Recurrent Acute and Chronic Pancreatitis in Two Brothers With Familial Chylomicronemia Syndrome

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1 CASE REPORT Recurrent Acute and Chronic Pancreatitis in Two Brothers With Familial Chylomicronemia Syndrome Kaspar Truninger, MD,* Peter A. Schmid, MD, Michael M. Hoffmann, PhD, Philipp Bertschinger, MD, and Rudolf W. Ammann, MD Abstract: The chylomicronemia syndrome is well recognized as a rare etiologic factor of acute pancreatitis; however, whether hypertriglyceridemia can cause chronic pancreatitis (CP) remains unclear. We describe the long-time course of 2 brothers with the familial chylomicronemia syndrome caused by identical compound heterozygous mutations in the lipoprotein lipase (LPL) gene with markedly reduced LPL activity. Other etiologic factors were excluded, including mutations in the PRSS1, SPINK1, and CFTR gene. Although both brothers had recurrent acute pancreatitis and the same LPL genotype, CP became evident in only one patient. Progression to CP was associated with a more severe disease course. Thus, the chylomicronemia syndrome may cause CP in the absence of other known causative factors, and similar to alcoholic and hereditary CP, a more severe disease course is associated with disease progression. Key Words: recurrent acute pancreatitis, chronic pancreatitis, familial chylomicronemia syndrome, hypertriglyceridemia, lipoprotein lipase deficiency (Pancreas 2006;32:215Y219) Hypertriglyceridemia (HTG) is an established cause of acute pancreatitis, accounting for 1.3% to 3.8% of all cases. 1 Mild to moderate HTG is observed much more often, particularly in alcoholic pancreatitis, with a reported frequency of up to 50%. The mechanisms by which HTG leads to pancreatitis remain unclear, and controversy surrounds the contribution of mild to moderate HTG in causing acute pancreatitis. HTG in acute pancreatitis has long been considered to be a transient epiphenomen but was later suggested to reflect an antecedent lipid disorder. 3Y5 By contrast, the data from Haber et al 6 indicate that elevated triglyceride levels do not account for individual susceptibility to alcoholic or gallstone pancreatitis. The chylomicronemia syndrome manifests clinically with recurrent abdominal pain with or without pancreatitis, Received for publication September 16, 2005; accepted October 11, From the *Clinic of Gastroenterology, University Hospital Berne, CH-3010 Berene, Switzerland; Division of Gastroenterology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland and Division of Clinical Chemistry, University of Freiburg, Freiburg, Germany. Reprints: Kaspar Truninger, MD, Clinic of Gastroenterology, University Hospital Berne, CH-3010 Berene, Switzerland ( kaspar.truninger@ insel.ch). Copyright * 2006 by Lippincott Williams & Wilkins eruptive xanthomatosis, lipemia retinalis, and hepatosplenomegaly. 7,8 Acute pancreatitis may be difficult to diagnose because HTG may produce multiple spurious laboratory results. The very rare hyperlipidemia type I is termed as the familial chylomicronemia syndrome, which results from genetic disorders, such as familial deficiency of lipoprotein lipase (LPL), circulating inhibitor of LPL, or deficiency of its activator apolipoprotein (apo) C-II. Familial LPL deficiency is inherited as an autosomal recessive trait, and the clinical manifestations usually begin in infancy or childhood. Most mutations causing familial LPL deficiency are located in exons 4, 5, and 6 of the LPL gene. The clinical diagnosis of LPL deficiency is confirmed by markedly reduced or absent LPL activity in postheparin plasma. Much more commonly, the chylomicronemia syndrome occurs in patients having familial combined hyperlipidemia or familial HTG with mildly to moderately elevated plasma triglyceride levels, which are exacerbated by a secondary acquired cause such as alcohol intake, obesity, diabetes mellitus, hypothyroidism, pregnancy, estrogen or tamoxifen use, $-blockers, glucocorticoid excess, or nephrotic syndrome 9 (Table 1). The clinical course of acute hyperlipidemic pancreatitis is similar to that from pancreatitis of other causes; however, whether HTG may cause chronic pancreatitis (CP) remains controversial. In the present study, we investigated the clinical course of 2 brothers with the familial chylomicronemia syndrome caused by LPL deficiency. In addition, other genes known to be associated with pancreatitis were investigated. CASE REPORT The 2 patients presented here are part of the large series of pancreatitis patients studied prospectively since 1963 according to a protocol published previously. 