Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity.

BACKGROUND & AIMS: Hepatitis B surface antigen (HBsAg) loss or functional cure (FC) is considered the optimal therapeutic outcome for patients with chronic hepatitis B (CHB). However, the immune-pathological biomarkers and underlying mechanisms of FC remain unclear. In this study we comprehensively interrogate disease-associated cell states identified within intrahepatic tissue and matched PBMCs (peripheral blood mononuclear cells) from patients with CHB or after FC, at the resolution of single cells, to provide novel insights into putative mechanisms underlying FC. METHODS: We combined single-cell transcriptomics (single-cell RNA sequencing) with multiparametric flow cytometry-based immune phenotyping, and multiplexed immunofluorescence to elucidate the immunopathological cell states associated with CHB vs. FC. RESULTS: We found that the intrahepatic environment in CHB and FC displays specific cell identities and molecular signatures that are distinct from those found in matched PBMCs. FC is associated with the emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes, and an activated innate response represented by liver-resident natural killer cells, specific Kupffer cell subtypes and marginated neutrophils. Surprisingly, we found MHC class II-expressing hepatocytes in patients achieving FC, as well as low but persistent levels of covalently closed circular DNA and pregenomic RNA, which may play an important role in FC. CONCLUSIONS: Our study provides conceptually novel insights into the immuno-pathological control of HBV cure, and opens exciting new avenues for clinical management, biomarker discovery and therapeutic development. We believe that the discoveries from this study, as it relates to the activation of an innate and altered immune response that may facilitate sustained, low-grade inflammation, may have broader implications in the resolution of chronic viral hepatitis. IMPACT AND IMPLICATIONS: This study dissects the immuno-pathological cell states associated with functionally cured chronic hepatitis B (defined by the loss of HBV surface antigen or HBsAg). We identified the sustained presence of very low viral load, accessory antigen-presenting hepatocytes, adaptive-memory-like natural killer cells, and the emergence of helper CD4 T cells with cytotoxic or effector-like signatures associated with functional cure, suggesting previously unsuspected alterations in the adaptive immune response, as well as a key role for the innate immune response in achieving or maintaining functional cure. Overall, the insights generated from this study may provide new avenues for the development of alternative therapies as well as patient surveillance for better clinical management of chronic hepatitis B.

Long-term outcomes following percutaneous hepatic vein recanalization for Budd-Chiari syndrome.

BACKGROUND & AIMS: A proportion of patients with Budd-Chiari Syndrome (BCS) associated with stenosis or short occlusion of the hepatic vein (HV) or upper inferior vena cava (IVC) can be treated with recanalization by percutaneous venoplasty ± HV stent insertion. We studied the long-term outcomes of this approach. METHODS: Single-centre retrospective analysis of patients referred for radiological assessment ± intervention over a 27-year period. Of 155 BCS patients, 63 patients who underwent venoplasty were studied and compared to a previously reported series treated by TIPSS (n = 59). RESULTS: Patients treated with HV interventions (32 venoplasty alone, 31 endovascular stents): mean age, 34.9 ± 10.9; M:F ratio 27:36; median follow-up, 113.0 months; 62% of patients had ≥1 haematological risk factor. Technical success was 100%, with symptom resolution in 73%. Cumulative secondary patency at 1, 5, 10 years was 92%, 79%, 79% and 69%, 69%, 64% in the stenting and venoplasty groups respectively. Where long-term patency was not achieved, 10 patients required TIPSS, and 8 underwent surgery. Actuarial survival at 1, 5, 10 years was 97%, 89% and 85%. When compared to TIPSS, HV interventions resulted in similar patency and survival rates but significantly lower procedural complications (9.5% vs 27.1%) and hepatic encephalopathy (0% vs 18%). Patient age predicted survival following multivariate analysis. CONCLUSIONS: Our data support the stepwise approach to management of BCS, with very good outcomes from venoplasty combined with stenting when required. TIPSS should only be offered where HV interventions are not feasible or unsuccessful.

The role of Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPSS) in the management of variceal hemorrhage.

