General Neurology
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Acromegaly and gigantism
- Updated 05.24.2024
- Released 04.01.1995
- Expires For CME 05.24.2027
Acromegaly and gigantism
Introduction
Overview
Acromegaly is a disease characterized by the gradual enlargement of the peaked (acral) parts of the body, including the nose, lips, tongue, lower jaw, hands, and feet and by hyperplastic alterations in the entire osseous system. Gigantism occurs before epiphyseal closure. AIP gene mutations (AIPmut) often predispose to familial isolated pituitary adenomas with clinical features that may negatively impact treatment efficacy. The clinical picture of acromegaly is influenced by many factors, including the levels of growth hormone and insulin-like growth factor, age, tumor size, and delay in diagnosis. Surgical excision of the adenoma by transnasal transsphenoidal approach or by endoscopic endonasal transsphenoidal surgery is recommended. Pegvisomant is a medical therapy that blocks growth hormone action at peripheral receptors, normalizes insulin-like growth factor-1 levels, reduces signs and symptoms, and corrects metabolic defects.
Key points
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• Acromegaly is characterized by the gradual enlargement of the acral parts of the body, with hyperplastic alterations in the entire osseous system due to growth hormone excess after epiphyseal closure. | |
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• Gigantism occurs with growth hormone excess before epiphyseal closure. | |
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• Acromegaly is usually diagnosed by increased insulin-like growth factor and growth hormone after an oral glucose tolerance test. | |
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• For the treatment of acromegaly, surgical excision of the responsible pituitary adenoma by the transnasal transsphenoidal approach or by endoscopic endonasal transsphenoidal surgery is recommended. Alternatively, gamma knife therapy is an option. | |
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• Pegvisomant, a growth-hormone-receptor antagonist, reduces signs and symptoms of acromegaly and corrects metabolic defects. |
Historical note and terminology
Acromegaly. Acromegaly is a disease characterized by the gradual enlargement of the peripheral (acral) parts of the body including the nose, lips, tongue, lower jaw, hands, and feet and by hyperplastic alterations, particularly in the osseous system.
Acromegaly, the first recognized pituitary syndrome, was described by the French neurologist Pierre Marie (1853-1940) working under Jean-Martin Charcot (1825-1893) at the Salpêtrière Hospital in Paris (136).
Marie realized that many of the arthritic patients had an unusual enlargement of the hands and feet, which inspired the name he gave to this disorder (acromegaly literally means large extremities) (128; 162; 57; 59; 135). Marie's description was based on two cases of his own and five obtained from the literature dating back to 1722. Marie initially attributed the disorder to general nutritional disease but later attributed it to subnormal functioning of the pituitary. However, cases of gigantism and acromegaly were present long before the cases that Marie identified; ancient skeletons with these features have been identified, such as a Fifth Dynasty skeleton at Gyza, Egypt (146) and a Roman skeleton from the Imperial Age (142).
In the 1700s, several famous Irish giants made their living exhibiting themselves in Britain and across Europe. The skeletons of several of them were studied in detail, including Cornelius Magrath (1736-1760), Patrick Cotter (1760-1806), and Charles Byrne (1761-1783). Cornelius Magrath was born in Tipperary, Ireland. In 1752, he traveled to Cork for saltwater treatments to alleviate the pain of his rapid growth. With prodding there, he began exhibiting himself for pay. After touring England, he did short stints throughout Europe, including Germany and Venice, Italy, but while he was in Flanders, his health rapidly began to decline.
He returned to Ireland but died before he reached his 24th birthday. Although he had made friends with medical students from nearby Trinity College in Dublin, they stole his body the day he died. After dissection, his bones were preserved and controversially remain on display at Trinity College, despite numerous efforts to have them properly buried (64). Magrath's skeleton was studied in the late 19th and early 20th centuries, revealing a barrel chest, mild scoliosis, extraordinarily enlarged hands and fingers, and genu valgum (knock knees). The skull showed protrusion of the lower jaw (mandibular prognathism) and an underbite that caused some misalignment between the teeth (malocclusion). The internal view of the skull base showed marked enlargement and erosion of the sella turcica.
In 1895, English-American physician Woods Hutchinson (1962-1930) reported the case of a "French giantess," "Lady Aama," who was to be exhibited in a museum in Iowa City, Iowa in 1893, shortly before her precipitous death from "quick consumption" (tuberculosis).
The pituitary gland was not examined at the time of her autopsy, but the gland was later inferred to have been enlarged based on the enlargement of the pituitary fossa and the destruction of the sella turcica.
Hutchinson commented, anticipating a modern understanding of gigantism as beginning before epiphyseal closure:
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The enlargement of the pituitary body would appear to be the principal pathological characteristic of this disease, as it has been found to be present in ten out of the twelve cases, hitherto reported, in which autopsies were held. Its probable size in this case would appear to conform pretty closely to the average hypertrophy reported... What connection, if any, exists between the acromegaly and the giantism? And although the facts at our disposal are so few that any speculation upon the subject must be purely tentative, yet one is tempted to string them together upon some sort of a theory. ... Would it not appear probable that at least one form of giantism is merely acromegaly beginning in foetal or infant life? And that the pituitary body has some title to be regarded as a "growth-centre" for the entire body (103). |
By the end of the 19th century, acromegaly was recognized as a multisystem disorder that typically resulted from a tumor or abnormal growth within the anterior pituitary gland, associated with erosion of the sella turcica and abnormal secretory activity of a subset of chromophilic cells (24). Common features included progressive facial and bony deformation, that could then be documented with x-rays (ie, following the report of the discovery of x-rays by German physicist Wilhelm Conrad Röntgen [1845-1923] in December 1895). These findings are well illustrated by a male and female case of acromegaly from the end of the 19th century and an early x-ray comparison of the hands of an acromegalic man and a large normal man (24).
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Drawing of a section of the hypertrophied anterior pituitary from a male acromegalic patient
The specimen was hardened in Lang's solution and embedded in paraffin. The section was stained with hematoxylin and eosin. "The section shows the glandular structure of the normal [pituitary] and consequently the hyperplastic n...
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Drawing of the histology of a pituitary adenoma from an acromegalic woman
The specimen was hardened in alcohol and embedded in paraffin. The section was stained with hematoxylin and eosin. "The uniformity of all the cells which make up the growth and their close resemblance to the chromophilic cells ...
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Comparison of hand x-rays from acromegalic (left) and a normal "large male" (right)
On the left is the hand x-ray of a 38-year-old acromegalic man. "[W]hile the bones of the fingers are apparently of normal length, the fingers, because of the outlines of the soft tissue, appear to be short in proportion to the...
Pituitary surgery rapidly developed in the first decade of the 20th century. In 1906, British neurosurgeon Sir Victor Horsley (1857-1916) reported several successful temporal and frontal transcranial surgeries performed between 1904 and 1906 in 10 patients with acromegaly (102).
In 1907, Austrian surgeon Hermann Schloffer (1868-1937) successfully resected a pituitary tumor by the transnasal-transsphenoidal route (170; 72; 132; 171).
In 1908, Austrian surgeon Julius Hochenegg (1859-1940) performed the first transsphenoidal approach for acromegaly (100; 59).
Shortly thereafter, in 1909, American neurosurgeon Harvey Cushing (1869-1939) performed his first transsphenoidal operation for acromegaly in 1909 but switched to the transcranial route in the late 1920s (59).
As early as 1909, Cushing deduced that the associated eosinophilic pituitary tumors are associated with states of hormonal overproduction and that the hypopituitarism that occurs concomitantly with some eosinophilic and chromophobe adenomas is due to compression of the remaining normal portion of the gland (49).
In the 1920s at the University of California at Berkeley, American anatomist and embryologist Herbert Mclean Evans (1882-1971), in collaboration with zoologist Joseph A Long, found that the injection of anterior pituitary extract caused gigantism in rats (71).
The impact of species specificity of growth hormone was clarified in 1957, and treatment with human growth hormone proved effective (131).
Pituitary gigantism. Gigantism refers to the increased linear growth in affected children when growth hormone levels are increased before epiphyseal closure. Historically, those affected by gigantism often wound up as sideshow performers in circuses. Some with gigantism and acromegaly were renowned for their superhuman strength and found work as cowboys and professional wrestlers.
In 1900, French internist Émile Charles Achard (1860-1944) reported a man, giant “K,” with gigantism, acromegaly, and diabetes; he stood approximately 6 feet 9 inches tall.
His hands were dramatically larger than those of a normal man, but the fingers were proportionately widened and appeared stubby, and the soft tissue was thickened. An extraordinary pituitary tumor was discovered at autopsy.
Another man with gigantism was (Joseph) Édouard Beaupré (1881-1904), Canada's tallest man. His height increased rapidly from age 3 years to around 21 years. His final height was variously given as from 2.40 meters (7 feet 10.5 inches) to 2.52 meters (8 feet 3 inches) with a weight of 166 to 170 kg (365-375 pounds). He was exceptionally strong and worked as a cowboy and as a sideshow performer. From age 17 (1897), he toured as “The Willow Bunch Giant” in circus side shows and at fairs throughout Canada and the United States. He was able to lift a horse weighing 363 kg (800 pounds) to shoulder height by crouching under it and extending his legs but he injured his back in an attempt to lift 408 kg (900 pounds). He died in 1904 at age 23 while he was performing at the “World’s Fair” held in St Louis, Missouri. The cause of death was pulmonary hemorrhage as a result of tuberculosis. After death, his body was displayed for money by a funeral parlor and then a museum before inclusion in the collection of the department of anatomy at the University of Montreal. A skull x-ray in 1967 showed an enlarged sella tursica (measuring 1.6 × 1.2 cm, or 0.6 × 0.5 inches) and overgrowth of the frontal bones (17; 18). Following a legal action, his body was returned to his relatives in 1989 and then cremated to prevent further exploitation and exposition.