10 The visits at regular intervals included documentation of pain, hospitalizations, alcohol intake and drug use, body weight, a clinical examination, routine laboratory tests, pancreatic function tests (serum amylase and lipase, fecal chymotrypsin test, fecal elastase test since 1996, postprandial blood glucose, and glycosylated hemoglobin), and plain radiography of the pancreatic area in 3 dimensions. The first diagnostic evaluation in 1966 included additionally a fecal fat study, the pancreozyminsecretin test (PST) and glucose tolerance test. Tissue blocks of surgical specimens were reexamined. DNA was extracted from white blood cells. All exons and a part of the promoter were amplified and sequenced in both directions as described previously. LPL activity and mass were determined in postheparin plasma as described previously. 11 To exclude an apo C-II deficiency, heat-inactivated serum of the patients was used as apo C-II source in a control experiment with bovine LPL. Pancreas & Volume 32, Number 2, March

2 Truninger et al Pancreas & Volume 32, Number 2, March 2006 TABLE 1. Lipoprotein Lipase Activity and Mass in the Postheparin Plasma of the 2 Brothers and Healthy Controls Time (min post injectionem) LPL Mass (ng/ml) LPL Activity (2mol FFA/h ml Plasma) HTGL Activity (2mol FFA/h ml Plasma) Case 1/Case 2 Case 1/Case 2 Case 1/Case 2 Patients 0 17/37 1.1/ / /89 3.6/ / /70 4.1/ /10.2 Controls (n = 5) 20* 401 T T T 2.7 FFA indicates free fatty acid; HTGL, hepatic triglyceride lipase. *Data are shown as mean T SD (control persons were all men). Genomic DNA was analyzed for the most common mutation in the PRSS1 (R122H, N29I, and A16V), in the SPINK1 (N34S), and in the CFTR gene (31 most common mutations) as described previously. Case 1 This patient is a 1946-born Swiss man who had recurrent episodes of abdominal pain since the age of 14 (Fig. 1A). In 1960, an appendectomy was performed, but the appendix was not inflamed; however, acute pancreatitis was noted intraoperatively. The first clinical diagnosis of acute pancreatitis was documented in During the following years, the patient experienced recurrent mild acute pancreatitis, which required no hospitalizations, except once. The episodes responded promptly to conservative management, and no complications occurred. The patient developed normal both physically and mentally. In 1966, at the age of 20, the patient entered military service, and at a routine laboratory examination, a lipemic serum was noted, and the patient was sent to our institution for further evaluation. He presented in good general condition (174 cm, 63 kg), and physical examination was normal; particularly, the spleen was not enlarged, and no skin xanthomas were present. There was no evidence of diabetes, nephrotic syndrome, hypothyroidism, or alcohol abuse, and the patient had no medication. The family history was negative for recurrent abdominal pain, pancreatitis, diabetes, lipid disorders, and cardiovascular disease, except for his younger brother, who had recurrent abdominal pain as described below (Fig. 2). The parental families were not related to each other, and they originated from different regions in Switzerland. A 12-hour fasting plasma showed chylomicrons, a marked elevation of triglycerides (28 mmol/l), and a normal cholesterol value. Other routine laboratory tests were normal. Pancreatic function assessed by the secretin test, fecal chymotrypsin, and fasting blood glucose were normal. In addition, no pancreatic calcifications were found on plain abdominal x-ray. The diagnosis of familial hyperlipidemia type I with recurrent acute pancreatitis was established without evidence of CP. A low-fat diet was initiated, and the patient was advised to avoid medications, alcohol consumption, and smoking. Since 1966, the patient was included in our prospective longterm pancreatitis study as published previously and examined regularly at our institution. He reported rare and mild episodes of abdominal pain, which were usually related to noncompliance to low-fat diet or by alcohol