Hyperparathyroid Crisis and Acute Necrotizing Pancreatitis Presenting ...

Hyperparathyroid Crisis and Acute Necrotizing Pancreatitis Presenting as Diabetic Ketoacidosis

James E. Payne, Jr., MD, Colonel, USAF, MC, Washington, D.C. Robert J. Tanenberg, MD,* Washington, D.C.

If a patient with known diabetes mellitus presents with a history of nausea and vomiting, dehydration and lethargy progressing to coma, most experienced physicians will suspect diabetic ketoacidosis. In some patients the syndrome of ketoacidosis may be the first manifestation of diabetes which causes the patient to seek medical attention. Sometimes the abdominal symptoms of ketoacidosis are so severe as to be clinically indistinguishable from acute pancreatitis, appendicitis or other causes of acute abdominal disorders. When ketoacidosis is confirmed by the typical laboratory findings of hyperglycemia, ketonemia and reduction of serum carbon dioxide content [I], treatment is appropriately directed at the metabolic abnormalities. The patient usually responds predictably. If the abominal symptoms continue or progress after correction of the metabolic abnormalities, the clinician may suspect another disease. For example, diabetics may develop acute pancreatitis. However, pancreatitis is unlikely to cause diabetes unless there has been extensive destruction of the pancreas [2]. Nausea, vomiting, dehydration, fever, abdominal pain and coma may be the presenting symptoms of many other diseases, including hyperparathyroid crisis [a]. The physical findings in hyperparathyroid crisis may occasionally simulate an acute surgical disorder of the abdomen [4]. If a patient presenting with hyperparathyroid crisis also has ketoacidosis, clinical diagnosis of the hyperparathyroidism might be easily overlooked because of the overlapping From the General Surgery Service and EndocrinologyService, Malcolm Grow U. S. Air Force Medical Center. Andrews Air Force Base. Maryland. Requests for reprints should’be addressed to James El Payne, Jr., MD, Wilford Hall U. S. Air Force Medical Center, Department of General Surgery, Lackland Air Force Base, Texas 76236. * Present Mess: Diabetes Research Laboratory, Georgetown University School of Medicine, Veterans Administration Hospital, Washington, D.C. 20422.

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symptoms and because ketoacidosis is seen so much more often than hyperparathyroid crisis. Recently, we treated a patient who presented with diabetic ketoacidosis, hyperparathyroid crisis and acute necrotizing pancreatitis occurring simultaneously. He also had marked phosphate depletion which may account for some of the neurologic and neuromuscular debility seen in patients with hyperparathyroidism or other conditions [5]. This case is remarkable not only for its considerable diagnostic and therapeutic challenges but also because the patient represents the first survivor of hyperparathyroid crisis presenting in association with acute necrotizing pancreatitis. Case Report A 34 year old Air Force pilot was brought to a local Air Force hospital on May 18 in a semicomatose state. His wife stated that 7 days before admission he had abdominal pain, recurrent nausea and vomiting. The vomiting continued until the day of admission. The abdominal pain was apparently never severe and was not associated with fever or chills. Several bowel movements over this period were described as black and tarry. Over the next several days he had become progressively weaker but refused to seek medical attention. He was finally brought to the emergency room by ambulance when he became delirious. Medical history obtained from the outpatient medical records and the patient’s wife revealed that he had had an episode suggesting ureteral colic 8 years earlier. Although no stone was recovered, the clinical picture and intravenous pyelograms were compatible with his having passed a calculus. A metabolic work-up at that time included serum calcium values of 11.0,lO.O and 10.6 mg/lOO ml with concomitant serum phosphorus levels of 3.3,3.0 and 2.7 mg/ 100 ml, respectively. There was no further evaluation and the patient had no further episodes of colic. There was no history of diabetes mellitus, peptic ulcer, pancreatitis or ethanol or drug abuse. An appendectomy had been per-

