Diagnostic Approach to Hyperammonemic Conditions in Young Dogs and Cats
World Small Animal Veterinary Association World Congress Proceedings, 2003
Tsukimi Washizu, DVM, PhD
Department of Clinical Pathology, Nippon Veterinary and Animal Science University
Tokyo, Japan

Hyperammonemia can develop from several different mechanisms, including 1) portosystemic shunt (PSS), 2) hepatic insufficiency, 3) reduced activity of urea cycle enzymes, 4) metabolic disorders of organic acids. In all these conditions, animals may demonstrate neurobehavioral abnormalities, which are called hepatic encephalopathy (HE) when they are caused by hepatic diseases.

Blood ammonia concentration has been measured routinely in animals with HE, because ammonia is one of the toxins that cause HE and it is the only one clinicopathologic parameter of HE which can be measured in a house laboratory. In this presentation, a diagnostic approach to hyperammonemic conditions in young dogs and cats is discussed.

The Metabolism of Ammonia

The gastrointestinal tract is the major site of ammonia production, although other tissues such as kidney and muscle also produce ammonia. Most of the ammonia produced in the intestine is derived from dietary amino and amide nitrogen. The ammonia absorbed in the intestine is transported to the liver via the portal vein and is mostly removed by the hepatocytes, so only a small fraction is passed into the systemic circulation. Blood ammonia concentration is high in the animals with PSS because the portal blood bypasses the liver and drains directly into the systemic circulation.

The ammonia taken up by the hepatocytes is moved into the mitochondria. In the mitochondria, citrulline is formed from ammonium ion, bicarbonate, and ornithine. Citrulline is moved to the cytoplasm and is converted to arginosuccinate, arginine, and then ornithine with the release of urea. This process is known as the urea cycle. Urea formed by the hepatocytes is excreted through the kidneys. A reduced number of functioning hepatocytes and any derangement of enzyme activities or intermediate metabolites in the urea cycle result in hyperammonemia.

Causes of Hyperammonemia in Young Dogs and Cats

The most common cause of hyperammonemia in young dogs and cats is congenital PSS, followed by acquired PSS as formed in various hepatic disorders. Thirdly, reduced enzyme activities or accumulation of suppressing compounds of the urea cycle are seen in animals with inborn errors of metabolism (IEM). Only a few reports concerning IEM resulting in hyperammonemia in the dog have been published, however, it should be included in differential diagnosis for hyperammonemia, especially in young animals.

Congenital Portosystemic Shunts

PSS are abnormal communications between the portal vein and systemic circulation. Portal blood contains hepatotrophic factors (hormones and nutrients) derived from the pancreas and the gastrointestinal tract, and these factors are necessary for normal liver growth and function. Decreased portal blood flow to the liver leads to hepatocellular atrophy, reduction in liver size, diminution of intrahepatic portal vasculature, and hepatocellular vacuolation.

Animals with PSS demonstrate a variety of clinical and laboratory abnormalities. Prominent physical abnormalities include stunted growth, anorexia, vomiting, diarrhea, ptyalism, polydipsia, and polyuria. Neurological signs include lethargy, aimless wandering, circling, head pressing, blindness, stupor, seizures, and coma. Most animals with congenital PSS demonstrate neurobehavioral abnormalities before they are one year old. Personality changes such as aggressiveness and hyperactivity may also be observed, especially in cats. However, some dogs may not show any clinical signs.

Clinicopathological changes include hypoproteinemia, hypoalbuminemia, low serum urea nitrogen, hyperammonemia and increased serum bile acid (SBA) concentration. SBA concentrations are good indicators of PSS, because SBA concentrations are dependent on hepatoportal circulation, functional hepatic mass, patent biliary system, and the enterohepatic bile acid circulation. Usually, liver enzyme activities are not elevated except alkaline phosphatase (ALP), which is probably an osseus isoenzyme, not a hepatic one. Microcytic normochromic erythrocytes are common in animals with PSS. A nonregenerative anemia is observed in approximately 50% of dogs and 20% of cats (1). Target cells are most commonly observed in blood smears from dogs and acanthocytes from cats with PSS. In urinalysis, ammonium biurate crystals are often observed.

The presence of PSS is best confirmed by mesenteric portography unless colorectal scintigraphy is employed which does not require a general anesthesia.

Acquired Portosystemic Shunts

Acquired PSS is formed in diseases associated with portal hypertension(2), such as hepatoportal fibrosis(3), arteriovenous fistula(4), lobular dissecting hepatitis(5), and cirrhosis. Both congenital and acquired PSS cause deranged hepatic function and clinical signs of hepatic encephalopathy.

