Acute Liver Disease and Failure

Acute liver failure is defined as a syndrome of acute hepatopathy with evidence of abnormal coagulation. Acute liver failure (ALF) occurs when over 70% of liver mass or function is lost so that insufficient capacity remains to maintain synthetic and excretory homeostasis. This compromise of liver function results in many of the clinical manifestations of ALF, including icterus, (low blood sugar) hypoglycemia, bleeding tendencies, hepatic en­cephalopathy (neurologic signs due to liver dysfunction), cerebral edema, and increased susceptibility to infection.

A clinical distinction must be made be­tween acute liver disease (ALD) and acute liver failure (ALF). ALD is defined as liver dysfunction occurring in the absence of known preexisting liver disease, whereas ALF includes these parameters plus the presence of encephalopathy and coagulopathy. ALF is a rare syndrome associated with high morbidity and mortality and in veterinary medicine, isolated case reports of ALF have mortality rates of 25% to 100%.

Etiology

Causes of acute liver disease includes adverse drug reactions (e.g. acetaminophen, carprofen, grieseofulvin, ketoconazole,(e.g. aflatoxins, Amanita mushrooms, cycad seeds, and blue-green algae), infectious diseases (e.g. viral, protozoal - toxoplasmosis, neosporosis, bacterial - leptosporosis, and fungal agents (histoplasmosis) as well as heartworm infection (caval syndrome), ischemia (hypotension, anemia), neoplasia (lymphoma, histiocytosis), metabolic disease (hepatic lipidosis, inborn disorders of copper metabolism), and miscellaneous (food additives such as xylitol and alternative medicines have been implicated in hepatotoxicity).

Clinicopathological Findings

Clinicopathologic evaluation helps verify the existence of liver disease and determine the degree to which other organ systems are affected. The initial database should include a biochemical profile, complete blood count, and urinalysis. In ALF, serum aminotransferases are moderately to markedly increased. Serum hyperbilirubinemia, hypoglycemia, and hypoalbuminemia may be present with compromised hepatic function. Given the long serum half-life of albumin, the presence of hypoalbuminemia should alert clinicians to a more chronic condition. However, hypoalbuminemia may occur in ALF secondary to concurrent vasculitis or blood loss. Assessment of the coagulation profile provides further information about the functional status of the liver. The presence of coagulopathy is required for a diagnosis of ALF.

Ancillary clinicopathologic testing that may be indicated includes serology for infectious disease (leptospirosis, ehrlichiosis, Rocky Mountain spotted fever, toxoplasmosis, neosporosis, histoplasmosis, dirofilariasis), assessment of serum lipase levels, and autoantibody testing (Coombs' or antinuclear antibody).

Diagnostic Imaging

Diagnostic imaging is indicated in most patients with suspected liver disease. Plain abdominal radiography may reveal visible hepatomegaly, choleliths, or the presence of abdominal effusion or free gas. Ultrasonographic findings are variable in cases of ALF. Typically, the liver is enlarged with normal to hypoechoic parenchyma. Thoracic radiography is indicated to evaluate for pulmonary metastases and, in patients with concurrent vasculitis or hypoproteinemia, may help identify pleural effusion or pulmonary edema.

Histopathology

Once the presence of ALF has been confirmed but no cause has been identified, the next step in defining a cause is to obtain a hepatic biopsy. Histopathology provides a definitive diagnosis in cases of ALF secondary to metabolic (feline hepatic lipidosis), infectious, and neoplastic disease. It also allows assessment of the duration of illness, which has prognostic significance, because end-stage liver disease marked by prominent fibrosis has a poor prognosis. In addition, biopsy provides tissue for special stains and cultures that aid in evaluating both metabolic (copper storage diseases) and infectious causes of ALF.

Although biopsy provides valuable information that might influence treatment strategies, acquisition of hepatic tissue is often contraindicated because of the presence of coagulopathy and encephalopathy. In cases in which infiltrative disease (e.g., hepatic lipidosis, lymphosarcoma) is suspected, fine-needle aspiration may be diagnostic and involves less risk. Because the clinical management of ALF may be similar regardless of the underlying cause, biopsy should be delayed until the patient has been stabilized.

Medical Management

Many human patients with acute liver failure ultimately require orthotopic liver transplant, especially if they present with severe encephalopathy (neurologic signs). This form of treatment is not available for our veterinary patients and therefore medical management to support the patient while providing time for the liver to heal is the cornerstone of management.

Medical management of ALF involves:

1. Identification and removal of the inciting cause or administration of a specific antidote

2. Provision of supportive care to promote hepatic regeneration

3. Anticipation, control, and prevention of complications

The early provision of nutrition is important in treating ALF. Animals with ALF typically have a profoundly negative nitrogen balance, resulting in rapid depletion and redistribution of protein stores. Protein depletion delays hepatic regeneration, compromises the immune system, and worsens encephalopathy. Although initially used only in human patients with acetaminophen-induced liver failure, acetylcysteine has also shown benefit in patients with acute liver failure from other causes. This has not been investigated in veterinary species. Broad spectrum antibiotics may be administered pre-emptively in patients with coagulopathy, encephalopathy or multiorgan failure.

Medical management of ALD/I patients can be performed on an inpatient or outpatient basis determine by patient hemodynamic stability. The goals of treatment is supportive and symptomatic care until the liver has time to regenerate.

Complications

Caring for patients with ALF requires vigilant monitoring and prompt treatment of secondary complications, including hypoglycemia, encephalopathy, coagulopathy, infection, acute renal failure, and acute res­piratory distress

Prognosis

The prognosis for patients with ALF is variable and depends more on the degree of insult than the nature of the inciting event. Several negative prognostic markers have been identified in humans with ALF that may be useful in veterinary patients. These markers include a PT of longer than 50 seconds, persistent acidemia despite fluid therapy (pH: <7.3), a serum bilirubin level >17.5 mg/dl, persistent hypernatremia, and the presence of cerebral edema.

Conclusion

Managing patients with ALF is challenging. Specific treatments and antidotes directed toward the inciting cause of liver damage are rarely available. Rapid identification of affected patients and referral to a critical care center offer the best chance to minimize morbidity and mortality. Treatment largely consists of intensive supportive care and vigilant monitoring. Anticipation and treatment of complications are required to improve outcome.

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