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Overview of Hepatic Disease in Large Animals


Jonathan H. Foreman

, DVM, DACVIM, College of Veterinary Medicine, University of Illinois at Urbana-Champaign

Reviewed/Revised May 2023
Topic Resources

Diseases of the liver produce clinical signs of depression, anorexia, icterus, and sometimes photosensitization. Chronic liver disease is often accompanied by weight loss. Abdominal ultrasonography enables documentation of liver enlargement (more common in acute disease) or atrophy (more common in chronic disease), and it provides guidance for liver biopsy as a diagnostic and prognostic test. Depending on the specific cause, treatment often includes the administration of antimicrobials (if an infectious process is suspected), anti-inflammatories, and intravenous fluids with glucose, as well as sedation if neurologic signs are present from hepatic encephalopathy.

Hepatic disease is common in large animals. Increases in plasma or serum hepatic enzyme activity and total bile acid concentration are indicative of hepatic abnormalities that include toxic insult, infectious disease, and failure. Although liver disease is common in horses and foals, progression to liver failure is not.

Diseases that frequently result in hepatic disease in horses include pyrrolizidine alkaloid toxicosis Pyrrolizidine Alkaloid Toxicosis Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , hepatic lipidosis Hepatic Lipidosis , cholangiohepatitis Cholangiohepatitis Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more , chronic progressive hepatitis Chronic Progressive Hepatitis in Large Animals Chronic progressive hepatitis, or "chronic active hepatitis," is any progressive fibrosing process within the liver, secondary to multiple etiologies. It is a histopathologic diagnosis in which... read more , Theiler disease Acute Hepatitis in Large Animals Acute hepatitis includes the acute or peracute onset of clinical signs of liver disease; however, it may be due to acute disease or acute exacerbations of chronic disease. The term "hepatitis"... read more , Tyzzer disease Tyzzer Disease Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more (in younger foals), and cholelithiasis Cholelithiasis, Choledocholithiasis, and Hepatolithiasis in Large Animals The presence of calculi ("liths") within the biliary system is named according to the specific location of the calculus within the bile duct (cholelithiasis), common bile duct (choledocholithiasis)... read more . Obstructive disorders (biliary stones, right dorsal colon displacement, neoplasia Hepatic Neoplasia in Large Animals Primary hepatic tumors are uncommon in horses and ruminants. They include hepatocellular carcinoma, cholangiocarcinoma, and, rarely, lymphoma, hepatoblastoma (in foals, young horses, alpaca... read more , duodenal ulceration and stricture, hepatic lobe torsion Hepatic Lobe Torsion Diseases of the gallbladder are rare in ruminants. Obstruction may be associated with liver fluke infestation, foreign bodies, abscesses, neoplasia, suppurative cholecystitis, or abdominal fat... read more , portal vein thrombosis), aflatoxicosis Aflatoxicosis in Animals Aflatoxicosis is a worldwide mycotoxicosis with production of potent hepatotoxins on animal feed both in the field and storage during hot temperatures (drought) and often occurs concurrent with... read more , fumonisin toxicosis Fumonisin Toxicosis in Animals Fumonisins are responsible for two well-described diseases of livestock, equine leukoencephalomalacia and porcine pulmonary edema. Equine leukoencephalomalacia is a mycotoxic disease of the... read more , pancreatic disease, Panicum toxicosis Panicum Grass Toxicosis Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more or alsike clover toxicosis Alsike Clover Toxicosis Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , portal caval shunts, hepatic abscesses Hepatic Abscesses Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more , and perinatal herpesvirus-1 infections sporadically result in hepatic disease. Less frequently, hepatic disease is associated with endotoxemia, corticosteroid administration, administration of inhalant anesthesia, systemic granulomatous disease, amyloidosis Amyloidosis , hyperammonemia of Morgan foals Hyperammonemia in Morgan Foals Diseases of the gallbladder are rare in ruminants. Obstruction may be associated with liver fluke infestation, foreign bodies, abscesses, neoplasia, suppurative cholecystitis, or abdominal fat... read more , parasite damage, iron toxicosis Iron Toxicosis Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , or neonatal isoerythrolysis Alloimmune Hemolysis Hemolytic anemia results from loss of RBCs. Immune-mediated destruction is the most common cause in dogs, although infections, tumors, and other causes also occur. Immune-mediated hemolytic... read more Alloimmune Hemolysis .

