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 Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 37  |  Issue : 2  |  Page : 72-75

Refractory hypercalcemia in a patient with disseminated tuberculosis: A successful case of prolonged treatment with corticosteroid


1 Department of Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan, Republic of China
2 Department of Medical Pulmonary and Critical Care, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan, Republic of China

Date of Web Publication21-Apr-2017

Correspondence Address:
Dr. Shih-Wei Wu
Department of Medical Pulmonary and Critical Care, Tri-Service General Hospital, No. 325, Cheng-Kung Road, Section 2, Neihu 114, Taipei, Taiwan
Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_92_15

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  Abstract 

Pulmonary tuberculosis (TB) is a major health problem worldwide. Hypercalcemia has been described in patients with TB. Symptomatic hypercalcemia is treated using aggressive hydration and short courses of systemic corticosteroid to decrease serum calcium levels. The duration and dosage of steroid treatment are not well established. The present report describes a case of a 66-year-old man diagnosed with pulmonary TB, who received anti-TB therapy for 4 months, after which he presented with an episode of hypercalcemia with acute kidney injury. Systemic corticosteroids were prescribed for 8 weeks and gradually tapered. Subsequently, the chest plain film revealed new infiltrates, and his hypercalcemia relapsed. Immune reconstitution inflammatory syndrome (IRIS) was suspected. Calcium levels normalized 1 week after the steroid was increased and the anti-TB drugs were maintained. Prednisolone was gradually withdrawn over a 1-month period and completely stopped during the 7th month of anti-TB therapy. The patient remained under observation for 1 more month, during which his calcium levels remained in the normal range. Therefore, the use of steroids for approximately 4 weeks might be suggested for TB-IRIS in HIV-uninfected patients.

Keywords: Pulmonary tuberculosis, hypercalcemia, acute kidney injury, immune reconstitution inflammatory syndrome


How to cite this article:
Huang IH, Wu SW. Refractory hypercalcemia in a patient with disseminated tuberculosis: A successful case of prolonged treatment with corticosteroid. J Med Sci 2017;37:72-5

How to cite this URL:
Huang IH, Wu SW. Refractory hypercalcemia in a patient with disseminated tuberculosis: A successful case of prolonged treatment with corticosteroid. J Med Sci [serial online] 2017 [cited 2019 Jul 23];37:72-5. Available from: http://www.jmedscindmc.com/text.asp?2017/37/2/72/204986


  Introduction Top


Hypercalcemia is most commonly caused by malignancy or primary hyperparathyroidism [1],[2],[3] and is also associated with granulomatous diseases. This asymptomatic endocrine dysfunction is common in patients with pulmonary tuberculosis (TB). The prevalence of hypercalcemia in these patients is estimated to be 16%–28% in the United States and India [4] and depends on Vitamin D status and calcium intake.[5] Hypercalcemia may provoke acute kidney injury (AKI). Symptomatic hypercalcemia is treated using aggressive hydration and short courses of systemic corticosteroids to decrease serum calcium levels. In general, renal function improves as serum calcium levels decrease. However, the duration and dosage of steroid treatment for symptomatic hypercalcemia are not well established.

Here, we describe a case of a patient with pulmonary TB having hypercalcemia who exhibited AKI during the 5th month of anti-TB therapy. AKI responded well to corticosteroids but relapsed when the prednisolone dose was reduced after 2 months of steroid treatment. The relapse was associated with immune reconstitution inflammatory syndrome (IRIS).


  Case Report Top


A 66-year-old indigenous man from Taiwan presented with a 4-month history of low back pain, which was being treated with nonsteroidal anti-inflammatory drugs. He had a poor appetite and cough and had experienced a weight loss of 10 kg in 3 months before hospitalization. He had no remarkable medical history and was not taking any regular medications. On examination, he was alert and febrile (38.4°C) and had a sinus tachycardia (127 beats/min), with blood pressure of 83/45 mmHg and oxygen saturation of 98% on ambient air. His respiratory rate was 20 breaths/min, and his chest examination revealed scattered crackles.

