A Longitudinal Study of Mitochondrial Hepatopathies (MITOHEP)

General Description

The MITOHEP study investigates mitochondrial hepatopathies in children and young adults, focusing on respiratory chain (RC) and fatty acid oxidation (FAO) defects. Because these disorders have not been subject to prospective, rigorous clinicopathological scrutiny there is little known about the full spectrum of severity and long-term natural history of mitochondrial hepatopathies. Investigators at 15 clinical 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.

Objectives

The specific aims of the MITOHEP study are (1) to determine the clinical phenotypes and natural history of hepatic RC defects 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.

Outcome Measure

Primary outcome measures include listing for liver transplant, liver transplantation, involvement of other organ systems known to be associated with mitochondrial diseases, and death. Growth failure (defined as weight or length Z-score for age < 2), worsening liver function (defined as PELD > 10), complications of portal hypertension, neurodevelopmental outcome, and health related quality of life will be assessed as secondary outcome measures.

Criteria

The study population consists of children and young adults up to 18 years of age divided into two groups: (1) subjects with suspected or documented mitochondrial hepatopathy disease and (2) subjects with suspected mitochondrial hepatopathy not meeting Group 1 enrollment criteria.
Group 1 includes subjects presenting with acute or chronic liver disease or acute liver failure as defined by the study protocol. Regardless of whether subjects have received a liver transplant, they must present with suspected or documented mitochondrial liver disease. Suspected mitochondrial liver disease is defined by presenting with any of the following: a prior history of extra-hepatic organ involvement accompanied by signs and symptoms associated with mitochondrial dysfunction; current or 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]); current or 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 current or prior history of an abnormal acyl carnitine profile.

Group 2 includes subjects who have suspected hepatic RC or FAO defects but who do not meet clinical inclusion criteria listed in the study protocol for acute or chronic liver disease or acute liver failure.

Outcome

This study is ongoing.