In ruminants, hepatobiliary disease is associated with hepatic lipidosis, hepatic abscesses, endotoxemia, pyrrolizidine alkaloid and other plant toxicoses, certain clostridial diseases Overview of Clostridial Diseases in Animals Clostridia are prokaryotic bacteria of the phylum Firmicutes, which are large, anaerobic, spore-forming, rod-shaped, gram-positive organisms. They can be living cells (vegetative forms) or dormant... read more Overview of Clostridial Diseases in Animals , liver flukes Overview of Fluke Infections in Ruminants Fluke infections cause economic losses in production systems throughout the world. Fasciola hepatica, the most important trematode of domestic ruminants, is the most common cause of liver... read more , mycotoxicoses Mycotoxicoses Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , and mineral toxicosis (copper Mycotoxicoses Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more , iron, zinc Zinc Toxicosis in Animals In small animals, zinc toxicosis is usually a result of ingestion of objects that contain or are coated with zinc, most commonly US pennies. In large animals, the main causes are contaminated... read more Zinc Toxicosis in Animals ) or deficiency (cobalt). In swine, vitamin E or selenium deficiency (hepatosis dietetica Nutritional Myopathy of Pigs Young Boer goat kid with white muscle disease. The patient can move its legs normally but is too weak to stand. CK and AST concentrations were elevated on serum biochemical evaluation. The goat... read more Nutritional Myopathy of Pigs ), aflatoxicosis, ascarid migration, bacterial hepatitis, and ingestion of toxic substances (eg, coal tar, cyanamide, blue-green algae, plants, gossypol) are associated with hepatic injury.

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 cholangiohepatitis (due to Salmonella spp, Escherichia coli, Listeria spp, or Clostridium spp), adenoviral hepatitis and pneumonia, fungal hepatitis (coccidioidomycosis Coccidioidomycosis in Animals Coccidioidomycosis (valley fever) is a dustborne, noncontagious infection due to Coccidioides spp fungi. These fungi form mycelial mats in shallow arid soil; the mycelium fragments form... read more Coccidioidomycosis in Animals ), toxic hepatopathy (due to ingestion of copper), halothane-induced hepatic necrosis, hepatic neoplasia (lymphosarcoma Lymphoid Tumors of the Skin Canine extramedullary plasmacytomas (atypical histiocytomas, cutaneous neuroendocrine tumors, reticulum cell sarcomas, cutaneous nodular amyloidosis) are relatively common cutaneous tumors.... read more Lymphoid Tumors of the Skin , hemangiosarcoma Vascular Tumors Collagenous nevi are benign, focal, developmental defects associated with increased deposition of dermal collagen. They are common in dogs, uncommon in cats, and rare in large animals. They... read more Vascular Tumors , adenoma), and liver fluke infestation have also been reported in camelids.

The liver can respond to insult in only a limited number of ways. Necrosis of hepatocytes indicates acute damage. The dead cells are removed by an inflammatory process and replaced with either new hepatocytes or fibrosis. The presence of fat droplets in the liver may be an early change, and it is often reversible. Biliary hyperplasia is also reversible, if the insult is removed early. Unless the dysfunction is acute and hepatocellular regeneration is evident, the prognosis for animals with liver failure is often 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 Findings of Hepatic Disease in Large Animals

Clinical signs of hepatic disease may not be evident until 70% or more 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), the primary site of injury (hepatocellular, biliary), and the specific cause. The onset of signs of hepatic encephalopathy and liver failure is often acute, although the hepatic disease process may be acute or chronic. Clinical signs and severity of hepatic pathology reflect the amount of compromise of one or more of the liver’s vital functions. These functions include blood glucose regulation; fat metabolism; production of clotting factors, albumin, fibrinogen, nonessential amino acids, and other 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, and abnormal behavior are common in horses with liver disease. CNS signs are often the initial and predominant clinical signs in horses with acute hepatic failure, whereas weight loss is a prominent clinical sign in most horses with chronic liver disease and failure. Photosensitization, diarrhea, constipation, and, less commonly, bilateral pharyngeal paralysis causing inspiratory stridor may be present. Affected cattle usually show inappetence, decreased milk production, and weight loss. Tenesmus and ascites occur in cattle but are not common in affected horses. Weight loss may be the only clinical sign associated with liver abscesses.

Icterus, which is most pronounced when the biliary system is diseased, is common in horses with acute liver failure but less consistently 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; it can be differentiated from true liver disease by documentation of normal plasma or serum liver enzyme activities. Occasionally, persistent hyperbilirubinemia (primarily indirect or unconjugated bilirubin) may occur 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 due to obstructive biliary conditions is rare in goats and sheep.

Hepatic encephalopathy is associated with behavioral changes in horses, ruminants, and swine and may result from either acute or chronic liver failure. The severity of hepatic encephalopathy often reflects the extent of hepatic failure. Clinical 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, and coma. Pharyngeal or laryngeal collapse with loud, stertorous inspiratory noises and dyspnea occurs in some cases of hepatic failure, especially in ponies. In this author's experience, one horse with hepatic encephalopathy manifested severe dyspnea due to hyperflexion at the poll and to head pressing, resulting in airway compromise so severe that a tracheostomy was required.

