Biochemical indicators of hepatic disorders

Normal values for routinely used biochemical indicators reflecting the status of the hepatobiliary system in newborn and growing puppies and kittens are given in Table 37-1.

TABLE 37-1 Normal values for routine biochemical indicators of hepatobiliary disorders in young dogs and cats (median [unless otherwise stated] and range)

Blood glucose

Hepatic gluconeogenesis and glycogen storage are the mainstays of blood glucose regulation. Newborns depend on their hepatic glycogen reserves during the first 24 hours, with minimal glucose derivation from gluconeogenic branched chain amino acids. Although the ability to synthesize glycogen develops early, stores of hepatic glycogen accumulate only near term. Hepatic glycogen stores may be low at birth subsequent to intrauterine malnutrition (i.e., multiple pregnancies) or maternal malnutrition. Within 12 hours of birth, hepatic glycogenolysis consumes most glycogen stores, necessitating nutritional intake and gluconeogenesis to maintain euglycemia. It is during this interval that newborns are most susceptible to hypoglycemia. Generally initial blood glucose concentrations in newborn dogs are lower than in adults, although values exceeding 200 mg/dl have been documented. However, puppies deprived of food, especially toy breeds, may develop symptomatic hypoglycemia within 48 hours in contrast to adults, which can fast for days or weeks without becoming hypoglycemic. Comparatively, symptomatic hypoglycemia is uncommon in neonatal cats and may reflect their carnivore-based metabolism. Neonatal dogs have overall poor glycemic regulation compared with adults, with slow recovery from either hypoglycemia or hyperglycemia. This is attributed to a relative insensitivity to endogenous insulin and suboptimal counterregulatory hormone responses (cortisol and epinephrine) in puppies. Consequently puppies can develop prolonged hyperglycemia after supplemental glucose administration.

Neonates have a relative deficiency of alternative energy sources (fat stores, gluconeogenic amino acids) to total body mass compared with adults. Only small amounts of fat are stored in the liver during the last trimester of gestation. Because lactate precedes use of alanine or glutamine for gluconeogenesis in puppies, and because lactate is preferentially used in the brain of hypoglycemic neonatal puppies, there may be an advantage in using lactate-containing fluids in symptomatic hypoglycemic puppies.

Maintaining euglycemia is important for the neonates’ neurologic status because they have a brain-to-body mass carbohydrate requirement 2 to 4 times greater than adults. Unfortunately, even though the neonatal brain may preferentially accept lactate as an energy substrate, lactate availability may be insufficient. Ketones, an important alternative fuel during starvation, are insufficiently synthesized in neonates owing to their limited body fat, slow fatty acid mobilization, low ketogenic abilities, and their inability to survive the adaptation interval that precedes effective ketosis.

Although glucose regulation improves with age, puppies and kittens up to 4 months of age should be considered predisposed to hypoglycemia when anorexic or dehydrated. Conditions and clinical signs associated with neonatal/pediatric hypoglycemia are provided in Box 37-1. It is notable that severity of clinical signs increases with age such that hypoglycemia is more easily recognized in older animals. Thus maintaining a high index of suspicion for hypoglycemia is essential to achieve early diagnosis in a neonate. Treatment is aimed at achieving euglycemia, normalizing body temperature and hydration status, avoiding stress, and eliminating underlying causal factors.

Urea cycle function and blood ammonia concentrations

Function of the urea cycle matures at varying stages of fetal and neonatal development in different species. Urea cycle enzymes have not been directly quantified in fetal or neonatal dog or cat liver. Nevertheless, baseline ammonia values in clinically normal dogs and cats as young as 2 months are within the normal adult range, with the exception of some Irish Wolfhounds with apparent delayed closure of the ductus venosus.

Plasma ammonia concentrations can reflect portosystemic shunting caused either by congenital malformations of the portal circulation or secondary to portal hypertension (e.g., hepatic fibrosis, cirrhosis, portal vein thrombosis). Unfortunately because ammonia is labile in blood, immediate analysis is imperative. Samples must be transported from patient to equipment on melting ice, eliminating the routine transport to a commercial laboratory. It is well acknowledged that enzymatic methods for measuring blood ammonia concentrations lack precision. Ammonia is not routinely used in the author’s clinical practice because of its unreliability and because there are better test alternatives: measurement of serum bile acids and detection of ammonium urate crystalluria.

