Therapeutic plasmapheresis in a young infant with severe hypertriglyceridemia: a case report

Abstract.

Familial lipoprotein lipase (LPL) deficiency typically occurs during childhood and is characterized by severe hypertriglyceridemia, accompanied by episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. The clearance of chylomicrons from plasma is impaired, causing triglyceride accumulation and giving the plasma a milky/lactescent/lipemic appearance. Symptoms typically resolve when total dietary fat is restricted to 20 g/d. Acute management focuses on maintaining triglyceride levels using insulin, plasmapheresis, blood exchange transfusion, and heparin, although few of these interventions have proven effective in infants. Here, we report a rare case of severe hypertriglyceridemia in a 40-d-old infant who presented with respiratory distress, xanthoma, hepatosplenomegaly, and lipemic samples. Plasmapheresis resulted in a reduction in triglyceride levels and clinical improvement, and further evaluation confirmed a diagnosis of LPL deficiency. Familial LPL deficiency can occur during early infancy, with life-threatening complications. A consensus on the acute management of hypertriglyceridemia in the pediatric population needs to be meticulously established after exploring possible treatment strategies, including plasmapheresis.

Highlights

● We report a 40-d-old infant who successfully underwent therapeutic plasmapheresis for hypertriglyceridemia.

● This case report describes a novel homozygous loss-of-function mutation located in exon 6 of the lipoprotein lipase gene.

Introduction

Hypertriglyceridemia is commonly associated with lifestyle diseases in adults, and its incidence is increasing in the pediatric population owing to rising rates of obesity. Although severe hypertriglyceridemia is extremely rare in infancy, its management remains challenging (1). Long-term management of hypertriglyceridemia involves dietary fat restriction and prevention of complications (2, 3), whereas acute management focuses on reducing triglyceride levels using insulin infusion, heparin, exchange transfusion, and plasmapheresis (1, 4,5,6). Once lipoprotein lipase (LPL) deficiency is identified as the underlying cause of severe hypertriglyceridemia, a fat-restricted diet is the mainstay of treatment after acute control of triglyceride levels is achieved. LPL deficiency is diagnosed through molecular genetic testing, which identifies biallelic pathogenic variants in the LPL gene using sequence analysis or gene-targeted duplication or deletion analysis (7).

Here, we report a rare case of severe hypertriglyceridemia in a 40-d-old infant who presented with respiratory distress and required plasmapheresis.

Patient Description

A 40-d-male, firstborn infant from a third-degree consanguineous marriage developed cough and breathing difficulty five days prior to admission. During treatment for pneumonia, the treating physician noted that blood samples drawn for routine investigations were extremely lipemic (milky), which prompted referral to our hospital.

The patient was born at term (38 wk) via vaginal delivery, with a birth weight of 2.80 kg and length of 50 cm, and had an uneventful perinatal course. He was exclusively breastfed from birth until hospitalization and had no history of fever. At admission, he was afebrile, with a pulse rate of 132/min, respiratory rate of 42/min, oxygen saturation of 80% on room air, and blood pressure of 86/48 mmHg. The patient exhibited signs of respiratory distress and hepatosplenomegaly. General examination revealed a solitary xanthoma on the lobule of the left ear (Fig. 1(a)). None of the immediate family members had skin xanthomas or any other manifestations associated with severe hypertriglyceridemia. Routine blood investigations could not be performed owing to the extremely milky lipemic sample (Fig. 1(b)). The only available report was for triglyceride and cholesterol levels, which had been measured externally (Table 1). Chest radiography revealed mild interstitial infiltration. Oxygen therapy and measures to reduce severe hypertriglyceridemia were initiated. Based on the literature, insulin infusion was initially attempted to lower triglyceride levels by targeting the rapid and potent activation of LPL through the stimulation of its synthesis. However, insulin therapy failed to produce a notable response in this patient, raising suspicion of an underlying LPL deficiency. Plasmapheresis was performed in two cycles, each involving 1.5 times the plasma exchange volume, 24 h apart. The procedure was performed at the bedside in the pediatric intensive care unit via the right internal jugular vein central line (4 French, triple-lumen) and apheresis machine with centrifugal flow (Fig. 1(c)). After two plasmapheresis sessions, his triglyceride level decreased to < 500 mg/dL (Table 1). An ophthalmic examination revealed a normal fundus. Table 2 presents the results of blood investigations after the first plasmapheresis session. The blood lipid profile of the parents was normal.

Fig. 1.

(a) Clinical presentation of severe hypertriglyceridemia in a 40-d-old infant as xanthoma over the left ear lobe. (b) A lipemic (milky) blood sample withdrawn from the infant with severe hypertriglyceridemia. (c) Acute management via plasmapheresis in the 40-d-old infant. The procedure was performed at bedside in the Paediatric Intensive Care Unit using a right internal jugular vein central line (4 French, triple-lumen) and an apheresis machine with centrifugal flow.

Table 1. Lipid profile of the index case during hospitalization and follow-up.

