Hyperlipidemic gestational pancreatitis

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GASTROENTEROLOGY Vol. 104, No. 5

9. Bushman E, Arceci RJ, Croop JM, Che M, Arias IM, Gousman DE, Gros P. Mouse mdr2 encodes P-glycoprotein expressed in the bile canalicular membrane as determined by isoform specific antibodies. J Biol Chem 1992;267: 18093- 18099. 10. Yahanda AM, Adler KM, Fisher GA, Brophy NA, Halsey J, Hardy RI, Gosland MP, Lum BL, Sikic BI. Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance. J Clin Oncol 1992;1624-1634. 11. lshikawa T, Muller M, Klunemann C, Schaub T, Keppler D. ATPdependent primary active transport of cysteinyl leukotrienes across liver canalicular membrane. Role of the ATP-dependent transport system for glutathione S-conjugates. J Biol Chem 1990;265: 19279- 19286. 12. Kitamura T, Jansen P, Hardenbrook C, Kamimoto Y, Gatmaitan 2, Arias IM. Defective ATP-dependent bile canalicular transport of organic anions rn mutant (TR-) rats with conjugated hyperbilirubinemia. Proc Natl Acad SCI USA 1990;87:3557-3561. 13. Kobayashi K, Sogame Y, Hara H, Hayashi K. Mechanism ofglutathione S-conjugate transport in canalicular and basolateral rat ltver plasma membrane. J Biol Chem 1990;265:7737-7741. 14. Nishida T, Hardenbrook C, Gatmaitan Z, Arias IM. ATP-dependent multi-specific organic anion transport system in rat liver canalicular membrane. Am J Physiol 1992;262:4. 15. Oude Elferink RPJ, Ottenhoff R, Liefting W, Haan JD, Jansen PLM. Hepatobiliary transport of glutathione and glutathione conjugate in rats with hereditary hyperbilirubinemia. J Clin Invest 1989;84:476-483. 16. Nishida T, Che M, Gatmaitan Z, Arias IM. Evidence for a single

ATP and membrane potential-dependent taurocholate transport system in rat liver canalicular membrane vesicles. Hepatology 1992;16:195. 17. Nishida T, Gatmaitan Z, Roy-Chowdhury J, Arias IM. Two distinct mechanisms for biltrubin glucuronide transport by rat bile canalicular membrane vesicles. J Clin Invest 1992;90:2 130-2 135. 18. Pflugl G, Kallen J, Schirmer T, Jansonius JN, Zurini MGM, Walkinshaw MD. X-ray structure of a decameric cyclophilin-cyclosporin crystal complex. Nature 1993;36 1:9 1. 19 Sippel CJ, Ananthanarayanan M, Suchy FJ. Isolation and characterization of the canalicular membrane bile acid transport protein of rat liver. Am J Physiol 1990;258:G728-G737. 20 Zimniak P, Ziller SA, Panfil I, Radominska A, Wolters H, Kuipers F. Sharma R, Saxena M, Moslen MT, Vore M, Vonk R, Awasthi YC, Lester R. Identification of an anion-transport ATPase that catalyzes glutathione conjugate-dependent ATP hydrolysis rn Canalicular plasma membranes from normal rats and rats with conjugated hyperbilirubinemia (GY mutant). Arch Biochem Biophys 1992;292:534-538. 21 Watanabe N, Tsukada N, Smith CR, Phillips MJ. Motility of bile canaliculi in the living animal: implications for bile flow. J Cell Biol 1991;l 13:1069-1080.

Address requests for reprints to: Irwin M. Arias, M.D., Department of Physiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02 111. 0 1993 by the American Gastroenterological Association

Hyperlipidemic Gestational Pancreatitis

P

regnancy

produces

tabolism.

