Histological species differences among chickens, rats, and mice in experimental cholestasis by bile duct ligation.

Cholestasis is a hepatic disease reported in humans, dogs, and chickens and is characterized by various signs. Bile duct ligation (BDL) is a standard model for research in cholestasis in male rats and mice. However, the timing and degree of structural changes in BDL-subjected liver differ in the two animal species. This study focused on chickens as a choice model for cholestasis. Specifically, we aimed to evaluate the features of BDL in hens and compare them with those in rats and mice. Eighteen hens, 19 female ICR mice, and 18 female SD rats were randomly divided into the sham-operated and BDL groups. At 2, 4, and 6 weeks after BDL, and 4 weeks after the sham operation, liver and blood samples were collected and analyzed histologically and biochemically. Histologically, bile duct proliferation in BDL-subjected livers was first observed in the chickens and then the rats and mice, whereas CD44-positive small hepatocytes were observed only in chickens in the BDL group. Biochemically, the mRNA expression of the hepatocyte growth factor was higher in BDL-subjected chickens, while Interleukin 6 expression was higher in the BDL-subjected rats and mice than in animals in the sham group. In addition, farnesoid X receptor mRNA expression was lower in the BDL-subjected chickens than in the sham chickens. The BDL group had significantly higher total bile acid blood concentration than the sham group. In conclusion, the signs of hepatopathy caused by BDL differ among animal species. Furthermore, we propose that compared to BDL-subjected mice and rats, BDL-subjected chickens are a novel cholestasis animal model that demonstrates severe hepatopathy and liver restructuring.

Diagnostic and predictive ability of hyperbilirubinemia severity in cats: A multicenter retrospective study.

BACKGROUND: Total serum bilirubin concentration (TBIL) can provide useful information on several pathophysiological conditions in cats. Nevertheless, whether the variable severity classification of hyperbilirubinemia can reliably indicate certain disease processes or predict a biliary obstruction (BO) has not been investigated. HYPOTHESIS/OBJECTIVE: Determine if hyperbilirubinemia of variable severity can assist clinicians to identify BO, which often is considered a surgical emergency. ANIMALS: Two-hundred sixteen client-owned cats. METHODS: Data were retrospectively collected from all cats (January 2015-August 2022) with an increased TBIL (>0.58 mg/dL [>10 µmol/L]) presented to 3 referral centers in the United Kingdom (UK). Presenting clinical features and diagnostic outcomes were collected. The predictive ability of TBIL to indicate BO was evaluated by multivariable binary logistic regression modeling and receiver operating characteristic (ROC) curves. RESULTS: Median TBIL was 1.73 mg/dL (range, 0.59-26.15; 29.5 µmol/L; range, 10.1-447.1) with severity classification of hyperbilirubinemia categorized as mild (>0.58-2.92 mg/dL; >10-50 µmol/L; 68.1%), moderate (>2.92-5.85 mg/dL; >50-100 µmol/L; 17.6%), severe (>5.85-11.70 mg/dL; >100-200 µmol/L; 9.7%) and very severe (>11.70 mg/dL; >200 µmol/L; 4.6%). Biliary obstruction was present in 17 (7.9%) cats, all of which received recommendation for emergency surgery. Median TBIL in cats with BO (9.69 mg/dL; 165.7 µmol/L) differed significantly from those without obstruction (1.51 mg/dL; 25.8 µmol/L; P < .01). The optimal TBIL cut-off to discriminate between cats with and without BO was ≥3.86 mg/dL (≥66 µmol/L) with a sensitivity of 94.1% and specificity of 82.4%. Using multivariable logistic regression, as age increased, the odds of BO increased significantly (odds ratio, 1.20; 95% confidence interval, 1.01-1.42; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: As part of a thorough clinical assessment, the severity classification of hyperbilirubinemia has the potential to predict the likelihood of a BO and to discriminate between cats that may or may not require surgery for BO at a suggested cut-off of ≥3.86 mg/dL (≥66 µmol/L). Alongside TBIL, age is also useful when assessing for the likelihood of BO in a cat presented with hyperbilirubinemia.

Surgical Management Of Feline Biliary Tract Disease: Decision-making and techniques.

