nonalcoholic chronic pancreatitis with pancreatic calcification

BRIEF COMMUNICATION

Nonalcoholic chronic pancreatitis with pancreatic

calcification: Presenting manifestation of occult celiac

disease

HUGH J FREEMAN MD,] Scon WH!TIAKER MD

HJ FREEMAN, JS WHITTAKER. Nonalcoholic chronic pancreatitis with pancreatic calcification: Presenting manifestation of occult celiac disease. Can J Gastroenterol l 994;8(5):319-322. A 62-year-old Canadian Caucasian female with nonalcoholic chronic pancreatitis, diabetes, exocrine failure and pancreatic calcification presented with weight loss, diarrhea and peripheral edema. Subsequent investigations revealed celiac disease that was responsive to a gluten-free diet. Calcification in the pancreas may reflect impaired absorption with severe protein-energy malnutrition and may be the initial presenting feature of occult celiac disease.

Key Words: Celiac disease, Chronic pancreatitis, Diabetes , Pancreatic calcification, Pancreatic insufficiency, Protein malnutrition

Pancreatite chronique non alcoolique avec calcification pancreatique : manifestation de la maladie coeliaque occulte

RESUME : Une femme de 62 ans, de race blanche, souf&ant de pancreatite chronique non alcoolique, de diabete et d'insuffisance exocrinienne, ainsi que de calcification pancreatique se presente pour perte de poids, diarrhee et oedeme peripherique. Des recherches plus approfondies ont revele la presence d'une maladie coeliaque qui a repondu a une alirnentation sans gluten. La calcification au niveau du pancreas pourrait etre le reflet d'une rnauvaise absorption, avec malnutrition proteinocalorique grave et peut se reveler etre la caracteristique initiale de la maladie coeliaque occulte.

Department of Medicine (Gastroenterology), University Hospital and University of British Columbia, Vancouver, British Columbia

Correspondence and reprints: Dr Hugh J Freeman, AC U F-13 7, University Hospital ( U BC Site), 22 1 I Wesbrook Mall, Vancouver, British Columbia V6T lWS. Telephone (604) 822-7216

Received for publication January 3 l, 1994 . Accepted February 8, 1994

CAN J GASTROENTEROL VOL 8 No 5 SEPTEMBER/OCTOBER 1994

CELIAC DISEA E (GLUTEN-SENSI

tive enteropathy) and chronic pancreatitis with exocrine insufficiency are both relatively frequent causes of impaired nutrient absorption, steatorrhea and weight loss. Occasionally, celiac disease has been associated with diabetes, but coexistence of celiac disease and advanced exocrine pancreatic insufficiency has only rarely been seen (1-7).

Pancreatic calcification i most frequently associated with chronic or persisting pancreatic inflammation which, in North America, is most often attributed to a high intake of alcohol. Atrophy, fibrosis and altered function of the pancreas has been observed in experimental animals treated with diets deficient in protein (8), in adults with protein-energy malnutrition (9), in children with kwashiorkor (10, 11) and in some early autopsy studies of patients with celiac disease (12). In addition, pancreatic calcification has been seen with chronic protein malnutrition in the Indian subcontinent and in some African countries (8). Finally, a patient with celiac disease and associated tropi-

319

FREEMAN ANO WHITTAKER

Figure 2) Plain abdominal film confirming /Jancreatic calcification

Figure 1) Barium radiographic study of the upper gastrointestinal tract revealing pancreatic calcification

cal calcific pancreatitis has recently been described (13 ).

The present report describes a diabetic female with pancreatic exocrine insufficiency and calcification. Persisting diarrhea and weight loss led to further investigations and, eventually, a diagnosis of celiac disease. In the absence of alcohol use, pancreatic calcification may be the presenting feature of occult celiac disease reflecting the presence of impaired absorption and longstanding severe protein-energy malnutrition.

