hereditary pancreatitis in a kinship associated with portal vein thrombosis

Hereditary Pancreatitis in a Kinship Associated with

Portal Vein Thrombosis

ROBERT MCELROY, M.D.

PHILIP A. CHRISTIANSEN, M.D.

Indianapolis, Indiana

From the Departments of Medicin’e, Vet- erans Administration Hospital and Indiana University School of Medicine, Indian- apolis, Indiana 46202. This study was supported by U.S. Public Health Service Grant AM 05223-08. Requests for re- prints should be addressed to Dr. Philip A.

Christiansen, Division of Gastroenterology, Indiana University School of Medicine,

1100 West Michigan Street, India,napolis, Indiana 46202. Manuscript received Feb-

ruary 25, 1971.

In this study we describe the eleventh family with hereditary pancreatitis. Of 131 family members, ten have definite pan-

creatitis, and sixteen are suspected of having pancreatitis. Clinical features include onset of symptoms usually before age twenty, male predominance in this family and absence of alcoholism or gallbladder disease at the onset of symptoms. Genetic transmission is autosomal dominant, modified by incomplete penetrance or sex-related expressivity. A particularly unique feature is the occurrence of portal vein thrombosis on three occasions and splenic vein thrombosis on one occasion and probably a second. The portal venous complications of pancreatitis in general are reviewed. The application of splenoportography has demonstrated that the frequency of splenic vein thrombosis in pancreatitis is much higher than previously suspected.

Pancreatitis is not commonly thought of as a hereditary disease. The first description of hereditary pancreatitis was by Com- fort and Steinberg in 1952 [l]. Since that time nine additional families have been described, the clinical features including the onset of symptoms of pancreatitis in childhood, approximately equal sex incidence and absence of associated alcoholism or biliary tract disease [2-lo]. A large kindred with this entity is the subject of this study. A unique feature is the occurrence of portal vein thrombosis associated with pancreatitis in several instances. The pedigree and description of the family are recorded, and a review of hereditary pancreatitis and portal hypertension complicating pancreatitis is presented.

SOURCE OF INFORMATION

One hundred thirty-one persons from six generations are known in this Caucasian family of which 106 members are living. Six family members were personally examined by one of us. Twelve additional family members or their wives were personally interviewed. All other information recorded was obtained from attending physicians: Data of varying completeness were obtained on ninety-five members excluding the twenty-three members of the sixth generation. Vir- tually all members of the sixth generation are less than ten years old, and none are known to be affected.

226 The American Journal of Medicine

HEREDITARY PANCREATITIS - MCELROY, CHRISTIANSEN

Figure 1. Pedigree of the S family.

DIAGNOSIS OF PANCREATITIS

The criteria for the diagnosis of definite pancreatitis include a history of characteristic recurrent abdominal

pain without other known cause, with any one or com-

bination of the following: (1) pancreatic calcification,

(2) surgical or postmortem confirmation of pancreatitis, (3) unequivocal evidence of pancreatic exocrine in-

sufficiency or (4) elevation of serum or urinary amylase levels during an episode of abdominal pain compatible with acute pancreatitis and otherwise unexplained.

The diagnosis of suspected pancreatitis was made when there was a history of characteristic recurrent abdominal pain, but the diagnosis of pancreatitis was not

confirmed by the aforestated criteria.

LABORATORY METHODS

The following laboratory tests were performed in

all patients admitted to the Indiana University Medical Center as a part of this study for evaluation of hereditary pancreatitis: complete blood count, blood urea nitrogen, serum creatinine, uric acid, serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase, bilirubin, serum and twenty-four hour urinary amylase, electrolytes, serologic reactions, urinalysis, serum total proteins, serum calcium and phosphorus, carotene, platelet count, reticulocyte count, prothrombin time, partial thromboplastin time, bleeding time, clotting time, fibrinogen level, clot retraction, fibrin split prod- ucts, bromsulfalein excretion, serum iron and iron-binding capacity, serum cholesterol, phospholipids, serum triglycerides, sweat chlorides, serum immunoglobulins, serum complement, urinary uroporphyrins, copropor-

phyrins and porphobilinogen, chest roentgenogram, flat plate of the abdomen, x-ray series of the upper gastrointestinal tract, intravenous pyelogram, oral cholecystogram, and liver and spleen scan. In several instances serum insulin radioimmunoassay utilizing the technic of Morgan and Lazarow [ll] was performed on speci- mens obtained during a standard oral glucose test. A seventy-two hour stool specimen was collected and analyzed for fat by the method of Van de Kamer et al. [12]: a normal value is less than 5 per cent of intake.

Duodenal drainage with secretin stimulation was performed by the method of Dreiling and Janowitz [13]. In three cases urinary amino acids were determined [14].

THE S FAMILY

In the six generations of this kindred ten members are definitely affected and sixteen are suspected of having pancreatitis (Figure 1). Three cases of portal vein thrombosis, including that in the propositus (V-23), and one case of splenic vein thrombosis have been documented in those with definite pancreatitis, and splenic vein thrombosis is suspected in another member with definite pancreatitis. The first generation concerning which information is available lived in Eastern Ken- tucky in the Appalachian Mountains where most of the family still reside. Several members of the third and subsequent generations have moved to Florida, Indiana, Michigan and Ohio. Consanguinity has not been documented.

Definite Pancreatitis

W-10. This thirty-four year old man first experienced

abdominal pain at age three. The pain lasted for one

to three days, recurred every two weeks to two months and caused him to “double up”; there was little vomit-

ing and no jaundice or gastrointestinal bleeding. The patient has never consumed significant quantities of

alcohol. In June 1959 he had an acute abdominal pain

for which an exploratory laparotomy was performed. ,The common bile duct was obstructed, a cyst was noted

in the head of the pancreas, and cholangitis was pres-

ent. Several stones were removed from the common bile duct, and a T tube was inserted. Because of persistent pain the patient was referred to another hospital

for definitive surgery. Preoperative studies revealed pancreatic calcification and a normal intravenous cholangiogram. At surgery the pancreas was enlarged and edematous, and there were multiple calculi primarily located in the head of the gland, including one large stone in the duct of Wirsung and numerous smaller

Volume 52, February 1972 229

HEREDITARY PANCREATlTlS - MCELROY, CHRISTIANSEN

stones in the ducts of Wirsung and Santorini. The duct of Wirsung was markedly dilated in the head of the

pancreas, and portions of both ducts were completely occluded. The gallbladder was normal, and minimal fi-

brosis was noted around the common bile duct. A

pancreatoduodenectomy was performed with preserva- tion of the distal half of the pancreas, with pancreatico-

jejunostomy. Biliary drainage was established by a cholecystojejunostomy.

The pancreatic duct was grossly trabeculated, pitted

and dilated to 3.5 cm in circumference in the resected

specimen of pancreas. Hard irregular calculi projected

into the duct lumen in many places, and the duct ter-

minated in a 4 cm cystic structure. Cut sections through

the duct revealed patches of coarsely lobulated gray-tan tissue with many hard, gritty calculi. The common bile duct was 2 cm in circumference and contained no

calculi. Analysis of the calculi revealed the presence

of calcium, ammonium, phosphate and carbonate. No uric acid or cystine was found. Since surgery, the pa-

tient has done well, with infrequent episodes of abdominal pain, none of which has been as severe as

before surgery or has required the patient’s hospitalization.

