Longitudinal Study of Mitochondrial Hepatopathies

  • STATUS
    Recruiting
  • End date
    May 28, 2024
  • participants needed
    67
  • sponsor
    Arbor Research Collaborative for Health
Updated on 8 September 2021
hepatic failure
encephalopathy
chronic liver failure
liver disease
liver transplant
cirrhosis
hyperbilirubinemia
mitochondrial hepatopathy
acyl carnitine
carnitine
prothrombin
liver failure
portal hypertension
fibrosis
acidosis
myopathy
mitochondrial disorder
glucose concentration
lactic acidosis

Summary

The specific aims of this study are (1) to determine the clinical phenotypes and natural history of hepatic RC and FAO disorders, (2) to determine the correlation between genotype and phenotype, (3) to determine if circulating biomarkers reflect diagnosis and predict liver disease progression and survival with the native liver, (4) to determine the clinical outcome of these disorders following liver transplantation, and (5) to develop a repository of serum, plasma, urine, tissue and DNA specimens that will be used in ancillary studies. To accomplish these aims, the ChiLDREN investigators at clinical sites (currently 15 sites) will prospectively collect defined data and specimens in a uniform fashion at fixed intervals in a relatively large number of subjects. Clinical information and DNA samples to be collected from subjects and their parents will enhance the potential for meaningful research in these disorders. A biobank of subject specimens and DNA samples will be established for use in ancillary studies to be performed in addition to this study.

Description

This study will be conducted as part of the NIH-supported Childhood Liver Disease Research and Education Network (ChiLDREN). ChiLDREN is investigating rare cholestatic liver diseases of childhood: alpha-1 antitrypsin deficiency (A1AT), Alagille's Syndrome (AGS), progressive familial intrahepatic cholestasis (PFIC), bile acid synthesis defects and mitochondrial hepatopathies (all previously studied by the Cholestatic Liver Disease Consortium [CLiC]); biliary atresia (previously studied by the Biliary Atresia Research Consortium [BARC]); neonatal hepatitis; and cystic fibrosis liver disease, which is studied by a new branch of ChiLDREN known as the Cystic Fibrosis Liver Disease (CFLD) Network.

In this protocol, mitochondrial hepatopathies in children and young adults will be investigated. The focus will be on respiratory chain defects (RC) and defects of fatty acid oxidation (FAO). There is little known about the full spectrum of severity and long-term natural history of mitochondrial hepatopathies. Moreover, these disorders have not been subject to prospective, rigorous clinicopathological scrutiny.

Details
Condition Acute hepatic failure, Metabolic disorder, End Stage Liver Disease, Mitochondrial Diseases, Hepatic Failure, Disorder of Fatty Acid Oxidation, Metabolic Disorders, Liver Failure, acute liver failure, mitochondrial disorder, chronic liver failure
Clinical Study IdentifierNCT01148550
SponsorArbor Research Collaborative for Health
Last Modified on8 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Children and young adults with suspected or documented hepatic RC defector FAO defect from birth to 18 years old (through 18 years)
Both genders, all races and ethnic groups
Participants must meet one of the following sets of criteria (A or B)
Potential subjects presenting with acute or chronic liver disease or acute liver failure but who have not had a liver transplant must meet one of Clinical Criteria 1 and one of Clinical Criteria 2 listed below
Clinical Criteria 1 (any one of the following)
Acute liver failure,defined as severe liver dysfunction and either 1) INR >1.5 or prothrombin time > 15 seconds with encephalopathy or 2) INR > 2.0 or prothrombin time > 20 seconds with or without encephalopathy; occurring within 8 weeks of onset of illness; with no known underlying chronic liver disease, or
Acute liver disease defined as elevated AST or ALT >1.25 ULN and CK <1000u/L or conjugated bilirubin >2.0 mg/dl and >20% of total bilirubin, or
Chronic liver disease defined as
elevated ALT or AST (>1.25 ULN) for > 6 months, or
conjugated hyperbilirubinemia (conjugated [direct] > 2.0 mg/dl and > 20% of total bilirubin) for > 6 months or
clinical stigmata of chronic liver disease, including chronic hepatomegaly, clinical findings or complications of cirrhosis or portal hypertension, impaired liver synthetic function, intractable pruritus explainable only by liver disease or end-stage liver disease, or
abnormal liver histology including hepatic fibrosis or cirrhosis, microvesicular steatosis, canalicular cholestasis, ballooned granular red hepatocytes (AKA onocytes), intralobular collapse/regeneration And
Clinical Criteria 2 (any one of the following
Prior history of extra-hepatic organ involvement accompanied by any one or more of the signs and symptoms associated with mitochondrial dysfunction (e.g
hypotonia, neuro-developmental delay, seizure disorder requiring treatment
with valproic acid, nystagmus, cardiomyopathy, renal tubulopathy, bone marrow
failure,myopathy, hearing loss), or
Lactic acidosis (arterial blood or free-flowing venous blood level >2.5 mmol/L or >22.5 mg/dl at any age and increased lactate:pyruvate ratio [>25.0]) or
Hypoglycemia (blood glucose <45 mg/dl on any measurement) and hypoketonuria (<1+ for urine ketones by dipstick on urine specimen obtained within 4 hours after collecting blood with low glucose concentration), or
Abnormal acyl carnitine profile, or
Documented biochemical (enzymatic) or genetic diagnosis 3b. Potential participants who have undergone a liver transplantation because of acute liver failure or end stage liver disease due to suspected or confirmed mitochondrial hepatopathy; the transplantation may have been performed at a non-ChiLDREN medical center or at a ChiLDREN Clinical Site. B. Potential subjects who have already had a liver transplant must meet criteria 1 and either criteria 2 or criteria 3 below
Previous liver transplantation, AND
Suspected mitochondrial liver disease, based upon meeting one or more of the following criteria
Had a prior history of extra-hepatic organ involvement accompanied by signs and symptoms associated with mitochondrial dysfunction (e.g., hypotonia, neuro-developmental delay, seizure disorder requiring treatment with valproic acid, nystagmus, cardiomyopathy, renal tubulopathy, bone marrow failure, myopathy, hearing loss), OR
A prior history of lactic acidosis (arterial blood or free-flowing venous blood level >2.5 mmol/L or >22.5 mg/dl at any age and increased lactate:pyruvate ratio [>25.0]), OR
A prior history of hypoglycemia (blood glucose <45 mg/dl on any measurement) and hypoketonuria (1+ for urine ketones by dipstick on urine specimen obtained within 4 hours after collecting blood with low glucose concentration), OR
A prior history of an abnormal acyl carnitine profile, OR
Documented biochemical (enzymatic) or genetic diagnosis of a mitochondrial disorder
A documented (confirmed) mitochondrial disorder based upon the confirmation criteria specified in protocol
Subjects in Group 2 (Suspected Mitochondrial Hepatopathy not meeting Group 1
enrollment criteria) must meet the following inclusion criteria
Children and young adults with suspected hepatic RC defect or FAO defect between birth through 18 years but who do not meet clinical inclusion criteria listed above for acute or chronic liver disease or acute liver failure
Both genders, all races and ethnic groups
Subjects in either Group 1 or 2 must not have any of the following exclusion
criteria
Inability to comply with the longitudinal follow-up described below
Failure of a family/patient to sign the informed consent/assent document or the HIPAA authorization form
Known Medium Chain Acyl CoA Dehydrogenase deficiency (MCAD)
Other known causes of liver disease
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