Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

STATUS

Recruiting
End date

May 28, 2024
participants needed

67
sponsor

Arbor Research Collaborative for Health

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Updated on 28 April 2022

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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 Liver Failure, Mitochondrial Diseases, End Stage Liver Disease, Respiratory Chain Deficiencies, Mitochondrial, Disorder of Fatty Acid Oxidation
Clinical Study Identifier	NCT01148550
Sponsor	Arbor Research Collaborative for Health
Last Modified on	28 April 2022

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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
	Abnormal acyl carnitine profile, 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
	Previous liver transplantation, AND
	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
	A prior history of an abnormal acyl carnitine profile, OR
	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
	Suspected mitochondrial liver disease, based upon meeting one or more of the
	Both genders, all races and ethnic groups
	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
	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
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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Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)