IV-22. At the age of twenty this man underwent cholecystectomy for recurrent episodes of epigastric pain,

with no subsequent improvement. In August 1958, at the age of forty-six, he was hospitalized with epi-

gastric pain, nausea, vomiting and tenderness in the

right upper quadrant. There was no history of al-

coholism. An x-ray series of the upper gastrointestinal tract and small bowel, as well as a barium enema were

normal; however, an intravenous cholangiogram showed

that the common bile duct was dilated to four times its normal size and irregular in the terminal portion. The

patient refused to undergo surgery initially, but he re-

turned within a month with the same symptoms and consented to operation. Two separate calcifications

were found in the head of the pancreas. The common

bile duct was approximately 2 cm in diameter. The

surgeon thought there was stenosis of the ampulla of Vater and stenosis of the common bile duct at the

point of entry into the pancreas. A sphincterotomy was

performed. The patient has continued to have epi-

sodes of epigastric pain approximately twice a year, although they are not as severe as they were previ-

ously.

Comment: Robechek [5] suggested that hyper- trophy of the smooth muscle of the sphincter of Oddi was the etiology of hereditary pancreatitis in the family he studied. Three members of this

family showed significant improvement after sphincterotomy, with a four year follow-up in each instance. Two of the five remaining patients with

hereditary pancreatitis, described in other series and treated primarily with sphincterotomy, have

shown no improvement. In the remaining three patients there was partial or complete relief of symptoms; however, follow-up was six months or

less.

IV-23. In 1948, at the age of thirty, this patient was admitted to a Veterans Administration Hospital for

evaluation of recurrent epigastric pain of more than ten years’ duration. The pain usually lasted from one

to seven days, recurred at two week intervals and radi-

ated into the back. It was partially relieved by flexing

the thighs on the abdomen and was occasionally associated with vomiting. Three previous hospitalizations had failed to yield a diagnosis. There was no history

of alcoholism. Examination revealed a poorly nourished, chronically ill man with epigastric and right upper

quadrant tenderness, The serum amylase level was

1,600 Somoygi units, and a glucose tolerance test was normal. An x-ray series of the upper gastrointestinal

tract was interpreted as consistent with carcinoma of

the pancreas. Exploratory laparotomy revealed the head and uncinate process of the pancreas to be greatly enlarged, irregular and indurated without palpable calculi. Upon section of the pancreas for biopsy,

opalescent fluid escaped and irregular honeycombing of the gland was noted. Numerous lymph nodes were present around the splenic and superior mesenteric

veins. The liver and gallbladder were reported to be

normal. Biopsies revealed chronic pancreatitis w’ith

ductular proliferation and dilatation, omentitis and

lymphadenitis.

Two weeks after discharge pain, nausea and vomiting

recurred, for which the patient was hospitalized else- where. Multiple paracenteses were necessary for ascites. An exploratory laparotomy was terminated be-

cause of shock after a large mass was found in the area of the pancreas. The patient was subsequently

managed medically and his condition improved. He continued to have intermittent episodes of ab-

dominal pain until March 1963 when, in addition, night

sweats, weakness and weight loss occurred. Spleno- megaly was found, and a diagnosis of agnogenic mye- loid metaplasia was established. A glucose tolerance

test was grossly diabetic. Serum calcium and serum

amylase levels were normal. In April 1964 splenectomy was performed because of increasing splenomegaly with pain. Portal or splenic vein obstruction was carefully

excluded at surgery. The diagnosis of agnogenic my- eloid metaplasia was confirmed by histologic examination of rib, liver and spleen. The patient died in July 1964. Permission for autopsy was not obtained.

IV-29. This thirty-eight year old man entered a Veter-

ans Administration Hospital in May 1961 with the complaint of recurrent abdominal pain since childhood. Initially the pain was epigastric in location, sharp and aching, and tended to occur after eating fatt) or spicy foods. It was frequently accompanied by anorexia, nausea and vomiting. The patient had lost 25 pounds


HEREDITARY PANCREATITIS - MeELRCW, CWtklSTIANSEN

over the previous year. He denied jaundice or acholic stools. One year earlier an ulcer was allegedly demonstrated on roentgenogram. His symptoms had not

abated with ulcer treatment. He had consumed 7 to 8 shots of whiskey a day for an indeterminate period until one year prior to admission after which there had been no alcohol consumption. Right upper quadrant tenderness was found. A complete blood count, serum lipase and liver function studies were normal. The serum amylase level was 240 Somoygi units, and a glucose tolerance test was grossly diabetic. An oral chol,ecys- togram and x-ray series of the upper gastrointestinal tract were normal. Pleural thickening at the right COS-

tophrenic angle was noted on chest roentgenogram. The episodes of pain worsened during the six months

prior to the patient’s second admission in December 1962. Characteristically the severe epigastric pain radiated into the right upper quadrant and back, and subsided to a dull ache in thirty to forty minutes. The patient had also noted constipation and a 10 pound weight loss. He appeared pale and poorly nourished, had tenderness to palpation in both upper abdominal quadrants and hyperactive bowel sounds. The hemoglobin value was 8.8 gm/lOO ml and serum amylase level 1,000 Somoygi units; the diagnosis of recurrent acute pancreatitis was made. The pain and elevated serum amylase levels persisted despite intensive medical management. An intravenous cholangiogram revealed punctate calcification in the head of the pancreas, a normal gallbladder and slight irregularity of the lower end of the common bile duct without dilatation or obstruction. The serum cholesterol and calcium levels were 110 and 9.1 mg/ 100 ml, respectively. Urinary amino acids were within normal limits.

In February 1963 the patient was taken to surgery where the entire pancreas was found to be very hard and fibrotic. A lemon-sized pseudocyst was found in the tail of the pancreas. A dense fibrotic reaction was present in the area of the tail of the pancreas and spleen. There was cavernous transformation of the portal vein with a portal pressure of 25 cm of saline solution. An operative cholangiogram showed dilatation of the common bile duct. No calculi were found; cholecystectomy and sphincterotomy were performed. A calculus was palpated in the pancreatic duct approximately 2 cm from the ampulla of Vater. After distal pancreatectomy a retrograde pancreatogram showed that 2 cm of the duct in the head of the gland was irregular and narrow, but the segment proximal to the point of nar- rowing was normal in size and drained into the duodenum via the duct of Santorini. A pancreaticojejunos- tomy was performed.

The postoperative course was complicated by wound drainage, bleeding, sepsis, jaundice and renal failure, and the patient died one month after surgery. Post- mortem examination revealed large subhepatic and retroperitoneal hematomas. The pancreas was firm and encased in fibrous tissue. The ampulla of Vater was identified, and the common bile duct was found to

be patent with an average circumference of 7 mm. The distal 2 cm of the pancreatic duct had an average circumference of 4 mm and opened into the duodenum ad- jacent to the common bile duct. The portal vein could not be identified, and many dilated veins were present in the pancreatic bed and gastroduodenal ligament. Interlobular and patchy intralobular fibrosis of the pan. cress were present, and dilated ducts contained inspis sated proteinaceous material (Figure 2). Patchy in. terlobular fibrosis and lymphocytic infiltration of the thyroid gland were present; the parathyroid glands were normal.

V-13. In November 1966 this thirty year old man, first cousin of the propositus, was admitted to Indiana University Medical Center with the chief complaint of vomiting blood. Since childhood he had experienced recurrent episodes of epigastric and periumbilical pain which lasted for several days. These episodes were reg- ularly preceded by diarrhea. At age sixteen he was hospitalized with ascites. Tuberculous peritonitis was suspected but not proved, and no therapy was insti- tuted. Although he had had occasional melena for six years prior to admission he did not seek medical at- tention until October 1966 when melena was accompanied by hematemesis. A diagnosis of diabetes mellitus had been made four years previously, for which he took 25 units of NPH insulin daily. Alcohol consumption had been moderately heavy for the ten years prior to admission.

