more depressed and recumbent. Neurologic signs such as tremors, star-gazing, incoordination, circling, and grinding the teeth may precede terminal depression. Differential diagnosis includes other periparturient diseases, such as mastitis and hypocalcemia, as well as polioencephalomalacia, enterotoxemia type D, and toxicoses.

Clinical Pathology and Diagnostic Tests

Ketonuria is usually present and detected before ketonemia. Hypoglycemia is not a consistent finding but is sometimes present. The ewes and does often are acidotic and may have lowered serum calcium and potassium levels. The BUN and creatine levels are elevated terminally in some cases. FFA concentration in the plasma is usually elevated above 500 μEq/L. Serum β-hydroxybutyrate concentrations are elevated (>1 mmol/L).169 A nonspecific but marked neutrophilia may be found in some affected animals and is particularly dramatic in does, sometimes reaching 35,000 neutrophils/μL.

Pathophysiology

See p. 915.

Epidemiology

The incidence of pregnancy toxemia is greater in ewes with more than one fetus, during the last 2 to 4 weeks of gestation,170 and in does with three or more fetuses. Poor-quality feed, cold weather, lack of exercise, and stress of movement also may increase the incidence. Many ewes are overly fat initially. Does seem to be more resistant to pregnancy toxemia than ewes, in that three or more fetuses are usually required to produce the condition.

Necropsy Findings

These animals have a pale, swollen, friable, fatty liver. The animals may be somewhat dehydrated, and the uterus usually has more than one fetus.

Prognosis and Treatment

Mortality is high unless treatment is started early and the fetuses are removed. The most important step is removing the fetuses, either by inducing parturition or by cesarean section. Parturition can be induced in ewes with 15 to 20 mg of dexamethasone; in does the dose is either 10 mg of dexamethasone or 10 μg of prostaglandin F2α.170 A cesarean section may be performed if the animal’s value warrants it and there does not seem to be enough time to induce parturition. Besides removing the fetuses, the ketotic condition should be treated; 250 to 500 mL of 10% to 20% glucose is given intravenously, followed by a slow IV drip of 5% to 10% glucose. Acidosis and hypocalcemia must be corrected if present. Many practitioners use B vitamins in an attempt to stimulate appetite. Transfaunation of rumen liquor from a normal ruminant (a cow is acceptable) is useful in promoting voluntary feed intake and rumen motility. Cyanocobalamin (vitamin B12) and biotin are particularly indicated as adjuncts to glucogenesis. The energy intake must be increased. Glucose precursors such as propylene glycol (15 to 30 mL every 12 hours) or sodium propionate are often used, but excess propylene glycol may lead to acidosis and cause diarrhea.

HYPERLIPEMIA/HYPERLIPIDEMIA IN PONIES

Definition and Etiology

Hyperlipemia occurs mainly in ponies and occasionally in horses and is characterized by a fatty liver and serum that is cloudy with accumulation of lipids. Triglycerides (TGs) are usually much higher than 500 mg/dL.171 The condition is caused by decreased caloric intake, which causes fat mobilization and fat accumulation in the liver and accumulation in the plasma.172 The decreased food intake may be secondary to other diseases. In horses, azotemia is usually also present and may block further TG uptake by the liver.171 Equine hyperlipemia is characterized by production of an abnormal very-low-density lipoprotein (VLDL) fraction (VLDL1), which has a reduced content of apolipoprotein B-100 and an increased content of apolipoprotein B-48.173 The substitution of B-48 for B-100 is thought to allow greater TG content because B-48 is the apolipoprotein of importance in chylomicrons. The activities of lipoprotein lipase and hepatic lipase, the enzymes responsible for VLDL catabolism, were increased in hyperlipemic ponies.173 It was concluded that overproduction of VLDL is the cause of hyperlipemia, and agents that reduce VLDL synthesis should be candidates for clinical investigation.173

Hyperlipidemia is a mild condition of ponies and horses characterized by mildly elevated TG concentrations (>500 mg/dL), clear plasma, and no evidence of hepatic dysfunction.171 An increase in caloric intake is usually sufficient to reverse the condition. The more severe condition, hyperlipemia, is discussed further.

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Clinical Signs

The clinical signs of hyperlipemia are not specific. Ponies usually are anorexic, depressed, weak, and incoordinated. Diarrhea is a common clinical sign.174

Clinical Pathology and Diagnostic Tests

Diagnosis is based on examination of the blood and plasma to detect the white to yellow opacity caused by the presence of lipids. Bilirubin usually is elevated, as in most horses that are fasted. TGs are increased to above 500 mg/dL in hyperlipemia. FFAs are also increased. Bromosulfophthalein clearances are delayed (see p. 897), and terminally a large base deficit may be caused by metabolic acidosis.171

Epidemiology

The incidence of hyperlipemia is greater in ponies than in horses. It is seen more often in the winter, especially from February to May in animals receiving poor feed. Pregnant animals and those that are lactating are affected more frequently.

Necropsy Findings

Postmortem examination reveals fatty infiltration of the liver and kidneys, which are pale and swollen and have a greasy texture. In ponies the liver is sometimes ruptured, resulting in intraabdominal hemorrhage and death. Renal lesions may be seen histologically. There may be a primary disease that produces anorexia and secondarily has resulted in hyperlipemia.

Treatment

It is most important to treat any primary disease to alleviate the cause of anorexia and to correct the negative energy balance, as described in the following paragraphs. Insulin, along with 100 g of glucose intravenously, has been used in some affected ponies.174 The recommended dose of protamine zinc insulin (PZI)* is 30 IU intramuscularly twice daily with 100 g of glucose orally for a 200-kg pony. This is continued on odd days; on even days, 15 IU of PZI intramuscularly and 100 g of galactose orally is given twice daily.171 A slow IV drip of glucose for several days or until lipemia clears may be indicated. Heparin (100 to 250 IU/kg twice daily) has been used to alter the lipoprotein lipase activity and inhibit hormone-sensitive lipase of adipose tissue, but it may alter coagulation enough to cause hemorrhage. Glucose administration also stimulates insulin levels, but overdoses may result in a more severe acidosis.123

Pathophysiology of Hepatic Lipidoses(Fig. 33-4)

Storage of excess energy as fat and the periodic mobilization of fat for use as energy by the body is crucial.175 The liver plays a major role in lipid metabolism and must process the absorbed chylomicrons, the volatile fatty acids, and many of the FFAs and much of the glycerol obtained by mobilization of fat from adipose tissue. The liver of large herbivores has unique functions because much of the dietary energy is absorbed as volatile fatty acids and not glucose. Glucose is still needed (in high amounts in lactating animals) and must be produced by gluconeogenesis, 85% of which takes place in the liver.176

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Fig. 33-4 Metabolism of fat in animals with hepatic lipidosis.

