Current concepts in the treatment of canine chronic hepatitis

Chronic hepatitis is a common disorder in dogs seen by general practitioners. Several new drugs have been marketed for treating this disease. Unfortunately, there are few controlled studies that examine the efficacy of these medications for the treatment of canine chronic hepatitis. A rational therapeutic approach can be implemented based on histopathologic findings of a liver biopsy. A liver biopsy is essential for establishing a definitive diagnosis and guiding the optimal therapy. The biopsy allows characterizing the inflammatory process, quantitating hepatic copper concentrations, and determining if fibrosis is present. Copper associated hepatopathy is treated with zinc and copper chelators. Idiopathic chronic hepatitis is thought to be immune mediated. The treatment of idiopathic chronic hepatitis consists of controlling inflammation (prednisone, azathioprine), reversing fibrosis (colchicine), and protecting against oxidant damage (vitamin E, ursodeoxycholic acid, S-adenosylmethionine). The prognosis for chronic hepatitis is quite variable. Dogs with end-stage disease have a poor prognosis, while dogs diagnosed earlier can have a mean survival of years. Early diagnosis and intervention are key to the successful treatment of dogs with chronic hepatitis.     

Plasma concentration of transforming growth factor-β1 and hepatic fibrosis in dogs

Liver fibrosis is a morphologic alteration that accompanies chronic liver diseases. Apart from analysis of liver biopsy specimens, there has been no means of diagnosing and evaluating the course of liver fibrosis in the dog. Several plasma markers, including transforming growth factor beta-1 (TGF-β1), are used to indicate liver fibrosis in humans, but none has been validated for use in dogs. There is a significant correlation between the presence and severity of hepatic fibrosis and the plasma concentration of TGF-β1 in humans with hepatic fibrosis and cirrhosis. The feasibility of using TGF-β1 as a marker for hepatic fibrosis in dogs was evaluated by comparing plasma concentrations in 29 healthy dogs and 18 dogs with liver disease. The plasma concentrations of TGF-β1, were 193 to 598 pg/mL in the healthy dogs, 143 to 475 pg/mL in the 7 dogs with mild hepatic fibrosis or none at all, and 427 to 1289 pg/mL in 11 dogs with moderate to severe hepatic fibrosis. The plasma concentrations of TGF-β1 in the dogs with moderate to severe fibrosis differed significantly (P < 0.001) from those in the other 2 groups, whereas the concentrations in the dogs with mild or no fibrosis did not differ significantly from those in the healthy dogs (P > 0.05). It was concluded that TGF-β1 is a potential plasma marker for hepatic fibrosis in dogs.     

Chronic hepatitis in the dog--a review.

Chronic hepatitis is a heterogeneous group of inflammatory-necrotizing diseases of the liver. There is controversy in both human and veterinary medicine about the classification of chronic hepatitis and this is likely to remain until a classification based on aetiology rather than on morphology is introduced. Controversy exists as to whether chronic hepatitis in dogs is comparable to the human disorder. The aetiology of chronic hepatitis in dogs is poorly understood, whereas in humans an increasing number of viral causes have been found. Liver biopsy is essential for the diagnosis of chronic hepatitis both in dogs and in humans. Histopathological evaluation of the liver is required to make the diagnosis, which is based on the presence of liver cell necrosis and inflammatory reaction. The proposed criteria for the classification of hepatitis in dogs are then as follows: aetiology is the primary denominator (infectious, drug induced, autoimmune, or, if unknown, idiopathic). The other criteria are histopathological, with severity reflecting the severity of the necro-inflammatory activity (minimal, mild, moderate or severe) and chronicity reflecting the extent of fibrosis (none, mild, moderate, severe or cirrhosis).     

Remifentanil/isoflurane anesthesia in five dogs with liver disease undergoing liver biopsy

Remifentanil is a synthetic opioid with direct action on μ opioid receptors. It has an ultrashort duration of action, and its elimination is independent of hepatic or renal function. The anesthetic management of five dogs with nonuniform liver disease and requiring liver biopsy via celiotomy is described. Remifentanil and isoflurane were used for induction and maintenance of anesthesia. Intraoperative analgesia was provided by a constant rate infusion of remifentanil. Remifentanil, in combination with isoflurane, was safely and successfully used in five cases for the balanced anesthesia of dogs with hepatic diseases requiring liver biopsy via celiotomy.     