BACKGROUND: Variceal bleeding in cirrhosis represents a lethal complication of their disease. In the last 20 years, management of AVH has improved greatly with reduction in mortality from 43% in 1980 to 15% in 2000. AIM: Advances in endoscopic therapy, pharmacologic agents including vasoconstrictor therapy and antibiotics have played a large part in improving outcomes, but the role of Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPSS) remains controversial, which this review will cover. METHODS: MEDLINE search for the following terms was performed to July 2011: variceal hemorrhage, portal hypertension, cirrhosis, transjugular intrahepatic portosystemic stent-shunt (TIPSS), PTFE, covered stents. Where possible randomized controlled studies were used for this review, although uncontrolled studies were also included if they made a significant contribution to the literature. RESULTS: Literature used for the present study was selected from a total of 252 publications and abstracts from meetings. RESULTS: TIPSS has been used as a salvage therapy after initial medical and endoscopic therapy for the bleed given its high success rate in arresting uncontrolled variceal bleeding. The recent trial by Garcia- Pagan et al. suggested beneficial effects of an earlier covered TIPSS in those at high risk of treatment failure (Childs C and those who are Childs B with active bleeding). CONCLUSIONS: TIPSS can reduce failure to control bleeding and rebleeding as well as mortality with no increase in the risk of hepatic encephalopathy.This needs to be confirmed in further trials. However, it is clear that prevention of rebleeding is the key to improved outcomes following a variceal bleed.

A case-controlled study of the safety and efficacy of transjugular intrahepatic portosystemic shunts after liver transplantation.

The role of transjugular intrahepatic portosystemic shunt (TIPS) insertion in managing the complications of portal hypertension is well established, but its utility in patients who have previously undergone liver transplantation is not well documented. Twenty-two orthotopic liver transplantation (OLT) patients and 44 nontransplant patients (matched controls) who underwent TIPS were analyzed. In the OLT patients, the TIPS procedure was performed at a median of 44.8 months (range = 0.3-143 months) after transplantation. Eight (36.4%) had variceal bleeding, and 14 (63.6%) had refractory ascites. The underlying liver disease was cholestatic in 10 (45.4%) and viral in 4 (18.2%). The mean pre-TIPS Model for End-Stage Liver Disease (MELD) score was 13.4 ± 5.1. There were no significant differences in age, sex, indication, etiology, or MELD score with respect to the control group. The mean initial portal pressure gradients (PPGs) were similar in the 2 groups (21.0 versus 22.4 mm Hg for the OLT patients and controls, respectively), but the final PPG was lower in the control group (9.9 versus 6.9 mm Hg, P < 0.05). The rates of both technical success and clinical success were higher in the control group versus the OLT group [95.5% versus 68.2% (P < 0.05) and 93.2% versus 77.2% (P < 0.05), respectively]. The rates of complications and post-TIPS encephalopathy were similar in the 2 groups, and there was a trend toward increased rates of shunt insufficiency in the OLT group. The mortality rate of the patients with a pre-TIPS MELD score > 15 was significantly higher in the OLT group [hazard ratio (HR) = 4.32, 95% confidence interval (CI) = 1.45-12.88, P < 0.05], but the mortality rates of the patients with a pre-TIPS MELD score < 15 were similar in the 2 groups. In the OLT group, the predictors of increased mortality were the pre-TIPS MELD score (HR = 1.161, 95% CI = 1.036-1.305, P < 0.05) and pre-TIPS MELD scores > 15 (HR = 5.846, 95% CI = 1.754-19.485, P < 0.05). In conclusion, TIPS insertion is feasible in transplant recipients, although its efficacy is lower in these patients versus control patients. Outcomes are poor for OLT recipients with a pre-TIPS MELD score > 15.

The outcomes of biliary drainage by percutaneous transhepatic cholangiography for the palliation of malignant biliary obstruction in England between 2001 and 2014: a retrospective cohort study.