Negative energy balance is induced by lactation, fetal growth, exercise, decreased feed consumption, environmental chilling, and diseases (Fig. 33-5). During these periods of negative energy balance and before lactation, blood glucose may drop slightly, the insulin/glucagon ratio drops, and these and other hormones (e.g., catecholamines, growth hormone) activate hormone-sensitive lipases that convert tissue fat to FFAs or nonesterified fatty acids (NEFAs) and glycerol (Fig. 33-6). In the liver the glycerol may be used to produce glucose or may be recombined with FFAs to make TGs. In addition to being recombined with glycerol to make TGs, the FFAs may be degraded through β-oxidation, and the two carbon fatty acids converted to acetyl coenzyme A (CoA). The acetyl CoA combines with oxaloacetate to enter the tricarboxylic acid cycle for the production of energy. This pathway is in competition with the use of oxaloacetate for gluconeogenesis.159 If there is not enough oxaloacetate available, the acetyl CoA is converted to ketone bodies, which in high concentrations can reduce feed consumption and perpetuate the negative energy balance.

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Fig. 33-5 Energy balance (megacalories per day) in normal-condition and obese dairy cows after parturition.

From Perkins B: PhD thesis, Ithaca, NY, 1983, Cornell University.

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Fig. 33-6 Plasma levels of glucose, insulin, and free fatty acids in dairy cows before and after parturition.

From Perkins B: PhD thesis, Ithaca, NY, 1983, Cornell University.

When the liver is overwhelmed with mobilized FFAs, greater amounts of TGs are deposited within the hepatocytes. These TGs eventually leave the liver as VLDLs, which are plasma-soluble complexes of phospholipid, cholesterol, TG, and apolipoprotein A. Hepatic lipidosis results when the rate of hepatic TG formation exceeds oxidation of fatty acids and the formation and release of VLDLs into the peripheral circulation. A number of factors have been incriminated for the inability of the liver to secrete adequate VLDLs to keep up with the deposition of TGs brought about by FFA mobilization from fat. Ruminants have a poor ability to export excess lipid from the liver as VLDLs. This is particularly true in bovine hepatic lipidosis177,178 and is theorized to result from a shortage of apolipoprotein A. Hepatic lipidosis can be induced in cows by inhibiting the production of apolipoprotein,179 and the lowest concentrations of lipoproteins occur in the serum of cows with the most severe hepatic lipidosis.178 Cows on low-protein diets in the dry period are more likely to develop hepatic lipidosis than those on higher protein diets, regardless of the energy content.177,180 Depression in dry matter intake in the final week before calving will increase the liver TG content after calving in dairy cows.181 In the past, a lack of phospholipid or its precursor choline has been incriminated but never substantiated. However, in the face of an energy shortage, it seems redundant and a waste of energy to repackage fat and send it back to the tissues, even if the liver is being overwhelmed with FFAs. Some of the same endocrine hormones that activate hormone-sensitive lipase and inhibit lipogenesis and glycogen synthesis may also inhibit the production of VLDLs.

It has also been suggested that subclinical liver damage may inhibit the production of VLDLs, but experimental studies have indicated no significant elevation in liver-specific enzymes before lipid accumulation.165,166 Function may eventually be impaired by the accumulation of fat, because fasted cows have a decrease in the surface area of rough endoplasmic reticulum and the number of mitochondria per unit volume.182 Changes in the liver seem to be functional and not degenerative.183 Hepatic lipidosis appears to be a reversible condition if the cause is removed and energy balance becomes positive (less negative). In cows fasted and refed, all major liver functions returned to normal within 18 days of refeeding,182 and all lactating dairy cows with postparturient hepatic lipidosis had normal liver fat (<15%) content at 6 months after calving.166

All high-producing dairy cows have increased amounts of fat (15% to 32% by weight) in the liver before calving and during the first few weeks after parturition165,166,183 (Fig. 33-7). These fat accumulations in the liver begin before calving as the animal prepares for lactation, and the blood glucose concentration is actually lower before calving.184 The amount of fat in the liver depends on the amount available and the extent of negative energy balance. Fatter cows tend to lose weight more rapidly and have more fat accumulation in the liver.165,166 Serum cholesterol values (lipoprotein) are inversely related to loss in condition.185

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Fig. 33-7 Liver fat as a percentage of total dry weight in normal-condition and obese dairy cows before and after parturition.

From Perkins B: PhD thesis, Ithaca, NY, 1983, Cornell University.

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Treatment of Hepatic Lipidosis

The most important principle in treating hepatic lipidosis is the elimination of negative energy balance and the factors or diseases causing it. Continual IV glucose at a rate of approximately 100 to 200 mg/kg/hour may provide continuing energy and induce an insulin/glucagon ratio that will decrease hormone-sensitive lipase mobilization of FFAs and stimulate production of VLDLs. Insulin itself may be given to alter this ratio directly. In cattle, 200 U of protamine zinc (NPH or Lente) insulin is given every 12 hours per 1000 pounds of cow, along with glucose.

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Precursors of lipoproteins such as choline, which is a component of phospholipid, have been advocated to increase the rate at which TGs leave the liver as phospholipids (VLDLs), but no controlled studies have proved their efficacy. Choline is degraded in the rumen,186 but theoretically, choline chloride (25 g in 250 mL of sterile saline) given subcutaneously could have limited efficacy. Choline should not be given intravenously because it acts as a neuromuscular blocking agent. Addition of inositol both before and after birth did not reduce the incidence or severity of hepatic lipidosis.187 Methionine at 40 to 50 g/day has also been used for the same purpose. Nicotinic acid (niacin) fed at 6 to 12 g/head/day may help reduce lipolysis at the tissue level and thus reduce the amount of fat presented to the liver.188 Treatment of hepatic lipidosis with nicotinic acid is often associated with a rebound of clinical signs, and its use as a preventive measure is recommended.

Corticosteroids to treat ketosis may be useful but should not be used repeatedly over a long-term period because they may make the animal less resistant to infections.188 Corticosteroids usually increase appetite, reduce milk production, and induce gluconeogenesis. Both vitamin E and selenium, which function as cellular antioxidants, have been found to be low in many of the cows with fatty liver syndrome;189 thus, supplementation may be helpful in selected cases.

Digestion in the forestomachs can be enhanced by transfaunating with rumen fluid from a normal cow. This may increase the absorption of volatile fatty acids used for energy and for glucose precursors.

