Parenchymal Liver Disease Research Articles

A Clinical Perspective on the Criteria for Liver Resection and the Use of Liver Function Tests

To the Editor, In a recently published survey of 100 liver centers, Breitenstein et al. [1] reported that on a global scale, (1) the average minimal remnant liver volume for resection is 25% (range = 15-40%) for normal liver parenchyma and 50% (range = 25–90%) for cirrhotic livers, (2) portal vein occlusion is employed in 89% of the centers for purposes of augmenting liver volume before surgery, and that (3) 38% of the centers employed liver function tests as part of their clinical routine, of which 76% used the ICG clearance test. The interesting survey provoked a few issues that we feel obliged to address. The authors contend that “below a certain volume, a remnant liver cannot sustain metabolic, synthetic, and detoxifying functions” [1]—a statement that is unequivocal and uncontested. However, it should be born in mind that liver volume is not a directly proportional measure of liver function. We have demonstrated a few fundamental aspects of the volume-function relationship that support this notion: (i) Whereas liver function correlates with volume in uncompromised livers [2], there is significantly less correlation between liver volume and function in patients with coexisting parenchymal liver disease [3, 4]. (ii) This discrepancy also applies to the regenerating liver [3]. (iii) The liver often exhibits functional heterogeneity [3]. These findings have been corroborated to some extent by others [5]. Consequently, a marginal remnant liver volume (e.g., 25% for cirrhotic livers [1]) may translate to functional deficiencies following resection and hence predisposes the organ to the “small-for-size” or, rather, the “small-for-function” syndrome. Likewise, allowing the organ to regenerate to a predetermined volume before resection bears comparable implications and strongly pleads for the use of dynamic liver function tests rather than CT volumetry as the gold standard, particularly for borderline surgical decisions. We emphasize specifically the use of quantitative dynamic liver function tests [i.e., ICG clearance, 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) [2–4], galactose elimination capacity (GEC) [5], and 99mTc-labeled galactosyl human serum albumin scintigraphy (GSAS)] inasmuch as conventional liver function tests such as prothrombin time, serum bilirubin, and the Child-Pugh score are relatively insensitive and are thus lagging indicators for determining whether a liver resection can be safely performed. It is well known that there are notable discrepancies between the above-mentioned dynamic liver function tests in the assessment of liver function. In our patient population, ICG and 99mTc-mebrofenin uptake exhibited similar pharmacokinetics in regenerating rat livers (that also corresponded well to the extent of hepatic damage), whereas the GSAS and GEC tests displayed an underestimation and an overestimation, respectively, of liver function in comparison to ICG and 99mTc-mebrofenin uptake (unpublished). This is because liver function encompasses a broad spectrum of processes, ranging from uptake, synthesis, biotransformation, and systemic and canalicular secretion, whereby each test measures a different component of that spectrum. In summary, criteria on the basis of which extended liver resections are performed should preferably be dictated by functional parameters rather than volume alone, especially when livers are resected to a minimally accepted remnant volume. Furthermore, we advocate the use of dynamic liver function tests such as ICG or 99mTc-mebrofenin uptake for testing liver function due to their sensitivity and prognostic strength. We acknowledge that each of these tests reflects a limited aspect of liver function only. However, currently no better, clinically viable alternatives are available.

Assessment of Future Remnant Liver Function Using Hepatobiliary Scintigraphy in Patients Undergoing Major Liver Resection

Background99mTc-mebrofenin hepatobiliary scintigraphy (HBS) was used as a quantitative method to evaluate liver function. The aim of this study was to compare future remnant liver function assessed by 99mTc-mebrofenin hepatobiliary scintigraphy with future remnant liver volume in the prediction of liver failure after major liver resection. MethodsComputed tomography (CT) volumetry and 99mTc-mebrofenin hepatobiliary scintigraphy were performed prior to major resection in 55 high-risk patients, including 30 patients with parenchymal liver disease. Liver volume was expressed as percentage of total liver volume or as standardized future remnant liver volume. Receiver operating characteristic (ROC) curve analysis was performed to identify a cutoff value for future remnant liver function in predicting postoperative liver failure. ResultsPostoperative liver failure occurred in nine patients. A liver function cutoff value of 2.69%/min/m2 was calculated by ROC curve analysis. 99mTc-mebrofenin hepatobiliary scintigraphy demonstrated better sensitivity, specificity, and positive and negative predictive value compared to future remnant liver volume. Using 99mTc-mebrofenin hepatobiliary scintigraphy, one cutoff value suffices in both compromised and noncompromised patients. ConclusionPreoperative 99mTc-mebrofenin hepatobiliary scintigraphy is a valuable technique to estimate the risk of postoperative liver failure. Especially in patients with uncertain quality of the liver parenchyma, 99mTc-mebrofenin HBS proved of more value than CT volumetry.