INTRODUCTION: Relieving obstructive jaundice in inoperable pancreato-biliary cancers improves quality of life and permits chemotherapy. Percutaneous transhepatic cholangiography with drainage and/or stenting relieves jaundice but can be associated with significant morbidity and mortality. Percutaneous transhepatic biliary drainage (PTBD) in malignant biliary obstruction was therefore examined in a national cohort to establish risk factors for poor outcomes. METHODS: Retrospective study of adult patients undergoing PTBD for palliation of pancreato-biliary cancer in England between 2001 and 2014 identified from Hospital Episode Statistics. Multivariate logistic regression analysis was used to examine associations with mortality and the need for a repeat PTBD within 2 months. RESULTS: 16 822 patients analysed (median age 72 (range 19-104) years, 50.3% men). 58% pancreatic and 30% biliary tract cancer. In-hospital and 30-day mortality were 15.3% (95% CI 14.7% to 15.9%) and 23.1% (22.4%-23.8%), respectively. 20.2% suffered a coded complication within 3 months. Factors associated with 30-day mortality: age (≥81 years OR 2.68 (95% CI 2.37 to 3.03), p<0.001), increasing comorbidity (Charlson score 20+, 3.10 (2.64-3.65), p<0.001), pre-existing renal dysfunction (2.37 (2.12-2.65), p<0.001) and non-pancreatic cancer (unspecified biliary tract 1.28 (1.08-1.52), p=0.004). Women had lower mortality (0.91 (0.84-0.98), p=0.011), as did patients undergoing PTBD in a 'higher volume' provider (84-180 PTBDs per year 0.68 (0.58-0.79), p<0.001). CONCLUSIONS: In patients undergoing PTBD for the palliation of malignant biliary obstruction, 30-day mortality was high at 23.1%. Mortality was higher in older patients, men, those with increasing comorbidity, a cancer site other than pancreas and at 'lower-volume' PTBD providers.

Improved Accuracy of Percutaneous Biopsy Using "Cross and Push" Technique for Patients Suspected with Malignant Biliary Strictures.

PURPOSE: Various methods have been used to sample biliary strictures, including percutaneous fine-needle aspiration biopsy, intraluminal biliary washings, and cytological analysis of drained bile. However, none of these methods has proven to be particularly sensitive in the diagnosis of biliary tract malignancy. We report improved diagnostic accuracy using a modified technique for percutaneous transluminal biopsy in patients with this disease. MATERIALS AND METHODS: Fifty-two patients with obstructive jaundice due to a biliary stricture underwent transluminal forceps biopsy with a modified "cross and push" technique with the use of a flexible biopsy forceps kit commonly used for cardiac biopsies. The modification entailed crossing the stricture with a 0.038-in. wire leading all the way down into the duodenum. A standard or long sheath was subsequently advanced up to the stricture over the wire. A Cook 5.2-Fr biopsy forceps was introduced alongside the wire and the cup was opened upon exiting the sheath. With the biopsy forceps open, within the stricture the sheath was used to push and advance the biopsy cup into the stricture before the cup was closed and the sample obtained. The data were analysed retrospectively. RESULTS: We report the outcomes of this modified technique used on 52 consecutive patients with obstructive jaundice secondary to a biliary stricture. The sensitivity and accuracy were 93.3 and 94.2%, respectively. There was one procedure-related late complication. CONCLUSION: We propose that the modified "cross and push" technique is a feasible, safe, and more accurate option over the standard technique for sampling strictures of the biliary tree.

The Role of Interventional Radiology in Treating Complications following Liver Transplantation.

Liver transplantation (LT) is used to treat both adult and pediatric patients with end-stage liver disease or acute liver failure. It has become more prevalent as both the surgical technique and postoperative care have improved resulting in a reduced morbidity and mortality. As a result, there are more patients surviving longer after liver transplantation. Despite this, there remain serious complications from the procedure that have a significant outcome on the patient and may result in retransplantation. At the same time, there have been significant advances in the field of interventional radiology both in terms of technology and how these apply to the patients. In this paper, we review the commonest complications, diagnostic tests, and interventional management options available.

