Steroids and/or Growth Hormone in Fulminant Hepatic Failure in the Pediatric Age Group

Condition(s) targeted: Fulminant Hepatic Failure

Intervention: prednisolone (Drug); methylprednisolone (Drug); growth hormone (Drug); growth hormone plus prednisolone (Drug); growth hormone plus methylprednisolone (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: National Liver Institute, Egypt

Official(s) and/or principal investigator(s):
Hanaa El-Araby, M.D., Principal Investigator, Affiliation: Pediatric Hepatology Department, National Liver Institute, Egypt
Mostafa M Sira, M.D., Study Director, Affiliation: Pediatric Hepatology Department, National Liver Institute, Egypt
Haydi M Zakaria, M.Sc., Study Chair, Affiliation: Quesna Central Hospital, Ministry Of Health, Egypt
Tahany A Salem, M.Sc., Study Chair, Affiliation: Pediatric Hepatology Department, National Liver Institute, Egypt

Overall contact:
Hanaa A El-Araby, M.D., Phone: +2-048-222-2740, Email: helaraby@liver-eg.org

Fulminant hepatic failure (FHF) in children is a potentially devastating disease. The mortality rate may reach 80-90% in the absence of liver transplantation. Liver injury is considered to be mainly immune mediated with augmentation of cytolytic pathways of infected hepatocytes. For that, it is suggested that corticosteroids modulate the activity of the disease by suppressing the immune system. As FHF results from liver cell death with insufficient hepatocellular regeneration, so we postulates that administration of agents that help liver cell regeneration as growth hormone may help to overcome this life threatening condition.

Official title: Safety and Efficacy of Steroids and/or Growth Hormone in the Management of Fulminant Hepatic Failure in the Pediatric Age Group

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Number of participants with adverse events as a measure of safety and tolerability

Secondary outcome:

Improvement in survival (without transplant).

Decrease of prothrombin time

Improvement of encephalopathy by one grade or more.

Reduction of consciousness recovery time (CRT) among survivors

Prolongation of time to death among non-survivors.

Detailed description: Fulminant hepatic failure (FHF) in children is a potentially devastating disease. The mortality rate may reach 80-90% in the absence of liver transplantation. FHF is the clinical manifestation of liver cell death of a critical degree with insufficient hepatocellular regeneration and characterized by coagulopathy with or without hepatic encephalopathy. Liver injury is considered to be mainly immune mediated with augmentation of cytolytic pathways of infected hepatocytes. For that, it was suggested that corticosteroids modulate the activity of the disease by suppressing the immune system. As FHF results from liver cell death with insufficient hepatocellular regeneration, so we postulates that administration of agents that helps liver cell regeneration may help to overcome this life threatening condition. In the liver, growth hormone (GH) transcriptionally activates hepatocyte nuclear factor-6 (HNF-6). Enhancing HNF-6 expression by GH was reported to be associated with upregulation of hepatic cyclin D1 and cytochrome P450, family 7, subfamily A, polypeptide 1 (Cyp7A1) and in turn, with increased hepatocyte proliferation and improved cholesterol clearance together with downregulation of transforming growth factor beta2 receptor (TGFb2R) to suppress the fibrogenic response. GH also mediates the transcriptional activation of albumin and improve hepatic synthetic function.

Minimum age: N/A. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: The patient is diagnosed to have FHF, if he fulfilled all the following criteria: 1. Evidence of liver dysfunction within 8 weeks of onset of symptoms (neonates may have only deranged liver functions without overt symptoms). 2. Uncorrectable coagulopathy (6-8 hours after administration of one dose of parenteral vitamin K) with International Normalized Ratio (INR) >1. 5 in patients with hepatic encephalopathy, or INR> 2. 0 in patients without encephalopathy. 3. No evidence of chronic liver disease. Exclusion Criteria: 1. Presence of absolute contra-indications to steroid therapy (as presence of an active gastrointestinal bleeding, renal failure, acute pancreatitis, active tuberculosis, uncontrolled diabetes and psychosis). 2. Presence of absolute contra-indications to growth hormone therapy (as active malignancy, benign intracranial hypertension, proliferative or pre-proliferative diabetic retinopathy)

Hanaa A El-Araby, M.D., Phone: +2-048-222-2740, Email: helaraby@liver-eg.org

National Liver Institute, Menoufiya 32511, Egypt; Recruiting
Hanaa A El-Araby, M.D., Phone: +2-048-222-2740, Email: helaraby@liver-eg.org
Haidy M Zakaria, M.Sc., Phone: +20100-5768-306, Email: drhaydi2000@gmail.com
Hanaa A El-Araby, M.D., Principal Investigator
Mostafa M Sira, M.D., Sub-Investigator
Haidy M Zakaria, M.Sc., Sub-Investigator
Tahany A Salem, M.Sc., Sub-Investigator

Related publications:

Cochran JB, Losek JD. Acute liver failure in children. Pediatr Emerg Care. 2007 Feb;23(2):129-35. Review.

Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet. 2010 Jul 17;376(9736):190-201. doi: 10.1016/S0140-6736(10)60274-7. Review.

Fujiwara K, Kojima H, Yasui S, Okitsu K, Yonemitsu Y, Omata M, Yokosuka O. Hepatitis A viral load in relation to severity of the infection. J Med Virol. 2011 Feb;83(2):201-7. doi: 10.1002/jmv.21958.

Fujiwara K, Yasui S, Yonemitsu Y, Fukai K, Arai M, Imazeki F, Suzuki A, Suzuki H, Sadahiro T, Oda S, Yokosuka O. Efficacy of combination therapy of antiviral and immunosuppressive drugs for the treatment of severe acute exacerbation of chronic hepatitis B. J Gastroenterol. 2008;43(9):711-9. doi: 10.1007/s00535-008-2222-5. Epub 2008 Sep 20.

Lahuna O, Rastegar M, Maiter D, Thissen JP, Lemaigre FP, Rousseau GG. Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone. Mol Endocrinol. 2000 Feb;14(2):285-94.

Wang M, Chen M, Zheng G, Dillard B, Tallarico M, Ortiz Z, Holterman AX. Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice. Am J Physiol Gastrointest Liver Physiol. 2008 Aug;295(2):G357-66. doi: 10.1152/ajpgi.00581.2007. Epub 2008 May 29.

Seshadri R, Feldman BM, Ilowite N, Cawkwell G, Pachman LM. The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: a propensity score analysis. Arthritis Rheum. 2008 Jul 15;59(7):989-95. doi: 10.1002/art.23829.

Bajpai A, Menon PS. Growth hormone therapy. Indian J Pediatr. 2005 Feb;72(2):139-44. Review.

Starting date: January 2015
Last updated: February 24, 2015