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Long-Term Course of Lipoprotein Lipase (LPL) Deficiency Due to Homozygous LPL_Arita in a Patient with Recurrent Pancreatitis, Retained Glucose Tolerance, and Atherosclerosis

Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Disease (M.K., T.H., M.M., M.T., S.K., K.M., T.N.), Department of Lipidology (A.N., H.M.), and Department for Life-Style-Related Diseases (J.Kob.), Graduate School of Medical Science, School of Health Science (A.I.), Faculty of Medicine, and Department of General Medicine (J.Koi.), Kanazawa University Hospital, Kanazawa University, Kanazawa, 920-8641, Japan

Address all correspondence and requests for reprints to: Masa-aki Kawashiri, M.D., Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Disease, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan. E-mail: masaaki{at}im2.m.kanazawa-u.ac.jp.

	Abstract

Top Abstract Introduction Patient and Methods Case Report Discussion References

 
Context: Lipoprotein lipase (LPL) deficiency is a rare autosomal recessive disorder caused by LPL gene mutation and is characterized by severe hyperchylomicronemia. Patients with LPL deficiency suffer from the frequent recurrence of acute pancreatitis, but the underlying mechanisms are not fully understood.

Case Report: A 22-yr-old male Japanese patient with severe hyperchylomicronemia was admitted to our hospital in 1973. He had no consanguinity and no family history of hyperlipidemia. He was genetically diagnosed as LPL deficiency (homozygous for LPL_Arita) with no LPL mass or activity in postheparin plasma. He has experienced recurrent acute pancreatitis 22 times during our 31-yr clinical follow-up, but no pancreatic pseudocyst, irregularity of the pancreatic duct, or abnormal pancreatic calcification was observed in computed tomography. Moreover, his pancreatic endocrine function, as assessed by the oral glucose tolerance test, has preserved more than 30 yr. Although he was a current smoker, no clinically significant atherosclerotic lesion had been observed.

Conclusions: From the long-term observation of this patient, we propose that LPL deficiency is not invariably associated with high mortality and that even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.

	Introduction

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LIPOPROTEIN LIPASE (LPL) is a 61-kDa glycoprotein enzyme that plays a central role in lipoprotein metabolism by catalyzing the hydrolysis of triglycerides (TGs) in chylomicrons (CMs) and very low-density lipoprotein particles (1). LPL deficiency is a rare autosomal recessive disorder caused by mutation of the LPL gene and is characterized by severe hypertriglyceridemia due to a marked increase in CMs (type 1 hyperlipoproteinemia) (1). The plasma levels of TGs and high-density lipoprotein cholesterol are often above 11 and less than 0.5 mmol/liter, respectively. The diagnosis is made on the basis of the absence of plasma LPL mass and activity after the injection of heparin.

Patients with LPL deficiency suffer from the frequent recurrence of acute pancreatitis, which has a large adverse effect on the patient’s quality of life (1). The underlying mechanisms are not fully understood, and no previous report has elucidated the long-term pancreatic function in hyperchylomicronemia. Moreover, whether hyperchylomicronemia induced by LPL deficiency is atherogenic remains controversial.

Here we report a male patient with LPL deficiency (homozygous for LPL_Arita), who had no major pancreatic malformations, vascular complications, or severe glucose intolerance, despite a 31-yr clinical history of pancreatitis recurring more than 20 times.

	Patient and Methods

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DNA isolation and mutation analysis

Genomic analysis was performed after obtaining written informed consent from our patient in accordance with the guidelines of the Bioethical Committee on Medical Research, School of Medicine, Kanazawa University. Genomic DNA was purified from peripheral leukocytes by a phenol-chloroform method and was amplified in vitro using the PCR as described previously (2). The LPL gene was sequenced with an ABI PRISM dye terminator cycle sequencing ready reaction kit (Applied Biosystems, Foster City, CA). After the detection of a homozygous one-base deletion of G at base 916 in exon 5 of the LPL gene, the mutation (LPL_Arita) was confirmed by a PCR restriction fragment length polymorphism method using restriction enzyme AluI (2).

Lipid measurements

Blood samples were obtained for lipid measurements after overnight fasting. The concentrations of serum total cholesterol (TC) and TGs were determined enzymatically, and those of high-density lipoprotein cholesterol were determined by direct method.

