Microbiota and Gut-Liver Axis: An Unbreakable Bond?

The gut microbiota, amounting to approximately 100 trillion (1014) microbes represents a genetic repertoire that is bigger than the human genome itself. Evidence on bidirectional interplay between human and microbial genes is mounting. Microbiota probably play vital roles in diverse aspects of normal human metabolism, such as digestion, immune modulation, and gut endocrine function, as well as in the genesis and progression of many human diseases. Indeed, the gut microbiota has been most closely linked to various chronic ailments affecting the liver, although concrete scientific data are sparse. In this narrative review, we initially discuss the basic epidemiology of gut microbiota and the factors influencing their initial formation in the gut. Subsequently, we delve into the gut-liver axis and the evidence regarding the link between gut microbiota and the genesis or progression of various liver diseases. Finally, we summarise the recent research on plausible ways to modulate the gut microbiota to alter the natural history of liver disease.

Randomized controlled trial of sustained release tacrolimus vs twice daily tacrolimus in adult living donor liver transplantation.

BACKGROUND: To compare the safety and efficacy of once-daily tacrolimus (ODT) versus twice-daily tacrolimus (BDT) in adult live donor liver transplantation (LDLT). METHODS: In this open-labelled randomized trial, 174 adult patients undergoing LDLT were randomized into ODT or BDT, combined with basiliximab induction and mycophenolate mofetil (steroid-free regimen). Tacrolimus was started at a total dose of 1 mg and the trough level was aimed at 3-7 ng/ml. The primary endpoint was eGFR at 1,3- and 6 months post-transplant, using CKD- EPI equation. Secondary endpoints included biopsy-proven acute rejection (BPAR), metabolic complications, post-operative bilio-vascular complications and patient survival. RESULTS: There was no statistically significant difference in eGFR between the two groups at 6 months (ODT -96 ± 19, BDT -91 ± 21, p value-0.164). BPAR was comparable (18/84 in ODT, 19/88 in BDT, p value-0.981). For a similar dosage of tacrolimus, the median trough tacrolimus levels attained were significantly lower for ODT than BDT during the first-month post-transplant (p value-0.001). Metabolic complications due to immunosuppression, post-operative bilio-vascular complications and patient survival was similar between the two groups at 6 months. CONCLUSION: Once-daily tacrolimus has similar renal safety and efficacy as twice-daily tacrolimus when used in combination with basiliximab induction and mycophenolate in adult LDLT.

Immunosuppression in Liver Transplant Recipients in the Setting of Sepsis.

Management of immunosuppression (IS) in liver transplant recipients in the setting of sepsis is an open stage for debate. The age-long practice of reduction or complete cessation of IS during sepsis has been followed by most centres across the world, although, their exact strategies are highly heterogeneous. On the other hand, the emergence of striking new evidence suggesting that there is, in fact, decreased mortality with the continuation of IS in sepsis, has raised doubts about our previously conceived intuitive notion that IS portends increased risk in sepsis. The theory postulated is that IS agents, perhaps reverse the state of dysregulated immune response in sepsis to that of an iatrogenically modulated immune response, thus dimming the inflammatory cascade and preventing its deleterious effects. Of note, none of these studies reported exaggerated rejection-related complications. These contrasting outlooks have made it rather onerous to formulate an evidence-based recommendation for liver transplant recipients afflicted with sepsis. Inclusion of transplanted patients in randomised controlled trials of sepsis-related interventions seems to be the need of the hour.

Open to robotic right donor hepatectomy: A tectonic shift in surgical technique.