PREVENTING HEPATIC LIPIDOSIS AND HANDLING NEGATIVE-ENERGY BALANCE AND OVERCONDITIONING

Hepatic lipidosis and associated conditions are most common in dairy cattle. Preventing obesity in cows during late lactation is an important factor in controlling this condition. This process involves a successful breeding program (maintaining a 12- to 13-month calving interval) and closely matching energy in the ration to the level of milk production during late lactation. Once the cow reaches 7 months of pregnancy and the dry period, any dietary restriction below requirements for maintenance and pregnancy are certain to be counterproductive.Table 33-10 lists the recommended nutrient requirements for a 600-kg cow.190

Table 33-10 Daily Nutrient Requirements for 600-kg Cow During Dry Period for Maintenance Plus Last 2 months of Gestation

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Adequate protein in the dry period is essential.176,179,180 It has been shown that cows fed higher protein diets during the dry period will perform better in the lactation that follows. Feeding good-quality to excellent-quality roughages (hay, silages) to meet most of these requirements is preferred. Additional grain (starch) 2 to 4 weeks before parturition is important to acclimate the ruminant to anticipated changes in the rations fed after calving. It must be stressed that high-quality dry cow rations be fed but not overfed. Dry matter consumption should be limited to approximately 2% of body weight per day while meeting requirements. Other factors in the dry cow ration also must be considered to prevent periparturient diseases such as milk fever, displaced abomasum, mastitis, metritis, ketosis, ruminal lactic acidosis, and retained placenta.191 Rations should be adequately supplemented with cobalt, the precursor of vitamin B12 that is a cofactor in the rate-limiting step in conversion of propionate (the primary glucose precursor) to succinyl CoA. Nicotinic acid has been included in the dry cow ration at 6 g/head/day and in the early-lactating cow ration at 12 g/head/day to aid in the prevention of ketosis, which is a major risk factor for the development of hepatic lipidosis. The use of monensin in the dry cow ration and the early-lactation ration shows promise to aid in the prevention of ketosis and thus may be of some benefit in preventing hepatic lipidosis.192,193

Nutrient requirements increase greatly for beef cattle during the third trimester of pregnancy; these requirements are listed in Chapter 9. As forage quality (digestibility) decreases, the time that feed material stays in the rumen increases (increased rumen turnover time). Therefore, as quality decreases, the maximum dry matter intake (DMI) decreases, which greatly decreases the maximum nutrient (energy) intake. This compounding effect of poor-quality forage on maximum intake is particularly important for preventing hepatic lipidosis and the accompanying protein-calorie malnutrition (PCM) of pregnant beef cattle in the winter. The approximate maximum DMI of forage of poor quality (oat straw, corn stover), medium quality (meadow grass hay), and excellent quality (alfalfa hay [25% crude fiber], corn silage) is 1% to 1.5%, 2%, and 2.5%, respectively. Environmental temperature can increase energy needs for beef cattle on pasture or range; as the temperature falls from 20° C (68° F) to 10° C (50° F), approximately 10% more energy is necessary for maintenance, and at freezing temperatures, 0° C (32° F), 20% additional energy is required. The key to preventing PCM and hepatic lipidosis in pregnant beef cattle is adequate body condition (scores 5 to 7) entering the third trimester and availability of good-quality to excellent-quality forage in adequate amounts.

Preventing pregnancy toxemia and the associated severe hepatic lipidosis in ewes and does requires measures similar to those outlined for PCM in beef cattle. Both overconditioned and thin ewes and does in the third trimester of pregnancy are at increased risk. Because of the common occurrence of twins and triplets, nutrient requirements for pregnant ewes greatly accelerate during this period. Good-quality to excellent-quality forage for feeding sheep is very important. An additional tool for diagnosing underfeeding in ewes is measurement of plasma β-hydroxybutyrate (BHB). This test greatly facilitates assessment of nutritional inadequacy in pregnant ewes.194 Plasma BHB concentrations of 0.8 mmol/L or higher are diagnostic of the need for increased energy consumption by pregnant ewes.194 This clinicopathologic tool is of great benefit in diagnosing malnutrition before irreversible pregnancy toxemia develops.

The nutrient requirements of horses and ponies have been covered elsewhere (see Chapter 9). The presence of hyperlipidemia is readily detected and easily solved by increasing caloric intake. Although therapy of hyperlipemic ponies and horses is often unrewarding, the diagnosis is relatively straightforward, and prevention depends on providing adequate feed of good quality.

CONGENITAL HYPERBILIRUBINEMIA

Erwin G. Pearson

GILBERT’s SYNDROME

Gilbert’s syndrome is an unconjugated hyperbilirubinemia in the presence of normal erythrocyte lifespan. It occurs in 7% of humans195 and has been described in Southdown sheep.196 Gilbert’s syndrome involves a failure of unconjugated bilirubin to cross the liver cell membrane and be conjugated. This is most likely caused by a defect in carrier proteins or the conjugating enzyme.197 Hepatic bilirubin clearance is about 30% of normal when tested with a loading dose of radiolabeled bilirubin.198

Affected Southdown sheep may have icterus or at least elevated plasma bilirubin levels, both conjugated and unconjugated. Affected sheep also cannot excrete sulfobromophthalein (Bromsulphalein, BSP) into the bile. No histopathologic lesions are present, other than some pigment in the hepatocytes. The condition is inherited as an autosomal dominant trait in humans.197 The bile acid levels are normal in humans, but one sheep exhibited defects in hepatic bile acid clearance.199

DUBIN-JOHNSON SYNDROME

Dubin-Johnson syndrome is a failure of conjugated bilirubin to enter the bile canaliculi. This has been diagnosed sporadically in humans and in Corriedale sheep.200 There may be an impairment not only in bilirubin but also in the excretion of other conjugated organic anions. Sheep affected by this syndrome may be jaundiced or have hyperbilirubinemia. Both conjugated and unconjugated bilirubin are increased, and BSP clearance is delayed. Bile acids are reported to be normal in humans, but delayed clearance was reported in three Corriedale sheep.199 Histologically, the hepatocytes contain a black, melanin-like pigment.200

PERSISTENT HYPERBILIRUBINEMIA IN THOROUGHBREDS

A persistent hyperbilirubinemia has been reported in a Thoroughbred racehorse that had no evidence of liver damage, cholistasis, or hemolysis and was not fasting.201 The horse was persistently icteric and had serum total bilirubin concentrations of 8.7 to 9.4 mg/dL; 90% or more of the plasma bilirubin was the unconjugated form. Serum bile acid concentration, along with the liver enzymes GGT, AST, and SDH, were within normal limits. The horse acted clinically normal, and the plasma FFA concentration was also within normal limits. The condition was similar to Crigler-Najjar type II syndrome in humans, which involves a deficiency in bilirubin—uridine diphosphate glucuronyltransferase needed to conjugate bilirubin, but this was not verified.

