National Liver Care Day｜Wang Rongqi: How to standardize the timing and mode of artificial liver intervention

Wang Rongqi, Department of Hepatology, Integrated Traditional Chinese and Western Medicine, The Third Hospital of Hebei Medical University

Artificial liver support system (ALSS), also known as artificial liver, is an extracorporeal support system that temporarily replaces some of the liver's functions. Its treatment mechanism is based on the powerful regenerative ability of liver cells. Through in vitro mechanical, physical, chemical and biological devices, it removes various harmful substances, supplements essential substances, improves the internal environment, creates conditions for liver cell regeneration and liver function recovery, or serves as a bridge before liver transplantation. Artificial livers are divided into three types: non-biological, biological and hybrid. At present, non-biological artificial livers are widely used in clinical practice and have been proven to be an effective extracorporeal liver support method. This article uses artificial liver to refer to non-biological artificial livers and introduces their intervention timing and mode selection in order to provide a reference for clinical practice.

How to choose the time of artificial liver intervention

Liver failure refers to massive or sub-massive necrosis or severe damage of liver cells caused by multiple factors such as viruses, drugs, and alcoholism, leading to severe disorders or decompensation of synthesis, detoxification, metabolism, and biotransformation functions, and a group of clinical syndromes with jaundice, coagulopathy, hepatorenal syndrome, hepatic encephalopathy, ascites, etc. as the main manifestations. The condition is dangerous and has a high mortality rate. Current treatment options include etiological treatment, comprehensive medical treatment, individualized artificial liver treatment, liver transplantation, and stem cell transplantation. However, due to the poor effect of medical drug treatment and the shortage of donors for liver transplantation, artificial liver has become an increasingly important part of liver failure treatment.

The "triple hit" theory is currently recognized as the main pathogenesis of liver failure, namely: in the early stage of the rising phase of liver failure, the body is hit mainly by immune damage plus ischemic hypoxic damage; in the middle and late stages of the rising phase of liver failure, endotoxemia begins to participate in the heavy blow to the body; in the middle and late stages of the plateau phase of liver failure and the early stage of the recovery phase, the body is in an immunosuppressive state and is mainly under pressure from endotoxemia. The occurrence and development of liver failure is a continuous evolutionary process, and the duration of each clinical stage varies. If the intervention is timely and effective, the disease can enter a relatively stable plateau phase and even reverse the disease process. The "2016 Guidelines for the Treatment of Liver Failure with Non-bioartificial Liver" and the "2018 Guidelines for the Diagnosis and Treatment of Liver Failure" both point out that early diagnosis and early treatment are the key to improving the rescue rate of liver failure. Once liver failure is diagnosed, the condition should be evaluated immediately, and artificial liver treatment should be carried out as soon as possible on the basis of comprehensive internal medicine treatment. For example: in the rising stage of liver failure, when there is a tendency of liver failure, artificial liver treatment can achieve the best therapeutic effect; in the 1st to 2nd week of the plateau stage of liver failure, artificial liver treatment should be started if there is no infection; in the recovery stage of liver failure, if the jaundice does not subside ideally, artificial liver treatment should be performed as soon as possible after excluding infection and obstructive jaundice, which can avoid the course of the disease exceeding 3 months; when the body has serious complications such as hepatic encephalopathy and hepatorenal syndrome, artificial liver treatment should also be started as soon as possible to avoid irreversible changes; when there is cirrhosis, hepatitis B virus reactivation, rebound after antiviral drug withdrawal, etc., it is also the time to intervene in artificial liver treatment as soon as possible.

How to choose the application mode of artificial liver

Artificial liver modes can be divided into simple mode and compound mode. Simple mode includes plasma exchange (PE), hemoperfusion, hemodialysis, hemofiltration, etc. Compound mode includes molecular absorbent recirculating system (MARS), double plasma molecular adsorption system (DPMAS), double filtration plasma exchange, plasma diafiltration (PDF), component plasma separation adsorption system, etc. Years of clinical experience have shown that individualized multi-mode combined application based on immune status and patient conditions can improve the therapeutic effect of artificial liver and reduce adverse reactions of treatment. With the continuous emergence of new artificial liver modes, its clinical efficacy has also been significantly improved.

1. Coagulation dysfunction : For patients with coagulation dysfunction, PE treatment is more targeted and can effectively supplement coagulation factors, albumin and other substances to improve the coagulation state of patients with liver failure. However, PE has a dose-effect relationship on toxin removal, and there may be risks of imbalance syndrome, infection and allergy. Prothrombin activity (PTA) <25% is an absolute indication for PE. Patients with bleeding complications should have a PTA >40% after treatment, and patients without bleeding tendency should have a PTA >30% after treatment. The recommended replacement volume of full PE is 1 to 1.3 plasma volumes, and the circulating plasma volume can be estimated by the following formula: Plasma volume = patient weight (kg) × 70 × [(1.0-hematocrit) × 0.91].

