How will you be assessed when dealing with a patient with acromegaly.

A 38 year old man comes to your OPD with a blood sugar fasting of 235 mg/dl, HbA1c of 11, and uncontrolled hypertension. His blood sugar always stays above the baseline values and is often high. He is a big bulky man 6’2″ in height with a BMI of 35. You notice that he has very large hands and feet so much so that he only wears rubber flip flops because he cannot find shoes to fit his feet. He has a large face with a tongue that tends to protrude when he talks, his lower jaw is large and he confirms that he has a problem taking a bit out of food so has to cut up fruit and vegetables before eating them. His forehead bulges because of frontal bossing. What do you suspect? Acromegaly.

He says that he has been like this for 10 years as he first noted the bodily changes when he was 28 years old. He was diagnosed as having a pituitary adenoma which secreted growth hormone. He was offered trans-sphenoidal resection but declined the surgery out of fear. He was put on bromocriptine as that was the only available drug where he was living. His bodily changes persisted and he became hypertensive.

Comment.

Bromocriptine is a dopamine receptor agonist which is least effective in the treatment of acromegaly. Carbigoline would have been a better choice. Both these drugs are oral and less costly than ocreotide, lanreotide or pasirotide. These however need to be injected every 14 or 28 days. An oral form of octreotide is also available. Another even more expensive choice could be pegvisomant, a GH receptor antagonist that is a mutated GH molecule to which polymers have been attached at several sites to prolong its half-life.

As the patient did not improve he was offered surgery again. This time he agreed specially as he realized that he could not always see from the periphery of his eyes. He thought he was going blind. His adenoma had increased in size on CT scan and MRI. A neurosurgeon with some experience in tran-sphenoidal technique operated on him. Obviously his physical features did not regress but his blood pressure was now controlled with one drug. His visual defect did not progress any further. His headaches improved. His GH level fell to 3.5 mcg/L. This is not the desirable level of 1 mcg/L.

What features are likely to improve with successful therapy?

  • Soft-tissue swelling, carpal tunnel syndrome, and snoring
  • Sleep apnea
  • Left ventricular mass and left ventricular function

He was seen 2 years later. He had developed diabetes mellitus which was not controlled with methformin in maximal dose and amaryl (a sulphonylurea). He declined insulin. His blood pressure was uncontrolled and he needed three classes of drugs to treat it. His headaches had come back. He complained of numbness on the left forehead and cheek.

What is happening to him? The adenoma was probably only partially resected and has recurred. It is producing local effects hence the headaches, the numbness is caused by invasion of the cavernous sinus and the nerve that is being compressed is the maxillary division of the trigeminal or 5th nerve, which runs in a sheath in the lateral wall of the cavernous sinus.

What other cranial nerves are likely to be affected?  The 3rd nerve also runs in the lateral wall of the cavernous sinus and the 4th nerve  and the ophthalmic division of the trigeminal nerve. hence there is a chance of diplopia, third nerve palsy, 4th nerve palsy and numbness of the forehead.

When should a patient be checked for biochemical remission after surgery? It takes about 12 weeks for the IGF-I and GH levels to normalize after successful tran-sphenoidal surgery. An MRI scan should also be done.

Should surgery be repeated? Yes if there is:

  • Residual intrasellar mass that compresses vital structures after initial surgery
  • Significant residual tumor in the sella that is resectable

Does adenoma size regress with medical therapy? Somatostatin analog therapy leads to a reduction in adenoma size of approximately 20 to 50 percent in 30 percent of patients.

He was started on carbigoline this time. He was initially unhappy because of GI symptoms but with a little persistence the symptoms subsided.

Somatostatin analogs are usually well tolerated. Approximately one-third of patients have nausea, abdominal discomfort, bloating, loose stools,  and fat malabsorption during the first several weeks of therapy, after which the symptoms usually subside spontaneously with continued use.

He agreed to use insulin (Mixtard 30/100) subcutaneously and with dose adjustment his diabetes came under control.

Octreotide and lanreotide transiently inhibit insulin secretion, but their clinical impact on glucose homeostasis is minimal. Gallstones may form with therapy.

Later oral octreotide was added to his therapy. He had developed signs of diastolic heart failure but improved with therapy. He dis not develop either aortic valve nor mitral valve regurgitation. He then got married but remained infertile. Why? Because of the prolactin his tumor was secreting.

The somatostatin analog pasireotide  is also effective in some patients with acromegaly and is approved for its treatment, but it frequently causes or worsens hyperglycemia.

Pegvisomant is administered as a daily, subcutaneous injection. The initial daily dose is 10 mg. The serum IGF-1 concentration should be measured every four to six weeks and the dose adjusted, in 5 mg increments, to a maximum of 30 mg/day, to keep the serum IGF-1 within the normal range. Liver function tests (LFTs) should be measured every six months, and if more than threefold elevated, the drug should be discontinued. The combination of a long-acting somatostatin analog and pegvisomant, in a few reports, decreased serum IGF-1 concentrations to normal in a majority of patients, but the combination was not clearly better than pegvisomant alone.

Better results are obtained with accurate localisation of the tumor and ablation with a gamma gun. This equipment is not universally available.  If trans-sphenoidal surgery results in normalization of serum insulin-like growth factor-1 (IGF-1) concentration and no evidence of residual tumor on magnetic resonance imaging (MRI),  no further therapy is needed. However biochemical monitoring should be carried out.

When should stereotactic surgery be used? When there is:

  • Residual intrasellar mass that compresses vital structures after initial surgery
  • Significant residual tumor in the sella that is resectable

Stereotactic radiosurgery (SRS) – Radiation can be administered as a single dose (often called “stereotactic radiosurgery,” or SRS, although there is no surgery), by linear accelerator, gamma radiation, or protons. It has the advantage of  faster control of hormonal hypersecretion. Gamma radiation has been available more widely than the other forms of single-dose radiation (protons and x-radiation from a linear accelerator), so more data are available about it. The most commonly used stereotactic method used is the Gamma Knife. This is radio-ablation. There is no physical gun.

A single dose of radiation cannot be used unless the adenoma is separated by several millimetres from the optic chiasma and optic nerves (to limit the exposure of the optic apparatus to less than 8 Gy), which would be severely damaged by such a high dose, resulting in blindness. In this situation, fractionated radiation must be used. Fractionated radiation therapy is the delivery of radiation therapy in multiple, small, daily doses, usually five days a week for five to six weeks.

What are the delivery systems for radiation?

Delivery systems

  • The linear accelerator is the most common device used for RT, ie, for conventional radiation. Modifications have been made to deliver the radiation to the desired location and dose.
  • Gamma knife – Gamma Knife is an SRS treatment unit. Gamma radiation can be administered from a cobalt source but only as a single, large dose.
  • Proton therapy – High-energy proton particles can be administered from a cyclotron in either a single, large dose or multiple fractions.

 It was suggested in an earlier study that use of a somatostatin analog at the time of RT may limit its effectiveness, but this consideration has been refuted by subsequent studies.

Radiation is s slow form of therapy. Few patients who undergo fractionated radiation achieve the current goal of therapy, ie, a basal serum GH concentration less than 1 mcg/L. Serum GH and IGF-1 concentrations decline on average approximately 20 percent per year, so that serum GH concentrations may not reach 5 to 10 mcg/L until 5 to 10 years or more after treatment if the initial value is very high.

The efficacy of SRS (the gamma gun) appears to be similar to conventional RT. However, SRS may be more appealing because the treatment duration is shorter. In three studies of 35 to 96 acromegalic patients followed after gamma radiation, cure rates (defined as normal age- and gender-adjusted IGF-1 concentrations and basal GH of <2.5 mcg/L or post-glucose load values of <1 mcg/L) were 46 to 60 percent in 5 to 10 years.

Any side effects of radiation? Which hormones will you have to replace eventually?

Hypopituitarism – Within 10 years, approximately 40 percent of patients treated with pituitary radiation develop deficiency of one or more pituitary hormones, and the incidence continues to increase thereafter. Gonadotropin deficiency is most common, followed by corticotropin (ACTH) and then thyroid-stimulating hormone (TSH) deficiency.

Other side effects are rare. Cranial-nerve palsies, loss of vision, and memory deficits usually occur only when the dose is high.

This patient is now on thyroxine as well. He has developed peripheral neuropathy and has difficulty in wearing flip flops as he cannot grip the slippers with his feet. An orthopedic specialty shop agreed to make large shoes to fit him and also sandals with back slings to make life easier for him. He has developed an ischemic ulcer on his ankle and has needed to be treated for cataract. He has early diabetic retinopathy. So you can see that treating acromegaly is not simply resection of the adenoma or reducing the IGF-I and GH to basal levels. You have to treat local symptoms, the complications of diabetes and hypertension and be careful about  replacement therapy of other hormones that are likely also to be suppressed with time either from the tumor or the therapy.

 

 

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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