A chest radiograph obtained at presentation revealed bilateral reticulonodular infiltration with upper and middle lung predominance and obliteration of the bilateral costophrenic angles [Figure 1]a. Laboratory results revealed anemia (10.8 g/dL), hyponatremia (125 mmol/L), and elevated C-reactive protein (18.48 mg/dL). White blood cell count was elevated (19330/μL), of which neutrophils was accounted for 79.7% and lymphocytes for 12.4%. The patient had renal impairment (creatinine, 1.6 mg/dL; estimated glomerular filtration rate [eGFR], 55 mL/min/1.73 m 2), with a serum calcium level of 8.2 mg/dL and low albumin level of 2.4 g/dL. Corrected calcium level of approximately 9.2 mg/dL was in the normal range.
Figure 1: (a) The chest radiograph shows bilateral reticulonodular infiltration with opacities and obliteration of the bilateral costophrenic angles, (b) computed tomography scan of the abdomen revealed erosive changes in the L1–L2 vertebral endplates along with a calcified mass within the left psoas muscle

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Because of TB infection, the patient was isolated in a private room with negative air pressure. Sputum smears and cultures were performed to detect acid-fast bacilli. The administration of broad-spectrum antibiotics was initiated. A computed tomography (CT) scan of the abdomen revealed erosive changes in the L1–L2 vertebral endplates along with a calcified mass within the left psoas muscle [Figure 1]b. A lumbar magnetic resonance imaging scan revealed a bony destruction of L1 and L2 vertebral bodies as well as the injury of the L1–L2 disc. An abscess of approximately 2.8 cm × 2.5 cm × 4.0 cm in size was noted in the left psoas muscle, with a connection to the L1–L2 disc. Pyogenic spondylodiscitis or tuberculous spondylitis with psoas abscess was suspected. CT-guided percutaneous drainage was performed, and aspirated abscess fluid was used for bacteriological analyses, including mycobacterial culture and periodic acid–Schiff staining. Sputum was smear-positive for acid-fast bacilli, and results were confirmed by the polymerase chain reaction method. TB was confirmed by abscess fluid culture. The patient tested negative for HIV. He was started on 600 - mg rifampicin, 400 - mg isoniazid, 1250 - mg ethambutol, and 1000 - mg pyrazinamide once daily for 2 months. Mycobacterium tuberculosis cultures of all specimens were positive and sensitive to first-line anti-TB drugs. Two months after initiating treatment, the patient's condition improved. His complete blood count was normal, renal function had improved (blood urea nitrogen, 43 mg/dL; creatinine, 0.9 mg/dL; and eGFR, 89.45 mL/min/1.73 m 2), and ionized calcium level was 5.3 mg/dL. The patient felt better and had gained 6 kg of weight. However, the acid-fast stain remained positive.

At approximately 4 months of anti-TB therapy, periodic acid–Schiff staining of sputum was still positive. The patient had decreased urine output and felt drowsy. Biochemical analyses revealed mild hypercalcemia (ionized calcium level, 6.08 mg/dL; normal range, 4.50–5.30 mg/dL). Therefore, appropriate volume repletion with isotonic sodium chloride solution and loop diuretic therapy was performed. Subsequent investigations revealed worsening hypercalcemia and renal impairment (ionized calcium level, 6.33 mmol/L; creatinine, 4.0 mg/dL; and eGFR, 15.99 mL/min/1.73 m 2). Adrenal insufficiency was excluded. A decrease in plasma parathyroid hormone was noted (8.0 pg/dL), suggesting a slight possibility of hyperparathyroidism. Unfortunately, his total (25-hydroxy) Vitamin D and 1,25-hydroxy Vitamin D levels were not measured. Hypercalcemia associated with TB was highly suspected, and therefore, the patient was asked to reduce his calcium intake and avoid sun exposure. Prednisolone was prescribed at 10 mg daily, and his serum calcium levels gradually decreased. Therefore, steroid dosage was decreased after 2 months of steroid treatment, i.e., during the 6th month of anti-TB therapy. The patient subsequently developed fever, malaise, and dyspnea. The chest plain film revealed new infiltrates and his had hypercalcemia relapsed. IRIS after long-term steroid use was suspected. Calcium levels normalized again 1 week after the steroid dose was increased and the anti-TB drugs were maintained. Prednisolone was then gradually withdrawn over a 1-month period and completely stopped during the 7th month of anti-TB therapy. The patient remained under observation for 1 more month, during which his calcium levels persisted within the normal range.


  Discussion Top


Hypercalcemia is a common clinical problem and is most commonly caused by malignancy, or primary hyperparathyroidism.[2],[3],[4] Hypercalcemia has also been associated with granulomatous diseases, such as sarcoidosis and TB.[1] Risk factors for hypercalcemia include intake of Vitamin D and calcium as well as sun exposure.[6] The etiology of hypercalcemia might be related to elevated serum calcitriol concentrations due to activated macrophages in granulomas.[7] Patients with hypercalcemia may be asymptomatic or may exhibit constipation, anorexia, muscle weakness, and fatigue. Hypercalcemia can also cause polyuria, dehydration, polydipsia, nocturia, AKI, cognitive dysfunction, coma, and cardiac arrest.[8]

Hypercalcemia treatment in patients with TB is aimed at controlling M. tuberculosis infection to decrease calcitriol synthesis and directly lower blood calcium levels. Initial treatment should involve aggressive hydration with a loop diuretic, such as furosemide, and avoidance of thiazide diuretics to increase the circulating volume and urinary output of calcium. In addition to these measures, calcitonin, bisphosphonates, and low-dose glucocorticoid therapy also play a role in hypercalcemia treatment.[9] Corticosteroid decreased calcitriol production by macrophages and lowered serum calcium levels within 3–5 days after the initial dose.[1] However, the duration and dose of corticosteroid are not well established, and it is unclear at which point in time the corticosteroids can be tapered.

