September 2009

Canine/Feline Liver
& Pancreatic Disease


David C. Twedt, DVM, Diplomate ACVIM
Colorado State University




Abnormal Liver Enzymes: A Practical Clinical Approach

The detection of abnormal liver biochemical tests in the asymptomatic as well as the symptomatic patient is a common finding on a routine blood screen. In humans it is reported that up to 4% of asymptomatic persons have increased serum liver enzymes. In a study of 1,022 blood samples taken from both healthy and sick dogs and cats 39% had ALP increases and 17% had ALT increases. The identification of liver biochemical abnormalities should suggest certain diagnostic possibilities and should guide a protocol for further investigation. Liver biochemical abnormalities are often nonspecific; the measured enzymes can be isoenzymes from another tissue or the same enzyme from a different tissue source. An understanding of the liver biochemical tests is essential when evaluating the patient in question. Liver biochemical test abnormalities are categorized into groups that reflect 1) hepatocellular injury, 2) cholestasis or 3) tests of impaired metabolic function or synthetic capacity.

Laboratory Tests


It is important to understand basic liver related laboratory tests in order to determine the possible etiologies for abnormal levels and to develop a course of action. Many liver tests are not specific only to the liver but can be abnormal from primary non-hepatic disease as well. Evaluation of liver biochemical tests must be interpreted in light of the history, medications and clinical findings. The magnitude and duration of increase is also dependent on the type, severity and duration of the stimulus and the species. They do not prognosticate the irreversibility of liver disease at one point in time. Also because the liver is involved in so many functions no single laboratory test in this category reflects the complete functional state of the liver.

Indicator of Hepatocellular Injury. A common presentation is the isolated increase in either alanine aminotransferase (ALT) or aspartate aminotransferase activity (AST). Canine and feline hepatocyte cytoplasm is rich in ALT and contains lesser amounts of AST. Altered permeability of the hepatocellular membrane caused by injury or a metabolic disturbance results in a release of this soluble enzyme. Conceptually ALT and AST should be thought of as hepatocellular "leakage" enzymes. Subsequent to an acute diffuse injury, the magnitude of increase crudely reflects the number of affected hepatocytes. It is however neither specific for the cause of liver disease or predictive of the outcome. The plasma half-life of ALT activity is 2.5 days and AST about 1 day, however ALT concentrations may take many days to decrease following an acute insult (possibly 2 weeks or longer). ALT elevations greater than 2X normal or persistent increases should be investigated. ALT increases are characteristic of chronic hepatitis in the dog.

Specific Evaluation of Increased ALT. Persistent ALT increases should be investigated or when they are greater than twice normal. The most important diagnosis to make is chronic hepatitis. Early diagnosis and prompt therapy improves patient survival. Hepatitis often begins in dogs 2-5 years of age with only ALT increases. Females are over-represented and breed associated hepatitis is well known. Dogs with significant hepatitis usually also have concurrent bile acid abnormalities. ALT elevations in young dogs under 1 year of age is sometimes associated with portal vascular anomalies and bile acid concentrations should be obtained to exclude that possibility. Occasionally I see young dogs evaluated prior to elective surgery having unexplained ALT increases for unknown reason that correct over time. Occasionally we will see dogs with mild increases in ALT and no histological evidence of disease and this probably reflects mild membrane changes not seen with light microscopy.

A variety of tissues, notably skeletal muscle and liver, contain high aspartate aminotransferase activity (AST). Hepatic AST is located predominately in hepatocyte mitochondria (80%) but also soluble in the cytoplasm. Skeletal muscle inflammation invariably causes a serum AST increase (and ALT to a much lesser extent) that exceeds the serum ALT activity and can be further defined as muscle origin by the measurement of the serum creatine kinase activity (CK) a specific muscle enzyme. Clinical experience in veterinary medicine indicates that there is value in the interpretation of the serum activities of ALT and AST for liver disease. Following an acute injury resulting in a moderate to marked increase in the serum ALT and AST concentrations, the serum AST will return to normal more rapidly (hours to days) than the serum ALT (days) due to their difference in plasma half-life and cellular location. By determining these values every few days following an acute insult, a sequential "biochemical picture" indicative of resolution or persistent pathology is obtained.

Markers of Cholestasis and Drug-Induction. Alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) show minimal activity in normal hepatic tissue but can become markedly increased in the serum subsequent to increased enzyme production stimulated by either impaired bile flow or drug-induction. These enzymes have a membrane bound location at the canalicular surface; ALP associated with the canalicular membrane and GGT associated with epithelial cells comprising the bile ductular system. With cholestasis, surface tension in the canuliculi and bile ductules increases and these surface enzymes are then up-regulated in production.

Specific Evaluation of Increased ALP. Elevations in only ALP in the dog is a common observation. It has a high sensitivity (80%) but a low specificity (51%). This is because of the multiple isoenzymes of ALP that can be induced into production. Alkaline phosphatase is present in a number of tissues but only two are diagnostically important, bone and liver. The plasma half-life for hepatic ALP in the dog is around 70 hours in contrast to 6 hours for the cat and the magnitude of enzyme increase (presumably a reflection of the synthetic capacity) is greater for the dog than the cat. Bone source from osteoblastic activity occurs in young growing dogs before their epiphysial plates close or in bone lesions (ie osteogenic sarcoma). In the adult dog without bone disease, an increased serum ALP activity is usually of hepatobiliary origin. However a recent study identified some dogs with osteogenic bone tumors to have increased ALP concentrations. ALP increase in those dogs indicates a poorer prognosis suggesting probable diffuse bone metastasis. GGT is not found in bones.

An increase in the serum ALP and GGT activity can also be associated with of glucocorticoids (endogenous, topical or systemic), anticonvulsant medications and possibly other drugs or herbs in the dog. There is remarkable individual variation in the magnitude of these increases and there is no concomitant hyperbilirubinemia. A moderate to marked increase in serum ALP activity without concurrent hyperbilirubinemia is most compatible with drug-induction and warrants a review of the patient's history (topical or systemic glucocorticoids) or evaluation of adrenal function. The increased ALP has long been attributed to a glucocorticoid-stimulated production of a novel ALP isoenzyme in the dog that can be distinguished from the cholestatically-induced hepatic ALP isoenzyme by several procedures. It was initially thought that the glucocorticoid-associated isoenzyme could be used as a marker of exogenously administered corticosteroids or increased production of endogenous glucocorticoids. The glucocorticoid-associated isoenzyme has a very high sensitivity in animals with Cushing's disease but a low specificity. Unfortunately, the glucocorticoid-associated isoenzyme is also associated with hepatobiliary disease as well.

A common condition observed in older dogs is an idiopathic vacuolar hepatopathy associated with increased ALP steroid isoenzyme. Investigation for hyperadrenocorticism is negative in these cases. It is postulated that other adrenal steroids may also be responsible in some cases. It is known that progesterones bind to the hepatocyte corticosteroid receptors and can induce ALP production. Scottish Terriers also have yet unexplained increases in serum ALP concentrations causing an idiopathic hyperalkalinephosphatasemia. Lastly, hepatic neoplasia and benign hepatic nodular hyperplasia both are sometimes associated with only ALP increases. Abdominal ultrasound should be performed to rule out neoplasia such as hepatic adenoma, adenocarcinoma or bile duct carcinoma. Multiple hyper or hypoechoic nodules in the liver of older asymptomatic dogs suggests nodular hyperplasia but wedge biopsy confirmation is advised,

Increased serum GGT activity is associated with impaired bile flow in the dog and cat and glucocorticoid administration in the dog. Bone does not contain GGT, therefore growth and bone disease are not associated with increased serum GGT activity. The administration of anticonvulsant medications to dogs is reported not cause an increase in the serum GGT activity. Colostrum and milk have high GGT activity and nursing animals develop increased serum GGT activity. As a marker of hepatobiliary disease, the measurement of serum GGT activity does not appear to provide a diagnostic advantage over the serum ALP determination in the dog, however it is reported to be a more sensitive marker in cats having biliary tract disease.

Evaluation of Liver Function. On a routine biochemical profile it is important to note the liver function tests including bilirubin, albumin, glucose, BUN, and cholesterol. Albumin is exclusively made in the liver and if not lost, sequestered or diluted, a low concentration would suggest significant hepatic dysfunction. It may take greater than 60% hepatic dysfunction for albumin concentrations to decline. Major clotting factors are also made in the liver (except factor 8) therefore prolonged clotting time suggests hepatic dysfunction. Liver disease and abnormal function tests suggests hepatic failure and a guarded prognosis.

One of the most sensitive function tests we have readily available in small animals are serum bile acids. The fasting serum total bile acid concentration (FSBA) is a reflection of the efficiency and integrity of the enterohepatic circulation. Pathology of the hepatobiliary system or the portal circulation results in an increased FSBA prior to the development of hyperbilirubinemia, negating its usefulness in the icteric patient. An increase is not specific for a particular type of pathologic process but is associated with a variety of hepatic insults and abnormalities of the portal circulation.

The current suggestion for the determination of the FSBA is to differentiate between congenital portal vascular anomalies and liver insufficiency prior to the development of jaundice. The determination of FSBA can contribute to the decision to obtain histological support for the diagnosis of this last group of hepatic diseases. When the fasting value is greater than 25 µmol/L for the dog and cat, there is a high probability that the histology findings will define a lesion. When the FSBA concentration is normal or in the "gray zone" the FSBA should be followed by a 2-hour postprandial serum total bile acid (PPSBA) looking for an increase greater than 25 µmol/L. The diagnostic value of determining PPSBA concentration is increased sensitivity for the detection of hepatic disease and congenital portal vascular anomalies. When using these guidelines it is prudent to recognize that a small number of healthy dogs have been reported with PPSBA values above 25 umol/L and dogs with mild liver disease may have normal bile acids.

We have occasionally observed the measurement of a FSBA value higher than the PPSBA value. The reason for this non sequitur is unclear but probably multifactorial. It has been shown that (1) the peak PPSBA concentration for individual dogs is variable, (2) fasted dogs store about 40% of the newly produced bile in the gallbladder and (3) a meal stimulates the release of only between 5 to 65% gallbladder bile. Undoubtedly these physiologic variables in addition to physiological variation in intestinal transit time and concurrent underlying intestinal disease contribute to the dichotomy.

Recently, urinary bile acids have become available as a diagnostic tool. Identifying increased urinary bile acids provides similar information to what is obtained from serum bile acids and neither test appears to be better than the other. The advantage of urinary bile acid measurements would be for the screening of litters of young puppies for suspected inherited vascular anomalies where urine collection is simpler than paired serum samples.

In summary, there are a variety of markers with variable sensitivity and specificity that reflect hepatic tissue and portal vasculature pathophysiology. We support the conclusion of another study that found that the optimal test combination is the serum ALT activity and bile acid concentrations. This pairing provided the best sensitivity and specificity, respectively. Clinical experience indicates that elevated serum AST concentration along with an elevated ALT helps to support a diagnosis of hepatocellular disease and that the PPSBA concentration enhances the evaluation of hepatic function.

Management Strategies


In the asymptomatic patient with an increased liver biochemical test(s) the increased value should be confirmed at least once to exclude a spurious result from laboratory error and to avoid unnecessary and costly additional testing. A careful history is essential to exclude drug associated enzyme elevations. The signalment of the patient may also provide an insight to the possible etiology of the enzyme increase. For example old dogs frequently have benign nodular hyperplasia, neoplasia or systemic disease while younger to middle aged dogs more commonly have chronic hepatitis. There are also certain breeds that are predisposed to developing chronic hepatitis. A careful physical examination may also provide clues to the diagnosis. The most common cause of abnormal liver enzymes is not primary liver disease but rather reactive hepatic changes occurring secondary to other non-hepatic diseases. These would include such conditions as intra-abdominal disorders (IBD, nutritional abnormalities), cardiovascular disease or metabolic derangements as just a few examples. Generally these secondary changes are reversible once the primarily disease is treated. Successful resolution of the non-hepatic disease and continued abnormal liver enzymes would be a strong indication for further investigation of the liver.

If no likely explanation for the laboratory abnormalities can be found there are two courses of action that one can take; either begin a diagnostic evaluation of the patient starting with bile acid determinations, or re-evaluate the patient's liver enzymes at a later date. A rational wait period for re-evaluation is 4-6 weeks giving consideration to the half-life of liver enzymes and the time needed for recovery from an acute occult hepatic injury. It is best not to delay retesting beyond 6-8 weeks in the event that an active disease process may progress.

Diagnostic Strategies


Once further work up has been elected, if the patient is not icteric, the next diagnostic step should be evaluation of urine or serum bile acids. Abnormal bile acids indicate hepatic or circulatory abnormalities and that the patient should undergo further evaluation at this time.

Imaging. Routine abdominal radiographs are helpful in determining liver size and shape and for detection of other intra-abdominal disorders. Ultrasonography is noninvasive, readily available and is the most informative initial imaging modality for liver disease. It often complements the clinical and laboratory findings and is useful for identifying focal liver lesions, diffuse liver disease or biliary disease. Frequently, fine needle aspiration (FNA) for cytological evaluation is performed in conjunction with ultrasound. Although FNA is safe and easy to perform, one must be cautious in the interpretation of the results and use the FNA findings in conjunction with clinical signs and other diagnostics to make a diagnosis. The sensitivity and specificity is not very high when results are compared to histopathology. We find the best correlation with hepatic neoplasia and diffuse vacuolar hepatopathies and the poorest in patients with chronic hepatitis.