Serum bile acids

Serum bile acids (SBAs) are well documented as a reliable method for estimating sufficiency of hepatic function and hepatoportal circulation. Bile acids are synthesized in hepatocytes from cholesterol, conjugated to an amino acid (taurine exclusively in cats; taurine or glycine in dogs), excreted into bile, and then undergo an efficient enterohepatic circulation. In adults, the enterohepatic circulation has 90% to 95% efficiency (each cycle). The utility of the endogenous meal-provoked bile acid challenge for assessment of liver function and perfusion has been fully investigated in neonatal, juvenile, and adult dogs and cats. In our laboratory, SBA concentrations in 1-day-old and 1-, 2-, and 4-week-old puppies and kittens are within the adult reference range. In older puppies and kittens, paired SBA samples (one before and one 2 hours after meal ingestion) concur with the adult reference range. The SBA test is reliable for detection of portal circulatory anomalies when paired samples (premeal and 2 hours postprandially) are evaluated. Random or fasted single samples are ill advised. Normal values may exist in animals with portosystemic vascular anomalies after a prolonged fast owing to circulatory delivery of arterial blood. Approximately 15% to 20% of dogs and 5% to 10% of cats have higher postprandial SBA concentrations relative to premeal values owing to delayed gastric emptying, intestinal transit, or perhaps gallbladder expulsion of bile (physiologic variation). Paired-sample (one before and one 2 hours after meal ingestion) SBA tests are recommended for vigorous routine assessments. Screening puppies for portosystemic vascular anomalies (PSVAs) using single random or fasted SBA concentrations is not recommended. Some animals with PSVA have normal fasting SBA values, and a few demonstrate the “backward” pattern described above. Physiologic variables influencing this test include (1) the gastric emptying rate, (2) the rate of gallbladder contraction and bile expulsion, (3) the rate of intestinal motility, (4) the functional status of the ileum where active bile acid transporters reside, and (5) the normalcy of the hepatobiliary structures and portal circulation.

Bilirubin metabolism

The fetal, neonate, and juvenile dog’s capacity for hepatic uptake, conjugation, and excretion of bilirubin is remarkably mature compared with humans and several nonhuman primates. The fetal dog has substantial concentrations of bilirubin-conjugating enzymes. The capacity of the liver in the fetal, neonatal, and juvenile cat has not been similarly investigated. Some individual puppies have total bilirubin values mildly increased during the first 72 hours of birth, but this resolves within 2 weeks. Some kittens at birth and up to 14 days of age have total bilirubin values as high as 1.0 mg/dl (adult reference range, 0 to 0.2 mg/dl); values normalize by 4 weeks of age. The etiology of such high neonatal bilirubin concentrations remains unclarified.

Liver enzyme activity

Age-appropriate reference intervals for serum liver enzyme activity are essential for interpreting laboratory data in neonatal puppies and kittens. Differences in serum enzyme activities between neonates and adults reflect physiologic adaptations during the transition from fetal and neonatal life stages, trauma associated with birthing, colostrum ingestion, maturation of metabolic pathways, growth effects, differences in volume of distribution and body composition, and nutrition. Activity of serum alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH) usually increase greatly during the first 24 hours of life. In kittens, ALP, CK, and LDH activity exceeds adult values through 8 weeks of age, whereas AST increases only transiently after birth. The early increases in AST, CK, and LDH likely reflect muscle trauma associated with birthing, whereas ALP activity reflects bone isoenzyme associated with bone growth. Enteric absorption of colostral macromolecules during the first day of life causes a substantial increase in ALP in puppies and kittens, and of gamma-glutamyltransferase (GGT) in puppies (Figure 37-1, A and B). This phenomenon is not unique to dogs and cats as it has also been documented in neonatal calves, lambs, pigs, foals, and human infants. Studies also have confirmed significant differences in ALP activities develop between colostrum-deprived and suckling pups and kittens within 24 hours of birth, with a similar change in GGT also observed in puppies. These differences are short lived, resolving within the first 2 weeks, but can be used as a surrogate marker of effective colostrum ingestion. Studies have confirmed that colostrum contains substantially higher GGT and ALP activity than that resident in the serum of the respective dam or queen. For example, colostral or milk GGT in bitches is 100-fold and ALP is tenfold greater than sera until day 10. However, by day 30, GGT and ALP activity in milk is significantly lower than before suckling had commenced. Although a marked influence of colostrum on serum ALP activity in neonatal kittens also occurs, the effect on GGT is modest compared with that in neonatal puppies. Sustained increases (first 6 to 12 months of life) in serum ALP activity in puppies and kittens (maximally threefold more than high normal adult reference values) reflect the bone ALP isoenzyme derived from osteoblast activity.

