Proceedings Saturday, October 14 Atlanta Marriott Century Center

Transcription

1 Proceedings Saturday, October 14 Atlanta Marriott Century Center

2 Feline Cardiomyopathy Kathryn M. Meurs, DVM, PhD Diplomate ACVIM (Cardiology) There are many forms of feline cardiomyopathy including hypertrophic, restrictive, dilated, arrhythmogenic and unclassified among others. Hypertrophic cardiomyopathy is by far the most common and this session will focus mainly on that although the treatment recommendations for management of heart failure and thromboembolic disease are very much the same regardless of the underlying form of cardiomyopathy. Myocardial disease, particularly hypertrophic cardiomyopathy, is the most common heart disease in the adult cat. Remember that valvular disease in the cat is very rare!!!! Cats do not develop endocardiosis and endocarditis is very rare, so always consider myocardial disease first when considering differentials for feline heart disease. As mentioned above, there are several forms of feline cardiomyopathy, hypertrophic (HCM), restrictive (RCM), dilated (DCM), arrhythmogenic (ARVC) and unclassified. In many cases, there is significant overlap between these different forms of cardiomyopathy with regard to clinical signs, ECG and radiographic findings. Echocardiography is needed to complete the diagnosis. Feline Hypertrophic Cardiomyopathy (HCM) Hypertrophic cardiomyopathy is defined by left ventricular hypertrophy w/o causative systemic or other cardiac disease. It is the most common form of heart disease in the cat! The etiology for the majority of cases is unknown. However, it is inherited in Maine Coon and Ragdoll breeds and is believed to be in the American Shorthair, Sphynx, Norwegian Forest and a few others. In the Maine Coon it has been shown to be an autosomal dominant trait (both genders are equally affected). In the Maine Coon and Ragdoll breeds a mutation has recently been identified as causative for the disease. Genetic tests based on a buccal swap are now available for these breeds ( It is a different mutation in both breeds and does not appear to be causative in other breeds. Hypertrophic cardiomyopathy is typically characterized by hypertrophy of the left ventricular free wall and/or interventricular septum. This results in myocardial stiffness and decreased ventricular lumen size and therefore is a diastolic dysfunction disease. Mitral regurgitation may develop from distortion of the left ventricular cavity and from systolic anterior motion of the mitral valve (SAM). An increased left atrial pressure develops to fill the stiffened left ventricle. Elevated pulmonary venous pressure and pulmonary edema may result. In some cases, pulmonary hypertension and right ventricular enlargement may occur secondary to the left sided heart disease and pleural effusion may develop. Thrombi may develop in the stretched, dilated atria and subsequently break free and lodge in the systemic circulation (typically the distal aorta). The clinical signs of affected cats are quite variable. Affected cats may be asymptomatic, but dyspnea, and shortness of breath may be presenting complaints due to congestive heart failure. Acute hindlimb paralysis suggests distal aortic embolization. Sudden death can occur. Physical exam findings may include a systolic murmur consistent with left ventricular outflow tract obstruction and/or mitral regurgitation. A gallop rhythm may be ausculted indicating abnormal left ventricular filling. Since asymptomatic cats may be affected, we recommend

3 screening with an echocardiogram if a murmur or gallop is ausculted. Tachypnea and dyspnea may be observed if heart failure is present but crackles are uncommon. The ECG is often within normal limits but conduction disturbances and arrhythmias (ventricular and supraventricular) may be noted. Radiographs may be useful to evaluate for cardiomegally, chamber enlargement patterns, and evidence of heart failure, but are NOT diagnostic for the specific form of feline heart disease. Radiographic findings may range from normal to significant cardiac enlargement depending on the stage of disease and may have evidence of heart failure with pulmonary venous distension and patchy pulmonary edema present. Echocardiography is the best diagnostic test!!! Generalized concentric left ventricular hypertrophy may be observed and localized left ventricular free wall and / or interventricular septal hypertrophy may be noted. Most clinicians use a cut-off of a wall thickness at diastole of greater than or equal to 6 mm as diagnostic in the absence of other causes of left ventricular hypertrophy such as hyperthyroidism, or systemic hypertension. Wall thickness measurements may be made on M-mode echocardiogram or by measurement of the wall on long axis. Multiple modes of echocardiography should be used for a thorough study including 2D echo to scan for regions of asymmetric hypertrophy, M-mode for LV measurements and Doppler to look for evidence of SAM and document obstruction. Left atrial or biatrial dilation may be noted. Since left ventricular hypertrophy can occur secondary to hyperthyroidism and systemic hypertension, these diseases should always be considered when evaluating a cat with left ventricular hypertrophy. BNP is a test that is being discussed with increasing frequency in both canine and feline cardiology. Prohormone BNP is released when the ventricles are dilated, hypertrophic or subjected to increased wall tension. However it is most specific for identifying cats that are in heart failure. The use of this has been somewhat limited in the past because it was largely a send out test and a clinician had to wait at least hours for results. Most recently a new bedside SNAP Feline ProBNP test (Idexx) has been developed for in clinic assessment. This kit has not been studied as much as the send out analysis but early results suggest that it is quite good especially at the higher levels of measurement. There is also some information suggesting that evaluation of pleural fluid is also a fairly accurate way to assess for increased BNP. Although the levels of BNP are higher in pleural fluid than in plasma, the identification of elevated levels would be suggestive of heart failure in comparison to other cause of pleural effusion and this may be a useful test in a dyspneic cat. ProBNP measurement can also be used to assess for the presence of occult cardiomyopathy in cats with heart murmurs and several studies have now shown that it quite specific and fairly sensitive when used this way using a cut off of 100 pmol/l. However, it may be less sensitive for detecting mild disease, particularly with the SNAP test (this requires further study) so false negatives may occur. Echocardiography is still indicated if possible for confirmation if BNP levels are found to be elevated. Treatment The value of treatment before the development of heart failure is not well understood and may vary a bit based on underlying cause of disease, severity of hypertrophy and several other factors. The optimal therapy for asymptomatic cats is uncertain. In general, mildly affected cats are not treated.

4 Many clinicians assess for specific factors of disease to determine the need for treatment. Indication Ace Anticoagulent Beta Vetmedin Furosemide inhibitor Blocker Left atrial enlargement X X Dynamic left ventricular X outflow track obstruction Atrial Fibrillation X Heart Failure X X X The most commonly recommended beta blocker is atenolol (B 1 selective) for heart rate and outflow track obstruction. Atenolol should decrease heart rate and left ventricular outflow tract gradient if SAM (systolic anterior motion of the mitral valve) is present. However, atenolol should never be started in cats with congestive heart failure (CHF). Supportive treatment for CHF should be given to these cats and once pulmonary edema is resolved (Furosemide, enalapril, Vetmedin) atenolol may be started. Calcium channel blockers (Diltaizem) are another option but these are not frequently used any more. They may be used to decrease heart rate (perhaps less than beta blockers) but the ability to decrease left ventricular outflow tract gradient (SAM) with oral medications is unclear. Calcium channel blockers should also probably be withheld until the congestive heart failure is resolved. Sotalol, a combination beta and potassium channel blocker is often used as an antiarrhythmic for both ventricular and supraventricular arrhythmias. Vetmedin has been shown to significantly increase survival in cats who have gone into heart failure in comparison to those not on it (626 vs 103 days, JAVMA 245: ) so this now should be added to management with furosemide and ace inhibitors (enalapril). The prognosis for HCM may vary dependent on etiology and some cats progress rapidly to CHF while others plateau and never progress and live with mild disease for years. It may be best to advise owners that prognosis may be best determined after observing progression over months and that cats with CHF or thromboembolic episodes have a poorer prognosis. Common doses for treating cats with heart disease Atenolol Enalapril Vetmedin Furosemide Clopidogrel 3 mg/kg PO BID 0.5 mg/kg PO BID 0.3 mg/kg PO BID 1-2 mg/kg PO SID BID mg/cat PO SID Arterial Thromboembolism Thromboembolism can occur with all forms of feline cardiomyopathy. Three factors are typically required for clot formation. Endomyocardial injury, blood stasis and altered coagulability. Endomyocardial injury is likely due to injury and fibrosis in the large dilated left atria. Exposed collagenous fibers as well as reactive substances that occur with fibrosis act as reactive substances for platelet adhesion and large, dilated atria may have areas of decreased contractility where blood pools. Finally, cats have large, sticky platelets and platelets release serotonin, as well we other factors that lead to a hyperaggregable state. Other coagulation abnormalities may be present in cats with cardiomyopathy

5 Historically, treatment was directed towards removal or lysis of clot. This is no longer recommended due to high mortality associated with rapid clot removal that is likely a result of reperfusion injury and hyperkalemia among other factors. Now, treatment is directed towards PAIN RELIEF that might include Butorphanol (+/- acepromazine as tranquilizer) and Epidural (requires skill in local anesthesia) or Fentanyl patch (does not provide immediate relief) The prognosis is frequently poor, but approximately 35-40% regain use of limbs. Although many cats will regain use of motor function within 1-2 weeks, risk of a second episode is high. Many owners elect euthanasia due to the patient s discomfort and concurrent heart disease Given the significant severe outcome of thromboembolic disease, prevention is the best policy for management. The platelet inhibitor, clopidogrel (Plavix), mg/cat q24 hrs (JAVMA, 2004;225: ) has been shown to be more effective than aspirin(81 mg every 72 hours). Although even cats with normal sized atria can have thromboembolic episodes, many use left atrial enlargement as an indication for starting Clopidogrel. Feline Dilated Cardiomyopathy (DCM) and Feline Restrictive Cardiomyopathy (RCM) These are both fairly uncommon forms of cardiomyopathy and will not be discussed today. The following information is provided to you as additional reference material. Feline Dilated Cardiomyopathy (DCM) Feline dilated cardiomyopathy is a functional abnormality of the myocardium causing systolic dysfunction similar to the canine form. It is uncommon in cats but can be associated with Taurine (an essential feline amino acid) deficiency. Although most commercial cat foods today are well supplemented, special diets or owner created diets may be deficient. A small percentage of cats have dilated cardiomyopathy and normal plasma taurine levels, the cause in these cases is unknown. Myocarditis may have preceded development of DCM in some of these cases. Radiographs may provide information about cardiomegaly and heart failure but the echocardiogram is needed for diagnosis. Additionally taurine levels should be evaluated. Whole blood taurine levels should always be measured (normal mean is >200 nmol/ml) even if the diet is thought to be balanced. Taurine levels are typically low (< 100 nmol/ml) with taurine deficiency. Since taurine supplementation is safe and inexpensive, Taurine supplementation should be given until Taurine deficiency is ruled out by blood levels. Taurine is given at mg PO q 12 hours, orally. Additionally, medications for heart failure (Lasix,enalapril) should be provided as needed and a positive inotrope should be started. Pimobenden (Vetmedin) could be provided (although not yet FDA approved for use in cats) at a dose of 1.25 mg/cat orally twice a day. The prognosis for cats that are Taurine deficient and that are supplemented is actually quite good and many cats will eventually be able to be removed from cardiac medications. The prognosis for cats with dilated cardiomyopathy that are not Taurine deficient is not good and many progress into advanced heart failure. Feline Restrictive Cardiomyopathy - (RCM) Restrictive cardiomyopathy is an uncommon myocardial disorder characterized by endomyocardial fibrosis, stiffened ventricular wall and impaired ventricular filling. This is mainly a diastolic disorder. Systolic function may be normal or decreased. Etiology is unknown.

6 Biventricular CHF with pleural effusion and thrombi commonly develop in the markedly dilated atria. ***** In many cases, there is significant overlap of clinical signs, ECG and radiographic findings between cats with hypertrophic, dilated and restrictive cardiomyopathy. Echocardiography is needed to complete the diagnosis.

7 CANINE DILATED AND ARRHYTHMOGENIC CARDIOMYOPATHY Kathryn M. Meurs, DVM, Ph.D. Diplomate ACVIM (Cardiology) In this lecture we will discuss canine dilated (DCM) and arrhythmogenic cardiomyopathy (ARVC). We will pay particular attention to breed specific findings. Canine Dilated Cardiomyopathy - DCM Strictly speaking, dilated cardiomyopathy (DCM) is defined as an idiopathic functional abnormality of the myocardium causing systolic dysfunction and/or arrhythmias. Definitive breed predispositions exist. Even though the disease is referred to as DCM in each breed, there are important clinical and pathological differences between the breeds mentioned. Although Boxer dogs can get dilated cardiomyopathy, most Boxers develop Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), a very different disease. Dilated cardiomyopathy is an adult onset disease, with the exception of the Portuguese Water Dog in which it is diagnosed between two and thirty-two weeks. There appear to be two stages of DCM, an asymptomatic stage, referred to as occult, which may be detected by careful screening, and a stage at which symptoms appear, referred to as overt. There is some preliminary evidence that early recognition of the occult stage may slow progression of the disease therefore, being aware of early signs may be beneficial to patient management. Clinical signs Clinical signs may include coughing, dyspnea, tachypnea, syncope and occasionally, ascites. Physical examination A soft systolic murmur consistent with mitral valve regurgitation and/or a gallop rhythm (S 3 ) may be ausculted at the left apex. A tachyarrhythmia of sinus, supraventricular or ventricular origin may be noted. In some cases, a murmur or an arrhythmia may be the first signs of the occult form of the disease and should not be overlooked. Since primary valvular disease is relatively uncommon in large breed dogs, and the detection of DCM before the development of congestive heart failure (CHF) may be beneficial in the long-term management of the case, identification of a new murmur, gallop or tachyarrhythmia in suspect breeds should be considered a red flag and may warrant a thorough cardiac work-up. Although canine DCM is predominantly a left ventricular disease, biventricular involvement and heart failure with jugular venous distension and ascites is frequently noted, particularly in the giant breeds. Electrocardiography Many dogs with DCM have normal electrocardiograms but atrial and/or ventricular enlargement patterns (R > 3.5 mv Lead II for the left ventricle) may be noted. Sinus tachycardia, atrial fibrillation or ventricular arrhythmias are common. In some cases, ventricular tachyarrhythmias can develop before any ventricular dilation or systolic dysfunction. Routine Holter monitoring may help detect these. 1

8 Radiography Dilated cardiomyopathy is a progressive myocardial disease. If the disease is diagnosed in the early stages, radiographic findings may be subtle. Therefore, depending on the stage of the disease, thoracic radiographs may be within normal limits or may indicate atrial and ventricular enlargement (typically left) with or without pulmonary venous distension and pulmonary edema. In some cases, biatrial and biventricular enlargement may be noted. Echocardiography Echocardiography is the diagnostic test of choice for diagnosing canine DCM and is also an important test for occult disease. Echocardiographic findings in the patient with overt disease should include left and sometimes right atrial and ventricular dilation and decreased contractility as characterized by shortening fraction (FS%). Typically the decrease in contractility is quite severe with decreased fractional shortening % (< 20%). A differential diagnosis for DCM is severe atrioventricular (AV) valve disease since severe ventricular dilation and systolic dysfunction may be occasionally observed in these cases. Consideration of the breed of dog may be helpful in differentiating between DCM and AV valve disease since it is uncommon for many of the large breed dogs to develop significant primary valve disease. An exception to this may be the cocker spaniel, a breed that has a high incidence of primary valve disease, and also is at increased risk of DCM. Biomarkers Prohormone BNP is released when the ventricles are dilated, hypertrophic or subjected to increased wall tension. Levels of BNP have been shown be increased in dogs with congestive heart failure and can be used to help diagnose, or exclude a diagnosis of heart failure in dogs that presented for cough or dyspnea. Etiology It is clear that several breeds appear to be over represented and some breeds seem to have unique characteristics of the disease that may suggest that this is unique disease for their breed. A familial form of DCM has now been identified in several breeds and is suspected in others. Genetic mutations have now been identified for both the Boxer and the Doberman pinscher ( Occasionally, atypical breeds of dogs develop DCM. The etiology of the disease in these cases is unknown and external factors that can insult the myocardium including infectious organisms or nutritional imbalances should be considered. Doberman pinscher DCM Etiology Dilated cardiomyopathy is a familial disease in the Doberman pinscher and appears to be inherited in an autosomal dominant fashion. Two genetic mutations have been identified and can now be tested for in breeding dogs for about $ 75.00/dog. While either mutation can lead to the development of the disease, the presence of both leads to a significant increase in risk. Generally affected dogs are mature adults (average 6.5 years) although it has been reported as young as 1 year. Clinical signs Most affected Doberman Pinschers present for an initial diagnosis of DCM already in left heart failure (cough, respiratory distress). Syncope and sudden death are reported frequently due to the presence of ventricular premature complexes (VPCs). Most affected Dobermans will die from congestive heart failure and/or euthanasia due to refractory heart failure, although about 30% are believed to die from sudden death secondary to a lethal ventricular tachyarrhythmia. 2

