Diagnosis of liver disease in dogs and cats (Proceedings)

Hepatobiliary disease

Functions of the liver include carbohydrate, lipid and fat metabolism, detoxification of metabolites, storage of vitamins, trace metals, fat and glycogen, fat digestion and immunoregulation.  The liver has great reserve capacity to perform these functions so signs of hepatobiliary dysfunction occur late in disease progression.  Early detection of liver disease usually requires laboratory testing and biopsy.

Since many early clinical signs of liver disease are non-specific, clues from the signalment, history and physical exam can help raise a clinician's suspicion of heptatobiliary disease as a differential.  Certain breeds are predisposed to congenital portosystemic vascular anomalies (portosystemic shunts), others have an abnormality in copper metabolism which leads to hepatotoxicity, chronic idiopathic hepatitis and hepatic amyloidosis occur most frequently in specific breeds (see below).

Table 1 Disease PSS Breeds commonly affected: Irish wolfhound, Australian cattle dog, Maltese, Cairn terrier, Yorkshire terrier, miniature schnauzer, Dachshund, Labrador, and golden retriever     Copper toxicity Bedlington terrier (well described/understood); also: Westie, Dalmatian, Skye terrier, Siamese cat, retrievers Idiopathic chronic hepatitis Doberman pincher, cocker spaniel, poodle, Labrador retriever Hepatic amyloidosis Shar pei, Abyssinian, Oriental, Siamese cats

Historical findings useful in the diagnosis of hepatobiliary disease include travel history, vaccination status, exposure to known hepatotoxins, and recent administration of possible hepatotoxic medications.  Juveniles with poor growth or those that have prolonged recovery from anesthesia, may have a congenital PSS.  Stressed out cats that become acutely anorexic should be evaluated for hepatic lipidosis.

Common, but non-specific clinical signs of hepatobiliary disease usually involve the GI, neurologic and urinary systems and include:  anorexia, depression, lethargy, vomiting, diarrhea, weight loss, poor growth, poor hair coat, bladder stones, and abdominal enlargement. Other clinical signs associated with liver disease include hepatic encephalopathy, icterus, polyuria, polydipsia and clotting disorders.

Pathophysiology of clinical signs of hepatobiliary disease:

Hepatic encephalopathy (HE)

Abnormal mentation and neurologic dysfunction occurs as a result of exposure of the cerebral cortex to absorbed intestinal toxins that have not been removed from the portal circulation by the liver.

Manifests clinically with behavioral changes (dementia, aggression),  neurologic signs (circling, staggering, aimless wandering, head-pressing, tremors, blindness, seizures or coma) and pytalism (especially in cats), anorexia, and vomiting.\

Causes

·         Congenital portosystemic shunts (PSS) are abnormal vascular channels between portal circulation and systemic circulation

·         Acquired portosystemic shunts develop secondary to severe primary hepatobiliary disease, such as chronic hepatitis that has progressed to cirrhosis and has resulted in sustained intrahepatic portal hypertension.

·         Acute fulminant hepatitis (usually toxic or viral) causing severe hepatocellular dysfunction and inability to metabolize absorbed toxins

·         Intrahepatic microscopic portosystemic shunting (microvascular dysplasia) is a congenital condition or results from chronic liver disease

Pathophysiology

Shunting of portal blood past the liver and/or severely decreased hepatocellular function cause accumulation of metabolic toxins absorbed from the GI tract and cause shifts in plasma amino acid (AA) composition. These factors, in combination with increased cerebral sensitivity to certain neurotransmitters, act synergistically to cause cerebral and brain-stem dysfunction characterized by depression, behavioral changes and/or seizures.

The primary toxin that contributes to he is ammonia.

Ammonia

Sources include intestinal tract (especially colon), kidneys and muscle.  Colon is the prime contributor of ammonia; produced from bacterial and enzymatic degradation of proteins, especially meat, urea, and blood. Other sources include metabolism of dietary amino acids in SI and from renal ammonia  production.  Hyperammonemia in synergy with other metabolic toxins interferes with cerebral  production of ATP and causes decreased cerebral O2 consumption

Magnitude of hyperammonemia may not correlate with the severity of the clinical signs

Relationship of acid-base balance to ammonia toxicity

·         At normal body fluid pH, 99% of ammonia exists as NH4+ and only 1% as NH3

·         Alkalosis causes conversion of NH4 to NH3

·         NH3 is lipid soluble and will passively diffuse across cell membranes. NH3 will always diffuse from an alkaline to an acid environment.  There it will accept a H+ ion, become NH4+ which is lipid insoluble, and in essence be "trapped." Therefore, conditions causing extracellular alkalemia (vomiting, potassium depletion, alkali therapy) may enhance intracellular NH3 toxicity

·         As NH3 in neurons accumulates, respiration is stimulated which can cause respiratory alkalosis, further increasing NH3 formation from NH4+.

