Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review

Abstract

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.

Keywords: MADD; case report; fatty liver; hypertransaminasemia; steatohepatitis.

Figure 1

(A) Massive micro-macrovacuolar steatohepatitis picture with minimal fibrosis at liver biopsy with hematoxylin-eosin 10× and (B) Periodic Acid-Schiff, 20×. (C) Magnetic Resonance examination in the pre-treatment showed the overall signal from thigh muscles slightly reduced and clearly inhomogeneous, due to the hypointensity of posterior muscles, compatible with a diffuse fat infiltration in a Fat-Suppressed acquisition technique. (D) After 10-month treatment the overall Magnetic Resonance signal from thigh muscles is higher and less inhomogeneous, with a signal increase of the posterior muscles indicating a reduced fat infiltration. (E) Pedigree of the family of the patient with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD).

Figure 2

(A) Fluctuating trend of Aspartate (AST) and Alanine (ALT) aminotransferases from the onset of the symptoms to the present moment. The arrow indicates the start of riboflavin treatment. ALT and AST upper normal values are 40 U/L. (B) Plasma C3 to C16 acylcarnitine concentrations in our patient in July 2019 at the onset of symptoms (blue), in February 2020 after three months from the start of therapy (red), and in August 2020 after 9 months of therapy (green).