Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency Workup

Updated: Jan 11, 2019
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
  • Print

Laboratory Studies

The studies listed below may be indicated in LCHAD deficiency

Blood glucose and urine ketones

The hallmark biochemical feature of this condition is acute hypoketotic hypoglycemia.

Collect urine ketones in the acute episode.

Creatine phosphokinase, ammonia, uric acid, liver enzymes, lactic acid

During acute episodes, elevated levels of creatine phosphokinase are observed.

Hyperammonemia may be observed in acute episodes.

Elevation of liver transaminases is also observed.

A high incidence of lactic acidemia accompanies the metabolic decompensation or acute episode.

Urine organic acids

Test for 3-hydroxylated dicarboxylic acids and nonhydroxylated dicarboxylic acids.

Nonhydroxylated dicarboxylic acids are nonspecific changes found in other beta-oxidation defects and in association with liver failure.

Plasma carnitine levels and acylcarnitine profile

Plasma carnitine levels are low.

Long-chain acylcarnitine levels are increased with 3-hydroxydicarboxylic derivatives of the C16:0, C18:1, and C18:2 species.

The profile may be completely normal during asymptomatic periods.

Serum fatty acid analyses

Serum fatty acid analysis may be diagnostic.

Look for 3-hydroxylated compounds even between exacerbations.

Fatty acid oxidation studies and enzyme assay

Diagnosis may be made by study of the oxidation of the 14C-labeled myristic (C14:0) and palmitic (C16:0) acids in fibroblasts.

The deficient activity of LCHAD may be diagnosed in fibroblasts, as well as the other enzyme activities of the trifunctional protein.

The enzyme usually is measured in fibroblasts in the reverse direction, with 3-oxopalmitoyl CoA as substrate and measurement of the decrease in absorbance at 340 nm of the nicotinamide adenine dinucleotide-reduced form (NADH) electron donor.

Fasting: In patients in whom the diagnosis has been difficult, an induced fast under strict medical supervision in a facility with expertise in the diagnosis of the inborn errors of metabolism may be considered.

Molecular studies : Molecular studies (sequencing) to identify the common mutation, G1528C, are available. In addition, if only one mutation is identified in one allele, the presence of deletions can be checked on the other allele by oligonucleotide-based array comparative genomic hybridization (CGH).

Prenatal diagnosis: Prenatal diagnosis using biochemical studies has been attempted. In appropriate families in whom the molecular defect is known, prenatal diagnosis is also possible by mutation analysis. Guidelines for prenatal screening have been established.

Newborn screening of blood spots with tandem mass spectrometry

Newborn screening of blood spots with tandem mass spectrometry is used to detect abnormal acylcarnitine profiles for both LCHAD and mitochondrial trifunctional protein (MTP) deficiencies. [28] Using umbilical cord blood for acylcarnitine analysis was shown to be effective and reliable in at-risk newborns. [29] However, further molecular or functional analysis is crucial for accurate diagnosis. [30]


Imaging Studies

Chest roentgenography may reveal enlargement of the cardiac silhouette if cardiomyopathy is present.

Echocardiography may reveal cardiac enlargement, poor contractility with decreased ejection fraction, and pericardial effusion in some cases.

Since LCHAD deficiency is often characterized by retinopathy, modern multimodal imaging techniques have been used to better assess photoreceptor dystrophy. [31, 32]


Other Tests

Abnormal nerve conduction velocities have been recorded in patients with LCHAD deficiency and peripheral neuropathy.

ECG may reveal left ventricular hypertrophy and cardiac arrhythmias.

Electroretinography may reveal progression of chorioretinopathy. [33]

Electroneurography (ENG) has been used in long-term studies to evaluate the development of polyneuropathy. [34]

Mitochondrial enzyme studies may reveal abnormal respiratory chain function in skeletal muscle specimens. A more generalized deficiency of mitochondrial enzymes or a more selective reduction of complex I may be noted.

If elevated C16-OH ± C18:1-OH and other long chain acylcarnitines are present on newborn screening, the pediatrician should do the following:

  • Contact the family to inform them of newborn screening results and determine clinical status and whether poor feeding, vomiting, and lethargy are present
  • Contact pediatric metabolic specialist
  • Evaluate infant for hepatomegaly, signs of hypoglycemia and metabolic acidosis and cardiomyopathy
  • Evaluate family history to determine whether a history of sudden death in a sibling and whether maternal liver disease was noted during pregnancy
  • Educate family about signs and symptoms of hypoglycemia and metabolic acidosis

A metabolic specialist needs to confirm or exclude diagnosis of LCHAD deficiency by requesting an acylcarnitine profile and urine organic acid analysis. If carnitine levels are low, consider carnitine supplementation. In addition, an evaluation should be done to exclude hypoglycemia, elevated liver transaminases, bilirubin, lactate, ammonia, and creatine phosphokinase, which could be suggestive of LCHAD and trifunctional protein deficiencies.

In addition, sequencing of the gene that encodes LCHAD is clinically available for molecular confirmation. [28] If only one mutation is found in one allele, a possible deletion should be screened in the other allele by using oligonucleotide-based array CGH.



Skin biopsy to obtain cultures of skin fibroblasts for fatty acid oxidation studies or specific enzyme assay is necessary for confirmation of diagnosis.

Muscle biopsy, although not necessary for diagnosis, may be performed because lactic acidosis present in this condition may suggest a respiratory chain defect.


Histologic Findings

Pathological evaluation has revealed microvesicular and macrovesicular accumulation of fat in skeletal muscle, heart, and liver. Necrotic myopathy without steatosis has been described, as well as degeneration of muscle fibers. Hepatic cirrhosis has also been observed.

Ultrastructurally, the mitochondria appear to be increased in size and number with swollen appearance. Condensation of the mitochondrial matrix and irregular cristae is noted.