On examination the patient was pale, with a blood pressure of 100/60 mm Hg while recumbent and 65/50 when sitting: his pulse rate was 125/minute. There was diminished excursion of the left hemithorax; a systolic thrill and grade 4/6 systolic ejection murmur were noted in the second left intercostal space; the second heart sound was normal. The bowel sounds were hypoactive, ascites was present, and altered blood was noted on rectal examination. The hemoglobin value was 7.2 gm/lOO ml. The prothrombin time, alkaline phosphatase and SGOT were normal. The serum total bilirubin was 3.0 mg/lOO ml with 0.75 mg/lOO ml


HEREDITARY PANCREATITIS - MCELROY. CHRISTIANSEN

Figure 3. V-l 3. Splenoportogram showing calcification throughout the pancreas. The portal vein is thrombosed. Gastric and esophageal varices are visualized.

direct; albumin was 2.6 gm/lOO ml, blood urea nitrogen 36 mg/lOO ml, platelets 131,OOO/cu mm and bromsulfalein retention 13 per cent. Chest roentgenogram revealed marked pleural thickening and calcifi-

cation in the left hemithorax. An x-ray series of the

upper gastrointestinal tract showed pancreatic calcification and esophageal varices. A splenoportogram demonstrated calcification of the pancreas and portal vein thrombosis (Figure 3). Despite vigorous medical

management for bleeding esophageal varices, hemorrhage continued, and the patient was taken to surgery

on the eighth hospital day for an emergency porto- systemic shunt. Approximately 2 L of ascitic fluid was

present. Although the liver appeared smaller than normal, it was not nodular and a liver biopsy was normal.

The pancreas was calcified, and the retroperitoneal

space was involved in a marked inflammatory and fibrotic reaction. After completion of a superior mesenteric-vena caval shunt, cardiac arrest occurred, and

the patient could not be resuscitated. Consent for autopsy was not obtained.

Comment: This was the first family member to be seen at Indiana University. Because of his history of moderately heavy alcohol intake, it was origi- nally thought that he had alcoholic liver disease with portal vein thrombosis. The relationship of chronic pancreatitis and portal vein thrombosis was not appreciated until the time of surgery. The familial nature of the disease was not sus-

pected until the subsequent admission of the propositus.

V-18. As part of the study this male first cousin of the propositus (and brother of V-13) was first admitted to Indiana University Medical Center for evaluation in September 1967 at the age of nineteen. At age five he began to have recurrent episodes of epigastric pain accompanied by nausea and bilious vomiting. Surgical exploration in 1956 revealed “rupture of the dia-

O! 0 30 00 90 120 150

180 -I

210 TIME IN MINUTES

Figure 4. Oral glucose tolerance tests.

phragm” according to the patient’s mother (these medical records are no longer available). Recurrent

episodes of abdominal pain lasting from a few hours to three days with occasional vomiting continued to occur

two to twelve times per year. The pain was unaffected

by postural change. The patient denied having back pain, hematemesis, melena, jaundice, dark urine, diarrhea and acholic or foul-smelling bulky stools. He had

lost 25 pounds in the year prior to admission. Alcohol consumption was limited to an infrequent bottle of beer. On examination he was a slender man with a left esotropia. The liver was of normal size to percussion,

but the spleen was palpable 4 cm below the left costal margin. The reflexes in the left upper and lower extremities were hyperactive, and there was weakness in

the left lower extremity with a positive Babinski sign on that side. These findings were attributed to an in- fantile hemiparesis and a left peroneal nerve palsy.

Except for the following, all laboratory and roentgenographic procedures for the study were within normal limits, however, the fecal fat collection was unsatisfac-

tory. The serum carotene level was 13 Pg/lOO ml (normal greater than 50 Pg/lOO ml). A xylose tolerance test was normal. An oral glucose tolerance test was

grossly abnormal (Figure 4), and there was no rise in the insulin levels with hyperglycemia (Figure 5). At- tempted duodenal drainage was unsuccessful. Scan of the liver and spleen revealed a normal-sized liver and

an enlarged spleen. The patient was rehospitalized in January 1969 hav-

ing experienced epigastric pain four days prior to admission. The findings on physical examination were unchanged. Complete blood count, serum and urinary amylase, and liver function studies were within normal limits except for an elevated alkaline phosphatase level. A liver biopsy was normal. The fecal fat was 50.8 gm/twenty-four hours on a 100 gm fat diet. Duodenal drainage was again unsuccessful. Splenoportography was performed which demonstrated splenic vein thrombosis with prominent collateral veins (Figure 6) and a splenic pulp pressure of 26 cm of saline solution; there was no evidence of portal vein obstruction. The pa-


HtREDITARY PANCREATITIS - MCELROY. CHRISTIANSEN

---------_ _*.______ *____-------

0 30 60 120 180 210

TIME IN MINUTES

Figure 5. Serum radioimmunoreactive insulin responses

during oral glucose tolerance tests.

tient was discharged and a regimen of Viokase was pre- scribed.

Comment: The typical history of pain, glucose intolerance with an absolute deficiency of insulin, steatorrhea and localized splenic vein thrombosis establish the diagnosis.

V-21. As part of the study in July 1969, this fourteen year old female cousin of the propositus (and sister of V-13) was admitted to Indiana University Medical Center for evaluation of abdominal pain. At age five she began to have recurrent episodes of epigastric pain with vomiting which usually lasted for one or two days. Partial relief was effected by flexing the knees on the abdomen. The episodes initially occurred four to six times a year, but had decreased in frequency to twice a year over the two years prior to admission. The patient had been hospitalized twice yearly for the three years prior to this admission for investigation of abdominal pain, but a definite diagnosis had not been established. She experienced back pain associated with epigastric pain in January 1968. An episode of abdominal pain in May 1969 lasted for two weeks and was preceded by diarrhea which consisted of five watery stools per day; the diarrhea persisted. During several episodes of abdominal pain she had noted spontane- ous flexion of the toes without other manifestations of neuromuscular irritability. Twice previously she had been treated for “worms.” On physical examination minimal epigastric tenderness was present; the re- mainder of the examination was normal. Laboratory and roentgenographic tests for the study were normal except for the following: splenomegaly on liver and spleen scan, a grossly diabetic glucose tolerance test and a fecal fat level of 8.26 gm/twenty-four hours on a 100 gm fat diet. Duodenal drainage with secretin stimulation yielded a total volume of 0.65 ml/kg/thirty minutes (normal greater than 1.1 ml/kg/thirty minutes), a maximum bicarbonate concentration of 75 mEq/L and total bicarbonate of 0.03 mEq/thirty minutes. Microscopic examination of the stool revealed the

Figure 6. V-18. Splenoportogram showing splenic vein

thrombosis with collaterals and a normal portal vein.

rhabditiform larva of Strongyloides stercoralis, but a course of thiabendazole had no effect on the diarrhea

prior to discharge. She was discharged on a regimen of oral sodium bicarbonate.

V-23. The propositus, a twenty-six year old man, entered the Veterans Administration Hospital of Indiana University Medical Center in January 1967 for evaluation of abdominal swelling, hematemesis and melena.

From age ten to sixteen he had experienced recurrent episodes of severe periumbilical pain with vomiting which lasted from several hours to seven days. The pain was partially relieved by “doubling up” and by paregoric. Three hospitalizations had failed to establish a diagnosis. After age sixteen these episodes of abdominal pain did not recur. In December 1966 the patient noted pallor, weakness, hematemesis and melena without abdominal pain. He was transferred from a local hospital for further evaluation. He had consumed from 6 to 12 bottles of beer per week for five years prior to January 1967 but none subsequently. Id- iopathic epilepsy had been documented in the Army prior to his discharge.