CASE PRESENTATION A 62-year-old Canadian Caucasian

female was referred in 1987 for evaluation of diarrhea and weight loss. Past history included diabetes treated for five years with oral hypoglycemic agents anJ a prior cholecystectomy for gallstones in 1980. An investigation for diarrhea in 1985 demonstrated anemia with a hemoglobin of 118 g/L (normal 120 to 140), hypoalbuminemia with a serum albumin of 32 g/L (normal 36 to

320

Figure 3) Small intestinal mucosa/ biopsy showing changes typical of celiac disease with crypt hyperplasia and absence of villi

48) and steatorrhea with a fecal fat of 45.3 g/day (normal less than 7). In addition, endoscopic and barium studies of the upper and lower intestine were normal but pancreatic calcification was noted (Figures 1,2). Fecal cultures and studies for ova and parasites were negative. Pancreatic enzyme supplements (pancrelipa e, to 15 capsules daily) and ranitidine 300 mg daily resulted in a reduction in the fecal fat to 9.1 g/day.

Because of continued diarrhea, weight loss of 14 kg and development of bilateral pitting edema in both lower extremities, the patient was reviewed at University Hospital in January 1987. In spite of pancreatic calcification, there was no prior alcohol use, abdominal trauma, hyperlipidemia, familial history or foreign travel. Laboratory tests revealed ( normal ranges in bracket"): hemoglobin, 108 g/L (120 to 140); normal white blood cells and platelets; prothrombin time, 16.4 (10 to 12.5); total protein, 43 g/L (60 to 77); serum albumin, 14 g/L (36 to 48); serum calcium, 7.6 mg/dL (8.6 to 10.6); and se-

rum magnesium, 1.5 mg/JL ( l .8 to 2.4). Alkaline phosphatase was 160 IU/L (normal 30 to 110), aspartate aminotransferase was 64 IU/L (normal 5 to 47), total bilirubin was 1.0 mg/dL (normal 0.14 to 1.34) and gamma-glutamyltransfera c was 32 (normal 5 tO 55). Hepatiti viru serology, antinuclear and antimitochondrial antibodies were negative, and serum ferritin, copper, ceruloplasmin, zinc, amylase and lipase were normal. Measurements of immunoglobulins G, A and M were normal. Urinalysis and 24 h urine protein determination were n rmal. An abdominal ultrasound confirmed the absence of a gallbladder and the presence of pancreatic calcification. The result of a 72 h fecal fat tudy on a daily oral intake of 100 g fat was 50.3 g of fecal fat/day. Prothrombin time corrected tO 11.8 s with vitamin K1 administration. With pancreatic enzyme upplements, fecal fat fell to 7.7 g/day (normal less than 7). Liver biopsy showed steatosis and periodic acid-Schiff reagent positive hepatocyte nuclear vacuoles typical nf


glycogen but no inflammation. In particular, changes of alcoholic hepatitis were ab ent and perivenular sclero i a well as Mallory's hyaline were not seen. mall intestinal biopsies revealed a se

vere 'flat' mucosa! lesion (ie, crypt hyperplastic villous atrophy) con istent with celiac disease (Figure 3 ). he was treated with a gluten-free diet, glyburide 10 mg daily, pancrelipa e capsules to 15 daily and ranitidine 300 mg daily.

The patient was re-evaluated in May 1987. Energy had improved, edema had resolved and her weight increased by 8 kg. Laboratory investigations revealed resolution of anemia (hemoglobin 125 g/L), hypoproteinemia (total protein 65 g/L) and hypoalbuminemia ( erum albumin 38 g/L).

In spite of her improved clinical rate and laboratory tests, a mall intes

tinal biopsy showed no morphological change. In February 1988, diarrhea recurred but poor gluten-free diet compliance was evident. Hemoglobin was 108 g/L and serum albumin was 20 g/L while other blood tests were normal. A barium radiographic tudy of upper gastrointestinal tract was normal with no radiological evidence of lymphoma. A computed tomography abdominal scan howed some fatty infiltration in the

