Emerging hepatobiliary diseases: know the syndromes

In veterinary medicine, patients often are diagnosed with a generalized hepatic disease or disorder.

Dr. David Twedt discussed these conditions in his presentation titled "Emerging New Hepatobiliary Disorders in the Dog" at the ACVIM 2006 Forum. He clinically and histopathologically categorized and defined four generalized syndromes:

• hepatocutaneous syndrome;

• gallbladder mucocoeles;

• portal vein hypoplasia;

• and hepatic vacuolar hepatopathy.

Hepatocutaneous syndrome, or superficial necrolytic dermatitis, is a distinctive, crusting dermatosis in dogs and, less commonly, cats. The skin lesions have characteristic histological changes and patients generally have concurrent diseases such as diabetes mellitus, pancreatic neoplasia or severe hepatic disease. It is not known if the dysfunction of the liver is a mediator of the skin lesions or whether another metabolic condition is involved.

Recent reports suggest that the syndrome can be associated with the chronic use of phenobarbital. Patients commonly present due to the abnormal skin appearance, including crusting plaques, erosions and alopecia. Blood work may demonstrate an elevation in alkaline phosphate (ALP) and elevated serum bile acids.

Ultrasonography may reveal a pathognomonic swiss-cheese, honeycomb or reticulated appearance to the entire liver, characterized by diffuse hyperechoic network surrounding hypoechoic areas.

It is believed the lesions are directly related to hypoaminoacidemia. This is supported partly by the fact that dogs fed a protein-deficient diet for a period of time will develop lesions in the liver consistent with changes seen in hepatocutaneous syndrome.

A recent study by Outerbridge et al. found that the plasma amino-acid concentrations of dogs with this condition were significantly lower than those of dogs with acute or chronic hepatitis. The cause of the deficient amino-acid concentration is not fully understood, but treatment is aimed at managing underlying disease.

Therapeutic considerations

Current therapy consists of either Aminosyn II (8.5%) or Aminosyn (10%). These are both amino-acid solutions that are administered intravenously at a dose of 24 ml/kg as a slow infusion. Encephalopathy can develop with rapid administration.

Frequency of administration can range from daily to weekly, depending on the response to therapy. Nutrition should be managed by supplementation of protein (often in the form of eggs) and calories. Fatty acids may be given as well as zinc and niacin. Antibiotics should be considered if secondary skin infection is present.

A gallbladder mucocoele is described as an enlarged and immobile gallbladder with fine striations (wagon-wheel appearance) visible on ultrasound. Small-breed dogs (Cocker Spaniels and Shetland Sheep Dogs) as well as geriatric dogs are over-represented. Clinical signs are generally non-specific but may include decreased appetite, vomiting and abdominal pain. Clinicopathologic abnormalities may include elevations in alkaline phosphatase, bilirubin and potentially alanine aminotransferase (ALT). Histopathological findings typically include biliary stasis and mucosal hyperplasia, which may be involved in the formation of a mucocoele. Patients present typically due to secondary effects of the mucocoele (complete or partial obstruction of the gallbladder), so it may be possible for a mucocoele to be found incidentally or to resolve on its own prior to diagnosis. However, due to the association with obstruction and even gallbladder inflammation and necrosis, cholecystectomy is considered the treatment of choice.

Evaluating the risk

Recent studies suggest that the prognosis may be guarded for the immediate post-operative period, although those that survive the early post-operative period generally have a good long-term prognosis. Risk factors include increasing age, gamma-glutamyltransferase activity, preanesthetic heart rate, blood urea nitrogen (BUN), phosphorus and bilirubin concentrations. It was found that the use of biliary diversion procedures was a risk factor for death, as was concurrent or resulting pancreatitis.

Hepatic portal vein hypoplasia, or microvascular dysplasia (MVD), is a congenital disorder associated with abnormal microscopic hepatic portal circulation. The defect results from abnormal embryologic development of the portal vasculature.

Breeds commonly associated with MVD include the Maltese, Cairn Terrier and Yorkshire Terrier. Clinical signs at presentation often mimic what is seen with portosystemic shunts (PSS) although are generally more mild. These signs include small size, poor growth and an unthrifty appearance. Other clinical signs may include anorexia, vomiting, diarrhea, polyuria and polydypsia, intermittent fever and drug intolerance. Hepatic encephalopathy may result in part from elevated levels of ammonia, mercaptans, short-chain fatty acids and other neurotoxins. Signs of hepatic encephalopathy may include behavior changes, aggression, ataxia, lethargy, circling, dementia, amaurosis, seizures and coma.

Serum bile acids are elevated, and liver enzymes can be normal or elevated. Histologically, changes are similar to findings in patients with macroscopic shunts; therefore the diagnosis is not always clear from a biopsy sample. Typically, there is decreased portal vein diameter or the absence of a portal vein and proliferation of the arterioles in the portal tracts. Hepatocytes are often atrophied and lobules are diminished in size. Treatment is supportive and symptomatic, primarily aimed at managing hepatic encephalopathy.

