February 2017



Signalment (JPC # 2415344):  An 11-week-old female smooth coated collie


HISTORY:  This dog presented with a three week history of unusual behavior and circling. Prior to euthanasia, she displayed excessive salivation, head pressing and opisthotonos. This puppy was approximately one-half the size of her three littermates.


HISTOPATHOLOGIC DESCRIPTION:  Brainstem: There are bilaterally symmetric, focally extensive areas of spongiform change throughout the white matter and at the junction with the grey matter, characterized by variably sized (up to 30 microns in diameter) and occasionally coalescing (up to 85 microns in diameter) round to oval, clear vacuoles within the neuropil. There are increased numbers of astrocytes with enlarged nuclei and an increased amount of cytoplasm (astrogliosis). Within the affected areas there are moderate numbers of single and occasionally paired Alzheimer type II astrocytes characterized by clear, swollen, vesiculate nuclei with marginated chromatin.  Occasionally, neurons are swollen and pale with a large round eccentric nucleus and prominent nucleolus and dispersal of Nissl substance (central chromatolysis). Axon sheaths are occasionally dilated and empty or rarely contain gitter cells (ellipsoids).


Liver: Diffusely, there is a loss of portal vein profiles within portal triads, and there is mild lobular hypoplasia with portal triads in close approximation to one another. There is mild bile duct and moderate arteriolar hyperplasia and ectatic lymphatic vessels (edema). Randomly, within hepatic sinusoids and portal areas there are small aggregates of extramedullary hematopoiesis.


MORPHOLOGIC DIAGNOSIS:  Brainstem, gray matter: Spongiform change, multifocal, bilaterally symmetrical, moderate, with astrogliosis and Alzheimer type II astrocytosis, smooth coated collie, canine.


Liver, portal areas:  Portal venous hypoplasia, diffuse, marked, with arteriolar and biliary hyperplasia, and mild lobular hypoplasia.


ETIOLOGIC DIAGNOSIS:  Hepatic encephalopathy


CAUSE:  Congenital portosystemic shunt



·       Hepatic encephalopathy is due to ammonia and other metabolites which accumulate causing (1) spongiform change in the white matter and (2) Alzheimer type II astrocytes

·       Causes abnormal neurotransmission in CNS and neuromuscular system

·       The condition is often associated with congenital or acquired portosystemic shunts in dogs and cats and due to hepatic failure in horses and ruminants

·       In dogs, congenital portosystemic shunts are more common in purebreds (miniature schnauzers, Irish wolfhound, Old English sheepdog, and Cairn terrier); intrahepatic shunts occur most often in large breed dogs; extrahepatic shunts occur most often in cats and small breed dogs; mixed breed cats more commonly affected than purebreds

o   Intrahepatic shunts can be left, central or right divisional; left divisional is via the left hepatic vein and is a failure of the ductus venosus (allows oxygenated blood to shunt from the umbilical vein directly into the caudal vena cava) to close

o   Extrahepatic shunts connect the portal vein or a tributary (commonly left gastric or splenic vein) with caudal vena cava cranial to the phrenicoabdominal vein



·       The precise mechanism in which hepatic dysfunction results in encephalopathy is uncertain; conditions that result in hyperammonemia are key to development of hepatic encephalopathy; hyperammonemia alone does cause the development of type II astrocytes and spongiosis, it is suspected that additional factors such as increased benzodiazepine-like molecules, and an imbalance in monoamine neurotransmission between excitatory and inhibitory amino acid neurotransmission, captans, thiols, and short-chain fatty acids play a role

·       Astrocytes are the site of ammonia detoxificationthrough the synthesis of glutamine by glutamine synthetase, and increased glutamine in astrocytes  causes osmotic swelling

·       Ammonia is directly neurotoxic

·       Conditions contributing to and causing hepatic encephalopathy in small animals include:  

o   Congenital or acquired portosystemic shunts which results in hyperammonemia derived from amines absorbed from the intestine but not cleared by the liver

o   Acquired hepatic disease that reduces the functional detoxifying capacity of the liver with resultant hyperammonemia, and are secondary to portal hypertension (ex. chronic hepatitis, cirrhosis, portal vein hypoplasia, lobular dissecting hepatitis, portal vein thrombosis; cats – lipidosis)

o   Congenital deficiency of urea cycle enzymes (arginosuccinate synthetase)

o   Changes in the blood-brain barrier

o   Blood composition of amino acids shifts to fewer branched-chain amino acids and more aromatic amino acids (phenylalanine, tyrosine and tryptophan) which are toxic to the CNS

o   Alimentary bacterial synthesis of gamma-aminobutyric acid, a potent inhibitory neurotransmitter

o   Excess consumption of high protein food

·       Conditions that contribute to hepatic encephalopathy in ruminants include:

o   Subacute or chronic phyto- or mycotoxic liver injury

o   In sheep, copper toxicosis may lead to massive myelin vacuolation

o   Ammonia toxicity is responsible for the major part of brain lesions and clinical signs; the ammonia is of dietary origin, derived from protein and urea by microflora in the large bowel and hepatic deamination of amino acids, and is generally removed by the liver on the first pass of portal blood