Robotic right live donor hepatectomy (r-LDRH) has been reported with reduced morbidity compared to open donor right hepatectomy (o-LDRH) in few recent series. Nevertheless, its routine use is debated. We present a large series comparing pure r-LDRH with o-LDRH. Consecutive r-LDRH performed from June 2018 to June 2020 (n = 102) were compared with consecutive donors undergoing o-LDRH (n = 152) from February 2016 to February 2018, a period when r-LDRH was not available at this center. Propensity score matched (PSM) analysis of 89 case-control pairs was additionally performed. Primary endpoints were length of high dependency unit (HDU) and hospital stay and Clavien-Dindo graded complications among donors. Although r-LDRH took longer to perform (540 vs. 462 min, P < .001), the postoperative peak transaminases levels (P < .001), the length of HDU (3 vs. 4 days, P < .001), and hospital stay (8 vs. 9 days, P < .001) were lower in in donors undergoing r-LDRH. Clavien-Dindo graded complications were similar (16.67% in r-LDRH and 13.16% in o-LDRH). The rates of early allograft dysfunction (1.6% vs. 3.3%), bile leak (14.7% vs. 10.7%), and 1-year mortality (13.7% vs. 11.8%) were comparable between r-LDRH and o-LDRH recipients. PSM analysis yielded similar results between the groups. These data support the safety and feasibility of r-LDRH in select donors.

A randomized, double-blinded, placebo-controlled trial analyzing the effect of synbiotics on infectious complications following living donor liver transplant-PREPRO trial.

BACKGROUND: Following liver transplantation (LT), bacterial infections occur in over 70% of recipients leading to significant morbidity and mortality. While synbiotics have been reported to decrease infectious complications in various surgical procedures, the evidence of their benefits following LT remains limited. METHODS: In this 18-month double-blinded, investigator-initiated, placebo-controlled trial, 100 recipients of live donor liver transplant (LDLT) were randomized to receive either the synbiotic drug Prowel® (Prepro arm) or a placebo, starting 2 days pretransplant and continued for 2 weeks. The primary endpoint was culture-proven bacterial infection in blood, urine or drain fluid within 30 days. Secondary endpoints were hospital stay, noninfectious complications, antibiotic usage and 30-day mortality. RESULTS: Overall infectious complications were significantly lower in the Prepro arm in comparison to the Placebo arm (44% vs 22%, P = .019, OR 0.359; CI: 0.150-0.858). Blood stream infections were significantly less in the study arm (21.7% vs 53.3%, P = .020, OR 0.243; CI: 0.072-0.826), whereas urinary tract and intra-abdominal infections were similar. Length of hospital stay, noninfectious complications, deviation from protocol antibiotics and 30-day mortality were comparable. CONCLUSION: Synbiotics administered for 2 weeks following LDLT significantly reduced overall and blood stream infectious complications in the early postoperative period. However, there was no difference in hospital stay, noninfectious complications, antibiotic usage and mortality. Clinical Trial Registry of India registration number - CTRI/2017/09/009869.

Extended criteria donors for robotic right hepatectomy: A propensity score matched analysis.

BACKGROUND: Robotic right donor hepatectomy (RDH) has been reported from experienced centers with reduced morbidity when compared to open RDH. However, outcomes in donors with large grafts/complex biliovascular anatomy are unknown. METHODS: Out of 170 robotic RDH, 100 had one or more of the following: graft weight ≥800 g, type 2/3 portal vein, >1 bile duct or hepatic artery and inferior hepatic veins >5 mm requiring reconstruction (extended criteria donors [ExRDH]), while the remaining 70 had standard anatomy (SRDH). After propensity score matching, 66 ExRDH were compared with 66 SRDH. Additionally, all robotic RDH performed were analyzed in three temporal phases (60, 60, and 50). RESULTS: Peak AST and ALT were higher amongst donors and recipients in the ExRDH arm compared to SRDH. Other intraoperative parameters and postoperative complications were similar between the two groups. During the last phase, donors demonstrated reduction in duration of surgery, postoperative complications, and hospital stay while recipients showed decreased blood loss and hospital stay. CONCLUSION: Robotic right hepatectomy performed in donors with extended criteria have similar perioperative outcomes as standard donors. However, a significant learning curve needs to be traversed. Further studies are required before safely recommending robotic RDH for all donors.

Technique of robotic right donor hepatectomy.

