Authors:
Haiqing Zhu1, Zhiqiang Cheng2, Bo Zhang1, Xiaoyan Xing1 and Wenhui Zhao1*
Affiliations:
1Department of Endocrinology, Centre of Endocrinology and Metabolism, China-Japan Friendship Hospital, China
2Department of Endocrinology, Third Affiliated Hospital of Hebei North University, China
Dates:
Received: 13 March, 2015; Accepted: 04 April, 2015; Published: 10 April, 2015
*Corresponding author:

Wenhui Zhao, Department of Endocrinology, Centre of Endocrinology and Metabolism , China-Japan Friendship Hospital, China; Tel: +86-010-8420-5664; Fax: +86-010-8420-5664; Email: @

Citation:
Zhu H, Cheng Z, Zhang B, Xing X, Zhao W (2015) Transient Hypoparathyroidism in Diabetic Ketoacidosis. Glob J Obes Diabetes Metab Syndr 2(1): 009-011. DOI: 10.17352/2455-8583.000008
Copyright:
© 2015 Zhu H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords:
Hypoparathyroidism; Diabetic ketoacidosis; Hypocalcemia; hypomagnesemia; Proton-pump inhibitors
Abbreviations:
DKA: Diabetic Ketoacidosis; PPI: Proton-pump Inhibitor; PTH: Parathyroid Hormone; HHS: Hyperglycemic Nonketotic Hyperosmolar Syndrome

Introduction: Diabetic ketoacidosispatients frequently develop a constellation of electrolyte disorders. These patientsare markedly potassium-, magnesium- and phosphate-depleted, but hypocalcemia due to transient hypoparathyroidism was seldom reported previously.

Methods: We describe the clinical history, physical examination findings and laboratory values of the patient and briefly review the relevant literature.

Result: A 43-year-old man with a history of diabetes mellitus presented with vomiting, diarrhea and fatigue for 2 days and his laboratory tests showed high serum glucose and diabetic ketoacidosis. CT scan of the abdomen showed no abnormity. Intravenous fluid resuscitation and continuous insulin infusion was initiated. Omeprazole was started for possible upper gastrointestinal hemorrhage. Hypocalcemia, hypophosphatemia, relative hypomagnesemia and transient hypoparathyroidism occurred in the recovering process of diabetic ketoacidosis. There was neither tetany nor spasmin this patient. Two days after the cessation of omeprazole, his serum total calcium, serum phosphateand PTH all returned to normal range.

Conclusion: Physicians should alert transient hypoparathyroidism in diabetic ketoacidosis patients, especially those treated with proton pump inhibitors.

Introduction

Diabetic ketoacidosis (DKA) is characterized by hyperglycemia, metabolic acidosis and increased ketones, caused by starvation of any cause in conjunction with an inter current illness and has been described mainly in type 1 diabetes but also in type 2 and gestational diabetes. Diabetic patients frequently develop a constellation of electrolyte disorders. These patients are often potassium-, magnesium- and phosphate-depleted, especially in the context of diabetic ketoacidosis or hyperglycemic nonketotic hyperosmolar syndrome(HHS). But hypocalcemia due to transient hypoparathyroidism was seldom reported previously. Transient impaired secretion of parathyroid hormone(PTH) from the parathyroid glands can lead to functional hypoparathyroidism, which is commonly seen in profound hypomagnesemia. In this proton-pump era, proton-pump inhibitor (PPI) is commonly used in DKA patients when their first onset is digestive symptom. We report one case of hypocalcemia, hypophosphatemia and transient hypoparathyroidism in diabetic ketoacidosis possibly associated with the use of PPI.

