Tag Archives: acute liver failure

NASPGHAN Postgraduate Course 2014 -Liver Module

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This blog entry has abbreviated/summarized the presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.  I’ve attached the course syllabus as well:

PG Course Syllabus – FINAL

Primary Sclerosing Cholangitis –Dennis Black (Le Bonheur Children’s Hospital)

  • Up-to-date review provided
  • GWAS (genome-wide association study) identified 16 significant risk loci which account for only 7.3% of overall risk; environmental influences need to be worked out
  • Pediatric studies –total of 328 patients reported to date

Is pediatric disease the same disease as in adults?

  • Incidence in pediatrics: 0.23/100,000 incidence vs 1.1/100,000 in adults
  • Mean age at diagnosis 13 years in pediatrics.
  • 30% of pediatric patients have overlap with autoimmune hepatitis which is higher than in adult patients.

Other pointers:

  •  Discussed “Autoimmune cholangitis.” Imaging needed in autoimmune hepatitis to look for primary sclerosing cholangitis.
  • IBD Association with PSC: IBD occurs in about 55% of PSC patients. If PSC diagnosed first, usually with right-sided colitis.  If IBD diagnosed first, than pancolitis is more commonly noted.
  • Add IgG4 as part of workup to rule out IgG4 cholangiopathy (sensitive to immunosuppression).

Treatment:

  • Supportive care for cholestasis (vitamins, pruritus management, etc
  • Monitoring for complications (rare cases of cholangiocarcinoma in pediatric population).  14 drugs tested to date –mainly in adults.  “All without proven positive impact on long-term outcome.”
  • Ursodeoxycholic acid –widely used but controversial because higher doses associated with worsened outcomes in adult study (Lindor et al).  Ongoing study in pediatric population with ursodeoxycholic acid.
  • Vancomycin (Aliment Pharm 37: 2013; 604.  Adults n=35). Both Flagyl and Vanc seemed to be helpful. Uncontrolled pediatric studies with vancomycin reviewed. Vancomycin study in the works for pediatric/adults.
  • No prospective randomized controlled trials in children and very little data in adults. Hard endpoints –very difficult in children/not practical in children (eg. portal hypertension, transplant, death).

PSC and Transplantation: PSC 2.6% of total transplants –long-term outcome is similar.

Related Blog Posts:

The Jaundiced Infant –Saul Karpen (Emory)

  •  “We don’t estimate jaundice very well… Our eyes do an awful job.”
  • Breastmilk Jaundice: Archives of Disease in Childhood 1978; 53: 506-16.  Only 12 of 853 had jaundice beyond 3 weeks of life.
  • Cholestasis. One of the best studies looking at etiology was recently published:  Hoerning A, et al Front Pediatr. 2014; 2: 65. N=82.  Only 1 patient had CMV.  41% had biliary atresia.

Biliary atresia (BA):

  • Reviewed study indicating that liver biopsy was most accurate means of making diagnosis of biliary atresia (blog comment: this study result may not be accurate in all settings as the interpretation relies on the ability/reliability of pathologist).  High utility of stool pigment & ultrasound (including flow).
  • In retrospective study (Pediatrics 2011; 128 e1428-33), all the BA patients had elevated direct bilirubin by 24-48 hrs of life.
  • Genetic panels and whole exome sequencing (~$4-7K) are happening now. Cost-effective.

Take-home message: Molecular understanding possible for conjugated/unconjugated hyperbilirubinemias. Direct bilirubin >1 is abnormal

Related blog posts:

Acute Liver Failure –Estella Alonso (Children’s Hospital of Chicago) (pg 43)

Points:

  • Few patients receive a full diagnostic workup (J Pediatr 2009;155:801‐6)–especially with regard to metabolic and autoimmune disorders.
  • Reviewed etiologies –most frequently “indeterminant” especially in younger patients.  Acetaminophen is most frequent etiology in teenagers and adults.
  • Systemic inflammation is common in acute liver failure (Bucuvalas, J JPGN 2013;56: 311–315). Soluble IL2 receptor alpha –significantly higher in patients that died.  Immune regulation important aspect regarding survival. Should steroids be used in cases with high inflammation?

Prognosis: Squires et al. J Pediatr 2006;148:652-8, Lee et al. JPGN 2005;40:575-81, Baliga et al. Liver Transpl 2004;10:1364-71

  • 33% ‐53% survival with native liver
  • 61% survival including LT
  • 70%‐80% after LT
  • Multiorgan failure is most common etiology of death. Bleeding is “a rare cause of mortality.”

