Saline is as effective as nitrogen scavengers for treatment of hyperammonemia.

Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series. Canine congenital portosystemic shunting (CPSS) is a naturally occurring model for hyperammonemia. Here, we performed cross-over, randomized, placebo-controlled studies in healthy dogs to assess safety and pharmacokinetics of SB and SPA (phase I). As follow-up safety and efficacy of SB was evaluated in CPSS-dogs with hyperammonemia (phase II). Pharmacokinetics of SB and SPA were comparable to those reported in humans. Treatment with SB and SPA was safe and both nitrogen scavengers were converted into their respective metabolites hippuric acid and phenylacetylglutamine or phenylacetylglycine, with a preference for phenylacetylglycine. In CPSS-dogs, treatment with SB resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste. Consequentially, treatment of hyperammonemia justifies additional/placebo-controlled trials in human medicine.

Use of Serum MicroRNAs as Biomarker for Hepatobiliary Diseases in Dogs.

BACKGROUND: Current biochemical indicators cannot discriminate between parenchymal, biliary, vascular, and neoplastic hepatobiliary diseases. MicroRNAs are promising new biomarkers for hepatobiliary disease in humans and dogs. OBJECTIVE: To measure serum concentrations of an established group of microRNAs in dogs and to investigate their concentrations in various types of hepatobiliary diseases. ANIMALS: Forty-six client-owned dogs with an established diagnosis of hepatobiliary disease and stored serum samples and eleven client-owned healthy control Labrador Retrievers. METHODS: Retrospective study. Medical records of dogs with parenchymal, biliary, vascular, or neoplastic hepatobiliary diseases and control dogs were reviewed. Concentrations of miR-21, miR-122, miR-126, miR-148a, miR-200c, and miR-222 were quantified in serum by real-time polymerase chain reaction. RESULTS: No different microRNA concentrations were found in the adenoma and congenital portosystemic shunt groups. In all other diseases, miR-122 concentrations were elevated with the highest concentration in the mucocele group (267-fold, CI: 40-1,768, P < .001). In dogs with biliary diseases, miR-21 and miR-222 were only increased in dogs with mucoceles (26-fold, CI: 5-141, P = .005 and 13-fold, CI: 2-70, P = .025, respectively). Uniquely increased microRNAs were found in the hepatocellular carcinoma group (miR-200c, 35-fold increase, CI: 3-382, P = .035) and the chronic hepatitis group (miR-126, 22-fold increase, CI: 5-91, P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: A microRNA panel consisting of miR-21, miR-122, miR-126, miR-200c, and miR-222 can distinguish between parenchymal, biliary, and neoplastic hepatobiliary diseases. Serum microRNA profiling is a promising new tool that might be a valuable addition to conventional diagnostics to help diagnose various hepatobiliary diseases in dogs.

Diagnostic value of the rectal ammonia tolerance test, fasting plasma ammonia and fasting plasma bile acids for canine portosystemic shunting.

Portosystemic shunting (PSS) often results in hyperammonaemia and, consequently, hepatic encephalopathy. This retrospective study evaluated the sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) and other test performance metrics for the ammonia tolerance test (ATT), serum fasting bile acids (FBA), serum fasting ammonia concentration (FA), and combinations of these tests for their association with PSS in dogs. Medical records of 271 dogs suspect for PSS (symptomatic group) and 53 dogs returning for evaluation after surgical closure of a congenital PSS (CPSS post-surgical control group) were analysed. In the symptomatic group, ATT at 40 min (T40), and the FBA had the highest sensitivity (100% and 98%, respectively) and NPV (100% and 96%, respectively) for PSS. The combination of increased FBA and FA had the highest specificity (97%), with a PPV of 97%, and a positive likelihood ratio of 29. In the CPSS post-surgical control group, the specificity and PPV of FA and the combination of increased FBA/FA were both 100%. In purebred populations, the NPV of all tests was 100%. Consequently, PSS would be ruled out in a symptomatic dog with normal FBA or ATT (T40) and would be highly probable when both FBA and FA are increased. Increased FA was conclusive for PSS in dogs evaluated for post-surgical closure of a CPSS. FBA was the most suitable test for screening purposes.

The canine hepatic progenitor cell niche: molecular characterisation in health and disease.

Hepatic progenitor cells (HPCs) are an adult stem cell compartment in the liver that contributes to liver regeneration when replication of mature hepatocytes is insufficient. In this study, laser microdissection was used to isolate HPC niches from the livers of healthy dogs and dogs with lobular dissecting hepatitis (LDH), in which HPCs are massively activated. Gene expression of HPC, hepatocyte and biliary markers was determined by quantitative reverse transcriptase PCR. Expression and localisation of selected markers were further studied at the protein level by immunohistochemistry and immunofluorescent double staining in samples of normal liver and liver from dogs with LDH, acute and chronic hepatitis, and extrahepatic cholestasis. Activated HPC niches had higher gene expression of the hepatic progenitor markers OPN, FN14, CD29, CD44, CD133, LIF, LIFR and BMI1 compared to HPCs from normal liver. There was lower expression of albumin, but activated HPC niches were positive for the biliary markers SOX9, HNF1ß and keratin 19 by immunohistochemistry and immunofluorescence. Laminin, activated stellate cells and macrophages are abundant extracellular matrix and cellular components of the canine HPC niche. This study demonstrates that the molecular and cellular characteristics of canine HPCs are similar to rodent and human HPCs, and that canine HPCs are distinctively activated in different types of liver disease.

