PETscan: measuring incidence of disease phenotypes to prioritize genetic studies in companion animals.

Reliable incidence measurement of diseases is necessary for identification of hereditary diseases in companion animal populations. The data collection system 'PETscan' was developed to facilitate standardized registration of diagnoses in veterinary practice. In the development, we attempted to counter challenges known from other primary practice data systems. PETscan includes a comprehensive list of potential diagnoses and supports the veterinary professionals in the diagnostic process. Demographics, individual data and standardized diagnostic data are collected through practice management software in a central database for epidemiological analysis. A preliminary data analysis from PETscan showed specific health issues in four canine breeds. As a real-time prospective monitoring tool, PETscan summaries can objectively assess the incidence of disorders in companion animal populations and can be used to prioritize disease-gene identification studies and evaluate the effects of breeding strategies, for example, after implementation of a new DNA test in the breeding strategy.

Canine hepacivirus and idiopathic hepatitis in dogs from a Dutch cohort.

Liver diseases are highly prevalent in the general dog population, though the etiology is often unknown. Recently a homolog of human hepatitis C virus was discovered in dogs with respiratory infections. Although this canine hepacivirus (CHV) was detectable in some liver samples, a clear link with liver disease has not been established. A recent study by Bexfield et al. showed that in a large cohort of dogs from the UK with idiopathic hepatitis, no evidence can be found for exposure to, or carrier state of CHV both in liver and in serum. The authors however state that 'the absence of CHV infection on dogs from the UK might not represent the global ecology of the virus'. We investigated CHV-infection in 267 liver biopsies from 120 dogs idiopathic hepatitis and 135 control animals, in a population from the Netherlands. Using a highly sensitive PCR assay for CHV-NS3, no CHV was detected in all 267 liver samples. Our data show that the lack of association between canine hepacivirus and chronic liver disease in dogs is not limited to the UK, but is also found in an independent cohort from the European continent.

[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.

Hepatic volume measurements in dogs with extrahepatic congenital portosystemic shunts before and after surgical attenuation.

BACKGROUND: In dogs with congenital portosystemic shunts (CPSS), the ability of the hypoplastic liver to grow is considered important for recovery after surgical shunt attenuation. OBJECTIVES: This study investigated hepatic growth after extrahepatic shunt attenuation in dogs using magnetic resonance imaging (MRI) and computed tomography (CT). ANIMALS: Ten client-owned dogs with single extrahepatic CPSS. METHODS: Abdominal MRI, CT, or both were performed before and 8 days, 1, and 2 months after shunt attenuation. Liver volumes were calculated from the areas of the MRI or CT images. RESULTS: Before surgery, median liver volume was 18.2cm3/kg body weight. Liver volume increased significantly after surgery. Growth was highest between days 0 and 8 and decreased afterward. Median liver volume was 28.8 cm3/kg at 2 months after attenuation. No significant differences in growth were found between dogs with complete or partial shunt closure or between dogs with complete or incomplete metabolic recovery. Volumes measured from consecutively performed MRI and CT images correlated well (r = 0.980), but volumes from MRI images were significantly larger than volumes from CT images (6.8%; P = .008). CONCLUSION AND CLINICAL IMPORTANCE: After shunt attenuation, rapid normalization of liver size was observed. Hepatic growth was not decreased in dogs after partial closure of CPSS or in dogs with subclinical, persistent shunting 2 months after surgery. CT is the preferred imaging method for volumetric estimation because of speed.

The progenitor cell compartment in the feline liver: an (immuno)histochemical investigation.

