Lipoprotein Lipase Deficiency: Benefits and Limitations of a Novel Therapeutic Surgical Approach

Most dietary triglycerides are absorbed through the small intestine into the lymphatic system. They are transported as chylomicrons and enter the systemic circulation via the thoracic duct. Chylomicrons are composed of triglyceride (90%), cholesterol (5%), phospholipid (4%), and apolipoproteins (Apo B-48, Apo E, Apo A-I, Apo A-II, Apo C-II, Apo C-III). They are removed from the circulation by the enzyme lipoprotein lipase (LPL), which is secreted primarily by muscle cells and adipocytes and binds to the luminal surface of capillary endothelial cells. Deficiency of LPL or its cofactor apolipoprotein C-II (Apo C-II) results in chylomicronemia and hypertriglyceridemia. Familial chylomicronemia is an autosomal recessive condition with an incidence of 1 in 1,000,000. The LPL gene is present on chromosome 8 and more than 60 mutations have been described (1). The diagnosis is confirmed by the absence of LPL activity in heparinised plasma in the presence of normal concentrations of Apo C-II. The disease usually presents in childhood with abdominal pain, acute pancreatitis, and hepatosplenomegaly (caused by triglyceride uptake by macrophages). Treatment is with a low-fat (< 20g/day) diet, supplemented with fat-soluble vitamins, calcium, and iron. None of the available lipid lowering drugs is of proven benefit. Medium-chain triglycerides are allowed because they are absorbed directly into the portal venous system and are not incorporated into chylomicrons. Factors known to increase plasma triglyceride concentrations such as alcohol, estrogens (e.g., the oral contraceptive pill), and steroids must be avoided. Hypertriglyceridemia itself is an independent risk factor for premature atherosclerosis; cardiovascular disease and hyperchylomicronemia may be particularly hazardous (2). Early morbidity and mortality in patients with familial LPL deficiency are largely a consequence of recurrent pancreatitis; these patients are also at risk for developing diabetes mellitus (3). Our patient was an 11-year-old girl who required repeated hospitalization for acute pancreatitis. Following the report by Gasbarrini et al. (3) of successful treatment of congenital LPL deficiency in adult and adolescent patients by biliopancreatic diversion and a similar report by Mingrone et al. (4), we undertook a similar operation in our patient and now report her outcome 2 years later. CASE REPORT A Pakistani child, born to consanguineous parents, presented at 7 months of age with vomiting. On examination, she had mild hepatosplenomegaly. Investigations revealed lipemic serum, anemia (hemoglobin 57 g/L), and normal creatinine, electrolytes, and liver function test results. Further investigation of the child's plasma lipids demonstrated a fasting triglyceride concentration of 19.2 mmol/L and a cholesterol level of 5.9 mmol/L. Lipoprotein electrophoresis was normal. The child's LPL activity was less than 1 mmol/L/hour (5–9) and Apo C-II was present (qualitative). A diagnosis of LPL deficiency was made and a low-fat diet of skim milk (Cadbury's, London, UK) implemented. The patient's calorie intake was supplemented with maxijul and caloreen (both Scientific Hospital Supplies, Liverpool, UK). At age 9 months, medium-chain triglyceride (MCT) oil (Liquigen; Scientific Hospital Supplies) was introduced for cooking. Subsequent genetic investigations revealed a novel homozygous mutation, leucine to proline at amino acid residue 303 within the amino terminal domain of the protein (5). Between 3 and 9 years of age, the child continued on a low-fat diet supplemented with MCT oil but, despite good dietary compliance, her plasma triglyceride concentrations were frequently grossly elevated. As the girl matured, however, it became apparent that she was not adhering to her diet. She was admitted to hospital 14 times with severe abdominal pain associated with hypertriglyceridemia; on many of these admissions, she had sonographic evidence of acute pancreatitis. Between 9 and 11 years of age, hospital admissions averaged four per year and gradually increased in frequency. Because of the patient's clinical course and increasing disruption to her schooling, we advised a novel surgical approach to management based on that of Scopinaro et al. (6). At 11 years of age, the patient underwent a biliopancreatic diversion and cholecystectomy (Fig. 1). The small bowel was divided midway along its length and the duodenum was divided just beyond the pylorus. The proximal small bowel (bilio-pancreatic limb) was anastomosed to the terminal ileum 50 cm from the ileocecal valve and the distal small bowel was anastomosed to the proximal duodenum just beyond the pylorus. The gallbladder was removed to prevent cholelithiasis. The girl made an uneventful postoperative recovery and, during the 2 years of follow-up, she has remained well. Because of the risk of ulceration, the patient was treated with ranitidine prophylactically for 6 months. Although random measurements of her plasma