Hepatic hydrothorax in the absence of ascites.

A previously well 66-year-old woman presented with a recurrent transudative right-sided pleural effusion. A nodular liver with coarse echotexture was demonstrated on ultrasound and subsequent MRI found hepatocellular carcinoma. In the absence of cardiopulmonary disease and significant protein uria, the recurrent pleural effusion was presumed to be hepatic hydrothorax despite the absence of ascites or other clinical features of chronic liver disease. The patient is currently awaiting liver transplantation.

A case-control study of transjugular intrahepatic portosystemic stent shunts for patients admitted to intensive care following variceal bleeding.

INTRODUCTION: Variceal bleeding has a 6-week mortality of 20%. Recent evidence suggests that early covered transjugular intrahepatic portosystemic stent shunts (TIPSS) can improve outcomes following a variceal bleed in selected patients. We aim to assess the outcomes following the insertion of covered TIPSS in a real-life intensive care setting. MATERIALS AND METHODS: This is a retrospective matched cohort study of all patients referred for TIPSS with variceal bleeding admitted to intensive care (2007-2009). Patients were matched with others admitted to intensive therapy unit following a variceal bleed but did not proceed to TIPSS. All TIPSS procedures were carried out using polytetrafluoroethylene-covered stents. RESULTS: Thirty-eight patients [mean age 55.2 years; mean model for end-stage liver disease (MELD)=14.0; and median follow-up 458 days] were assessed. Nineteen underwent TIPSS and were well matched to the controls. All patients received terlipressin and antibiotics and 86% had active bleeding at endoscopy. Indication for TIPSS was salvage therapy (47%), rebleeding after day 5 (11%) and as secondary prophylaxis (42%). There was 34% all-cause inpatient mortality. The TIPSS group had lower mortality than the non-TIPSS group at 6 weeks (10.5 vs. 47.4%, P<0.05) that persisted at 1 year (21.1 vs. 52.6%, P<0.05). Multivariate analysis indicated MELD [HR 1.131, 95% confidence interval (CI) 1.018-1.257] and TIPSS (HR 0.301, 95% CI 0.091-0.995) as significant predictors of mortality (P<0.05). TIPSS was found to significantly reduce the incidence of failure to control bleeding and rebleeding (HR 0.120, 95% CI 0.015-0.978, P<0.05). CONCLUSION: Patients with recent severe variceal bleeding admitted to intensive care have significantly better outcomes following covered TIPSS insertion. These findings should be validated in randomized-controlled trials.

Transhepatic embolisation of a traumatic broncho-biliary fistula: a novel approach.

Bronchobiliary fistula is a rare and challenging condition that most commonly presents worldwide following infection with hydatid cystic disease of the liver but is increasingly seen in cases of trauma involving the right upper quadrant. The most common presenting complaint is biliptysis. Treatment is initially aimed at decompressing the biliary tree which allows a considered approach for closure of the fistulous tract. Options range from conservative management to endoscopic and percutaneous approaches. Traditionally definitive treatment would have been surgical and may ultimately have resulted in hepatic and/or pulmonary segmentectomy. Current management strategies of this potentially serious condition are variable. We describe a particularly challenging case in which interventional embolisation with microcoils was used in an attempt to treat persistent post-traumatic bronchobiliary fistula in a tertiary centre. We describe this technique and hope that it is may be of useful reference for those contemplating a similar approach.

Embolization of bleeding stomal varices by direct percutaneous approach.

Stomal varices can occur in patients with stoma in the presence of portal hypertension. Suture ligation, sclerotherapy, angiographic embolization, stoma revision, beta blockade, portosystemic shunt, and liver transplantation have been described as therapeutic options for bleeding stomal varices. We report the case of a 21-year-old patient with primary sclerosing cholangitis and colectomy with ileostomy for ulcerative colitis, where stomal variceal bleeding was successfully treated by direct percutaneous embolization. We consider percutaneous embolization to be an effective way of treating acute stomal bleeding in decompensated patients while awaiting decisions regarding shunt procedures or liver transplantation.