The hepatic progenitor compartment is of vital importance in liver regeneration when hepatocellular replication is impaired, as it occurs in acute fulminant hepatitis or severe liver fibrosis. It consists of resident progenitor cells in the normal liver, and ductular reaction and intermediate hepatobiliary cells in diseased livers. An histologic and immunohistochemical study was conducted to demonstrate putative hepatic progenitor cells in the normal liver (n = 5) and in a range of hepatic diseases (n = 13) in the cat. Formalin-fixed, paraffin-embedded specimens were stained with HE, the van Gieson stain, and the reticulin stain according to Gordon and Sweet, and immunohistochemically stained for cytokeratin-7 (CK7), human hepatocyte marker 1 (Hepar1), and multidrug resistance-binding protein-2/ATP binding cassette C2 (MRP2). The normal feline liver contains a liver progenitor cell morphologically similar to humans and dogs, which resides in the canal of Hering. In acute and chronic feline liver diseases a ductular reaction is present, whether in the parenchyma or in a portal or septal location. The putative progenitor cells could easily be demonstrated by staining for CK7, whereas they were generally negative for Hepar1 and MRP2. In a parenchymal ductular reaction mitotic figures and cells with an intermediate hepatobiliary phenotype could be demonstrated. This is the first account of hepatic progenitor cells in feline liver.

Soy protein isolate versus meat-based low-protein diet for dogs with congenital portosystemic shunts.

BACKGROUND: Both presurgical preparation and long-term support of nonoperable dogs with congenital portosystemic shunts (CPSS) require optimal dietary management. Studies suggested that protein source may play an important role, with vegetable and dairy protein sources having better effects on hepatic encephalopathy (HE) than meat proteins. OBJECTIVES: Determine whether a low-protein test diet with soy as its main protein source results in better scores than a control diet with the same composition but with poultry as its main protein source in dogs with CPSS. METHODS: In a double-blind cross-over study, 16 dogs received each diet for 4 weeks. Dogs in group T first received the test diet and then the control diet, whereas dogs in group C were fed the diets in the opposite order. Different variables (body weight, body condition score, HE score, fecal score, CBC, plasma tests of liver function including NH3, and coagulation tests) were measured at the start of the study and after completion of each diet. RESULTS: One-way repeated measures ANOVA was performed. Plasma NH3 was significantly lower after the test diet than after the control diet. The test diet also resulted in significantly higher fibrinogen concentrations and lower prothrombin times. The HE score improved with both diets, with no significant difference between the 2 diets. CONCLUSIONS: Both diets achieved a significant improvement in HE score. The influence of the soy-based diet on plasma NH3 concentration and coagulation parameters suggests that such a diet decreases the risk for HE and gives better support of liver function.

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.

Evidence of inheritance of intrahepatic portosystemic shunts in Irish Wolfhounds.

BACKGROUND: The etiogenesis of congenital portosystemic shunt in dogs is not understood. In Irish Wolfhounds, intrahepatic portosystemic shunt (IHPSS) is thought to be hereditary, but the mode of inheritance is unknown. OBJECTIVES: To document the genetic background and investigate the potential mode of inheritance of IHPSS in Irish Wolfhounds. ANIMALS: Three mature, privately owned, affected siblings and their progeny produced in 2 litters. METHODS: Prospective, observational study. Two test matings of 1 affected sire with 2 of his affected sisters were used to determine the inheritance pattern. Affection status was determined by measuring venous blood ammonia concentrations, detection of the shunt by ultrasonography and confirmation during surgical attenuation of the intrahepatic shunting vessel. RESULTS: In 1 litter of 5 pups all had an IHPSS. In the other litter 5 of 11 pups were affected. Both left- and right-sided shunts occurred in both litters. No sex predisposition was evident among affected dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Our results show that IHPSS in Irish Wolfhounds is a familial disorder that is likely genetic. It is unlikely that the mode of inheritance is monogenic. A digenic, triallelic trait could explain the observed occurrence of IHPSS but other modes of inheritance cannot be excluded.

Dietary management of hepatic copper accumulation in Labrador Retrievers.

