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Keywords:

  • sepsis;
  • systemic inflammatory response syndrome;
  • multiple organ dysfunction syndrome;
  • hypercalcemia;
  • 1α,25- dihydroxyvitamin D

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Vignette
  5. Discussion
  6. References

A 54-year-old man was transferred to our ICU because of systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). He died after 38 days of intensive care. During treatment, his serum calcium (Ca) levels continued to increase and reached 3.95 mmol/L, while the ionized Ca levels reached 2.30 mmol/L before his death. He presented with severe kidney injury, pancreatitis, and hemorrhagic gastric erosion that worsened his prognosis; these were possibly associated with the hypercalcemia. His circulating 1α,25-dihydroxyvitamin D [1,25(OH)2D] level was elevated (75.7 to 204 pg/mL), whereas the levels of 25-hydroxyvitamin D, parathyroid hormone, and parathyroid hormone–related peptide were not. Liver histology revealed immunoreactivity for 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1) in some of the hepatocytes, in which the localization pattern was similar to that of lysozyme-positive hepatocytes. Our ICU has previously encountered 22 similar MODS patients who presented with hypercalcemia over the last 8 years. SIRS with severe kidney and liver injuries are common clinical findings in hypercalcemic patients with MODS. Of the 23 hypercalcemic MODS patients, including the present patient, 17 had circulating 1,25(OH)2D levels exceeding 70 pg/mL despite severe kidney injury. Extrarenal activation of CYP27B1 seems to play a role in the development of hypercalcemia in this disease condition. Clinicians need to be aware that severe hypercalcemia may occur in MODS patients. © 2010 American Society for Bone and Mineral Research


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Vignette
  5. Discussion
  6. References

Multiple organ dysfunction syndrome (MODS) is a critical condition that requires intensive treatment. Control of serum mineral and electrolyte levels is essential in these patients. Hypercalcemia must be avoided in these patients because it is likely to worsen the prognosis by inducing renal dysfunction, gastrointestinal hemorrhage, and acute pancreatitis.1

Hypocalcemia is thought to be a common clinical symptom among critically ill patients, particularly those with sepsis.2, 3 However, we have recently observed that some patients with MODS actually present with progressive hypercalcemia. Here, we present a typical case and discuss the pathophysiologic background of this disease.

Clinical Vignette

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Vignette
  5. Discussion
  6. References

A 54-year-old man was transferred to our ICU for intensive treatment. He had no prior history of sarcoidosis or other chronic granulomatous inflammatory diseases. He had suffered from end-stage liver failure owing to primary biliary cirrhosis and had received a living-related-donor partial liver transplantation (LLT)4 3 months before the present episode. The operation was performed successfully without any major complications. However, massive ascetic fluid appeared 3 months after the operation, and jaundice appeared subsequently. Urinary volume decreased gradually, and the patient then was transferred to the ICU because of anuria, dyspnea, and conscious loss.

On admission to the ICU, his height was 172.6 cm, and his body weight was 72.9 kg. Arterial blood pressure was 73/47 mmHg, and his pulse rate was 113 beats/min. His body temperature was 38.2°C, and his respiratory rate was 28 breaths/min. His Glasgow Coma Scale score was E2V2M4. Systemic jaundice was evident. Decreased respiratory sound with coarse crackles was audible at the bilateral lower back. Facial and limb edema was noted, and ascitic signs were positive. Bowel helminth sounds were not audible. Laboratory findings were as follows: total protein 3.8 g/dL, albumin 2.5 g/dL, total bilirubin 46.9 mg/dL, direct bilirubin 39.3 mg/dL, amylase 301 IU/L, ammonium 117 mg/dL, urea nitrogen 112 mg/dL, creatinine 3.02 mg/dL, sodium 134 mEq/L, potassium 6.3 mEq/L, chloride 98 mEq/L, calcium 1.33 mmol/L, inorganic phosphate 5.3 mg/dL, magnesium 1.5 mg/dL, C-reactive protein 4.13 mg/dL, and white blood cell count 18,340/µL. His PaO2 was 58 mmHg and PaCO2 was 31 mmHg under oxygen inhalation (10 L/min) via a facial mask.

Artificial ventilation support was started immediately after the ICU admission with continuous catecholamine infusion. Acute blood purification therapy, including continuous hemodiafiltration (CHDF), plasma exchange, and polymyxin B hemoperfusion,5 was performed subsequently. Antibacterial agents were administered because Staphylococcus aureus and Escherichia coli were detected in his sputa and pleural/ascitic fluid.

Although his serum calcium (Ca) level was below the standard level on admission to the ICU, the level continued to increase during treatment. However, biochemical examination repeatedly revealed that his circulating levels of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), and parathyroid hormone–related peptide (PTHrP) were not above the standard level. On the other hand, despite severe kidney injury, his 1α,25-dihydroxyvitamin D [1,25(OH)2D] level was very high. However, the fluctuation in his serum 1,25(OH)2D level was not parallel with that of the Ca level (Fig. 1). The hypercalcemia was refractory to treatment with incadronate disodium.

