Acute liver disease and hepatoencephalopathy (Proceedings)


Liver disease is common in both dogs and cats, but acute liver disease is far less common than chronic hepatic disease in either species. Also, it should be noted that many patients with an acute onset of clinical signs suggestive of liver disease actually do have chronic liver disease.

Liver disease is common in both dogs and cats, but acute liver disease is far less common than chronic hepatic disease in either species. Also, it should be noted that many patients with an acute onset of clinical signs suggestive of liver disease actually do have chronic liver disease. This is because chronic liver disease often remains subclinical for quite some time and clinical signs only occur when the disease process becomes more severe or has destroyed a significant portion of hepatic function leading to acute signs of liver failure. One such example would be chronic hepatitis due to phenobarbital administration. Most of these patients have no clinical signs for years even though biochemically hepatic disease is evident. Only when hepatic function has been compromised significantly do these patients present with an apparently acute onset of clinical signs, such as anorexia, vomiting, ascites, hepatoencephalopathy (HE), and even bleeding diathesis. Thus, hepatoencephalopathy and other clinical signs of hepatic failure are not necessarily associated with acute hepatic disease, but are instead associated with hepatic failure.

Acute liver disease – Acute hepatitis

Both infections and toxicities can lead to acute hepatitis. While infections, for example with infectious canine hepatitis or leptospirosis lead to hepatic necrosis and secondary inflammation due to the infectious organism, toxic causes through chemicals or medications lead to hepatocellular necrosis due to the toxic substance with secondary inflammation.

Clinical signs

Acute hepatitis may be associated with fever, anorexia, vomiting, depression, and dehydration. In severe cases, clinical signs of liver failure maybe seen in addition, such as HE, jaundice, ascites, and/or bleeding diathesis. Also, the underlying disease process may affect other organ systems and may thus be associated with additional clinical signs. For example, most cases of canine leptospirosis are associated with renal failure and acute hepatitis.


A serum chemistry profile in patients with acute hepatitis usually shows severe increases of all serum hepatic enzyme activities, most importantly alanine amino transferase (ALT). Biochemical changes can also indicate hepatic failure and may include hyperbilirubinemia, hypoalbuminemia, decreased BUN concentration, or hypoglycemia. Hyperammonemia, thrombocytopenia, and alterations on a coagulation profile may also be observed.

Ultimately, a diagnosis of acute hepatitis is dependent on a biochemical diagnosis of hepatic injury with or without hepatic failure, a history of a potential etiology, and the histopathologic confirmation of hepatic necrosis and inflammation. Histopathology may also be helpful in suggesting a specific etiology (e.g., frequent mitotic figures in canine patients with leptospirosis). Also, serology is useful to diagnose leptospirosis as an underlying cause of the acute hepatitis.


The therapeutic goals in patients with acute hepatitis are to treat a confirmed or suspected underlying cause, administer supportive care, and employ symptomatic therapy for hepatic failure. If leptospirosis is confirmed or heavily suspected the patient should be treated with ampicillin (22 mg/kg IV q 6-8 hrs) or preferably doxycycline (5 mg/kg IV or PO q 12 hrs). In cases of suspected acetaminophen or phalloidin intoxication the patient should be treated with silymarin (50 mg/kg PO q 24 hrs). Also, N-acetylcysteine and vitamin C may be useful to treat patients with acetaminophen intoxication. Patients with mild hyperbilirubinemia, but no evidence of fulminant hepatic failure may benefit from treatment with ursodeoxycholic acid.

Patients with bleeding diathesis need to be treated with fresh frozen plasma. Patients with HE need to be treated as described below.

Hepatoencephalopathy (HE)

The liver has a large functional reserve. However, at the same time, some hepatic function is required to sustain life. The exact proportion of hepatic function that needs to be lost before clinical signs ensue is unknown and also depends on the type of function. The liver is a metabolic powerhouse and there are a variety of different functions, such as synthetic functions for albumin, coagulation factors, acute phase proteins, and many other proteins. The liver also synthesizes non-protein substances such as urea, bilirubin, or bile acids. Another important function of the liver is to metabolize substances that are no longer needed by the body or are there in excess, such as bilirubin from hemoglobin from senescent red cells or cholesterol. Finally, the liver is also responsible for metabolizing organic compounds, such as toxins and medications. Naturally, any one of these functions needs a minimal functional reserve. When this minimal functional reserve for one of these functions is reached, biochemical changes can be observed that may or may not be associated with clinical signs. For example, failure to extract bilirubin from the blood or to conjugate it in hepatocytes will lead to hyperbilirubinemia and if severe enough to jaundice. Similarly, failure of the liver to convert ammonia into urea will lead to hyperammonemia and, if severe enough, hepatic encephalopathy.


HE is the result of a dysfunction of several neurotransmitter systems in the brain, including the glutamate, the dopamine/noradrenaline, the gamma-aminobutyric acid, and the benzodiazepine neurotransmitter systems. All of these systems are dependent on metabolites from the gastrointestinal tract that are modified in the liver before reaching the brain.

