Hepatic portal-vein hypoplasia has been suggested as better terminology, better reflecting the cause.
Q. Could you review some new hepatobiliary diseases in dogs?
A. Dr. David C. Twedt gave a lecture on emerging new hepatobiliary disorders in the dog at the 2006 American College of Veterinary Internal Medicine Forum. A review of the lecture is provided.
Hepatocutaneous syndrome, known as superficial necrolytic dermatitis, is an uncommon disease observed in middle-aged to older dogs.
The skin lesions have characteristic superficial necrolytic dermatitis or necrolytic migratory erythema. When these characteristics are combined with hepatic changes, it typifies this syndrome. The liver has mistakenly been described by some as cirrhotic because of the nodular appearance of the liver. The hepatic changes are best described as an idiopathic hepatocellular collapse with nodular regeneration. Changes generally are devoid of major inflammation. The hepatic nodular regeneration consists of vacuolated hepatocytes. To date the pathogenesis of the hepatic disease is unknown. Nor is it known if the liver dysfunction is the major mediator of the necrolytic skin lesions or whether another metabolic disease produced both the skin and hepatic lesions. Affected dogs almost all have pronounced reductions in amino acid and albumin concentrations. Diabetes mellitus occurs in some dogs. Recently hepatocutaneous syndrome has been associated with chronic long-term phenobarbital therapy.
Most dogs are presented because of the atypical skin disease. Abnormal serum liver enzymes are identified and, in most, serum ALP and bile acids are increased. The serum albumin is typically below normal and almost every affected dog is hypoaminoacidemic. The liver has a characteristic ultrasound appearance, looking like "Swiss cheese" due to the hypoechoic nodules.
It is thought that the necrolytic skin lesions are directly related to the hypoaminoacidemia, which may be responsible for the hepatic changes as well. This is supported in part by observations that dogs fed a protein-deficient diet for prolonged periods develop hypoalbuminemia and hepatic changes that resemble hepatic changes described in the hepatocutaneous syndrome; however, skin lesions were not observed. The importance of hypoaminoacidemia in this disease is further supported in that administration of intravenous amino-acid solutions transiently improved the skin lesions in many but not all dogs. The cause of the amino acid deficiency is unknown. The affected dogs appear to have been fed adequate protein-content diets. The prognosis for this disease is grave and invariably most succumb either due to liver dysfunction or to the severity of the skin lesions, or both.
Our current therapy includes administration of intravenous amino acid solution — approximately 500 milliliters of aminosyn (10% solution, Abbott) over eight to 12 hours. If administered too rapidly, hepatic encephalopathy can occur. Repeated infusions are given weekly. If after four weekly amino acid infusions and if there is no improvement, it is unlikely the dog will respond to therapy. With a positive response, the amino-acid infusions are given as needed. In addition, the dog is given a dietary protein supplement of egg yolks (as an amino acid source) and other protein supplements. Additional support includes antibiotics if a secondary skin infection exists, omega 3 fatty acids, ursodeoxycholic acid, vitamin E and/or zinc.
Gallbladder mucocele is seen in an enlarged gallbladder with immobile stellate or finely striated patterns within the gallbladder on ultrasound study. Changes often result in biliary obstruction or perforation. Smaller breeds and older dogs were over-represented, with Cocker Spaniels being most commonly affected. Most dogs are presented for nonspecific clinical sign,s such as vomiting, anorexia and lethargy. Abdominal pain, icterus and hyperthermia are common findings. Most have serum elevations of total bilirubin, ALP, GGT and variable ALT. Ultrasonographically, mucoceles are characterized by the appearance of stellate or finely striated bile patterns (wagon wheel or kiwi fruit appearance) and differ from biliary sludge by the absence of gravity-dependent bile movement. The gallbladder-wall thickness and wall appearance are variable and nonspecific. The cystic, hepatic or common bile duct may be of normal size or dilated, suggesting biliary obstruction. Gallbladder-wall discontinuity on ultrasound study indicates rupture, whereas neither of the bile patterns predicted the likelihood of gallbladder rupture. Mucosal hyperplasia is present in all gallbladders examined histologically, but infection is not present with all cases, suggesting biliary stasis and mucosal hyperplasia as the primary factors involved in mucocele formation. Cholecystectomy is the treatment for mucoceles.