Clinical presentations and clinicopathologic features in animals with acquired PSS are similar to those with congenital PSS. Both blood ammonia and serum bile acid concentration are definitely increased in both animals with congenital PSS and acquired PSS. In addition, activities of liver enzymes such as alanine aminotransferase, ALP, and -glutamyltranspeptidase, and bilirubin concentration increase moderately in many cases with acquired PSS. The most significant difference between congenital PSS and acquired PSS is the presence of ascites in acquired PSS. Histopathological examination is essential to distinguish each disease entity resulting in acquired PSS. Diagnosis and classification of hepatobiliary diseases in young animals have not been fully established yet and sometimes we encounter cases that cannot be categorized into known hepatobiliary diseases.

Hyperammonemia Caused by Inborn Errors of Metabolism

Animals with congenital and acquired PSS show increased blood ammonia and SBA concentrations. If young animals with hepatic encephalopathy are only hyperammonemic, i.e., not associated with increased SBA concentrations, other causes of hyperammonemia must be looked for.

In human medicine, neonatal screening for the diagnosis of inborn errors of metabolism (IEM) has been implemented for the effective prevention and subsequent management of clinical symptoms. Recently, gas chromatograph-mass spectrometer (GC/MS) has been employed for the screening of urine. Several IEM cases with hyperammonemia in the dogs and cats were identified by GC/MS in Japan.

Two dogs and 2 cats were chemically diagnosed as IEM. All animals were very young (2 to 18 month old) and showed neurologic signs similar to HE seen in animals with PSS. They were all hyperammonemic; however, fasting and postprandial serum bile acid concentrations were within normal range.

Table 1. Cases chemically diagnosed as IEM

Case

Breed

Age (months)

Sex

1

Pekingese

3

Female

2

Yorkshire Terrier

2

Female

3

Maine Coon

2

Male

4

American Shorthair

18

Female

Positive-contrast portography was performed in cases 1 and 4 before referral, however, shunt vessels were not demonstrated on radiographs. Results of GC/MS analysis of their urine are shown in the following table.

Table 2. Metabolites identified in the urine and chemical diagnosis of each animal.

Case

Metabolites identified in the urine

Chemical diagnosis

1

isovalerylglycine

isovaleric acidemia

2

2-aminoadipate, 2-hydroxyadipate

2-ketoadipic aciduria

3

citrulline

citrullinuria

4

orotic acid, uracil

OTC deficiency

Metabolic causes of hyperammonemia in mammals include (1) disturbance in the urea cycle, (2) disturbance in salvage pathway of purine bases, (3) secondary hyperammonemia in metabolic disorders of organic acids. Cases 3 and 4 had urea cycle disturbances. Case 3 was an arginosuccinate synthetase deficiency and case 4 was an ornithine transcarbamylase deficiency. Case 1 was an isovaleryl-CoA dehydrogenase deficiency, which is one of the organic acid metabolic disorders. Case 2 was a 2-ketoadipate dehydrogenase deficiency, which is also an organic acid metabolic disorder. Any of the abnormal metabolites, which were found in these cases, were not identified in the urine of the dogs and cats with PSS. Analyzing the urine by GC/MS seems to be a noninvasive and accurate method to detect IEM in dogs and cats.

References

1.  Center SA, Magne M, Historical, physical examination, and clinicoathologic features of portosystemic vascular anomalies in the dog and cat. Sem Vet Med Surg(Sm Anim) 5:83-93, 1990

2.  Bunch SE, Johnson SE, Cullen JM. Idiopathic noncirrhotic portal hypertension in dogs: 33 dases (1982-1998). J Am Vet Med Assoc 218: 392-399, 2001.

3.  Rutgers HC, Haywood S, Kelly DF. Idiopathic hepatic fibrosis in 15 dogs. Vet Rec 133: 115-118, 1993.

4.  Rogers WA, Suter PF, Breznock EM, et al. Intrahepatic arteriovenous fistulae in a dog resulting in portal hypertension, portacaval shunts, and reversal of portal blood flow. J Am Anim Hosp assoc 13: 470-475, 1977.

5.  Bennett A.M, Davies JD, Gaskell CJ, et al. Lobular dissecting hepatitis in the dog. Vet. Pathol 20: 179-188, 1983.

Speaker Information
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Tsukimi Washizu, DVM, PhD
Department of Clinical Pathology, Nippon Veterinary and Animal Science University
Tokyo, Japan


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