ALTERATIONS OF HORMONAL REGULATION

Syndrome of Inappropriate Antidiuretic Hormone Secretion

Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is characterized by high levels of ADH in the absence of normal physiologic stimuli for its release. SIADH can complicate malignancies, pulmonary disorders, central nervous system disorders, surgical procedures and the use of certain medications.

The most common cause of elevated levels of ADH is ectopically produced ADH. SIADH is associated with some forms of cancer, apparently because of the ectopic secretion of ADH by tumor cells. Tumors that have been reported in association with SIADH include small cell carcinoma of the lung, duodenum, stomach, and pancreas; cancers of the bladder, prostate, and endometrium; lymphomas; and sarcomas.⁶ Pulmonary disorders associated with SIADH include pneumonia (e.g., tuberculosis), asthma, cystic fibrosis, and respiratory failure requiring mechanical ventilation. Central nervous system disorders that may cause SIADH include encephalitis, meningitis, intracranial hemorrhage, tumors, and trauma.⁶

Any surgery can result in postoperative fluid volume shifts that result in increased ADH secretion for as long as 5 to 7 days after surgery. The precise mechanism is uncertain but is likely related to fluid and volume changes following surgery, the amount and type of intravenous fluids given, and the use of narcotic analgesics. Transient SIADH is especially common after pituitary surgery because stored ADH is released in an unregulated fashion. Medications are an important cause of SIADH, especially in older adults. These include hypoglycemic medications (chlorpropamide), antidepressants, antipsychotics, narcotics, general anesthetics, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs, and synthetic ADH analogs.⁶ These drugs serve either to simulate ADH release or enhance the physiologic effects of ADH or have a biologic action similar to ADH.

PATHOPHYSIOLOGY The cardinal features of SIADH are the result of enhanced renal water retention. Water retention results from the action of ADH on renal collecting ducts, where it increases their permeability to water thus increasing water reabsorption by the kidneys. (Renal function is discussed in Chapter 35.) This results in an expansion of extracellular fluid volume that leads to dilutional hyponatremia (low serum sodium), hypoosmolarity, and urine that is inappropriately concentrated with respect to serum osmolarity.^6,7

CLINICAL MANIFESTATIONS The symptoms of SIADH are primarily the result of hypotonic (dilutional) hyponatremia. The severity and rapidity of onset of the hyponatremia determine the extent of the symptoms. Thirst, impaired taste, anorexia, dyspnea on exertion, fatigue, and dulled sensorium occur when the serum sodium decreases rapidly from 140 to 130 mEq/L. Peripheral edema is usually absent. Symptoms resolve with correction of hyponatremia. Severe gastrointestinal symptoms, including vomiting and abdominal cramps, occur with a drop in sodium from 130 to 120 mEq/L. With a serum sodium level below 115 mEq/L, confusion, lethargy, muscle twitching, and convulsions may occur. Even if hyponatremia develops slowly, serum sodium levels below 110 to 115 mEq/L are likely to cause severe and sometimes irreversible neurologic damage.

EVALUATION AND TREATMENT A diagnosis of SIADH requires the following signs: (1) serum hypoosmolality (<280 mOsm/kg) and hyponatremia (serum sodium <135 mEq/l); (2) urine hyperosmolarity (i.e., the osmolality of the urine is greater than expected for the concomitant serum osmolality); (3) urine sodium excretion that matches sodium intake; (4) normal renal, adrenal, and thyroid function; and (5) absence of conditions that can alter volume status (e.g., recent diuretic use, heart failure, hypervolemia from any cause, or renal insufficiency).^6,8 In order to make the diagnosis of SIADH, the individual should have both normal adrenal and thyroid function because thyroid hormone and glucocorticoids are essential for free water clearance by the kidneys.⁶

The treatment of SIADH involves the correction of the underlying causal problems; emergency correction of severe hyponatremia by administration of hypertonic saline; and, most importantly, fluid restriction to 600 to 800 ml/day. Careful monitoring is important. If hyponatremia is too rapidly corrected, a severe neurologic syndrome, central pontine myelinolysis, can ensue.⁶ Resolution usually occurs within 3 days, with a 2- to 3-kg weight loss resulting from enhanced free water clearance. No drug therapy is available to suppress ectopically produced ADH; however, demeclocycline, which causes the renal tubules to develop resistance to ADH, may be used to treat resistant or chronic SIADH. An ADH-receptor agonist, conivaptan, has been approved for the treatment of hospitalized individuals with hyponatremia caused by ADH excess.^6,9 Oral forms of ADH receptor antagonists are being developed.^9,10