The pathogenesis of hepatic encephalopathy is unknown, but proposed theories include ammonia as a neurotoxin, which easily crosses the blood-brain barrier; alterations in monoamine neurotransmission (serotonin, tryptophan) or catecholamine neurotransmitters; imbalance between aromatic and short branch chain amino acids, resulting in increased inhibitory neurotransmitters (gamma-aminobutyric acid, l-glutamate); neuroinhibition due to increased cerebral concentrations of endogenous benzodiazepine-like substances; increased permeability of the blood-brain barrier; and impaired CNS energy metabolism due to decreased available blood glucose or failure to use available glucose in the brain. Although the clinical signs can be dramatic, hepatic encephalopathy is sometimes reversible, if the horse can survive long enough for the underlying hepatic disease to be reversed.

The photosensitization Photosensitization that can occur secondary to acute or chronic liver failure must be differentiated from primary photosensitization. Secondary photosensitization develops when compromised hepatic function results in accumulation of phylloerythrin, a photodynamic metabolite of chlorophyll, in the skin. Phylloerythrin in the skin reacts with ultraviolet light and releases energy, causing inflammation and skin damage. Clinical signs of photosensitization vary; they 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 is affected. Blindness, pyoderma, loss of condition, and occasionally death are possible sequelae. Pruritus may result from photosensitization or from the deposition of bile salts in the skin secondary to alterations in hepatic excretion.

Diarrhea or constipation may occur in animals with hepatic disease. Ponies and horses with hyperlipemia Hyperlipemia and Hepatic Lipidosis in Large Animals Hyperlipemia is the abnormal accumulation of lipids in blood, resulting from excessive mobilization of body fat in the face of pregnancy, anorexia, or dietary insufficiency. Lipid deposition... read more Hyperlipemia and Hepatic Lipidosis in Large Animals and subsequent hepatic failure may develop diarrhea, laminitis Laminitis in Horses The horse hoof. Median section through the horse digit. Equine laminitis is a crippling disease in which there is a failure of attachment of the epidermal laminae connected to the hoof wall... read more Laminitis in Horses , and ventral edema. Some animals with liver disease have alternating diarrhea and constipation. Horses with liver failure and hepatic encephalopathy frequently develop colonic impaction as a result of 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 occur in horses with choleliths that obstruct the bile canaliculi, hepatic ducts, and/or 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 occurs 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 clinical signs of colic. In ruminants, pain may be localized to the liver by palpation over the craniolateral aspect of the ventral abdomen or the last few ribs on the right side. Tenesmus followed by rectal prolapse occurs in some ruminants with liver disease. It may be associated with diarrhea, hepatic encephalopathy, or edema of the bowel from portal hypertension.

Hypoalbuminemia is sometimes associated with liver disease in horses. Because of the long half-life (19 days in horses, ~16 days in cows) and liver reserve for albumin production, hypoalbuminemia is usually a very late event in the disease process. Total protein concentrations may be normal or increased because of an increase in beta-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 can also be related to portal hypertension due to venous blockage, increased hydrostatic pressure, and protein leakage into the peritoneal cavity. The abdominal fluid present with liver disease usually is a modified transudate. Hypoalbuminemia can cause intermandibular, sternal, or ventral edema, or can exacerbate ascites. 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 occur in animals with liver dysfunction that is due to parasitic disease, chronic copper toxicosis Copper Toxicosis Hepatotoxins manifest their effects by one or more mechanisms: centrilobular necrosis, midzonal necrosis, periportal necrosis, cholestasis, biliary hyperplasia, fatty or hydropic change near... read more (in ruminants), some plant poisonings, or chronic inflammatory disease. Anemia in acute fascioliasis results from severe hemorrhage into the peritoneal cavity as the liver fluke larvae penetrate the liver capsule. Trauma and the feeding activity of adult flukes within the bile ducts cause anemia and hypoproteinemia in animals with chronic fascioliasis. Chronic inflammatory disease (eg, hepatic abscesses, neoplasia) may cause anemia without accompanying hypoproteinemia.

Clinical signs of severe or terminal hepatic failure include coagulopathies due to decreased production of clotting factors by the liver and possibly increased consumption of clotting factors in septic or inflammatory processes. A prolonged prothrombin time may be evident first, because factor VII has the shortest plasma half-life. Horses may develop a terminal hemolytic crisis as a result of increased RBC fragility. This finding has not been reported in ruminants.

