CASE-LETTER
Essential Hypernatremia: Evidence of Reset Osmostat in the Absence of Demonstrable Hypothalamic Lesions
S
erum sodium concentration and serum osmolality are tightly regulated by water homeostasis, which is mediated by thirst, antidiuretic hormone (ADH) and the kidneys.1 Hypernatremia, which is defined as serum sodium concentration greater than 145 mEq/L, represents a water deficit due to water loss or net solute gain.2 The term “Essential hypernatremia” originally coined by Welt in 1962 refers to patients who have sustained chronic hypernatremia, intact renal tubular function with normal creatinine clearance and hypodipsia despite elevated plasma osmolarity (usually greater than 290mOsml/L) with inability to correct their plasma osmolarity despite fluid loading.3 It is frequently characterized as a shift of the set point for thirst and osmoregulation.4,5 In these cases, structural abnormalities in the hypothalamic-pituitary axis, as a result of trauma, tumor or infiltrative diseases such as Langerhans cell histiocytosis are usually identified.6 We describe a hypodipsic hypernatremic patient with no demonstrable hypothalamic-pituitary lesions with a shift in the osmotic threshold for vasopressin secretion and thirst toward a plasma osmolarity higher than normal. A 46-year-old man with medical history significant for diabetes mellitus type 1 and paroxysmal atrial fibrillation presented to our institution with decreased oral intake, nausea and vomiting, in the setting of uncontrolled blood sugars. On presentation, he had a blood pressure of 100/70 mm Hg, heart rate of 110 beats/min with no orthostatic blood pressure changes. Physical examination revealed dry mucous membranes but was otherwise unremarkable. Laboratory data were notable for marked hypernatremia with a serum sodium concentration of 168 mEq/L and elevated blood urea nitrogen/creatinine ratio (Table 1). Because he was clinically volume depleted secondary to osmotic diuresis from hyperglycemia, he received a total of 8 L of 0.45% normal saline over a period of 48 hours. Subsequently, his renal function returned to baseline. After correction of his volume status, he developed water diuresis, despite being hypernatremic and hyperosmotic (at a serum sodium of 154 mEq/L, his urine osmolality was 140 mOsm/L). He also remained hypodipsic at these elevated plasma osmolality values. He was unable to maintain a normal plasma sodium (plasma sodium remained between 155 and 160 mEq/L) during the rest of his hospital stay and even on outpatient follow-up after discharge. He was again readmitted 6 months later with for asymptomatic hypernatremia. At presentation, he had a blood pressure of 125/70 mm Hg, heart rate of 85 beats/min with no evidence of orthostasis. His examination was unremarkable. Laboratory data revealed a blood sugar of 130 mg/dL and hypernatremia (serum sodium concentration 159 mEq/L and plasma osmolality 345 mOsm/L) with a normal kidney function (Table 1). The plasma ADH level measured by radioimmunoassay at this time was appropriately high (10 pg/mL). He was started on continuous infusion of dextrose in water solution (D5W: 8 L over 3 days), which decreased his serum sodium from a peak of 159 mEq/L to a nadir of 154 mEq/L as shown in Table 1. During this presentation, there was clear evidence of The American Journal of the Medical Sciences
water diuresis when serum sodium was 154 mEq/L (urine osmolarity of 142 mOsm/L). The plasma ADH level measured by radioimmunoassay was very low (0.1 pg/mL) despite a plasma osmolarity of 308. After the D5W infusion was stopped, the serum sodium gradually increased and remained between the ranges of 155 to 160 mEq/L without any thirst perception. Subsequently, we administered a desmopressin challenge (1 mg subcutaneous injection). Serum and urine osmolarity at baseline, 30 minutes and 60 minutes after desmopressin administration were measured. Plasma and urine osmolarity were similar across these different time points. Other pertinent laboratories included a normal serum cortisol (8:00 AM cortisol was 19.8 mg/dL) and a normal prolactin level (13.4 ng/mL). In the setting of his sustained hypernatremia and hypodipsia, we suspected a hypothalamic-pituitary lesion. A brain magnetic resonance imaging with and without contrast was negative for any lesions in the hypothalamic-pituitary axis but was notable for the “absence of the posterior pituitary bright spot.” Patient on subsequent follow-up continues to be hypernatremic with baseline serum sodium ranging between 155 and 160 mEq/L and with minimal sensation of thirst. Our patient has chronic hypernatremia with no evidence of a clinically significant deficit