PRACTICAL RELEVANCE: Diseases of the hepatobiliary system are not uncommon in first-opinion practice. The anatomy of the feline hepatobiliary tract differs from that of dogs and may predispose cats to inflammatory hepatobiliary disease. Case management can be challenging, and the prognosis is variable and dependent on the underlying disease process. CLINICAL CHALLENGES: Biliary tract disease in the cat has non-specific clinical signs that overlap with those of diseases of other body systems. Diagnostic tests of the hepatobiliary system are widely available, but interpretation of results can be challenging. Deciding on medical or surgical management can also be challenging; for example, various degrees of cholestasis may be seen with different diseases and disease severities, and will influence the decision to manage the patient medically or surgically. Surgery is indicated in cases of bile peritonitis, severe cholestasis, focal neoplasia or disease that is refractory to medical management. Intensive perioperative and postoperative management, with 24 h hospitalisation facilities, is essential. AUDIENCE: This review article is written for the small animal general/primary care practitioner, with an emphasis on decision-making in the surgical management of feline hepatobiliary disease. EVIDENCE BASE: Evidence available in the published literature is reviewed and presented, and the inherent limitations are discussed.

Ellagic acid from whole pomegranate fruit reduces liver injury in a rat model of hepatic cholestasis.

Background: Cholestasis is a health problem, both in humans and animals, which in the disease's course involves oxidative stress, inflammation, and liver fibrosis. EA has been proven to have beneficial effects on various diseases. Aim: This study was conducted to determine the effect of EA in protecting liver damage because of cholestasis. In addition, to understand the underlying mechanism of liver damage in rats as a model animal by bile duct ligation (BDL) technique. Methods: In this study, male adult rats were used and randomly divided into three treatment groups. S is the sham-operated group, BDL is the group that is treated with BDL and the BDL-EA group is treated with BDL and given EA by gavage at a dose of 60 mg/kg bw/day, starting on the second day after BDL and given for 21 days. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) were evaluated using spectrophotometer; tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-ß1) were evaluated using sandwich ELISA and histopathological examination using HE and Massion's Trichrome staining. Results: In this study, BDL significantly increased serum levels of AST, ALT, ALP, and hepatic GGT. In addition, BDL also increased levels of TNF-α, and TGF-ß1 compared to sham-operated controls. Histological studies in the BDL group also showed that the BDL increased the degree of necro-inflammation and collagen deposition area in the liver compared to the sham-operated group. Administration of EA has been shown to significantly improve liver morpho-function of the liver. I attenuated these changes in the BDL-EA group, where all observed study variables appeared to have improved. Conclusion: EA has been shown to reduce cholestasis that causes liver injury and improves liver enzyme profiles, and is suspected to have occurred because of its activities as an antioxidant, anti-inflammatory, and anti-fibrotic.

Post mortem computed tomography as a complementary tool for diagnosing cholangiohepatitis in a giant panda (Ailuropoda melanoleuca).

A geriatric female giant panda developed grave signs of illness and was diagnosed with suspected hepatobiliary tract obstruction or other severe hepatic disease such as advanced cholangiohepatitis. The giant panda was euthanized and post mortem computed tomography was performed prior to necropsy. Common bile duct obstruction at the major duodenal papilla by a mineral attenuating calculus causing dilatation of common bile and gallbladder with concurrent multiple areas of liver abscess were detected by postmortem computed tomography. These were confirmed with gross necropsy. This is the first case report of common bile duct obstruction by mineral calculus with concurrent severe cholangiohepatitis in a giant panda.

Canine hepatobiliary anatomy, physiology and congenital disorders.

The biliary system is an integral component of normal physiologic homeostasis and essential for survival. It acts as a conduit for the removal of detoxified and catabolised compounds as well as aids in fat digestion and absorption. Derangements in this system can have dangerous sequela that are associated with varying degrees of morbidity and mortality. Moreover, abnormalities in development of the biliary system can have varied and unpredictable changes on function and long-term outcome. The aims of this article were to review canine hepatobiliary anatomy, physiology and cholestasis as well as summarise congenital biliary disorders including human corollaries.

Percutaneous-endoscopic rendezvous cholangiography with biliary stent placement in a dog with extra-hepatic biliary duct obstruction.

A middle-aged male springer spaniel was presented for investigation of acute vomiting, lethargy and icterus. Marked distension of the gall bladder and common bile duct was evident at ultrasound due to obstruction by mineralised intraluminal material. After 48 hours of hospitalisation with intravenous fluid therapy, analgesia and antimicrobial therapy, intervention was deemed necessary to relieve the obstruction. A percutaneous-endoscopic rendezvous approach was used to achieve placement of a pigtail stent into the distal common bile duct, successfully relieving the obstruction. Serial biochemistry measurements postprocedure confirmed marked improvements in serum bilirubin. The patient remains clinically well 24 months postprocedure, and all hepatic enzyme activities have normalised. Based on the literature search performed, this is the first successful application of this technique in the management of canine extrahepatic biliary duct obstruction.