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Figure 1. Changes in the Ca and ionized calcium (iCa) levels during the ICU stay. On admission, the patient's Ca and iCa levels were below the standard range (indicated by the gray zone). Thereafter, his Ca and iCa levels increased progressively, and the Ca level reached 3.95 mmol/dL and the iCa level reached 2.30 mmol/L before his death. His circulating 25(OH)D, parathyroid hormone, and parathyroid hormone–related peptide levels were not elevated, whereas 1,25(OH)2D levels remained above the standard range (10 to 70 pg/mL) during treatment. However, the 1,25(OH)2D levels did not fluctuate synchronically with the levels of Ca or iCa. The patient was refractory to incadronate disodium treatment. The patient died 38 days after admission. PEX = plasma exchange; PMX = polymyxin B hemoperfusion; PTH = parathyroid hormone; PTHrP = parathyroid hormone–related peptide.

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His water balance was managed by CHDF and drainage of ascitic fluid because his anuric/oliguric condition was sustained throughout the clinical course. Abdominal CT images obtained on the twenty-eighth day of his ICU stay revealed a swollen pancreas with neighboring fluid collection, indicating acute pancreatitis. Gastrointestinal perforation was not detected. Gastrointestinal bleeding appeared on day 30. Hemorrhagic gastric erosion without esophageal/gastric varices rupture or gastric/duodenal ulcers was detected by emergency upper gastrointestinal endoscopy. His systemic bleeding tendency progressed gradually, and he died on day 38 in the ICU owing to shock. His serum ionized calcium (iCa) level was 2.30 mmol/L just before his death.

Liver tissue was obtained by needle necropsy immediately after his death. Numerous CD68+ macrophages (Kupffer cells) had infiltrated from the portal triad to the liver lobules through the sinusoids (Fig. 2B). Intense lysozyme immunoreactivity was detected in the CD68+ Kupffer cells, whereas less intense immunoreactivity was detected in the sinusoidal epithelial cells and in some of the hepatocytes (Fig. 2C, D). An immunohistochemical examination was performed to detect the expression of 25(OH)D 1α-hydroxylase (CYP27B1) using a modified method, as reported elsewhere.6 The immunoreactivity of CYP27B1 was detected in hepatocytes, of which the localization pattern was similar to that of lysozyme-positive hepatocytes (Fig. 2E, F).

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Figure 2. Histochemical examination of liver tissue obtained by needle necropsy performed immediately after the death of the present patient. CD68+ macrophages (Kupffer cells) have infiltrated from the portal triad to the liver lobules through the sinusoids (A, B). Lysozyme immunoreactivity was detected in the CD68+ Kupffer cells and in the sinusoidal epithelial cells and some of the hepatocytes (C, D). The localization pattern of CYP27B1 immunoreactivity+ cells is similar to that of lysozyme+ hepatocytes but not to CD68+ Kupffer cells (E, F). (A, B: CD68 staining; C, D: lysozyme staining; E, F: CYP27B1 staining; G, H: negative control.)

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Vignette
  5. Discussion
  6. References

In the present case, hypercalcemia progressed along with SIRS and MODS. Pneumonia, intraperitoneal infection, acute pancreatitis, and acute liver graft rejection are possible background diseases for his SIRS. Although the Ca level in the dialysate and substitution fluid in the CHDF was 1.75 mmol/L, his serum Ca level exceeded this level. Ca and vitamin D agents were not administered during his treatment in the ICU. His hypercalcemia might have been responsible for the pancreatitis, hemorrhagic gastric erosion, protracted kidney injury, and loss of consciousness. Thus hypercalcemia seemed to have significantly worsened his prognosis.

To our knowledge, very few reports have described an association between hypercalcemia and MODS.7, 8 However, this is not the first patient with hypercalcemic MODS to be treated in our ICU. Between 2002 and 2009, 415 patients with MODS were treated in our ICU. The standard range for iCa is 1.12 to 1.32 mmol/L in our institution, and most patients with MODS presented with iCa levels below 1.12 mmol/L. However, of the 415 patients treated in our ICU, 23, including the present patient, had iCa levels exceeding 1.32 mmol/L. The characteristics of these patients are shown in Table 1. All 23 patients presented with SIRS and severe acute kidney injury. Renal replacement therapy was performed for water and electrolyte management in all 23 patients at the onset of hypercalcemia. The circulating 1,25(OH)2D level exceeded the upper limit of the standard physiologic range of 70 pg/mL in 17 of these 23 patients and exceeded 200 pg/mL in patients 2, 6, 15, 20, and 23. None of the patients presented with elevated levels of circulating PTH or PTHrP. Thus the elevated 1,25(OH)2D level seemed to play an important role in the development of hypercalcemia. However, none of the patients had a history of chronic granulomatous inflammatory diseases, and none was treated with exogenous vitamin D agents.

Table 1. Clinical Features of 23 MODS Patients Treated in Our ICU Between 2002 and 2009 Who Presented with Ionized Calcium Levels Exceeding 1.32 mmol/L
CaseAge/sexiCa (mmol/l)Ca (mmol/l)TB (mg/dl)Cre (mg/dl)PTH (pg/ml)PTHrP (pmol/l)1,25D (pg/ml)recipient for liver transplantation
  1. Note: Case 23 is the patient presented herein. For this case, the data represent the ranges of values observed during the patient's ICU stay. For the other 22 cases, the data were obtained at same time as the 1,25(OH)2D level to determine the cause of hypercalcemia. All these hypercalcemic patients were associated with SIRS, anuric/oliguric acute kidney injury that required renal replacement therapy at the time of blood sample collection, and severe liver injury with severely elevated total bilirubin levels. The circulating 1,25(OH)2D level was above the standard range (10 to 70 pg/mL) in 17 patients despite severe acute kidney injury. None of the patients had elevated levels of parathyroid hormone or parathyroid hormone–related peptide. Nevertheless, the 1,25(OH)2D and Ca levels were not significantly associated with each other among these patients.

146 M1.512.8523.91.3019.2107yes
246 M1.933.5842.63.225.3234yes
349 M1.743.4336.71.4116<.1130yes
455 M1.372.5840.01.1912<.1128no
572 M1.602.9825.82.6017.373no
667 M1.402.6022.01.4023<.1204no
760 M1.492.6827.92.449.233no
869 M1.582.9321.92.3822.392no
948 M1.512.8330.12.8118<.1101yes
1044 F1.673.2817.41.8412<.1142no
1167 M1.352.6514.32.8521<.162no
1279 F1.432.6834.00.9112.383no
1340 M1.512.8820.21.7617<.1110no
1452 M1.472.7012.82.1019.360yes
1562 M1.332.5327.93.5715<.1217no
1657 M1.392.6331.42.4519<.1110yes
1751 M1.482.7330.61.6722.23yes
1857 M1.683.2040.94.5817<.1124yes
1969 F1.863.5352.41.8617<.1102yes
2065 M1.422.6812.23.2921.2278no
2129 M1.583.1549.62.3718<.151no
2260 F1.472.7344.72.2417<.16yes
2351 M0.54–2.301.33–3.9537.8–61.21.26∼5.1214∼18<.175.7∼204yes

Of the 415 patients with MODS, 18 received LLT, and 11 of these patients presented with hypercalcemia. The other 12 patients with hypercalcemic MODS were not recipients of liver transplantation but did present with severe liver injury and marked jaundice (Table 1). Thus liver injury is likely to be another key factor in the development of hypercalcemia in this disease condition.

Because kidney function was severely impaired in these patients, the elevated circulating 1,25(OH)2D levels must be derived from extrarenal 1α-hydroxylation of 25(OH)D. In patients with granulomatous inflammatory diseases, hyperactive macrophages cause hypercalcemia through extrarenal 1α-hydroxylation of 25(OH)D.9 Similarly, the activation of macrophages through toll-like receptors (TLRs) is considered to be a key mechanism in immune abnormalities associated with SIRS/sepsis.10–12 TLR stimulation by lipopolysaccharide (LPS), a causative factor of sepsis, activated CYP27B1 expression in human macrophages.13, 14 Moreover, the liver is the organ that contains the greatest number of macrophages.15 Thus we anticipated that the liver-resident macrophages, namely, Kupffer cells, are the main cause of extrarenal 1α-hydroxylation of 25(OH)D in these patients.

Nevertheless, CYP27B1 immunoreactivity was unexpectedly not detected in the CD68+ Kupffer cells but was detected in some of the hepatocytes in the present patient. Another remarkable finding was the localization of lysozyme immunoreactivity. Since lysozyme is an enzyme responsible for bacteriolysis,16 its immunoreactivity is localized to cells performing phagocytosis, such as Kupffer cells. However, in the present patient, CD68+ cells and some hepatocytes showed immunoreactivity for lysozyme.

Liver plays a critical role in the removal of pathogens from the bloodstream, mainly through phagocytosis by Kupffer cells.17, 18 However, in a pathologic condition in which the demand for pathogen removal is increased while macrophage function is impaired, hepatocytes can acquire the ability to assimilate pathogens into the cytoplasm through “macrophage-like” phagocytosis.19 Lysozyme immunoreactivity also was detected in “macrophage-like” hepatocytes. In the present patient, this pathologic condition presumably was the result of sepsis and immunosuppressive therapy. Thus macrophage function was impaired in this patient, which may be related to the finding that CD68+ cells did not show CYP27B1 immunoreactivity. Moreover, the distribution pattern of CYP27B1-immunoreactive hepatocytes was similar to that of lysozyme-immunoreactive hepatocytes, namely, cells substituting for the functions of the impaired macrophages (Fig. 2CF). We need to examine more samples and apply additional techniques, such as dual-labeling immunohistochemistry, to confirm the localization of CYP27B1 immunoreactivity in similar cases.

In conclusion, we treated a patient with septic MODS who presented with critical hypercalcemia. Septic MODS is sometimes associated with hypercalcemia and severe kidney injury. Liver injury and enhanced extrarenal CYP27B1 activation are possible factors underlying the development of this condition. Clinicians should be aware that severe hypercalcemia may occur in patients with MODS.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Clinical Vignette
  5. Discussion
  6. References