WANG Min-min Therapeutic Blood Purification Research Center, University of Rostock, Germany; CHEN Shi-jun Department of Artificial Liver Therapy, Jinan Infectious Diseases Hospital, Jinan, Shandong 250021, China; YE Qi-fa Xiangya Transplantation Medical Academy, Central South University, Changsha, Hunan 410013, China; YANG Yi-jun Department of Artificial Liver Therapy, Nanjing Second People’s Hospital, Southeast University Medical College, Nanjing, Jiangsu 210003, China; CHEN Shi-bin Division of Infectious Diseases, First Affiliated Hospital of Jiangxi Medical College, Nanchang, Jiangxi 330006, China; ZHOU Xin-min Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 400038, China; GUO Li-min ICU & Artificial Liver Support Center, Beijing Ditan Hospital, Beijing 100011, China; ZHANG Yue-xin Institute of Hepatology, First Hospital, Xinjiang Medical University, Urmqi, Xinjiang 830000, China; DING Xiao-qiang Department of Nephrology, Fudan University Zhongshan Hospital, Shanghai 200032, China; HU Xiao-bin Department of Artificial Liver Therapy, Guangzhou No. 8 Hospital, Guangzhou, Guangdong 510060, China; LUO Hong-tao ITU & Blood Purification Center, First People’s Hospital of Foshan, Foshan, Guangdong 528000, China; LIU Yi-he Tianjin First Central Hospital, Tianjin Organ Transplantation Institute, Tianjing 300192, China; WANG Wen-ya Department of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Correspondence to: WANG Min-min Therapeutic Blood Purification Research Center, University of Rostock, Germany (Tel:86-21-63403775 Fax:86-21-63404976 Email:minminwang @yahoo.com.cn ) Keywords: liver failure·artificial liver·Hepatitis B Abstract: Background A liver support therapy, named molecular adsorbents recirculating system (MARS), has been used for more than 700 liver failure patients in China. We made here a summary to evaluate the effects of MARS treatment in different applications with emphasis on hepatitis B virus (HBV) based liver failure. Methods This report analyzed data of 252 patients (mean age (44.9±12.7) years) in three groups: acute severe hepatitis (ASH), subacute severe hepatitis (SSH) and chronic severe hepatitis (CSH). The largest group was CSH (156 patients, 61.9%), and 188 patients (74.6%, 188/252) were infected with HBV. Results MARS treatments were associated with significant reduction of albumin bound toxins and water-soluble toxins. Most of the patients showed a positive response with a significant improvement of multiple organ function substantiated by a significant increase in prothrombin time activity (PTA) and median arterial pressure (MAP). There was a decrease in hepatic encephalopathy (HE) grade and Child-Turcotte-Pugh (CTP) scale. Thirty-nine of 188 HBV patients (20.7%) dropped out of the commendatory consecutive therapy ending with lower survival of 43.6% while the rest of the 149 patients had a survival rate of 62.4%. Survival within the ASH and SSH groups were 81.2% and 75.0%, respectively. In the CSH group, end stage patients were predominant (65/151, 43%), whereas the early and middle stage patients had a better prognosis: early stage survival, including orthotopic liver transplantation (OLT) survival of 91.7%, middle stage survival of 75%, end stage survival of 33.8%. Conclusions MARS continues to be the most favorable extracorporeal treatment for liver support therapy in China for a wide range of conditions, including the majority of hepatitis B related liver failure conditions. The appropriate application of MARS for the right indications and stage of hepatic failure, as well as the fulfillment of prescribed treatments, will lead to the optimal therapeutic result.
2008;121(21):2197-2201 ·LogIn/LogOut ·Fulltext PDF(177K) Free ·Abstract downloadTXT XML ·Articles in CMJ by WANG Min-min CHEN Shi-jun ·Articles in PubMed by WANG MMCHEN SJ ·Put into my bookshelf ·Email to Friend ·Email to author ·Visit:78 ·Download:25 ·Advanced Search ·Related Articles ·Change font size: ·Cannot read some characters Liver failure (LF) is a syndrome resulted from massive hepatocyte death leading to hepatic dysfunction. This loss of liver function causes coagulopathy, hemodynamic instability, encephalopathy with cerebral edema and increased susceptibility to infection and often culminates in multiorgan failure. Despite maximum medical therapy the mortality rate in these patients remains unacceptably high.1
Orthotopic liver transplantation (OLT) has significantly improved the survival of these severely ill patients. However, transplantation opportunities are not readily available for most patients due to the shortage in cadaveric organs and/or unstable clinical conditions for the operation.2 Artificial liver support systems (ALSS) have been used for several decades now as a bridging therapy prior to liver transplantation and as an addendum to standard medical therapy.3
Although various forms of hepatitis are found in China, hepatitis B is the predominant underlying etiology causing LF.4 In patients with severe hepatitis, which primarily leads to severe hepatic failure, mortality is 65%–90%. Complicated by hepatic encephalopathy (HE), despite the advanced intensive care medical treatment, the mortality can be as high as 90%–95%.5
Research and use of ALSS in China has been on-going now for 30 years. One of the former more popular ALSS in China was plasma-exchange (PE); in some cases used in combination with other extracorporeal detoxification techniques such as dialysis and perfusion. These were conventionally used in China, but continuously criticized for their poor clinical results due to low detoxification efficiency, the removal of factors essential for regenerating the liver and the potential danger of cross-infection.6
The novel advanced liver support therapy, named molecular adsorbents recirculating system (MARS), has been available commercially in China now since the middle of 2001. So far, more than 700 LF patients have been treated with MARS, with more than 2000 treatments in more than 40 hospitals throughout China.7
We submit here a systematic review to evaluate the effects of the MARS treatment on the different applications with emphasis on HBV related LF; we consider a combination which we rarely found when reviewing the literature of larger scale studies.
The MARS (University of Rostock, Rostock, Germany) is the extracorporeal device that has the most widespread use in intensive care units and hepatology centers worldwide. MARS enables the selective removal of water-soluble and albumin-bound substances, in which human serum albumin serves as a carrier to facilitate the diffusion between a hemodialysis membrane on one side and a set of adsorbent columns with a conventional dialysis unit on the other sides.7,8
There are still differences in the definition and/or criteria for classifying liver failure between China and western countries. In China, classification criteria are summarized by the Chinese Medical Association (CMA). In general, liver failure based on the various etiologies is named severe hepatitis in China, of which there are three types of severe viral hepatitis in China; acute, subacute and chronic severe hepatitis.9 All data were originally considered within the framework of these criteria, which ensured comparability in our review of this multicenter study.
Most treated patients were followed for short-term outcomes while in hospital. Only a few had as long as 3 months survival. Our study in terms of outcome focused only on the short-term definition.
Statistical analysisData in this review study were presented as percentage incidences and as mean ± standard deviation (SD). Comparisons between groups were obtained using the χ2 test and Student's t test. A P <0.05 was considered statistically significant. All calculations were carried out using the SPSS11.5 software package.
Indications and general surveyThis report analyses data of patients treated with MARS through May 2005. During that time, despite having treated more than 700 patients with MARS, only data on 252 patients with 514 treatments from 14 hospitals in China were eligible for this review. The mean age was (44.9±12.7) years with a range from 15–80 years, 184 were male and 68 were female.
We divided the 252 liver failure patients into 3 major groups including acute severe hepatitis (ASH), subacute severe hepatitis (SSH) and chronic severe hepatitis (CSH). Besides other miscellaneous indications such as primary non-function (PNF) and severe acute respiratory syndrome (SARS) for example, the largest group was the CSH group with 156 patients, 61.9%. The others groups were as follows: ASH had 44 patients (17.5%), SSH with 23 patients (9.1%), PBC 12 patients (4.8%), PNF 9 patients (3.6%), 1 SARS case and a 7-patient-group which included hepatectomy and Budd-Chiari syndrome.
Looking at the subgroups of the etiology classification, we found that hepatitis B was predominant in the hepatic failure patients: 22 of the 44 patients (50%) in the ASH group, 15 of the 23 patients (65.2%) in the SSH group and 151 of the 156 (96.8%) in the CSH group. Thus, the overall hepatitis B cases included 188 patients, overlapping of hepatitis C or hepatitis D. We will study the outcome focusing on the extracted data of the 188 severe hepatitis B patients.
The total number of treatments was 514, giving an average of 2.04 treatments per patient. Although this seems to be less than the average found in some other reports, after closer investigation it was observed that contrary to medical prescription, many patients did not complete the MARS treatment schedule and stopped after the first treatment due to economical reasons; in the hepatitis B group, it was noted that 39 of 188 patients (20.7%) rejected the prescription for consecutive treatments. The actual average number of treatments for the remaining patients who completed the therapy is therefore higher than the 2.04 treatment per patient.
Safety profileMARS treatments were performed according to standard guidelines which included standard medical therapy. All procedures ran smoothly and safely even for critically ill patients. Except for slight chills, nausea or anaphylaxis, which is related to extracorporeal therapies and transitorily present in some patients, hemodynamic instability was rarely observed. Recovery was uneventful without the need for any special medical intervention. Possible thrombocytopenia was asymptomatic and seldom required a patient to be weaned off the MARS therapy.10 Unlike some of the other extracorporeal devices, the use of MARS is not associated with a loss of clotting factors, growth factors, hormone binding proteins or acute phase reactants.
In extracorporeal systems however, activation of the coagulation system is a well recognized complication. Disseminated intravascular coagulation (DIC) was trigged during one MARS treatment, due to the critical coagulation condition of the patient and lead to the termination of treatment. It was suggested that there is a need to improve the monitoring of the coagulation system before and during MARS treatment.11
Survival analysisWe herewith make a critical review in terms of the survival study, focusing on the predominant group of 188 HBV based LF patients. It was a rational for us to take the final survival results for the bridged OLT patients into consideration, which we considered to be more critical, rather than looking at the outcome simply ending in OLT (Table 1).
view in a new window Table 1. Hepatitis B patients' outcomes (n (%))
The “quit” problemMany patients terminated the prescribed schedule of consecutive treatments even after starting the first MARS treatment. Of the total of 188 hepatitis B LF patients, 39 (20.7%) patients stopped additional treatments. It is worth while to take a closer look at these patients since they were considered for return to mucosal tumor (SMT), which included some other “cheaper” ALSS methods, mainly PE but not OLT. Interestingly, there was a higher proportion of terminated treatments in the early stage of CSH. It was suggested that the first 1 or 2 treatments contributed tremendously to the positive clinical results due to the minor state of illness. Hence any additional treatment was considered unnecessary. The final survival rate was 63.6%, which was 20% less than the survival rate within the group that completed the prescribed therapy, 83.3% survival rate. Taking the surviving OLT group into consideration (95.8% if bridging to OLT was included), this would have further increased to 91.7%.
Moreover, for the most severe end stage CSH cases, we found fewer patients terminating the prescribed therapy. Whether this is to be explained by the fact that these patients were primarily relying on MARS, or partly because of their potentially higher mortality rate, is unclear. In the group of 149 patients, those with ASH and SSH to OLT had a final survival rate about 30% higher than the group terminating the prescribed MARS therapy (ASH 62.5% vs 33.3%; SSH 66.7% vs 33.3%). For the CSH, the prescribed therapy enhanced the recovery of the early stage liver failure cases by 20% (83.3% vs 63.6%), the middle stage liver failure cases by 15% (65.6% vs 50.0%), and the end stage liver failure cases by 5% (27.7% vs 22.2%). Including the surviving OLT cases further improved survival rates; survival was 28% (91.7% vs 63.6%) higher in the early stage liver failure cases, 25% (75.0% vs 50.0%) higher in middle stage liver failure cases and 9% (30.8% vs 22.2%) higher in the end stage liver failure cases.
To summarize, in comparison to the survival rate of those patients terminating the prescribed therapy (43.6%, 39 patients) the group of patients completing the prescribed MARS therapy (149 patients of the HBV group) achieved a significantly improved recovery rate 62.4% (bridged to OLT included, P <0.05, Table 2).
view in a new window Table 2. Recovery rates between patients terminating and completing the prescribed MASR therapy
ASHAs shown on the data sheet the recovery rate of the ASH group was 50.0%, despite the 81.2% recovery rate including the surviving OLT bridged patients, the final survival rate, including the surviving OLT patients, was 62.5%. It can be easily concluded that OLT offers substantial benefits in ASH for this indication and that MARS may contribute significantly, not only in avoiding OLT, but also in supporting a stable bridging. This prognosis would be improved even further if the capability for OLT were more readily available within the hospitals involved.12
SSHFor the SSH group, the recovery was 66.7% and the survival outcome till OLT was 75%. The final survival rate was 66.7%, as only one OLT patient died.