Figure 37-1 Liver enzyme activity in puppies (A) and kittens (B) immediately after birth showing the influence of colostrum ingestion on associated enzyme concentrations.

Albumin, globulins, coagulation factors, and protein C

Synthesis of albumin, many globulins, most coagulation, and many anticoagulant factors depends on the liver. Total protein and albumin concentrations in young dogs up to 4 weeks of age are below normal limits for adults, whereas protein concentrations in young cats are more variable (see Table 37-1). By 8 weeks of age, puppies have normal adult albumin concentrations, whereas total globulin values increase with age, reflecting cumulative antigenic challenge. Although coagulation assessments are uncommonly completed in neonatal puppies and kittens, limited observations suggest that values fall within the normal adult ranges for prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen in animals as young as 8 weeks of age. Protein C, recently shown to discriminate normal puppies from puppies with PSVA, is influenced by adequacy of portal venous perfusion. Although liver failure and severe enteric protein loss also can compromise protein C activity, this anticoagulant factor is useful for differentiating PSVA from microvascular dysplasia (MVD) in young dogs.

Cholesterol

Serum cholesterol concentration can reflect hepatic functional and circulatory disturbances. Because cholesterol is synthesized in the liver, synthetic failure can cause marked hypocholesterolemia. Portosystemic shunting, either congenital or acquired, also causes mild to marked hypocholesterolemia. Because cholesterol is excreted into the biliary tree in bile, cholestasis can increase in cholesterol concentrations. A mild to moderate increase in cholesterol is apparent with acute obstructive jaundice and in some animals with acute severe hepatic inflammation (lacking synthetic failure). In 1- to 3-day-old puppies but not kittens, mild hypocholesterolemia is common (see Table 37-1). In puppies and kittens older than 2 to 4 weeks of age, serum cholesterol concentrations are within the adult normal range.

Hepatic hematopoiesis

Extramedullary hematopoiesis can develop in the liver of puppies or kittens through 4 months of age. However, in older juveniles, hematopoietic activity in the liver is usually restricted to disorders associated with a brisk regenerative anemia.

Hepatic mineral storage

Age-related variations in hepatic concentrations of iron, copper, zinc, and selenium (per gram of dry liver weight) have been reported for Beagle dogs from 8 to 193 days of age (Table 37-2). A decrease in hepatic iron concentrations during the first 20 days after birth likely reflects mobilization of iron for hemoglobin synthesis in bone marrow, the relative iron deficiency of a milk diet, and decrease in hepatic extramedullary hematopoiesis. In many species, hepatic copper concentrations are higher in pediatric individuals relative to adults. In dogs, hepatic copper concentrations change little with advancing age unless challenged with a copper-rich diet. In dogs with copper-associated hepatopathy (primary metabolic or copper transport disorder, dietary copper loading, cholestatic liver injury), hepatic copper concentrations significantly increase over time (see later discussion on Copper Storage Hepatopathy).

