Chapter 7 Endocrinology
Long Cases
Congenital adrenal hyperplasia
Background information
Congenital adrenal hyperplasia (CAH) refers to a number of inherited defects in adrenal steroidogenesis, which cause impaired synthesis of cortisol from cholesterol in the adrenal cortex. The most common of these is 21-hydroxylase deficiency (21-OHD), which is caused by a range of mutations in one gene—the CYP21A2 gene on chromosome 6p21.3, which codes for 21-hydroxylase (P450C21). The end result is a lack of cortisol (and usually aldosterone) synthesis by the adrenal cortex. This leads to increased adrenocortical stimulation by hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH), which induces adrenal glandular hyperplasia—hence the term CAH. CAH is inherited in an autsomal recessive manner. This long case deals with the common form of CAH due to 21-OHD, the preferred term for which, under current nomenclature, is 21-OHD CAH.
Females with classic 21-OHD CAH are born with ambiguous genitalia. The degree of virilisation of the external genitalia is scored by the Prader scale (see the short case on ambiguous genitalia in this chapter). Males with classic salt-wasting 21-OHD CAH appear normal at birth, but then deteriorate with adrenal insufficiency after 1–4 weeks. In these babies, adrenal aldosterone production is insufficient for the distal tubules to reabsorb sodium, leading to salt loss as well as deficiency of cortisol and an excess of androgens. Symptoms can include poor feeding, failure to thrive, vomiting, loss of weight, dehydration, hypotension, hyponatraemia and hyperkalaemic metabolic acidosis, leading to adrenal crisis with vascular collapse and a significant mortality rate. Some degree of aldosterone deficiency occurs in all forms of 21-OHD CAH.
Females with non-classic 21-OHD CAH may present with clitoromegaly, early development of pubic hair, hirsutism, acne, increased growth rate, and gynaecological problems such as oligomenorrhoea, abnormal menses or infertility. Males with non-classic 21-OHD CAH may develop early penile growth, pubic hair, increased growth rate and increased musculature. Deficiency of cytochrome P450 enzyme 21-hydroxylase (CYP21A2) causes 90% of 21-OHD CAH cases. Ten types of mutation in CYP21A2 account for more than 90% of affected cases, although well over 100 have been described, including point mutations, small deletions, small insertions and complex rearrangements of the gene. 21-OHD CAH demonstrates a heterogeneous phenotype, with concordance between phenotype and genotype. The Human Gene Mutation Database, Cardiff (http://www.hgmd.org) lists all known mutations.
Diagnosis
21-OHD CAH can be diagnosed at different ages, as follows.
High-risk pregnancies: prenatal diagnosis of 21-OHD CAH
If the fetus is female, and the proband has two CYP21A2 disease-causing mutations, then molecular testing of fetal DNA is undertaken to identify whether the fetus has inherited both disease-carrying alleles. If the fetus is female and unaffected, dexamethasone is stopped. If the fetus is female and is found by DNA analysis to have classic 21-OHD CAH, dexamethasone is continued to term. Prenatal treatment is solely to prevent virilisation of the genitalia in affected females. It has no effect on any later requirement for hormone replacement therapy. There are no significant side effects of dexamethasone treatment; there is no increased risk of congenital anomalies, and no effect on birth weight, length or head circumference.
Preimplantation genetic diagnosis (PGD) of 21-OHD CAH
This may be offered to families in which the disease-causing mutations have been identified.
Other forms of CAH
There are five forms of CAH. Patients with other forms of CAH (<2% of CAH patients) may present at various ages. Impaired enzyme function at each step of adrenal steroidogenesis leads to a unique set of excess precursors and reduced products. 17-OHD CAH is due to mutation in the gene CYP17A1 on chromosome 10q24.3, which codes for 17-hydroxylase (P450C17). CAH caused by deficiency of 3 beta-hydroxysteroid dehydrogenase (3Beta-HSD) is due to mutation in the gene HSD17B10, on chromosome Xp11.2. HSD17B10 encodes 3-hydroxyacyl-CoA dehydrogenase type II, a mitochondrial protein that catalyses a number of steroids, fatty acids and alcohols. CAH caused by deficiency of steroidogenic acute regulatory protein (StAR) is due to mutation in the STAR gene; the protein encoded by the STAR gene allows the transfer of cholesterol across the mitochondrial membrane, after which it is converted into pregnenolone. For further discussion, see the short case on ambiguous genitalia.