Common bile duct obstruction palliated with common bile duct re-implantation (choledochoduodenostomy) in a cat.

A cat was presented with complete biliary obstruction at the level of the distal common bile duct (CBD), with loss of normal architecture. The area was excised and submitted for histopathology. Concurrent cholecystitis and gall bladder necrosis necessitated cholecystectomy. The proximal CBD was preserved and re-implanted adjacent to the original duodenal papilla. The cat recovered and remained asymptomatic for 6 months. At clinical relapse a carcinoma of suspected biliary origin was confirmed, and the cat was euthanized. In situations in which the CBD lumen cannot be re-established, the pathology is limited to the distal CBD, and the gall bladder is not available for cholecystoenterostomy, CBD re-implantation may be an option to salvage and retain a functional biliary tree.

Remédiation d'une obstruction du canal cholédoque par réimplantation du canal cholédoque (cholédochoduodenostomie) chez un chat. Un chat fut présenté avec une obstruction biliaire complète au niveau du canal cholédoque distal (CBD), avec perte de l'architecture normale. La région a été excisée et soumise pour examen histopathologique. Une cholécystite concomitante et une nécrose de la vésicule biliaire ont nécessité une cholécystectomie. Le CBD proximal fut préservé et réimplanté de manière adjacente à la papille duodénale originale. Le chat a récupéré et est demeuré asymptomatique pendant 6 mois. Lors d'une rechute clinique une suspicion de carcinome d'origine biliaire fut confirmée, et le chat euthanasié. Dans des situations où la lumière du CBD ne peut être ré-établie, que la pathologie est limitée au CBD distal, et que la vésicule biliaire n'est pas disponible pour une cholécystoenterostomie, la réimplantation du CBD peut être une option pour sauvegarder et maintenir un système biliaire fonctionnel.(Traduit par Dr Serge Messier).

Relationship of serum leptin concentration with pituitary-dependent hyperadrenocorticism and cholestatic disease in dogs.

OBJECTIVES: To measure serum leptin concentration in dogs with pituitary-dependent hyperadrenocorticism and varying degrees of cholestatic disease and determine whether serum levels differed between dogs with pituitary-dependent hyperadrenocorticism and those with gall bladder mucocoele. MATERIALS AND METHODS: Client-owned healthy dogs (n=20), dogs diagnosed with gall bladder mucocoele (n=20) and dogs diagnosed with pituitary-dependent hyperadrenocorticism (n=60) were enrolled. Only dogs of normal body condition score were included. Dogs with pituitary-dependent hyperadrenocorticism were divided into three groups according to the severity of cholestatic disease: normal gall bladder (n=20), cholestasis (n=20) and gall bladder mucocoele (n=20). Serum leptin levels were measured using sandwich enzyme-linked immunosorbent assay. RESULTS: Serum concentrations of leptin were similar between dogs with gall bladder mucocoele and those with pituitary-dependent hyperadrenocorticism accompanied by gall bladder mucocoele; these concentrations were significantly higher than those in healthy control dogs. In dogs with pituitary-dependent hyperadrenocorticism, circulating leptin concentration significantly increased with the severity of cholestasis: higher in the cholestasis group than the normal gall bladder group and higher in the gall bladder mucocoele group than the cholestasis group. CLINICAL SIGNIFICANCE: Elevated circulating leptin concentration was associated with canine pituitary-dependent hyperadrenocorticism and gall bladder mucocoele. Homeostatic imbalance of leptin concentration might be associated with severity of cholestatic disease in pituitary-dependent hyperadrenocorticism.

Ganglioneuromatosis of the Gallbladder in a Dog with Cholecystitis and Cholestasis.

A 2-year-old entire female mixed-breed dog was presented with signs of cholestasis. Abdominal ultrasonography revealed a gallbladder with a thickened and hyperechoic wall and luminal calculi. Exploratory laparotomy with cholecystectomy was performed and histopathological examination of the specimens from the cholecystectomy demonstrated extensive proliferation of large, prominent nerves containing ganglion cells with no atypia mainly located in the gallbladder mucosa. The neural nature of these components was confirmed by immunohistochemical labelling with antibodies specific for synaptophysin, glial fibrillary acidic protein, S100 protein and neurofilaments. Based on these findings, the lesion was diagnosed as ganglioneuromatosis. Reports of ganglioneuromatosis in animals have so far been restricted to the intestine. This is the first case of ganglioneuromatosis affecting the gallbladder in an animal in which no intestinal involvement was apparent.

Anti-Inflammatory Activity of Dehydroandrographolide by TLR4/NF-κB Signaling Pathway Inhibition in Bile Duct-Ligated Mice.