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 liver 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; in other words, the presentation may be an acute exacerbation of an underlying chronic liver disease process. Early, vague signs of depression and decreased appetite may be overlooked. Liver biopsy to determine the type of pathology, the extent of hepatic fibrosis present, and the regenerative capabilities of the liver parenchyma may be necessary to develop a treatment plan and give an accurate prognosis.

Diagnosis of Hepatic Disease in Large Animals

Laboratory tests often detect liver disease or dysfunction before hepatic failure occurs. Routine biochemical tests, such as the measurement of serum enzyme activities, are sensitive indicators of liver disease; however, they do not assess hepatic function. Dynamic biochemical tests that assess hepatic clearance provide quantitative information regarding hepatic function, but unfortunately are rarely available clinically; dye excretion tests are one such example.

Plasma or Serum Enzymes

Systemic concentrations of liver-specific enzymes are generally higher in acute liver disease than in chronic liver disease, unless the chronic patient is experiencing an acute exacerbation. Enzyme activities may be within normal limits in the later stages of subacute or chronic hepatic disease, as the condition becomes quiescent. Hepatic enzyme activity is used to determine the presence of disease but not necessarily the extent of hepatic dysfunction. The magnitude of increases in the activity of hepatic enzymes does not directly correlate with the prognosis, but serum concentrations of bile acids, total bilirubin, and amyloid A (SAA) have been shown to be higher in nonsurvivor horses compared to survivors of hepatic disease. Careful interpretation of laboratory values in conjunction with clinical findings is essential.

Sequential measurements of serum gamma-glutamyl transferase (GGT), sorbitol dehydrogenase (SDH), glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, and bile acid concentrations are commonly used to assess hepatic dysfunction and disease in large animals. GGT is associated primarily with microsomal membranes in the biliary epithelium and thus is associated with cholangitis. However, elevations in GGT activity are common secondary to hepatocellular swelling and subsequent bile canaliculi obstruction. Therefore, elevations in GGT activity are a common sensitive indicator of hepatobiliary disease in horses; however, they are not always specific for biliary disease alone. In acute hepatic disease in horses, GGT activity may continue to increase for 7–14 days despite clinical improvement and a return toward normal of other laboratory tests. Reportedly, plasma GGT activity increases within a few days of liver damage and remains increased until the terminal phase. Chronic hepatic fibrosis is the only liver disease in which an abnormal increase in GGT activity might not occur. GGT activity may also be increased with colonic displacement in horses or the administration of drugs (eg, corticosteroids, rifampin, benzimidazoles, anthelmintics).

Neonatal foals, calves, and lambs have higher GGT activity because of the presence of GGT in colostrum and milk. Younger adult horses, especially those in active training, may show a nonspecific increase in GGT activity that is not associated with liver disease or with increases in the activity of other liver enzymes or in serum bile acid concentration. Serum GGT, bilirubin, and total bile acid concentrations, as well as bromosulfophthalein (BSP) clearance, are not sensitive indicators of liver disease in young calves. Serum alkaline phosphatase (AP) concentration may also be elevated in normal calves and foals deriving from bone, not hepatic, origin. Serum activities 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.

Measurements of the activity of SDH, arginase, ornithine carbamoyltransferase (OCT), LDH, GLDH, AST, 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 a hepatic intracellular enzyme that is the most predictive of active hepatocellular disease; enzyme activity increases markedly after hepatocellular damage. Mild increases in SDH activity can occur with obstructive GI lesions, endotoxemia, hypoxemia from shock, acute anemia, hyperthermia, and anesthesia. Because of the short half-lives of SDH and LDH, measurements of their activity levels are useful in assessing the resolution or progression of liver insult. Both enzymes usually return to near-normal values 4 days after a singular liver insult, and neither is usually increased in chronic liver disease. Rarely, in severe cases of hepatic failure, SDH activity may return to normal, despite an eventual fatal outcome. Arginase and GLDH are considered specific for acute liver disease because both have high levels of activity in liver tissue and short half-lives in the blood.

AST is highly sensitive for liver disease but lacks specificity, because high activity levels come from both liver and skeletal muscle. Other sources of AST include cardiac muscle, erythrocytes, intestinal cells, and kidneys. When creatine kinase (CK) activity is simultaneously measured to exclude muscle disease and the serum is not hemolyzed, increases in AST and LDH activity are interpreted to indicate hepatocellular disease. AST activity may remain increased 10 or more days after an acute, transient insult to the liver. AST activity values are often normal in chronic hepatic disease. SDH and AST activity levels may be markedly increased with intrahepatic cholestasis and mildly increased with extrahepatic cholestasis.