Current understanding of osteoporosis associated with liver disease

Osteoporosis is a common complication of many types of liver disease. Research into the pathogenesis of osteoporosis has revealed that the mechanisms of bone loss differ between different types of liver disease. This Review summarizes our current understanding of osteoporosis associated with liver disease and the new advances that have been made in this field. The different mechanisms by which cholestatic and parenchymal liver disease can lead to reduced bone mass, the prevalence of osteopenia and osteoporosis in patients with early and advanced liver disease, and the influence of osteoporotic fractures on patient survival are discussed along with the advances in our understanding of the molecular pathways associated with bone loss. The role of the CSF1-RANKL system and that of the liver molecule, oncofetal fibronectin, a protein that has traditionally been viewed as an extracellular matrix protein are also discussed. The potential impact that these advances may have for the treatment of osteoporosis associated with liver disease is also reviewed.

Is juvenile liver biopsy unsafe? Putting an end to a common misapprehension

Percutaneous needle biopsy of the liver is the most common procedure used in clinical hepatology for histopathological examination and assessment of liver disease, and remains the cornerstone in the evaluation and management of parenchymal liver diseases. Liver biopsy is generally regarded as a safe procedure, but mortality rates up to 1:10,000 have been reported. In 2003, our group showed that routine use of US as a guide to liver biopsy reduces the rate of complications and provides a higher diagnostic yield. To report our experience of US-guided liver biopsy in children. We retrospectively reviewed all 421 liver biopsies performed in our department from October 2003 to December 2008. All samples had been obtained by the US-guided technique. All patients had a liver US examination performed prior to the procedure by the same radiologist performing the biopsy. US guidance allowed constant visualization of the needle leading to appropriate tissue sampling in all 421 children (including 221 obese children), and in 79% of children with only one pass. Pain in the right upper quadrant after liver biopsy was experienced by 36% of patients. US-guided percutaneous biopsy of the liver in children, performed in a specialized tertiary care paediatric centre by experienced and skilled physicians, can be considered safe and effective.

Anaesthesia for hepatic resection surgery

The liver is the only mammalian organ that can regenerate functionally active parenchyma after tissue loss. Exploitation of this physiological property has allowed for the liver resection surgery to develop, and it is now a commonly performed procedure. During the 1970s, perioperative mortality for hepatic resection was quoted around 20%, commonly because of uncontrollable bleeding and postoperative liver failure. Improvements in the understanding of liver anatomy, patient selection, and also surgical and anaesthetic techniques have contributed to a reduction in quoted perioperative mortality to around 3%, although patients with parenchymal liver disease (e.g. cirrhosis) have significantly higher rates of complications and mortality.

Bile duct ligation in rats: A reliable model of hepatorenal syndrome?

The two most widely used experimental models of advanced liver disease are the administration of carbon tetrachloride, and common bile duct ligation (BDL), however, neither has been systematically evaluated as a model of hepatorenal syndrome (HRS). The BDL model in rats, studied at diverse time points, induced a progressive renal dysfunction without structural changes in the kidney. The authors concluded that BDL is a good model for further studies of HRS and its treatment. However, the renal impairment observed at the acute phase of the BDL model is based on a different pathophysiology than that of HRS. Specifically, in acute obstructive jaundice, cholemia predominates over parenchymal liver disease (reversible at this stage without portal hypertension or cirrhosis) and independently induces negative inotropic and chronotropic effects on the heart, impaired sympathetic vasoconstriction response and profound natriuresis and diuresis that might lead to volume depletion. In addition, systemic endotoxemia contributes to the prerenal etiology of renal impairment and promotes direct nephrotoxicity and acute tubular necrosis. On the other hand, the renal failure observed in the chronic BDL model (with development of biliary cirrhosis, portal hypertension and ascites) shares pathophysiological similarities with HRS, but the accordance of the chronic BDL model to the diagnostic criteria of HRS (e.g. absence of spontaneous bacterial peritonitis, no renal function improvement after plasma volume expansion) should have been confirmed. In conclusion, we think that the BDL model is not suitable for the study of the natural history of HRS, but the chronic BDL model might be valid for the study of established HRS and its potential therapies.

