© 2023 MJH Life Sciences™ and dvm360 | Veterinary News, Veterinarian Insights, Medicine, Pet Care. All rights reserved.
Emerging liver diseases (Proceedings)
Several hepatobiliary disorders have recently come under increased awareness in dogs.
Several hepatobiliary disorders have recently come under increased awareness in dogs. Understanding theses specific conditions is essential in the diagnosis and management of canine liver disease. Conditions presented below include vacuolar hepatopathies, biliary mucoceles, hepatocutaneous syndrome, and portal vein hypoplasia.
Several recent studies report this condition as an enlarged gallbladder with immobile stellate or finely striated patterns within the gallbladder on ultrasound. Changes often result in biliary obstruction or perforation. Smaller breeds and older dogs were overrepresented, with Cocker Spaniels being most commonly affected. Most dogs are presented for nonspecific clinical signs such as vomiting, anorexia and lethargy. Abdominal pain, icterus and hyperthermia are common findings on physical examination. 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 normal size or dilated suggesting biliary obstruction. In one series, loss of gallbladder wall integrity and gallbladder rupture was present in 50% of the dogs and positive aerobic bacterial culture was obtained from bile in a majority of these dogs. Gallbladder wall discontinuity on ultrasound indicated rupture whereas neither of the bile patterns predicted the likelihood of gallbladder rupture. Cholecystectomy is the treatment for mucoceles.
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. Based on information to date, the recommended course of action with an immobile ultrasonographic stellate or finely striated bile gallbladder with clinical or biochemical signs of hepatobiliary disease a cholecystectomy should be performed.
Portal Vein Hypoplasia
Portal vein hypoplasia also referred to as microvascular dysplasia (MVD) is a confusing syndrome associated with abnormal microscopic hepatic portal circulation. The condition has been initially referred to as hepatic microvascular dysplasia. Hepatic portal vein hypoplasia has been suggested as a better terminology by the WSAVA Liver Standardization Group that may better reflect the etiology 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 a 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 thus by-passing 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 also occurs that results in hepatic iron granuloma formation. Ascites or portal hypertension generally do not occur in this condition.
Because similar histological changes occur in dogs having congenital macroscopic portosystemic shunts the diagnosis can be confusing. If an intrahepatic or extrahepatic macroscopic shunt is not observed then portal vein hypoplasia (MVD) becomes the probable diagnosis. Angiography or transcolonic portal scintigraphy fail 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.
The condition that was first described in Cairn terriers and now is felt to occur in other breeds of dogs. Yorkshire Terriers and Maltese may be over represented. Two presentations are observed; either subclinical animals with no signs or those with signs typical of portal systemic shunts and hepatic encephalopathy. All patients have abnormal serum bile acid concentrations (usually moderate elevations) and variable 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 relative new disease.
Portal Vein Hypoplasia and Secondary Portal Hypertension
Portal vein hypoplasia with portal hypertension and ascites occurs as a fibrosis variant. It is generally regarded that dogs having congenital portosystemic vascular anomalies with a single intra 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. This condition has also been referred to as idiopathic noncirrhotic portal hypertension or congenital hepatic fibrosis because there is significant fibrosis in the portal areas.
The hepatic histology demonstrates portal tracts associated with multiple arterioles, small or absent portal veins with variable portal fibrosis, lymphatic distention and variable bile duct proliferation. The pathology is void of inflammatory infiltrates. There are also 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 latter condition is observed in dogs are 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 intra or extrahepatic shunts except most dogs have ascites. The liver enzymes are generally increased with a hypoalbuminemia and very high bile acid concentrations. Work up of these patients 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 is often helpful showing microhepatia, hepatofugal portal blood flow and multiple abnormal extrahepatic collateral shunts. Portal contrast studies demonstrate acquired portal shunts and pressure measurements document portal hypertension. The prognosis for this condition is generally guarded but some dogs are reported to have a prolonged survival using anti-fibrotic agents and hepatic encephalopathy therapy.
Hepatocutaneous syndrome, better known as superficial necrolytic dermatitis or metabolic dermatosis is an uncommon disease observed in middle aged to older dogs. The skin lesions have characteristic histological changes (superficial necrolytic dermatitis or necrolytic migratory erythemia) and when combined with the hepatic changes typify 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 are generally devoid of major inflammation. The hepatic nodular regeneration consists of vacuolated hepatocytes. To date the pathogenesis of the hepatic disease is still controversial. In humans other types of liver disease have been noted to produce the similar cutaneous lesions however the hepatocellular collapse described in the canine hepatocutaneous syndrome has not been reported. It is not 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. Some authors believe this condition to be the result of exaggerated amino acid catabolism. Uncommonly some dogs and humans have hyperglucagonemia secondary to a glucagon-secreting tumor. Diabetes mellitus occurs in some dogs. Recently hepatocutaneous syndrome has also been associated with chronic long-term phenobarbital therapy.
