Clinical Spectrum of Children with Acute Hepatitis of Unknown Cause.

BACKGROUND: Since January 2022, there has been an increase in reports of cases of acute hepatitis of unknown cause in children. Although cases have been reported across multiple continents, most have been reported in the United Kingdom. Investigations are ongoing to identify the causative agent or agents. METHODS: We conducted a retrospective study involving children referred to a single pediatric liver-transplantation center in the United Kingdom between January 1 and April 11, 2022. These children were 10 years of age or younger and had hepatitis that met the case definition of the U.K. Health Security Agency for confirmed acute hepatitis that was not hepatitis A through E and did not have a metabolic, inherited or genetic, congenital, or mechanical cause, in the context of a serum aminotransferase level greater than 500 IU per liter. We reviewed medical records and documented demographic characteristics, clinical features, and results of liver biochemical, serologic, and molecular tests for hepatotropic and other viruses, as well as radiologic and clinical outcomes. The outcomes were classified as an improving condition, liver transplantation, or death. RESULTS: A total of 44 children had hepatitis that met the confirmed case definition, and most were previously healthy. The median age was 4 years (range, 1 to 7). Common presenting features were jaundice (in 93% of the children), vomiting (in 54%), and diarrhea (in 32%). Among the 30 patients who underwent molecular testing for human adenovirus, 27 (90%) were positive. Fulminant liver failure developed in 6 patients (14%), all of whom received a liver transplant. None of the patients died. All the children, including the 6 who received liver transplants, were discharged home. CONCLUSIONS: In this series involving 44 young children with acute hepatitis of uncertain cause, human adenovirus was isolated in most of the children, but its role in the pathogenesis of this illness has not been established.

Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative).

BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.

Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.

The effect of end-ischaemic normothermic machine perfusion on donor hepatic artery endothelial integrity.

BACKGROUND: Ex vivo normothermic machine liver perfusion (NMLP) involves artificial cannulation of vessels and generation of flow pressures. This could lead to shear stress-induced endothelial damage, predisposing to vascular complications, or improved preservation of donor artery quality. This study aims to assess the spatial donor hepatic artery (HA) endothelial quality downstream of the cannulation site after end-ischaemic NMLP. METHODS: Remnant HA segments from the coeliac trunk up to the gastroduodenal artery branching were obtained after NMLP (n = 15) and after static cold storage (SCS) preservation (n = 15). Specimens were fixed in 10% neutral buffered formalin and sectioned at pre-determined anatomical sites downstream of the coeliac trunk. CD31 immunohistostaining was used to assess endothelial integrity by a 5-point ordinal scale (grade 0: intact endothelial lining, grade 5: complete denudation). Endothelial integrity after SCS was used as a control for the state of the endothelium at commencement of NMP. RESULTS: In the SCS specimens, regardless of the anatomical site, near complete endothelial denudation was present throughout the HA (median scores 4.5-5). After NMLP, significantly less endothelial loss in the distal HA was present compared to SCS grafts (NMLP vs. SCS: median grade 3 vs. 4.5; p = 0.042). In NMLP specimens, near complete endothelial denudation was present at the cannulation site in all cases (median grade: 5), with significantly less loss of the endothelial lining the further from the cannulation site (proximal vs. distal, median grade 5 vs. 3; p = 0.005). CONCLUSION: Loss of endothelial lining throughout the HA after SCS and at the cannulation site after NMLP suggests extensive damage related to surgical handling and preservation injury. Gradual improved endothelial lining along more distal sites of the HA after NMLP indicates potential for re-endothelialisation. The regenerative effect of NMLP on artery quality seems to occur to a greater extent further from the cannulation site. Therefore, arterial cannulation for machine perfusion of liver grafts should ideally be as proximal as possible on the coeliac trunk or aortic patch, while the site of anastomosis should preferentially be attempted distal on the common HA.