History
Initial diagnosis
2. Immediate pre-diagnosis symptoms:
3. Where, when and how the diagnosis was made, length of hospital stay, education given, any treatment of the mother with steroids while the embryo was in utero, treatment in hospital, treatment at discharge.
Progress of the disease
1. Details of subsequent hospitalisations (frequency, indications, usual length of stay, usual outcome).
2. Complications of the disease; for example, the need for corrective genital surgery, episodes of adrenal crisis, abnormal growth and development, psychosexual developmental aspects (for example, girls with male-type play, physical aggression, low interest in babies or maternal nurturing behaviours; increased incidence of lesbian relationships), inadequately treated hyperandrogenism, hypoglycaemic reactions.
3. Complications of treatment; for example, overtreatment with steroids causing deceleration of linear growth, too much fludrocortisone causing hypertension, degree of control (number of episodes of adrenal crisis).
4. Monitoring of the disease: how often seen in clinic, the usual investigations performed, how often seen by local doctor.
5. Changes in management; for example, the usual increases in steroid dosage on sick days.
6. At what age was the patient administering his or her own steroids?
7. Compliance; for example, previous refusal to take steroids in teenage males.
Current status
1. General health: lethargic or energetic.
2. Current medications: type (e.g. hydrocortisone, fludrocortisone, salt supplement, antiandrogens dose), regimen (how much, when, given by whom, modifications with intercurrent illness), salt craving (not enough fludrocortisone), hypertension (too much fludrocortisone), compliance with treatment.
3. Adrenal insufficiency: how often, what symptoms (e.g. vomiting, lethargy, crying, convulsions, near-syncope, syncope, loss of consciousness), usual precipitants, anticipatory strategies for prevention, response.
4. Hypoglycaemia: any episodes, any suggestion of this (e.g. sweating, pallor, tremulousness, hunger, headache, odd behaviour, lethargy, crying, bad temper, lack of coordination, dizziness, vomiting, convulsions, loss of consciousness).
5. Symptoms attributable to virilisation: acne, increased linear growth, amenorrhoea.
6. Other problems; for example, adolescent self-image, compliance problems.
Social history
1. Impact on child: self-image, reaction of school friends, effects (e.g. virilisation), coping with taking steroids, amount of school missed.
2. Impact on siblings: sibling rivalry, risk of CAH.
3. Impact on parents: family finances, employment, concern regarding future complications, genetic counselling.
4. Social supports: parents groups, access to social worker, government benefits obtained.
5. Coping: who attends the clinic with the patient, the level of education of the child and parents, contingency plans for intercurrent illnesses or severe adrenal crisis causing loss of consciousness, access to local doctor, paediatrician, hospital.
Management
All patients with CAH, regardless of type, require treatment with glucocorticoids. These replace cortisol (which is deficient) and provide negative feedback, suppressing ACTH secretion. This then prevents continued adrenal stimulation, inhibiting excess androgen production (as 17-OHP is not available as a substrate for excess androgen production; this prevents virilisation). Patients with the salt-losing form (for practical purposes, all those with a raised plasma renin activity) also require mineralocorticoid replacement to normalise the sodium balance associated with aldosterone deficiency. Girls with moderate to severe clitoral enlargement and all those with fused labia are offered corrective surgery. The timing of this, and the place of surgery for mild degrees of clitoromegaly, is now a very controversial area, as previous surgical approaches are considered to have led to some loss of clitoral sensation. The overall principles of treatment are given below.
Control of steroid requirements
Prevention of acute complications
Adrenal crises can be averted by anticipatory strategies. All patients with CAH need extra steroid cover for stress: this includes any acute medical condition (such as gastroenteritis, or other viral illnesses), any surgical procedure requiring an anaesthetic and any significant orthopaedic injury (such as a major fracture). Treatment may include hydrocortisone 25–100 mg parenterally (IM or IV), repeated 4–6 hourly until recovery from the acute aspect of the illness: triple the usual dose for 2 days, then double the usual dose for 3 days.
Psychological support
The following basic principles are important:
1. Minimise the number of days off school.
2. Involve the child in management of his or her CAH as appropriate to age and ability.
3. In times of ‘adolescent rebellion’, support and encourage; never resort to threats.
4. Identify and treat negative family responses to CAH, including overindulgence, over-anxiousness, neglect and disinterest, resentment and overcontrolling parents.