Liver Biopsy. Although our diagnostic techniques continue to improve, in most instances imaging and biochemical testing cannot replace a liver biopsy. This is by far the best examination for a definitive determination of the nature and extent of hepatic damage and to appropriately direct the course of treatment. The method for liver biopsy procurement may be surgery, needle biopsy or laparoscopy. Each has certain advantages and disadvantages and the decision of which procedure to use should be made in light of all the other diagnostic information, always considering what is in the best interest of the patient and client.

Summary


Abnormal liver enzymes should not be ignored and should be investigated in a systematic manner as previously discussed. Asymptomatic animals with no evidence of significant or treatable disease or in situations where financial constraints limit further work up the patient should be fed a quality maintenance diet for the patient's stage of life and the possibility of instituting specific liver support therapy should be explored.

REACTIVE HEPATOPATHIES

The so-called "reactive hepatopathies" which occur secondary to non-hepatic disease can result in increased serum biochemical hepatic tests and histomorphologic abnormalities. Most of the reactive hepatopathies cause increases in laboratory tests that evaluate hepatocellular integrity (ALT, AST) and tests of hepatic cholestasis (ALP, GGT). In most cases there are little if any changes in tests that evaluate hepatic function (bilirubin, albumin, glucose, and BUN). Most of the animals with secondary liver disease also retain normal serum bile acid concentrations, which again supports a concept that there is generally minimal hepatocellular dysfunction in most of these disease conditions.

This group is characterized by nonspecific hepatocellular degeneration or necrotic changes without evidence of significant chronic progressive inflammation. Again, these changes are usually secondary to manifestations of a primary non-hepatic disease. The reason the liver often undergoes these changes revolves from the fact that the liver is involved in many metabolic and detoxification functions. Endogenous toxins, anoxia, metabolic changes, nutritional changes and endogenous stress related glucocorticoid release are all examples of conditions responsible for the majority of these changes. Non-specific mild liver changes routinely also occur following general anesthesia.

A good example that helps explain this concept is inflammatory bowel disease in which it is not unusual to observe mild inflammatory changes around portal triads presumed to be the result of abnormal portal uptake of gastrointestinal "toxins". Throughout the liver and closely associated with portal areas are Kupffer cells (fixed macrophages) that function to filter the blood of injurious toxins, inflammatory mediators and bacteria. When this macrophage system is abnormally insulted Kupffer cells release their own inflammatory mediators that in turn insult the hepatocytes.

Another example could be the sick septic dog having vacuolar change thought to be due to endogenous cortisol release for endogenous stress and hepatic cholestasis from presumed endotoxin or cytokine alteration of bilirubin metabolism.

Histological findings associated with secondary reactive changes include descriptors such as vacuolar degeneration, hydropic degeneration, swollen hepatocytes, lipidosis, intracellular or intrahepatic cholestasis, mild multifocal hepatitis and periportal or variable hepatic necrosis. These changes are devoid of the typical progressive chronic inflammatory cell infiltrates characteristic of chronic hepatitis.

In a review of consecutive liver biopsies at Colorado State University histology grouped as non-specific reactive changes made up the largest category of abnormalities (approximately 25%) In this group we were able to identify an associated disease in many that could explain the likely cause for the hepatic enzyme increases and histological changes observed. Concurrent diseases identified included neoplasia, gastrointestinal, renal, autoimmune, dermatologic, dental, infectious and cardiac disease as a few examples. In some cases an underlying disease is not identified. The ALT values on the average are 1-2 X normal and the ALP values 1-3 X normal. It is interesting to note that in a series of 32 dogs having reactive hepatopathies, 8/8 cases in which serum bile acids were run, all were within the normal reference range again suggesting hepatic function remains intact.

This category appears to be the most common histological change to occur in dogs and is by far the most common cause of elevated liver enzymes. Based on this fact, dogs presented with elevations in ALT and ALP should always have primary non-hepatic disease ruled out first. These changes are usually very reversible and no specific hepatic therapy is required short of treating the primary disease. The liver changes resolve once the primary etiology is successfully treated. Therapy providing good liver support such as antioxidants may be warranted.



Chronic Hepatitis in Dogs

Chronic hepatitis is an etiologic diverse and morphologically variable condition associated by mixed inflammatory cell infiltrates. It is characterized by hepatocellular apoptosis or necrosis, a variable mononuclear or mixed inflammatory infiltrate, regeneration and fibrosis. The proportion and distribution of these components vary widely. Plasma cells, lymphocytes and macrophages predominate with a lesser number of neutrophils. Because we see non-specific mild portal inflammation as a common non-specific reactive change I always ask the pathologist to tell me the severity of inflammation and chronicity of the disease. The presence of fibrosis in the hepatic biopsy usually denotes to me more serious consequences. As damage progresses cirrhosis can result with diffuse fibrosis, alteration in hepatic lobular architecture with the formation of regenerative nodules and abnormal vascular anastomoses. Cirrhosis, a sequel of some chronic hepatitis cases, is often associated with portal hypertension, ascites and multiple portosystemic collateral veins. Some may show manifestations of liver failure, e.g., hyperbilirubinemia, coagulopathies, edema due to hypoalbuminemia, ascites and hepatoencephalopathy. Inflammation in the liver has been given a number of different classifications (ie chronic active hepatitis, cholangiohepatitis etc) but the WSAVA liver standardization group believes we are not able to subclassify hepatitis and suggests we call the condition simply chronic hepatitis. This type of chronic inflammation is uncommon in the cat as their inflammatory disease is directed at bile ducts causing cholangitis.

Etiology. The etiology of this chronic inflammatory condition is generally never determined. Copper associated chronic hepatitis has been documented in a number of breeds as an inherited etiology. The hepatic copper accumulation increases to a level that then becomes toxic to the hepatocyte causing cellular death. The copper accumulation may also result as secondary copper retention from altered biliary copper excretion (see copper associated hepatitis below).
Infectious causes of chronic hepatitis have been associated with leptospirosis and experimental and spontaneous infectious canine hepatitis virus infection. Chronic liver injury has also been reported in dogs with aflatoxicosis and various drug-induced hepatitis. Some dogs treated with anticonvulsant drugs primidone, phenytoin and phenobarbital can develop chronic hepatitis. We have also observed dogs treated with NSAIDs to have hepatitis and there may be a casual relationship in some cases. More commonly however we see acute liver necrosis as a NSAID related drug reaction.

Alpha1-antitrypsin (AAT- also referred to as alpha one protease inhibitor) deficiency in the serum leading to accumulation of AAT in the hepatocytes, is known to cause chronic hepatitis and cirrhosis in man. Investigations by researchers in Sweden using immunostaining for AAT in hepatocytes found some dogs with chronic hepatitis to be positive. The breed most often associated with AAT accumulation was the cocker spaniel.

Finally immune associated hepatitis may occur in the dog. Circulating autoantibodies are important diagnostic markers used to identify autoimmune liver disease in humans. It appears that autoantibodies (ANA, antimitochrondial antibodies [AMA], smooth muscle antibodies [SMA], liver membrane autoantibodies [LMA]) are of a minor importance in classifying canine chronic hepatitis and thought to occur in most cases secondary to the liver damage. Nonetheless, immune-mediated mechanisms are thought to be associated with certain cases of chronic hepatitis and this is supported by the fact that some dogs respond favorably to immunosuppressive therapy.

There is lastly a lobular dissecting hepatitis characterized by a rapid diffues spread of inflammation throughout the liver lobule. This condition is observed in younger dogs and is associated with hepatic encephalopathy and ascites.

Breed Predisposition. There are a number of breeds that have an increased incidence and suspected genetic basis. Some of these breeds have copper associated chronic hepatitis (discussed below). Other breeds not yet associated with copper include the standard poodle, Cocker spaniel and Scottish terrier. The mechanism of their hepatitis is unknown.

Copper Associated Hepatitis. Abnormal hepatic copper accumulation may be the result of either a primary metabolic defect in copper metabolism or as a secondary event from abnormal hepatic function altering hepatic copper excretion. When we reviewed a number of dogs having chronic hepatitis not associated with genetic copper accumulation we found many dogs had increases in both copper and iron hepatic concentrations. A number of these dogs were also deficient in hepatic zinc. The interrelationship of the heavy metals and liver disease needs further investigation.

The diagnosis of abnormal Cu accumulation requires a liver biopsy. The measurement of serum copper or ceruloplasm levels to make the diagnosis. Excess Cu within the liver can be demonstrated using histochemical staining for hepatic Cu using rhodanine or rubeanic acid stain. Definitive determination of excess hepatic Cu requires a quantitative analysis of tissue Cu measured on the biopsy sample. Normal canine hepatic Cu concentrations are less than 400 µg/g (ppm) dry weight liver. Hepatic Cu concentrations in dogs with secondary Cu accumulation generally fall in the range less than 1,000 µg/g dry weight while breed associated hepatotoxicities generally have higher concentrations (>750 µg/g). The location of copper secondary to hepatic cholestasis is generally in zone 1 (periportal) location.

Hepatic copper toxicity was first identified in Bedlington Terriers. It was subsequently shown that affected Bedlington terriers have an inherited autosomal recessive defect, which results in reduced biliary excretion of copper due to hepatic metallothionein sequestration of the metal in hepatic lysosomes. Clinically there is a progressive hepatic Cu accumulation with age ranging from 1,000 to 12,000 µg/g per dry weight of liver. The extent of hepatic damage tends to parallel the increasing hepatic Cu concentrations. In this breed a specific gene has been identified to be responsible for this disease.

During the last decade an increasing number of breeds other than the Bedlington terrier have been linked with concurrent chronic hepatitis and increases in the hepatic Cu content. Liver disease with concurrent Cu accumulation is reported in the Doberman pinscher, West Highland white terrier, Skye terrier, Dalmatian and most recently the Labrador retriever (but not all labs having chronic hepatitis). Occasionally we see other pure breed dogs as well as mixed-breed dogs with high copper concentrations thought to be due to primary copper retention.

Clinical findings. The incidence of chronic hepatitis makes up approximately one fourth of the cases having liver biopsies at Colorado State University (based on a review of 150 consecutive liver biopsies). Chronic hepatitis is more common in female dogs. The average of presentation ranges from 4 to 10 years. It is interesting to note that in both our series and in studies by others it is uncommon to observe chronic hepatitis/cirrhosis in dogs older than 10 years of age. As a general rule old dogs (> 11 years of age) don't generally present with chronic hepatitis/cirrhosis or if they do they are at or near end stage disease.
The clinical signs parallel the extent of hepatic damage. Early in the disease there are usually no or minimal clinical signs. Only after the disease progresses do the clinical signs specific for liver disease becomes evident. Frequent early signs are gastrointestinal associated with vomiting, diarrhea and poor appetite or anorexia. Ascites, jaundice and hepatic encephalopathy may then occur as the disease progresses. With development of these late signs the long-term prognosis is generally poor.

The laboratory findings include consistently elevated ALT and ALP. The magnitude of rise need not be marked however. One report found 75% of the cases at diagnosis had abnormal bilirubin elevation (mean elevation of 2.6 mg/dl). Serum proteins are variable. As the lesions become more severe albumin levels decline. Serum bile acids are abnormal in most cases having significant chronic hepatitis and measurement of bile acids appear to be a good screening test for the patient with unexplained elevations in ALT and ALP. In our study all dogs evaluated with chronic hepatitis had abnormal bile acid concentrations. In a second study only 8/26 dogs with chronic hepatitis had normal fasting bile acids. However, postprandial samples were not determined in these cases. Determining postprandial bile acids has been shown to increase the sensitivity of this test.

A presumptive diagnosis is made based on the clinical features and persistent increases of ALP and ALT values. A definitive diagnosis requires a hepatic biopsy showing characteristic morphological patterns. Needle aspirates are not helpful in making the diagnosis of chronic hepatitis because it is important to see the architecture of the liver and location and extent of the inflammation. One must work with the pathologist when making the diagnosis of chronic hepatitis and to be certain that characteristic abnormalities found in chronic hepatitis are present

Prognosis. There is little information of the prognosis with and without therapy. The prognosis in dogs with advanced chronic hepatitis and cirrhosis is guarded. In a study by Strombeck found mean survivals ranging from 6 to 16 months with therapy. This study also identified that dogs with hypoalbuminemia, hypoglycemia and coagulopathies have very guarded prognostic factors and many died within 1 week of diagnosis. A second study of 79 dogs found that dogs with cirrhosis had a survival of less than one month and dogs with chronic hepatitis had a mean survival in the range of about 20 to 30 months. Most of these dogs were not advanced in their disease and had concurrent corticosteroid treatment. Low albumin, ascites and hepatic encephalopathy are all poor prognostic indicators.