Diabetes Insipidus

Diabetes insipidus (DI) is an insufficiency of ADH, leading to polyuria (frequent urination) and polydipsia (frequent drinking).^11,12 There are two forms: neurogenic (central), and nephrogenic (renal). Neurogenic DI is the form encountered most often in clinical practice and is caused by insufficient amounts of ADH.¹³ The nephrogenic form is caused by an inadequate renal response to ADH.¹⁴

Neurogenic DI occurs when any organic lesion of the hypothalamus, pituitary stalk, or posterior pituitary interferes with ADH synthesis, transport, or release.^12,13 Causative lesions include primary or secondary brain tumors, hypophysectomy, aneurysms, thrombosis, infections, and immunologic disorders. DI is a well-recognized complication of closed-head trauma.¹⁵ Genetic mutations have been identified as a cause of central DI, including those that affect ADH genes directly and those that affect ADH copeptides.¹² Uncommonly, central DI can be a hereditary disorder (1% to 2% of cases) characterized by structural changes in the pituitary gland.

Nephrogenic DI is associated with an insensitivity of the renal collecting tubules to ADH. The nephrogenic form of DI can be genetic or acquired.¹⁶ Several genetic abnormalities that affect the vasopressin receptor have been noted in DI.^12,14,17,18 One of the best described is a mutation in the gene that codes for aquaporin-2, which is one of the four water transport channels in the renal tubule.^18,19 Acquired nephrogenic DI is generally related to disorders and drugs that damage the renal tubules or inhibit the generation of cAMP in the tubules. These disorders include pyelonephritis, amyloidosis, destructive uropathies, polycystic disease, and intrinsic renal disease, all of which lead to irreversible DI. Drugs that may induce a reversible form of nephrogenic DI include lithium carbonate, colchicines, amphotericin B, loop diuretics, general anesthetics such as methoxyflurane, and demeclocycline.^12,14,16

Psychogenic (primary) polydipsia may be confused with a partial deficiency of ADH. It is caused by the chronic ingestion of extremely large quantities of fluid that wash out the renal medullary concentration gradient, which results in a partial resistance to ADH (see Chapter 36). This condition resolves with effective management of water ingestion.

PATHOPHYSIOLOGY Individuals with DI have partial or total inability to concentrate urine. In neurogenic DI, insufficient ADH is produced. In nephrogenic DI, ADH levels are normal but the collecting ducts do not respond to ADH stimulation. Both of these conditions lead to an inability of the kidney to increase permeability to water. This causes excretion of large volumes of dilute urine, leading to an increase in plasma osmolality. In conscious individuals the thirst mechanism is stimulated and induces polydipsia. For unknown reasons the person usually craves cold drinks. The urine output is varied but can increase from the normal output of 1 to 2 L/day to as much as 8 to 12 L/day. The urine specific gravity is low, from 1.00 to 1.005, which is consistent with the failure to reabsorb water. Dehydration develops rapidly without ongoing fluid replacement. If the individual with DI cannot keep up with the urinary loss of water, serum hypernatremia and hyperosmolality occur. Other serum electrolytes generally are not affected.

CLINICAL MANIFESTATIONS The signs and symptoms of DI include polyuria, nocturia, continuous thirst, and polydipsia. Untreated individuals with long-standing DI may develop a large bladder capacity and hydronephrosis (see Chapter 36).

Idiopathic neurogenic DI usually has an abrupt onset, and many individuals can specifically recall the date of onset of their symptoms. Those with posttraumatic or postneurosurgical DI may develop a classic three-phase syndrome.^15,20 Initially, significant diuresis occurs, apparently as a result of acute damage to the hypothalamic centers involving ADH secretion.¹³ The second phase is one of antidiuresis, which may represent necrosis of denervated tissue of the posterior pituitary with release of ADH into the circulation. The final phase is one of polyuria and polydipsia, reflecting a permanent loss of the ability to secrete adequate amounts of ADH, which does not have to be completely absent for polyuria and polydipsia to occur. Nephrogenic DI usually has a more gradual onset.

