Hydrocortisone malabsorption due to polyethylene glycols (Macrogol 3350) in a girl with congenital adrenal insufficiency
© Stagi et al.; licensee BioMed Central Ltd. 2014
Received: 9 June 2014
Accepted: 4 September 2014
Published: 26 September 2014
Primary adrenal insufficiency is relatively rare in children and, if unrecognized, may present with cardiovascular collapse, making it a potentially life-threatening entity.
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).
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.
Adrenal insufficiency is relatively rare in children and may be categorized as primary or secondary and congenital or acquired . 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 ; however, correct management is also essential .
Chronic idiopathic constipation is frequently reported and reduces patient quality of life ,. 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 . 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 . Therefore, managing chronic constipation in children effectively and early in its course is important in preventing long-term defecation disorders .
Polyethylene glycols (PEGs, or macrogols) are hydrophilic polymers of ethylene oxide  used in many drugs such as bowel preparations, dispersing agents, and excipients, and in cosmetics . 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 . 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 . When PEG is administered orally, the resulting hydration of the colonic content facilitates transit and painless defecation in a linear dose-dependent fashion . 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 . 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 .
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.
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.
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.
Typical causes of primary adrenal insufficiency
1) Genetic disorders
Other signs and symptoms
Mutations of ABCD1 2, ABCD2 3
Weakness, diminished visual acuity, deafness, cerebellar ataxia, hemiplegia, convulsions, dementia
Congenital adrenal hyperplasia
Mutations of CYP21A2 4
Hyperandrogenism, ambiguous genitalia in females
Mutations of CYP11B1 5
3β-hydroxysteroid dehydrogenase type 2 deficiency
Mutations of HSD3B2 6
Ambiguous genitalia in boys, postnatal virilisation in girls
Mutations of CYP17A1 7
Pubertal delay in both sexes, primary amenorrhea, lack of secondary sexual characteristics, hypertension
P450 oxidoreductase deficiency
Mutations of POR 8
Skeletal malformations, especially craniofacial; severe abnormal genitalia
P450 side-chain cleavage deficiency
Mutations of CYP11A1 9
XY sex reversal
Congenital lipoid adrenal hyperplasia
Mutations of STAR 10
XY sex reversal
Mutations of DHCR7 11
Mental retardation, craniofacial malformations, growth failure, cholesterol deficiency
Adrenal hypoplasia congenita
Mutations of NR0B1 12
Hypogonadotropic hypogonadism in boys (occasionally in carrier females for skewed X-chromosome inactivation)
Xp21 deletion syndrome
Deletion of GK 13, DMD 14, and NR0B1
Duchenne muscular dystrophy, glycerol kinase deficiency psychomotor retardation
Mutations of NR5A1 15
XY sex reversal
Mutations of CDKN1C 16
Intrauterine growth retardation, metaphyseal dysplasia, genital abnormalities
Deletions of mitochondrial DNA
Deafness; heart, ocular and cerebral involvement; skeletal muscle myopathy; intestinal disorders; hormonal deficits
Mutations of LIPA 17
Bilateral adrenal calcification, hepatosplenomegaly
Mutations of ABCG5 18 and ABCG8 19
Xanthomata, arthritis, premature coronary artery disease, short stature, gonadal failure
Familial glucocorticoid deficiency or corticotropin insensitivity syndromes
Mutations of MC2R 20
Hyperpigmentation, tall stature, typical facial features, lethargy and muscle weakness with normal blood pressure
Mutations of MRAP 21
Hyperpigmentation, normal height, hypoglycaemia, lethargy, and muscle weakness with normal blood pressure
Variant of familial glucocorticoid deficiency
Mutations of MCM4 22
Growth failure, increased chromosomal breakage, natural killer cell deficiency
Primary generalised glucocorticoid resistance
Mutations of GCCR 23
Fatigue, hypoglycaemia, hypertension, hyperandrogenism
Triple A syndrome (Allgrove's syndrome)
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
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
Tuberculosis, HIV-1, histoplasmosis, cryptococcosis, coccidioidomycosis, syphilis, trypanosomiasis
Disease-associated manifestations in other organs
APS type 1 (APECED)
Mutations of AIRE 25
Chronic mucocutaneous candidosis, hypoparathyroidism, other autoimmune diseases
APS type 2
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
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.
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.
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 -. 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 . 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 .
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  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 . 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 .
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 .
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) . 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% .
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 .
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.
Written informed consent was obtained from the parents of the patient for publication of this Case Report and any accompanying images.
We thank Prof. Paolo Lionetti for an invaluable help in revising our manuscript.
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sectors.