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formed 13 years earlier. There was no family history of diabetes or other metabolic diseases. On admission the patient was stuporous but arousable, although incoherent and disoriented. Blood pressure was 160/92 mm Hg, pulse 100 beats/min, respiratory rate 32 and temperature 99.3’F rectally. He appeared to be severely dehydrated. The abdomen was soft and bowel sounds were present. Rectal examination revealed decreased sphincter tone and guaiac-positive stool. Laboratory values on admission are listed in Table I. Diabetic ketoacidosis was diagnosed and treated with intravenous insulin and fluid replacement with saline solution. Two units of whole blood were administered. He also received 100 mEq of potassium chloride and 1 ampule of sodium bicarbonate during the first 24 hours of treatment. Although vital signs and laboratory parameters of

TABLE I

Crisis, Pancreatitis and Ketoacidosis

ketoacidosis were improved by the next day, the patient’s mental status was unchanged and he was transferred to Malcolm Grow Air Force Medical Center for further evaluation and treatment. On admission there the patient was confused, disoriented and responsive only to pain. He was still very dehydrated, as evidenced by dry mucous membranes, sunken eyeballs and tenting of the skin of the chest and abdomen. His blood pressure was 144/68 mm Hg, pulse 104 beats/ min, respiratory rate 18 and temperature 1Ol’F rectally. The abdomen was scaphoid and seemed diffusely tender, and no bowel sounds were heard. A lumbar puncture revealed a normal opening pressure with no cells; glucose was 286 and total protein 65 mg/lOO ml. Cultures of the cerebrospinal fluid subsequently proved negative. Blood and urine cultures were also taken on admission. Both stool

Summary of Laboratory Data

Normal Range Chemistry Sodium (mEq/liter) Potassium (mEq/liter) Chloride (mEq/liter) CO* (mEq/liter) Glucose (mg/lOO ml) Acetone Blood urea nitrogen (mg/lOO ml) Creatinine (mg/lOO ml) Uric acid (mg/lOO ml) Calcium (mg/lOO ml) Phosphorus (mg/lOO ml) Magnesium (mEq/liter) Albumin (g/l00 ml) Total protein (g/100 ml) Total bilirubin (mg/lOO ml) SGOT (units/ml) Alkaline phosphatase (units) Amylase (units/l00 ml) Lipase (units) Osmolality serum water (mOsmol/kg) Hematology Hemoglobin (g/l00 ml) Hematocrit White blood cell count Segmented neutrophillband Lymphocytelfvlonocyte Urine Glucose Acetone Protein White blood cells/ red blood cells Calcium (g)/total volume Amylase (units/hr) Osmolality

135-148 3.5-5.5 90-109 21-32 70-100 0 a-23

Admission, Dover AFB, May 18

122 5.9 83 9.8 1200 1:8 116

Admission, MGMC, May 19

138 4.2 104 28 205 1:i 117

2 Days Before Parathyroid Surgery, June 11

133 4.4 104 20 185 21

0.4-1.5 2.5-7.0

1.9 25.9

8.9-11.0 2.5-4.5 1.4-2.3 3.5-5.2 5.9-8.2

.. .

15.9 2.2 1.9 2.9 5.1

0.5-1.5

.

1.3

0.5

117 11.1

13 6.4

63 0.7 369

279’on 612

a-33 4.5-12.0 38-200 O-1.0 281-297

14.0-18.0 42-52 4,000-10.000 40-7010-5 20-5010-15

. ... . . 431245

. .

78

. 10.4 31.2 17,300 8813 613

11.3 33.1 17,100 54130 719

4-F Large 5.0 25-3074-5

4+ Small 6.0 26-5Olrare

. . . .

6.70 0 (in 9,500 ml/24O) 450 on 5124

1.4 7.0 on 5122; 4.4 on 6122 10.7 4.6 2.2 2.8 5.3

6.7 29.3 16,900 84/4 514 3+ Negative 7.0 occ/occ

. . . .

Occ = occasional.

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C4** 16.0

. 2.5

6.