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MISCELLANEOUS LIVER DISEASES

Erwin G. Pearson

RIFT VALLEY FEVER

Rift Valley fever, also known as enzootic hepatitis, is an acute febrile arthropod-borne disease of sheep, goats, cattle, and humans present in most countries of sub-Saharan Africa.202 With the current threat of bioterrorism, it could appear in other parts of the world. Rift Valley fever is caused by a virus of the genus Phlebovirus. More than 20 species of mosquitoes have been implicated as possible vectors for the virus, including some North American mosquitoes that are competent laboratory vectors.203 The disease causes abortion in pregnant females and a febrile condition with rapid death in lambs, kids, and calves. The mortality rate in young animals approaches 100%, but it is much less (20% to 30%) in older animals.203 Clinical signs may include fever, anorexia, weakness, salivation, diarrhea, and sometimes abdominal pain, and almost all pregnant animals will abort.202 The primary gross lesion is hepatomegaly and hemorrhage. Histologically, a focal hepatic necrosis is identified, and eosinophilic intranuclear inclusion bodies are present.203 Confirmation of the diagnosis is made in the laboratory by virus isolation or immune tests. If the disease is suspected, state and federal regulatory veterinarians should be contacted.

TELANGIECTASIA

Hepatic telangiectasia, commonly known as “sawdust livers” in packing houses, is a focal degeneration in liver lobular circulation characterized by red-brown foci 1 to 5 mm in diameter.204 These lesions account for more than 10% of the bovine liver condemnations but do not result in any clinical signs.205 Microscopically, hepatocytes are distorted and sinusoids congested.206 Hypotheses proposed to explain the pathogenesis of the lesions include necrotizing hepatitis, ischemia induced by emboli or other vascular pathologies,207 dilation of Disse’s spaces, reduced density of reticulin framework, vitamin E–selenium deficiency, alteration of the sinusoidal barrier, and immune-mediated disease.204,205 Some human pathogens have been isolated from these livers as well as normal livers, but livers are condemned on the basis of aesthetics according to current U.S. Department of Agriculture (USDA) regulations.205

ISCHEMIA, HYPOXIA, AND CONGESTION

Ischemia and hypoxia can lead to death of hepatocytes, but less severe insults cause fatty infiltration, because lipoprotein synthesis depends on oxidative metabolism.204 This damage is more apparent in the centrilobular areas, which are the last to receive blood and oxygen.

Chronic passive congestion causes the grossly visible nutmeg liver. This is caused by the distention of the sinusoids and central veins with blood. The liver may be enlarged in these cases, but other signs related to the liver are not usually present. More significant findings will be detected in the cardiovascular system.

Portocaval shunts are rare in large domestic species but have been described in several foals.208

FETAL LIVER DAMAGE

The liver of the fetus may be damaged by infectious and toxic agents, but the result is usually abortion or birth of a weak neonate with signs related to other systems. The lesions in the liver may be diagnostic of the disease. Equine herpesvirus infection of the fetus causes hepatocyte necrosis, with acidophilic intranuclear inclusion bodies in more than 50% of the hepatocytes. Aborted fetuses of cattle caused by infectious bovine rhinotracheitis may have some focal necrosis of the liver, but not enough to be diagnostic.

FAILURE OF DRUG METABOLISM AND EXCRETION

A number of drugs are excreted by the liver and may have delayed clearance with hepatic insufficiency. These include antimicrobials such as chloramphenicol, erythromycin, and tetracycline. Chlorthiazide, most steroids, digitalis, morphine, many tranquilizers and anesthetic agents, and lecithin also are removed by the liver, and excretion may be reduced with hepatic insufficiency.209

NEOPLASIA OF THE LIVER

Erwin G. Pearson

Primary neoplasia of the liver is uncommon in large domestic species. Only 0.011% of abattoir animals seen in one study had liver tumors.210 Metastatic tumors are more common, but the clinical signs of these are more likely to reflect changes at the primary site. Metastasis of lymphosarcoma in cattle is most common, but signs produced by growth in other organs, such as the lymph nodes, abomasum, heart, uterus, and spinal cord, are more predominant. In the horse, lymphosarcomas and carcinomas have metastasized from the digestive tract.211

Horses

Although uncommon, a number of different primary hepatic neoplasias have been reported in horses.212 The nomenclature seems inconsistent throughout the years of reporting, and the signs are usually more consistent with neoplasia in general than with hepatic failure. Weight loss, weakness, anorexia, lethargy, and occasionally colic may be seen in these animals. Serum concentrations of liver-derived enzymes are elevated in many cases. The tumor can often be located by ultrasonography, but the definitive diagnosis of the type of tumor is based on histopathologic examination of biopsy tissue.

Hepatoblastoma has been reported in foals, young horses, and an equine fetus.213 Young horses present with weight loss or failure to grow, lethargy, anorexia, and possibly icterus. Serum concentrations of several hepatic enzymes are increased. Ultrasonography reveals hepatomegaly and a heterogenous appearance of the hepatic parenchyma. Erythrocytosis is seen in some cases because of a paraneoplastic syndrome and increased production of erythropoietin.

Hepatocellular carcinoma is seen in both old and young horses. These horses lose weight and are listless. Serum concentrations of LDH, GGT, and AST are often elevated. Erythrocytosis with a normal concentration of serum protein is seen in most cases as a result of paraneoplastic syndrome with elevated erythropoietin.212,214

Cholangiocarcinoma or cholangiocellular carcinoma arises from the intrahepatic bile duct epithelium and appears to be a disease of older horses.215 Lethargy, fever, abdominal pain, anorexia, and ventral edema have been reported with this tumor. Some of these animals have anemia rather than the erythrocytosis reported with hepatocellular tumors. GGT and ALP concentrations may be elevated, but SDH (which comes from hepatocytes) is usually within normal range.

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Cattle

In addition to the lymphosarcomas, primary hepatocellular carcinomas have been described in cattle.216 Liver-derived enzymes may be elevated, and polycythemia (erythrocytosis) is a common laboratory finding in these cases.217

HEMOCHROMATOSIS

John Maas

Erwin G. Pearson

Hemochromatosis is a disorder caused by deposition of hemosiderin in the parenchymal cells, resulting in tissue damage and dysfunction of the liver and other tissue. It is most frequently seen in humans and mynah birds, but hemochromatosis has been described as a new disease of Salers cattle218 and has been reported in three horses.219 In people the types include idiopathic hemochromatosis, an autosomal recessive familial condition associated with increased iron stores, cirrhosis, and saturation of the iron transport capacity.220 Both horses and cattle show increased iron deposits in the liver; histopathology of liver biopsy specimens reveals brown pigment that stains for iron in the hepatocytes as well as Kupffer’s cells. An increased concentration of iron can be measured in the liver, and there is fibrosis and elevated liver-derived enzymes.

