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Familial pancreatitis
Familial
Pancreatitis*
ARCH LOGAN, JR., M.D., CARL P. SCHLICKE, M.D., AND GILBERT B. MANNING,
Spokane,
From the Defiartments of Medicine and Surgery, Rockwood Clinic, and Sacred Heart Foundation for Medical Research, Spokane,Washington.
HRONI~
RELAPSING
PANCREATITIS
as
age of eighteen she began having attacks of moderately severe pain once or twice a year, often seemingly precipitated by emotional upsets. In March 1963, at the age of twenty, she was hospitalized on the third day of the most severe attack she had ever experienced. The serum amylase on admission was 542 units (Smith and Roe). A plain film of the abdomen, roentgenograms of the upper gastrointestinal tract, and a cholecystogram revealed no abnormalities. Determinations of blood sugar, serum lipase, and serum calcium gave results within normal limits. Total lipids were 733 mg. per cent, cholesterol 180 mg. per cent, phospholipids 276 mg. per cent, and triglycerides 314 mg. per cent. Her condition improved with conservative treatment and she was discharged seven days after admission. One week later she was readmitted, never having been completely free from pain. Her course was stormy for the next seventeen days with severe abdominal pain, ileus, and a fever of 103O~. On the third hospital day an exquisitely tender mass was palpable in the upper part of the abdomen. There was no improvement with conservative therapy which included nasogastric suction, anticholinergics, and antibiotics. On the eighteenth hospital day celiotomy was performed. A stony hard phlegmonous mass measuring 6 by 8 by 10 cm. with areas of necrosis and liquefaction was present in the tail of the pancreas. Resection of the distal body and tail of the pancreas with incidental splenectomy was accomplished and followed by distal pancreaticojejunostomy with a Roux-Y jejunojejunostomy. The postoperative course was relatively smooth and she left the hospital on the twelfth postoperative day. Eleven days later high epigastric pain radiating to the right side and right subcapsular area developed and was associated with vomiting. The pain was described as being different from that of her previous attacks. She was readmitted to the hospital at which time the serum amylase was found to be 60 units and the leukocyte count 33,850 per mm3. The following day the serum amylase was still within normal limits and the
re-
ported by Gross [I ] in 1958, may occasionally be found to follow a recognized genetic pattern, The first kindred with this disease was described by Comfort and Steinberg in 1952 [Z]. Since that time five more thoroughly documented kindreds have been reported in some detail by the Mayo Clinic group and they and others have reported on families in which multiple instances of pancreatitis have occurred [3-91. The purpose of this report is to present a family in which five members have documented evidence of pancreatitis. In addition, several other members of this kindred show evidence of pancreatic disease although information about them is incomplete. Figure 1 depicts the pedigree of this kindred with familial pancreatitis. c
CASE REPORT OF THE PROPOSITUS The patient (B. W.), a twenty-four year old white woman, had her first attack of abdominal pain, nausea, and vomiting when she was four years old. At the age of nine she began to have recurrent similar episodes at six to twelve month intervals until her first hospitalization at the age of twelve. Serum amylase obtained on the fourth day of her illness was 272 units (Smith and Roe; normal range 19.8 to 134 units). She was discharged improved after sevShe was eral days of conservative management. free from pain for four years until at the age of sixteen she was again admitted to the hospital twenty-four hours after the onset of an episode of abdominal pain and vomiting. At this time the serum amylase was 943 units and the leukocyte count 17,000 per mm3. Her condition improved rapidly and she was well for the next two years. At the * Presented
PH.D.,
Washington
at the Eighth Annual Meeting of the Society for Surgery of the Alimentary Atlantic City, New Jersey, June 17 and 18, 1967. 112
American
Tract,
Journal of Surgery
Familial Pancreatitis PEDIGREE
OF KINDRED
WITH
* propositus
leukocyte count was 40,000 per mm3. The pain became more severe, her condition became desperate, and eighteen hours after admission she underwent exploratory laparotomy. The head of the pancreas which had appeared normal at the previous operation was now described as thickened into a hard mass “about the size and consistency of an apple.” Celiac ganglion block with a 1 per cent solution of Xylocaine@ was performed and her recovery after operation was uneventful. Since that time she has had mild attacks of abdominal pain once or twice a year but her general health has been good and she has had two children. CASE
SUMMARIES
Proved Pancreutitis CASE I. The mother of the propositus (LuD.), at the age of three, began to experience attacks of abclominal pain associated with nausea and vomiting. These attacks were recurrent until age fifteen when she underwent operation at the University Hospitals at Iowa City. Calculi were removed from the pancreatic duct, and the gallbladder was said to be normal. Because of continued episodes of similar pain a second operation was performed a year later. The surgeon found a stricture between the duct of Wirsung and the duodenum. The patient continued to experience attacks of abdominal pain and vomiting for the next twelve years. One year prior to the time of this writing, shortly after experiencing her first attack of abdominal pain in fourteen years, diabetes mellitus developed which was controlled by tolbutamide. She uses no alcohol but, like her Vol. 115, January
1968
FAMILIAL
0
113 PANCREATITIS
OTHER DISEASEOF PANCREAS
daughter, thinks her attacks may be triggered by emotional upset. CASE II. A maternal aunt of the propositus, now thirty-nine years of age, was found by roentgenographic examination at the age of thirty-three to have pancreatic stones. At the age of eighteen she began to have recurrent attacks of abdominal pain thought to be due to gallbladder disease until a cholecystogram revealed a normal gallbladder. She has not undergone any surgical procedures and she does not use alcohol. CASE III. A forty-eight year old first cousin once removed of the propositus was operated on at the age of twenty-seven and told that he had a carcinoma of the pancreas. For four years prior to operation he had complained of intermittent abdominal pain, and just before he was examined at the University of Iowa Hospitals jaundice and an epigastric mass had developed. The surgeon’s note described a hard, irregular mass measuring 16 by 16 by 8 cm. in the head of the pancreas displacing the second portion of the duodenum to the right but showing no sign of invasion. The surgeon’s impression was that he was dealing with an inoperable, rapidly growing malignant lesion. The gallbladder was normal, and cholecystoduodenostomy was performed. Biopsy of regional lymph nodes revealed lymphoid hyperplasia. Shortly after operation the patient was found to have glycosuria which was controlled by diet and insulin. At the present writing, twentyone years later, he is still living. Obviously the diagnosis of pancreatic carcinoma is untenable and the diagnosis of pancreatitis inescapable.