Congenital hepatic fibrosis and cystic bile duct formation in Swiss Freiberger horses

Congenital hepatic fibrosis with autosomal recessive or dominant inheritance has been described in humans, cats, piglets, and dogs. In horses, only two cases of congenital hepatic fibrosis have been previously reported. This retrospective study of records from the Institute for Animal Pathology, University of Berne, identified 30 foals with liver lesions compatible with congenital hepatic fibrosis. Anamnestic data revealed clinical signs of severe liver injury in most affected animals. Pathologic examination showed severely enlarged, firm livers with thin-walled cysts. Histologically, the livers showed diffuse porto-portal bridging fibrosis with many small, irregularly formed and sometimes cystic bile ducts. All foals belonged to the Swiss Freiberger breed. Pedigree analysis revealed that the diseased animals could be traced back to one stallion. These results strongly suggest that congenital hepatic fibrosis in Swiss Freiberger horses is a recessively inherited autosomal genetic defect.     

Copper-induced hepatitis: the COMMD1 deficient dog as a translational animal model for human chronic hepatitis

Chronic inflammatory liver disease regardless of aetiology leads to failing regeneration and fibrosis, ending in cirrhosis. Both in man and in animals this worldwide health problem has no definitive cure. Chronic liver injury causes hepatic stellate cells to proliferate and differentiate into matrix-producing cells. New therapeutic options will be developed upon detailed understanding of the molecular mechanisms driving liver fibrosis. This may lead to new anti-fibrotic therapies which need to be tested in suitable models before application in the veterinary and human clinic. On the other side, to restore the failing regenerative capacity of the diseased liver cells, adult progenitor cells are of interest, as an alternative to whole organ transplantation. In order to find the most suitable large animal model it is important to recognise that the typical histopathological reaction pattern of the liver can differ between mammalian species. It is therefore imperative that specialists in veterinary internal medicine and pathology, being familiar with the diseases and pathologies of the liver in different animal species, are teaming-up in finding the best models for veterinary and human liver diseases. Several large animal models have been mentioned, like pigs, sheep, and dogs. Based on the observations that man and dog share the same hepatopathies and have identical clinical, pathological and pathogenetic reaction patterns during the development of liver disease, the dog seems to be a properly suited species to test new therapeutic strategies for pets and their best friends.     

Colchicine treatment in a dog with hepatoportal fibrosis

A two-year-old female spayed English setter with hepatic encephalopathy was found to have hepatoportal fibrosis and acquired portosystemic shunts on laparotomy and liver biopsy. The dog was treated symptomatically with a low-protein diet, lactulose and metronidazole, while colchicine was given as antifibrotic therapy. There was a gradual improvement in clinical signs and liver function until 30 months after first presentation, when the dog developed severe haematuria caused by renal infarction of unknown aetiology. Post mortem examination revealed hepatic fibrosis to be unchanged. This case illustrates that long term survival may be possible in canine hepatoportal fibrosis and suggests that colchicine may be effective in improving liver function and slowing progression of hepatic fibrosis.     

HEPATIC ULTRASONOGRAPHIC AND PATHOLOGIC FINDINGS IN DOGS WITH CANINE SURPERFICIAL NECROLYTIC DERMATITIS

A unique, "honeycomb" pattern was found on ultrasonographic evaluation of the liver of 5 dogs with canine superficial necrolytic dermatitis (hepatocutaneous syndrome). This pattern consisted of variably-sized, hypoechoic regions measuring 0.5–1.5 cm in diameter surrounded by highly echogenic borders. Histologically, the hypoechoic regions corresponded to distinct regenerative nodules bounded by severely vacuolated (fat-laden) hepatocytes, numerous bile ductules, and a network of reticulin and fine collagen fibers representing remnants of collapsed hepatic lobules. While certain features of the architectural disruption were characteristic of cirrhosis, the lesion lacked the extensive fibrosis and reduced liver size usually associated with chronic cirrhosis. To our knowledge, this hepatic ultrasonographic pattern has only been seen with canine superficial necrolytic dermatitis. Therefore, it appears to be pathognomonic in a dog with questinable skin lesions. A liver biopsy is required to confirm the unique histopathologic features of the hepatopathy found in this syndrome.     

