Clinico-pathological conferenceedited by H.M. MoutsopouIos

Hyponatremia due to inappropriate secretion of antidiuretichormone in a patient with systemic lupus erythematosus

M.S. Elisaf, H.J. Milionis, A.A. Drosos

Department of Internal Medicine, MedicalSchool, University of loannina, loannina,Greece.

Moses S. Elisaf, MD, FRSH, Associate

Professor of Medicine; Haralampos J.AJilionis, MD, House Officer; Ale:xandrosA. Drosos, MD, FACR, Associate Professor

of Medicine/Rheumatology.

Please address correspondence and reprint

requests to: Pro! Alemndros A. Drosos,

MD, FACR, Department of Internal

Medicine, Medical School, University ofloannina, GR 451 10 Ioannina, Greece.

Clin Exp Rhellmatol 1999; 17: 223-226.

© Copyright CLINICAL AND

EXPERIMENTAL RHEUMATOLOGY 1999.

Key words:hyponatremia, hypokalemia,syndrome of inappropriate antidiuretichormone, systemic lupus erythemato­sus.

Case presentation

(HJ. Milionis)A 70 year old man was admitted to ourhospital in November 1996 because offever, arthralgias, and myalgias. He hadbeen in very good health untillune 1996when he presented with photosensitiv­ity, butterfly rash, and a maculo-papularrash affecting the anterior surface of thechest and forearms. Immunologic evalu­ation revealed positive antinuclear anti­

bodies (ANA) at a titer of 1/320 with afine speckled pattern. The remainder ofthe immunologic and laboratory testswere negative or within normal limits.He was treated with hydroxychloroquine200 mg twice daily and methylpred­nisolone 8 mg daily. His past medical andfamily history were unremarkable.On admission, the patient's temperaturewas 38.5°C. There were discoid skin le­sions over the forehead and the V area

of the chest. A butterfly rash was alsopresent. The physical examination wasotherwise negative. Chest x-ray revealedmild bilateral pleural effusions. The PPDwas negative. ANA were positive at atiter of 1/320 with a fine speckled pat­tern (indirect immunofluorescence) andon counter-immunelectfophoresis Ro­(SSA) antibodies were present.Laboratory evaluation on the patient'sadmission revealed anemia, leukopeniaand a number of metabolic abnormali­

ties (Table I). Specifically, the patientpresented hypoalbuminemia, metabolicalkalosis coexisting with respiratory al­kalosis, hyponatremia with inappropri­ate natriuresis, hypokalemia with renalpotassium wasting, hypophosphatemia,and hypouricemia with renal urate wast­ing. Methylprednisolone was then stop­ped, while the administration of hydro x­ychloroquine was continued. Renal func­tion revealed no abnormality. Twenty-

223

four bour urine protein excretion was 80mg. A thorough investigation for under­lying infections was negative. No symp­toms relating to hypotonicity were evi­dent and there was no prior history ofcardiac, renal or hepatic failure. Posrn was261 mosmol/kg with a simultaneousurine osmolality (Uosrn) of380 mosmoV

kg. The results of liver and thyroid func­tion tests were normal, while the morn­

ing plasma cortisol concentration was0.48 !lmol/L (normal values 0.22 - 0.68!lmollL). Plasma renin activity (PRA)was 1.2 nglml/h (normal values 0.9 - 3.3nglml/h) and serum aldosterone levelswere 133 ngIL (normal values 10 - 160ngIL). All the hormonal determinationswere carried out two days following ad­mission.

Serum sodium remained unchanged dur­ing a two-day administration of 2 Udaynormal saline, while at the same time the

fractional excretion of sodium (FENa+)was increased by 0.9% (from 0.54 to1.4%). However, a significant increasein serum sodium levels (from 126 to 134mmollL) was achieved by fluid restric­tion and a high potassium intake, whichnormalized the serum potassium levels.At the same time an increase in serumuric acid levels with a simultaneous de­crease in the fractional excretion of urate

(FE urate) was observed (serum uric acidbecame 250 ~lmollL and FE urate 8%).A complete normalization of the serumsodium concentration (from 134 to 143mmollL) with a simultaneous increasein the electrolyte free water clearance(from 0.8 Llday to 1.2 Llday) was ob­tained following a 4-day course of intra­venous albumin infusion (2 x 20 glday).Cerebrospinal fluid (CS F) examinationand electrophoresis, computed tomogra­phy (Cf), as well as magnetic resonanceimaging (MRI) of the central nervous

CLlNICO-PATHOL CONFERENCE

Table I. Laboratory investigations carried outon the patient's admission.

Differential diagnosis(M.S. Elisaf)Our patient fulfilled the criteria of theAmerican College of Rheumatology forsystemic lupus erythematosus (SLE) (1).

M.S. Elisaf cl al.

..'l~~

in hypothyroidism (4). However, in ou~jpatient both thyroid function tests and .~serum cortisol levels were normal. Tak- .~

ing into account that our patient had nor- ~mal renal function and was not given ~diuretics, a urine sodium level > 40 ":f.

mmoIIL was suggestive of the syndrome:!of inappropriate antidiuresis (5). This )'.diagnosis was reinforced by the absence;~of any clinical or laboratory indications :~of hypovolemia (i.e., postural hypoten­sion, abnormal PRA, serum aldosteroneor serum albumin levels, abnormal ureal

creatinine ratio) which represents themost common cause of hyponatremia inevery day clinical practice.However, even though the assessment ofthe extracellular fluid volume is impor­tant in evaluating the cause and deter­mining the best treatment for hyponatre­mic patients, the accuracy of the clinico­laboratory investigation of the extracel­lular fluid volume remains uncertain. Re­

cently, Musch et al. have confirmed thata Iow fractional sodium excretion «

0.5%) combined with a Iow fractionalurea excretion « 55%) are the optimaltests to diagnose hypovolemic hypona­tremia and to predict the saline response(6). In other words, the increased frac­tional sodium and urea excretion ob­

served in our case (Table I) were com­patible with the inappropriate secretionof antidiuretic hormone (SIADH).Additionally, the response of the serum

Additionally, he presented with hypo­natremia. In such cases, the detection of

the underlying cause of the hyponatremiais of paramount importance for the evalu­ation and proper management of the pa­tient. The diagnosis is based on the pa­tient's history, a physical examinationwith emphasis on extracellular volumestatus, and on the correct interpretationof laboratory tests (Table 11).The first step must be to exclude pseudo­hyponatremia due to severe hyperIipi­demia or hyperproteinemia or to hyper­glycemia (2). In our case the effectiveserum osmolality (measured Posm minusurea/6) was decreased, while the serumglucose, total protein and triglycerideconcentrations were within normal lim­

its; thus, a diagnosis of pseudohypona­tremia could be excluded. Once it was

demonstrated that the patient was hypo­osmolar, the Uosm was measured to de­termine whether his water excretion was

normal or impaired. Since the Uosmmarkedly exceeded 100 mosmol/kg, hy­ponatremia due to impaired water excre­tion was diagnosed (3).The next step in the differential diagno­sis of hyponatremia is the determinationof urine sodium in a spot urine speci­men, in addition to assessing adrenal andthyroid function (3). The latter is of par­ticular importance in SLE patients. whocommonly exhibit other autoimmuneconditions, such as thyroiditis resulting

Table 11. Major steps in the initial evaluation of hyponatremia.

Plasma osmolality

Low: True hyponatremia

Normal or elevated: Pseudohyponatremia or renal failure

Urine osmolality

< 100 mosmol/kg: primary polydipsia or reset osmostat

> 100 mosmol/kg: true hyponatremia in which wata excretion is impaired

Urine sodium concentration'

Less than 25 mmoIlL: effective circulating volume depletion (including heart failure and ascites)

Greater than 40 mmollL: Syndrome of inappropriate anti diuresis (SIADH)Renal failure

Diuretics (when drug still acting)

Adrenal insuftlciency

Cerebral salt wasting

Thyroid function tests and serum cortisol levels to diagnose hypothyroidism or adrenal insuftlciency

• In patients in whom the findings are equivocal the determination of both FENa+ and FE urea. as wellas the response of serum sodium levels to the administration of sodium chloride may be helpful.