Increases in AP and GGT activity levels are associated with irritation or destruction of biliary epithelium and with biliary obstruction. AP comes from the placenta, bone, macrophages, intestinal epithelium, and liver. AP activity is increased in very young calves and foals because of increased bone activity. In young calves, AP concentrations of 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 neonatal foals, and AP activity may remain high compared with adult levels for 1–2 months. In calves (< 6 weeks old), none of the common tests (measuring bilirubin, GGT, GLDH, AP, LDH, AST, or alanine transaminase) for liver damage or function are clinically useful for the detection of hepatic disease when used alone. AST and GLDH are the most sensitive of the enzymes in the case of hepatic injury; however, AST activity also increases with muscle damage. AST activity in foals may be high, compared with values in 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 months old.

Total Serum Bile Acids

The concentration of bile acids in serum 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 serum bile acid concentrations remain increased in horses with chronic liver disease. Bile acid concentrations in horses show no diurnal variation, no postprandial rise, and no appreciable hour-to-hour variation. The total serum bile acid concentration in most healthy horses is < 10 mcmol/L. Concentrations of serum or plasma bile acids of > 20 mcmol/L have a high sensitivity and positive predictive value for determining liver disease in horses but not in ruminants. Higher elevations of bile acids are associated with higher mortality; horses that survive generally have lower bile acid concentrations. Although bile acid concentrations of > 30 mcmol/L can be an early predictor of liver failure, caution must be used in the interpretation of mild increases, because bile acid concentrations of up to 20 mcmol/L may occur in horses with anorexia. Prolonged, but not short-term (< 14 hours), fasting may cause increased serum bile acid concentrations in horses.

The interpretation of total bile acid concentrations is difficult in foals < 1 week old. Compared with those in healthy adult horses, serum bile acid concentrations in healthy foals are considerably greater during the first 6 weeks 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, the measurement of serum bile acid concentration is of little value in recognizing fatty liver or liver disease or failure, because of marked hour-to-hour variations. In recently freshened cows, total serum bile acid concentrations are substantially higher than in cows at midlactation or in 6-month-old heifers.

The total serum bile acid concentration may be the best single test for hepatic disease in young calves. Concentrations of> 35 mcmol/L in calves may indicate liver disease, bile obstruction, or a portosystemic shunt.

Reported reference ranges for serum concentrations of bile acids are 1.1–22.9 mcmol/L for llamas > 1 year old and 1.8–49.8 mcmol/L for llamas < 1 year old. Bile acid concentrations in individual llamas may vary with feeding or sampling time of day, remaining within the reference interval.

Serum Bile Pigments

Evaluation of serum bilirubin (direct and indirect) concentration is useful to determine hepatic dysfunction in horses and ruminants. Increases in bilirubin result from hemolysis (prehepatic), hepatocellular disease (hepatic), cholestasis (posthepatic), or physiologic causes. Anorexia in horses causes a physiologic increase in total serum bilirubin concentration to usually < 8 mg/dL and rarely as high as 12 mg/dL, accumulating at a rate of ~1 mg/dL for each day of anorexia. The indirect bilirubin increases two- to three-fold, while the direct bilirubin remains within the reference range, so the accumulation with anorexia is prehepatic.

Mild, transient physiologic hyperbilirubinemia and icterus may occur in newborn foals and calves. Although the mechanism(s) are 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 hours old, total bilirubin may be as high as 1.5 mg/dL and up to 0.8 mg/dL in 1-week-old calves. The concentration of 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 to 4.5 mg/dL, with most being unconjugated bilirubin (0.8–3.8 mg/dL). Bilirubin concentrations in healthy foals should be within adult reference ranges by the time they are 2 weeks old. Normal values for total bilirubin in goats are 0–0.1 mg/dL.

In foals, indirect more than direct bilirubin may be increased with prematurity, neonatal isoerythrolysis Alloimmune Hemolysis Hemolytic anemia results from loss of RBCs. Immune-mediated destruction is the most common cause in dogs, although infections, tumors, and other causes also occur. Immune-mediated hemolytic... read more Alloimmune Hemolysis , septicemia, or a portocaval shunt. Enteritis, umbilical infection, intestinal obstruction, and certain drugs (corticosteroids, heparin, halothane) may also cause hyperbilirubinemia. Direct bilirubin may be elevated in septic foals with intestinal ileus and minimal evidence of hepatocellular dysfunction.

Horses with hepatic disease and failure most often have substantial increases in both indirect and direct bilirubin. As with bile acids, higher elevations of bilirubin concentration are associated with higher mortality.

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 due to hepatic necrosis results in increases in both indirect and direct bilirubin fractions. 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.