BACKGROUND: Copper-associated chronic hepatitis (CACH) recently has been recognized in the Labrador Retriever as an inherited disorder with a late onset of clinical signs. No studies have investigated dietary management for the long-term treatment of this disease or for its potential in delaying the onset of clinical signs in subclinical cases. OBJECTIVES: To investigate the effects of a low-copper diet and zinc gluconate on hepatic copper concentrations in Labrador Retrievers with abnormal hepatic copper concentrations. ANIMALS: Twenty-four client-owned Labradors that were related to patients affected with CACH and that had been diagnosed with increased hepatic copper concentrations. METHODS: Hepatic copper concentrations were assessed before and after an average of 8 and 16 months of treatment. During this time, all dogs were fed exclusively a low-copper diet. In addition, dogs were assigned to 1 of 2 groups in a randomized double-blind manner to receive a supplement of zinc gluconate or placebo. RESULTS: Twenty-one dogs completed the study. Hepatic copper concentrations decreased in both groups at recheck 1 (n = 21; group 1, P < .001; group 2, P= .001) and at recheck 2 (n= 16; group 1, P= .03; group 2, P= .04). No difference in hepatic copper concentrations was found between the 2 groups before treatment (P= .65), at recheck 1 or at recheck 2 (P= .52-.79). CONCLUSIONS AND CLINICAL RELEVANCE: Feeding low-copper diets to Labradors is effective in decreasing hepatic copper concentrations. Adjunctive treatment with zinc does not appear to increase the copper-lowering effects of dietary management.

Transient hyperammonemia due to urea cycle enzyme deficiency in Irish wolfhounds.

BACKGROUND: Irish Wolfhounds frequently have a congenital portosystemic shunt, but a considerable proportion of the 6- to 8-wk-old pups has hyperammonemia in the absence of portosystemic shunting. This hyperammonemia causes no signs and is transient, normalizing at the age of 3-4 months. HYPOTHESIS: Transient hyperammonemia has a metabolic basis in Irish Wolfhounds. ANIMALS: Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied. METHODS: Integrity of the portal circulation was examined by ultrasonography and scintigraphy. Absence of parenchymal liver disease was verified by liver biopsy. Amino acid profiles were measured in 4 pups and repeated in 2 of these pups when ammonia concentrations had normalized. The amino acid profiles were compared with those of healthy Irish Wolfhound pups. RESULTS: Fasting venous ammonia concentrations were high (113-622 microg/dL, 65-345 micromol/L) in all pups, whereas bile acids were within reference range in all but 1. The ammonia and bile acid concentrations from all parents were within reference range. Portosystemic shunting was excluded in all but 1 pup. Liver biopsy excluded significant lesions in all 10 pups examined. Hypercitrullinemia was found and persisted even when ammonia had normalized, at the expense of an increase in glutamine and asparagine. CONCLUSIONS AND CLINICAL IMPORTANCE: Citrulline concentrations are controlled by the urea cycle enzymes argininosuccinase and argininosuccinate synthetase, and a defect in either of these enzymes may be responsible for the transient hyperammonemia in Irish Wolfhounds. Resolution of the hyperammonemia is associated with increased activity of alternative metabolic pathways forming glutamine and asparagine. Confirmation requires measurement of enzyme activities in liver tissue.

Disease burden in four populations of dog and cat breeds compared to mixed-breed dogs and European shorthair cats.

Current public and professional opinion is that many dog breeds suffer from health issues related to inherited diseases or extreme phenotypes. The aim of this historical comparative observational study was to evaluate the breed-related disease burden in three purebred dog populations (Chihuahua, French bulldog, Labrador retriever) and one purebred cat breed (Persian cats) in the Netherlands by comparison to a control population of mixed-breed dogs and European Shorthair cats. A qualitative query was performed, consisting of a literature review and collecting the expert opinions of University veterinary specialists, to gather insight into potential diseases of the study population. Next, a referral clinic case control study of the patients referred to specific medical disciplines in the University Clinic was performed. The odds ratio (OR) was calculated to determine the likelihood of a patient referred to a particular medical discipline being a certain breed. Together, the qualitative query and the case control study resulted in a list of potentially relevant diseases limited to five organ systems per breed. These were analysed in data from primary practices. Patient files from ten primary practices over a period of two years were manually extracted and examined. Four-hundred individual patient records per breed as well as 1000 non-breed records were randomly selected from the 10 practices, weighted per practice size. Records were then examined and the presence or absence of certain diseases was identified. To evaluate the disease burden per breed, proportional difference (PD) was estimated, as well as the animal's age at presentation in months. The results of the referral clinic case control study showed an overrepresentation (Odds Ratio>1.5) of the selected breeds in several medical specialties, while median age at presentation was in some cases significantly lower than in the non-breed animals. Results of the practice-based extended cross-sectional study showed that only a few of the selected diseases contribute to the disease burden in these purebred populations, which was different from the expectations derived from the literature or expert opinion. Additional results included age difference at presentation, which may be interpreted as age of onset, and could indicate a higher disease burden for the individual animal. Also, only a small percentage of purebred dogs was registered with the national kennel club. Our final recommendation is that population-based data mining is needed to evaluate country-specific companion animal health and welfare.

