Tag Archives: liver transplantation

“More to It Than Meets the BMI”

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This blog post title is quoted from a clever editorial which reviews the use of BMI and the effect of obesity with outcomes after liver transplantation (Liver Transpl 2014; 20: 253-54, related article pages 281-90.)

Key points from editorial and study:

  • Study enrolled 202 consecutive adult (mean 51 years) patients (200-2010) as part of cohort study.  Data was obtained at time of transplantation and reviewed with retrospective analysis. NAFLD was transplant indication in 7%.
  • “Use of BMI as a marker of obesity is flawed.” Authors showed only 86% agreement between calculated BMI and percent body fat as measured with DXA.
  • Patients with high BMI due to greater lean muscle mass may have improved outcomes.  Sarcopenia (loss of muscle mass) likely has greater effect on outcomes.
  • The study shows that the combination of diabetes and obesity increases the risk of complications and prolongs hospital stays (5.81 days, P<0.01).
  • Metabolic risk factors had no effect on 30-day, 1-year, or 5-year patient survival.

Another article in same issue: Liver Transpl 2014; 20: 311-22. This study retrospectively examined 148 normal-weight, 148 overweight, and 74 obese patients who underwent living donor liver transplantation. Key finding: “there were no differences in graft survival [hazard ratio (HR) =0.955] or recipient survival [HR = 0.90]” between these groups.  Obese patients do require larger grafts which can delay identifying suitable donor.

Bottomline from editorial: “this study shows us that the combination of diabetes and obesity dramatically increases the risk of complications” but not survival.  “If there comes a day when the cost of a human life is less than the cost of a 6- to 7-day hospital stay, that is the day to reckon. None of us may survive.”

Related blog post:

Sarcopenia, fatigue, and nutrition in chronic liver … – gutsandgrowth

It is a Question of Fairness

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One of my professors in medical school frequently described ethical issues in terms of some things being unfair and some things being unfortunate.  A report in this month’s Liver Transplantation (2013: 19: 1330-42; editorial 1287-88) indicates that sometimes an individual does not receive a liver transplant due to an unfair allocation policy.  One potential problem with the current UNOS distribution is the use of exception points.  Because the Model for End-Stage Liver Disease (MELD) score does not work well for all patients, there are both recognized exceptional diagnoses (REDs) (eg. hepatocellular carcinoma) and non-REDs (eg. cholangitis).  The purpose of these exception points is to account for some conditions that may increase the risk of dying on the transplant list in which the MELD score is not an adequate predictor.

In this study of adult liver transplant candidates between 2002-2011, the authors examined non-REDs; among a cohort of 58,641, 7.4% applied for a non-RED.  The number of non-REDs increased over the course of the study.  In addition, approval rates which were <50% in 2002 increased to nearly 75% in 2010. Candidates with approved exceptions were more likely to undergo transplantation (68.3% vs. 53.4%, P <0.001).

There was significant variability among transplant centers with regard to requesting exception points. Centers with higher median MELD score at transplantation were more likely to have candidates with non-RED applications. The net result was that women, African-Americans, Hispanics, and patients with Medicaid insurance were statistically less likely to have an exception application.

In pediatrics, non-RED applications are more common. Thus, the problem of equitable distribution could be even greater among pediatric patients.

Bottomline: While physicians have a duty to their patients, it is vital to make sure that every effort is made to allocate organs in a fair manner.  Since the use of non-RED applications is inconsistent, it suggests that some transplant centers are utilizing this tool inappropriately (?too often, ?too few).  This report indicates that more work is needed to have a fair transplant allocation system.

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Reference for Mitochondrial Hepatopathies

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This morning’s blog discussed mitochondrial liver disease.

Another useful reference:

The Journal of Pediatrics Volume 163, Issue 4 , Pages 942-948, October 2013  Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes  Way Seah Lee, MD and Ronald J. Sokol, MD

Growth after Liver Transplantation

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A retrospective chart review of patients from Australia and Japan who underwent liver transplantation between 1985-2004 provides some insight into the growth potential after liver transplantation (J Pediatr 2013; 163: 537-42).  The study included height data from 98 patients and weight data from 104 patients.

