Why Do Some People Recover from Acute Liver Failure and Some People Don’t?

Briefly noted: T Lin et al. Hepatology 2022; 322-337. Open Access: Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure

Design: After preliminary work in 19 patients with acute liver failure (ALF) and in a zebrafish model, a prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin (FST) levels in prevalence and mortality of acute-on-chronic liver failure.

Key findings: Recovered patients with ALF robustly express HNF4α in either LPCs (liver progenitor cells) or remaining hepatocytes. Serum FST levels could predict the incidence and mortality of acute-on-chronic liver failure.

Implication of study: “Our results indicate that serum FST levels might be a surrogate marker reflecting the extent of hepatocyte death and hepatic insulin resistance, which point to the danger of coagulopathy and clinical deterioration. The hypothesis requires further confirmation in the future.”


Hormone-controlled activin-HNF4α-coagulation factor axis in LPCs

Bookmark This Article on Pediatric Acute Liver Failure

JE Squires et al. JPGN 2022 – Volume 74 – Issue 1 – p 138-158. doi: 10.1097/MPG.0000000000003268. Open Access: North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Diagnosis and Management of Pediatric Acute Liver Failure

This article provides a terrific summary of the most urgent issues with regard to caring for children with PALF; this article provides helpful information for diagnosis, and management, as well as information on pathophysiology, and associated outcomes.

PDF version: PALF in Children Position Paper

The article makes a number of recommendations for testing/treatment -here are a few of them:

  • While the initial testing does list ferritin, it does not list soluble IL2R as an early test (listed lower in Table 4 under section of hepatic encephalopathy). My colleagues at Emory who specialize in liver transplantation have frequently recommended this test early in the evaluation of severe liver disease/acute liver failure (ALF) as a potential marker of HLH and immune dysregulation.
  • With regard to coagulopathy: “Coagulopathy secondary to vitamin K deficiency should rapidly correct following appropriate repletion. Notably, if coagulopathy persists, efforts to “correct” abnormal coagulation profiles with fresh frozen plasma or other pro-coagulation products should generally be avoided” [in the absence of bleeding or need for invasive procedure].
  • Initial IV Fluids: ” In the absence of the need for volume resuscitation, total intravenous fluids should initially be restricted to around 90% of maintenance fluids to avoid overhydration. Initial fluids should be similar to hypertonic glucose (D10) one-half normal saline and supplemented with 15 mEq of potassium (K+)/L.”
  • Nutritional support: “Patients with PALF are likely catabolic and require more calories than basal needs. Enteral feeding is often preferred over total parenteral nutrition (TPN), and both naso-gastric or naso-jejunal feeds should be considered before TPN.”
  • Neonatal ALF: “GALD results from an intrauterine alloimmune liver injury and is suspected to be the single most common cause of neonatal acute liver failure… Characteristic clinical features of GALD include an ALF presentation usually at birth and almost always in the first days of life. The majority (70–90%) of affected infants are born premature and a history of maternal sibling death is common. Timely exchange transfusion and high-dose intravenous immunoglobulin (IVIG) is the preferred treatment to remove offending antibodies and block their action, including activation of complement (88,91). The mechanism of GALD places subsequent pregnancies at risk, and intrapartum IVIG should be used to prevent recurrences.”
  • Table 8 list common medications implicated in PALF. “Acetaminophen (APAP) …remains the most common cause of DILI, and is the most common identified cause of ALF in children.” 

Related blog posts:

Figure 3: Etiology of acute liver failure in children.
(A) Etiology for 1144 children from the Pediatric Acute Liver Failure Study Group (PALFSG) 1999–2014. (B) Final diagnosis by age (note: figure B includes information on only 985 participants)

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Genetic Underpinnings of Acute Liver Failure in Children

R Hegarty et al. J Pediatrics; 236: 124-130. Open Access: Study of Acute Liver Failure in Children Using Next Generation Sequencing Technology

Background: “Despite the progress made over the last 40 years the rate of indeterminate cases [of acute liver failure] remains ~30%”

Methods: The authors identified 41 children (<10 yrs) with DNA sample availability who were admitted to King’s College Hospital, London, with ALF of indeterminate etiology (2000-2018). In addition, trio exome sequencing was performed on 4 children admitted during 2019.

Key Findings:

  • Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively
  • The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings.

My take: Genetic testing for underlying metabolic/metabolic disorders is important to further determine the reasons for ALF. Given the potential need for liver transplantation, obtaining these results quickly will be crucial. In addition, interpretation of the results in some cases will be difficult.