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 concentration. 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 of > 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 suggest 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, decrease it by intestinal bacteria, or absorb it from the ileum. The correlation between urobilinogen concentration and hepatocellular disease in animals is poor. Urobilinogen is unstable in urine; thus, analysis must be done within 1–2 hours of micturition, or the amount will be decreased or undetectable.

Plasma and Serum Proteins

Serum albumin and protein concentrations vary in horses and cattle with hepatic disease. Hypoproteinemia is not common in horses with acute liver disease. Serum albumin is most likely to be decreased in chronic liver disease because of 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.(1 References Diseases of the liver produce clinical signs of depression, anorexia, icterus, and sometimes photosensitization. Chronic liver disease is often accompanied by weight loss. Abdominal ultrasonography... read more References ) Hyperproteinemia due to hyperglobulinemia (polyclonal gammopathy or increase in beta-globulins) may develop in horses with severe acute or chronic liver disease. The total plasma protein concentration is often normal; the albumin-to-globulin ratio, however, 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 (and failure to produce fibrinogen) or disseminated intravascular coagulopathy (and increased consumption of fibrinogen). A high fibrinogen or serum amyloid A (SAA) concentration is associated with an inflammatory response in horses with cholangiohepatitis Cholangiohepatitis Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more .

Clotting Times

Abnormalities in prothrombin time (PT) are often the first clotting abnormalities detected because factor VII, a liver-synthesized vitamin K–dependent factor, has the shortest half-life of the liver-derived clotting factors. Serum PT may be prolonged early in the course of 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 the possibility of coagulopathy due to vitamin K deficiency. Prolonged activated partial thromboplastin time (PTT) or other indications of coagulopathy may be noted in animals with severe hepatic disease.

Urea, Glucose, Ammonia, and Other Alterations

The serum concentration of urea may be decreased in both acute and chronic liver failure. In cases of liver failure, hypoglycemia is common in foals and less common in adult horses and ruminants; it is more likely in chronic liver disease. Blood glucose concentrations in adult horses with hepatic dysfunction are frequently normal or increased (probably because of stress). Plasma triglyceride concentrations are markedly increased in ponies, miniature horses and donkeys with hepatic lipidosis 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 triglyceride concentrations than adult horses have.

Plasma ammonia concentrations may be increased with hepatic insufficiency; however, they do not correlate well with the severity of hepatic encephalopathy, except in portocaval shunts. Increased concentrations of blood ammonia and clinical signs of hepatic encephalopathy without hepatic failure are reported in Morgan weanlings with hyperornithinemia, hyperammonemia Hyperammonemia in Morgan Foals Diseases of the gallbladder are rare in ruminants. Obstruction may be associated with liver fluke infestation, foreign bodies, abscesses, neoplasia, suppurative cholecystitis, or abdominal fat... read more , and normocitrullinuria syndrome, as well as 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 treatment 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 common in horses with hepatic and/or hemolytic disease.

Dye Excretion and Clearance Tests

Bromosulfophthalein (BSP) and indocyanine green dye have been used to measure liver function by assessing hepatobiliary transport. These tests, however, are now 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.


Ultrasonography can be used to evaluate liver size, appearance (shape, texture), and location in horses and ruminants for diagnosis of hepatomegaly, hepatolithiasis Cholelithiasis, Choledocholithiasis, and Hepatolithiasis in Large Animals The presence of calculi ("liths") within the biliary system is named according to the specific location of the calculus within the bile duct (cholelithiasis), common bile duct (choledocholithiasis)... read more , biliary dilatation, cholelithiasis Cholelithiasis, Choledocholithiasis, and Hepatolithiasis in Large Animals The presence of calculi ("liths") within the biliary system is named according to the specific location of the calculus within the bile duct (cholelithiasis), common bile duct (choledocholithiasis)... read more , or focal lesions. Tumors, cysts, abscesses, and/or granulomas may be evident. Compared to focal processes, diffuse diseases are harder to detect because they cause less distortion of normal hepatic architecture. A diagnosis of diffuse liver disease should be substantiated by biopsy and histopathology. Ultrasonography can be used to guide the collection of liver biopsy specimens and to perform cholecystocentesis and aspiration of abscesses, masses, or bile samples; the latter can be sampled to screen for fluke eggs, determine the concentration of bile acids, or for culture. Ultrasonography 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 patient. In older horses, the liver may be difficult to find in the classic right-sided biopsy window because of age-related right liver lobe atrophy.

Liver Biopsy

Percutaneous liver biopsy is the definitive way to diagnose hepatic disease. Histologic evaluation of the liver provides valuable information regarding the cause and severity of the disease process. Most cases of liver disease are diffuse, so the sample should be representative of the disease. Samples may 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 (PT, PTT, fibrinogen, fibrin degradation products, and optional platelet count) should be performed before liver biopsy to decrease the risk of hemorrhage; abnormalities, however, are rare. Liver biopsy may not be advised in a patient with clinical or clinicopathologic evidence of a coagulopathy or a hepatic abscess Hepatic Abscesses Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more , because hemorrhage or contamination of the peritoneal cavity may result.


