Neonatal pancreatitis associated with familial lipoprotein lipase deficiency.

Abstract

The etiology of childhood pancreatitis is diverse in nature (1). Major predisposing factors include structural anomalies (pancreas divisum, biliary duct anatomic abnormalities, and stones), systemic diseases (sepsis/shock, vasculitis), infections, trauma, drugs, metabolic disorders (hyperlipidemia, hypercalcemia, cystic fibrosis), and positive family history. Precipitating factors are not identified in up to 25% of children with acute pancreatitis (1). We report the case of a 3-week-old neonate with bilious emesis and abdominal distension secondary to pancreatitis. The displacement of duodenal loops from the inflamed and edematous pancreas, gave the radiographic appearance of malrotation, and a laparotomy was performed. The patient was subsequently found to have massive hypertriglyceridemia, which was caused by deficiency of the enzyme lipoprotein lipase. This is an early presentation of pancreatitis related to this metabolic disorder. CASE REPORT A 3-week-old full-term boy was referred for evaluation from a local hospital. He had symptoms of fever (temperature, 38.5°C), irritability, decreased oral intake, and several episodes of bilious emesis. The symptoms had started a few hours earlier. His medical history was otherwise unremarkable. There was no consanguinity between the parents. On arrival, the patient was lethargic, tachypneic (respiratory rate 70/min), with grunting and tachycardia (heart rate 190/min) and decreased perfusion of the extremities. Chest auscultation was clear, and there were no murmurs or gallops heard. The abdomen was distended and diffusely tender with decreased bowel sounds but absent peritoneal signs. Liver and spleen were not palpable. There were no rashes or any other skin lesions present. The optic discs were sharp. The baby's weight and height were both at the 50th percentile for age. The patient was initially intubated and received bolus intravenous fluids with substantial improvement in mental and cardiovascular status. A nasogastric tube was also placed, and bilious material was drained. A sepsis work-up consisting of blood, urine, and cerebrospinal fluid specimens was performed, and intravenous antibiotic therapy was begun. The laboratory evaluation revealed a leukocyte count 10 × 103/ml, hemoglobin 10.4 g/dl, hematocrit 36%, and platelets 519 × 103/ml. The differential leukocyte count included 49% segments, 9% bands, 40% lymphocytes, and 2% monocytes. The total bilirubin level was 63.2 µmol/l (normal, <17 µmol/l), aspartate aminotransferase (AST) 102 IU/l (normal, 15-60 IU/l), albumin 18 g/l (normal, 35-50 g/l), and normal amylase level (<30 IU/l). Serum sodium was 127 mmol/l (normal, 135-145 mmol/l), potassium was 4.9 mmol/l, chloride was 108 mmol/l, and bicarbonate level was 15 mmol/l (normal, 20-25 mmol/l). Glucose, creatinine, and blood urea nitrogen were within normal limits. Cerebrospinal fluid and urine examinations were unremarkable. A chest radiograph was normal. An echocardiogram revealed normal cardiac function. An abdominal radiograph showed multiple dilated loops of bowel, and an upper gastrointestinal contrast series showed an abnormal inferior displacement of the duodenojejunal junction with malpositioned jejunum. There was no evidence of obstruction; however, the small bowel loops were distended, thickened, and aperistaltic. The patient was prepared for surgery for presumed malrotation with volvulus. At exploratory laparotomy, milky fluid was seen within the peritoneal cavity. There was no evidence of intestinal necrosis. The pancreas was inflamed, displacing the duodenojejunal junction. The root of the small bowel mesentery, which was coated with a whitish plaque material, was edematous and fore-shortened. At surgery, the patient's blood was noted to have a creamy appearance. The lipase level, which was measured after surgery, was 960 IU/l (normal, <208 IU/l), and the cholesterol level was 15.7 mmol/l (608 mg/dl) with normal values 1.8 to 4.5 mmol/l. The triglyceride level was 73.4 mmol/l (6507 mg/dl) with normal values for age less than 1.12 mmol/l. A detailed family history, which was obtained after laparotomy, was significant for elevated cholesterol but mainly for triglyceride levels in both father and paternal grandfather. The cause of dyslipidemia in them was not known. They were consuming a low-fat diet and had a negative previous history for cardiovascular disease and pancreatitis (Table 1).TABLE 1: Lipid levels of family membersLipoprotein electrophoresis revealed the presence of chylomicrons at the origin. Low-density (LDLs) and high-density lipoproteins (HDLs) were not present in appreciable concentrations. The patient's serum, which was obtained after 75 U/kg bolus heparin administration, was analyzed for lipoprotein lipase. The lipoprotein lipase activity (University of Washington Lipid Metabolism Laboratory) in the serum was absent, consistent with lipoprotein lipase deficiency. Adding apolipoprotein C-II to the patient's serum did not produce lipoprotein lipase activity. The patient was maintained on total parenteral nutrition, without lipid infusion, for 4 days after the operation until oral feedings were initiated. Portagen (Mead Johnson, Evansville, IN, U.S.A.), a formula with