1Department of Nephrology and 2Department of Endocrinology and Diabetology, University Hospital, Lausanne, Switzerland
Correspondence and offprint requests to: Frédéric Barbey, Department of Nephrology, University Hospital, Bugnon 17 avenue, 1011 Lausanne, Switzerland. Email: frederic.barbey{at}chuv.hospvd.ch
Keywords: arginin vasopressin; cysteine-aminopeptidase; dDAVP; diabetes insipidus; pregnancy
Case
A 32-year-old black woman, gravida 1, para 0, was admitted in our hospital in her 29th week of a gemellar pregnancy because of the risk of preterm delivery and suspicion of pre-eclampsia. The patients pregnancy had been uneventful until her hospitalization and no previous history of gestational diabetes or hypertension was elicited. The patients past medical history was unremarkable. Weight gain during pregnancy had been appropriate and serial ultrasounds had demonstrated adequate growth of both fetuses. On admission, she complained of right abdominal pain but reported no fever, vaginal bleeding or discharge, headache, blurry vision or oedema. Physical examination revealed an afebrile patient with normal skin turgor, and a tender but not enlarged liver. Her blood pressure was 100/70 mmHg, and pulse 80 beats per minute. An abdominal ultrasound showed a gemellar pregnancy with normal amniotic fluid, a normal hepatic size and appearance, and a slight distension of the urinary tract. The patient was kept under observation. Laboratory values at entry showed an elevation in liver-function tests, uric acid and creatinine levels (Table 1). Haemoglobin, platelet count, coagulation and thyroid function studies, as well as potassium, calcium and glycaemia levels were within normal range. HIV as well as hepatitis serologies were negative. A urine culture remained sterile. A presumptive diagnosis of acute fatty liver of pregnancy was made.
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8-D-arginin vasopressin (dDAVP) was not introduced since the course of pregnancy was marked, some hours later, by a premature rupture of the membranes with rapid labour initiation. Two healthy female babies weighing 1630 and 1650 g were delivered vaginally without complication, at 31 2/7 weeks. The patient delivered a placenta 1.5 times (640 g) the expected weight for the gestational age. Post-partum, the patient nursed her babies normally. On day 13 (1 day after delivery), the plasma level of arginin vasopressin (AVP) was 0.6 pg/ml (normal values 0.22.5 pg/ml). Symptoms of polyuria-polydipsia and laboratory abnormalities regressed rapidly after delivery (Table 1). Plasmatic and urinary osmolality measured 3 months after delivery, with the patient being asymptomatic, were within normal range (Table 1). The final diagnosis was transient DI of the pregnancy, probably mediated by an excessive activity of placental vasopressinase, and associated with acute fatty liver.
Discussion
Pregnancy is associated with physiological osmoregulatory changes. To explain this well recognized phenomenon, two mechanisms have been put forward: a resetting of the osmotic threshold, i.e. the set-point for plasma osmolality at which pregnant women experience thirst and release AVP, and the placental release of a cysteine-aminopeptidase (vasopressinase), an enzyme that rapidly inactivates AVP. The lowering of the osmotic threshold leads to a decrease of the plasma osmolality by 10 mOsm/kg at 10 weeks of pregnancy, after which a new steady state is maintained until term [1]. Thus, AVP release is not suppressed at the usual levels of tonicity and free water is retained, causing a fall in plasma sodium concentration by
5 meq/l. Despite the increase in the clearance of AVP due to vasopressinase effect, AVP plasma concentrations remain unchanged, suggesting a compensatory increase in secretion to maintain fluid balance.
DI is generally caused either by failure of AVP secretion (central DI) or by resistance of the renal collecting duct to AVP (nephrogenic DI). Central DI may occur secondary to pituitary or brain tumours, infiltrative diseases such as sarcoidosis or histiocytosis, after trauma, surgery or rupture of intracranial aneurysm, or be idiopathic [2]. Nephrogenic DI can be congenital or acquired, linked with chronic interstitial nephritis, potassium deficiency or hypercalcaemia, or related to drugs [2]. During pregnancy, and in the absence of glycosuria, hypokalaemia or hypercalcaemia, DI can be established if a patient with a syndrome of polyuria-polydipsia has a serum osmolality >285 mOsm/kg associated with persistent hyposthenuria (Table 2) [1,3]. DI can be confirmed by a hypertonic saline infusion or a water deprivation test (Table 3). Women with DI will not concentrate their urine osmolality, in contrast to women with psychogenic polydipsia. However, dehydration is problematic in pregnancy because the resulting decrease in plasma volume may lead to utero-placental insufficiency [4]. Therefore, a water deprivation test should be performed only if signs of polyuria or polydipsia persist more than 6 weeks post-partum.
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Vasopressinase is a cystine aminopeptidase elaborated by placental tissue (trophoblast), which inactivates AVP, oxytocin, and some other small peptides, by sequentially cleaving amino acids from the N-terminus [1]. Its physiological function remains however unclear. Vasopressinase activity increases by 1000-fold from week 4 to 38 of gestation, remains elevated until delivery, than decreases at a logarithmic rate of 25% a day post-partum, having virtually no activity by the 12th post-partum day. The release of vasopressinase results in an 4-fold increase in AVP catabolism rate, which requires a compensatory synthesis to maintain AVP plasma concentration and fluid balance unchanged [1]. Serum vasopressinase activity is proportional to the weight of the placenta, explaining that in multiple pregnancies, an increased plasma vasopressinase activity is encountered [5]. The site of vasopressinase metabolism is not known, but is likely to take place in the liver. After delivery and placental removal, vasopressinase levels decreased rapidly, resulting in normalization of the fluid balance, and consequent resolution of the DI.