Most dogs are presented because of the skin disease. Abnormal liver enzymes are identified and in most, ALP and bile acids are increased. The albumin is typically below normal and almost every affected dog is hypoaminoacidemia. 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. The hypoaminoacidemia 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 hypoalbumenia 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 lesions in many but not all dogs. The cause of the amino acid deficiency is unknown. The affected dogs appear to have been feed adequate protein content diets. The reported 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. We give approximately 500 milliliters of Aminosyn™ (10% solution, Abbott) over 8-12 hours. If given too fast, 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 patient will respond to therapy. Some dermatologists suggest that daily infusions of amino acids for the first week results in a quicker response. With a positive response repeated the amino acid infusions are given as needed. In addition, we generally treat the patient with 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.
Drug Associated Liver Toxicity
With more and more drugs being used for treatment of disease we have observed an increased incidence of drug induced liver injury. Drugs can affect the liver in one of two ways. First they can have a direct toxicity to the hepatocyte or become metabolized to a toxic compound that then causes damage. This type of direct hepatotoxin is dose related and reproducible. An example would be acetaminophen poisoning. More commonly we observe drug associated liver toxicity that is an idiosyncratic drug reaction. Idiosyncratic drug reactions are unpredictable and not dose related but most often associated with abnormal or aberrant metabolism of the drug to a toxic compound. The common incriminators causing an idiosyncratic reaction include the NSAIDs, trimethoprim sulfa, azathioprine, lysodren, ketoconazole (and other antifungals), and diazepam (in cats) to name but a few. Damage to the liver is generally acute hepatic necrosis and can extend to massive hepatic necrosis resulting in fulminate hepatic failure. The mechanism of drug toxicity is complex and not completely understood.
Damage may range from focal or mild to moderate hepatic necrosis with minimal clinical signs to acute massive necrosis that will produce significant clinical signs. The signs of severe acute hepatic necrosis are variable but usually will include anorexia, depression, lethargy and vomiting. Jaundice may be present. In hepatic failure hemorrhage and hepatic encephalopathy ensues and this is then often followed by coma or seizures. Hepatic pain may be observed on abdominal palpation.
The clinicopathologic changes reflect necrosis and loss of hepatocytes. The hepatic transaminases (ALT and AST) are released when the cell membrane is damaged and the cytosol enzymes leak out. A marked increase in AST to ALT ratio suggests more severe hepatocellular damage. Generally ALP increases associated with hepatic necrosis are only mild to moderate. Hyperbilirubinemia is common when significant hepatic necrosis is present and frequently very high when massive necrosis occurs. Changes in the liver function test will reflect the magnitude of hepatic damage. When the necrosis is massive and liver function is compromised changes will occur. Clotting factors decline and may contribute to hemorrhage. Hypoglycemia, low BUN hypoalbuminemia, and increase in ammonia all reflect hepatic failure. It is however important to note that because of the acute nature of necrosis and half-life of clotting factors (hours to days) and albumin (2 weeks) that albumin concentrations may remain normal early in the disease. Frequently platelet number and function are also compromised in massive liver failure and DIC is a common complication.
Hepatic failure from massive hepatic necrosis can lead to a spectrum of metabolic abnormalities. Hepatic encephalopathy (HE) accompanies liver failure. There are also secondary metabolic factors that also contribute to HE formation and include hypoglycemia, hypoxia, GI hemorrhage, impaired renal perfusion and cerebral edema.
The prognosis of hepatic necrosis depends on the amount of damage and the secondary complications that occur. It has been stated that a prothrombin time greater than 100 seconds indicates a grave prognosis. Also following acute hepatic necrosis either complete recovery or progression to cirrhosis or chronic hepatitis may occur. In general terms supportive care and management of metabolic complications is provided until hepatocyte regeneration returns the liver to normal function. Addition of antioxidants is warranted in drug associated liver disease including vitamin E and S-Adensosylmethionine (SAMe). There is now evidence that SAMe protects against liver damage from acetaminophen toxicity in dogs and cats. The use of N-acetylcysteine (NAC, Mucomyst™) is recommended for acetaminophen toxicity and given at 70 mg/kg tid intravenously. We have also used NAC for other drug induced liver toxicities as well for glutathione replacement. An advantage of NAC over SAMe in some cases is that it can be administered intravenously. Milk thistle (Silymarin or silibin (Marin™) is reported to work as an antioxidant, scavenging free radicals and inhibiting lipid peroxidation and may be of benefit in drug-associated toxicity. One canine study showed that dogs poisoned with amanita mushrooms treated with milk thistle had less clinical signs and complete survival than untreated dogs.
The prognosis for acute hepatic necrosis and hepatic failure depends on the extent of hepatic damage, metabolic complications and the ability to maintain the patient until hepatic regeneration is possible. Aggressive management and anticipation of potential complications will improve survival. With biochemical and clinical evidence of loss of hepatic function the prognosis becomes guarded.