9 Screening for early (occult) DCM Dilation of the ventricle may precede the development of systolic dysfunction and be an early indicator of DCM. It has been suggested that Doberman Pinschers with a left ventricular end diastolic dimension of greater than 4.6 centimeters and an end systolic dimension of 3.8 are at risk of developing DCM within a 1-2 year period. Caution- these numbers are based on average sized Dobermans (60-80 pounds) and may be less accurate if very large dogs (>100 pounds) Additionally, Holter monitoring has been suggested to be a good screening device for this breed. Adult Dobermans with greater than 10 VPCs per 24 hours, or couplets or triplets are suspect for the development of DCM. Dilated cardiomyopathy is an adult onset disease with a variable age of onset. It is highly heritable and often a fatal disease so screening breeding dogs and screening dogs for concerned owners has become greatly desired. However, there is no single perfect test. Many would recommend starting with genetic testing ( If both genetic tests are negative, there is a pretty low risk of a problem developing and no further testing is needed. If one, or both genetic tests are positive, it does not mean that the dog will become ill, but the risk is definitely increased. This should lead to a discussion of an annual echocardiogram and a Holter monitor after 3 years of age. However, keep in mind that sometimes variations on the echocardiogram and Holter monitor can be due to other systemic diseases and if questionable should be repeated in 6 12 months. A less expensive option would be to do an annual BNP. Although this is not as sensitive or specific as annual Holtering and echocardiograms it would be a reasonable place to start. Prognosis Many affected Doberman pinschers have a poor prognosis. Once clinical signs have developed, death usually occurs due to heart failure or sudden death within 6 months, therapy is palliative at best. Preliminary work has suggested that starting enalapril when ventricular dilation has occurred but before CHF develops, may slow rate of progression. Additionally, treatment with pimobenden as discussed below may have a significant positive effect on survival (increase survival to many months) but is still not a cure. Giant Breed Dog Cardiomyopathy Clinical presentation Giant breeds like the Great Dane also typically starts with a left apical systolic murmur. However, there is some evidence to suggest that in some cases, the first sign of DCM is the development of atrial fibrillation, even before the development of left ventricular dilation and decreased systolic function. Additionally, these dogs are much more likely to develop biventricular failure with ascites and jugular venous distension. Treatment for DCM and heart failure would be the same as for the Doberman pinscher. Although this is still a fatal heart disease, the prognosis is better than that for the Doberman pinscher. Taurine related cardiomyopathy The development of dilated cardiomyopathy due to low taurine is much less common in the dog than in the cat since dogs have a much greater ability to synthesize taurine than cats. However, as mentioned above, a relationship between taurine and L-carnitine abnormalities and DCM has been previously described in the cocker spaniel. There have now been additional, reports of the development of DCM in the dog in which low blood or plasma levels of taurine have been documented. The dogs were all adult at the time of onset and were breeds that would be considered to be in the large breed dog groups. A common factor observed in several dogs that developed DCM and were determined to have low taurine was the feeding of a diet of 3

10 a dry dog food with lamb meal, rice or both as the primary ingredient. It has been hypothesized that rice bran or whole rice products may result in decreased taurine levels in some dogs. A diagnosis of taurine deficiency is indicated by a blood level of less than150 nmol/ml or plasma levels less than 40 nmol/ml. If taurine deficiency is suspected, taurine supplementation should be started while waiting for the results of the blood or plasma levels. Published doses for taurine supplementation appear to vary slightly, although 1000 mg/day (divided or once a day) appears to be a consistent recommendation. Additional cardiac medications should be provided as needed including inotropic support such as pimobenden and treatment of heart failure if needed as discussed below. Taurine deficient dogs with dilated cardiomyopathy appear to respond to supplementation fairly rapidly and improvement in echocardiographic measurement should be observed in 3-6 months. Ideally blood levels of taurine should be reevaluated in 1-2 months to confirm that the levels have increased. Rhodesian Ridgeback cardiomyopathy We have recently identified an inherited ventricular arrhythmia in Rhodesian Ridgebacks. It can lead to sudden death. The arrhythmia is most prevalent between months and many dogs appear to outgrow it. Dogs with the arrhythmia should be managed with standard ventricular antiarrhythmics like Sotalol. Treatment of the dog with occult (asymptomatic) dilated cardiomyopathy Administration of angiotensin converting enzyme (ACE) inhibitors may have some benefit for the dog with early ventricular dilation, with or without systolic dysfunction. The use of ACE inhibitors in the Doberman pinscher with ventricular dilation was found to prolong the amount of time before the onset of CHF. Although this study was limited to evaluation of Doberman pinschers, the use of ACE inhibitors for other breeds of dogs with occult DCM may be considered (Enalapril, 0.5 mg/kg orally twice a day). Vetmedin has now also been shown to increase survival when started at the stage of dilation and should be part of the management plan of dogs in this stage of the disease. Treatment of the dog with dilated cardiomyopathy and congestive heart failure Dogs with DCM and heart failure will benefit from inotropic support. Ideally, this would be with pimobenden, a phosphodiesterase III and V inhibitor with calcium sensitizing properties that acts as a positive inotrope as well as vasodilator (inodilator). Pimobenden has balanced vasodilatation and positive inotropic effects and has been shown to increase survival (median of 130 days versus a median of 14 days for the placebo in one study) in Doberman pinschers with DCM. Additionally, it appears to be a mild appetite stimulant. Generally, it is dosed at approximately 0.25mg/kg orally q12 hours. Additional medications for heart failure such as ACE inhibitors (Enalapril, 0.5 mg/kg orally BID) and diuretics (Furosemide, 1-4 mg/kg orally q 6-8 hours) should be started as needed. Nonspecific treatments including nutritional supplementation by switching to a diet which contains supplements like taurine, L-carnitine and fatty acids (Royal Canin, Early Cardiac EC) should be considered. Treatment of the dog with ventricular arrhythmias There is little consensus for the decision of when and how to treat ventricular arrhythmias in the dog with DCM. Rapid ventricular tachycardia, complex ventricular arrhythmias or the combination of ventricular arrhythmias, ventricular dilation and systolic 4

11 dysfunction are thought to be associated with a higher risk of sudden cardiac death and to be indications for treatment, but this has not been well studied. Additionally, some dogs die suddenly without having any of these arrhythmias documented. If treatment is warranted, consideration might be given to the use of one of several ventricular antiarrhythmics. Sotalol, a combination beta-blocker and potassium channel blocker, may be beneficial in some cases, but should be used a bit more cautiously (Sotalol, low dose, 1.0 mg/kg BID) if systolic dysfunction is present. Mexiletine at a dose of 5-6 mg/kg, q8hr, orally can be very effective at decreasing the arrhythmia. In a small number of cases it can cause nausea but this can be significantly reduced if it is given with at least a small meal, so it should never be given on an empty stomach. Although the goals of treatment include decreasing the number of ventricular premature complexes, decreasing symptoms and decreasing the risk of sudden death, the ability of any antiarrhythmic to reach these goals has not been well studied. Boxer Cardiomyopathy (CM) There are two forms of myocardial disease in the boxer, DCM and Arrhythmogenic right ventricular cardiomyopathy (ARVC) (most common). Dilated Cardiomyopathy (less common myocardial disease in the boxer) Boxers with DCM present with similar clinical signs to other breeds (syncope, cough, dyspnea). They may have a soft left apical murmur, an arrhythmia and sometimes have biventricular heart failure (ascites, jugular venous distension). Diagnosis is confirmed by echocardiography. CAUTION!!!- Many boxers have a left basilar systolic murmur, this is more suggestive of a potential aortic stenosis or physiologic flow murmur than cardiomyopathy! The treatment is similar to that in other breeds with DCM (as above) except that some Boxers with DCM may benefit from L- Carnitine (50 mg/kg orally three times a day) available at most health food stores) as well as possibly switching to a supplemented food such as Royal Canin early cardiac EC. Arrhythmogenic right ventricular cardiomyopathy The more common form of boxer myocardial disease is arrhythmic and is named Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). This is a familial (autosomal dominant) disease in the boxer. A genetic mutation has now been identified for boxer arrhythmogenic right ventricular cardiomyopathy although it is not yet known if this will be responsible for all cases of the disease since in human beings there are several known mutations. Screening for the disease in breeding animals is highly recommended with either a buccal swab or blood sample. Dogs that have one copy of the gene are at risk of developing the disease, but dogs with two copies are very likely to develop the disease and often will develop the dilated form of the disease. Therefore, dogs with two copies (homozygous) should never be bred and one should never breed two dogs with one copy (heterozygous) to each other since they are at risk of producing homozygous dogs. The classical presentation is an adult boxer with VPCs. The dog may be asymptomatic, or symptomatic with episodes of syncope. The VPCs are typically wide and upright QRS in leads I, II, III, and AVF. The arrhythmia may be quite intermittent and in many cases, may require a 24 hour Holter monitor for documentation. Interpretation of the Holter results can sometimes be challenging because strict criteria for this diagnosis does not exist. However the observation of > 100 VPCs, or periods of couplets, triplets or runs of ventricular tachycardia are abnormal. A 5

12 larger number of VPCs or a greater complexity of the arrhythmia (ventricular tachycardia, bigeminy, etc) has been associated with the development of clinical signs. Supraventricular premature complexes may be seen but not frequently, and are more commonly associated with the myocardial dysfunction form of the disease. Treatment Asymptomatic dogs with ventricular tachyarrhythmias If an arrhythmia is detected on routine examination, a Holter monitor should be performed to evaluate for the frequency and complexity of the arrhythmia. Although a strict relationship between the development of symptoms and the number of VPCs does not exist, treatment is generally started if > 1000 VPCs/24 hours, runs of ventricular tachycardia or evidence of the R on T phenomenon exist. Owners should be advised that ventricular antiarrhythmics have the potential for proarrhythmic effects. Dogs with syncope Dogs with syncope and ventricular arrhythmias are generally started on treatment. Sotalol ( mg/kg, q 12hr, orally) is well tolerated and have been shown to decrease VPC number and complexity. In some cases, sotalol and mexiletine (5-6 mg/kg, q 8hr, orally WITH FOOD) may be needed. Prognosis Sudden death is always possible. However, many dogs may live for years on antiarrhythmics without symptoms, some of these may eventually develop ventricular dilation and systolic dysfunction. 6

13 Mitral Valve Disease in the Dog New Concepts for Early Intervention & Longterm Treatment Kathryn M. Meurs, DVM, PhD Diplomate ACVIM (Cardiology) Chronic myxomatous valvular disease is the most common form of heart disease and most the common cause of heart failure in the dog. Most commonly the mitral valve is involved, but occasionally the tricuspid valve is also involved or may even be the primary sight of disease. Infrequently the aortic valve is also involved but patients rarely show clinical signs associated it. This lecture will emphasize discussion of the disease of the mitral valve. Chronic mitral valve disease is an age related disease of small breed dogs. Some reports suggest that it may occur in nearly % of the older small breed dog population, especially in breeds like the Cavalier King Charles Spaniel, toy poodle, and Yorkshire Terrier, among others. Large breed dogs can be affected as well. The prevalence of the disease increases with age with many dogs developing it at some point after 5 years of age disease however, the Cavalier King Charles Spaniel may develop it as young as 1 year of age. The first sign of disease is typically the development of a systolic apical heart murmur over the left apex of the heart (5-6th rib space) although many dogs likely have had early disease for some time before the murmur is apparent. Some dogs also have myxomatous disease of the tricuspid valve and will have a murmur on the right side of the chest as well. The most common sign of mitral valve disease that an owner will identify will be a cough. The two most common reasons that dogs with mitral valve disease cough are left atrial enlargement with main stem bronchus compression and congestive heart failure. However, dogs with mitral valve endocardiosis are also older dogs that may suffer from other causes of cough including tracheal collapse, chronic bronchitis and neoplasia. The severity and progression of chronic valve disease is quite variable. Some dogs remain asymptomatic for years without treatment while others progress very rapidly into congestive heart failure. Predicting the rate of progression for an individual dog can be quite difficult. Left atrial enlargement and left ventricular enlargement with decreased systolic function appear to be indicators of more severe disease. Large elevations in NTProBNP also has been shown to be an indicator of worsening disease. A standard diagnostic work up for a dog with mitral valve disease should include at least thoracic radiographs and a systolic blood pressure measurement. An echocardiogram can be included particularly if there are unusual aspects about the case (fever, neutrophilia) but is often not needed for diagnosis of this common disease. The

14 case management will be typically based on the radiographic findings (left atrial enlargement, heart failure). A blood pressure measurement is very important since dogs of these breeds and age are also dogs at risk of developing systemic hypertension secondary to other causes. Systemic hypertension can increase the amount of mitral valve insufficiency and should be addressed medically if present. Treatment should be based on the problems identified for each individual case. For the dog with mitral valve disease, normal blood pressure and a normal heart size there is no clear indication for treatment. If systemic hypertension is present, blood pressure management with an ACE inhibitor (enalapril) or Amlodipine is strongly recommended to help decrease the amount of mitral regurgitation. There is no consensus among veterinary cardiologists on how to manage the asymptomatic dog with cardiac enlargement. However, these dogs do clearly have more significant disease and we believe that using enalapril (0.5 mg/kg orally twice a day) in an asymptomatic dog with obvious evidence of cardiac enlargement (left atrial and/or left ventricular enlargement) is beneficial. Since many of these cases will eventually progress to heart failure, the owners should be counseled to watch the dog for a cough or shortness of breath so that reevaluation occurs promptly if necessary. Dogs that are coughing due to left main stem bronchus compression can be extremely frustrating. A cough suppressant such as butorphanol or hydrocodone bitarate may be tried. An ACE inhibitor like enalapril might be tried to attempt to decrease afterload and potentially decrease the size of the atrium. If there is evidence of airway disease it may be beneficial to consider an anti-inflammatory dose of steroids. The owners should be advised that continual coughing is likely to occur, but if the cough gets worse or the patient becomes short of breath, immediate reevaluation may be needed so that they do not ignore the development of congestive heart failure. Therapy for congestive heart failure almost always requires a combination of medications including furosemide, an ACE inhibitor (enalapril, benazepril), and pimobenden. Occasionally additional medications like spironolactone (an aldosterone blocker) may be added. Some of these patients may develop a tachyarrhythmia (atrial fibrillation, ventricular tachycardia). This is particularly common in dogs with very large dilated atria and will complicate management of the case until the heart rate is controlled. Controlling the heart rate with digoxin and diltiazem should be strongly considered for comprehensive management. Finally, there is significant interest in surgical valve repair and valve replacement for affected dogs. Good success has occurred in Japan with a unique approach. Discussion of this for the very dedicated owner could be discussed with your local cardiologist before the disease has had significant progression.