CSHMore interesting results were found in the CSH group. First, end stage liver failure patients were the biggest population within this group (65/151, 43%), while the early and middle stage liver failure patients had a lower proportion (early stage liver failure: 24/151, 15.9%; middle stage liver failure: 32/151, 21.1%). Looking at the outcome, statistical analysis indicated that the early stage liver failure group had a tendency towards an improved survival rate (survival including surviving OLT cases of 91.7%) in comparison to the middle stage liver failure group However, the middle stage liver failure group had a significantly improved prognosis when compared to the end stage liver failure group (survival, including surviving OLT cases, of 30.8%, P <0.005, Table 3).
view in a new window Table 3. Analysis of recovery rate within the CSH group
Substance removalMARS treatments were associated with a significant reduction of albumin bound toxins including bilirubin, NO and various cytokines, as well as water-soluble toxins such as Cr and ammonia (Table 4).
view in a new window Table 4. Bio-chemical and clinical data before and after MARS treatments
These survival data are comparative with the single center experience with smaller groups of patients; 30.7% survival rate in 13 end stage CSH patients with multiple organ dysfunction syndrome (MODS),13 30% survival rate in this group of 10 end stage CSH patients,14 and 36.7% survival rate for the group of 30 CSH patients mostly in end stage.15 These results do present a better life saving outcome for MARS when compared to the traditional liver support therapies such as PE and/or hybrid therapies. Another recent big review on 235 CSH patients described the early and middle stage liver failure survival rates of 87.5% and 61.8% respectively, whereas the end stage liver failure survival rate was only 17.0%.9 The results show that patients in early and middle stage liver failure will gain a more favorable outcome than those in end stage liver failure; which in turn highlights the importance of early clinical intervention with liver support therapy.
Chen et al16 reported an interesting comparison with the PE method on the effective removal of bilirubin. They found that MARS treatments resulted in a significantly decreased bilirubin rebound level on the second day as compared to PE (P <0.01). Furthermore, despite the lower difference in bilirubin removal for single treatments between PE and MARS (25.5% and 39.3% respectively), Guo et al17 showed that the rebound rate in bilirubin levels is as much as 45% higher with PE as compared to MARS, which is only 12%. This shows that MARS is more effective and stable in bilirubin clearance.
The indications for which MARS has been used in clinical practice have already been mentioned. The overall experience spans more than 500 treatment sessions in more than 250 patients. The results of MARS therapy can be best assessed by the impact on the function of the individual organ systems.
Many cases showed an increase in mean arterial pressure (MAP), or stabilization in hemodynamics. The basis for this improvement may be the effective removal of the nitric oxide-albumin adduct (S-nitrosothiol), which in high levels in the circulation may in part be responsible for the hyperdynamic circulation in liver failure.18
It is recognized that lipopolysaccharides (LPS) and endotoxins are potent inducers for the release of cytokines such as tumor necrosis factor α, interleukin-6 and interleukin-8. These may lead to an inflammatory cascade and consequently result in the systemic inflammatory response syndrome (SIRS); SIRS and other infections are frequently associated with the development and aggravation of the acute respiratory distress syndrome (ARDS). It was observed that MARS can modulate the oxygenation function in hypoxemia patients by improving SaO2 and PaO2 parameters. This may be due to the effective removal of the afore mentioned inflammatory cytokines and mediators, thus alleviating lung injury to the extent of allowing patients to withdraw from assisted respiration support.19 This was also validated in the successful treatment of a SARS patient.20
We found that improvement of synthetic liver function following MARS therapy may not occur after a single treatment session (unlike improvement in the biochemical profile). The prothrombin time activity (PTA) (international normalized ratio) and Child-Turcotte-Pugh (CTP) index significantly decreased through a course of MARS treatment. Nonetheless further investigation is necessary since much of contributed data lacked a detailed description of blood substitutions, such as clotting factors, which will influence the prescribed standard medical therapy during hospitalization.
A significant improvement in HE grade indicated the therapeutic neurological changes. Part of the benefits from MARS may be due to a marked reduction in plasma ammonia levels and a shifting of the amino acid profile towards the more favorable branched chain amino acids. These results in an increase in the Fischer's index.21
Improvement in renal function was represented by the decrease in creatinine and urea, an increase in urine output, and the resolution of obstinate ascites and HRS. This may be in part the result of the substances being cleared by the system but may, to a greater extent, be the result of improved renal blood perfusion, which contributes to the renal protection of the MODS LF patients for a better outcome.22
In conclusions, the MARS continues to be one of the most popular extracorporeal devices used for providing liver support. It has been successfully used in a wide range of indications, ranging from acute liver failure to acute on chronic liver failure, with an excellent safety profile. However, without indication guidelines, including therapeutic protocols, the use of MARS is not standardized. Its widespread adoption requires further proof from evidence-based medicine.