intake. As soon as the patient felt abdominal pain, he started fasting, and the pain subsided without any further therapy within 1 or 2 days. No further hospitalizations were required, and the patient worked full time until 2002 in a post office 216 with almost no absence from work. Since 1986 (26 years in total), the patient reported no more abdominal pain. The patient did not receive any lipid-lowering medication. He was married, and his healthy asymptomatic daughter had no evidence for any lipid abnormality or recurrent pancreatitis in a recent investigation. At the last visit of this patient in our institution in November 2001, the physical examination was normal (174 cm, 65 kg); particularly, no xanthomas and no hepatosplenomegaly were noted. Routine laboratory tests were normal. Exocrine pancreatic function was checked regularly since study entry by fecal chymotrypsin and elastase testing, and no insufficiency became apparent. In addition, blood glucose and glycosylated hemoglobin levels were always normal. Repeated x-ray studies revealed no pancreatic calcifications. Twelve-hour fasting plasma always disclosed chylomicrons and variable elevations of triglycerides (10Y30 mmol/l) and cholesterol (3.5Y15 mmol/l). In 1990, thrombocytopenia (100,000 g/l) was observed without other hematologic abnormalities. Thrombocyte values ranged between 93,000 and 143,000 in the next years. An ultrasonographic examination in 1993 disclosed splenomegaly ( cm) and a slightly enlarged liver without focal lesions, but no pathological lymph nodes or any other abnormality. The thrombocytopenia was thought to be caused by hypersplenism, and no further investigations were performed. In November 2001, an inoperable lung cancer was diagnosed, and palliative chemotherapy was started. The patient, who had stopped smoking in 1983 (20 pack-years), died in October 2002 at the age of 56 years from metastatic disease. Case 2 This 1948-born patient is the younger brother of the patient described as Case 1. The patient had severe recurrent episodes of abdominal pain since the age of 6 years 3 to 4 times per year, which always lasted several days (Fig. 1B). In 1959, an appendectomy was performed, which revealed no inflamed appendix; however, as in his older brother, acute pancreatitis was noted intraoperatively. In the following years, the patient experienced again severe and frequent episodes of abdominal pain. In 1966, the patient was referred to our institution after the diagnosis of familial hyperlipidemia type I was made in his older brother. The patient had no medication, and he was a nonsmoker and drank no alcohol. The 18-year-old patient was emaciated with a habitus like a 14-year-old boy without signs of puberty (170 cm, 53 kg). The physical examination showed a slightly enlarged liver and marked splenomegaly. Multiple xanthomas were present on the back, legs, and hands. Analysis of a 12-hour fasting plasma disclosed chylomicrons, a marked elevation of triglycerides (34 mmol/l) and a slight elevation of cholesterol (7.2 mmol/l). No other laboratory abnormalities were recorded. The PST was pathological, and the fecal chymotrypsin decreased. A low-fat diet was started leading to less frequent and less severe episodes of abdominal pain. The patient was again hospitalized in a regional hospital in 1969 because of a severe attack of abdominal pain. The diagnosis of recurrent acute pancreatitis caused by hyperlipidemia type 1 was obviously not realized, and a laparotomy was performed. The pancreas was reported to be edematous, and pancreatic biopsies were taken. In addition, splenectomy was performed because of the markedly enlarged spleen. Histology of the pancreas showed acute necrosis, chronic inflammation, and fibrosis, findings consistent with CP. The spleen weighed 1 kg, and histology revealed a large amount of foamy cells, but no other abnormal structures. In the following years, he continued diet and had only rarely mild abdominal pain. No hospitalizations were required, and the * 2006 Lippincott Williams & Wilkins

