Rare case of primary carnitine deficiency presenting as acute liver failure

Abstract

Systemic primary carnitine deficiency (PCD) is an autosomal recessive disorder caused by mutations in the SLC22A5 gene that encodes carnitine transporter, OCTN2. Transporter deficiency leads to defective fatty acid oxidation. Signs and symptoms ranging from liver injury in children to cardiomyopathy and skeletal myopathy in adults, manifest during periods of stress and fasting. Though acute liver failure is infrequently described, young children presenting as acute liver failure should be screened for fatty acid oxidation defects including PCD by testing plasma for amino acids and further confirmed by genetic sequencing. Early identification and treatment using L-carnitine is lifesaving. Our patient presented as acute liver failure and diagnosis of PCD was confirmed by metabolic screening and genetic sequencing. He responded to the treatment.

Background

Carnitine is needed for β-oxidation by transfer of long-chain fatty acids across the inner mitochondrial membrane. Carnitine is synthesised by the body and is also obtained by diet (meat and dairy products)¹. Systemic primary carnitine deficiency (PCD; Online Mendelian Inheritance in Man (OMIM): 212140) is an autosomal recessive disorder.

Affected infants present with metabolic decompensation symptoms, hypoketotic hypoglycaemia, encephalopathy, hepatomegaly, elevated transaminase levels and hyperammonaemia. The myopathic presentation characterised by hypotonia, skeletal muscles weakness, cardiomyopathy and elevated serum creatine kinase levels is seen in children aged between 2 and 4.² Early diagnosis and treatment with oral L-carnitine (50–400 mg/kg/day) improves skeletal and cardiac muscle function.

Although liver injury is a part of the clinical phenotype, liver failure is infrequently described. We report an unusual case of a male child presented with acute liver failure (ALF) in whom we identified a heterozygous PCD gene mutation.

Case presentation

A previously healthy male infant presented with complaints of fever for 5 days, loose stools and vomiting for 4 days and altered sensorium for 3 days. On eliciting further, it was found that altered sensorium developed gradually after his oral intake reduced following acute gastroenteritis. He was third in birth order, born out of non-consanguineous marriage, with no significant perinatal and family history. Postnatal period was uneventful with appropriate development for age.

General examination was normal and anthropometric evaluations revealed a weight of 11 kg (median and +2 SD), height of 78 cm (median and −2 SD) and head circumference of 47.5 cm (median and +1 SD). He was haemodynamically stable on admission. Abdominal examination revealed soft, non-tender hepatomegaly with a liver span of 15 cm. He was in grade 2 encephalopathy with deranged international normalised ratio (INR; 2.1). His deranged INR did not correct after parenteral vitamin K administration. In view of grade 2 encephalopathy and persistently deranged INR, diagnosis of ALF was made using paediatric ALF study group criteria and was managed as per protocol. The viral markers for hepatitis (hepatitis A, B, C, E, CMV, HSV 1 and 2) were negative.

Laboratory findings have been summarised in table 1. His reports revealed leucocytosis, high transaminases with normal bilirubin and renal function tests along with hypoketotic hypoglycaemia, hyperammonaemia and metabolic acidosis that were suggestive of a possible underlying metabolic disorder. Urine and bloods were sent for metabolic screening: plasma amino acids, urine organic acids and acylcarnitine profile. Blood and urine cultures were sterile. Further worsening of coagulopathy and encephalopathy (stage 3) was documented over next 24 hours requiring mechanical ventilation. Ultrasonography of the abdomen showed enlarged liver with normal echogenicity with minimal ascites and normal vasculature.

Table 1.

Laboratory parameters at admission

Investigations	At admission
Haemoglobin 111–141 g/L	72 g/L
TLC 6–16 * 10ˆ9/L	16.5 * 10ˆ9/L
DLC	N50% L39.5%
Platelet count 200–550 thousand/mm3	237 thousand/mm3
Total bilirubin 0.3–1.2 mg/dL	1.0 mg/dL
Direct bilirubin <0.30 mg/dL	0.7 mg/dL
SGOT 15–60 U/L	10260 U/L
SGPT <50 U/L	8080 U/L
Albumin 3.5–5.2 mg/dL	3 g/dL
GGT <73 U/L	79 U/L
CRP <5 mg/L	2 mg/L
INR 0.9–1.2	2.1
Blood ammonia 9–30 mmol/L	200 mmol/L
Urea 13–43 mg/dL	60 mg/dL
Creatinine 0.9–1.3 mg/dL	1.0 mg/dL
Sodium 136–145 meq/L	141 meq/L
Potassium 3.5–5.1 meq/L	3.4 meq/L

CRP, C reactive protein; DLC, differential leucocyte count; GGT, gamma glutamyltranspeptidase; INR, international normalised ratio; SGOT, aspartate aminotransferase; SGPT, alanine aminotransferase; TLC, total leucocyte count.