John Aasen (1890-1938), also known as the “Minneapolis giant”, was an American silent film actor and sideshow performer who was one of the tallest actors in history. By 1917, he began his career as a circus sideshow performer who was known as “Johnny the Gent.” He started his acting career in 1922 and acquired a new nickname of “Harold Lloyd Giant”. Aasen is shown in this photograph standing next to a normal-sized man. Aasen's height has variously been reported from 2.68 meters to 2.74 meters (8 feet 9.7 inches to 8 feet 11.5 inches). Aasen never underwent pituitary surgery nor was he treated with pituitary radiotherapy. Just before his death, at age 46, he was measured during a medical evaluation at 7 feet 0.9 inches, but by this time he had lost some height due to aging and could not stand completely straight anymore. He died at age 48 from pneumonia. In June 2008, Loma Linda University confirmed that the 7-foot-2.4-inch (219 cm) skeleton they had in their collection was his.
The tallest man who ever lived for whom there is irrefutable evidence was the American giant Robert Pershing Wadlow (1918-1940), also known as the Alton Giant and the Giant of Illinois. Wadlow reached 2.72 meters (8 feet 11.1 inches) in height, weighed 199 kg (439 pounds), and had a U.S. shoe size of 37 AA at the time of his death at age 22. His great size and his continued growth in adulthood were due to hyperplasia of his pituitary gland. He required leg braces to walk and had little feeling in his legs and feet. He became a celebrity after his 1936 U.S. tour, at age 18, with the Ringling Brothers Circus, with appearances at Madison Square Garden and the Boston Garden. During his circus appearances, he always appeared in the center ring (never in the sideshow), always wearing his regular clothes, and consistently refusing the circus's request that he wear a top hat and tails. In 1938, he began a promotional tour with the International Shoe Company, which provided him with free shoes. Wadlow considered himself as a celebrity who worked in advertising, not as a freak who was being exhibited. He possessed great physical strength until shortly before his death. He died of sepsis that resulted from an infection of his ankle brought on by chafing from a faulty brace.
Perhaps the most famous acromegalic giant, certainly within living memory, was André René Roussimoff (1946-1993), better known as André the Giant. Roussimoff worked as a professional wrestler and actor. He was diagnosed with gigantism and acromegaly when he was in his mid-20s and wrestling professionally in Japan. By the late 1980s, Roussimoff was 7 foot 4 inches tall (224 cm) and then weighed 520 pounds, a result of gigantism caused by excess growth hormone, which later resulted in acromegaly. By this point, the features of acromegaly had become much more apparent. In 1988, he defeated Hulk Hogan (Terry Eugene Bollea) to win the World Wrestling Federation's World Heavyweight Championship. Outside of wrestling, he was best known for appearing as Fezzik the Giant in The Princess Bride, a 1987 American fantasy adventure comedy film. He declined medical treatment for his acromegaly that may have prolonged his life because he was worried it would adversely affect his professional wrestling career. He died of congestive heart failure at age 46. At that time, he wore a size 24 shoe and weighed 555 pounds.
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Professional wrestler André the Giant walking to the ring in the late 1980s
André René Roussimoff (1946-1993), better known as André the Giant, was a French professional wrestler and actor. Since an earlier image from 1973, the features of acromegaly are much more prominent. (Photograph by John McKeon....
Clinical manifestations
Presentation and course
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• The most prevalent symptoms at the time of diagnosis of acromegaly are acral enlargement, headaches, macroglossia, and visual field defects. | |
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• Physical examination in patients with acromegaly reveals prominent supraorbital ridges, prognathism with teeth separation due to continued growth of the mandible, macroglossia, large, doughy and sweaty hands, goiter, osteoarthritis, increased anterior-posterior diameter of the chest, spinal and thoracic deformities, cardiomegaly, hepatomegaly, and skin tags. | |
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• Neurologic manifestations of acromegaly develop as a consequence of both the endocrine disturbance and the local mass effect of the underlying pituitary adenoma, but most neurologic complications are neuromuscular. | |
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• A mild (often subclinical) peripheral polyneuropathy is present in approximately half of the patients with acromegaly and is independent of associated diabetes. | |
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• Carpal tunnel syndrome may develop due to enlargement of the transverse carpal ligament and surgical release may precede the diagnosis of underlying acromegaly by years. | |
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• Features of hypopituitarism, visual field loss (ie, bitemporal defects including bitemporal hemianopsia), and ophthalmoplegia (due to compression of cranial nerves III, IV, and VI in the cavernous sinus) may be seen when a pituitary tumor enlarges to compress adjacent neural tissue. |
The clinical features of acromegaly develop insidiously, with most patients able to date symptoms back 15 years or longer (159). Common symptoms and signs include enlargement of the skull, hands, feet, nose, lips, and ears; lower jaw protrusion (prognathism) and macroglossia with consequent difficulty biting or chewing food; arthralgias (especially cervical); headaches; hypertrichosis, hyperpigmentation, and hyperhidrosis with an oily texture of the skin; skin tags; generalized weakness; carpal and cubital tunnel syndromes; paresthesias; decreased libido; and amenorrhea. The most common symptoms at the time of diagnosis are acral enlargement (81%), headaches (29%), macroglossia (29%), and visual field defects (19%). Affected people must progressively enlarge their rings, hats, gloves, and shoes. Other manifestations can include loud snoring, nocturnal coughing fits, and obstructive sleep apnea (97).
Men present slightly earlier on average than do women. In addition, hypogonadism and greater IGF-1 values were more frequently observed in men with acromegaly (19).
Physical examination reveals prominent supraorbital ridges; prognathism with teeth separation due to continued growth of the mandible; macroglossia; large, doughy and sweaty hands; goiter; osteoarthritis; increased anterior-posterior diameter of the chest; spinal and thoracic deformities; cardiomegaly; hepatomegaly; and skin tags. Clinical signs and symptoms with the highest weighted mean prevalence at diagnosis include acral enlargement (90%), facial features (65%), oral changes (62%), headache (59%), fatigue/tiredness (53%; including daytime sleepiness: 48%), hyperhidrosis (47%), snoring (46%), skin changes (including oily skin [37%] and thicker skin [35%]), weight gain (36%), and arthralgia (34%) (176); the clinical signs and symptoms vary across studies by year of publication, reflecting changes in recognition, management, and probably variations in reporting.
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Clinical signs and symptoms at time of diagnosis for two groups according to publication date
(Source: Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary ...
Acromegalic individuals may present for orthodontic surgery because of mandibular prognathism (91).
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Facial photographs of a 22-year-old man with acromegaly who presented for orthodontic surgery because of mandibular prognathism
The patient was found to have a growth hormone-producing macroadenoma with secondary hyperprolactinemia and deficiency of the gonadotropin axis. (Source: Gosau M, Vogel C, Moralis A, Proff P, Kleinheinz J, Driemel O. Mandibular...
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Intraoral photograph of a 22-year-old man with acromegaly showing malocclusion (Angle class III) due to mandibular prognathism
(Source: Gosau M, Vogel C, Moralis A, Proff P, Kleinheinz J, Driemel O. Mandibular prognathism caused by acromegaly - a surgical orthodontic case. Head Face Med 2009;5:16. Creative Commons Attribution 2.0 License, creativecommo...
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Coronal and sagittal cranial MRI of a 22-year-old man with acromegaly
MRI shows an extensive tumor extending in and above the sella turcica with a total volume of 4.7 × 2.9 × 2.2 cm3. The entire calvarium is thickened. (Source: Gosau M, Vogel C, Moralis A, Proff P, Kleinheinz J, Driemel O. Mandib...
In one such case, histological examination showed a highly vascularized pituitary adenoma with a diffuse (solid) growth pattern. Higher magnification showed uniform cells with broad eosinophilic cytoplasm and round-to-oval nuclei.
The proliferation index was very low, with approximately 3% of cells showing immunoreactivity against MiB-1.
MiB-1 immunostaining of a pituitary adenoma from a 22-year-old man with acromegaly
(x 200) The proliferation index is very low with approximately 3% of cells showing immunoreactivity against MiB-1. The MIB-1 monoclonal antibody recognizes the Ki-67 protein, which is expressed over the entire cell cycle except...
The MiB-1 monoclonal antibody recognizes the Ki-67 protein, which is expressed over the entire cell cycle except for the G0 phase; it has been used as an operational marker of cell proliferation for various types of tumors. Some tumor cells showed immunopositivity for prolactin in the peripheral areas of the cytoplasm.
Prolactin immunostaining of a pituitary adenoma from a 22-year-old man with acromegaly
(x 200) Some tumor cells show immunopositivity for prolactin in the peripheral areas of the cytoplasm. (Source: Gosau M, Vogel C, Moralis A, Proff P, Kleinheinz J, Driemel O. Mandibular prognathism caused by acromegaly - a surg...
However, no immunoreactivity was evident for human growth hormone.
Human growth hormone immunostaining of a pituitary adenoma from a 22-year-old man with acromegaly
(x 200) No immunoreactivity was evident for human growth hormone. Absence of immunostaining for growth hormone is found in a subset of patients with acromegaly (Schroeder JL, Spiotta AM, Fleseriu M, Prayson RA, Hamrahian AH, We...