In Salers cattle the condition appears to be a homozygous recessive condition more like the human familial type. There is an inappropriate absorption of iron (Fe) by the GI tract, with subsequent hepatic storage (Fe overload) and eventual loss of hepatic function. It has been reproduced by experimental breeding in Salers cattle.221 The primary clinical signs in cattle are decreased weight gains, poor body condition, dull hair coat, loss of incisor teeth, and sometimes diarrhea. Serum concentrations of liver enzymes are elevated, and there is marked hepatic fibrosis, in addition to the hemosiderin deposits in the liver. Total serum Fe, total iron-binding capacity (TIBC), and saturation of transferrin (>60%) are increased, similar to the familial disease in humans. Liver iron concentration will be greater than 5000 μg/g (ppm) on a wet basis (normal herdmates of affected cattle, 84 to 100 ppm).222

Horses with hemochromatosis present with evidence of liver disease. Serum concentrations of the liver enzymes ALP, GGT, and AST are elevated; and serum total bile acids are greater than 40 μM/L. In the cases reported, total serum iron was not elevated, and unlike the idiopathic human condition or the cattle cases, there was no saturation of the iron-binding capacity. Total liver iron has been as high as 6700 ppm (normal, 100 to 300 ppm).219

Hemochromatosis should be suspected in animals with emaciation or elevated liver enzymes and in Salers cattle with greater than 60% saturation of transferrin. It is confirmed by histopathologic examination of the liver, with excessive iron accumulation in hepatocytes. Clinicians should differentiate hemochromatosis from hemosiderosis, in which iron accumulates in the reticuloendothelial system and not hepatocytes, and which can be caused by hemolysis and other conditions.

In humans, hemochromatosis is treated by reducing the iron stores through phlebotomies and blood removal. The one horse on which this was tried had advanced disease with severe cirrhosis, and it succumbed a few days after the blood removal. Removal of 160 L of blood over 12 months failed to reduce liver iron concentration in one heifer218 but produced some improvement in other calves.221 Deferoxamine is given to some human patients to induce a negative iron balance and reduce the rate at which iron accumulates.

GALLBLADDER AND BILIARY TRACT DISEASE

Terry C. Gerros

Biliary tract disease in large animal medicine is rare and results from both intrahepatic and extrahepatic causes. Intrahepatic causes of cholestasis include cholangitis, cholecystitis, choledocholithiasis, and presence of a foreign body. Extrahepatic causes include abscess formation, inflammatory disease near the common bile duct, and neoplasia.

CHOLEDOCHOLITHIASIS, CHOLELITHIASIS, HEPATOLITHIASIS

By definition, cholelithiasis describes the presence of biliary calculi in either the bile ducts or the gallbladder, whereas choledocholithiasis describes stones found in the common bile duct. Hepatolithiasis indicates the presence of calculi in the intrahepatic bile ducts above the right and left hepatic ducts and is a variation of cholelithiasis. These conditions have been described in horses, cattle, sheep, and pigs; however, they do not seem to be recognized as a clinical problem in sheep, and rarely in cattle.223-244 Choledocholithiasis is the most common cause of biliary obstruction in large animals and occurs more frequently in horses.223-236

Biliary stone formation begins with the precipitation or aggregation of normally soluble components of bile. Other mechanisms involved in the pathogenesis include ascariasis, ascending biliary infection or inflammation, biliary stasis, changes in bile composition, and presence of a foreign body.228,243 Several pathogenic bacteria (Salmonella species, Escherichia coli, Aeromonas species, Citrobacter species, group D Streptococcus species, Clostridium perfringens) have been cultured from the bile ducts of horses and cows with cholelithiasis.224,234,238,245 Whether these bacteria were the cause or the result of the stone formation remains unclear. In most reports the chemical analysis has shown that choleliths have a mixed composition, containing bilirubin, bile pigments, cholesterol esters, esters of cholic and carboxylic acid, calcium phosphate, and sodium taurodeoxycholate.225,228,234,236,238 In one study, 80% of the choleliths contained less than 10% cholesterol.238

Clinical Signs, Diagnostic Test, and Differential Diagnosis

Cholelithiasis should be suspected in horses when a triad of clinical signs exists: recurrent abdominal pain, pyrexia, and icterus. Hyperammonemic hepatic encephalopathy, photosensitization, and weight loss are other, less common features of cholelithiasis.226-229,233,234,243,245 A subclinical presentation, caused by partial obstruction of the biliary tree, may be recognized only on postmortem examination.239 A large cholelith was the cause of duodenal obstruction in a horse presented for colic.240

Elevations in the serum activity of ALP, AST, GGT, SDH, and total bilirubin are associated with cholelithiasis.226-229,234,238,243,245 The rise in total bilirubin is caused by an elevation in both direct and indirect bilirubin. In the horse, cholestasis should be suspected if more than 25% to 30% of the total bilirubin is the direct type.223 Serum bile acid concentrations also increase when bile flow is obstructed.246 Other laboratory abnormalities that may be seen include hyperammonemia, increased urine bilirubin, and prolonged partial thromboplastin and thrombin times.225,229,233,234,238 The most common alterations in the leukogram include a neutrophilic leukocytosis. Elevations in globulin and fibrinogen may also occur.225,226,228,233

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Ultrasound examination of the liver is a safe, noninvasive tool for diagnosing cholelithiasis. Hepatomegaly and bile duct dilation are seen in horses with biliary calculi. The echogenicity of the hepatic parenchyma is increased compared with that of normal horses and may approach that of the spleen; the bile ducts are thick and distended. The parallel channel sign (dilation of interhepatic biliary radicals adjacent to portal vein) may also be seen. Several choleliths generally are seen, but a single stone may be present. Choleliths may be hyperechoic, casting acoustic shadows, or they may be sonolucent. Choleliths are most likely to be visualized in the cranioventral part of the right hepatic lobe, especially in the sixth to eighth intercostal spaces. Cholelithiasis can accurately be diagnosed by ultrasound in at least 75% of horses if an adequate scanning image of the liver is obtained and bile duct dilation and choleliths are visualized.236

The differential diagnosis for a horse with the clinical signs associated with cholelithiasis include other causes of liver disease and mild, recurrent abdominal discomfort, including verminous arteritis, mesenteric abscesses, enterolithiasis, abdominal neoplasia, and urolithiasis.226,227

Necropsy Findings

Hepatomegaly is usually noted at necropsy, although a shrunken liver may be observed. The liver is firmer than normal, has a consistent texture, and varies in color from red to green-brown. The hepatic ducts and common bile duct are generally dilated and may contain the calculi. Histologically, periportal fibrosis is a common finding. Bile duct stasis and hyperplasia are usually noted; suppurative cholangitis is less common.225,238,243,245

Treatment

Treatment of cholelithiasis includes relief of biliary flow obstruction and management of hepatitis and associated complications. Choledocholithotomy and choledocholithotripsy, described in horses, have had limited success.233-235 Because the potential for bacteremia with surgical manipulation for cholelithiasis is high, treatment with potentiated sulfa drugs, ampicillin, tetracycline, or chloramphenicol before surgical intervention is warranted. In humans, chenodeoxycholate or ursodeoxycholate is used to dissolve cholesterol gallstones;247 their use has not been reported in animals. Dietary management for cholelithiasis has yet to be determined.