Administration of AVP can differentiate the two forms of gestational DI (Table 3) [3]. In central sub-clinical DI exacerbated during pregnancy, urine should concentrate within an hour after administration of AVP i.m., in contrast to transient AVP-resistant DI. However, most central sub-clinical DI respond only partially to AVP since part of the exogenous AVP is degraded by normal levels of vasopressinase. If the urine still does not concentrate 2 h after AVP administration, dDAVP, an AVP analogue with a different N-terminus that renders it resistant to the vasopressinase action, may be given [6]. Both forms of transient DI are exquisitely responsive to dDAVP which constitutes the treatment of choice. In the 17 cases reviewed by Krege et al. [3], only dDAVP successfully established anti-diuresis. Women with complete central DI require more exogenous AVP to control polyuria during pregnancy, probably because of the increased clearance of AVP due to increased vasopressinase activity, and present a gradual return of their usual replacement doses in the post-partum period [7]. Pre-existing symptomatic central DI should therefore be treated with dDAVP during pregnancy. No adverse maternal or fetal effects from dDAVP use during pregnancy have been reported [6]. Moreover, dDAVP has no pressor effect which is important in view of transient DI associated with pre-eclampsia.
One recent important finding, in the majority of women with transient DI of the pregnancy, is the simultaneous occurrence of anomalies of the liver-function tests. Krege et al. [3] reviewed reports of 17 women with transient DI and found associated abnormal liver tests in 16 of them (in one case liver functions were not reported). Moreover, they found a diastolic blood pressure 90 mmHg in 12 patients, proteinuria >250 mg/24 h in six of them, and elevated uric acid levels in 12 cases (not reported in five). One woman had recurrence of the DI in a subsequent pregnancy [3]. In another study, Kennedy et al. [4] reported six cases of transient DI of the pregnancy in association with abnormal liver tests and biopsy-proven acute fatty liver of pregnancy. Five out of six were primigravida. Elevated blood pressure (>140/90 mmHg), without significant proteinuria, was present in four of them. There was an increase in uric acid levels (>400 µmol/l) in all but one patient. Three women have since had uneventful pregnancies. Recently, Hamai et al. [8] reported six cases of DI during pregnancy, and observed that pregnancies in which clinical symptoms of DI became apparent were associated with hypertension and abnormal biochemical data compatible with pre-eclampsia, whereas pregnancies preceded by DI were uneventful as long as dDAVP was appropriately administered.
To explain the association of DI with elevated liver function tests, one advanced hypothesis is that acute liver dysfunction could impair degradation of vasopressinase, thereby extending vasopressinase half-life activity, resulting in greater clearance of AVP. It has been suspected that pre-eclampsia associated with excessive vasopressinase activity might be explained if the products of AVP degradation by vasopressinase retained pressor activity, even after anti-diuretic activity has been destroyed. However, Gordge et al. [9] have shown in a recent study that AVP degradation products had no significant pressor activity and are therefore unlikely to be pathogenic in hypertensive pregnancy. An important point is that pregnancies in women with transient DI should be considered at high risk because of the potential to develop pre-eclampsia, or fatty liver. Moreover, the manifestations of DI, i.e. diluted and abundant urine output, may mask emerging severe pre-eclampsia.
In our patient, a de novo syndrome of polyuria-polydipsia associated with hepatic, uric acid, and renal function abnormalities developed during the third trimester of pregnancy, while glycaemia, potassium and calcium levels were in the normal range. It was characterized by slightly elevated plasmatic osmolality, hypernatraemia and hyposthenuria. The increase of uric acid and creatinine plasma levels was attributed to a probable pre-renal component. Prior to the liver-function test abnormalities, our patient had neither hypertension nor proteinuria, excluding the diagnosis of pre-eclampsia. A toxic, pharmacological, or viral cause to the elevated liver enzymes was ruled out, and a diagnosis of fatty liver of pregnancy was at this state the most probable diagnosis [10]. The rapid amendment of the symptoms and of laboratory abnormalities after delivery, was consistent with a transient DI of the pregnancy. The gemellar nature of the pregnancy that could induce excessive vasopressinase activity, and the hepatic dysfunction (acute fatty liver) which could reduce the catabolism of vasopressinase were consistent with an AVP-resistant DI of the pregnancy. The normal plasma AVP level 1 day after delivery (0.6 pg/ml), and an urinary osmolality spontaneously above 750 mOsm/kg 3 months post-partum render unlikely the diagnosis of a partial central DI. This case and others previously reported demonstrate that transient DI appears to be associated with gemellar pregnancy, pre-eclampsia or acute fatty liver [3,4,8].
Teaching points
Transient DI of pregnancy can occur in the third trimester and disappears rapidly post-partum. It is associated with gemellar pregnancy, pre-eclampsia or acute fatty liver. There are two distinctive formsthe central sub-clinical and the AVP-resistant DI. Both forms respond to dDAVP.
Conflict of interest statement. None declared.
References