Absence of immunostaining for growth hormone is found in a subset of patients with acromegaly (172).
Temporally, the earliest observed signs and symptoms tend to be enlarged hands and feet, hypertension, and carpal or cubital tunnel syndrome, which may precede diagnosis by years. Morphologic changes, snoring, and fatigue are all present in about 80% of patients at the time of diagnosis (30).
The acral manifestations of acromegaly may be asymmetric, although this is uncommon.
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Asymmetric involvement of the arms and hands in a young man with acromegaly
Note the marked asymmetric involvement of the arms, with the left arm and hand markedly larger than the left. The left index finger has also grown in deformed manner. This is one of a series of five photographs of cases of acro...
In severe acromegaly, acanthosis nigricans can occur involving the axillae and back of the neck, where the skin becomes dark, soft, and velvety with delicate folds and papillae. Rare manifestations include cutis verticis gyrata (ie, visible folds, ridges, or creases of the scalp resulting from thickening of scalp tissues) and psoriasis.
In patients with advanced disease, large-joint and axial arthropathy develops that may include thickened articular cartilage, periarticular calcifications, osteophyte overgrowth, synovitis, degenerative osteoarthritis, scoliosis, kyphosis, and vertebral fractures (88; 86).
Growth hormone has a marked effect on the development of orofacial structures, including eruption and shedding patterns of teeth (09).
Hypertension (67%) and diabetes mellitus (24%) are common and a majority display insulin resistance (116). Secondary diabetes mellitus is encountered in from 23% to 55% of cases (116; 144). The presence of secondary diabetes is associated with increased cardiovascular morbidity, increased malignancy rate, and overall mortality (144). The pathophysiologic mechanism of secondary diabetes in acromegalics is increased insulin resistance due to excessive lipolysis, altered fat distribution, and dysfunctional adipose tissue (144). Cardiac findings include left ventricular hypertrophy, asymmetric septal hypertrophy, cardiomyopathy, hypertension, and congestive cardiac failure.
Neurologic manifestations develop as a consequence of both the endocrine disturbance and the local mass effect of the underlying pituitary adenoma, but most neurologic complications are neuromuscular (31). At least one abnormal finding in the peripheral nervous system is found in most patients (88%) (05). A mild (often subclinical) peripheral polyneuropathy is present in approximately half of patients and is independent of associated diabetes (106). Paresthesias in the lower extremities, as well as sensory loss, hyporeflexia, and weakness, may be seen in a length-dependent distribution. Nerve biopsy indicates an increase in fascicular connective tissue elements and some loss of myelinated and unmyelinated nerve fibers. Peripheral nerve (median and ulnar) enlargement has been reported and appears to correlate with disease control, IGF-1 levels, and duration of disease (31). A prospective observational study (using dynamometers to measure muscle strength) found that patients with acromegaly tend to have increased muscle bulk, normal proximal strength, and reduced grip strength (79); grip strength improved after biochemical treatment was achieved.
Carpal tunnel syndrome may develop due to enlargement of the transverse carpal ligament, and surgical release may precede the diagnosis of underlying acromegaly by years (169). A proximal myopathy has also been described but is rare (117). Very rarely, a compressive myelopathy may occur secondary to overgrowth of spinal bony and soft tissue.
Neurocognitive dysfunction has been documented, with acromegaly patients manifesting worse executive functioning than normal controls (177).
Obstructive sleep apnea secondary to the associated anatomic changes of the air passages may produce lethargy and hypersomnolence.
Features of hypopituitarism, visual field loss, (ie, bitemporal defects including bitemporal hemianopsia) and ophthalmoplegia (due to compression of cranial nerves III, IV, and VI in the cavernous sinus) may be seen when a pituitary tumor enlarges to compress adjacent neural tissue.
Pituitary apoplexy (due to ischemic necrosis or hemorrhage into the tumor) or cerebrospinal fluid leakage may also occur.
Neuropathic foot ulcers in acromegalic gigantism are a common and significant problem, frequently impairing the daily activities of these individuals (61).
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Schematic recording of the “cutaneous sensations” demonstrating sensory defects in the lower legs
Schematic recording of the “cutaneous sensations” of the American acromegalic giant Robert Wadlow (1918-1940) from 25 March 1935, age 17 years and 1 month (height 244 cm, weight 170 kg) demonstrating sensory defects in the lowe...
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Deformities of both legs, knees, and feet in American acromegalic giant Robert Wadlow
Photograph of the American acromegalic giant Robert Wadlow (1918-1940) from October 19, 1936, age 18 years and 8 months (height 255.9 cm, weight 197.7 kg), showing deformities of both legs (genu valga), knees and feet. Photogra...
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Deformities and amputations of toes, because of recurrent ulcerations and infections in Icelandic acromegalic giant Johann Petursson
Photographs of the left and right foot of the Icelandic acromegalic giant Johann Petursson (1913-1984, final height 220.5 cm), showing deformities and the situation after amputations of the third and fourth toes, because of rec...
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American acromegalic giant Cecil Boling learning to walk on artificial legs
Photograph of the American acromegalic giant Cecil Boling (1920-2000, final height 235 cm) learning to walk again on artificial legs (which reduced his height to 213 cm) at The University Hospital in Seattle, July 2, 1960. Phot...
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American acromegalic giant Max Edmund Palmer hospitalized because of an “infected toe”
Photograph of the American acromegalic giant Max Edmund Palmer (1927-1984, final height 224.8 cm) hospitalized at Charity Hospital in New Orleans because of an “infected toe,” January 4, 1952. Photograph from the private collec...
Neuropathies in these patients (with or without impaired fasting glucose or diabetes) can lead to hypoesthesia and hypoalgesia of the lower legs and feet, as well as neuropathic foot. Potential contributing factors include leg and foot deformities, muscle weakness, and poor-quality footwear.
Clinical vignette
Case 1. Acromegaly (85; 82). In 1899, Senior Assistant Physician to the Edinburgh Royal Infirmary GA Gibson reported a case of acromegaly. MC, a 42-year-old Scottish woman, was hospitalized with complaints of weakness and stiffness in the back and limbs and "enlargement of the body" for 17 years. There was no family history of similar problems. She was healthy until the age of 25, when her hands, particularly the phalangeal joints, began to swell and become painful, especially at night. Soaking them in hot water helped some. Several months later, she stopped having menstrual periods. By her late 20s, she felt languid, "perspired very freely," fatigued easily with mild exertion, and developed daytime somnolence. Her hands, then feet, and then jaw began to steadily enlarge, and her somnolence and languor increased so much that she "finally took to bed" in her late 30s. She developed a mild goiter. Her tongue became thickened and enlarged and "protruded a good deal between the lips," so she had difficulty with distinct articulation and developed hypogeusia. Next, her lower lip increased in size, her face "became very large and swelled in appearance," her nose and ears increased in size, and her hair became much coarser and thicker.
Her entire body slowly increased in size, with severe enlargement of the face and mandible, and she became so weak that she was bedridden. Around the age of 40, she accidentally discovered that her right eye was blind. Her skin became very pale, which she described as a "deadly whiteness." She developed transient nausea and lightheadedness when she sat up, which was occasionally accompanied by vomiting, and two or three times she had syncope while sitting. With administration of "thyroid gland," her goiter decreased; her tongue diminished in size, and she was able to keep it in her mouth; her hypogeusia improved; and her weight decreased (from 180 pounds to 146 pounds). She returned home, was again able to do simple tasks with significantly improved exertional tolerance, felt less languid and sleepy, and was able to walk with difficulty using a stick.
By the age of 42, her right eye was blind, and she had a right esotropia (divergent squint) affecting her blind eye. There had been significant progression of facial changes, and numerous acneiform lesions were apparent on her face. Her mandible had markedly enlarged, which was particularly evident in profile and was emphasized in a lateral radiograph. Her hands and feet had also enlarged.
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Acromegaly: radiograph of the jaws in profile in the 17th year of disease
Patient, 42 years of age. Compared to her photograph at the age of 26, there has been significant progression of facial changes. The right eye became blind in the 15th year of disease (age 40), and a right esotropia (divergent ...
By the age of 49, the 24th year of her disease, there had been continued progression of facial changes since her photograph at the age of 42, and the right esotropia (divergent squint) was worse. She died in Edinburgh the following year, in 1907, and a postmortem photograph was taken to show her facial and hair changes at the end of her illness.
In 1911, 4 years after her death, British physician and anatomist Auckland Campbell Geddes (1879–1954) reported further concerning her skeletal abnormalities (82). He referred to her simply as "EAS 07" (for "Edinburgh Acromegalic Subject 1907"). Among other prestigious positions, Geddes was later Professor of Anatomy at McGill University in Montreal, but his academic career was interrupted by World War I, during which he served as a Brigadier General in the War Office. He was elected to Parliament in 1917 and was appointed British Ambassador to the United States in 1920. From 1924 to 1947, he was the Chairman of the Rio Tinto Company and Rhokana Corporation. He returned to public service during World War II, when he served as Commissioner for Civil Defence for the South-East Region from 1939 to 1944 and for the North-West Region from 1941 to 1942. In 1942, he was raised to the peerage as Baron Geddes.
Among the bony photographs of MC, Geddes focused on the skull and mandible. In particular, Geddes noted (1) the antero-posterior reduction in the size of the foramen magnum and (2) the great size of the pituitary fossa, which measured 31 mm in its antero-posterior diameter, 39 mm in its transverse diameter, and 26 mm in depth.