Contrast abdominal radiography in foals may aid the diagnosis of gastroduodenal obstructions and secondary cholangiohepatitis. Portosystemic shunts in foals or young calves can be identified with mesenteric portovenography by the injection of radiopaque contrast solution into a jejunal mesenteric vein, followed by fluoroscopy or sequential survey radiographs to monitor the hepatic blood flow.


Biliary patency and hepatocyte function, structure, and blood flow may be evaluated by hepatobiliary scintigraphy. Radionuclide liver scans and biliary scans can detect alterations in blood flow or hepatic masses and biliary obstruction (atresia, cholangitis, cholelithiasis Cholelithiasis, Choledocholithiasis, and Hepatolithiasis in Large Animals The presence of calculi ("liths") within the biliary system is named according to the specific location of the calculus within the bile duct (cholelithiasis), common bile duct (choledocholithiasis)... read more ), respectively. Scintigraphy has been used in pigs, foals, and lambs to differentiate biliary obstruction from other causes of hyperbilirubinemia. When radionuclide is administered sufficiently proximally per rectum, scintigraphy has been used to identify the presence of a hepatobiliary shunt.

Treatment and Management of Hepatic Disease in Large Animals

  • Control of self-trauma if hepatic encephalopathy is present

  • Intravenous fluids, including glucose

  • Anti-inflammatories

  • +/- Antimicrobials

  • +/- Nutritional support

  • Protect from sunlight in case of photosensitization

Initial treatment of animals with clinical signs of hepatic disease or insufficiency is often supportive and is started before the underlying cause and extent of hepatic damage are known. History, clinical signs, and laboratory data may indicate a hepatic disease process, but liver biopsy is usually required to make a definitive diagnosis and to determine the extent of hepatic injury. Specific treatments for hepatic disease depend on the cause, presence of liver failure, chronicity, extent of hepatic fibrosis or biliary obstruction, and species affected.

Treatment of hepatic disease 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 important, to prevent injury to the patient and those working with the patient. Animals with hepatic encephalopathy often show aggressive and unpredictable behavior that can result in injury to themselves or their handlers.

Hepatic Encephalopathy

Horses with hepatic encephalopathy may be aggressive or demonstrate repetitive behaviors that make restraint difficult. To ensure the safety of the patient 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 patient responds to low dosages. Alpha-2 agonists (xylazine, detomidine, dexmedetomidine) given in small doses to effect can be used to control horses exhibiting abnormal behavior. Intramuscular sedation approximating double the intravenous dose may be necessary if the horse is not safe for intravenous injections. Diazepam should not be given to animals with hepatic encephalopathy, because it may enhance the effect of gamma-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 intravenous fluids. To aid in reversing clinical signs of hepatic encephalopathy, glucose as a 5%–10% solution should be given if hypoglycemia is present. Glucose also helps decrease blood ammonia concentrations and decreases catabolic gluconeogenesis and protein catabolism. Unless the patient is hyperglycemic, a continuous intravenous infusion of glucose (5% at 2 mL/kg per hour or 10% at 1 mL/kg per hour) 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 concentration, and glucosuria should be avoided. Intravenous glucose should be used in combination with balanced electrolyte fluids and not as the sole fluid source.

Initially, a balanced polyionic solution should be administered for rehydration. Potassium supplementation may be added (10–40 mEq/L, depending on the infusion rate), if the patient is hypokalemic or anorectic. If intravenous infusion is not possible in ruminants, rehydration may be attempted by oral administration of fluids, if rumen motility is intact. Rarely, some horses with hepatic disease are polycythemic, making the evaluation of hydration status by PCV difficult; plasma protein concentration is the better measure in that situation, although the occasional horse may also be hypoproteinemic because of chronic liver disease.

Acidosis may be present because of inappetence, dehydration, and lactate accumulation from reduced liver metabolism. Because rapid correction of the acidosis may exacerbate neurologic signs, acidosis should be corrected gradually by intravenous administration of fluids with a high concentration of electrolytes. If this treatment fails or if blood pH is < 7.1 (bicarbonate or total CO2 < 14 mEq/L), bicarbonate may be administered cautiously. Supplemental vitamins are optional; vitamin B1 (thiamine) may stimulate appetite. Adequate fresh water, and electrolyte water if practicable, should be made available if the patient is not dysphagic. Alternatively, acidosis associated with hepatic disease may be offset by hypoalbuminemia from decreased liver production of plasma proteins, and may not therefore be clinically apparent.

