Open Access

Hydrocortisone malabsorption due to polyethylene glycols (Macrogol 3350) in a girl with congenital adrenal insufficiency

  • Stefano Stagi1Email author,
  • Paolo Del Greco1,
  • Franco Ricci1,
  • Chiara Iurato1,
  • Giovanni Poggi1,
  • Salvatore Seminara1 and
  • Maurizio de Martino1
Italian Journal of Pediatrics201440:78

https://doi.org/10.1186/s13052-014-0078-2

Received: 9 June 2014

Accepted: 4 September 2014

Published: 26 September 2014

Abstract

Background

Primary adrenal insufficiency is relatively rare in children and, if unrecognized, may present with cardiovascular collapse, making it a potentially life-threatening entity.

Case presentation

The proposita, 11 months old of age, was admitted for lethargy and severe dehydration. Blood pressure was 62/38 mm Hg, and biochemical measurements showed hyponatraemia, hypochloraemia, hyperkalaemia, and metabolic acidaemia. Renin activity was 1484 μU/mL; cortisol, 1.03 μg/dL (normal, 5-25 μg/dL); and corticotropin (ACTH), 4832 ng/L (normal, 9-52 ng/L). Adrenal deficiency was diagnosed, and replacement therapy with glucocorticoids and mineralocorticoids was initiated. After 40 days, ACTH was 797 ng/L.

During follow-up, the patient started taking macrogol twice daily for constipation and experienced a significant increase in ACTH (3262 ng/L), which dropped to 648 ng/L when macrogol was stopped. After arbitrary reintroduction of macrogol, the child presented with hypoglycaemia, lethargy, weakness, and hypotonia; ACTH was 3145 ng/L. After again stopping macrogol, her ACTH was near normalized (323 ng/L).

Conclusion

Hydrocortisone malabsorption may be caused by macrogol use. Because chronic constipation is frequently reported in children, the possibility that macrogol contributes to adrenal crisis should be taken in account.

Keywords

Macrogol Hydrocortisone Adrenal insufficiency Malabsorption Polyethylene glycol Constipation

Introduction

Adrenal insufficiency is relatively rare in children and may be categorized as primary or secondary and congenital or acquired [1]. Primary adrenal insufficiency can be caused by a deficiency in steroid biosynthesis or abnormal adrenal gland development. It is a life-threatening disorder that can result from primary adrenal failure or secondary adrenal disease resulting in impairment of the hypothalamic-pituitary axis. Prompt diagnosis and urgent mineralocorticoid and glucocorticoid replacement is mandatory [2]; however, correct management is also essential [3].

Chronic idiopathic constipation is frequently reported and reduces patient quality of life [4],[5]. In fact, chronic constipation is associated with long-term problems including megarectum, reduced sensitivity of the rectum to the presence of faeces, and abnormal gut motility [4]. In many children, constipation is triggered by painful bowel movements caused by factors such as toilet training, changes in routine or diet, stressful events, intercurrent illness, or delaying defecation [4]. Therefore, managing chronic constipation in children effectively and early in its course is important in preventing long-term defecation disorders [4].

Polyethylene glycols (PEGs, or macrogols) are hydrophilic polymers of ethylene oxide [6] used in many drugs such as bowel preparations, dispersing agents, and excipients, and in cosmetics [7]. Water makes up 75-80% (wt/wt) of the normal stool, and a difference of only 10% in hydration results in marked changes in stool consistency [8]. Because PEG is a large molecular weight water-soluble polymer, it has the capacity to form hydrogen bonds with 100 molecules of water per molecule of PEG [9]. When PEG is administered orally, the resulting hydration of the colonic content facilitates transit and painless defecation in a linear dose-dependent fashion [10]. Therefore, PEG-based laxatives, when used in escalating doses, can also be used to completely remove faecal loading in preference to rectally-administered treatments. Standard management of chronic constipation tends to begin with correction of dietary and lifestyle factors that predispose to the condition and focus on increasing dietary fibre and fluid intake [11]. Dietary manipulation alone, including the use of corn syrup, was successful in resolving all symptoms of constipation in 25% of children aged up to 2 years in one US study [5].

We describe a girl with adrenal insufficiency managed with hydrocortisone and fluorocortisone who showed an adrenal crisis after administration of macrogol 3350, and we discuss this aspect, focusing on the aetiology of adrenal insufficiency in childhood.

Case report

The proposita, 11 months old of age, was admitted to Anna Meyer Children's University Hospital for lethargy and severe dehydration without history of vomiting or diarrhoea. She was the first child of non-consanguineous, young, healthy Italian parents, born at term (39 wks of gestation) by natural childbirth. Birth weight was 3200 g (0.12 standard deviation score [SDS], 50th-75th centile), length, 51 cm (1.12 SDS, 75th-90th centile), and head circumference, 35 cm (1.04 SDS, 75th-90th centile). There were no perinatal problems or familial history of similar presentations or features of endocrine disease. Neuromotor development was normal; she was sitting at 5 months.

At 10 months, 20 days of age, she started showing weight loss, lethargy, weakness, hypotonia, and dark skin. She was mildly dehydrated. Her body weight, length, and head circumference were 10.850 kg (1.89 SDS, 97th centile), 73 cm (0.61 SDS, 50th-75th centile), and 46.5 cm (1.30 SDS, 90th centile), respectively. There were no dysmorphic features. External genitalia were normal female type with no ambiguity. There was no abdominal or inguinal mass discovered upon abdominal examination. Blood pressure was 62/38 mm Hg; respiration, 35/min; pulse, 121/min; and body temperature, 37.3°C.

Biochemical measurements indicated hyponatraemia (Na, 125 mEq/L), hypochloraemia (Cl, 86 mEq/L), hyperkalaemia (K, 5.7 mEq/L), metabolic acidaemia by arterial venous blood gas, elevated serum urea nitrogen (60 mg/dL), and normal creatinine (0.3 mg/dL). Glucose was 56 mg/dL (normal, 55-110 mg/dL). An extensive endocrine work-up, carried out at 8 am after an overnight fast, showed free thyroxin was 1.27 ng/dL (normal, 0.80-1.90 ng/dL); thyrotropin, 3.96 μIU/dL (normal, 0.4-4.0 μIU/dL); aldosterone, 0.19 nmol/L (normal, 0.96-8.31 nmol/L); renin activity, 1484 μU/mL per h (normal, 2-10.2 μU/mL per h); 17-OH-progesterone, < 0.5 nmol/L; dehydroepiandrosterone sulfate, < 15 μg/dL; cortisol, 1.03 μg/dL (normal, 5-25 μg/dL); ACTH, 4832 ng/L (normal, 9-52 ng/L; Figure 1), luteinizing hormone, 2.3 IU/L; and follicle stimulating hormone, 5.6 IU/L.
Figure 1

MRI scan of the bilateral adrenal glands revealing agenesis of the right (A) and hypoplasia of the left (B) adrenal glands.

Serum cortisol and plasma ACTH levels were measured routinely using an Immulite 2000 chemiluminescence immunometric assay (Diagnostic Products Corporation, xLos Angeles, CA, USA). The cortisol inter-assay and intra-assay coefficients of variation were < 9.5% and 7.4%, respectively. The ACTH inter-assay and intra-assay coefficients of variation ranged from 6.1% to 10.0% and from 6.7% to 9.5%, respectively.

The patient was hydrated with normal saline and required vasopressors. Adrenal deficiency was diagnosed considering the hyponatraemia, hyperkalaemia, metabolic acidaemia, and cortisol and corticotropin levels.

The usual causes of primary adrenal insufficiency were ruled out (Table 1). Family history was negative for autoimmune diseases and endocrinological or genetic syndromes. Renal Doppler ultrasonography was performed and was normal. Autoimmune Addison, in the context of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or other autoimmune syndromes was ruled out by clinical and biochemical evaluation. Mantoux was negative and Veneral Disease Research Laboratory (VDRL) was non-reactive. Human immunodeficiency virus was seronegative. Plasma levels of very long chain fatty acids (VLCFAs) were normal. We performed a synthetic ACTH stimulation test intravenously at 8 am after an overnight fast, and the cortisol response, measured at 0, 30, and 60 minutes after infusion was blunted (0.98, 1.39, and 2.01 μg/dL, respectively). An MRI scan of the bilateral adrenal glands revealed agenesis of the right and hypoplasia of the left adrenal glands (Figures 1A and B).
Table 1

Typical causes of primary adrenal insufficiency

1) Genetic disorders

OMIM1(gene map)

Etiologic mechanisms

Other signs and symptoms

 Adrenoleukodystrophy

300100 (Xq28)

Mutations of ABCD1 2, ABCD2 3

Weakness, diminished visual acuity, deafness, cerebellar ataxia, hemiplegia, convulsions, dementia

 Congenital adrenal hyperplasia

   

  21-hydroxylase deficiency

201910 (6p21.33)

Mutations of CYP21A2 4

Hyperandrogenism, ambiguous genitalia in females

  11β-hydroxylase deficiency

202010 (8q24.3)