Jaundice, bilirubinuria are due to cholestasis, or back up of bile

Abdominal Effusion is usually pure transudate due to severe hypoproteinemia but occasionally a modified transudate occurs due to portal hypertension               

·         Hypoalbuminemia

·         Sustained portal hypertension

·         Renal retention of sodium

Electrolyte and acid-base imbalances

·         Patients with chronic liver failure are often hypokalemic, alkalotic, and prone to sodium retention.  Alkalosis potentiates hepatic encephalopathy by enhancing the formation of NH3 which rapidly diffuses into cells where it becomes trapped; hypokalemia potentiates alkalosis

Uroliths

·         Stranguria, pollakiuria and hematuria may occur due to bladder stones

·         Ammonia biurate stones form secondary to chronic hyperammonemia and decreased hepatic processing of uric acid

Coagulopathy

·         Decreased  synthesis of clotting factors by liver

·         Decreased vitamin K absorption if severe cholestasis present

·         Disseminated intravascular coagulation (DIC)

Polydipsia and polyuria:  unknown mechanism

·         Psychogenic polydipsia

·         Decreased hepatic urea synthesis leads to decrease renal medullary concentrating mechanism

·         Abnormal neurotransmitters in brain caused by imbalance of amino acids

·         Low potassium causes nephrosis

·         Altered portal vein osmoreceptor function

·         Treatment aimed at supportive measures to restore metabolic balance as discussed above

Bacterial infection or sepsis

·         Occur due to decreased hepatic clearance of gut-origin bacteria from portal circulation.  Coliforms and anaerobic bacteria are most likely involved

Assessment of a routine serum biochemistry panel is also useful in the diagnosis of hepatobiliary disease.  It is important to remember that significant disease can be present even when elevations in ALP, ALT and total bilirubin are not present.  Evaluation of liver function values (BUN, albumin, cholesterol, glucose) is also important.  Additionally, measurement of PT , PTT, bile acids and/or ammonia may help one consider hepatobiliary disease as a possible differential. Hepatic disease is not always easy to distinguish from small intestinal disease.

Imaging of the liver via abdominal radiographs and ultrasound may be beneficial.  I always perform abdominal radiographs in patients in which hepatic disease is a differential.  It is the best imaging modality to evaluate liver size.  The 3 causes of a small liver include congenital portovascular abnormalities, cirrhosis and acute hepatic necrosis.  Hepatomegaly may be caused by many more diseases.  Abdominal ultrasound is most useful in evaluating the biliary tract and to rule in/out hepatic mass lesions.  Changes in echogenicity are non-specific and should not be used to make a histologic diagnosis.  Hepatic nodules may represent metastatic neoplasia or benign nodular hyperplasia.  A solitary liver mass may be due to either benign or malignant neoplasia.

Liver aspirate cytology has limitations, but is useful in diagnosing hepatic lipidosis, many neoplasms, glycogen storage and sometimes amyloidosis (if appropriate stains are used).  Hepatitis or cholangitis/cholangiohepatitis, fibrosis, cirrhosis and excess copper accumulation can only be confirmed via liver biopsy.

Additionally, ultrasound-guided aspiration of the gall bladder can be useful in diagnosis of infectious cholangitis.  Both cytology and culture of bile (aerobic and anaerobic cultures) are recommended.  When aspirating the gall bladder, it is recommended to remove as much bile as possible in order to minimize the risk of gall bladder rupture.

Rarely, biliary scintigraphy is indicated in order to rule in/out a complete biliary obstruction.  Although there are cases in which abdominal/hepatic CT or MRI may be useful, in many cases hepatic biopsy is needed to determine a definitive diagnosis.  Whenever performing a liver biopsy, it is recommended to collect samples for histopathology as well as copper measurement.  I routinely culture both bile and liver.