Introduction:
Extracorporeal liver support (ELS) systems can be used to remove harmful metabolites that tend to that accumulate in liver failure. This could be due to a primary insult like shock liver, hepatitis, or alcoholic liver cirrhosis. Insufficient clearance of toxic metabolites tends to intensify the decline in a cirrhotic liver. The liver has a fantastic potential to regenerate and function to near-normal capacity. This provides the rationale to develop extracorporeal liver support systems that can provide support while keeping the patient alive and allowing adequate time for cellular regeneration. Furthermore,

ELS systems can be utilized in liver failure as a bridge   when liver transplantation is needed. Patients with hepatic encephalopathy or hepatorenal syndrome can benefit while awaiting longer transplantation times. The concern with liver dialysis is adequate membrane structure and inadequacy of plasma filtration. The use of a regular pore size plasma filter vs. selective filter has been linked to increased mortality and poor survival rates [1]. More recent observations of the hydrophobic nature of toxic molecules and their dependence of transport by serum albumin have initiated a pathway for artificial ELS systems. ELS devices allow blood or plasma passage through a special filter to remove circulating toxins. In 2004, the use of hemodiabsorption was introduced by Ash et al. [2]. This process used a dialyzer that had a dialysate composed of sorbent particles. In 2006, the Prometheus system was introduced utilizing a similar approach as by Ash et al. However, the separation membrane was more permeable for albumin, and fixed columns achieved increased adsorption than mobile sorbent suspension [3]. One widely studied mechanism is the use of albumin in dialysis. Albumin-bound toxins can be dialyzed via dialysis membranes with albumin dialysate as a molecular acceptor [5]. The use of albumin allows maintenance of the dialysis process selectivity through small pore membranes and their removal of albumin-bound toxins [4].

Main text:
Principles of liver dialysis

ELS support consists of biological or artificial devices. Biological devices combine hepatocytes and mechanics to provide a system to detoxify a patient's blood. Conversely, artificial devices do not use any biological components.

Albumin based systems:

To date, the best-studied artificial devices are based on the albumin dialysis principle.   Albumin has multiple roles, and it functions as a vital plasma binder. In liver failure, albumin production is affected with the binding capacity of circulatory toxins reduced leading to a toxin burden in the human body resulting in liver failure [5]. Albumin dialysis supports this function and removes the toxic burden while giving the native liver time to recover. The molecular adsorbent recirculating system (MARS) is one of the best studied ELS devices. In this device, blood circulates across an albumin-impermeable membrane against a human albumin solution dialysate [6]. MARS has been widely studied in patients with acute and acute on chronic liver failure. It has not been shown to have a statistically significant mortality benefit in acute liver failure. However, it does have definitive benefits in acute on chronic liver failure [7]. In patients with acute on chronic liver failure, beneficial effects include improved portal hypertension, hepatic encephalopathy, renal function, and pruritus [6, 8, 9]. MARS demonstrated a significant reduction in serum creatinine, bilirubin, and hepatic encephalopathy grade in the RELIEF study, which compared MARS therapy and standard therapy for acute on chronic liver failure. In a French multicenter randomized controlled trial called the FULMAR study MARS therapy showed no difference in 6-month survival compared to conventional therapy with a non-significant primary outcome of 28-day survival [10, 11]. However, a subsequent meta-analysis reported improved 10-day and 30-day survival with five or more sessions being required for a meaningful response [12].

Prometheus is another ELS device that uses the principles of albumin dialysis. It separates albumin from the blood by fluxing whole blood across a larger cutoff membrane into a secondary circuit with two filters. These filters help improve albumin adsorption capabilities [13]. Prometheus was compared to standard medical therapy in the HELIOS study which demonstrated a reduction in bilirubin levels but no improvement in 28 or 90-day survival. Improvement in serum creatinine and ammonia levels was also been reported [14].

Plasma exchange:

Two comprehensive clinical trials were conducted using High-volume plasma exchange (HVP) which allows for plasma separation and elimination from whole blood. A significantly improved 90-day survival and median survival was shown for the hepatitis B virus cohort [15]. Improvement in transplant-free survival to hospital discharge was also reported along with reduced systemic inflammatory response syndrome and sequential organ failure assessment scores [16].

Biological ELS systems:

The Extracorporeal Liver Assist Device (ELAD) utilizes a biological dialyzer. These dialysis cartridges are composed of hollow fibers and contain human hepatoblastoma cells which mimic in vivo albumin synthesis and cytochrome P450 activity. Currently, no trials have demonstrated any survival benefit using ELAD and these devices have poor ammonia detoxification capabilities limiting hepatic encephalopathy benefits [17].

Indications for ELS support:

Hypoperfusion of liver:

One of the main indications for ELS is to provide improved blood supply in acute or acute on chronic liver failure. Prior MARS treatments have demonstrated an increased systemic vascular resistance index and patients presenting with systemic hypotension have improved mean arterial pressures after treatment [18,19]. MARS treatments provide isolated organ perfusion that mainly affects the liver Another phenomenon is improved renal blood flow which can be beneficial l in hepatorenal syndrome [18]. Lastly, patients have been shown to have increased cerebral perfusion after MARS treatments [20].

Hepatic encephalopathy and cerebral edema:

Acute and chronic liver failure can result in hepatic encephalopathy which is correlated with worsening morbidity and mortality. Liver dialysis is beneficial for acute on chronic liver failure patients with grade III and IV hepatic encephalopathy [21]. Improvement in intracranial pressure was also reported however, evidence is currently lacking [20]. One study using animal models demonstrated a reduction in increased cranial pressure after initiating dialysis. Furthermore, patients undergoing liver dialysis have reduction in ammonia concentration in blood [22].

Hepatorenal syndrome:

Albumin based ELS devices have reported improved kidney function during treatments with a decrease in serum creatinine improving urine output and resolution of hepatorenal syndrome [18,23, 24]. These findings were studied in patients with type I hepatorenal syndrome (HRS) and the mechanism is poorly understood [6]. However, these results could be secondary to reduced plasma renin concentrations in patients with acute on chronic liver failure resulting in increased renal perfusion. Albumin-based ELS could be a viable option for HRS [25, 26]. Unfortunately, no meaningful data currently points towards synthetic improvement in liver function while receiving Albumin-related ELS [27,28There is a current need for trials is to make a definitive conclusion on the utility of Albumin-related ELS

Liver transplantation:

Patients with acute liver failure could be candidates for Albumin based ELS while awaiting liver transplantation. This treatment option is reportedly safe, and benefits include improved patient survival and sustained liver regeneration. A study by Koivusalo et al. showed a one-year survival of 84% after MARS treatment. Recovery of native liver function was reported in 30 out of 56 patients with a one-year survival of 79%.  Patients who underwent liver transplantations had a one-year survival of 94% [29]. One multicenter randomized controlled trial investigated the role of Albumin based ELS as a tool to bridge patients with acute liver failure to transplantation however, it was unable to provide superior efficacy secondary to many patients receiving transplantation before appropriate intervention could occur [10].

Symptoms of chronic liver disease:

ELS has a positive response in refractory symptoms of chronic liver disease such as pruritis. Multiple liver diseases and their association with pruritus have been studied including primary sclerosing cholangitis, chronic viral hepatitis, and primary biliary cirrhosis. Symptom relief lasted up to three months but not every patient was responsive to therapy [30, 31]. The mechanism behind improved pruritus symptoms is poorly understood but could be explained by the removal of hydrophobic bile acids resulting in a bile acid pattern shift [32]. Another use for albumin based ELS, particularly MARS, is intoxication due to medication overdose with substances such as acetaminophen [33,34] This therapy allows for the removal of albumin-based drugs and improved acute liver failure in the settings of toxins.

Current prospects:

Current liver dialysis major studies are summarized in table 1:

Table 1: Prominent extracorporeal liver support devices trials.

ELS: Extracorporeal Liver support.

ELAD: Extracorporeal liver assist device.

MARS: molecular adsorbents recirculating system.

SMT: Standard medical therapy.

Patients with acute, chronic liver failure who did not respond to standard medical therapy should  be considered for extracorporeal liver support as early introduction of ELS could be beneficial Patients who have sepsis or septic shock may need to delay their ALS treatment and instead initially receive antibiotic therapy. Patients with acute on chronic liver failure coagulopathy with platelet count less than 50,000, INR greater than 2 or 3, or concurrent kidney failure requiring dialysis may not benefit from extracorporeal liver dialysis [35]. Treatment regimens should vary depending upon patient comorbidities and during treatment, anticoagulation might be necessary [35]. In the last ten years MARS was the most studied artificial liver dialysis technology and it has the potential for wide clinical application [36].

Conclusion:
While extracorporeal liver dialysis devices have had limited benefit in previous clinical trials they have provided symptomatic relief of refractory symptoms of chronic liver disease Recent  trials and new devices have helped provide  better understanding of acute and acute on chronic liver cirrhosis management especially in regards to treatment duration and initiation of therapy. These devices could provide a bridge between the occurrence of liver failure and transplantation. Albumin dialysis may have better outcomes however, biological devices have not been widely tested. Further comparative data is currently needed to assess survival benefits. Complications such as hepatic encephalopathy, pruritus secondary to increased bilirubin, and hepatorenal syndrome may all be managed with ELS.

Abbreviations:

ELS: Extracorporeal liver support

MARS: Molecular adsorbent recirculating system

HVP: High-volume plasma exchange

ELAD: Extracorporeal Liver Assist Device

HRS: Hepatorenal syndrome

Declarations:

Author contributions: The author contributed solely to the work

Conflicts of interest: The authors declare that they have no conflicts of interest.

Ethical approval: Not applicable

Consent to participate: Not applicable

Consent to publication: Not applicable

Availability of data and materials: Not applicable

Funding: Not applicable