Dynamic associations between glucose and ecological momentary cognition in Type 1 Diabetes.

Type 1 diabetes (T1D) is a chronic condition characterized by glucose fluctuations. Laboratory studies suggest that cognition is reduced when glucose is very low (hypoglycemia) and very high (hyperglycemia). Until recently, technological limitations prevented researchers from understanding how naturally-occurring glucose fluctuations impact cognitive fluctuations. This study leveraged advances in continuous glucose monitoring (CGM) and cognitive ecological momentary assessment (EMA) to characterize dynamic, within-person associations between glucose and cognition in naturalistic environments. Using CGM and EMA, we obtained intensive longitudinal measurements of glucose and cognition (processing speed, sustained attention) in 200 adults with T1D. First, we used hierarchical Bayesian modeling to estimate dynamic, within-person associations between glucose and cognition. Consistent with laboratory studies, we hypothesized that cognitive performance would be reduced at low and high glucose, reflecting cognitive vulnerability to glucose fluctuations. Second, we used data-driven lasso regression to identify clinical characteristics that predicted individual differences in cognitive vulnerability to glucose fluctuations. Large glucose fluctuations were associated with slower and less accurate processing speed, although slight glucose elevations (relative to person-level means) were associated with faster processing speed. Glucose fluctuations were not related to sustained attention. Seven clinical characteristics predicted individual differences in cognitive vulnerability to glucose fluctuations: age, time in hypoglycemia, lifetime severe hypoglycemic events, microvascular complications, glucose variability, fatigue, and neck circumference. Results establish the impact of glucose on processing speed in naturalistic environments, suggest that minimizing glucose fluctuations is important for optimizing processing speed, and identify several clinical characteristics that may exacerbate cognitive vulnerability to glucose fluctuations.

Acute liver failure in children: A regional experience.

OBJECTIVE: To review the outcome of acute liver failure (ALF) and the effect of liver transplantation in children in Australia. METHODOLOGY: A retrospective review was conducted of all paediatric patients referred with acute liver failure between 1985 and 2000 to the Queensland Liver Transplant Service, a paediatric liver transplant centre based at the Royal Children's Hospital, Brisbane, that is one of three paediatric transplant centres in Australia. RESULTS: Twenty-six patients were referred with ALF. Four patients did not require transplantation and recovered with medical therapy while two were excluded because of irreversible neurological changes and died. Of the 20 patients considered for transplant, three refused for social and/or religious reasons, with 17 patients listed for transplantation. One patient recovered spontaneously and one died before receiving a transplant. There were 15 transplants of which 40% (6/15) were < 2 years old. Sixty-seven per cent (10/15) survived > 1 month after transplantation. Forty per cent (6/15) survived more than 6 months after transplant. There were only four long-term survivors after transplant for ALF (27%). Overall, 27% (6/22) of patients referred with ALF survived. Of the 16 patients that died, 44% (7/16) were from neurological causes. Most of these were from cerebral oedema but two patients transplanted for valproate hepatotoxicity died from neurological disease despite good graft function. CONCLUSIONS: Irreversible neurological disease remains a major cause of death in children with ALF. We recommend better patient selection and early referral and transfer to a transplant centre before onset of irreversible neurological disease to optimize outcome of children transplanted for ALF.

Hepatectomy for pyogenic liver abscess.

BACKGROUND: Commensurate with the advances in diagnostic and therapeutic radiology in the past two decades, percutaneous needle aspiration and catheter drainage have replaced open operation as the first choice of treatment for both single and multiple pyogenic liver abscesses. There has been little written on the place of surgical resection in the treatment of pyogenic liver abscess due to underlying hepatobiliary pathology or after failure of non-operative management. METHODS: The medical records of patients who underwent resection for pyogenic liver abscess over a 15-year period were retrospectively reviewed. The demographics, time from onset of symptoms to medical treatment and operation, site of abscess, organisms cultured, aetiology, reason for operation, type of resection and outcome were analysed. There were 49 patients in whom the abscesses were either single (19), single but multiloculated (11) or multiple (19). The median time from onset of symptoms to medical treatment was 21 days and from treatment to operation was 12 days. The indications for operation were underlying hepatobiliary pathology in 20% and failed non-operative treatment in 76%. Two patients presented with peritonitis from a ruptured abscess. RESULTS: The resections performed were anatomic (44) and non-anatomic (5). No patient suffered a recurrent abscess or required surgical or radiological intervention for any abdominal collection. Antibiotics were ceased within 5 days of operation in all but one patient. The median postoperative stay was 10 days. There were two deaths (4%), both following rupture of the abscess. DISCUSSION: Except for an initial presentation with intraperitoneal rupture and, possibly, cases of hepatobiliary pathology causing multiple abscesses above an obstructed duct system that cannot be negotiated non-operatively, primary surgical treatment of pyogenic liver abscess is not indicated. Non-operative management with antibiotics and percutaneous aspiration/drainage will be successful in most patients. If non-operative treatment fails, different physical characteristics of the abscesses are likely to be present and partial hepatectomy of the involved portion of liver is good treatment when performed by an experienced surgeon.