Transarterial chemoembolization of hepatocellular carcinoma before liver transplantation and risk of post-transplant vascular complications: a multicentre observational cohort and propensity score-matched analysis.

BACKGROUND: Transarterial chemoembolization (TACE) in patients with hepatocellular cancer (HCC) on the waiting list for liver transplantation may be associated with an increased risk for hepatic artery complications. The present study aims to assess the risk for, primarily, intraoperative technical hepatic artery problems and, secondarily, postoperative hepatic artery complications encountered in patients who received TACE before liver transplantation. METHODS: Available data from HCC liver transplantation recipients across six European centres from January 2007 to December 2018 were analysed in a 1 : 1 propensity score-matched cohort (TACE versus no TACE). Incidences of intraoperative hepatic artery interventions and postoperative hepatic artery complications were compared. RESULTS: Data on postoperative hepatic artery complications were available in all 876 patients (425 patients with TACE and 451 patients without TACE). Fifty-eight (6.6 per cent) patients experienced postoperative hepatic artery complications. In total 253 patients who had undergone TACE could be matched to controls. In the matched cohort TACE was not associated with a composite of hepatic artery complications (OR 1.73, 95 per cent c.i. 0.82 to 3.63, P = 0.149). Data on intraoperative hepatic artery interventions were available in 825 patients (422 patients with TACE and 403 without TACE). Intraoperative hepatic artery interventions were necessary in 69 (8.4 per cent) patients. In the matched cohort TACE was not associated with an increased incidence of intraoperative hepatic artery interventions (OR 0.94, 95 per cent c.i. 0.49 to 1.83, P = 0.870). CONCLUSION: In otherwise matched patients with HCC intended for liver transplantation, TACE treatment before transplantation was not associated with higher risk of technical vascular issues or hepatic artery complications.

Lay Summary Patients with liver cancer may be treated with transarterial chemoembolization (TACE) during the period on the transplant waiting list. With TACE, chemotherapeutic coils are injected directly into the small arteries supplying the tumour, after which these vessels are closed. The aim of this therapy is to decrease the tumour size and slow down tumour growth. However, concerns are raised that manipulation of the main hepatic artery by TACE may cause damage to the artery itself. If this would result in problems during or after liver transplantation when the artery is connected to the artery supplying the donor liver, this may endanger the donor liver graft survival. The present study shows no increased risk in problems to connect the artery during liver transplantation after TACE treatment. Also, arterial complications after liver transplantation did not occur more frequently if patients had received TACE treatment. The authors therefore conclude that TACE treatment before liver transplantation could be considered a safe approach.

Ex situ Normothermic Split Liver Machine Perfusion: Protocol for Robust Comparative Controls in Liver Function Assessment Suitable for Evaluation of Novel Therapeutic Interventions in the Pre-clinical Setting.

Background: Ex situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results. Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial hemoglobin-based oxygen carrier solution for 6 h. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored. Results: Trends in hepatic artery and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalized for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes. Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions.

Current Treatment Approaches to HCC with a Special Consideration to Transplantation.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The mainstay of treatment of HCC has been both resectional and transplantation surgery. It is well known that, in selected, optimized patients, hepatectomy for HCC may be an option, even in patients with underlying cirrhosis. Resectable patients with early HCC and underlying liver disease are however increasingly being considered for transplantation because of potential for better disease-free survival and resolution of underlying liver disease, although this approach is limited by the availability of donor livers, especially in resectable patients. Outcomes following liver transplantation improved dramatically for patients with HCC following the implementation of the Milan criteria in the late 1990s. Ever since, the rather restrictive nature of the Milan criteria has been challenged with good outcomes. There has also been an increase in the donor pool with marginal donors including organs retrieved following cardiac death being used. Even so, patients still continue to die while waiting for a liver transplant. In order to reduce this attrition, bridging techniques and methods for downstaging disease have evolved. Additionally new techniques for organ preservation have increased the prospect of this potentially curative procedure being available for a greater number of patients.