The prognosis remains guarded for horses with cholelithiasis or choledocholithiasis.

DISEASES OF THE GALLBLADDER

CHOLANGITIS

Clinical disease of the bovine gallbladder is rare. Obstructive gallbladder disease has been associated with abdominal fat necrosis, choleliths, fascioliasis, foreign bodies, hepatic abscesses, neoplasia, and suppurative cholecystitis.248,249 Adenomas and adenocarcinomas (most common tumors found in gallbladder), papillomas, and lymphosarcoma (rare) can cause obstruction.248,250 Rupture of the gallbladder was found on necropsy of a cow in which icterus, anorexia, decreased milk production, and diarrhea had been present.251

Cholangitis is considered the most common cause of bile duct obstruction in large animals and has also been observed in horses with chronic active liver disease. Clinical signs associated with cholangitis in the horse may include anorexia, subtle behavioral changes, chronic weight loss, colic, and icterus. Alterations in hepatic enzyme activity may indicate either hepatocellular damage or cholestasis, or both. Histopathologic examination and bacterial culture are indicated to further identify the causative agent. In cases of suspected bacterial etiology, long-term antibiotic therapy is indicated.252 The antibiotic choice should be based on bacterial sensitivity; however, in cases in which no bacterial organism is identified, an antibiotic that is secreted or cleared in the bile is warranted.

Several foreign bodies have been recovered from the biliary tract, including grain, nails, sticks, stones, and sand. Retrograde motion of the intestine may have allowed these foreign bodies to enter the duodenal papilla and become lodged.

CHOLANGIOHEPATITIS

Cholangiohepatitis has been reported both as a primary disease and as occurring secondary to cholelithiasis, duodenal inflammation, intestinal obstruction, neoplasia, parasitism, and certain toxins.253 Sporidesmin, a fungal toxin from Pithomyces chartarum, causes cholangiohepatitis in cattle and sheep.254 Horses with cholangiohepatitis, either primary or secondary, may show anorexia, icterus, pyrexia, and intermittent signs of colic.243,253 Biochemical analysis revealing elevated cholestatic and hepatocellular enzyme activity and conjugated hyperbilirubinemia, combined with inflammatory leukogram, supports a diagnosis of cholangiohepatitis. Hyperammonemic hepatic encephalopathy may also be a feature. Cholangiohepatitis can be successfully treated in the horse, which primarily depends on long-term antimicrobial therapy and supportive treatment with IV fluids.255 Treatment failure is associated with hepatic biopsy results and inadequate treatment duration. Severe periportal and bridging fibrosis with or without hyperammonemic hepatic encephalopathy carries a poor prognosis. Clinical recovery may be seen before normalization of biochemical indices of hepatobiliary function. GGT levels may increase during the early stages of treatment, before they decrease. It is recommended that treatment be continued until GGT levels return to normal.255

THERAPY OF LIVER FAILURE

Thomas J. Divers

Hepatic failure usually is treated medically and supportively, although surgery may be indicated in a few cases. Therapy is best indicated in cases of acute liver failure without chronic fibrosis, such as with serum hepatitis, suppurative cholangitis, and toxic hepatopathies other than with pyrrolizidine alkaloids, because these animals have the best long-term prognosis for regeneration. Prognosis is generally poor if severe hepatoencephalopathy or hemolysis or severe acidosis or diarrhea is present. The initial therapy for hepatic failure should be directed toward any abnormal behavior (hepatoencephalopathy) the patient may be exhibiting.256

Hepatoencephalopathy (HE) is a metabolically induced, potentially reversible, functional disorder of the brain. The pathophysiologic mechanisms of HE are undoubtedly complex but mostly result from abnormal protein metabolism.257,258 Cerebral edema is characteristic of HE in humans, but it is rarely observed on microscopic examination of the brain in dying horses with HE. Complex interactions of both excitatory and inhibitory neurotransmitters determine if the patient is depressed or manic.259

If the animal is extremely agitated or convulsing, sedation should be accomplished before attempting further therapy. Detomidine will provide adequate sedation in most cases and is the drug of choice for horses with manic behavior caused by the HE. Most sedatives and tranquilizers are metabolized by the liver, so their use should be kept to a minimum, and doses of detomidine that cause marked lowering of the head or abnormally low respiration should be avoided. Diazepam should be avoided in animals with HE because it may enhance the effect of GABA on inhibitory neurons and worsen HE signs.260 The use of the benzodiazepine receptor antagonist flumazenil has been reported to lessen HE signs temporarily in humans.261 The overall success of flumazenil in treating HE in humans and dogs has been low, and it has rarely been used in the horse. Sarmazenil, which has a different mechanism of action, appears to be more promising for reversing signs of HE in some humans and has been used for treating moxidectin intoxication in a foal.262,263

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After chemical restraint of the affected animal, therapy can be directed at the physiologic events that may be causing HE. If the blood glucose concentration is low, 0.2 to 0.4 mL/kg of a 10% glucose solution should be initially administered intravenously. This may result in a dramatic alleviation of the clinical signs of HE in a few cases (e.g., Theiler’s disease, hepatic neoplasia, Tyzzer’s diseases). Therapeutic measures directed toward decreasing the blood ammonia concentration are also indicated. These include oral administration of neomycin at 10 to 30 mg/kg two or four times daily for 1 or 2 days, either alone or in combination with oral lactulose (90 to 120 mL per adult horse three or four times daily), or oral acetic acid at 0.5 mL/kg twice daily.264,265 A carbohydrate and prebiotic, lactulose is poorly absorbed from the small intestine and in the large intestine may decrease colonic pH and enteric ammonia concentration. Vinegar (acetic acid) should do the same. Metronidazole (10 to 15 mg/kg twice daily) may also be used to decrease ammonia-producing bacteria but is not preferred because it is metabolized by the liver, and signs of toxicity may mimic HE.

