Recurrent Parotid Swelling, Arterial Hypertension, and Pancreatitis

Vol. 55, No.2 Printed in U .S.A.

GAsTROENTEROLOGY

Copyright© 1968 by The Williams & Wilkins Co.

CASE REPORTS

RECURRENT PAROTID PANCREATITIS

SWELLING,

ARTERIAL

HYPERTENSION,

AND

JoN I sENBERG, M .D., AN D JAMES D. BoYLE, M.D.

Medical Service, Wadsworth Hospital, Veterans Administration Center, Los Angeles, California, and Department of Medicine, University of California, Los Angeles, School of Medicine, Los Angeles, California

For the past 8 years we have observed a patient with the unique association of recurrent attacks of pancreatitis and transient arterial hypertension, preceded by parotid gland enlargement and hypersalivation. The combination of parotid enlargement with pancreatic insufficiency has been described, usually in association with malnutrition,I- 4 but the parotid enlargement of these earlier reports was not transient, nor was it associated with hypertension. In our patient, investigation has failed to suggest a mechanism for this association. Case Report C. C., a 24-year-old Negro male, was first admi tted to Wadsworth Hospital on September 9, 1959, with a 4-day history of continuous deep epigastric pain radiating to the back, which began after a 24-hr period of unusually heavy alcohol intake, and a large spicy meal. Two similnr episodes of pain of lesser severity, RP-ccived D ccemhPr 13, 1967. Accepted M arch 2 1968. Add rPss requests for reprin ts to: J . D. Boyle, M.D ., Warl swo rth Hospital, Vete rans Administration Center, Los Angeles, California 90073 . This work was supported by Veterans Administration research funds. The authors are indebted to Doctor Morton I. Grossman for performing the enzyme determinations on the duodenal aspirates, to Doctor R. M . Blizzard (Department of Pediatri cs, Johns Hopkins Hospital, Baltimore, Maryland) for performing the anti tissue antibody studies, and to Doctor E. Barnett (Department of M edicine, University of California, Los Angeles, M edical School, Los Angeles, California) for performing t he immunoelectrophoretic studies. 277

for which he did not seek medical advice, had occurred within the previous 7 months. The patient had consumed large quantities of alcohol since his discharge from the Marine Corps in 1957. He had no prior history of gastrointestinal symptoms. There was no previous known hypertension ; nor was there a family history of hypertension, diabetes mellitus, pancreatitis, or parotid enlargement. He had mumps as a child. Pertinent physical findings included an arterial blood pressure of 240/160 mm Hg and deep epigastric tenderness. The parotid glands were not enlarged on this occasion. The hemogram and serum calcium, phosphorus, transaminase, bilirubin, protein bound iodine, and blood glucose were normal, as were the hemoglobin electrophoresis and urine porphobilinogen . Chest X-ray, upper gastrointestinal series, and electrocardiogram were not remarkable. The init ial urinalysis disclosed 3-plus protein, but subsequent urinalyses were normal. The serum amylase was 208 Somogyi units per 100 ml on admission and 136 units 48 hr later (normal 60 to 160 units) . He wa s t reated with a liquid diet, atropin e, meperidine, phenobarbital, and antacids . Symptoms abated within 48 hr, and the blood pressure decreased to 140/ 00 mm Hg. In August and September of 1960 the patient wa s admitted for two further episodes of acute pancreatitis. Each followed excessive alcohol intake and was associated with transient arterial hypertension. Parotid enlargement was not observed on either of t hese hospitalizations. In December of 1960, prior to his fourth admission, the patient experienced increased salivary secretion and bilateral parotid gland enlargement 3 hr before the onset of his typical abdomina.! pain. Physical examination disclosed that both parotid glands were swollen to approximately 3 times normal size; they re-

278

Vol. 55, No. 2

CASE REPORTS

Fw. 1. The usual appearance of an enlarged parotid gland accompanymg an attack of pancreatitis.

turned to normal size in 24 hr. Pancreatic calcification was observed for the first time and it has persisted. Since that admission, he has discontinued all alcohol intake. On subsequent admissions, bilateral parotid enlargement (fig. 1) and increased salivation preceded almost every attack of pancreatitis by 3 to 6 hr (fig. 2). Arterial hypertension (160/ 140 to 190/ 160 mm Hg) has also been present with almost every attack of pancreatitis, but has disappeared on bed rest alone within the first week of each hospitalization. On the 13th and three subsequent admissions, bilateral tender testicular enlargement was noted which resolved within 72 hr. In .Tannary 1965, upper gastrointestinal radiographs first disclosed anterior displacement of the stomach. Oral cholecystogram and intravenous cholangiograms were normal. In May 1965, the patient had a severe episode of hrmatemesis and melena which was treated surgically. At operation, the body and tail of the pancreas were enlarged and firm, and the duodenal bulb was scarred and thickened. The bleeding site was not identified. A vagotomy and pyloroplasty were performed. During the patient's 26th admission for pancreatitis, in December 1965, a pulsatile epigastric mass and left upper quadrant bruit were noted. Celiac axis angiography disclosed communication of the splenic artery with a cystic mass in the midpancreatic area.• Splenectomy was performed, with ligation of

the splenic artery on either side of the false aneurysm. Biopsy of the pancreas disclosed chronic inflammatory cell infiltration with moderate fibrosis. The gall bladder and common bile duct were normal. An operative pancreaticogram did not demonstrate ductal obstruction. The sphincter of Oddi was incised for a distance of 1 em. In March 1966 steatorrhea appeared, for which he has been given pancreatin, one tablet hourly during the day. In May 1966 prednisone, 40 mg daily, was begun as a therapeutic trial, following which he developed overt diabetes requiring insulin for control. The attacks of parotid enlargement, transient arterial hypertension, and acute pancreatitis continued without change and, after 4 months, the prednisone was discontinued. The attacks persist to the present and he requires intermittent hospitalization every 2 to 5 months.

Special Studies Pancreas. Seventy-two-hour stool fatty acid determinations by the van de Kamer method• have ranged from 7 to 217 mEq per 72 hr (normal less than 56). While on pancreatin, stool fat was 41 mEq per 72 hr. Duodenal drainage 2 hr after a Lundh test meal showed the concentrations of chymotrypsin, trypsin, and lipase to be 8.3, 24.8, and 42.9 p.moles per ml per min, respectively (lower limits of normal = 82, 103, and 278 p.moles per ml per min, respectively)." Duodenal aspiration following secretin (Vitrum) stimulation, 1 unit per kg, was as follows: volume = 3.3 ml per kg per 80 min; 28 mEq maximum bicarbonate concentration per ml ; maximum ch~·motrypsin and trypsin 10 :md 37 p.moles per ml per concentrations min , rr~pr ct ivcly. Oral glucose tolerance test in November Hl6n gave fasting, 1-, 2-, and 3-hr values of 160, 405, 320, and 260 mg per 100 ml, respcctiYcly. These studies indicated both exocrine and endocrine pnncreatic insufficiency. Structnrnl evaluation of the pancreas has included several upprr gastrointestinal radiographs, celiac :1xis angiography, direct examination of the pancrens nt surgery on two occasions, :1nd pancreatic biopsy. There was gross and histological evidence of nonspecific chronic pancreatitis and communication of a pancre:1tic pseudocyst with a false aneurysm of the splenic artery. Parotid. On almost every admission when parotid enlargement wns associated with acute pancreatitis, profuse hypersalivation was observed. X o quantitative :malysis was made of the salivar~· juice under these circumstances.