The rheological profile of chronic liver disease patients in Nigeria

In chronic liver diseases, liver function is adversely affected and the consequent alterations in blood constituents are known to affect vascular and rheological parameters. The aim of the study was to analyze the rheological profile in chronic liver disease (CLD) patients in Nigeria. Seventy consecutive CLD patients attending the Gastroenterology Clinic of the University of Benin Teaching Hospital, Benin City, Nigeria were studied prospectively over an 8 month period (May-December, 2007). Fifty apparently healthy age-and-sex matched individuals who were prescreened and found serologically negative to HIV 1 and 2, HBsAg and HCV were used as controls. Diagnosis of CLD was based upon histological findings of chronic parenchymal liver disease in the presence of stigmata of CLD. Plasma fibrinogen level was determined by the clot-weight technique. Plasma viscosity, erythrocyte sedimentation rate, haematocrit and platelet count were analysed. Clinico-demographic features, treatment modalities and the complications were analyzed. A total of 120 subjects comprising 70 CLD patients (50 males (71.4%) and 20 females (28.6%)) and 50 controls were studied. Alcoholic cirrhosis (44.3%) was the main risk factor closely followed by viral hepatitis (41.4%). Haematocrit and platelet count of CLD patients were significantly lower than the controls (p<0.001). Plasma fibrinogen concentration and plasma viscosity in CLD patients were significantly lower compared to the controls (p<0.001). CLD patients had low blood viscosity and low fibrinogen level (hypofibrinogenamia) when compared to controls. This may have contributed to the hypocoagulable state and therefore the bleeding tendency encountered in these patients.

Quantitative and qualitative comparison of 3.0 T and 1.5 T MR imaging of the liver in patients with diffuse parenchymal liver disease

Purpose The purpose of our study was to compare signal characteristics and image qualities of MR imaging at 3.0 T and 1.5 T in patients with diffuse parenchymal liver disease. Materials and methods 25 consecutive patients with diffuse parenchymal liver disease underwent abdominal MR imaging at both 3.0 T and 1.5 T within a 6-month interval. A retrospective study was conducted to obtain quantitative and qualitative data from both 3.0 T and 1.5 T MRI. Quantitative image analysis was performed by measuring the signal-to-noise ratios (SNRs) and the contrast-to-noise ratios (CNRs) by the Students t-test. Qualitative image analysis was assessed by grading each sequence on a 3- and 4-point scale, regarding the presence of artifacts and image quality, respectively. Statistical analysis consisted of the Wilcoxon signed-rank test. Results the mean SNRs and CNRs of the liver parenchyma and the portal vein were significantly higher at 3.0 T than at 1.5 T on portal and equilibrium phases of volumetric interpolated breath-hold examination (VIBE) images ( P < 0.05). The mean SNRs were significantly higher at 3.0 T than at 1.5 T on T1-weighted spoiled gradient echo (SGE) images ( P < 0.05). However, there were no significantly differences on T2-weighted short-inversion-time inversion recovery (STIR) images. Overall image qualities of the 1.5 T non-contrast T1- and T2-weighted sequences were significantly better than 3.0 T ( P < 0.01). In contrast, overall image quality of the 3.0 T post-gadolinium VIBE sequence was significantly better than 1.5 T ( P < 0.01). Conclusions MR imaging of post-gadolinium VIBE sequence at 3.0 T has quantitative and qualitative advantages of evaluating for diffuse parenchymal liver disease.