liver and pancreatic calcification. Thyroid studie revealed serum triiodothyronine (T3) levels of 0.9 and 0.7 nmol/L (normal 1.2 to 2.8) and erum thyroxine (T 4) levels of 92 and 7 6 nmol/L (normal 58 to 154) while thyroid antibodies were positive at a dilution of 1 :6400. Small inte tinal biopsies ·howed no improvement. A trict gluten-free diet was urged. By October 1988, her bowel habit wa normal and her weight had increased by a further IO kg. Laboratory studies were normal including: hemoglobin (148 g/L), prothrombin time ( 11.0 s), serum albumin (41 g/L), erum iron, ferritin, folic acid, vitamin B1 2, carotene, calcium, pho·phate, magnesium, alkaline phosphatase, a partate aminotransferase and gamma-glutamyltransferase. An abdominal ultra oun<l showed pancreatic calcification but fatty infiltration of the liver had resolved. Biopsies of the small intestine showed morphological

improvement with reappearance of the villi, and biopsies of the gastric mucosa were normal with none of the feature of lymphocytic gastritis ( 14) or mucosa! glandular atrophy. A repeat fecal fat study on a 100 g fat gluten-free diet with supplemental pancreatic enzymes was 5 g fat/day.

Sub equent follow-up laboratory tudies (hemoglobin, white blood cell

count, carotene, iron and iron binding capacity, red cell folate, vitamin B12, calcium, total protein and serum albumin) in April 1989, April 1990, April 1991, May 1992 and September 1993 have been normal. Repeated small intestinal biopsies at each of these visits revealed villi while gastric and colonic biopsies in May 1992 were normal with no epithelial lymphocytosis (15).

DISCUSSION The patient described in this report

initially presented with weight lo s and steatorrhea. Chronic pancreatitis with pancreatic calcification that re ponded to pancreatic enzymes was diagnosed. In the presence of steatorrhea, it was believed that evere pancreatic insufficiency wa responsible (16). However, in spite of supplemental pancreatic enzymes, further weight loss developed along with hypoalbuminemia and peripheral edema. Further studies led to detection of occult ce liac di ea e that was responsive to a gluten-free diet. This report further emphasizes the need to establish firmly the cause or causes for impaired nutrient absorption and weight loss in patients with steatorrhea. In celiac disease, it has long been recognized (1) that an incomplete clinical response to a gluten-free diet may be due to occult pancreatic disease. Conver ely, as in the present report, a poor clinical response to pancreatic enzyme upplements in a patient with chronic

pancreatic in ufficiency, even with calcific pancreatitis, should lead to reevaluation and exclu ion of a pos ible superimposed small intestinal cause for impaired ab orption and steatorrhea, such as celiac disease.

Pancreatic exocrine insufficiency in patients with small intestinal disease may lead to steatorrhea through a number of possible mechanisms. First - and


Celiac disease and pancreatic calcification

possibly more frequent than is appreciated - impaired elaboration and/or release of pancreatic stimulating hormones from disea ed proximal small intestine may result (17). Previous quantitative immunocytochemical studies from our laboratory demonstrated significant alterations in the numbers of entero-endocrine cells in proximal small intestinal biopsies from seven celiac patients compared with five nonceliac controls (18). In particular, a complete absence of muco al secretin cells in biopsies from celiac patients was noted (18). Studies with test meals in celiac patients also suggested that impaired secretion of cholecystokinin-pancreozymin (and, consequently, pancreatic enzyme stimulation) and intraluminal dilution of pancreatic lipase rather than lipase deficiency per econtributes to steatorrhea in some patients with celiac disease (19). Second, a deficiency of amino acids may re ult, in part, from impaired small intestinal transport of amino acids and this deficiency could result in a diminution in the precursors available for pancreatic enzyme synthesis (4). Third, protein malnutrition per se may result in structural changes in the pancrea , including acinar cell atrophy and pancreatic fibrosi (12,19) with resultant impairment in pancreatic exocrine function.

Although studies of pancreatic pathology with chronic alcohol use have revealed pancreatitis with calcification as the cause of exocrine failure (20), the present report emphasizes that other causes, in addition to chronic alcohol use, should be con idered, including celiac di ease with severe malab orption and concomitant protein deficiency. ln an earlier report (7) a woman of Russian origin wa described with celiac disease and chronic calcific pancreatitis but no information was provided on alcohol consumption. In a recent report from India ( 13) tropical calcific pancreatitis was associated with celiac disease in a patient who did not consume alcohol. The authors suggested that the celiac disease may have contributed to the development of calcification of the pancreas.