Indirect computed tomography lymphangiography with aqueous contrast for evaluation of sentinel lymph nodes in dogs with tumors of the head

Sentinel lymph node evaluation is widely used in human medicine to evaluate the first lymph node(s) to which a tumor drains. Sentinel lymph node biopsy allows avoidance of extensive lymphadenectomies in cases where the sentinel lymph node is negative for metastasis, thereby reducing patient morbidity. It has been shown that regional lymph nodes are not always the sentinel lymph node, thus identification and sampling of sentinel lymph nodes allows for more accurate staging, which is critical for treatment and prognostication in dogs with cancer. The objective of this prospective, pilot study was to determine if indirect computed tomography (CT) lymphangiography with aqueous contrast agent would successfully allow identification of sentinel lymph nodes in dogs with masses on the head. Eighteen dogs underwent CT lymphangiography. The sentinel lymph node was successfully identified within 3 min of contrast injection in 16 dogs (89%). Compression of lymphatic vessels from endotracheal tube ties and/or the patient's own body weight delayed or prevented identification of sentinel lymph nodes in two dogs (11%). Computed tomography lymphangiography with aqueous contrast can be used successfully to rapidly identify sentinel lymph nodes in dogs with masses on the head.     

Effects of long-term phenobarbital treatment on the liver in dogs

Long-term administration of phenobarbital has been reported to cause hepatic injury in dogs. Phenobarbital induces hepatic enzymes, and it may be difficult to distinguish the effect of enzyme induction on serum liver enzyme activities from actual hepatic damage. The hepatotoxicity of phenobarbital and the impact of enzyme induction on serum liver enzyme activity were investigated prospectively in 12 normal dogs. Phenobarbital was administered for 29 weeks at 5 mg per kilogram of body weight (range, 4.8— 6.6 mg/kg) PO q12h, resulting in therapeutic serum phenobarbital concentrations (20–40 μg/mL). Serum alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyltransferase (GGT), fasted bile acids (fBA), total bilirubin, and albumin were determined before and during treatment. Lateral abdominal radiographs, abdominal ultrasounds, and histopathologic examinations of liver tissue obtained by ultrasound-guided biopsy were performed before and during treatment. Radiographs revealed a moderate increase in liver size in most dogs. Ultrasonographic examination revealed no change in liver echogenicity or architecture. No evidence of morphologic liver damage was observed histopathologically. ALP and ALT increased significantly ( P < .05), GGT increased transiently, and albumin decreased transiently during the study. There were no significant changes in AST, bilirubin, and fBA. These results suggest that increases in serum ALP, ALT, and GGT may reflect enzyme induction rather than hepatic injury during phenobarbital treatment in dogs. Serum AST, fBA, and bilirubin, and ultrasonographic evaluation of the liver are not affected by the enzyme-inducing effect of phenobarbital and can therefore be helpful to assess liver disease in dogs treated with the drug.     

Canine epilepsy: what can we learn from human seizure disorders?

Epilepsy is a common neurological disorder in both dogs and humans. It is refractory to therapy in approximately one-third of canine patients, and even with the advent of new antiepileptic drugs for humans, appropriate treatment options in dogs remain limited. The pathogenesis and pathophysiology of epilepsy is being studied extensively in both human patients and rodent models of experimental epilepsy at the cellular and molecular level, but very little is known about the aetiologies of epilepsies in dogs. In this review, canine epilepsy will be discussed with reference to the human epilepsies and experimental epilepsy research. There is much work to be done in order to classify canine seizure types and breed-specific epileptic syndromes, particularly with reference to electroencephalographic abnormalities and possible genetic abnormalities. The review considers the appropriate use of antiepileptic drugs: phenobarbitone and potassium bromide are effective in most canine patients, although dosing regimes need to be carefully tailored to the individual, with serum concentration measurement. However, a significant proportion of patients remains refractory to these drugs. Work is currently underway to test the efficacy of newer antiepileptic drugs in the treatment of canine epilepsy, and preliminary data suggest that human drugs such as levetiracetam and gabapentin are of benefit in dogs with refractory epilepsy.     