TB infection was associated with IRIS in immunodeficiency patients.[10] Patients recovering from immunodeficiency experience overwhelming inflammatory responses that paradoxically appear as symptoms of worsening infection, such as clinical or radiological worsening of preexisting tuberculous lesions or the development of new parenchymal opacities in a patient who had initially exhibited improvement. The mechanism underlying paradoxical reactions is not well understood, but changes in the ability to respond to tuberculin proteins following the initiation of anti-TB therapy has been proposed as the possible mechanism. The frequency of TB-IRIS has been estimated to be 2%–23% in different studies.[10],[11] Although daily short- or long-term low doses of corticosteroids (<20 mg of prednisone or equivalent) does not cause significant immunocompromised, immune deficiencies can aggravate by other factors, such as stress, old age, poor nutrition, and disseminated infection. To date, there is no consensus on the standard treatment of TB-IRIS. Prolonged anti-TB treatment may be required. Treatment with systemic corticosteroids, anti-inflammatory therapy, or immunomodulatory therapy may be considered. A double-blind, randomized, placebo-controlled clinical trial revealed that a 4-week course of prednisone reduces the need for hospitalization and accelerates the improvements in symptoms of TB-IRIS.[12]

In this case, systemic corticosteroids were prescribed for 8 weeks and gradually tapered because serum calcium levels had normalized and acid-fast bacilli smear of sputum tested positive. Subsequently, hypercalcemia (ionized calcium level, 5.65 mg/dL) followed by an acute exacerbation of chronic renal failure (serum creatinine, 2.5 mg/dL) with transient worsening of radiographic abnormalities were noticed, which later normalized after steroid dose was increased and anti-TB drugs were maintained. IRIS was suspected. Prednisolone was gradually withdrawn again over a 1-month period. The patient remained under observation for 1 more month, during which his calcium level remained in the normal range.


  Conclusion Top


Steroid use for approximately 4 weeks might be suggested for TB-IRIS in HIV-uninfected patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ariyan CE, Sosa JA. Assessment and management of patients with abnormal calcium. Crit Care Med 2004;32 4 Suppl: S146-54.  Back to cited text no. 1
    
2.
Dent DM, Miller JL, Klaff L, Barron J. The incidence and causes of hypercalcaemia. Postgrad Med J 1987;63:745-50.  Back to cited text no. 2
    
3.
Edelson GW, Kleerekoper M. Hypercalcemic crisis. Med Clin North Am 1995;79:79-92.  Back to cited text no. 3
    
4.
Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med 1979;90:324-8.  Back to cited text no. 4
    
5.
Fuss M, Karmali R, Pepersack T, Bergans A, Dierckx P, Prigogine T, et al. Are tuberculous patients at a great risk from hypercalcemia? Q J Med 1988;69:869-78.  Back to cited text no. 5
    
6.
Davies PD, Brown RC, Woodhead JS. Serum concentrations of Vitamin D metabolites in untreated tuberculosis. Thorax 1985;40:187-90.  Back to cited text no. 6
    
7.
Dylewska M, Wieliczko M. Hypercalcemia. Wiad Lek 2013;66:307-10.  Back to cited text no. 7
    
8.
Deftos LJ. Hypercalcemia in malignant and inflammatory diseases. Endocrinol Metab Clin North Am 2002;31:141-58.  Back to cited text no. 8
    
9.
Lai RP, Nakiwala JK, Meintjes G, Wilkinson RJ. The immunopathogenesis of the HIV tuberculosis immune reconstitution inflammatory syndrome. Eur J Immunol 2013;43:1995-2002.  Back to cited text no. 9
    
10.
Cheng SL, Wang HC, Yang PC. Paradoxical response during anti-tuberculosis treatment in HIV-negative patients with pulmonary tuberculosis. Int J Tuberc Lung Dis 2007;11:1290-5.  Back to cited text no. 10
    
11.
Jung JW, Shin JW, Kim JY, Park IW, Choi BW, Seo JS, et al. Risk factors for development of paradoxical response during anti-tuberculosis treatment in HIV-negative patients with pleural tuberculosis. Tohoku J Exp Med 2011;223:199-204.  Back to cited text no. 11
    
12.
Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381-90.  Back to cited text no. 12
    


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