Faecal microbiota transplantation beneficial in advanced cirrhosis

28th June 2023

Using faecal microbiota transplantation in patients with advanced cirrhosis improves gut flora microbiota and ammonia metabolism, according to a feasibility trial by UK and Swedish researchers.

Data from the prospective, randomised placebo controlled feasibility trial of faecal microbiota transplantation (PROFIT) trial was presented at the European Association for the Study of the Liver (EASL) 2023 congress.

Gut flora and bacterial translocation play an important role in the pathogenesis of the complications of cirrhosis such as hepatic encephalopathy (HE). The antibiotic rifaximin reduces the risk of HE recurrence and HE-related hospitalisations in cirrhosis, possibly through its effects on metabolic function of the gut microbiota and a reduction in ammonia-producing bacteria.

But whether faecal transplantation, by modifying the gut microbiota, could benefit those with cirrhosis is unclear and this was the subject of an abstract (GS-007) presented at the congress. For the study, 50 g of frozen faecal microbiota transplants (FMT) were administered into the jejunum via endoscopy in a ratio of 3:1 (FMT vs placebo). The study was single-blind, so only the investigators were aware of the intervention received by patients. Blood and stool samples were collected at baseline and then after seven, 30 and 90 days.

Faecal transplantation in advanced cirrhosis

A total of 32 patients were included in the study. FMT significantly reduced the stool carriage of Enterococcus faecalis and other pathobionts. There was also a significant reduction after 30 days in plasma ammonia (p = 0.0006), with a corresponding higher faecal ammonia (p = 0.011) in the FMT group compared to placebo.

In addition, after 30 days, there was enhancement in the enzymes required for nitrogen assimilation and excretion via the urea cycle, with greater secretion of urinary hippurate (p = 0.0299) in the FMT group.

It was also clear that the use of FMT reduced biomarkers of inflammation but increased biomarkers for gut barrier repair.

The researchers concluded that their data supported a role for FMT in patients with cirrhosis.

Following the PROFIT trial, the same group are about to embark on the PROMISE trial, in which patients with cirrhosis take capsules containing dried stool from a healthy donor, rather than via endoscopy as in the PROFIT trial.

A recent Cochrane review found that faecal transplantation improves clinical and possibly endoscopic remission in ulcerative colitis.

Novel extracorporeal liver device deemed safe and effective in severe liver failure

2nd June 2023

A novel extracorporeal liver device has been found to be safe and able to reduce endotoxaemia and improve albumin function in patients with acute-on-chronic liver failure (ACLF) in a recent randomised trial.

Published in the Journal of Hepatology, researchers demonstrated that the novel extracorporeal liver device, DIALIVE, was as safe as standard care (SC) for patients with ACLF. DIALIVE is designed to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. However, prior to the recent trial, this had not been tested in humans.

ACLF is a syndrome that occurs in hospitalised patients with cirrhosis who present with acute decompensation and carries a high short-term mortality in excess of 15% after 28 days. It is characterised by intense systemic inflammation and associated with multiple organ failures.

Safe and effective for ACLF

Some 32 patients with alcohol-related ACLF were included in the trial and treated with either DIALIVE for up to five days or SC. The study endpoints were assessed at day 10. The primary outcome of interest was safety, defined in terms of the percentage of patients who experienced at least one serious adverse event (SAE) between days one and 10. A number of secondary outcomes were assessed including the change in plasma endotoxin level, albumin function, 28-day mortality and changes in individual organ function.

A total of 17 ACLF patients were randomised to receive DIALIVE and 15 to standard care. The DIALIVE therapy was administered for a median of three sessions and each session lasted for between eight and 12 hours.

The presence of any adverse event was similar in the two groups of ACLF patients (76.5% vs 80%, DIALIVE vs SC, p = 1.00). Similarly, the incidence of serious adverse events in those assigned to the novel extracorporeal device was also not significantly different (p = 0.76). There were also no differences in 28-day mortality.