of extracellular fluid volume, as reflected by the absence of oliguria, azotemia or decreased urinary sodium content at his baseline. Spontaneous fluid intake was low, relative to the elevated plasma osmolality. In addition, he had evidence of an impaired ADH response to osmotic stimuli with a partially intact volume response. During his first admission, he was able to partially concentrate his urine in response to volume depletion. After volume resuscitation, he manifested evidence of brisk water diuresis, while still being hypernatremic and hyperosmotic. During his second admission, he was clinically euvolemic and acute water loading failed to normalize plasma osmolality as he again manifested brisk water diuresis despite being hypernatremic. On both admissions, his ability to maximally concentrate his urine was also partially impaired as he was not able to achieve urine osmolalities higher than 670 mOsm/L. In addition, he was able to dilute his urine close to 140 mOsm/L, at a plasma sodium concentration of 154 mEq/L reflecting some residual ADH activity. In a steady state of hypernatremia, the natriuretic effect of chronic hypernatremia would be expected to result in some level of volume depletion.4 This patient had baseline serum sodium (between 155 and 160 mEq/L) with urine osmolalities ranging between 600 and 670 mOsm/L. This would suggest that chronic hypernatremia is probably associated with some subclinical volume depletion.4,5 Hypovolemia in these cases may not be clinically detected because it is mild and could be missed on clinical examination. His ability to dilute urine (osmolality as low as 140 mOsm/L) and concentrate it (osmolality as high as 670 mOsm/L), along with the range of urine sodium concentrations noted after acute water loading and volume depletion indicate relatively intact renal tubular function. In addition, failure of increased fluid intake to completely normalize plasma osmolarity in our patient indicates that defective thirst is not the sole explanation for his presentation. Although essential hypernatremia can be associated with diabetes insipidus (either complete or partial), this was not the case in our patient.6 This was evident by minimal change in serum and urine osmolarity with desmopressin administration. Although essential hypernatremia is usually described in association with hypothalamic-pituitary structural lesions, this was not the case in our patient. The only potentially significant finding was the absence
Volume 347, Number 4, April 2014
341
Case-Letter
TABLE 1. Serum and urine electrolytes in our patient during the first and second admissions First admission
Second admission
Days of hospitalization
Day 1
Day 2
Day 3
Day 1
Day 2
Day 3
Serum sodium (mEq/L) Blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) Plasma osmolarity (mOsm/L) Urine sodium (mEq/L) Urine osmolarity (mOsm/L) Urine creatinine (mg/dL)
168 96 3 378 ,10 670 156.8
163 75 2.1 339 74 485 52.5
154 13 1.1 320 80 140 50.8
159 18 1.1 345 79 608 169
155 15 1.1 314 60 250 130
154 14 1.1 308 40 142 50
of “posterior pituitary bright spot” on T1 imaging on magnetic resonance imaging. “Posterior pituitary bright spot” is defined as a neurohypophyseal T1 hyper intense signal in the sella behind the adenohypophysis.7,8 Its presence is an index of normality and its ectopia has been associated with growth hormone deficiency.7 Some authors claim that it is an accumulation of proteins, whereas others claim that it is an accumulation of phospholipid vesicles or ADH products.7 The absence of pituitary bright spot has been associated with Langerhans cell histiocytosis, diabetes insipidus and craniopharyngioma.9 The presence and size of the bright spot are thought to be reflective of the pituitary gland functional status.7,9 Our patient had evidence of essential hypernatremia with loss of the posterior pituitary bright spot. We hypothesized that these clinical findings could be secondary to small vessel disease or a small ischemic stroke in the thirst and osmoregulation center. The presence of multiple risk factors for stroke (poorly controlled diabetes, African American race and history of paroxysmal atrial fibrillation) supports this hypothesis. A second possibility could be an autoimmune disease involving antibodies against the osmoregulatory center.5 In summary, this case demonstrates that essential hypernatremia can occur in the absence of obvious hypothalamicpituitary lesions revealing a potential link with the absence of posterior pituitary bright spot. Further research is still needed to better elucidate this association and gain better understanding of the mechanisms underlying essential hypernatremia.