On examination the extremities were thin but mus- cular, and there was a notable lack of subcutaneous tissue. The liver was 8 cm in height to percussion and the spleen was palpable; a fluid wave was present. The hemoglobin value was 8.6 gm/lOO ml, white blood cell count 2,4OO/cu mm with normal differential, platelet count 88,OOO/cu mm and reticulocyte count 2.7 per cent. The serum bilirubin, serum protein electrophore- sis, prothrombin time and serum calcium and phosphorus levels were normal. The SGOT was 52 units, alkaline phosphatase 31.2 King-Armstrong units, bromsulfalein retention 20 per cent, serum iron 23 /*g/100 ml and iron-binding capacity 323 Wg/lOO ml. Urine porphyrins were normal, and no porphobilinogen was present. An x-ray series of the upper gastrointestinal tract and barium enema were normal. Esophagoscopy revealed moderate-sized esophageal varices. The bone marrow showed pan-marrow hyperplasia with micro-



Figure 7. V-23. Splenoportogram demonstrating extrahepatic portal vein obstruction.

cytic, hypochromic red cells. Sigmoidoscopy and rectal biopsy were normal. A liver scan revealed patchy uptake, the liver being markedly reduced in size. Sev- eral attempts at liver biopsy were unsuccessful. An electroencephalogram showed a left temporal grade 3 dysrhythmia. The patient was given blood transfusions and discharged.

In June 1967 he was readmitted because of painless upper gastrointestinal bleeding. His hemoglobin level was 7.9 gm/lOO ml. Bleeding was controlled with iced saline lavage and he was given 8 units of whole blood over the first twenty-four hours. A coagulation evaluation was normal. lmmunoglobulins determined by immunodiffusion were normal. The plasma copper was 54 ,g/lOO ml (normal 70 to 140 ,g/lOO ml) and urine copper 8.8 pg/twenty-four hours (normal less than 100 pg/twenty-four hours). A twenty-four hour urinary amylase determination was normal. An oral glucose tolerance test (Figure 4) was flat, with delay in insulin response (Figure 5). Esophagoscopy again demonstrated esophageal varices but no gastric le- sions. A splenoportogram demonstrated extrahepatic portal obstruction with marked venous collaterals (Figure 7). An inferior venacavagram demonstrated thrombosis of the left external iliac and common iliac veins with many collateral veins.

Thirteen days after admission the patient was taken to surgery for splenorenal shunt. Upon entering the abdomen, the surgeon found the liver to be approximately one fourth the normal size and finely granular. The pancreas was small and firm, without calcification; however, the area surrounding the pancreas was involved in a marked fibrotic reaction. In the area of the porta hepatis there were many large, dilated, tortuous veins. The superior and inferior mesenteric veins as well as several of the omental veins were thought to be undergoing recanalization. The spleen and splenic pedicle were involved in a dense fibrotic reaction, mak- ing the proposed anastomosis impossible. Therefore,

a branch of the splenic vein was anastomosed to a large left adrenal vein. Pathologically the spleen showed chronic passive congestion and phlebosclerosis of the splenic vein. A liver biopsy specimen demonstrated minimal cirrhosis and moderate fatty change, and special stains did not reveal either iron or copper. The postoperative course was uneventful, with no further gastrointestinal bleeding and return of hema- tologic values to normal. The SGOT level remained elevated at 90 units and alkaline phosphatase at 62 King-Armstrong units.

In November 1967 the patient was readmitted with a two day history of burning epigastric pain followed by hematemesis, melena and weakness, The hemoglobin was 10 gm/lOO ml and an x-ray series of the upper gastrointestinal tract revealed a large antral ulcer. Liver function remained as before. He was given transfusions of whole blood and antacids hourly, with symptomatic improvement and no further bleeding. Follow-up studies revealed complete healing of the ulcer.

In February 1969 he re-entered the hospital with complaints of blurred vision, nyctalopia, photophobia, a persistent infection of the upper respiratory tract of six weeks’ duration, fatigue, yellow stools and excessive flatus. Examination revealed xerosis of both eyes. A complete blood count was normal. The serum carotene was less than 9 ,g/lOO ml and the fecal fat

26.3 gm/twenty-four hours on a 100 gm diet. The SGOT was 181 units, bilirubin 1.8 mg/lOO ml with 0.8 mg/lOO ml direct, al,kaline phosphatase 76 King-Arm- strong units and serum albumin 4.2 gm/lOO ml. Serum calcium and phosphorus, cholesterol, fatty acids, phospholipids and triglycerides were normal. Therapy with Viokase and oral vitamin A effected amelioration of virtually all symptoms.

Comment: Prior to surgery the possibility of hereditary pancreatitis had been entertained because of the marked similarity between the patient’s symptoms and his cousin’s (V-13), who had

been seen eight months earlier. The preoperative findings of left external and common iliac vein obstruction raised the question of a primary disorder of coagulation with multiple venous thromboses. However, this was not demonstrated. The surgical finding of marked fibrosis in the retroperitoneal space led to the consideration of idiopathic retroperitoneal fibrosis which has been reported to produce extrahepatic portal venous obstruction [15-181. The absence of symptoms of retroperitoneal fibrosis and medial deviation of the ureters made this diagnosis unlikely. Paraf et al. [19] have recorded instances of primary pancreatic inflammatory disease confused with retroperitoneal fibrosis.


PEREDITARY PPNCREATITIS - MCELROY. CHRISTIANSEN

V-38. This nineteen year old man first noted ab-

dominal pair at age nine. It was frequently associated with nausea and vomiting, which occurred after eat-

ing. The pain usually lasted for three or four days. In 1958, at age eight, he underwent an exploratory operation for abdominal pain. Ascites was found and a Meckel’s diverticulum and the appendix were removed. The pathologic report was subacute appendicitis with

fecolith. In October 1959 an x-ray series of the upper gastrointestinal tract and an oral cholecystogram were obtained because of recurrent abdominal pain; no abnormalities were found. In May 1960 the patient was again hospitalized with severe abdominal pain; the serum amylase level was 400 units. He responded to medical treatment for pancreatitis. A repeat oral cholecystogram was normal. In January 1961 he was rehospitalized because of severe epigastric pain radiating into the back; the serum amylase level was 900 units. Similar episodes occurred in January and November 1962. In December surgery was planned with a presumptive diagnosis of congenital stenosis of the ampulla of Vater with pancreatitis. At surgery the gallbladder was normal. The common bile duct was 1 cm in diameter and no stones were palpable. The pancreas was nodular and twice the normal size. The ampulla of Vater admitted a 3 mm sound with some difficulty. An operative cholangiogram was normal, and an only partially successful pancreatogram did not reveal stones within the ducts. Sphincterotomy was performed and a T tube was left in the common bile duct, A biopsy specimen from the ampulla of Vater was normal, The postoperative course was un- remarkable, and the T tube was removed.

The frequency and severity of attacks of abdominal pain decreased until March 1966 when the patient was hospitalized again because of severe abdominal pain. The serum amylase level was 1,040 units. Subse- quently he has had two episodes of pancreatitis for which he was hospitalized.

