Longitudinal Study of Mitochondrial Hepatopathies



Status:Recruiting
Conditions:Gastrointestinal
Therapuetic Areas:Gastroenterology
Healthy:No
Age Range:Any - 18
Updated:1/16/2019
Start Date:July 2010
End Date:May 2019
Contact:Terese Howell, BS, CCRC
Email:terri.howell@arborresearch.org
Phone:734-369-9683

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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.

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.

Subjects in Group 1 (Mitochondrial Hepatopathy group) must meet all of the following
inclusion criteria:

1. Children and young adults with suspected or documented hepatic RC defector FAO defect
from birth to 18 years old (through 18 years).

2. Both genders, all races and ethnic groups.

3. Participants must meet one of the following sets of criteria (A or B):

A. 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:

1. Clinical Criteria 1 (any one of the following)

- 1.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

- 2.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

- 3.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

2. Clinical Criteria 2 (any one of the following:

- 1.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

- 2.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

- 3.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

- 4.Abnormal acyl carnitine profile, or

- 5.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:

- 1.Previous liver transplantation, AND

- 2.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

- 3.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:

1. 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.

2. Both genders, all races and ethnic groups.

Subjects in either Group 1 or 2 must not have any of the following exclusion criteria:

1. Inability to comply with the longitudinal follow-up described below.

2. Failure of a family/patient to sign the informed consent/assent document or the HIPAA
authorization form.

3. Known Medium Chain Acyl CoA Dehydrogenase deficiency (MCAD).

4. Other known causes of liver disease.
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Cincinnati, Ohio 45229
Principal Investigator: Jorge Bezerra, MD
Phone: 513-636-7818
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Childrens Hospital Los Angeles Children's Hospital Los Angeles is a 501(c)(3) nonprofit hospital for pediatric...
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1 Gustave L Levy Pl # 271
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201 Presidents Circle
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1405 Clifton Road NE
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Chicago, Illinois 60614
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6621 Fannin St
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705 Riley Hospital Dr
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3414 Fifth Avenue
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660 S Euclid Ave
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555 University Avenue
Toronto, Ontario M5G 1X8
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