Liver support system

Both types of hepatic insufficiency, ALF and ACLF, can potentially be reversible and liver functionality can return to a level similar to that prior to the insult or precipitating event.

By stabilizing the patient's clinical state, or by creating the right conditions that could allow the recovery of native liver functions, both detoxification and synthesis can improve, after an episode of ALF or ACLF.

Potential side effects that have been documented include immunological issues (porcine endogenous retrovirus transmission), infectious complications, and tumor transmigration.

The overall design varies between different BAL systems, but they largely follow the same basic structure, with patient blood or plasma flow through an artificial matrix housing hepatocytes.

[30] Primary human hepatocytes sourced from donor organs present several problems in their cost and difficulty to obtain, especially with the current lack in transplantable tissue.

[34] However, these structures have their limitations, with convectional transport issues, nutritional gradients, non-uniform seeding, inefficient immobilisation of cells, and reduced hepatocyte growth restricting their effectiveness in BAL designs.

[35] Cryogel scaffolds demonstrate good mechanical strength and biocompatibility without triggering an immune response, improving their potential for long-term inclusion in BAL devices or in-vitro use.

[37] Another advantage of cryogels is their flexibility for use in a variety of tasks, including separation and purification of substances, along with acting as extracellular matrix for cell growth and proliferation.

Expanding upon prior research indicating its potential as a blood perfusion device for detoxification, some studies have explored the application of Arg-Gly-Asp (RGD)-containingPoly(2-hydroxyethyl methacrylate) (pHEMA)-alginate cryogels as scaffolds for BAL.

These cryogels, incorporating alginate to mitigate protein fouling and functionalized with an RGD-containing peptide to enhance hepatocyte adhesion, represent a promising avenue for BAL scaffold development.

Compared to the column configuration, the stacked bioreactor demonstrated significantly elevated production of albumin and urea, alongside enhanced cell colonization and proliferation over time.

This is generally due to inherent design limitations, causing convectional transport issues, nutritional gradients, non-uniform seeding, inefficient immobilisation of cells, and reduced hepatocyte growth.

171 patients with ALF stemming from viral hepatitis, paracetamol overdose or other drug complications, primary non-function (PNF), or of indeterminate aetiology, were involved in the study and were randomly assigned to either the experimental or control groups.

The investigators noted that exclusion of PNF patients is justifiable due to early retransplantation and lack of intercranial hypertension, so HepatAssist would give little benefit to this group.

Biomarker measurements showed a significantly reduced level of bilirubin and alkaline phosphatase in ELAD patients, though neither improvement translated into increased survivability rates.

[43] A randomized, phase 3 trial of the ELAD device in patients with severe alcoholic hepatitis failed to show benefit on overall survival and development was discontinued.

Most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional renal dialysis techniques, such as hemofiltration, hemodialysis or hemodiafiltration are not able to adequately eliminate them.

These systems use conventional dialysis methods with an albumin containing dialysate that is later regenerated by means of adsorption columns, filled with activated charcoal and ion exchange resins.

The treatment for two consecutive days for more than four hours significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH.

The albumin dialysate is then regenerated in a close loop in the MARS circuit by passing through the fibres of the low-flux diaFLUX filter, to clear water-soluble toxins and provide electrolyte/acid-base balance, by a standard dialysis fluid.

Evidence suggests that HE develops as some neurotoxins and neuro active substances, produced after hepatocellular breakdown, accumulates in the brain as a consequence of a portosystemic shunt and the limited detoxification capability of the liver.

In 4 patients with acute decompensation of chronic liver disease, they observed after MARS therapy, an attenuation of hyperdynamic circulation and a reduction in the portal pressure gradient was measured.

Splanchnic vasodilatation triggers the production of endogenous vasoactive substances that produce renal vasoconstriction and low glomerular filtration rate, leading to oliguria with a concomitant reduction in creatinine clearance.

[74][81][82][87][97] Results are confirmed in a randomized controlled trial published by Mitzner et al..[93] in which 13 patients diagnosed with hepatorenal syndrome type I was treated with MARS therapy.

Although mechanisms explaining previous findings are not yet fully understood, it has been reported that there was a decrease in plasma renin concentrations in patients diagnosed with acute on chronic liver failure with renal impairment that were treated with MARS.

In the study from Stadbauer et al..,[105] that was specifically addressing the topic, it is reported that MARS and Prometheus systems lower to the same extent biliary acids plasma concentration.

Pruritus is one of the most common clinical manifestations in cholestasis liver diseases and one of the most distressing symptoms in patients with chronic liver disease caused by viral hepatitis C. Many hypotheses have been formulated to explain physio pathogenesis of such manifestation, including incremental plasma concentration of biliary acids, abnormalities in the bile ducts,[106] increased central neurotransmitters coupling opioid receptors,[107][108] etc.

Despite the number of historical drugs used, individually or combined (exchange resins, hydrophilic biliary acids, antihistamines, antibiotics, anticonvulsants, opioid antagonists), there are reported cases of intractable or refractory pruritus with a dramatic reduction in patients’ quality of life (i.e. sleep disorders, depression, suicide attempts...).

It is also necessary to adjust the dosing for those drugs that are exclusively metabolized by the liver, and have low affinity for prioteins and high distribution volume, such as fluoroquinolones (Levofloxacin and Ciprofloxacin).

In the meta-analysis published by Khuroo et al..[101] which included 4 randomized trials[74][89][93][103] an improvement in survival for the patients with liver failure treated with MARS, compared with SMT, was not observed.