*Manish Suneja, MD Nader Makki, MD Sarat Kuppachi, MD Division of Nephrology Department of Internal Medicine University of Iowa Hospitals and Clinics Iowa City, Iowa *E-mail: [email protected]
342
The authors have no financial or other conflicts of interest to disclose. REFERENCES 1. Gennari FJ. Current concepts. Serum osmolality. Uses and limitations. N Engl J Med 1984;310:102–5. 2. Colombo N, Berry I, Kucharczyk J, et al. Posterior pituitary gland: appearance on MR images in normal and pathologic states. Radiology 1987;165:481–5. 3. Mahoney JH, Goodman AD. Hypernatremia due to hypodipsia and elevated threshold for vasopressin release. Effects of treatment with hydrochlorothiazide, chlorpropamide and tolbutamide. N Engl J Med 1968;279:1191–6. 4. Oh MS, Carroll HJ. Essential hypernatremia: is there such a thing? Nephron 1994;67:144–5. 5. Hiyama TY, Matsuda S, Fujikawa A, et al. Autoimmunity to the sodium-level sensor in the brain causes essential hypernatremia. Neuron 2010;66:508–22. 6. Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: a case report of reversibility with 2-chlorodeoxyadenosine. J Pediatr Hematol Oncol 2003;25:575–7. 7. Zuccoli G, Ferrozzi F, Troiso A, et al. An unusual MR presentation of the neurohypophyseal “bright spot” in pituitary dwarfism. Clin Imaging 2001;25:9–11. 8. Pivonello R, De Bellis A, Faggiano A, et al. Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab 2003;88:1629–36. 9. Ross EJ, Christie SB. Hypernatremia. Medicine (Baltimore) 1969;48: 441–73.
Volume 347, Number 4, April 2014
Essential Hypernatremia: Evidence of Reset Osmostat in the Absence of Demonstrable Hypothalamic Lesions
S
erum sodium concentration and serum osmolality are tightly regulated by water homeostasis, which is mediated by thirst, antidiuretic hormone (ADH) and the kidneys.1 Hypernatremia, which is defined as serum sodium concentration greater than 145 mEq/L, represents a water deficit due to water loss or net solute gain.2 The term “Essential hypernatremia” originally coined by Welt in 1962 refers to patients who have sustained chronic hypernatremia, intact renal tubular function with normal creatinine clearance and hypodipsia despite elevated plasma osmolarity (usually greater than 290mOsml/L) with inability to correct their plasma osmolarity despite fluid loading.3 It is frequently characterized as a shift of the set point for thirst and osmoregulation.4,5 In these cases, structural abnormalities in the hypothalamic-pituitary axis, as a result of trauma, tumor or infiltrative diseases such as Langerhans cell histiocytosis are usually identified.6 We describe a hypodipsic hypernatremic patient with no demonstrable hypothalamic-pituitary lesions with a shift in the osmotic threshold for vasopressin secretion and thirst toward a plasma osmolarity higher than normal. A 46-year-old man with medical history significant for diabetes mellitus type 1 and paroxysmal atrial fibrillation presented to our institution with decreased oral intake, nausea and vomiting, in the setting of uncontrolled blood sugars. On presentation, he had a blood pressure of 100/70 mm Hg, heart rate of 110 beats/min with no orthostatic blood pressure changes. Physical examination revealed dry mucous membranes but was otherwise unremarkable. Laboratory data were notable for marked hypernatremia with a serum sodium concentration of 168 mEq/L and elevated blood urea nitrogen/creatinine ratio (Table 1). Because he was clinically volume depleted secondary to osmotic diuresis from hyperglycemia, he received a total of 8 L of 0.45% normal saline over a period of 48 hours. Subsequently, his renal function returned to baseline. After correction of his volume status, he developed water diuresis, despite being hypernatremic and hyperosmotic (at a serum sodium of 154 mEq/L, his urine osmolality was 140 mOsm/L). He also remained hypodipsic at these elevated plasma osmolality values. He was unable to maintain a normal plasma sodium (plasma sodium remained between 155 and 160 mEq/L) during the rest of his hospital stay and even on outpatient follow-up after discharge. He was again readmitted 6 months later with for asymptomatic