Case Presentation

A 43-year-old man presented to the emergency room with vomiting, diarrhea and fatigue for 2 days. He passed liquid stool more than 30 times a day and only had gruel and soft drinks. His vomit sample contained blood. His medical reviews showed he was diagnosed as diabetes mellitus for 11 years with first onset of thirsty, polydipsia and polyuria. He was prescribed with insulin on diagnosis and in poor treatment compliance. He suffered from diabetic ketosis and acute pancreatitis 2 years ago. Laboratory investigation showed the following: serum glucose 36.2mmol/L, total cholesterol 6.93mmol/L, total triglyceride 2.81mmol/L, low density lipoprotein cholesterol 4.06mmol/L, serumα-amylase 213U/L. On admission, his serum total calcium and magnesium were both within the normal range(Ca2+ 2.26mmol/L, reference range 2.00-2.75 mmol/L; Mg2+ 1.26 mmol/L, reference range 0.78-1.27 mmol/L), his serum phosphate was a little higher than the upper limit of normalrange (1.84mmol/L, reference range 0.81-1.78 mmol/L). Arterial blood gazes demonstrated metabolic acidosis (pH 6.98, HCO3-<3mmol/L) with negative lactic acid. Further work-up revealed ketonuria (15mmol/L). His HbA1C was 13.9%. CT scan of the abdomen showed no abnormity. He was diagnosed as diabetic ketoacidosis. Intravenous fluid resuscitation and continuous insulin infusion was initiated. Omeprazole was started for possible upper gastrointestinal hemorrhage. After about six hours of initial fluid resuscitation and continuous insulin infusion, hypocalcemia became obvious and calcium supplement was added into the fluid. One day after intensive fluid resuscitation, pH and bicarbonate level returned to normal range. Urinalysis showed no ketonuria. Serum PTH was severely below the normal range with hypophosphatemia and a decrease of serum magnesium. Standard meal test showed absolute insulin/c-peptide deficiency. He was finally diagnosed as type 1 diabetes mellitus and switched to subcutaneous lispro insulin and glargine insulin treatment. On the four day after admission, fecal occult blood was negative and omeprazole was stopped. We intensively tested the serum electrolyte. On the sixth day after admission, his serum total calcium, serum phosphate and PTH all returned to normal range. There was neither tetany nor spasmin this patient. Hypocalcemia, hypophosphatemia, relative hypomagnesemia and transient hypoparathyroidism occurred in the recovering process of diabetic ketoacidosis (Table 1). Unfortunately we didn’t monitor the serum magnesium level as frequently as we monitored the serum calcium level, so we were unable to figure out the lowest level of serum magnesium. But a U-shape of the serum magnesium level could be predicted based on Table 1.

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    Table 1:

    Changes of laboratory test during treatment of diabetic ketoacidosis.

Discussion

Significant Ca2+ and Mg2+ losses have been demonstrated during ketoacidosis and the first hours of recovery. Negative Ca2+ and Mg2+ balance occurs immediately following insulin withdrawal, progresses with acidosis and continues through the first few days of recovery. Martin et al measured serum and urine Ca2+ and Mg2+ concentrations in 29 patients with ketoacidosis and found that 28% were hypocalcemic when first seen [1Martin HE, Smith K, Wlison ML (1958) The fluid and electrolyte therapy of severe diabetic acidosis and ketosis. Am J Med 24: 376-389.]. Balance studies demonstrated that with standard treatment, large amouts of both Ca2+ and Mg2+ continued to be lost through the urine. After 12h of therapy, 73% of the patients were hypocalcemic and 55% were hypomagnesemic. Since hypocalcemic states are associated with defective pancreatic β-cell insulin release [2Yasuda K, Hurukawa Y, Okuyama M, Kikuchi M, Yoshinaga K (1975) Glucose tolerance and insulin secretion in patients with parathyroid disorders- effect of calcium on insulin release. N Engl J Med 292: 501-504.], it is possible that the impairment of residual insulin secretion that occurs after ketoacidosis is in part secondary to prolonged negative Ca2+ balance. The etiology of Ca2+ and Mg2+ loss is thought to be osmotic diuresis and the increased mobilization from bone of both ions induced by acidosis [3Wacker WE, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278: 712-717.,4Butler AM (1950) Diabetic coma. N Engl J Med 243: 648-659.]. Glycosuria, without acidosis, has been shown to triple urinary Ca2+ and double urinary Mg2+ excretion [5al-Ghamdi SM, Cameron EC, Sutton RA (1994) Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis 24: 737-752.]. Acidosis might also inhibit renal tubular reabsorption of Ca2+ ions. Administration of insulin, 0.1U/kg, has been shown to cause small increase in urinary Mg2+ excretion [6Lindeman RD (1969) Influence of various nutrient and hormones on urinary divalent cation excretion. Ann NY Acad Sci 162: 802-809.]. When Mg2+ depletion becomes severe, a reversible state of hypoparathyroidism can occur. Hypomagnesemia appears to inhibit both synthesis and releases of PTH and also decreases peripheral responsiveness to PTH [7Rude RK, Oldham SB, Sharp CF Jr, Singer FR (1978) Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 47: 800-806.]. There is evidence that diabetic patientsare relatively hypoparathyroid [8McNair P, Christensen MS, Madsbad S, Christiansen C, Transbøl I (1981) Hypoparathyroidism in diabetes mellitus. Acta Endocrinol (Copenh) 96: 81-86.]. In fact, a mild shift downwards in the set-point for PTH secretion in patients with insulin-dependent diabetes mellitus as well as a diminished parathyroid gland responsiveness to hypocalcemia in uremic diabetic patients have been reported [9Schwarz P, Sørensen HA, Momsen G, Friis T, Transbøl I, et al. (1992) Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clampstudy. Acta Endocrinol (Copenh) 126: 260-263.,10 Heidbreder E, Götz R, Schafferhans K, Heidland A (1986) Diminished parathyroid gland responsiveness to hypocalcemiain diabetic patients with uremia. Nephron 42: 285-289.]. The state of hypoparathyroidism would abolish the homeostatic Ca2+ control mechanisms that normally maintain serum Ca2+ concentrations despite continued loss. The patient in our study had evidence of impaired parathyroid responsiveness.