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I1 9 6

L

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I I 13

11 10

12

I 15 14

I 17 16

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guaiac and a nasogastric aspirate were positive for occult blood. Laboratory values on admission (May 19) are listed in Table I. At that time the cause of the continued stuporous mental condition was unclear. Although he had no prior indication of diabetes mellitus, it seemed obvious that the original presenting signs were characteristic of diabetic ketoacidosis, and this diagnosis had been confirmed by the initial laboratory data. These abnormalities had been largely corrected by the time of admission to our institution. We were initially unwilling to accept the markedly elevated serum calcium as a true value, especially when associated with low serum albumin. The patient was admitted to the intensive care unit, a central venous pressure catheter placed, and vigorous fluid replacement started. Because of the likelihood of sepsis of unknown cause, clindamycin and gentamicin were initiated after appropriate cultures were taken. When repeated serum calcium and phosphorus determinations confirmed the admission value, it was strongly suspected that the patient’s condition was at least partially due to acute hypercalcemia. For the next 2 days he was treated with furosemide, 100 mg/hour, and intravenous fluids, and serum and urine electrolytes were carefully monitored and urine loss replaced to maintain a normal extracellular fluid volume. He also received a single dose of mithramycin intravenously (25 pg/kg). The serum calcium level responded dramatically to the treatment, falling to 9.7 mg/lOO ml by May 22 (Figure 1). The patient’s mental status, however, remained unchanged. With the serum phosphorus level falling from 2.2 to 1.3 mg percent by the fourth day of hospitalization we suspected a phosphate depletion syndrome [6-g]. Thirty mmol of intravenous potassium

I 19 16

#,,I, 21 23 20

22

25 24

27 26

29 28

30

1

Figure 1. Summaty of serum calcium and phosphorous levels.

phosphate was administered over the next 24 hours, which raised the serum phosphorus to 3.4 mg/lOO ml. During the first 8 hours of the potassium phosphate infusion, the patient’s mental status returned to normal. During the calcium washout with saline solution and furosemide, the patient continued to have a high fever, up to 104’F rectally. Abdominal examination showed persistent mild peritoneal irritation. A blood culture taken on admission was growing E. coli. Gastroscopy revealed exudative esophagitis, but the stomach and duodenal mucosa were normal and no source of bleeding was found. An abdominal roentgenogram was compatible with adynamic ileus. An intravenous pyelogram was normal. An upper gastrointestinal series using Gastrografine revealed a large mass posterior to the stomach and medial to the C-loop with depression of the duodenal junction. In addition, the presence of mottled gas suggested an abscess in the lesser sac (Figure 2). Surgical exploration of the abdomen on the fifth hospital day revealed acute necrotizing pancreatitis associated with a large retroperitoneal abscess. The pancreas was almost totally excised by aspirating and scooping out the necrotic remains. The large abscess cavity was adequately drained externally. The patient’s postoperative course was very difficult due to multiple catastrophic problems. Recurring hypercalcemia required repeated administration of saline solution and furosemide diuresis, additional intravenous mithramycin, and the subsequent use of oral neutral phosphate and intravenous calcitonin (Figure 1). The diabetes mellitus was controlled by daily NPH insulin with supplemental regular insulin based on blood sugar values. Nutritional support included supplements given by intravenous hyperalimentation, enteric hyperalimentation

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Figure 3. Large parathyroid adenoma diameter 3 cm excised from the right tracheoesophageai groove.

Comments

Figure 2. Upper gastrointestinal roentgeuogram showing a large abscess in the lesser sac.

through a nasogastric tube, and the addition of pancreatic enzymes to the diet. There was no further evidence of gastrointestinal bleeding, although anemia persisted. Parenteral antibiotics were continued. By June 11the patient’s clinical condition was markedly improved and he was afebrile. The laboratory values are listed in Table I. A parathormone value of 171 pg/ml (with a calcium value of 14.4 mg/lOO ml) was obtained from an outside laboratory. Despite this low parathormone value (normal range 163 to 347 pg/ml) and a laboratory report of a “98 percent chance that hypercalcemia was not due to parathyroid disease,” a parathyroid tumor was strongly suspected. Neck exploration was performed on the 29th hospital day. At surgery a parathyroid adenoma with a diameter of 3 cm was found in the tracheoesophageal groove on the right side (Figure 3). No other parathyroid abnormality could be identified. Surgery was prolonged and complicated by division of the right recurrent laryngeal nerve, which was splayed out over the tumor, and by laryngeal edema, which required tracheostomy postoperatively. The calcium level fell below 10 mg/lOO ml several hours after surgery and remained 8 to 9 mg/lOO ml throughout recovery. The patient was discharged on the 47th hospital day on a full diabetic diet, 18 units of NPH insulin daily, and supplemental pancreatic enzymes. Six weeks after discharge the tracheostomy tube was removed and his voice was grossly normal. He has remained asymptomatic and normocalcemic.


