Tag Archives: HLH

Liver Briefs: HLH in Infancy, Maralixibat for Alagille Syndrome, Liver Disease Due to Inborn Errors of Immunity

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N Hadzic et al. J Pediatr 2022; 250: 67-74. High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy In this retrospective study of pediatric acute liver failure (PALF, n=78) in children <24 months of age: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The mortality in this group was 33% (n=10). The authors conclude that targeted genetic analysis (ie perforin, SIAP, XIAP, and GRA) or whole exome sequencing should become a standard part of PALF workup.

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BM Kamath et al. J Pediaatr 2023; 252: 68-75. Open Access! Maralixibat Treatment Response in Alagille Syndrome is Associated with Improved Health-Related Quality of Life. Twenty of the 27 patients (74%), all with moderate-to-severe pruritus at enrollment, achieved an Itch-Reported Outcome (Observer) treatment response at week 48. “The significant improvements in pruritus seen with maralixibat at week 48 of the ICONIC study are clinically meaningful and are associated with improved HRQoL.”

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D Sharma et al. Hepatology 2022; 76: 1845-1861. Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity This articles reviews inborn errors of immunity (IEI) and their liver manifestations. This includes the following:

  • T-cell/B-cell deficiency: SCID, CD40 ligand deficiency, DOCK8 deficiency, IL-21R deficiency, and Activated P13K delta syndrome
  • Antibody deficiency: CVID, X-linked aggamoglobulinemia
  • Phagocytic disorders: CGD
  • Primary Immune Regulatory Disorders: STAT1 GOF, STAT3 GOF, IPEX, APECED
  • Others: Wiskott-Aldrich syndrome, Immunodeficiency-centromeric instability-facial anomalies syndrome, Hepatic veno-occlusive disease with immunodeficiency, STAT3-deficient hyper IgE syndrome

In patients with IEIs with liver abnormalities, one needs to consider infectious etiologies (eg. HAV, HBV, HCV, HEV, CMV, EBV, HSV, cryptosporidium, liver abscess), autoimmune disorders (eg. AIH), drug-induced liver disease, and sclerosing cholangitis

Royal Terns at Siesta Key, FL

Acute Liver Failure –Is There a Role for Steroids?

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The title is not a simple question.

Some who support the use of steroids (for acute liver failure) should remember Galen’s assertion about a different treatment, circa 100 AD:   “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.”

Two recent publications offer conflicting advice about steroids for acute liver failure (ALF):

  • Hepatology 2014; 59: 612-21.
  • J Pediatr 2014; 164: 407-409.

The first study involved a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF from patients (n=361) prospectively enrolled in the ALF Study Group between 1998-2007.

  • Autoimmune, n=66, mean age 46 years
  • Indeterminate, n=164, mean age 39 years
  • Drug-induced, n=131, mean age 44 years

Outcomes:  Steroid use was associated with increased spontaneous survival (35% vs 23%) but this benefit did not persist with multivariate analysis.  In addition, steroid use was associated with lower survival in patients with the highest MELD scores. Furthermore, the authors discount the possibility of selection bias, noting that INR was higher in the no-steroid group.

In contrast, the second article, a case presentation/pediatric grand rounds article, states that “in our experience over the past decade, more than one-half of the children (56%) presenting with indeterminate acute hepatitis or ALF (after being evaluated) comprehensively …had a markedly elevated sIL-2R level (>5000 U/mL) concerning for immune activation but never fulfilling diagnostic criteria for HLH [hemophagocytic lymphohistiocytosis] during their course.”

“Notably, of the patients presenting with elevation of sIL-2R to >5000 U/mL, most who survived with their native liver had received treatment with steroids.” (JPGN 2013; 56: 311-5.) “We propose that children presenting with indeterminate, progressive hepatitis or indeterminate ALF are candidates for prompt initiation of anti-inflammatory therapy when there is concomitant evidence of immune activation.”