3 Pancreas & Volume 32, Number 2, March 2006 Recurrent Acute and Chronic Pancreatitis patient worked full time as a butcher. Because of lack of symptoms, he denied further controls for many years (1967Y1988). Thereafter, the patient was seen again at yearly intervals at our institution. In 1989, he presented in excellent condition, having gained 20 kg and grown 11 cm since the last controls (181 cm, 84 kg). Xanthomas were present over the elbows and knees, but physical examination was otherwise normal. Chylomicrons were present on the top of the overnight plasma probe, and triglycerides (65 mmol/l) and cholesterol (maximum, 12.7 mmol/l) were markedly increased. Indirect pancreatic function tests showed persistent exocrine insufficiency, but the patient had no diarrhea or evidence of malabsorption. No diabetes or calcifications were noted. No lipidlowering medication or enzyme replacement therapy was started. No relevant changes were noted at the last check in FIGURE 1. Disease Course of the Two Brothers with the Familial Chylomicronemia Syndrome. A, Case 1 with age at onset of 14 years, normal pancreozymin-secretin test (PST) and persistent negative markers of chronic pancreatitis (fecal enzymes, diabetes, calcification) during follow-up of 42 years. B, Case 2 with age at onset of 6 years, pathological PST and fecal enzyme studies demonstrating persistent severe exocrine insufficiency, no calcification and no diabetes during follow-up of 50 years, but chronic pancreatitis was proved histologically 15 years after disease onset. * 2006 Lippincott Williams & Wilkins 217

4 Truninger et al Pancreas & Volume 32, Number 2, March 2006 FIGURE 2. Pedigree of the Two Brothers With The Familial Chylomicronemia Syndrome. Except for the two cases presented here, no other family members suffered from recurrent acute pancreatitis. The daughter of case 1 and the three children of case 2 had no lipid abnormalities in a recent blood analysis. Serum lipids were also normal in the patient s father, whereas the lipid values in other family members are unknown. The patient s 3 children, aged 13, 11, and 10, do not have abdominal pain, and no lipid abnormalities were found in recent testing (Fig. 2). Laboratory Results Direct sequencing of all exons leads to the detection of the formerly described mutation Pro207Leu in exon 5. In exon 9, a second mutation (Ser447Ter) was detected. Both brothers were heterozygous for both mutations. Hepatic triglyceride lipase activity was normal; however, LPL activity and mass were markedly reduced in both brothers. None of the above mentioned mutations in PRSS1, SPINK1, and CFTR were detected. DISCUSSION Several aspects are of interest regarding the long-term course described in these 2 brothers with recurrent pancreatitis caused by familial chylomicronemia syndrome, that is, the delay in diagnosis combined with operations, the progression from recurrent acute to CP, HTG being the only cause of CP in 1 patient, and a different disease course despite an identical LPL genotype. Both brothers had recurrent abdominal pain since childhood, and lipemic serum was noted on several occasions; however, the diagnosis of recurrent acute pancreatitis was not established until laparotomy was performed. The diagnostic delay of 12 and 6 years may be not surprising because, in 1966, hyperlipidemia was thought to be secondary rather than vice versa. In addition, acute pancreatitis may be difficult to diagnose because serum pancreatic enzymes may be normal even in the presence of severe pancreatitis. 2 Once the diagnosis of recurrent hyperlipidemic pancreatitis was established, both patients remained free of symptoms with an 218 appropriate diet, except for few episodes of abdominal pain related to malcompliance. Prevention of recurrent pancreatitis is directed toward elimination of the cause of HTG; that is, individuals with the rare genetic LPL defects will require restriction of fat intake to 15% to 30% of total daily calorie intake. Control of the secondary factors is the mainstay of treatment in patients with the more common form of chylomicronemia caused by familial HTG. 2 The initial clue to the diagnosis of an inherited chylomicronemia syndrome is presentation at an early age in the absence of a secondary cause of HTG. The diagnosis of familial LPL deficiency was confirmed in both brothers by the analysis of LPL activity and mass, which were markedly reduced in postheparin plasma. By genetic analyses, an identical compound heterozygote LPL genotype consisting of the Pro207Leu mutation in exon 5 and the Ser447Ter mutation in exon 9 was detected in both patients. Until now, more than 100 disease-causing mutations in this gene have been reported. The missense mutation at residue 207 has been described by Ma et al 13 as the most frequent mutation causing LPL deficiency in the French-Canadian population. The Ser447Ter mutation is a polymorphism; however, Kobayashi et al 14 describedthismutationinaheterozygote state in a patient with LPL deficiency. Thus, this mutation appears to have a contributing effect on reducing LPL activity because both brothers were heterozygous for this mutation. In our patients, in whom clinical manifestations began in childhood, all secondary factors contributing to elevated triglyceride levels were excluded. In addition, all other factors known to cause recurrent acute pancreatitis were excluded. Finally, mutations in the PRSS1, SPINK1, and * 2006 Lippincott Williams & Wilkins

5 Pancreas & Volume 32, Number 2, March 2006 Recurrent Acute and Chronic Pancreatitis CFTR gene have recently been described mainly in patients with hereditary and idiopathic CP, but were not detected in our patients. 12 Thus, the familial chylomicronemia syndrome caused by LPL deficiency was the only etiologic factor for recurrent acute pancreatitis identified in these patients. This emphasizes that the familial chylomicronemia syndrome may be the only lipid disorder that can cause acute pancreatitis in the absence of all other etiologic factors. The relationship between acute and CP has long been debated, and controversy also exists as to the relationship between HTG and CP. In 1946, Comfort et al 15 suggested that CP was the consequence of repeated attacks of acute pancreatitis, whereas according to the Marseille classification, acute and CP have been separated into 2 distinct entities. 16 Clinical and morphological studies from Ammann et al, 17,18 however, are consistent with the view that alcoholic CP evolves from recurrent acute pancreatitis with disease progression being closely related to the number and severity of acute attacks. Recent studies in hereditary pancreatitis and the identification of the PRSS1 provided further evidence that CP is the result of repeated episodes of acute pancreatitis, a hypothesis now referred as to the Bnecrosis-fibrosis sequence.^15 In the patient described as Case 2, recurrent abdominal pain started at a younger age, and he experienced more frequent and more severe episodes of acute pancreatitis compared with his older brother. The PST was abnormal 12 years after disease onset, and the fecal enzyme studies documented persistent severe exocrine insufficiency since No diabetes and no calcifications were noted, but the diagnosis of CP was confirmed histologically in By contrast, there was no evidence of CP in the patient described as Case 1 during follow-up of 42 years. Surprisingly, this patient, but not his younger brother, was a smoker, and smoking has been shown to accelerate progression in alcoholic CP. 20 These findings suggest that the progression from acute to CP applies for various etiologies. Whether progression to CP could have been prevented in the younger brother by early dietary intervention remains speculative. Finally, despite an identical genotype in the LPL gene and the exclusion of other etiologic factors, the disease course was clearly different in these 2 brothers with a follow-up from onset of disease of 42 and 50 years, respectively. Thus, hyperlipidemia type I may cause recurrent acute pancreatitis as documented in both brothers. However, the underlying mechanisms driving disease progression to develop CP in only 1 of the 2 brothers remain unclear as in CP of other etiologies. In conclusion, the familial chylomicronemia syndrome may lead to CP, and early diagnosis and adequate therapy are imperative. Similar to pancreatitis caused by other etiologies, a more severe clinical course may be associated with disease progression to CP, and the underlying driving forces remain to be identified. REFERENCES 1. Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am. 1990;19:783Y Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol. 2003;36:54Y Wang C, Adlersberg D, Feldman EB. Serum lipids in acute pancreatitis. Gastroenterology. 1959;36: Guzman S, Nervi F, Llanos O, et al. Impaired lipid clearance in patients with previous acute pancreatitis. 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