Serum bile acids and the assessment of hepatic function in dogs and cats

Current literature in veterinary internal medicine regarding the clinical use of the serum bile acids test to assess hepatobiliary function in dogs and cats is reviewed. The test is best used in cases where clinical signs and routine laboratory tests are suggestive of liver disease. It is a highly sensitive and specific test of hepatic function, and is the best method of assessing liver function available to the private practitioner. Abnormal results do not determine etiology, severity, or prognosis of the disorder. They merely indicate the need for hepatic biopsy. The serum bile acids concentration should always be measured in both a fasting and a two-hour postprandial sample.     

QUANTITATIVE HEPATIC SCINTIGRAPHY IN THE DOG

Quantitative hepatic scintigraphy is a noninvasive test for measurement of relative arterial and portal blood flow to the liver. This technique has been used to evaluate human patients with known or suspected liver tumors or diffuse hepatocellular disease. A computer program to assess the hepatic perfusion index (HPI) in the normal dog is described. Factors affecting study quality and accuracy include injection technique, cardiac function, patient position, respiration, gross patient motion, and user intervention during data processing. HPI for a group of 12 normal dogs was 0.9±0.4 (X±SD). Quantitative scintigraphy could be used to evaluate dogs with primary or secondary liver tumors, portacaval shunts, or chronic liver disease     

Plasma interleukin-6 response is predictive for severity and mortality in canine systemic inflammatory response syndrome and sepsis

BACKGROUND: Sepsis is still a major cause of death in both human and veterinary medicine. Early diagnosis is essential for appropriate treatment. Identification of patients at risk for developing sepsis is already possible in human medicine through the measurement of plasma interleukin-6 (IL-6) levels. In veterinary medicine, however, this has been investigated only in canine experimental models. OBJECTIVES: The purpose of this study was to measure IL-6 plasma levels in dogs with naturally occurring systemic inflammatory response syndrome (SIRS) and sepsis and to analyze the value of IL-6 as a predictive parameter for severity and mortality. METHODS: Included in the study were 79 dogs that had been admitted to the small animal clinics of Munich and Berlin from July 2004 to July 2005 and that satisfied the diagnostic criteria for SIRS and sepsis as defined using established parameters. Measurement of plasma IL-6 levels on days 0, 1, and 2 was performed by the use of a colorimetric bioassay based on IL-6-dependent cell growth. RESULTS: Septic foci were identified in 43 patients (septic group), and 36 patients were enrolled in the SIRS group. The frequency of positive blood cultures was 11%. The overall mortality rate was 48%. Higher plasma IL-6 levels on the day of admission were significantly correlated with a more severe degree of disease, increased mortality rate, and earlier fatality. CONCLUSIONS: Plasma IL-6 concentration is predictive of outcome in canine SIRS and sepsis and may be a valuable laboratory parameter for assessing critically ill dogs.     

Primary Hepatitis in Dogs: A Retrospective Review (2002–2006)

Background: Little is known about etiology, disease progression, treatment outcome, survival time, and factors affecting prognosis in dogs with primary hepatitis (PH).
Objectives: To review retrospectively different forms of hepatitis in a referral population, by the World Small Animal Veterinary Association Standardization criteria.
Animals: One-hundred and one dogs examined for histologically confirmed PH between 2002 and 2006. Dogs with nonspecific reactive hepatitis were excluded.
Methods: Retrospective study. Medical records were reviewed for prevalence, signalment, clinical and clinicopathologic manifestation, outcome, survival time, and prognostic factors for shortened survival.
Results: PH occurred in 0.5% of dogs in this referral population. Acute (AH) and chronic hepatitis (CH) were diagnosed in 21 and 67 dogs, respectively. Progression from AH to CH occurred in 5/12 of the repeatedly sampled dogs. CH was idiopathic in 43 (64%) dogs, and was associated with copper accumulation in 24 (36%) dogs. Median survival time was longer in dogs with AH than in dogs with CH (either idiopathic or copper associated), and dogs with lobular dissecting hepatitis had the shortest survival time. Prognostic factors predicting shortened survival were associated with decompensated liver function and cirrhosis at initial examination.
Conclusions and Clinical Importance: The majority of PH in dogs is CH. Previous studies appear to have underestimated the etiologic role of copper in both AH and CH. Prognosis is reduced in dogs with hepatic cirrhosis or cirrhosis-related clinical findings. Further research into etiology and treatment effectiveness in all PH forms is needed.     