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August 1968

279

CASE REPORTS ACUTE PANCREATITIS

ARTERIAL '1 HYPERTENSION ,

II IIIII I I I I

II

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1960

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1. UPPER G I BLEED VAGOTOMY & PYLOROPLASTY 2. PAROTID BIOPSY 3. RESECTION OF SPLENIC ARTERY "FALSE" ANEURYSM

4. PREDNISONE 40 mg./d.

Fw. 2. This chart represents the course over the past 8 years. The darkened areas indicate the presence of acute pancreatitis, arterial hypertension, parotid enlargement, or testicular enlargement; as listed on the left of the chart. Empty boxes represent the absence of these findings. The 'bar graph in the lowest line demonstrates the highest serum amylase during that particular admission. Numbers 1 through 4 indicate diagnostic or therapeutic procedures, as listed at the bottom of the chart.

During October 1965 a parotid biopsy was performed but it failed to disclose any definite abnormality. In September 1966, during a symptom-free period, each parotid duct was cannulated and pooled juice was collected during a 30-min basal period and for two 30-min periods of continuous lemon juice stimulation. The basal volume was less than 3 ml per 30 min. Pooled volume for both glands during the hour of stimulation wns 77 mi. During stimulation, parotid juice concentrations of sodium, potassium, nnd bicarbonate were 55, 16, and 14.5 mEq per liter, respectively; protein concentration wns 0.11 g per 100 ml, and amylase was 3450 Somogyi units per mi. A sialogram demonstrated borderline accentuation of the fine duct:1l radicles, but was otherwise normal. In .Tul~· 1967 parotid juice was collected following intr.wenous administr:1tion of 5 mg of pilocarpine. Twelve milliliters were collected during th0 5 min following inj0ction (norm:1l 3 to 12 m])s

=

Although there wns consistent h~· pers~liva­ tion with e:1ch :1ttack of p:1ncre:1titis nnd the si:1 logmm w:1~ on the borderline of abnormality, p:1 rotid structure :1nd function were otherwise normaL Liver. M:1ny liver function tests h:1ve been performed during the p:1st 8 ye:1rs. These have included: serum bilirubin, serum glutamic ox:1lopyruvic trans:1.minase, serum glutamic p~· ruvic tmnsamin:1se, thymol turbidity, ceph:llin flocculation, alkaline phosphatase, total protein, and serum protein electrophoresis, total :1nd fractional serum lipids, nnd Bromsulph:1lein excretion. These studies have all been within normal limits. Percutaneous liver biopsy,

performed in December 1965, was entirely normaL There has been no evidence of hepatomegaly on examination or other stigmata of liver disease. Arterial hypertension. Investigations included serial urinalyses, creatinine clearances, urine cultures, electrolyte determinations, urinary excretion of 17-hydroxysteroids and urine vanillo-mandelic acid, Regitine tests, rapid sequence intravenous pyelograms, and radioactive renogram. Except for initial albuminuria these studies have been within normal limits. Immunological status. Serum protein electrophoreses, serum immunoelectrophoresis in agar, lupus erythematosus cell preparations, latex fixation tests, examination of serum for antibodies and for antithyroid, antigastric, and antiadrenal antibodies have all been normaL Nutrition. Prior to December 1960, and while t he patient wns consuming large amounts of alcohol, dietary intake had been poor. For the past 6 years and since discontinuing all alcohol, his nutritional intake, however, has been good. Physical examinations have failed to demonstrate any stigmata of malnutrition, and serial body weights have remained essentially un· changed.

Discussion Causes of parotid enlargement have been well reviewed 9 - 12 and include ingestion of such compounds as starch, heavy metals, isoproterenol, and thiouracil and such conditions as sarcoidosis, lymphoma, Sjogren's syndrome, local infection, allergy, pregn ancy, and lactation. In addition, parotid