Glutamate is an important excitatory neurotransmitter in the brain. The level of glutamate in the brain is directly related to blood ammonia concentration. Ammonia is produced in the intestinal lumen through the metabolism of nitrogenous compounds by members of the intestinal microbiota. Ammonia freely enters mucosal cells and then into the circulation. Under physiologic conditions ammonia is removed very efficiently by the liver and is converted to urea, which is then excreted through the kidneys. However, in patients with liver failure ammonia accumulates in the blood and freely enters into the brain through the blood-brain barrier. The small amount of ammonia that usually enters the brain is detoxified by the production of glutamine in astrocytes. As the amount of ammonia increases that enters the brain, this process is overwhelmed and ammonia and glutamine enter presynaptic neurons. This ultimately leads to a depletion of the excitatory neurotransmitter glutamate at postsynaptic neurons. It should also be pointed out that HE can be potentiated by alkalosis and hypokalemia as both of these conditions will increase the mucosal uptake of ammonia. Thus, alkalosis and hypokalemia should be avoided or treated in patients with HE.

It is important to note that other neurotransmitters are also believed to play an important role in the pathogenesis of HE, though their exact role is poorly understood. For example, the aromatic amino acids tyrosine, tryptophane, and phenylalanine are physiologically absorbed by the intestinal mucosa. If they are not adequately removed by the liver they accumulate in the brain. In the brain increased concentrations of these amino acids overwhelm the synthetic pathway to generate dopamine and noradrenaline, leading to the generation of false neurotransmitters that, while binding to the receptors of catecholamines, do not have the same function.

Clinical Signs

As the name of the clinical syndrome, hepatoencephalopathy, suggests, clinical signs of HE are mostly neurologic and are divided into 4 stages. Patients with stage 1 HE may show depression, decreased mental alertness, staring, and unawareness of surroundings. Patients with stage 2 HE may show ataxia, circling, head pressing, and blindness. Patients with stage 3 HE may show stupor and are usually unarousable. Finally, patients with stage 4 HE are comatose. In many patients stages of HE will alter over time and it is not unusual for a patient to have stage 2 or 3 HE for a few days and then improve to stage 1 HE spontaneously a few days later. It is not exactly known why this happens, but it may be related to the decreased food intake in patients with higher stage HE patients, which leads to a decrease of nitrogenous waste products in the GI tract and in turn to a decreased plasma ammonia concentration. Seizures can also be seen in patients with HE, but are fortunately not very common. In addition to neurological signs patients with HE may also show PU/PD, salivation, vomiting, ascites, or bleeding diathesis as these clinical signs can also be observed in patients with liver failure. It is interesting to note that humans with HE often have severe headaches long before any other clinical signs are observed, but it is unknown whether dogs and cats suffer the same sensation.


A diagnosis of hepatoencephalopathy is made biochemically or based on clinical signs and biochemical support. Many dogs and cats with biochemical evidence of HE don't have any apparent clinical signs. Also, sometimes the clinical signs are not correctly interpreted by the owner of the patient. For example, many owners of dogs with portosystemic vascular anomalies that have HE don't recognize that their dog is depressed until the shunt has been surgically corrected and the dog shows a much higher level of activity or playfulness.

The measurement of plasma ammonia is complicated by the fact that it is not very stable. Thus, plasma ammonia has to be measured within 30 minutes of collection of the sample and the sample has to be kept on ice until measurement. Fortunately, several in-clinic ammonia analyzers are now available that are relatively accurate for the measurement of ammonia. Plasma concentrations of less than approximately 50 μg/L are considered normal, while values higher than 50 μg/L are considered abnormal and are considered to represent evidence of HE. Plasma concentrations above 100 μg/L should prompt aggressive treatment of HE.


The treatment of hepatoencephalopathy has two major goals, cessation of clinical signs and biochemical normalization. Thus, observation of the patient, while important, is not sufficient to track treatment response and repeated measurement of plasma ammonia concentration is crucial. The rare patient that is presented actively seizing is very challenging to treat as such a patient may need to be treated with an antiepileptic agent. This is highly controversial as most antiepileptic agents are detoxified by the liver and some have been hypothesized to have counterproductive effects in seizing patients. Also, the patient must be immediately assessed for hypoglycemia, as severe hypoglycemia could also occur in patients with hepatic failure and could also lead to neurological signs and seizures. If hypoglycemia has been ruled out the patient may be treated with flumazenil (0.01 mg/kg IV; flumazenil has a very short half-life of approximately 1 hour). This benzodiazepine antagonist is aimed at decreasing the tone of the benzodiazepine neurotransmitter system in the brain and thus at reducing the seizure threshold. However, overall this treatment approach is not believed to be very effective. Though generally believed to be contraindicated, diazepam may be cautiously employed. A single dose in a seizing patient can be given and if efficacious maybe repeated if another seizure episode is encountered. However, diazepam should be avoided whenever possible. If a patient continues to seize, anesthesia with propofol may be unavoidable until plasma ammonia concentration can be decreased. In a patient that is not seizing, the primary goal of treatment is to decrease plasma ammonia concentration below 50 μg/L. This is achieved by a warm water enema with removal of as much colonic content as possible. After conclusion of the procedure, lactulose (20 – 60 ml) is instilled into the colon with a red-rubber catheter. These simple steps often lead to dramatic decreases in plasma ammonia concentration and improvement of mentation of the patient. Once the patient has improved an oral treatment protocol of lactulose (starting dose 5-15 ml PO q 8-12 hrs) and neomycin (20 mg/kg PO q 6-8 hrs) is started immediately. The amount of lactulose should be adjusted so that liquid diarrhea is avoided, but stools are kept semi-formed. In addition, the diet should be changed to a low-protein diet to decrease the amount of nitrogenous waste products that are generated in the small intestine.

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