5. When the initial diagnosis is made, be aware of depression in patients, siblings and parents, and counsel accordingly. It is important that the parents and child have a full understanding of the pathophysiology of CAH, and all aspects of the psychosexual aspects that can arise should be openly discussed with the parents, and when it is age-appropriate, with the child. There should be no secretive aspects to the family’s handling of this diagnosis, as this could be damaging. There is significant value in sexual counselling for many of these patients and their families.
For the purposes of the long case, the usual problem is that of a non-compliant adolescent. Unfortunately, it is in adolescence—the least receptive time of the patient’s life—that it is crucial to avoid serious complications. For a teenager, immediate peer acceptance, which may involve nights out at parties or hotels, far outweighs the long-term benefits of adequate steroid replacement. Most teenagers with CAH require additional emotional support, which may be achieved through attendance at discussion groups or talking one-on-one with a clinical psychologist.
Types of corticosteroids
The examiners will expect you to be familiar with the various types of steroids and their equivalents. Table 7.1 is a brief guide; refer to the latest MIMS, British National Formulary or equivalent publication for the names of the various preparations available.
| Steroid | Relative glucocorticoid activity | Relative mineralocorticoid activity |
|---|---|---|
| Hydrocortisone (cortisol) | 1 | 1 |
| Cortisone acetate (11-deoxycortisol) | 0.8 | 0.8 |
| Prednisone | 4 | 0.8 |
| Prednisolone | 4 | 0.8 |
| Methylprednisolone (6 alpha-methylprednisolone) | 5 | 0.5 |
| Fludrocortisone (9 alpha-fluorocortisol) | 10 | 125 |
| Betamethasone (9 alpha-fluoro-16 beta-methylprednisolone) | 25 | 0 |
| Dexamethasone (9 alpha-fluoro-16 alpha-methylprednisolone) | 25 | 0 |
21-OHD CAH prenatal diagnosis and intervention
This area may be mentioned in the long-case discussion. Prenatal treatment of CAH attributable to 21-OHD by administration of corticosteroids (dexamethasone) to the mother is most commonly performed in females with a previously affected child. Informed consent must be obtained from the parents before prenatal treatment is contemplated. There are possible maternal adverse effects with CAH, the genital outcome is variable and there may be long-term effects on children, which are presently unknown. Masculinisation of the external genitalia begins at 6–7 weeks’ gestation; if treatment before this suppresses the fetal pituitary–adrenal axis, it could prevent ambiguous genitalia. Of reported cases where prenatal treatment has occurred, it was successful in three quarters of them (one third normal genitalia, two thirds mildly virilised) and unsuccessful in a quarter.
Management of acute adrenocortical insufficiency (adrenal crisis)
Immediate management
1. Assess and secure the airway, breathing and circulation (the ABCs).
2. Insert an IV cannula; take blood as above.
3. Restore the circulating volume with an infusion of normal saline (isotonic, 0.9%) with added glucose to make up to 5% glucose. Start with a 20 mL/kg bolus. Correct hypoglycaemia. Aim to replace fluid and electrolytes over the next 24–48 hours.
4. Give bolus hydrocortisone IV (or IM if IV access is difficult):
5. Hyperkalaemia may need further correction with insulin and glucose.
Diabetes mellitus
Background information
T1DM affects 1 in 1000 children (and 1 in 400 by adolescence). Incidence increases with age. The main genetic factor determining susceptibility to T1DM lies within the major histocompatibility complex (termed IDDM1). There is an association with certain HLA haplotypes: more than 90% of patients with T1DM have HLA-DR3 and/or HLA-DR4 (class II antigens located on the short arm of chromosome 6, at 6p21); 55% have a DR3/DR4 combination, most commonly DR4-DQ8/DR3-DQ2 (1 in 5 in families of diabetics versus 1 in 25 of the general population). DR3/DR4 heterozygosity is seen most frequently in children who develop T1DM under 5 years of age. For children who carry both of the highest-risk HLA haplotypes (DR4-DQ8/DR3-DQ2), the risk of being diagnosed with T1DM by 15 years is 1 in 20; if there is a sibling with T1DM and the same haplotypes, the risk is then 55%. One non-HLA gene is recognised as contributing to around 10% of the family aggregation of T1DM: this is termed IDDM2 and is situated on chromosome 11p5.5. This locus maps to a variable number of tandem nucleotide repeats (VNTR) of the insulin gene. Different sizes of the VNTR are associated with a risk of T1DM, the long form of VNTR being associated with protection from T1DM. A meta-analysis of data combined from most of the genomewide studies of linkage to T1DM, has been carried out by the Type 1 Diabetes Genetics Consortium; this shows that most of the genetic risk for T1DM is conferred by the class II genes encoding HLA-DR and HLA-DQ, as well as one or more additional genes within the HLA region. At least 50 inherited susceptibility loci for T1DM are known. An excellent resource noting all the genes implicated in T1DM, and constantly updated, is T1Dbase (http://www.t1dbase.org); it includes a table of all known T1DM loci, and clear diagrams of chromosomes, showing the position of each locus. Almost every chromosome has at least one locus identified. Apart from the genes in the HLA region, the majority of these loci affect T-cell function, including antigen-driven T-cell activation and cytokine signalling, proliferation or maturation.
Prevention of complications of T1DM
The DCCT Study (Diabetes Control and Complications Trial) involved 1441 volunteers with T1DM, ages 13–39, who had had T1DM for at least 1 but less than 15 years, and no, or minimal, diabetic eye disease; it compared intensive control of blood glucose (keeping HbA1c [glycosylated haemoglobin] as close to 6% as possible) versus standard control of blood glucose. Patients were studied for an average of 6.5 years. The DCCT study showed that intensive blood glucose control decreases the risk of eye disease (retinopathy) by 76%, kidney disease by 50% and nerve disease (neuropathy) by 60%. The trial ended, and was reported, in 1993, but 90% of patients were followed up, and a second study, the EDIC Study (Epidemiology of Diabetes Interventions and Complications), reporting in 2005, assessed both microvacular (eye, kidney and nerve) and macrovascular disease, including incidence and predictors of various forms of cardiovascular disease (including myocardial infarction, cerebrovascular accidents, and requirement for cardiac surgery). The EDIC study showed that intensive blood glucose control decreases the risk of any cardiovascular disease event by 42%, and non-fatal myocardial infarction, cerebrovascular accident or death from any cardiovascular cause by 57%. The EDIC study showed that the benefits noted for the microvascular complications involving the eyes, kidneys and nerves during the DCCT study persisted after that study was completed. This longer-lasting benefit from tight glucose control has been termed ‘metabolic memory’.
Diagnosis
Type 1 diabetes can be diagnosed in children as follows:
• Patients with the ‘classic’ symptoms of T1DM, namely the triad of polydypsia, polyuria and weight loss despite polyphagia, are diagnosed by having a random blood sugar level (BSL; the commonly used term for plasma glucose level) above 11 mmol/L. Some units recommend a level of 14 mmol/L, but in practice the diagnosis is usually clear cut, and the level much higher than either figure.
• Asymptomatic patients require two criteria: a fasting BSL above 7.8 mmol/L, plus a 2-hour postprandial BSL above 11 mmol/L. Alternatively, a formal oral glucose tolerance test (GTT) demonstrating a sustained elevation in BSL above 11 mmol/L at 2 hours is required, as well as a similarly elevated intervening value taken between the time the glucose load (which is 1.75 g/kg, up to 75 g) is given and the 2-hour value. Again, this is fairly theoretical, as doubtful cases requiring a GTT for diagnosis are very rare.
History
Initial diagnosis
1. Initial symptoms: for example, early symptoms preceding the classic triad, lack of weight gain, nocturia, behaviour change, altered school performance, changed vision (blurring), tempo of onset (developing over days, weeks or months pre-diagnosis).
2. Immediate pre-diagnosis symptoms: polydypsia, polyuria, weight loss despite polyphagia.
3. Symptoms associated with ketoacidosis: for example, vomiting, abdominal pain, clouding of consciousness.
4. Where, when and how the diagnosis was made, length of hospital stay, education given, treatment in hospital, treatment at discharge.
Progress of the disease
1. Details of subsequent hospitalisations (frequency, indications, usual length of stay, usual outcome).
2. Complications of the disease: for example, eye problems with cataracts, retinopathy, joint problems with limited joint mobility (LJM), severe hypoglycaemic reactions.
3. Complications of treatment (e.g. fat atrophy or hypertrophy, insulin allergic reactions); degree of control (number of episodes of ketoacidosis, frequency of hypoglycaemic symptoms).
4. Monitoring of the disease: how often seen in clinic, usual investigations performed, how often seen by local doctor.
5. Changes in management: for example, increase in insulin administration from daily to twice daily, twice daily with additional short/ultra-short-acting or basal bolus regimen, use of insulin pump, altered dosages due to occult nocturnal hypoglycaemia, changeover from human insulin to analogues.