It is now well recognized that pancreatitis and hyperparathyroidism may be associated [IO-121, although the cause is not clear [13,14]. It is also known that chemical or clinical diabetes mellitus may result from severe pancreatitis [Z-1 71. It is unusual, however, for a previously healthy patient to present with diabetic ketoacidosis as a result of acute necrotizing pancreatitis. Root [18] described four patients with ketoacidosis and coma unresponsive to insulin and intravenous fluid therapy who were subsequently found to have acute necrotizing pancreatitis at autopsy. However, in all of these cases the diagnosis of diabetes had been made at least 10 months before the fatal episode of necrotizing pancreatitis and ketoacidosis. Although there have been other similar patients [19], review of the literature suggests that diabetic ketoacidosis as a result of acute necrotizing pancreatitis from any cause is relatively uncommon. Clearly, the operative finding of a totally necrotic pancreas and an associated retroperitoneal abscess in our patient could account for the destruction of both total exocrine and endocrine gland function. Hyperparathyroid trisis (parathyrotoxicosis) was first described by Hanes [20] in 1939. The most common symptoms are vomiting, constipation, anorexia, weight loss, abdominal pain, fever and coma. Renal insufficiency usually occurs rapidly and is evidenced by increasing levels of blood urea nitrogen and serum phosphorus. The serum calcium is usually 17 mg/lOO ml or greater. Fink and Finfrock [3] reviewed the literature up to 1961 and collected 56 cases of hyperparathyroid crisis, 34 percent of which had associated pancreatitis. Mixter et al [21] postulated that pancreatitis in these patients was caused by an inspissation of calcium phosphate salts within pancreatic ductal systems or excess activation of trypsinogen to trypsin by the calcium ion. Baer and

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[22] suggest that microthrombi may play a role. Various investigators [23-251 have reported on patients with hyperparathyroid crisis who were found to have acute necrotizing pancreatitis or acute hemorrhagic pancreatitis at autopsy or who died during therapy. Others have reported the development of acute necrotizing or hemorrhagic pancreatitis after resection of a parathyroid tumor [22,26], occasionally with survival [27]. Until now, however, there have been no reported instances, to our knowledge, of successful treatment of a patient presenting with acute hyperparathyroid crisis and acute necrotizing pancreatitis simultaneously. Clinically, we were presented with a markedly volume-depleted patient who had not responded to appropriate treatment for diabetic ketoacidosis and who was apparently hypercalcemic from an unknown cause. In making the diagnosis of hyperparathyroid crisis, we theorized that the relatively moderate serum calcium elevation (15.9 mg/lOO ml) was spuriously low due to the low level of serum proteins. Since ionized calcium is in dynamic equilibrium with calcium bound to circulating proteins and anions (and since this equilibrium is maintained during alterations in serum proteins), one would expect total serum calcium to be 10 to 20 percent higher if serum proteins were normal. In retrospect, the underlying pancreatitis was probably also a factor in lowering the serum calcium level. We began the calcium washout technique using furosemide and saline solution recommended by Suki et al [28] and others [29,30] and intravenous administration of mithramycin. The sheer volume of fluid exchanged during this phase was phenomenal. During the first 24 hours of this treatment, the patient received 42,500 cc of fluid intravenously and had a urine output of 43,400 cc. (During subsequent regimens of furosemide and saline solution after abdominal surgery, fluid exchange of 25,000 cc/24 hours was not uncommon.) While highly successful in lowering serum calcium to a safer level, this treatment probably contributed initially to a further reduction of serum phosphorus (Figure 1). Hypophosphatemia can result from both diabetic ketoacidosis and hyperparathyroidism. It has been postulated that decreased intake, transcellular ionic shifts, and renal loss are factors in depressing serum phosphorus in both of these conditions [31]. Fasting, excessive vomiting, sepsis and treatment with insulin and intravenous fluids may have contributed to the hypophosphatemia in our patient. Severe muscle weakness, hyporeflexia, mental obtundation, coma New