Hepatic lobe torsion in 3 dogs and a cat

OBJECTIVE: To describe the clinical features of hepatic lobe torsions in 3 dogs and 1 cat. STUDY DESIGN: Retrospective clinical study. ANIMALS: Three client-owned dogs and 1 client-owned cat. METHODS: Medical records were reviewed, and information regarding signalment, clinical signs, physical-exam findings, diagnostic tests performed, treatment, outcome, and follow-up was retrieved. RESULTS: Clinical signs existed for 4 hours to 1 week before examination. Signs were nonspecific in 2 animals that did not have an obvious cause for the hepatic torsion. These signs consisted of lethargy (2), polyuria/polydypsia (2), and anorexia (1). In the other 2 animals, signs were suggestive of the underlying cause of the hepatic lobe torsion. In 1 dog, the torsion was associated with a traumatic diaphragmatic hernia. The cat had a concurrent hemoabdomen secondary to a ruptured hepatocellular carcinoma. Bloodwork abnormalities were nonspecific. Twisted liver lobes included the left lateral lobe (2), the caudate lobe (1), and the right medial lobe (1). Surgical resection (2) or repositioning (1) of the affected liver lobe was attempted in the 3 dogs, and was successful in 2. CONCLUSION: Hepatic lobe torsion is a rare problem but has been reported in humans, rabbits, dogs, pigs, a cat, and a horse. The left lateral liver lobe is most frequently affected. This condition may be idiopathic or associated with neoplasia or absence of ligamentous support (congenital or traumatic) to the liver. CLINICAL RELEVANCE: Prompt surgical resection or repositioning of the involved liver lobe can lead to a successful outcome, avoiding the deleterious effects of venous obstruction such as thrombosis and subsequent necrosis.     

Chronic hepatitis in the English springer spaniel: clinical presentation, histological description and outcome

Medical records and liver histology of 68 English springer spaniels (ESS) with a histological diagnosis of CH were reviewed retrospectively. PCR was performed on liver tissue for canine adenovirus-1 (CAV-1), canine parvovirus, canine herpesvirus and pathogenic Leptospira species. Follow-up information was obtained to calculate survival times. Median age at presentation was three years seven months (range, seven months to eight years five months) and there were 48 female and 20 male dogs. Clinical signs were non-specific and five dogs were asymptomatic. All dogs had an increase in serum activity of one or more hepatobiliary enzymes. Histopathology demonstrated hepatocyte necrosis and apoptosis with varying amounts of fibrosis. A predominantly lymphoplasmacytic infiltrate throughout the hepatic parenchyma was found in all 68 dogs, but 45 of these dogs also had a neutrophilic component to the inflammatory infiltrate. There was no significant copper accumulation and no aetiological agent was identified by PCR. The median survival time was 189 days (range, 1 to 1211 days), 38 dogs died within three months and 12 dogs survived more than a year following diagnosis.     

Liposomal clodronate treatment for tumour macrophage depletion in dogs with soft‐tissue sarcoma

Increased numbers of tumour‐associated macrophages correlate with rapid tumour growth and metastasis in tumours. Thus, macrophage depletion has potential as a novel cancer therapy and positive responses have been reported in rodent tumour models. To investigate the effectiveness of this approach in dogs with cancer, we evaluated the effects of the macrophage‐depleting agent liposomal clodronate (LC) in dogs with soft‐tissue sarcoma (STS). To this end, we conducted a clinical trial of LC therapy in 13 dogs with STS. Repeated LC administration was well tolerated clinically. Preliminary examination of tumour biopsy sets from 5 of the 13 dogs demonstrated that the density of CD11b⁺ macrophages was significantly decreased after LC treatment. Circulating concentrations of interleukin‐8 were also significantly reduced. These preliminary studies are the first to suggest that LC can be used as a systemic macrophage‐depleting agent in dogs to reduce numbers of tumour‐associated macrophages.