In the pre ent report, chronic calcific pancreatitis was documented in an

321

FREEMAN AND WHITTAKER

elderly patient who did not consume alcohol and had no foreign travel or familial history of pancreatic disease; in this patient, calcific pancreatitis, possibly due to her protein deficient state,

REFERENCES l. Benson GD, Kowlessar OD, Sleisenger

MH. Adult celiac disease with emphasis upon response to the gluten-free diet . Medicine (Baltimore) 1964;43:l-40.

2. Pink IJ, Creamer B. Response to a gluten-free diet of patients with the coeliac yndrome. Lancet 1967;i:300-4.

3. Bustos Femanez L, De Paula A, Prizonr R, et al. Exocrine pancreatic insufficiency secondary to glutenentcropathy. Am J Ga troenterol 1970;53:564-9.

4. Weinstein LO, Her kovic T. Rectal seepage of oil in a patient with celiac di ease and econdary pancreatic in ufficiency. AmJ Dig Dis i 968;13:762-5.

5. Regan PT, OiMagno EP. Exocrine pancreatic insufficiency in celiac sprue. A cause of treatment failure. Gastroenterology 1980;78:484-7.

6. Fitzgerald 0, Fitzgerald P, Fennelly J, et al. A clinical study of chronic pancreatitis. Gut 1963;4:193-216.

7. Pitchumoni CS, Thomas E, Balthazar E, Sherling B. Chronic calcific pancreatitis in association with celiac

322

was the major pre enting manifestation of unrecognized and, presumably, longstanding, severe celiac disease. Prospective studies, including detailed investigations on the effects of altered

<lisease. Am J Ga troenterol 1977;68:358-61.

8. Pitchumoni CS. Pancreas in primary malnutrition disorders. Am J Clin Nutr 1973;26:374-9.

9. Tandon BN, George PK, Sama SK, Ramachandran K, Gandhi P Exocrine pancreatic function in protein-caloric malnutrition disease of adults. Am J Clin Nutr 1969;22: 1476-82.

JO. Davis JNP. Essential pathology of kwashiorkor. Lancet l 948;i:3 l 7-20.

11. Thompson MD, Trowell HG. Pancreatic enzyme activity in duodenal contents of children with a rype of kwashiorkor. Lancet 1952;i:l031-3.

12. Adlersberg D, Schein J. Clinical and pathologic studies in sprue. JAMA 1947; 134:1459-67.

13. Nanda R, Anand BS. Celiac <liscase and tropical calcific pancrcatitis. Am J Gastroenterol 1976;66:117-39.

14. Wolber R, Owen D, DelBuono L, Appleman H, Freeman HJ. Lymphocytic gastritis in patients with celiac ·prue or sprue-like intestinal disease. Gastroenterology l 990;98:310-5.

protein metabolism on the human pancreas, are still required to define more precisely the pathogene is of exocrine and endocrine pancreatic failure in ce

liac di ease.

15. Wolber R, Owen D, Freeman HJ. Colonic lymphocytosis in patients with celiac sprue. Hum Pathol 1990;21:1092-6.

16. OiMagno EP, Go VLW, Summerskill WHJ. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl] Med 1973;288:813-5.

17. OiMagno EP, Go VLW, ummer ·kill WHJ. lmpaired cholecystokinin-pancreozymin secretion, intraluminal dilution, and maldigestion of fat in sprue. Gastroenterology l 972;63:25-32.

18. Buchan AMJ, Grant , Brown J, Freeman HJ. A quantitative study of a range of regulatory peptide containing cells in celiac sprue. J Pe<liatr Gastroenterol Nutr 1984;3:665-71.

19. Freeman HJ, Kim YS, Sleisenger MH. Protein dige tion and absorption in man. Normal mechanisms and protein-energy malnutrition. Am J Med 1979;67:1030-6.

20. arles H, Sahel J. Pathology of chronic calcifying pancreatitis. Am J Gastroenterol 1976;66: 117 -39.

CAN J G ASTROENTEROL VOL 8 No 5 SEIYfEMBER/0CTOBER 1994

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