Liver Transplantation Using Grafts From Donors After Circulatory Death: A Propensity Score-Matched Study From a Single Center.

The use of livers from donation after circulatory death (DCD) is increasing, but concerns exist regarding outcomes following use of grafts from "marginal" donors. To compare outcomes in transplants using DCD and donation after brain death (DBD), propensity score matching was performed for 973 patients with chronic liver disease and/or malignancy who underwent primary whole-liver transplant between 2004 and 2014 at University Hospitals Birmingham NHS Foundation Trust. Primary end points were overall graft and patient survival. Secondary end points included postoperative, biliary and vascular complications. Over 10 years, 234 transplants were carried out using DCD grafts. Of the 187 matched DCDs, 82.9% were classified as marginal per British Transplantation Society guidelines. Kaplan-Meier analysis of graft and patient survival found no significant differences for either outcome between the paired DCD and DBD patients (p = 0.162 and p = 0.519, respectively). Aspartate aminotransferase was significantly higher in DCD recipients until 48 h after transplant (p < 0.001). The incidences of acute kidney injury and ischemic cholangiopathy were greater in DCD recipients (32.6% vs. 15% [p < 0.001] and 9.1% vs. 1.1% [p < 0.001], respectively). With appropriate recipient selection, the use of DCDs, including those deemed marginal, can be safe and can produce outcomes comparable to those seen using DBD grafts in similar recipients.

Adult liver transplantation in the congenital absence of inferior vena cava.

Whereas congenital absence of inferior vena cava observed in paediatric population more often than not, as an isolated or syndromic variety, this is seldom encountered in adult liver transplant recipients. There appear few sporadic reports in the literature on experience of such anomaly in adults. Given the rarity of situation, surprising encounters of such anomalies may pose challenge to the unprepared transplant surgeon and unfavourable outcomes may even have resulted in under-reportage of this condition. In this brief report we document our recent experience with two such cases and this is supplemented with extensive reference to the literature on classification of such anomalies with the endeavour to document implications of such in the adult liver transplant setting.

Comparison of energy metabolism in liver grafts from donors after circulatory death and donors after brain death during cold storage and reperfusion.

BACKGROUND: Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts. METHODS: Microdialysis samples from DCD and DBD allograft parenchyma from cold storage to 48 h after reperfusion were analysed by colorimetric methods. Interstitial lactate, pyruvate and glycerol levels were measured and the lactate/pyruvate ratio was calculated to estimate energy depletion of the grafts. Histological features of ischaemia and reperfusion injury were assessed. RESULTS: Donor age, extent of steatosis and cold ischaemia time were comparable between ten DCD and 20 DBD organs. DCD grafts had higher levels of interstitial lactate (median 11.6 versus 1.2 mmol/l; P = 0.015) and increased lactate/pyruvate ratio (792 versus 38; P = 0.001) during cold storage. There was no significant difference in glycerol levels between DCD and DBD grafts (225.1 versus 127.5 µmol/l respectively; P = 0.700). Rapid restoration of energy levels with lactate clearance, increased pyruvate levels and reduced lactate/pyruvate ratio was seen following reperfusion of functioning DCD grafts, parallel with levels in DBD grafts. Histology revealed more pronounced glycogen depletion in DCD grafts. Three allografts that failed owing to primary non-function showed energy exhaustion with severe glycogen depletion. CONCLUSION: Liver grafts from DCD donors exhibited depletion of intracellular energy reserves during cold storage. Failed allografts showed severe energy depletion. Modified organ preservation techniques to minimize organ injury related to altered energy metabolism may enable better utilization of donor organs after circulatory death.

Current opinion on the role of resection and liver transplantation for hepatocellular cancer.