While there was a trend towards a reduced endotoxaemia severity in the DIALIVE group, this difference was non-significant (p = 0.14). In contrast, there were significant differences favouring DIALIVE for the improvements in liver, kidney, coagulation and brain damage scores. In addition, there was a greater improvement in albumin function in the DIALIVE group. Finally, a higher proportion of patients achieved ACLF resolution with DIALIVE treatment (43% vs 27%). 

The authors concluded that DIALIVE achieved its aims of reducing the level of endotoxin and improving albumin function in those with severe liver failure, ultimately leading to a greater proportion of patients whose condition resolved.

Modest reduction in COVID-19 infection among vaccinated cirrhosis patients

19th July 2021

Vaccinated patients with cirrhosis had a delayed and reduced protection against COVID-19 infection but avoided hospitalisation and death.

Cirrhosis patients are immunocompromised and thus susceptible to infections. In fact, bacterial infections occur in up to 34% of those with cirrhosis admitted to hospital. Furthermore, data have shown that cirrhosis patients have a reduced response to pneumococcal vaccination. Although recent consensus guidelines advocate the use of COVID-19 vaccines for patients with liver diseases such as cirrhosis, this is based on expert opinion rather than facts. In recognition of this lack of evidence, a team from the Division of Hepatology, Bruce W Carter Medical Centre, Miami, US, undertook a retrospective cohort study of patients with cirrhosis who had received at least one dose of a COVID-19 vaccine. Eligible participants were those with cirrhosis aged 18 years and older and who received either the BNT162b (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccines. The team propensity matched these individuals based on 5 categories: sex, ethnicity, duration of follow-up, co-morbidities, alcohol-associated liver disease and finally, the severity of their liver disease. The team defined the index date, as the date of vaccination and each participant was matched to a control. The primary outcome of interest was PCR-defined COVID-19 infection, 28 days after the first dose of either vaccine. The team used this cut-off because it was anticipated that the benefits of either vaccine should be apparent after this period of time. Secondary outcomes included hospitalisation because of COVID-19 or death, again within 28 days of the first vaccine dose.

Findings
The team propensity-matched 20,037 cirrhosis patients with an equal number of controls. Among the cirrhosis group, the mean age was 69.2 years (96.8% male) and the majority (59.5%) were of white ethnicity, with 58.4% having alcohol-associated cirrhosis. Following the first dose of either vaccine, a total of 83 cirrhosis patients and 105 in the control group developed COVID-19 infection. After the first 28 days, receipt of a single dose of either vaccine was associated with a 64.8% reduction in COVID-19 infections. In addition, 28 cirrhosis patients (versus 29 in the matched control group), developed COVID-19-related hospitalisation. However, after 28 days, none of those with cirrhosis were hospitalised compared to 3 in the control group.

Seven days after the second vaccination dose, there were only 3 cases of COVID-19 infection among cirrhosis patients but 15 in the control group. The authors calculated that full vaccination was associated with a 78.6% reduction in COVID-19 infections and none of the cirrhosis patients were subsequently hospitalised because of COVID-19. Comparing decompensated and compensated cirrhosis patients, there was a 50.3% and 66.8% respectively, reduction in COVID-19 infections. Equally, none of either patient group (i.e., decompensated or compensated cirrhosis) were hospitalised because of COVID-19.

The authors noted that while individuals with cirrhosis, especially those with decompensated disease are known to be hypo-responsive to several commonly used vaccines, the current data indicated that while a single vaccination was not associated with a reduction in COVID-19 infections, fully vaccinated individuals experienced a significant reduction in infection. In other words, the response among those with cirrhosis was delayed and reduced, indicating a lower benefit among this patient cohort.

Citation

John BV et al. Association of BNT162b2 mRNA and mRNA-1273 Vaccines With COVID-19 Infection and Hospitalisation Among Patients With Cirrhosis. JAMA Intern Med 2021