K. C. L. Lee

Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study

Background & Aims In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. Methods Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n = 9); Acetaminophen plus Control Device (n = 7); and Control plus Control Device (n = 4). Device treatment was initiated two h after onset of irreversible acute liver failure. Results The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio = 0.33, p = 0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p = 0.046); 54% reduction in overall severity of endotoxaemia (p = 0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. Conclusions The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients.

A reproducible, clinically relevant, intensively managed, pig model of acute liver failure for testing of therapies aimed to prolong survival

A clinically relevant, translational large animal model of acute liver failure (ALF) is required for testing of novel therapies to prolong survival in acute liver failure, to permit spontaneous liver recovery or to act as a bridge to transplantation.

Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats.

BACKGROUND & AIMSnIn liver failure, ammonia homeostasis is dependent upon the function of the ammonia metabolising enzymes, glutamine synthetase (GS) and glutaminase (GA) but data about their protein expression and activity are lacking. The aims of this study were to determine the protein expression and activity of GS and GA in individual organs in a rat model of chronic liver disease and to test whether the treatment with the ammonia-lowering agent ornithine phenylacetate (OP) modulates their activities.nnnMETHODSn49 SD rats were studied 35 days after sham-operation or bile duct ligation (BDL). The BDL group received: L-ornithine (0.6 mg/kg/day), Phenylacetate (0.6 mg/kg/day), OP (0.6 mg/kg/day) or placebo (saline) for 5 days prior to sacrifice. Arterial ammonia, amino acids and liver biochemistry were measured. Expressions of GS and GA were determined by Western-blotting and activities by end-point methods in liver, muscle, gut, kidney, lung, and frontal cortex.nnnRESULTSnIn BDL rats, hepatic GS enzyme activity was reduced by more than 80% compared to sham rats. Further, in BDL rats GA activity was reduced in liver but increased in the gut, muscle and frontal cortex compared to sham rats. OP treatment resulted in a reduction in hyperammonemia in BDL rats, associated with increased GS activity in the muscle and reduced gut GA activity.nnnCONCLUSIONSnIn a rat model of chronic liver failure, hyperammonemia is associated with inadequate compensation by liver and muscle GS activity and increased gut GA activity. OP reduces plasma ammonia by increasing GS in the muscle and reducing GA activity in the gut providing additional insights into its mechanism of its action. GS and GA may serve as important future therapeutic targets for hyperammonemia in liver failure.

Computed tomographic findings in 44 dogs and 10 cats with grass seed foreign bodies

OBJECTIVEnTo supplement recent reports of computed tomographic (CT) findings in dogs and cats with grass seed foreign bodies.nnnMETHODSnRetrospective review of cases that had CT scan and subsequent retrieval of a grass seed during the same period of hospitalisation from a site included in the scan.nnnRESULTSnRecords of 44 dogs and 10 cats were reviewed. Most were presented in the months July to December. Median duration of clinical signs was 4 weeks (range 2 days to 2 years). The most frequent clinical signs were soft tissue swelling (30% cases), coughing (28%), sneezing (28%) and discharge (26%). Grass seeds were retrieved from the thorax (35% cases), nasal cavity (31%), ear (7%), other sites in the head and neck (22%), sublumbar muscles (2%) and pelvic limb (2%). The grass seed was visible in CT images in 10 (19%) cases. Secondary lesions were visible in CT images of 52 (96%) cases, including collection of exudate (37%), abscess (24%), enlarged lymph nodes (22%) and pulmonary consolidation (20%). CT images appeared normal in 4% animals.nnnCLINICAL SIGNIFICANCEnGrass seeds within the respiratory tract are frequently visible in CT images, but in general CT appears to be more useful for localisation of secondary lesions than as a method of definite diagnosis.

