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Indian Pediatr 2017;54:925-929 |
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Non-Autoimmune
Subclinical and Overt Hypothyroidism in Idiopathic
Steroid-resistant Nephrotic Syndrome in Children
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Vidhya Marimuthu,
Sriram Krishnamurthy and *Medha
Rajappa
From the Departments of Pediatrics and
*Biochemistry, Jawaharlal Institute of Postgraduate Medical Education
and Research (JIPMER), Puducherry, India.
Correspondence to: Dr. Sriram Krishnamurthy,
Additional Professor, Department of Pediatrics, JIPMER,
Puducherry-605006, India.
Email: [email protected]
Received: September 29, 2016;
Initial Review: February 08, 2017;
Accepted: July 28, 2017.
Published online:
August 24, 2017.
PII:S097475591600085
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Objective: To
evaluate the frequency of non-autoimmune subclinical and overt
hypothyroidism in children with idiopathic steroid-resistant nephrotic
syndrome (SRNS). Methods: This cross-sectional study recruited 30
children (age 1-18 y) with idiopathic SRNS; and 30 healthy controls.
Serum T3, T4 and TSH were performed in cases as well as controls.
Anti-thyroid peroxidase and anti-thyroglobulin antibody tests were
performed in all cases. Results: Non-autoimmune subclinical or
overt hypothyroidism was detected in 10 out of 30 children with
idiopathic SRNS; 2 had overt hypothyroidism, while 8 patients had
subclinical hypothyroidism. Children with SRNS had a mean (SD) TSH value
4.55 (4.64) mIU/L that was higher as compared to controls (1.88 (1.04)
mIU/L) (P<0.01). Focal segmental glomerulosclerosis (FSGS) was
the commonest histopathological condition, seen in 13 (43.3%). Children
with overt hypothyroidism (2 cases) and grade III subclinical
hypothyroidism (1 case) were subsequently started on levothyroxine
therapy. Conclusions: The prevalence of subclinical and overt
hypothyroidism seems to be high in idiopathic SRNS, with almost
one-third of children having overt or subclinical non-autoimmune
hypothyroidism.
Keywords: Glomerulonephritis, Minimal change disease, Thyroid
function tests.
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Approximately 10% of children with nephrotic syndrome
are classified as steroid-resistant (SRNS) [1]. Children with SRNS often
have protracted proteinuria, which might lead to loss of thyroxine
binding globulin (TBG), transthyretin and albumin eventually, resulting
in low levels of thyroid hormone [1,2]. Long-standing proteinuria
in patients with SRNS might damage the renal tubules progressively,
resulting in reduced absorption of low molecular weight (LMW) proteins.
This might further exhaust the thyroid reserve causing
overt hypothyroidism [3]. There is a paucity of data regarding the
prevalence of hypothyroidism in SRNS [3-5]. Derangements in thyroid
metabolism are known to have effects on renal blood flow, bone mineral
density, lipid profile, fluid and electrolyte homeostasis, proteinuria
and cardiovascular function, including development of premature
atherosclerosis [2]. These parameters are already known to be adversely
affected in SRNS; and hypothyroidism can further compromise them. In the
present study, we evaluated the prevalence of non-autoimmune subclinical
and overt hypothyroidism in SRNS in comparison with healthy controls.
Methods
This cross-sectional study was conducted at the
Pediatric nephrology outpatient department of JIPMER, Puducherry from
March 2015 through July 2016 after obtaining approval from the Institute
ethics committee. Written informed consent was obtained from the parents
prior to enrolment of the children.
Children (age 1-18 y) with SRNS presenting to the
pediatric nephrology clinic were included. Those with secondary
nephrotic syndrome (e.g., IgA nephropathy, lupus nephritis,
Henoch Schonlein purpura nephritis), hypothyroidism of autoimmune
origin, critical sickness requiring intensive care unit treatment and
congenital hypothyroidism were excluded. Age- and sex-matched healthy
controls were recruited after obtaining informed consent from the
parents. They were selected from children attending the general
pediatric outpatient department. They were required to have clinically
undetectable thyroid swelling; no feature suggestive of hypothyroidism,
hyperthyroidism or autoimmune disorders; and not on thyroid hormone or
carbimazole; with absence of proteinuria.
Steroid resistance was defined as failure to achieve
remission despite 2 mg/kg/day of daily prednisolone for 4 weeks [6].
Complete remission in SRNS was defined as urine protein: urine
creatinine <0.2 g/g, serum albumin >2.5 g/dL and no edema. Partial
remission in SRNS was defined as urine protein: urine creatinine between
0.2 and 2 g/g, serum albumin >2.5 g/dL or edema. No remission in SRNS
was defined as Up: Uc >2, serum albumin <2.5 g/dL or edema. Overt
hypothyroidism was defined as low Free T4 (normal: 0.7-2 ng/mL) and
elevated serum Thyroid stimulating hormone (TSH) above the upper limit
of the reference range (> 4.5 mIU/L) [7]. Subclinical hypothyroidism was
defined as an elevation in serum TSH above the upper limit of the
reference range with a normal serum FT4 concentration. Subclinical
hypothyroidism was classified as follows – Grade 1: subclinical
hypothyroidism was defined as TSH greater than 4.5 mIU/L and <6 mIU/L,
Grade 2:TSH between 6 -12 mIU/L, grade 3: TSH >12 mIU/L; with normal FT4
concentration [8]. Initial resistance was defined as lack of remission
at the first episode of nephrotic syndrome. Late resistance was defined
as being steroid sensitive initially, but demonstrating steroid
resistance during a subsequent relapse.
Children with SRNS were investigated and managed as
per Indian Pediatric Nephrology Group guidelines [6]. Following clinical
parameters were recorded: age, sex, age of onset of nephrotic syndrome,
duration of disease, edema, anthropometry (height, weight and body mass
index), blood pressure recordings, immunosuppressants being prescribed,
type of steroid resistance, remission state, and histopathological
profile. Following laboratory parameters were recorded in cases and
controls (through intravenous blood sample and early morning urine
sample): blood urea, serum creatinine, urine protein: urine creatinine
ratio, serum albumin, serum cholesterol, free T3, free T4 and thyroid
stimulating hormone (TSH), and anti-thyroglobulin and anti-thyroid
peroxidase (TPO) antibodies. Z scores for height were recorded from the
following source: www.int/growthref/tools/en/
Fasting blood samples were collected and levels of
FT3, FT4 and TSH were analyzed for both cases and controls. In cases
with abnormal thyroid profile, antibodies against thyroid peroxidase and
thyroglobulin were measured. FT3 and FT4 measurement was performed by
competitive immunoassay using direct chemiluminescent technology (ADVIA
Centaur CP). Intra-assay coefficient of variation was <2.3% for TSH,
2.3% for FT4 and 7.8% for FT3. The inter-assay coefficient of variation
was <2.9% for TSH, 2.5% for FT4 and 12.3% for FT3. Blood samples for
anti-thyroid peroxidase and anti-thyroglobulin antibodies were stored at
4oC, and the levels were
determined using the standard ELISA (Calbiotech Inc, USA)
Statistical analysis: Student’s t test was
used to compare continuous variables and proportions were compared using
chi-square or Fisher Exact test. The outcome variables between more than
2 subgroups of SRNS (such as histopathological groups, state of
remission, and type of steroid resistance) were analyzed using ANOVA.
Correlations between serum T3, T4 and TSH levels; and duration of
disease, serum albumin, serum creatinine, and urinary protein:
creatinine ratios were studied using scatter diagrams. Pearson’s
Correlation coefficient (r) was used to measure linear correlation
between two continuous variables. P value <0.05 was considered
significant. Data were analyzed using SPSS version 19.0.
The sample size was calculated to be a minimum of 52
subjects (26 cases, 26 controls) assuming proportion of cases with
subclinical hypothyroidism to be 30%; proportion of controls with
subclinical hypothyroidism to be 2% based on the results of previous
study [4,9] with a
error 0.05, b
error 0.2 and ratio of cases and controls as 1:1.
Results
We assessed 36 children with SRNS for eligibility; 5
were excluded due to secondary SRNS, and one was excluded because of
anti-TPO and anti-thyroglobulin positivity. Clinical and biochemical
characteristics of included children with SRNS are depicted in
Table I. All children received enalapril for reduction in
proteinuria. Table II compares the characteristics
and thyroid profile in cases and controls. The prevalence of
hypothyroidism (subclinical or overt) among the cases and controls was
33.3% (n=10) and 3.3% (n=1), respectively. TSH values
between cases and controls were significantly different (Table
II). Two SRNS patients had overt hypothyroidism, while 8 SRNS
patients had subclinical hypothyroidism (1 case with grade 1, 6 cases
with grade 2 and 1 case with grade 3). Only one control child had
hypothyroidism (subclinical) with TSH level 5 mIU/L. His T3 level was
3.51 pg/mL and T4 level was 1.21 ng/dL (normal for age). Cases with
overt hypothyroidism (2 cases) and grade 3 subclinical hypothyroidism (1
case) subsequently received levothyroxine therapy.
TABLE I Clinical and Biochemical Characteristics of Children with SRNS (N=30)
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Characteristic |
Value |
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Age at enrolment (y) |
7.2 (3.9) |
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Age at onset of NS (y) |
4.5 (3.3) |
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Duration of NS (y) |
2.4 (2.0) |
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Age of onset of Steroid resistance (y) |
5.8 (3.3) |
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Weight (kg) |
22.2 (9.5) |
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Height Z score |
-1.5 (1.1) |
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Height (cm) |
113.3 (22.6) |
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egfr (mL/min/1.73m2) |
73.7 (32.1) |
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Type of SRNS |
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Initial resistance |
12 (40%) |
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Late resistance |
18 (60%) |
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Immunosuppressants received* |
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Cyclosporin with prednisolone |
23 (73.3%) |
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IV Cyclophosphamide with prednisolone |
14 (46.7%) |
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Mycophenolate mofetil with prednisolone |
10 (33.3%) |
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Tacrolimus with prednisolone |
3 (9.9%) |
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Rituximab |
1 (3.3%) |
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Remission state |
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Complete |
11 (36.7%) |
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Partial |
8 (26.6%) |
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None |
11 (36.7%) |
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Hypertension |
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Systolic blood pressure >95th centile |
5 (16.7%) |
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Diastolic blood pressure >95th centile |
4 (13.3%) |
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Histopathological profile |
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Focal segmental glomerular sclerosis |
13 (43.3%) |
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Minimal change disease |
9 (30%) |
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Mesangioproliferative glomerulonephritis |
8 (26.7%) |
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NS: nephrotic syndrome, SRNS: steroid resistant NS, eGFR:
estimated glomerular filtration rate, *Indicates the
immunosuppressive agents received at various points of time.
Hence the total would be more than 100%. All values are
expressed in mean (SD) or n (%). |
TABLE II Comparison of Characteristics (Clinical and Laboratory) and Thyroid Profile in Cases and Controls
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Parameter |
Cases |
Controls |
P value |
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(SRNS) |
(n=30) |
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(n=30) |
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Age (y) |
7.2 (3.9) |
7.0 (3.8) |
0.82 |
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Males* |
16 (53.3%) |
17 (56.7%) |
1.00 |
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Body mass index (kg/m2) |
16.7 (2.9) |
13.8 (1.6) |
<0.01 |
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Body surface area (m2) |
0.8 (0.2) |
0.7 (0.2) |
0.25 |
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Blood urea (mg/dL) |
44 (40.1) |
18.7 (4.4) |
<0.01 |
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Serum creatinine (mg/dL) |
1.0 (0.9) |
0.7 (0.2) |
0.04 |
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eGFR (mL/min/1.73m2) |
72.9 (32.4) |
73 (20.3) |
0.99 |
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Serum albumin (g/dL) |
2.6 (1.0) |
3.8 (0.4) |
<0.01 |
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Serum cholesterol (mg/dL) |
373.9 (187.6) |
142.5 (25.9) |
<0.01 |
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Free T3 (pg/ml) |
3.1(1.3) |
2.8 (0.7) |
0.30 |
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Free T4 (ng/ml) |
1.8 (1.7) |
1.2 (0.2) |
0.05 |
|
TSH (mIU/L) |
4.6 (4.6) |
1.9 (1.0) |
<0.01 |
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Hypothyroidism*# |
10 (33.3%) |
1 (3.3%) |
0.006 |
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Values are expressed in mean (SD) or *n (%); #Subclinical
or overt. |
On subgroup analysis (Web Table I)
between SRNS children with hypothyroidism versus those without
hypothyroidism, there was no difference in terms of age of onset of NS,
age of onset of steroid resistance and duration of the disease. There
was no association between the prevalence of subclinical/overt
hypothyroidism (as well as FT4, FT3 and TSH values) with various
histopathological subgroups and with different remission states
(complete, partial or no remission). There was a weak positive
correlation between proteinuria and serum TSH levels (r= 0.329);
and negative correlation between serum albumin and TSH levels (r
= –0.375). Weak negative correlations were also noted between
proteinuria and serum T3 levels (r= –0.301); and between
proteinuria and serum T4 levels (r= –0.129).