Mutations of CYP11B1 5

Hyperandrogenism, hypertension

  -hydroxysteroid dehydrogenase type 2 deficiency

201810 (1p12)

Mutations of HSD3B2 6

Ambiguous genitalia in boys, postnatal virilisation in girls

  17α-hydroxylase deficiency

202110 (10q24.32)

Mutations of CYP17A1 7

Pubertal delay in both sexes, primary amenorrhea, lack of secondary sexual characteristics, hypertension

  P450 oxidoreductase deficiency

201750 (7q11.23)

Mutations of POR 8

Skeletal malformations, especially craniofacial; severe abnormal genitalia

  P450 side-chain cleavage deficiency

613743 (15q24.1)

Mutations of CYP11A1 9

XY sex reversal

  Congenital lipoid adrenal hyperplasia

201710 (8p11.23)

Mutations of STAR 10

XY sex reversal

 Smith-Lemli-Opitz syndrome

270400 (11q13.4)

Mutations of DHCR7 11

Mental retardation, craniofacial malformations, growth failure, cholesterol deficiency

 Adrenal hypoplasia congenita

   

  X-linked

300200 (Xp21.2)

Mutations of NR0B1 12

Hypogonadotropic hypogonadism in boys (occasionally in carrier females for skewed X-chromosome inactivation)

  Xp21 deletion syndrome

300679 (Xp21)

Deletion of GK 13, DMD 14, and NR0B1

Duchenne muscular dystrophy, glycerol kinase deficiency psychomotor retardation

  SF1-linked

612965 (9q33.3)

Mutations of NR5A1 15

XY sex reversal

 IMAGe syndrome

614732 (11p15.4)

Mutations of CDKN1C 16

Intrauterine growth retardation, metaphyseal dysplasia, genital abnormalities

 Kearns-Sayre syndrome

 

Deletions of mitochondrial DNA

Deafness; heart, ocular and cerebral involvement; skeletal muscle myopathy; intestinal disorders; hormonal deficits

 Wolman disease

278000 (10q23.31)

Mutations of LIPA 17

Bilateral adrenal calcification, hepatosplenomegaly

 Sitosterolaemia

 

Mutations of ABCG5 18 and ABCG8 19

Xanthomata, arthritis, premature coronary artery disease, short stature, gonadal failure

 Familial glucocorticoid deficiency or corticotropin insensitivity syndromes

   

  Type 1

202200 (18p11.21)

Mutations of MC2R 20

Hyperpigmentation, tall stature, typical facial features, lethargy and muscle weakness with normal blood pressure

  Type 2

607398 (21q22.11)

Mutations of MRAP 21

Hyperpigmentation, normal height, hypoglycaemia, lethargy, and muscle weakness with normal blood pressure

  Variant of familial glucocorticoid deficiency

609981 (8q11.21)

Mutations of MCM4 22

Growth failure, increased chromosomal breakage, natural killer cell deficiency

 Primary generalised glucocorticoid resistance

(5q31.3)

Mutations of GCCR 23

Fatigue, hypoglycaemia, hypertension, hyperandrogenism

 Triple A syndrome (Allgrove's syndrome)

231550 (12q13.13)

Mutations of AAAS 24

Achalasia, alacrima, deafness, mental retardation, hyperkeratosis

2) Acquired diseases

   

 Bilateral adrenal haemorrhage

-

Meningococcal sepsis, antiphospholipid syndrome

Symptoms and signs of underlying disease

 Bilateral adrenal metastases

-

Lung, stomach, breast, and colon cancers

Disease-associated clinical manifestations

 Bilateral adrenalectomy

-

Adrenal masses, phaeochromocytoma unresolved Cushing's syndrome

Symptoms and signs of underlying disease

 Bilateral adrenal infiltration

-

Adrenal lymphoma, amyloidosis, haemochromatosis

Disease-associated clinical manifestations

 Drug-induced adrenal insufficiency

-

Anticoagulants, ketoconazole, fluconazole, etomidate, phenobarbital, phenytoin, rifampicin, troglitazone

None, unless related to drug

 Infectious adrenalitis

-

Tuberculosis, HIV-1, histoplasmosis, cryptococcosis, coccidioidomycosis, syphilis, trypanosomiasis

Disease-associated manifestations in other organs

 Autoimmune adrenalitis

-

  

  Isolated

  

None

  APS type 1 (APECED)

240300 (21q22.3)

Mutations of AIRE 25

Chronic mucocutaneous candidosis, hypoparathyroidism, other autoimmune diseases

  APS type 2

269200

 

Thyroid autoimmune disease, type 1 diabetes, other autoimmune diseases

  APS type 4

  