Treatments directed toward decreasing either ammonia production in or absorption from the intestine include the 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 due to decreased clotting factors may be difficult to control. If the patient can swallow, oral drugs may 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.

Oral administration of neomycin (10 mg/kg, every 8–12 hours for 1–2 days) has been used to decrease ammonia-producing bacteria in the intestine. Lactulose (333.3 mg/kg, PO, every 8 hours) is metabolized to organic acids by bacteria in the ileum and colon; the resultant decrease in colonic pH reportedly fosters an increased bacterial assimilation of ammonia, decreased ammonia production, ammonia trapping in the gut, 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, every 6, 8, or 12 hours) decreases ammonia-producing organisms in horses but should not be used in food-producing animals.

Neomycin, lactulose, and metronidazole may all potentially induce mild to severe diarrhea (salmonellosis) because of GI flora disruption, and they should be used cautiously. 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, and could exacerbate, hepatic encephalopathy.

Antimicrobials and Anti-inflammatories

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 (TMS) combination is a good empiric choice because of its activity against gram-negative bacteria and its high concentration in the biliary tract. 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; however, drugs such as TMS or ceftiofur, which have extensive enterohepatic circulation, have superior penetration in the liver. 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 Cholangiohepatitis Tyzzer disease is caused by Clostridium piliforme (previously Bacillus piliformis) and results in acute necrotizing hepatitis, myocarditis, and colitis in foals 8–42 days old.... read more . Metronidazole may be administered when anaerobic infection is suspected in horses. Specific antimicrobial treatment 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 or PO, every 12 hours; or phenylbutazone, 4.4 mg/kg, IV or PO, every 12 hours). Vitamin K1 (1 mg/kg, SC or IM, every 24 hours) 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) treatment may be useful. Mannitol has been recommended for the treatment of suspected brain edema in fulminant hepatic encephalopathy.

Dietary Management

Dietary management is an essential component of treatment for 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 long term 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 the need for hepatic glucose synthesis.

Feeds used successfully in horses with hepatic disease include grass or oat hay, corn, and sorghum. Small amounts of molasses may be added to improve palatability and to add energy and potassium. Fat and salt should not be added to the diet. Linseed meal and soybean meal have an excellent ratio of branched-chain amino acids to aromatic amino acids and may be used as a protein supplement in small quantities. Beet pulp may be substituted for oat or grass hay; beet pulp should always be soaked before feeding, to prevent choke.

The feeding of alfalfa hay, alfalfa-containing feeds, or other legume hays to horses with hepatic disease is controversial; the general recommendation, however, is to withhold legume products. Although alfalfa hay has a better ratio of branched-chain amino acids to aromatic amino acids than grass hay has, it may have too high a protein content. Feeding grass hay is preferred for animals with hyperammonemia or clinical signs of hepatic encephalopathy. A mixed grass/alfalfa hay may be fed to horses without neurologic signs, if weight loss is a problem and if the added protein is tolerated. Grazing grass pastures is allowable as long as clinical signs of hepatic encephalopathy are controlled and exposure to sunlight is avoided when photosensitization has been a problem previously for the patient.

Other feeds high in branched-chain amino acids include sorghum, bran, or milo; these grains are rarely fed alone, but often they are components of sweet feeds or other mixed-grain meals. Parenteral or enteral supplementation 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, nor are they 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 with rumen fluid (see Ruminal Fluid Transfer Ruminal Transfaunate Esophageal obstruction due to a foreign body leads to severe discomfort and acute free-gas bloat. Physical removal of the object may be hampered by marked spasm of the surrounding muscle. Specific... read more ) 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 brewers' 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. Intravenous polyionic fluids with 5% dextrose, potassium chloride, and B vitamins may also be needed in animals not consuming adequate amounts.

Key Points

  • Clinical signs of hepatic disease include anorexia, depression, icterus, weight loss, occasionally abdominal pain, hepatic encephalopathy and secondary photosensitization.

  • Serum concentrations of bile acids, total bilirubin, and serum amyloid A (SAA) are higher in nonsurvivor horses compared to survivors of hepatic disease.

  • Treatment typically includes administration of antimicrobials and/or anti-inflammatories, IV fluids, nutritional support, and sedation to control CNS signs if necessary.

  • Ultrasonography is a valuable tool for initial diagnosis, sampling, and serial monitoring of hepatobiliary disease.


  • Parraaga ME, Carlson GP, Thurmond M. Serum protein concentration in horses with severe liver disease: A retrospective study and review of the literature. J Vet Intern Med. 1995;9(3):154–161.

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