- Shulman DI, Palmert MR, Kemp SF: Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007, 119: e484-e494. 10.1542/peds.2006-1612.View ArticlePubMedGoogle Scholar
- Evliyaoğlu O, Dokurel İ, Bucak F, Özcabı B, Ercan Ö, Ceylaner S: Primary adrenal insufficiency caused by a novel mutation in DAX1 gene. J Clin Res Pediatr Endocrinol. 2013, 5: 55-57. 10.4274/Jcrpe.895.PubMed CentralView ArticlePubMedGoogle Scholar
- Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet. 2014, pii: S0140-S6736.Google Scholar
- Candy D, Belsey J: Macrogol (polyethylene glycol) laxatives in children with functional constipation and faecal impaction: a systematic review. Arch Dis Child. 2009, 94: 156-160. 10.1136/adc.2007.128769.PubMed CentralView ArticlePubMedGoogle Scholar
- Loening-Baucke V: Prevalence, symptoms and outcome of constipation in infants and toddlers. J Pediatr. 2005, 146: 359-363. 10.1016/j.jpeds.2004.10.046.View ArticlePubMedGoogle Scholar
- Sohy C, Vandenplus O, Sibille Y: Usefulness of oral macrogol challenge in anaphylaxis after intra-articular injection of corticosteroid preparation. Allergy. 2008, 63: 478-479. 10.1111/j.1398-9995.2007.01610.x.View ArticlePubMedGoogle Scholar
- Napke E, Stevens DGH: Excipients and additives: hidden hazards in drug products and in product substitution. CMAJ. 1984, 131: 1449-1452.Google Scholar
- Bernier JJ, Donazzolo Y: Effect of low-dose polyethylene glycol 4000 on fecal consistency and dilution water in healthy subjects. Gastroentérol Clin Biol. 1997, 21: 7-11.PubMedGoogle Scholar
- Schiller LR, Emmett M, Santa Ana CA, Fordtran JS: Osmotic effects of polyethylene glycol. Gastroenterology. 1998, 94: 933-941.Google Scholar
- Hammer HF, Santa Ana CA, Schiller LR, Fordtran JS: Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest. 1989, 84: 1056-1062. 10.1172/JCI114267.PubMed CentralView ArticlePubMedGoogle Scholar
- Corazziari E: Need of the ideal drug for the treatment of chronic constipation. Ital J Gastroenterol Hepatol. 1999, 31 (Suppl 3): S232-S233.PubMedGoogle Scholar
- Belsey JD, Geraint M, Dixon TA: Systematic review and meta analysis: polyethylene glycol in adults with non-organic constipation. Int J Clin Pract. 2010, 64: 944-955. 10.1111/j.1742-1241.2010.02397.x.View ArticlePubMedGoogle Scholar
- Taylor RR, Guest JF: The cost-effectiveness of macrogol 3350 compared to lactulose in the treatment of adults suffering from chronic constipation in the UK. Aliment Pharmacol Ther. 2010, 31: 302-312.View ArticlePubMedGoogle Scholar
- Lee-Robichaud H, Thomas K, Morgan J, Nelson RL: Lactulose versus polyethylene glycol for chronic constipation. Cochrane Database Syst Rev. 2010, 7:Google Scholar
- Grossman A, Johannsson G, Quinkler M, Zelissen P: Therapy of endocrine disease: Perspectives on the management of adrenal insufficiency: clinical insights from across Europe. Eur J Endocrinol. 2013, 169: T165-T175. 10.1530/EJE-13-0450.View ArticleGoogle Scholar
- Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. The Lancet. 2014, 383: 2152-2167. 10.1016/S0140-6736(13)61684-0.View ArticleGoogle Scholar
- Tooson JD, Gates LK: Bowel preparation before colonoscopy. Choosing the best lavage regimen. Postgrad Med. 1996, 100: 203-214.PubMedGoogle Scholar
- Lennernäs H, Skrtic S, Johannsson G: Replacement therapy of oral hydrocortisone in adrenal insufficiency: the influence of gastrointestinal factors. Expert Opin Drug Metab Toxicol. 2008, 4: 749-758. 10.1517/17425255.4.6.749.View ArticlePubMedGoogle Scholar
- Perry R, Kecha O, Paquette J, Huot C, Van Vliet G, Deal C: Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. 2005, 90: 3243-3250. 10.1210/jc.2004-0016.View ArticlePubMedGoogle Scholar
- Avgerinos PC, Cutler GB, Tsokos GC, Gold PW, Feuillan P, Gallucci WT, Pillemer SR, Loriaux DL, Chrousos GP: Dissociation between cortisol and adrenal androgen secretion in patients receiving alternate day prednisone therapy. J Clin Endocrinol Metab. 1987, 65: 24-29. 10.1210/jcem-65-1-24.View ArticlePubMedGoogle Scholar
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