Decompensated diabetes mellitus with ketoacidosis is associated with excessive phosphate loss due to osmotic diuresis. Despite phosphate depletion, the serum phosphate concentration at presentation is usually normal or even high, because both insulin deficiency and metabolic acidosis cause a shift of phosphate out of cells [11Kebler R, McDonald FD, Cadnapaphornchai P (1985) Dynamicchanges in serum phosphorus levels in diabetic ketoacidosis. Am J Med 79: 571-576.]. Administration of insulin and fluids, and correction of ketoacidosis may reveal phosphate deficiency and cause a sharp decrease in plasma phosphate concentration due to intracellular shift [12Fisher JN, Kitabchi AE (1983) A randomized study of phosphatetherapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 57: 177-180.]. The routine administration of phosphate during treatment of DKA and HHS is not recommended since randomized trials failed to show any clinical benefit from phosphate administration [12Fisher JN, Kitabchi AE (1983) A randomized study of phosphatetherapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 57: 177-180.-15Wilson HK, Keuer SP, Lea AS, Boyd AE, Eknoyan G (1982) Phosphate therapy in diabetic ketoacidosis. Arch Intern Med 142: 517-520.]. What is more, correction of hypophosphatemia may have adverse effects, such as hypocalcemia and hypomagnesemia [12Fisher JN, Kitabchi AE (1983) A randomized study of phosphatetherapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 57: 177-180.,13Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA (2006) Hyperglycemic crises in adult patients with diabetes: aconsensus statement from the American Diabetes Association. Diabetes Care 29: 2739-2748.,16Winter RJ, Harris CJ, Phillips LS, Green OC (1979) Diabetic ketoacidosis. Induction of hypocalcemia and hypomagnesemiaby phosphate therapy. Am J Med 67: 897-900.]. Careful phosphate replacement is required in patients with severe hypophosphatemia of less than 1.0 mg/dl (0.32mmol/L) and in patients who develop cardiac dysfunction, hemolytic anemia, or respiratory depression [13Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA (2006) Hyperglycemic crises in adult patients with diabetes: aconsensus statement from the American Diabetes Association. Diabetes Care 29: 2739-2748.,17Evans KJ, Thompson J, Spratt SE, Lien LF, Vorderstrasse A (2014) The implementation and evaluation of an evidence-based protocol to treat diabetic ketoacidosis: a quality improvement study. Adv Emerg Nurs J 36: 189-198.].