15 1 Practical Genetics for Cardiac Disease Kathryn M. Meurs, DVM, PhD Diplomate ACVIM (Cardiology) Feline Heart Disease Feline heart disease may develop as the result of a variety of different etiologies including nutritional, infectious, endocrine and inherited among others. This discussion will focus on what is know about inherited heart disease in cats. Inherited congenital heart disease in the cat is not common. Endomyocardial fibrosis is characterized by left atrial and ventricular dilation with severe endocardial thickening. It has been shown to be inherited in the Siamese, Burmese breeds and domestic short hair cats. The most common adult onset disease is cardiomyopathy. There are several different forms of cardiomyopathy in the cat, although hypertrophic in the most common the form best shown to be inherited. Causative genetic mutations have now been identified in both the Ragdoll and the Maine Coon. A number of small families of cats with affected members have been reported in additional breeds including the Norwegian Forest cat, American shorthair, Siberian, Bengal and Scottish Fold, among others. A useful and frequently updated website for veterinarians and cat breeders interested in future developments in familial feline hypertrophic cardiomyopathy as well as other feline inherited diseases is maintained by the Feline Advisory Board Hypertrophic cardiomyopathy is the most common form of heart disease in the cat. It is an adult onset myocardial disease known to be inherited in the Maine Coon and Ragdoll breeds and thought to be inherited in Norwegian Forest, Siberian, Sphynx and Bengal cats among others. Causative genetic mutations have now been identified in the Maine Coon and Ragdoll. Hypertrophic cardiomyopathy is inherited as autosomal dominant trait in the Maine Coon. Autosomal dominant traits should have the following criteria: males and females are generally equally affected, every affected individual should have at least one affected parent, and the trait is generally observed in every generation. In the Maine Coon, a genetic mutation has been identified in the myosin binding protein C (MYBPC3) gene. Myosin binding protein C is the second most commonly mutated gene responsible for the human form of the disease. In the Maine Coon cat, the mutation is a single base pair change from a guanine to a cytosine in the 31 st codon of the gene. This mutation changes the structure of myosin binding protein C and alters the ability to interaction with other contractile proteins. The Maine Coon mutation appears to be quite breed specific. It is unlikely to be associated with hypertrophic cardiomyopathy in other breeds of cats unless they are closely related to the Maine Coon breed. A substitution mutation has also been identified in the myosin binding protein C gene in the Ragdoll cat. However, the Ragdoll mutation is different from the Maine Coon mutation and is a cytosine to thymine substitution in the 820 th codon. It is

16 extremely unlikely that the Maine Coon and Ragdoll mutations were inherited from a common ancestor since the mutations are different and are located in such different regions of the gene. Although the mode of inheritance of this mutation in the Ragdoll has not been identified through breeding studies, it is most likely an autosomal dominant trait as well. In the Ragdoll, homozygous cats appear to be very severely affected with development of heart failure and thromboembolic episodes often before 2 years of age. Heterozygous cats appear to have a much more mild form of the disease that may include only mild papillary muscle hypertrophy. The Ragdoll mutation also appears to be breed specific to the Ragdoll. Genetic testing is now available to test a cat for either mutation by submitting a DNA sample to a reputable screening laboratory. Good quality DNA samples can be obtained either from a blood sample in an EDTA tube or by brushing the oral gums of the cat with a special buccal swab, although many labs will even accept samples submitted on a cotton swab. The test results should verify that the cat is negative, heterozygous or homozygous for the mutation. Cats that test negative do not have the mutation. This does not mean that they cannot ever develop hypertrophic cardiomyopathy, it simply means that they will not develop the form of the disease caused by the specific genetic mutation. Although these mutations have been shown to be the cause of hypertrophic cardiomyopathy in many Maine Coons and Ragdoll cats, there are some cats that are echo positive for hypertrophic cardiomyopathy that do not have the specific mutations. Due to an apparently fairly high prevalence of the mutation in both breeds, it would seem to be unwise to recommend that all cats with the mutation be removed from the breeding programs since this could result in dramatically altering the genetic makeup of these breeds. Additionally, it should be emphasized that not all cats that have the mutation, particularly if they are heterozygous, will develop a clinical form of the disease. Our current recommendations for both breeds are to not use cats that are homozygous for the mutation for breeding purposes since they will certainly pass on the mutation and they have the highest risk of developing the disease. Heterozygous cats should be carefully evaluated. Cats that have many strong positive breed attributes and are disease negative at time of breeding could be bred to a mutation negative cat. Their lack of clinical disease may suggest that they have a less penetrant form of the disease or that they just do not show evidence of this adult onset clinical disease yet. Therefore these cats should only be used if they are exceptional for the breed and they should be clinically evaluated for the disease every year. If they develop the clinical disease, they should no longer be kept in the breeding program. The offspring of the mating of a positive heterozygous and a negative should be screened for the mutation, and if possible, a mutation negative kitten with desirable traits should be selected to replace the mutation positive parent in the breeding colony. Over a few generations this will decrease the prevalence of the disease mutation in the population, hopefully without greatly altering the genetic makeup of the breed too significantly. Finally, disease negative but mutation positive cats should be evaluated annually for presence of disease. 2

17 Canine Heart Disease The most commonly reported congenital heart defects in the dog include the patent ductus arteriosus (PDA), subaortic stenosis and pulmonic stenosis. The PDA has been demonstrated to have a familial origin in the poodle, subaortic stenosis has been demonstrated to be familial in the Newfoundland and pulmonic stenosis has been demonstrated to be familial in the beagle. The mode of inheritance has been difficult to ascertain and in many cases it may be a polygenic defect. Although an inherited nature has not been well documented in many of the other commonly identified predisposed breeds with these defects, caution should be relayed to owners that this may be simply due to a lack of investigation as opposed to a lack of evidence. The most commonly reported inherited heart diseases in the dog are cardiomyopathies. Dilated cardiomyopathy is characterized by cardiac enlargement and impaired systolic function of one or both ventricles. In human beings, the disease has been shown to be familial in at least 20-40% of the cases and causative mutations have been identified in twenty-four genes. Dilated cardiomyopathy appears to be familial in many breeds of dogs as well although significant variation in the presenting complaint, clinical evaluation and rate of progression has been observed depending on the breed of dog and there is likely to be genetic variation with regards to the mutation as well. Dilated cardiomyopathy in the Doberman pinscher appears to be familial. An autosomal dominant mode of inheritance has been defined. Evidence that the disease is familial and the suggestion that early intervention may increase survival has lead to significant interest in screening asymptomatic dogs for signs of occult disease. Annual echocardiography and ambulatory electrocardiography (Holter monitoring) are believed to be the best predictors of early DCM. Criteria that are believed to be indicators of occult disease include an echocardiographically determined left ventricular endiastolic diameter greater than 4.6 cm and a left ventricular end systolic diameter greater than 3.8 cm, even in the absence of systolic dysfunction. These numbers are based on average sized DCM dogs and may be less valid for very large dogs. Annual Holter monitoring has also been recommended to detect Doberman pinschers that may develop ventricular arrhythmias before ventricular dilation and systolic dysfunction. Adult Doberman pinschers with greater than 50 ventricular premature complexes (VPCs) per 24 hours, or with couplets or triplets are suspect for the development of DCM. Measurement of BNP or NT- probnp may also be useful for early detection of disease. Owners should be advised that since this is an adult onset disease with variability in the age of onset, screening tests should be performed annually. Since the early 1980 s, the term boxer cardiomyopathy has been used to describe adult boxer dogs that present with ventricular arrhythmias, and sometimes, syncope. Recent studies have demonstrated that the disease has many similarities to a human disease called Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The similarities between the diseases include clinical presentation, etiology and a fairly unique histopathology that includes a fibrous fatty infiltrate of the right ventricular free wall. The disease is most commonly characterized by ventricular arrhythmias, syncope and sudden death. However, systolic dysfunction and ventricular dilation are seen in a small percentage of cases. Arrhythmogenic right ventricular cardiomyopathy is a familial disease in the boxer and appears to be inherited as an autosomal dominant trait. Unfortunately, the disease 3

18 4 also appears to be a disease of variable genetic penetrance and affected dogs can have many different presentations including asymptomatic, syncope, sudden death and systolic dysfunction with CHF. A genetic mutation has now been identified for boxer arrhythmogenic right ventricular cardiomyopathy although it is not yet known if this will be responsible for all cases of the disease since in human beings there are several known mutations. Individuals interested in screening for the disease in breeding animals may do so with either a buccal swab or blood sample. In human beings with ARVC, there are multiple genetic mutations that can lead to the development of the disease. At this time we do not know if this mutation is the only cause in the Boxer, therefore, clinical screening is still recommended. Since ARVC presents as an electrical abnormality more often than one of myocardial dysfunction, screening efforts should be based on annual Holter monitoring as well as annual echocardiography. Unfortunately, clear criteria for the diagnosis of occult ARVC do not exist. However, dogs that are symptomatic (syncope, heart failure) or have evidence of ventricular tachycardia on a Holter should not be used for breeding. Additionally, dogs that have over 100 left bundle branch block morphology VPCs/24 hours are probably highly suspicious of being affected. However, not all affected dogs will ever develop clinical signs and many may live a normal lifespan. It is likely that there are multiple factors that may influence which dogs become symptomatic for the disease. To help decrease the risk of making an error when adding or removing a dog from a breeding program, owners should be encouraged to screen annually rather than putting significant emphasis on a single Holter monitor reading. Until a greater understanding of disease inheritance and disease progression exists, caution should be used when advising breeders to remove dogs from breeding programs. Overzealous removal of animals based on the results of a single Holter monitor may have a significant negative impact on the breed.

19 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 A Case-based Approach to the Feline Patient with vomiting and Increased Liver Enzymes (Part 1: Hepatic Lipidosis) Joseph Taboada, DVM, Dipl. ACVIM (Internal Medicine) School of Veterinary Medicine, Louisiana State University Baton Rouge, Louisiana Most of the noninvasive techniques used in evaluating the feline patient with suspected hepatobiliary disease, such as hepatic enzymology, liver function tests, and hepatobiliary imaging are useful in localizing disease to the liver or biliary system, however, they can rarely be used to establish a definitive diagnosis or an accurate prognosis. Invasive techniques are usually required for this purpose. Invasive (laparotomy, laparoscopic, ultrasound guided percutaneous, or blind percutaneous) techniques are necessary to obtain liver tissue for cytologic or histopathologic evaluation. Techniques for biopsy of the liver may require anesthesia, special equipment, and carry the risk of complications. Fine needle aspiration (FNA) can be utilized to obtain liver tissue for cytology. FNA of the liver is a relatively safe procedure that is simple to perform while requiring no special equipment and minimal patient sedation. Together with the rest of the diagnostic evaluation, FNA can be a useful tool in establishing a diagnosis and prognosis in selected patients with hepatobiliary disease. Additionally, it is a non-invasive technique that can be useful in deciding which subset of patients may require biopsy. Hepatic Ultrasonography and Ultrasound Guided Biopsy Ultrasonography is becoming more and more routine in the evaluation of the patient with hepatobiliary disease, especially in the referral setting. Indeed, the availability of ultrasound is often used by the primary care practitioner when making the decision whether or not to refer a patient. Hepatobiliary ultrasonography is readily available and often considered the noninvasive procedure of choice for trying to differentiate between primary hepatic and post-hepatic causes of cholestasis, for identifying portosystemic vascular anomalies, and for identifying focal or multifocal hepatobiliary abnormalities. Recent work has tried to correlate hepatic ultrasonographic images with histopathologic findings. Hepatic lipidosis in cats and hepatocutaneous syndrome (superficial necrolytic dermatitis, necrolytic migratory erythema) in dogs are examples of diseases where findings on hepatic ultrasonography are helpful in making a diagnosis. Care must be taken not to over-interpret results, however, because unfortunately, 2017 J.Taboada

20 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 there can be tremendous variability in the echogenic pattern produced by a given disease. It is usually difficult, if not impossible, to predict the histopathologic infiltrate from the echogenic pattern observed. One of the advantages of ultrasonographic evaluation of the liver is that ultrasound may be used to guide placement of needles for biopsy or FNA. This technique is especially useful when investigating focal or multifocal disease that might be missed by blind techniques. Biopsy guides are available for most transducers to facilitate ultrasound-guided biopsy. Visualization of the needle and biopsy site during the procedure may improve accuracy of biopsy and detection of complications. Ultrasound guided biopsy is widely considered safer than other biopsy techniques but studies supporting or refuting this contention are lacking. The small gauge needle used for biopsy in many of the percutaneous ultrasound guided techniques can be a limiting factor when trying to interpret hepatic biopsies obtained. Numerous liver biopsy techniques have been described. Blind percutaneous techniques are the simplest and most cost effective in many situations. There is a perception, however, that they are less accurate than other techniques and carry a higher risk of complication. Few studies have looked at the relative risk and diagnostic accuracy of percutaneous biopsy in the dog and cat. A 0% to 8.4% risk of complication has been reported in the few small studies reported. There was positive correlation between biopsy and necropsy findings in 80% of the cases in one study. In man, larger studies (189,085 people biopsied) have identified a complication rate of 0.28% and a mortality rate of 0.03%. Anemia and cancer would appear to be factors positively correlating with an increased risk of complication. Type of needle used, operator experience, biopsy technique (transabdominal vs. transthoracic), and platelet count are not. Hepatic Fine Needle Aspirate (FNA) Fine needle aspirate of the liver is simple and requires no special equipment. It can be performed with a 6- or 12-cc syringe and a 22-gauge, 1.5- to 3.5-inch disposable hypodermic or spinal needle. The 22-gauge spinal needle is useful in larger animals because of the longer sizes available but is rarely necessary when being used in cats. The needle is inserted into the liver via a percutaneous transabdominal (in cats and most dogs) or transthoracic approach (in large deep chested dogs) and gentle suction (3-5 ml) is applied. While maintaining suction, the needle is gently but quickly thrust into the liver parenchyma and then brought back to the original position without exiting the liver. The suction is then released and the needle is 2017 J.Taboada

21 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 withdrawn. If the technique is properly performed, blood will rarely be noted in the syringe or needle hub as the entire specimen should remain in the needle. To transfer the specimen to a clean glass slide detach the needle, draw a few milliliters of air into the syringe, reattach the needle, and gently expel the liver sample onto the slide. Do not forcibly "blow" the specimen onto the slide as this may damage the cells and result in preparation artifacts. Squash prep smears or blood film techniques may be used to smear hepatic samples. The transabdominal technique can be performed either in dorsal or right lateral recumbency with the pelvis of the animal positioned slightly lower than the head. I prefer lateral recumbency because patient restraint is generally easier. With the animal in lateral recumbency the needle is inserted at the point where the left costal arch begins its dorsal ascent. It is angled at about 45 O the body wall. The left caudal thoracic mammary gland is usually just ve ntral and slightly caudal to the point where the needle is to be inserted. Once the peritoneal cavity has been entered the needle is brought parallel to the body wall and slowly advanced while gently feeling down for the liver with the tip of the needle. Once the liver is felt the needle is again angled at 45 O, the needle tip is placed into the liver parenchyma, and the aspirate is performed. FNA is most useful in evaluating patients with hepatomegaly but it often gives valuable information in patients with normal sized livers as well Diffuse infiltrative, inflammatory, and neoplastic diseases lend themselves best to an FNA diagnosis. FNA is less applicable to focal or multifocal diseases or diseases in which cells do not exfoliate easily, such as fibrosis or sarcoma. Kristensen, et al. recently described a classification scheme for interpretation of hepatic cytology: their categories include normal, hyperplastic, inflammatory, degenerative, necrotic, cholestatic, neoplastic, mixed reactions, other reactions, and non-diagnostic. Hepatic Cytology The predominant cell type in a normal hepatic FNA is the hepatocyte, often found in cohesive clusters or regular sheets. Hepatocytes are large polyhedral to rounded cells with abundant gray to basophilic cytoplasm. They have a single (occasionally two) eccentric nucleus with uniformly course chromatin and a small, distinct nucleolus. The cytoplasm is usually granular with a small amount of green bile pigment occasionally present. Small columnar epithelial cells of biliary origin may also be observed. Low numbers of macrophages (Kupffer's cells) with or without intracellular hemosiderin are sometimes seen. Because of the highly 2017 J.Taboada