Therapy. The management for chronic hepatitis involves removing the primary etiology. Short of treating the primary etiology all other therapies suggested are unproven in the management of chronic hepatitis in dogs. We are still waiting for good clinical studies proving efficacy in treatments. Such studies are hindered even from the start owing to the multiple etiologies of hepatitis and the inconsistent histological descriptions. To date we have only limited case studies and clinical impressions of efficacy in the management of chronic hepatitis.



Treatment of Liver Disease

The discussion below is directed at therapy for chronic hepatitis but much of what is presented can also be extrapolated to other types of liver disease in both the dog and cat. I have four general goals in therapy: 1) remove the etiology, 2) provide an adequate diet, 3) give specific therapy and 4) providing general liver support. First step in the therapy for chronic hepatitis and other liver diseases involves removing the primary etiology if it can be identified. Short of treating the primary etiology all other therapies suggested are unproven in the management of liver disease in dogs. Much of the therapy is directed at providing adequate liver support. This often involves the use of multiple therapies.

Diet. Adjusting diet therapy should be considered in all cases however only general guidelines should be given. First, palatability is important to assure adequate energy requirements are met. Next, there is a misconception about diet and liver disease that liver patients should be placed on a protein restricted diet. Protein restriction should only be instituted in the patient that has clinical evidence of protein intolerance (i.e. hepatic encephalopathy). The goal of dietary therapy is to adjust the quantities and types of nutrients to provide nutrient requirements but to avoid the production of excess nitrogen by-products associated with liver disease. As a general recommendation the dietary protein should represent 17 to 22% of digestible Kcal.

High carbohydrate and moderate fat content is important to supply caloric needs. Mineral supplementation containing high concentrations of both copper and iron should be avoided.
There is also evidence that fiber may have several beneficial actions in patients having liver disease. First, dietary fiber effectively binds bile acids in the intestinal tract and promotes their removal. Secondly soluble fiber appears to have some benefit in managing hepatic encephalopathy by generation of fermentation products (short chain fatty acids). These act by impairing the intestinal uptake of the surrogate marker of HE, ammonia. Soluble dietary fiber has a similar effect as lactulose and would provide a logical long-term nutritional approach in the management of some animals with hepatic encephalopathy. Psyllium, as a source of soluble fiber given at a dose of 1-3 tsp/day can be used as a dietary supplement.

Diets low in copper are recommended for the dogs that have copper associated liver disease based on biopsy. The restriction of dietary copper may do little to lower hepatic copper concentrations in diseased dogs having large amounts of hepatic copper. Diet will lessen further absorption of the metal. It is difficult to limit dietary copper because most commercial dog foods contain supplemental copper that meet, or more frequently exceed the minimal dietary requirements. Most formulated "liver diets" have lower copper concentrations and are often supplemented with additional zinc. Homemade diets can also be prepared that do not to contain excess copper. These diets should exclude liver, shellfish, organ meats and cereals that are all high in copper content. Vitamins or mineral supplements should not contain copper or iron.

Antiinflammatory Therapy. Decreasing inflammation as a specific therapy for chronic hepatitis in the dog or cholangitis in the cat is unproven although the author's clinical impression suggests anti-inflammatory therapy is beneficial in some cases. The treatment of chronic hepatitis is quite controversial and there are as yet no good controlled studies in animals to support corticosteroids use in every case. Antiinflammatory therapy is indicated in suspected immune mediated chronic hepatitis.

In a study by Strombeck found that some dogs with chronic hepatitis tend to have a prolonged survival when treated with corticosteroids. This retrospective study is one with a wide diversity of diseases and concurrent therapies. But none-the-less, it appears that corticosteroids offer benefit in at least some cases (possibly around 25%). A suggested dose of 1 to 2 mg/kg/day using either prednisone or prednisolone should be instituted. When clinical improvement is suspected or after several weeks the dose is then gradually tapered eventually to a dose of 0.5 mg/kg/day or every other day. The only accurate way to evaluate a response to any therapy is to re-biopsy the patient in 6 months to 1 year because the patient will develop a concurrent steroid hepatopathy with increased liver enzymes making laboratory determination of any improvement impossible. Alternatively one could stop steroids and recheck enzymes in 1 to 2 months. There is also evidence of improvement of immune hepatitis in humans when treated with budesonide. These patients had also less clinical signs because of the more "topical" effect on the liver subsequent hepatic clearance.

Because of the side effects of corticosteroids and the failure to successfully monitor liver enzymes while receiving steroids other immune suppressive therapy may be more rational approach. Azathioprine is an effective immunosuppressant drug that has shown to increase survival in man when treated for chronic hepatitis in conjunction with corticosteroids. This therapy may also be beneficial in dogs (don't use in cats) by increasing the immunosuppressive response and enabling a reduction of both steroid dose and their side effects. A dose of 2.2 mg/kg/day is the suggested starting dose and after several weeks given every two days. The level of glucocorticoids can frequently be reduced when using azathioprine. It is important to note that azathioprine has been infrequently been associated with a drug induced hepatic necrosis or acute pancreatitis. We have more recently been using cyclosporine A in some cases with a good clinical response. Our experience using 5 mg/kg bid or q 24 hrs (without steroids) has been very encouraging in dogs that are thought to have immune mediated chronic hepatitis. The veterinary formulation Atopica™ is a microemulsified preparation with the identical properties to Neoral™ that ensures more consistent bioavailability and better than the other human product Sandimmune™. Generally after 48 hours or longer I will get a blood level at the trough (right before the next pill). The ideal range of blood levels are within 400-600 ng/ml. Many dogs will develop gingival hyperplasia at the higher concentrations of cyclosporine. Azithromycin 10 mg/kg/day for 4-6 weeks will decrease the gingival hyperplasia. With evidence of clinical response at 5 mg/kg bid I will often decrease to once a day therapy. Using cyclosporine alone one can follow the liver enzymes making the need for a liver biopsy less frequently required.

Copper Reduction. If the liver biopsy of a dog with chronic hepatitis indicates significant abnormal hepatic copper accumulation, copper chelators or zinc therapy should be considered. Hepatic copper levels of greater than 1000 µcg/g dry weight liver requires therapy to reduce copper concentrations (zinc or chelator). Animals having greater than 2,000 µcg/g dry weight copper content should all have chelator therapy for at least some period of time.

Zinc therapy has a number of potential benefits in dogs with chronic hepatitis. Zinc has anti-fibrotic and hepatoprotective properties. Zinc given as the acetate, sulfate, gluconate or other salt has also been proven effective in preventing hepatic copper re-accumulation in Wilson's disease humans that have been decoppered with chelators. When patients were given oral zinc hepatic copper concentrations did not increase. Oral zinc therapy works by causing an induction of the intestinal copper-binding protein metallothionein. Dietary copper binds to the metallothionein with a high affinity that prevents transfer from the intestine into the blood. When the intestinal cell dies and is sloughed, the metallothionein bound copper becomes excreted through the stool. An initial induction dose of 15 mg/kg body weight (or 100 mg BID) of elemental zinc given twice a day is suggested. Following one to 3 months of induction the dose can be reduced in approximately half. The goal is to get serum zinc concentrations greater than 200µg/dl but less than 500. The zinc must be administered on an empty stomach and has the frequent side effect of vomiting. Replacement zinc therapy is administered at a dose of 2-3 mg/kg/day and is given for its antioxidant effects and replacement value in animals having zinc depletion in their liver.

Chelator treatment has a proven beneficial effect in dogs with abnormal hepatic copper concentrations. Chelators bind with copper either in the blood or the tissues and then promote copper removal through the kidneys. Penicillamine (Cuprimine™ -250 mg capsules) is the most frequent copper chelator recommended for use in dogs. The dose is 15 mg/kg bid given on an empty stomach. Side effects include anorexia and vomiting. Therapy using penicillamine is a slow and prolonged process taking months to years to cause a substantial reduction in hepatic copper concentrations however recent studies suggest penicillamine also has a protective effect in the liver beyond chelation therapy. It is believed penicillamine induces a hepatic copper binding protein, metallothionein, thus binding and sequestering copper in a nontoxic form in the liver. A second copper chelator is trientine (Syprine™) that has been produced to use in patients intolerant to penicillamine. This drug is also given at a dose of 15 mg/kg bid and has less gastrointestinal adverse side effects. It is an "orphan drug" and must be special ordered by the pharmacist. In one study of Dobermans with hepatitis and copper penicillamine therapy for 3 months resulted in reduction of copper and the inflammatory damage.

Antifibrotic Drugs. Corticosteroids, zinc and penicillamine all have anti-fibrotic effects. Colchicine is a drug that has been used in treating persons with chronic hepatitis and other types of liver fibrosis. This drug interferes with the deposition of hepatic collagen and also stimulates collagenase activity to breakdown deposited fibrous tissue in the liver. It also is shown to have anti-inflammatory properties. There is still the lack of convincing data in humans and dogs with liver disease that colchicine is beneficial. A critical appraisal of colchicine in human liver disease having chronic hepatitis now questions its effectiveness. There are only 3 case reports of colchicine in dogs having questionable results. A dose of 0.03 mg/kg/day has been suggested. The drug given as a generic is inexpensive with only minimal gastrointestinal side effects sometimes noted at high doses.

Choleretic Drugs. Decreasing cholestasis has been shown to be of benefit in humans and animals having cholestatic hepatobiliary disease. As serum bile concentrations increase (these are predominately cytotoxic bile acids) they can cause cell membrane permeability changes and fibrogenesis. Ursodeoxycholic acid (Ursodiol -Actigall™- 300 mg caps) is a choleretic agent developed to dissolve gallstones but later fond to have positive effects in patients with chronic hepatitis. This drug is a synthetic hydrophilic bile acid that essentially changes the bile acid pool from the more toxic hydrophobic bile acids to less toxic hydrophylic bile acids. Ursodeoxycholic acid has been shown to increase bile acid dependent flow, reduce hepatocellular inflammatory changes, fibrosis and possibly some immunomodulating effects. The hepatoprotective characteristics makes one believe ursodeoxycholic acts as an antioxidant. The dose for ursodeoxycholic acid is 15 mg/kg daily. No toxicity has been observed in dogs and cats at this dose. There has been a concern raised by some that it should not be used if there is any possibility of a bile duct obstruction for fear of biliary rupture. Although with obstruction surgery is indicated ursodeoxycholic acid is not a prokinetic and will not cause a rupture. In fact in experimental bile duct obstructions there was less secondary "toxic" changes in the liver in rats given ursodiol than placebo.

Antibiotics. Antibiotics are indicated for primary hepatic infections. There however may be evidence that bacterial colonization may take place in a diseased liver. Kupffer cell dysfunction could be a reason for secondary bacterial infections. It may be prudent for antibiotic therapy or trial for several weeks in patients having significant hepatic disease (i.e. chronic hepatitis). Amoxicillin, cephalosporin, or metronidazole are suggested. Metronidazole may have some immunosuppressive properties as well as antibacterial mechanisms. For liver disease I would use 7.5-10 mg/kg bid a much lower dose used for other bacterial infections because of hepatic metabolism of the drug.

Antioxidants. There has been recent interest in the management of certain types of liver disease using antioxidants. Antioxidants in general provide liver support to promote optimal hepatic function. Considerable evidence shows that free radicals are generated in chronic hepatitis and participate in the pathogenesis of oxidative liver injury in dogs and cats. Normally there is an extensive system of cytosolic and membrane bound enzymatic and non-enzymatic antioxidants which function to prevent oxidative damage by "scavenging" or "quenching" free radicals that are formed. It is reported that close to half the dogs and cats with liver disease have reduced glutathione concentrations in the blood and liver supporting that oxidative damage is present.

Vitamin E, d-alpha tocopherol, functions a major membrane bound intracellular antioxidant, protecting membrane phopspholipids from peroxidative damage when free radicals are formed. Vitamin E is shown to protect against the effects of copper, bile acids and other hepatotoxins. In a small study of dogs having chronic hepatitis we found all dogs had evidence of oxidative damage. In a three-month placebo controlled study treating only with vitamin E there was evidence improvement in the oxidant status of the treated dogs however we did not identify changes in clinical, laboratory or histology during this short treatment period.

A suggested vitamin E dose is 50 to 400 IU a day. The d-alpha tocopheryl formulation is much more potent than the most common commercial form (dL-alpha tocopheryl). Since bile acids are required for fat-soluble vitamin E absorption and may be reduced in cholestatic liver disease, a water-soluble formulation is suggested. For a water soluble form I use Twin labs Liqui-E. The vitamin E is derived from TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) and has a rapid absorption. Because of the potential benefits of vitamin E, the lack of side effects and since the drug is inexpensive I place most all my liver patients on E therapy.

S-Adensosylmethionine (SAMe) [Denosyl™. Nutramax Laboratories] is a naturally occurring molecule found in all living organisms and is involved in a number of metabolic pathways that appear to be beneficial to the liver as well as other tissues. SAMe is involved in three major biochemical pathways. It is involved in cell replication and protein synthesis, has a modulating influence on inflammation and plays a role as a precursor of the antioxidant glutathione in the hepatocyte. Research has demonstrated that the exogenous administration of SAMe to have potential beneficial effects for a number of types of liver damage. In one study giving acetaminophen to cats at a sub-lethal dose we observed protective effects of SAMe when measuring markers of hepatic oxidative damage and RBC fragility.

Studies investigating naturally occurring liver disease in animals are required to determine the benefit of SAMe administration in liver disease. I will routinely prescribe SAMe (Denosyl™) in patients having acute liver toxicity and in many cases having chronic liver disease or other liver disorders. A recommended dose range is 20 mg/kg/day. It should be given on an empty stomach and the tablets not broken. There are numerous commercial sources of SAMe each having variable concentration or purity of the compound. Foil wrapped tablets produced by a company that provides reliable purity and potency is recommended.

Milk thistle has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Silymarin the active extract consists of bioflavonoligans that have been reported to work as antioxidants, scavenging free radicals and inhibiting lipid peroxidation. Several recent human clinical trials have assessed the efficacy of silymarin in the treatment of liver disease. The data is somewhat difficult to interpret because of the limited number of patients, poor study design, variable etiologies, lack of standardization of silymarin preparations with different dosing protocols. There is however compelling evidence to suggest silymarin has a therapeutic effect in acute viral hepatitis, alcoholic liver disease, patients with cirrhosis, and in toxin or drug-induced hepatitis. Unfortunately, the purity of commercial products, and therapeutic dosage is unknown. Clinical trials are limited in small animals and reported success is only anecdotal. Dosage of milk thistle ranges from 50 to 250 mg bid. Milk thistle is reported to have an extremely low toxicity in humans and animals and has been used extensively in clinical patients with little concern for side effects.

To date there is only one published clinical study evaluating the efficacy of silymarin in the treatment of liver disease in dogs. In this placebo controlled experimental study dogs were poisoned with the Amanita phalloides mushroom. Researchers showed silymarin to have a significant effect on liver enzymes, the extent of histological liver damage and survival outcome. Based on this canine study and several clinical reports in humans poisoned with Amanita and treated with silymarin having a favorable outcome many physicians in Europe now accept silymarin as part of the standard protocol for mushroom poisoning.

Silibin appears to be a principle active isomer of the silymarin extract. Although silibin is a potent compound GI absorption is poor. Bioavailibility is increased by complexing with phosphatidylcholine (siliphos™). We have evaluated a commercially available complex (Siliphos™, Indea labs) in a preliminary pharmacokinetic study normal cats and found no clinical outward signs of toxicity giving a dose up to 5 mg/kg and have found improvement in oxidant status in the blood of normal cats and cats having liver disease. Marin™ (Nutramax Labs) contains silybin-phosphatidylcholine complex and for cats it contains vitamin E and for dogs it has zinc and vitamin E. A new compound Denamarin™ is available containing SAMe and silybin and is available in a chewable formulation. It appears that the combination of both compounds have good a absorption. The Denamarin product appears to be very stable and not oxidized like the other SAMe products. I personally have no experience with other SAMe or milk thistle products.

General Support Therapy. The remainder of the therapy for chronic hepatitis involves treatment of secondary complications. These occur as the disease becomes advanced. Hepatic encephalopathy, GI ulceration and ascites are common clinical occurrences in advanced hepatitis or cirrhosis.

The first step in the management of hepatic encephalopathy includes the use of enemas to clean the colon of both bacteria and protein substrates for ammonia production. Slightly acidic enemas will lower the pH of the colon thus ionizing ammonia and reducing its absorption. Povidone iodine (betadine) can safely be given by enema as a 10% solution (weak tea color) that will both acidify the colon and have an antiseptic action reducing bacterial numbers.

Nonabsorbable intestinal antibiotics are used to alter bowel flora and suppress urease-producing organisms important in formation of factors causing hepatic encephalopathy. Antibiotic suggestions include oral ampicillin, aminoglycosides (neomycin, kanamycin or gentamicin) or metronidazole. Metronidazole given at 7-10 mg/kg BID has been useful in controlling anaerobic urease producing bacteria. One should be careful as metronidazole is partially metabolized in the liver and a lower dose range is suggested.

A nondigestible disaccharide lactulose (Cephulac™ or Chronulac™) given orally acidifies the colon converting ammonia to ammonium that is poorly absorbable thus trapping ammonia in the colon. The fermentation products of lactulose will also act as an osmotic laxative reducing colonic bacteria and protein substrates. A dose of 1-10 ml orally TID is generally effective. Lactulose is not absorbed systemically and thus considered safe. The dose should be adjusted to cause 3 or 4 soft stools a day. If diarrhea develops the dose should be reduced. Lactulose can also be given by enema in treating the severe case of hepatic encephalopathy.

Gastrointestinal ulceration not only causes gastrointestinal signs such as vomiting and anorexia but blood loss into the intestinal tract promotes hepatic encephalopathy as blood is an excellent protein source for ammonia production. Gastric ulcers should be treated with the H2 blocker such as ranitidine (2-5 mg/kg BID/TID) and oral sucralfate (Carafate™ 1 mg tab/25 kg TID given 1 hour before ranitidine). Cimetidine is to be avoided in liver disease because it is metabolized by the liver and is an enzyme suppressor altering hepatic metabolism of other drugs.

Ascites occurs in chronic hepatitis when portal hypertension, hypoalbuminemia and renal sodium and water retention work in concert to cause fluid exudation. Diuretics are the major means of managing ascites in small animals. Too rapid removal of ascitic fluid can cause metabolic complications and can precipitate hepatic encephalopathy. The goal of diuretic therapy should be a gentle water diuresis. The loop diuretic furosemide (Lasix) is generally the treatment of choice. They can however cause marked dehydration and loss of potassium. In most cases furosemide provides a suitable diuresis. With hyperaldosteronism secondary to liver disease, sodium reabsorption at the distal tubule may be great and counter the effects of furosemide. If the patient does not respond to furosemide then spironolactone (Aldactone) should be tried in those cases. Often diuretics do not begin to work until improvement in hepatic function occurs. If an animal has tense ascites, paracentesis should be performed to decrease the intra-abdominal pressure, relieve compression of the venous circulation, and to increase patient comfort.



Emerging Newer Liver Disease

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, cholecystitis, hepatocutaneous syndrome, and portal vein hypoplasia.

Gallbladder Mucocele


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 gallbladder perforation. Smaller breeds and older dogs were overrepresented. Shetland sheepdogs and Cocker Spaniels are 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. Medical management is not recommended. A mucoele is reported the most common cause of a gallbladder perforation. Following cholecystectomy and recovery of postoperative period the prognosis is excellent.

Cholecystitis/cholelithiasis


Bacterial cholangitis and cholecystitis occasionally is found in dogs but is quite common in cats (see feline liver disease). These animals often present with acute signs and laboratory findings of cholestatic liver disease. Fever, leukocytosis and icterus are common. Biliary tract perforation results in bile peritonitis. Ultrasonography is a sensitive and specific indicator of extrahepatic biliary tract disease. Thickness of gallbladder and duct wall is common. In suspected cases it is reasonable to perform an ultrasound directed or laparoscopic assisted gallbladder aspirate. Occasionally gas within the lumen or wall is observed as an emphysematous cholecysitis. Emphysematous cholecystitis is usually secondary to a combination of gallbladder wall ischemia and proliferation of gas-forming bacteria such as E. coli and Clostridium perfringens and has been associated with diabetes mellitus but has also been observed in nondiabetic dogs. However, the most common isolates in bacterial cholecystitis are Escherichia coli, followed by Enterococcus, Enterobacter, Klebsiella, Streptococcus, Pseudomonas, Bacteroides, and Clostridium spp. Treatment involves 3-4 weeks of appropriate antibiotic therapy based on culture. With fear or evidence of gallbladder perforation a cholecystectomy is indicated.

Cholelithiasis and choledocholithiasis account for less than 1% of patients with liver disease. Cholesterol gallstones are common in humans but very rare in dogs and cats. Most often canine and feline choleliths are bilirubin pigment gallstones with variable amounts of calcium salts. I believe most develop secondary to biliary infection and deconjugation of soluble bilirubin and precipitation of bile. Cholelithiasis is a reported to be of higher incidence in miniature schnauzers and toy poodles. Most choleliths are clinically typically silent however clinical signs associated with cholelithiasis are usually related to cholecystitis associated with vomiting, anorexia, icterus, fever and abdominal pain. We have seen some dogs with vague abdominal pain to have choleliths. In some cases a bile duct obstruction or biliary tract rupture and peritonitis may occur. In clinical cases surgical removal is indicated and appropriate antibiotic therapy initiated.

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 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 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.

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


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.

Acute Liver Failure


Acute liver failure (ALF) is an uncommon condition that results in rapid deterioration of liver function occurring in a previously healthy animal. It is generally characterized by severe hepatocyte death due to aptoposis or cytolytic necrosis. The extent and location of the hepatocyte death depends on the etiology.

Drugs are the most common known cause of ALF in dogs and cats. Drugs can affect the liver in one of two ways. First, they may have a direct toxicity to hepatocytes or becomes metabolized to a toxic compound that then causes damage. This first classification is referred to as a direct hepatotoxin and is dose related and reproducible. An example would be acetaminophen poisoning. More common however are drugs associated with 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. Listed below are some of the more common drug associated hepatotoxicities. It should be noted however any drug metabolized by the liver has the potential to be a hepatotoxin. The common incriminators causing an idiosyncratic reaction include the NSAIDs, trimethoprim-sulfa, lysodren, ketoconazole (and other antifungals), and diazepam (in cats) to name but a few. We have more recently identified toxicity associated with azathioprine. See table of common drug associated with liver disease. Some herding breed dogs lack p-glycoprotein that plays an important role in metabolism of many drugs. Thus it is not surprising that lack of P-glycoprotein, which occurs in many herding-breed dogs leads to increased susceptibility to drug toxicosis. Other causes of acute liver failure include infectious agents such as Leptospirosis. Environmental toxins such as industrial solvents, plants, insects, chemicals, envenomation, sago palm seeds, heavy metals, Amanita phalloides (mushroom) and aflatoxin have been incriminated to cause liver disease. Several years ago there was a large outbreak of liver failure in many dogs in the Eastern part of the United States due to contaminated dog food with aflotoxin. In most cases aflotoxin is an isolated event. Xylitol an artificial sweetener found in chewing gum can result in a sudden drop in glucose due to increase insulin release and in some cases also causes acute liver disease as well.

Damage to the liver may range from mild to moderate hepatic necrosis resulting in minimal clinical signs. Signs may be associated with vomiting, lethargy and anorexia. Massive hepatic necrosis will result in ALF and produce significant clinical signs of liver failure and possibly death. The signs of ALF are variable but usually will always include anorexia, depression, lethargy and vomiting. Neurological signs from hepatic encephalopathy may progress to coma or seizures. Jaundice is invariably present. ALF can also result in evidence of hemorrhage either from lack of coagulation factors or from DIC. GI ulceration is common. Septicemia may occur from uptake of enteric bacteria. Hepatic pain may be observed on abdominal palpation.

The clinicopathologic changes reflect the extent of necrosis and loss of hepatocyte numbers. 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 and GGT increases are associated with hepatic necrosis and are only mild to moderately elevated. 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 these function 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 important to note that with acute severe necrosis albumin concentrations may remain normal early in the disease due to the longer half-life of albumin (2 weeks) as compared to clotting factors being only (hours to days). Frequently platelet numbers and function are also compromised in massive liver failure and DIC is a common complication. With recovery the AST will decline prior to ALT and could be prognostically helpful.

When there is acute ingestion of a toxin vomiting should be induced followed by administration of activated charcoal to prevent absorption of the toxin. The next step is to prevent further hepatocyte damage by providing an environment for optimal hepatic function. N-acetylcysteine (NAC, Mucomyst™) is thiol (SH) donor and promotes glutathione production; the most important detoxifier of toxic cellular xenobiotics. There is also evidence that NAC protects against hepatic ischemia-reperfusion damage possibly by inhibiting Kupffer cell function. NAC has beneficial effects on liver blood flow, oxygen extraction, and the formation of non-glutathione products that protect against cell injury. Experimentally NAC has protective effects against aflatoxin damage as well. The suggested dose for NAC is 140 mg/kg IV followed by 70 mg/kg IV bid or tid for one to three days. The injectable NAC should be diluted 1:4 in 5% dextrose and water and given slowly over 30 minutes to 1 hour. When vomiting has resolved NAC can be given orally. S-Adensosylmethionine (SAMe) also protects against liver damage from acetaminophen toxicity in dogs and cats by increasing hepatocyte glutathione concentrations being a SH donor. It also acts as a methyl donor and enzyme activator for key reactions that maintain membrane structure and function. SAMe (Denosyl™) is given orally at the dose of 20 mg/kg bid or daily. SAMe can be given orally in place of NAC when vomiting is not a concern.