Transjugular liver biopsy: What to do and what not to do

The presence of ascites or deranged bleeding parameters in patients with significant liver parenchymal disease precludes percutaneous liver biopsy (PLB). Transjugular liver biopsy (TJLB) is an important and safer alternative to the traditional method of PLB. This article highlights the technical aspects of the procedure and describes the standard way of performing the procedure, the common problems encountered, and the ways of overcoming them. A transjugular approach to reach the liver was first described by Weiner et al. Transjugular liver biopsy (TJLB)[1,2] is a technique for obtaining liver biopsy without causing a transcapsular injury. Using a transvenous approach, the biopsy needle is inserted into the liver via the hepatic vein, avoiding the peritoneum and the liver capsule. Thus, if there is any bleeding related to the procedure, it will be back into the venous system. Earlier, when aspiration needles[3] were used for biopsy, the quality of the specimen was considered to be inferior to that obtained by percutaneous liver biopsy (PLB). With the advent of the Tru-Cut (Quick-Core biopsy needle, Cook, Bloomington), TJLB specimens have been found to be of the same quality as the PLB specimens.[4–7]

This Month in Gastroenterology

This Month in Gastroenterology

Performing a percutaneous liver biopsy in parenchymal liver diseases

There are many ways of obtaining a liver biopsy sample but the percutaneous method is deemed as one of the simplest and safest methods. Percutaneous liver biopsy (PLB) is a commonly performed procedure carried out for the diagnosis and management of patients with parenchymal liver diseases. It plays a central role in providing histological assessment for either diagnostic or therapeutic purposes. This article describes how PLB is performed at the Royal Free Hospital radiology department, London, under ultrasound guidance, along with indications, contraindications, complications and advantages/disadvantages this method offers. Nursing implications are discussed in terms of assisting, caring and managing for these patients safely. This article aims to raise awareness of PLB and inform the reader how this tissue sample is taken, thus enabling further understanding of this procedure. It is concluded that the percutaneous route of obtaining a liver biopsy enables a good size and quality of sample to be taken in a safe and effective manner, with usually one pass being required with minimal associated complications.

In-vivo-Messung von Geweberelaxationszeiten mit lokalisierter31P- und1H-MR-Spektroskopie

Methods of in vivo determination of 31P longitudinal relaxation times within image-determined volume selected MRI spectroscopy have been investigated. T1 values for phosphor compounds in skeletal muscle and in brain have been measured. The 1H relaxation times of T1 and T2 of diffuse parenchymal liver disease, using inversion recovery and spin echo sequences were compared with quantitative MR tomography. Clinically, spectroscopic techniques are particularly useful where there is superimposition of water and lipid signals during MR imaging.

Liver adenomatosis: re‐evaluation of aetiology and management

Liver adenomatosis (LA) is a rare benign parenchymal liver disease with unknown aetiology. In recent reports, LA has been associated with hepatic steatosis, with potential implications for the management of this disease. The aim of this study was to determine prognosis and optimal management of patients with LA. Clinical presentation, diagnostic studies and management of patients with LA were analysed in our centre. Furthermore, a Medline search of all published case reports and series of LA patients was performed. Ninety-four patients with LA have been reported in the literature. Fifty-two per cent of females had a history of oral contraceptive use. Eighteen per cent of patients had steatosis in nontumoral tissue. In our own series, five of six patients had histologically confirmed steatosis. Forty-three per cent of patients presented with acute pain, of whom 46% had a haemorrhagical complication, in contrast to 2% of nonsymptomatic patients. Tumours <5 cm tended to increase in size during follow-up and only in four patients tumour regression was observed. Liver adenomatosis is a progressive, benign parenchymal disease mainly occurring in females. There is a potential link with hepatic steatosis with implications for the management of patients with LA. Noninvasive diagnosis is difficult because of the variety of tumoral and nontumoral components. Management should primarily be conservative.

Gray-level histogram analysis in the sonographic diagnosis of diffuse parenchymal liver disease

Increased echogenicity is one of the major diagnostic criteria for the subjective evaluation of liver echograms. In our approach to ultrasonic tissue characterisation by B-scan image analysis echogenicity is expressed by parameters deriving from the grey-level histogram. In this study the grey level histograms of a group of normals and patients with diffuse parenchymal liver disease are analysed. When employing the two parameters mean grey level (G) and standard deviation of grey levels (SG) the diagnostic accuracy was 90% (specificity 95%, sensitivity 85%). For subjective evaluation the liver echograms of a randomly selected sub-group of normals and patients were blindly evaluated by three observers who positively correlated the finding of increased echogenicity with the diagnosis of a pathological liver echogram. As demonstrated by our results the two-parameter analysis of the grey-level histogram leads to a quantification of the subjective diagnostic criterion of echogenicity, thus providing useful information for image interpretation.