22 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 vascular nature of the hepatic sinusoidal milieu a background of erythrocytes and blood-borne leukocytes is invariably present. Degenerative diseases are characterized by cytoplasmic vacuolar changes. The differential diagnosis for hepatic vacuoles includes fat, glycogen, hydropic degeneration, and storage diseases. Feline hepatic lipidosis is the characteristic example of diseases of this type. In the dog, glycogen deposition associated with steroid hepatopathy or hydropic degeneration associated with an ischemic or toxic insult is more likely. Extracellular deposition of amorphous material is seen in hepatic amyloidosis. It is not uncommon to see mild hepatocellular vacuolization in cats with a large variety of chronic diseases so care must be taken in interpreting the finding vacuolar hepatopathy in this species. Inflammatory specimens are characterized by increased numbers of inflammatory cells interspersed between normal and/or reactive hepatocytes. The predominant inflammatory cell type characterizes the inflammation present. A definitive diagnosis can be made in some protozoal or systemic fungal diseases based on the presence of identifiable organisms. Histoplasmosis is the systemic fungal disease most likely to be diagnosed via hepatic FNA. One of the most useful applications of hepatic FNA is the diagnosis of hepatic neoplasia. Lymphosarcoma, biliary carcinoma, or metastatic neoplasias are the most likely hepatic tumors to be diagnosed. Because FNA is usually a blind tissue sampling technique it is most applicable when the clinical evaluation suggests diffuse parenchymal disease. Focal diseases are less likely to be diagnosed by blind aspirate techniques. The accuracy of hepatic FNA can be improved by obtaining multiple aspirates so at least 3 aspirates taken from slightly different angles should be routinely obtained. Complications of hepatic FNA are extremely rare. Bleeding is rarely a clinically significant problem even in animals with coagulation abnormalities. Using a blind technique to aspirate cells from the liver will occasionally result in inadvertent gall bladder aspiration. Aspiration of the gall bladder rarely causes serious problems for the patient. In fact, with ultrasound guidance the technique is routinely used to sample bile in cases of suspected cholangitis or liver fluke infestation. It should be noted that while FNA is a quick and easy technique, the sample does not always accurately reflect the underlying histopathologic diagnosis. Few studies have looked at correlation between FNA cytology and histopathology in the dog and cat. There was a 66% correlation in one study. The fact that correlation is not 100% stresses the point that care should be taken when interpreting results that do not seem to fit the presenting clinical picture. Liver biopsy is still often needed for definitive diagnosis J.Taboada

23 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 Feline Hepatic Lipidosis Feline hepatic lipidosis is the most common feline liver disease in many studies. It is characterized by massive hepatocellular accumulation of triglycerides accompanying a disruption in hepatic lipid metabolism that often results in severe liver dysfunction. Most cases are idiopathic but diabetes mellitus, prolonged starvation, over-nutrition, hyperthyroidism, and hyperparathyroidism are possible initiating causes. Female cats are affected almost twice as frequently as males. Chronic vomiting is the most common presenting sign. Anorexia, weight loss, icterus, and hypersalivation are also seen. Many affected cats are (or were) obese yet show significant muscle wasting at the time of diagnosis. Not all cats with hepatic lipidosis are obese. Total bilirubin, SAP, SALT, SAST, and GGT are usually increased (>2-5 times normal about 75% of the time). About half of affected cats will be hyperglycemic (glucose > 200 mg/dl). Abdominal radiographs may reveal mild hepatomegaly and ultrasound may reveal increased hepatic echogenicity. Diagnosis is dependent on demonstration of heavily vacuolated hepatocytes on fine needle aspirate or liver biopsy. Aggressive treatment is important. If an underlying disease process is evident it should be treated. General therapy should include treating dehydration, hypoglycemia (if present), hypokalemia, hypophosphatemia, and hepatoencephalopathy (lactulose 1-3 ml/cat adjust to maintain soft stool and metronidazole 7-10 mg/kg PO bid-tid). Vitamin K1 (0.5 to 1.5 mg/kg SQ) can be administered if cholestasis has resulted in a bleeding tendency. PIVKA will be increased if vitamin K1 is needed. Nutritional support is the most important aspect of therapy. Total caloric intake should be Kcal/kg/day. Protein supplementation is important. Diets based solely on carbohydrates may worsen the disease so moderate or even high protein diets such as Hills Prescription Diet p/d or a/d, Eukanuba Veterinary Diets Nutritional Recovery Formula /Canine & Feline, or Abbott Animal Health Clinicare Canine/Feline Liquid Diet or Clinicare RF should be used. Switch to a lower protein diet if signs of hepatoencephalopathy ensue. Dietary supplements that have been recommended but not critically evaluated in cats with hepatic lipidosis include l- carnitine ( mg/day), taurine ( mg/day), B-complex, zinc (7-10 mg/kg elemental Zn/day), and vitamin E ( mg/day). Force feeding or enteral feeding is invariably necessary to maintain appropriate caloric intake. Appetite stimulants may assist the owner who wishes to force feed their cat but will rarely result in enough of an increase in appetite to meet the nutritional needs appropriate to treatment goals. Cyproheptadine [Periactin ] 2 mg/cat, mirtazapine [Remeron ] 1/8 to ¼ of a 15 mg tablet per cat, and oxazepam [Serax ] 1 mg/kg 2017 J.Taboada

24 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 sid-bid may be used. Diazepam (0.1 ml IV) and Midazolam (2-5 mcg/kg IV) can also result in appetite stimulation. The effect of diazepam is usually short lived and causes significant sedation. Midazolam may cause a more lasting stimulation and less sedation. Care must be taken if benzodiazepines such as oxazepam or diazepam are used because they may worsen hepatoencephalopathy. Oral diazepam has been noted to occasionally be hepatotoxic. Enteral feeding will probably be needed in most cats with hepatic lipidosis. Esophagostomy, gastrostomy, or nasoesophageal feeding may all be used successfully. Gastrostomy and esophagostomy feeding is tolerated well by most cats. The tubes can be placed surgically or percutaneously via endoscopy or blind techniques. Enteral feeding may need to be continued for months in some cases. With aggressive nutritional support 75-95% of cats have a good prognosis while without aggressive nutritional support less than 10% of cats will do well. Pancreatitis as a concurrent disease process should be considered in cats not responding to therapy. Refeeding induced hypophosphatemia is a rare complication that can cause hemolysis or neurologic signs that may mimic hepatoencephalopathy. Feline Inflammatory Liver Disease Cholangitis and cholangiohepatitis is a complex of related inflammatory hepatobiliary disorders. They accounted for approximately 26% of the liver diseases reported in cats in one large retrospective study (Gagne, et al. JAVMA, 1999; 214:513). This was second to hepatic lipidosis which accounted for approximately 50% of the cases. Inflammatory liver diseases are characterized by the predominant inflammatory cell infiltrate seen histopathologically. The inflammation is usually seen in the portal areas; and can be characterized as suppurative (neutrophilic), non-suppurative (lymphocytic/plasmacytic); sclerosing lymphocytic cholangitis, or biliary cirrhosis (fibrosis). There have been many terms used in the veterinary literature to describe inflammatory liver diseases prompting the World Small Animal Veterinary Association (WSAVA) Liver Standardization Group to suggest standardized criteria for diagnosis of liver diseases of dogs and cats. The standards define three main forms of cholangitis which are recognized to occur in feline patients: neutrophilic cholangitis, lymphocytic cholangitis, and chronic cholangitis associated with liver fluke infestation. Cholangitis is often associated with periportal necrosis. Neutrophilic cholangitis can be further subdivided into acute (also termed suppurative by some authors) in which neutrophils are seen and chronic in which a mixture of neutrophils and lymphocytes/plasma cells are seen. Lymphocytic cholangitis (formerly lymphocytic portal hepatitis) is the term that has become accepted to describe the histologic 2017 J.Taboada

25 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 classification in which lymphocytes and/or plasma cells are noted to infiltrate the portal areas. This replaces the older term, lymphocytic/plasmacytic cholangiohepatitis. Lymphocytic cholangitis was more common than neutrophilic cholangitis; being seen in 61% of the cats with inflammatory liver disease in the study by Gagne, et al. Although other studies have noted that chronic neutrophilic cholangitis may be more common. Whether these classifications represent different stages in the progression of one disease or are separate etiologic entities is not known. Nor is the underlying etiology of inflammatory liver disease in cats. Bacterial, allergic, and immune mechanisms have all been speculated to be involved. Bacterial cholangitis may either initiate the inflammatory process or perpetuate it early in the disease course. Immune mechanisms probably also play a role especially in chronic neutrophilic cholangitis and lymphocytic cholangitis. Cats with inflammatory hepatobiliary disease, especially those with suppurative disease, may also have pancreatitis and inflammatory bowel disease. The relationship between these three inflammatory conditions is not well worked out but it has been speculated that the underlying initiator of the inflammatory process may affect the liver, the pancreas, and the small intestine concurrently. The term, triaditis has been coined to describe those situations in which inflammation of the liver, pancreas, and small intestine are seen to occur concurrently. While not a very accurate description, the term seems to have stuck. The clinical findings seen in cats with inflammatory liver disease are similar to those seen with hepatic lipidosis and other liver diseases. Vomiting, anorexia, lethargy, and weight loss are typical. Fever is occasionally seen. Diarrhea while not usual is more common than in cats with hepatic lipidosis and may represent the subset of cats with concurrent inflammatory bowel disease. Affected cats are rarely obese. Cats with neutrophilic cholangitis tend to be younger and are more likely to be severely systemically ill when compared to those cats with lymphocytic cholangitis. Any age cat can be affected. Males predominate in populations of cats with neutrophilic cholangitis as compared to those with lymphocytic cholangitis. Suppurative disease often has an acute course while disease characterized by lymphocytic/plasmacytic inflammation may be more chronic. In evaluating liver enzymes, alkaline phosphatase tends not to be as elevated as in cats with hepatic lipidosis and transaminase activities tend to be higher. It is important to note that liver enzymes can be normal, even in cats with significant hepatobiliary inflammation. Neutrophil counts, transaminase activities, and total bilirubin concentrations tend to be higher in cats with neutrophilic cholangitis when compared to cats with lymphocytic cholangitis. All liver enzymes may be normal early in the course of disease, however. Diagnosis is usually dependent on biopsy as FNA is often normal or reveals non J.Taboada

26 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 specific changes. Biopsy for both histopathology and culture should be performed if inflammatory liver disease is suspected. The advent of readily available ultrasonography has resulted in Tru-cut needle biopsy becoming the most popular method of obtaining tissue for histopathology. The diagnostic accuracy of Tru-cut obtained biopsies has been questioned (Cole, et al. JAVMA, 2002; 220: ). In the study by Cole, et al. liver biopsies obtained from dogs and cats by tru-cut techniques were compared to wedge biopsies. Paired 18 g Trucut needle biopsies commonly yielded a different diagnosis than wedge biopsy. If it is assumed that the wedge biopsy is the gold standard then the 18 g Tru-cut biopsies were highly inaccurate. Larger samples obtained with a 14 g needle may be more accurate. Laparoscopically obtained samples should be considered when feasible. Prior to biopsy, coagulation parameters should be evaluated. PIVKA may be the most sensitive indicator of potential bleeding tendencies. Vitamin K1 ( mg/kg SQ given within 24 hours of biopsy may decrease the risk of bleeding. In addition to the supportive and nutritional support used to manage cats with hepatic lipidosis, antibiotics should be used when treating cats with inflammatory liver disease. For patients with suspected loss of hepatic function, it is ideal to select drugs that rely on the kidneys for elimination rather than hepatic biotransformation. In the case of antibiotic therapy, the β-lactam antibiotics (penicillin, ampicillin, cephalosporins) are the best choice. (Hepatic reactions observed in people caused by amoxicillin-clavulanate were associated with a specific leukocyte antigen and have not been reported in animals.) The fluoroquinolones (enrofloxacin, marbofloxacin, orbifloxacin, difloxacin) have had a good safety record and increased risk of toxicity in animals with hepatic disease has not been documented. Although some of these drugs are metabolized, the clearance is low and probably not affected unless there is substantial loss of hepatic function. These drugs are also cleared by the kidneys. Fluoroquinolones have been known to cause central nervous system (CNS) problems in susceptible individuals. This is most likely caused by penetration across the blood-brain-barrier (BBB) and inhibition of the action of the GABA neurotransmitter. Problems observed have been seizures, excitement, and disorientation. Animals with seizure disorders caused by hepatic encephalopathy may be more prone to CNS problems caused by fluoroquinolones. If a complication is observed after prescribing a fluoroquinolone drug, a switch to a safer drug is appropriate. Macrolides (erythromycin, azithromycin, and similar drugs) are sometimes used for infections in animals with hepatic disease. There are no specific problems identified in patients with hepatic disease, but these antibiotics are often associated with gastrointestinal problems in 2017 J.Taboada

27 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 animals (diarrhea and vomiting). Therefore, when prescribing these drugs, veterinarians should be careful not to mistake a drug-related problem for an underlying disease, or complicate an already-existing problem. Metronidazole and related drugs (tinidazole, ronidazole) are sometimes used in patients with hepatic disease because of the anaerobic spectrum. They have been safe drugs when prescribed according to standard dose recommendations, but when doses have been exceeded, problems may arise. The most serious problem caused by metronidazole has been attributed to CNS toxicity and include seizures, ataxia, nystagmus, tremors, and rigidity. These signs have been attributed to inferring with the inhibitory neurotransmitter GABA. Because animals with hepatic disease also may be prone to CNS disorders that also share these clinical signs, veterinarians should understand the risks of metronidazole, and become familiar with the signs associated with toxicity. When using other antimicrobials, veterinarians should be aware of the common adverse effects that may occur if a drug accumulates because of a deficiency in metabolism. Drugs to avoid, if possible, include: trimethoprim-sulfonamides, tetracyclines, rifampin, nitrofurantoin, and chloramphenicol. Immunosuppressive agents should be added to the treatment regime in cats with lymphocytic disease and in cats with neutrophilic disease that fail to respond to antibiotics alone or antibiotics and nutraceuticals. Prednisolone (2-4 mg/kg/day initially then slowly tapered to 1 mg/kg QOD) is used most commonly. Other immunosuppressives that may be used in cats responding poorly to glucocorticoids include chlorambucil (1.5 to 4 mg/m 2 twice a week to every other day; approximately 1 mg < 7 lb cat, 2 mg > 7 lb cat) [probably a safer alternative to azathioprine in the cat], azathioprine (0.3 mg/kg q24-72 hrs) [Note that cats are much more sensitive to the myelosuppressive effects of azathioprine than dogs], methotrexate (0.4 mg divided into 3 doses and given over 24 hours and repeated every 7-10 days has been advocated as a pulse therapy but has not been extensively studied). Ursodeoxycholic acid (Actigall ) mg/kg PO SID is a safe treatment alternative that can be used in cats with either suppurative or non-suppurative disease. The drug appears to have multiple actions including shifting the bile acid pool to a less toxic hydrophilic population, a choleretic effect, reducing expression of Class 2 major histocompatibility complex, and an antiinflammatory effect. Vitamin E (aqueous alpha tocopherol, IU/kg/day) has been advocated for its antioxidant effects. SAMe ( mg PO SID; Denosyl NutraMax) is a precursor of glutathione. Glutathione is an important antioxidant that has been shown to be reduced in dogs and cats with liver disease. The nutriceutical SAMe may help replace glutathione. It also may have hepatoprotective effects in preventing programed cell death (apoptosis) that occurs during 2017 J.Taboada