EVALUATION AND TREATMENT DI must be distinguished from other polyuric states, including diabetes mellitus, osmotically induced diuresis, and psychogenic polydipsia. The basic criteria for the diagnosis of DI includes polyuria, polydipsia, low urine specific gravity (<1.010), low urine osmolality (<200 mOsml/kg), hypernatremia, high serum osmolality (300 mOsm or more depending on adequate water intake), and continued diuresis despite a serum sodium of 145 mEq/L or greater.^11–13

The diagnosis of DI is generally established through water deprivation testing and by correlating the clinical presentation with serum osmolarity and plasma ADH levels.¹⁴ Water restriction is a useful test because people without DI respond with a rapid decrease in urine volume and an increase in urine osmolality. People with DI have no decrease in urine volume or increase in urine osmolarity, thus serum osmolality is always higher than urine osmolality in DI after 8 hours of water deprivation. In individuals with severe DI, water deprivation testing can be hazardous. If the individual loses more than 3% of the pretest body weight, circulatory collapse and shock can ensue. The diagnosis of psychogenic polydipsia can be extremely difficult, and differentiation from nephrogenic DI (caused by the washout of renal concentrating gradient) is based on plasma ADH levels.

Treatment for neurogenic DI is based on the extent of the ADH deficiency and on individual variables such as age, endocrine and cardiovascular status, and lifestyle. Individuals who have a urine output in excess of 9 L/day and a urine osmolality of less than 100 mOsm/kg after a dehydration or water restriction test generally require ADH replacement. Replacement therapy for symptomatic neurogenic DI includes administration of the synthetic vasopressin analog desmopressin acetate (DDAVP) given intranasally or orally. Drugs that potentiate the action of otherwise insufficient amounts of endogenous ADH, such as chlorpropamide, carbamazapine, and clofibrate, may be used in individuals with incomplete ADH deficiency.¹²

Treatment for nephrogenic DI requires treatment of any reversible underlying disorders, discontinuation of etiologic medications, and correction of associated electrolyte disorders. Although the use of thiazide diuretics has been implicated as a cause for DI, they improve salt and water absorption at the proximal tubule and may be helpful in moderate DI.^12,14,16

Hypopituitarism

The most common causes of hypopituitarism lie within the pituitary gland itself. Anterior pituitary hypofunction may result from infarction of the gland, removal or destruction of the gland, or space-occupying lesions such as pituitary adenomas or aneurysms. Adenomas and aneurisms may compress otherwise normal secreting pituitary cells and lead to compromised hormonal output.^21,22

One cause of hypopituitarism is pituitary infarction (death of tissue). Infarction may be seen in conjunction with Sheehan syndrome (ischemic pituitary necrosis) caused by severe postpartum hemorrhage. Pituitary infarction is also seen with shock, pituitary apoplexy, sickle cell disease, and during pregnancy in women with diabetes mellitus. Other more common causes of hypopituitarism are genetic abnormalities, head trauma, pituitary tumors, infections (e.g., meningitis, syphilis, tuberculosis), vascular malformations, subarachnoid hemorrhage, surgical ablation related to tumor removal, and granulomatous lesions.^22,26

PATHOPHYSIOLOGY The pituitary gland is highly vascular and is therefore extremely vulnerable to ischemia and infarction. In addition, the pituitary relies heavily on portal blood flow from the hypothalamus. In traumatic brain injury, disruption of blood flow can cause infarction with subsequent necrosis and fibrosis of pituitary tissue.^21,26 After tissue necrosis, edema with swelling of the gland occurs. Expansion of the pituitary within the fixed compartment of the sella turcica further impedes blood supply to the pituitary. Over time the pituitary undergoes shrinkage, and symptoms of hypopituitarism develop.²⁷

The likelihood of infarction is increased during pregnancy when there is increased size and vasculature of the gland and a rare condition known as Sheehan syndrome may develop. In 1961 Sheehan and Stanfield proposed that the primary pathologic mechanism in postpartum pituitary infarction is vasospasm of the artery supplying the anterior pituitary. A commonly identified cause is some event that leads to circulatory collapse (such as postpartum hemorrhage) and compensatory vasospasm. If vasospasm is sustained for more than several hours, tissue necrosis occurs. The pituitary gland may be particularly susceptible to necrosis because its blood supply, through the hypophyseal system, is already partially deoxygenated and, especially in the hyperplastic pituitary of pregnancy, oxygen demands are increased. A second mechanism that may be involved in pituitary infarction in the postpartum woman with Sheehan syndrome is an increased risk for intravascular coagulation. In such individuals, excessive fibrin is deposited in the pituitary vessels, predisposing the woman to decreased blood supply and infarction of the pituitary.