high concentration of medium-chain triglycerides, was used. Subsequently, the serum lipase levels decreased and normalized within 1 week. The cholesterol level dropped to normal within 2 days after the operation. The triglyceride level decreased to 1.45 mmol/l (129 mg/dl), while the patient was fed by parenteral nutrition exclusively, but increased to 3.73 mmol/l (330 mg/dl) when oral feedings were initiated. On monthly follow-up evaluations 3 months after hospital admission, the patient remained asymptomatic, maintained adequate growth, and had triglyceride levels consistently below 4.5 mmol/l (400 mg/dl). DISCUSSION Lipoprotein lipase is a glycoprotein located in the luminal surface of capillary endothelial cells. It is present mainly in adipose tissue but also in muscle, adrenal glands, kidney, intestine and neonatal liver. The enzyme has binding sites for heparin, with which it binds to heparan sulfate on the surface of endothelial cells, lipids, and apolipoprotein C-II, a cofactor of lipoprotein lipase. In addition, it has a separate catalytic site for triglyceride hydrolysis. Intravenous heparin displaces LPL from endothelium into plasma where enzyme activity can be assayed (2). Lipoprotein lipase plays an important role in chylomicron metabolism. Chylomicrons formed in the enterocyte contain newly formed fatty acids, in the form of triglycerides and apoproteins. They also contain cholesterol and phospholipids. The serum concentration of chylomicrons peaks 3 to 5 hours after a meal, giving the serum a milky appearance. In the systemic circulation, chylomicrons acquire apolipoprotein C-II from HDL cholesterol. Apolipoprotein C-II activates lipoprotein lipase, which subsequently hydrolyzes triglycerides into free fatty acids and monoglycerides. These products are either oxidized to provide energy for muscle or other tissues or are stored in adipose tissue. The chylomicron remnant, the residual particle after hydrolysis by lipoprotein lipase, is further processed by the liver (2). In children, fasting chylomicronemia may result from lipoprotein lipase deficiency, apolipoprotein C-II deficiency, or from the presence of an inhibitor to lipoprotein lipase (2). Familial lipoprotein lipase deficiency is a rare autosomal recessive disorder characterized by a massive increase in serum of chylomicrons with a correspondent increase of triglycerides. It is estimated to occur in less than 1 in 106 people (2). The gene for lipoprotein lipase is located on chromosome 8. More than 30 structural defects in the gene have been reported to result in lipoprotein lipase deficiency (2). The disorder is usually manifested in childhood, and clinical symptoms include recurrent bouts of abdominal pain, recurrent episodes of pancreatitis, hepatosplenomegaly, lipemia retinalis, and eruptive cutaneous xanthomas. It is postulated that patients with lipoprotein lipase deficiency in all tissues (classic form) experience symptoms earlier in life, than do those with abnormal activity of the enzyme in one tissue but normal activity in other tissues (variant forms) (2,3) (for a listing of variant forms, see: http://www.ncbi.nlm.nih.gov/Omin [case 238,600]). In a review of 43 cases of familial lipoprotein lipase deficiency, 30% showed symptoms in infancy (4). All were asymptomatic as neonates. The initial clinical symptoms were hepatosplenomegaly, eruptive xanthomas, and multiple colicky episodes. The severity of symptoms appears to be proportional to the degree of chylomicronemia, which is dependent on dietary fat intake. However, there are reported cases of patients who were completely asymptomatic with massive hypertriglyceridemia up to 327.5 mmol/l (29 g/dl) (2). The most common clinical manifestation of lipoprotein lipase deficiency in patients of all ages is episodic abdominal pain (2). The pain may be epigastric with radiation to the back, or diffuse, mimicking acute abdomen. Affected infants may experience multiple colicky episodes. Painful episodes may be accompanied by nausea, vomiting, diarrhea, anorexia, fever, and leukocytosis (4). The pain has led to surgery, as in our patient, during which pancreatitis, erythema of the serosal surfaces with small amounts of milky peritoneal fluid, or no abnormalities at all have been found. Diabetes, steatorrhea, or pancreatic calcifications, common complications of chronic recurrent pancreatitis, are unusual for patients with lipoprotein lipase deficiency (2). The diagnosis of lipoprotein lipase deficiency is made on finding absent or low lipoprotein lipase activity in the serum, after heparin administration, or directly from analysis of biopsy specimens of adipose tissue. It may also be confirmed by demonstration of the structural defect of the lipoprotein lipase gene. Heterozygotes for this disorder have normal or slightly elevated plasma chylomicrons. Serum lipoprotein lipase activity decreases by 50% after heparin infusion. Familial lipoprotein lipase deficiency does not seem to be associated with atherosclerosis and premature heart disease (2). Recurrent pancreatitis can be life threatening. Restriction of fat to 15% of energy is usually adequate to reduce triglyceride levels sufficiently and to prevent symptoms (2,5). Unsaturated as well as saturated fat must be decreased. Provision of adequate calories to promote