280

CASE REPORTS

enlargement has been reported in certain nutritional disturbances: alcoholic liver disease,I 3 - 15 simple malnutrition,I 6 - 18 refeeding of starved patients,1 9 obesity ,20 and diabetes mellitus. 21 Mumps is not uncommonly associated with acute pancreatitis,2 2 and Paget described 23 patients with parotitis due to injury or disease of the abdomen, 23 but did not specifically mention pancreatitis. Isolated case reports may be found of abdominal pain of uncertain cause accompanied by parotid swelling, but not resembling the present case. 24 - 26 From India, Alapatt and Ananthachari recently reported 23 patients with parotid enlargment, pancreatic calcification, and diabetes mellitus. 4 The clinical features and course of their patients were not described in detail. They observed an abnormal increase in parotid secretion during 5 min of chewing chocolate, while the amylase concentration was normal. In these patients, normal sialograms were reported in 7 cases and a "leafless tree" pattern in 16 cases. In 14 cases parotid biopsy disclosed enlarged acini with the individual cells appearing swollen. They also observed varying degrees of round cell infiltration around the intra- and interlobular ducts in 13 cases. In our patients, with each episode of parotid enlargement the parotid basal secretory volume was grossly increased, but, following disappearance of parotid enlargement, basal and stimulated secretion was normal in volume and in electrolyte and amylase concentration. Sialography disclosed only a questionable change in the terminal ductal radicles. In the parotid hypertrophy of nutritional origin, biopsy has shown an increase in secretory granules/ 3 fatty infiltration, 14 or serous inflammation. 27 In our patient, no significant changes were observed. Sarnoff and Yamada demonstrated in the cat that occlusion of the small arteries of the abdominal viscera, especially the pancreas, caused a sustained elevation of arterial blood pressure. 28 This was thought to be caused by stimulation of the Pacinian corpuscles within the pancreas with the re-

Vol. 55, No. 2

flex elevation of blood pressure. In man, arterial hypertension has not previously been reported in association with either parotid swelling or pancreatitis, although we have noted transient hypertension in 3 other patients with acute pancreatitis. The hypertension might simply represent a nonspecific response to pain or it might be caused by the mechanism postulated by Sarnoff and Yamada. It is unlikely that our patient represents the same syndrome described by Alapatt and Ananthachari 4 and others.I-3 It is probable that these patients had parotid enlargement, as well as pancreatic insufficiency, either on the basis of malnutrition, diabetes, or both, although insufficient information is given to confirm or refute this. Although our patient was once an intermittent alcoholic, neither the general clinical features, laboratory data, nor the parotid findings suggest malnutrition as an etiological factor in the parotid enlargement. An autoimmune etiology, involving an antigen common to pancreas, parotid, and testis, seemed an attractive explanation at first, but we were unable to develop suggestive evidence. At present, we do not know the cause of this syndrome. Summary

A 37-year-old male has been observed for the past 8 years during 36 attacks of acute pancreatitis. For the past 6 years almost all attacks of pancreatitis have been preceded by transient parotid enlargement and have also been associated with transient arterial hypertension . Extensive investigation has failed to suggest the cause of this relationship. REFERENCES I. Zuidema, P. J. 1959. Cirrhosis and dissemi-

nated calcification of the pancreas in patients with malnutrition. Trop. Geogr. Med. 11: 70-74. 2. Shaper, A. G . 1960. Chronic pancreatic disease and protein malnutrition. Lancet 1:

1223-1224. 3. Wegmann, T., and W. Sollberger. 1960. Die symmetrische asymptomatische Parotishypertrophie Symptom einer chronischen

August 1968

4.

5.

6.

7.

8.

9.

10. 11.

12. 13.

14.

15.