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Acromegaly: mandible, anterior view
Picture shows the shape of the condyles and the asymmetry of the bone. (Gibson case “MC” and Geddes case “EAS 07.”) (Source: Geddes AC. Report upon an acromegalic skeleton. J Anat Physiol 1911;45[Pt 3]:256-92. Public domain.)
Mandibles of child, adult woman, and acromegalic adult woman after 25 years of diseaseComparative photograph showing the mandible of a child (A), the mandible of an adult woman (B), and the mandible of a 50-year-old acromegalic woman after 25 years of disease. (Gibson case “MC” and Geddes case “EAS 07.”) (Source...
Prognosis and complications
Historically, patients with acromegaly and gigantism rarely lived past their mid-50s, with some dying as young as their early 20s from complications of their disease. Even today, acromegaly is associated with a 2- to 3-fold increase in mortality, particularly from cardiovascular and cerebrovascular disease (41; 31; 88). The overall standardized mortality ratio of patients with acromegaly is 1.48 (101; 113). In longitudinal studies, multivariate analyses indicate that growth hormone levels of less than 2.5 µg/L, younger age, shorter duration of disease, and the absence of hypertension independently predict longer survival. Hypertension is a major contributor to cardiovascular mortality in acromegaly (88). Untreated or uncontrollable acromegaly has a high mortality rate usually due to cardiopulmonary complications and diabetes mellitus. Quality of life remains poor over the long-term despite biochemical control (119).
Psychological disturbances and poor quality of life are major consequences of acromegaly and the stigma associated with the disease (88; 126; 120; 130). Mental state and quality of life are the most important determinants of biopsychosocial complexity in patients with acromegaly, whereas the biochemical normalization is of lesser importance (120). Acromegalic patients exhibit critically high levels of perceived stigma, leading to psychological distress and disruptions in daily life (130). Among 171 adult acromegalic patients recruited in a cross-sectional Italian multicentric study, a very high proportion (up to 28%) were depressed (27).
Acromegaly is associated with significant medical morbidities (41; 118; 163; 75; 176). More than 50% of patients have coexisting cardiac, metabolic, and endocrine disturbances, and only 5% of patients do not suffer from any of these diseases. Medical comorbidities in acromegalic patients include impaired glucose tolerance, diabetes mellitus, hypocortisolism, hypothyroidism, hyperprolactinemia, hypertension, left ventricular hypertrophy, hypogonadism, obstructive sleep apnea, arthropathy and arthropathy-associated pain, vertebral deformities, osteoporosis, vertebral and other fractures, and growth of benign and malignant neoplasms (152; 151; 155; 70; 118; 124; 75; 176). Biochemical control of acromegaly reduces progression of left ventricular hypertrophy and improves other markers of structural cardiac dysfunction, including left ventricular ejection fraction (88).
Comorbidities more often present at diagnosis of acromegaly than in age- and sex matched controls and include hypertension, left ventricle hypertrophy, dia/systolic dysfunction, cardiac arrhythmias, (pre)diabetes, dyslipidemia, intestinal polyps, and malignancy (176); comorbidities vary across studies by year of publication, reflecting changes in recognition, management, and probably variations in reporting, although it is noteworthy that cardiovascular comorbidity was lower in more recent studies.
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Comorbidities at time of diagnosis for two groups according to publication date
(Source: Slagboom TN, van Bunderen CC, De Vries R, Bisschop PH, Drent ML. Prevalence of clinical signs, symptoms and comorbidities at diagnosis of acromegaly: a systematic review in accordance with PRISMA guidelines. Pituitary ...
Impaired glucose tolerance and diabetes mellitus are the most frequent metabolic comorbidities associated with acromegaly and are present in 30% to 50% of affected patients at diagnosis (88). Excess growth hormone stimulates gluconeogenesis and lipolysis, causing hyperglycemia and elevated free fatty acid levels. In addition, excess growth hormone leads to both hepatic and peripheral insulin resistance, with compensatory hyperinsulinemia, whereas conversely IGF-1 increases insulin sensitivity. The presence of diabetes in patients with acromegaly is associated with increased overall mortality as well as increased cardiovascular mortality and morbidity (69).
Pituitary dysfunction in acromegaly may also be manifest as hypocortisolism, hypothyroidism, hyperprolactinemia, and hypogonadism. Hyperprolactinemia in acromegalic patients may result either from co-secretion of growth hormone and prolactin by the tumor or from pituitary stalk compression. Hypogonadism is detected in approximately 50% of patients and results from tumor mass effect or the normal portion of the pituitary gland on concomitant hyperprolactinemia (88); hypogonadism may compromise sexual function, fertility, muscle function, bone health, and well-being.
Obstructive sleep apnea is present in 50% to 80% of newly diagnosed acromegaly patients and results mainly from the pharyngeal soft-tissue swelling that occurs with the disease (88; 28; 35; 97).
Arthropathy-associated pain is one of the most prominent symptoms negatively affecting quality of life in patients with acromegaly and can result in significant deterioration of functional abilities over time, potentially compromising independent functioning (88). Patients with acromegaly are at increased risk of vertebral fractures, primarily because of deterioration in bone microarchitecture (124; 76; 161). Diagnostic delay in acromegaly has a significant adverse impact on vertebral fracture risk (38).
Neurologic complications can include headache, bitemporal hemianopsia, olfactory dysfunction (60), pituitary apoplexy (197), peripheral neuropathy, carpal tunnel or cubital tunnel syndrome (169; 191), and development of intracranial meningiomas (67). Most, but not all, patients with acromegaly-associated carpal tunnel syndrome show symptomatic improvement with acromegaly control (88). Rarely, pituitary apoplexy produces "autohypophysectomy" with a spontaneous resolution of acromegaly (77; 123; 04). Other rare complications include myelopathy due to ossification of posterior longitudinal ligament with resulting paraplegia (110).
Although the frequency of hyperostosis frontalis interna is 22% in patients with acromegaly, apparently neither excess growth hormone nor hyperprolactinemia plays a role in its etiopathogenesis because acromegalic individuals with and without hyperostosis frontalis interna have similar basal growth hormone, IGF-1, and prolactin levels; IGF-1 index; diagnosis lag time; and insulin resistance (147).
Biochemical control remains the strongest predictor of patient outcomes and specifically produces improvements in glucose metabolism, obstructive sleep apnea, cardiovascular disease, and bone mineral density and fracture risk (73). However, structural heart and joint changes are unlikely to resolve (73).
A metaanalysis of 19 studies showed that acromegalic patients have a modestly increased chance of cancer as compared to the general population (194). The overall incidence of cancer, as well as that of thyroid, gastrointestinal (gastric, small intestine, colorectal, anal, and pancreatic), brain/CNS, urinary, hematological, and connective tissue cancers was higher among patients with acromegaly than among the general population. No association between acromegaly and hepatobiliary, respiratory, reproductive, skin, breast, or prostate cancer was observed.
Acromegaly should be treated as early as possible to prevent development of irreversible adverse outcomes and then relieve selected comorbidities (eg, hypertension and type-2 diabetes) (15).
Biological basis
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• Growth hormone-releasing hormone and somatostatin, both released by the hypothalamus, have opposing effects on release of growth hormone; growth hormone-releasing hormone induces the synthesis and secretion of growth hormone whereas somatostatin suppresses the secretion of growth hormone. | |
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• Insulin-like growth factor-1 (IGF-1) mediates most of the growth-promoting effects of growth hormone. | |
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• Acromegaly and gigantism are due to an overproduction of growth hormone (98%) most commonly by a benign pituitary adenoma. | |
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• If the overproduction begins early, before epiphyseal closure, long bone growth accelerates, leading to linear growth of up to 1 foot per year with heights of 8 feet or above being recorded (gigantism). | |
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• Increased growth hormone after puberty leads to widening of the bones, excess tissue growth at the ends of bones, and then arthritic changes (acromegaly). | |
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• Familial GH-secreting tumors are seen in association with multiple endocrine neoplasia type 1, Carney complex, and familial isolated pituitary adenomas. |
Etiology and pathogenesis
Growth hormone is a 191-amino acid polypeptide, secreted in a pulsatile fashion by somatotroph cells of the anterior pituitary. Growth hormone-releasing hormone and somatostatin, both released by the hypothalamus, have opposing effects on release of growth hormone; growth hormone-releasing hormone induces the synthesis and secretion of growth hormone whereas somatostatin suppresses the secretion of growth hormone. Growth hormone release is also known to be influenced by age, nutritional state, and sleep. Insulin-like growth factor-1 (IGF-1) mediates most of the growth-promoting effects of growth hormone. The development and proliferation of somatotrophs are largely determined by a gene called the Prophet of Pit-1 (PROP1), which controls the embryonic development of cells of the Pit-1 (POU1F1) transcription factor lineage as well as gonadotroph hormone-secreting cells (139).
Acromegaly and gigantism are due to an overproduction of growth hormone (98%) most commonly by a benign pituitary adenoma (148). Growth hormone-cell adenoma make up 60%, whereas mixed growth hormone-cell and prolactin-cell adenoma constitute 25% and mammosomatotroph-cell adenoma 10%, with the rest comprised of the rare causes including plurihormonal adenoma, GGGH-cell carcinoma, multiple endocrine neoplasia, ectopic pituitary adenoma, and extra pituitary neuroendocrine tumors (138; 196). Acromegaly develops when somatotrophs (cells in the anterior pituitary gland that produce growth hormone) proliferate and over-secrete the hormone. When tumors arise in pituitary somatotroph cells, aberrant secretion of growth hormone leads to the distinctive features of acromegaly. Somatotroph adenomas make up some 20% of functioning pituitary adenomas. If the overproduction begins early, before epiphyseal closure, long bone growth accelerates, leading to linear growth of up to 1 foot per year with heights of 8 feet or above being recorded (gigantism). Increased growth hormone after puberty leads to widening of the bones, excess tissue growth at the ends of bones, and then arthritic changes (acromegaly).
