Subclinical chronic pancreatitis in type I hyperlipoproteinemia

Subclinical Chronic Pancreatitis in Type

I

Hyperlipoproteinemia

RONALD M. KRAUSS,

M.D.*

ARNOLD G. LEVY, M.D.+ Bethesda, Maryland

From the Molecular Disease Branch of the National Heart and Lung Institute, and the Digestive Disease Branch of the National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr. Ronald M. Krauss. Manuscript accepted February 23, 1976. * Present address: Donner Laboratory, University of California, Berkeley, California 94720. + Present address: Division of Gastroenterology, Department of Medicine, The George Washington University Medical Center, Washington, D.C. 20037.

144

January

1977

Severe pancreatic exocrlne insufficiency was demonstrated in a 41 year old man with famlllal type I hyperlipoproteinemla (fat-induced hyperlipemia). Plasma triglyceride concentration failed to increase significantly with increased dietary fat intake, and fecal fat excretion was markedly increased. Indices of intestinal function were normal. Pancreatic enzyme therapy resulted in reduced fat excretion and increased plasma triglyceride concentration. Secretin stimulation tests revealed impaired duodenal fluid volume, blcarbonate and pancreatic enzyme responses. Insulin-dependent diabetes mellitus had been diagnosed three years earlier. No attacks of acute pancreatitis had occurred in the preceding 20 years, and it is suggested that pancreatic damage may have resulted from repeated subclinical pancreatic insults due to elevated plasma lipid levels.. This report is the first to indicate that pancreatic exocrine insufficiency may occur as a late complication of hyperlipemic disorders in the absence of recurrent acute pancreatitis. Steatorrhea may not be apparent because of therapeutic restriction of dietary fat, and the first manifestation of pancreatic exocrine disease may be an amelioration of fat-induced hyperlipemia. The association of hyperlipemia with acute pancreatitis is well established [l-6]. There has been uncertainty as to whether lipid abnormalities are primary, secondary or unrelated to the development of pancreatic inflammation and damage. The premise that they have a primary role is supported by clinical observations that hypertriglyceridemia and, specifically, chylomicronemia can precede and apparently predispose patients to attacks of acute pancreatitis [1,4,7-lo] and that control of plasma triglyceride levels may prevent recurrent attacks [ 1,4,7]. One of the conditions in which hyperlipemia appears to precipitate attacks of acute pancreatitis is familial type I hyperlipoproteinemia [ 7,8]. This rare disease is characterized by hyperchylomicronemia due to impaired clearance of dietary fat [7,8,11]. The responsible metabolic defect appears to be reduced activity of lipoprotein lipase (a major determinant of chylomicron uptake from the blood) as measured in adipose tissue [ 121 and in plasma after the administration of heparin [ 11,13,14]. Control of chylomicronemia may be achieved by reducing dietary fat intake, but sustained normalization of plasma triglyceride concentration is rarely possible during outpatient treatment [B], and there is no conclusive information on the results of long-term dietary therapy. In this report we describe a patient with familial type I hyperlipoproteinemia in whom severe pancreatic exocrine insufficiency de-

The American Journal of Medicine

Volume 62

SUBCLINICAL

TABLE

I

Effect of Dietary

PANCREATITIS

Fat on Plasma Lipid Concentrations

AND HYPERLIPOPROTEINEMIA-KRAUSS.

LEVY

and Stool Fat Content Plasma Lioid Concentrations

D ietarv Date 1955 1965 1969 1970 1972 1973

1974 March

May

1975 March

Fat

No. of Davs’

(g/d&)

Stool

on Diet’

Triglyceride

Cholesterol 387

. . .

3.770 2,969 238 1,920 476 5,264 528 4,698 2,415 538

6;; 442 177

522 548 504 495 1,332 1,595 861 2,486 t

132 134 129 117 225 278 182 308 +

1,176 464 1,602

238 149 270

.

30-50 100 -200 100 30-50 100 30 loot

4 4 4

30-50 <5 100

5 4

l

veloped secondary to chronic pancreatitis prolonged symptom-free interval of dietary ment.

5 1 5

a;:1 a& 7;:;

t

ski.

of days prior

to the value listed was variable

during a manage-

CASE REPORT The patient

(g/day)

30-50 30-50 <5 30-50 <5 30-50 <5 30-50 30-50 <5

When dietary fat = 30 to 50 g/day, the number ? During pancreatic enzyme replacement

(r&/100 ml)

Fat

(N.I.H. No. 01-01-70-S) is a 41 year old black male employee at the National Institutes of Health (N.I.H.) who has had hyperlipemia since the age of seven [ 151. Prior to age 18 (but not since), he also had recurrent (four to five times a year) upper respiratory tract infections which were followed by abdominal pain, nausea and vomiting. Alcohol consumption did not exceed 12 ounces of beer per week. The patient’s past medical history is otherwise unremarkable, being free from documented gallbladder or biliary tract disease. In 1955 (at age 22), the patient was seen at N.I.H. for the first time. Hyperlipemia (Table I), sickle cell trait and normal oral glucose tolerance (Table II) were recorded at that time. Of the patient’s first degree relatives, three siblings had hyperlipemia, and his father was subsequently found to have diabetes mellitus. The patient and two affected brothers have been studied at the N.I.H. on multiple occasions since 1955 [ 8,11,13,14]. lipoprotein analyses were perforked on plasma obtained after an overnight fast using preparative and analytical ultracentrifugation, and paper and agarose electrophoresis, and observation of plasma allowed to stand at 4°C for 16 hours [7,8]. These studies showed that chylo-

238 108 1.4; 502

but was always

greater

than

30.

microns were the predominant lipoprotein species contributing to the lipemia observed when the patient consumed a fat-containing diet. Concentrations of very low density lipoproteins were increased to a much lesser extent. Chylomicronemia was shown repeatedly to disappear after removal of fat from the diet, with resultant marked reduction in plasma triglyceride concentrations (Table I). The syndrome comprising these abnormalities has been designated familial type I hyperlipoproteinemia [8]. References to this patient are included in other publications which further delineate the type I disorder[8,14]. The patient was treated with a fat-restricted diet beginning in 1955 and, although he has not always adhered strictly to TABLE

II

Oral Glucose Tolerance Tests Sept. 1973

Oct. 1955 Plasma Time (hr) 0 l/2 1 2 3 4 *Determined

January 1977

Plasma

Plasma

Glucose (mg/lOO ml)

Glucose (mg/lOO ml)

60 137 146 110 63 49

90 128 220 330 385

by radioimmunoassay

Insulin Wml)

*

12 20 15 22 30

[33].

The American Journal of Medicine

Volume 62

145

SUBCLINICAL PANCREATITIS AND HYPERLIPOPROTEINEMIA-KRAUSS,

the diet, he remained well until 1970, with the exception of one period of illness in 1961. This was characterized by generalized abdominal pain without nausea, vomiting or diarrhea. Evaluation at that time revealed Entamoeba histolytica and Giardia lamblia in the stool, 5 to 15 per cent eosinophilia and an elevated serum alkaline phosphatase level. Serum transaminase, lipase and amylase levels, an oral cholecystogram and an x-ray series of the upper gastrointestinal tract, including small bowel follow-through, were all within normal limits. Plasma triglyceride concentration after his admission was 532 mg/lOO ml, with absence of chylomicronemia. Physical examination and x-ray studies did not reveal any evidence of hepatosplenomegaly. As on previous examinations, no xanthomas were present. Although pancreatitis could not be excluded definitively, it appeared likely that this episode represented protozoan enteritis. In fact, antiamebic therapy resulted in clearance of parasites from the stool and relief of symptoms, although mild eosinophilia and elevated serum alkaline phosphatase levels have been noted intermittently since the time of treatment. In 1970, the patient was found to have mild hypertension. Evaluation at that time revealed normal electrolyte levels, no abnormalities on an intravenous pyelogram and normal levels of urinary vanillyl mandelic acid. In 1972, following three months during which his blood pressure-was controlled with chlorthalidone therapy, symptoms of polyphagia, polydipsia and polyuria developed, with a 6 kg weight loss. Plasma glucose had increased from a fasting level of 83 mg/lOO ml to 975 mg/ 100 ml. There had been no apparent precipitating illness, and no change in diet except for an increase in alcohol intake (to 12 ounces of beer per day) in the preceding year. The patient was hospitalized and treated with insulin, a diabetic diet and withdrawal of diuretic. At no time during the illness were ketones detectable in the urine, and plasma bicarbonate levels did not fall below 23 meq/liter. After one week, normal plasma glucose concentrations were maintained without insulin treatment, and the patient was discharged with instructions to adhere to a 2,000 calorie ADA diet containing 30 to 50 g of fat and 30 to 40 g of mediumchain triglycerides per day. After the patient was discharged, reserpine therapy was instituted and his blood pressure was controlled with a dose of 0.25 mg/day. Plasma glucose remained normal over the next three years until September 1973 when the concentratlon Increased to 383 mg/lOO ml during an acute viral respiratory tract infection. Again, there was no ketonuria or metabolic acidosis. Plasma glucose levels became normal after the administration of insulin and then remained normal with diet alone. The results of a glucose tolerance test performed at this time, however, were abnormal (Table II). In March 1974, left Ilngular pneumococcal pneumonia precipitated a third episode of nonketotic hyperglycemia. Although the pneumonia responded to penicillin treatment, daily insulin therapy (NPH 7 units; regular 2 units) had to be instituted in order to maintain adequate control of the patient’s diabetes. Upon hospitalization, it was noted that the patient’s plasma triglyceride concentration was lower than on previous admissions (Table I). Postheparin plasma lipoprotein lipase activity measured by a specific assay was markedly diminished and not significantly different from previous mea-

146

January

1977

The American Journal of Medicine

LEVY

surements (values listed in [ 141). Dietary fat tolerance was tested by increasing the patient’s fat intake from the 30 to 50 g/day range to 100 g/day for five days, and then to 200 g for an additional day. There was no resultant increase in plasma triglyceride concentration (Table I), and only faint chylomicronemia developed. The patient, however, noted the onset of lower abdominal discomfort and foul-smelling, floating stools on the fifth day of the 100 g fat per day diet. A 72hour fecal fat determination (100 g/day fat intake) revealed the excretion of 87.1 g/day. Serum carotene (147 pg/lOO ml) and d-xylose absorption (Bhour serum concentration = 80 mg/lOO ml) were both normal. In May 1974, the patient was readmitted to the N.I.H. for further investigation of his recently discovered steatorrhea and its possible relationship to his primary lipid disease. METHODS While the patient continued to adhere to his regular outpatient 2,000 calorie ADA diet containing 30 to 50 g/day of fat and 30 to 40 g/day of medium-chain triglycerides, numerous studies were undertaken to determine the existence of either maktigestion (secondary to pancreatic exocrine insufficiency) or malabsorption. The results of those studies are listed in the “Results” section. The d-xylose absorption test was performed by obtaining a 5-hour urine and a 2-hour serum sample following a 25 g oral load. A per oral jejunal mucosal biopsy specimen was obtained with a fluoroscopically-placed standard Rubin tube. Secretin tests were performed by intravenously administering 1 U/kg body weight of porcine secretin prepared by Boots Company Ltd. A 20-minute basal and four 20-minute postsecretin collections of duodenal fluid were obtained using a fluoroscopically-placed double-lumen Dreiling tube (for simultaneous and continuous manual aspiration of duodenal and gastric contents). Duodenal fluid obtained was analyzed for bicarbonate content [ 151, and amylase [17],lipase [18],trypsin [19],chymotrypsin [19] and carboxypeptidase [20] activities. Plasma cholesterol [21] and tryglyceride [22] concentrations were determined while the patient was consuming diets containing 20 per cent protein and 5,30 or 100 g of fat per day, with adjustment of carbohydrate intake to maintain constant body weight. Fecal fat determinations were performed during the administration of 100 g fat per day diets for three days, both wlth and without oral pancreatic enzyme therapy (Cotazyme, 2 capsules flve times/day). Variation in the standard fecal fat measurement was less than 5 per cent. RESULTS

Documentation of Pancreatic Exocrlne huff iclency. Pertinent laboratory data revealed normal hemoglobin, red blood cell indices, iron and total iron-binding capacity, protein electrophoresis and quantitative immunoglobulins, calcium, phosphorus, prothrombin time, liver chemistries, lipase and amylase. In addition, levels of both serum vitamin A (normal = 65 to 275 IU/lOO ml) and serum carotene (normal = X0 pgll00 ml) were normal at 235 IU/lOO ml and 178 pg/lOO ml, respectively. Three stool examinations and cultures revealed no pathogens, ova, parasites or occult blood.

Volume 62

SUBCLINICAL

An x-ray series of the upper gastrointestinal tract and small bowel follow-through revealed no abnormalities except for some minimal thickening of fold in the second and third portions of the duodenum. No calcifications in the pancreatic bed could be identified in any x-ray study, and results of a barium enema were within normal limits. A repeat d-xylose absorption test revealed 6.7 g&hour urine sample (normal = >5 g) and a e-hour serum concentration of 60 mg/lOO ml (normal = >40 mg/ 100 ml). Seventy-two hour fecal fat excretion was again increased (89.5 g/day). A jejunal biopsy specimen appeared entirely normal and was free of parasites. Secretin stimulation produced an abnormally low duodenal fluid volume response (1.4 ml/kg body weight/80 min; normal = >2.0 ml/kg body weight180 min), and a reduced bicarbonate response (never exceeding 24 meq/liter in any of four 20 minute samples; normal = >85 meq/liter), while amylase activity responded normally (20 Somogyi units/kg/min; normal = >6 Somogyi units/kg/min). Trypsin, chymotrypsin and carboxypeptidase activities, however, were not detectable in duodenal fluid either before or after the administration of secretin (simultaneously examined enzyme controls excluded the possibility of a faulty assay). Although lipase activity was detectable, interpretation of the data must await establishment of normal lipase values in duodenal fluid for the Searcy technic [ 181 employed by the N.I.H. laboratory. A rough estimate of the normal range may be derived from the results of Diamond et al. who measured lipase activity in Cherry-Crandall units [23]. Conversion of CherryCrandall units to Searcy units would appear justifiable, based on the correlation between these two methods shown for measurement of serum lipase [ 181. In the present study, the duodenal fluid lipase response (23.4 Searcy units/kg/80 min) falls well below the normal range extrapolated from the data of Diamond et al. [23] (2,400 Searcy units/kg/80 min). Plasma Lipid Concentrations as Affected by Dietary Fat and Pancreatic Enzyme Therapy (Table I). The data in Table I reveal that since 1955, plasma triglyceride concentration in this patient has been a function of dietary fat intake. However, when steatorrhea was first documented (March 1974), the patient’s plasma triglyceride concentration during intake of his maintenance 30 to 50 g/day fat diet was lower (522 mg/lOO ml) than on previous occasions (2,415 to 5,264 mg/ 100 ml). In addition, as indicated, there was no significant change (from 522 to 548 to 504 mg/lOO ml) in the plasma triglyceride concentration when dietary fat was increased to 100 and then 200 g/day. In May 1974, base line (30 to 50 g/day fat diet) plasma triglyceride was 1,332 mg/ 100 ml; an increase in dietary fat to 100 g/day once again produced minimal change in plasma

PANCREATITIS

AND HYPERLIPOPROTEINEMIA-KRAUSS,

LEVY

triglyceride concentration. Pancreatic enzyme replacement, however, resulted in a marked increase in triglyceride to 2,486 mg/lOO ml, with a simultaneous reduction in stool fat content from 89.5 to 72.7 g/day (100 g/day fat intake) (Table I). Enzyme treatment was discontinued after only four days to avoid possible complications of rapidly rising lipid levels. Follow-Up of Pancreatic Exocrine Function. In March 1975, 10 months after the initial studies, the secretin test was repeated to ascertain any changes in pancreatic exocrine status. Volume and bicarbonate responses were unchanged. Amylase activity was reduced to an abnormally low level (3 Somogyi units/ kg/80 min). Lipase activity was also lower (6.9 units/ kg/80 min) than on initial measurement. Trypsin, chymotrypsin and carboxypeptidase assays were not repeated. The result of a 72-hour fecal fat determination was similar to the values previously obtained (Table 1). COMMENTS Acute pancreatitis is known to occur in patients with fat-induced hyperlipemia [l-lo]. Development of chronic pancreatic insufficiency, however, has been reported previously in only two such patients, both of whom had a history of recurrent attacks of acute pancreatitis [7,24]. Our patient showed evidence of pancreatic exocrine insufficiency after a period of more than 20 years during which plasma triglyceride levels were repeatedly elevated and episodes of abdominal pain, suggestive of acute pancreatitis, were notably absent. Reduced fat absorption was first suspected when challenge with dietary fat failed to produce a significant increase in plasma triglyceride concentration. Stool fat excretion was subsequently shown to be markedly increased on three studies over the course of one year. Pancreatic enzyme replacement resulted in a 20 per cent reduction in fecal fat excretion and a concomitant increase in plasma triglyceride concentration. No evidence of primary intestinal disease was obtained as a consequence of x-ray, jejunal biopsy or d-xylose absorption studies. Serum carotene concentration (which was normal) did not provide an accurate measure of digestive capacity, particularly since intake of carotene-rich fruits and vegetables was high, and clearance of dietary fat from the blood was deficient in this patient. Further documentation of pancreatic exocrine impairment was provided by secretin stimulation tests. Possible inaccuracies in duodenal fluid bicarbonate and enzyme measurements due to contaminating gastric fluid [25] were minimized in these studies by use of a fluoroscopically-placed double-lumen tube for separate manual gastric and duodenal aspirations. Duodenal fluid

January 1977

The American Journal of Medicine

Volume 62

147

SUBCLINICAL

PANCREATITIS

AND HYPERLIPOPROTEINEMIA-KRAUSS,

volume and bicarbonate responses were significantly reduced on two separate tests, and were compatible with the findings reported in patients with long-standing pancreatitis [26,27]. Trypsin, chymotrypsin and carboxypeptidase activities were not detectable in duodenal fluid either before or after the administration of secretin. The amylase response, normal initially, was reduced on retesting 10 months later. The lipase response, detectable on both occasions, appears to have been abnormally low; however, the assumed normal range requires validation using the present assay method. The foregoing studies suggest that absorption of dietary fat in this patient was limited by reduced pancreatic exocrine function. Since clearance of plasma chylomicrons is severely impaired in the type I disorder [7,&l 11, small changes in dietary fat digestion and subsequent absorption may result in disproportionately large changes in plasma triglyceride concentrations. This phenomenon may account for the observed fluctuations in plasma lipid levels when the same diet was fed on different occasions (Table I). Although clinical and experimental data suggest that pancreatic damage can result from hyperlipemia [ 1,4,7-l 0,281, it has been proposed by some investigators that pancreatitis itself may elevate plasma lipid levels [29-311. Inhibition of lipoprotein lipase, detected in the presence of certain forms of clinical [29,30] and experimental [32] pancreatitis, has been suggested as a possible mechanism for this phenomenon. In patients with type I hyperlipoproteinemia, however, the deficiency of lipoprotein lipase is a primary disorder which is often detected in early infancy [8]. Furthermore, evidence has recently been brought forth suggesting that many other patients with acute pancreatitis and

LEVY

hyperlipemia have underlying disorders of lipid metabolism not necessarily associated with reduced lipoprotein lipase activity [6]. It, therefore, seems likely that pancreatic damage in this patient resulted from chronic or recurrent increases in plasma chylomicron concentrations. The mechanism may be similar to that responsible for the development of acute pancreatitis. It has been suggested [7] that high chylomicron levels may result in exposure of large amounts of triglyceride to lipase in pancreatic capillaries and interstitial fluid. Subsequent enzymatic hydrolysis with release of free fatty acids might then initiate an inflammatory reaction in the pancreas. In the present case, small repeated insults may have resulted in progressive destruction of pancreatic tissue, without producing a clinical episode of acute pancreatitis. The appearance of insulindependent diabetes mellitus three years prior to the diagnosis of pancreatic exocrine insufficiency may represent another manifestation of extensive pancreatic damage, although familial factors may also have been contributory. Development of exocrine pancreatic disease over the past several years may well have been obscured by therapeutic restriction of dietary fat intake with consequent reduction of steatorrhea. In fact, the development of chronic pancreatitis with reduced fat digestion and absorption is a complication which may prove to protect this patient from additional medical problems produced by his primary lipid disease. ACKNOWLEDGMENT We appreciate the assistance of Dr. Peter Herbert in carrying out the inpatient studies. Plasma insulin assays were kindly performed by Dr. Phillip Gorden.

REFERENCES 1.

2. 3.

4. 5.

6.

7. 8.

148

Klatskin G, Gordon M: Relationship between relapsing pancreatitis and essential hyperlipemia. Am J Med 12: 3, 1952. Wang C, Adlersburg, D, Feldman EB: Serum lipids in acute pancreatitis. Gastroenterology 36: 832, 1959. Greenberger NJ, Hatch FT, Drummey GD, et al.: Pancreatitis and hyperlipemia-a study of serum lipid alterations in 25 patients with acute pancreatitis. Medicine (Baltimore) 45: 161, 1966. Farmer RG. Winkelman El, Brown HB, et al.: Hyperlipoproteinemia and pancreatitis. Am J Med 54: 161, 1973. Cameron JL, Capuzzi DM, Zuidema GD, et al.: Acute pancreatitis with hyperlipemia-the incidence of lipid abnormalities in aucte pancreatitis. Ann Surg 177: 483, 1973. Cameron JL, Capuzzi DM, Zuidema GD, et al.: Acute pancreatitis with hyperlipemia-evidence for a persistent defect in lipid metabolism. Am J Med 56: 482, 1974. Have1 RJ: Pathogenesis, differentiation, and management of hypertriglyceridemia. Adv Intern Med 15: 117, 1969. Fredrickson DS, Levy RI: Familial Hyperlipoproteinemia. Metabolic Basis of Inherited Disease. (Stanbury JB, Wyn-

9.

10.

11.

12.

13.

14.

January 1977 The American Journal of Medlclne Volume 62

gaarden JB, Fredrickson DS, eds), New York, McGraw-Hill, 1972, p 545. Glueck CJ, Scheel D, Fishback J: Estrogen-induced pancreatitis in patients with previously covert type V hyperlipoproteinemia. Metabolism 21: 657, 1972. Brunzell JD, Schrott HG: Interaction of familial and secondary causes of hypertriglyceridemia. Role in pancreatitis. Clin Res 21: 723, 1973. Have1 RJ, Gordon RS Jr: Idiopathic hyperlipemia. Metabolic studies in’an affected family. J Clin Invest 39: 1777, 1960. Harlan WT Jr, Winesett PS, Wasserman AT: Tissue lipoprotein lipase in normal individuals and in individuals with exogenous hypertriglyceridemia and the relationship of this enzyme to assimilation of fat. J Clin Invest 46: 239, 1967. Fredrickson DS, Ono K, Davis LL: Lipolytic activity of postheparin plasma in hyperglyceridemia. J Lipid Res 4: 24, 1963. Krauss RM, Levy RI, Fredrickson DS: Selective measurement of two lipase activities in postheparin plasma from normal

suBci_lNlc~L PANCREAT~TI~AND HYPERL~POPROTE~NEMIA-KRAUSS, LEVY

15.

16.

17.

18.

19.

20. 21.

22.

23.

subjects and patients with hyperlipoproteinemia. J Clin Invest 54: 1107, 1974. Gaskins AL, Scott RB, Kessler AD: Report of three cases of idiopathic familial hyperlipemia. Use of ACTH and cortisone. Pediatrics 11: 480, 1953. Skeggs LT Jr: An automatic method for the determination of carbon dioxide in blood plasma. Am J Clin Patho133: 181, 1960. O’Neal WR, Gochman N: An automated saccharogenic method for determining serum amylase activity. Clin Chem 16: 985, 1970. Seamy RJ, Shinichiro H, Berk JE: A modified technique for serum lipase determination. Clin Biochem 1: 311, 1968. Schwert GW, Takenaka Y: A spectrophotometric determination of trypsin and chmyotrypsin. Biochim Biophys Acta 16: 570, 1955. Bergmeyer HU, ed: Methods of Enzymatic Analysis, vol. 2, Academic Press, 1974, p 993. Technicon Corporation: Total cholesterol procedure N-24A. AutoAnalyzer Manual, Ardesley, N.Y., Technicon Corporation, 1964, p 345. Kessler G, Lederer H: Fluorometric measurement of triglycerides. Automated Analytical Chemistry Techniques Symposium, 1966, p 341. Diamond JS, Siegel SA, Gall MB, et al.: The use of secretin as a clinical test of pancreatic function. J Digest Dis 6: 366, 1939.

24.

25. 26.

27.

28. 29.

30.

31. 32.

33.

January 1977

Salen S, Kessler JI, Janowitz HD: The development of pancreatic secretory insufficiency in a patient with recurrent pancreatitis and type V hyperlipoproteinemia. Mt. Sinai J Med 37: 103, 1970. Wormsley KG, Goldberg DM: The interrelationships of the pancreatic enzymes. Gut 13: 398, 1972. Dreiling DA, Janowitz HD, Perrier CV: Pancreatic Inflammatory Disease-a Physiologic Approach. New York, Harper & Row, 1964, p 129. Burton P, Evans DG, Harper AA, et al.: A test of pancreatic function in man based on the analysis of duodenal contents after administration of secretin and pancreozymin. Gut 1: 111, 1960. Haig THB: Experimental pancreatitis intensified by a high fat diet. Surg Gynecol Obstet 131: 914, 1970. Kessler JI, Kniffen JC, Janowitz HD: Lipoprotein lipase inhibition in the hyperlipemia of acute alcoholic pancreatitis. N Engl J Med 269: 943, 1963. Stackhouse KL, Glass DD, Zimmerman B: Relationships of lipoprotein lipase and hyperlipemia in pancreatitis. Surg Forum 17: 343, 1966. Wang C, Strauss L, Adlersberg D: Experimental pancreatitis and plasma lipids. Gastroenterology 35: 465, 1958. Kessler Jl, Finkel M, Ho P, Janowitz HD: Lipoprotein lipase inhibition in rabbits with experimental pancreatitis. Proc Sot Exp Biol Med 110: 24, 1962. Yalow RS, Berson SA: Immunoassay of endogenous plasma insulin in man. J Clin Invest 39: 1157, 1960.

The American Journal of Medicine

Volume 62

149