TABLE 37-2 Hepatic mineral concentrations in Beagles (mean ± standard deviation; µg/g dry weight)

Gallbladder

Congenital malformations of the gallbladder are most common in the cat. Congenital division of the gallbladder is most common and is also referred to as an accessory, cleft, diverticular, or bilobed gallbladder (Figure 37-2). These malformations involve the initial subdivision of the primary cystic diverticulum or a bud from the neck of the embryonic gallbladder. Although such malformations do not cause clinical illness, they can cause confusion when recognized during abdominal ultrasonography as they may be mistaken for a cyst.

Figure 37-2 Bilobed gallbladders representing developmental anomalies in two cats.

(From Hoskins J: Veterinary pediatrics: dogs and cats from birth to 6 months, ed 3, Philadelphia, 2001, Saunders, p 201.)

Common bile duct diverticulum

A cystic diverticular outpouching of the common bile duct near the sphincter of Oddi has been recognized in some cats. These may become a nidus of infection (rather like the human appendix), eventually leading to septic choledochitis and pancreatitis. Clinical signs are initially vague but may involve inappetence and vomiting. Thereafter, features cannot be differentiated from other causes of hepatobiliary jaundice until gross inspection during exploratory laparotomy. Resection of the cystic diverticulum, often combined with cholecystoenterostomy, and judicious antimicrobial therapy and supportive care are usually curative. Adequate hydration, ursodeoxycholate (7.5 mg/kg orally twice daily with meals) and S-adenosylmethionine (20 mg/kg orally daily 1 to 2 hours before feeding) are used to promote choleresis for several months postoperatively.

Biliary atresia

Congenital maldevelopment of the biliary tree is an unusual anomaly recognized in puppies and kittens. These patients are jaundiced and fail to thrive. There is no treatment.

Cystic hepatobiliary lesions

Congenital and acquired hepatic cysts occur in both dogs and cats. Acquired cysts are uncommon in juvenile patients but may develop subsequent to trauma or inflammation and are usually solitary. Congenital or developmental cysts are commonly multiple and variable in size. Polycystic renal and liver lesions have been identified in Cairn Terriers and Persian cats during the first few months of life. Whereas cystic lesions may be parenchymal or ductal in origin, most hepatic cysts are ductal. These arise from primitive bile ducts and lack continuity with the normal biliary tree. If lining epithelium produces fluid, cysts transform into retention cysts. Cysts may be solitary or multiple in the polycystic disorder and vary in size from a few millimeters to several centimeters. Cats with polycystic liver malformations sometimes also have cystic lesions in the kidneys or pancreas. Although hepatic cysts are often asymptomatic, they may become symptomatic when they encroach on normal tissue or organs. Cysts adjacent to the gallbladder are most problematic. In polycystic feline liver disease, prolific production of extracellular matrix surrounding dysplastic ductal structures causes intrahepatic portal hypertension and subsequently development of acquired portosystemic shunts, abdominal effusion, and signs of hepatic encephalopathy.

Clinical illness associated with biliary cystic lesions in juvenile or young adult dogs and cats may be lacking or may remain vague (e.g., inappetence or vomiting caused by cyst compression of the stomach). Diagnosis is accomplished with radiographic or ultrasonographic imaging. Ultrasonography discloses the cystic nature of lesions, as well as the extent of tissue involvement. When abdominal ultrasonography was used to phenotype Persian cats with the polycystic renal mutation, renal cysts were identified at 6 to 7 weeks of age in many cats. Cats lacking cystic lesions at 6 months were deemed unaffected. Although the diagnostic performance of abdominal ultrasonography in detecting the cystic renal lesions was exceptional (specificity, 100%; sensitivity, 75% at <16 weeks of age; and specificity, 100%; sensitivity, 91% at <36 weeks of age), this procedure has not been evaluated for detection of polycystic liver disease.