Rarely, acromegaly is caused by ectopic secretion of either growth hormone or growth hormone-releasing hormone (GHRH) (168; 138; 16; 06; 22; 81; 158; 122; 156; 196). Ectopic growth hormone secreting tumors have been reported, for example, with a pituitary adenoma in the sphenoid sinus (158), an islet cell tumor (140), and non-Hodgkin lymphoma (16). A case has also been reported with secretion of both growth hormone and IGF-1 from a pulmonary neuroendocrine tumor (NET) (122). Ectopic GHRH-secreting tumors are usually extracranial (79%) (138; 22; 81; 196). Most patients with ectopic GHRH-induced acromegaly have hyperplastic pituitaries (156). Histopathological evaluation of 121 tumors showed that 98% were neuroendocrine tumors with only two exceptions (a pituitary diffuse large B-cell lymphoma and an adenoid cystic carcinoma of the lung) (196). Most extracranial GHRH-secreting tumors originate in the lung or pancreas (50% and 35%, respectively) (196); bronchial carcinoid is the most common histopathological diagnosis (168; 06; 196), but cases are also reported with a variety of malignant tumors, including pancreatic islet cell tumors (182). The most common GHRH-secreting tumor of the para-sellar region is mixed gangliocytoma-pituitary adenoma (78% of intracranial cases) (196). GHRH secretion rarely occurs with other tumors, including pheochromocytoma, lymphoma, paraganglioma, and thymoma (196).
The clinical picture of acromegaly is influenced by many factors, including the levels of growth hormone and insulin-like growth factor (IGF-I), age, tumor size, and the time to diagnosis (134).
Genetics of acromegaly and gigantism
Growth hormone-secreting pituitary tumors are the most genetically determined type of pituitary tumor (20). Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as in some currently unknown genes (ie, as indicated by familial cases with no mutations in known genes) (20).
A genetic basis can be identified in half of the cases of gigantism (20).
Hereditary growth-hormone-secreting pituitary adenoma can manifest as isolated tumors, familial isolated pituitary adenoma, including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG), or it can be a part of systemic diseases like multiple endocrine neoplasia types 1 or 4, McCune-Albright syndrome, Carney complex, and the so-called "3P association" of pituitary adenoma and pheochromocytoma/paraganglioma (93; 20).
The vast majority of symptomatic pituitary tumors occur sporadically and are not part of syndromic disorders (129). However, germline mutations in genes known to predispose individuals to familial pituitary adenomas can be found in a small percentage of patients with sporadic pituitary adenomas. Mutations in the AIP gene are the most frequently observed germline mutations, occurring in about 4% of patients with sporadic pituitary adenomas, but the prevalence can increase to 8% to 20% in young adults with macroadenomas or gigantism and also in affected children. Germline mutations in MEN1 (encoding menin) on the long arm of chromosome 11 (at the 11q13 locus) result in multiple endocrine neoplasia type 1 and are found in very young patients with isolated sporadic pituitary adenomas.
Fifteen to twenty percent of familial isolated pituitary adenomas occur in association with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene; 50% to 80% of cases with AIP mutation exhibit a somatotropinoma. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family (150). Many somatotrophic tumors are monoclonal, arising from a single cell (98; 65). In up to half of the somatotroph adenomas associated with acromegaly, a mutation in the alpha-subunit of the stimulatory G protein is a consequence of the presence of an oncogene (178); this mutation results in increased stimulation of cyclic adenosine monophosphate, leading to somatotroph hyperplasia and elevated circulating growth hormone levels.
An extraordinary example of familial gigantism due to a mutation in AIP was that of Irish giant Charles Byrne (1761-1783), who was shown in 2011 to have a mutation in AIP (36). On its way to be buried at sea, Byrne's skeleton was snatched by agents of Scottish anatomist John Hunter (1728-1793), against Byrne's expressed wishes before death. Byrne's 2.31-meter (7 foot, 7 inch) skeleton was subsequently purchased in 1799 by the Hunterian Museum of the Royal College of Surgeons in London, where it has been displayed for over 2 centuries.
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Scottish anatomist John Hunter and the suspended feet of the Irish giant Charles Byrne
The skeleton of Irish giant Charles Byrne (1761-1783) was snatched by agents of John Hunter (1728-1793) on its way to be buried at sea, against Byrne's expressed wishes before death. Engraving by Sir Joshua Reynolds (1723-1792)...
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The skeleton of Irish giant Charles Byrne displayed at the Royal College of Surgeons of England in 1900
Byrne's 2.31-meter (7 foot 7 inch) skeleton was subsequently purchased in 1799 by the Hunterian Museum of the Royal College of Surgeons in London, where it has been displayed for over 2 centuries. It remains an issue of content...
It remains an issue of contention and controversy today (133). American neurosurgeon Harvey Cushing opened Byrne's skull with Scottish anatomist and anthropologist Sir Arthur Keith (1866-1955) in 1909 at the Museum of the Royal College of Surgeons of England, at a time when Cushing was marshalling evidence for endocrine functions of the pituitary. Oddly, Keith misattributed the source of the skeleton to another Irish giant, Patrick Cotter O'Brien (1760-1806), also known as the Bristol Giant. In 1911, Keith presented drawings of Byrne's pituitary fossa and sella turcica and a lateral view of his skull (both misattributed to O'Brien) (115); these show remarkable enlargement of the pituitary fossa with erosion of the sella turcica.
X-linked acrogigantism is a form of early-onset growth hormone excess resulting from the germline or somatic duplication of the GPR101 gene on chromosome Xq26.3 (186; 53; 111). The GPR101 gene codes for a G protein-coupled receptor that is normally expressed in the central nervous system and at particularly high levels in the hypothalamus. During development before birth and again at adolescence, the GPR101 protein is predominantly expressed in the pituitary gland, where it is thought to be involved in the growth of cells in the pituitary gland, in the release of growth hormone from the gland, or both. Histopathology in X-linked acrogigantism shows pituitary hyperplasia or pituitary adenoma with or without associated hyperplasia (104). Although affected females present with germline mutations, the sporadic male patients have been somatic mosaics. No differences in the clinical phenotype have been observed between patients with germline or somatic duplication.
Epidemiology
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• Pituitary tumors account for about 15% of primary intracranial neoplasms. | |
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• Acromegaly carries an increased risk of malignancy, particularly colon cancer and thyroid cancer. | |
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• Hypertension is more frequent than in the general population. | |
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• Carpal tunnel syndrome can be seen in 50% of patients. | |
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• Increased soft-tissue swelling, nasal polyps, macroglossia, and pneumomegaly lead to obstructive sleep apnea in 50% to 80% of patients. |
Pituitary tumors account for about 15% of primary intracranial neoplasms (107; 84).
Pituitary gigantism is very rare, particularly among children younger than 3 years of age (149).
Acromegaly is a rare clinical entity occurring equally among men and women, although a single-center experience may show gender differences (105). The estimated prevalence is 50 to 70 cases per million and the annual incidence is three to four cases per million population. In a meta-analysis of 22 studies, the pooled prevalence was 5.9 (95% CI: 4.4-7.9 per 100,000 persons), whereas the incidence rate was 0.38 cases per 100,000 person-years (95% CI: 0.32-0.44 per 100,000 person-years) (46). Peak age of onset is in the fourth decade (25).
Acromegaly carries an increased risk of malignancy, particularly colon and thyroid cancer. Prospective, controlled studies of colonoscopy screening indicate that the risk of colon cancer in patients with acromegaly is about twice that of the general population (160), which may reflect an effect of trophic insulin growth factor-1 (IGF-1) on the proliferation of epithelial cells (33). The prevalence of thyroid cancer is also strikingly elevated compared to the prevalence in the general population, affecting 5.6% versus 0.093%, respectively, in one study (183). Sustained exposure to high serum IGF-1 levels likely plays a role in the development of thyroid cancer in this disease, in combination with the autocrine/paracrine action of locally produced IGF-1.
Hypertension is more frequent than in the general population (180).
Carpal tunnel syndrome can be seen in 50% of patients (05). Compared with the general population, patients with acromegaly have a 6-fold higher incidence of carpal tunnel syndrome surgery before the diagnosis of acromegaly (191).
Increased soft-tissue swelling, nasal polyps, macroglossia, and pneumomegaly lead to obstructive sleep apnea in 50% to 80% of patients with acromegaly (88; 28; 35).
Achieving biochemical control is associated with improvements in treatment costs, quality of life, and mortality but not to the level of the general population (192).