Limited utility of conventional criteria for predicting unresectable disease in patients with advanced stage epithelial ovarian cancer

Objective To evaluate the predictive value of conventional criteria for identifying surgically unresectable disease among patients with ovarian cancer undergoing initial operative intervention at tertiary referral centers employing a so-called aggressive approach to surgical cytoreduction. Methods All patients with advanced epithelial ovarian cancer undergoing primary surgery between August 1997 and August 2006 were identified. Surgical/pathological documentation of disease extent pre/post-cytoreduction was extracted from the medical record retrospectively. All patients meeting conventional criteria for unresectable disease criteria (ascites> 1000 mL, omental extension to spleen > 1 cm, parenchymal liver disease > 1cm, porta hepatis involvement > 1 cm, diaphragmatic disease > 1 cm, carcinomatosis > 1 cm, and suprarenal adenopathy > 1 cm) were selected for further study. Results A total of 180 consecutive patients had disease meeting conventional criteria for unresectability at = 1 site(s). Optimal cytoreduction (residual disease = 1 cm) was achieved in 166 patients (92.2%). Optimal resection rates according to the most common individual unresectable disease criteria were as follows: ascites > 1000 mL = 91.3% (116/127), carcinomatosis > 1 cm = 91.0% (81/89), and splenic involvement > 1 cm = 84.9% (45/53). For patients with ascites > 1000 mL alone, optimal cytoreduction was achieved in 95.8% (46/48) of cases. Optimal resection rates according to the total number of unresectable disease sites were as follows: 1 site = 95.0% (19/20), 2 sites = 93.8% (61/65), 3 sites = 81.5% (22/27), 4 sites = 93.3% (14/15), and 5 sites = 80.0% (4/5). Conclusions These data suggest that commonly accepted criteria of surgically unresectable disease for women with advanced ovarian cancer lack the necessary precision to guide clinical management. Pre-operative assessment of resectability should be made by an experienced surgical team prior to deferring the initial attempt at surgical cytoreduction.

Percutaneous liver biopsy in clinical practice

Percutaneous liver biopsy (PLB) is the standard procedure for obtaining hepatic tissue for histopathological examination, and remains an essential tool in the diagnosis and management of parenchymal liver diseases. The use of liver biopsy (LB) is increasing with the advent of liver transplantation and the progress being made in antiviral therapeutic agents. While blind percutaneous needle biopsy is the traditional technique, the use of ultrasound (US) guidance has increased considerably. Literatures were reviewed to assess the existing clinical practice of PLB with an emphasis on the technique, the operator, types of biopsy needles, quality of LB specimens and the risk of complications. The best available evidence indicates that the use of ultrasound-guided biopsy (UGB) is superior to blind needle biopsy (BNB). The odds ratios of the controlled studies showed that BNB carried a higher risk for major complications, postbiopsy pain and biopsy failure. Therefore, percutaneous LB under US control is superior to BNB and it is recommended that UGB be considered the standard of care for this important and widely used invasive procedure in the field of clinical hepatology.