7.52

28.5

47

0.48

30

7.9

7

14.8

70

Values

32

2 x 109

120 x 109

48

7

236

4.4

7.8

80

126

3.1

1.8

0.8

101

0.75

24

55

1.8

23

Parameters

Hematocrit (%)

White blood cells (IL)

Platelet count (IL)

Erythrocyte sedimentation rate (mmJh)

Anion gap (mmoVL)

Serum uric acid (I4moVL)

Serum glucose (mmoVL)

Serum urea (mmoVL)

Serum creatinine (l4ffioVL)

Serum sodium (mmoVL)

Serum potasium (mmoVL)

Serum calcium (mmoVL)

Serum phosphate (mmoVL)

Serum chloride (mmoVL)

Serum magnesium (mmollL)

Serum albumin (gIL)

Serum to~al protein (gIL)

Serum triglycerides (mmoUL)

Serum bicarbonate (mmoIJL)

Arterial pH

Arterial PC02 (mmHg)

Urine sodium (mmoVL)

Fractional excretion of sodium (%)*

Urine potassium (mmol/L)

Fractional excretion of potassium (%)*

Transtubular potassium gradient (TTKG)

Fractional excretion of urat~ (%)*

Fractional excretion of urea (l"'c)*

Standard formulae were used to determine the frac­

tional excretion of electrolytes.

The transtubular potassium gradient was calculatedas follows: TTKG = Urine F'Otassium I Uo,m I Po,m

I serum potassium.* Two hoors' fasting urine sample was used for thedetermination.

system did not disclos~ any abnormali­ties. The search for an occult tumor was

negative. As th~ serum potassium levelsnormalized, we increased the dose ofcorticosteroids. Two weeks later, an im­

provement in both the clinical and labo­ratory picture was noticed. Serum so­dium levels were at the lowest normal

limits (135 mmollL) and serum potas­sium levels were 3.6 mmoIlL.

224-0

1\1.5. Elisar et at.

Ectopic production: Cancer (particularly oat cell lung carcinoma)

Table Ill. Major causes of inappropriate secretion of antidiuretic hormone.

Neurologic disorc~~s: ~Ieninfitis. tumors. phychiatric disorders. subarachnoid hemorrhage. herpeszoster. \\'ercnicke's encephalopathy

Pulmonary disord~~s: Acute asthma. atelectasis. empyema. pneumothorax. tuberculosis. carcinoma.pneumonia. acute respiratory failure

sequence of abnormal thirst regulationoriginating in the central nervous system.In such cases, the increased ADH secre­

tion effects would only become evidentin situations where a superimposed dis­turbance of urine diluting ability, trans­cellular ion shifts or increased water in­

take will supervene. We would thereforesuggest that - despite the negative find­ings on both er and MRI examinationof the central nervous system, and theabsence of abnormal findings on CSF

electrophoresis - an abnormal primaryhypersecretion of ADH originating fromclinically undetectable SLE-inducedCNS disease may have been responsi­ble for the patient's decreased serum so­dium levels.

In our patient the coexistent hypoka­lemia, which was in part due to the low­dose corticosteroid treatment and in partto the hyponatremia-induced elevationin aldosterone secretion (14), could havealso played a role in the development ofhyponatremia, since in such cases thereis a transcellular cation exchange inwhich potassium leaves the cell to re­place the extracellular stores, and elec­troneutrality is in part maintained by so­dium movement into the cells (17). Thehypothesis of the importance of hypo­kalemia for the development of hypo­natremia is strengthened by the findingof increased sodium levels after potas­sium supplementation.Interestingly, the coexistent hypoalbum­inemia may have contributed to the de­velopment of hyponatremia, since it hasbeen suggested that hypoalbuminemia isan important cause of appreciable hypo­natremia, and infusions of plasma albu­min may reverse the biochemical andclinical findings of hyponatremia (18).In fact. in our case albumin infusion was

followed by a complete normalization ofthe serum sodium levels with a simulta­

neous increase in electrolyte-free waterclearance, a finding not previously dem­onstrated after albumin infusion (19).