The use of other antioxidants is warranted in management of the liver disease including vitamin E and milk thistle or its by-products. Vitamin E, d-alpha tocopherol, functions a major membrane bound intracellular antioxidant, protecting membrane phopspholipids from peroxidative damage when free radicals are formed. Vitamin E is shown to protect against the effects of copper, bile acids and other hepatotoxins. A suggested vitamin E dose is 50 to 400 IU a day. Milk thistle (silymarin or the most active ingredient silibin (Marin™) is reported to work as an antioxidant, scavenging free radicals and inhibiting lipid peroxidation and may be of benefit in the management of drug-associated or other hepatic toxicities. One canine study showed that dogs poisoned with amanita mushrooms treated with milk thistle had fewer clinical signs and complete survival than untreated dogs. Unfortunately, the purity of commercial products, and therapeutic dosage is unknown. Clinical trials are limited in small animals and reported success is only anecdotal. Dosage of milk thistle ranges from 50 to 250 mg bid. Milk thistle is reported to have an extremely low toxicity in humans and animals and has been used extensively in clinical patients with little concern for side effects. It appears to have a synergistic effect with vitamin E.

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. In humans artificial livers or liver transplant are used in severe cases.

Drugs associated with liver toxicity.


Acetaminophen
Arsenicals
Ketoconazole
Sulfonamides
Halothane
Carprofen (NSAIDs)
Griseofulvin
Itraconazole/ketoconazole
Mitotane (lysodren)
Trimethoprim-sulfa
Diazepam
Anabolic steroids
Tetracycline (doxycycline)
Anticonvulsant drugs
Azathioprine
Antineoplastic drugs
Amiodarone



Update on Feline Liver Disease

There are a number of specific liver diseases unique to the cat and very different than the liver diseases observed in the dog. This is due in part to specific anatomical and metabolic differences of the cat. The following are brief descriptions and updates and newer information on common feline hepatic diseases. The clinician should however be aware that the liver pathology might also be secondary to a variety of primary non-hepatic disease conditions. This category is grouped into the classification of a reactive hepatopathy. The histology of reactive hepatopathies are nonspecific often with a variable degrees of lipidosis.

Overview of Liver Enzymes in Cats


In a study evaluating the utility of liver biochemistries in the diagnosis of feline liver disease found the best predictive tests for primary liver disease includes ALP, GGT, total bilirubin and bile acids. The ALT and AST are quite variable and elevations don't always predict primary inflammatory liver disease or hepatic lipidosis. ALP is unique in cats in that the half-life is short (6 hours) and the feline liver is reported to contain only one-third the concentrations found in dogs. Consequently, increases in serum ALP with cholestasis are not expected to increase with the same magnitude as observed in dogs with similar diseases. ALP is also not induced by corticosteroids nor does it cause a steroid hepatopathy. Gamma-glutamyl transpeptidase (GGT) is a similar enzyme to ALP that increases with cholestasis and is more sensitive for feline inflammatory liver disease than ALP. Uniquely cats with idiopathic hepatic lipidosis usually have marked increases in SAP while GGT concentrations show only mild increases.

Increases in total bilirubin generally greater than 3.0 mg/dl cause clinical icterus and usually indicates primary liver disease. Biochemical increases in total bilirubin (but less than 3.0 mg/dl) can sometimes increase with secondary reactive hepatopathies and does not always indicate a primary hepatopathy is present. In the non-icteric cat abnormal bile acids are also indicators of significant liver disease or portosystemic shunting.

Liver Diseases in Cats


The incidence of liver disease in cats is common. When we reviewed 175 liver biopsies it was evident there were several large categories of conditions observed. Making up 87% of the liver biopsies were 4 large groups: Idiopathic and secondary lipidosis (26%), Cholangitis (25%), Neoplasia (20%) and Reactive hepatopathies (16%). Hepatic cysts are also an occasional finding in some cats and rarely cause problems. Lipidosis and cholangitis will be discussed below. Reactive hepatopathies refer to changes in the liver felt to be secondary to a primary non-hepatic disorder such as inflammatory bowel disease, hyperthyroidism and cardiac disease as examples. Hepatic neoplasia was also common. Cats are different than dogs in the fact that benign tumors and more common than malignant hepatic neoplasia. Bile duct adenomas (cyst adenomas) were the most common benign tumor and bile duct carcinoma the most common malignant neoplasia when hematopoietic tumors are excluded.

Idiopathic Hepatic Lipidosis. Hepatic lipidosis can occur as a primary idiopathic disease syndrome or secondary to a number of other primary disease conditions. Lipid accumulation in the liver is simply the result of nutritional, metabolic or toxic insults to the liver and the degree of lipid accumulation can be quite variable. For example, a common secondary disease associated with significant hepatic triglyceride accumulation is diabetes mellitus. This diagnosis is generally obvious (hyperglycemia and glycosuria) and the lipidosis resolves with appropriate therapy. Hepatic lipid accumulation can also result secondary to a number of other disease syndromes such as pancreatitis, starvation or other organ dysfunction. These conditions generally have less severe lipidosis than the clinical syndrome associated with idiopathic hepatic lipidosis in which there is no identifiable etiologic factor.

The etiology of idiopathic hepatic lipidosis is unknown and many theories have been put forward without substantial documentation. A current novel proposal is that there is a defect in hepatic lipid mobilization and decreased ability for hepatic fat oxidation, decreased synthesis of apoproteins and decreased lipoprotein removal from the liver. Supporting this theory is identification of ultrastructural changes including reduction of hepatic peroxisomes, altered mitochondria and altered endoplasmic reticulum. The cause for the rapid mobilization of peripheral fat is as yet unknown. A second novel theory put forth is that the disease is a central CNS disorder causing the anorexia and the lipidosis then results. It is important to investigate any possible disorder causing anorexia and initiating the typical cascade of hepatic lipidosis.

Affected animals generally are older obese cats that have undergone a stressful episode and with associated anorexia. There does not appear to be a breed or sex predisposition. Cats will present with an acute history of rapid weight loss (40-60% body weight over 1-2 weeks), depression and icterus. The weight loss is significant with loss of significant muscle mass while abdominal and inguinal fat stores are often spared. Typical neurological signs commonly associated with hepatic encephalopathy in the dog are uncommon. Complete anorexia, lethargy and depression may however be the result of hepatic encephalopathy.
The diagnosis of idiopathic hepatic lipidosis is supported by the clinical history and laboratory findings. Icterus and marked elevations in ALP are consistent findings. ALT (SGPT) levels are generally abnormal but quite variable. GGT concentrations are only moderately elevated in these cats. Icterus with a very high ALP and normal GGT should be a clue to probable idiopathic lipidosis given appropriate clinical features. Hypercholesterolemia, hyperammoniemia and abnormal bile acid levels are characteristic. Protein levels are usually normal, glucose levels moderately elevated but a few cats may actually have concurrent diabetes and recently several cats were reported to have pancreatitis and measurement of fPLI is warrented. About 1/3 of the cats have a nonregenerative anemia, hypokalemia and clotting abnormalities and about 1/2 the cats demonstrate poikilocytes in the RBC's. Severe hypokalemia, anemia or other concurrent disease (ie pancreatitis) in lipidosis cats that had a poor survival.

The liver size may be normal or enlarged on palpation or radiographically. A definitive diagnosis requires a liver biopsy or hepatic cytology. A fine needle aspirate of the liver with cytological evidence of many vacuolated hepatocytes helps support a diagnosis. Be aware that cytological diagnosis does not always correlate with histology. A needle aspirate can be performed with the cat in dorsal recumbency and a 22 g needle on a syringe directed slightly cranial and lateral to the left from the left xyphoid space. The aspirate can be stained with Diff-quick or Sudan stain. A hepatic tissue biopsy confirms the diagnosis. Care should be taken when obtaining a liver biopsy as some cats may have coagulation abnormalities.

The therapy for idiopathic hepatic lipidosis requires aggressive management. Approximately 80% or higher survival rate should be expected in cats given appropriate therapy and no underlying disease. Initial therapy requires rehydration with balanced electrolyte solutions. Replacement of potassium depletion is imperative as normokalemia improves survival. Some cats may require magnesium supplementation as well. Administration of glucose containing solutions may actually cause marked hyperglycemia in these patients. Cats also have a tendency to develop lactic acidosis and therefore lactate -containing fluids (i.e. Lactated Ringers) should be avoided. The practice of adding B-vitamins to the fluids should be avoided because prolonged exposure to light in the fluid bag will inactivate them. Parenteral administration is a better option.

Adequate nutrition then becomes the most important part of the therapy for hepatic lipidosis. Since these animals are not eating forced feeding becomes necessary. In the authors experience these drugs to stimulate the appetite only produce sedation, enhance encephalopathy and rarely do cats eat their caloric needs given these drugs. Hand forced feeding may be used but it is usually difficult to supply adequate caloric support through this method and this becomes a major stress factor to the cat.

Tube feeding is the best way to administer adequate calories. Nasogastric tubes can be used but due to the small size limit the consistency of food administered and appears to be less tolerated than gastrostomy tubes. I suggests placement of an esophageal or gastrostomy feeding tube. In our practice we find that esophageal tubes to be well tolerated and having less complications than gastric tubes. One should refer to specific articles on tube placement techniques. We find the 20 French red rubber feeding tubes ideal for the esophagus.

The nutritional recommendations for idiopathic hepatic lipidosis are completely empirical and poorly documented. There are numerous reports in the literature suggesting various diets (with a variety of protein and fat content recommendations) and various dietary supplements. There is evidence that L-carnitine supplementation in cats may protect against hepatic lipid accumulation and consequently may be an appropriate dietary adjunct for patients with liver disease. Carnitine is required for transport of long chain fatty acids into the mitochondria for subsequent oxidation and energy production. A deficiency of carnitine may lead to impaired mitochondrial function. It appears that carnitine deficiency could result in chronic liver disease and that supplementation may help protect against encephalopathy, hypoglycemia, and subcellular damage. Studies have however have failed to show carnitine deficiency in cats with hepatic lipidosis. Suggested dose is 250-300 mg/day. Supplementation is reported to be associated with better survival rates, however this is poorly documented.

The author also believes that stress plays a major role in this disease process and the sooner a patient can be stabilized and sent home away from the hospital environment the better. Most owners generally can manage tube feeding the cats at home. The tube should not be removed until the cats are voluntary eating adequate calories on their own. Tube feeding often averages about 4-6 weeks.

Considerable interest and research is being directed at various nutrient supplements and at this time many of the recommendations are only speculative or anecdotal. Some suggest arginine (1000 mg/day), thiamine (100 mg/day) and taurine (500 mg/day) however if feeding an adequate diet this should not be required. Some suggest L carnitine (250 mg/day) supplementation and there may be some benefit in this supplementation though not well documented Other supplements suggested include zinc, fish oil, and potassium. There is also evidence to suggest many cats with hepatic lipidosis have cobalamin deficiency. Studies found cobalamin (vitamin B12) was depleted in many cats with lipidosis. Experimental cobalamin deficiency results in lethargy, anorexia and weight loss. Anecdotal reports suggest cats improve faster with high doses of cobalamin given 250 µg SQ weekly. Serum cobalamin levels can be determined to document the deficiency.

Other therapies suggested include S-Adensosylmethionine (SAMe) Denosyl SD4 (Nutramax) is a nutraceutical that is a naturally occurring molecule found in all living organisms involved in the metabolism of glutathione (GSH). GSH participates in many metabolic processes and plays a critical role in detoxification mechanisms of the cell. Depletion of hepatic GSH can indirectly cause toxic effects in these cells by increasing oxidative stress. Exogenous administered SAM has been shown to increase intracellular GSH levels in hepatocytes and prevents GSH depletion when exposed to toxic substances thus acting indirectly as an antioxidant. SAMe is also important in hepatocyte membrane integrity and function. The suggested dose is 100 mg/day. The benefit of SAMe or other antioxidants in hepatic lipidosis is unknown. Another antioxidant hepatoprotectant is milk thistle or its extract silybin (Marin™), a safe hepatic support therapy.

The prognosis is guarded however has markedly improved with aggressive nutritional therapy and treating secondary complications. It is reported that about 2/3 of the cats with hepatic lipidosis survive with such therapy. There is a need for good controlled studies evaluating various therapies. Weight reduction appears to be essential in prevention as obesity plays a role in this disease.

Feline Inflammatory Liver Disease (Cholangitis). Cholangitis is an inflammatory disorder of the hepatobiliary system. It appears to be a disease complex that may be concurrently associated with duodenitis, pancreatitis, cholecystitis and/or cholelithiasis. The terminology is somewhat confusing and pathologists describe the condition differently. Based on the histological classification of the WSAVA Liver Standardization Group this complex has been separated into three histological groups; acute neutrophilic (suppurative) cholangitis, chronic neutrophilic (mixed inflammatory infiltrates) cholangitis, and lymphocytic cholangitis. It is probable that the neutrophilic acute and chronic forms of cholangitis represent different stages of one disease.

Acute Neutrophilic (Suppurative) Cholangitis. This is an acute neutrophilic inflammation of the portal triads and bile ductules. It is thought to be the result of an ascending bacterial infection. Usually coliforms (E. coli) are cultured from the liver or bile. Inflammation can also extend into the hepatic parenchyma causing a cholangiohepatitis. There is in some cats an association of pancreatitis, cholelithiasis or even biliary obstruction.

