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Acromegaly (Greek for appendage enlargement) is a rare but very serious disease frequently referred to as Gigantism or Giantism. It is the direct result of an overproduction and secretion of the adenohypophyseal growth hormone GH. True to its name, the disease is characterized by an enlargement of the organs, bones, and soft tissues, as well as a thickening of the skin and bodily membranes; and is frequently difficult to diagnose, as symptoms often do not appear until middle age. Typically the disease results in heart failure caused by an enlargement of the heart, organ failure due to pressure or thickening of the outer membrane of the organ, or brain hemorrhaging caused by a benign or malignant pituitary adenoma. To date, there are three known forms of the disease: Cushings disease, Nelson Syndrome, and Prolactinoma. Each is characterized by different phenotypic attributes commonly linked by an enlargement of all or some particular body parts.
Prolactinoma is the most frequently recognized form of giantism. It is characterized by an overall enlargement of the body, and was brought to public attention nearly twenty years ago by pro-wrestler and actor Andre the Giant, who later died of heart failure in the early 1990 s. Nelsons disease and Cushing Syndrome are similar to each other, however there is now controversy as to whether these two diseases are even linked to Prolactinoma since they are not commonly characterized by an overall enlargement of the body, but rather an extreme overproduction of soft and fatty tissue. These diseases cause thickening of the bones, skin, and soft tissue, but often appear after the person has finished growing, making the patient appear overweight and unable to speak and move with fluidity since the tongue and hands are hindered.
All three diseases tend to have the same outcome: organ failure or brain hemorrhaging. In the past twenty years, controversy has arisen as to whether there are in fact three forms of the disease, what characterizes differentiation between each one, and how should each be treated accordingly. The problem is until recently, scientists have based their diagnoses almost entirely upon phenotypic characteristics and what is known about pituitary adenoma ta; only now are scientists beginning to analyze the genes and hormones involved on the micro level. The following articles examine methods in which testing for the disease takes place.
Recent studied tend to revolve mainly around the IGF-binding protein, the proposed cause of pituitary adenoma. However, it is not entirely known just how to test for this protein; whether to measure free IGF or total IGF-binding proteins. Article Summaries: Note: there are ten articles attached to this document; the first five of which are primary and summarized below. The remaining five are not summarized here and are used for supplementary purposes.
How and when to measure insulin-like growth factor-I and related growth hormone-dependent proteins: The IGF (insulin-like growth factor) -binding protein is a crucial structure to the ability of the body to produce the growth hormone GH. Patients who are GHD (growth hormone deficient) either secrete too much or too little GH. In the case of Acromegaly, a massive influx of GH is produced by the pituitary gland leading to expansion of tissues and bone mass. GH affects the ability to not grow as well. Other patients who are GHD do not produce enough of the hormone, and therefore display little soft tissue, weak bones, and a generally small stature.
This article examines the ability to determine GHD in a patient before irreversible damage is done to the body. Though there are several forms of GHD, most are hereditary and caused by a number of factors including tumors and dysfunctional IGF-binding proteins. Typically, the amount of Igf's is not a contributor to GHD, though in some cases, it may be an indicator of problems involving the IGF type I receptor structure. On average, the body will produce Igf's at a constant rate but if they are not used, production slows, making it difficult to use the level of Igf's to indicate receptor obstructions. When the Igf's do not bond correctly, a negative feedback response causes the pituitary gland to cease secretion of GH, while overactive IGF receptors raise the level of GH dramatically. The body produces Igf's to match the activity level of the receptors, leaving the amount at a fairly constant total.
The question arises then how IGF type I receptors should be tested and measured. Only about 1 % of IGF type I and type II receptors are unbound, so the hypothesis is that only free and unused IGF receptors should be measured for activity level to indicate a problem. Unfortunately, the binding process is not always constant and at any given second, up to 20 % may be unbound and accessible to tissues. An oral glucose level test indicates free IGF receptors so many tests could be performed to take an average, however GHD is often coupled with hypoglycemia which skews the data since the body is already not processing glucose as expected.
Recently, experiments have been conducted to test the levels of IGFBP- 3, a newly discovered protein known as the GH dependent IGF binding protein. The amount of this protein tends to have more accurate results in that high levels are often found in children with early signs of acromegaly, while low levels tend to run in children of short stature. IGFBP- 3 also tends to run at a sensitivity level about 83 %, significantly higher and more accurate than IGF receptor testing. Acromegaly: the significance of serum total and free IGF-I and IGF-binding protein- 3 in diagnosis: This article discusses a conflicting view with the previous document. The authors here argue that the levels of IGF receptors and Igf's in the body are crucial to the diagnosis of acromegaly, rather than the IGFBP- 3 measurement which indicates only GHD instead of specific diseases. The van der Lelyde Herder experiments indicate that acromegaliac's show no reliable correlation between the levels of IGF and the levels of IGFBP- 3 proteins.
The levels of IGFBP- 3 and IGF in fact decrease with age at different rates so testing very early or very late in the patients life may give inaccurate results. When normal middle-aged (mean age 47) males and females were compared to acromegalic middle-aged males and females, the results showed that the level of Igf's in the GH serum are much higher in the acromegaly patients. Specifically, the amount of free IGF-I differ the most from normal to diseased patients, followed by the total IGF-I with another dramatic differentiation. The IGFBP- 3 levels, however, show two distinct clouds when plotted, with many overlapping portions.
The scientists conclude that testing for the levels of IGFBP- 3 is not completely without benefits. These levels are very sensitive to GH and are a strong indicator of the severity of the disease, however they can only be used to diagnose acromegaly in severe cases. Acromegaly With Normal Basal Growth Hormone Levels: This very short article indicates that acromegaly cannot in fact be diagnosed based on IGF-I nor IGFBP- 3 levels alone. The 42 -year-old male patient observed in this experiment had been for five years a known acromegalic.
His diagnosis is based on a pituitary adenoma which crushes the pituitary gland, forcing the influx of GH production. This is not an uncommon form of acromegaly, often found in patients with prolactinoma specifically. The individual shows no visible signs of acromegaly; bone density and tissue size and sexual functionality have not visibly changed, nor has the patient developed gynecomastia nor galactorrhoea. This stability in condition is also not uncommon in patients with acromegaly.
Often visible physical changes do not occur for several years when adenoma ta are involved. What is striking about this patient however, is that the IGF-I and IGFBP- 3 levels are liken to that of a normal person. The GH level is also completely within range of a normal person. Though the IFG-I free level is slightly elevated, there are almost no signs of acromegaly in the patient. The article concludes that this may not be as uncommon as previously thought...
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