Sensitivity and Specificity of Plasma ALT, ALP, and Bile Acids for Hepatitis in Labrador Retrievers.

BACKGROUND: Biochemical indicators for diagnosing liver disease are plasma alanine aminotransferase activity (ALT), alkaline phosphatase activity (ALP), and bile acid concentration (BA). OBJECTIVES: To determine the sensitivity and specificity of ALT, ALP, and BA for detecting primary hepatitis (PH) in clinically healthy Labrador retrievers and investigate whether ALT and ALP can discriminate between dogs with PH and nonspecific reactive hepatitis (RH). ANIMALS: 191 clinically healthy and 51 clinically ill Labrador retrievers with hepatic histopathology. METHODS: Retrospective study. Medical records were reviewed for ALT, ALP, preprandial BA, liver histopathology, and hepatic copper concentrations. RESULTS: In 64% (122/191) of the clinically healthy Labrador retrievers, hepatic histology revealed inflammatory infiltrates. This frequency might be biased because part of them was included as first-line relatives of dogs with copper-associated hepatitis. Sensitivity of ALT, ALP, and BA in this population for detecting acute hepatitis was 45, 15, and 15%, respectively. For chronic hepatitis, sensitivity was 71, 35, and 13%, respectively. Specificity of ALT, ALP, and BA was >90% for AH, CH, and RH. When increased liver enzymes were present, median ALT was significantly higher in PH cases (312 U/L, range 38-1,369) compared to RH cases (91 U/L, range 39-139) (P < .001). There was no difference in ALP between dogs with a PH and a RH (P = .361). CONCLUSIONS AND CLINICAL IMPORTANCE: Histopathologic abnormalities in the liver were present in the majority of apparent clinically healthy Labrador retrievers. The sensitivity of ALT, ALP, and BA for detecting acute and chronic hepatitis in this population was low. More sensitive biomarkers are needed for early detection of liver disease in apparent clinically healthy dogs.

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.

High complication rate of an automatic Tru-Cut biopsy gun device for liver biopsy in cats.

BACKGROUND: Liver biopsies taken with an automatic Tru-Cut biopsy gun device caused unexpected fatal shock reactions in cats. The goal of the present study was to determine if this biopsy device caused more frequent fatal complications than did a semiautomatic device. ANIMALS: All cats referred to the Utrecht University, between October 1, 2002, and October 31, 2004, in which ultrasound-guided Tru-Cut liver biopsies were taken. The indications for liver biopsy were increased liver enzyme activity, increased bile acid concentrations, ultrasonographic abnormalities of the liver, ultrasonographic abnormalities of the bile ducts, or some combination of these findings. Coagulation parameters were normal. METHODS: From October 1, 2002, until October 31, 2003, 26 cats were biopsied with an automatic biopsy device. Between November 1, 2003, and October 31, 2004, 19 cats underwent liver biopsy with a semiautomatic biopsy device. RESULTS: In the first period. 5 of the 26 cats (19%) developed severe shock within 15 minutes. Resuscitation was not successful. In the second period, none of the 19 cats experienced any major adverse effect. There were no significant differences between the 2 groups with respect to diagnosis, clinical signs, clinicopathologic findings, or the use of anesthetics. CONCLUSIONS AND CLINICAL IMPORTANCE: We conclude that the difference in complication rate is explained by the biopsy technique used. The pressure wave, which occurs when firing the automatic device, may have caused intense vagotonia and shock. Use of this automatic biopsy device should be avoided in cats because of the high risk of fatal complications.

Copper-associated chronic hepatitis in Labrador Retrievers.