2. Hyperbilirubinemia: Hyperbilirubinemia can cause central nervous system dysfunction, secondary biliary cirrhosis, renal insufficiency, immune dysfunction and other multi-system damage. Artificial liver treatment of hyperbilirubinemia should be performed before cholestasis as much as possible. If the total bilirubin is >300μmol/L or >200μmol/L for more than 1 week, artificial liver intervention should be considered. The plateau phase of liver failure is the most effective time to reduce bilirubin. In the early stage of the plateau phase, inflammatory edema is the main feature, and PE or PDF is recommended. In the late stage of the plateau phase, cholestasis and endotoxemia are the main features, and the recommended mode is specific bilirubin adsorption, DPMAS or DPMAS+PE.

The specific bilirubin adsorption mode can specifically adsorb bile acid and bilirubin, but has poor adsorption for ammonia, thiol, r-aminobutyric acid, etc. It is mainly used for the treatment of jaundice in severe hepatitis and cholestatic hepatitis, and has the advantages of low risk of infection and allergy, and low cost. DPMAS is a new artificial liver mode composed of bilirubin adsorption combined with resin adsorption. It can completely remove medium and large molecular toxins and protein-bound toxins without changing the osmotic pressure. It has a large plasma processing volume, but there is a certain degree of coagulation factor and protein loss. PE mainly supplements coagulation factors to ensure the safety of treatment. DPMAS+PE perfectly combines the two treatment methods, complementing each other's advantages, and can significantly improve clinical efficacy.

3. Hepatic encephalopathy (HE): HE is a neuropsychiatric syndrome with varying degrees of severity and based on metabolic disorders, caused by acute or chronic severe liver dysfunction or various portal vein-systemic circulation shunt abnormalities. When liver failure is combined with HE, on the basis of medical treatment, some artificial liver modes that can improve HE can be used for HE: DPMAS, resin plasma perfusion isotonic removal of HE-related toxins; continuous renal replacement therapy (CRRT) can not only remove HE-related toxins, but also dehydrate and reduce brain edema. Patients with acute liver failure and risk of brain edema should use CRRT, which is better than hemodialysis/hemoperfusion and PE in terms of consciousness and final survival rate. If HE is severe, the treatment dose should be increased accordingly; DPMAS + continuous veno venous hemofiltration (CVVH), plasma exchange combined with hemofiltration, MARS and other composite modes can be used to reduce intracranial pressure in patients. In addition, it is worth noting that hemodialysis is not recommended for HE because it can lead to osmotic imbalance syndrome, inducing or aggravating cerebral edema; large-scale PE alone is not recommended for HE above stage 2, because the citrate contained in fresh frozen plasma is alkaline and the colloid osmotic pressure is generally lower than the patient's plasma colloid osmotic pressure, so PE may aggravate HE. Patients with obvious HE are advised to choose other modes or choose PE combined with other modes.

4. Hepatorenal syndrome (HRS): HRS is a serious complication that occurs in patients with severe liver diseases such as cirrhosis with ascites, acute liver failure, and alcoholic hepatitis, with renal damage as the main manifestation. In 2005, the American Association for the Study of Liver Diseases pointed out that when HRS requires dialysis support, it is recommended to use continuous rather than intermittent methods. In 2010, the European Association for the Study of the Liver mentioned that MARS and The Prometheus system may be beneficial for type I HRS, but the efficacy has not yet been determined. The 2011 Acute Disease Quality Initiative pointed out that CRRT may be beneficial in the treatment of HRS with acute renal failure, and can be used for type I HRS with reversible components or waiting for liver transplantation. Therefore, HRS can choose plasma exchange combined with hemofiltration, PDF, DPMAS+CVVH/hemodiafiltration (HDF) and other modes.

Plasma exchange combined with hemofiltration is currently the most widely used mode and the most efficient mode. In two consecutive plasma exchange treatments, continuous hemofiltration treatment is interspersed, which can effectively remove toxins, inhibit bilirubin rebound, and maintain water and electrolyte stability. It is used for liver failure with multiple organ dysfunction, HRS, HE, electrolyte disorders, etc. The disadvantage is that sufficient plasma is required. PDF is a new technology that uses a plasma separator to perform plasma exchange, hemodialysis and filtration at the same time. Some of the plasma components lost during dialysis and filtration are supplemented by post-dilution fluid (plasma). Continuous PE+HDF usually requires 6 to 8 hours or longer treatment, but the amount of plasma required is reduced compared with PE. The combination of DPMAS+CVVH/HDF has complementary advantages, comprehensively removes toxins and pathogenic factors in the patient's blood, and regulates water and electrolyte balance, thereby achieving a balance in the internal environment.

-summary-

At present, artificial liver treatment is becoming an increasingly important part of the treatment of severe liver disease/liver failure. Giving appropriate treatment mode at the right time is an important guarantee for improving the efficacy. Different artificial liver treatment modes have different advantages and disadvantages, and their detoxification, support metabolism and other functions have different emphases. Therefore, it is an inevitable requirement for non-biological artificial liver to adopt an individualized treatment strategy for the treatment of liver failure.