28 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 inflammatory liver disease. Milk thistle (silymarin) is a nutriceutical that is widely used for its hepatoprotective effects. It may be of benefit as an antioxidant, as an antifibrotic agent, or as an aid in hepatic regeneration. Many studies have evaluated its use in people and show mixed results. Studies in dogs and cats are lacking. Anecdotal evidence would suggest it may be useful at a dose of mg/kg PO SID. NutraMax markets a product for cats, Marin, that is a combination of silybin and vitamin E. Silybin is one of the active ingredients in milk thistle. In Marin it is complexed with phosphatidylcholine to increase the bioavailability. The amount of vitamin E in the tablets is lower than is generally recommended in treating liver disease. A combination of silybin and SAMe is available as the nutriceutical Denamarin J.Taboada

29 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 A Case-based Approach to the Feline Patient with Liver Disease (Part 2: Inflammatory Liver Disease and Pancreatitis) Joseph Taboada, DVM, Dipl. ACVIM (Small Animal Internal Medicine) School of Veterinary Medicine, Louisiana State University Baton Rouge, Louisiana Pancreatitis is a common inflammatory disease that has historically probably been over diagnosed in dogs and under diagnosed in cats. It can be acute, recurring, or chronic. Acute necrotizing pancreatitis is most common in dogs. It is a pathophysiologic process in which intrapancreatic enzymes are activated resulting in increases in capillary permeability, initiating of vasoactive amines, and direct tissue damage. Vascular injury and tissue necrosis within the pancreas often extends locally to the stomach, duodenum, colon, and liver. Systemic inflammatory response syndrome (SIRS) is a common sequel. Acute necrotizing pancreatitis is seen less commonly than chronic pancreatitis in cats. Chronic pancreatitis is associated with inflammation and fibrosis. Pancreatic stellate cells appear to be important in the pathophysiology of chronic pancreatitis. Stimulated by oxidative stress and cytokines involved in the inflammatory process, activated stellate cells migrate to the periacinar areas to deposit collagen and fibronectin. The fibrosis contributes to obstruction of pancreatic ductules which in turn contributes to inflammation. Fibrosis appears to be important to the pathophysiology of disease in cats. The pathologic characteristics of feline pancreatitis appear to be similar to those in people; especially when compared to that of dogs. Signalment Any age or breed of cat or dog may develop pancreatitis. In the dog middle-aged, obese females are overrepresented. In cats most cases are domestic short-haired cats but Siamese and Persian cats may be overrepresented. Clinical signs The typical presentation in dogs includes sudden onset of vomiting, anorexia, depression, and abdominal pain. There is often a history of recent ingestion of a fatty meal or dietary indiscretion. Presenting clinical signs in cats include anorexia, lethargy, dehydration, hypothermia, and weight loss. Vomiting and abdominal pain are noted less frequently in cats 2017 J.Taboada

30 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 than in dogs with pancreatitis. Diarrhea is occasionally noted. Dogs and cats with severe pancreatitis may develop ascites and dyspnea associated with pleural effusion. Icterus is a variable finding. An abdominal mass may be noted and was noted in as many as a third of cats in some studies. This is probably representative of only those cats with very severe pancreatitis. Hypotension and shock are severe complications seen commonly in acute necrotizing pancreatitis. While usually idiopathic, pancreatitis has been associated with hyperlipoproteinemia and hypertriglyceridemia, cholinesterase inhibitors such as organophosphates, trauma resulting in hypoperfusion, and drugs such as thiazide diuretics, furosemide, estrogens, azathioprine, L-asparaginase, sulfonamides, tetracycline, metronidazole, H2-receptor blockers, acetaminophen, procainamide, and nitrofurantoin in dogs. In cats toxoplasmosis, FIP, hepatic lipidosis, liver and pancreatic flukes, lymphosarcoma, trauma, fenthion toxicity, idiopathic chylomicronemia, and diabetes mellitus have all been implicated. Potential risk factors for pancreatitis in dogs, such as obesity, dietary indiscretion, a high fat meal, high fat diets, and pre-existing endocrine diseases do not appear to be risk factors in cats. Diagnosis Hematology and serum biochemistry findings are generally non-specific. A mild normocytic, normochromic non-regenerative anemia and leukogram findings consistent with a stress or mild inflammatory leukogram are typical in cats. In dogs a more significant inflammatory leukogram and hemoconcentration would be more likely. A severe neutrophilia with a left shift is usually only seen in severe acute necrotizing pancreatitis. Thrombocytopenia may be noted and is usually mild. Increased ALT, AST, GGT, and alkaline phosphatase activities are typically noted. Bilirubin may be mildly increased but this is not a consistent finding. Dogs are often azotemic but cats are less likely to be azotemic than dogs with pancreatitis. Hyperglycemia is common and may be associated with stress or with the development of diabetes mellitus. The relationship between pancreatitis and diabetes mellitus is well documented in dogs but not well described in cats. However, cats with diabetes mellitus caused by chronic pancreatic inflammation appear to be very sensitive to insulin administration. Anorexia may result in hypokalemia. Hypocalcemia is common but it is rarely severe enough to cause clinical signs. Hypocalcemia may indicate a poor prognosis in cats with pancreatitis. Occasionally hypercalcemia may be noted. Hypoalbuminemia may be noted, especially in dogs and cats with severe disease or concurrent liver disease. Serum cobalamin is low in a high percentage of cats with pancreatitis J.Taboada

31 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 A lack of sensitive and specific markers of pancreatitis may make antemortem diagnosis of pancreatitis difficult, especially in cats. Serum amylase and lipase have long been used as screening tests for pancreatitis in dogs but are of little use in the diagnosis of pancreatitis in cats. Serum lipase is thought to be the better of the two enzymes for diagnosing pancreatitis in dogs because it is less likely to be increased in renal or other intraabdominal disease. That said, it is neither sensitive nor specific. Feline trypsin-like immunoreactivity (ftli) has been used as a test for pancreatitis in cats but has not proven sensitive. Feline TLI appears to increase acutely but returns to normal very early in the disease course in most cats making it less than ideal as a diagnostic test. It has been suggested that serum concentration of ftli > 100 µg/l is approximately 80-90% specific and 30-60% sensitive for feline pancreatitis. An abnormal result is therefore usually, but not always, associated with pancreatitis. Azotemia may increase ftli and increases have been noted in cats with severe inflammatory bowel disease. An immunoassay for measuring pancreatic lipase [pancreatic lipase immunoreactivity (PLI)] has been developed by the Texas A&M Gastrointestinal Diagnostic Laboratory and licensed to Idexx Laboratories. It is now considered to be the most sensitive and specific test for diagnosing pancreatitis in dogs and cats. Studies in cats with experimental pancreatitis would indicate that fpl increases rapidly after the development of pancreatitis and stays increased for much longer than ftli. In one published study (Forman et al., J Vet Inten Med 2004;18: ), fpl was found to be 80% sensitive for feline pancreatitis, but there was not a significant difference between cats with pancreatitis and healthy cats. The use of fpl is recommended in combination with abdominal ultrasound (see below). Commercial assays for measurement of cpli (Spec cpl ) and fpl (Spec fpl ) are based on the original cpli and fpli technology. The Spec fpl has become available through IDEXX Laboratories. Diagnostic Imaging Radiographs are usually non-specific. Decreased serosal detail may be noted if ascites is present. Decreased detail in the upper right quadrant on the ventrodorsal view may be noted but is seen less commonly in cats than in dogs with pancreatitis. A mass effect may be noted in severe cases. Pleural effusion may be noted on thoracic radiographs. Ultrasound of the pancreas in pancreatitis may reveal a mixed or hypoechogenic pattern, cavitary lesions, dilation of the pancreatic ducts, or evidence of peripancreatic edema and effusion. The pancreas may appear normal on ultrasound in many cats with pancreatitis, but a recent study (Forman et al.) found 80% sensitivity and 88% specificity for ultrasound in diagnosing feline pancreatitis J.Taboada

32 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 Because of the similar sensitivity and higher specificity of abdominal ultrasound vs. fpli found in this study, ultrasound could be considered the more useful diagnostic test. Further study is needed before firm recommendations can be made. Abdominal computed tomography (CT) has not been shown to be useful in diagnosing pancreatitis in cats. Biopsy The gold standard in diagnosis of pancreatitis is histopathology. Findings in cases of acute pancreatitis include peri-pancreatic fat necrosis, and focal to multifocal pancreatic acinar cell necrosis and inflammation. The inflammation can be quite variable making evaluation of multiple biopsies from different sites critical. Chronic pancreatitis is more common in cats and is usually characterized by variable degrees of fibrosis and lymphocytic inflammation. Fibrosis appears to be more important than inflammation in chronic pancreatitis in cats. The pancreas may appear grossly normal so biopsy is warranted even in cases where the pancreas appears normal at laparotomy or laparoscopy. In a recent study the prevalence of pancreatitis based on histopathology was 67% in cases with GI and other disease and 45% in apparently healthy cats. Treatment (Canine) Depending on the severity of the pancreatitis, treatment of dogs can at times be both difficult and frustrating. In most cases of canine pancreatitis a specific underlying etiology cannot be determined but if it is, specific treatment for that cause should be initiated. Treating shock, rehydration and maintenance of normovolemia are the initial goals of therapy. Fluids such as 0.9% NaCl or lactated Ringers should initially be given. Potassium should be added to the fluids to maintain normal potassium, and glucose should be added if hypoglycemia is noted. Maintaining pancreatic microcirculation may be enhanced by plasma (20ml/kg IV) or colloid (10-20ml/kg/day IV) administration. Plasma transfusion is widely recommended in veterinary medicine but has not been critically evaluated in dogs and cats with pancreatitis. Studies in human patients with pancreatitis have not shown an advantage of plasma therapy. Dextran 70 and hetastarch may have antithrombotic effects that help maintain the microcirculation in addition to their colloidal effects. An external source of heat may be necessary to treat hypothermia, especially in smaller dogs with a larger surface area to weight ratio. Antibiotics should be directed against a bacterial infection if one is suspected. Even if a primary bacterial infection is not suspected, a broad spectrum antibiotic should be given to minimize the effects of bacterial translocation. Abdominal pain is common so analgesics should be used as needed to 2017 J.Taboada

33 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 keep the patient comfortable. When pain is present, parenteral administration of opioid agonists such as hydromorphone, morphine, and fentanyl provide relief to most patients with severe pain. A fentanyl patch can be applied as an effective means of delivering analgesia in a dog that is likely vomiting. An epidural catheter can be placed for epidural delivery of analgesic medications or local anesthetic can be administered into the caudal thoracic space or cranial peritoneal cavity. Corticosteroids are indicated in acute pancreatitis only if shock is present. There is some controversy as to whether steroids may have negative effects on patients with pancreatitis but there is little convincing evidence that steroids are either helpful or detrimental except in situations such as shock. Immune-mediated pancreatitis, especially in association with systemic lupus erythematosus, is increasingly recognized as an important cause of pancreatitis in people, and steroid therapy has been shown to reduce mortality significantly in these patients. Primary immune-mediated pancreatitis has not been described in dogs and cats, but it should be considered that a definitive cause is not found in most dogs and cats with pancreatitis. Conventional therapeutic approach to patients with pancreatitis would indicate that the patient should be fasted to allow the pancreas to rest. Fasting should result in a physiologic state in which less pancreatic enzyme is being produced and released which may result in reduced pancreatic damage during periods of pancreatic inflammation. The conventional approach is to fast the patient until the clinical signs associated with the pancreatitis have stopped. In some cases the clinical signs may linger for quite some time and nutritional support may become indicated. Dogs are metabolically suited for long fasts and one should not be too quick to start feeding in canine patients with pancreatitis. If nutritional support is deemed necessary, however, ideally, jejunostomy tube feeding or TPN should be considered to reduce pancreatic activity. It should be noted that even when jejunostomy feeding or TPN is used pancreatic activity will be increased over the basal fasted state. The common practice of fasting dogs with pancreatitis is somewhat questionable. The underlying mechanism of pancreatic damage involves abnormally high levels of cholecystokinin, resulting in activation of digestive enzymes within the pancreatic parenchyma and suppression of pancreatic secretion. One could argue that feeding to restore more normal pancreatic secretion might be advantageous. In fact, large-scale studies in human pancreatitis have shown decreased morbidity and mortality when patients are not fasted. Some veterinary internists recommend feeding of dogs with pancreatitis unless vomiting prevents it, and the practice of fasting these patients should probably be reconsidered J.Taboada

34 Treatment (Feline) Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 Therapy for cats with pancreatitis is not well described or agreed upon. If a specific underlying etiology is noted it should be treated. Cats with acute necrotizing pancreatitis should be treated with fluids such as 0.9% NaCl or Lactated Ringers. Potassium should be added to the fluids to maintain normal potassium and glucose should be added if hypoglycemia is noted. Treating shock, rehydration and maintenance of normovolemia are the goals. Maintaining pancreatic microcirculation may be enhanced by plasma (20ml/kg IV) or colloid (10-20ml/kg/day IV) administration. Dextran 70 and hetastarch may have antithrombotic effects that help maintain the microcirculation. An external source of heat may be necessary to treat hypothermia. Antibiotics are indicated if bacterial infection or toxoplasmosis is suspected but are not necessary to prevent the bacterial translocation that appears to be common in dogs. Abdominal pain is not common so analgesics are not indicated in most cases. When pain is present, butorphanol ( mg/kg every 4 6 hours) can be given. Buprenorphine ( mg/kg SQ q6-12hrs) or oxymorphone ( mg/kg cats IM, SQ q1-3hrs can also be used but may have a negative effect on respiration. Non-steroidal antiinflammatory agents should probably not be used. Corticosteroids are indicated in acute pancreatitis only if shock is present. Corticosteroids may be indicated in cats with chronic pancreatitis and should be used if concurrent inflammatory bowel disease or liver disease is present. Because cobalamin deficiency is common, supplemental parenteral cobalamin should be considered. Injectable cobalamin can be administered at a dose of 250 ug subcutaneously once a week for 6 weeks, then every 2 weeks for 6 doses, then monthly. Most generic cobalamin preparations contain 1 mg/ml (1000 ug/ml). Most multi-vitamin and B-complex injectable formulations contain significantly lower concentrations of cobalamin. This practice of fasting the patient to rest the pancreas is more controversial in the cat because hepatic lipidosis can be a concurrent problem or a sequela to fasting. Ideally, jejunostomy tube feeding or TPN should be considered but if the patient is not vomiting gastrostomy tube, esophagostomy tube, or nasoesophageal tube feeding are probably appropriately used. Some authors would suggest that treatment indications include use of antioxidants such as vitamin E, SAMe, or Silybin. Supportive studies are lacking but the possible association with inflammatory liver disease and the mechanisms of actions of such nutraceuticals make their use logical. Feline Inflammatory Liver Disease Cholangitis and cholangiohepatitis is a complex of related inflammatory hepatobiliary 2017 J.Taboada