Management:

  • Reviewed including coagulopathy/bleeding, cardiovascular collapse, hepatic encephalopathy/cerebral edema
  • Pediatric N-acetylcysteine Trial Squires, et al Hepatology 2013;57:1542‐9 N=182.  Patients with NAC seemed to do worse, but not statistically proven.  This study has stopped the widespread use of NAC in acute liver failure.
  • Discussed approach to neurological complications in ALF. Hussain et al, JPGN 2014;58:449‐56. Retrospective study (n=18). Early EEGs obtained. Hypertonic saline may be more effective than mannitol.  Hypothermia may be helpful adjunct.
  • Timing of Transplantation discussed (pg 54 in syllabus). Difficult to predict spontaneous survival.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

This Year's Pumpkin

This Year’s Pumpkin

Link to NASPGHAN Lectures and Postgraduate Course

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Later this week, our national pediatric GI meeting (North American Society for Pediatric Gastroenterology Hepatology and Nutrition) is starting in Atlanta.  Many in my group are involved and presenting.

The following link (with permission from NASPGHAN) is to the website with links to all of these lectures:

NASPGHAN 2014 Atlanta meeting

For those interested only in the Syllabus for the Postgraduate Course:  NASPGHAN 2014 Postgraduate Course.

Topics include in this 200 page (online) book: primary sclerosing cholangitis, jaundiced infant, acute liver failure, “dreaded” endoscopy wake up calls, endoscopy for biliary tract disease, extraesophageal manifestations of gastroesophageal reflux, constipation, eosinophilic esophagitis, motility disorders, FODMAPs diet, nutrition for neurologically impaired, early onset inflammatory bowel disease, “luminitis” due to non-IBD causes, new IBD treatments, and diet-microbiome.

Should be great!

Also, to plan your meeting -go to NASPGHAN home page and use mobile guidebook: NASPGHAN 2014 has gone mobile using Guidebook!

OTCD –Another Reason for Acute Liver Failure

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A recent study shows that a significant number of patients with Ornithine Transcarbamylase Deficiency (OTCD), which is the most common urea cycle defect (UCD), can present with significant hepatic involvement and even acute liver failure (ALF) (J Pediatr 2014; 164: 720-25).

This retrospective study reviewed 71 patients with OTCD at 2 centers.  Longitudinal data collected over 10 years was analyzed.

Key result:

  • 57% of the 49 patients with symptomatic OTCD had liver involvement and 29% of these patients met criteria for ALF

“Although the urea cycle enzymes are active in the liver, standard liver function generally has been considered to be largely unaffected in UCD.”   This study shows that this concept is mistaken.OTCD has been viewed mainly as a disorder that presents with marked hyperammonemia in the newborn period.  However, there is variable clinical expression and some may remain asymptomatic throughout their lifetime.

Take-home message: Check plasma amino acids, urine organic acids and urine orotic acids when patients do not have an established etiology for hepatic dysfunction, including ALF.

 

Related blog posts:

Living on MARS

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As anyone who follows this blog knows, I really like good acronyms.  MARS which stands for molecular adsorbents recirculating system is another good one.  Data regarding the use of MARS for acute liver failure (ALF) due to Wilson disease in children has been recently reported (JPGN 2014; 58: 160-64, editorial 140-41).

Background: MARS is a form of dialysis to remove albumin-bound toxins via a specialized membrane. MARS has been studied as a potential bridge to liver transplantation or as a support to try to avoid liver transplantation in some cases.

The present study with only four children is not terribly informative.  However, both the article and the editorial provide references on small randomized controlled trials which concur with the conclusions of the authors that “biological and clinical improvement is demonstrated in the MARS treatment group compared with the standard medical treatment group.”  Yet, recent large multicenter randomized controlled trials are inconclusive with regard to whether MARS improves survival.

Bottomline (from editorial): “MARS does not prevent transplantation, and survival outcome post transplantation is unclear.  There is no robust evidence to justify the financial implications of this intervention in a clinical setting. The present role of MARS remains within the research setting.”