In patients with ALF, part of the evaluation needs to include sIL-2R. Other assessments for immune dysregulation would include serum triglycerides, ferritin, “CD107a expression, perforin/granzyme B protein expression, and assessment for macrophage activation (soluble CD163).”

Bottomline: If HLH criteria are not met, but patients have marked elevation of sIL-2R (>5000 U/mL), empiric corticosteroids need to be considered. Perhaps there is a window of opportunity (before a patient develops a high MELD score).  At the same time, we need to acknowledge that our knowledge base remains incomplete and it is unclear whether this will improve the outcome.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Don’t forget HLH

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A recent clinical challenge (Gastroenterol 2013; 145: 289, 489) regarding a a 78-year-old with a 12-year history of ulcerative colitis serves as a good reminder to remember hemophagocytic lymphohistiocytosis (HLH) in inflammatory bowel disease patients with high fever, even in the presence of recognized viral infections like cytomegalovirus and Epstein-Barr virus which can trigger HLH.  Patients receiving immunosuppressive medications are at risk.

Other clinical points:

  • Consider HLH when cytopenias are present in addition to fever
  • Ferritin values >10,000 mcg/L serves as a good screen

Take-home point: HLH has a significant mortality rate.  Quick recognition can improve outcome.

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Diagnosing hemophagocytic lymphohistiocytosis … – gutsandgrowth

Diagnosing hemophagocytic lymphohistiocytosis (HLH)

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HLH is difficult to diagnose –patients without HLH can meet the established criteria (see links below); and, especially early in the disease, patients with HLH may not meet the established criteria.  A study which will help with this difficulty has been published (J Pediatr 2012; 160: 984-90 and summary pg A1).  For pediatric gastroenterologists, HLH is important because some of our IBD patients may develop HLH and because some patients presenting with liver disease have HLH.

This study examined 756 consecutive patients with fever in Hematology/Oncology unit of China’s Children’s Hospital of Zhejiang between 2005-2010.  Three control groups also were studied: hematology-oncology patients without fever (n=202), healthy children (n=100), and previously-healthy children with bacterial sepsis (n=85).

A highly discriminating cytokine pattern was identified in 71 episodes of HLH.

  • Highly elevated IFN-γ : 94% sensitivity, 97% specificity for HLH using a cutoff of 100 pg/mL
  • Highly elevated IL-10
  • Modestly elevated IL -6
  • Combined use of IFN-γ (>75 pg/mL) & IL-10 (>60 pg/mL) had sensitivity of 93% and specificity of 99% for HLH

Using these cytokines may help establish a more rapid diagnosis of HLH and allow institution of critical therapy while avoiding implementation of the wrong treatment in patients who have other conditions.  In other studies (see below), there are other useful markers that have been identified.

Additional references:

  • -J Pediatr 2011; 159: 808.  HLH increased with Crohn’s Rx.  If fever >5days, can screen for HLH with ferritin (>500mcg/L) & lymphopenia.  Need to discontinue immunosuppression.  100-fold increase risk of HLH.  Diagnostic criteria for HLH pg 809. Newer criteria: molecular, low/absent NK activity & soluble CD-25 (ie. soluble IL-2 receptor) >2400 U/mL.
  • Hemophagocytic Syndrome  Link with powerpoint case presentation including diagnostic criteria for primary and secondary HLH.
  • Hemophagocytic lymphohistiocytosis (HLH) and related disorders  Link with review article by leader in field (A Filipovich, 2009).
  • -J Peds 2006; 149: 134-7.  Aftrican-american infants c HLH often have a specific defect in perforin gene -50delT-PRF1
  • -NEJM 2004; 351: 1120. case of twins c FELS. Impaired NK cell activity is key with absence of NK intracytoplasmic perforin in 20-40%.
  • -JPGN 2002; 34: 3A (pg 433.)  Liver failure with HLH.  mortality 84%, n=25.