Metabolic syndrome: a clinical and molecular perspective. Moller DE and Kaufman KD. Annu Rev Med 2005;56:45-62.
The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol levels). According to recently defined criteria, the metabolic syndrome is prevalent and is associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Primary defects in energy balance that produce obesity (and visceral adiposity in particular) are sufficient to drive all aspects of the syndrome. Increased free fatty acids and lipid accumulation in certain organs are mediators of insulin resistance. Obesity also leads to a proinflammatory and prothrombotic state that potentiates atherosclerosis. Pathways leading directly from adiposity to the genesis of dyslipidemia and hypertension have been elucidated. Recent knowledge implies a role for fat-derived “adipokines,” including TNFα and adiponectin, as pathogenic contributors or protective factors. Current therapies include diet and exercise as well as agents indicated for the treatment of individual components of the syndrome. Future therapies may accrue from the aggressive pursuit of newer molecular drug targets that have the potential to prevent or treat multiple aspects of the metabolic syndrome.
The cluster of disorders that constitute the metabolic syndrome are familiar risk factors for liver transplantation. Only within the past few years has increased association been made among these individual disorders that a name could be attached. While the metabolic syndrome has relevance in the field of internal medicine—since it can lead to the development of type 2 diabetes and cardiovascular disease—it also has relevance to the field of transplantation since these same problems adversely affect transplant survival.
The authors provide a useful table (Table 1) summarizing the features of the metabolic syndrome.
|Clinical features||NCEP ATPIII criteria: ≥3 of the criteria below||WHO criteria: impaired glucose regulation/insulin resistance and ≥2 other criteria|
|Impaired glucose regulation/insulin resistance||Fasting plasma glucose ≥110 mg/dL||Type 2 diabetes mellitus or impaired fasting glycemia (≥6.1 mmol/L [110 mg/dL]), or impaired glucose tolerance, or glucose uptake below lowest quartile under hyperinsulinemic, euglycemic conditions|
|Abdominal obesity||Waist circumference >102 cm (40 inches) in men, >88 cm (35 inches) in women||Waist/hip ratio >0.90 in men, >0.85 in women or body mass index >30 kg/m2|
|Hypertriglyceridemia||≥150 mg/dL||≥1.7 mmol/L (150 mg/dL)|
|Low levels of HDL cholesterol||<40 mg/dL in men; <50 mg/dL in women||<0.9 mmol/L (35 mg/dL) in men, <1.0 mmol/L (39 mg/dL) in women|
|High blood pressure*||≥130/85 mmHg||≥140/90 mm Hg|
|Microalbuminuria||Not included||≥20 μg/minute or albumin: creatinine ratio ≥30 mg/gm|
As with the metabolic syndrome itself, the relevance of the metabolic syndrome to transplantation outcomes has only recently been noticed, with review of the literature uncovering only 1 article overtly connecting the metabolic syndrome and transplantation.1 Yet the clinical features of the metabolic syndrome as risk factors for transplantation have been cited separately and extensively in the transplant literature. Examples are diabetes,2 obesity,3 and nonalcoholic steatohepatitis.4 With the advent of the metabolic syndrome as a recognized entity, it is now realized that all these separate risk factors are most likely part of the same overall problem.
The most important clinical sequel of the metabolic syndrome is coronary vascular disease. This puts transplant patients who have the metabolic syndrome at increased risk in 2 ways: 1) it is one more risk factor to be considered in the pretransplantation workup, along with any other risk factors the patient may have; and 2) the combined risk of cardiovascular disease posttransplantation as a side effect of immunosuppressive medication (especially steroids) together with the risk from cardiovascular disease stemming from the metabolic syndrome might put a posttransplantation patient at vastly increased risk for a cardiovascular event. Immunosuppression (especially prednisone, which increases central obesity) might even set up a vicious circle of either causing or exacerbating previously existing metabolic syndrome, increasing the likelihood of poor transplant outcome.
Other ways in which the metabolic syndrome might adversely affect transplant patients is the associated increased risk of arteriothrombosis, which may reflect impaired fibrinolysis. Patients with the metabolic syndrome also have low levels of nitrous oxide, which results in reduced vasodilatation and endothelial dysfunction.
At present, the best treatment for the metabolic syndrome is weight loss, increased physical activity, and improved diet. Since these are recommendations given to all transplant patients (and indeed to everyone), it might be difficult to know how affixing the label of “metabolic syndrome” to affected patients will improve transplant survival. Nevertheless, Moller and Kaufman report an incidence of the metabolic syndrome in 20 to 30% of the population, with the incidence in people >60 yr of age rising to 40%. The metabolic syndrome therefore affects almost half of all transplant donors and recipients, and cannot be ignored.
The metabolic syndrome has evolved into an important clinical entity that must be recognized by all transplant teams. It has a significant effect on transplantation, not only because of the serious risks it poses to successful transplant outcomes, but because of the sheer numbers of people who have the syndrome. It is not hard to imagine that this newly-named syndrome will soon become a prominent topic of discussion.
- 1de Vries AP, Bakker SJ, van Son WJ, van der Heide JJ, Ploeg RJ, The HT, et al. Metabolic syndrome is associated with impaired long-term renal allograft function; not all component criteria contribute equally. Am J Transplant 2004;4:1675-1683.
- 2Shields PL, Tang H, Neuberger JM, Gunson BK, McMaster P, Pirenne J. Poor outcome in patients with diabetes mellitus undergoing liver transplantation. Transplantation 1999;68:530-535.
- 3Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105-109.
- 4Burke A, Lucey MR. Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation. Am J Transplant 2004;4:686-693.
Quality Takes Center Stage in Transplantation
Using root cause analysis to improve survival in a liver transplant program. Perkins JD, Levy AE, Duncan JB, Carithers RL Jr. J Surg Res 2005;129:6-16.
Background:With the advent of programs such as the American College of Surgeons–National Surgical Quality Improvement Program, surgical services will be compared with their peers across the United States. At times, many programs will experience lower-than-expected outcomes. During July 1, 1998, to June 30, 2000 our 1-year graft (76.86%, P = 0.23) and patient (80.61%, P = 0.016) survivals after liver transplantation were lower than our expected rates (graft 81.89% and patient 88.3%), according to the U.S. Scientific Registry of Transplant Recipients (SRTR).
Methods:We used aggregate root cause analysis to determine underlying reasons for our patient deaths. Two of our surgeons performed a systematic review of all our center's liver transplant patient deaths from January 1, 1995, to December 31, 2000. Each phase of the transplant process was reviewed.
Results:Of 355 patients receiving their first transplant, there were 90 deaths, with 188 root causes identified. The apportionment according to phase of the transplant process was patient selection, 50%; transplant procedure, 17%; donor selection, 15%; post-transplant care, 8%, and psychosocial issues, 10%. Risk reduction action plans were developed, and several important changes made in our care protocol. In April 2004, SRTR data revealed that for patients transplanted between January 1, 2001 and June 30, 2003, our 1-year liver graft survival of 90.73% (P = 0.018) was significantly higher than the national expected rate of 84.48%. Our 1-year patient survival rate of 92.66% (P = 0.285) was higher than the expected rate of 89.29%.
Conclusions:Lower-than-expected outcomes can provide an impetus for improving patient care and raising the quality of a surgical service. Aggregate root cause analysis of adverse events is a valuable method for program improvement.
“Quality,” the best outcome for the patient, has always played a role in transplantation. As the practice of liver transplantation has matured, the formal science of quality has now been introduced. Terms such as quality metrics, decreased variation, root cause analysis, six sigma, etc., formerly in the exclusive domain of administrators or nurses in charge of quality, are appearing with increasing frequency in the medical literature. This trend tends to dampen the enthusiasm of many physicians and surgeons, who feel they have always been trying to give excellent care to their patients.