Related blog posts:

How Reliable is an Acetaminophen Level in Patients with Acetaminophen Overdose?

A recent study (TM Leventhal et al. Clin Gastroenterol Hepatol 2019; 17: 2110-6) provides more data indicating that acetaminophen levels are frequently undetectable even in patients suspected of developing acute liver failure (ALF) due to acetaminophen overdose.

The authors performed a retrospective study with 434 subjects from the ALF study group who met criteria for either ALF (coagulopathy and hepatic encephalopathy w/in 26 weeks of first symptoms) or Acute Liver Injury (ALI) (severe liver injury with coagulopathy but no encephalopathy).  In this group, all of the patients had liver disease attributed to acetaminophen (APAP) toxicity.

Key findings:

  • 227 patients (52%) had undetectable acetaminophen levels
  • Transplant-free survival rate was 79.5% (including both ALF and ALI patients)
  • APAP-protein adduct data was available for 37 patients in cohort; all patients with this assay had evidence of APAP toxicity regardless of whether APAP level was detected

Discussion Points:

  • Symptoms from APAP toxicity frequently emerge >24 hours after ingestion.  APAP, though, has a short half-life, approximately 2-2.5 hours.  Thus, most patients will have APAP clearance from plasma in 18 hours
  • Unintentional overdose, often with multiple doses over therapeutic limit of 4 g/day (in adults), more frequently is associated with an undetectable APAP level than a single large intentional overdose which results in a higher peak level

My take: This study shows that APAP levels are unreliable in determining APAP ingestions and not predictive of ALF.  The use of N-acetylcysteine should not be determined by APAP levels in patients with suspected overdose.

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

Atlanta Botanical Garden

#NASPGHAN19 Liver Symposium (Part 2)

Although I was unable to attend this year’s liver symposium at NASPGHAN19, I reviewed the lecture notes.  There is some terrific content.  Here are some of the slides (borrowed with permission from NASPGHAN).

Link to complete NASPGHAN Chronic Liver Disease Symposium 2019

SESSION II – FRONTIERS IN LIVER THERAPEUTICS

Keynote Speaker: Outcomes for the future: How do we improve on the status quo? Ronald J. Sokol, MD, FAASLD, Children’s Hospital Colorado  (SLIDES NOT AVAILABLE in onliine handout)

Recognition and stabilization of the pediatric patient with acute liver failure Robert Squires MD Children’s Hospital of Pittsburgh at UPMC

Should I offer treatment for my patients with Hepatitis B or Hepatitis C? Regino P. Gonzalez-Peralta MD, AdventHealth for Children

Are there any medical therapies for NASH?   Marialena Mouzaki, MD, Cincinnati Children’s Hospital Medical Center

This lecture describes a lot of the emerging pharmacologic treatments; none of these are currently recommended.

Hereditary Fructose Intolerance

A recent case series (Li H, A Diaz-Kuan, M Vos et al. Mol Genet Metab. 2018 Apr;123(4):428-432) highlights the importance of dietary history in infants with liver failure (abstract below).  Congratulations to my colleague Miriam Vos one of the coauthors.

Commentary on this publication from Emory News (from Kipp Ellsworth’s twitter feed):

Babies with inherited intolerance of fructose face a risk of acute liver failure if they are fed certain widely available formulas containing fructose, pediatricians and geneticists are warning. Baby formula manufacturers should remove fructose or sucrose, or explicitly label their products to allow parents to avoid those sweeteners if necessary, the doctors say.

In a recent paper in Molecular Genetics and Metabolism, Emory geneticists Hong Li, MD, PhD and Michael Gambello, MD, PhD together with Children’s Healthcare of Atlanta pediatric hepatologist Miriam Vos, MD and colleagues report four cases of hereditary fructose intolerance (HFI), all diagnosed in early infants. All had acute liver failure that resolved when the infants switched to formula without fructose.

HFI is estimated to occur in 1 out of 20,000 live births. It comes from mutations in the aldolase B gene, resulting in an inability to metabolize fructose. Early symptoms include nausea, vomiting, abdominal pain and failure of an infant to gain weight. If unrecognized, HFI can result in liver and kidney damage, seizures or death.

