A recent study (B Fischler et al. JPGN 2019; 68: 700-05) compared the similarities and differences in allocation experience among 15 countries based on a survey completed by a representative hepatologist in each country.
- The number of liver transplants was 4 to 9 million inhabitants younger than 18 years for 13 of the 15 respondents. USA had the 5th highest rate at ~7 per million inhabitants (Figure 2)
- USA had the 3rd highest donation rate per million inhabitants, ~26 per million. Spain had highest rate at 35 per million. This is partly related to Spain allocating all nonugent pediatric cadaveric donors to pediatric candidates.
- USA had the 3rd lowest rate of living-related liver transplantation percentage in children < 2 yrs, approximately 10%. Both Turkey and Poland had rates near 90%.
- USA had one of the lowest rates of %split liver transplantations for children <2 yrs, less than 10%. Italy, Netherlands, and New Zealand had rates near 90%.
- USA had the 4th highest waitlist mortality for children <2 yrs, approximately 11%
My take: This study indicates that the rate of split liver transplants and living related liver transplants are much lower in USA than in other countries. This is likely to reduce donor pool and contribute to increased waiting list mortality.
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ED Bethea et al. Clin Gastroenterol Hepatol 2019; 17: 739-47. Using a Markov-based mathematical model, the authors “found transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy to a cost-effective strategy that could improve health outcomes.”
A Villanueva. NEJM 2019; 1450-62. This is a succinct review of hepatocellular carcinoma (HCC). Some points:
- More than 1 million patients will die from liver cancer in 2030.
- The rate of death from liver cancer increased 43% from 2000 to 2016,. The 5-year survival rate is grim at only 18%. Only pancreatic cancer is more lethal.
- HCC is rare among patients without preexisting liver disease. Cirrhosis is the main risk factor, though hepatitis B has direct oncologic effects even in the absence of cirrhosis.
- The authors note that cancer surveillance has no “high-quality randomized controlled trials.” However, this may be due to difficulties with enrollment. In one study, 99%of patients declined to assume the risk of being randomly assigned to the nonsurveillance group. Nonetheless, mathematical models, and lower quality studies all show survival benefits of surveillance.
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- Liver Shorts April 2019 Obesity/NAFLD and alcoholic liver disease are driving an increase in HCC and liver cancer mortality
Briefly noted: A recent study (NM Gorgis et al. Hepatology 2019; 69: 1206-18, editorial 940-2 by Elizabeth Rand) indicates that cirrhotic cardiomyopathy (CCM) is very important factor for survival for biliary atresia (BA) patients requiring liver transplantation.
CCM was defined based on two-dimensional echocardiographic criteria: LV mass index ≥95 g/meter-squared or relative wall LV thickness of LV ≥0.42.
- Overall, 11 of 69 patients died, 4 while awaiting liver transplantation and 7 following transplantation.
- 34 of 69 BA patients in this cohort had BA-CCM
- All 11 who died had BA-CCM compared with no deaths in the 35 patients without CCM.
My take: Severe BA-CCM needs to be examined further; if severe, it may merit changing allocation policy.
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A recent retrospective study (JD de Boer et al. Liver Transplantation 2019; 25: 260-74) helps address the question of whether/when a geriatric liver is too old for donation.
The authors culled data from 2000-2015 from 17,811 first liver transplantations performed in the Eurotranplant region.
- 2394 (13%) transplants were performed with livers ≥70 years old
- Graft survival was reduced from donors with a history of diabetes (HR 1.3) and in recipients with hepatitis C virus (HCV) antibody (HR 1.5)
- “Although donor age is associated with a linearly increasing risk of graft loss between 25 and 80 years old, no differences in graft survival could be observed when “preferred” recipients were transplanted” with older grafts (HR 1.1).
- Preferred recipients: 1. HCV-Ab neg, 2. Recipient >45 years old, 3. BMI <35 kg/m2, 4. cold ischemia time < 8 hours. 26% of recipients were considered “preferred” recipients
- Utilization of livers from donors ≥70 years old increased from 42% (2000-2003) to 76% (2013-2015).
- The median donor age increased from 42 to 55 years old from 2000 to 2015.
- The oldest transplanted liver was 98 years old!
The overall Kaplan-Meier survival curves are given in Figure 2 and there is a clear trend of better graft and patient survival with donors <70 years of age. However, Figure 4 shows that graft survival with “preferred” recipients was essentially identical when comparing grafts from donors <70 compared to >70. However, when comparing graft survival from donors <40 compared to donors >70, there appeared to be a small advantage for the younger organs, though this did not meet statistical significance. (HR 1.2 CI 0.96-1.37).