Portal-vein hypoplasia, also referred to as microvascular dysplasia (MVD), is a confusing syndrome associated with abnormal microscopic hepatic portal circulation. Initially, the condition has been referred to as hepatic microvascular dysplasia. Hepatic portal-vein hypoplasia has been suggested as better terminology that may better reflect the cause of this condition. It is believed that the primary defect in affected dogs is the result of hypoplastic small intrahepatic portal veins.
This condition is thought to be a defect in embryologic development of the portal veins. With paucity in size or presence of portal veins, there is a resultant increased arterial blood flow in attempt to maintain hepatic sinusoidal blood flow. The hepatic arteries become torturous and abundant in the triad. Sinusoidal hypertension occurs under this high-pressure system. Lymphatic and venous dilation results with opening up of embryologic sinusoidal vessels and, thus, acquired shunts develop to transport some of the blood to the central vein, bypassing the sinusoidal hepatocytes.
This results in abnormal hepatic parenchymal perfusion and lack of normal trophic factors bathing the sinusoids, causing hepatic atrophy. With portal shunting of blood, increased iron uptake occurs that results in hepatic iron granuloma formation. Ascites or portal hypertension generally does not occur in this condition. Angiography or transcolonic portal scintigraphy fails to demonstrate macroscopic shunting in this condition.
Often a needle biopsy is not sufficient to provide enough portal areas to make the diagnosis, and consequently a wedge or laparoscopic biopsy may be necessary. All dogs have abnormal serum bile acid concentrations (usually moderate elevations) and variable serum liver enzymes. Therapy is symptomatic and includes management of hepatic encephalopathy. Evidence of oxidative damage to livers of shunt dogs provides evidence for antioxidant supplementation. The long-term prognosis is uncertain because of lack of experience with this relatively new disease.
Portal vein hypoplasia with portal hypertension (also known as idiopathic noncirrhotic portal hypertension or congenital hepatic fibrosis) and ascites occurs as a fibrosis variant. It is generally accepted that dogs having congenital portosystemic vascular anomalies with a single intrahepatic or extrahepatic shunting vessel have signs associated with hepatic encephalopathy but do not have portal hypertension or ascites. However, there is a subgroup of dogs with portal-vein hypoplasia that have moderate to marked fibrosis of the portal tracts, sometimes resulting in portal to portal fibrosis and a varying proliferation of arterioles and bile ductules, particularly at the periphery of the portal area.
Ascites, portal hypertension and secondary acquired portosystemic shunts occur. The hepatic pathology is void of inflammatory infiltrates. There are increased amounts of hepatic iron deposited in the liver. The fibrosis and bile-duct replication may be a non-specific reaction from increased growth factors promoting arterial proliferation. This condition is observed in dogs under 2.5 years of age and there is no breed prevalence; however, Doberman Pinschers, Cocker Spaniels and Rottweilers may be over-represented. The clinical presentation is similar to dogs having either congenital intrahepatic or extrahepatic shunts except most dogs have ascites. The serum liver enzymes generally are increased with a hypoalbuminemia and very high serum bile acid concentrations. Work-up of these dogs fails to identify a single shunting vessel, but rather these cases have marked portal hypertension associated with multiple acquired portosystemic shunts. These dogs present with ascites and signs of hepatic encephalopathy. Ultrasound study often is helpful, showing microhepatica, hepatofugal portal blood flow and multiple abnormal extrahepatic collateral shunts. Portal contrast studies indicate acquired portal shunts and pressure measurements document portal hypertension. The prognosis for this condition generally is guarded, but some dogs are reported to have a prolonged survival using anti-fibrotic agents and hepatic encephalopathy therapy.
Diffuse vacuolar hepatopathies can be very frustrating in determining the underlying cause. When hepatocytes become injured, one response is for them to swell and become vacuolated. Hepatocellular vacuoles distending the cytosolic compartment may contain fat, glycogen, intracellular water (edema), or other metabolic wastes or intermediates. Vacuolar hepatopathies may occur in conjunction with hydropic degeneration in which there is cytosolic swelling but the hepatocytes are devoid of distinct vacuoles. A number of conditions can be responsible for vacuolar hepatopathies.
Glucocorticoid (steroid) hepatopathies occur in the dog secondary to exogenous or endogenous glucocorticoids. The vacuolar lesions contain glycogen that is not easily differentiated from other vacuolar contents without specialized histopathologic processing. The development of steroid hepatopathies is linked with marked increases in serum ALP. The glucocorticoid-associated ALP (G-ALP) is unique to the dog and dogs having steroid hepatopathies are associated with a large component of G-ALP.
Determining the G-ALP portion of ALP has been suggested as a screening test for hyperadrenocorticism but unfortunately many other conditions are associated with increased G-ALP that is most likely secondary to chronic stress of the disease. Hence, many question the diagnostic usefulness of G-ALP.
Dogs having increased serum ALP and evidence of vacuolar hepatopathy always should be investigated for hyperadrenocorticism or glucocorticoid administration. The diagnosis of canine hyperadrenocorticism requires specific testing, such as a low-dose dexamethasone test or ACTH-stimulation test.
This is a diagnosis frequently observed in older dogs. These cases appear typical of steroid hepatopathies based on histopathologic examination and abnormal serum ALP, but without clinical or laboratory evidence of hyperadrenocorticism. The liver of these dogs contains excess glycogen, and they have laboratory findings of predominately G-ALP isoenzymes. One is unable to make the diagnosis of hyperadrenocorticism based on lack of typical clinical signs and normal conventional adrenal testing (i.e., ACTH stimulation or low-dose dexamethasone suppression test). Several dogs recently discovered having vacuolar hepatopathy and increased serum ALP without overt hyperadrenocorticism have abnormal concentrations in some of the other adrenal steroids (i.e., sex hormones such as progesterone and 17alpha-hydroxy-progesterone). It has been documented that progestin steroids bind to hepatic glucocorticoid receptors and will induce a steroid hepatopathy when given orally to dogs. There is now speculation that increases in progestin steroid hormones may result in the hepatic changes and serum ALP increase. It appears that most, if not all, of these dogs live a prolonged life without adverse consequences from their liver disease. The reason for abnormal progestin levels may be secondary to adrenal adenomas, adrenal enzyme deficiency for converting precursors to cortisol or inapparent adrenal masses. Adrenal adenomas have been shown to secrete high levels of 17-hydroxyprogesterone in dogs.
Recently a disproportionate number of Scottish terriers have elevated serum ALP and hepatic vacuolar changes, suggesting a breed predisposition for this condition. They may have a genetic defect in ALP production.
Nodular hyperplasia is a benign process causing an increase in serum hepatic values and histomorphologic changes that include macroscopic or microscopic hepatic nodules containing vacuolated hepatocytes. Liver function remains unchanged. Grossly, the appearance may be suggestive of chronic hepatitis or neoplasia. The cause is unknown but appears to be an aging change in dogs; most of those affected are older than 10 years of age. Laboratory findings include a serum ALP increase, but some may have mild increases in serum ALT and AST concentrations as well. Ultrasound study may be normal or may demonstrate larger nodules (many can be only microscopic and not observed on ultrasound study). Biopsy confirms the diagnosis; however, a wedge section is preferred, as a needle biopsy may not demonstrate the nodules. There is no specific therapy.
Dr. Hoskins is owner of DocuTech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: email@example.com.