CLINICAL MANIFESTATIONS The signs and symptoms of hypofunction of the anterior pituitary are highly variable and depend on the affected hormones. If all hormones are absent (a condition termed panhypopituitarism), the individual experiences cortisol deficiency from lack of ACTH, thyroid deficiency from lack of TSH, and gonadal failure and loss of secondary sex characteristics from absence of FSH and LH. A decrease in GH and, consequently, insulin-like growth factor-1 results in delayed growth in children (Figure 21-2) and a vague, multisymptom syndrome in adults.^21,22 Children also have dwarfism with GH insensitivity (Laron syndrome), in which the GH receptor is altered.²⁸ Menses may cease from absence of FSH and LH. In addition, postpartum women are unable to lactate because of the absence of prolactin.

ACTH deficiency is a potentially life-threatening disorder because cortisol is required for many aspects of cellular metabolism. ACTH deficiency is usually encountered with generalized pituitary hypofunction and rarely occurs as an isolated event. Within 2 weeks of the complete absence of ACTH, symptoms of cortisol insufficiency develop, including nausea, vomiting, anorexia, fatigue, and weakness. Hypoglycemia is caused by increased insulin sensitivity, decreased glycogen reserves, and decreased gluconeogenesis associated with hypocortisolism. In women, loss of body hair and decreased libido may be caused by decreased adrenal androgen production. ACTH deficiency has a limited effect on aldosterone secretion.

TSH deficiency also is rarely seen in isolation but most often occurs in conjunction with other pituitary hormone deficiencies. The effects of decreased TSH levels may become apparent 4 to 8 weeks after the onset of hypothyrotropinemia. Cold intolerance, dryness of skin, mild myxedema, lethargy, and decreased metabolic rate occur as a result of hypothyroidism induced by decreased TSH levels. The symptoms are usually less severe than those associated with primary hypothyroidism, in which lack of thyroxine is related to disease in the thyroid gland (see p. 739).

The onset of FSH and LH deficiencies in women of reproductive age is associated with amenorrhea and atrophic vagina, uterus, and breasts. In postpubertal males, atrophy of the testes and decreased beard growth occur. Men as well as women experience a decrease in body hair and diminished libido. FSH and LH deficiencies often occur as a result of pressure on the gonadotropes from other sources, such as tumors. If there is enlargement caused by tumor, symptoms may include headache and visual disturbances with blurring and field defects from pressure on the optic chiasm.

GH deficiency occurs in children and adults. In children it may be genetic or it may be the result of tumors such as craniopharyngiomas.^28,29 Several genetic defects have been identified in the GH axis that account for impaired GH action.³⁰ The more common type is a recessive mutation in the GHRH gene resulting in a failure of GH secretion. A rare mutation, loss of the GH gene itself, has been observed. Mutations that cause GH insensitivity also have been reported. These mutations may involve the GH receptor, insulin-like growth factor 1 (IGF-1) biosynthesis, IGF-1 receptors, or defects in GH signal transduction.^30,31 Individuals with GH insensitivity do not respond normally to exogenously administered GH. Lastly, structural lesions of the pituitary or hypothalamus also may cause GH deficiency and may be associated with other anterior pituitary hormone deficiencies. In adults, GH deficiency is most often caused by structural or functional abnormalities of the pituitary. A decline in GH production is an inevitable consequence of aging and the significance of this phenomenon is poorly understood.³²

GH deficiency in children is manifested by growth failure, but not all children with short stature have GH deficiency. Other causes of growth failure not related to GH deficiency include systemic illness, hypothyroidism, malnutrition, and emotional deprivation. Another feature of GH deficiency in children is fasting hypoglycemia, likely due to impaired substrate mobilization for gluconeogenesis and enhanced insulin sensitivity.

An adult GH deficiency syndrome has been described in those who have complete or even partial failure of the anterior pituitary. Symptoms of adult GH deficiency syndrome are vague and include social withdrawal, fatigue, loss of motivation, and a diminished feeling of well-being. Several studies also have documented increased mortality in adults who are GH deficient. Osteoporosis and alterations in body composition (i.e., reduced lean body mass) are common concomitants of adult GH deficiency.

GH replacement therapy has become relatively simple with the introduction of recombinant human growth hormone. In children, GH replacement therapy is monitored by measuring linear growth and IGF-1 levels.²⁸ GH replacement in adults is much more controversial and is generally reserved for those with symptomatic hypopituitarism.^21,33

EVALUATION AND TREATMENT The diagnostic evaluation of suspected pituitary disease is often challenging and must be carefully interpreted together with the individual’s signs and symptoms. Simultaneous measurements of the tropic hormones from the pituitary and target endocrine glands are crucial and, in some cases, dynamic testing of the various axes is indicated.^21,22 Radiographic assessment of the pituitary (magnetic resonance imaging [MRI] or computed tomography [CT] scans) may demonstrate enlargement of the pituitary, abnormal areas of enhancement suggestive of an adenoma, deviation of the pituitary stalk, or evidence of a locally aggressive tumor. However, some radiographic findings may be nonspecific and require clinical correlation to establish a diagnosis.

In general, treatment of hypopituitarism involves replacing target gland hormone(s) that are deficient because of lack of tropic anterior pituitary hormones.^21,22,34 In cases of circulatory collapse, immediate therapy with glucocorticoids and intravenous fluids is critical. Thyroid and cortisol replacement therapy must be maintained. Gender-specific sex steroid replacement therapy is also initiated to improve general well-being and to prevent osteoporosis.

Hyperpituitarism: Primary Adenoma

Pituitary adenomas are usually benign slow-growing tumors that arise from cells of the anterior pituitary, most commonly those that secrete GH and prolactin. The molecular pathogenesis of pituitary adenomas is not clearly understood. The incidence of pituitary adenomas may be as high as 22%, but most of these are microadenomas found incidentally on high-resolution MRI scanning and are asymptomatic.³⁵ The vast majority of pituitary microadenomas are hormonally silent and do not pose significant hazards to the individual.³⁶ More significant adenomas are associated with morbidity and mortality attributable to alterations in hormone secretion or to invasion or impingement of surrounding structures. Primary pituitary carcinomas are rare, representing about 0.2% of all pituitary tumors.³⁷

PATHOPHYSIOLOGY Local expansion of pituitary adenomas may cause both neurologic and secretory defects. Neurologically, the tumor may impinge on the optic chiasm if it extends upward from the sella turcica. This causes a variety of visual disturbances, depending on the area of the optic chiasm that is compressed. If the tumor is locally aggressive, it may invade the cavernous sinus and cause cavernous sinus thrombosis with impairment of the function of the oculomotor, trigeminal, trochlear, and abducens cranial nerves, evoking symptoms relative to their function. Extension also may involve the hypothalamus, disturbing hypothalamic control of wakefulness, thirst, appetite, and temperature.

The adenomatous tissue secretes the hormone of the cell type from which it arose, without regard to physiologic needs and without benefit of regulatory feedback mechanisms. GH-, LH-, and FSH-secreting cells in the pituitary are most sensitive to pressure from expanding tumors within the rigid sella turcica, and as a consequence, hyposecretion of these hormones is most often seen in people with a large pituitary gland.

CLINICAL MANIFESTATIONS The clinical manifestations of pituitary adenomas are related to tumor growth and hormone hypersecretion or hyposecretion. Effects from an increase in tumor size include such nonspecific complaints as headache and fatigue. Visual changes produced by pressure on the optic chiasm include visual field impairments (occasionally beginning in one eye and progressing to the other) and temporary blindness. If the tumor infiltrates other cranial nerves, neurologic function is affected.

Pituitary adenomas arise from hormone-producing cells of the pituitary, and most often are associated with increased secretion of GH and prolactin. Paradoxically, the pressure produced by a pituitary adenoma is also associated with decreased function of neighboring anterior pituitary cells, which results in hyposecretion of other anterior pituitary hormones. For example, gonadotropic hyposecretion often results in menstrual irregularity in women, decreased libido, and receding secondary sex characteristics in men and women. If the tumor exerts sufficient pressure, thyroid and adrenal hypofunction may occur because of lack of TSH and ACTH. These result in the symptoms of hypothyroidism and hypocortisolism.

