Impact of Graft Steatosis on Post-operative Complications After Liver Transplantation

1. Clinical impact of graft steatosis on postoperative complications after OLT.
2. Recommendations to improve outcomes after transplantation of steatotic livers and increase donor pool.

Study Overview

• Status: Completed
• Conditions: Post-operative Complications
• Intervention / Treatment: Procedure: steatosis

Detailed Description

Introduction Solid organ transplantation has become the standard of care for selected patients with end-stage organ dysfunction. With improved surgical techniques, more effective immunosuppressive therapies, and better anti-infective medications, outcomes after solid organ transplantation have improved over the last several years.

The excellent survival rates reported after orthotopic liver transplantation (OLT) have increased the demand for liver transplants and have enhanced the disparity between the number of available donor organs and the need for such organs.

The lack of available organs for liver transplantation (LT) associated with the increased death rates among patients on most waiting lists for LT has triggered the use of so-called extended criteria donor (ECD) grafts, previously called ''suboptimal grafts''. Among the wide range of these ECD livers, hepatic steatosis is one of the most frequent disorders, which is mostly related to an increasing prevalence of non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease (NAFLD) is increasingly significant in healthy individuals for its high worldwide prevalence, an association with the metabolic syndrome such as insulin resistance, diabetes, dyslipidemia and obesity, and an association with liver-related morbidity and mortality.

Clinical evaluation and current imaging modalities, and serological and laboratory tests can be strongly suggestive of the presence of hepatic steatosis, but none of these is capable of distinguishing steatohepatitis (SH) from uncomplicated steatosis; likewise, these evaluations can generally detect advanced liver disease (e.g. portal hypertension), but none can truly assess the degree of liver necroinflammatory injury, lesser stages of fibrosis and architectural remodeling. Liver biopsy evaluation, therefore, remains the 'gold standard' to unequivocally diagnose SH and to document the severity of hepatic injury and fibrosis.

Steatosis is assessed according to the pattern and the amount of fatty infiltration in hepatic tissue sections. Traditionally, fatty accumulation has been classified morphologically as macrovesicular or microvesicular. Macrovesicular steatosis is characterized by a single, bulky fat vacuole in the hepatocyte that displaces the nucleus to the edge of the cell. The less conspicuous microvesicular steatosis, usually related to toxins or metabolic disorders, is characterized by accumulation of tiny lipid vesicles in the cytoplasm of hepatocytes without nuclear dislocation. Current quantification and grading of liver steatosis originates from studies performed in the early 1990s, when steatosis was classified as mild, moderate, or severe if, less than 30%, 30-60%, or more than 60% of hepatocytes, respectively, display fatty infiltrations.

Although usually benign, fatty liver may associate with serious injury, with inflammation and hepatocyte necro-apoptosis, non-alcoholic steatohepatitis (NASH), in 20-30% of subjects. Those patients are at risk of developing fibrosis, one fifth progressing to liver cirrhosis. It is apparently more slowly progressive than other chronic liver diseases, such as alcohol or viral-induced disease. Moreover, the problem of hepatocytes being fatty, overcomes the liver itself, as it increases the risk for cardiovascular disease and death and duplicates the risk for type 2 diabetes mellitus (T2DM), independently of the severity of liver injury.

Severe fatty livers are more susceptible to warm and cold ischemia reperfusion injury than normal ones. The type of damage is not through the pathway of cellular apoptosis, but necrosis.

The use of steatotic grafts for orthotopic liver transplantation (OLT) is associated with a high rate of primary graft dysfunction and decreased graft and patient survival particularly with macro-steatosis.

• Study Type: Observational
• Enrollment (Actual): 271

Contacts and Locations

Study Locations

• Italy
  • AN
    • Ancona, AN, Italy, 60126
      • Polytechnic University of Marche

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

All adult patients candidate for liver transplantation are included in this study

Description

Inclusion Criteria:

• All adult patients candidates for liver transplantation are included in this study

Exclusion Criteria:

• Pediatric patients are excluded.
• Re- transplanted patients.
• cases with no histopathological examination records

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
mild steatosis; 5% - 30% of hepatocytes have fatty infiltration	Procedure: steatosis; Liver Transplantation with graft steatosis
moderate steatosis; 30% - 60% of hepatocytes have fatty infiltration	Procedure: steatosis; Liver Transplantation with graft steatosis
No steatosis; No or less than 5% of hepatocytes have fatty infiltration	Procedure: steatosis; Liver Transplantation with graft steatosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-operative complications rate	according to the Clavien- Dindo classification system	through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biliary complications: stricture or leakage	the outcome will be measured retrospectively from the hospital records and prospectively in the recent cases of transplantation	through study completion, an average of 1 year
early graft dysfunction (EGD), which is defined as impaired initial allograft function with high peak serum transaminase and persistent high bilirubin levels.	the outcome will be measured retrospectively from the hospital records and prospectively in the recent cases of transplantation	through study completion, an average of 1 year
Primary graft non-function (PNF), which is defined as primary failure of the graft followed by death or re-transplantation within the first post transplantation week.	the outcome will be measured retrospectively from the hospital records and prospectively in the recent cases of transplantation	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Sohag University
• Collaborators: Università Politecnica delle Marche
• Investigators: Study Director: Alaa A. Redwan, Professor, Sohag University; Study Director: Marco Vivarelli, Professor, Università Politecnica delle Marche

Publications and helpful links

General Publications

• Nocito A, El-Badry AM, Clavien PA. When is steatosis too much for transplantation? J Hepatol. 2006 Oct;45(4):494-9. doi: 10.1016/j.jhep.2006.07.017. Epub 2006 Jul 31. No abstract available.
• El-Badry AM, Jang JH, Elsherbiny A, Contaldo C, Tian Y, Raptis DA, Laczko E, Moritz W, Graf R, Clavien PA. Chemical composition of hepatic lipids mediates reperfusion injury of the macrosteatotic mouse liver through thromboxane A(2). J Hepatol. 2011 Dec;55(6):1291-9. doi: 10.1016/j.jhep.2011.04.019. Epub 2011 May 19.
• Trevisani F, Colantoni A, Caraceni P, Van Thiel DH. The use of donor fatty liver for liver transplantation: a challenge or a quagmire? J Hepatol. 1996 Jan;24(1):114-21. doi: 10.1016/s0168-8278(96)80195-4. No abstract available.
• Lee JY, Kim KM, Lee SG, Yu E, Lim YS, Lee HC, Chung YH, Lee YS, Suh DJ. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol. 2007 Aug;47(2):239-44. doi: 10.1016/j.jhep.2007.02.007. Epub 2007 Mar 6.
• McCormack L, Dutkowski P, El-Badry AM, Clavien PA. Liver transplantation using fatty livers: always feasible? J Hepatol. 2011 May;54(5):1055-62. doi: 10.1016/j.jhep.2010.11.004. Epub 2010 Nov 13.
• Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013 May;58(5):1007-19. doi: 10.1016/j.jhep.2012.11.021. Epub 2012 Nov 23.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: January 11, 2016
• First Submitted That Met QC Criteria: January 15, 2016
• First Posted (Estimate): January 20, 2016

Study Record Updates

• Last Update Posted (Estimate): October 13, 2016
• Last Update Submitted That Met QC Criteria: October 12, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Liver Transplantation - Steatosis - Fatty Liver
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fatty Liver; Postoperative Complications
• Other Study ID Numbers: 28/9/2014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided