The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1203-1205
Copyright © 1999 by The Endocrine Society
Prevention of Recurrent Pancreatitis in Familial Lipoprotein Lipase Deficiency with High-Dose Antioxidant Therapy
A. P. Heaney,
N. Sharer,
B. Rameh,
J. M. Braganza and
P. N. Durrington
University of Manchester, Departments of Medicine and
Gastroenterology, Manchester Royal Infirmary, Manchester M13 9WL,
United Kingdom
Address all correspondence and requests for reprints to: P. N. Durrington, Department of Medicine, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom.
 |
Abstract
|
|---|
We describe a dramatic response to antioxidant therapy in three
patients with familial lipoprotein lipase deficiency complicated by
frequent severe episodes of pancreatitis who had failed to respond to
other dietary and pharmacological measures. Antoxidant therapy may be
an important advance in the management of this type of patient.
|
Introduction
|
|---|
Lipoprotein lipase removes triglycerides from the
circulating triglyceride-rich lipoproteins (chylomicrons and
very-low-density lipoproteins) and is located on the capillary
endothelium of tissues such as adipose tissue and skeletal and cardiac
muscle. Familial lipoprotein lipase deficiency (FLLD) (1, 2) is an
autosomal recessive disorder caused by mutation of the gene for
lipoprotein lipase (3). Frequently, the disorder is associated with
grossly elevated serum triglyceride levels, sometimes as high as 100
mmol/L. It is refractory to lipid-lowering drug therapy; and often, the
only long-term means of treatment is the adoption of a diet that is low
in all types of fat. Unfortunately, even with extremely restrictive
diets (intended to contain as little as 10 g of fat each day),
serum triglyceride levels are rarely maintained at values less than 20
mmol/L (2). Many patients with the disorder are prone to attacks of
pancreatitis, and these are the source of considerable morbidity and
premature mortality. We describe a novel approach to the prevention of
pancreatitis using high-dose antioxidant therapy, which was highly
effective in three patients with FLLD in whom attacks of pancreatitis
were particularly frequent before the introduction of the new
treatment.
|
Case Reports
|
|---|
In none of the three patients with FLLD, in this report, was
lipoprotein lipase activity detectable in postheparin plasma, despite
the demonstration of apolipoprotein CII (the circulating activator of
lipoprotein lipase) in all three. The patients all had FLLD,
complicated by pancreatic disease, and are a consecutive series treated
with oral antioxidant therapy (AOT), initially as
selenium-ß-carotene-C-E, two tablets three times daily
(Wassen, Mole Park, UK), which provided 
-tocopherol (270
IU/day), ß-carotene (9000 IU/day), vitamin C (540 mg/day), and
organic selenium (600 µg/day), and a separate tablet of methionine
(0.5 g qds; Evans, Chessington, UK) (4, 5). More
recently Antox (Pharmanord, Morpeth, UK) has replaced this
combination of supplements in similar doses (6). These maintain blood
glutathione, plasma vitamin C and serum selenium levels towards the
upper end of the reference range (4, 5, 6) and are pharmacological with
respect to vitamin E and ß-carotene (Table 1
).
View this table:
[in this window]
[in a new window]
|
Table 1. Serum concentrations of vitamin C, selenium, vitamin
E, and ß-carotene and whole-blood concentration of glutathione of
three patients (TS, BS and CW) with familial lipoprotein lipase
deficiency before and after administration of antioxidant vitamins
(Antox, 1 tablet four times daily) for 10 weeks
|
|
In none of the patients was there any discernible diminution in serum
lipid levels after treatment (Table 2). None
of the patients had diabetes mellitus, as defined by the World Health
Organization, and none had an excessive alcohol intake.
View this table:
[in this window]
[in a new window]
|
Table 2. Range and median values for serum triglycerides and
cholesterol, before and after AOT, in three patients (TS, BS, CW) with
familial lipoprotein lipase deficiency
|
|
Patient TS had been always ill as a child. Lipoprotein lipase
deficiency was diagnosed when she was 6 yr old. At the age of 18, after
diagnostic laparotomy for severe abdominal pain, pancreatitis was
diagnosed, and she required intensive care support, followed by
surgical drainage of a pseudocyst. She experienced a total of 93
attacks of pancreatitis in the next 10 yr (Fig. 1), such that she used opiate analgesia
daily. Diet and bezafibrate were unsuccessful in controlling her
hypertriglyceridemia. Small-duct diffuse noncalcific pancreatitis was
diagnosed. Further surgery included cholecystectomy, partial
pancreatectomy with splenectomy, and gastroenterostomy; and finally,
total pancreatectomy was attempted but abandoned after 9 h. A
percutaneous transhepatic cholangiogram showed intrahepatic duct
dilatation, caused by biliary stricture. Other measures for pain
control were tried without success (including high doses of pancreatic
extracts, two celiac plexus blocks, and splanchnicectomy). No further
surgery was possible; and at this stage, in 1995, she was referred to
Manchester Royal Infirmary. Transjugular liver biopsy showed
histological features of suppurative cholangitis, and paraaminobenzoic
acid excretion index was reduced, at 0.78 (normal, >0.84), in keeping
with moderately impaired pancreatic exocrine function. AOT was
commenced in 1995 when she was 27 yr old. Since then, she has had only
two mild episodes of pancreatitis, associated with acknowledged
temporary noncompliance with AOT, and her liver alkaline phosphatase
has decreased to 250 IU/L (upper limit of normal, 330 IU/L), from a
pretreatment value of 2000–4000 IU/L (probably as the result of
decreased inflammation of the head of her pancreas, previously causing
biliary obstruction).