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and other neuromuscular syndromes have been described in patients with hypophosphatemia. We were gratified by our patient’s rapid response to intravenous potassium phosphate for treatment of his phosphate depletion syndrome. We did not consider continuing that treatment for hypercalcemia, however, because of the known serious complications of intravenous phosphate administration in patients with hypercalcemia [32-341. We now felt able and obligated to determine the cause of sepsis and anemia. Peptic ulceration is another abdominal condition associated with hyperparathyroid crisis but was not found on endoscopy. Gastrointestinal hemorrhage is characteristic of parathormone poisoning in experimental animals [20] and is occasionally seen in patients with acute pancreatitis [35]. When roentgenographic studies demonstrated the retroperitoneal mass and surgery confirmed that the large lesser sac abscess was secondary to a totally necrotic pancreas, we were better able to account for the confusing aspects of the early symptoms and laboratory findings. While the patient recovered from a postoperative course that was initially very stormy, we were able to maintain control of the serum calcium level by the previously described methods. Because of this we were able to delay neck exploration to “buy time” for control of sepsis and nutritional rehabilitation. After neck surgery the patient’s metabolic condition was quite good. He showed no inclination to hypoparathyroidism, as is seen in many patients [29]. During surgery we were concerned about missing a second tumor (which proved fatal in the patient of Kleppel et al [23]), thus prolonging the operation and probably contributing to laryngeal edema. Finally, this case supports early operation in patients with minimal symptoms of primary hyperparathyroidism. Our patient probably had diagnosable hyperparathyroidism for 8 years before his severe illness. Earlier elective surgery might have avoided the severe life-threatening illness and its sequelae. Summary The case history of a patient who presented with diabetic ketoacidosis and was subsequently found to have hyperparathyroid crisis complicated by acute necrotizing pancreatitis and phosphate depletion syndrome is reviewed. The interaction of these diseases and their treatment is discussed. The simultaneous presentation of hyperparathyroid crisis and acute necrotizing pancreatitis is rare, and no instance of survival has been reported previously.

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References 1. Steinke J, Soeldner JS. Diabetes mellitus. Harrison’s principles of internal medicine. Chap 95. 8th ed. New York: McGrawHill, 1977: 577. 2. Walsh CH, Soler NG, Malins JM. Diabetes mellitus and primary hyperparathyroidism. Postgrad Med J 1975;51:446. 3. Fink WJ, Finfrock HD. Fatal hyperparathyroid crisis associated with pancreatitis. Am Surg 1961;27:424. 4. Bradlow BA, Segal N. Acute hyperparathyroidism with electrocardiographic changes. Br Med J 1956;2:197. 5. Moser CR, Fessel WJ. Rheumatic manifestations of hypophosphatemia. Arch Intern Med 1974;134:674. 6. Lotz M, Zisman E, Bartter FL. Evidence for a phosphate depletion syndrome in man. N Engl J Med 1968;278:409. 7. Sugarman H, Travis S, Pollock T, et al. Alterations in oxygen transport and red cell metabolism as a consequence of hypophosphatemia in intravenous hyperalimentation (IVH). Clin Res 1971;19:487. 8. Weintraub MI. Hypophosphatemia mimicking acute GuillainBarre-Strohl syndrome: a complication of parenteral hyperalimentation. JAMA 1976;235:1040. 9. Lichtman MA. Miller DR, Cohan J, Waterhouse C. Reduced red cell glycolysis,2,3 diphosphoglycerate and adenosine triphosphate concentration and increased hemoglobin-oxygen affinity caused by hypophosphatemia. Ann Intern Med 1971;74:562. 10. Cope 0, Culver PJ, Mixter CG, Nardi GL. Pancreatitis, a diagnostic clue to hyperparathyroidism. Ann Surg 1957;145: 857. 11. Meltzer LE, Palmon FR Jr, Paik YK, Custer RP. Acute pancreatitis secondary to hypercalcemia of multiple myeloma. Ann Intern Med 1962;57:1008. 12. Rosin RD. Pancreatitis and hyperparathyroidism. Postgrad Med J 1976;52(604):95. 13. Paloyan E, Lawrence AM, Straus FH. Paloyan D, Harper PV, Cummings D. Alpha cell hyperplasia in calcific pancreatitis associated with hyperparathyroidism. JAMA 1967;200: 757. 14. Paloyan E, Paloyan D, Harper PV. The role of glucagon hypersecretion in the relationship of pancreatitis and hyperparathyroidism. Surgery 1967;62:167. 15. DeTakats G, MacKenzie WD. Acute pancreatitic necrosis and its sequelae. Ann Surg 1932:96:418. 16. Polayes SH, Linder W, Rothenberg RE. Pancreatic necrosis. JAMA 1933;100:1155. 17. Gambill EE, Baggenstoss AH, VanPatter WG, Power MH. Acute hemorrhagic pancreatitis. Gastroenterology 1948; 11:37 1.



