ACROMEGALY DR INDHU PRAKASH REDDY MEDICINE PG KURNOOL MEDICAL COLLEGE

Definition Disproportionate skeletal tissue and soft

tissue overgrowth Results from hyperplasia of pituitary

somatotroph cells and excessive growth hormone production

First described by Verga in 1864

GH physiology• Produced in anterior pituitary gland• Stimulated by

– GHRH from hypothalamus– Ghrelin (gut)

• Inhibited by – somatostatin via SSTR 2 and 5 receptor subtypes

• SS regulates the timing and amplitude of GH release

• GH receptors widely expressed in liver, fat and muscle

Loss of pulsatility of GH in acromegaly (umIU/L)

INVESTIGATION AND MANAGEMENT OF

ACROMEGALY

Siti hamidahMed student UniSZA

Clinical presentation depends on the age of onset of the GH excess

If there is GH excess in child hood or adolescence prior to epiphyseal fusion gigantism results (extreme tall stature)

If the GH excess occurs in adult hood or after fusion of the epiphysis enlargement of acral parts or tips of body (nose;lips;hands and feet) in addition soft tissues &internal parts of the body enlarge except brain

Symptoms

Typical feature

s:

Abnormally large hands

and feet

Large, prominent

facial features

Enlarged tongue

Abnormally tall

Clinical ManifestationsMASS EFFECTS OF TUMOR SYSTEMIC EFFECTS OF

GH/IGF-I EXCESS Headache Visual field defects Hyperprolactinemia Pituitary stalk section Hypopituitarism Hypothyroidism,

hypogonadism, hypocortisolism

Visceromegaly Soft tissue and skin

changes Thickening of acral parts Increased skin thickness

and soft tissue hypertrophy

Hyperhidrosis/Oily texture Skin tags and acanthosis

nigricans

CARDIOVASCULAR FEATURES RESPIRATORY MANIFESTATIONS

Hypertrophy (biventricular or asymmetric septal)

Congestive Heart Failure (systolic and/or diastolic)

Coronary disease Arrhythmias Hypertension Cardiomyopathy

Macroglossia Jaw malocclusion Upper airway

obstruction Sleep disturbances Sleep apnea (central

and obstructive) Ventilatory

dysfunction

METABOLIC FEATURES BONE AND JOINT MANIFESTATIONS

Impaired glucose tolerance Diabetes mellitus Insulin resistance Other endocrine

consequences Goiter Hypercalciuria Galactorrhea Decrease libido, impotence Menstrual abnormalities

Increased articular cartilage thickness

Arthralgias and arthritis

Carpal tunnel syndrome

Osteopenia

Investigation 1) Assessment of GH:

Random GH: often not diagnostic because of episodic secretion and short half-life of the hormone.

Glucose tolerance test: GH is normally inhibited by glucose. If the glucose load fails to suppress the GH level below 1 mU/L and the IGF-1 level is elevated then the diagnosis of acromegaly can be confirmed.

IGF-1: long half-life and so is a useful measurement

to assess GH secretion and therefore screen for acromegaly and monitor the effect of therapy.

A normal IGF-1 together with GH < 5 mU/L (2.5 ng/L) may be taken to exclude acromegaly if the diagnosis is clinically unlikely

IGF-binding protein-3 (IGFBP-3): is the main binding protein for circulating IGF and is increased in acromegaly. Can be useful in the diagnosis of acromegaly.

2) Visual field examination – defects are common, e.g. bitemporal hemianopia (partial blindness where vision is missing in the outer half of both the right and left visual field)

3) MRI scan of pituitary if above tests abnormal. This will almost always reveal the pituitary adenoma.

4) Pituitary function – partial or complete anterior hypopituitarism is common.

5) Prolactin – mild to moderate hyperprolactinaemia occurs in 30% of patients. In some, the adenoma secretes both GH and prolactin.

Pictures show the normal eyes view and bitemporal hemianopia view

MRI scan:- pituitary adenoma

6) chest and abdominal radiology: to detect an ectopic source of growth hormone may detect cardiomegaly due to

cardiomyopathy

7) hands radiology reveals: tufting of terminal phalanges increased joint spaces due to cartilage

hypertrophy

Complication of acromegaly

Heart disease acromegaly increases the risk of ischemic

heart disease leading to a worsening of risk of heart attacks and angina.

Risk of heart failure also rises with enlargement of the heart and imbalance between demands of the body to the capacity of the heart to pump blood.

The risk of diabetes mellitus rises to a great extent among those with acromegaly.

Pregnant women with acromegalyhave a heightened risk of developing gestational diabetes and pregnancy induced hypertension. This may raise the risk of preterm birth or still birth.

Those with acromegaly are at risk of arthritis and joint pains as well. This is called Acromegalic arthropathy and affects up to 70% of patients. Both the axial and peripheral skeleton may be affected. This involves the spine as well as the joints of the limbs. Due to compression of nerves of the hand, patient may develop Carpal tunnel syndrome.

Due to overgrowth of structures of the back of the throat and tongue, there may be development of obstructive sleep apnoea and this leads to interrupted sleep.

There is a high risk of development of colonic polyps. These polyps, if not detected early and removed, may go on to form adenocarcinoma of the colon or bowel cancer. Those with acromegaly thus require early and regular screening for bowel cancer.

MANAGEMENT OF ACROMEGALY

Aim= to achieve a mean growth hormone level below5 mU/L (or 2.5 ng/L)

Siti hamidah mahbud 030480

SurgeryTrans-sphenoidal surgery is the appropriate

first-line therapy. It will result in clinical remission in a majority of cases (60–90%) with pituitary microadenoma.

Very high pre-operative GH and IGF-1 levels are also poor prognostic markers of surgical cure.

Transfrontal surgery is rarely required except

for massive macroadenomas.

Pituitary radiotherapy.External radiotherapy is normally used after

pituitary surgery fails to normalize GH levels oftencombined with medium-term treatment with a somatostatin analogue or a dopamine agonist because of the slow biochemical response to radiotherapy.

Stereotactic radiotherapy is used insome centres.

Medical therapy. three receptor targets for the

treatment of acromegaly pituitary somatostatin receptors, dopamine (D2) receptors and growth hormone receptors in the periphery.

Medical therapy. Somatostatin receptor agonists.Octreotide and lanreotide are synthetic

analogues of somatostatinused as a short-term treatment but now are

sometimes used as primary therapy. They reduce GH and IGF levels in most patients.

Both drugs are typically administered as monthly depot injections and are generally well tolerated but are associated with an increased incidence of gallstones

Dopamine agonists.act on D2 receptors and can be given to shrink

tumours prior to definitive therapy or to control symptoms and persisting GH secretion;

most effective in mixed growth-hormone-producing and prolactin producing tumours.

The doses are bromocriptine 10–60 mg daily or cabergoline 0.5 mg daily which should be started slowly.

Given alone they reduce GH to ‘safe’ levels (only a minority of cases) but they are useful for mild residual disease or in combination with somatostatin analogues.

Growth hormone antagonistsPegvisomant (a genetically modified analogue

of GH) is a GH receptor antagonist which has its effect by binding to and preventing dimerization of the GH receptor.

does not lower growth hormone levels or reduce tumour size but has been shown to normalize IGF-1 levels in 90% of patients.

main role = treatment of patients in whom GH and IGF levels cannot be reduced to safe levels with somatostatin analogues alone, surgery or radiotherapy.

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