Iatrogenic bile duct injury: the scourge of laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy (LC) has become the first-line surgical treatment of calculous gall-bladder disease and the benefits over open cholecystectomy are well known. In the early years of LC, the higher rate of bile duct injuries compared with open cholecystectomy was believed to be due to the 'learning curve' and would dissipate with increased experience. The purpose of the present paper was to review a tertiary referral unit's experience of bile duct injuries induced by LC. METHODS: A retrospective analysis was performed on all patients referred for management of an iatrogenic bile duct injury from 1981 to 2000. For injuries sustained at LC, details of time between LC and recognition of the injury, time from injury to definitive repair, type of injury, use of intraoperative cholangiography (IOC), definitive repair and postoperative outcome were recorded. The type of injury sustained at open cholecystectomy was similarly classified to allow the severity of injury to be compared. RESULTS: There were 131 patients referred for management of an iatrogenic bile duct injury that occurred at open cholecystectomy (n = 62), liver resection (n = 5) and at LC (n = 64). Only 39% of bile duct injuries were recognized at the time of LC. Following conversion to open operation, half the subsequent procedures were considered inappropriate. When the injury was not recognized during LC, 70% of patients developed bile leak/peritonitis, almost half of whom were referred, whereas the rest underwent a variety of operative procedures by the referring surgeon. The remainder developed jaundice or abnormal liver function tests and cholangitis. An IOC was performed in 43% of cases, but failed to identify an injury in two-thirds of patients. The bile duct injuries that occurred at LC were of greater severity than with open cholecystectomy. Following definitive repair, there was one death (1.6%). Ninety-two per cent of patients had an uncomplicated recovery and there was one late stricture requiring surgical revision. CONCLUSIONS: The early prediction that the rate of injury during LC would decline substantially with increased experience has not been fulfilled. Bile duct injury that occurs at LC is of greater severity than with open cholecystectomy. Bile duct injury is recognized during LC in less than half the cases. Evidence is accruing that the use of cholangiography reduces the risk and severity of injury and, when correctly interpreted, increases the chance of recognition of bile duct injury during the procedure. Prevention is the key but, should an injury occur, referral to a specialist in biliary reconstructive surgery is indicated.

Liver transplantation: current status and future prospects.

The enormous progress that has been made in liver transplantation over the past two decades has culminated in survival approaching 90% at 12 months. The success of the procedure combined with the widening spectrum of disease processes deemed amenable to liver transplantation has meant that there are too few donors for those awaiting transplantation. This has extrapolated to many patients having such advanced disease by the time a suitable donor liver is available, that they are almost non-transplantable. The immediate options facing the transplant community are to decrease the number of patients listed or to increase the number of living donor transplants. Alternatives to liver transplantation such as hepatocyte transplantation, gene therapy, xenotransplantation and the bioartificial liver are being sought but, at best, are some way from clinical application. It is anticipated that a number of liver diseases that are indications for liver transplantation at this time will have progression arrested or will be cured by medical therapy in the future.

J.H. Louw Memorial Lecture. Liver surgery: 'traveller, there is no path, a path is made by walking'.

