Long Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (LCHADD)
These acute illness materials are a guideline for healthcare professionals treating the sick infant/child who has previously been diagnosed with long chain hydroxy acyl-CoA dehydrogenase deficiency (LCHADD), a fatty acid oxidation disorder (FAOD). The materials were developed at Boston Children’s Hospital under the direction of Dr. Harvey Levy, Senior Physician in Medicine/Genetics and Dr. Jonathan Picker, Fragile X Program Director.
Metabolic crises in infants/children with FAOD are medical emergencies and must be treated as such to avoid death or serious brain injury.
Disclaimer
Metabolic crises in infants and children with FAOD are complex medical emergencies and must be treated as such to avoid death or serious brain injury. This protocol is only a guideline and should NOT be used for definitive treatment without metabolic consultation. It is essential to call or page the on-call genetics/metabolism fellow, or failing this, the on-call metabolic attending at your hospital or nearest pediatric tertiary care center, as rapidly as possible. Please read our Terms of Use.
Introduction
LCHADD is caused by a defect in the intramitochondrial β-oxidation of fatty acids. It can cause severe hypoketotic hypoglycemia, lethargy, liver dysfunction with hepatomegaly, clotting defect, metabolic acidosis, hyperammonemia cardiomyopathy, and sudden death.
Pathophysiology
Below is the fatty acid β-oxidation metabolic pathway indicating the LCHADD block.
The pathophysiological process begins with reduced glucose intake as a result of a fasting state or increased energy needs from a catabolic state (infection, stress, fever, etc...) not sufficiently satisfied by caloric intake. The resulting hypoglycemia leads to mobilization of free fatty acids (FFAs) which enter the mitochondria via the carnitine cycle. In the mitochondria, as shown in the diagram above, the fatty acids in the hydroxy form are normally oxidized to acetyl-CoA which is used to produce the ketones that can supply the energy needs to compensate for the lack of adequate glucose. A deficiency of LCHAD however, prevents this. The block at LCHAD also results in the accumulation of fatty acid intermediates that inhibit gluconeogenesis (thus preventing endogenous glucose production), have a toxic effect on the liver and produce metabolic (including lactic) acidosis. Muscle, particularly myocardium, requires a lot of energy and, therefore, becomes functionally impaired resulting in lethargy, hypotonia and cardiomyopathy.
Presentation
Hypotonia and weakness
Lethargy
Hypoglycemia- with absence or ‘trace’ ketones
developmental delay
peripheral neuropathy
retinitis pigmentosa
seizures
hepatomegaly- with liver dysfunction (rarely liver failure or cirrhosis)
coagulopathy
cardiomyopathy
‘Reye’ like syndrome
coma
sudden death
Affected infants and children usually present by 2 years of age. However, neonatal cases do occur. Conversely some patients will not present until adulthood with myoglobinuria and peripheral neuropathy. LCHAD is frequently precipitated by intercurrent illnesses. Children or their sibs affected with fatty acid oxidation disorders have often been misdiagnosed as having Reye syndrome or idiopathic cardiomyopathy; some who have died have also been labeled as SIDS deaths. Such family history should be viewed as suspicious for FAOD.
NOTE that in the acute crises, patients can be seriously ill WITHOUT hypoglycemia, although typically FAOD crises are associated with hypoglycemia. At these times the urine typically tests ‘absent’ or ‘small’ for the presence of ketones. Liver function tests may be mildly elevated; hyperammonemia and hyperuricemia are often present during acute episodes.
Assessment
Assess for cardiorespiratory stability, dehydration, fever, infection or any other physical stressor (e.g. surgery), as a potential precipitant for metabolic decompensation. Assess hepatic and neurological status.
Blood glucose
Electrolytes, CO2 and blood gas
Ammonia (1.5 ml blood in sodium- heparin tube sent STAT to lab on ice)
Lactate
LFTs (AST,ALT,AlkPO4, bilirubin)
Clotting studies (PT, PTTK)
EKG and CXR for preliminary cardiac assessment. Cardiomyopathy is often present.
If there is a past history of cardiomyopathy or current cardiac concerns, cardiology services should be notified immediately for emergency evaluation and input for management.
Treatment
1. INDICATION FOR IV (NEVER less than 10% dextrose IV infusion) (One or more indication is sufficient for IV)
Vomiting
Hypoglycemia
lacticacidosis
Poor PO intake
Dehydration
Decreased alertness
Metabolic Acidosis
Cardiac decompensation
Start 10% glucose continuous infusion at 1.5x maintenance, to provide 7-8mg/kg/min.
2. Hypoglycemia
Push 25% dextrose 2ml/kg and follow with a continuous 10% dextrose infusion at 1.5x maintenance, to provide 7-8 mg/kg/min glucose.
3. Metabolic Acidosis (Bicarbonate level <16mEq/L)
Must be treated aggressively with IV sodium bicarbonate (1mEq/kg). Treating conservatively in the expectation of a re-equilibration of acid/base balance as other biochemical /clinical parameters are normalized can lead to tragic consequences.
4. Precipitating Factors
Should be treated aggressively to help minimize further catabolism
5. Cardiac Considerations
A cardiology assessment is necessary to properly evaluate a child with acute symptomatic LCHADD (specifically for heart failure or pericardial effusion).
5. Apparently well
If drinking oral fluids well, and none of the above factors present, there is no need for emergent IVI. But history of earlier vomiting, pyrexia, or other stressor should be taken seriously and a period of observation undertaken to ensure that PO fluids are taken frequently and well tolerated, with glucose status monitored periodically.
Post-Emergency Management
1. Child unable to take/maintain PO intake
Start, or continue, 10% glucose continuous infusion at 1.5x maintenance.
Blood glucose and acid/base status should be monitored regularly. If the child is physically stressed keep the blood sugar levels elevated (glucose levels should be kept between 120-170 mg/dl)
2. Carnitine
The use of carnitine in FAODs is controversial and there are concerns that excessive long chain acylcarnitines which may be produced, may induce arrhythmias. Consult with the metabolic physician for guidance regarding this in each individual case.
3. DO NOT ADMINISTER LIPIDS IN ANY FORM
4. Avoidance of fasting when stop IVI
this may include complex carbohydrate in the form of cornstarch supplementation to get through the night as the child gets older; and a high carbohydrate/low fat diet.
LCHADD chronic management is complicated as many children take a significant amount of time (days to weeks) to improve clinically even once their biochemical parameters have normalized. Particular problems include improvement in mental status, hypotonia, hepatomegaly and cardiomyopathy. It is important to be aware that despite therapy children with LCHADD have died or been left with chronic neurologic, cardiac and hepatic problems. Though the long-term prognosis for children with LCHADD is unclear treatment can be optimized by:-
avoidance of fasting (this may include complex carbohydrate in the form of cornstarch supplementation to get through the night as the child gets older)
high carbohydrate/low fat intake
Early detection of physiologic stresses inc. infection, surgery with especial
attention to REGULAR feedings/source of glucose AROUND the clock.
Regular review by cardiology and ophthalmologic services.
Note that the pregnant mother carrying a fetus with LCHADD is at risk for the HELLP syndrome (hemolysis, elevated liver enzymes and low platelets). She should be closely followed up for counseling and antenatal care for future pregnancies as there will be a 25% risk of each future pregnancy having an affected LCHADD fetus.
Any questions about the patient or this protocol please call or have paged the Genetics/Metabolism Fellow-on-call or, failing this, the Metabolic Attending on call at your hospital or nearest pediatric tertiary care center.
Additional information may be obtained via OMIM at http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?600890#TEXT