Approach to Elevated Succinic Acid Levels
When elevated succinic acid (SA) is detected, immediately measure blood or urine SA levels for confirmation and initiate urgent evaluation for tyrosinemia type I (HT-1), as this is a life-threatening but treatable condition requiring immediate NTBC therapy. 1
Primary Diagnostic Considerations
The differential diagnosis for elevated SA is narrow and specific:
Tyrosinemia Type I (Most Critical)
- SA is a specific and sensitive marker for HT-1 and should be the primary concern when elevated 1
- This is a medical emergency requiring immediate intervention to prevent hepatic failure, renal dysfunction, and death 1
- Normal tyrosine levels do NOT exclude HT-1—approximately 28% of HT-1 patients may have normal tyrosine at presentation 1
Mitochondrial Disorders
- Cytosolic phosphoenolpyruvate carboxykinase deficiency presents with elevated tricarboxylic acid cycle metabolites including succinic acid, fumaric acid, malic acid, and α-ketoglutaric acid 1
- Succinate-CoA ligase deficiencies (SUCLA2 and SUCLG1) cause elevated methylmalonic acid, methylcitric acid, and other organic acids 1
- Succinate dehydrogenase (SDH) deficiency causes significant elevation of succinic acid with brain white matter changes and developmental regression 2
Other Metabolic Conditions
- Riboflavin transporter defects can present with ethylmalonic acid, adipic acid, and other dicarboxylic acids including succinic acid 1
Immediate Confirmatory Testing
First-Tier Laboratory Evaluation
- Blood or urine SA level (most important initial test) 1
- Plasma amino acids (PAA) to assess tyrosine and phenylalanine levels 1
- Liver function tests: PT, INR, PTT, transaminases 1
- Alpha-fetoprotein (AFP) (markedly elevated in HT-1) 1
- Serum ammonia if lethargy, poor feeding, or vomiting present 3
- Comprehensive metabolic panel including glucose, electrolytes, renal function 3
Second-Tier Specialized Testing
- Urine organic acid analysis to identify the complete metabolic profile and distinguish between disorders 1, 3
- Plasma acylcarnitine profile 1
- Brain MRI with MRS if neurological symptoms present—look for high succinate peak at 2.4 ppm in SDH deficiency or white matter changes 2
- Molecular genetic testing for definitive diagnosis once biochemical abnormalities identified 1
Critical Management Algorithm
If HT-1 is Suspected (Elevated SA with or without Elevated Tyrosine):
Immediate Actions:
- Start NTBC 1 mg/kg/day immediately—do not wait for confirmatory testing 1
- Administer IV 10% dextrose/normal saline at 1.5-2.0 times maintenance rate to maintain normoglycemia 1
- Correct coagulopathy with fresh frozen plasma and vitamin K 1
- Treat metabolic acidosis if present 1
- Consult pediatric hepatology and metabolic specialists urgently 1
Within 24-48 Hours:
- Urinary SA should normalize after 24 hours of NTBC therapy 1
- Introduce low phenylalanine/tyrosine diet with small amount of complete protein (0.25-0.5 mg/kg/day) by 36-48 hours 1
- If no improvement after 1 week or SA remains elevated, increase NTBC to 2 mg/kg/day 1
- If no response after 1 week at higher dose, initiate liver transplantation evaluation 1
If Mitochondrial Disorder is Suspected:
Based on Clinical Context:
- SDH deficiency: Initiate mitochondrial cocktail (coenzyme Q10, riboflavin, carnitine, thiamine) 2
- Obtain brain MRI/MRS looking for white matter hyperintensities and succinate peak 2
- Whole exome sequencing for definitive diagnosis 2
Common Pitfalls to Avoid
- Never use tyrosine as the sole screening marker—it misses 28% of HT-1 cases 1
- Do not delay NTBC therapy while awaiting confirmatory testing in suspected HT-1—clinical response occurs within 1 week and can be life-saving 1
- Do not assume normal tyrosine excludes HT-1—many infants with HT-1 have normal tyrosine levels at initial presentation 1
- Document plasma SA levels in normal range before excluding HT-1 diagnosis 1
- Be aware that some laboratories report SA as "undetectable" in normal individuals due to low sensitivity—clarify the laboratory's normal reference range 1