triglycerides remained significantly elevated, they were generally reduced and she had no further episodes of pancreatitis and no further acute admissions to hospital. The patient's plasma cholesterol concentration is greatly reduced (Table 1). She is not taking medication but is prescribed fat-soluble vitamins and calcium supplements (with which she is not compliant). She has developed biochemical evidence of rickets and her vitamin D supplementation has been increased. She is fully active, enjoying uninterrupted schooling, and has continued to grow well. Her biochemical parameters and anthropometric indices are shown in Tables 2 and 3. She currently opens her bowels twice per day and does have steatorrhoea. She has been advised to continue on a low-fat diet but has relaxed her fat restriction because she has remained pain-free.TABLE 1: Pre-and postoperative cholesterol and triglyceride levelsTABLE 2: Pre-and postoperative biochemical measurementsTABLE 3: Pre-and postoperative anthropometric measurementsFIG. 1.: Modified biliopancreatic diversion.DISCUSSION Life-threatening pancreatitis, which may even occur in the neonatal period, is the most serious complication of familial LPL deficiency. The precise cellular mechanisms involved in the pathogenesis are not well characterized (7). One theory is that severe hyperchylomicronemia leads to hypoperfusion within the pancreatic microcirculation, which results in pancreatic ischemia and the release of free radicals. Free radical activity coupled with a disruption in glutathione homeostasis in the pancreatic acinar cells may then be responsible for triggering acute pancreatitis. Another theory is that chylomicrons passing through the pancreatic capillaries are hydrolyzed by pancreatic lipase-releasing fatty acids, which lead to further cell-membrane damage and release of pancreatic enzymes. During an episode of pancreatitis, plasma amylase levels may be normal because of interference with the amylase assay by the hypertriglyceridemia. Plasma lipase activity or urinary amylase may be useful diagnostic markers in these cases (8). Despite concerted efforts to achieve strict compliance with dietary management, our patient suffered from repeated attacks of abdominal pain and pancreatitis that necessitated frequent hospital admissions. In addition to her disrupted education and poor quality of life, she was at significant risk of developing diabetes mellitus (and cardiovascular disease in the long term), although she was never hyperglycemic during hospital admissions. After detailed discussion with the family, we considered that a novel surgical approach was justified. The successful operation described by Gasbarrini et al. (3), which had been carried out in an 18-year-old woman with familial LPL deficiency, involved both a biliopancreatic diversion and partial gastrectomy. This was modified in our patient for three reasons: 1) to avoid the numerous and potentially serious adverse effects of partial gastrectomy (9); 2) to reduce the likelihood of the weight loss that occurs when a similar operation is undertaken for morbid obesity (7); and 3) to enable restoration of normal gastrointestinal anatomy at a later date, if necessary. The latter is particularly important for a child considering the potential for future novel medical interventions in LPL deficiency. Successful antioxidant therapy with selenium-β-carotene-C-E (α-tocopherol, β-carotene, organic selenium, and methionine) has recently been reported in the treatment of three adult patients with LPL deficiency (10). Orlistat, a gastrointestinal lipase inhibitor, has been shown to reduce dietary fat absorption by 30% in adults and may have a potential but as yet untested role in the management of LPL deficiency. Although the novel surgical approach taken with our patient did not result in a normal plasma triglyceride concentration, it has reduced plasma triglyceride concentrations and, in the short term, prevented further attacks of symptomatic acute pancreatitis. We speculate that the patient may have reduced risk of developing insulin-dependent diabetes mellitus as a result of the procedure. This reduction in risk was achieved without surgical morbidity while preserving the potential to restore normal gastrointestinal continuity. Complete normalization of plasma triglyceride levels may require the combination of biliopancreatic diversion and the malabsorption induced by partial gastrectomy (3). Compliance with a low-fat diet may result in a further improvement of our patient's lipid profiles, which is important in view of her future risk of developing cardiovascular disease. She has developed vitamin D deficiency as a consequence of fat malabsorption and poor compliance with calcium and vitamin supplementation. The long-term implications for bone growth have been discussed and compliance has now improved. Acknowledgement: The authors thank Professor Marco Castagneto, M.D., F.A.C.S., of the Universita Cattolica del Sacro Cuore, Rome, for generously providing further details of the outcome of his published case (3).