Vomiting in a 40-day-old Infant with Consanguineous Parents

A 40-day-old girl of Ghanaian descent presents to a general hospital with a 1 day history of nonbloody, nonbilious emesis. She was born to consanguineous parents who are first cousins. Her health has been good since her birth at term apart from a brief course of phototherapy for breastfeeding jaundice.Given her history of vomiting, she underwent an ultrasound evaluation to exclude pyloric stenosis at the general hospital. This revealed irregular gall bladder thickening, but, more impressively, a lobulated soft tissue mass at the pancreatic head that was 2 cm in diameter and surrounded by a moderate volume of complex ascites (Fig 1). Given her unusual presentation and imaging findings suggesting pancreatitis, she is transferred to a pediatric center for further diagnostic clarification and management.Initial laboratory investigations are remarkable for an elevated lipase of >1,200 U/L (reference range, 4 to 39), a C-reactive protein of 91 mg/L (reference range, 0.1 to 1), triglycerides of 276 mmol/L (reference range, <1.7), high density lipoprotein (cholesterol) of 27 mmol/L (reference range, 3.2 to 4.5). A complete blood count, extended electrolyte panel, liver enzyme tests, and international normalized ratio are normal.She is admitted to general pediatrics and made nil per os, with maintenance fluids running through a peripheral intravenous (IV) catheter. She subsequently has an improvement in her blood work revealing triglycerides of 7.4 mmol/L and lipase of 470 U/L.The following night she becomes febrile and tachycardic with prolonged capillary refill time. Her peripheral IV catheter ceases functioning, and only after multiple attempts is access attained. The blood drawn at the time of IV insertion is pictured, after the syringe was left on its side for a short period (Fig 2). The repeat blood work reveals triglycerides of 117 mmol/L and lipase of 694 U/L.Due to the clinical picture of hyperviscosity and evolving systemic inflammatory response, the patient is transferred to the PICU where she is receives plasmapheresis. Additionally, blood and urine cultures are drawn and empiric ceftriaxone and vancomycin were administered. Further testing reveals the diagnosis underlying this patient’s presentation.On initial presentation to the children’s hospital, the patient’s presentation was most consistent with pancreatitis secondary to hypertriglyceridemia. Pancreatitis secondary to hypertriglyceridemia in the near neonate has a very limited differential, with metabolic causes being at the forefront. There are various familial hyperlipidemias but most present in older childhood or adulthood. Deficiencies in apolipoprotein C-II, a cofactor of lipoprotein lipase, and in lipoprotein lipase itself are the only conditions with marked triglyceride elevations in neonates and infants and can present similarly to our case. (1) Both conditions typically present with symptoms of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. (2) Another finding that can be seen in these conditions is lipemia retinalis. This is a reversible, pink discoloration of the retina due to light scattering caused by large chylomicrons and does not affect vision. (2) The severity of symptoms tends to correlate with the extent of chylomicronemia.In this case genetic testing revealed a homozygous mutation (Y338X) in the LPL gene, and the diagnosis of lipoprotein lipase deficiency was made.Lipoprotein lipase deficiency is a rare, autosomal recessive disorder of triglyceride metabolism. It has a prevalence of 1 in 1 million (as reported in the United States) and is more common in the French-Canadian population of Quebec and those of consanguineous lineage. (2)(3)(4) Boys and girls are affected equally. As alluded to, it is a condition that usually presents early in life with ¼ of affected children becoming symptomatic prior to the age of 1 year. (2)Lipoprotein lipase is required for the hydrolysis of triglycerides that are carried by 2 different types of lipoproteins that is chylomicrons and very low density lipoprotein. Fat from the intestine, which is taken in from the diet, is transported to the bloodstream by chylomicrons, and very low density lipoprotein carries triglycerides from the liver to the bloodstream. Lipoprotein lipase deficiency results in profound increases in circulating chylomicrons that can lead to life-threatening pancreatitis with resulting systemic inflammatory response syndrome.Patients with lipoprotein lipase deficiency can be diagnosed by low or absent enzyme activity in an assay system that contains either normal plasma or apolipoprotein C-II (the cofactor of LPL). The absence of LPL enzyme activity in postheparin plasma is diagnostic of LPL deficiency. (2) However, this assay is not routinely available, and DNA testing has become the standard, which led to diagnosis for our patient.Management of lipoprotein lipase deficiency can be divided into acute and chronic management. The acute management targets the severe hypertriglyceridemia, aiming to prevent secondary pancreatitis. If there is pancreatitis at the time of presentation, then management focuses on this. Long-term management aims to prevent acute symptomatic presentations and thereby reduce the risk of sequalae from recurrent pancreatitis such as diabetes mellitus. (5)In the acute setting, fasting is indicated to prevent additional chylomicron formation. (6)(7) There are no guidelines to direct triglyceride level targets, though it is known that increasing levels are associated with increased risk of pancreatitis. It is generally accepted that the risk is markedly increased in plasma levels exceeding 20 mmol/L, but there is no clear consensus around threshold for treatment. Our treatment target at the Hospital for Sick Children is 10 mmol/L or lower. In situations of extreme hypertriglyceridemia such as in the clinical vignette, plasmapheresis has been used to diminish the risk of acute pancreatitis, (7) however, its usefulness is questionable. (8)The goal of long-term management is to keep triglyceride and chylomicron levels low and thus reduce the risk of recurrent acute pancreatitis and secondary diabetes. Understandably, children with lipoprotein lipase deficiency benefit from a low-fat diet. It has been proposed that daily dietary fat should be restricted to 10% to 20% of total daily energy intake. (8) However, cornerstone of successful management is the replacement of nutritional long-chain fat (that gets absorbed from the intestine and converted to chylomicrons) with medium-chain triglycerides (MCT).Human milk contains 50% of its energy as fat. (6) Regular infant formulas also contain large amounts of long-chain fat and cannot be used for patients with this condition. As such, diagnosed neonates need to be placed on a specialized medical formula that consists of low long-chain fat and is MCT enriched. Later in life, the child’s diet should be one low in fat with MCT oil and essential fatty acid supplements.In the long-term, patients should avoid agents known to increase endogenous triglyceride concentrations such as alcohol, oral estrogens, isotretinoin, glucocorticoids, selective serotonin uptake inhibitors, fish oil supplements and β-blockers. (2)Lipid lowering drugs such as fibrates have been used in patients with lipoprotein lipase deficiency, though there is little evidence to support their use and they are no longer part of standard treatment. (8)Lastly, an adeno-associated virus gene therapy known as alipogene tiparvovec has been pioneered and, when combined with immunosuppressants, appears promising in reducing triglyceride levels in human subjects. (9)As with any genetic condition, genetic counseling for the individual and their family forms an important aspect of management. Given that it is an autosomal recessive condition, parents of the affected individual are usually obligate heterozygotes. As such they are generally asymptomatic but may have elevated triglyceride levels.Upon being admitted to the PICU, our patient was treated with plasma exchange, and over the next 2 days her plasma triglyceride levels fell into the normal range. Her fever does not persist, and blood as well as urine cultures return negative, so antibiotics are discontinued. She was started on an MCT formula, her pancreatitis subsequently resolved, and her triglyceride levels remained well below 10 mmol/L. She was discharged home in the care of her parents just 1 week after presenting to the hospital.On follow-up she was tolerating her MCT lipid formula, and her repeat blood work showed she had a triglyceride level of 5.49 mmol/L and her lipase was 16 U/L.

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