114
Logan, Schlicke, and Manning ~R~N.~R~AMINO
Urinary Amino Acids Cysteic acid Taurine Aspartic acid Threonine Serine Glutamic acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Tryptophan Histidine Arginine
TABLE I ACIDS(M~./TWENTY-FOURHO~RS)IN
THEPROPOSITUS
Normal Range
A. D.
M. D.
0.76.3 9.7- 38.0 0.5 7.7 6.P 24.0 18.1- 81.1 1.6- 10.0 0.47.5 12.7-135.0 1.8 37.0 2.4- 11.9 8.P 26.1 0.32.6 0.73.2 2.6 8.1 8.0- 27.0 3.0- 17.0 0.6- 13.4 7.8 53.4 2.6 50.0 50.&196.0 0.4 4.6
0.45 4.92 0.30 3.13 9.09 1.34
2.51 32.67 0.18 5.19 14.86 1.34 1.25 36.16 1.79 3.04 8.41 1.52 0.63 3.85 8.86 3.04 1.70 41.44 25.33 69.72 0.90
41187 5.51 1.19 4.17 0.45 0.30 1.34 1.94 1.04 1.19 4.92 29.20
27.27 0.60
CASE IV. A first cousin of the grandfather of the propositus had his first attack of acute pancreatitis at age twenty-nine. The diagnosis was confirmed by a serum amylase level of over 2,000 units according to a communication from his physician in Des Moines, Iowa. The patient was hospitalized on two occasions three years later with similar attacks of pain and vomiting. Six years after his first attack the presence of diabetes mellitus was discovered which has since been controlled by oral hypoglycemic drugs. Attacks of abdominal pain requiring hospitalization have continued to the present. Repeated cholecystograms have revealed no abnormalities. He does not drink alcohol to excess.
Other Pancreatic Disease CASE I. The great-grandmother of the propositus died at the age of seventy-eight of carcinoma of the pancreas. For many years she had had recurrent pain in the left upper abdominal quadrant. According to the autopsy protocol, stoneswere found embedded in the carcinomatousmass. There were no stones in the gallbladder and no history of jaundice prior to the final four days of life. This represents a possible instance of pancreatitis terminating as carcinoma of the pancreas. CASEII. Very little information is available concerning a distant cousin who has been told he has a “petrified pancreas” and was instructed to take insulin. This may be only simple diabetes mellitus but could representpancreatic lithiasis.
ANDHERFAWLY
Lit. D.
Ly. D.
4.05
5.32 45.22 6.08 15.96 14.63 4.18 6.12 71.63 24.70 7.41 26.02 0.76 1.90 3.42 14.06 6.46 7.60 212.42 9.12 150.86 3.99
37.95
0.30 8.85 20.85 3.90 0.75 123.30 20.10 2.70 35.10 1.80 2.55 0.60 11.70 4.20 2.40 7.80 49.65 102.00 2.70
B. W. 2.96
81.20 1.66 9.56 31.53 27.58 1.54 113.40 23.01 2.41 24.31 2.53 0.68 0.92 9.93
5.18 3.58 26.41 2.59 93.17 1.54
CASE III. The maternal grandfather is alleged to have died of carcinoma of the pancreas at the age of sixty. CASE IV. A great-uncle is said to have died of complications of diabetes at thirty-four years of age.