Serum triglyceride

logically third

during

trimester

many changes

gestation

levels increase

and appear

of pregnancy.

in maternal to peak

l-9 During

me-

physioin the

pregnancy,

both very low-density lipoprotein (VLDL) and lowdensity lipoprotein (LDL) triglyceride levels increase significantly. This phenomenon is similar to that found with oral contraceptive preparations’ but occurs to a greater triglyceride

extent and with an even lower cholestrol/ ratio. Several factors have been proposed

to explain this observation, including estrogenic effect and increased transport of VLDL from the liver into the circulatioq3 decreased lipoprotein lipase activity or apoprotein C-II levels,‘,’ overproduction of VLDL, increased mobilization of free fatty acids from adipose tissue to the liver, skeletal muscle, and uterus, and increased circulating triglyceride levels in preparation for postpartum milk production.’ The increases in both triglyceride and cholesterol levels correlate with 17P-estradiol, progesterone, human chorionic gonadotropin, human placental lactogen, and insulin levels.4 Pregnancy also increases free fatty acid transport, but not triglyceride transport, across the placenta. Fetal triglyceride levels decrease exponentially during gestation, according to a study by Economides et al. based

on blood correlation

obtained

with maternal

interpretation triglyceride cron

via cordocentesis.”

that occurs

triglyceride

triglyceride

no significant across

This

lack of

levels favors the transport

the placenta.

of intact

Net chylomi-

removal is similar to that found in state. 3 The total serum triglyceride

the nonpregnant level, although higher in normal pregnancy, is usually less than 300 mg96. This elevation is not sufficient to cause acute pancreatitis, however. Pancreatitis is a well-known complication of severe Hypertriglyceridemia causes hypertriglyceridemia. pancreatitis by an unknown mechanism. Most cases of severe hypertriglyceridemia (levels >2000 mg?/o) are a result of abnormalities of either apoprotein (apo) C-II or lipoprotein lipase metabolism.“~‘2 Fully functional apoprotein C-II is necessary for optimal lipoprotein lipase activity. Mutations in the apo C-II gene produce abnormal messenger RNA premature stop codons, splicing, and abnormal initiation of protein translation that result in dysfunctional or absent apo C-II Several lipoprotein lipase gene mutations proteins.“,12 may result in dysfunctional or absent lipoprotein lipase activity. A circulating lipoprotein lipase inhibitor has also been identified. The classic (type I) hyperlipidemit phenotype includes the onset of attacks of pancre-

May 1993

EDITORIALS

atitis in childhood megaly,

hyperchylomicronemia,

eruptive

xanthomas.

lipoprotein or normal

These

levels,

lipemia individuals

depending

retinalis, often

and

have no

on the genotype.

is autosomal-dominant,

The more microns

hepatospleno-

lipase activity and normal apo C-II levels, lipoprotein lipase activity and low or absent

apo C-II tance

and may also include

common

and the disorder

type V (elevations

and VLDL)

Inheri-

of both

hypertriglyceridemic

tein lipase activity

may be normal,

may be higher.

tacks of pancreatitis triglyceride

in adulthood,

levels

are

VLDL at-

elevated

as

During

pregnancy,

gestation

idemia?

mother acute preg-

mortal-

acute pancreatitis (of any etiology) is rare. How often is pancreatitis

directly

In one report,

cases of pancreatitis

attributable Jouppila

to hypertriglycer-

et al. noted

of any etiology

over

Lipapheresis

uses a

that removes only large-mo(such as lipoproteins) from

immunoglobulins,

albumin,

and

factors.

Relapses

of pancreatitis

may

be prevented

in the serum is lowered

to extreme

if the

in patients

hypertriglyceridemia.