Liver resection today is a product of rapid development over the past two decades. The description of the functional anatomy of the liver was the foundation of modern liver surgery. However, it has been the technological advances in radiology that have had the biggest impact in the management of hepatobiliary disease. Major hepatectomies dominated the earlier experience of modern liver surgery, but segment-orientated resections now play a more prominent role. Resections may be performed for both malignant and benign lesions or as an emergency procedure for trauma or other catastrophic event. At Princess Alexandra Hospital, Brisbane, 1,108 liver resections have been undertaken. Of the elective resections, 45% were for metastases, 29% for primary malignancy and 26% for benign disease. Two-thirds of the 102 emergency hepatectomies were for severe liver trauma. The 30-day mortality was 3.2% for the total series, 2.6% for the elective cases and 1.5% for the elective, non-jaundiced patients. Innovative graft reduction techniques have become a major component in liver transplantation. The successful transplantation of a reduced-size segmental graft from an adult donor liver to an infant paved the way for other procedures such as split-liver, auxiliary partial orthotopic and living-donor transplantation.

Surgical complications and long-term outcome in pediatric liver transplantation.

BACKGROUND/AIMS: Liver transplantation has been widely accepted for the treatment of children with end-stage liver disease over the last 10 years particularly with the advent of reduced-size liver transplant technique. This study reviewed the perioperative and long-term results in the pediatric program of the Queensland Liver Transplant Service, Brisbane, Australia. METHODOLOGY: Retrospective analysis was performed in 153 children who received 176 liver grafts between 1985 and 1995, including 109 (62%) reduced-size and 67 (38%) whole liver grafts. Median follow-up period was 5.3 years. RESULTS: One-, 5-, and 10-year patient and graft survival rates were 82% and 74%, 75% and 63%, and 70% and 60%, respectively. Normal physical and intellectual development was observed in 98% of survivors. There were no significant differences in patient or graft survival rates between transplants using reduced-size and whole liver grafts. Portal vein thrombosis was the most common vascular complication, occurring in 8%. Hepatic artery thrombosis occurred in 7%, including 11% of children less than 1 year old and 8% of those under 10 kg. Biliary complication was found in 16% and posttransplant gastrointestinal perforation in 19%. CONCLUSIONS: Liver transplantation has the potential to cure and allow development in children with end-stage liver disease.

Transplantation for liver and biliary cancer.

The early survival of patients transplanted for liver and biliary cancer is excellent, but the overall mid- to long-term survival is poor. In an era of severe donor organ shortage, it is not justified to allocate donor liver to patients with a suboptimal outcome. Patients with non-resectable hepatocellular carcinoma in a non-cirrhotic liver should not be assigned to liver transplantation. Although patients with the fibrolamellar variant have a somewhat better outlook, they are still likely to recur, and the young age of many of these patients is likely to overwhelm any rational approach. The results of transplantation for early-stage hepatocellular carcinoma in a cirrhotic liver are similar to those achieved with benign disease. The inclusion of such cases as a group is justified, but attempts should be made to resect tumors whenever possible and to not assign the entire group to transplantation as the first and only option. The value of pre- and postoperative adjuvant therapy for this group is still under debate, but the present waiting period is so long that some form of therapy to slow growth and prevent dissemination of tumor cells is probably required. The results following transplantation for cholangiocarcinoma can only be regarded as dismal, and the diagnosis of cholangiocarcinoma is a contraindication for the procedure. Liver transplantation has a definite place in the treatment of epithelioid hemangioendothelioma and unresectable chemo-responsive hepatoblastoma when confined to the liver, and in a limited number of metastatic neuroendocrine tumors.

Fibrous obliterative lesions of veins contribute to progressive fibrosis in chronic liver allograft rejection.

Fibrosis in liver allografts undergoing chronic rejection (CR) is variable and poorly understood. The temporal and spatial relationships of venous, arterial, and biliary lesions were studied to clarify their potential contributions to graft fibrosis. The severity, prevalence, and morphology of intimal lesions of vessels were analyzed and compared with the fibrosis stage. Three groups were found; group 1 (n = 5) with no hepatic vein (HV) lesions, group 2 (n = 5) with HV lesions only, and group 3 with lesions of both HV and portal veins (PV). The earliest lesion to develop, in 71% of grafts, was concentric intimal thickening of small HV. This was significantly more severe and frequent in grafts from group 3. With increasing frequency and severity of small HV sclerosis, fibrosis developed in medium/large veins. The morphology of larger vessel lesions suggested organized thrombus. Centrilobular fibrosis was significantly more severe in group 3 and developed unpredictably and sometimes rapidly. Conversely, portal fibrosis scores were significantly higher in grafts with ductular proliferation and did not correlate with venous lesions. This suggests that in CR, veno-occlusive-like lesions develop commonly in terminal hepatic venules, probably caused by immune-mediated damage. In only a proportion, with increased frequency and severity of the lesions, stasis and thrombosis in portal and larger veins occur and could result in loss of hepatic and portal venous outflow, which leads to ischemia and fibrosis. The stage of fibrosis did not correlate with foam-cell arteriopathy. A second pathway of portal fibrosis occurs in patients with longstanding biliary proliferation.