Cats with this syndrome are usually young (~3-5 years) and present with acute illness usually a week or less in duration. They may have evidence of a fever, anorexia, vomiting or lethargy. A leukocytosis is generally identified on the CBC. The ALT and ALP are increased but variable and these cats are frequently icteric. Ultrasound should be performed to rule out pancreatitis and biliary obstruction. In some cases we will perform an ultrasound-guided cholecystocentesis for cytology and culture. A liver biopsy is required for histology and will confirm the diagnosis. The liver should be cultures too. If obstruction is identified surgery becomes indicated to decompress and flush the biliary system. I always try to avoid surgical diversion surgeries unless it is the last resort.

Therapy for these cats first includes fluid and electrolyte therapy if needed. Antibiotics are a critical part of the therapy as well. Ampicillin, cephalosporin and metronidazole have been suggested as effective antibiotics. Unless a culture and sensitivity says otherwise ampicillin is my choice because of the likelihood of E coli and the fact that it is concentrated in the bile. It is recommended that cats be treated for at least 1-2 months with antibiotics. Short duration of therapy may result in reoccurrence of clinical signs. Ursodeoxycholic acid (Actigall 10-15 mg/kg/day) should be used as well.

Chronic Neutrophilic Cholangitis. Chronic (neutrophilic, mixed or lymphocytic-plasmacytic) cholangitis may be the result of progression of the acute neutrophilic cholangitis. In the chronic stage the liver lesions are associated with the presence of a mixed inflammatory infiltrates in the portal areas consisting of neutrophils, lymphocytes and plasma cells. Possibly fibrosis, ductular proliferation or extension of inflammation into the hepatic parenchyma can occur as well.

There is also a direct relationship between chronic cholangitis and inflammatory bowel disease and chronic pancreatitis. One study found 83% of affected cats had inflammatory bowel disease and 50% had concurrent chronic pancreatitis. The association of the three together has been referred to as triaditis (see below). Possibly the common channel theory where the pancreatic ducts and bile ducts join before entering the duodenum explain this triad of clinical signs. Ascending bacteria initiate the acute disease and then over time it becomes chronic. In a recent abstract presented at the ACVIM Forum in 2009 we reported that many >60% of the cats having chronic neutrophilic cholangitis had bacteria in the liver associated with portal areas and specifically bile ducts based on non-culture methods using FISH immulogic staining for bacteria. The most common bacteria included E coli and Enterococcus.

Affected cats are usually middle aged or older and have a long duration of signs being weeks to months. Presenting complaints are often vomiting, lethargy and anorexia. Signs may wax and wan and weight loss may be present. Physical findings identify jaundice in most, possibly hepatomegaly and rarely abdominal effusion.

The laboratory findings are variable. Most cats are icteric and there are variable increases in ALP/GGT or ALT/AST. Hyperglobulinemia is observed in over 50% if the cases. Ultrasound may reveal pancreatic, bile duct or gallbladder changes. The liver generally has a mixed echoegnicity pattern with prominent portal areas. Cats with concurrent pancreatitis may have increases feline pancreatic lipase immunoreactivity (fPLI). A liver biopsy confirms the diagnosis.

The primary treatment involves immunosuppressive therapy using prednisolone at 2-4 mg/kg daily and then slowly tappering over 6 to 8 weeks to 0.5-1 mg/kg given once or every other day. This therapy does not appear to resolve this chronic disease but generally slows the progression and minimizes the clinical signs. A course of antibiotic therapy for several weeks is administered for the possibility of a bacterial component. Icterus, very high serum bile acids and biliary cholestasis are the norm. Since high concentrations of hydrophobic bile acids are toxic to hepatocytes and biliary epithelium reducing toxic bile acids is reasonable. Ursodeoxycholic acid is a nontoxic hydrophilic bile acid that when administered changes the bile acid milieu. Ursodeoxycholic acid (10-15 mg/kg/day) is nontoxic and suggested for these cats. This drug will increase bile flow, change bile acid concentrations to less toxic concentrations, reduce inflammation and fibrosis and improve liver enzymes. Observations by some believe that ursodeoxycholic acid may actually be more beneficial than corticosteroids.

The disease is slow and progressive often scattered with flair ups. Approximately 50% of the cases will have a prolonged survival. The final stage of this disease complex is biliary cirrhosis having extensive fibrosis and bile duct proliferation that may end with liver failure associated with ascites and hepatic encephalopathy.

Mild Lymphocytic Portal Hepatitis. This is a common incidental histological finding observed in older cats. It is thought to be a nonspecific inflammatory reaction (probably from intestinal inflammation) and does not progress. The mild inflammation is limited to the portal triad and does not progress beyond the limiting plate of the triad. It is reported to be a finding in 82% of the cats over 10 years of age. Liver enzymes are quite variable or can be normal. Icterus is uncommon. There is no specific therapy is required for this condition.

Lymphocytic Cholangitis. This is an uncommon condition apparently more common in Europe. It is characterized by a consistent moderate to marked infiltration of small lymphocytes in and restricted to the portal areas, often associated with variable portal fibrosis and biliary proliferation. There may be lymphoid aggregates, obliteration of bile ducts and biliary hyperplasia and fibrosis or bridging portal fibrosis. The etiology is unknown. It is postulated this condition is the result of immune mediated mechanisms based on immunologic studies performed in some cats. This disease appears to be very chronic associated with weight loss, anorexia and variable icterus. Ascites and hepatic encephalopathy may occur. The enzymes are variable but hypergammaglobulinemia is common. In one study prednisolone had no effect on the disease and those authors suggested ursodeoxycholic acid might be more beneficial. The long-term prognosis is guarded.

Complications of Cholangitis Syndromes. The following are conditions often observed with the cholangitis cases. Bile sludge and or cholithiasis often occur with inflammatory biliary tract disease. Thick inspissated bile or choleliths are thought to be the result of deconjugation of the normally soluble conjugated bilirubin from the action of bacterial enzymes or inflammatory products present in the biliary tree. The certain bacteria such as E. coli are capable of producing the enzyme beta glucuronidase that can deconjugate bilirubin resulting in pigment precipitation. Choleliths in cats are primarily bilirubin pigment stones that contain various amounts of calcium and other precipitates. Some choleliths may be radiopaque if enough calcium is incorporated in the cholelith. Primary cholesterol choleliths as occur in humans do not naturally occur in cats or dogs. Bile sludge or choleliths may block bile flow and can cause complete obstruction. Obstructive choleliths should be removed surgically. Occasionally a clear viscous fluid devoid of bile pigments is seen in the gallbladder of some cats thought to be the result of severe intrahepatic cholestasis and reabsorption of intraductal bile.

Bile sludging is best managed by treating the primary cholangitis, treating any biliary tract infection, and by the use of choleretic agents to increase the flow of bile. Ursodeoxycholic acid (Actigall®) should be prescribed. Corticosteroids have a similar effect on bile flow and may also be useful. Complete obstructions may require surgery and in rare conditions a cholecystoduodenostomy or cholecystojejunostomy is required.
Cholecystitis is inflammation of the gall bladder and occurs frequently in the cholangitis syndrome. Radiographically gas within the gall bladder may be observed due to bacterial fermentation. Characteristic thickening of the gall bladder wall may be seen with ultrasound examination. Rarely is there the need for a surgical cholecystectomy if the primary disease is adequately identified and treated.

Feline triaditis is a syndrome that has been observed in many cats having cholangitis. This condition is associated with a concurrent chronic cholangitis-cholangiohepatitis, chronic pancreatitis and duodenitis. Since the common bile duct and pancreatic ducts join a common channel before they enter the duodenum extension of inflammation and luminal contents in both directions is common. Chronic fibrosing pancreatitis with ductal inflammation and nodular hyperplasia is reported frequently with inflammatory biliary disease in the cat. Some of these cats to also have lymphocytic-plasmacytic infiltrates within the duodenum (IBD) as well.

Each part of the traid alone can have a similar clinical presentation often associated with chronic intermittent vomiting, lethargy, and anorexia. Liver enzymes are variable and pancreatic amylase and lipase concentrations are not helpful however fPLI levels may be abnormal.



Acute Pancreatitis in the Dog

The incidence of pancreatitis characterized by significant histological changes identified at necropsy in cats and dogs range from 1.3-1.5% respectfully. This is where the similarities diverge. Most dogs have acute pancreatitis while most cats have chronic pancreatitis. Clinical presentation and diagnostic criteria differ as well between species and type. Acute pancreatitis is potentially reversible but can also be fatal while chronic pancreatitis has irreversible changes and rarely fatal. The following will deal with the latest information on acute forms of pancreatitis in the dog. There are a number of misconceptions of pancreatitis and will be covered below. Some of those include: presence of abdominal pain, the confusion of amylase, lipase and the newer test pancreatic lipase, when to feed pancreatitis and is surgery ever indicated for pancreatitis.

Pathophysiology. The pancreas secretes high quantities of enzymes required for digestion of a meal. If these enzymes become activated within the pancreas serious (autodigestion) damage to the organ will take place. Under normal conditions this does not take place due to a number of protective mechanisms. Enzymes produced by the pancreas are secreted inactive as zymogens and these zymogens or proenzymes must become activated prior to being functional. Normal enzyme activation takes place only in the intestine. It is generally believed that pancreatitis develops when there is activation of digestive enzymes within the gland and subsequent autodigestion. The location of the initiation of enzyme activation is thought to begin at the intercellular level by zymogen activation. Studies have indicated that there is an abnormal secretory process of zymogen granules their subsequent fusion with lysosomes. Lysosome enzymes then activate trypsinogen that begins the autodigestive process.

Other observations suggest that the depletion of acinar glutathione in the pancreas may stimulate oxidative stress and that contributes to tissue injury. Disturbances in glutathione, a tissue antioxidant, may alter zymogen protein processing, impair zymogen transport and assist in activation of pancreatic enzymes. In animals, superoxide dismutase and catalase treatment reduced experimental pancreatitis and suggest that antioxidant therapy started early in the course of pancreatitis may be of benefit.

Once there is activation of trypsinogen all zymogens become activated. Damage is amplified by elastase and phospholipase. The proteases will activate the kinin, coagulation, fibrinolytic and complement cascades. Local complement activation induced by certain toxins or from local ischemia to the pancreatic microcirculation may play a role in initiating the cascade of events. So simply local pancreatic damage is associated with autodigestion by enzymes and systemic effects are generally associated with inflammatory cytokines and other mediators.

Experimental studies suggest that the severity of acute pancreatitis is determined by the degree of either pancreatic ischemia or the amount of protease-inhibitor imbalance. Released proteases normally bind to alpha1-protease inhibitor that is then transferred to alpha 2 macroglobulin. This complex is then removed from the plasma by the reticuloendothelial system. Associated with the systemic inflammatory response is the release of C-reactive protein from the liver as an acute phase response protein. It appears that elevations in C-reactive protein may correlate with the severity of the pancreatitis.

CLINICAL CONDITIONS. THERE IS CONSIDERABLE CONFUSION AND CONTROVERSY REGARDING THE PATHOGENESIS, DIAGNOSIS AND TREATMENT OF ACUTE PANCREATITIS IN THE DOG. THE SPECTRUM OF CLINICAL DISEASE CAN RANGE FROM MILD SIGNS TO THOSE WHICH ARE FULMINATE AND FREQUENTLY FATAL. THE DISCUSSION OF MEDICAL MANAGEMENT IN THIS SECTION WILL COVER THE MORE COMPLEX CASES OF PANCREATITIS.

In most all cases of pancreatitis the etiology is never determined. In many cases nutrition is a common factor causing pancreatitis. The ingestion of high fat diets especially in the obese patient is a well-accepted etiology. Animals getting into the trash have a higher risk of developing pancreatitis. Hyperlipoproteinemia is also common in pancreatitis. Whether or not this is a result of fat necrosis secondary to the pancreatitis or the cause of it is unknown. It is postulated that high concentrations of triglycerides become activated by pancreatic lipase and produce pancreas. Pancreatitis is common in Schnauzers and other dogs that have a primary hyperlipidemia. A number of drugs are also shown to cause pancreatitis and include thiazides, furosemide, tetracycline, L asparginase and azathioprine. The role of corticosteroids as a cause of pancreatitis is suggested but as yet unproved and is still controversial. Other factors include the reflux of duodenal fluid into the pancreatic ducts and conditions that may result in obstruction of the pancreatic ducts. Parasites, calculi, surgery, tumors and inflammation are potential causes of ductular obstruction. Hypercalcemia secondary to hyperparathyroidism is a reported etiology of pancreatitis in humans and has been associated with clinical pancreatitis in dogs. Additional important factors associated with clinical pancreatitis include trauma and factors causing local pancreatic microcirculatory ischemia. Blunt abdominal trauma and surgical trauma are the common associations in animals. Shock and gastric dilation-volvulus syndrome are examples of pancreatic ischemia and has been associated with a secondary pancreatitis. This latter mechanism is felt to be secondary to ischemia with reperfusion injury.

In a study of 70 dogs confirmed having pancreatitis certain risk factors were identified (note animals included in this study were all necropsy cases). It was concluded that the breed, overweight body condition, small breed size, prior gastrointestinal diseases, diabetes mellitus, hyperadrenocorticism and hypothyroidism are at risk for developing acute pancreatitis. No concurrent medications, glucocorticoid therapy, anesthesia or trauma were at increased risk. Dogs with surgery in the two weeks prior had more pancreatitis than the control population in this study. The breeds at most risk were Yorkshire terriers, toy poodles and miniature Schnauzers.