This study summarizes the clinical and pathologic findings in 15 Labrador Retrievers with copper-associated chronic hepatitis (CACH). Our hypothesis was that this form of hepatitis is caused by a defect in hepatic copper metabolism, which most likely originates from a genetic defect. Affected Labradors consisted of 11 female and 4 male Labrador Retrievers. Eight family members of 2 of these patients were examined prospectively, as were 6 unrelated healthy Labrador Retrievers. All dogs were registered at the breed club. The average age at clinical presentation was 7 years (range, 2.5-10.5 years). All dogs were presented for anorexia, which was associated with vomiting in 8 patients. The diagnosis of CACH was based on histologic examination of liver biopsy specimens in all dogs, including semiquantitation of copper. A disproportionate increase in alanine aminotransferase (ALT) activity relative to alkaline phosphatase (ALP) activity, as well as the centrolobular localization of copper and the association of copper accumulation with hepatic lesions, suggested a primary copper storage disease rather than primary cholestatic liver disease causing copper accumulation. Mean hepatic copper concentration measured in related Labradors was 1,317 microg/g dry weight liver (range, 402-2,576 microg/g). Mean hepatic copper concentration of unrelated normal Labradors was 233 microg/g dry weight liver (range, 120-304 microg/g). Our findings support the hypothesis that a hereditary form of hepatitis occurs in Labrador retrievers and is caused by a defect in hepatic copper metabolism.

Diagnostic value of fasting plasma ammonia and bile acid concentrations in the identification of portosystemic shunting in dogs.

Portosystemic shunting occurs frequently either as congenital anomalies of the portal vein (PVA) or as acquired shunting (AS) due to portal hypertension secondary to parenchymal liver disease or portal vein thrombosis. The 2 most commonly used screening tests for portosystemic shunting are bile acid and plasma ammonia concentrations. The purpose of this study was to compare the 12-hour fasting plasma ammonia (AMM) and bile acid concentration (BA) as tests for diagnosing portosystemic shunting. Medical records of 337 dogs were used in which AMM and BA were measured simultaneously and in which portosystemic shunting was confirmed or excluded. These dogs were divided into 2 groups (group 1: portosystemic shunting present, n = 153, and group 2: portosystemic shunting absent, n = 184). Group 1 was subdivided into 2 subgroups (group 1a: PVA, n = 132 and group 1b: AS, n = 21). The sensitivity of AMM in detecting PVA was 100% and of BA was 92.2%. For portosystemic shunting in general (PVA or AS), the sensitivity of AMM was 98% and that of BA was 88.9%. The specificity in the total population of AMM was 89.1% and that of BA was 67.9%. If only dogs with liver diseases were included with (n = 153) or without (n = 28) shunting, the specificity of AMM to detect shunting was 89.3% and that of BA was 17.9%. In conclusion, AMM is a highly sensitive and specific parameter to detect PVA and portosystemic shunting in a general population and in dogs with liver disease, whereas BA is somewhat less sensitive and considerably less specific.

Morbidity and mortality in 928 Dobermanns born in the Netherlands between 1993 and 1999.

The morbidity and mortality among 928 dobermann dogs born between 1993 and 1999 were investigated by sending questionnaires to their owners; 340 (37 per cent) responded. Eighty-one of the dogs had died. Proportional mortality was high for heart failure (14.8 to 22.2 per cent), behavioural problems (19.8 per cent) and cancer (13.6 per cent), but low for hepatitis (3.7 per cent) and cervical spondylomyelopathy (2.5 per cent). Of the 259 surviving dogs, 132 were suffering from various disorders, with a high prevalence of skin problems (22.4 per cent) and urinary incontinence (15.8 per cent).

Transient erythropoietic protoporphyria associated with chronic hepatitis and cirrhosis in a cohort of German shepherd dogs.