Metabolic screening showed decreased levels of free carnitine and normal acylcarnitine profile suggestive of systemic carnitine deficiency. This was confirmed by whole exome sequencing showing a heterozygous missense variant c.1354G>A (p.Glu452Lys) in exon 8 of the SLC22A5 gene that results in the amino acid substitution from glutamic acid to lysine at codon 452 (p.Glu452Lys).

L-carnitine was started at a dose of 100 mg/kg/day. Clinical and laboratory parameters showed significant improvement over the next 7 days and on further follow-up. He was discharged on L-carnitine supplementation and advised for regular carnitine levels.

Treatment

Carnitine should be added before irreversible organ damage occurs. Frequent food intake and avoidance of fasting should be adhered to. Patients with PCD must receive carnitine administration (50–200 mg/kg/day)³ and an adequate dietary intake of carnitine.

Outcome and follow-up

L-carnitine was started at a dose of 100 mg/kg/day. Clinical and laboratory parameters showed significant improvement over the next 7 days and on further follow-up. He was discharged on L-carnitine supplementation and advised for regular carnitine levels.

Discussion

Metabolic liver diseases are an important cause of paediatric acute liver failure, which accounts for 13%–43% of ALF in younger children.⁴ A high index of suspicion is required as immediate intervention with dietary manipulation may be lifesaving.⁵ Our child responded to L-carnitine and within 48 hours marked improvement was seen.

Carnitine transport system disorders are the least common fatty acid oxidation defect(FAOD) subtypes, with an incidence of 1:750 000 to 1:2 000 000.⁶ Transport defect results in impaired fatty acid oxidation in skeletal, liver and heart muscle, impairing ketogenesis and subsequent energy failure. Signs and symptoms may manifest in infants during times of increased metabolic demand, such as fasting or during illness when the body’s glycogen stores are lessened or depleted.³ Our child had preceding gastrointestinal complaints following which he developed ALF suggesting energy failure in times of increased metabolic needs. An unidentified infection might have triggered gastrointestinal complaints leading to ALF in a child with underlying carnitine deficiency.

In our case, acylcarnitine profile and free carnitine level was suggestive of PCD. The diagnosis can be suspected on newborn screening but is confirmed by low plasma free carnitine concentration (<5 µM, normal 25–50 µM), reduced fibroblast carnitine transport, and finally testing of the SLC22A5 gene.

PCD is caused by both homozygous or compound heterozygous mutations in SLC22A5 on chromosome 5q31. Heterozygous variant c.1354G>A (p.Glu452Lys) on exon 8 was detected on whole exome sequencing. Heterozygous missense variant has previously been reported by Wang et al⁷ and found to correlate with symptoms.⁸ Tandem mass spectrometry (TMS) can show abnormal levels in liver disease, hence confirmation with next generation sequencing (NGS) is required.

Carnitine should be added before irreversible organ damage occurs. Frequent food intake and avoidance of fasting should be adhered to. Patients with PCD must receive carnitine administration (50–200 mg/kg/day)³ and an adequate dietary intake of carnitine. We observed complete clinical and biochemical improvement after carnitine administration.

Patient’s perspective.

My child was admitted with loose motions and vomiting. Little did I know that he will get even more sick in a matter of few hours. I was informed that my child’s liver is failing. Luckily, doctors were able to diagnose and my child started improving. Today after 6 months, he is doing well and growing healthy.

Learning points.

• Primary carnitine deficiency is one of the rare treatable causes of acute liver failure (ALF).

• Diagnosis should be suspected especially in young children presenting with ALF.

• Positive metabolic screening should be confirmed by using molecular testing of the SLC22A5 gene or study of carnitine transport in fibroblasts.

• If clinical correlation is suggestive, heterozygous mutations should be considered as the aetiology. This case also emphasises early need for metabolic screening in young children with ALF.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).