Nasogastric intubation should be performed with care because excessive trauma to the nasal cavity, esophagus, or stomach may result in severe and prolonged hemorrhage, swallowing of blood, and worsening of HE. Therefore, I prefer to administer oral drugs by dose syringe mixed with molasses and Karo syrup. Neomycin administration should not be prolonged because this may have a toxic effect on the intestinal mucosa266 and cause severe diarrhea in some horses. Following neomycin therapy, probiotics can be given, some of which may result in decreased intestinal ammonia production.267 Some clinicians prefer not to treat with oral drugs that affect intestinal flora, but rather to rely mainly on a low-protein diet and a laxative.

Acidosis may be severe in many horses with hepatic failure, but attempts at correction must be made slowly.264 Too rapid an increase in pH may exacerbate the HE. I recommend bicarbonate therapy only when the venous pH is less than 7.1 and IV therapy with an alkalizing, balanced electrolyte fluid has failed to improve the acidosis. The prognosis is poor in horses that maintain persistent acidosis. It is of utmost importance that dehydration be corrected with a balanced electrolyte solution (preferably without lactate), dextrose (20 to 50 g/L), and supplemental potassium (20 to 40 mEq/L). Additional potassium should also be given orally (5 to 20 g twice daily). Maintaining potassium intake is important because low potassium increases production and absorption of ammonia from the kidney.268

Urine dipstick and plasma glucometer measurements should be used to monitor glucose concentration. Although most adult horses with hepatic failure have normal blood glucose concentration, it is important to supplement the fluids with glucose unless the horse is hyperglycemic. Glucose decreases ammonia concentration, reduces the reliance on catabolic gluconeogenesis, decreases protein catabolism, and spares hepatic energy consumed in hepatic gluconeogenesis. Glucose must not be given as the sole source of fluid. It is also important that glucose be continually maintained within the normal range (90 to 120 mg/dL). Polycythemia may be relatively unresponsive in some cases of hepatic failure and should not be used as the primary guide for judging adequate fluid therapy. Fresh or fresh-frozen plasma can be used, to increase colloidal oncotic pressure, clotting-factor transport proteins, and antiproteases. Stored whole blood should not be used because ammonia levels may be high. Hetastarch should also not be used in hepatic failure.

Antioxidant, antiinflammatory, and antiedema therapy may be useful in some cases of acute hepatic disease and failure. Dimethyl sulfoxide (DMSO), acetylcysteine, vitamin E, and mannitol are antioxidant and antiedema drugs that may be useful.269 S-adenosylmethionine (SAMe) appears to have protective effects against oxidative hepatic injury and is the preferred antioxidant for therapy in equine hepatic disease.270 Antiinflammatory therapy should include flunixin meglumine and pentoxifylline (7.5 mg/kg PO every 12 hours). Horses with acute hepatic failure that cannot be controlled by this therapy would require extracorporeal liver support systems. Although these have not been used in the horse, dialysis, charcoal adsorption, or plasma exchange methods are available.271

Treatment of ponies with hyperlipemia is covered in the section on hepatic lipidosis. If the hyperlipemia is thought to be associated with a pituitary adenoma, the treatment with pergolide (1 to 5 mg/day) is warranted and may be successful. Hyperlipidemia may also occur in horses in late pregnancy associated with diarrhea and azotemia.272 If the pony or horse is in late pregnancy, it may be advisable to abort the mare.273 Fatty liver in ruminants is discussed on p. 912. Hepatic failure in cattle associated with septic metritis or mastitis and in those with biliary obstruction from hepatic abscesses can often be successfully treated by forced feeding (e.g., alfalfa gruel, electrolytes) and systemic antibiotics.274 Treatment of hepatic fascioliasis is discussed on pp. 909 and 910.

Animals with hepatic disease that maintain a fair appetite often are best treated by dietary management. Dietary management is important in the recovery of animals with acute hepatitis or hepatopathy and in prolonging the life of those with chronic hepatic disease. Energy and protein requirements (especially branched-chain amino acids) should be met.275 An example of a reasonable diet is one part beet pulp with one-quarter to one-half part cracked corn mixed with molasses four to six times daily. Milo or sorghum may also be used as a grain mix. Small meals given frequently are ideal because of difficulties with gluconeogenesis and insulin regulation. Sorghum, oat hay, or grass hay may be substituted for beet pulp. If the affected horse will not eat, forced feeding should be considered, but nosebleeds should be avoided. An oral paste with a high branched-chain/aromatic amino acid ratio can be formulated or purchased for forced feeding.276 Vitamin B1, folic acid, vitamin K1, or fresh plasma transfusion might be indicated with chronic biliary obstruction. Grazing of mixed grasses is permitted and should be encouraged, as long as affected horses can be protected from sunlight. Spring-cut hay or grass should be limited because these can be very high in protein. Alfalfa is also generally high in protein and is best avoided with hepatic dysfunction, except in cows that seem to be more tolerant of high-protein feeds. It is important that a horse with hepatic failure eat something, even if it is not one of the more desirable feeds previously mentioned.

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Bactericidal antibiotic therapy is indicated for horses with bacterial cholangitis and in cattle with liver abscesses. A diagnosis of suppurative bacterial cholangitis usually is made before the organism or its antibiogram is known. Therefore, broad-spectrum aerobic drug therapy, such as a combination of ampicillin and gentamicin, trimethoprim-sulfa, ceftiofur, or enrofloxacin, is preferred for the initial therapy. Anaerobic organisms may also be involved, and metronidazole can be added to any of these drug therapies. Antimicrobial therapy can be adjusted if the offending organism can be identified from a liver biopsy. Gram-negative enteric organisms are the most common causative organisms, and in my experience, only 50% or less are sensitive to trimethoprim-sulfa. This is unfortunate, since prolonged (2 weeks to 3 months) antibacterial therapy is usually required for suppurative cholangitis.277 Ultrasound examination is important in treating equine suppurative cholangitis because some cases are associated with biliary stones, which makes the treatment more difficult and worsens the prognosis. If there are small obstructing stones or sludge, DMSO (0.5 to 1.0 g/kg IV for 3 to 5 days) may help dissolve the calcium bilirubinate stones or debris.278 IV crystalloids may also thin secretions and promote bile flow. Ursodeoxycholic acid, a commercially prepared bile acid, is used for a variety of chronic biliary disorders in humans and small animals and will induce choleresis. This drug’s benefit in horses has not been proved, and safety is a concern because rabbits, which have a GI system similar to the horse, metabolize this bile acid into noxious bile acids.279 If a large, obstructing stone is present, surgery is indicated. Although the most distal bile duct opening into the duodenum cannot be visualized by ultrasound examination, it can be seen during gastroduodenal endoscopy.