BACKGROUND: Although minimally invasive right donor hepatectomy (RDH) has been reported, this innovation is yet to be widely accepted by transplant community. Bleeding during transection, division of right hepatic duct (RHD), suturing of donor duct as well as retrieval with minimal warm ischemia are the primary concerns of most donor surgeons. We describe our simplified technique of robotic RDH evolved over 144 cases. PATIENTS AND METHODS: Right lobe mobilization is performed in a clockwise manner from right triangular ligament over inferior vena cavae up to hepatocaval ligament. Transection is initiated using a combination of bipolar diathermy and monopolar shears controlled by console surgeon working in tandem with lap CUSA operated by assistant surgeon. With the guidance of indocyanine green cholangiography, RHD is divided with robotic endowrist scissors (Potts), and remnant duct is sutured with 6-0 PDS. Final posterior liver transection is completed caudocranial without hanging manoeuvre. Right lobe with intact vascular pedicle is placed in a bag, vascular structures then divided, and retrieved through Pfannenstiel incision. CONCLUSION: Our technique may be easy to adapt with the available robotic instruments. Further innovation of robotic platform with liver friendly devices could make robotic RDH the standard of care in future.

Middle hepatic vein reconstruction in adult living donor liver transplantation: a randomized clinical trial.

BACKGROUND: In adult right lobe living donor liver transplantation (LDLT), venous drainage of the anterior sector is usually reconstructed on the bench to form a neo-middle hepatic vein (MHV). Reconstruction of the MHV for drainage of the anterior sector is crucial for optimal graft function. The conduits used for reconstruction include cryopreserved allografts, synthetic grafts, or the recipient portal vein. However, the ideal choice remains a matter of debate. This study compares the efficacy of the native recipient portal vein (RPV) with PTFE grafts for reconstruction of the neo-MHV. METHODS: Patients in this equivalence-controlled, parallel-group trial were randomized to either RPV (62 patients) or PTFE (60 patients) for use in the reconstruction of the neo-MHV. Primary endpoint was neo-MHV patency at 14 days and 90 days. Secondary outcomes included 90-day mortality and post-transplant parameters as scored by predefined scoring systems. RESULTS: There was no statistically significant difference in the incidence of neo-MHV thrombosis at 14 days (RPV 6.5 per cent versus PTFE 10 per cent; P = 0.701) and 90 days (RPV 14.5 per cent versus PTFE 18.3 per cent; P = 0.745) between the two groups. Irrespective of the type of graft used for reconstruction, 90-day all-cause and sepsis-specific mortality was significantly higher among patients who developed neo-MHV thrombosis. Neo-MHV thrombosis and sepsis were identified as risk factors for mortality on Cox proportional hazards analysis. No harms or unintended side effects were observed in either group. CONCLUSION: In adult LDLT using modified right lobe graft, use of either PTFE or RPV for neo-MHV reconstruction resulted in similar early patency rates. Irrespective of the type of conduit used for reconstruction, neo-MHV thrombosis is a significant risk factor for mortality. REGISTRATION NUMBER: CTRI/2018/11/016315 (www.ctri.nic.in).

Randomized trial of steroid free immunosuppression with basiliximab induction in adult live donor liver transplantation (LDLT).

BACKGROUND: Corticosteroids are an integral part of immunosuppression following solid organ transplantation, despite their metabolic complications. We conducted a randomized trial to evaluate the efficacy of steroid-free immunosuppression following live donor liver transplantation (LDLT). METHODS: We randomized 104 patients stratified based on pre-transplant diabetic status to either a steroid-free arm (SF-arm) (Basiliximab + Tacrolimus and Azathioprine,n = 52) or Steroid arm (S-Arm) (Steroid + Tacrolimus + Azathioprine,n = 52). The primary endpoint was the occurrence of metabolic complications (new-onset diabetes after transplant (NODAT), new-onset systemic hypertension after transplant (NOSHT), post-transplant dyslipidemia) within 6 months after transplant. Secondary endpoints included biopsy-proven acute rejection (BPAR) within six months, patient and graft survival at 6 months. RESULTS: The incidence NODAT was significantly higher in S-arm at 3 months (64.5%vs. 28.1%,p-0.004) and 6 months (51.6% vs. 15.6%,p-0.006). Likewise, the incidence of NOSHT (27.8% vs. 4.8%,p-0.01) and hypertriglyceridemia (26.7% vs. 8%,p-0.03) at six months was significantly higher in S-arm. However, there were no differences in BPAR (19.2% vs. 21.2%, p-0.81), time to first rejection (58 vs. 53 days, p-0.78), patient and graft survival (610 vs. 554 days,p- 0.22). CONCLUSION: Following LDLT, basiliximab induction with tacrolimus and azathioprine maintenance resulted in significantly lower metabolic complications compared to the triple-drug regimen of steroid, tacrolimus, and azathioprine.