AMINOACID STUDIES Urinary amino acid levels were determined by automatic ion exchange chromatography employing a Technicon@ amino acid analyzer. The studies on the propositus were carried out after her acute illness in April 1963. Subsequently these levels were determined for the mother (Lu.D.) and three apparently healthy siblings (A. D., M.D., and Ly.D.). Renal clearance of amino acids as outlined by Cusworth and Dent [IO] was performed on the propositus and her mother. Results of urine amino acid studies are shown in Table I. Only one of the five subjects (Lu.D.) excreted slightly greater than normal quantities of cystine. The propositus (B.W.) and one sibling (Ly.D.) showed increased levels of taurine, an oxidized end product of cystine metabolism. The same sibling also exhibited marked elevation of lysine excretion whereas the propositus did not. Studies of renal clearance of amino acids were carried out on the propositus and her mother and showed elevated cystine clearance (3.8 ml. and 7.8 ml/min./l.73 M2. compared to American
Journal of Surgery
Familial
Pancreatitis
115
TABLE II AMINO ACIDS &G./TWENTY-FOUR HOURS) ACUTE NONFAMILIAL
URINARY
PANCREATITIS
Urinary Amino Acid
Normal Range
0. H.
w. s.
B. McS.
M. H.
Cysteic acid Taurine Aspartic acid Threonine Ser ine Glotamic acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalinine Ornithine Lysine Tryptophan Histidine Arginine
0.76.3 9.7- 38.0 0.57.7 6.4 24.0 18.1- 81.1 1.6- 10.0 0.47.5 12.7-135.0 1.8 37.0 2.4- 11.9 8.4- 26.1 0.32.6 0.73.2 2.68.1 8.0- 27.0 3.0- 17.0 0.6- 13.4 7.8 53.4 2.6 50.0 50.0-196.0 0.4 4.6
16.86 405.41 6.18 28.74 56.05 7.60 1.66 76.24 55.34 7.60 55.58 4.28 8.79 9.50 35.15 19.95 3.33 66.74 21.38 202.83 14.73
6.84 87.97 3.42 25.08 56.81 6.84 4.37 103.17 19.19 11.78 92.42 0.95 2.85 11.21 29.45 15.01 4.94 142.88 18.81 286.14 7.98
11.90 315.80 14.80 71.60 123.60 15.30 2.40 83.50 40.10 47.70 45.30 1.40 2.40 6.20 35.30 20.50 26.20 39.60 21.00 229.90 26.20
15.80 312.89 12.74 55.29 107.02 42.04 7.64 152.63 95.04 31.59 345.96 5.61 5.86 23.19 65.99 41.28 18.35 170.97 16.82 245.12 13.50
a normal range of 0.3 to 0.8ml./min./1.73 M2.). No other elevations of amino acid clearance were noted. Blood levels of amino acids of the propositus and her mother were within normal limits. 17or comparison amino acid excretion was studied in four patients with acute nonfamilial pancreatitis. In all patients the serum amylase level at the time of the acute illness was markedly elevated, reaching 2,920 units in one patient (M. H.) . Results of urinary amino acid determinations are shown in Table II. In all cases greater than normal excretion of cystine and taurine was evident. In three subjects lysine excretion was excessive. Tyrosine, arginine, and histidine were excreted in higher than normal amounts by all subjects and the other amino acids in varying excessive amounts by one or another of the subjects. COMMENTS Hereditary pancreatitis is said to be transmitted as an autosomal dominant trait [Z]. This mode of inheritance may exist in the family being reported. There is, however, an insufficient number of family members in successive generations with proved pancreatitis to be certain that other patterns of heredity are not involved. The clinical characteristics of familial panVol. 115, Januwy
1968
creatitis are little different from those of the nonhereditary form of pancreatitis. Typical of the disease when it is hereditary are an early age at onset with attacks often starting in the first decade of life, an absence of associated biliary tract disease, and no history of alcoholism. Pancreatic calcification is common in hereditary pancreatitis and is chiefly in the form of calculi in the larger pancreatic ducts rather than diffuse calcinosis of the gland. Aside from these characteristics the hereditary form of the disease usually follows the pattern of chronic relapsing pancreatitis in producing recurrent severe prolonged attacks of abdominal pain and sequelae of steatorrhea, diabetes, pseudocyst formation, and calcification of the gland. According to Gerber [4] and Beall et al. [6] a number of the patients operated on for hereditary pancreatitis or examined at autopsy have an anatomic defect in the larger pancreatic ducts which predisposes to obstruction by inspissated secretions or ductal metaplasia. Such a defect was said to exist in the mother of the operative pancreapropositus. Although tography was not carried out on the propositus, a probe was passed easily for a distance of 10 cm. down the pancreatic duct into the head of the gland after resection of the body and tail. This would indicate no gross ductal distortion
116
Logan,
Schlicke,