BACKGROUND/AIMS: Clinically, biliary obstruction is often accompanied by progressive inflammation. Dehydroandrographolide (DA) possesses anti-inflammatory properties. However, the anti-inflammatory activities of DA in cholestatic liver injury remain unclear. METHODS: Mice were administered with DA by intraperitoneal injection after bile duct ligation (BDL) on day 1. Then mice were subjected to an ileocecal vein injection of lipopolysaccharide (LPS). Liver function markers, histology, pro-inflammatory cytokine levels, NF-κB activation and fibrosis formation were evaluated in BDL mice with LPS. LPS binding to primary Kupffer cells was examined by high-content cytometers. RESULTS: DA was shown to greatly lower initially higher than normal levels of alanine aminotransferase (ALT) and total bilirubin (TBIL) in the serum and liver of BDL mice with LPS. DA exerted hepatic protective effects that were also confirmed by prolonged survival of BDL mice with LPS. Liver histopathology showed reduced inflammatory cellular infiltration, bile duct proliferation, and biliary necrosis with DA treatment. Furthermore, DA reduced the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 in liver tissue and plasma and showed decreased NF-κB activation in BDL mice with LPS. DA could prevent LPS binding to primary Kupffer cells in the normal liver and BDL mice liver. DA also suppressed LPS-stimulated inflammatory responses by blocking the interaction between LPS and TLR4 in primary Kupffer cells and human LX-2 cells, thereby inhibiting NF-κB activation. CONCLUSION: DA inhibition of inflammation against liver damage following BDL with LPS may be a promising agent for the treatment of cholestatic liver injury.

Evaluation of gallbladder and common bile duct size and appearance by computed tomography in dogs.

The feasibility of using computed tomography (CT) to identify the common bile duct (CBD) and comparison with ultrasonography (US) results were evaluated in normal beagle dogs and dogs without hepatobiliary and pancreatic diseases. In addition, CBD diameters were obtained from CT at the level of the porta hepatis and the duodenal papilla level in dogs with underlying diseases that may cause cholestasis. US is a useful modality in the estimation of gallbladder volume because ejection fraction and CBD diameter from US were not significantly different from those of CT. The normal biliary tract was visible on CT images in 68% of the normal dog group. CBD diameter was not over 3 mm and 3.5 mm at the porta hepatis and duodenal papilla levels, respectively in normal dogs weighing less than 15 kg. Dogs suspected to have cholestasis associated with hepatobiliary or pancreatic diseases had significantly larger CBD than that in normal dogs.

Mast cell stabilization with ketotifen decreases il-13 and cgrp in the ascitic fluid of rats with microsurgical cholestasis

Ascites is one of the most severe complications of cirrhosis with portal hypertension. Since mast cells by type 2 immunity could be involved in the production of portal hypertensive ascites, we are studying the effectiveness of Ketotifen administration, a mast cell stabilizer, to modulate the production of interleukin-13, a type-2 associated cytokine, as well as calcitonin gene-related peptide (CGRP), one important regulator of its production, in the ascitic fluid of microsurgical extrahepatic cholestatic rats. The increased IL-13 and CGRP release in the ascitic fluid of the rats with obstructive cholestasis and its significant reduction after both, prophylactic plus therapeutic and delayed therapeutic oral administration of Ketotifen, allows for proposing that mast cells could play an important role in the etiopathogeny of portal hypertensive ascites

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Laboratory Evaluation of the Liver.

Laboratory evaluation of the hepatobiliary system has an important role in the diagnosis, monitoring, and assessment of patients with hepatobiliary diseases. Serum liver enzyme activities can be divided into markers of hepatocellular injury and cholestasis. Liver function can be assessed in several ways, including assessment of synthetic capacity, measurement of ammonia, and measurement of bile acids. It is essential to have an understanding of the performance characteristics and limitations of these tests in order to use them appropriately. This article reviews the laboratory parameters commonly used to aid diagnosing hepatobiliary disorders in dogs and cats.

Evaluation of coagulation in dogs with partial or complete extrahepatic biliary tract obstruction by means of thromboelastography.