Radial Artery Pseudoaneurysm in a Maine Coon Cat

OBJECTIVEnTo report the diagnosis and treatment of a radial artery pseudoaneurysm in a cat.nnnSTUDY DESIGNnClinical report.nnnANIMALnMaine Coon cat (8-year-old neutered male).nnnMETHODSnUltrasonographic and angiographic examination of a fluctuant, nonpainful, 3 cm × 1.5 cm subcutaneous swelling on the craniomedial distal aspect of the right radius that occurred 40 days after suspected cat bite trauma was consistent with a radial artery pseudoaneurysm. After ligation of the radial artery proximal to the lesion, the pseudoaneurysm was surgically excised.nnnRESULTSnThe excised tissue had hemorrhage and fibrin surrounded by a thick fibrous granulating capsule of variably mature fibroblasts and focal areas of inflammatory cells (lymphocytes, plasma cells, and macrophages) consistent with a pseudoaneurysm. Surgical excision resulted in resolution of clinical signs.nnnCONCLUSIONSnUltrasonography enabled prompt, noninvasive diagnosis of pseudoaneurysm. Angiography or computed tomography may be useful to aid diagnosis and assess the collateral blood supply to the manus before surgical treatment.

Clinical findings and results of diagnostic imaging in 82 dogs with gastrointestinal ulceration

OBJECTIVESnTo describe clinical and imaging findings in dogs with confirmed gastrointestinal ulceration, to compare findings in dogs with perforated and non-perforated ulcers and to estimate the sensitivities of radiography, ultrasonography and computed tomography (CT) for gastrointestinal ulceration and perforation.nnnMETHODSnRetrospective review of medical records of 82 dogs that had a macroscopic ulcer in the gastric or intestinal mucosa diagnosed directly at endoscopy, surgery or necropsy and had survey radiography, ultrasonography or a CT scan of the abdomen during the same period of hospitalisation.nnnRESULTSnThe most frequent clinical signs were vomiting in 88% dogs, haematemesis in 32%, melaena in 31% and weight loss in 7%. The most frequent imaging findings in dogs with non-perforated ulcers were gastrointestinal mural lesion in 56%, mucosal defect compatible with an ulcer in 44% and peritoneal fluid in 21%. In dogs with perforated ulcers the most frequent imaging findings were peritoneal fluid in 83%, gastrointestinal mural lesion in 48%, peritoneal gas in 31% and mucosal defect compatible with an ulcer in 29%. Sensitivities of radiography, ultrasonography and CT were 30, 65 and 67% in dogs with non-perforated ulcers and 79, 86 and 93% in dogs with perforated ulcers, respectively.nnnCLINICAL SIGNIFICANCEnIn dogs with non-perforated ulcers, survey radiography was usually negative whereas ultrasonography and CT frequently enabled detection of the site of the ulcer; in dogs with perforated ulcers, radiography was frequently positive for peritoneal gas and CT was a sensitive modality for both the ulcer and signs of perforation.

Salmonella hepatic abscess as a sequel to liver lobectomy and biopsy in a dog with hepatocellular adenoma

A dog underwent complete surgical excision of a hepatocellular adenoma by right lateral liver lobectomy and incisional biopsy of a regenerative hepatic nodule of the left lateral lobe. The dog re-presented eight months later with weakness, pyrexia and elevated liver enzymes. CT demonstrated a large irregular isodense left liver mass. The mass was resected by left lateral liver lobectomy. Histopathology and culture revealed hepatic abscess with Salmonella species. Surgery was followed by a six-week course of cephalexin, resulting in cure. This is the first report of successful treatment of hepatic abscess involving Salmonella species in a dog, following liver lobectomy and liver biopsy for management of hepatocellular adenoma. This report highlights hepatic abscesses as a potential late complication of surgery for hepatocellular neoplasia; reviews potential challenges in diagnosing hepatic abscesses on the basis of ultrasound and CT; and demonstrates successful treatment of hepatic salmonellosis, a potential zoonotic infection.