Study characteristics:

  • 58% were Australian and 42% were Japanese
  • 76 of 98 patients were transplanted for biliary atresia
  • 47% were younger than 2 years at the time of transplantation
  • Measurements were recorded pre-transplant, 1, 5, 10 and 15 years later

Findings:

  • Height recovery continued for at least 10 years to reach the 26th percentile (Z-score -0.67) 15 years after transplant.  Australian patients had better height recovery, reaching the 47th percentile (Z-score -0.06).
  • Weight recovery was most pronounced in 1st year after transplantation but also continued for 15 years.
  • The median height, weight, and BMI Z-scores are listed in Table II for all time periods
  • Those most malnourished and growth impaired at transplant exhibited the most catchup but remained significantly shorter and smaller 15 years later.

While the Australian patients had better growth in this study, this may be attributable to the fact that nearly all the Japanese in this study were transplanted before 1996 whereas Australian patients were transplanted over the entire period of the study.  Improvements in post-operative management with improved immunosuppressive treatment regimens (eg. reduced steroids) may have played a role.

Take-home message:  Most pediatric liver transplantation patients can expect to be normal-sized adults.  Those who are very malnourished at the time of transplantation, though, are likely to have some reduction in growth potential.

Related blog posts:

Once Daily Tacrolimus for Liver Transplant Recipients

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A recent study shows that once daily tacrolimus can be effective in patients who have been stable following liver transplantation (LT) (Liver Transplantation 2013; 19: 529-33).

In this retrospective, single center study with 394 adult LT patients, the authors examined the results of conversion to once daily dosing of tacrolimus.  Patient demographics noted an mean age of 53 years & mean time post-transplant was 74 months.

Criteria for conversion:

  1. At least 6 months posttransplant
  2. No rejection in >3 months
  3. Tacrolimus bid was changed to the same total daily dose at once a day and then modified based on levels.

Results after a 24 month followup:

  • 358 of 394 were able to maintain once a day dosing. 6 patients had been converted to cyclosporine, 14 patients had stopped all calcineurin inhibitors, 16 patients had returned to BID dosing.
  • Acute rejection episode was noted in 7 patients
  • Mean serum tacrolimus trough decreased after conversion from 6.1 to 4.9 ng/mL

Take-home message:

Once daily tacrolimus appears to be a reasonable strategy for stable LT patients.  It is possible that once daily administration will improve adherence.

Related blog links:

Predicting outcome in Pediatric Acute Liver Failure

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In a recent study, soluble interleukin 2 receptor alpha (sIL2Rα) was identified as a marker associated with patient outcome in pediatric acute liver failure (JPGN 2013; 56: 311-5).

Because systemic inflammatory response and immune function have potential effects on the outcomes of patients with acute liver failure (ALF), the authors decided to study markers of T-cell immune activation in patients enrolled in the pediatric ALF (PALF) cohort. The PALF cohort was derived from the PALF study group which consists of 20 sites.  All of the enrollees from this study were from the 17 U.S. sites.

Design: Blood was collected within 48 hours of enrollment into the PALF cohort.  Blood had to received by the testing laboratory within 24 hours of collection.  The final study group included 77 patients, though outcomes for two patients (who were discharged alive within 10 days of enrollment) were not known.  Blood was tested for numerous markers including “CD56 bright,” perforin, Natural Killer T-cell (NKT) perforin, NK lytic activity, granzyme B, CD8, CD16, CD56 and others.  Outcomes were assessed within 21 days of enrollment.

Results:

  • Acetaminophen was the most common identifiable reason for PALF (n=13) and all acetaminophen patients survived without liver transplantation.
  • Other etiologies included autoimmune marker positive-ALF (n=8), Drug-induced ALF (n=2), viral ALF (n=6), metabolic (n=7), hemophagocytic lymphohistiocytosis (HLH) (n=3), and shock/ischemia (n=3).  Besides indeterminant ALF (n=27), all other diagnosis had n=1.
  • Age was distributed across all pediatric groups: < 5 years (n=24), 5-9 years (n=19), >9 years (n=34).
  • Of all the markers of T-cell immune activation, only sIL2Rα was identified as being able to discriminate between survival with native liver, liver transplantation, and death.
  • Of the 15 subjects with markedly elevated sIL2Rα (>5000 IU/mL), 5 (33%) survived with native liver, 2 died, and 8 underwent liver transplantation. In contrast, all 37 patients with normal sIL2Rα lived, 30 (81%) with their native livers.

Study limitations included the cross-sectional design which entailed measuring sIL2Rα at a single point in time.  In addition, it is not clear whether sIL2Rα levels reflect a causal role in liver injury or a response to liver injury.

Take home message:

sIL2Rα along with traditional measures could improve the ability to predict hepatic recovery in PALF.

Related blog posts:

Practice guidelines and 93 OLTx recommendations

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While checklists have a role (Checklists for Crisis and Daily Care | gutsandgrowth), most will not be workable if each has 93 recommendations like the 2012 AASLD Adult Liver Transplant Practice Guidelines (Liver Transplantation 2013; 19: 3-26).

While the guidelines are comprehensive including topics like vascular thrombosis, immunosuppression, late rejection, bone health, kidney diseases, metabolic syndrome, reproductive health, and infectious disease, they are not easily organized.  Some recommendations include the following:

  1. “the frequency of monitoring with liver tests should be individualized by the transplant center (grade 1, level a)”
  2. “depending on the pattern of liver tests, magnetic resonance imaging, computed tomography, ERCP, and ultrasound may be appropriate (grade 1, level a)”
  3. “frequent handwashing reduces the risk of infection…(grade 1, level a)”
  4. “shoes, socks, long-sleeve shirts and long pants should be worn for activities that will involve soil exposure..(grade 1, level a)”
  5. Patients “with PSC and inflammatory bowel disease…should undergo an annual screening colonoscopy ..(grade 1, level b)”
  6. “the ideal immunosuppression for pregnancy is tacrolimus monotherapy”

Thus, the recommendations are sometimes almost worthless like #1-3, sometimes difficult to implement like #4, and sometimes specific like #5-6.

Bottom-line:

While not useful as a practical checklist for routine care, this guideline offers useful information on a broad range of problems for transplant recipients.

Vision and persistence in developing liver transplantation

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A concise perspective article examines the history and challenges of developing liver transplantation into an accepted treatment for end-stage liver disease (NEJM 2012; 367: 1483-86).

Key points:

  • Thomas Starzl 1st attempted liver transplant in 1963.  The 3-year-old boy with biliary atresia did not survive the operation; the next 5 attempts were failures as well with the longest survivor lasting only 23 days.  A moratorium of nearly 4 years was placed after these initial failures.
  • Improvements in immunosuppression were a key advance, including antilymphocyte serum in 1966.  During the 1970s, 70% of liver-allograft recipients died shortly after surgery.
  • Brain death concept, accepted in 1968, allowed for better donor organs (less ischemia)
  • Key immunosuppression advance was in 1979 when Roy Calne (Cambridge) reported the use of cyclosporin for organ transplantation.  Between 1980-81, 70% (n=40) of Starzl’s patients survived more than one year.
  • In 1983, National Institutes of Health at a consensus conference concluded that liver transplantation should be considered a ‘clinically applicable, lifesaving procedure.’
  • Other improvements, such as better organ procurement protocols and preservation along with further improvements in immunosuppression have helped improve 1-year and 5-year survival rates to climb, >85% and >70% respectively in 2010.
  • In 2010, 6291 patients underwent liver transplantation.
  • Remaining challenges include inadequate organ supply, recurrent primary hepatic disease (eg. hepatitis C), adverse drug effects, and post-transplantation complications.

The persistence and vision of Starzl and Calne has been recognized with the Lasker-Debakey Award (Lasker-DeBakey Clinical Medical Research Award – Wikipedia, the …).

Alagille and liver transplantation

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Alagille syndrome (ALGS) is an autosomal dominant disorder which affects 1 in 30,000.  More information is available regarding the outcome of ALGS patients who have undergone liver transplantation (Liver Transpl 2012; 18: 940-48).

Using the SPLIT (studies of pediatric liver transplantation) database, the outcome of 91 ALGS patients was compared with 236 age-matched biliary atresia (BA) patients in a retrospective review (1995-2009).

  • 1-year survival was 87% for ALGS and 96% for BA (p=0.002).  Most of the ALGS deaths occurred in the initial 30 days.  No pretransplant factors could be identified which were associated with mortality.
  • Renal insufficiency worsened after liver transplantation in ALGS patients with 22% having glomerular filtration rate <90 mL/minute/1.73 meter squared; 8% of BA had similar renal insufficiency.
  • ALGS patients were more likely to receive special education: 50% compared to 30% for BA patients.
  • Increased mortality risk was not apparent after the 1st year following transplantation.  At 60 months post-transplantation, survival was 86% for ALGS group and 94.4% for BA group.
  • One other interesting finding was that 21% of ALGS group had undergone Kasai procedure prior to liver transplantation which may have a detrimental effect on liver outcome.

Since ALGS is a systemic disorder, it is not surprising that outcomes are inferior.  These patients frequently have a wide range of heart disease, renal dysfunction, and vascular disorders, including risk for intracranial hemorrhage.  In this series, intracranial hemorrhage occurred in one patient in each group.  It is noted that chidren with ALGS did have a vascular complication in 21% in the first 30 days after transplantation.

Information on Alagille:

There is family-oriented information on the ChiLDREN website.
http://childrennetwork.org/

There is also an Alagille Syndrome Alliance website.
http://www.alagille.org/

Additional Alagille references:

  • -JPGN 2010; 50: 11. Alagille Syndrome and Liver Transplantation
  • -JPGN 2011; 52: 84. King’s College experience.n=117.  HIDA scan w/o excretion in 60%.
  • -JPGN 2010;  51: 319.  Kasai procedure likely worsens outcome. N=19 out of 430 cohort.
  • -JPGN 2010; 50: 526.  TB >6.5, DB >4.5 & cholesterol >520 indicate likely severe liver dz in infancy & should be referred.
  • -JPGN 2010; 51:66.  Frequent bone fractures (esp LE), with peak age ~5yrs.
  • -Gastorenterol Clin N Am; 2003; 32: 857-75.  “Heritable disorders of the bile ducts” Kamath BM, Piccoli DA
  • -JPGN 2008; 47: 623. Urso may help c milder dz. n=42.
  • -JPGN 2005; 41: 676.  Increased risk of HCC.
  • -NASPGHAN 2003:  Can place peg-like tube in gallbladder for biliary diversion (done at CHOP)
  • -Pediatrics 2003; 111: 167-70.  Increased bleeding episodes, 38 of 174pts had bleeding complication; lethal in 4 pts
  • -Hepatology 2002; 35: 1501-6.  Review of partial biliary diversion for Alagille.
  • NASPGHAN 2009, Postgraduate course, pg 51.  95% c JAG1mutation identifiable with commercial lab (others c NOTCH2 mutation can be identified in research lab)

Pregnancy after Liver Transplantation

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As there are about 14,000 women of reproductive age in the U.S. who have undergone liver transplantation (LT), data about the outcomes of pregnancy are important for counseling.  A review and meta-analysis (Liver Transpl 2012; 18: 621-29) provides some information; going forward the National Transplantation Pregnancy Registry (NTPR) which was established in 1991 offers the promise of additional insight.

In the current review, Deshpande et al found 8 of 578 studies which met inclusion criteria; in total 450 pregnancies in 306 LT recipients were examined.  While healthy live births were the most common outcome, there were several pertinent risks identified.  The main concerns were development of preeclampsia, rejection/graft loss as well as the potential for birth defects.  While miscarriage rates were similar to the general population (15.6% compared with 17.1%), the following were much higher:

  • preeclampsia 21.9% vs. 3.8% in general population
  • cesarean section delivery 44.6% vs. 31.9% in general population
  • preterm birth 39.4% vs. 12.5% in general population

While rates of rejection and graft loss are not given for the entire cohort, specific study results were discussed.  In one study, rates of acute rejection ranged from 2% to 8% and loss of graft within two years of pregnancy occurred in 6-11%.

Similar to rejection data, the data for birth defects was not uniformly reported.  Specific study results were discussed and included several birth defects: 1 patient with total anomalous pulmonary venous return, 1 with pyloric stenosis, 2 with hypospadias, 1 with tracheoesophageal fistula, 1 with unilateral cystic kidney, and 2 with ventricular septal defects.

Take-home message:

Liver transplant recipients can have successful pregnancies but should be considered high risk.  Active reporting to established registries can give more accurate and up-to-date information.

Related post:

Alive and well? 10 years after liver transplantation