Table 2. Blood investigations after the first cycle of plasmapheresis.

Considering the age at presentation, the presence of ear xanthoma, lipemic blood, elevated triglyceride levels, familial hypertriglyceridemia, familial dysbetalipoproteinemia, and storage disorder (type 1 glycogen storage disorder) were considered. With the parents’ informed consent, whole-exome sequencing was performed, revealing a novel homozygous likely pathogenic variant in the LPL gene: a loss-of-function mutation on exon 6, variant c.945T>A (p.Tyr315Ter), consistent with LPL deficiency. Genetic analysis of the parents was not possible owing to financial constraints.

After acute control of hypertriglyceridemia, the patient was started on a low-fat diet, providing only 10–15% of calories, as recommended for long-term management. Implementing this diet was challenging in this infant, given his age, need for exclusive breastfeeding, non-availability of recommended low-fat formula feeds in India, and financial constraints. After consulting with a dietician, he was started on low-fat packaged milk from a local brand, which contained 0.1 g total fat, 5 g carbohydrate, 3.5 g protein, 40 mg sodium, and 150 mg calcium per 100 mL, which was well tolerated. With this diet, triglyceride levels were maintained below 350 mg/dL (Table 1). At the time of discharge, respiratory distress had resolved, and hepatosplenomegaly had decreased.

A follow-up performed at 12 mo of age revealed his growth was between –2 and –3 Z-scores according to weight-for-age and height-for-age, according to World Health Organization standards. Additionally, the hepatosplenomegaly and xanthoma resolved. Figure 2 illustrates weight and length trajectories of the patient from birth to 1 yr of age.

Fig. 2.

(a) Weight trajectory of the patient from birth to 1 yr of age, showing progressive weight gain from 2800 g at birth, 3680 g at hospitalization, and 5300 g at 1-yr follow-up. (b) Length trajectory of the patient from birth to 1 yr of age, showing progressive length gain from 50 cm at birth, 51 cm at hospitalization, and 67 cm at 1-yr follow-up.

Discussion

Familial LPL deficiency is a rare autosomal recessive genetic disorder that affects lipid metabolism and can lead to severe hypertriglyceridemia (triglyceride level > 1000 mg/dL), an endocrine emergency associated with acute pancreatitis and hyperviscosity syndrome (1). It is caused by mutations in the LPL gene, which encodes LPL enzyme responsible for triglyceride breakdown (1). In this patient, the stop-gain variant (nonsense mutation) c.945T>A (p.Tyr315Ter) was identified as a novel mutation that has not been previously reported as either a pathogenic or benign variant. This variant is predicted to form a stop codon, leading to the loss of normal protein function through premature protein truncation. Loss-of-function variants have been reported to be disease-causing. Therefore, this variant was classified as likely pathogenic.

The patient presented with respiratory distress, xanthoma, and hepatosplenomegaly. The accumulation of lipids in the blood as a result of LPL deficiency is known to cause injury to the lung capillaries and alveoli, thus increasing lung tissue permeability and fluid accumulation. This may cause respiratory distress in patients with hypertriglyceridemia along with capillary plugging due to increased plasma viscosity (8).

Long-term management of familial hypertriglyceridemia focuses on a low-fat diet and monitoring for complications (2, 3). Acute management of hypertriglyceridemia is challenging owing to the lack of an established consensus. Intravenous insulin, plasmapheresis, and exchange transfusion have been reported as useful strategies (4,5,6). In 2012, Lutfi et al. reported the case of a 10-yr-old patient with diabetic ketoacidosis and hypertriglyceridemia, who markedly benefited from plasmapheresis (4). In 2013, Pungni et al. successfully managed a 23-d-old male with severe hypertriglyceridemia using exchange transfusion (5). In 2018, Ghoor et al. described the case of a 7-wk-old infant with severe hypertriglyceridemia and multiorgan failure, who recovered following exchange transfusion (6).

To date, only a few cases of hypertriglyceridemia treated with plasmapheresis have been reported in infants, including a 40-d-old infant with chylomicronemia due to a GPIHP1 gene mutation in 2017, and in a 1-mo and 8-d infant with familial chylomicronemia syndrome caused by an LPL gene mutation in 2022 (9, 10).

Plasmapheresis helps remove lipoprotein particles, thereby reducing plasma viscosity and plasma proteases associated with pancreatitis. Nevertheless, its use is limited owing to the scarcity of equipment and technical difficulties, particularly in young children, and has been reported in only a few case reports in the literature. To the best of our knowledge, this study reports one of the youngest cases of severe hypertriglyceridemia managed with plasmapheresis.

Familial LPL deficiency can occur during early infancy with life-threatening complications. In centers with adequate facilities, plasmapheresis can be considered a rescue intervention when faced with severe hypertriglyceridemia. A consensus on the acute management of hypertriglyceridemia in the pediatric population must be meticulously established after exploring possible treatment strategies, including plasmapheresis.

Conflict of interests

The authors declare no conflicts of interest.