A number of cases of PPI therapy causing hypomagnesemia and hypomagnesemic hypoparathyroidism are reported in literature [18 Epstein M, McGrath S, Law F (2006) Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med 355: 1834-1836.,19François M, Lévy-Bohbot N, Caron J, Durlach V (2008) Chronic use of proton-pump inhibitors associated with giardiasis: A rare cause of hypomagnesemic hypoparathyroidism? Ann Endocrinol (Paris) 69: 446-448.]. PPI-induced hypocalcemia maybe due to hypomagnesemia, which may cause a functional hypoparathyroidism, resulting in suppressed parathyroid hormone secretion [20 Rude RK, Oldham SB, Singer FR (1976) Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf) 5: 209-224]. It is usually believed that hypomagnesemic hypoparathyroidism does not respond to calcium supplementation until magnesium levels are replenished, but recent case reports show the serum calcium levels normalized before magnesium supplementation was introduced. This sequence of events differed from the typical pattern, which might explain why hypomagnesemic hypoparathyroidism has been unrecognized.

Conclusion

The clinical implication of this case is important. Physicians should alert transient hypoparathyroidism in diabetic ketoacidosis patients. We suggest that magnesium and calcium levels should be measured in diabetic ketoacidosis patients especially those treated with proton-pump inhibitors.

Conflict of Interest

The authors have no multiplicity of interest to disclose.

  1. Martin HE, Smith K, Wlison ML (1958) The fluid and electrolyte therapy of severe diabetic acidosis and ketosis. Am J Med  24: 376-389.
  2. Yasuda K, Hurukawa Y, Okuyama M, Kikuchi M, Yoshinaga K (1975) Glucose tolerance and insulin secretion in patients with parathyroid disorders- effect of calcium on insulin release. N Engl J Med 292: 501-504.
  3. Wacker WE, Parisi AF (1968) Magnesium metabolism. N Engl J Med 278: 712-717.
  4. Butler AM (1950) Diabetic coma. N Engl J Med 243: 648-659.
  5. al-Ghamdi SM, Cameron EC, Sutton RA (1994) Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis 24: 737-752.
  6. Lindeman RD (1969) Influence of various nutrient and hormones on urinary divalent cation excretion. Ann NY Acad Sci 162: 802-809.
  7. Rude RK, Oldham SB, Sharp CF Jr, Singer FR (1978) Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 47: 800-806.
  8. McNair P, Christensen MS, Madsbad S, Christiansen C, Transbøl I (1981) Hypoparathyroidism in diabetes mellitus. Acta Endocrinol (Copenh) 96: 81-86.
  9. Schwarz P, Sørensen HA, Momsen G, Friis T, Transbøl I, et al. (1992) Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clampstudy. Acta Endocrinol (Copenh) 126: 260-263.
  10. Heidbreder E, Götz R, Schafferhans K, Heidland A (1986) Diminished parathyroid gland responsiveness to hypocalcemiain diabetic patients with uremia. Nephron 42: 285-289.
  11. Kebler R, McDonald FD, Cadnapaphornchai P (1985) Dynamicchanges in serum phosphorus levels in diabetic ketoacidosis. Am J Med 79: 571-576.
  12. Fisher JN, Kitabchi AE (1983) A randomized study of phosphatetherapy in the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab  57: 177-180.
  13. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA (2006) Hyperglycemic crises in adult patients with diabetes: aconsensus statement from the American Diabetes Association. Diabetes Care  29: 2739-2748.
  14. Keller U, Berger W (1980) Prevention of hypophosphatemia byphosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma. Diabetes 29: 87-95.
  15. Wilson HK, Keuer SP, Lea AS, Boyd AE, Eknoyan G (1982) Phosphate therapy in diabetic ketoacidosis. Arch Intern Med  142: 517-520.
  16. Winter RJ, Harris CJ, Phillips LS, Green OC (1979) Diabetic ketoacidosis. Induction of hypocalcemia and hypomagnesemiaby phosphate therapy. Am J Med 67: 897-900.
  17. Evans KJ, Thompson J, Spratt SE, Lien LF, Vorderstrasse A (2014) The implementation and evaluation of an evidence-based protocol to treat diabetic ketoacidosis: a quality improvement study. Adv Emerg Nurs J 36: 189-198.
  18. Epstein M, McGrath S, Law F (2006) Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med 355: 1834-1836.
  19. François M, Lévy-Bohbot N, Caron J, Durlach V (2008) Chronic use of proton-pump inhibitors associated with giardiasis: A rare cause of hypomagnesemic hypoparathyroidism? Ann Endocrinol (Paris) 69: 446-448.
  20. Rude RK, Oldham SB, Singer FR (1976) Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf) 5: 209-224.

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