but would not preclude distortion of the major ducts near their point of entry into the duodenum. It is interesting to note the high incidence of calcification of the pancreas among various members of this kindred although the propositus has no evidence of this to date. Approximately half the patients with hereditary pancreatitis studied were found to have pancreatic calcification. In contrast to this, in one hundred cases of nonhereditary chronic pancreatitis reported by Paulino-Netto, Dreiling, and Baronofsky [11] only twenty-four exhibited calcification. It was pointed out in this same survey that carcinoma of the pancreas appeared in 25 per cent of the patients with calcific pancreatitis and not at all in the absence of calcification. One might therefore anticipate a higher incidence of malignancy of the pancreas in the familial type of pancreatitis. Of three of Gross’ patients reported to have died, two died of carcinoma of the pancreas at ages forty-eight and fifty-two, respectively. In our kindred there was one patient with proved carcinoma of the pancreas who very possibly had pancreatic stones and therefore chronic pancreatitis, and one with incompletely documented evidence of the same disease although an antecedent history of pancreatitis in this case was unproved. Close surveillance of all members of such a kindred over a period of years may help to clarify the question of increased incidence of pancreatic carcinoma. The results of our amino acid excretion studies performed on the propositus and members of her family are not in accord with the observations of Gross, Ulrich, and Jones [12]. In patients with familial pancreatitis they reported daily excretions as high as 1,600 mg. of lysine and 848 mg. of cystine and suggested that this specific amino aciduria might represent a genetic tubular defect or some other inborn metabolic error. In the family we studied the propositus and one sibling showed a modestly elevated excretion of taurine. The same sibling excreted a moderately increased amount of lysine and the mother showed slightly higher than normal cystine excretion. The propositus and her mother both showed elevated cystine clearance. All other plasma and urinary amino acid studies gave normal results. None of these persons was acutely ill at the time determinations were carried out. By way of contrast there was a distinct increase in most of the levels of amino
and Manning acids excreted by the four patients with acute nonfamilial pancreatitis. These findings suggest that amino aciduria may be a manifestation of acute pancreatitis, whether familial or not, rather than a genetically related defect. It may be that the pancreas exercises a hormonal influence on the renal tubular resorptive capacity in response to the need of excretion of high levels of enzyme, such as amylase. Hormones, such as pitressin, are known to exercise a profound effect on the transport mechanism of the renal tubule and are thought to exert such influence by changes in the conformation of the proteins of the diffusion barrier [13-161. SUMMARY
A kindred has been described in which five persons have pancreatitis and one other probably has this disease. Urinary amino acid excretion of the propositus and four members of her immediate family has been investigated employing ion exchange chromatography. The results suggest that amino aciduria may be a manifestation of acute pancreatitis, whether familial or not, rather than a genetically related defect. The possibility exists that there is a relationship between pancreatic carcinoma and hereditary pancreatitis. The diagnosis of hereditary pancreatitis should be considered when the disease is seen in persons of any age, particularly in the absence of biliary tract disease or alcoholism when there is a history of attacks beginning in childhood. REFERENCES
1. GROSS, J. B. Some recent developmentspertaining to Dancreatitis.Ann. Int. Med.. 49: 796. 1958. 2. COMPORT, M. W. and STBINBB&, A. G.‘Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology, 21: 54, 1952. 3. GROSS, J. B., GAMBILL, E. E., and ULRICH, J. A. Hereditary pancreatitis. Am. J. Med., 33: 358, 1962. 4. GERBER, B. C. Hereditary pancreatitis. Adz. Surg., 87: 70, 1963. 5. JACKSON, C. E. Hereditary hyperparathyroidism associated with recurrent pancreatitis. Ann. Int. Med., 49: 829, 1958. 6. BEALL, J. H., JR., BELL, J. W., JOSEPH, J. E., and NYHUS, L. H. Fatal acute hemorrhagic pancreatitis occurring simultaneously in identical twins. Gastroenterology, 39: 215, 1960. 7. POULSBN. H. M. Cited by Gross, J. B., Gambill, E. E., and Ulrich, J. A. 131. _ 8. MELLINKOFF, S. H. Cited by Gross, J. B., Gambill, E. E., and Ulrich, J. A. [3]. 9. BUTT, J. H. and FLESHLER, B. Cited by Gross, J. B., Gambill, E. E., and Ulrich, J. A. [3]. American
Journal of Surgery
Familial Pancreatitis 10. CUSWORTH, D. C. and DENT, C. E. Renal clearance of amino acids in normal adults and in patients with aminoaciduria. Biochem. J., 74: 550, 1960. 11. PAULINO-NETTO,A., DRIZILING,D. A., and BARONOFSKY, I. D. The relationship between pancreatic calcification and cancer of the pancreas. Ann. Surg., 151: 530, 1960. 12. CROSS, J. B., ULRICH, J. A., and JONES, H. D. Urinary excretion of amino acids in a kindred with hereditary pancreatitis and aminoaciduria. Gastroenterology, 47: 41, 1964. 13. CAFRUNY, E. J., CARHART, E., and FARAH, A. Effects of hypophysectomy and hormones on
Vol. 115, January 1968
sulfhydryl
117 concentrations
in rat kidney
cells.
Endocrinology, 61: 143, 1957. 14. FONG, C. T. O., SCHWARTZ, I. L., POPENOE, E. H., SILVER, L., and SCHOESSLER, M. A. Molecular bonding of lysine vasopressin at its renal receptor site. J. Am. Chem. Sot., 81: 2592, 1959. 15. FONG, C. T. O., SXLVER,L., CHRISTMAN, D. R., and SCHWARTZ, I. L. The mechanism of action of the anti-diuretic hormone (Vasopressin). Proc. Nat. Acad. Sci., 46: 1273, 1960. 16. SCHWARTZ, 1. L., RASMUSSEN, H., SCHOESSLER, M. A., SILVER, L., and FONG, C. T. 0. Relation of chemical attachment to physiological action of vasopressin. Proc. Nat. Acad. Sci., 46: 1288, 1960.