Confirmation of the role of the Mayo Risk Score as a predictor of resource utilization after orthotopic liver transplantation for primary biliary cirrhosis.

Resource utilization is an important consideration when patients are selected for orthotopic liver transplantation (OLT). The Mayo Risk Score has been proposed to help predict optimum time for OLT. We assessed the relation between Mayo risk score, Child-Pugh score, and resource utilization and outcome after OLT for primary biliary cirrhosis. The mean Mayo risk score was greater in patients who died than in the survivors (8.6 +/- 1.4 v 7.1 +/- 1.8; P <.05). There was a positive correlation between Mayo risk score and the 4 resource variables studied (intraoperative blood requirements, time ventilated, and duration of intensive care unit and hospital stays). Patients with a Mayo risk score greater than 7.8 used almost twice the resources of patients with a risk score less than 7.8. A positive correlation also existed between Child-Pugh score and duration of hospital stay. The mean Child-Pugh score in patients who died was greater than that in survivors (10.7 +/- 2.0 v 8.5 +/- 2.8, P =.03). This study confirms that Mayo Risk score is an important predictor of resource utilization and outcome after OLT.

Liver transplantation for familial amyloidotic polyneuropathy in Australia.

Familial amyloidotic polyneuropathy type 1 (FAP-1) is a type of systemic amyloidosis caused by mutant transthyretin (mTTR) that is mainly produced in the liver. Most patients have progressive peripheral and autonomic neuropathy. Ten patients with FAP underwent orthotopic liver transplantation (OLT) at the Queensland Liver Transplant Service (Princess Alexandra Hospital, Brisbane, Australia). Nine patients are still alive, and one patient died of cardiac failure 10 days after OLT. Some symptoms of FAP were alleviated in some of the patients. OLT seems to be a worthwhile treatment for FAP, because it halts the progression of symptoms and achieves improvement in some patients.

Clinicopathological analysis of liver allograft biopsies with late centrilobular necrosis: a comparative study in 54 patients.

BACKGROUND: Centrilobular necrosis (CLN) in liver allografts can be a difficult lesion to interpret histologically. Although long recognized in association with developing chronic rejection, recent studies have described the lesion in association with a number of other disease processes. To clarify the histologic features that could allow a specific diagnosis to be made and to determine the outcome in different diagnostic groups, we assessed biopsies from 54 patients with CLN. METHODS: Biopsies were classified as CLN with acute cellular rejection (ACR), CLN with hepatitis, CLN with developing chronic rejection (CR), and CLN of other etiology. Histologic features were assessed and then compared between groups, and clinical outcomes were noted. RESULTS: Discriminating features for the different groups were as follows: CLN and ACR showed bile duct injury, endothelialitis, and acinar congestion. CLN and CR showed severe bile duct injury, bile duct loss, or centrilobular swelling. CLN and hepatitis was often a diagnosis of exclusion, although interface hepatitis was more common in this group. Cases of autoimmune hepatitis usually demonstrated plasma cell predominance in the portal and acinar inflammatory infiltrate. Significantly, there was considerable overlap in the histologic features between the groups, accounting for the diagnostic difficulty. Patients in whom the CLN was associated with CR or vascular complications generally required retransplantation or died, but in the groups with ACR and hepatitis, the outcome was more favorable. CONCLUSIONS: With regard to most liver allograft biopsies showing late CLN, it is possible to make a specific diagnosis despite overlapping histologic features; this allows specific therapy to be instituted. Ultimately this is likely to contribute to improved graft survival.

Expression of cytokines and factors modulating apoptosis by human sinusoidal leucocytes.