Quality in transplantation is actually uppermost on everyone's mind around the world since members of the public are encouraged to be organ donors. In the United States, the Centers for Medicare and Medicaid Services (CMS) has recently proposed the appointment of quality officers for transplantation. The Organ Procurement and Transplantation Network/United Network for Organ Sharing is emphasizing the increased commitment to quality by enhanced transplant center reporting processes, more rigorous standards, and more intense monitoring.1
With this increased emphasis on quality, consideration of quality must take higher precedence. Fortunately, in the United States we have one of the best risk-adjusted national databases in all areas of medicine, provided by the United Network for Organ Sharing and reported biannually as transplant center-specific data by the Scientific Registry of Transplant Recipients.
Using this database, the authors discovered that their program outcomes were below the current national standards. Instead of using simple benchmarking to evaluate the difference between their program's statistics and the national standard, they chose to use aggregate root cause analysis to focus on specific areas of improvement to enhance their clinical protocols in order to improve the quality of their transplant system. As outlined in the article, aggregate root cause analysis is a 10-step process that allowed this program to do 3 things: 1) identify the specific areas contributing to their liver posttransplantation deaths; 2) analyze why certain groups of root causes reoccurred in their system; and 3) develop strategies to overcome the deficiencies. A follow-up aggregate root cause analysis revealed that the authors were successful in changing their patient management practices, resulting in higher-than-expected results in a subsequent Organ Procurement and Transplantation Network/United Network for Organ Sharing center-specific report.
This article on using root cause analysis will be a first of many articles in the field of transplantation as quality efforts become more prevalent. As public scrutiny increases, so will the study of quality.
- 1United Network for Organ Sharing, “OPTN/UNOS Board Addresses Monitoring of Compliance and Quality.” Available at: http://www.unos.org/news/newsDetail.asp?id=508. Accessed December 7, 2005.
Increasing the Liver Donor Pool Through Donation After Cardiac Death
Donation after cardiac death: the University of Wisconsin experience with liver transplantation. Foley DP, Fernandez LA, Leverson G, Chin LT, Krieger N, Cooper JT, Shames BD, Becker YT, Odorico JS, Knechtle SJ, Sollinger HW, Kalayoglu M, D'Alessandro AM. Ann Surg 2005;242:724-731.
Objective:To determine whether the outcomes of liver transplantation (LTx) from donation after cardiac death (DCD) donors are equivalent to those from donation after brain death (DBD) donors.
Summary Background Data:Because of the significant donor organ shortage, more transplant centers are using livers recovered from DCD donors. However, long-term, single-center outcomes of liver transplantation from DCD donors are limited.
Methods:From January 1, 1993, to July 31, 2002, 553 liver transplants were performed from DBD donors and 36 were performed from DCD donors. Differences in event rates between the groups were compared with Kaplan-Meier estimates and the log-rank test. Differences in proportion and differences of means between the groups were compared with Fisher exact test and the Wilcoxon rank sum test, respectively.
Results:Mean warm ischemic time at recovery in the DCD group was 17.8 ± 10.6 minutes. The overall rate of biliary strictures was greater in the DCD group at 1 year (33% versus 10%) and 3 years (37% versus 12%; P = 0.0001). The incidence of hepatic artery thrombosis, portal vein stenosis/thrombosis, ischemic-type biliary stricture (ITBS), and primary nonfunction were similar between groups. However, the incidence of both hepatic artery stenosis (16.6% versus 5.4%; P = 0.001) and hepatic abscess and biloma formation (16.7% versus 8.3%; P = 0.04) were greater in the DCD group. Trends toward worse patient and graft survival and increased incidence of ITBS were seen in DCD donors greater than 40 years compared with DCD donors less than 40 years. Overall patient survival at 1 year (DCD, 80%; versus DBD, 91%) and 3 years (DCD, 68%; versus DBD, 84%) was significantly less in the DCD group (P = 0.002). Similarly, graft survival at 1 year (DCD, 67%; versus DBD, 86%) and 3 years (DCD, 56%; versus DBD, 80%) were significantly less in the DCD group (P = 0.0001).
Conclusions:Despite similar rates of primary nonfunction, LTx after controlled DCD resulted in worse patient and graft survival compared with LTx after DBD and increased incidence of biliary complications and hepatic artery stenosis. However, overall results of LTx after controlled DCD are encouraging; and with careful donor and recipient selection, LTx after DCD may successfully increase the donor liver pool.
As the liver shortage intensifies, there is a continual search for ways to expand the organ donor pool. Ethicists and critics have recommended that before putting donors at risk with living liver transplants, we should maximize other alternatives, including extended criteria donors,1 split livers,2 and donation after cardiac death donors, formerly known as non-heart-beating donors.
Liver transplantation, as most surgical fields, has not had many randomized controlled trials. Relying instead on experience and circumstantial evidence, most published studies on alternative sources of donor organs have been in the form of case reports, many with very small numbers of patients. It is therefore encouraging to see recent papers with larger patient numbers.
This present review by Foley et al. focuses on one of the transplant centers having the largest patient base and most longstanding experience with donation after cardiac death. The authors describe the University of Wisconsin's results with 36 liver transplants from donation after cardiac death (DCD) donors compared to 553 liver transplants from donation after brain death (DBD) donors. Details are given on the University of Wisconsin's protocol for organ procurement from DCD donors and preservation, which has become a standard in the field. An interesting modification to the Wisconsin protocol has been that all recipients of DCD organs are now treated with intravenous prostaglandin E1, vitamin E, and N-acetylcysteine before reperfusion of the liver.
Comparison between the outcomes from DCD and DBD donors revealed several interesting results. The biliary stricture rate 1 yr posttransplantation was significantly greater in the DCD group (33% in the DCD group vs. 10% in the DBD group). The incidence of hepatic artery stenosis was significantly higher in the DCD group (16% vs. 5.4% in the DBD group). There was no difference in the incidence of portal vein thrombosis or portal vein stenosis between the 2 groups. There was a significant occurrence of hepatic abscess/bilomas in the DCD group (16%), as compared to the DBD group (8.3%). In contrast to other smaller reports and this center's earlier report,3 the DCD donors resulted in lower patient survival than in the DBD group at 1 yr (80% for the DCD group vs. 91% for the DBD group), and at 3 yr (68% for the DCD group vs. 84% for the DBD group, P = 0.002). There was also significantly lower graft survival in the DCD group as opposed to the DBD group. Finally, there was a trend toward worse patient survival following use of older DCD livers (>40 yr old).
The authors project that using DCD donors could increase the number of organ donors by 15 to 25%. At the same, the authors acknowledge that liver transplantation with DCD donors results in inferior patient and graft survival when compared to that with DBD donors. Nevertheless, they conclude that further experience and careful selection of donors and recipients should allow continued exploration of liver transplantation using DCD donors.
So—have we answered the ethicists and critics by expanding the donor pool appropriately before performing living related liver transplantation? The answer is “probably not”; however, long-term studies such as this one by Foley et al. are beginning to appear, which indicate that more experience in areas such as donation after cardiac death might yield productive results. Recent papers have shown that with extended donor criteria,1 split livers2 and DCD: 1) there are problems and increased cost; 2) there is poorer patient and graft survival; but yet 3) we need to continue to evaluate them. What should be the criteria by which we measure the success of a given donor type? Should it be a strict comparison between patient and graft survival rates among the different donor sources following transplantation, or should consideration of waiting list survival rates be taken into account? Even though survival after transplantation using DCD is somewhat lower, survival on the wait list might be higher, resulting in an overall increased long-term survival benefit for these recipients.
Hopefully, we will see larger reports with increased scientific standards, helping produce new solutions to the scarcity of donor organs.