Discussion
The prevalence of subclinical or overt hypothyroidism
in children with idiopathic SRNS in this study was 33.3% which appears
to be higher than previously published reports [4,5]. Pathogenetic
mechanisms for hypothyroidism in SRNS include higher urinary excretion
of T3 and T4 during nephrosis [10]. It has been speculated that TSH
(being a LMW protein with molecular weight of 28,500 Daltons) may also
be lost in the urine of these children [11]. It has also been shown in
previous studies that when SRNS deteriorated to end stage renal disease
(ESRD), the thyroid hormone profile normalized and the patients could be
taken off levothyroxine therapy [3]. This observation indicates the
central role of proteinuria and urinary thyroxine loss in the
pathogenesis of hypothyroidism in SRNS. However, the results of the
present study as well as previous studies [4] indicate that
hypothyroidism can occur even in complete or partial remission.
Few studies have evaluated the prevalence of
hypothyroidism in SRNS [3-5]. Dagan, et al. [3] published a
series of 5 children with SRNS aged 3-11 years, who on follow-up (5-42
months) developed non-autoimmune hypothyroidism. All these 5 children
eventually deteriorated to ESRD and required dialysis and/or
transplantation. Kapoor, et al. [4] studied 20 children
with SRNS, out of whom 30% had non-autoimmune subclinical
hypothyroidism. Sharma, et al. [5] enrolled 50 children with
SRNS, and the prevalence of subclinical hypothyroidism was 20% with a
positive correlation between TSH levels and proteinuria. The differences
observed in the prevalence of hypothyroidism between the present study
and previously published observational studies [4,5] might be due to
heterogeneities in study designs and patient populations.
In our study, only one child with SRNS had grade III
subclinical hypothyroidism, in contrast with 9 children who had grade I
or grade II hypothyroidism. This could be related to the usage of
glucocorticoids, which decrease TRH messenger RNA levels in the
hypothalamus leading to lower TSH secretion [12,13]. There are no
guidelines for thyroxine supplementation in SRNS children with
subclinical hypothyroidism, though studies in adults have found
beneficial effects in individuals with TSH >10 mIU/L [14]. We chose to
treat only overt and grade III hypothyroidism; and follow-up grade I and
grade II hypothyroidism for possible hormone supplementation.
We recruited a population of exclusively idiopathic
SRNS in order to ensure homogeneity with regard to histopathological
profile; and therefore excluded secondary SRNS. Thyroid dysfunction has
been earlier reported with IgA nephropathy, membranous nephropathy and
membranoproliferative glomerulo-nephritis and is often due to autoimmune
mechanisms in these disorders [15]. We studied the prevalence of
non-autoimmune acquired hypothyroidism only; and ruled out autoimmune
causes by appropriate investigations. The present study is limited by
cross-sectional design. Data regarding prospective development of overt
or subclinical hypothyroidism, as well as follow-up serum T3, T4 and TSH
levels could not be collected. The study did not venture into molecular
and biochemical mechanisms for development of subclinical hypothyroidism
e.g., estimation of urinary loss of T3, T4 and TSH levels. Additionally,
the study is not powered to examine the relationship between
histopathological profile, duration of the disease and thyroid status.
On the basis of the findings of this study,
estimation of thyroid hormone status in children with SRNS seems to be a
rational approach. This may help in optimizing preventive and
therapeutic strategies for early recognition of hypothyroidism in SRNS.
Acknowledgements: Dr. Renitha Raghavan, former
Assistant Professor, Department of Pediatrics, JIPMER, Puducherry for
her support to secure intramural grant for this work; Mrs. Kalaiselvi
Rajendiran, PhD student, for help in performing the laboratory assays;
and Dr Bhuwan Sharma for the help rendered in statistical analysis.
Contributors: VM and SK: collected the data,
reviewed the literature and drafted the manuscript. SK conceptualized
the study, reviewed the literature and critically reviewed the
manuscript. MR supervised the laboratory tests and critically reviewed
the manuscript. All authors approved the final version of the
manuscript.
Funding: The study was supported by an intramural
funding from JIPMER, Puducherry. Competing interests: None
stated.
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What This Study Adds?
•
Almost one-third of children
with idiopathic steroid-resistant nephrotic syndrome have overt
or subclinical non-autoimmune hypothyroidism.
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References
1. Benvenga S. When thyroid hormone replacement is
ineffective? Curr Opin Endocrinol Diabetes Obes. 2013;20:467-77.
2. Iglesias P, Díez JJ. Thyroid dysfunction and
kidney disease. Eur J Endocrinol. 2009 ;160:503-15.
3. Sharma S, Dabla PK, Kumar M. Evaluation of thyroid
hormone status in children with steroid resistant nephrotic syndrome: A
North India Study. Endocr Metab Immune Disord Drug Targets.
2015;15:321-4
4. Kapoor K, Saha A, Dubey NK, Goyal P, Suresh CP,
Batra V, et al. Subclinical non-autoimmune hypothyroidism in
children with steroid resistant nephrotic syndrome. Clin Exp Nephrol.
2014;18:113-7.
5. Dagan A, Cleper R, Krause I, Blumenthal D,
Davidovits M. Hypothyroidism in children with steroid-resistant
nephrotic syndrome. Nephrol Dial Transplant. 2012;27:2171-5.
6. Indian Pediatric Nephrology Group, Indian Academy
of Pediatrics, Bagga A, Ali U, Banerjee S, Kanitkar M, et al.
Management of steroid sensitive nephrotic syndrome: revised guidelines.
Indian Pediatr. 2008;45:203-14.
7. McLean RH, Kennedy TL, Rosoulpour M, Ratzan SK,
Siegel NJ, Kauschansky A, et al. Hypothyroidism in the congenital
nephrotic syndrome. J Pediatr. 1982;101:72-5.
8. Guo QY, Zhu QJ, Liu YF, Zhang HJ, Ding Y, Zhai WS,
et al. Steroids combined with levothyroxine to treat children with
idiopathic nephrotic syndrome: a retrospective single-center study.
Pediatr Nephrol. 2014;29:1033-8.
9. Rapa A, Monzani A, Moia S, Vivenza D, Bellone S,
Petri A, et al. Subclinical hypothyroidism in children and
adolescents: a wide range of clinical, biochemical, and genetic factors
involved. J Clin Endocrinol Metab. 2009;94:2414-20.
10. Ito S, Kano K, Ando T, Ichimura T. Thyroid
function in children with nephrotic syndrome. Pediatr Nephrol.
1994;8:412-5.
11. Khurana M, Traum AZ, Aivado M, Wells MP, Guerrero
M, Grall F, et al. Urine proteomic profiling of pediatric
nephrotic syndrome. Pediatr Nephrol. 2006;21:1257-65.
12. Haugen BR. Drugs that suppress TSH or cause
central hypothyroidism. Best Pract Res Clin Endocrinol Metab.
2009;23:793-800.
13. Alkemade A, Unmehopa UA, Wiersinga WM, Swaab DF,
Fliers E. Glucocorticoids decrease thyrotropin-releasing hormone
messenger ribonucleic acid expression in the paraventricular nucleus of
the human hypothalamus. J Clin Endocrinol Metab. 2005;90:323-7.
14. Gharib H, Tuttle RM, Baskin HJ, Fish LH, Singer
PA, McDermott MT. Subclinical thyroid dysfunction: a joint statement on
management from the American Association of Clinical Endocrinologists,
the American Thyroid Association, and the Endocrine Society. J Clin
Endocrinol Metab. 2005;90:581-5.
15. Saha A, Bagri N, Mehera N, Dubey NK, Batra V.
Membranoproliferative glomerulonephritis associated with autoimmune
thyroiditis. J Pediatr Endocrinol Metab . 2011;24:789-92.
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