Double-blind placebo-controlled randomized trial of N-acetylcysteine infusion following live donor liver transplantation.

BACKGROUND: The role of N-acetylcysteine (NAC) in improving outcomes following live donor liver transplantation (LDLT) is not well established. We designed a randomized double-blind placebo-controlled trial to study the role of NAC infusion in recipients undergoing LDLT. METHODS: We assigned 150 patients who underwent LDLT by computer-generated random sequence on 1:1 ratio to either NAC group or placebo group. Patients in the NAC group received NAC infusion which was started at beginning of graft implantation at an initial loading dose of 150 mg/kg/h over 1 h, followed by 12.5 mg/kg/h for 4 h and then at 6.25 mg/kg/h continued for 91 h. Placebo group received normal saline. The primary endpoint was composite occurrence of acute kidney injury (AKI) and early allograft dysfunction (EAD) in the recipient. Secondary endpoints included levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, INR, primary graft non-function, intraoperative bleeding, post-transplant hospital stay and in-hospital mortality. RESULTS: The composite endpoint did not show any significant difference between the NAC and placebo group (21.3% vs 29.3%, p = 0.35). Peak AST (425.65 IU/L vs 702.24 IU/L, p = 0.02) and peak ALT (406.65 IU/L vs 677.99 IU/L, p = 0.01) levels were significantly lower in the study group. Time to normalization of transaminases was also significantly low in the study group. CONCLUSIONS: Perioperative NAC infusion following LDLT resulted in significantly lower postoperative AST and ALT levels. Rapid normalization of transaminases was also observed. This, however, did not translate to improvement in AKI or EAD.

Voluntary perioperative colorectal cancer registry from Kerala-An initial overview.

BACKGROUND: Although colorectal cancer (CRC) may not be uncommon in India, accurate data regarding its demographics and surgical outcomes is sparse. METHODS: With an aim to assess demographics and perioperative outcomes of CRC in Kerala, all members of Association of Surgical Gastroenterologists of Kerala (ASGK) were invited to participate in a registry. Data of operated cases of CRC were entered on a web-based questionnaire by participating members from January 2016. Analysis of accrued data until March 2018 was performed. RESULTS: From 25 gastrointestinal surgical centers in Kerala, 15 ASGK member hospitals contributed 1018 CRC cases to the database (M:F 621:397; median age-63.5 years [15-95 years]). Rectum (39.88%) and rectosigmoid (20.33%) cancers comprised the majority of the patients. Among them, preoperative bowel preparation was given to 37.68%, minimally invasive surgery (MIS) was performed in 73%, covering stoma in 47% and had an overall leak rate of 3.58%. In colonic malignancies, MIS was performed in 56.74%, covering stoma created in 13% and had a leak rate of 2.71%. Of 406 patients with rectal cancers, neo-adjuvant radiotherapy/chemoradiotherapy was given to 51.23%. The mean hospital stay for MIS in both rectal and colonic cancer patients was significantly shorter than open approach (10.46 ± 5.08 vs. 12.26 ± 6.03 days; p = 0.001and 10.29 ± 4.58 vs. 12.46 ± 6.014 days; p = <0.001). Mortality occurred in 2.2% patients. CONCLUSION: A voluntary non-funded registry for CRC surgery was successfully created. Initial data suggest that MIS was performed in majority, which was associated with shorter hospital stay than open approach. Overall mortality and leak rate appeared to be low.

Liver Transplant in Acute Liver Failure - Looking Back Over 10 Years.

