45. Congenital adrenal hyperplasia. Osteoporosis

Congenital adrenal hyperplasia

Definition and epidemiology

Congenital adrenal hyperplasia (CAH), sometimes called adrenogenital syndrome, is a group of autosomal recessive defects in the enzymes responsible for secretion of adrenal cortical hormones.

The name comes from the compensatory adrenal hyperplasia which occurs due to decreased negative feedback on the pituitary, causing ACTH to increase.

Thanks to neonatal screening the more severe forms are rare nowadays, so the clinical presentation has shifted from presenting acutely with shock in the neonatal period to presenting with symptoms of increased androgens in young adults.

Classification

There are three enzymes which can be affected, each giving one type of CAH:

  • 21β-hydroxylase – accounts for 95% of cases
  • 11β-hydroxylase – accounts for approx. 5% of cases
  • 17α-hydroxylase – very rare

We’ll focus on the most common type. When we speak about CAH we generally mean 21β-hydroxylase deficiency.

There are two main types of CAH depending on the degree to which 21β-hydroxylase is deficient. In the early onset type, the deficiency is severe. In the late onset type, the deficiency is mild. The latter is most common. There are two subtypes of early onset CAH, the salt-wasting type and the virilizing type, with the former being the most severe.

  • Early onset CAH (or classic CAH)
    • Salt-wasting type
    • Simple virilizing type
  • Late onset CAH (or non-classic CAH)

In salt-wasting type the 21β-hydroxylase activity is insufficient to maintain the aldosterone and cortisol level. In the virilizing type the activity is sufficient to maintain aldosterone levels but not cortisol. In late-onset CAH, the deficiency is even milder and so the patient presents much later.

Clinical features

Salt-wasting CAH presents in the neonatal period. Patients present with symptoms of adrenal crisis, like hyponatraemia, hyperkalaemia, metabolic acidosis, hypotension, and shock, because of insufficient aldosterone and cortisol. Females also have ambiguous genitalia at birth because of increased androgens.

Virilizing CAH is diagnosed at different times in the different sexes. Males present with puberty at age 2 – 4, while females present in the neonatal period with ambiguous genitalia.

Late onset CAH is diagnosed in young adulthood. A typical late onset CAH patient is female, has hirsutism and menstrual disturbances due to increased androgens. Male patients are almost always asymptomatic.

Diagnosis and evaluation

Nowadays early-onset CAH is screened for during neonatal screening and is therefore rare. 17-hydroxy-progesterone is measured in neonates and is elevated in both 21β-hydroxylase and 11β-hydroxylase deficiency.

Late onset CAH is screened for by 17-hydroxy-progesterone levels as well. The diagnosis is confirmed if 17-hydroxyprogesterone levels are high after ACTH stimulation.

Treatment

All early onset CAH patients should receive lifelong hormone replacement therapy of glucocorticoids and mineralocorticoids. Glucocorticoid doses must be increased in periods of stress, infection, surgery, etc.

Like any adrenal crises, salt-wasting CAH presenting with adrenal crisis is acutely treated with fluid replacement and glucocorticoids, as well as supportive treatment to correct glucose and electrolytes.

Late onset CAH can be treated by oral contraceptives or glucocorticoids in females. Men do not require treatment.

Osteoporosis

Definition and epidemiology

Osteoporosis refers to the decreased bone density, which increases the risk for fractures. It’s defined according to the results of a DEXA (dual-energy x-ray absorptiometry) scan. The scan calculates the bone mineral density and gives a T-score. Osteoporosis is defined as a T-score of less than -2,5 standard deviations. This means that a person with osteoporosis has 2,5 standard deviations lower bone density than an average young adult female.

T-score between -1 and -2,5 is less severe and is called osteopaenia.

Etiology

  • Female gender
  • Old age
  • Smoking
  • Low calcium intake
  • Low vitamin D intake
  • Low levels of physical exercise
  • Alcohol consumption

Osteoporosis can also be secondary to:

  • Corticosteroids
  • PPIs
  • Hyperthyroidism
  • Chronic kidney disease

Clinical features

Most patients with osteoporosis are asymptomatic, but the condition predisposes to so-called pathological fractures. These are fractures which are caused by normal activities which would otherwise not cause fracture in healthy people. Fractures can occur during bending over, sneezing, or falling from small height. These fractures most commonly affect the vertebrae.

Vertebral compression fractures can occur in the absence of trauma. These are often asymptomatic but lead to decreased height and increased kyphosis over time.

Diagnosis and evaluation

Even though osteoporosis is defined based on the DEXA scan, it can be diagnosed in patient with risk factors who present with pathological fractures. In the absence of pathological fractures, a DEXA scan is required for diagnosis. Even though the pathological fracture is enough to make the diagnosis, a DEXA scan of these patients is usually performed anyway as part of the evaluation.

Some countries recommend screening for osteoporosis in persons at risk, like postmenopausal persons above a certain age, or patients on long-term glucocorticoid therapy. In other countries (like Norway) patients are only evaluated after a pathological fracture has occurred.

Treatment

Bisphosphonates like alendronate and risedronate are the first-line drugs in the treatment and is recommended for all patients with osteoporosis. To prevent these drugs from causing esophagitis they should be taken at least 30 minutes before meals, with plenty of water, and the patient should not lie down for 30 minutes after.

Second-line drugs include teriparatide (PTH analogue), raloxifene and denosumab (anti-RANKL).


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