Retrospective comparison of prednisolone and ursodeoxycholic acid for the treatment of feline lymphocytic cholangitis.

A retrospective study was performed to evaluate the effect of treatment with prednisolone or ursodeoxycholic acid (UDCA) on the survival times of 26 cats with lymphocytic cholangitis, and to determine prognostic factors. Most affected cats were males (76.9%, P=0.006) and a breed predisposition for the Norwegian Forest Cat was demonstrated (P=0.021). Clinical signs included weight loss, icterus, anorexia, vomiting, and listlessness. Blood analyses revealed elevated hepatic enzymes, bile acids and hypergammaglobulinaemia. Breed, sex, and therapeutic regimen were significantly associated with survival times. Prednisolone treatment resulted in a statistically longer survival time compared to UDCA.

Detection of bacterial DNA in bile of cats with lymphocytic cholangitis.

In this study, we have successfully used molecular methods based on the amplification of the 16S ribosomal RNA gene on feline bile samples to show that bile of cats with LC is not sterile. This is probably due to the fact that the inflammatory process in the biliary tree causes dilatations. As a result, bacteria can easily migrate from the intestines via the common bile duct. The diversity of species identified and the presence of Helicobacter spp. DNA in both patients and controls suggests that bacteriobilia is secondary to the disease and is not the cause of LC.

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.

[Cholangitis in cats: symptoms, cause, diagnosis, treatment, and prognosis]. / Cholangitis bij kat symptomen, oorzaak, diagnose, therapie en prognose.

Inflammation of the bile ducts is common in cats. This review article reports on what is currently known about the various types of cholangitis (i.e., cholangitis caused by liver flukes, neutrophilic cholangitis, and lymphocytic cholangitis). Treatment is available for cholangitis caused by liver flukes and for neutrophilic cholangitis, and the prognosis is good. However, the cause of lymphocytic cholangitis is not known and there is currently no evidence-based therapy. Several causes are mentioned in the literature, but more research is needed in order to establish the cause of this disease and to develop an appropriate therapy.

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.

Essential thrombocythaemia in two dogs.

In this report two dogs with essential thrombocythaemia (ET) are described. Both dogs were presented more or less at the same time with a combination of reduced exercise tolerance and pale mucous membranes without any report of blood loss. Moderate-to-severe, Coomb's-negative anaemia and thrombocytosis (> 1249 x 10'/l) were present. In addition, the peripheral blood smear revealed the presence of basophilia and large numbers of abnormally shaped megakaryocytes in the bone marrow of both dogs. Treatment with vincristine (0.7 mg/m2 once intravenously) and hydroxyurea (500 mg/m2 p.o. per day) was started. Because of insufficient response to treatment after 3 weeks, the dosage of hydroxyurea was increased in both dogs to 2000 mg/m2 p.o. per day. The dogs deteriorated further, however, and were euthanized at 6 weeks after the start of treatment. Blood examination revealed pancytopenia in both dogs, most likely due to the myelosuppressive effects of high-dose hydroxyurea. A survey of veterinary literature on ET is presented, including a comparison of ET in humans.

Large body size in the dog is associated with transient GH excess at a young age.

The main determinants of body size are GH and IGFs. The aim of this study was to investigate whether differences in adult body size of medium-sized and giant dog breeds can be explained by differences in GH release and/or in plasma IGF-I and IGF-II concentrations at a young age. The basal plasma concentrations of GH, IGF-I and IGF-II were determined once weekly in six Great Danes and six beagles from the age of 6 weeks until the age of 24 weeks. In addition, the 6 h secretory profile of GH was determined every 2 weeks. Basal plasma GH concentrations as well as the total area under the curve (AUC) and the AUC above the baseline for GH were significantly higher in Great Danes than in beagles of the same age. In contrast, plasma IGF-I and IGF-II concentrations did not differ significantly between the two breeds. Compared with values in adults, the basal plasma GH concentrations were high until the age of 7 weeks in the beagles, whereas in the Great Danes the basal plasma GH levels remained high during the entire observation period, albeit with a gradual decline. The mean frequency and the mean amplitude of GH pulses tended to be higher in Great Danes than in beagles, although a significant difference was only reached at the age of 19 and 23 weeks for the frequency and at the ages of 9, 11 and 13 weeks for the amplitude. An age-dependent decrease in pulse frequency occurred in the Great Danes. The results of this study demonstrate that differences in adult body size of medium-sized and giant dog breeds are preceded by differences in GH release and not by differences in circulating IGF-I or IGF-II concentrations. Both young Great Danes and young beagles experience a period of high GH release, but this period persists much longer in Great Danes. It is discussed that this difference may be due to delayed maturation of the inhibitory influences of somatostatin on pituitary GH release in the latter dogs.