Prevention
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• AIP mutations are rare in individuals with sporadic acromegaly but occur more commonly in individuals with pituitary gigantism, familial isolated pituitary adenomas, and macroadenomas diagnosed by age 30 years. | |
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• Acromegaly may occasionally be identified by screening members of families with multiple endocrine neoplasia type 1, which results from mutations in the MEN1 gene. | |
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• Because acromegaly is a significant risk factor for the development of colon and thyroid cancers, acromegalic patients should have regular colonoscopy screening and monitoring of thyroid function and morphology. | |
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• Patients with acromegaly should also be screened for obstructive sleep apnea because of the extremely high incidence (50% to 80%) in this group. |
In 2006, germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were found to predispose to development of pituitary adenoma (190). The AIP gene helps regulate the proliferation and differentiation of cells and acts as a tumor suppressor. AIP mutations are rare in individuals with sporadic acromegaly but occur more commonly in individuals with pituitary gigantism, familial isolated pituitary adenomas, and macroadenomas diagnosed by age 30 years (52; 50; 164; 51); targeted genetic screening for AIP mutations is recommended in these latter three groups of patients with pituitary adenoma. AIP mutations are most prevalent in patients with pituitary gigantism (29%) but occur in 15% to 25% of cases of familial isolated pituitary adenoma. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, with resultant improved outcomes (164).
Acromegaly may occasionally be identified by screening members of families with multiple endocrine neoplasia type 1, which results from mutations in the MEN1 gene.
In addition, because acromegaly is a significant risk factor for the development of colon and thyroid cancers, acromegalic patients should have regular colonoscopy screening and monitoring of thyroid function and morphology.
Patients with acromegaly should also be screened for obstructive sleep apnea because of the extremely high incidence (50%-80%) in this group (88).
Differential diagnosis
Confusing conditions
Because of the typically insidious nature of the clinical syndrome, acromegaly is often underrecognized, with a long delay from disease onset to diagnosis.
In the transition from adolescence to adulthood (15 to 25 years), it is important but challenging to distinguish high constitutional stature from gigantism (165). Tall stature is a height greater than the threshold of more than 2 standard deviations above the average population height for age, sex, and ethnicity.
The differential diagnosis of gigantism secondary to a pituitary tumor during the transition age (15 to 25 years) includes many rarer genetic overgrowth syndromes (165):
• Familial isolated pituitary adenomas (FIPA): AIP gene mutation (11q13.3) | |
• Carney complex: a rare genetic disorder associated with one of the multiple endocrine neoplasia (MEN) syndromes; PRKA1A gene mutation (17q24.2) (48) | |
• Werner syndrome (MEN 1): MEN1 gene mutation (11q13) | |
• MEN 4 syndrome: CDKN1B gene mutation (12p13) | |
• 3P association ("3PAs syndrome"): pituitary adenoma and pheochromocytoma/paraganglioma with SDHx gene mutations, MAX gene mutations (14q23.3) (93; 181; 188; 193; 143; 189; 154; 23) | |
• Neurofibromatosis type I: NF1 gene mutation (17q11.2) | |
• McCune-Albright syndrome: GNAS gene mutation (20q31) |
Gigantism also occurs in androgen-deficient states, such as Klinefelter syndrome, and other genetic syndromes like Simpson-Golabi-Behmel syndrome, Sotos syndrome, Marfan syndrome, homocystinuria, and fragile X syndrome (121).
Sotos syndrome is a genetic disorder that presents with acromegalic features, mental retardation, advanced bone age, and typical oral features, including premature eruption of teeth; high, arched palate; pointed chin; and, rarely, prognathism (157).
Similar facial features or acral enlargement may be seen in severe hypothyroidism, pachydermoperiostosis, and some forms of leprosy.
The local effects of a somatotrophic pituitary adenoma are similar to those of other tumors in the region of the sella.
Associated or underlying disorders
Acromegaly occurs as a symptom of several syndromes, such as multiple endocrine neoplasia type 1 (MEN-1), McCune-Albright syndrome, and NAME syndrome (Carney complex type I) (114).
McCune-Albright syndrome results in hypersecretion of hormones in peripheral endocrine tissues (39). This can be expressed as precocious puberty, mainly in girls, primary hyperthyroidism, growth hormone or prolactin excess, hyperparathyroidism, and hypercortisolism. The incidence of growth hormone excess among patients with McCune-Albright syndrome has been assessed as up to 21%. The diagnosis often relies heavily on the physician recognizing the distinctive physical features of the disease.
Diagnostic workup
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• Once a patient with suggestive physical features has been identified, the diagnosis of acromegaly is relatively straightforward. | |
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• Random growth hormone levels are not recommended for screening because they may be raised in renal failure and diabetes and sometimes even in normal controls, especially if monitored around the time of sleep. | |
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• The glucose-suppressed growth hormone level (60 to 120 min after 100 mg of oral glucose) is less than 2 µg/L in normal individuals but is always greater than 10 µg/L in patients with acromegaly. | |
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• A sensitive screening test is the level of insulin-like growth factor-1 (IGF-1). | |
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• All individuals with biochemical or clinical evidence of acromegaly should have contrast-enhanced MRI of the brain. | |
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• Most acromegalic patients have readily visible pituitary adenomas, as over 65% of growth hormone-secreting adenomas are either invasive or macroadenomas. | |
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• Diffuse pituitary enlargement without a discrete adenoma should raise suspicion of an ectopic source of growth hormone-releasing hormone or growth hormone in the lung, pancreas, or gastrointestinal tract. | |
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• For individuals older than 50 years of age, an electrocardiogram, echocardiograph, and colonoscopy are recommended as part of the initial workup. |
Unfortunately, the diagnosis of acromegaly is delayed in most patients due to the slowly progressive onset of symptoms, allowing development of irreversible disease-related complications (63; 25). Multiple clinical features can suggest the disease: (1) symptoms related to the pituitary tumor (eg, headaches, bitemporal hemianopsia), including clinical signs of associated prolactin hypersecretion (ie, erectile dysfunction in men or cycle disorder in women); or (2) complications of the disease (eg, dysmorphic syndrome of insidious onset; coarse, oily, thickened skin; excess sweating and body odor; carpal tunnel syndrome; joint pain and other musculoskeletal abnormalities; multinodular goiter; colonic polyps, cardio pulmonary, dental, etc.) (25). The clinical features that most often lead to diagnosis of acromegaly are the typical physical changes (acral enlargement, facial changes, and prognathism), local tumor effects (headache and visual defect), and associated endocrine disorders (eg, diabetes, thyroid cancer, and menstrual disorders) (176).
Once a patient with suggestive physical features has been identified, the diagnosis of acromegaly is relatively straightforward.
Laboratory studies
Measurement of insulin-like growth factor-1 (IGF-1) levels is the most important laboratory test in the diagnosis and monitoring of acromegaly, but basal and nadir growth hormone levels following oral glucose tolerance test (OGTT) are also useful to demonstrate a lack of growth hormone suppression (02; 13; 68; 25). The IGF-1 level (a marker of growth hormone output) is positively correlated with the severity of the disease, only reaching a plateau when growth hormone levels reach 20 µg/L.
Random growth hormone levels are not recommended for screening because they may be raised in renal failure and diabetes and sometimes even in normal controls, especially if monitored around the time of sleep. In addition, measurements of growth hormone are confounded by heterogeneity in reference standards and technical differences among assays (179), altered hypothalamic activity associated with initiation of sleep, and the age and nutritional status of the patient (99).
Comparison of serial growth hormone levels in normal and acromegalic patients
In normal subjects (left panel), growth hormone can fluctuate between undetectable levels (most of the time) and peaks of up to 30 μg/L (90 mIU/L). In patients with acromegaly (right panel), growth hormone hypersecretion is con...
The glucose-suppressed growth hormone level (60 to 120 min after 100 mg of oral glucose) is less than 2 µg/L in normal individuals but is always greater than 10 µg/L in acromegaly patients. However, occasionally disorders other than acromegaly can also be associated with failure of normal growth hormone suppression, including chronic renal insufficiency, liver failure, active hepatitis, hyperthyroidism, diabetes mellitus, anorexia nervosa, and other forms of malnutrition.
Awareness of limitations of current growth hormone and IGF-1 assays, as well as interpretation of growth hormone testing in conjunction with serum IGF-1 levels within the appropriate clinical context, will help to avoid potential pitfalls to the diagnostic assessment of acromegaly (78).
In some cases, acromegaly can be linked to a genetic predisposition, especially when it occurs at a young age or in a familial context (25).
Preoperative evaluation of pituitary function in acromegalic patients should include the following (185):
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• Serum IGF-I, thyroid function, and prolactin should be measured in all patients with a sellar mass. | |
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• Patients with a macroadenoma or other large (1 cm or greater) sellar mass should undergo evaluation for hypoadrenalism (ie, secondary adrenal insufficiency). | |
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• Patients with a sellar mass who present with symptoms or signs suggestive of hypoadrenalism should undergo evaluation of adrenal reserve (ie, ACTH stimulation test). | |
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• Evaluation of gonadal function is advisable in patients with symptoms suggestive of hypogonadism, those with a large (1 cm or greater) sellar mass, and those with a functioning tumor regardless of size. | |
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• Evaluation for diabetes insipidus is advisable in patients with a sellar mass who present with polyuria or hypernatremia. |
Imaging
All individuals with biochemical or clinical evidence of acromegaly should have a contrast-enhanced MRI of the brain.
Most acromegalic patients have readily visible pituitary adenomas as over 65% of growth hormone-secreting adenomas are either invasive or macroadenomas, although growth hormone secreting microadenomas also occur (141).
Diffuse pituitary enlargement without a discrete adenoma should raise suspicion of an ectopic source of growth hormone-releasing hormone or growth hormone in the lung, pancreas, or gastrointestinal tract.
MRI also is useful for surgical planning and assessing chiasmal compression, cavernous sinus invasion or compression, the extent of extrasellar growth, and the position of the carotid arteries (112).