Acute pancreatitis is one of the most difficult diseases to diagnose and there is no one diagnostic test having a very high sensitivity for pancreatitis. One must have a degree of suspicion based on the risk factors listed above and the clinical findings however the signs can be quite variable. Acute or chronic vomiting is a major clinical sign associated with pancreatitis. The clinical spectrum can vary dramatically from case to case. In a study of 70 dogs with severe pancreatitis, vomiting (90%), weakness (79%), abdominal pain (58%), dehydration (46%), and diarrhea (33%) was reported. Severe cases had systemic clinical signs such as fever or even cardiovascular shock.

Diagnosis. Laboratory findings are quite variable and to some extent parallel the severity of the clinical disease. Leukocytosis is usually present and represents the inflammatory nature of the disease. The biochemistry profile will show variable changes. Azotemia may occur secondary to dehydration however acute renal failure from acute tubular necrosis can also be present. Elevated liver enzymes are also expected in pancreatitis. Increases in ALT, AST and ALP are most often observed. In experimental pancreatitis in dogs histological evidence secondary hepatopathies occurred in all cases. Occasionally partial or complete blockage of the common bile duct from periductal inflammation can result in icterus with increases in total bilirubin concentrations. Hyperglycemia and hypokalemia may also be present. Acid base changes are quite variable. Severe cases may have a marked acidosis however severe vomiting can also result in a metabolic alkalosis. When DIC and coagulopathies occur it generally reflects a poor prognosis.

Amylase and lipase have been used for years to diagnose pancreatitis in the dog. Unfortunately they are not consistently reliable. The specificity of both of these parameters only approximates 50%. Factors such as azotemia will increase serum amylase and lipase due to decreased renal removal and dexamethasone will increase serum lipase levels. Further complicating matters is that both amylase and lipase are found in a number of other organs that will contribute to total measurement. Decreased concentration of trypsin-like immunoreactivity (cTLI) is specific for the diagnosis of exocrine pancreatic insufficiency in the dog. Elevated cTLI concentrations can occur in pancreatitis but the sensitivity of serum cTLI concentration for pancreatitis in dogs is around 35% making it a poor test to diagnose pancreatitis.

Recently a new test has become available for the diagnosis of pancreatitis in the dog and cat, pancreatic specific lipase (cPLI and fPLI at Texas AM GI Lab or Spec cPL, IDEXX Labs). The advantage of this test is that a number of organs synthesize and secrete lipases but PLI measures lipase that only originates from the exocrine pancreas. The sensitivity of cPLI for the diagnosis of pancreatitis in the dog was over 90% and a specificity of around 25% Data would suggest that serum cPLI can be used as a diagnostic test for pancreatitis even in dogs with renal failure and prednisone does not have any effect cPLI values. In a recent abstract presented at the ACVIM Forum in June 2009 a prospective study of cases with clinical evidence of pancreatitis found the test had a 93% sensitivity and a 78% specificity. When the Spec cPL was < 200 µg/L (normal) it was highly unlikely that the patients did not have pancreatitis. The Spec cPL also was reported to decline during recovery in a second abstract presented at the Forum suggesting it would be useful to monitor the patient during recovery.

The SNAP cPL correlates well with the Spec cPL values as regard to cutoff values of normal and abnormal.

Abdominal radiographs may reveal increased density, diminished contrast and granularity in the right cranial abdomen with displacement of the stomach to the left and widening of the angle between the stomach and the duodenum. A non-homogenous mass and loss of echodensity in the area of the pancreas is often noted on ultrasonographic examination. One study found the sensitivity of ultrasound to be 68% but this varies based on operator skill but appears to be more accurate than amylase and lipase. We will frequently perform a fine needle aspiration of suspected areas of pancreatitis and finding cytology showing suppurative inflammation supports the diagnosis.

We also find abdominocentesis to be very helpful if effusion is present. Suppurative non-septic inflammation is the typical finding and is rarely septic. Recently we have combined abdominal fluid analysis with measurement of abdominal fluid lipase concentrations. Finding the abdominal lipase concentration markedly higher than serum lipase supports the diagnosis of pancreatitis in many cases. A negative abdominal paracentesis but with radiographic or ultrasound evidence of effusion a diagnostic peritoneal lavage is indicated.

Finally biopsy provides the definitive diagnosis. Surgery and laparoscopy are two options to consider for biopsy. Although acute pancreatitis is not considered to be a surgical condition indications for surgery would include septic peritonitis, pancreatic abscess or to place a jejunostomy feeding tube.

Treatment. Treatment of pancreatitis is supportive and should be tailored for the individual case. Basic therapy involves correction of fluid and electrolyte imbalance, nutritional considerations, pain management and the control of secondary complications. The material in the following section deals with the management considerations for the severe and often life-impending acute pancreatitis case. Mild cases of pancreatitis may require minimal or only a portion of the recommendations included below.

Pancreatic rest in the form of fasting is the traditional recommendation for any patient with pancreatitis by giving nothing per os (NPO) for several days. The belief is that feeding results in the release of pancreatic secretagogues that will stimulate pancreatic secretions and exacerbate the pancreatitis. Short term fasting is probably justified in patients that have acute vomiting and before treatments have taken effect or are predicted to resolve in a few days. There is however little evidence to justify placing patients NPO that do not vomit. Current literature suggests that feeding a patient with acute pancreatitis does not further stimulate pancreatic secretions in the inflamed pancreas. Vomiting or pain associated with eating would be reasonable reasons to fast patients. (See below for nutritional management considerations)

Fluid and electrolyte therapy is given in virtually every case of pancreatitis. The effects of fluid loss into the peritoneal cavity and vomiting losses coupled with the vasoactive factors released from the pancreas produce a hypovolemic or possibly endotoxic shock. Fluid losses through vomiting may also result in a hypochloremic metabolic alkalosis. Most cases however usually have a metabolic acidosis with depletion of total potassium stores. A balanced electrolyte solution such as Normosol supplemented with additional potassium is indicated in most all cases. Careful monitoring of electrolyte concentrations and patient hydration and renal output is essential in the severe pancreatitis case. Colloids such as hetastarch may be beneficial in improving pancreatic blood flow.

When protein levels decline plasma therapy has been suggested for improving oncotic pressure, pancreatic perfusion and replacing protease inhibitors. There is now the question of the benefit of plasma for protease replacement. Probably the most important use of plasma is for factor replacement associated with coagulopathies or DIC.

Antibiotics should be considered for the severe case or whenever there is evidence of sepsis. Infectious complications of pancreatitis are rare in dogs and prophylactic use of antibiotics is always to be questioned. In one experimental pancreatitis study in dogs antibiotic therapy improved survival. Broad-spectrum antibiotics effective against aerobes and anaerobes should be given. I generally place my severe pancreatitis cases a second-generation cephalosporin or a combination of ampicillin and enterofloxacin for this purpose.

Antiemetics are given if the vomiting is severe and there is significant fluid loss from vomiting. Metoclopramide is given for antiemetic effects and to improve gastrointestinal tone (0.2-0.4 mg/kg qid PO or SC, or 0.01-0.02 mg/kg/hr constant rate infusion). Anticholinergic agents are not indicated because of the profound effects on GI motility. Alternative is ondansetron (Zofran™ 0.1mg/kg BID to TID IV slowly over 2-5 minutes) or dolasetron (Anzemet™ 0.6-3.0 mg/kg daily IV). Current the antiemetic of choice is maropitant (Cerenia 1 mg/kg SQ q 24 hrs). It is a broad spectrum antiemetic that works both centrally and peripherally and is very effective and may also be beneficial in blocking visceral pain as well based on a recent abstract we published showing it blocks ovarian ligament pain.

Analgesics should be considered in all patients with pancreatitis, even if there is no outward evidence of abdominal pain. For mild pain meperidine hydrochloride (5-10 mg/kg IV, IM prn) or butorphanol tartrate (0.1 - 1.0 mg / kg SC q 1 to 6 hr.) is suggested. Other considerations include transdermal fentanyl patch that maintains effective plasma concentrations of fentanyl providing continuous anesthesia for up to three days. The patch is applied to the skin that has been clipped usually over the dorsal neck or rump and then bandaged to prevent dislodgment. Patches are available in four sizes, delivering 25, 50, 75, or 100 g/hour. Empirically, small dogs (<10 kg) receive a 25 g patch, medium dogs (10-29 kg) receive a 50 g patch and large dogs (>30 kg) receive a 75 g patch. Small dogs or cats may receive a half of a 25 g patch.

With moderate pain fentenyl is given as a continuous infusion (3-5 µg/kg/hr). With severe pain we increase the dose of fentanyl (5-10 µg/kg/hr and add ketamine (0.2-0.4 mg/kg/hr constant rate infusion. The animals should be monitored for side effects particularly respiratory depression.

We have treated some patients having severe abdominal pain with some success using intrathoracic placement of local anesthesia. Lidocaine (1.5 mg/kg) followed by bupivacane (Marcaine 1.5 mg/kg). The lidocaine is given first because bupivacane is initially painful. Following injections the dog is placed on their back so the anesthesia will drain into the area of the vagal nerves. We generally use a butterfly catheter for the injection and given as needed for control of the pain before systemic analgesics kick in.
Nutritional supplementation in severe pancreatitis is very important. Studies have shown adequate nutrition to improve survival in experimental pancreatitis. If the patients are not predicted to be eating on their own within 3-4 days nutritional support indicated. The type and route of administration is still controversial. Partial or total parenteral nutrition (PPN or TPN) has been used with pancreatitis and this route does not stimulate pancreatic enzyme secretion. The expense, difficulty in administration and complications of sepsis are of concern with parenteral feeding.

It has been shown that enteral feeding of elemental diets or polymeric diets (e.g. Clinicare™) via jejunostomy feeding tube does not significantly increase pancreatic exocrine secretions and has the advantage of being easier to perform, prevents intestinal mucosal atrophy and bacterial translocation that accompany fasting or parenteral nutrition. Jejunostomy tube feeding also does not appear to stimulate significant pancreatic enzyme secretion. Jejunostomy feeding tube placement requires surgery or laparoscopy. Alternatively "J" tubes can be placed endoscopically using a Cook Jejunal Feeding tube set™. Some have suggested adding pancreatic enzymes to the enteral feeding but the benefit is unknown.

When beginning to feed orally the diet should be a carbohydrate-rich and low-fat diet given as small frequent meals. A final recovery diet is then prescribed that is low in fat content.

Unproven therapy should be considered only after careful evaluation of the individual case. The use of corticosteroids is contraindicated. Attempts to reduce pancreatic secretion by using atropine, glucagon, antacids, cimetidine or other acid blockers or nasogastric suctioning are also of unproved benefit in human studies.

DIC is a complication of severe acute pancreatitis. In patients with severe pancreatitis and with a suspicion that DIC as a complication plasma (for factors) and heparin 120 units/kg SC tid may be considered. Heparin may also prevent microclots formation in pancreatitis as well. One can also add the first dose of heparin to a plasma transfusion and administer it IV.

Somatostatin, a hormone that decreases pancreatic secretion, has also been proposed as a therapy. Experimentally, somatostatin will reduce severity of pancreatitis in dogs when given before induction of pancreatitis. The benefit after the onset of pancreatitis is of questionable value in experimental animals and in human patients. We often use somatostatin to pretreat patients undergoing pancreatic surgery (i.e. insulinoma cases) to attempt to reduce enzyme secretion and postoperative pancreatitis. Dose is 1-2 mcg / kg SC BID.

Low dose dopamine was found to preserve vascular permeability during experimental pancreatitis in cats and may be a beneficial adjunctive therapy in the management of clinical pancreatitis. Dosage used in this study was 2-5 g/kg/minute IV infusion.

Because oxidative damage is thought to be the result of cellular membrane death antioxidants may be of benefit in the acute management of cases. Studies show that perfusion of the pancreas with free radical scavengers ameliorate the severity of pancreatitis in experimental canine models. Vitamin E is a potent membrane antioxidant and SAMe replaces glutathione stores that may have some benefit in pancreatitis.

Peritoneal lavage removes inflammatory products in the peritoneal cavity before they are absorbed. Problems encountered include tube placement, adequate fluid recovery, and bacterial contamination. Approximately 5-8 ml/kg of fluid is lavaged four times a day with a dwell time of one hour. Careful patient monitoring is critical in these patients. Alternative techniques include open peritoneal lavage performed during surgery.

Surgery is rarely indicated for pancreatitis. Surgery may be considered with obstructive jaundice, intestinal obstruction, and to treat a possible pancreatic abscess, cyst or intestinal perforation. It is however questionable if obstructive jaundice is an indication for surgery. We have had a number of patients with secondary bile duct obstructions recover over 3 to 4 weeks as the pancreatitis resolves.

Pancreatic enzyme supplementation has been reported to decrease the pain that accompanies chronic pancreatitis in humans by the feedback inhibition by endogenous pancreatic enzyme secretion. It is not known if enzymes are helpful in the acute cases but such supplementation may have some benefit in early nutrition of patients with acute pancreatitis.