Hepatocellular carcinoma (HCC) represents one of the most common cancers worldwide with rising incidence in developed countries. The best treatment options with curative intent for patients with HCC are liver resection or transplantation, although the role of hepatic ablative therapies has also been recognized. Surgical resection has emerged as the primary treatment in carefully selected patients of HCC. With the advances in surgical and radiological techniques, the perioperative mortality has been reduced to less than 5 % depending on the extent of resection and hepatic reserve. The role of liver transplantation (LT) as the mainstay of treatment for the majority of patients with HCC has evolved in the last few decades. Historically, the Milan criteria have been considered the gold standard for selecting patients; more expanded selection criteria to include those with more advanced tumors have been implemented in recent years. Living donor liver transplantation (LDLT) has emerged as a way to expand the donor pool and has influenced the role of transplantation for HCC, especially in communities with little access to cadaveric transplantation. Salvage transplantation is an alternative option as it allows a window for the biologically less favorable lesions to declare tumor behavior. Salvage transplantation also decreases the burden on transplant resources. Sirolimus, a novel immunosuppressant drug with anti-tumor effect, may have a role in limiting the severity of recurrent disease after transplantation for HCC, and play an important role in the future management of transplant recipients. This article examines the literature on current status of management of HCC.

Liver resection for metastatic soft tissue sarcoma: an analysis of prognostic factors.

AIM: The aim of this retrospective study was to analyse the outcome following hepatic resection for metastatic STS and to identify factors predicting survival. METHODS: All patients who underwent hepatic resection for metastatic STS between August 1997 and April 2009 were included. The data was obtained from a prospectively maintained database. Patients' demographics, clinico-pathological parameters, overall survival and the factors predicting survival were analysed. RESULTS: Thirty-six patients underwent hepatic resection for metastasis, with a median age of 58 years. The predominant site of primary tumour was the gastro-intestinal tract (50%). Leiomyosarcoma was the most common histological type (54%). The median interval between the primary and metastatic resections was 17 months. Thirteen patients had synchronous tumours. 24 patients had major liver resections and 10 patients had bi-lobar disease. The median number of liver lesions resected was 1(1-6) and the median maximum diameter was 11 cm (1-26 cm). R0 resection was performed in 31 patients. The 1-, 3- and 5-year overall survival from the time of metastasectomy was 90.3%, 48.0% and 31.8% respectively, with a median survival of 24 months. Factors associated with poor survival on univariate analysis were the presence of high grade tumours (p = 0.04), primary leiomyosarcoma (p = 0.01) and positive resection margin of liver metastasis (p = 0.04), whilst multivariate analysis predicted primary leiomyosarcoma as a risk factor for poor survival (p = 0.01). CONCLUSION: Hepatic resection for metastatic STS appears to be valuable in carefully selected patients with acceptable long-term survival. The aim of surgery must be an R0 resection to offer a chance of cure.

Risk factors for litigation following major transectional bile duct injury sustained at laparoscopic cholecystectomy.

BACKGROUND: Bile duct injuries after laparoscopic cholecystectomy often cause long-term morbidity, with a number of patients resorting to litigation. The present study aimed to analyze risk factors for litigation and to quantify the subsequent medicolegal burden. METHODS: A total of 67/106 patients (26 male) with major laparoscopic cholecystectomy bile duct injuries (LCBDI) and a minimum 2-year follow-up, replied to a questionnaire covering patient perception toward the complication, physical/psychological recovery, and subsequent litigation. These data were collated with prospectively collected data related to the LCBDI and subsequent management, and a multivariate regression model was designed to identify potential risk factors associated with litigation. RESULTS: Most patients felt they had been inadequately informed prior to surgery [47/67 (70%)] and after the LCBDI [50/67 (75%)], and a majority remained psychologically traumatized at the time of evaluation [50/67 (75%)]. Of these, 22 patients had started litigation by means of a "letter of demand" (LOD; n = 10) or prosecution (n = 12). Nineteen (19/22%) cases have been closed in favor of the plaintiff. There was no difference between the awards for LOD versus prosecution cases, and average compensation was £40,800 versus £89,875, respectively (p = n.s). On multivariate analysis, age < 52 years (p = 0.03), associated vascular injury (p = 0.014), immediate nonspecialist repair (p = 0.009), and perceived incomplete recovery following LCBDI (p = 0.017) were identified as independent predictors for possible litigation. CONCLUSIONS: On the basis of the present study, nearly one third of patients with major transectional LCBDI are likely to resort to litigation. Younger patients and those in whom repair is attempted prior to specialist referral are likely to initiate litigation.