In the absence of a pituitary tumor detected on MRI, an extra-pituitary source of growth hormone needs to be excluded (eg, ectopic production of GHRH with resultant growth hormone hypersecretion). Localization of neuroendocrine tumors (that ectopically secrete growth hormone) can be facilitated with In-111 DPTA octreotide scintigraphy (173).
Acromegaly with an empty sella on MRI is rare; this combination should raise consideration of prior pituitary apoplexy or an extra-pituitary source of growth hormone (56).
Other studies
For individuals older than 50 years of age, an electrocardiogram, echocardiograph, and colonoscopy are recommended as part of the initial workup (73).
Management
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• Acromegaly ultimately becomes a life-threatening condition that requires aggressive treatment. | |
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• The goals of treatment in patients with acromegaly are to return the levels of circulating growth hormone and insulin-like growth factor-1 (IGF-1) to normal and to reduce the size of a compressive pituitary tumor while attempting to preserve pituitary function and relieve the signs and symptoms. | |
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• Growth hormone levels of less than 2 µg/L with normal IGF-1 levels are reasonable criteria for an endocrine "cure." | |
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• Normalization of both growth hormone and IGF-1 levels can normalize life expectancy in patients with acromegaly but does not relieve all symptoms. | |
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• Surgical excision of the adenoma (usually by means of a transsphenoidal approach), leaving the normal pituitary as intact as possible, is potentially curative and is the first line of therapy. | |
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• Radiation therapy may be used to augment partial surgical resection or as a moderately effective primary mode of treatment in those patients who cannot be managed surgically or who have failed medical therapy. | |
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• Stereotactic radiosurgery with the use of the gamma knife is replacing conventional external-beam radiotherapy administered over a period of several weeks. | |
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• The mainstays of medical therapy are treatment with dopamine agonists and somatostatin analogues. | |
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• Dopamine agonists (eg, bromocriptine) bind to D2 receptors and suppress growth hormone hypersecretion, but their clinical effectiveness is modest. | |
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• There are currently four medical therapies approved by the U.S. Food and Drug Administration (FDA) for patients with acromegaly: octreotide (Sandostatin LAR) and pasireotide (Signifor), lanreotide (Somatuline Depot injection), and pegvisomant (Somavert). | |
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• In general, medical treatment can produce a rapid clinical and endocrine response but causes only minimal tumor shrinkage, and growth hormone levels immediately rise again after stopping the drug. | |
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• Medical treatment alone is seldom sufficient to achieve an adequate response and is most often useful as an adjunct to other treatment modalities. | |
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• All treated patients with acromegaly require radiographic and endocrine monitoring for recurrence. |
Acromegaly ultimately becomes a life-threatening condition that requires aggressive treatment. The goals of treatment are to return the levels of circulating growth hormone and insulin-like growth factor-1 (IGF-1) to normal, and to reduce the size of a compressive pituitary tumor while attempting to preserve pituitary function and relieve the signs and symptoms. Growth hormone levels of less than 2 µg/L with normal IGF-1 levels are reasonable criteria for an endocrine "cure." Normalization of both growth hormone and IGF-1 levels can normalize life expectancy in patients with acromegaly but does not relieve all symptoms (87).
Therapeutic modalities for the treatment of pituitary gigantism are the same as those for acromegaly (83).
Surgery
Surgical excision of the adenoma (usually by means of a transsphenoidal approach), leaving the normal pituitary as intact as possible, is potentially curative (in more than two thirds of patients) and is the first line of therapy (125; 141; 45; 84; 89; 47; 68; 25; 37). There is a rapid therapeutic response following surgery: growth hormone levels may drop within hours and a reversal of soft tissue abnormalities begins soon thereafter. Recent rates of hormonal remission are about 70% to 80% following the resection of growth hormone-secreting pituitary adenomas, and rates increase to over 85% with the addition of medical therapy in patients who do not achieve remission with surgery alone (37).
Preoperative hormone replacement should include the following (185):
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• Patients with hypoadrenalism should receive glucocorticoid replacement. | |
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• Patients with hypothyroidism should receive thyroid hormone replacement. | |
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• Stress dose glucocorticoid administration is recommended in patients with known or suspected adrenal insufficiency. |
The most important predictors of the likelihood of achieving surgical remission are invasiveness of surrounding structures (particularly the cavernous sinus), tumor size, and preoperative growth hormone levels (90; 01; 89; 43). Smaller, less invasive tumors and tumors with lower preoperative levels of growth hormone and IGF1, have better remission rates (90; 01; 43). Metabolic complications (eg, impaired blood sugar control) and facial features (eg, nose width) also improve (44; 66).
Signal intensity on T2-weighted MRI has been proposed as another prognostic factor (03). In a surgical series of 124 patients, total resection was achieved in 69% of the T2-hyperintense group, 77% of the T2-hypointense group, and 69% of the T2- isointense group. The surgical remission rates for the T2-hyper-, hypo-, and isointense groups were 55%, 81%, and 69%, respectively.
Lowering of growth hormone and IGF-I has consistently been associated with improved outcomes, including increased longevity, although targeting biochemical "normalization" in asymptomatic individuals with mild growth hormone or IGF-I elevations would result in the need for combination pharmacotherapy in many patients without proven benefit (40). Growth hormone nadir lower than 1 μg/L after oral glucose tolerance test was defined by a Consensus Group in 2000 as a marker of postsurgical remission and later revised in 2020 to 0.4 μg/L based on use of ultrasensitive growth hormone assays (89). Failure of growth hormone suppression after glucose stimulation is associated with tumor recurrence (40). IGF-I levels measured 6 weeks postoperatively can be also used to assess remission, although patients with mildly elevated IGF-I levels may not normalize until 3 to 6 months postoperatively (88; 73). Endocrine remission is seen in 65% to 90% of microadenomas but in less than 50% of macroadenomas greater than 1 cm in diameter following excision (90). Other studies have reported postoperative remission rates from 30% to 85% (167). In specialized referral centers, remission can be achieved in 80% to 90% of microadenomas and about 50% to 75% of macroadenomas (89). Preoperative treatment of macroadenomas with a somatostatin analogue may improve postoperative remission rates (12).
Most tumors are accessible via a direct endoscopic endonasal transsphenoidal approach, which can be augmented if needed with extended approaches to gain access to suprasellar, clival, and parasellar compartments (37). In one study, outcomes of endoscopic endonasal transsphenoidal surgery for pituitary tumor removal were at least equivalent to that of the standard traditional transnasal transsphenoidal approach, with an excellent postoperative course (29). Postsurgical hospital stay was significantly shorter after endoscopy as compared to the transnasal transsphenoidal approach (29). Stereotactic radiosurgery is usually reserved for medically resistant tumors in surgically inaccessible compartments (37).
Postoperative endocrine evaluation should include the following (185):
|
• Serum sodium should be monitored. | |
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• Morning serum cortisol should be monitored for 1 to 5 days postoperatively. | |
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• Full evaluation of pituitary function should be conducted 6 to 12 weeks after transsphenoidal surgery. | |
|
• Serum IGF-I should be obtained to evaluate endocrine remission at 6 weeks postoperatively. If elevated, serum IGF-I should be rechecked at 12 weeks postoperatively to document persistent disease activity before making treatment decisions. | |
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• Thyroid function should be assessed at 6 to 8 weeks postoperatively. | |
|
• Dynamic testing (ie, ACTH stimulation test) should be used to evaluate the pituitary adrenal axis at 6 to 12 weeks postoperatively, if morning serum cortisol is insufficient to ensure adequate adrenal function. | |
|
• Gonadal function should be evaluated for all patients, including men and women of premenopausal age, at 6 to 12 weeks postoperatively. | |
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• Patients in endocrine remission of acromegaly should be evaluated biochemically for recurrence annually (or sooner if clinically indicated). |
Medical management
Medical treatments are most often proposed in patients not controlled by surgical removal, for example, with residual or recurrent disease (25; 37). In a cross-sectional study, medical treatment achieved a quality of life comparable to surgery, and it may also be associated with better quality of life in physical subdomains (08). Primary medical therapy is a reasonable option, especially for elderly patients with acromegaly (34).
The mainstays of medical therapy have been treatment with dopamine agonists and somatostatin analogues.
Dopamine agonists (eg, bromocriptine, capergoline) bind to D2 receptors and suppress growth hormone hypersecretion but their clinical effectiveness is modest (62; 89). Cabergoline, a relatively long-acting dopamine agonist, has the advantages of limited cost and an oral route of administration compared to somatostatin receptor ligands (89). Cabergoline therapy is effective in normalizing IGF-I levels, even in patients with normoprolactinemic acromegaly, when IGF-I levels are mildly or moderately elevated during somatostatin receptor ligand therapy (96).
There are currently four medical therapies approved by the U.S. Food and Drug Administration (FDA) for patients with acromegaly: octreotide (Sandostatin LAR) and pasireotide (Signifor), lanreotide (Somatuline Depot injection), and pegvisomant (Somavert).
Octreotide, a somatostatin analogue, effectively lowers growth hormone levels in up to 50% of patients with acromegaly and causes modest tumor regression, but the injectable form of the drug must be given several times a day by subcutaneous injection and there is a significant risk of cholelithiasis (141). A more effective and practical approach is the use of a longer-acting preparation of octreotide or lanreotide, which is administered as depot intramuscular injections. Overall, the octreotide long-acting release formulation (octreotide-LAR) is well tolerated and is an effective agent in alleviating symptoms, suppressing growth hormone, normalizing IGF-1, and inducing tumor shrinkage in many patients with acromegaly. It is recommended for patients who are not cured by surgery, and it should also be considered as primary therapy for selected unoperated cases with a low probability of surgical cure (108).