hypernatremia. At presentation, he had a blood pressure of 125/70 mm Hg, heart rate of 85 beats/min with no evidence of orthostasis. His examination was unremarkable. Laboratory data revealed a blood sugar of 130 mg/dL and hypernatremia (serum sodium concentration 159 mEq/L and plasma osmolality 345 mOsm/L) with a normal kidney function (Table 1). The plasma ADH level measured by radioimmunoassay at this time was appropriately high (10 pg/mL). He was started on continuous infusion of dextrose in water solution (D5W: 8 L over 3 days), which decreased his serum sodium from a peak of 159 mEq/L to a nadir of 154 mEq/L as shown in Table 1. During this presentation, there was clear evidence of The American Journal of the Medical Sciences
water diuresis when serum sodium was 154 mEq/L (urine osmolarity of 142 mOsm/L). The plasma ADH level measured by radioimmunoassay was very low (0.1 pg/mL) despite a plasma osmolarity of 308. After the D5W infusion was stopped, the serum sodium gradually increased and remained between the ranges of 155 to 160 mEq/L without any thirst perception. Subsequently, we administered a desmopressin challenge (1 mg subcutaneous injection). Serum and urine osmolarity at baseline, 30 minutes and 60 minutes after desmopressin administration were measured. Plasma and urine osmolarity were similar across these different time points. Other pertinent laboratories included a normal serum cortisol (8:00 AM cortisol was 19.8 mg/dL) and a normal prolactin level (13.4 ng/mL). In the setting of his sustained hypernatremia and hypodipsia, we suspected a hypothalamic-pituitary lesion. A brain magnetic resonance imaging with and without contrast was negative for any lesions in the hypothalamic-pituitary axis but was notable for the “absence of the posterior pituitary bright spot.” Patient on subsequent follow-up continues to be hypernatremic with baseline serum sodium ranging between 155 and 160 mEq/L and with minimal sensation of thirst. Our patient has chronic hypernatremia with no evidence of a clinically significant deficit of extracellular fluid volume, as reflected by the absence of oliguria, azotemia or decreased urinary sodium content at his baseline. Spontaneous fluid intake was low, relative to the elevated plasma osmolality. In addition, he had evidence of an impaired ADH response to osmotic stimuli with a partially intact volume response. During his first admission, he was able to partially concentrate his urine in response to volume depletion. After volume resuscitation, he manifested evidence of brisk water diuresis, while still being hypernatremic and hyperosmotic. During his second admission, he was clinically euvolemic and acute water loading failed to normalize plasma osmolality as he again manifested brisk water diuresis despite being hypernatremic. On both admissions, his ability to maximally concentrate his urine was also partially impaired as he was not able to achieve urine osmolalities higher than 670 mOsm/L. In addition, he was able to dilute his urine close to 140 mOsm/L, at a plasma sodium concentration of 154 mEq/L reflecting some residual ADH activity. In a steady state of hypernatremia, the natriuretic effect of chronic hypernatremia would be expected to result in some level of volume depletion.4 This patient had baseline serum sodium (between 155 and 160 mEq/L) with urine osmolalities ranging between 600 and 670 mOsm/L. This would suggest that chronic hypernatremia is probably associated with some subclinical volume depletion.4,5 Hypovolemia in these cases may not be clinically detected because it is mild and could be missed on clinical examination. His ability to dilute urine (osmolality as low as 140 mOsm/L) and concentrate it (osmolality as high as 670 mOsm/L), along with the range of urine sodium concentrations noted after acute water loading and volume depletion indicate relatively intact renal tubular function. In addition, failure of increased fluid intake to completely normalize plasma osmolarity in our patient indicates that defective thirst is not the sole explanation for his presentation. Although essential hypernatremia can be associated with diabetes insipidus (either complete or partial), this was not the case in our patient.6 This was evident by minimal change in serum and urine osmolarity with desmopressin administration. Although essential hypernatremia is usually described in association with hypothalamic-pituitary structural lesions, this was not the case in our patient. The only potentially significant finding was the absence
