Pathology of the Gastrointestinal Tract in Patients with Primary Hyperparathyroidism

Aim. To present data of Russian and foreign studies on the prevalence, pathogenesis and clinical picture of gastrointestinal tract (GIT) pathology in patients with primary hyperparathyroidism (PHPT).

Key point. At the beginning of the 20th century PHPT was considered a severe endocrine disease with specific bone and kidney complications, however in 1957 W.T. St Goar proposed a mnemonic triad to recognize this pathology as “diseases of stones, bones and abdominal groans”. A high frequency of gastrointestinal complaints, peptic ulcer, pancreatitis, cholelithiasis in patients with PHPT has been reported. Hyperparathyroidism has been shown to cause smooth muscle atony with specific upper and lower GI symptoms such as nausea, heartburn and constipation. The prevalence of peptic ulcer in patients with PHPT, according to studies of the 50s–60s of the last century, ranged from 10 to 25 %. However, studies linking PHPT to peptic ulcer development were performed before the advent of proton 1). On the other hand, the development of pancreatitis in PHPT is one of the most studied pathologies. In developing countries its frequency can reach 10–20 % due to the absence of routine screening for blood calcium. Some authors report the impact of elevated parathyroid hormone levels on the formation of gallbladder stones by inhibiting of gallbladder emptying, hepatic bile secretion and mobility of the sphincter Oddi, and changing of the bile composition. A number of studies have found an increased risk of developing malignant neoplasms of the intestine, especially the colon, in patients with PHPT.

Conclusion. The digestive manifestations of parathyroid dysfunction in patients can often be overlooked, and serum calcium levels should be included in the routine examination in the presence of abdominal symptoms.

1. Walker M.D., Silverberg S.J. Primary hyperparathyroidism. Nat Rev Endocrinol. 2018; 14(2):115–125. doi:10.1038/nrendo.2017.104

2. Rozhinskay L.Ya., Rostomyan L.G., Mokrysheva N.G., Mirnaja S.S., Kirdjankina N.O. Epidemiology of primary hyperparathyroidism. Lechashii vrach. 2010;11:50-56. (In Russ.)]

3. St Goar W.T. Gastrointestinal symptoms as a clue to the diagnosis of primary hyperparathyroidism: a review of 45 cases. Ann Intern Med. 1957;46(1):102–118. doi: 10.7326/0003-4819-46-1-102

4. Gardner Jr E.C., Hersh T. Primary hyperparathyroidism and the gastrointestinal tract. South Med J. 1981;74(2):197–199. doi: 10.1097/00007611-198102000-00019

5. Tsurkan A.Y. Surgical treatment of primary hyperparathyroidism. Scientific and Medical Bulletin of the Central Chernozem Region. 2006;25:56-57. (In Russ.)]

6. Ismailov S.I., Uzbekov K.K., Gajbullaev A.A. Comparative characteristics of diagnostic methods of primary hyperparathyroidism in patients with urolithiasis. Urologiia. 2002;6:8-11. (In Russ.)]

7. Ellis C., Nicoloff D.M. Hyperparathyroidism and peptic ulcer disease. Arch Surg. 1968; 96(1):114-118. doi: 10.1001/archsurg.1968.01330190116026

8. Rogers H.M. Parathyroid adenoma and hypertrophy of the parathyroid glands. J Am Med Assoc. 1946;130:22-28. doi: 10.1001/jama.1946.02870010024005

9. Hellstrom J. Primary hyperparathyroidism; observation in a series of 50 cases. Acta Endocrinol (Copenh). 1954 May;16(1):30-58. doi: 10.1530/acta.0.0160030

10. Jacob J.J., John M., Thomas N., Chacko A., Cherian R., Selvan B., et al. Does hyperparathyroidism cause pancreatitis? A South Indian experience and a review of published work. ANZ J Surg. 2006;76(8):740-744. doi: 10.1111/j.1445-2197.2006.03845.x

11. Carnaille B., Oudar C., Pattou F., Combemale F., Rocha J., Proye C. Pancreatitis and primary hyperparathyroidism: forty cases. Aust N Z J Surg. 1998;68(2):117-119.

12. Cope O., Culver P.J., Mixter C.G., Nardi G.L. Pancreatitis, a diagnostic clue to hyperparathyroidism. Ann Surg. 1957;145(6):857–63. doi:10.1097/00000658-195706000-00007

13. Selle J.G., Altemeier W.A., Fullen W.D., Goldsmith R.E. Cholelithiasis in hyperparathyroidism: a neglected manifestation. Arch Surg. 1972;105(2):369–374. doi 10.1001/archsurg.1972.04180080213036

14. Farr H.W. Hyperparathyroidism and cancer. CA Cancer J Clin. 1976;26(2):66-74. doi: 10.3322/canjclin.26.2.66

15. Nilsson I.L., Zedenius J., Yin L., Ekbom A. The association between primary hyperparathyroidism and malignancy: nationwide cohort analysis on cancer incidence after parathyroidectomy. Endocr Relat Cancer. 2007;14(1):135-140. doi: 10.1677/erc.1.01261

16. Chan A.K., Duh Q.Y., Katz M.H., Siperstein A.E., Clark O.H. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study. Ann Surg. 1995;222(3): 402-412; discussion 412-414. doi: 10.1097/00000658-199509000-00017

17. Mokrysheva NG. Pervichnyi giperparatireoz. Epidemiologiya, klinika, sovremennye printsipy diagnostiki i lecheniya [dissertation] Moscow; 2011. (in Russ).]