BACKGROUND/AIMS: Liver sinusoids contain a large population of spontaneously cytotoxic cells (NK cells), CD8+ T cells and macrophages. The physiological role of these leucocytes remains unclear. They may participate in immune surveillance and peripheral tolerance by deleting tumour cells, virus-infected cells and activated T cells as they traffic through the liver. In order to gain further information about the function of these leucocytes within the hepatic sinusoids, we examined their production of immunomodulatory cytokines and apoptosis-related molecules. METHODS: Semi-quantitative polymerase chain reaction and immunohistochemistry were used to determine the spontaneous production of cytokines and apoptosis-related molecules by sinusoidal leucocytes isolated from donor liver preservation solution. RESULTS: In comparison with matched peripheral blood mononuclear cells, sinusoidal leucocytes produced more mRNA for IL-10, IL-15, TNF-alpha, IL-18, IFN-gamma, FasL, perforin and granzyme. IL-4 and IL-12 were not detected and IL-2 was only faintly detected in the liver-derived CD4+ population. Less bcl-2 was expressed in liver-derived CD4+ and CD8+ cells in comparison with matched peripheral blood cell populations. CONCLUSIONS: The cytokines produced spontaneously by sinusoidal leucocytes are consistent with their high level of activation and spontaneous cytotoxicity. Their strong expression of apoptosis-mediating molecules (FasL, perforin, granzyme and TNF-alpha) support a role for these cells in immune surveillance and peripheral tolerance induction.

The effects of circulating interleukin-8 and adhesion molecules on pulmonary dysfunction in pediatric orthotopic liver transplantation.

We investigated the effects of circulating inflammatory cytokines and adhesion molecules induced by ortho-topic liver transplantation (OLT) on pulmonary function. Although the plasma interleukin-8 (IL-8) levels increased gradually, peaking at the end of the operation, these increases were considered minimal. The baseline endothelial adhesion molecule (E-selectin) level was several times higher than the normal value, but after reperfusion of the new transplanted liver, the plasma E-selectin concentrations decreased to within the normal range and remained almost normal during the postoperative period. Similar changes were observed in the plasma levels of other types of adhesion molecules. Although PaO(2)/FIO(2) showed a significant inversed correlation with the peak IL-8 concentration, after the exclusion of two patients, one of whom died and one of whom rejected the transplanted liver, no correlation was able to be found between the PaO(2)/FIO(2) ratio and the maximum IL-8 concentration. Furthermore, there was no correlation between the adhesion moleclues and PaO(2)/FIO(2). These results suggest that IL-8 exerts only a slight effect on respiratory function following successful pediatric liver transplantation, and that circulating adhesion molecules do not affect perioperative lung function.

1998 Distinguished Academician Lecture: hepatic resection--a Western perspective.

During the past two decades, resection of the liver has progressed from a rarely to a commonly performed operation with a low morbidity and mortality. The description of the functional anatomy of the liver was instrumental in the change from non-anatomic to anatomic resections. Major hepatectomies dominated the early experience but segment orientated resections now play a more prominent role. Resections may be performed for a variety of malignant or benign lesions or as an emergency for trauma or other catastrophic event. In the author's institution, 923 liver resections have been performed. The indications for the 825 elective resections were: metastases (46%), primary malignancy (30%) and non-malignant disease (24%). Two-thirds of the 98 emergency hepatectomies were for severe liver trauma. The 30-day mortality was 3.6% for the total series; 2.9% for elective resection, 1.6% for the non-jaundiced patients. In the last 300 elective resections, there has been one postoperative death and the median blood transfusion was zero. The development of innovative graft reduction techniques has made a major contribution to liver transplantation. The lack of suitable whole liver grafts for paediatric recipients was addressed by volume of reduction of adult donor livers so that the left lateral segment could be implanted safely in an infant's abdomen. This technique was the forerunner of split-liver transplantation, auxiliary partial orthotopic transplantation and living-related liver transplantation.

The management of blunt liver injuries.

Although the general surgeon who takes emergency call may be confronted with a patient who has sustained a blunt liver injury, the decrease in road trauma and work-place accidents has meant that this will be an infrequent occurrence. Minimal exposure will, of necessity, extrapolate to difficulty in coping with a catastrophic event which comes unheralded, at an inconvenient time and usually when there is less than ideal support. During the past 15 years, there has been an evolution in the treatment of liver injuries which is exemplified by a non-operative approach in selected patients and more conservative procedures in those who require operative intervention. At present, 'damage control' is in vogue; do the least possible to control life-threatening injuries and come back another day. This is a cogent and admirable philosophy, provided that the pendulum does not swing too far and that a planned course of action is in place. This paper reviews the present status of managing blunt liver injuries, with an emphasis on the general surgeon who has little cause to be involved with surgery of the liver.