Volume 347, Number 4, April 2014
341
Case-Letter
TABLE 1. Serum and urine electrolytes in our patient during the first and second admissions First admission
Second admission
Days of hospitalization
Day 1
Day 2
Day 3
Day 1
Day 2
Day 3
Serum sodium (mEq/L) Blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) Plasma osmolarity (mOsm/L) Urine sodium (mEq/L) Urine osmolarity (mOsm/L) Urine creatinine (mg/dL)
168 96 3 378 ,10 670 156.8
163 75 2.1 339 74 485 52.5
154 13 1.1 320 80 140 50.8
159 18 1.1 345 79 608 169
155 15 1.1 314 60 250 130
154 14 1.1 308 40 142 50
of “posterior pituitary bright spot” on T1 imaging on magnetic resonance imaging. “Posterior pituitary bright spot” is defined as a neurohypophyseal T1 hyper intense signal in the sella behind the adenohypophysis.7,8 Its presence is an index of normality and its ectopia has been associated with growth hormone deficiency.7 Some authors claim that it is an accumulation of proteins, whereas others claim that it is an accumulation of phospholipid vesicles or ADH products.7 The absence of pituitary bright spot has been associated with Langerhans cell histiocytosis, diabetes insipidus and craniopharyngioma.9 The presence and size of the bright spot are thought to be reflective of the pituitary gland functional status.7,9 Our patient had evidence of essential hypernatremia with loss of the posterior pituitary bright spot. We hypothesized that these clinical findings could be secondary to small vessel disease or a small ischemic stroke in the thirst and osmoregulation center. The presence of multiple risk factors for stroke (poorly controlled diabetes, African American race and history of paroxysmal atrial fibrillation) supports this hypothesis. A second possibility could be an autoimmune disease involving antibodies against the osmoregulatory center.5 In summary, this case demonstrates that essential hypernatremia can occur in the absence of obvious hypothalamicpituitary lesions revealing a potential link with the absence of posterior pituitary bright spot. Further research is still needed to better elucidate this association and gain better understanding of the mechanisms underlying essential hypernatremia.
*Manish Suneja, MD Nader Makki, MD Sarat Kuppachi, MD Division of Nephrology Department of Internal Medicine University of Iowa Hospitals and Clinics Iowa City, Iowa *E-mail: [email protected]
342
The authors have no financial or other conflicts of interest to disclose. REFERENCES 1. Gennari FJ. Current concepts. Serum osmolality. Uses and limitations. N Engl J Med 1984;310:102–5. 2. Colombo N, Berry I, Kucharczyk J, et al. Posterior pituitary gland: appearance on MR images in normal and pathologic states. Radiology 1987;165:481–5. 3. Mahoney JH, Goodman AD. Hypernatremia due to hypodipsia and elevated threshold for vasopressin release. Effects of treatment with hydrochlorothiazide, chlorpropamide and tolbutamide. N Engl J Med 1968;279:1191–6. 4. Oh MS, Carroll HJ. Essential hypernatremia: is there such a thing? Nephron 1994;67:144–5. 5. Hiyama TY, Matsuda S, Fujikawa A, et al. Autoimmunity to the sodium-level sensor in the brain causes essential hypernatremia. Neuron 2010;66:508–22. 6. Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: a case report of reversibility with 2-chlorodeoxyadenosine. J Pediatr Hematol Oncol 2003;25:575–7. 7. Zuccoli G, Ferrozzi F, Troiso A, et al. An unusual MR presentation of the neurohypophyseal “bright spot” in pituitary dwarfism. Clin Imaging 2001;25:9–11. 8. Pivonello R, De Bellis A, Faggiano A, et al. Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology. J Clin Endocrinol Metab 2003;88:1629–36. 9. Ross EJ, Christie SB. Hypernatremia. Medicine (Baltimore) 1969;48: 441–73.
Volume 347, Number 4, April 2014