Treat-

ment regimens have included low-fat diet (<20 g/ day),‘3>‘s,‘: total parenteral nutrition,‘* and plasma exchange. In this issue of GASTIIOENTEROLOGY, Swoboda tional

et al. report

using

exchange

alone,

plasma alone,

their

pancreatitis and

results

three

immunospecific

apheresis

of both

woman

with

methods.”

of pancreatitis;

had failed. This unique treatment

has many

Their

type V hyperlipo-

in her 24th week of pregnancy,

an attack

gesta-

modalities:

a combination

a 23-year-old

in treating

different

subsequent

had had

dietary

therapy

case shows that this method advantages

over

total

of

parenteral

nutrition and total plasma exchange. First, a central line is not necessary-the apheresis uses a peripheral venovenous approach. Second, the risks of standard plasma exchange include bleeding and infection.

only eight

Third,

an &year

fit apheresis. These investigators used an apheresis column coated with anti-apo B antibodies. Apheresis re-

period encompassing over 16,000 deliveries.15 None of the patients were taking thiazide diuretics or other drugs that cause acute pancreatitis. cases were thought to be secondary

successfully.

retaining

proteinemia

pancreatitis

to both

in a 20% rate of maternal

pregnancy

during

of acute

consequences

child. The literature suggests that secondary to hyperlipidemia during

nancy may result ity. 13,14Fortunately, during

an attack

devastating

and unborn pancreatitis

clotting

patient,

type I patients. may have

the plasma,

predisposed

but have

that are not as severely

method complexes

chylo-

may develop however,

double-filtration lecular-weight

level of triglycerides

patients

and hepatic

Patients

used

is rare.

often diabetic, obese, and hyperuricemic. Clearance of triglyceride carrying lipoproteins is reduced, lipoproproduction

sis’” has been

1561

Five of the eight to cholelithiasis

serum

protein

loss is small with immunospeci-

moved both cholesterolfrom the plasma with

and triglyceride-rich particles a high degree of success and

specificity, because VLDL B-100 and chylomicrons

(besides LDL) contains apo carry apo B-48. Immuno-

and were treated surgically. None of the patients in this series died, but there were three fetal deaths. Unfortunately, this series did not give serum triglyceride

pheresis should be considered in any pregnant patient with hypertriglyceridemic pancreatitis who shows no

levels

response

mise

in the cases of pancreatitis. that

three

hyperlipidemia. women

of the

One

cases may

Lykkesfelt

can only

have

been

followed

with type V hyperlipidemia

up

during

sur-

due to on

five

pregnancy,

but only one of them developed acute pancreatitis.” De Chalain et al. reported on three pregnant patients with type I hyperlipidemia and low lipoprotein lipase activity with triglycerides ranging from mg?h.13 One patient died of fulminant pancreatitis;

the other

two responded

3000 to 8000 hemorrhagic

to restricted

fat

intake..12 Glueck et al. followed up on three women during gestation: two patients with type V hyperlipidemia and one with type III hyperlipidemia. All responded to dietary manipulation and all pregnancies went to term with normal deliveries.” Sanderson et al. also described a hyperlipidemic pregnancy that was carried to term successfully with diet therapy alone.14 When dietary therapy fails, modalities such as total parenteral nutrition’* and lipaphere-

to dietary

Although sparse,

most

therapy.

the data on pancreatitis cases are secondary

in pregnancy

to gallstone

are

passage.

After gallstone-induced pancreatitis is ruled out, any patient with an attack of acute pancreatitis with fasting lipemic serum levels during pregnancy should undergo lipoprotein electrophoresis. Specific evidence of deficient or abnormal forms of apo C-II or lipoprotein lipase can be determined if the electrophoresis shows increases in levels of chylomicrons and VLDL. INC;RAM hf.ROBERTS Division of Gastroenterologl! Department of Medicine George Washington Universi?y Medical Center Washington, D. C.

References 1. Herrera E, Gomez-Coronado D, Lasuncior- MA. Lipld metabolism In pregnancy. Biol Neonate 1987;51:70-77.