35 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 disorders. They accounted for approximately 26% of the liver diseases reported in cats in one large retrospective study (Gagne, et al. JAVMA, 1999; 214:513). This was second to hepatic lipidosis which accounted for approximately 50% of the cases. Inflammatory liver diseases are characterized by the predominant inflammatory cell infiltrate seen histopathologically. The inflammation is usually seen in the portal areas; and can be characterized as suppurative (neutrophilic), non-suppurative (lymphocytic/plasmacytic); sclerosing lymphocytic cholangitis, or biliary cirrhosis (fibrosis). There have been many terms used in the veterinary literature to describe inflammatory liver diseases prompting the World Small Animal Veterinary Association (WSAVA) Liver Standardization Group to suggest standardized criteria for diagnosis of liver diseases of dogs and cats. The standards define three main forms of cholangitis which are recognized to occur in feline patients: neutrophilic cholangitis, lymphocytic cholangitis, and chronic cholangitis associated with liver fluke infestation. Cholangitis is often associated with periportal necrosis. Neutrophilic cholangitis can be further subdivided into acute (also termed suppurative by some authors) in which neutrophils are seen and chronic in which a mixture of neutrophils and lymphocytes/plasma cells are seen. Lymphocytic cholangitis (formerly lymphocytic portal hepatitis) is the term that has become accepted to describe the histologic classification in which lymphocytes and/or plasma cells are noted to infiltrate the portal areas. This replaces the older term, lymphocytic/plasmacytic cholangiohepatitis. Lymphocytic cholangitis was more common than neutrophilic cholangitis; being seen in 61% of the cats with inflammatory liver disease in the study by Gagne, et al. Although other studies have noted that chronic neutrophilic cholangitis may be more common. Whether these classifications represent different stages in the progression of one disease or are separate etiologic entities is not known. Nor is the underlying etiology of inflammatory liver disease in cats. Bacterial, allergic, and immune mechanisms have all been speculated to be involved. Bacterial cholangitis may either initiate the inflammatory process or perpetuate it early in the disease course. Immune mechanisms probably also play a role especially in chronic neutrophilic cholangitis and lymphocytic cholangitis. Cats with inflammatory hepatobiliary disease, especially those with suppurative disease, may also have pancreatitis and inflammatory bowel disease. The relationship between these three inflammatory conditions is not well worked out but it has been speculated that the underlying initiator of the inflammatory process may affect the liver, the pancreas, and the small intestine concurrently. The term, triaditis has been coined to describe those situations in which inflammation of the liver, pancreas, and small intestine are seen to occur concurrently. While not a very accurate description, the term seems to have stuck J.Taboada

36 Diagnosis Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 The clinical findings seen in cats with inflammatory liver disease are similar to those seen with hepatic lipidosis and other liver diseases. Vomiting, anorexia, lethargy, and weight loss are typical. Fever is occasionally seen. Diarrhea while not usual is more common than in cats with hepatic lipidosis and may represent the subset of cats with concurrent inflammatory bowel disease. Affected cats are rarely obese. Cats with neutrophilic cholangitis tend to be younger and are more likely to be severely systemically ill when compared to those cats with lymphocytic cholangitis. Any age cat can be affected. Males predominate in populations of cats with neutrophilic cholangitis as compared to those with lymphocytic cholangitis. Suppurative disease often has an acute course while disease characterized by lymphocytic/plasmacytic inflammation may be more chronic. In evaluating liver enzymes, alkaline phosphatase tends not to be as elevated as in cats with hepatic lipidosis and transaminase activities tend to be higher. It is important to note that liver enzymes can be normal, even in cats with significant hepatobiliary inflammation. Neutrophil counts, transaminase activities, and total bilirubin concentrations tend to be higher in cats with neutrophilic cholangitis when compared to cats with lymphocytic cholangitis. All liver enzymes may be normal early in the course of disease, however. Diagnosis is usually dependent on biopsy as FNA is often normal or reveals nonspecific changes. Biopsy for both histopathology and culture should be performed if inflammatory liver disease is suspected. The advent of readily available ultrasonography has resulted in Tru-cut needle biopsy becoming the most popular method of obtaining tissue for histopathology. The diagnostic accuracy of Tru-cut obtained biopsies has been questioned (Cole, et al. JAVMA, 2002; 220: ). In the study by Cole, et al. liver biopsies obtained from dogs and cats by tru-cut techniques were compared to wedge biopsies. Paired 18 g Trucut needle biopsies commonly yielded a different diagnosis than wedge biopsy. If it is assumed that the wedge biopsy is the gold standard then the 18 g Tru-cut biopsies were highly inaccurate. Larger samples obtained with a 14 g needle may be more accurate. Laparoscopically obtained samples should be considered when feasible. Prior to biopsy, coagulation parameters should be evaluated. PIVKA may be the most sensitive indicator of potential bleeding tendencies. Vitamin K1 ( mg/kg SQ given within 24 hours of biopsy may decrease the risk of bleeding. Treatment In addition to the supportive and nutritional support used to manage cats with hepatic 2017 J.Taboada

37 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 lipidosis, antibiotics should be used when treating cats with inflammatory liver disease. For patients with suspected loss of hepatic function, it is ideal to select drugs that rely on the kidneys for elimination rather than hepatic biotransformation. In the case of antibiotic therapy, the β-lactam antibiotics (penicillin, ampicillin, cephalosporins) are the best choice. (Hepatic reactions observed in people caused by amoxicillin-clavulanate were associated with a specific leukocyte antigen and have not been reported in animals.) The fluoroquinolones (enrofloxacin, marbofloxacin, orbifloxacin, difloxacin) have had a good safety record and increased risk of toxicity in animals with hepatic disease has not been documented. Although some of these drugs are metabolized, the clearance is low and probably not affected unless there is substantial loss of hepatic function. These drugs are also cleared by the kidneys. Fluoroquinolones have been known to cause central nervous system (CNS) problems in susceptible individuals. This is most likely caused by penetration across the blood-brain-barrier (BBB) and inhibition of the action of the GABA neurotransmitter. Problems observed have been seizures, excitement, and disorientation. Animals with seizure disorders caused by hepatic encephalopathy may be more prone to CNS problems caused by fluoroquinolones. If a complication is observed after prescribing a fluoroquinolone drug, a switch to a safer drug is appropriate. Macrolides (erythromycin, azithromycin, and similar drugs) are sometimes used for infections in animals with hepatic disease. There are no specific problems identified in patients with hepatic disease, but these antibiotics are often associated with gastrointestinal problems in animals (diarrhea and vomiting). Therefore, when prescribing these drugs, veterinarians should be careful not to mistake a drug-related problem for an underlying disease, or complicate an already-existing problem. Metronidazole and related drugs (tinidazole, ronidazole) are sometimes used in patients with hepatic disease because of the anaerobic spectrum. They have been safe drugs when prescribed according to standard dose recommendations, but when doses have been exceeded, problems may arise. The most serious problem caused by metronidazole has been attributed to CNS toxicity and include seizures, ataxia, nystagmus, tremors, and rigidity. These signs have been attributed to inferring with the inhibitory neurotransmitter GABA. Because animals with hepatic disease also may be prone to CNS disorders that also share these clinical signs, veterinarians should understand the risks of metronidazole, and become familiar with the signs associated with toxicity. When using other antimicrobials, veterinarians should be aware of the common adverse effects that may occur if a drug accumulates because of a deficiency in metabolism. Drugs to avoid, if possible, include: trimethoprim-sulfonamides, tetracyclines, rifampin, nitrofurantoin, and chloramphenicol J.Taboada

38 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 Immunosuppressive agents should be added to the treatment regime in cats with lymphocytic disease and in cats with neutrophilic disease that fail to respond to antibiotics alone or antibiotics and nutraceuticals. Prednisolone (2-4 mg/kg/day initially then slowly tapered to 1 mg/kg QOD) is used most commonly. Other immunosuppressives that may be used in cats responding poorly to glucocorticoids include chlorambucil (1.5 to 4 mg/m 2 twice a week to every other day; approximately 1 mg < 7 lb cat, 2 mg > 7 lb cat) [probably a safer alternative to azathioprine in the cat], azathioprine (0.3 mg/kg q24-72 hrs) [Note that cats are much more sensitive to the myelosuppressive effects of azathioprine than dogs], methotrexate (0.4 mg divided into 3 doses and given over 24 hours and repeated every 7-10 days has been advocated as a pulse therapy but has not been extensively studied). Ursodeoxycholic acid (Actigall ) mg/kg PO SID is a safe treatment alternative that can be used in cats with either suppurative or non-suppurative disease. The drug appears to have multiple actions including shifting the bile acid pool to a less toxic hydrophilic population, a choleretic effect, reducing expression of Class 2 major histocompatibility complex, and an antiinflammatory effect. Vitamin E (aqueous alpha tocopherol, IU/kg/day) has been advocated for its antioxidant effects. SAMe ( mg PO SID; Denosyl NutraMax) is a precursor of glutathione. Glutathione is an important antioxidant that has been shown to be reduced in dogs and cats with liver disease. The nutriceutical SAMe may help replace glutathione. It also may have hepatoprotective effects in preventing programed cell death (apoptosis) that occurs during inflammatory liver disease. Milk thistle (silymarin) is a nutriceutical that is widely used for its hepatoprotective effects. It may be of benefit as an antioxidant, as an antifibrotic agent, or as an aid in hepatic regeneration. Many studies have evaluated its use in people and show mixed results. Studies in dogs and cats are lacking. Anecdotal evidence would suggest it may be useful at a dose of mg/kg PO SID. NutraMax markets a product for cats, Marin, that is a combination of silybin and vitamin E. Silybin is one of the active ingredients in milk thistle. In Marin it is complexed with phosphatidylcholine to increase the bioavailability. The amount of vitamin E in the tablets is lower than is generally recommended in treating liver disease. A combination of silybin and SAMe is available as the nutriceutical Denamarin. Concurrent pancreatitis, inflammatory bowel disease, and liver disease in cats Clinicians have noted an apparent relationship between inflammatory bowel disease, pancreatitis, and liver disease in cats. Damage to intestinal mucosal epithelial integrity occurs during inflammation such as that seen in IBD which may permit inflammatory mediators, 2017 J.Taboada

39 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 endotoxins, and microbial components access to the portal circulation. The concentration of these inflammatory mediators may exceed the capacity of hepatic macrophages to remove and degrade them resulting in deposition of immune complexes in the liver, complement system activation, and eventually hepatocellular inflammation and necrosis. The anatomic association between the common bile duct and the pancreatic duct may allow for ascending bacterial infections to affect both organs. While this association is often referred to, there is little objective evidence in the literature that documents it well. The relationship was confirmed in a study designed to determine whether cats with inflammatory hepatic disease had concurrent IBD, pancreatitis and interstitial nephritis. [Weiss DJ, et al. JAVMA 209:1114; 1996] In Weiss s study, the prevalence of IBD (83%) and pancreatitis (50%) was significantly greater for cats with cholangiohepatitis (suppurative cholangitis) compared to cats without inflammatory liver disease. However, the relationship was not apparent in cats with lymphocytic portal hepatitis (lymphocytic cholangitis). In studies of cats with pancreatitis, an association between hepatobiliary disease and pancreatitis has been observed. [Akol KG, et al. JVIM 15:327; 2001], [Hill RC, et al. JVIM 7:25; 1993], [Clark JEC, et al. JFMS 13:570; 2011] There appears to be a detrimental effect on prognosis for cats with both pancreatitis and hepatic lipidosis and pancreatitis and inflammatory liver disease. An association with inflammatory bowel disease was implied in Clark s study. In a study evaluating cats with subnormal serum concentrations of cobalamin, 22 of 49 cats had simultaneous presence of inflammatory disease of the intestines, pancreas, or hepatobiliary system. [Simpson KW, et al. JVIM 15:26; 2001] While none of these studies conclusively makes an association, the evidence is compelling that inflammatory disease can at times affect multiple gastrointestinal organs. Based on the limited data available it would appear that cats with pancreatitis that die are more likely to have multiple organ systems affected. Treatment of cats with concurrent inflammatory bowel disease and pancreatitis is generally based on management of the inflammatory bowel disease (or inflammatory liver disease). The effect of corticosteroids on cats with pancreatitis is not known but there is no evidence that steroids would have a detrimental effect in cases that are not of primary bacterial origin. In chronic pancreatitis, the anti-inflammatory effect of the corticosteroids may be of benefit for similar reason to the benefit achieved when treating inflammatory bowel disease or inflammatory liver disease. Steroids have long been considered a cause of pancreatitis in dogs, but a clear cause and effect relationship has not been established. It s possible that steroidinduced pancreatitis has been over-diagnosed in the past. Studies have shown that steroids 2017 J.Taboada

40 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 are associated with increases in serum amylase and lipase independent of any detectable pancreatic pathology. Nutritional support probably plays a more important role in the management of cats with concurrent inflammatory bowel disease and pancreatitis because of the potential association with hepatic lipidosis. Fasting cats with concurrent disease is not recommended J.Taboada

41 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 A Case-based Approach to the Canine Patient with Increased Liver Enzymes (Part 1) Joseph Taboada, DVM, Dipl. ACVIM School of Veterinary Medicine Louisiana State University Baton Rouge, Louisiana These lectures are interactive case-based presentation in which the audience will work through a series of cases that present for increased liver enzymes, with or without clinical signs. The first case is a young dog that presents for a yearly check-up, the second is an older dog that presents for gastrointestinal signs, and the third is a dog that has gotten into potentially hepatotoxic substances. The sessions will work through the diagnosis and treatment options for these cases. What would you do? INTRODUCTION Liver disease is a problem occasionally encountered in older animals with acquired liver disease and younger animals with both acquired and congenital disease. In some instances the underlying problem may have been caused by drug therapy. Many drugs commonly used in older pets have the potential to cause hepatic damage and inflammatory, immune mediated, and neoplastic liver diseases occur more frequently as an animal ages. In cats, hepatic lipidosis is common and inflammatory liver disease can occur singly or in combination with inflammation involving the gastrointestinal tract and/or the pancreas. Liver disease may be acute and resolve with proper management, or it may be a chronic, slowly-developing or waxing and waning condition. In dogs, chronic liver disease tends to progress to an eventual outcome of severe fibrosis or cirrhosis while in cats progressive disease rarely results in the same type of end stage changes. In either case, the disease may affect drug therapy. Managing the underlying disease relies on good supportive measures. There is no magic bullet that restores a failing or compromised liver. The clinical signs associated with liver disease are often vague leading one to suspect potential liver disease for the first time, only when a chemistry panel is evaluated and increased liver enzymes are noted. Unfortunately, increased liver enzymes are not specific for liver 2017 J.Taboada

42 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 disease; the liver often being affected as an innocent bystander to disease in other organ systems or liver enzymes being increased as an apparently incidental finding, especially in older animals. Metabolic disease such as hyperthyroidism or diabetes mellitus and gastrointestinal diseases such as inflammatory bowel disease and pancreatitis often result in increases in liver enzymes. Diseases resulting in adrenal gland hyperplasia and increases in either glucocorticoids or adrenal androgens also commonly present for increased liver enzymes. Suspecting liver disease Animals with liver disease usually show nondescript clinical signs such as anorexia, lethargy, weakness, and weight loss. Gastrointestinal signs such as vomiting and diarrhea are common. The signs may be severe in acute disease but tend to develop insidiously in chronic diseases. As chronic liver disease becomes end stage neurologic signs, most often characterized by depressive signs and behavior changes may be noted. Edema, most often noted as ascites, and evidence of bleeding due to coagulopathies may also be seen as liver disease becomes more chronic. In patients with cholestatic liver disease icterus may be noted. Icterus noted on physical exam is often a sign that leads the clinician to consider liver disease early in the evaluation of the older patient. The most common reason for a veterinarian to suspect liver disease is an increase is liver enzyme activities. A chemistry panel is a common part of the evaluation of older patients as part of routine senior care management, as a preanesthetic screen, or as part of the minimum database for a patient that presents ill. Increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or gamma-glutamyltransferase (GGT) activities are common findings. While they may be indicative of liver disease they are not predictive of hepatocellular disfunction. Increased transaminase activities (ALT, AST) are an indication of leakage of the hepatocellular enzymes from the hepatocytes. Increased serum activities may indicate hepatocellular membrane damage, hepatocellular necrosis, or increased hepatocellular enzyme concentration secondary to enzyme induction. Hepatocellular membrane damage is the most common reason for ALT and AST increases and may or may not indicate significant liver disease. It is common for animals with intestinal disease such as inflammatory bowel disease or metabolic diseases such as hyperthyroidism or diabetes mellitus to have increased transaminase activity. A complete drug history is important for patients with increased liver enzyme activities, as many drugs can damage hepatocellular membranes, induce inflammation or necrosis, or induce enzyme production. Questioning the pet owners about 2017 J.Taboada