Pancreatitis*
ARCH LOGAN, JR., M.D., CARL P. SCHLICKE, M.D., AND GILBERT B. MANNING,
Spokane,
From the Defiartments of Medicine and Surgery, Rockwood Clinic, and Sacred Heart Foundation for Medical Research, Spokane,Washington.
HRONI~
RELAPSING
PANCREATITIS
as
age of eighteen she began having attacks of moderately severe pain once or twice a year, often seemingly precipitated by emotional upsets. In March 1963, at the age of twenty, she was hospitalized on the third day of the most severe attack she had ever experienced. The serum amylase on admission was 542 units (Smith and Roe). A plain film of the abdomen, roentgenograms of the upper gastrointestinal tract, and a cholecystogram revealed no abnormalities. Determinations of blood sugar, serum lipase, and serum calcium gave results within normal limits. Total lipids were 733 mg. per cent, cholesterol 180 mg. per cent, phospholipids 276 mg. per cent, and triglycerides 314 mg. per cent. Her condition improved with conservative treatment and she was discharged seven days after admission. One week later she was readmitted, never having been completely free from pain. Her course was stormy for the next seventeen days with severe abdominal pain, ileus, and a fever of 103O~. On the third hospital day an exquisitely tender mass was palpable in the upper part of the abdomen. There was no improvement with conservative therapy which included nasogastric suction, anticholinergics, and antibiotics. On the eighteenth hospital day celiotomy was performed. A stony hard phlegmonous mass measuring 6 by 8 by 10 cm. with areas of necrosis and liquefaction was present in the tail of the pancreas. Resection of the distal body and tail of the pancreas with incidental splenectomy was accomplished and followed by distal pancreaticojejunostomy with a Roux-Y jejunojejunostomy. The postoperative course was relatively smooth and she left the hospital on the twelfth postoperative day. Eleven days later high epigastric pain radiating to the right side and right subcapsular area developed and was associated with vomiting. The pain was described as being different from that of her previous attacks. She was readmitted to the hospital at which time the serum amylase was found to be 60 units and the leukocyte count 33,850 per mm3. The following day the serum amylase was still within normal limits and the
re-
ported by Gross [I ] in 1958, may occasionally be found to follow a recognized genetic pattern, The first kindred with this disease was described by Comfort and Steinberg in 1952 [Z]. Since that time five more thoroughly documented kindreds have been reported in some detail by the Mayo Clinic group and they and others have reported on families in which multiple instances of pancreatitis have occurred [3-91. The purpose of this report is to present a family in which five members have documented evidence of pancreatitis. In addition, several other members of this kindred show evidence of pancreatic disease although information about them is incomplete. Figure 1 depicts the pedigree of this kindred with familial pancreatitis. c
CASE REPORT OF THE PROPOSITUS The patient (B. W.), a twenty-four year old white woman, had her first attack of abdominal pain, nausea, and vomiting when she was four years old. At the age of nine she began to have recurrent similar episodes at six to twelve month intervals until her first hospitalization at the age of twelve. Serum amylase obtained on the fourth day of her illness was 272 units (Smith and Roe; normal range 19.8 to 134 units). She was discharged improved after sevShe was eral days of conservative management. free from pain for four years until at the age of sixteen she was again admitted to the hospital twenty-four hours after the onset of an episode of abdominal pain and vomiting. At this time the serum amylase was 943 units and the leukocyte count 17,000 per mm3. Her condition improved rapidly and she was well for the next two years. At the * Presented
PH.D.,
Washington
at the Eighth Annual Meeting of the Society for Surgery of the Alimentary Atlantic City, New Jersey, June 17 and 18, 1967. 112
American
Tract,
Journal of Surgery
Familial Pancreatitis PEDIGREE
OF KINDRED
WITH
* propositus
leukocyte count was 40,000 per mm3. The pain became more severe, her condition became desperate, and eighteen hours after admission she underwent exploratory laparotomy. The head of the pancreas which had appeared normal at the previous operation was now described as thickened into a hard mass “about the size and consistency of an apple.” Celiac ganglion block with a 1 per cent solution of Xylocaine@ was performed and her recovery after operation was uneventful. Since that time she has had mild attacks of abdominal pain once or twice a year but her general health has been good and she has had two children. CASE
SUMMARIES
Proved Pancreutitis CASE I. The mother of the propositus (LuD.), at the age of three, began to experience attacks of abclominal pain associated with nausea and vomiting. These attacks were recurrent until age fifteen when she underwent operation at the University Hospitals at Iowa City. Calculi were removed from the pancreatic duct, and the gallbladder was said to be normal. Because of continued episodes of similar pain a second operation was performed a year later. The surgeon found a stricture between the duct of Wirsung and the duodenum. The patient continued to experience attacks of abdominal pain and vomiting for the next twelve years. One year prior to the time of this writing, shortly after experiencing her first attack of abdominal pain in fourteen years, diabetes mellitus developed which was controlled by tolbutamide. She uses no alcohol but, like her Vol. 115, January
1968
FAMILIAL
0
113 PANCREATITIS
OTHER DISEASEOF PANCREAS
daughter, thinks her attacks may be triggered by emotional upset. CASE II. A maternal aunt of the propositus, now thirty-nine years of age, was found by roentgenographic examination at the age of thirty-three to have pancreatic stones. At the age of eighteen she began to have recurrent attacks of abdominal pain thought to be due to gallbladder disease until a cholecystogram revealed a normal gallbladder. She has not undergone any surgical procedures and she does not use alcohol. CASE III. A forty-eight year old first cousin once removed of the propositus was operated on at the age of twenty-seven and told that he had a carcinoma of the pancreas. For four years prior to operation he had complained of intermittent abdominal pain, and just before he was examined at the University of Iowa Hospitals jaundice and an epigastric mass had developed. The surgeon’s note described a hard, irregular mass measuring 16 by 16 by 8 cm. in the head of the pancreas displacing the second portion of the duodenum to the right but showing no sign of invasion. The surgeon’s impression was that he was dealing with an inoperable, rapidly growing malignant lesion. The gallbladder was normal, and cholecystoduodenostomy was performed. Biopsy of regional lymph nodes revealed lymphoid hyperplasia. Shortly after operation the patient was found to have glycosuria which was controlled by diet and insulin. At the present writing, twentyone years later, he is still living. Obviously the diagnosis of pancreatic carcinoma is untenable and the diagnosis of pancreatitis inescapable.