Acute pancreatitis can vary in severity of signs and often results in multi-system involvement. Despite the extensive literature on the pathogenesis of pancreatitis and its complications, there have been very few advances made in the management of this disease. It is possible that future research on modification of enzymatic disturbances will result in an effective treatment for acute pancreatitis. The more systemic organ involvement there is the poorer the prognosis.



Common Liver Diseases and Chronic Hepatitis in Dogs

There are many causes of abnormal liver enzymes in the dog. Perhaps the most common cause is a primary non-hepatic condition with secondary liver envolvement. There is also a large category of vacuolar hepatopathies involving the liver and will be discussed under emerging liver conditions. The most important liver disease in dogs to diagnose is chronic hepatitis. Appropriate identification and therapy is often successful.

REACTIVE HEPATOPATHIES


The so-called "reactive hepatopathies" which occur secondary to non-hepatic disease can result in increased serum biochemical hepatic tests and histomorphologic abnormalities. Most of the reactive hepatopathies cause increases in laboratory tests that evaluate hepatocellular integrity (ALT, AST) and tests of hepatic cholestasis (ALP, GGT). In most cases there are little if any changes in tests that evaluate hepatic function (bilirubin, albumin, glucose, and BUN). Most of the animals with secondary liver disease also retain normal serum bile acid concentrations, which again supports a concept that there is generally minimal hepatocellular dysfunction in most of these disease conditions.

This group is characterized by nonspecific hepatocellular degeneration or necrotic changes without evidence of significant chronic progressive inflammation. Again, these changes are usually secondary to manifestations of a primary non-hepatic disease. The reason the liver often undergoes these changes revolves from the fact that the liver is involved in many metabolic and detoxification functions. Endogenous toxins, anoxia, metabolic changes, nutritional changes and endogenous stress related glucocorticoid release are all examples of conditions responsible for the majority of these changes. Non-specific mild liver changes routinely also occur following general anesthesia.

A good example that helps explain this concept is inflammatory bowel disease in which it is not unusual to observe mild inflammatory changes around portal triads presumed to be the result of abnormal portal uptake of gastrointestinal "toxins". Throughout the liver and closely associated with portal areas are Kupffer cells (fixed macrophages) that function to filter the blood of injurious toxins, inflammatory mediators and bacteria. When this macrophage system is abnormally insulted Kupffer cells release their own inflammatory mediators that in turn insult the hepatocytes.

Another example could be the sick septic dog having vacuolar change thought to be due to endogenous cortisol release for endogenous stress and hepatic cholestasis from presumed endotoxin or cytokine alteration of bilirubin metabolism.

Histological findings associated with secondary reactive changes include descriptors such as vacuolar degeneration, hydropic degeneration, swollen hepatocytes, lipidosis, intracellular or intrahepatic cholestasis, mild multifocal hepatitis and periportal or variable hepatic necrosis. These changes are devoid of the typical progressive chronic inflammatory cell infiltrates characteristic of chronic hepatitis.

In a review of consecutive liver biopsies at Colorado State University histology grouped as non-specific reactive changes made up the largest category of abnormalities (approximately 25%) In this group we were able to identify an associated disease in many that could explain the likely cause for the hepatic enzyme increases and histological changes observed. Concurrent diseases identified included neoplasia, gastrointestinal, renal, autoimmune, dermatologic, dental, infectious and cardiac disease as a few examples. In some cases an underlying disease is not identified. The ALT values on the average are 1-2 X normal and the ALP values 1-3 X normal. It is interesting to note that in a series of 32 dogs having reactive hepatopathies, 8/8 cases in which serum bile acids were run, all were within the normal reference range again suggesting hepatic function remains intact.

This category appears to be the most common histological change to occur in dogs and is by far the most common cause of elevated liver enzymes. Based on this fact, dogs presented with elevations in ALT and ALP should always have primary non-hepatic disease ruled out first. These changes are usually very reversible and no specific hepatic therapy is required short of treating the primary disease. The liver changes resolve once the primary etiology is successfully treated. Therapy providing good liver support such as antioxidants may be warranted.

Chronic Hepatitis


Chronic hepatitis is an etiologic diverse and morphologically variable condition associated by mixed inflammatory cell infiltrates. It is characterized by hepatocellular apoptosis or necrosis, a variable mononuclear or mixed inflammatory infiltrate, regeneration and fibrosis. The proportion and distribution of these components vary widely. Plasma cells, lymphocytes and macrophages predominate with a lesser number of neutrophils. Because we see non-specific mild portal inflammation as a common non-specific reactive change I always ask the pathologist to tell me the severity of inflammation and chronicity of the disease. The presence of fibrosis in the hepatic biopsy usually denotes to me more serious consequences. As damage progresses cirrhosis can result with diffuse fibrosis, alteration in hepatic lobular architecture with the formation of regenerative nodules and abnormal vascular anastomoses. Cirrhosis, a sequel of some chronic hepatitis cases, is often associated with portal hypertension, ascites and multiple portosystemic collateral veins. Some may show manifestations of liver failure, e.g., hyperbilirubinemia, coagulopathies, edema due to hypoalbuminemia, ascites and hepatoencephalopathy. Inflammation in the liver has been given a number of different classifications (ie chronic active hepatitis, cholangiohepatitis etc) but the WSAVA liver standardization group believes we are not able to subclassify hepatitis and suggests we call the condition simply chronic hepatitis. This type of chronic inflammation is uncommon in the cat as their inflammatory disease is directed at bile ducts causing cholangitis.

Etiology. The etiology of this chronic inflammatory condition is generally never determined. Copper associated chronic hepatitis has been documented in a number of breeds as an inherited etiology. The hepatic copper accumulation increases to a level that then becomes toxic to the hepatocyte causing cellular death. The copper accumulation may also result as secondary copper retention from altered biliary copper excretion (see copper associated hepatitis below).
Infectious causes of chronic hepatitis have been associated with leptospirosis and experimental and spontaneous infectious canine hepatitis virus infection. Chronic liver injury has also been reported in dogs with aflatoxicosis and various drug-induced hepatitis. Some dogs treated with anticonvulsant drugs primidone, phenytoin and phenobarbital can develop chronic hepatitis. We have also observed dogs treated with NSAIDs to have hepatitis and there may be a casual relationship in some cases. More commonly however we see acute liver necrosis as a NSAID related drug reaction.

Alpha1-antitrypsin (AAT- also referred to as alpha one protease inhibitor) deficiency in the serum leading to accumulation of AAT in the hepatocytes, is known to cause chronic hepatitis and cirrhosis in man. Investigations by researchers in Sweden using immunostaining for AAT in hepatocytes found some dogs with chronic hepatitis to be positive. The breed most often associated with AAT accumulation was the cocker spaniel.

Finally immune associated hepatitis may occur in the dog. Circulating autoantibodies are important diagnostic markers used to identify autoimmune liver disease in humans. It appears that autoantibodies (ANA, antimitochrondial antibodies [AMA], smooth muscle antibodies [SMA], liver membrane autoantibodies [LMA]) are of a minor importance in classifying canine chronic hepatitis and thought to occur in most cases secondary to the liver damage. Nonetheless, immune-mediated mechanisms are thought to be associated with certain cases of chronic hepatitis and this is supported by the fact that some dogs respond favorably to immunosuppressive therapy.

There is lastly a lobular dissecting hepatitis characterized by a rapid diffues spread of inflammation throughout the liver lobule. This condition is observed in younger dogs and is associated with hepatic encephalopathy and ascites.

Breed Predisposition. There are a number of breeds that have an increased incidence and suspected genetic basis. Some of these breeds have copper associated chronic hepatitis (discussed below). Other breeds not yet associated with copper include the standard poodle, Cocker spaniel and Scottish terrier. The mechanism of their hepatitis is unknown.

Copper Associated Hepatitis. Abnormal hepatic copper accumulation may be the result of either a primary metabolic defect in copper metabolism or as a secondary event from abnormal hepatic function altering hepatic copper excretion. When we reviewed a number of dogs having chronic hepatitis not associated with genetic copper accumulation we found many dogs had increases in both copper and iron hepatic concentrations. A number of these dogs were also deficient in hepatic zinc. The interrelationship of the heavy metals and liver disease needs further investigation.

The diagnosis of abnormal Cu accumulation requires a liver biopsy. The measurement of serum copper or ceruloplasm levels to make the diagnosis. Excess Cu within the liver can be demonstrated using histochemical staining for hepatic Cu using rhodanine or rubeanic acid stain. Definitive determination of excess hepatic Cu requires a quantitative analysis of tissue Cu measured on the biopsy sample. Normal canine hepatic Cu concentrations are less than 400 µg/g (ppm) dry weight liver. Hepatic Cu concentrations in dogs with secondary Cu accumulation generally fall in the range less than 1,000 µg/g dry weight while breed associated hepatotoxicities generally have higher concentrations (>750 µg/g). The location of copper secondary to hepatic cholestasis is generally in zone 1 (periportal) location.

Hepatic copper toxicity was first identified in Bedlington Terriers. It was subsequently shown that affected Bedlington terriers have an inherited autosomal recessive defect, which results in reduced biliary excretion of copper due to hepatic metallothionein sequestration of the metal in hepatic lysosomes. Clinically there is a progressive hepatic Cu accumulation with age ranging from 1,000 to 12,000 µg/g per dry weight of liver. The extent of hepatic damage tends to parallel the increasing hepatic Cu concentrations. In this breed a specific gene has been identified to be responsible for this disease.

During the last decade an increasing number of breeds other than the Bedlington terrier have been linked with concurrent chronic hepatitis and increases in the hepatic Cu content. Liver disease with concurrent Cu accumulation is reported in the Doberman pinscher, West Highland white terrier, Skye terrier, Dalmatian and most recently the Labrador retriever (but not all labs having chronic hepatitis). Occasionally we see other pure breed dogs as well as mixed-breed dogs with high copper concentrations thought to be due to primary copper retention.

Clinical findings. The incidence of chronic hepatitis makes up approximately one fourth of the cases having liver biopsies at Colorado State University (based on a review of 150 consecutive liver biopsies). Chronic hepatitis is more common in female dogs. The average of presentation ranges from 4 to 10 years. It is interesting to note that in both our series and in studies by others it is uncommon to observe chronic hepatitis/cirrhosis in dogs older than 10 years of age. As a general rule old dogs (> 11 years of age) don't generally present with chronic hepatitis/cirrhosis or if they do they are at or near end stage disease.
The clinical signs parallel the extent of hepatic damage. Early in the disease there are usually no or minimal clinical signs. Only after the disease progresses do the clinical signs specific for liver disease becomes evident. Frequent early signs are gastrointestinal associated with vomiting, diarrhea and poor appetite or anorexia. Ascites, jaundice and hepatic encephalopathy may then occur as the disease progresses. With development of these late signs the long-term prognosis is generally poor.

The laboratory findings include consistently elevated ALT and ALP. The magnitude of rise need not be marked however. One report found 75% of the cases at diagnosis had abnormal bilirubin elevation (mean elevation of 2.6 mg/dl). Serum proteins are variable. As the lesions become more severe albumin levels decline. Serum bile acids are abnormal in most cases having significant chronic hepatitis and measurement of bile acids appear to be a good screening test for the patient with unexplained elevations in ALT and ALP. In our study all dogs evaluated with chronic hepatitis had abnormal bile acid concentrations. In a second study only 8/26 dogs with chronic hepatitis had normal fasting bile acids. However, postprandial samples were not determined in these cases. Determining postprandial bile acids has been shown to increase the sensitivity of this test.

A presumptive diagnosis is made based on the clinical features and persistent increases of ALP and ALT values. A definitive diagnosis requires a hepatic biopsy showing characteristic morphological patterns. Needle aspirates are not helpful in making the diagnosis of chronic hepatitis because it is important to see the architecture of the liver and location and extent of the inflammation. One must work with the pathologist when making the diagnosis of chronic hepatitis and to be certain that characteristic abnormalities found in chronic hepatitis are present

Prognosis. There is little information of the prognosis with and without therapy. The prognosis in dogs with advanced chronic hepatitis and cirrhosis is guarded. In a study by Strombeck found mean survivals ranging from 6 to 16 months with therapy. This study also identified that dogs with hypoalbuminemia, hypoglycemia and coagulopathies have very guarded prognostic factors and many died within 1 week of diagnosis. A second study of 79 dogs found that dogs with cirrhosis had a survival of less than one month and dogs with chronic hepatitis had a mean survival in the range of about 20 to 30 months. Most of these dogs were not advanced in their disease and had concurrent corticosteroid treatment. Low albumin, ascites and hepatic encephalopathy are all poor prognostic indicators.

Therapy. The management for chronic hepatitis involves removing the primary etiology. Short of treating the primary etiology all other therapies suggested are unproven in the management of chronic hepatitis in dogs. We are still waiting for good clinical studies proving efficacy in treatments. Such studies are hindered even from the start owing to the multiple etiologies of hepatitis and the inconsistent histological descriptions. To date we have only limited case studies and clinical impressions of efficacy in the management of chronic hepatitis.


© 2009 - David C. Twedt, DVM, Diplomate ACVIM - All rights reserved