LPL mass and activity

LPL mass and activity in postheparin plasma were measured following previously reported methods. Briefly, postheparin plasma was obtained 15 min after an injection of 30 U/kg heparin. LPL mass in postheparin plasma was measured by a sandwich enzyme immunoassay (3). The LPL activity in postheparin plasma was measured using Triton X-100-emulsified [¹⁴C]triolein (4).

	Case Report

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A 22-yr-old male Japanese patient was admitted to Kanazawa University Hospital for further examination of recurrent abdominal pain and chylous serum in 1973. He had a past history of recurrent mild abdominal pain and diarrhea since he was 17 yr old. At admission, his height and body weight were 162 cm and 54 kg (body mass index, 20.6 kg/m²), respectively. He had an eruptive cutaneous xanthomatosis on his right upper arm. He smoked approximately 20 cigarettes and consumed approximately 20 g alcohol per day. He had no family history of hyperlipidemia or pancreatitis. No consanguinity was present. His mother had type 2 diabetes mellitus and had received insulin therapy since she was 45 yr old.

The maximum serum TG levels of the patient were as high as 40 mmol/liter, whereas his TC level was 5.6 mmol/liter. A diagnosis of LPL deficiency was later confirmed by the extremely low levels of LPL mass and activity of postheparin plasma (<20 ng/ml and 0.027 µmol/ml·min, respectively), and a one-base deletion of G at base 916 in exon 5 of the LPL gene (LPL_Arita) (2).

He was advised to consume less than 20 g fat per day and to stop drinking alcohol. His lack of full compliance with these restrictions resulted in his plasma levels of TGs occasionally reaching 11 mmol/liter.

Acute pancreatitis requiring hospitalization had recurred usually after consuming a diet rich in fat since his first attack in 1973 (Fig. 1). His abdominal pain disappeared each time after a cessation of diet and the infusion of protease inhibitor. Plasma-exchange therapy was performed in 1978, 1982, 1983, 1985, and 1993, because his serum levels of TGs were extremely high and needed to be reduced rapidly (Fig. 1). Protease inhibitor was infused continuously into the superior mesenteric and celiac arteries during 1997 and 2003 due to the pancreatitis being extremely severe and highly resistant to conventional peripheral infusion therapy (Fig. 1). The threshold serum TG level for the onset of acute pancreatitis appeared to reduce gradually. Despite the recurrent pancreatitis, no anatomical findings suggesting chronic pancreatitis, such as pancreatic pseudocysts, dilatation or irregularity of pancreatic duct, or abnormal pancreatic calcification, were observed by computed tomography and endoscopic retrograde cholangiopancreatography.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Changes in serum TC and TG levels. Acute pancreatitis requiring hospitalization had recurred 22 times since the patient was 22 yr old. Serum levels of TGs were usually above 5.0 mmol/liter except for the period when he fasted for the treatment of acute pancreatitis. As he aged, acute pancreatitis seemed to occur at lower serum TG concentrations than before. , Acute pancreatitis; , plasma exchange; #, continuous protease inhibitor infusion therapy into the pancreatic arteries.

View larger version (25K): [in this window] [in a new window]   FIG. 2. Results of oral glucose tolerance test. Plasma glucose and serum immunoreactive insulin were measured before and at 30, 60, 90, 120, and 180 min after the oral ingestion of 75 g glucose. Open triangles, filled triangles, open circles, and filled circles indicate the data when he was 22, 33, 42, and 52 yr old, respectively. Open squares and filled squares indicate the data when he was 53 yr and 1 month and 53 yr and 11 months, respectively. Serum levels of immunoreactive insulin were not measured when he was 22 yr old. 53–1, Fifty-three years and 1 month; 53–11, 53 yr and 11 months.

	Discussion

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The present case was genetically diagnosed as LPL_Arita (2), which is one of the most common LPL mutations in Japanese subjects (5). In the current case, acute pancreatitis requiring hospitalization occurred 22 times during the 31-yr clinical course.

Although the mechanisms by which hyperchylomicronemia induces acute pancreatitis are not fully understood (1), oral antioxidant therapy reduces the frequency of pancreatitis in LPL deficiency (6), indicating that oxidative damage to the pancreas may cause acute pancreatitis. To our knowledge, acute pancreatitis had not occurred in the current case before he was 22 yr old, even when on a normal diet. Moreover, the threshold serum TG level for the onset of acute pancreatitis appeared to decrease to less than 20 mmol/liter after he reached 40 yr old. Oxidative stress generally increases with age and is considered to be one of the major causes of age-related diseases (7). Taking our observations together with the findings of Heaney et al. (6), we speculate that oxidative stress plays a role in the onset of acute pancreatitis in patients with LPL deficiency.