View larger version (25K):
[in this window]
[in a new window]
|
Figure 1. The number of episodes of pancreatitis
documented by hospital admissions each year in three patients before
and after the introduction of antioxidant therapy (AOT).
|
|
The initial diagnosis of FLLD was made in patient BS, after biopsy of
eruptive xanthomata, at the age of 7 yr. She spent a significant part
of her adolescent years in the hospital, with abdominal pain, despite a
low-fat diet and inappropriate therapy with cholestyramine and later,
more appropriately, with clofibrate. Laparotomy was subsequently
carried out on two occasions. The second occasion was after severe
abdominal pain and shock, after spontaneous vaginal delivery of a
stillborn infant. Abruptio placenta and acute pancreatitis were
confirmed, and acute renal failure complicated her recovery. She was
referred to the Manchester Royal Infirmary in 1989. Despite
intensification of diet and attempts at treatment with fibric acid
derivatives and fish oil, she continued to have recurrent episodes of
pancreatitis. AOT was commenced in 1993, when she was 41 yr old, and no
further episodes of pancreatitis have occurred (Fig. 1
).
Eruptive xanthomata in childhood were also an early feature of FLLD in
patient CW. Dietary fat restriction and clofibrate were instituted at
the age of 15 yr. Episodes of pancreatitis began in his late teenage
years; and on average, he had 4–5 admissions per year (Fig. 1). A
variety of lipid-lowering agents were tried (including fish-oil;
bezafibrate; and later, simvastatin), but his symptoms failed to abate,
and he commenced AOT in 1991 at the age of 42 yr. He has had only three
episodes of minor abdominal pain since commencing AOT.
|
Discussion
|
|---|
The reason for the susceptibility to acute pancreatitis in some
patients with FLLD, and indeed in severe hypertriglyceridemia from
other causes, is (at present) not adequately explained. There is no
doubt, however, that patients of the type described here all too often
succumb to complications of their pancreatitis, and this represents an
enormous therapeutic challenge (2). Our treatment with AOT seemed to
have a dramatic effect on the course of the disease in the patients
reported in whom all other attempts at treatment by dietary
restriction, drug therapy, or surgery had failed. Furthermore, the
abolition of pancreatitis attacks after AOT, in the three patients in
this report, occurred without any change in serum triglyceride
concentration. Occasionally, in chronic pancreatitis, the frequency and
severity of attacks can tail off as the result of bout after bout of
inflammation, causing effacement of acinar tissue. However, the sudden
and sustained reduction in attacks in all three patients argues against
the disease naturally burning itself out in such a way in any of
them.
The dose of antioxidants chosen was the result of earlier studies in
recurrent pancreatitis from other causes and in animal models of acute
pancreatitis (4, 5, 6). The rationale for this approach is supported by
recent experimental studies suggesting that disruption of glutathione
homeostasis, associated with a burst of free-radical activity, in
pancreatic acinar cells, may be an initiating event in acute
pancreatitis (7, 8, 9). Although the precise sequence of events leading to
pancreatitis in FLLD is not established, studies in the isolated
perfused pancreas (10) lead us to speculate that heightened
free-radical activity in patients with FLLD may relate to periods of
pancreatic ischemia, resulting from a sluggish pancreatic
microcirculation caused by high concentrations of chylomicrons. Under
normal conditions, there is some leakage of lipase into the pancreatic
microcirculation, but this is heightened by free-radical damage to
acinar cells (8, 9, 10). Once lipase is present in the capillaries in
FLLD, the abundant triglyceride substrate there will be rapidly
hydrolyzed, and the resultant nonesterified fatty acids are intensely
inflammatory. Chylomicrons and very-low-density lipoproteins are the
source not only of proinflammatory nonesterified fatty acids from
triglycerides (11) but also of polyunsaturated fatty acyl groups from
triglycerides and phospholipids. These are, themselves, highly
susceptible to free-radical attack, leading to lipid peroxidation with
subsequent breakdown, to form cytotoxic lysolipids, aldehydes, and
ketones (12). These will further intensify the inflammatory process,
and their formation may be an additional stage in the process against
which antioxidants can provide protection.