Liver Update: Headlines and Links Only

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  1. From AGA: Hepatic failure flagged as unexpected boceprevir safety signal in adverse event review. GI & Hep News: http://ow.ly/rSCEF 
  2. From NY Times: Spike in Harm to Liver Is Tied to Dietary Aids nyti.ms/JPN9fK 
  3. From Jeff Schwimmer (The Liver Post): First case report of Liver Cancer in a child with Nonalcoholic Fatty Liver Disease. He is only 7 years-old. http://goo.gl/6dJbzs 
  4. “Recurrence of Hepatopulmonary Syndrome Post-Orthotopic Liver Transplantation in a Patient with Noncirrhotic Portal Hypertension” Hepatology 2013; 58: 2205-06.
  5. “Management of Hepatitis B: Our Practice and How It Relates to the Guidelines” Clin Gastroenterol Hepatol 2014; 12: 16-26.  Terrific review and insights.
  6. “Acute Liver Failure” NEJM 2013; 369: 2525-34.
  7. “Cesarean Section Reduces Perinatal Transmission of Hepatitis B Virus Infection from Hepatitis B Surface Antigen-Positive Women to Their Infants” Clin Gastroenterol Hepatol 2013; 11: 1349-55. Retrospective, nonrandomized study -“performing elective cesarean section only in highly viremic mothers with pre-delivery HBV DNA levels ≥1,000,000 copies/mL may be advisable.”

Related Blog Posts:

NASPGHAN Preview

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I had a few free minutes so I decided to take a look at a bunch of upcoming lectures from the 2013 NASPGHAN upcoming meeting.  With electronic media, it is easy to take a quick glance.  Here’s the master link to all of the following talks:

Annual Meeting page.

Some of the power point lectures that I’ve seen so far:

  • Is my PPI dangerous for me? Eric Hassall MBChB, University of British Columbia One point in his slides that I had not seen much about was a hypothesis that PPI use may predispose to the development of eosinophilic esophagitis by allowing food proteins to be more intact ( attributed to Merwat, Spechler. Am J Gastro ’09).  He explains that “acid reflux” is a clever marketing term and has a slide with Madmen actors.  If there is “acid,” one must need acid suppression.
  • My child doesn’t go to school Lynne Walker MD, Vanderbilt University.  Lynne shows an interesting fax from a parent that asks if the problem is physical, how will she help? And, if it is psychological, how can this be remedied?  She outlines a lot of pain theory and indicates that parents need to become health coaches, avoid catastrophizing (?spelling), and encourages mental health evaluation.  Use the parents words ‘I’m going to refer xxx for relaxation and stress management.’
  • My child’s H. pylori will not go away – (the resistant bug) Benjamin Gold MD, Children’s Center for Digestive Healthcare. Ben manages to stuff so much information into his talk.  His talk is like one of those clown cars where more and more people keep coming out.  He has slides with worldwide resistance maps, slides with treatment regimens and algorithms, and the reasons for treatment failure. Perhaps I can convince him to give a live preview.
  • Administrative/executive functioning Richard Colletti MD, Fletcher Allen Healthcare. Offers personal and pragmatic advice for career advancement.  His slides indicate that he started his GI fellowship at age 40.  One of his quotes, “80% of success is showing up” (Woody Allen) is definitely true.  It’s pretty much akin to what I learned about success in medical school.  You need the three As: availability, affability, and ability.  My mentor said the first was what people needed most.
  • The changing face of intestinal transplantation
    Simon Horslen MD, Seattle Children’s Hospital.  Lecture notes that number of intestinal transplants have decreased dramatically, particularly in children. In 2012, only about 100 intestinal transplants were performed whereas it had peaked at nearly 200.  Much of the credit is due to intestinal rehabilitation work and adjustments in parenteral nutrition (eg. lipid minimization, line care).  Two most common reasons for intestinal transplantation at this time are gastroschisis and volvulus.
  •  Gluten sensitivity: Fact or fiction Alessio Fasano MD, MassGeneral Hospital for Children. This blog has covered a lot of the same material, but Alessio’s slides are pretty impressive.  Also, I was not aware that Lady Gaga consumes a gluten-free diet
  • Controversies in parenteral nutrition Christopher Duggan MD, Boston Children’s Hospital.  This lecture provides a timely update on nutrient deficiencies due to component shortages and discusses lipid minimization compared with fish oil-based lipid emulsions.
  • Vitamin D and immunity James Heubi MD, Cincinnati Children’s Hospital and Medical Center.  In the beginning of the slides, Jim provides a very user-friendly definition of an expert and a suitable picture.  He indicates that in 2011 there were 3746 vitamin D publications but inexplicably only chooses to review a tiny fraction.

At the time of this posting, I haven’t had a chance to look through these talks:

 

 

Neutrophil function as a biomarker for Acute Liver Failure

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More data on impaired neutrophil function in acute liver failure (ALF) and subacute liver failure (SALF) is available (Hepatology 2013; 57: 1142-52).

This study examined 15 ALF patients and 10 SALF patients in a cross-sectional case-control cohort design who were admitted to the liver ICU at King’s College Hospital between 2008-2010.  The median age for the ALF group was 33 and for the SALF group it was 52.5.  Ultimately 10 survived without liver transplantation; the remainder either died or underwent liver transplantation.