1. Jalan R, Williams R. Acute-on-chroni liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002; 20: 252-261.
2. Brown KA. Liver transplantation. Curr Opin Gastroenterol 2005; 21: 331-336.
3. Palmes D, Qayumi AK, Spiegel HU. Liver bridging techniques in the treatment of acute liver failure. J Invest Surg 2000; 13: 299-311.
4. Sun Z, Ming L, Zhu X, Lu J. Prevention and control of hepatitis B in China. J Med Virol (Chin) 2002; 67: 447-450.
5. Bernstein D, Tripodi J. Fulminant hepatic failure. Crit Care Clin 1998; 14: 181-197.
6. Siami GA, Siami FS. Membrane plasmaapheresis in the United States: a review over the last 20 years. Ther Apher 2001; 5: 315-320.
7. Mitzner SR, Stange J, Klammt S, Peszynski P, Schmidt R. Albumin dialysis using the molecular adsorbent recirculating system. Curr Opin Nephrol Hypertens 2001; 10: 777-783.
8. Tan HK. Molecular adsorbent recirculating system (MARS). Ann Acad Med Singapore 2004; 33: 329-335.
9. Li L, Yang Q, Huang J, Xu X, Chen Y, Chen Y, et al. Treatment of hepatic failure with artificial liver support system. Chin Med J 2001; 114: 941-945.
10. Zhou XM, Miao JY, Yang Y, Zhou L, Wang X, Ling J, et al. Clinical experience with molecular adsorbent recirculating system (MARS) in patients with drug-induced liver failure. Artif Organs 2004; 28: 483-486.
11. Wang X, Zhou XM, Miao JY, Yang Y, Zhao L, Ding J, et al. Side-effects and management of continuous MARS artifical liver for patients. Chin J Hepatol (Chin) 2004; 12: 15.
12. Yuan JZ, Ye QF, Ming YZ, Hang ZF, Zhao LL, Zhao XY, et al. Preoperation risk factor analysis in orthotopic liver transplantation with pre-transplant artificial liver support therapy. Chin J Hepatol (Chin) 2005; 13: 175-178.
13. Guo LM, Liu JY, Xu DZ, Li BS, Han H, Wang LH, et al. Application of molecular adsorbents recirculating system to remove NO and cytokines in severe liver failure patients with multiple organ dysfunction syndrome. Liver Int 2003; 23: 16-20.
14. Hu XB, Yang Z, Tang XP, Wang MM, Zhou Y, Li SP. Improvement of molecular adsorbent recirculating system on chronic severe hepatitis patients with multiple organ failure. Chin J Hepatol (Chin) 2003; 11: 629-630.
15. Ding YT, Xu QX, Qiu YD, Yang YJ. Molecular adsorbent recirculating system in treating patients with acute liver failure: a bridge to liver transplantation. Hepatobiliary Pancreat Dis Int 2004; 3: 508-510.
16. Chen S, Zhang L, Shi Y, Yang X, Wang M. Molecular adsorbent recirculating system: clinical experience in patients with liver failure based on hepatitis B in China. Liver 2002; 22 Suppl 2: s48-s51.
17. Guo LM. Application of blood purification technique in artificial liver support therapy. Chin J Hepatol (Chin) 2003; 11: 43.
18. Schmidt LE, Sorensen VR, Svendsen LB, Hansen BA, Larsen FS. Hemodynamic changes during a single treatment with the molecular adsorbent recirculating system in patients with acute-on-chronic liver failure. Liver Transpl 2001; 7: 1034-1039.
19. Luo HT, Guo LM, Liu QM, Wu M, Bai HL, Luo YH, et al. Therapeutic application of molecular adsorbent recirculation system in the treatment of multiple organ dysfunction syndrome patients. Chin Med J 2005; 118: 1113-1117.
20. Luo HT, Wu M, Wang MM. Case report of the first severe acute respiratory syndrome patient in China: successful application of extracorporeal liver support MARS therapy in multiorgan failure possibly induced by severe acute respiratory syndrome. Artif Organs 2003; 27: 847-849.
21. Jalan R, Williams R. Improvement in cerebral perfusion after MARS therapy: further clues about the pathogenesis of hepatic encephalopathy? Liver Transpl 2001; 7: 713-715.
22. Sen S, Mookerjee RD, Davies NA, Williams R, Jalan R. Review article: the molecular adsorbents recirculating system (MARS) in liver failure. Aliment Pharmacol Ther 2002; 16 Suppl 5: s32-s38.