114
Logan, Schlicke, and Manning ~R~N.~R~AMINO
Urinary Amino Acids Cysteic acid Taurine Aspartic acid Threonine Serine Glutamic acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalanine Ornithine Lysine Tryptophan Histidine Arginine
TABLE I ACIDS(M~./TWENTY-FOURHO~RS)IN
THEPROPOSITUS
Normal Range
A. D.
M. D.
0.76.3 9.7- 38.0 0.5 7.7 6.P 24.0 18.1- 81.1 1.6- 10.0 0.47.5 12.7-135.0 1.8 37.0 2.4- 11.9 8.P 26.1 0.32.6 0.73.2 2.6 8.1 8.0- 27.0 3.0- 17.0 0.6- 13.4 7.8 53.4 2.6 50.0 50.&196.0 0.4 4.6
0.45 4.92 0.30 3.13 9.09 1.34
2.51 32.67 0.18 5.19 14.86 1.34 1.25 36.16 1.79 3.04 8.41 1.52 0.63 3.85 8.86 3.04 1.70 41.44 25.33 69.72 0.90
41187 5.51 1.19 4.17 0.45 0.30 1.34 1.94 1.04 1.19 4.92 29.20
27.27 0.60
CASE IV. A first cousin of the grandfather of the propositus had his first attack of acute pancreatitis at age twenty-nine. The diagnosis was confirmed by a serum amylase level of over 2,000 units according to a communication from his physician in Des Moines, Iowa. The patient was hospitalized on two occasions three years later with similar attacks of pain and vomiting. Six years after his first attack the presence of diabetes mellitus was discovered which has since been controlled by oral hypoglycemic drugs. Attacks of abdominal pain requiring hospitalization have continued to the present. Repeated cholecystograms have revealed no abnormalities. He does not drink alcohol to excess.
Other Pancreatic Disease CASE I. The great-grandmother of the propositus died at the age of seventy-eight of carcinoma of the pancreas. For many years she had had recurrent pain in the left upper abdominal quadrant. According to the autopsy protocol, stoneswere found embedded in the carcinomatousmass. There were no stones in the gallbladder and no history of jaundice prior to the final four days of life. This represents a possible instance of pancreatitis terminating as carcinoma of the pancreas. CASEII. Very little information is available concerning a distant cousin who has been told he has a “petrified pancreas” and was instructed to take insulin. This may be only simple diabetes mellitus but could representpancreatic lithiasis.
ANDHERFAWLY
Lit. D.
Ly. D.
4.05
5.32 45.22 6.08 15.96 14.63 4.18 6.12 71.63 24.70 7.41 26.02 0.76 1.90 3.42 14.06 6.46 7.60 212.42 9.12 150.86 3.99
37.95
0.30 8.85 20.85 3.90 0.75 123.30 20.10 2.70 35.10 1.80 2.55 0.60 11.70 4.20 2.40 7.80 49.65 102.00 2.70
B. W. 2.96
81.20 1.66 9.56 31.53 27.58 1.54 113.40 23.01 2.41 24.31 2.53 0.68 0.92 9.93
5.18 3.58 26.41 2.59 93.17 1.54
CASE III. The maternal grandfather is alleged to have died of carcinoma of the pancreas at the age of sixty. CASE IV. A great-uncle is said to have died of complications of diabetes at thirty-four years of age.