V-49. This twenty-five year old man was admitted to another university medical center in February 1966 for evaluation of abdominal pain. He had noted intermittent epigastric and right upper quadrant dis- tress lasting from several hours to several days, OC-

curring approximately every two months for as long as he could remember. His mother stated he was jaundiced at the age of nine. The pain was not associated with nausea, vomiting or back pain, and there had been no hematemesis or melena. He drank moderately on weekends only. Admission was prompted by a typical attack of pain which was somewhat more severe and lasted longer than previously. On examination slight epigastric tenderness without rebound was noted. A complete blood count, serum calcium and phosphorus levels, alkaline phosphatase, SGOT, bilirubin, cholesterol, triglycerides, phospholipids and glucose tolerance test were normal. The serum amylase

and lipase levels were normal. An oral cholecystogram

was normal. An x-ray series of the upper gastroin-

testinal tract demonstrated calcification in the area of the head of the pancreas and an impression on the medial side of the second portion of the duodenum consistent with an enlarged pancreas. There was no increase in urine lysine, cystine or arginine by two- dimensional chromatography. The patient was discharged on an anticholinergic regimen with the diagnosis of hereditary pancreatitis.

Suspected Pancreatitis

11-3. Ill-6 recalls that her father (11-3) had had recurrent episodes of abdominal pain for as long as she could remember. The episodes were intermittently associated with vomiting and accompanied by back pain. He would “double up” with pain on occasion. The cause of his death was unknown.

111-l. The grandmother of the propositus died in her forties. She had had recurrent episodes of abdominal pain causing her to “double up,” according to her sister (111.6). These episodes were accompanied by nausea and vomiting, and had started before she was twenty years old.

111-2 and 111-3. These two children died at ages six and seven, respectively. Their older sister (111-6) recalls that both had recurrent episodes of abdominal pain that caused them to “double up” and that were associated with vomiting. The pain had begun at least three years prior to their death, and they both died during episodes of abdominal pain which had lasted for

a few days.

111-4. This man died in his twenties in a mining acci- dent; however, his sister (111-6) recalls that since childhood he had had recurrent episodes of abdominal pain causing him to “double up” and that they were associated with vomiting.

111-5. The father of IV-10 died at age thirty-seven, approximately twenty-five years ago. His wife relates that

he had had recurrent episodes of abdominal pain which lasted for several days with radiation into the back and caused him to “double up.” These episodes were identical with those of his son and similarly started in childhood. There was no known jaundice, steatorrhea, diabetes mellitus or gastrointestinal bleeding. He died at home, reputedly of typhoid fever, after a week long episode of abdominal pain.

111-10. This family member was in his fifties when he died suddenly of unknown cause. He had had recurrent episodes of abdominal pain causing him to “double up” dating back to his childhood according to his sister (111.6). She remembers that he also complained of back pain and that the episodes were sometimes associated with vomiting.


HEREDITARY PANCREATITIS- MCELROY, CHRISTIANSEN

W-3. An uncle of the propositus had had recurrent episodes of epigastric pain radiating into the back since childhood. The episodes lasted from three to seven days, were associated with vomiting and abdominal distention, and occurred almost monthly. The wife had been told by several doctors that her husband had pancreatitis. There was no history of alcohol consumption. In his mid-thirties diabetes mellitus developed, for which he required insulin. He had been hospitalized on four occasions during the eighteen months prior to his death at age forty-four. Findings during these hospitalizations included progressive retinopathy with blindness, hypertension, marked proteinuria and edema associated with progressive renal and congestive heart failure. No abdominal roentgenograms or pancreatic function tests were recorded,

W-5. An older sister (W-4) recalled that this child had had recurrent episodes of abdominal pain causing him to “double up.” These had begun two or three years prior to his death of unknown cause at age six. The episodes were similar to those subsequently experienced by her own children.

W-6. This forty-seven year old man, father of the propositus, was admitted to Indiana University Medical Center in August 1967 as part of the study for evaluation of hereditary pancreatitis. Since early childhood he has had. frequent episodes of nonradiating periumbilical pain which were partially relieved by flexing the knees on the abdomen. These attacks were occasionally accompanied by nausea and vomiting. At the age of twenty the attacks decreased in frequency to once yearly. He had been hospitalized for abdominal complaints on two occasions in the two years prior to admission and had been told that he was anemic. An x-ray series of the upper gastrointestinal tract and a barium enema were reportedly normal. There had been no alcohol intake for ten years prior to admission, and moderate intake for the ten years prior to that. On examination his height was 162 cm, and the antero- posterior diameter of the skull was increased with a prominent forehead. An indirect inguinal hernia was present, otherwise the examination was within normal limits. Blood, urine and roentgenographic studies were normal with the following exceptions: An oral glucose tolerance test was grossly diabetic (Figure 4) with an abnormal insulin response (Figure 5); the serum cholesterol was 351 mg/lOO ml, the serum triglycerides 238 mg/lOO ml and the serum calcium 8.0 and 8.7 mg/lOO ml. The right kidney and collecting structures were not visualized on intravenous pyelogram, and there was contraction of the cortex as well as blunting and dilatation of the calices of the left kidney. Fecal fat studies and duodenal drainage could not be performed during this hospitalization, and the patient has not been available for further study.

V-15. A deceased twelve year old sibling of V-13, V-18 and V-21, and first cousin of the propositus, had had reCUrrent episodes of abdominal pain in childhood causing him to “double up.” He was jaundiced at age one. An appendectomy was performed in later years for abdominal pain, without relief. Hematemesis first occurred before age six and resulted in his hospitalization on at least two occasions. His death was attributed to gastrointestinal hemorrhage. No postmortem examination or additional information is available, although the parents consider his illness and death as due to the “family illness.”

V-25. This seventeen year old girl, sister of the propositus, was admitted to Indiana University Medical Center in August 1967 as part of the study for evaluation of hereditary pancreatitis.

The onset of recurrent episodes of dull aching periumbilical pain occurred before age four; the pain was accompanied by nausea and vomiting. The attacks would occur as frequently as monthly and last as long as two weeks; pain was partially relieved by assuming the knee-chest position. Other family members describe her as “writhing about in bed for days with pain.” She was hospitalized at ages four, ten and fourteen because of abdominal pain, but no diagnosis was established. On the latter two occasions an x-ray series of the upper gastrointestinal tract was reportedly normal. This patient does not use alcohol. Results of a physical examination were normal. Lab- oratory studies were also normal except for a serum calcium of 8.0 and 8.9 mg/lOO ml and an oral glucose tolerance test which was grossly diabetic (Figure 4) with an abnormal insulin response (Figure 5). Fecal fat studies and duodenal drainage could not be performed during this hospitalization, and the patient has not been available for further study. Esophagoscopy dis- closed no abnormalities.

V-26. This sister of the propositus died at age two and a half years after a one hour episode of abdominal pain. She was thought to have had episodes of abdominal pain for approximately one year prior to her death. Vomiting would accompany the episodes of abdominal pain which would last for several days.

V-40. This five year old daughter of definitely affected IV-22 has had several episodes of abdominal pain associated with vomiting. In 1966 she was hospitalized because of abdominal pain and vomiting. Physical findings included marked abdominal tenderness, distention and rebound tenderness in the right lower

quadrant. Vomiting persisted in the hospital. The white blood cell count was 21,OOO/cu mm, a urinalysis was normal; the amylase level was not determined. Upon abdominal exploration a “large amount” of straw- colored fluid was encountered. A few lymph nodes were found around the terminal ileum, and the re-


PEREDITARY PANCREATITIS - McELRCY, CHRISTIANSEN

mainder of the exploration was described as “negative,” although no description of the pancreas was included. Grossly and pathologically the appendix was normal.

The patient has continued to have occasional episodes of abdominal pain.

V-41. Since age ten this nineteen year old daughter of definitely affected IV-23 has had epigastric pain with radiation into the back associated with abdominal swelling and vomiting. The attacks last for several hours, are somewhat relieved by flexing the knees on the abdomen and, according to her mother, are in all respects “identical to those of her father.”