Neutrophil function was assessed on admission and then serially every 3-4 days in several ways; these assays were compared with 6 septic controls and 11 healthy controls.  Phagocytic activity was measured with a “Phagotest,” which quantifies opsonization of labeled E. coli. Oxidative burst was measured with the “Burtest,” which determines the percentage of phagocytic cells that produce a reactive oxygen species.  Other tests examined neutrophil phenotype and cytokine measurements (TNF-α, IL-1β, IL-6, CXC8/IL-8, IL-10, and IL-17).

Key findings:

  • Impaired neutrophil phagocytic activity in both ALF and SALF cohort on admission predicted non survival without liver transplant (p=0.01).
  • Neutrophil expression of CD-16 was significantly reduced in ALF cohort on day 1 (p<0.001).

Take-home message:

This study demonstrates specific defects in neutrophil function in ALF/SALF that are similar to impaired bactericidal function in severe sepsis.  Neutrophil function assays, while not available at the bedside at this time, are important biomarkers in ALF/SALF for increased susceptibility for sepsis and death.

Related blog posts:

LIU Score

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The LIU acronym interested me in part because I work with Steven Liu. The LIU score refers to a Liver Injury Unit scoring system which is used to predict survival in pediatric acute liver failure (J Pediatr 2013; 162: 1010-6).

The LIU score and admission value LIU (aLIU) were examined in individuals enrolled in the Pediatric Acute Liver Failure (PALF) Study group.  LIU score was determined in 461 patients and aLIU in 579 patients.

  • LIU =[3.584 x peak total bilirubin (mg/dL)] + [1.809 x peak prothrombin time (PT) (sec)] + [0.307 x peak ammonia (μmold/L)]

or alternatively, using INR instead of PT:

  • LIU =[3.507 x peak total bilirubin (mg/dL)] + [45.51  x peak INR] + [0.254 x peak ammonia (μmold/L)]

Results: The LIU score was shown to be strongly predictive of transplant-free survival with a c-index 0.81.  The aLIU score was less predictive with a c-index of 0.76.  In this population, the LIU score predicted the likelihood of receiving a liver transplant better than the risk of death.

Bottom-line: The LIU score may have similar utility as a MELD/PELD score but is easier to calculate.

N-acetylcysteine for Acute Liver Failure

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A study which took 8 years to complete (2001-2009) and involved more than 20 pediatric liver transplant centers has shown that N-acetylcysteine (NAC) is NOT effective for nonacetaminophen acute liver failure in the pediatric population (Hepatology 2013; 57: 1542-49).

Eligible patients were drawn from a registry of pediatric acute liver failure (PALF) patients.  Among 607 who were enrolled in the registry, 271 were eligible for the NAC trial and 184 of these patients (families) agreed to participate.  The most common reasons for patients to be ineligible for the study included acetaminophen toxicity, previous NAC treatment, sepsis, and “reason unknown.”

The design of the study was doubly masked with patients stratified by age and hepatic encephalopathy.  Patients either received intravenous NAC (150 mg/kg/d) or D5W for up to 7 consecutive days.

Key findings:

  • No significant difference in 1-year survival: 73% of NAC patients and 82% of placebo patients
  • NAC patients had lower 1-year liver transplant free survival (p = 0.03): 35% in NAC group compared to 53% of placebo patients.

The study did have several limitations.  Despite the lengthy enrollment period, the absolute number of patients was only 92 in each group.  In addition, there were differences in the diagnoses in both groups and the ages of the groups, though these were unlikely to change the results.  With regard to diagnoses, both groups had ~60% with an indeterminate reason for PALF.  However, the NAC group had an increased number with metabolic diseases (14% compared with 5% in placebo group); the most common metabolic disease was Wilson’s disease (7 in NAC group and 3 in placebo group).  The NAC group had a median age of 3.7 years compared with 4.5 years for the placebo group.

Another limitation was in testing for acetaminophen-cysteine adducts (A-CA) which can be used as a marker of acetaminophen exposure.  This was performed retrospectively in 84 of the participants.  A-CA was positive in 9 (six from placebo and three from treatment arm).  Again, this was unlikely to change the results as there were no statistical differences in clinical features of those who were tested for A-CA compared with those who were not.

In some ways, the results are surprising due to prospective studies in adults showing benefit of NAC in ALF and a previous retrospective uncontrolled pediatric study suggesting efficacy in PALF.  Ultimately, this study proves again that pediatric patients are not “small adults” and highlights the need for prospective pediatric drug trials.

Bottom-Line:

NAC works for acetaminophen-induced ALF but is not helpful for other causes of PALF.

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: