Congenital hypothyroidism presenting with reversible renal impairment: an under-recognised problem?

Abstract

Background

Hypothyroidism with impairment of renal function and raised creatinine phosphokinase (CPK) is described in adults and children with acquired hypothyroidism, but not in congenital hypothyroidism.

Case presentation

A male infant born at term weighing 3390 g was seen aged 2 months with prolonged jaundice. Examination showed somnolence, umbilical hernia, enlarged fontanelles and lower limb edema; length 55 cm (−1.5 SD), weight 5.4 kg (−0.13 SD). Biochemistry showed fT4 < 1 pmol/L, TSH = 1044.36 μUI/mL, creatinine 77 μmol/L(normal <35 μmol/L), estimated glomerular filtration rate (GFR) 26 ml/min/1.73 m², CPK 3952.5 IU/L (normal<400 IU/L). Ultrasound showed no thyroid tissue in the neck. In view of the renal impairment, peritoneal dialysis was initially contemplated but postponed and the child received levothyroxine 10 μg/kg/day. Two months later thyroid function tests, CPK and renal function had all normalized with creatinine 19 μmol/L and GFR 116 ml/min/1.73m².

Discussion

Reversible renal impairment is attributable to severe congenital hypothyroidism causing decreased myocardial contractility and cardiac output and to a direct effect on the kidneys. Thyroid function should be checked in infants with renal impairment of unknown cause. Cautious fluid management is indicated in hypothyroid infants. Hypothyroidism may also be associated with elevated serum CPK levels but resolves with thyroxin therapy.

Introduction

Thyroid hormones (TH) are of prime importance in human growth and development [1]. They affect the function of several organs including the brain, heart and kidney, and deficiency causes a wide range of abnormalities. The functional association between hypothyroidism and kidney failure has been described previously in adults. The mechanisms for renal insufficiency in hypothyroidism are not fully understood but appear to involve heterogeneous processes based on the direct or indirect effects of thyroid hormones on renal hemodynamics [2, 3]. As a matter of fact, TH have a direct influence on kidney function by increasing sodium tubular reabsorption, stimulating renin secretion, controlling sulfate homeostasis and increasing calcium tubular reabsorption [2]. Both renal plasma flow (RPF) and glomerular filtration rate (GFR) are influenced by thyroid hormones. There is also an indirect impaction the kidneys via the hemodynamic effects of thyroid hormones on myocardial contractility and cardiac output [4]. Thus hypothyroid-associated renal dysfunction in adults include elevation of serum creatinine levels, reduction of GFR and renal plasma flow (RPF), impaired capacity to excrete free water; and hyponatremia [2].

In contrast to adults, the effect of hypothyroidism on renal function in children is less well established. Elgadi et al. have studied kidney function in children with acquired hypothyroidism and found that recovery is slow and sometimes partial following thyroxine replacement [5] but we can find no reports on children with severe primary hypothyroidism. We describe a child with reversible renal impairment and raised CPK levels secondary to severe congenital hypothyroidism.

Case report

A 2-month-old male Caucasian infant was admitted to our department for further investigation with a history of prolonged jaundice and facial dysmorphism. He was a first-born child of 2nd degree consanguineous parents. There was a family history of acquired hypothyroidism in the paternal aunt and fatal renal failure in his father’s cousin. The patient was born after an uneventful pregnancy at term with a birth weight of 3990 g and birth length of 50 cm. Delivery was by Caesarean section for failure to progress. Newborn screening for hypothyroidism was not performed. Following birth the infant remained well but in view of the persistent jaundice his parents sought medical advice.

The baby was both breast and bottle-fed since birth and didn’t receive any medication prior to presentation.

Physical examination aged 2 months revealed a child with mucocutaneous jaundice, reduced movements and a sleepy expression, dry scaly skin, palpebral edema, macroglossia, a hoarse voice, open anterior fontanelle and umbilical hernia (Fig. 1). There was non-pitting edema over the lower extremities, heart rate was 130 beats/min and there were slow-relaxing ankle reflexes. The thyroid gland was not palpable. Weight was 5400 g (−0,13 SD), length 55 cm (−1.93 SD) and head circumference 41 cm (+ 0.61SD). The laboratory results are summarized in Table 1. There was indirect hyperbilirubinemia, with elevation of serum creatinine at 77 mmol/L (reference range for age 15–35 μmol/L) and lactate dehydrogenase (LDH) at 1764 IU/L (normal range: 225–600 IU/L). Rhabdomyolysis was initially suspected as a cause of renal failure and CPK was elevated at 3952,5 IU/L (normal range < 400 IU/L). Blood gas showed an uncompensated metabolic alkalosis. Urine examination showed no albumin or glucose, 6–8 WCC per high field and no growth on culture. Urinary myoglobin was not detected. Oligo-anuria was noted, with an estimated diuresis of 0.22 ml/kg/h. Chest Xray showed no pleural nor pericardial effusions. Abdominal ultrasonography showed normal morphology and size of both kidneys (length 49 and 50 mm on right and left) and patent renal arteries on Doppler scan. Hypothyroidism was suspected clinically. Laboratory values confirmed severe primary congenital hypothyroidism with TSH 1044,36 mU/l and free T4 < 1 pmol/l. Ultrasound of neck showed no true thyroid tissue in the thyroid fossa while scintigraphy showed no radionuclide uptake in the thyroid position.

Fig. 1.

Infant with severe congenital hypothyroidism at diagnosis, 2 months later and aged 3 years

Table 1.

Laboratory findings at presentation in a 2-month-old male infant with jaundice. Reference range values for age are given in the right-hand column

*BEecf = Standard base excess of the extracellular corrected fluid

Peritoneal dialysis was contemplated in view of the edema and renal impairment with anuria and acid-base disturbances but postponed because of the anesthetic risk.

There was no indication of fluid overload.

Levothyroxine therapy(10 μg/kg/day) was started and the dose modulated to maintain TSH levels within the lower half of the normal range (Fig. 1). A remarkable recovery of renal function was observed with normal diuresis rate on day 4 of treatment and normal serum creatinine by day 9. No other medication had been given during this time and the child remained exclusively breast fed. In the following 2 months thyroid function and CPK levels normalized (see Table). Developmental progress remains under review by a neuropaediatrician, with current milestones including sitting unsupported at 10 months, first word with meaning at 11 months, walking unaided at 18 months with good social interaction, using word sentences and pronouns and running at 3 years. Aged 18 months the child was admitted with acute intussusception which was successfully reduced surgically. During follow-up, his height remains at +2SDS in accordance with his parental heights. Aged 3 years, he measures 100 cm and wheighs 15 kg.

Discussion

Hypothyroidism in neonates and very young infants is usually caused by thyroid dysgenesis- associated with an absent, ectopic, or hypoplastic gland - or by dyshormonogenesis of thyroid hormones [6]. Neonatal screening is performed systematically in some countries and is key in detecting hypothyroidism before it becomes clinically evident. Symptomatic primary congenital hypothyroidism in infancy is therefore rare when a newborn screening service is established [6] but only too common in countries such as ours where no service currently exists. In our case, severe congenital hypothyroidism caused by athyreosis was only detected at two months of age.

An unusual feature of our case was the impaired renal function noted at presentation, which resolved when thyroid function had been normalized. This association between hypothyroidism and kidney failure has been described in adults. As many as 55% of patients with hypothyroidism have an increase in serum creatinine level [7] which seems to be reversible after hormone substitution therapy [4, 8–10]. This phenomenon has also been described in children aged 7 to 14 years with acquired hypothyroidism by Al-Fifi et al. who found a significant reduction in renal function (40%) which was reversible with hormonal replacement [11]. The most common kidney derangements associated with hypothyroidism are an increase in serum creatinine levels, reduction in GFR and renal plasma flow, decreased capacity of free water excretion and hyponatremia [2]. The serum creatinine level can be used as a surrogate for GFR using the Schwartz formula where estimated GFR in ml/min/1.73 m² = 0.413 × body length (in centimeters) divided by serum creatinine in mg/dL which has been validated in children [12]. In normal children, tubular secretion of creatinine accounts for approximately 20% of urine creatinine excretion. With renal insufficiency, this proportion typically increases, causing the creatinine clearance to overestimate the true GFR as renal function declines. Nevertheless, the application of this formula to hypothyroid children appears no more problematic than in euthyroid patients [11].

The mechanisms for renal insufficiency lies on direct and indirect TH effects: On one hand thyroid hormone deficiency decreases myocardial contractility and cardiac output. On the other hand, an impaired endothelial-mediated vasodilatation in hypothyroidism increases peripheral and renal vascular resistance via endocrine and paracrine mediators such as insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) [13, 14]. Elevation of plasma creatinine levels and decrease in its clearance might result from both these mechanisms [15]. Thyroid hormones also have an influence upon tubular transport of sodium via their actions on the sodium-potassium adenosine triphosphate pump (Na/K ATP-ase) and on the potassium permeability in the membrane of the proximal tubules [8]. One child with acquired hypothyroidism was found to have renal growth arrest which paralleled linear growth [11]. However ultrasound assessment of kidney size in our patient was normal for age. .

Review of the pediatric literature reveals that the effects of prolonged hypothyroidism on renal function in children are poorly addressed [11]. We have found two studies dealing with acquired hypothyroidism and impaired renal function in children: Al fifi et al. [11] demonstrated that five children aged 7 to 14 years with prolonged acquired hypothyroidism had a significant reduction in renal function (40%) which was reversible with hormonal replacement, Elgadi et al. [5] studied GFR and effective renal plasma flow (ERPF) in 31 patients aged 11 ± 3.3 years with symptomatic acquired hypothyroidism compared with 50 healthy children. These authors found that acquired hypothyroidism during childhood may have a long term impact on renal function so that when GFR and effective renal plasma flow (ERPF) were studied 1 to 5 years after start of treatment, GFR was still significantly lower in patients than controls, with initial GFR 75% and follow up GFR 90% of control values. Thus, determining GFR by means of a sensitive and accurate method showed that renal function did not normalize completely even after 5 years of therapy in some patients, which might not be revealed with serum creatinine measurement. However the clinical long-term consequences of these findings are still unclear [5]. Only one study has examined renal function in infants with congenital hypothyroidism [16]. In this study 80 infants suffering from congenital hypothyroidism were assessed and it was found that 16 severely hypothyroid infants had serum creatinine levels which were significantly elevated compared with mild to moderately hypothyroid and to euthyroid infants. The increased creatinine values significantly decreased (by 41.3%) with thyroxin therapy [16]. No timeline to normalization of renal functions in hypothyroidism has been specified in all these studies (9 days in our case) and none of those infants showed clinical signs or symptoms suggesting renal failure.

To our knowledge, this is the first case report of symptomatic renal failure with edema in congenital hypothydroidism. Our experience indicates that children with moderately elevated creatinine or moderately decreased glomerular filtration rates should be evaluated for signs and symptoms of hypothyroidism as the cause of their renal impairment.

Another feature of our case was the markedly elevated serum CPK levels. High CPK indicates myopathy with hypothyroidism. Such elevation, along with other muscle enzymes (LDH) has been described in adults [6, 17] but only rarely in infants [18]. It has been reported in congenital hypothyroidism [16]. The pathophysiological mechanism through which the hypothyroidism could lead to rhabdomyolysis is unknown but serum CPK levels has been considered as an indicator for the complication which can lead to acute renal failure [16]. In our patient, negative urine myoglobin makes rhabdomyolysis less likely to be the cause of this acute renal insufficiency. Interestingly, CPK and LDH rapidly decreased with the thyroxine replacement therapy [6].

Conclusion

Hypothyroidism is an underappreciated cause of renal impairment. The classical clinical signs and symptoms may be subtle or absent, even in severe hypothyroidism. The presence of reversal renal failure as the consequence of hypothyroidisms is usually subtle and frequently overlooked. Knowledge of the association between hypothyroidism and deterioration of renal function is very important in clinical practice to avoid invasive treatment such as dialysis. Accurate diagnosis followed by thyroid hormone replacement is the key to management.

Compliance with ethical standards

Conflict of interest

All the authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from the child’s parents.