growth and prevent essential fatty acid deficiency, as the total fat intake is decreased, are important aspects in the management of these patients. Medium-chain triglycerides can also be used, because they are directly absorbed into the portal circulation without becoming incorporated into chylomicrons. Lipid-reducing drugs are not effective (2). More recent data indicate that long-term supplementation of diet with (n-3) fatty acids favors lower levels of triglycerides and chylomicrons (6). A fasting triglyceride level of less than 5.6 mmol/l (500 mg/dl) would be the ideal goal; however, levels below the range of 11.3 to 22.6 mmol/l (1000-2000 mg/dl) (2,7) are adequate for symptomatic control. Alcohol and drugs such as estrogens, diuretics, and β-adrenergic blocking agents may increase endogenous triglyceride production and lead to recurrence of the symptoms (2). Familial apolipoprotein C-II deficiency is another rare autosomal recessive disorder with impaired chylomicron clearance, which has a later onset and similar, but less severe symptoms, than does lipoprotein lipase deficiency. Recurrent bouts of abdominal pain and pancreatitis may be present, but cutaneous fat deposits are absent. The diagnosis is based on measurement of decreased plasma lipoprotein lipase activity after heparin administration, in the absence of apolipoprotein C-II, and correction to normal when apolipoprotein C-II is added to the assay. Transfusion of normal plasma in patients has resulted in a significant decrease in plasma triglyceride level, and it is recommended in cases of severe pancreatitis. The management is similar to familial lipoprotein lipase deficiency, although these patients can tolerate a higher dietary fat intake. Familial lipoprotein lipase inhibitor has been described as an autosomal dominant disorder leading to accumulation of chylomicrons and very low-density lipoproteins. These patients have elevated adipose tissue lipoprotein lipase activity, rather than familial lipoprotein lipase deficiency; however, they are characterized by the presence of a lipoprotein lipase inhibitor in their plasma. The inhibitor can be verified by inhibition of the enzyme's activity when a source of active lipoprotein lipase is added to the plasma (2). Lipoprotein lipase deficiency was diagnosed in our patient from the pattern of lipoprotein lipase electrophoresis and from the absence of serum lipoprotein lipase activity after administration of heparin in the presence of apolipoprotein C-II. Genetic testing was not performed. The dyslipidemias of the father and paternal grandfather have not yet been delineated, but lipid levels of the relatives are shown in Table 1. Both parents were obligate heterozygotes for the disorder. The parents said they had no familial relationship with each other. Consanguinity is commonly seen with this disorder, which denotes that the abnormal alleles for LPL deficiency are rare. An autosomal recessive pattern of inheritance is suspected, because multiple siblings can be affected, both sexes are equally involved, and there is no parent-to-child transmission. However, this mode of inheritance has not been confirmed by studies at the gene level. The parents or relatives of lipoprotein lipase-deficient patients have been observed to have normal or mildly elevated lipid levels (2). Pancreatitis, manifested by abdominal pain, irritability, and bilious emesis developed in our patient and led to cardiovascular compromise. Bilious emesis is seen in 10% of patients with pancreatitis (8). It is likely that hypertriglyceridemia was the predisposing factor of pancreatitis. Hyperglyceridemia has been reported in 12% to 22% of cases of acute pancreatitis (2). The mechanism by which hypertriglyceridemia causes pancreatitis is not known. It has been hypothesized that disturbances in microcirculation, caused by increase in plasma viscosity, are responsible (6). The pancreatitis was diagnosed late in the operating room where the patient was taken for treatment of presumed malrotation with volvulus. The laparotomy could have been avoided if the milky serum had been noted earlier. Amylase levels can be normal in hyperlipidemia, as they were in our patient. It is postulated that plasma lipids interfere with the amylase assay (9), or an inhibitor of the assay is present in the serum or urine (10). Sodium level is also artificially decreased (11). In conclusion, we report an early presentation of pancreatitis in a 3-week-old neonate with hyperlipidemia. The underlying metabolic defect was found to be familial lipoprotein lipase deficiency. The patient's symptoms included abdominal pain, abdominal distension, and bilious emesis. An upper gastrointestinal contrast series gave a false impression of malrotation, because the duodenal loops were displaced by the inflamed pancreas, and led to an unnecessary laparotomy. A high index of suspicion is therefore required for diagnosing disorders of fasting chylomicronemia. Infants or children with multiple episodes of abdominal pain manifested in colic, abdominal distension, pancreatitis, hepatosplenomegaly, lipemia retinalis, eruptive xanthomas, or milky appearance of plasma should be evaluated for chylomicronemia. Pancreatic lipase level should always be requested, because amylase level may be artificially low.