AMINOACID STUDIES Urinary amino acid levels were determined by automatic ion exchange chromatography employing a Technicon@ amino acid analyzer. The studies on the propositus were carried out after her acute illness in April 1963. Subsequently these levels were determined for the mother (Lu.D.) and three apparently healthy siblings (A. D., M.D., and Ly.D.). Renal clearance of amino acids as outlined by Cusworth and Dent [IO] was performed on the propositus and her mother. Results of urine amino acid studies are shown in Table I. Only one of the five subjects (Lu.D.) excreted slightly greater than normal quantities of cystine. The propositus (B.W.) and one sibling (Ly.D.) showed increased levels of taurine, an oxidized end product of cystine metabolism. The same sibling also exhibited marked elevation of lysine excretion whereas the propositus did not. Studies of renal clearance of amino acids were carried out on the propositus and her mother and showed elevated cystine clearance (3.8 ml. and 7.8 ml/min./l.73 M2. compared to American
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TABLE II AMINO ACIDS &G./TWENTY-FOUR HOURS) ACUTE NONFAMILIAL
URINARY
PANCREATITIS
Urinary Amino Acid
Normal Range
0. H.
w. s.
B. McS.
M. H.
Cysteic acid Taurine Aspartic acid Threonine Ser ine Glotamic acid Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalinine Ornithine Lysine Tryptophan Histidine Arginine
0.76.3 9.7- 38.0 0.57.7 6.4 24.0 18.1- 81.1 1.6- 10.0 0.47.5 12.7-135.0 1.8 37.0 2.4- 11.9 8.4- 26.1 0.32.6 0.73.2 2.68.1 8.0- 27.0 3.0- 17.0 0.6- 13.4 7.8 53.4 2.6 50.0 50.0-196.0 0.4 4.6
16.86 405.41 6.18 28.74 56.05 7.60 1.66 76.24 55.34 7.60 55.58 4.28 8.79 9.50 35.15 19.95 3.33 66.74 21.38 202.83 14.73
6.84 87.97 3.42 25.08 56.81 6.84 4.37 103.17 19.19 11.78 92.42 0.95 2.85 11.21 29.45 15.01 4.94 142.88 18.81 286.14 7.98
11.90 315.80 14.80 71.60 123.60 15.30 2.40 83.50 40.10 47.70 45.30 1.40 2.40 6.20 35.30 20.50 26.20 39.60 21.00 229.90 26.20
15.80 312.89 12.74 55.29 107.02 42.04 7.64 152.63 95.04 31.59 345.96 5.61 5.86 23.19 65.99 41.28 18.35 170.97 16.82 245.12 13.50
a normal range of 0.3 to 0.8ml./min./1.73 M2.). No other elevations of amino acid clearance were noted. Blood levels of amino acids of the propositus and her mother were within normal limits. 17or comparison amino acid excretion was studied in four patients with acute nonfamilial pancreatitis. In all patients the serum amylase level at the time of the acute illness was markedly elevated, reaching 2,920 units in one patient (M. H.) . Results of urinary amino acid determinations are shown in Table II. In all cases greater than normal excretion of cystine and taurine was evident. In three subjects lysine excretion was excessive. Tyrosine, arginine, and histidine were excreted in higher than normal amounts by all subjects and the other amino acids in varying excessive amounts by one or another of the subjects. COMMENTS Hereditary pancreatitis is said to be transmitted as an autosomal dominant trait [Z]. This mode of inheritance may exist in the family being reported. There is, however, an insufficient number of family members in successive generations with proved pancreatitis to be certain that other patterns of heredity are not involved. The clinical characteristics of familial panVol. 115, Januwy
1968
creatitis are little different from those of the nonhereditary form of pancreatitis. Typical of the disease when it is hereditary are an early age at onset with attacks often starting in the first decade of life, an absence of associated biliary tract disease, and no history of alcoholism. Pancreatic calcification is common in hereditary pancreatitis and is chiefly in the form of calculi in the larger pancreatic ducts rather than diffuse calcinosis of the gland. Aside from these characteristics the hereditary form of the disease usually follows the pattern of chronic relapsing pancreatitis in producing recurrent severe prolonged attacks of abdominal pain and sequelae of steatorrhea, diabetes, pseudocyst formation, and calcification of the gland. According to Gerber [4] and Beall et al. [6] a number of the patients operated on for hereditary pancreatitis or examined at autopsy have an anatomic defect in the larger pancreatic ducts which predisposes to obstruction by inspissated secretions or ductal metaplasia. Such a defect was said to exist in the mother of the operative pancreapropositus. Although tography was not carried out on the propositus, a probe was passed easily for a distance of 10 cm. down the pancreatic duct into the head of the gland after resection of the body and tail. This would indicate no gross ductal distortion
116
Logan,
Schlicke,