18. Black B.M., Zimmer J.F. Hyperparathyroidism, with particular reference to treatment: review of 207 proved cases. AMA Arch Surg. 1956; 72(5):830-837. doi: 10.1001/archsurg.1956.01270230094012

19. Donegan W.L., Spiro H.M. Parathyroids and gastric secretion. Gastroenterology. 1960; 38:750-759.

20. Barreras R.F., Donaldson R.M.Jr. Role of calcium in gastric hypersecretion, parathyroid adenoma and peptic ulcer. New Eng J Med. 1967;276(20):1122-1124. doi: 10.1056/NEJM196705182762005

21. Wesdorp R.I., Wang C.A., Hirsch H., Fischer J.E. Plasma and parathyroid tumor tissue gastrin and hyperparathyroidism. Am J Surg. 1976;131(1):60–63. doi: 10.1016/0002-9610(76)90421-9

22. Dent R.I., James J.H., Wang C.A., Deftos L.J., Talamo R., Fischer J.E. Hyperparathyroidism: gastric acid secretion and gastrin. Ann Surg. 1972;176(3):360-369. doi: 10.1097/00000658-197209000-00012

23. Black B.M. Hyperparathyroidism and peptic ulcer. Surg Clin North Am. 1971;51(4):955-60. doi: 10.1016/s0039-6109(16)39491-9

24. Frame B., Haubrich W.S. Peptic ulcer and hyperparathyroid¬ism: a survey of 300 ulcer patients. Arch Intern Med. 1960;105:536-541. doi: 10.1001/archinte.1960.00270160034006

25. Rikhsieva N.T. Primary hyperparathyroidism: etiology, pathogenesis, clinical features, diagnosis, treatment, quality of life (literature review). International Endocrinology Journal. 2014;57 (1):103-108 (in Russ.)].

26. Ostrow J.D., Blanshard G., Gray S.J. Peptic ulcer in primary hyperparathyroidism. Am J Med. 1960;29:769-779. doi: 10.1016/0002-9343(60)90111-x

27. Linos D.A., van Heerdan J.A., Abboud C.F., Edis A.J. Primary hyperparathyroidism and peptic ulcer disease. Arch Surg. 1978;113(4):384-386. doi: 10.1001/archsurg.1978.01370160042005

28. Ellison E.H., Abrams J.S., Smith D.J. A postmortem analysis of 812 gastroduodenal ulcers found in 20,000 consecutive au¬topsies, with emphasis on associated endocrine disease. Am J Surg 1959; 97(1):17-30. doi: 10.1016/0002-9610(59)90269-7

29. Heidarpour M., Karami M., Hedayat P., Aminorroaya A. Two rare manifestations of primary hyperparathyroidism: paralysis and peptic ulcer bleeding. Endocrinol Diabetes Metab Case Rep. 2017;2017:17-0059. doi: 10.1530/EDM-17-0059

30. Efremidou E.I., Liratzopoulos N., Papageorgiou M.S., Karanikas M., Pavlidou E., Romanidis K., et al. Peptic ulcer perforation as the first manifestation of previously unknown primary hyperparathyroidism. Case Rep Gastroenterol. 2007;1(1):21–26. doi: 10.1159/000104224

31. Jodkowska A., Tupikowski K, Szymczak J., Bohdanowicz-Pawlak A., Bolanowski M., Bednarek-Tupikowska G. Interdisciplinary aspects of primary hyperparathyroidism: symptomatology in a series of 100 cases. Adv Clin Exp Med. 2016;25(2):285-93. doi: 10.17219/acem/42626

32. Broulik P., Adamek S., Libansky P., Kubinyi J. Changes in the pattern of primary hyperparathyroidism in Czech Republic. Prague Med Rep. 2015;116(2):112-21. doi: 10.14712/23362936.2015.50

33. Ebert E.C. The Parathyroids and the gut. J Clin Gastroenterol. 2010;44(7):479-82. doi: 10.1097/MCG.0b013e3181cd9d4c

34. Jackson C.E. Hereditary hyperparathyroidism associated with recurrent pancreatitis. Ann Intern Med. 1958;49: 829–836. doi: 10.7326/0003-4819-49-4-829

35. Abboud B., Daher R., Boujaoude J. Digestive manifestations of parathyroid disorders. World J Gastroenterol. 2011;17(36):4063-4066. doi: 10.3748/wjg.v17.i36.4063

36. Hochgelerent E.L., David D.S. Acute pancreatitis secondary to calcium infusion in a dialysis patient. Arch Surg. 1974;108(2):218-219. doi: 10.1001/archsurg.1974.01350260072016