Over the course of one year, slight jaundice and ascites suggestive of chronic liver disease occurred in 17 German shepherd dogs from one breeding colony. Blood analyses, performed twice with a six-month interval, revealed elevated serum activities of liver enzymes in 13 dogs. In addition, four young adult German shepherd dogs that showed severe ascites, slight jaundice and increased serum liver enzyme activities were referred for further evaluation. Because of their poor prognosis these four dogs were euthanased. There were no signs of photosensitivity. Postmortem examinations revealed macronodular darkened livers, which were characterised histopathologically by cirrhosis associated with aggregates of brown pigments showing a striking orange birefringence in polarised light. Ultrastructurally, the crystalline pigments were typical of protoporphyrins. High-performance liquid chromatographic analysis of liver samples revealed very high levels of protoporphyrins (mean 9550 nmol/g wet liver, reference value 0.41 nmol/g wet liver) and low activities of ferrochelatase (mean 0.274 mmol/mg protein/hour, reference value 0.684 nmol/mg protein/hour). Twenty-six months after the onset of the hepatopathies, the clinical condition of the 13 surviving dogs had improved and their serum liver enzyme activities were normal. The clinical histories and pedigree analyses were not in concordance with an inherited form of protoporphyria. There was no known history of exposure to toxic substances or drugs. The findings are in accordance with a transient erythropoietic protoporphyria associated with hepatic complications, presumably caused by exposure to a porphyrinogenic, ferrochelatase-inhibitory substance of unknown origin.

Characterisation of 11 beta-hydroxysteroid dehydrogenases in feline kidney and liver.

11 Beta-hydroxysteroid dehydrogenases type 1 and 2 (11 beta-HSD1 and 11 beta-HSD2) are microsomal enzymes responsible for the interconversion of cortisol into the inactive form cortisone and vice versa. 11 beta-HSD1 is mainly present in the liver, and has predominantly reductase activity although its function has not yet been elucidated. 11 beta-HSD2, present in mineralocorticoid target tissues such as the kidney, converts cortisol into cortisone. Reduced activity due to inhibition or mutations of 11 beta-HSD2 leads to hypertension and hypokalemia resulting in the Apparent Mineralocorticoid Excess Syndrome (AMES). Like humans, cats are highly susceptible for hypertension. As large species differences exist with respect to the kinetic parameters (K(m) and V(max)) and amino acid sequences of both enzymes, we determined these characteristics in the cat. Both enzyme types were found in the kidneys. 11 beta-HSD1 in the feline kidney showed bidirectional activity with predominantly dehydrogenase activity (dehydrogenase: K(m) 1959+/-797 nM, V(max) 766+/-88 pmol/mg*min; reductase: K(m) 778+/-136 nM, V(max) 112+/-4 pmol/mg*min). 11 beta-HSD2 represents a unidirectional dehydrogenase with a higher substrate affinity (K(m) 184+/-24 nM, V(max) 74+/-3 pmol/mg*min). In the liver, only 11 beta-HSD1 is detected exerting reductase activity (K(m) 10462 nM, V(max) 840 pmol/mg*min). Sequence analysis of conserved parts of 11 beta-HSD1 and 11 beta-HSD2 revealed the highest homology of the feline enzymes with the correspondent enzymes found in man. This suggests that the cat may serve as a suitable model species for studies directed to the pathogenesis and treatment of human diseases like AMES and hypertension.

Improvement in liver pathology after 4 months of D-penicillamine in 5 doberman pinschers with subclinical hepatitis.

Five female Doberman Pinschers with increased hepatic copper concentrations and persistent (3-4 years) subclinical hepatitis were treated with D-penicillamine for 4 months. Before and after treatment, the dogs underwent clinical, hematologic (red blood cell, white blood cell, and differential and thrombocyte counts), and clinical chemistry (creatinine, alkaline phosphatase, alanine aminotransferase, and total bile acid concentrations) examinations, and liver biopsies were examined histologically and their copper content measured quantitatively. No adverse effects were observed during treatment, and CBC and serum chemistry test results did not change. The mean liver copper concentration was 1,036 mg/kg dry matter before treatment and decreased to 407 mg/kg after treatment (P = .03). The copper concentrations had decreased (by between 134 and 1,135 mg/kg dry matter) in all of the dogs. The histopathologic appearance had improved or returned to normal in all 5 dogs. We conclude that D-penicillamine effectively reduced copper retention in these dogs and improved the histopathologic appearance of the lesions. However, because D-penicillamine has both copper-chelating and anti-inflammatory properties, it is not possible to draw conclusions on the etiology of this disease.