My take: Given the shortage of available livers, the use of older donor organs is a necessity and can be accomplished without significant loss of grafts in selected patients.
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A recent study (S Feng, JC Bucuvalas, et al. Gastroenterol 2018; 155: 1838-51) found a high prevalence of chronic histologic injury even among highly selected long term liver transplant recipients with consistently normal liver biochemical tests. The authors were able to enroll 157 patients. In addition to histology, the authors examined gene expression/microarray transcriptional analysis, and immunohistochemical staining.
- Three clusters of patients were identified: interface activity (group 1, n=34), periportal/perivenular fibrosis without interface activity (group 2, n=45), and a group with neither (group 3, n=78).
- In this cohort, 96 (61%) had Ishak Fibrosis of Stage 0-1, 27 (17%) had Stage 2, 33 (21%) had Stage 3, and 1 (1%) had Stage 4-5.
- The authors identified a module of genes that regulate T-cell-mediated rejection that were associated with interface activity. Thus, interface activity in these patients connotes subclinical rejection, even in patients with consistently normal liver biochemistries.
What to do with this information:
“For patients whose biopsy samples harbor neither inflammation nor fibrosis, immunosuppression dose reduction may be reasonable…For patients, whose biopsy samples show fibrosis in the absence of inflammation, our data do not support any recommendations…for patients whose biopsy samples show interface hepatitis, our data indicate that dose reduction may be unwise. Although the intuitive response may be to escalate immunosuppression, data evidencing the benefit of this approach are lacking.”
My take: This study shows why a liver biopsy has been important prior to reducing immunosuppression (in liver transplantation and autoimmune hepatitis). My question is whether the authors could identify a gene signature/biomarker (like their gene module) that could be used as an alternative to a liver biopsy.
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J Ge et al. Hepatology 2018; 68: 1101-10. This study reviewed liver donation offers between 2010 to 2014. This study found that 5.6% of men (293/5202) and 6.2% of women (179/2899) received a pediatric donor as a first offer. Women, but not men, who received a pediatric first offer had a lower risk of waitlist mortality than with those who received adult organ offers. The authors recommend that “offers of pediatric donor liver be prioritized to women, who are generally shorter stature, once alllocation to the entire…pediatric waitlist pool has occurred.”
CA Chapin et al. Hepatology 2018; 68: 1087-1100. This study found that patients with indeterminate pediatric acute liver failure (iPALF) have a unique pattern of dense CD8+ T-cell infiltrate that is also perforin-positive adn CD103-positive. These CD8+ cells are a biomarker for immune dysregulation. These CD8+ dense pattern was found in the 27 of 33 patients with iPALF; 3 had moderate and 3 had minimal staining pattern (per table 2). The dense CD8+ pattern was seen in 3 of 9 with autoimmune hepatitis and in 1 of 14 with other liver diseases.
E-D Pfister et al. Liver Transplantation 2018; 24: 1186-98. This study examined patient (n=338) and graft survival in the pediatric population (median age 14.0 years) with Wilson’s disease (1968-2013). Overall, patient survival was 87% at 1 year, 84% at 5 years, and 81% at 10 years. Though, the survival was much improved since 2009.
JA Bezzerra et al. Hepatology 2018; 68: 1163-73. This review summarized a research workshop (June 2017) focused on the clinical and research challenges for biliary atresia.
An important metric of liver transplantation outcome is not readily available: acceptance of organ offers. A recent study (E Mitchell et al. Liver Transplantation 2018; 24: 803-809) showed a great deal of variability among pediatric liver transplantation centers in this metric.
The authors examined data from 2007-2015 with 4088 unique patients and 27,094 match runs. The range in organ acceptance rates was 5.1% to 14.6% with a median of 8.9%.
- “Center-level acceptance rates were associated with wait-list mortality, with a >10% increase in the risk of wait-list mortality for every 1% decrease in a centers adjusted liver offer acceptance rate (odds ratio, 1.10, CI 1.01-1.19)
As noted in a previous post, Pediatric Liver Transplantation -Past Time to Split, larger centers generally have higher acceptance rates.
My take: This study adds to the literature regarding the inequities that some patients unknowingly face when listed in some centers.
Related article: HPJ van der Doef et al. Liver Transplantation 2018; 24: 810-9. This article describes the wait-list mortality of young patients with biliary atresia. Those listed before age 6 months and with higher MELD scores (>20) were at increased risk. Recognition of these factors may help improve allocation.
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Hate it when this happens!