Cats with cystic liver lesions should be DNA tested for the renal polycystic gene mutation if they are intended for breeding. It remains unclarified if there are variants of this disorder associated with primary liver involvement. DNA testing is done using a cheek swab kit (available from felinegenome@ucdavis.edu). Treatment is usually not indicated for congenital cystic liver lesions unless a large cyst causes abdominal discomfort or fluid accumulation causes pressure effects on adjacent organs or tissues. Periodic aspiration of large problematic cysts has been used to manage some patients. Other alternatives include partial cyst wall resection, entire cyst excision, or removal of an involved liver lobe. In some Persian cats, the polycystic renal or hepatic involvement is recognized during the first few months of life. In some of these, polycystic kidney disease is rapidly lethal. In others, the disorder is mild, does not cause overt signs, and is recognized incidentally later in life.

Portal hypoplasia versus portal hypoperfusion

Increased arteriole blood flow is a physiologic response to decreased portal venous perfusion and is a consistent histologic feature of any condition impairing hepatic portal venous perfusion (e.g., thrombi, venous obstruction). This adaptive response is associated with arteriolar tortuosity (coiling) and thickening of the arteriolar smooth muscle. Rather than portal hypoplasia, the functional terminology of portal hypoperfusion more accurately depicts the observed perfusion abnormality.

Hepatoportal microvascular dysplasia

MVD was originally well characterized in a family of Cairn Terriers with an increased incidence of PSVA. Extensive studies including organic anion dye clearance, colorectal scintigraphy, hepatic and portal ultrasonography, contrast radiographic portography, and liver biopsy (multiple liver lobes in each dog) confirmed MVD is associated with abnormal microscopic hepatic blood flow and a lack of macroscopic portosystemic shunting. In dogs with PSVA, hepatic ultrasonography detected a subjectively small liver, abnormal portal to systemic vascular communications, and hypovascular intrahepatic portal perfusion. In dogs with MVD, intrahepatic portal vasculature was less well defined than in normal dogs; liver size was subjectively normal; and no large shunting vessels were identified. Radiographic portography confirmed macroscopic shunting only in dogs with PSVA but disclosed inconsistent portal venous perfusion among liver lobes in dogs with MVD. Dogs with only MVD demonstrated contrast retention in some liver lobes, consistent with differential perfusion among liver lobes, and a lack of well-distinguished tertiary portal branches. These findings correspond nicely with scintigraphic features described as portal streamlining in dogs scrutinized for PSVA that lacked a macroscopic shunt. Microscopic features in dogs with only MVD overlap with those observed in dogs with PSVA depending on the liver lobe sampled; lesions are inconsistent among different liver lobes. Cytologic imprints of liver biopsies in dogs with either MVD or PSVA usually demonstrate small binucleate hepatocytes.

Dogs with MVD are typically asymptomatic and do not develop hyperammonemia, ammonium biurate crystalluria, or uroliths. The MVD lesion is irreversible and often accompanies PSVA. Its presence explains why some dogs undergoing surgical PSVA ligation maintain increased SBA concentrations yet lack clinical signs. Definitive diagnosis of MVD from PSVA cannot be made based on the liver biopsy as lesions are similar. Because MVD lesions vary among liver lobes, a minimum of three biopsies from different liver lobes is recommended for definitive diagnosis. Needle biopsies are notoriously poor for ascertaining the presence of either MVD or PSVA because of small sample size and restricted lobe sampling.

The MVD phenotype explains why some dogs suspected of having PSVA based on abnormal liver function (SBA) and hepatic histology lack macroscopic shunting vasculature on contrast radiographic study, colorectal scintigraphy, and surgical inspection. It is important to realize the differences between MVD and PSVA. Dogs with MVD usually remain asymptomatic and do not require special liver diets or therapeutic interventions with lactulose, metronidazole, neomycin, antioxidants, or ursodeoxycholic acid. The typical liver affected with MVD has no necroinflammatory component. High bile acids in these dogs represent the circulatory flux of the enterohepatic bile acid circulation rather than injurious bile acids retained in tissues. Dogs with MVD followed long term (up to 15 years) maintained on a canine maintenance diet without additional therapies do not develop progressive liver injury. Because many small Terrier-type dog breeds have a 30% to 35% incidence of MVD, puppies should be tested using a paired SBA test at 4 months of age before adoption into a pet home. Knowing a dog’s SBA status is important for future health care and assessments.

Portosystemic vascular anomaly

Several different types of PSVA have been described in dogs and cats, including but not limited to (1) persistent patent fetal ductus venosus (large breed dogs especially, inheritable in Irish Wolfhounds and Irish Deerhounds), (2) direct portal vein to caudal vena cava shunt, (3) direct portal vein to azygos vein shunt, (4) combination of portal vein with caudal vena cava into azygos vein shunt, (5) left gastric vein to vena cava shunt (common in cats and many small breed dogs), (6) portal vein hypoplasia or atresia with secondary multiple portosystemic shunts (comparatively rare), and (7) anomalous malformations of the caudal vena cava (rare). Additional subclassifications of PSVA are clinically useful to consider; these involve the different types of vascular malformations (extrahepatic and intrahepatic histologic lesions) in an individual.

Most animals with PSVA are diagnosed at a young age (4 weeks to 2 years), although some dogs have been 13 years of age at first diagnosis. There is no sex predilection. In dogs, Terrier breeds, especially Yorkshire Terriers, Maltese, Cairn Terriers, and several others, are commonly afflicted. Families of dogs have been studied in which a genetic predisposition is obvious (e.g., Yorkshire Terriers, Cairn Terriers, Tibetan Spaniels, Maltese, Havanese, Shih Tzu, Miniature Schnauzers, Irish Wolfhounds, and Scottish Deerhounds).

Although not commonly appreciated, not all dogs with PSVA are symptomatic. Most symptomatic dogs are “unthrifty” in appearance and often are the litter “runt.” If not stunted early, most fail to keep up with growth expectations. Neurobehavioral signs (hepatic encephalopathy [HE]) may manifest early during the first few weeks of life owing to hypoglycemia (especially in toy breeds). Signs of HE also may manifest as the puppy or kitten is weaned onto growth-formulated diets from milk or when older animals are cutting teeth and swallowing blood. Failure to demonstrate overt signs of HE in the neonatal period relates to the protein and carbohydrate composition of the milk diet. Signs of HE are episodic and typically associated with meals. However, enteric parasitism can also provoke neurologic signs as a result of enteric inflammation and bleeding. Blood within the intestinal canal is highly encephalogenic in patients prone to HE. Neurobehavioral signs may involve propulsive circling, amaurosis (unexplained transient blindness), dementia (head pressing, staring, vocalizing), aggression (especially in cats), seizure, lethargy, or coma. Gastrointestinal signs may include anorexia, vomiting, constipation (worsens HE), diarrhea, or ptyalism (excessive salivation, in cats especially, often confused with upper respiratory tract infection). Urinary tract signs may include abnormally increased water consumption and increased urine production (polydipsia/polyuria) as a result of the effect of neurologic toxins or dysfunctional hepatic osmostats. Dogs with PSVA often have a markedly increased glomerular filtration rate (GFR) owing to their remarkable water flux. Ammonium biurate urolithiasis may cause stranguria or dysuria and hematuria. Rarely acute abdominal pain reflects ureteroliths. Fever (intermittent) may occur as a result of circulatory bypass of the hepatic reticuloendothelial system that normally provides immune surveillance against infectious material transported from the gut. Intolerance to certain drugs requiring hepatic biotransformation or first-pass elimination may be noted at the time of neutering (general anesthesia) or when anticonvulsant medications are needed to control seizure activity. Animals with PSVA become extraordinarily ill when challenged by infectious disorders (e.g., abscess, puncture wound, rickettsial infections).

Physical findings usually include a small body stature and unthrifty appearance. Abdominal palpation often discloses prominent kidneys. Large kidney size may relate to increased GFR, renal gluconeogenesis, and other designated metabolic functions not normally conducted by the kidney, as well as renal cell hypertrophy induced by high ammonia concentrations. Rarely cystic calculi are palpated. A unique copper-colored iris is observed in non–blue-eyed cats (Figure 37-3); this color is similar to the eye color in Persians and thus must not be interpreted out of context.

Figure 37-3 Copper-colored iris of a cat with a portosystemic vascular malformation.

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