OBJECTIVE: To characterize in vitro coagulation status in a cohort of dogs with extrahepatic biliary tract obstruction (EHBO) and to evaluate these patients for hypercoagulability by means of thromboelastography. DESIGN: Prospective cohort study. Animals-10 dogs with EHBO and 19 healthy control dogs. PROCEDURES: Partial or complete EHBO was confirmed via exploratory celiotomy. Venous blood samples were collected for evaluation of prothrombin time (PT) and activated partial thromboplastin time (APTT); fibrinogen and D-dimer concentrations; protein C and antithrombin activities; and factor VII, VIII, and XI coagulant activities in plasma as well as thromboelastography in whole blood. Thromboelastography variables were measured from the thromboelastography tracing, and a coagulation index was calculated. Thromboelastography results were compared with those of healthy control dogs previously evaluated by the same laboratory. RESULTS: Hypercoagulability was diagnosed in all dogs with EHBO on the basis of a high coagulation index. Thromboelastography variables, including maximal amplitude, α-angle, and coagulation index, were significantly higher, and K (clot formation time) and R (reaction time) were significantly lower in these dogs than in control dogs. All dogs with EHBO had PT and APTT within respective reference ranges. Plasma D-dimer and fibrinogen concentrations were above reference ranges in 8 and 7 dogs, respectively, and protein C and antithrombin activities were below reference ranges in 3 and 1 dogs, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: In vitro hypercoagulability was commonly detected in dogs with naturally occurring EHBO. The traditional view of EHBO as a disease that causes hypocoagulability may need to be reconsidered.

[The use of ultrasonography for diagnosing the cause of colic in cows. A review]. / Kolikdiagnostik mittels Ultraschall beim weiblichen Rind. Eine Übersicht.

Ultrasonography is a very useful technique for diagnosing the cause of colic in cows. It allows visualisation of abnormal reticular contour and occasionally of abnormal contractility in cows with reticuloperitonitis. In right-displaced abomasum, the dilated abomasum can be detected between the right abdominal wall and the liver. Fluid ingesta are seen ventrally and a gas cap of varying size dorsally. Dilated loops of small intestines that are almost always static are the main diagnostic criterion for ileus of the small intestine, but the cause of the ileus can only rarely be determined. Cholestasis can almost always be diagnosed by imaging a dilated biliary system. With obstruction at the level of the hepatic portal, only the intrahepatic biliary ducts are dilated, while a dilatation of the entire biliary tract, including the gallbladder, occurs in the case of an obstruction near the duodenal papilla. Urinary tract diseases cause colic in cows when concrement or inflammatory products become lodged in a ureter. The importance of ultrasonography in the diagnosis of diseases causing colic in cows varies. For example, with colic attributable to ileus of the small intestines, cholestasis or urinary tract disease, ultrasonography is a very useful diagnostic tool. On the other hand, for diagnosis of left or right displacement of the abomasum or caecal dilatation, ultrasonography is generally not required, but it is helpful in difficult cases to confirm or rule out a tentative diagnosis and to avoid an unnecessary exploratory laparotomy.

Cholestasis and cholelithiasis in a domestic ferret (Mustela putorius furo).

A 3-year-old female spayed domestic ferret (Mustela putorius furo) was presented for evaluation of severely increased liver enzyme activities noted prior to anesthesia. The ferret showed no clinical signs of liver or gall bladder disease. Serum biochemical profile confirmed elevations in alanine aminotransferase and alkaline phosphatase activity and total bilirubin concentration. Abdominal ultrasound revealed a distended and convoluted common bile duct although no obstruction was seen. Upon exploratory laparotomy, a large amount of sediment was found within the bile duct that appeared to be obstructing it, but no other cause for the obstruction was found. A choledochoduodenostomy was performed, and the ferret recovered uneventfully from surgery. Liver enzyme activities returned to normal by 5 days post-operatively. Biopsy and culture results yielded no definitive cause of the bile duct obstruction. Cholestasis is a rarely reported disease in ferrets and generally has been described in connection with neoplasia or parasitism, neither of which was found in the current case.

A series of six cases of sphincter of Oddi pathology in the cat (2008-2009).

The sphincter of Oddi (SO) is located within the wall of the duodenum as the terminal part of the common bile duct. Six cats are reported with obstructive processes within their SO. Three of them may have had some form of sphincter dysfunction associated with the pre-existing complex known as 'inflammatory bowel disease' (IBD), two may have had the equivalent of the infant human condition known as 'bile plug syndrome' and the sixth had sphincter dysfunction associated with a tumour at the confluence of the common and right hepatic duct. In all six cases, the sphincter obstructions were surgically managed. The outcomes for 4/6 were favourable but 1/6 was euthanased intraoperatively, and 1/6 had a metastatic neoplasia and was euthanased 2 months postoperatively.

Important clinical syndromes associated with liver disease.

Several clinical syndromes can develop in many different liver diseases. They are important to understanding the clinical manifestations of hepatobiliary diseases. The signs, diagnostic procedures, and specific diseases associated with these syndromes are discussed.