BACKGROUND: Acute liver failure (ALF) is the leading cause for emergency liver transplantation (LT) all over the world. We looked at the profile of cases who required LT for ALF from a single centre to identify the possible predictors of poor outcomes. METHODOLOGY: During the 10-year period starting from 2007, 320 cases of ALF were treated at our institution, of which 70 (median age 24 years, Male:Female 1:2) underwent LT. Retrospective analyses of these 70 patients were performed. RESULTS: Etiology was identifiable in 73% (n = 51) of cases (yellow phosphorous [YP] poisoning [n = 16], Hepatitis A virus [HAV] [n = 15], Hepatitis B virus [HBV] [n = 5], Hepatitis E virus [HEV] [n = 1], anti-tubercular therapy [ATT] induced [n = 6], acute Wilson's [n = 3], and autoimmune [n = 5]]. Upon meeting King's College Hospital criteria, 69 had live donor LT (61 right lobe grafts, three left lobe grafts, five left lateral segment grafts) and one had deceased donor LT. Among these, there were five auxiliary partial orthotopic grafts and four ABO-incompatible transplants. Overall, 90-day mortality was 35.7% (n = 25), predominantly due to sepsis. Significant risk factors for mortality on multivariate analysis included indeterminate etiology, pre-op renal dysfunction, and Grade IV hepatic encephalopathy (HE). Cumulative 10-year survival of the remaining survivors was 95.6% (n = 45). CONCLUSION: LT for ALF carries high perioperative mortality (35.7%) in those presenting with indeterminate etiology, pre-op renal dysfunction, and Grade IV HE. Nevertheless, if they survive the perioperative period, long-term survival is excellent.

Dengue virus transmission from live donor liver graft.

Arboviral transmission through transplanted organs is rare. We report a highly probable case of dengue viral transmission during live donor liver transplantation. Fever with severe thrombocytopenia was observed in the donor and recipient within 6 and 9 days after transplantation, respectively. Dengue diagnosis was confirmed by testing blood and explant tissue from the donor and recipient using dengue-specific NAT (nucleic acid testing) and serology. Serology indicated the donor had secondary dengue infection that ran a mild course. However, the dengue illness in the recipient was severe and deteriorated rapidly, eventually proving fatal. The recipient's explant liver tissue tested negative for viral RNA indicative of a pretransplant naïve status. The prM-Envelope gene sequence analysis of the donor and recipient viral RNA identified a similar serotype (DENV1) with almost 100% sequence identity in the envelope region. Molecular phylogenetic analysis of donor and recipient viral envelope sequences with regional and local dengue strains further confirmed their molecular similarity, suggesting a probable donor-to-recipient transmission via organ transplantation. Screening of living donors for dengue virus may be considered in endemic regions.

Living Donor Liver Transplantation Using Small-for-Size Grafts: Does Size Really Matter?

BACKGROUND: In living donor liver transplantation (LDLT), graft-to-recipient weight ratio (GRWR) > 0.8% is perceived as the critical graft size. This lower limit of GRWR (0.8%) has been challenged over the last decade owing to the surgical refinements, especially related to inflow and outflow modulation techniques. Our aim was to compare the recipient outcome in small-for-size (GRWR < 0.8) versus normal-sized grafts (GRWR > 0.8) and to determine the risk factors for mortality when small-for-size grafts (SFSG) were used. METHODS: Data of 200 transplant recipients and their donors were analyzed over a period of two years. Routine practice of harvesting middle hepatic vein (MHV) or reconstructing anterior sectoral veins into neo-MHV was followed during LDLT. Outcomes were compared in terms of mortality, hospital stay, ICU stay, and occurrence of various complications such as functional small-for-size syndrome (F-SFSS), hepatic artery thrombosis (HAT), early allograft dysfunction (EAD), portal vein thrombosis (PVT), and postoperative sepsis. A multivariate analysis was also done to determine the risk factors for mortality in both the groups. RESULTS: Recipient and donor characteristics, intraoperative variables, and demographical data were comparable in both the groups (GRWR < 0.8 and GRWR ≥ 0.8). Postoperative 90-day mortality (15.5% vs. 22.85%), mean ICU stay (10 vs. 10.32 days), and mean hospital stay (21.4 vs. 20.76 days) were statistically similar in the groups. There was no difference in postoperative outcomes such as occurrence of SFSS, HAT, PVT, EAD, or sepsis between the groups. Thrombosis of MHV/reconstructed MHV was a risk factor for mortality in grafts with GRWR < 0.8 but not in those with GRWR > 0.8. CONCLUSION: Graft survival after LDLT using a small-for-size right lobe graft (GRWR < 0.8%) is as good as with normal grafts. However, patency of anterior sectoral outflow by MHV or reconstructed MHV is crucial to maintain graft function when SFSG are used.