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EDITORIALS

2. Herrera E, Lasuncion MA, Gomez-Coronado D, Aranda P, LopezLuna P, Maier I. Role of lipoprotein lipase activity on lipoprotem metabolism and the fate of circulating triglycerides in pregnancy. Am J Obstet Gynecol 1988; 158: 1575- 1583. 3. Knopp RH, Warth MR, Charles D, Childs M, Li JR, Mabuchi H, Van Allen Ml. Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate 1986;50:297-3 17. 4. Desoye G, Schweditsch MO, Pfeiffer KP, Zechner R, Kostner GM. Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum. J Clin Endocrinol Metab 1987;64:704-7 12. 5. Fahraeus L. Larsson-Cohn U, Wallentin L. Plasma lipoproteins including high density lipoprotein fractions during normal pregnancy. Obstet Gynecol 1985;66:468-472. 6. Knopp RH, Bergelin RO, Wahl PW, Walden CE. Effects of pregnancy, postpartum lactation, and oral contraceptive use on the lipoprotein cholesterol/triglyceride ratio. Metabolism 1985;34: 893-899. 7. Darmady JM, Postle AD. Lrpid metabolism In pregnancy. Br J Obstet Gynecol 1982;89:2 1 l-2 15. 8. Ordovas JM, Pocovi M, Grande F. Plasma lipids and cholesterol esterification rate during pregnancy. Obstet Gynecol 1984;63: 20-25. 9. Rosing U, Samsioe G, Olund A, Johansson B, Kallner A. Serum levels of apolipoprotein A-l, A-II and HDL-cholesterol in the second half of normal pregnancy and in pregnancy complicated by pre-eclampsia. Horm Metabol Res 1989;2 1:276-382. 10. Economides DL, Crook D, Nicolaides KH. Hypertriglyceridemia and hypoxemia tn small-for-gestational-age fetuses. Am J Obstet Gynecol 1990; 162:382-386. 11. Fojo SS, Brewer HB. Hypertriglycemia due to genetic defects in lipoprotein lipase and apolipoprotein C-II. J Intern Med 1992;23 1:669-677. 12. Chait A, Brunzell JD. Chylomicronemia syndrome. Adv intern Med 1992;37:249-273.

GASTROENTEROLOGY Vol. 104, No. 5

De Chalain nancy and 473. 14. Sanderson pregnancy.

13.

TMB, Mrchell WL, Berger GMB. Hyperlipidemla, pregpancreatitis. Surg Gynecol Obstet 1988; 167:469SL, lverius P-H, Wilson DE. Successful hyperlrpemic JAMA 199 1;265:1858- 1860.

15. Jouppila P, Mokka R, Larmi TKI. Acute pancreatibs in pregnancy. Surg Gynecol Obstet 1974; 139:879-882. 16.

Lykkesfeldt G, Bock JE. Pedersen FD, Memertz H, Faergeman 0. Excessive hypertriglyceridemia and pancreatitis in pregnancy: association with lipoprotein lipase deficiency. Acta Obstet Gynecol Stand 1980;60:79-82.

17. Glueck CJ, Christopher C, Mishkel MA, Tsang RC, Melltes MJ. Pancreatitis, familial hypertriglyceridemia and pregnancy. Am J Obstet Gynecol 1980; 136:755-76 1, 18. Weinberg RB, Sitrin MD, Adkms GM, Lin CC. Treatment of hyperlipidemic pancreatitis in pregnancy with total parenteral nutrition. Gastroenterology 1982;83: 1300- 1305. 19. Achard JM, Westeel PF, Moriniere P, Lalau JD. de Cagny B, Fournier A. Pancreatitis related to severe acute hypertriglycendemia during pregnancy: treatment with lipoprotein apheresrs. Intensive Care Med 199 1;17:236-237. 20.

Swoboda K, Derfler K, Koppenstemer R, Langer M, Pamberger R, Brehm R, Ehringer H, Drum1 W, Widhalm K. Extracorporeal lipid elimination for treatment of gestational hyperlipidemic pancreatitis. Gastroenterology 1993; 104: 1527- 153 1.

Address requests for reprints to: Ingram M. Roberts, M.D., Division of Gastroenterology, Department of Medicine, George Washington University Medical Center, Room 5-401, 2150 Pennsylvania Avenue Northwest, Washington, D.C. 20037. Supported by the National Institutes of Health (FIRST Award R29DK38729). The author thanks Drs. John LaRosa and William Steinberg for helpful comments.