Dietary/hydration considerations

It is important to manage fluid, glucose and electrolyte imbalances. Diet should be highly digestible, low in protein content and have high levels of zinc and vitamin E. Lactulose may be indicated to manage encephalopathy; ursodiol (actigall) to reduce hepatic inflammation and/or injury and promote choloresis may also be of benefit. Ursodiol also appears to have beneficial immunomodulatory effects (decrease immunoglobulin and interleukin responses). S-Adenosyl-L-methionine (SAMe) may be of benefit as a precursor to antioxidants in the hepatocyte and is involved in the restoration of glutathione (GSH) levels.

GSH plays an important role in detoxification mechanisms of the cell and depletion can indirectly cause toxic effects by increasing oxidative stress.

If patients continue to exhibit seizure activity, anticonvulsant therapy may be indicated. Long-term prognosis is typically poor if clinical signs are difficult to manage. There are many instances, however, where clinical signs never become apparent in dogs with MVD.

Vacuolar hepatopathy results in alterations of hepatic function as well as structure due to hepatocytes becoming vacuolated or infiltrated with fat, glycogen, edema, amyloid or other metabolic wastes. Cytosolic swelling is seen cytologically or histologically. Determining an underlying etiology in patients with vacuolar hepatopathies can prove difficult or may be more obvious as in patients with known exogenous or elevated endogenous glucocorticoids (steroid hepatopathy). Neoplasia, or other hepatobiliary diseases are commonly found concurrently in patients with vacuolar hepatopathy, possibly supporting the theory that illness-evoked physiologic response could be related to the development of vacuolar changes.

Increases in ALP are seen in cases of steroid hepatopathy. G-ALP (glucocorticoid-associated ALP) is unique to the canine and generally comprises the majority of ALP concentration; however, the diagnostic usefulness of G-ALP is still under debate.

If a patient has evidence of vacuolar hepatopathy and elevated ALP, glucocorticoid use must be ruled out. If there is no history of corticosteroid administration, the patient should be screened for hyperadrenocorticism. Some of these patients also have abnormally high concentrations of sex hormones such as progesterone and 17a-Hydroxy-progesterone.

It has been hypothesized that increases in progestin steroid hormones may result in vacuolar hepatic changes as well. Abnormal progestin levels may be due to adrenal enzyme deficiency, adrenal adenomas, or other unidentifiable adrenal masses. Recent studies are investigating the Scottish Terrier as a breed potentially over-represented for this condition.

Vacuolar hepatopathy often is considered "idiopathic" when steroid use and Cushing's disease are ruled out.

Clinical signs may vary depending on the patient and my range from no signs, to vague signs of lethargy, vomiting, diarrhea or signs of the underlying disease such as polyuria, polydipsia, weight gain and polyphagia with hyperadrenocorticism.

Most patients with idiopathic vacuolar hepatopathy live a normal life without adverse consequences, but further research is needed to better understand this disorder. Several patients have had a response (decreases in ALP) to ketoconazole, lysodren and trilostane administration.

Nodular hyperplasia is an age-related phenomenon, which is commonly seen in dogs greater than 8 years of age. There does not appear to be any breed or sex predilection. The condition is not generally associated with clinical signs, but mild to moderate elevations in ALP (alkaline phosphatase) and ALT (alanine aminotransferase), and may be appreciated. When these nodular changes are seen during ultrasonography or surgery, benign hyperplasia must be considered in addition to malignancy.

Histologically, it may prove difficult to distinguish hyperplasia from hepatocellular adenoma or adenocarcinoma especially in cases in which cytology is submitted for analysis. Wedge biopsies are the preferred sample of choice.

Liver disease in dogs can develop as a result of many different insults. Due to the regenerative capability of the liver, damage may repair itself. Severe or chronic damage, however, may lead to progressive and self-perpetuating chronic liver disease.

The clinical signs of liver disease often are often non-specific and laboratory and tissue sampling is essential for its recognition and evaluation. A definitive diagnosis is usually based on a combination of laboratory tests, radiography and/or ultrasound, and ultimately on histological examination of a liver biopsy.

Ongoing research to better understand the pathophysiology and etiology of these hepatic diseases is constantly underway.

Dr. Howe is a resident in small animal internal medicine at The Center For Specialized Veterinary Care in Westbury, N.Y. Her interests include diagnostic ultrasound and renal physiology. A Ross University veterinary graduate, she completed her clinical training at Auburn University and a medicine and surgery internship at The Center For Specialized Veterinary Care.

Bethany Howe

Dr. Levitan graduated with honors from the University of Pennsylvania School of Veterinary Medicine in 1991. She did an internship in small animal medicine and surgery at the Animal Medical Center in New York City, and then completed a residency in Internal Medicine (small animal) at Tufts University School of Veterinary Medicine. Dr. Levitan has since been a consultant for Antech Diagnostics, owns Mobile Veterinary Ultrasound & Endoscopy, PC (a veterinary consulting service) and is the founder and director of the Center For Specialized Veterinary Care in Westbury, N.Y.

Diane Levitan