·       Neurologic signs are usually intermittent, often correlating with postprandial deamination of dietary protein

·       Ataxia, staggering, propulsive walking or circling, head pressing, staring into space, blindness, inappropriate vocalization, aggression, agitation, depression, lethargy, collapse, convulsion, coma and death

·       Excessive salivation common in affected cats

·       Stunted growth with congenital portosystemic shunts

·       Hepatic disease signs:  Polydipsia/polyuria, vomiting, diarrhea, weight loss, anorexia, +/- ascites



·       Elevated fasting and postprandial bile acids

·       Elevated blood ammonia; abnormal ammonia tolerance test

·       Excessive sulfobromophthalein retention

·       Hypoalbuminemia (in the absence of proteinuria), low BUN, hypoglycemia and hypocholesterolemia indicate reduced hepatic synthesis and metabolism and decreased functional mass

·       Elevated serum cortisol

·       Ammonium biurate crystals in urine with portosystemic shunts

·       Leptocytes are associated with PSS; +/- microcytosis



·       No gross brain lesions

·       With congenital portosystemic shunts there is typically microhepatica; may see single shunt (usually represents a congenital shunt) or multiple (usually represents acquired shunts)

·       Urinary bladder with green ammonium biurate crystals – urate urolithiasis is caused by increased excretion of ammonia and uric acid, leading to renal, cystic or urethral calculi



·       Central nervous system (acute liver failure produces minimal brain lesions):

·       Bilaterally symmetrical spongiform change in the white matterof the cerebral cortex (peripheral fibers of the corona radiata) at the junction with the gray matter; polymicrovacuolation also occurs in the internal capsule, thalamus, hypothalamus, cerebellar medulla and peduncles, pons, and medulla oblongata; in the spinal cord the lesions are at the junction of the gray and white matter (fasciculus proprius); this is not a consistent finding in cats or ruminants; horses do not have significant spongiform change

·       Alzheimer type II astrocytes are the hallmark of hepatic encephalopathy; Alzheimer type II astrocytes have swollen, visible cytoplasm and an enlarged open-faced, vesiculate nucleus with a prominent nucleolus; although the cytoplasm is increased to be visible by light microscopy, glial fibrillary acid protein intermediate filaments are not increased during this process;  consequently Alzheimer type II astrocytes have absent or weak intracytoplasmic staining with GFAP immunohistochemical stains; Alzheimer type II astrocytes may appear as single cells or in clusters but are frequently in pairs; they are especially common in horses and are in reduced numbers in other species 

·       Liver (portosystemic shunt):

o   Hepatocyte atrophy, small hepatic acini, a dearth of portal venous branches, and a proliferation (reduplication) of hepatic arterial branches in the portal triad

o   Thick walled arteries and distended portal vein branches

o   Sinusoidal congestion, periportal vacuolization, biliary hyperplasia, lipogranulomas, increased periportal connective tissue



·       Alzheimer type II astrocytes contain nuclear bodies (found in many conditions) and glycogen particles



·       Clinical chemistry

·       Imaging with mesenteric venograms for detection of portosystemic shunt

·       Alzheimer type II astrocytes exhibit negative or weak GFAP immunoreactivity but retain S-100 immunoreactivity




·       Dogs and cats

o   Hepatic microvascular dysplasia, ductal plate malformation of boxer dogs

o   Congenital urea enzyme deficiency

o   Severe renal disease may cause similar brain lesions to include Alzheimer type II cells (renal encephalopathy) but this condition is rare in animals

o   Infectious diseases: Canine distemper (may see viral intranuclear and intracytoplasmic inclusions and nonsuppurative inflammation in Virchow-Robin space), FIP (pyogranulomatous periventriculitis, perivasculitis), FIV (nonsuppurative encephalomyelitis), FeLV, toxoplasmosis

o   Hydrocephalus

o   Idiopathic epilepsy

o   Metabolic disorders: Hypoglycemia, thiamine deficiency, citrullinemia

·       Ruminants, horses

o   Branched-chain a-ketoacid decarboxylase deficiency (maple syrup urine disease): White matter; cattle (increased amino acids in plasma and CSF)  

o   Hexachlorophene toxicosis: Diffuse spongiform change in white matter (doesn’t center at the gray matter/white matter junction)

o   Bovine citrullinemia: Autosomal recessive disease in Holstein-Friesian due to deficiency of arginosuccinate synthetase

o   Scrapie and related encephalopathies

o   Chronic copper poisoning in sheep - look for intravascular hemolysis and hemoglobinuric nephrosis

o   Intestinal disease in horses can produce hyperammonemia with clinical signs of colic and encephalopathy; possibly due to bacterial overgrowth



·       Diseases that result in hepatic encephalopathy:

o   Ruminants:  Plant toxicosis (pyrrolizidine alkaloids); hepatic lipodystrophy in Galloway calves, metabolic disorders

o   Horses:  Plant toxicosis (pyrrolizidine alkaloids); Theiler’s disease (serum hepatitis); Alzheimer type II astrocytes common; spongiosis uncommon



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