CASE REPORTS

Pancreasinsuffizienz? Schweiz. Med. Wschr. 90 : 508-511. Alapatt, J. L., and M. D. Ananthachari. 1967. A preliminary study of the structure and function of enlarged parotid glands in chronic relapsing pancreatitis by sialography and biopsy methods. Gut 8: 42-45. Kadel!, B. M., and J. M. Riley. 1967. Major arterial involvement by pancreatic pseudocysts. Amer. J. Roentgen. 99: 632-636. van de Kamer, J. H. 1958. Total fatty acids in stool, p. 34-39. In D. Seligson (ed.), Standard methods of clinical chemistry, Vol. II. Academic Press, New York. Ventzke, L. E ., W. A. Davidson, and M. I. Grossman. 1964. Diagnostic value of pancreatic enzymatic response to a test meal (abstr.). Gastroenterology 46 : 765. Curry, R. C., and D. H. Patey. 1964. A chemical test for parotid function . Brit. J . Surg. 51: 891-892. Silverman, M., and R. L. Perkins. 1966. Bilateral parotid enlargement and starch ingestion. Ann. Intern. M ed. 64: 842-846. Beck, A. L. 1942. Inflammation of the salivary glands. Surg. Gynec. Obstet. 74: 604-615. Patey, D. H. 1965. Inflammation of the salivary glands with particular reference to chronic and recmrent parotitis. Ann. Roy. Col!. Surg. Eng. 36: 26-44. Pearson, R. S. 1961. Recurrent swellings of the parotid gland. Gut 2 : 210-217. Borsanyi , S., and C. L. Blanehard. 1960. Asymptomatic e nlar~cnwnt of the parotid glands, its diagnostic significance and particular relation to Laennec's cirrhosis. J . A. M. A. 174: 20-23. Rothbell, E. N ., and J. J. Duggan. 1957. Enlargement of the parotid gland in disease of the liver. Amer. J . MPd. 22: 367-372. Wolfe, S. J., W. H. J. Summl'rskill , and C. S. Davidson. 1957. Parotid swelling, alcoholism and cirrhosis. New Eng. J. Med. 256: 491495.

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16. Sandstead, H. R., C. J. Koehn, and S. M. Sessions. 1955. Enlargement of the parotid gland in malnutrition. Amer. J. Clin. Nutr: 3: 198-214. 17. Hoelzel, F. 1955. Personal experience with parotid enlargement (letter to the editor) . Amer. J . Clin. Nutr. 3: 513-515. 18. DuPlessis, D. J. 1956. Parotid enlargement in malnutrition. S. Afr. Med. J. 30: 700-703 . 19. McCance, R. A., R. F. A. Dean, and A. M. Barrett. 1951. Studies of undernutrition, Wuppertal 1946-1949, VI. Enlargement of the parotid glands, p. 135-139. In Med. Res. Counc. Spec. Rep. (London) Series no. 275. His Majesty's Stationery Office, London. 20. Sprinzels, H. 1912. P arotisvergri.isserung bei Fettleibigen. Wien. Klin. Wschr. 25: 19011904. 21. Flaum, E. 1932. Parotishypertrophie ein Symptom des Diabetes Mellitus. Klin. Wschr. 11: 1704-1705. 22. O'Brien, P. K., D. S. Smith, and 0. P . Galpin. 1965. Acute pancreatitis and haemolytic anaemia associated with mumps-virus infection. Brit. Med. J . 2: 1529. 23. Osler, W. 1892. Principles and practice of medIcme, p. 329. Appleton-Century-Crofts, Inc., New York. 24. Wolff, S. 1926. Uber rezidivierende Schwellungen der Parotis. Jahrbuch f. Kinderh. 112 : 334-335. 25. RPuss, A. V. 1909. Uber chronische Erkrankungen der Parotis im Kindesalter. Jahrbuch f. Kinderh. 70: 161-173. 26. Londe, S., and M . D. Pelz . 1933. Chronic sialodocho-paro titis with recurrent subacute exaeerbations. J. Pediat. 2: 594-602 . 27. Katsilambros, L. 1961. Asymptomatic enlargemf'nt of the parotid glands. J. A. M. A. 178: 513-514. 28. Sarnoff, S. J ., and S. I. Yamada. 1959. Evidence for reflex control of arterial pressure from abdominal receptors with special reference to the pancreas. Circ. Res. 7: 325-335.