Life-threatening bleeding from duodenal varices due to pancreatic arterio-venous malformation: role of emergency pancreatoduodenectomy.

Life-threatening gastrointestinal bleeding due to arterio-venous malformation around the pancreatic head is a rare clinical entity. Herein we report a 60-year-old male patient with uncontrolled bleeding from varices of the duodenum due to pancreatic arterio-venous malformation, who was treated by emergency surgery. Upper GI endoscopy revealed bleeding from juxta-ampullary duodenal varices. While contrast-enhanced CT demonstrated a hypervascular mosaic lesion in the region of the pancreatic head, subsequent selective angiography confirmed the presence of the malformation. The patient underwent selective transcatheter arterial embolization, but despite successful embolization of the gastroduodenal artery, bleeding continued and the patient became hemodynamically unstable, at which point he was referred to our department. He underwent an emergency pancreatoduodenectomy with exteriorization of pancreatic juice. During surgery the superior mesenteric vein was very thin (3mm) and was misdiagnosed as a right colic vein, and subsequently divided in this situation. After accomplishing pancreatoduodenectomy, the superior mesenteric vein was reconstructed. During reconstruction of the vein, small bowel congestion became apparent and a temporary porto-systemic bypass was created. Reconstruction was performed by the standard modified Child procedure except for exteriorization of the pancreatic juice. The patient made an uneventful postoperative recovery. Pancreatojejunostomy (2nd stage) was carried out three months after the emergency surgery. Emergency pancreatoduodenectomy is a definitive life-saving procedure when other forms of management such as transcatheter arterial embolization have been exhausted. In this rare situation, the superior mesenteric vein is extremely thin and therefore care should be taken not to damage it.

Sexual and urinary dysfunction following rectal dissection compared with segmental colectomy.

INTRODUCTION: The aim of this study was to assess the impact of nerve sparing surgery and major abdominal surgery on sexual and urinary function in men and women with colorectal cancer undergoing rectal dissection and segmental colectomy. METHOD: Forty-eight patients (group A: 22 males, 26 females; median age 55 years) undergoing rectal dissection were compared with 24 having segmental colectomy (group B: 12 male, 12 female; median age 55 years). Preoperative data were also compared with age- and gender-matched controls (group C). RESULTS: More patients after rectal dissection vs segmental colectomy had urinary tract infections [15 (31%) vs 3 (17.5%), P = 0.04]. At 37 months, urinary dysfunction after rectal excision was seen in 29 (60%; 20 men) vs nine (37.5%; eight men) after segmental colectomy. Postoperative urinary symptoms were significant in group A, but not in group B (pre: vs post; groups A and B: poor stream--13%vs 38%, P = 0.001 and 21%vs 21%, P = NS; incontinence--4.2%vs 17%, P = 0.008 and 8%vs 8%, P = NS; hesitancy--13%vs 35%, P = 0.034 and 17%vs 21%, P = NS). Sexual health was worse after rectal excision compared with segmental colectomy (men--62.5%, women--25%vs 44% of men) respectively. Erectile dysfunction was the chief cause (rectal excision--50%vs segmental colectomy - 33%). After rectal excision, 6% of women had dyspareunia and 19% reported reduced orgasm but none after segmental colectomy. Conclusion More men than women had urinary and sexual impairment after rectal excision than after segmental colectomy. Its aetiology is multifactorial.