Resection for hepatic hemangiomas

A retrospective analysis of outcomes in 34 patients referred to the Academic Medical Center of the University of Amsterdam for management of hepatic hemangiomas appears in this edition of the Journal.1 Fourteen patients underwent resection of hemangiomas because of severe symptoms or diagnostic uncertainty. Only one patient had persisting abdominal pain after resection; however, the follow-up period in this article was relatively short. Liver surgery is becoming increasingly safe as a result of surgical specialization, improvements in the technology used for liver resection, changes in anesthetic practice, and improvements in postoperative care. Consequently, the indications for liver surgery have been extended beyond malignant disease. Increasingly, there are reports in the literature from large institutions describing experience in the management of hepatic hemangiomas.2 The evolution of safe laparoscopic surgery is likely to further this trend. In skilled hands, the argument is no longer about the morbidity and mortality of operative intervention because open and laparoscopic surgical techniques in such units are now of well proven safety, even in the presence of significant parenchymal liver disease. The issue is now appropriate selection of patients for resection of benign liver tumors. It is important to clearly define the indications for surgery for hepatic hemangiomas. In the Amsterdam experience,1 Erdogan et al. state that the indications for resection of hemangiomas remain controversial. It could also be stated that the indications remain limited. For example, it is not entirely clear from their article what is meant by ‘progressive abdominal pain’. Is this continuous abdominal pain, or worsening of abdominal pain, or both? Nor is it clear what is meant by ‘mechanical complaints’. Certainly, the need to exclude other causes of abdominal pain should be stressed, given that the majority of patients who have hepatic hemangiomas will, in fact, have another cause for abdominal pain if pain is present. Erdogan et al. also recommend surgical intervention in patients where there is diagnostic doubt.1 There is no clear statement about what earlier CT scans or other investigations may have found. No mention is made of the role of PET scanning in cases of diagnostic doubt, particularly where an earlier PET has shown glucose avidity of the primary tumor. Clearly an algorithm is required for the investigation of hepatic hemangiomas, especially where risk factors for hepatocellular carcinoma are present, or when there is a past history of gastrointestinal cancer. Furthermore, the importance of reviewing old investigations, particularly previous imaging and operation reports should be emphasized. All these should be seen as routine aspects of the functioning of appropriately specialized hepatobiliary and liver units. Hepatic hemangiomas tend to follow a benign course and some authors recommend a nonoperative approach for the majority of these lesions.3 Many readers of Journal of Gastroenterology and Hepatology will be part of networks of those involved in detection, investigation, and referral of such patients, yet be outside the specialized units which manage them. Clinicians therefore need to be aware of the appropriate algorithms for investigation of liver lesions thought to be hemangiomas and of the factors leading to selection for surgical intervention. They should also be aware of the risks of invasive investigations, especially fine needle aspiration cytology or core biopsy. Finally, they should be aware of the need to refer such patients to hepatobiliary units able to address all the issues encountered in managing these problems. In doing so, clinicians also need to avoid compromising patient outcomes by inappropriate referrals, delays, or invasive investigations. A recent systematic review has given rise to the recommendation for large long-term randomized clinical trials.4 A trial would have to be focused on the issues of relevance, including the various aspects of case selection and the investigation algorithm, a well-defined use of the concept of ‘diagnostic doubt’, and complications of the underlying disease process rather than the complications of surgical therapy and long-term symptom resolution. Unfortunately, largely for logistic reasons, it is unlikely that such trials will be performed. However, some information will accumulate from reported individual unit experiences and comparisons across these. This will improve our understanding of the management of this disease, provided the units involved are appropriately sophisticated and the data collection is of adequate quality.

Liver Embolizations in Oncology. A Review. Part II. Arterial Radioembolizations, Portal Venous Embolizations, Experimental Arterial Embolization Procedures

Arterial embolization of the liver may temporarily retard the growth of its primary and secondary tumors which are both mainly nourished arterially. Addition of radioisotopes, mostly (131)I or (90)Y, results in radioembolizations which predominantly act by radiation and less by ischemia. They may therefore be utilized in the absence of portal venous flow when conventional embolization is hazardous. (131)I-oily radioembolization seems to prolong short-term survival in such patients with unresectable hepatocellular cancers, and to improve the prognosis after resection of hepatocellular cancer. The procedure does however not palliate better than "cold" chemoembolization in patients with preserved portal flow, except for having milder side effects. Embolization with (90)Y-coupled microspheres may shrink primary and secondary liver tumors but has so far unproven effects on survival. Embolization of portal venous branches gives compensatory hypertrophy of the non-embolized liver and can increase the volume of the future remnant liver before resection. This diminishes the risk for postoperative liver failure after extensive resection and/or in the presence of chronic liver disease, and permits wider surgical indications. Tumor growth may however be accelerated, and the hypertrophy is inhibited by severe liver parenchymal disease in which situation the method would be most needed. Experimental use of liver arterial embolizations includes combined arterial and portal embolizations, i.e. "chemical hepatectomy," arterial embolizations before external radiotherapy, administration of boron for neutron capture therapy, immunoembolizations, and future gene therapy.

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 μg/dL, 65–345 μmol/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.

Transient Hyperammonemia Due to Urea Cycle Enzyme Deficiency in Irish Wolfhounds

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. Transient hyperammonemia has a metabolic basis in Irish Wolfhounds. Two related (same sire) litters of Irish Wolfhounds (17 pups) and their parents were studied. 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. 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. 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.