18. Root HF. Diabetic coma and acute pancreatitis with fatty liver. JAMA 1937;108:777. 19. Tully GT, Lowanthal JJ. The diabetic coma of acute pancreatitis. Ann Intern Med 1958;48:310. 20. Hanes FM. Hyperparathyroidism due to parathyroid adenoma, with death from parathormone intoxication. Am J Med Sci 1939;197:85. 21. Mixter CG, Keynes WM, Cope 0. Further experience with pancreatitis as a diagnostic clue to hyperparathyroidism. N Engl J Med 1962;266:265. 22. Baer L, New HC. Intravascular clotting and acute pancreatitis in primary hyperparathyroidism. Ann Intern Med 1966;64: 1062. 23. Kleppel NH, Goldstein MH, LaVeen HH. Hypercalcemic crisis and pancreatitis in primary hyperparathyroidism. JAMA 1965;192:916. 24. Henricksson C. Acute hyperparathyroidism and acute pancreatitis. Acta Pathol Microbial Stand 1960;50:42. 25. Schwhan D, Dabels J, Pietsch P. Zur klinik und therapie des primaren hyperparathyreodismus. Abt Endokrinol Stoffwechselkrankh. Klin Inn Med. Univ. Restock. Z Gesamte Inn Med 1974;29/22:919. 26. Bell GO, Arnold WT. Primary hyperparathyroidism: report of two unusual cases. Lahey Clin Bull 1950;6:197. 27. Cattell RB, Warren KW. Surgery of the pancreas. Philadelphia: WB Saunders, 1954:91. 28. Suki WN, Yuim JJ, VonMinden M, Saller-Herbert C, Eknoyan G. Martinez-Maldonado M. Acute treatment of hypercalcemia with furosemide. N Engl J Med 1970;283:836. 29. Schweitzer VG, Thompson NW, Harness JK, Nishiyama RH. Management of severe hypercalcemia caused by primary hyperparathyroidism. Arch Surg 1978; 113:373. 30. O’Dorisio TM. Hypercalcemic crisis. Heart Lung 1978;7:425. 31. Fitzgerald FT. Hypophosphatemia. Adv Intern Med 1978;23: 137. 32. Breuer RI, LaBauer J. Caution in the use of phosphates in the treatment of severe hypercalcemia. J Clin Endocrinol 1967;27:695. 33. Shakney S, Hasson J. Precipitious fall in serum calcium, hypotension, and acute renal failure after intravenous phosphate therapy for hypercalcemia. Ann Intern Med 1967; 66:906. 34. Fulmer DH, Dimick AB, Rothschild EO, Laird Myers WP. Treatment of hypercalcemia: comparison of intravenously administered phosphate, sulfate, and hydrocortisone. Arch Intern Med 1972;129:923. 35. Sahebjam H, Gillespie L, Ferris PJ, Danovitch SH. Rectal bleeding as the presenting symptom of acute pancreatitis. Am J Gastroenterol 1970;54:388.

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