Oral octreotide capsules that combine octreotide with a transient permeability enhancer technology were approved by the U.S. Food and Drug administration in 2020 and are the first and only oral somatostatin receptor ligands approved in the United States for acromegaly. Oral octreotide capsules are a treatment option for patients with acromegaly who previously responded to injectable somatostatin receptor ligands (166; 195). In four clinical trials involving 238 patients with acromegaly, oral octreotide capsules produced effective suppression of serum growth hormone and insulin-like growth factor 1 (IGF-1) levels, maintained disease control and biochemical response, and had a safety profile comparable to injectable somatostatin receptor ligands.
Pasireotide long-acting release is a multi-somatostatin receptor-ligand that is now also approved for acromegaly and appears to be more effective than octreotide in both treatment-naive patients and those already on octreotide (42; 80). This agent has a higher affinity for the receptor than first-generation drugs such as somatostatin. About half of the patients who are refractory to a first-generation somatostatin analogue experience normalization of IGF-1 levels on the drug, although many patients experience a decline in their glucose control (174; 02). Pasireotide may be an effective monotherapy option in patients who were controlled on both a long-acting somatostatin analogue and pegvisomant previously (145).
Lanreotide is a long-acting analogue of somatostatin. Lanreotide is available in two formulations: a sustained-release formulation (trade name Somatuline LA), which is injected intramuscularly every 10 or 14 days, and an extended-release formulation (trade name Somatuline Autogel in the UK, or Somatuline Depot in the US), which is administered subcutaneously once a month. Extended-dosing intervals (greater 4 weeks) for 120 mg lanreotide may be effective among selected patients previously controlled with long-acting somatostatin receptor ligands (SRLs) (73). The main side effects are injection site pain and gastrointestinal disturbances (eg, diarrhea, nausea, and vomiting). Primary treatment with lanreotide 120 mg provides early significant tumor shrinkage with rapid improvement of visual symptoms at the end of the first month in approximately half of patients (14). Lanreotide use over long periods of time has been associated with development of gallstones. Older age, female sex, lower IGF-I levels, and tumor T2 hypointensity on MRI at baseline predict more favorable long-term biochemical responses to primary lanreotide therapy (73).
Pegvisomant blocks growth hormone action at peripheral receptors, normalizes IGF-1 levels in most patients, reduces signs and symptoms, and corrects metabolic defects (41; 89; 74). It has relatively few serious adverse effects and is the most effective drug treatment for acromegaly in normalizing IGF-1 and producing a clinical response (74). Abnormal liver function can occur early, and consequently liver function studies should be monitored (89; 74). Pegvisomant is the most likely agent to achieve maximal improvement in glucose tolerance and insulin sensitivity; it is, therefore, the preferred medical therapy for patients with preexisting hyperglycemia or diabetes mellitus who do not respond to octreotide LAR/lanreotide (89; 73). It is also the preferred agent in patients resistant to or intolerant of somatostatin analogs: in patients resistant to somatostatin analogues, beginning pegvisomant early facilitates improvement in glucose control (153). It is effective in controlling acromegaly in 60% to 90% of patients (87). Because higher rates of control may be achieved as the dose is escalated, pegvisomant treatment should be started at a low dose and gradually increased as tolerated until control is achieved (89). Patients with diabetes mellitus and those who are obese require higher doses of pegvisomant and more rapid up-titration to achieve IGF-I normalization (73). Over a period of 10 years, the drug was well-tolerated and produced normalization of IGF-1 levels in 73% of subjects (26). A reported increase in tumor volume under therapy has been attributed to either actual growth or re-expansion after cessation of somatostatin receptor ligand therapy (94). The high cost of pegvisomant has limited its use in several countries (94).
Combination therapy with a somatostatin receptor ligand plus pegvisomant is recommended for patients with acromegaly who do not reach hormonal targets after a maximizing dose on monotherapy (73). In patients who do not reach hormonal targets with first-generation depot somatostatin analogs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with somatostatin analogs) should be offered (45). A regimen incorporating low-dose somatostatin receptor ligand therapy plus weekly pegvisomant is a novel dosing option for achieving cost-effective biochemical control in patients with uncontrolled acromegaly requiring combination therapy (21).
In general, medical treatment can produce a rapid clinical and endocrine response but causes only minimal tumor shrinkage and growth hormone levels immediately rise again after stopping the drug (11). Medical treatment alone is seldom sufficient to achieve an adequate response and is most often useful as an adjunct to other treatment modalities.
Primary medical treatment should be offered to patients who are either not surgical candidates because of comorbidities or complications of their illness, or who refuse surgery (45).
All treated patients with acromegaly require radiographic and endocrine monitoring for recurrence.
Given the frequency of bony abnormalities and particularly of fractures, as well as the frequency of associated hypogonadism, imaging studies to assess bone morphometry are suggested in all patients at diagnosis, regardless of disease status (88a). Note, though, that bone mineral density is not a good reflection of bone quality in patients with acromegaly and may be normal as assessed on standard dual energy x-ray absorptiometry studies (88a).
Because of the risk of colon and thyroid cancers, acromegalic patients should have regular colonoscopy screening and monitoring of thyroid function and morphology (as determined by physical examination). Some authors have suggested that patients with acromegaly undergo screening colonoscopy at diagnosis, although there are no conclusive data linking screening frequency to colon cancer mortality rates in patients with this disease (88a). Current evidence does not support routine screening for thyroid cancer at acromegaly diagnosis, although thyroid ultrasound and consideration of fine-needle aspiration are recommended in those with palpable thyroid nodules and other risk factors for thyroid cancer (88a).
Radiotherapy
Radiotherapy is a third-line option for management of acromegaly but nevertheless continues to have a role in the management of these patients (89).
Radiation therapy may be used to augment partial surgical resection or as a moderately effective primary mode of treatment in those patients who cannot be managed surgically or who have failed medical therapy (45; 137). The full benefit of radiation therapy may develop slowly over a period of years, and medical treatment is required in the intervening period. Postradiation hypopituitarism is common, and most patients require lifelong hormonal replacement therapy.
Stereotactic Gamma knife radiosurgery is replacing conventional external-beam radiotherapy administered over a period of several weeks (32). Gamma knife delivers a single radiation fraction to a small tumor target, minimizing radiation scatter and vulnerability of adjacent structures, including optic tracts (32). Gamma knife radiosurgery is most commonly applied as an adjuvant treatment; in this regard, Gamma knife radiosurgery is generally safe and effective in controlling growth hormone and IGF-1 levels, increasing remission rates, improving endocrine control, and reducing tumor diameter in persistent active acromegaly patients after surgery (187). The lowest complication rates of Gamma knife radiosurgery are associated with accurate MRI-based treatment planning and single stereotactic radiosurgery treatment, whereas more than one radiation treatment (stereotactic radiosurgery or fractionated radiotherapy) is associated with increased visual complications (175).
Approximately half of the patients treated with stereotactic Gamma knife radiosurgery or fractionated radiotherapy achieve and maintain biochemical control (73). However, up to one third of such patients with otherwise normal pituitary function ultimately develop hypopituitarism, confirming the need for ongoing monitoring (73).
Treatment-related growth hormone deficiency. Individuals with "cured" acromegaly may eventually develop growth hormone deficiency (184). Growth hormone deficiency in adults is associated with decreased quality of life, abnormal body composition, decreased exercise capacity, dyslipidemia, insulin resistance, and increased cardiovascular risk (184). Diagnosis of growth hormone deficiency in adults with cured acromegaly generally requires stimulation testing, with the exception of patients with very low serum IGF-1 levels and multiple additional pituitary hormone deficiencies (184). In adults with cured acromegaly, growth hormone replacement is generally well-tolerated and may have beneficial effects on body adiposity, muscle endurance, serum lipids, and quality of life, although there is evidence of increased cardiovascular risk (184).
Special considerations
Pregnancy
Assisted reproductive therapy is frequently necessary, although most pregnancies in acromegalic women occur without this (109).
Pregnancy in women with acromegaly is frequently associated with disease control with fetal and maternal outcomes comparable to women without acromegaly. A retrospective study found that active acromegaly did not have an evident adverse bearing on pregnancy outcomes (54).
A systematic review and meta-analysis of 19 studies encompassing a total of 273 pregnancies in 211 women with acromegaly found that the overall frequency of acromegaly control of during pregnancy was 62%, and of tumor growth was 9% (10). There were no fetal or maternal deaths. The overall frequency of worsening of previous diabetes or development of gestational diabetes was 9%, and of previous hypertension or preeclampsia/eclampsia was 6%. Among adverse pregnancy outcomes, the overall frequencies were as follows: premature labor 9%, spontaneous miscarriage 4%, small for gestational age 5%, and congenital malformations 1%.
Anesthesia
Special care should be taken with intubation in patients with acromegaly due to the abnormal anatomy of the air passages in response to growth hormone. In addition, positioning of the neck during surgery should take into account the high incidence of cervical arthritis.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile
Former Authors
- Richard J Robbins MD FACP
- Andrew P Rose-Innes MD
- Sarika Shirsat MD
- Tarakad S Ramachandran MD
- Arun Ramachandran MD
- Carolyn Goldschmidt DO
- Ryan Jacobson MD
Patient Profile
- Age range of presentation
-
- 1 month to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Acromegaly and pituitary gigantism: E22.0
- ICD-11
-
- Acromegaly or pituitary gigantism: 5A60.0
- OMIM
-
- Acromegaly: #102200
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