43 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 treatment with such drugs as NSAIDs, corticosteroids, anticonvulsants, anthelmintics, antibiotics, imidazole antifungals, and antithyroid drugs is especially important. Increased alkaline phosphatase (ALP) activity may be induced by cholestasis. Increased gammaglutamyltransferase (GGT) activity represents similar changes. The clinically significant isoenzymes of ALP in cats are hepatic and bone derived. Additionally a corticosteroid-induced isoenzyme (C-ALP) is important in dogs. Pregnant queens may have increased ALP activity due to a placental isoenzyme. These isoenzymes have a half-life of approximately 72 hours in dogs but are significantly less in cats. Disease affecting the liver or biliary tree commonly increases concentrations of the hepatic isoenzyme of ALP. Disease increasing bone turnover increases osseous ALP and the presence of exogenous or endogenous corticosteroids induce increased concentrations of C-ALP in dogs. Even short courses of steroids can cause significant increases in C-ALP activity concentrations that may remain elevated for a month or more after the steroids are discontinued in dogs. Increased ALP activity is a common finding on the chemistry panel of older dogs. The hepatic isoenzyme becomes increasingly more important as dogs age. When seen without concurrently increased transaminase activity liver disease is probably less likely than steroid influences such as hyperadrenocorticism, exogenous steroid administration, or increased adrenal production of adrenal androgens. Regenerative changes common in older dogs may result in increased ALP activity but other poorly understood derangements of adrenal steroid hormones are increasingly being recognized as causes of ALP activity increase in older dogs. This finding is much less common in cats. Increased liver enzyme activities alone in a dog without clinical signs or other blood work abnormalities consistent with liver disease should not automatically be considered evidence of significant hepatocellular damage. Increased liver enzyme activities in a cat is a more significant finding and should lead to earlier evaluation but may still not represent significant hepatocellular disease. When increased liver enzyme activities are noted, other parts of the chemistry panel that may become abnormal in animals with hepatocellular disfunction should be scrutinized carefully. Increased bilirubin or decreased albumin in the patient with increased liver enzyme activities should cause the clinician to thoroughly evaluate the patient for liver disease. Decreased BUN or hypoglycemia may be signs of reduced hepatic function but are more commonly noted in young animals with portosystemic vascular anomalies than in older animals with acquired liver disease. If the rest of the chemistry panel is normal and the patient is 2017 J.Taboada

44 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 otherwise healthy the panel should be repeated in 1 to 3 months. Persistent increases or other evidence of liver disease should cause the clinician to consider further evaluation. Increased liver enzyme activities does not necessarily indicate reduced hepatic function so a test of liver function should be considered as part of the further evaluation of the patient with suspected liver disease. Fasting and postprandial serum bile acids are the most commonly used liver function test in dogs and cats. Fasting blood ammonia or ammonia tolerance testing are liver function tests that are also sensitive and specific. Evaluating blood ammonia is the preferred test in animals with signs of hepatoencephalopathy or in icteric animals where cholestasis will have an impact on serum bile acid concentrations. Although these tests may identify loss of hepatic function, they do not correlate well with measurements of drug clearance. Diagnosing most specific liver diseases is dependent on a tissue diagnosis; a step that can be invasive and expensive. Hepatic cytology can be used to guide the clinician but cytology can be misleading when compared to histopathology. It may be useful in infiltrative diseases such as hepatic lipidosis or neoplasia but is generally less helpful in the diagnosis of inflammatory and fibrosing conditions or in vascular diseases such as portosystemic shunts. Because of the higher prevalence of infiltrative diseases in the cat, feline liver diseases lend themselves to cytologic diagnosis more than canine diseases do J.Taboada

45 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 A Case-based Approach to the Canine Patient with Increased Liver Enzymes (Part 2): Clinical Update on the Use of Nutraceuticals in the Management Liver Disease Joseph Taboada, DVM, DACVIM Department of Veterinary Clinical Sciences School of Veterinary Medicine Louisiana State University Baton Rouge, Louisiana INTRODUCTION Liver disease is a problem occasionally encountered in small animal practice. In some instances the underlying problem may have been caused by drug therapy or exposure to hepatotoxic compounds such as xylitol or sago palm. Inflammatory, immune mediated, and neoplastic liver diseases occur more frequently as an animal ages and congenital disease such as PSS may be seen in younger animals. Bacterial infections are occasionally seen. In cats, hepatic lipidosis is common and inflammatory liver disease can occur singly or in combination with inflammation involving the gastrointestinal tract and/or the pancreas. Liver disease may be acute and resolve with proper management, or it may be a chronic, slowly-developing or waxing and waning condition. In dogs, chronic liver disease tends to progress to an eventual outcome of severe fibrosis or cirrhosis while in cats progressive disease rarely results in the same type of end stage changes. Oxidative damage is present in most forms of liver disease. Managing the underlying disease relies on good supportive measures and management of oxidative damage. There is no magic bullet that restores a failing or compromised liver. There are a number of compounds classified as nutraceuticals that have proven effective in supporting the diseased or damaged liver. EVALUATING THE PATIENT WITH SUSPECTED LIVER DISEASE The clinical signs associated with liver disease are often vague, leading one to at times suspect potential liver disease for the first time only when a chemistry panel is evaluated and increased liver enzyme activities or total bilirubin are noted. Unfortunately, increased liver enzyme activity is not specific for liver disease; the liver often being affected as an innocent bystander to disease in other organ systems or liver enzymes being increased as an apparently 2017 J.Taboada

46 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 incidental finding; especially in older animals. Metabolic disease such as hyperthyroidism, hyperadrenocorticism, diabetes mellitus, or hepatocutaneous syndrome and gastrointestinal diseases such as inflammatory bowel disease and pancreatitis often result in increases in liver enzymes. Diseases resulting in adrenal gland hyperplasia and increases in either glucocorticoids or adrenal androgens also commonly present for increased liver enzyme activities. Clinical signs may be nondescript such as anorexia, lethargy, weakness, and weight loss. Gastrointestinal signs such as vomiting (and less often diarrhea) are common. The signs may be severe in acute disease but tend to develop more insidiously in chronic disease. As chronic liver disease becomes end stage neurologic signs, most often characterized by depressive signs and behavior changes, may be noted. Edema, most often noted as ascites, and evidence of bleeding associated with coagulopathies may be seen as liver disease becomes more chronic. In patients with cholestatic liver disease icterus may be noted. The most common reason for a veterinarian to suspect liver disease is an increase is liver enzyme activity. Increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) activities are common findings that may be indicative of liver disease but are not predictive of hepatocellular dysfunction. Increased transaminase activities are an indication of leakage of the hepatocellular enzymes from the hepatocytes. Increased serum activities may indicate hepatocellular membrane damage, hepatocellular necrosis, or increased hepatocellular enzyme concentration secondary to enzyme induction. Membrane damage is the most common reason for ALT and AST increases and may or may not indicate significant liver disease. It is common for animals with intestinal disease such as inflammatory bowel disease or metabolic diseases such as hyperthyroidism or diabetes mellitus to have increased transaminase activity. A complete drug history is important for patients with increased liver enzyme activities, as many drugs can damage hepatocellular membranes, induce inflammation or necrosis, or induce enzyme production. Questioning the pet owners about treatment with such drugs as NSAIDs, corticosteroids, anticonvulsants, anthelmintics, antibiotics, imidazole antifungals, and antithyroid drugs is especially important. Increased alkaline phosphatase (ALP) or gamma-glutamyltransferase (GGT) activity may be induced by cholestasis. The clinically significant isoenzymes of ALP are hepatic and bone derived in dogs and cats and corticosteroid-induced (C-ALP) in dogs. These isoenzymes have a half-life of approximately 72 hours in dogs but are significantly less in cats. Disease affecting the liver or biliary tree commonly increases activities of the hepatic isoenzyme of ALP. Disease increasing bone 2017 J.Taboada

47 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 turnover increases osseous ALP activity, and the presence of exogenous or endogenous corticosteroids induces increased activities of C-ALP in dogs. Even short courses of steroids can cause significant increases in C-ALP activity that may remain increased for a month or more after the steroids are discontinued. Increased ALP activity is a common finding on the chemistry panel of older dogs. The hepatic isoenzyme becomes increasingly more important as dogs age. When seen without concurrently increased transaminase activity liver disease is probably less likely than steroid influences such as hyperadrenocorticism, exogenous steroid administration, or increased adrenal production of adrenal androgens. Regenerative changes common in older dogs may result in increased ALP activity but other poorly understood derangements of adrenal steroid hormones are increasingly being recognized as causes of ALP activity increase in older dogs. Increased liver enzyme activities alone in a dog without clinical signs or other blood work abnormalities consistent with liver disease should not automatically be considered evidence of significant hepatocellular damage. Increased liver enzyme activities in a cat are a more significant finding and should lead to earlier evaluation but may still not represent significant hepatocellular disease. When increased liver enzyme activities are noted, other parts of the chemistry panel that may become abnormal in animals with hepatocellular dysfunction should be scrutinized carefully. Increased bilirubin or decreased albumin in the patient with increased liver enzyme activities should cause the clinician to thoroughly evaluate the patient for liver disease and consider treatment. Decreased BUN or hypoglycemia may be signs of reduced hepatic function but are more commonly noted in young animals with portosystemic vascular anomalies than in older animals with acquired liver disease. If the rest of the chemistry panel is normal and the patient is otherwise healthy the panel should be repeated in 1 to 3 months. Persistent increases or other evidence of liver disease should cause the clinician to consider further evaluation. Increased liver enzyme activities does not necessarily indicate reduced hepatic function so a test of liver function should be considered as part of the further evaluation of the patient with suspected liver disease. Fasting and postprandial serum bile acids are the most commonly used liver function test in dogs and cats. Fasting blood ammonia or ammonia tolerance testing are liver function tests that are also sensitive and specific. Evaluating blood ammonia is the preferred test in animals with signs of hepatoencephalopathy or in icteric animals where cholestasis will have an impact on serum bile acid concentrations. Because the liver produces most of the clotting factors and other cofactors involved in coagulation it is common for patients 2017 J.Taboada

48 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 with decreased liver function to have abnormalities of tests of coagulation such as PT, PTT, ACT, and PIVKA. Although these tests may identify loss of hepatic function, they do not correlate well with measurements of drug clearance. Diagnosing most specific liver diseases is dependent on a tissue diagnosis; a step that can be invasive and expensive. Hepatic cytology can be used to guide the clinician but cytology can be misleading when compared to histopathology; especially in the dog. It may be useful in diffuse or infiltrative diseases such as hepatic lipidosis or neoplasia but is generally not helpful in the diagnosis of inflammatory and fibrosing conditions. Because of the higher prevalence of diffuse or infiltrative diseases in the cat, feline liver diseases lend themselves to cytologic diagnosis more than canine diseases do. TREATMENT CONSIDERATIONS In addition to supportive and nutritional support, antimicrobials, antiinflammatories, and immunosuppressive therapy play a role in managing dogs and cats with liver disease. Nutraceuticals may play an important role for their antioxidative, anti-inflammatory and immunosuppressive properties. For patients with suspected loss of hepatic function, it is ideal to select drugs that rely on the kidneys for elimination rather than hepatic biotransformation. In the case of antibiotic therapy, the β-lactam antibiotics (amoxicillin-clavulanate, ampicillin, cephalosporins) and fluoroquinolones are the best choice. (Hepatic reactions observed in people caused by amoxicillin-clavulanate were associated with a specific leukocyte antigen and have not been reported in animals.) The fluoroquinolones (enrofloxacin, marbofloxacin, orbifloxacin, difloxacin) have had a good safety record and increased risk of toxicity in animals with hepatic disease has not been documented. Although some of these drugs are metabolized, the clearance is low and probably not affected unless there is substantial loss of hepatic function. These drugs are also cleared by the kidneys. Fluoroquinolones have been known to cause central nervous system (CNS) problems in susceptible individuals. This is most likely caused by penetration across the blood-brain-barrier (BBB) and inhibition of the action of the GABA neurotransmitter. Problems observed have been seizures, excitement, and disorientation. Animals with seizure disorders caused by hepatoencephalopathy may be more prone to CNS problems caused by fluoroquinolones. If a complication is observed after prescribing a fluoroquinolone drug, a switch to a safer drug is appropriate. Macrolides (erythromycin, azithromycin, and similar drugs) are sometimes used for infections in animals with hepatic disease. There are no specific problems identified in patients 2017 J.Taboada

49 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 with hepatic disease, but these antibiotics are often associated with gastrointestinal problems in animals (diarrhea and vomiting). Therefore, when prescribing these drugs, veterinarians should be careful not to mistake a drug-related problem for an underlying disease, or complication an already-existing problem. Metronidazole and related drugs (tinidazole, ronidazole) are sometimes used in patients with hepatic disease because of the anaerobic spectrum. They have been safe drugs when prescribed according to standard dose recommendations, but when doses have been exceeded, problems may arise. The most serious problem caused by metronidazole has been attributed to CNS toxicity and include seizures, ataxia, nystagmus, tremors, and rigidity. These signs have been attributed to inferring with the inhibitory neurotransmitter GABA. Because animals with hepatoencephalopathy also may be prone to CNS signs that may be similar to those seen with metronidazole toxicity, veterinarians should become familiar with the signs associated with toxicity. When using other antimicrobials, veterinarians should be aware of the common adverse effects that may occur if a drug accumulates because of a deficiency in metabolism. Drugs to avoid, if possible, include: trimethoprim-sulfonamides, tetracyclines, rifampin, nitrofurantoin, and chloramphenicol. Immunosuppressive agents should be added to the treatment regime in cats with nonsuppurative hepatic inflammation, in cats with suppurative hepatic disease that fail to respond to antibiotics alone, and dogs with inflammatory hepatopathies in which secondary fibrotic changes are occurring. Prednisolone (2-4 mg/kg/day initially then slowly tapered to 1 mg/kg QOD) is used most commonly. Other immunosuppressives that may be used in cats responding poorly to glucocorticoids include chlorambucil (1.5 to 4 mg/m 2 twice a week to q48 hrs; approximately 1 mg < 7 lb cat, 2 mg > 7 lb cat) [probably a safer alternative to azathioprine in the cat] or azathioprine (0.3 mg/kg q24-72 hrs) [Note that cats are much more sensitive to the myelosuppressive effects of azathioprine than dogs]. Azathioprine (1-2 mg/kg PO q24h to q48h) may be a more appropriate agent in dogs although a study comparing chlorambucilprednisolone combination with an azathioprine-prednisolone combination in the treatment of dogs with chronic protein-losing enteropathy suggested that chlorambucil may be more efficacious. Cyclosporine (5 mg/kg PO q24h) has been used with some success in dogs with inflammatory liver disease and may be effective without concurrent prednisolone reducing steroid-induced complications and making it easier to follow liver enzymes as an indicator of treatment efficacy. Ursodeoxycholic acid (Actigall ) mg/kg PO SID is a safe treatment alternative that can be used in cats with suppurative or non-suppurative disease. The drug appears to have multiple actions including shifting the bile acid pool to a less toxic hydrophilic 2017 J.Taboada