37. Ward J.B., Petersen O.H., Jenkins S.A., Sutton R. Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis? Lancet. 1995;346(8981):1016-1019. doi: 10.1016/s0140-6736(95)91695-4

38. Felderbauer P., Karakas E., Fendrich V., et al. Pancreatitis risk in primary hyperparathyroidism: relation to mutations in the SPINK1 trypsin inhibitor (N34S) and the cystic fibrosis gene. Am J Gastroenterol. 2008;103(2):368–374. doi: 10.1111/j.1572-0241.2007.01695.x

39. Lenz J.I., Jacobs J.M., Op de Beeck B., Huyghe I.A., Pelckmans P.A., Moreels T.G. Acute necrotizing pancreatitis as first manifestation of primary hyperparathyroidism. World J Gas¬troenterol. 2010;16(23):2959-2962. doi: 10.3748/wjg.v16.i23.2959

40. He J.H., Zhang Q.B., Li Y.M., Zhu Y.Q., Li X., Shi B. Primary hy¬perparathyroidism presenting as acute gallstone pancreati¬tis. Chin Med J (Engl). 2010;123:1351-1352.

41. Minisola S., Gianotti L., Bhadada S., Silverberg S.J. Classical complications of primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 2018;32(6):791-803. doi: 10.1016/j.beem.2018.09.001

42. Bhadada S.K., Udawat H.P., Bhansali A., Rana S.S., Sinha S.K., Bhasin D.K. Chronic pancreatitis in primary hyperparathy¬roidism: comparison with alcoholic and idiopathic chronic pancreatitis. J Gastroenterol Hepatol. 2008;23(6):959-964. doi: 10.1111/j.1440-1746.2007.05050.x

43. Kazantsev G.B., Nash D.W., Prinz R.A. Pancreatic pseudocyst resolution after parathyroidectomy for hyperparathyroidism. Arch Surg. 1994;129(6):655–658. doi: 10.1001/archsurg.1994.01420300099017

44. Bess M.A., Edis A.J., van Heerden J.A. Hyperparathyroidism and pancreatitis. Chance or a causal association? JAMA. 1980;243(3):246–247.

45. Arya A.K.., Bhadada S.K., Mukhjee S., et al. Frequency and predictors of pancreatitis in symptomatic primary hyperparathyroidism. Indian J Med Res. 2018;148(6):721-727. doi: 10.4103/ijmr.IJMR_353_16

46. Misgar R.A., Bhat M.H., Rather T.A., Masoodi S.R., Wani A.I., Bashir M.I., et al. Primary hyperparathyroidism and pancreatitis. J Endocrinol Invest. 2020;43(10):1493-1498. doi: 10.1007/s40618-020-01233-5

47. Broulik P.D., Haas T., Adamek S. Analysis of 645 patients with primary hyperparathyroidism with special references to cholelithiasis. Intern Med. 2005; 44(9):917–921. doi: 10.2169/internalmedicine.44.917

48. Shah V.N., Bhadada S.K., Bhansali A., Behera A., Bhattacharya A., Nahar U., et al. Effect of gender, biochemical parameters and parathyroid surgery on gastrointestinal manifestations of symptomatic primary hyperparathyroidism. Indian J Med Res. 2014;139(2):279-84.

49. Bhadada S.K., Bhansali A., Shah V.N., Behera, A., Ravikiran, M., & Santosh, R. (2011). High prevalence of cholelithiasis in primary hyperparathyroidism: a retrospective analysis of 120 cases. Indian J Gastroenterol. 2011;30(2):100–101. doi:10.1007/s12664-011-0101-0

50. Mok L.L., Nickols G.A., Thompson J.C., Cooper C.W. Parathyroid hormone as a smooth muscle relaxant. Endocr Rev. 1989;10(4):420–436. doi: 10.1210/edrv-10-4-420

51. Christensson T., Einarsson K. Cholelithiasis in subjects with hypercalcaemia and primary hyperparathyroidism detected in a health screening. Gut. 1977;18(7):543–546. doi: 10.1136/gut.18.7.543

52. Kawamura Y.J., Kazama S., Miyahara T., Masaki T., Muto T. Sigmoid colon cancer associated with primary hyperparathyroidism: report of a case. Surg Today. 1999;29(8):789-790. doi: 10.1007/BF02482329

53. Lupton J.R., Chen X.Q., Frolich W. Calcium phosphate supplementation results in lower rat fecal bile acid concentrations and a more quiescent colonic cell proliferation pattern than does calcium lactate. Nutr Cancer. 1995;23(2):221-231. doi: 10.1080/01635589509514376

54. Pence B.C., Dunn D.M., Zhao C., Patel V., Hunter S., Landers M. Protective effects of calcium from nonfat dried milk against colon carcinogenesis in rats. Nutr Cancer. 1996;25(1):35-45. doi: 10.1080/01635589609514426

55. Whitfield J.F., Bird R.P., Chakravarthy B.R., Isaacs R.J., Morley P. Calcium-cell cycle regulator, differentiator, killer, chemopreventor, and maybe, tumor promoter. J Cell Biochem Suppl. 1995;22:74-91.