Autoimmune gastritis, vitiligo, coeliac disease, alopecia, excluding thyroid disease and type 1 diabetes

Modified by Charmandari et al., 2014 [16]: 1OMIM: Online Mendelian Inheritance in Man database; 2 ABCD1: atp-binding cassette subfamily D, member 1; 3 ABCD2: atp-binding cassette, subfamily D, member 2; 4 CYP21A2: cytochrome P450, family 21, subfamily A, polypeptide 2; 5 CYP11B1: cytochrome P450, subfamily XIB, polypeptide 1; 6 HSD3B2: 3-beta-hydroxysteroid dehydrogenase 2; 7 CYP17A1: cytochrome P450, family 17, subfamily A, polypeptide 1; 8 POR: cytochrome P450 oxidoreductase; 9 CYP11A1: cytochrome P450, subfamily XIA, polypeptide 1; 10 STAR: steroidogenic acute regulatory protein; 11 DHCR7: 7-dehydrocholesterol reductase; 12 NR0B1: nuclear receptor subfamily 0, group B, member 1; 13 GK: glycerol kinase; 14 DMD: dystrophin; 15 NR5A1: nuclear receptor subfamily 5, group A, member 1; 16 CDKN1C: cyclin-dependent kinase inhibitor 1C; 17 LIPA: lipase A, lysosomal acid; 20 MC2R: melanocortin 2 receptor; 21 MRAP: melanocortin 2 receptor accessory protein; 22 MCM4: minichromosome maintenance, Saccharomyces Cerevisiae, homolog of, 4; 23 GCCR: glucocorticoid receptor; 24 AAAS: AAAS GENE; 25 AIRE: autoimmune regulator.

Replacement therapy with standard doses of glucocorticoid (hydrocortisone, 15 mg/m2/day), mineralocorticoid (fluorocortisone, 0.2 mg/day), and sodium chloride (NaCl, 1 g/day) was initiated.

Routine cytogenetic investigations revealed an apparently normal female karyotype (46, XX). Molecular karyotyping was performed using an array comparative genomic hybridization analysis using proband's DNA and a 44 K array platform (Agilent Technologies) with a resolution of approximately 100 kilobase. This examination yielded normal results.

After replacement therapy, electrolyte abnormalities were corrected during the first week, and the patient was discharged in good clinical condition. During follow-up, she maintained good condition, good appetite, weight gain, and normal laboratory results with reduced ACTH (Figure 2). After 10 days, ACTH was 3214 ng/L; renin activity, 165.3 μU/mL; Na, 139 mEq/L; K, 4.4 mEq/L; and Cl, 96 mEq/L, and after 40 days ACTH was 797 ng/L.
Figure 2

Corticotropin (ACTH) serum levels (ng/L) at diagnosis of adrenal insufficiency and the start of hydrocortisone (10 months, 20 days of age), after the start of macrogol (14 and 18 months of age), and after the termination of macrogol (17 and 19 months of age).

At 14 months of age, the patient started taking macrogol twice daily for constipation, about 30 to 60 minutes after taking hydrocortisone and fluorocortisone. Testing revealed that ACTH was 300 ng/L, and renin activity was 24.2 μU/mL. Analysis of the SF1 gene was normal with the exception of a c.437G > C polymorphism.

After 3 months of macrogol therapy, Na was 135 mEq/L; Cl, 106 mEq/L; K, 5.3 mEq/L; renin activity, 124.2 μU/mL; aldosterone, 0.13 nmol/L; cortisol, 1.78 μg/dL; and ACTH, 3262 ng/L. The macrogol was stopped, resulting in a rapid reduction of corticotropin; after 28 days it was 648 ng/L. At this time, faecal elastase was 548 μg/g (normal, > 200 μg/g), and steatocrit was 0% (normal, < 3%). Screening for celiac disease was negative (IgA, 38 mg/dL; tTG, 1.0 U/mL).

Unfortunately, the family arbitrarily reintroduced macrogol (once daily, more than 2 hours after taking hydrocortisone and fluorocortisone) for chronic constipation. After 1 month, during a respiratory tract infection, the child presented with hypoglycaemia, lethargy, weakness, and hypotonia. Vitals were measured: pulse, 134/min; blood pressure, 65/42 mm Hg; and respiration, 38/min. Glucose was 36 mg/dL; Na, 132 nEq/L; Cl, 92 mEq/L; K, 5.4 mEq/L; and ACTH, 3145 ng/L. During recovery, we treated the adrenal deficiency and stopped the macrogol with near normalization of corticotropin (323 ng/L) after 23 days (Figure 2). Neuro-metabolic tests (plasma aminoacidogram, urine aminoacidogram, acylcarnitine profile analysis, and redox state) were again normal.

Discussion

A variety of laxatives are available for treating constipation: bulk forming, osmotic, and stimulant laxatives. Osmotic laxatives, particularly PEG preparations, are popular because they are relatively safe, inexpensive, and better than lactulose in improving stool frequency and consistency [12]-[14]. Hydrocortisone is a hydrophilic drug used to treat many conditions, such as primary or secondary adrenal insufficiency, hypopituitarism, and adrenogenital syndrome.

Nevertheless, treatment of children suffering from adrenal insufficiency is frequently problematic for a number of reasons. For example, it requires use of pharmaceutical formulations that do not fully address the pharmacokinetic and pharmacodynamic problems of dosing infants. Therefore, children require careful monitoring of dose and dosage regimen. In fact, patients with adrenal insufficiency continue to have increased mortality and morbidity despite treatment and monitoring [15]. However, many drugs, for example, anticonvulsants such as phenytoin, phenobarbital, and carbamazepine, stimulate cytochrome P450 3A4, induce hepatic enzymes, and lead to accelerated glucocorticoid metabolism and reduced glucocorticoid effect, possibly causing acute adrenal insufficiency [16].

Hydrocortisone preparations are commonly combined with pharmaceutically acceptable carriers, typically inert, to facilitate their administration. Polyethylene glycol contains a mixture of inert water-soluble molecules of different sizes, whose absorption is independent of dosage, displaying decreasing mucosal transport with increasing molecular size. Macrogol solutions are commonly used for their efficacy and low rate of absorption (0.2%) after oral administration [17] and typically have a safe profile with minimal reported side effects.

A drug's solubility in water is an important factor influencing its release into the body. In addition, macrogol softens the faecal mass by osmotically drawing water into the GI tract. As our case showed, it is possible that macrogol reduces the absorption of hydrocortisone, facilitating the appearance of adrenal insufficiency. The case seems to support our hypothesis, considering the significant changes in corticotropin after starting and stopping macrogol. Furthermore, we could also speculate that the introduction of macrogol close to that of hydrocortisone or fluorocortisone could cause or contribute to the reduced absorption of these drugs, triggering the adrenal crisis. In fact, it is recognised that many physiological gastrointestinal factors may strongly influence the plasma concentration-time profile of hydrocortisone [18]. However, hydrocortisone has a high permeability in both the small and large intestines, and the short elimination half-life (near 1.5 h) requires two or more dose administrations per day [18].

This aspect is of great concern because patients with primary or secondary adrenal insufficiency have more than twofold increased mortality than the general population. However, recent data have demonstrated that the metabolic cardiovascular risk in hypopituitarism is related to the daily dose of hydrocortisone [15].

Our case report, while not demonstrating a genetic aetiology (polymorphism of SF1 was the only abnormality), gives evidence of a possible genetic primary cause of adrenal insufficiency, based on clinical and laboratory examinations and the age of onset. In children, congenital primary adrenal insufficiency is very rare, accounting for about 1% of all cases. The importance of elucidating a genetic basis is emphasised by the ever-increasing number of genetic causes of adrenal insufficiency (Table 1) [16]. In fact, in a series of 103 children with Addison's disease, genetic forms were very frequent, accounting for 72% of congenital adrenal hyperplasia; other genetic causes accounted for 6%, whereas autoimmune disease was diagnosed in only 13% [19].

As stressed by this case, prompt diagnosis is also important because acute adrenal insufficiency is a life threatening disease. Typically, patients with this disease present with severe hypotension to hypovolaemic shock, vomiting, acute abdominal pain, and often fever. However, children often present with hypoglycaemia and hypoglycaemic seizures. On the other hand, the primary non-specific symptoms of chronic adrenal insufficiency in children are fatigue, reduced muscle strength, weight loss, anorexia, or failure to thrive [20].

Conclusions

This case report suggests that macrogol 3350 could interfere with the absorption of hydrocortisone. It is of particular importance considering the risk of adrenal insufficiency in these patients, and careful attention should be paid to the concomitant use of macrogol and hydrocortisone in subjects with primary or secondary glucocorticoid deficiencies.

Consent

Written informed consent was obtained from the parents of the patient for publication of this Case Report and any accompanying images.

Declarations

Acknowledgment

We thank Prof. Paolo Lionetti for an invaluable help in revising our manuscript.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Authors’ Affiliations

(1)
Department of Health Sciences, University of Florence, Anna Meyer Children's University Hospital

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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