RESULTS OF COMPUTED TOMOGRAPHY IN DOGS WITH SUSPECTED WOODEN FOREIGN BODIES

Detection of wooden foreign bodies in dogs can be challenging. A retrospective, cross-sectional study was done to describe computed tomographic (CT) signs associated with wooden foreign bodies, and to estimate the accuracy of CT for detection of wooden foreign bodies. Patient records and CT images were reviewed for 72 dogs that had a history of suspected stick injury and CT of the affected body part, or possible wooden foreign object reported on CT, and had surgical exploration during the same period of hospitalization. Duration of clinical signs was acute in 48 (67%) dogs and chronic in 24 (33%). Wood was removed from 55 dogs, including a piece of a tree or shrub in 33 (60%) instances, kebab stick in 8 (15%), piece of bamboo garden cane in 2 (4%), cocktail stick in 2 (4%), thorn in 1 (2%), and unidentified wood in the remaining nine instances. Based on review of CT images with knowledge of the surgical findings, sensitivity of CT for wooden foreign bodies was 79% (95% CI 65%-89%), specificity 93% (78%-98%), positive likelihood ratio 11.5 (2.9-44.1), and negative likelihood ratio 0.23 (0.13-0.41). Wooden foreign bodies were predominantly rectangular or linear, with median length 48 mm (range 2-270 mm), median thickness 3 mm (range 1-22 mm), and median attenuation 111 HU (range -344 to +640 HU). A CT finding of gas in soft tissues was significantly associated with acute cases, whereas suspected foreign material, cavitary lesions, fat stranding, and periosteal reaction on adjacent bones were associated with chronic cases.

PTU-008 A reproducible, clinically-relevant, intensively-managed, pig model of acute liver failure for testing of therapies aimed to prolong survival

Introduction Hospitalisations from acetaminophen poisoning are increasing (1999, n=39u2008045; 2010, n=52u2008707. UK, NHS admissions). For the most serious cases there are no effective therapies to assist recovery or prolong survival apart from liver transplantation, which remains a limited resource. We report a clinically-relevant, intensively-managed, model of ALF, which mimics the human condition and has a predictable survival time, for testing of new potential therapies. Methods Nine, 30–40u2005kg, female pigs were anaesthetised and instrumented for continuous monitoring and management of respiratory and cardiovascular systems and acid-base and electrolyte status, using standardised intensive care protocols and intermittent positive pressure ventilation. Intracranial pressure (ICP) was monitored but not treated. Six animals were induced to ALF with acetaminophen administered via an oroduodenal tube: a loading dose of 0.25u2005g/kg was followed by hourly doses of 0.5–4.0u2005g adjusted according to serum acetaminophen concentrations. At irreversible ALF (defined as prothrombin time >3 times normal), continuous renal replacement therapy (CRRT) was initiated. Three animals acted as controls with initiation of CRRT at 20u2005h and termination at 40u2005h. Results Following onset of acetaminophen dosing, peak serum acetaminophen concentrations of 367±30u2005mg/l were achieved at 12u2005h and irreversible ALF at 19.3±1.8u2005h. Death occurred predictably 12.6±2.7u2005h after irreversible ALF. Development of ALF was associated with progressive hypotension (p<0.001) and metabolic acidosis (p=0.001), not observed in controls. Mean arterial pressure (MAP) was maintained with aggressive fluid therapy, noradrenaline and terlipressin. Metabolic acidosis was corrected successfully with bicarbonate and CRRT. In ALF, there was significant (p<0.001) rise in ICP compared to controls with sudden marked increase prior to death: at study end, ICP in ALF and controls was 41.2±8.6u2005mmu2002Hg and 22.7±2.5u2005mmu2002Hg respectively. Death was preceded by abrupt increase in central venous pressure, fall in MAP and bradycardia. Histopathology confirmed moderate to marked acute centrilobular to midzonal hepatocyte degeneration and necrosis in ALF. Conclusion A predictable model of ALF, with death due to multi-organ failure, has been successfully validated for translational studies for therapies designed to prolong survival in man. Competing interests None declared.