EVALUATION AND TREATMENT Diagnosis of pituitary adenoma involves physical and laboratory evaluations, including pertinent hormone assays and radiographic examination of the skull. This may be accomplished by CT scanning or dynamic MRI used in conjunction with contrast material. Dynamic MRIs provide superior imaging and greater sensitivity for small lesions in comparison with CT scans.³⁸

The goal of treatment is to protect the individual from the effects of tumor growth and to control hormone hypersecretion or hyposecretion while minimizing damage to appropriately secreting portions of the pituitary. Depending on the tumor size and type, individuals may be treated with specific medications to suppress tumor growth, transsphenoidal tumor resection, or radiation therapy.³⁹

Hypersecretion of Growth Hormone: Acromegaly

Acromegaly occurs in adults who are exposed to continuously excessive levels of GH and concomitant elevation of IGF-1.⁴⁰ In children and adolescents whose epiphyseal plates have not yet closed, the effect of increased GH levels on long bone growth is termed giantism (Figure 21-3).

Acromegaly is a rare disease with an estimated prevalence of 70 persons per million.⁴⁰ Approximately 15% of all pituitary tumors release excessive GH. The most common cause of acromegaly is a primary autonomous GH-secreting pituitary adenoma.^40,41 Acromegaly occurs more often in women than men and is diagnosed most often in adults in their 40s and 50s, although the disease is usually present for years preceding the diagnosis.

Acromegaly is a slowly progressive disease that if untreated is associated with a decreased life expectancy. The increased number of deaths associated with acromegaly are caused by cardiac hypertrophy, hypertension, atherosclerosis, and type 2 diabetes mellitus that lead to coronary artery disease.⁴² Malignancies, including colon, breast, and lung cancer, are also more common in individuals with acromegaly.^40,41

PATHOPHYSIOLOGY With a GH-secreting adenoma, the usual GH baseline secretion pattern is lost, as are sleep-related GH peaks. A totally unpredictable secretory pattern ensues. With only slight elevations of GH, IGF-1 levels increase, stimulating growth. In the adult, epiphyseal closure has occurred and increased amounts of GH and IGF-1 cannot stimulate further long bone growth. Instead, these elevations cause connective tissue proliferation, an increase in the extracytoplasmic matrix, and bony proliferation. Thickening of the articular cartilage with fibrosis is followed by narrowing of the joint spaces and formation of osteophytes, leading to chronic arthritis. These changes affect large joints and the vertebrae, limiting mobility and causing pain.⁴⁰

GH acts on the renal tubules to increase phosphate reabsorption, leading to mild hyperphosphatemia. The metabolic effects of GH hypersecretion include impaired carbohydrate tolerance and increased metabolic rate. Hyperglycemia may be seen as a result of GH’s inhibition of peripheral glucose uptake and increased hepatic glucose production, followed by insulin resistance and, finally, compensatory hyperinsulinism. Not surprisingly, because of the aforementioned changes in glucose use, approximately one third of people with GH abnormalities have glucose intolerance and half of those individuals develop type 2 diabetes mellitus.⁴⁰ Type 2 diabetes mellitus occurs when the pancreas is unable to secrete enough insulin to offset the effects of GH.

CLINICAL MANIFESTATIONS As a result of connective tissue proliferation, individuals with acromegaly have enlarged tongues, interstitial edema, increase in the size and function of sebaceous and sweat glands (leading to increased body odor), and coarse skin and body hair. The coarse skin condition becomes very apparent when procedures such as inserting an intravenous needle are performed; the skin is very thick and difficult to penetrate. Bony proliferation results in large joint arthropathy with swelling and decreased range of motion and periosteal vertebral growth, which causes kyphosis.⁴⁰ Enlargement of the facial bones and the bones of the hands and feet result in protrusion of the lower jaw and forehead and a need for increasingly larger sizes of shoes, hats, rings, and gloves (Figures 21-4 and 21-5).

Because IGF-1 stimulates cartilaginous growth, the increased IGF-1 levels cause elongation of ribs at the bone-cartilage junction, leading to a barrel-chest appearance and increased proliferation of cartilage in joints. This in turn causes backache, arthralgia, and arthritis. These are early manifestations of acromegaly. When shaking hands with an individual with acromegaly, one can palpate the large soft tissues. With bony and soft tissue overgrowth, entrapment of nerves may occur, leading to peripheral nerve damage as manifested by weakness, muscular atrophy, footdrop, and sensory changes in the hands.

Although the associated pathophysiology is not clearly understood at present, hypertension and left heart failure are seen in one third to one half of individuals with acromegaly. Cardiomyopathy associated with progressive and unrestrained myocardial growth is a significant factor.⁴⁰ Headache occurs in 50% to 87% of cases and does not appear related to GH levels, size of the tumor, or presence of hypertension. Because of a space-occupying lesion, central nervous system symptoms of headache, seizure activity, visual disturbances (e.g., bitemporal hemianopia from compression of the optic chiasm), papilledema, and compression hypopituitarism may occur.