HFI-related problems do not appear if an infant is being breastfed exclusively. It is normally recognized when fructose-containing solid foods, such as fruit, are introduced into the diet several months after birth. However, some baby formulas – often soy-based – contain sweeteners such as high-fructose corn syrup or sucrose (table sugar), which is made of fructose and glucose linked together. Sometimes, the label only says “sugar” instead of sucrose…

Since HFI is a treatable disease, Li urges pediatricians to consider HFI as a potential diagnosis if there is a feeding problem, elevated transaminase enzymes or jaundice (a sign of liver damage) and the infant has been fed formula containing fructose or sucrose.

Some information about a young patient’s condition can be obtained from urine carbohydrate tests, but the only way to confirm HFI is by genetic sequencing.

Abstract:

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ALDOB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose. Exposure to formula containing fructogenic compounds is an important, but often overlooked trigger for severe metabolic disturbances in HFI. Here we report four neonates with undiagnosed HFI, all caused by the common, homozygous mutation c.448G>C (p.A150P) in ALDOB, who developed life-threatening acute liver failure due to fructose-containing formulas. These cases underscore the importance of dietary history and consideration of HFI in cases of neonatal or infantile acute liver failure for prompt diagnosis and treatment of HFI.

Related blog post: Changing Approach to Neonatal Acute Liver Failure

Chattahoochee River Near Island Ford

 

Acute Liver Failure -Pediatric ICU Management

Full Text Link: Intensive Care Management of Acute Liver Failure

This article provides a very good overview of this topic starting withe diagnosis, epidemiology and proceeding to specific management issues/outcomes.

Table 1 reviews etiologies –indeterminant is most common. Table 2 shown below reviews management principles and Table 3 reviews specific treatments based on etiology. Table 4 reviews grades of encephalopathy.

My take (from authors): “Despite recent advances in supportive care and the improvements in outcomes observed…the practical intensive care management of PALF remains poorly defined…Current treatment options are merely supportive and based on incomplete adult data and local institutional experience.”

Related blog posts:

March 2017 Briefs

MC Montana, AS Evers. J Pediatr 2017; 181: 279-84. This commentary reviewed recent studies regarding anesthetic neurotoxicity. “Two recently published human studies suggest a lack of harm in otherwise-healthy children following a short duration anesthetic (approximately 1 hour)” References: Lancet 2016; 387: 239-50 & JAMA 2016; 315: 2312-20.

Related posts:

NR Santucci et al. JPGN 2017; 64: 186-93.  This systematic review selected 31 studies (out of 916 citations) and found there is no consensus concerning diagnostic criteria for biliary dyskinesia and the data supporting the concept of biliary dyskinesia in children is weak.  The uncontrolled studies were generally observational, retrospective designs with relatively small numbers.

Related posts

I Youngster et al. J Pediatr 2017; 182: 239-44.  This study examined large prescription databases (more than 74 million person years) and identified wide discrepancy in antibiotic use among the six different countries.  For example, among children less than 2 years of age, South Korea had the highest rate of antimicrobial use, with 3.41 prescribed courses per child-year; in contrast, the rates were 1.4 in Italy, 1.5 in Spain, 1.1 in the U.S., 1.0 in Germany, and 0.5 in Norway.

A Srivastavai et al. JPGN 2017; 64: 194-9. In this retrospective study with 262 children with liver disease-related ascites, the authors found spontaneous bacterial peritonitis (or culture-negattive neurocytic ascites) in 28.6%. Half of these patients were asymptomatic.  SBP/CNNA was defined by having a polymorphonuclear leukocyte count of >250 cells/mm3.  There was a 24% one-year mortality rate for those who had SBP/CNNA.

MR Narkewicz et al. JPGN 2017; 64: 210-7. Using data from the pediatric acute liver failure group, the researchers identified a high rate of autoantibodies (28%) among 986 pediatric subjects with acute liver failure. The presence of autoantibodies was not significantly associate with 21-day outcomes and steroid treatment was not associated with survival; in fact, those without a known diagnosis of autoimmune hepatitis, had a higher risk of death with steroid therapy. In the setting of acute liver failure, autoantibody positivity does not obviate the need for a complete diagnostic workup.

A Lauterio et al. Liver Transplantation 2017; 23: 184-93.  Italian review of living donor safety found that major complications occurred in 12.6% (31 or 246)  but there were no mortalities. 5 (2%) required reoperation.

 

from Twitter's 'This Week in Church Signs' feed

from Twitter’s ‘This Week in Church Signs’ feed

NASPGHAN Postgraduate Course 2014 -Liver Module

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

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!