(7). SIADH may be caused by enhancedhypothalamic antidiuretic hormone(ADH) secretion, ectopic hormone pro­duction (usually due to cancer), poten­tiation oftheADH effect (as with chlor­propamide), or by administration of me­dications withADH activity (3,11) (Ta­ble Ill). In about one-third of patients,SIADH is associated with a re-setting ofthe hypothalamic osmostat. Since ourpatient did not present with any knowncauses of inappropriate ADH secretion,including pulmonary or neurologic dis­orders, neoplasia, drugs or coexistinginfection, it is most probable that his syn­drome was caused by the underlying dis­ease, that is SLE.SIADH has been infrequently describedin patients with SLE (12-15). The un­derlying pathogenetic mechanisms ofinappropriate ADH secretion in suchpatients are not well delineated. How­ever, Trachman et al. found elevated

plasmaADH levels in euvolemic patientswith SLE, in spite of an apparently nor­mal renal function (16). It has been sug­gested that the underlying mechanismsof this hypersecretion of ADH are cen­tral, even subclinical, neuroendocrinelesions due to vasculitis, or to focal le­

sions by specific antineuronal antibod­ies. Nevertheless, the majority of SLEpatients. as well as the patients studiedby Trachman. were normonatremic (16).It has been stated that these normal so­

dium levels would result from hypo­dipsia, which can be considered as a con-

sodium concentration and fractional so­dium excretion to the administration of

normal saline (1-2 Uday for two days)is also useful to establish a correct diag­

nosis, especially in patients whose find­ings are equivocal (5). The less than 5mmollL increase in serum sodium lev­els and the increase in FENa+ of more

than 5% observed in our case were sug­gestive of SIADH. The diagnosis ofSIADH was also supported by the lowserum urea and phosphate levels, as wellas by the significant hypouricemia (se­rum uric acid levels < 4 mg/dl) combinedwith an increased (> 10%) urinary urateexcretion (7).It should be mentioned, however, that

hyponatremia with inappropriate natriu­resis combined with hypouricemia is alsoevident in the cerebral salt wasting syn­drome (8-10). In these cases the highurinary sodium concentration representsinappropriate salt wasting rather than aresponse to normal tissue perfusion (ashappens in SIADH) (8-10). The etiologyof this putative syndrome is uncertain;it has been proposed that there may bean increased release of natriuretic sub­

stances from hormone-producing neu­rons in the brain that are activated bycentral neuron dysfunction (10). In ourcase, there was no evidence of the extra­

cellular volume depletion commonlyfound in these patients, and neither hy­pouricemia nor increased urate excretionpersisted after correction of the hypo­natremia, thus excluding this possibility

Drugs: Intravenous cyclophosphamide, carbamazepine. chloropropamide, omeprazole,non-steroidal anti-inllammatory drugs. cisplatin

Following major surgery

Administration oi ~xogen()us A.DH or oxytocin

Symptomatic HI\' iniection

Idiopathic'

• In such cases it is important to continue periodic monitoring for an underlying disorder: in particular,

carcinoma or vasculitis (such as temporal arteritis) should be considered when no other etiology is apparent.

Final diagnosisSince the patient did not present anyother known cause of SIADH, it is pos­

sible that an abnormal hypersecretion ofADH, originating from a subclinicalCNS lupus disease, was responsible forthe hyponatremia observed. Therefore,

225

, i\I.S. EIi'af tI al.

we believe that our patient has SlADHin association with SLE.

Patient follow-up(A.A. Drosos)

The patient was treated with methyl­prednisone 32 mg/day/per os with sub­stantial clinical and laboratory improve­ment (serum sodium levels: 135 mmol/L and serum potassium 3.6 mmol!L) andhe was discharged from our clinic twoweeks later.

After a month he continued to experi­ence clinical improvement, without rash,fever or weakness. The serum sodium

and potassium levels were 140 mmol!Land 4.0 mmol!L, respectively, The ster­oid dose was tapered. Six months laterthe patient was asymptomatic on main­tenance therapy with 8 mg methylpredni­sone every other day, while the serumlevels of sodium and potassium werewithin normal limits.

AcknowledgmentThe authors wish to thank Mrs. EleniHorti for her secretarial assistance.

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