6. At what age did the patient begin to administer his or her own insulin?
Current status
1. General health: lethargic or energetic.
2. Insulin type, dose, regimen (which sort, how much, when, given by whom, where, rotation of sites; modifications with raised BSL, sporting activities, intercurrent illness or dining out), compliance with treatment.
3. Diet prescribed (whether portions/exchanges used, glycaemic index, recommended foods), diet actually taken, alcohol intake (adolescents), involvement of dietician, any restrictions (adhered to or not).
4. Hypoglycaemia: how often, what symptoms (e.g. sweating, pallor, tremulousness, hunger, headache, odd behaviour, lethargy, crying, bad temper, lack of coordination, dizziness, vomiting, convulsions, loss of consciousness, early morning headaches after nocturnal ‘hypo’, restless sleep); usual precipitants; anticipatory strategies for prevention of ‘hypos’; response to ‘hypos’ such as taking fast-acting sugars (e.g. glass of orange juice with added sugar, glass of lemonade, jelly beans) followed by a small protein and complex carbohydrate snack (e.g. bread, biscuits); ever any need for intramuscular glucagon? (Note: if no ‘hypos’ have occurred, BSL may have been too high.) Any evidence of ‘hypoglycaemia unawareness’?
5. Control: hypoglycaemia (see above); hyperglycaemia (e.g. any nocturia, polyuria, blurred vision, weight loss, excessive weight gain, disturbance of menstrual periods in postpubertal girls); BSL readings (usual levels, when performed, how often, by whom, response to high level); usual HbAlc levels; urine testing (how often, what indications); amount of school missed in the last few months, vaginal thrush, other infections such as pilonidal sinus, infected ingrown toenail.
6. Other problems: for example, adolescent self-image, compliance issues.
Social history
1. Impact on child: self-image, reaction of school friends, coping with giving insulin, dietary restrictions, exercise, amount of school missed.
2. Impact on siblings: sibling rivalry, risk of diabetes.
3. Impact on parents: family finances, employment, concern regarding future complications, genetic counselling.
4. Social supports: Diabetes Association, access to social worker, government benefits obtained.
5. Coping: who attends the clinic with the patient, level of education of the child and parents, contingency plans for intercurrent illnesses or severe hypoglycaemia causing loss of consciousness, access to local doctor/paediatrician/hospital.
Management
This involves the use of insulin, diet and regular exercise, with the following aims:
1. Control of BSL: maintaining close to normoglycaemia; see below.
2. Prevention of acute complications; for example, hypoglycaemia, ketoacidosis.
3. Ensuring optimum growth and development.
4. Maintaining a normal lifestyle.
5. Adequate education of the patient and parents.
6. Early detection and treatment of associated disease (e.g. Hashimoto’s thyroiditis).
7. Provision of psychological support and counsel.
8. Ensuring adequate access to appropriate social supports.
9. Reducing long-term complications by maintaining good metabolic control.
10. Regular screening for complications and early intervention when they appear (ACE inhibitors for hypertension or proteinuria, etc).
Age-specific aspects of control
The expectations at different ages vary. There are three groups:
1. Infants to preschoolers. The main goal is to avoid hypoglycaemia and preserve cognitive function (in line with the findings of the DCCT). The acceptable range for BSLs at this age is between 6 and 15 mmol/L, and the HbA1c between 8.0 and 9.5 gm%.
2. School-age to puberty. Again, avoidance of hypoglycaemia is a top priority. Acceptable ranges: BSL 4–10 mmol/L; HbA1c 8.0 gm%.
3. Adolescence. Acceptable ranges: BSL 4–8 mmol/L; HbA1c as low as possible. It may be that postpubertal control is more important than prepubertal; this is unclear.
Insulin therapy
Average dosage requirements are as follows:
1. ‘Honeymoon’ period: 0.5 units per kilogram per day (or less).
2. Preadolescent: 1.0 unit per kilogram per day.
3. Adolescent: 1.0–2.0 units per kilogram per day (increase with pubertal growth spurt and reduce later when growth has finished).
Candidates should be familiar with the various insulin regimens. These include:
1. Daily (longer-acting only, or mixed short and longer).
3. Twice daily with additional short or ultrashort.
4. Basal bolus (three pre-meal short or ultra-short, plus longer in evening; only used in motivated adolescents).
5. Premixed (biphasic) insulin (only used for non-compliance, or inability to mix insulin).