Cattle with singular or multiple liver abscesses often respond to penicillin therapy, but long-term therapy is required, and there is a significant rate of recurrence of clinical signs after therapy is withdrawn. Abscesses of small to medium size and echolucent have the best prognosis. Abscesses with echodense appearance are difficult to treat. Single, large abscesses are best treated by surgical drainage, especially those interfering with vagal nerve function. High levels of IV penicillin and an aminoglycoside should be administered to foals with suspected Tyzzer’s disease. Penicillin in high dosages and/or metronidazole should also be used for treating suspected anaerobic abscesses of the liver. Foals with salmonellosis should be given antimicrobial therapy based on culture and sensitivity results from previously affected foals on the same farm and from results of blood and fecal cultures of the affected foal.

Surgery may be indicated as part of the therapy for liver failure in foals with duodenal stricture or in horses with colonic displacements (usually 180 degrees volvulus) that result in biliary obstruction.280 Foals and calves with portosystemic shunts require surgical repair if desirable growth and performance are expected.281 Surgery for cholelithiasis is indicated if there is an obstructing stone and unless diffuse fibrosis is already present. Cattle with a single, large hepatic abscess or calves with an umbilical vein hepatic abscess are best treated by surgical drainage.

Horses thought to have chronic active hepatitis with bridging necrosis that is not believed to be associated with a bacterial infection may be given corticosteroids, pentoxifylline, and/or colchicine (0.03 mg/kg orally every 24 hours), but the therapeutic benefits of these drugs appears to be variable. If steroids are to be used, 200 mg of prednisolone orally per day for the adult horse is recommended.

PANCREATIC DISEASE

Terry C. Gerros

Pancreatic disease is rare in both cattle and horses. In the horse, acute and chronic disease has been reported, whereas only chronic disease has been reported in cattle.

Recognized causes of pancreatitis include migrating parasites; bacterial and viral infections; immune-mediated damage; biliary or pancreatic duct inflammatory disease; deficiencies of vitamin A or E, selenium, and methionine; and vitamin D toxicity.282-285 Drugs known to induce pancreatitis in humans that are used frequently in horses include furosemide, tetracycline, estrogen, and certain corticosteroids and sulfonamides.282,284 One case report in a pony suggests an association with Cushing’s syndrome.286 The cause of acute pancreatitis in the horse is unknown; however, it has been associated with grain overload and severe abdominal pain.287 The final common pathway may result from autodigestion by activated enzymes, but the exact mechanism remains speculative. Pancreatitis was also diagnosed postmortem secondary to severe gastroduodenal ulceration in a foal.288

The clinical signs associated with acute pancreatitis are not specific and mimic those associated with an acute GI crisis. The characteristic clinical features are moderate to severe abdominal pain, gastric reflux, hypovolemic shock, and cardiovascular compromise.282,285,289,290 Gastric distention accounts for the pain and gastric reflux associated with acute pancreatitis. Hypovolemic shock, occurring secondary to fluid losses into the peritoneal cavity and bowel lumen, results from the release of vasoactive substances from the pancreas. Tachycardia, tachypnea, prolonged capillary refill, and congested mucous membranes result from hypovolemia and cardiovascular compromise.

Laboratory confirmation of pancreatic disease is difficult and not routinely attempted. The diagnosis is usually confirmed on histologic evaluation of the pancreas after necropsy. Laboratory tests that may be of value in the diagnosis of pancreatitis in the horse include measuring serum amylase and lipase activity, peritoneal fluid (PF) amylase concentrations, fractional excretion of amylase, and plasma trypsin levels.285 Serum amylase values from normal horses range from 14 to 35 IU/L (mean, 21 ± 6), whereas PF values range from 0 to 14 IU/L (mean, 5 ± 4).291 Elevations of pancreatic enzyme activity are difficult to interpret, because the enzymes may be elevated in horses with proximal enteritis, colic, primary renal failure, and damage to intestinal mucosal cells, as well as in pancreatitis.285,291,292 Amylase also originates from the salivary glands, and lipase can be released from the liver. Clinical cases documented at necropsy had serum amylase activity greater than 700 IU/L; this magnitude of elevation may be helpful in differentiating acute pancreatitis from other causes. In acute pancreatitis, PF amylase levels are higher than serum levels.292 Plasma trypsin levels increase in horses with suspected pancreatic damage and may be a better indicator of pancreatic disease.293 Trypsin is specific to the pancreas and activates its own zymogen and those of all the other pancreatic enzymes. In one study, in horses with acute abdominal disease in which pancreatic damage was suspected, trypsin activity was significantly higher than in healthy horses (196 ± 128.2 ng/mL vs. 28.5 ± 19.2 ng/mL).293 Pancreatitis has not been imaged successfully in the horse with ultrasonography.294 A technique for ultrasound examination of the right lobe of the pancreas in healthy cattle has been described.295

Medical management of acute pancreatitis is symptomatic. Prevention of gastric rupture by continuous gastric decompression and control of abdominal pain are crucial in the treatment of pancreatitis.284 Large volumes of balanced polyionic electrolyte solutions are necessary to maintain the circulating volume and prevent shock. Because hypocalcemia may be a problem, serum calcium concentration should be monitored. Broad-spectrum antibiotics are warranted because of the potential for secondary bacterial infection. NSAIDs and analgesics are used to control inflammation and pain.

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Chronic interstitial pancreatitis (CIP) in horses and cattle seldom has clinical significance. In horses, Strongylus equinus and Stronglyus edentatus are most often identified as the etiologic agent of CIP; however, Parascaris equorum has been identified in one case report.284,296,297 In cattle, CIP has been primarily associated with the trematodes Eurytrema pancreaticum and E. coelomacticum; these parasites have not been isolated in the United States.292

Reports of pancreatic disease in adult cattle have been limited to endocrine dysfunction.298-300 The most frequently reported disorder is type I diabetes mellitus; however, the etiology in most cases is not determined.298-300 Histopathologic examination generally reveals an absence of β-cells in the islet tissue. Foot-and-mouth disease virus has been associated with diabetes mellitus in cattle following convalescence.292 Hypoplasia of the acinar pancreatic tissue has been described in calves.292 Clinical signs include steatorrhea and diarrhea. Adenocarcinoma of the exocrine pancreas is reported in rare equine cases and should be considered in horses exhibiting the clinical signs of pyrexia, depression, weight loss, and icterus.283,301,302

Pancreatic calculi found in older cattle (>5 years) during necropsy are considered incidental findings.292,303 The calculi are composed primarily of calcium carbonate and calcium phosphate. Their presence may be associated with grazing on silica-rich soil, vitamin A deficiency, or chronic inflammation of the pancreatic ducts.292

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* Jorgenson Laboratories, Loveland, CO.

† MWI, Meridian, ID.

* References 46,47,51,53,57,58.

* AM Craig Laboratory, c/o VDL, Oregon State University, Corvallis, OR.

* Extraction by solvent and stereologic postcounting for estimation of fat volume.

* Protamine zinc and iletin insulin, Lilly, Indianapolis, IN.