but would not preclude distortion of the major ducts near their point of entry into the duodenum. It is interesting to note the high incidence of calcification of the pancreas among various members of this kindred although the propositus has no evidence of this to date. Approximately half the patients with hereditary pancreatitis studied were found to have pancreatic calcification. In contrast to this, in one hundred cases of nonhereditary chronic pancreatitis reported by Paulino-Netto, Dreiling, and Baronofsky [11] only twenty-four exhibited calcification. It was pointed out in this same survey that carcinoma of the pancreas appeared in 25 per cent of the patients with calcific pancreatitis and not at all in the absence of calcification. One might therefore anticipate a higher incidence of malignancy of the pancreas in the familial type of pancreatitis. Of three of Gross’ patients reported to have died, two died of carcinoma of the pancreas at ages forty-eight and fifty-two, respectively. In our kindred there was one patient with proved carcinoma of the pancreas who very possibly had pancreatic stones and therefore chronic pancreatitis, and one with incompletely documented evidence of the same disease although an antecedent history of pancreatitis in this case was unproved. Close surveillance of all members of such a kindred over a period of years may help to clarify the question of increased incidence of pancreatic carcinoma. The results of our amino acid excretion studies performed on the propositus and members of her family are not in accord with the observations of Gross, Ulrich, and Jones [12]. In patients with familial pancreatitis they reported daily excretions as high as 1,600 mg. of lysine and 848 mg. of cystine and suggested that this specific amino aciduria might represent a genetic tubular defect or some other inborn metabolic error. In the family we studied the propositus and one sibling showed a modestly elevated excretion of taurine. The same sibling excreted a moderately increased amount of lysine and the mother showed slightly higher than normal cystine excretion. The propositus and her mother both showed elevated cystine clearance. All other plasma and urinary amino acid studies gave normal results. None of these persons was acutely ill at the time determinations were carried out. By way of contrast there was a distinct increase in most of the levels of amino
and Manning acids excreted by the four patients with acute nonfamilial pancreatitis. These findings suggest that amino aciduria may be a manifestation of acute pancreatitis, whether familial or not, rather than a genetically related defect. It may be that the pancreas exercises a hormonal influence on the renal tubular resorptive capacity in response to the need of excretion of high levels of enzyme, such as amylase. Hormones, such as pitressin, are known to exercise a profound effect on the transport mechanism of the renal tubule and are thought to exert such influence by changes in the conformation of the proteins of the diffusion barrier [13-161. SUMMARY
A kindred has been described in which five persons have pancreatitis and one other probably has this disease. Urinary amino acid excretion of the propositus and four members of her immediate family has been investigated employing ion exchange chromatography. The results suggest that amino aciduria may be a manifestation of acute pancreatitis, whether familial or not, rather than a genetically related defect. The possibility exists that there is a relationship between pancreatic carcinoma and hereditary pancreatitis. The diagnosis of hereditary pancreatitis should be considered when the disease is seen in persons of any age, particularly in the absence of biliary tract disease or alcoholism when there is a history of attacks beginning in childhood. REFERENCES
1. GROSS, J. B. Some recent developmentspertaining to Dancreatitis.Ann. Int. Med.. 49: 796. 1958. 2. COMPORT, M. W. and STBINBB&, A. G.‘Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology, 21: 54, 1952. 3. GROSS, J. B., GAMBILL, E. E., and ULRICH, J. A. Hereditary pancreatitis. Am. J. Med., 33: 358, 1962. 4. GERBER, B. C. Hereditary pancreatitis. Adz. Surg., 87: 70, 1963. 5. JACKSON, C. E. Hereditary hyperparathyroidism associated with recurrent pancreatitis. Ann. Int. Med., 49: 829, 1958. 6. BEALL, J. H., JR., BELL, J. W., JOSEPH, J. E., and NYHUS, L. H. Fatal acute hemorrhagic pancreatitis occurring simultaneously in identical twins. Gastroenterology, 39: 215, 1960. 7. POULSBN. H. M. Cited by Gross, J. B., Gambill, E. E., and Ulrich, J. A. 131. _ 8. MELLINKOFF, S. H. Cited by Gross, J. B., Gambill, E. E., and Ulrich, J. A. [3]. 9. BUTT, J. H. and FLESHLER, B. Cited by Gross, J. B., Gambill, E. E., and Ulrich, J. A. [3]. American
Journal of Surgery
Familial Pancreatitis 10. CUSWORTH, D. C. and DENT, C. E. Renal clearance of amino acids in normal adults and in patients with aminoaciduria. Biochem. J., 74: 550, 1960. 11. PAULINO-NETTO,A., DRIZILING,D. A., and BARONOFSKY, I. D. The relationship between pancreatic calcification and cancer of the pancreas. Ann. Surg., 151: 530, 1960. 12. CROSS, J. B., ULRICH, J. A., and JONES, H. D. Urinary excretion of amino acids in a kindred with hereditary pancreatitis and aminoaciduria. Gastroenterology, 47: 41, 1964. 13. CAFRUNY, E. J., CARHART, E., and FARAH, A. Effects of hypophysectomy and hormones on
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sulfhydryl
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in rat kidney
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Endocrinology, 61: 143, 1957. 14. FONG, C. T. O., SCHWARTZ, I. L., POPENOE, E. H., SILVER, L., and SCHOESSLER, M. A. Molecular bonding of lysine vasopressin at its renal receptor site. J. Am. Chem. Sot., 81: 2592, 1959. 15. FONG, C. T. O., SXLVER,L., CHRISTMAN, D. R., and SCHWARTZ, I. L. The mechanism of action of the anti-diuretic hormone (Vasopressin). Proc. Nat. Acad. Sci., 46: 1273, 1960. 16. SCHWARTZ, 1. L., RASMUSSEN, H., SCHOESSLER, M. A., SILVER, L., and FONG, C. T. 0. Relation of chemical attachment to physiological action of vasopressin. Proc. Nat. Acad. Sci., 46: 1288, 1960.