V-51. This twenty-one year old brother of V-49, who is definitely affected, has had episodes similar to those of his brother since childhood. No diagnostic studies have been performed.

Additional Family Members

At the present time there is no information concerning either I-1 or l-2. Of the fourth generation, IV-I has had several episodes of abdominal pain, the characteristics and duration of which are unknown. An x-ray series

of the upper gastrointestinal tract was reportedly normal within the past five years. IV-2 underwent cholecystectomy at age fifty-four after having had abdominal pain for ten years and diabetes mellitus, for which he required insulin. Pancreatic disease was suspected, however chronic cholecystitis with cholelithiasis was found at surgery. The pancreas was described as “slightly thickened.” The common bile duct was explored and a cholangiogram was normal although the sphincter of Oddi was described as “slightly tight” for which dilatation was performed. He has been pain-free since surgery. IV-4 has been f:ospitaIized on many occasions because of abdominal pain, nausea and vomiting which has not responded to treatment for peptic ulcer disease. No definite diagnosis has been established.

In the fifth generation V-2, V-4 and V-7 are said to have abdominal pain, according to a brother (V-6); however, no further details are available. V-37 has had several episodes of abdominal pain, the characteristics of which are unknown. The remaining sixty-two persons of the ninety-five on whom data were obtained do not t:ave symptoms or a medical history suggesting pancreatic or related disease.

COMMENTS

The family described here represents the eleventh

family in which more than two persons definitely have pancreatitis without any known etiologic factor. Several other families have been described in which two persons definitely had pancreatitis and other family members were suspected of having the disease [20,21-j; the occurrence of pain in

childhood probably justifies inclusion of the latter

families. In the present kindred ten members are

definitely affected, and sixteen members are sus-

pected of having hereditary pancreatitis. An additional seven members have or have had abdominal complaints without sufficient information

available to justify their inclusion or exclusion. The ccnsistent feature of the illness has been the onset of recurrent abdominal pain before age twenty and usually by age ten in all definitely affected members.

The mode of transmission of hereditary pancreatitis has been considered to be autosomal dominant. Incomplete recessiveness and poor penetrance have not been excluded [4]. In the S family the only instances of definite or suspected pancreatitis without a parent having either definite or suspected pancreatitis are IV-4 and IV-25. IV-4 has a long history of abdominal pain and could have pancreatitis. IV-25, however, does not have abdominal pain or known complications of pancreatitis. Painless pancreatitis without symptomatic sequelae, incomplete penetrance, sex-related expressivity are possible alternatives to her not being affected. In the first five families reported the sex incidence in both definite and suspected pancreatitis was essentially equal. In the families

reported by Robechek [5], Adham et al. [6] and Logan et al. [7] the sex incidence was approximately equal. However, in the families reported by Davidson et al. [8] and Cornet et al. [9] there has been a male predominance. In the present family there IS a striking male predominance with nine

definitely affected males and only one female; of thore with suspected pancreatitis eleven are male and five female. Although the male to female ratio in the known affected II through V generations is 62 : 40, it does not explain the increased frequency of affected males. In the six female sub-

jects with either definite or suspected pancreatitis the course of the disease has been relatively benign, with one exception (V-26). The possibility of poor penetrance or, more likely, a sex-related expressivity in the female, is raised. This would also explain the lack of symptoms i-n IV-25. An autosomal recessive trait with unrecognized consanguinity is virtually excluded by the large patient sample and involvement of five branches of the family in the fifth generation. Future genetic

linkage studies and pancreatic function studies in

a larger number of family members, including

asymptomatic members, might resolve this ques-



tion. The genetic pattern is basically that of an autosomal dominant trait.

Cholelithiasis has not been found in any member of the present family with definite or suspected pancreatitis. Stenosis of the sphincter of Oddi was

considered to be present at surgical exploration in IV-22 and V-38, however sphincterotomy has not prevented further episodes of pancreatitis. The significance of these two members and the family with hypertrophic smooth muscle of the sphincter of Oddi described by Robechek [5] remains to be determined. Alcohol intake was significant in two

members (IV-29 and V-13), but in both symptoms and signs of pancreatitis occurred prior to age ten, before any alcohol consumption. Alcohol may have been an aggravating factor, but it is highly unlikely as the etiologic factor. The history did not suggest an infectious etiology in any patient. Hy- perparathyroidism, trauma, hemochromatosis, porphyria, nutritional factors or chemotoxic agents could not be implicated. Hypertriglyceridemia associated with hypercholesterolemia was present in only one instance.

Glucose intolerance was present in five patients with definite pancreatitis, in three patients suspected of having pancreatitis and in one additional family member. Serum insulin levels are reported in two patients definitely affected and in two patients suspected of having pancreatitis. An absolute insulin deficiency was demonstrated in V-18 by a low fasting insulin level without a rise in re-

sponse to the oral administration of glucose with elevation of blood glucose to hyperglycemic levels. V-23 showed a slight delay in reaching peak blood

glucose and serum insulin levels which was of

questionable significance. In both IV-6 and V-25 glucose tolerance curves and insulin responses were typical of adult onset diabetes mellitus [22]. Joffe et al. [23] have found significantly impaired insulin responses with maximal beta cell stimulation using glucose, glucagon and tolbutamide in sixteen patients with chronic pancreatitis. The im- pairment of insulin response paralleled the severity of glucose intolerance. In addition to the occurrence of microangiopathy in IV-3, the insulin responses of IV-6 and V-25 suggest the independent occurrence of diabetes mellitus not solely as a consequence of chronic pancreatitis.

Steatorrhea has been documented in three cases and calcification of the pancreas in five. Pseudocyst of the pancreas complicated one case and pleural disease was found in two others.

Ascites occurred in three cases. Carcinoma of

the pancreas has not been noted in this family. Another feature found in this family has been

the “plateau effect” [6] in which attacks of pain occur at less frequent intervals and are less severe

than earlier in the course of the disease. The pain may occur for a limited number of years as ex- emplified by the propositus who experienced pain from ages ten to sixteen and none subsequently. The frequency of pain does not seem to have a direct relationship to the complications of pancreatitis or to the development of pancreatic insuf- ficiency.

Aminoaciduria with abnormally large amounts of cystine and lysine in association with hereditary

pancreatitis was first described by Gross et al. [3,24]. A genetic relationship was proposed between hereditary pancreatitis and aminoaciduria, however no etiologic relationship to pancreatitis was suggested. In subsequent families studied no significant aminoaciduria has been found. Lo- gan et al. [7] noted increased cystine clearance in two patients with hereditary pancreatitis, but

attributed this finding to acute pancreatitis per se rather than to an inherited renal tubular defect after demonstrating increased urinary cystine, lysine and taurine in four cases of acute nonhereditary pancreatitis. Neither Davidson [8] nor Cornet [lo] found aminoaciduria in five and ten patients studied, respectively. Urinary amino acids were determined in five members of the present family (IV-6, IV-29, V-18, V-25 and V-49) and no abnormality was found.

The distinctly unusual feature in this family is the frequency with which thrombosis of the portal and splenic veins has occurred. Only one previous case of splenic vein thrombosis has been recorded in patients with hereditary pancreatitis. In contrast three of the S family members had portal vein thrombosis and one (probably two) had splenic vein thrombosis. Local venous thrombosis with pancreatic disease, particularly carcinoma [25], has been recognized for many years, but splenic and portal vein thrombosis have also been reported in association with acute hemorrhagic pancreatitis, pancreatic necrosis and pseudocyst of the pancreas [26].