Despite recurrence of acute pancreatitis 22 times in the present case, no irreversible morphological changes compatible with chronic pancreatitis (such as cysts, pseudocysts, irregularity of the pancreatic duct, or abnormal pancreatic calcification) were detected. It is generally recognized that recurrent acute pancreatitis, especially alcoholic pancreatitis and idiopathic pancreatitis, is a cause of chronic pancreatitis (8). However, our case and other reported cases may indicate that acute pancreatitis induced by hyperchylomicronemia is not associated with chronic pancreatitis.

This is the first case report on glucose tolerance of a patient with recurring LPL deficiency and a very long clinical follow up. The patient’s insulin response after oral glucose loading decreased gradually during the clinical course (Fig. 2); however, his plasma glucose levels were well controlled by diet therapy alone (his hemoglobin A1c was <6.0% at the age of 54 yr).

Whether or not LPL is atherogenic remains controversial. Benlian et al. (9) reported four cases of familial chylomicronemia, in whom peripheral and coronary atherosclerosis developed at an age of less than 55 yr despite low levels of LDL cholesterol. In contrast, Ebara et al. (10) reported a 66-yr-old female with LPL deficiency who showed no significant atherosclerosis in the carotid and femoral arteries. LPL is considered as antiatherogenic protein via lipoprotein metabolism. In an animal study, the overexpression of human LPL resulted in a consistent reduction of atherosclerosis due to a significant reduction in plasma TC and TG levels (11, 12). In contrast, LPL is considered as proatherogenic via the promotion of lipoprotein retention on the arterial walls functioning as a bridge between apolipoprotein B-containing lipoproteins and proteoglycans on vessel walls (13). The influx of lipoproteins into the arterial wall depends on the size and concentration of the lipoprotein particles, the permeability of the arterial wall, and the blood pressure. CM particles are believed to be too large to penetrate vessel walls (14, 15). The present case of LPL_Arita supports the notion that LPL deficiency is not associated with the development and progression of atherosclerotic cardiovascular disease. Ebara et al. (10) proposed that the effect of LPL deficiency on atherogenicity differed between their study and that of Benlian et al. (9) due to all four LPL-deficient cases in the latter study showing a considerable amount of dysfunctional LPL mass, whereas subjects in the former study did not exhibit detectable LPL mass in postheparin plasma. LPL_Arita is also a nonsense mutation with no detectable LPL mass (2). Thus, combining the information from these cases with the present case suggests that catalytically inactive LPL protein is proatherogenic.

There are some case reports of LPL deficiency who underwent biliopancreatic diversion surgery to reduce lipids absorption (16, 17, 18). Although favorable outcomes were derived from those patients, surgical treatment itself is potentially dangerous. Our case had been treated conservatively during every acute pancreatitis and showed no severe irreversible organ damage. Thus, our findings do not support the necessity of surgical treatment for LPL deficiency.

In summary, we experienced a 53-yr-old male Japanese hyperchylomicronemic patient based on a nonsense mutation in the LPL gene (LPL_Arita), who suffered from recurrent acute pancreatitis. Despite the recurrent acute pancreatitis, there was no significant finding of chronic pancreatitis, and glucose tolerance was preserved when controlled only by diet therapy. No atherosclerotic changes in carotid arteries or significant findings suggesting myocardial ischemia on exercise-stress electrocardiography were seen despite a continuous smoking habit and the presence of type 2 diabetes mellitus. From our long-term observation of this patient, we propose that LPL deficiency is not invariably associated with high mortality and that, even with repeated episodes of acute pancreatitis, pancreatic function may be slow to decline.

	Acknowledgments

 
We are indebted to Mayumi Yoshida and Sachio Yamamoto for their outstanding technical assistance and to Dr. Toshihide Okada for helpful discussions.

	Footnotes

 
First Published Online September 20, 2005

Abbreviations: CM, Chylomicrons; LPL, lipoprotein lipase; TC, total cholesterol; TG, triglyceride.

Received May 18, 2005.

Accepted September 12, 2005.

	References

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