50 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 population, a choleretic effect, reducing expression of Class 2 major histocompatibility complex, and an antiinflammatory effect. Vitamin E (aqueous alpha tocopherol, IU/kg/day) has been advocated for its antioxidant effects. NEUTRACEUTICALS Neutraceuticals such as vitamin E, milk thistle extracts, S-adenosylmethionine, and L- carnitine can play a significant role in ameliorating oxidative stress. Oxidative stress plays an important role in hepatocellular injury and injury perpetuation during liver disease; especially inflammatory liver disease and hepatocellular toxicity. Oxidative stress is defined as an imbalance between oxidant and antioxidant systems (such as an excess of reactive oxygen species [ROS] or a deficiency in antioxidants). The liver possesses a complex antioxidant network that can be divided into enzymatic and nonenzymatic pathways. Nonenzymatic defenses include glutathione (GSH), vitamin E, and ascorbate. GSH is one of the most critical parts of the liver defense against the effects of oxidative stress and is an important site of neutraceutical activity. N-acetylcysteine N-acetylcysteine is a stable formulation of the amino acid L-cysteine. It can be given parenterally to replenish intracellular cysteine and GSH levels. N-acetylcysteine is primarily recognized as an antidote for acetaminophen-induced red blood cell and hepatocyte toxicity. It has been evaluated and shown benefit in models of acute liver failure where positive cytoprotective effects are primarily mediated through increased GSH concentrations. Additionally N-acetylcysteine improves sinusoidal microcirculation, increases the efficiency of oxygen delivery, and decreases inflammation. High level evidence is available showing improved survival in children with acute liver failure. The recommendation in acute liver failure in dogs and cats is the same as for acetaminophen toxicity. It is to give an initial dose of 140 mg/kg followed by doses of 70 mg/kg intravenously every 6 hours for seven treatments. N- acetylcysteine should be administered through a nonpyrogenic filter (0.25 mm) using a 10% solution diluted 1:2 or more with saline. Oral administration often results in gastrointestinal irritation and vomiting. If a patient can tolerate oral medications it is better to give SAMe or SAMe and Silybin combinations. Indications for N-acetylcysteine use in veterinary medicine include acetaminophen toxicity, Heinz body anemia, suspected toxin-related liver injury, and acute liver failure (regardless of underlying etiology) J.Taboada

51 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 S-adenosylmethionine (SAMe) S-adenosylmethionine (SAMe) is generated from L-methionine and ATP in a two-step reaction catalyzed by methionine adenosyltransferase (MAT). The activity of this enzyme is decreased in many types of liver disease, which results in decreased concentrations of SAMe in the hepatocyte. SAMe is an important intermediate in the metabolism of methionine to GSH. SAMe has been shown to have important cytoprotective effects that include antioxidant activity through augmentation of hepatocyte GSH levels, modification of the balance between pro- and anti-inflammatory cytokine expression, alterations in DNA/histone methylation, improvement in membrane fluidity, modulation of apoptosis, by reducing TNF-alpha induced necrosis, and decreasing malignant transformation of hepatocytes. SAMe has been evaluated in a number of animal models of liver disease, experimental liver insult, and human clinical trials and has shown to be effective in treating a number of different hepatocellular toxicities (alcohol, acetaminophen, galactosamine, pyrazole, and thioacetarsamide induced hepatotoxicity) as well as cholestatic liver disease and alcoholic cirrhosis in humans. It has been shown to significantly increase hepatic GSH concentrations in healthy dogs and cats and to reduce acetaminophen induced hepatic and red blood cell damage in cats (85 mg/kg for 3 days followed by 40 mg/kg) and dogs (40 mg/kg followed by 20 mg/kg). SAMe is available commercially as a stable tosylate salt complex (Denosyl, Nutramax Laboratories, Inc., Lancaster, South Carolina; Zentonil, Vetoquinol, Buena, New Jersey). Tablets are blister packed and enteric coated because SAMe is hygroscopic and sensitive to light and heat. The tablets must not be split or crushed. Food interferes with absorption, requiring that SAMe be given on an empty stomach. Denosyl is also available in a chewable form in which the SAMe itself is protected by a granular barrier. While it still needs to be given on an empty stomach, a more consistent absorption is seen in dogs with the chewable formulation versus the enteric coated tablet. The recommended oral dose is 20 mg/kg/d. SAMe is well tolerated when given orally with mild gi signs being occasionally reported. While trials in dogs and cats with hepatic disease have not been conducted, work in humans and other animal models would predict that there may be value in using SAMe in the management of disorders such as acute intrahepatic or extrahepatic cholestatic disorders, necroinflammatory diseases such as feline cholangitis or canine inflammatory liver disease, metabolic diseases such as feline hepatic lipidosis or hepatic copper toxicosis, and toxic or ischemic hepatopathies. SAMe may have additive or synergistic effects when used with ursodeoxycholic acid J.Taboada

52 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 Milk Thistle Extracts The major active ingredient of benefit in milk thistle is silymarin; a group of several closely related flavinoids, primarily silybin, isosilybin, silydianin, and silychristin. Silybin is a major active component of silymarin. Silymarin has been shown to have antioxidant, antiinflammatory, and antifibrotic activities in the treatment of patients with liver disease. Additionally, it has choleretic effects and is hepatoprotective following exposure to a number of different hepatotoxins, including acetaminophen, CCNU, ethanol, carbon tetrachloride, aflatoxin, Amanita phalloides toxins and others. Silybin was found to be completely protective against A. phalloides intoxication in Beagles at a dose of 50 mg/kg when given 5 and 24 hours after ingesting an LD50 dose of A. phalloides. Silymarin s bioavailability is low due to erratic absorption from the gastrointestinal tract. It is excreted in bile as a glucuronide and sulfo-glucuronide conjugate and undergoes some enterohepatic circulation. Bile concentrations are 100 times those seen in serum. Silybin complexed with phosphatidylcholine, is three to five times more bioavailable than silymarin. Phosphatidylcholine also may have antifibrotic effects. Silybin complexed with phosphatidylcholine is the form used in the Nutramax products Marin (combined product with vitamin E and zinc), Marin plus (combined with vitamen E, zinc, and Curcumin longa extract), and Denamarin (combined with SAMe). A dose of 6 mg/kg of silybin-phosphatidylcholine complex is recommended. Toxicity studies in dogs and cats as well extensive use in humans have not shown any untoward effects. Reports of gastrointestinal signs in dogs taking the Nutramax product Marin may be associated with the Zinc in the combination and recommendations that Marin be taken with food have been made to reduce the potential for gastrointestinal signs. Silymarin may have benefit in cases of hepatotoxicity, hepatobiliary disease associated with cholestasis, and chronic necroinflammatory hepatopathies. Silymarin use is indicated in the treatment of Amanita mushroom toxicity, although high doses are needed to inhibit uptake of the phalloidin toxin. The combination product that is Marin plus contains Curcumin in addition to Vitamin E, Zinc, and Silybin-phosphatidylcholine. Curcumin has shown to protect liver against hepatic injury and fibrogenesis by suppressing hepatic inflammation, attenuating hepatic oxidative stress, and increasing expression of the xenobiotic detoxifying enzymes. This combination product is less expensive than Denamarin and has been suggested for patients that need support for oxidative injury but cannot afford Denamarin J.Taboada

53 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 SAMe and Silybin Combined Nutramax markets a combined product, Denamarin, that includes both silybin complexed with phosphatidylcholine and SAMe in enteric coated and chewable tablets. The product is ideally given on an empty stomach to maximize SAMe absorption. A prospective randomized controlled trial in dogs receiving CCNU with or without Denamarin showed decreased liver enzyme activities and potentially reduced hepatotoxicity associated with dogs in the CCNU Denamarin group and a higher percentage of dogs receiving Denamarin finishing the chemotherapy protocol. The results of this study beg the question as to whether Denamarin would have similar cytoprotective effects in treatment protocols with other potentially hepatotoxic drugs in dogs. Vitamin E Vitamin E is an essential nutrient made up of a family of highly lipophilic antioxidant compounds, the most bioavailable and active of which is Alpha-tocopherol. It plays a number of important protective roles, the most important of which is the protection of membrane phospholipids from oxidative damage. It suppresses activation of inflammatory cytokines and of activation of Kupffer and stellate cells. The effects of vitamin E supplementation in veterinary patients with hepatobiliary disease have not been reported except for a small pilot study of 20 dogs with chronic hepatitis fed a vitamin E supplemented diet for 3 months. In these dogs, increases in serum and hepatic vitamin E concentrations were accompanied by an increased hepatic GSH:GSSG ratio, suggestive of an improved hepatic redox status. A dose of 10 to 15 IU/kg/d of alpha-tocopherol is recommended for dogs and cats that have necroinflammatory or cholestatic liver disorders. Probiotics: Do they have a place in treating liver disease Much is being learned about the intestinal microbiota and the influences that changes in the microbiota (dysbiosis) can have on the gastrointestinal tract and the liver. The liver is an important first pass organ impacting toxins, nutrients, bacterial metabolites, and bacteria that translocate across the gastrointestinal mucosa. The role of microbiota in liver disease largely derives from the inflammatory pathway that is triggered from the interaction between gut bacteria, the liver, and the immune system. These changes may result in increased bacterial metabolites and cytokines such as lipopolysaccharides, peptidoglycans, toll-like receptor 2017 J.Taboada

54 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 agonists, and bacterial DNA that can have an impact on hepatocellular health. Increased oxidative stress and hepatocellular inflammation may result in a self-perpetuating pattern of inflammation and fibrosis or in metabolic liver disease such as non-alcoholic fatty liver disease (NAFLD/NASH) in people. Manipulation of the microbiota may have an effect of reducing oxidative stress and decreasing inflammation, decreasing fibrosis, and reducing clinical signs of hepatoencephalopathy. Administration of Lactobacillus spp and Bifidobacterium spp have been shown to improve hepatic function and hepatic biomarkers in humans and rodent models of alcoholic liver disease, NAFLD/NASH as well as in cirrhosis induced hepatoencephalopathy. There are many probiotics marketed for use in veterinary patients. Most are derived from a single strain of bacteria such as an Enterococcus or Lactobacillus. The number of CFU s vary considerably between products. Nutramax has two probiotic products, Proviable DC and Proviable Forte each containing multiple different strains of bacteria. Proviable Forte contain multiple different strains of bacteria as well as prebiotics (Synbiotic). It contains at least 10 billion CFU s of seven bacterial strains including Enterococcus, Streptococcus, Lactobacillus, and Bifidobacterium spp. While studies specific to benefits of probiotics in dogs and cats have not been performed evidence in other species would suggest a potential benefit. Cobalamin (vitamin B 12) supplementation in liver disease As many as two-thirds of dogs and cats with diffuse small intestinal, pancreatic, and liver disease have been shown to be cobalamin deficient and treatment of the deficiency may be necessary to improve clinical signs. Diagnosis can be based on decreased serum vitamin B 12 concentrations but some patients with cobalamin deficiency on a cellular level do not have severely decreased serum cobalamin concentrations. Because of this cobalamin supplementation should be considered in all patients with liver and/or pancreatic disease, especially if they are not responding as well to treatment as one would hope. Traditionally, cyanocobalamin has been administered parenterally because of concern for ileal malabsorption of oral cobalamin. Subcutaneous injection of 250 ug in cats and ug in dogs depending on size should be given weekly for 6 weeks and then after another month. Serum cobalamin should be within the supranormal at that time. If clinical signs have not completely resolved and cobalamin concentrations are within the normal range treatment should be continued monthly. However, recent studies in both dogs and cats have shown efficacy when chronic oral supplementation has been used. Nutramax markets a cobalamin product, Cobalequin J.Taboada

55 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 Formulated specifically for dogs and cats as a once-daily chicken flavored chewable tablet. Oral supplementation should be continued for at least 3 months. Dosing schedule for oral cobalamin supplementation: Cyanocobalamin orally once a day for 3 months 250 ug in cats or dogs up to 10 kg in body weight 500 ug in dogs weighing over 10 kg but less than 20 kg 1000 ug in dogs weighing more than 20 kg Re-evaluation of serum cobalamin concentration one week after stopping supplementation Antifibrotics When treating canine hepatic disease ongoing fibrosis is a concern as in dogs, unlike most cats, progression to and endstage cirrhotic liver is common with most chronic hepatitis causes. A number of drugs have been proposed as potential antifibrotics, including colchicine, spironolactone, angiotensin II receptor blockers, statins, phosphatidylcholine, penicillamine, Silybin, SAMe, and glucocorticoids. None of the drugs have proven to be very good antifibrotics in other species and have not been critically evaluated in the dog. No recommendation was made by the ACVIM chronic hepatitis consensus group on this topic. Anstee QM, Day CP. S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility. J Hepatol (2012), [Epub ahead of print] Au AY, Hasenwinkel JM, Frondoza CG. Hepatoprotective effects of S-adenosylmethionine and silybin on canine hepatocytes in vitro. J Anim Physiol Anim Nutr 2013; 97(2): Cesaro C, Tiso, A, Del Prete A, et al. Gut microbiota and probiotics in chronic liver diseases. Dig Liv Dis : Dandrieux JRS, Noble PJM, Scase TJ, Cripps PJ, German AJ. Comparison of a chlorambucilprednisolone combination with an azathioprine-prednisolone combination for treatment of 2017 J.Taboada

56 Georgia Veterinary Medical Association Fall Convention Atlanta, Georgia October 13-15, 2017 chronic enteropathy with concurrent protein-losing enteropathy in dogs: 27 cases ( ). J Am Vet Med Assoc 2013; 242: Filburn CR, Kettenacker R, Griffin DW. Bioavailability of a silybin-phosphatidylcholine complex in dogs. J Vet Pharmacol Therap 2007; 30: Filburn CR, Kettenacker R, Griffin D. Safety and Bioavailability in Beagles of Zinc and Vitamin E Combined with Silybin and Phosphatidylcholine. Intern J Appl Res Vet Med 2006; 4: Haque TR, Barritt AS. Intestinal microbiota in liver disease. Best Pract Res Clin Gastroenterol 2016; 30: Skorupski KA, Hammond GM, Irish AM, Kent MS, Guerrero TA, Rodriquez CO, Griffin DW. Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs. J Vet Intern Med 2011; 25: Toresson L, Steiner JM, Suchodolski JS, Spillmann T. Oral cobalamin supplementation in dogs with chronic enteropathies and hypocobalaminemia. J Vet Intern Med. 2016; 30: Toresson L, Steiner JM, Suchodolski JS, et al. Oral cobalamin supplementation in cats with hypocobalaminemia. J Vet Intern Med. 2016; 30:417(abstract). Webster CRL, Cooper J. Therapeutic use of cytoprotective agents in canine and feline hepatobiliary disease. Vet Clin N Amer Small Anim 2009; 39: J.Taboada

57 Telemedicine: Legal Issues Veterinary Business Advisors, Inc. It is the year You are sitting in your office and your certified veterinary technician (CVT) has just video conferenced you from the living room of a longtime client of yours. The patient in question is Willow, a 7-month-old female spayed Mastiff with an area of alopecia on her head. The CVT completes and shares with you her thorough physical exam and you both determine no other significant findings. She performs a deep skin scraping of the area, examines the slide through the microscope in her truck, and finds Demodex mites. You prescribe Ivermectin for the puppy and, since it is a commonly used pharmaceutical, your technician is able to dispense it from her truck. The client will schedule a video-conference recheck in three weeks. As you hang up from the call, your second technician buzzes in right on time for your next appointment. Telemedicine in the Human World The scenario above depicts the future for veterinary medicine general practice. In fact, it is already a current practice in the human medical realm. There is actually an organization called the American Telemedicine Association (ATA) whose members are physicians, academicians, policy makers, and others who promote the safe and effective use of telemedicine to promote the health and well-being of people. They define telemedicine as the use of medical information exchanged from one site to another via electronic communications to improve a patient s clinical health status. 2 The ATA developed practice guidelines for primary and urgent care as part of their mission to establish standards promoting patient safety and quality services provided via telemedicine. 6 These guidelines include rationale for the use of telemedicine in a primary care setting, and they have determined that both acute and chronic medical conditions can be managed effectively by video-based telemedicine. These conditions include but are not limited to allergies, dermatologic issues, genitourinary conditions, otitis media, upper respiratory infections, congestive heart failure, and diabetes, a list that sounds all too familiar, also being common conditions seen in veterinary medicine general practice. The difference, however, is that with organizations such as the ATA, telemedicine is generally accepted and more developed in human medicine than it is in veterinary medicine. The smart phone revolution has provided the human medical would with a powerful set of tools. Many of these tools are taking the form of mobile applications: ECG monitoring and analyzing, mental health monitoring, and rash diagnostics plus apps with attachments, such as those needed to perform an eardrum exam. Wireless sensors can track pulse, oxygen, glucose, VBA 2016 All rights reserved. 1