A careful review of the English literature revealed that in 1905 Fitz and Packard [27] described a patient with portal vein thrombosis associated with acute pancreatitis and a second patient with splenic vein thrombosis complicating


HEREDITARY PANCREATITIS - MCELROY CHRISTIANSEN

hemorrhagic pancreatitis. Neither patient had gastrointestinal bleeding. In 1910 Opie [28] noted

a patient w,th sple:lic and portal vein thrombosis

associated with liemorrhagic necrosis of the pancreas and a second patient with thrombosis of the portal, splenic and superior mesenteric

veins resulting in hemorrhagic infarction of the bowel. In the second patient gastrointestinal bleed- Ing had occurred for one year prior to death. Sub-

sequently portal vein thrombosis has been reported as a complication of acute or chronic pancreatitis by several investigators [29-331. Spo- radic cases of splenic vein thrombosis [34-421 or compression [43] have been recorded. Isolated thrombosis of the superior mesenteric vein complicating pancreatitis has been reported in association with esophageal varices and gastrointestinal bleeding [44], and without gastrointestinal bleed-

ing [45]. Several studies have dealt more specifically with

the frequency of these complications. In 1954 a pathologic study of sixteen patients with chronic pancreatitis was recorded by Berens et al. [46]. Six instances of portal vein thrombosis were reported; however, no information as to the clinical significance was mentioned. Howard and Jordan [47] described one patient with splenic vein thrombosis, one patient with superior mesenteric vein thrombosis and two patients with portal vein thrombosis, in a review of 377 cases of acute and chronic pancreatitis. Gambill et al. [48], in a review of fifty-six cases of chronic relapsing pancreatitis, noted one case each of thrombosis of the splenic vein, gastric veins and superior mesenteric vein, and two cases of portal vein thrombosis. Whether these were clinically significant was not recorded. Reporting on seventy-five cases of chronic pancreatitis seen in 1956, Gross [49] found single cases of splenic vein thrombosis and portal vein thrombosis.

The development of splenoportography has led to a more systematic approach to determining the incidence of abnormalities of the portal venous system in pancreatic disease. In 1961 Arner and Fernstrom [SO] revit led their findings in 200 splenoportograms wh ,h included sixteen cases of partial or complete obstruction of the splenic vein: three of these were secondary to pancreatitis. One patient had splenic vein thrombosis, splenomegaly and gastrointestinal hemorrhage; another had splenic vein thrombosis without splenomegaly or gastrointestinal bleeding: and the third had

partial occlusion of the splenic vein. In 1962

Rosch and Herfort [51] reported “advanced or

co’mplete occlusion” of the splenic vein in four of

ninety-five patients with pancreatitis who underwent splenoportography. The clinical course of these patients was not recorded. These investiga-

tors concluded that splenic vein thrombosis was a rare complication of pancreatitis, and portal vein thrombosis even rarer, occurring only in the

most severe cases. However, in 1968 Rignault, Mine and Moine [52] performed splenoportography in twenty patients with chronic pancreatitis. Splenic vein thrombosis was noted in nine patients. Splenomegaly and/or gastrointestinal

bleeding was noted in three patients; in one patient the splenic vein thrombosis extended into the portal vein. In 126 cases of surgically proved chronic pancreatitis, Leger, Lenriot and Lemaigre

[53] described abnormal splenoportograms in sixty-nine patients, including thirty with splenic

vein thrombosis. No instances of portal vein thrombosis were recorded, and in only two cases were esophageal varices present. In these two cases the left gastric vein was either small or not opaci-

fied, and these workers concluded that esophageal varices occur with splenic vein thrombosis only when a normal left gastric vein is not present for

collateral flow. In the previously described families with

hereditary pancreatitis, one member who presented with complaints of anemia and melena was found to have splenic vein thrombosis, with collaterals noted at the time of surgery [49]. Al- though gastrointestinal bleeding occurred the source was not documented to be from esophageal or gastric varices. In the present family, bleeding from esophageal varices was the presenting complaint of the propositus, V-23 and V-13; both patients required surgical decompression of the portal hypertension. The history in V-15 suggests a similar occurrence as the cause of death. IV-29

had cavernous transformation of the portal vein and portal hypertension secondary to portal vein thrombosis, however esophageal varices or gastrointestinal hemorrhage were not found. V-18 has splenic vein thrombosis with splenomegaly and no evidence of gastric or esophageal varices. V-21

probably has splenic vein thrombosis with splenomegaly, but this has not been confirmed by sp!enoportography. The occurrence of abnormalities and thrombosis of the splenic vein is not surprising in view of its intimate contact with the

Volume 52. February 1972 239


pancreas over most of its course [54]. The superior mesenteric and portal veins, although variable, are usually in direct contact with the pancreas. Splenoportographic, pathologic and clinical studies indicate that portal vein thrombosis is a rare complication of chronic pancreatitis.

For this reason the frequent occurrence of portal venous thrombosis associated with a rare form of

pancreatitis in this family is all the more striking. Adham et al. [6] found increased serum trypsin- binding activity in two patients with hereditary pancreatitis in contrast to decreased levels usually accompanying chronic nonhereditary pancreatitis. The trypsin-binding alpha, macroglobulin also binds thrombin [55] and plasmin [56]. It would have been of particular interest in the present family to determine the serum trypsin-binding ac-

tivity. An untested hypothesis, following from Ad- ham’s work, is that a localized or generalized ab-

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

normality of the fibrinolytic system may be related to abnormal trypsin-binding, resulting in the high incidence of portal venous thrombosis. Although pancreatic venous thrombosis has been shown to produce severe pancreatitis in dogs [57], present

evidence is insufficient to suggest this as the pathogenesis of pancreatitis in this family.

Another perplexing question the family has pre-

sented is frequent, unexplained, early and sudden death associated with relatively short episodes of abdominal pain. The history from various family

members is remarkably constant in this respect. However, no acceptable explanation for the cause of death was elucidated.

ACKNOWLEDGMENT

We are indebted to Dr. Roy H. Benke for advice and criticism of this study.

REFERENCES

Comfort MW, Steinberg AG: Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 21: 54, 1952.

Gross JB, Comfort MW: Hereditary pancreatitis. Re- port ,on two additional families. Gastroenterology 32: 829, 1957.

Gross JB, Ulrich JA, Maher FT: Further obs’ervations on the hereditary form of pancreatitis, Ciba Foun- dation Symposium; Normal and Abnormal Func- tions of the Exocrine Pancreas, London, J&A Churchill Ltd, 1962, p 278.

Gross JB, Gambill EE, Ulrich JA: Hereditary pancreatitis. D,escription of a fifth kindred and sum- mary of clinical features. Amer J Med 33: 358, 1962.

Robechek PJ: Hereditary chronic relapsing pancreatitis. Am.er J Surg 113: 819, 1967.

Adham NF, Dyce B, Haverback BJ: Elevated serum trypsin binding activity in pati’ents with hereditary pancreatitis. Amer J Dig Dis 13: 8, 1968.

Logan A, Schlicke CP, Manning GB: Familial pancreatitis. Amer J Surg 115: 112, 1966.

Davison P, Costanza D, Swieconek JA, Harris JB: Hereditary pancreatitis. A kindred without gross aminoaciduria. Ann Intern Med 68: 88, 1968.

Corn,et E, Hardy M, Dupon H, Gord’eff A: Pancrea- tite chronique familiale primitive avec ectasies canalaires (6 cas operes). Rev Medicochir Mal Foie 38: 1, 1963.