The safety profile of AOT is high, but caution is needed in patients
with renal impairment (selenium is renally excreted) or a family
history of organic psychoses (which may be precipitated by methionine)
and in the presence of an iron storage disease [in which retention of
iron in its ferrous (FeII) form could favor its
participation in Fenton and other free-radical-generating reactions
(13)]. We recommend interval monitoring of blood levels of
glutathione, vitamin C, and selenium to ensure that optimal levels are
obtained.
Received July 24, 1998.
Revised November 26, 1998.
Accepted November 30, 1998.
|
References
|
|---|
-
Brunzell JD. 1995 Familial lipoprotein lipase
deficiency and other causes of the chylomicronemia syndrome. In:
Scriver CR, Beaudet AL, Sly WS, Valle D, eds. Metabolic and molecular
basis of inherited disease. 7th ed. New York: McGraw-Hill;
1913–1932.
-
Durrington PN. 1995 Hyperlipidaemia. Diagnosis,
management. 2nd ed. Oxford: Butterworth Heinemann.
-
Lalonel J-H, Wilson DE, Luerius P-H. 1992 Lipoprotein lipase and hepatic triglyceride lipase: molecular and
genetic aspects. Curr Opin Lipidol. 3:86–95.[CrossRef]
-
Uden S, Bilton D, Nathan L, Hunt LP, Main C, Braganza
JM. 1990 Antioxidant therapy for recurrent pancreatitis:
placebo-controlled trial. Aliment Pharmacol Ther 4:357–371.
-
Uden S, Schofield D, Mitter PF, Day JP, Bothiglieri T,
Braganza JM. 1992 Antioxidant therapy for recurrent pancreatitis:
biochemical profiles in a placebo-controlled trial. Aliment Pharmacol
Ther 6:229–240.
-
Schofield D, Rameh B, Leach FN, Braganza JM. 1997 Antioxidant profiles after three antioxidant regimens for ten weeks:
implication for clinical trial design. Digestion. [Suppl 2]58
:26 (Abstract).
-
Guyan PM, Uden S, Braganza JM. 1990 Heightened
free radical activity in pancreatitis. Free Radic Biol Med8
:347–354.
-
Braganza JM. 1996 The pathogenesis of chronic
pancreatitis. Q J Med. 89:243–250.[Free Full Text]
-
Braganza JM, Chaloner C. 1995 Acute pancreatitis. Curr Opin Anaesthesiol. 8:126–131.
-
Sanfey H, Buckley GB, Cameron JC. 1984 The role of
oxygen derived free radicals in the pathogenesis of acute pancreatitis. Ann Surg. 200:405–413.[Medline]
-
Havel RJ. 1969 Pathogenesis, differentiation, and
management of hypertriglyceridaemia. Adv Intern Med. 15:117–154.[Medline]
-
Esterbauer H. 1995 The chemistry of oxidation of
lipoproteins. Chapter 3. In: Rice-Evans C, Bruckdorfer KR, eds.
Oxidative stress, lipoproteins and cardiovascular dysfunction. London:
Portland Press; 55–79.
-
Sharer N, Taylor PM, Linnker BD, Gutteridge JMC,
Braganza JM. 1995 Safe and successful use of vitamin C to treat
painful calcific chronic pancreatitis despite iron overload from
primary haemachromatosis. Clin Drug Invest. 10:310–315.
This article has been cited by other articles:
|
|
|
|
 
M.-a. Kawashiri, T. Higashikata, M. Mizuno, M. Takata, S. Katsuda, K. Miwa, T. Nozue, A. Nohara, A. Inazu, J. Kobayashi, et al.
Long-Term Course of Lipoprotein Lipase (LPL) Deficiency Due to Homozygous LPLArita in a Patient with Recurrent Pancreatitis, Retained Glucose Tolerance, and Atherosclerosis
J. Clin. Endocrinol. Metab.,
December 1, 2005;
90(12):
6541 - 6544.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Hoffmann, S. Jacob, D. Luft, R.-M. Schmülling, K. Rett, W. März, H.-U. Häring, and S. Matthaei
Type I Hyperlipoproteinemia Due to a Novel Loss of Function Mutation of Lipoprotein Lipase, Cys239{->}Trp, Associated with Recurrent Severe Pancreatitis
J. Clin. Endocrinol. Metab.,
December 1, 2000;
85(12):
4795 - 4798.
[Abstract]
[Full Text]
|
|
|
Top
Abstract
Introduction