- 1Renz JF, Kin C, Kinkhabwala M, Jan D, Varadarajan R, Goldstein M, et al. Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg 2005;242:556-563; discussion 563-565.
- 2Broering DC, Wilms C, Lenk C, Schulte am Esch J 2nd, Schönherr S, Mueller L, Kim JS, et al. Technical refinements and results in full-right full-left splitting of the deceased donor liver. Ann Surg 2005;242:802-812; discussion 812-813.
- 3D'Alessandro AM, Hoffmann RM, Knechtle SJ, Odorico JS, Becker YT, Musat A,et al. Liver transplantation from controlled non-heart-beating donors. Surgery 2000;128:579-588.
Predicting Posttransplantation Infection Risk With Gene Polymorphisms
Mannose binding lectin gene polymorphisms confer a major risk for severe infections after liver transplantation. Bouwman LH, Roos A, Terpstra OT, de Knijff P, Van Hoek B, Verspaget HW, Berger SP, Daha MR, Frölich M, van der Slik AR, Doxiadis II, Roep BO, Schaapherder, AF. Gastroenterology 2005;129:408-414.
Background & Aims:Infection is the primary cause of death after liver transplantation. Mannose binding lectin (MBL) is a recognition molecule of the lectin pathway of complement and a key component of innate immunity. MBL variant alleles have been described in the coding region of the MBL gene, which are associated with low MBL serum concentration and impaired MBL structure and function. The aims of our study were to establish the role of the liver in production of serum MBL and to evaluate the effect of MBL variant alleles on the susceptibility to infection after liver transplantation.
Methods:We investigated 49 patients undergoing orthotopic liver transplantation. MBL exon 1 and promoter polymorphisms were determined in patients and in liver donors. MBL serum concentration was determined before and during 1 year after transplantation. The incidence of clinically significant infections during this period was assessed.
Results:Transplantation of MBL wildtype recipients with donor livers carrying MBL variant alleles resulted in a rapid and pronounced decrease of serum MBL levels. This serum conversion was associated with the disappearance of high molecular weight MBL. No indication for extrahepatic production of serum MBL could be obtained. The presence of MBL variant alleles in the MBL gene of the donor liver, but not in the recipient, was associated with a strongly increased incidence of clinically significant infections after transplantation.
Conclusions:Serum MBL is produced by the liver under strong genetic control. After liver transplantation, the MBL genotype of the donor liver is a major risk determinant for life-threatening infections.
The study of gene polymorphisms in liver transplantation has not yet seen many successes. This is changing, however, with this present report on how the mannose binding lectin (MBL) status in liver transplant patients can be identified, paving the way toward knowing which patients might be susceptible to severe post-transplant infection and receive treatment.
MBL is important for the proper functioning of the innate immune system. The MBL lectin domains bind carbohydrate structures of such microorganisms as bacteria, viruses, and fungi, leading to complement activation via the lectin pathway.1 There are 3 known single-nucleotide polymorphisms of the mbl-2 gene, and these single-nucleotide polymorphisms are associated with low serum concentrations, disturbed polymerization, and impaired function of MBL.1, 2
Interestingly, this article reports for the first time that the MBL concentration in patients following transplant is determined by the genotype of the donor liver rather than the recipient extrahepatic tissue. In other words, most of the serum MBL comes from hepatic production. The authors show that the MBL serum concentrations in liver transplant recipients were a direct result of the MBL genotype of the donor livers, and those patients having low concentration of MBL following transplantation were at markedly increased risk for developing severe infections. As the authors point out, the current donor shortage makes it inconceivable to base donor selection on MBL genotype; however, to be able to identify a group of patients prone to severe infection post-transplant would be of significant clinical value.
This may be one of the first reports showing that gene polymorphism studies can prove beneficial in liver transplantation. It is now on the horizon to administer MBL-replacement therapy to post-liver transplantation patients who are determined to have low levels of MBL. Randomized controlled clinical trials are needed to weigh the benefits and potential hazards.3, 4
We eagerly await further discoveries in this field.