Cornret E, Dupon H, Hardy M, Gordeef A: Pan- creatite chronique familial’e primitive avec ,ectasies canalaires (6 cas operes). J Chir (Paris) 84: 527, 1962.

Morgan CR, Lazarow A: Immunoassay of insulin: two antibody system. Plasma insulin levels of normal, subdiabetic and diabetic rats. Diabetes 12: 115, 1963.

Va,n die Kamler JH, ten Bokkel H, Weijers HA: Rapid method of determination of fat in the feces. J Biol Chem 177: 347, 1949.

Dreiling DA, Janowitz HD: The laboratory diagnosis

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24. serum ‘and urinary amino acids in hereditary and nonhereditary pancreatitis. Trans Ass Amer Physi- cians 70: 127, 1,957.

25. Rosch J, Herfort K: Contribution of splenoportog-

26.

of pancreatic disease. The secretin test. Amer J Gastroent 28: 268, 1957.

Moore S, Stein W: A modified ninhydrin reagent for photometric determination of amino acids and related compounds. J Biol Chem 211: 907, 1954.

Partington PF: Diffuse idiopathic fibrosis. Amer J Surg 101: 239, 1961.

Eiseman B, Yeoh KS: Portal hypertension associated with idiopathic retroperitoneal fibrosis. Brit J Surg 50: 225, 1962.

Saxton HM, Kilpatric FR, Kinder CH, Lessof MH, McHardy-Young S, Wardle DFH: Retroperitoneal fibrosis. A radiological and follow-up study of fourteen cases. Quart J Med 38: 159, 1969.

lnkley SR, Abbott GR: Unilateral pulmonary arterio- sclerosis. Arch Intern Med (Chicago) 108: 903, 1961.

Paraf A, Menager Cl, Texier J: Panniculites m&en- teriques, lipodystrophies retroperitonealses et af- fections du pancreas. Presse Med 76: 2263, 1968.

Gerber BC: Hereditary pancreatitis. The role of surnical intervention. Arch Sura 87: 70, 1963.

Whit& DM, Feingold M, EisenkLm EJ: Hereditary pancreatitis. Amer J Dis Child 116: 426, 1968.

Yalow RS, Berson SA: Immunoassay of endogenous plasma insulin in man. J Clin Invest 39: 1157, 1960.

Joffe BI, Bank S, Jackson WPU, Keller P, O’Reilly IG, Vinik Al: Insulin reserve in patients with chronic pancreatitis. Lancet 2: 890, 1968.

Gross JB. Comfort MW. Ulrich JA: Abnormalities of

raphy to diagnosis of diseases ‘of th’e pancreas. I. Tumorous disease. Acta Med Stand 171: 251, 1962.

Varriale P, Bonanno CA, Grace WJ: Portal hypertension secondary to pancreatic pseudocysts.


HEREDITARY PANCREATITIS - MCELROY. CHRISTIANSEN

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

Arch Intern Med (Chicago) 112: 191, 1963. Fitz RH, Packard FA: Diseases of the Liver, Pan-

creas, and Suprarenal Capsules, Philadelphia, WB Saunders & Co., 1905, pp 120, 234.

Opie EL: Diseases of the Pancreas, Philadelphia, JB Lippincott Co., 1910, pp 136, 219.

Saphir W: Acute hemorrhagic pancreatitis. Amer J Dig Dis 17: 409, 1950.

Roberts NJ, Baggenstoss AH, Comfort MW: Acute pancreatic necrosis. Amer J Clin Path 20: 742, 1950.

Kelsey MP, Robertson HE, Giffin HZ: The role ‘of chronic thrombosis of the portal vein and its tributaries in the syndrome of splenic anemia. Surg Gynec Obstet 85: 289, 1947.

Doubilet H, Mulholland JH: The surgical treatment of pancreatitis. Surg Clin N Amer 29: 339, 1949.

Case Records of the Massachusetts General Hos- pital. New Eng J Med 233: 443, 1945.

Williams G: Acute pancreatic necrosis as cause of sudden death. Brit Med J I: 1184, 1954.

Clark E: Pancreatitis in acute and chronic alcoholism. Amer J Dig Dis 9: 428, 1942.

Rogers WN: Systemic changes in blood vessels and connective tissues and acute necrosis of thme pancreas. Glascow Med J 142: 195, 1944.

McWhorter GL: Acute pancreatitis. Arch Surg 25: 958, 1932.

Figley MM: Splenoportography: Some advantages and disadvantages. Amer J Roentgen 80: 313, 1958.

Edmondson HA, Bullock WK, Mehl JW: Chronic pancreatitis and lithiasis. A clinicopathologic study of 62 cases of chronic pancreatitis. Amer J Path 25: 1227, 1949.

Fraser J, Brown AK: A clinical syndrome associated with a rare anomaly of the vena portae system. Surg Gynec Obstet 78: 520, 1944.

Sarles H, Sarles J, Camatte R, Mutore R, Gaini M, Guien C, Pastor J, L’eRoy F: Observations of 205 confirmed cases of acute pancreatitis, recurring pancreatitis, and chronic pancreatitis. Gut 6: 545, 1965.

Marks IN, Louw JH, Bank S: The management of severe acute pancreatitis. Postgrad Med J 43: 31, 1967.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

Marks IN, Bank S, Louw JH, Farman J: Peptic ul. ceration and gastrointestinal bleeding in pancreatitis. Gut 8: 253, 1967.

Wilcox AY, Bovill EG, Olivetti RG: Patterns of col-

lateral circulation in the portal system following extrahepatic inflammatory processes. Gastro- enterology 21: 375, 1952.

Comfort MW, Gambill EE, Baggenstoss AH: Chronic relapsing pancreatitis. A study of twenty-nine cases without associated disease of the biliary or gastrointestinal tract. Gastroenterology 6: 239.

1946. Berens JJ, Baggenstoss AH, Gray HK: Ductal

changes in chronic pancreatitis. Arch Surg 68: 723, 1954.

Howard JM, Jordan GL: Surgical Diseases of the Pancreas, Philadelphia, JB Lippincott Co., 1960.

Gambill EE, Baggenst’oss AH, Priestly JT: Chronic relapsing pancreatitis. Gastro,enterology 39: 404, 1960.

Gross JB: Some recent developments pertaining to pancreatitis. Ann Intern Med 49: 796, 1958.

Arner 0, Fernstrom I: Obstruction of the splenic vein. Acta Chir Stand 122: 66, 1961.

Rosch J, Herfort K: Contribution of splenoportography to the diagnosis of diseases of the pancreas. II. Inflammatory diseases. Acta Med Stand 171: 263, 1962.

Rignault D, Mine J, Moine D: Splenoportographic changes in chronic pancreatitis. Surgery 63: 571, 1968.

Leger L, Lenriot J, Lemaigre G: L’hypertension et la stase portales segmentaires dans les pancreatites chronique. J Chir (Paris) 95: 599, 1968.

Romanes GJ, Ed: Cunningham’s Textbook of Anat- omy, 10th ed, New York, Oxford University Press, 1965, p 937.

Lanchantin GF, Plesset ML, Friedmann JA, Hart DW: Dissociation of esterolytic and clotting activities of thrombin by trypsin-bi’nding macroglobulin. Proc Sot Exp Biol Med 121: 444, 1966.

Ganrot PO: Inhibition of plasmin by +macroglobulin. Clin Chim Acta 16: 328, 1967.

Adams TW, Musselman MM: Pancreatic venous thrombosis as an etiologic factor in acute necro- tizing pancreatitis. Surg Forum 4: 401, 1953.


hereditary pancreatitis in a kinship associated with portal vein thrombosis

Documents