Sad Truth: Job Security in Hepatology

A recent study (ND Parikh et al. Hepatology 2019; 70: 487-95, and associated editorial JA Marrero. 459-61) provide a forecast of increasing liver disease and liver disease severity, driven mainly by fatty liver disease and obesity.

Key findings:

  • Nonalcoholic fatty liver disease (NAFLD) related additions to the liver transplant waitlist expanded from 391 in 2000 to 1605 in 2014.  This corresponded to an overall increase in obesity of 44.1% during that time period.
  • NAFLD-related wait-list additions were predicted by the prevalence of obesity 9 years prior.
  • The authors anticipate that obesity population will increase to over 92 million adults by 2025.
  • The authors project that NAFLD-related wait-list additions will increase to 2104 by 2030, a 55% increase

Because the decrease in complications related to new treatments for Hepatitis C is not expected “until well into the next decade,” the burden of chronic liver disease will continue to rise.

The editorial notes that overall graft survival rates for obese patients with BMI less than 40 do not appear different than those of lean individuals.  Those with BMI >40 had reduced 5-year graft and survival rates.  Also, obese patients have higher morbidities, even in those without reduced survival.

My take: This study identifies a marked increase in end-stage liver disease in the growing population of obese patients.

Related blog posts:

How Does USA Compare to Other Countries in Pediatric Liver Transplantation

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.

Key findings:

  • 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.

Related blog posts:

Liver Shorts: May 2019

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.

Related blog post:

  • Liver Shorts April 2019 Obesity/NAFLD and alcoholic liver disease are driving an increase in HCC and liver cancer mortality

Best Predictor for Mortality from Biliary Atresia Liver Transplantation Candidates –Cardiomyopathy?

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.

Key points:

  • 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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Joshua Tree National Park

Teaching an Old Liver New Tricks

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.

Key findings:

  • 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.

Related blog posts:

Joshua Tree National Park

 

Subclinical Liver Transplant Rejection

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.

Key findings:

  • 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.

Related blog post:

View from Golden Gulch Trail, Death Valley

Liver Shorts November 2018

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.

Banff