If compression hypopituitarism does occur because of a large GH-secreting adenoma, the secretion of the gonadotropins may be affected. This causes amenorrhea in women and loss of libido and erectile dysfunction in men because of pituitary stalk compression. Dopamine delivery to the anterior pituitary is impaired in 30% to 40% of individuals with acromegaly resulting in hyperprolactinemia. In addition, co-secretion of GH and prolactin by the same neoplastic cell line has been documented.⁴⁰

EVALUATION AND TREATMENT Diagnosis of acromegaly is accomplished by documenting GH suppression during oral glucose tolerance testing and elevated IGF-1 levels.⁴¹ The goals of treatment are to normalize GH and IGF-1 serum levels, restoring normal pituitary function and relieving or preventing complications related to tumor expansion. The treatment of choice for acromegaly is transsphenoidal surgical removal of the GH-secreting adenoma.⁴³ Treatment by radiation therapy may be effective when rapid control of GH levels is not essential, when the individual is not a good surgical candidate, or when hyperfunction persists after subtotal resection. Octreotide, octreotide long acting and lanreotide are somatostatin analogs that have been shown to be effective in lowering elevated GH levels, reversing many of the clinical manifestations of the disease, and causing tumor shrinkage in nearly half of individuals.^40,43,44 Pegvisomant is an effective drug that induces tissue insensitivity to GH.^40,45

Hypersecretion of Prolactin: Prolactinoma

Pituitary tumors that secrete prolactin are called prolactinomas and are the most common of the hormonally active pituitary tumors encountered in clinical medicine.^46,47 The physiologic actions of prolactin include breast development during pregnancy, postpartum milk production, and suppression of ovarian function in nursing women.

In addition to pituitary tumors, many conditions or medications can elevate prolactin in the absence of pituitary pathologic condition. For example, renal failure, polycystic ovarian disease (see Chapter 22), primary hypothyroidism, breast stimulation, or even venipuncture can increase prolactin levels.^47,48 Prolactin is under tonic inhibitory hypothalamic control through the secretion of dopamine (prolactin inhibitor factor [PIF]).⁴⁶ Thus medications that block the effects of dopamine at the pituitary can increase prolactin and stimulate proliferation of prolactin-secreting cells (lactotrophies). These include antipsychotics (risperidone, chlorpromazine), metoclopramide, tricyclic antidepressants, methyldopa, and estrogens.⁴⁶ Any process that interferes with the delivery of dopamine from the hypothalamus to the lactotrophies (pituitary stalk tumor, pituitary stalk transection, or compressive pituitary tumor) also results in hyperprolactinemia. Because thyrotropin-releasing hormone (TRH) stimulates prolactin secretion in addition to enhancing TSH release, prolactin may be elevated in individuals with primary hypothyroidism.

PATHOPHYSIOLOGY The hallmark of a prolactinoma is sustained increases in serum prolactin. Indeed, tumor size roughly correlates with the degree of prolactin elevation. Hyperprolactinemia has several reproductive consequences. Prolactin suppresses GnRH pulses at the hypothalamus, impairs pulsatile pituitary gonadotropin release, and blunts the gonadal responsiveness to gonadotropins. In estrogen- and progesterone-primed breasts, milk production is stimulated.

CLINICAL MANIFESTATIONS Pathologic elevation of prolactin in women results in amenorrhea, nonpuerperal milk production (galactorrhea), hirsutism (excessive body hair in a masculine distribution pattern), and osteopenia caused by estrogen deficiency.^46,47 Menstrual abnormalities and galactorrhea are alarming symptoms in women, and, as a result, women generally present earlier in the course of the illness and are found to have microadenomas (less than 1 cm in size). Men, on the other hand, are more likely to have larger tumors at the time of diagnosis with associated compressive or impingement symptoms such as headache or visual impairment. Hyperprolactinemia in men causes hypogonadism, erectile dysfunction, impaired libido, oligospermia, and diminished ejaculate volume.⁴⁷

EVALUATION AND TREATMENT The diagnostic evaluation of hyperprolactinemia starts with a careful history to exclude medications that may cause elevations in prolactin. Symptoms of hypothyroidism should be elicited, and screening with a serum TSH is mandatory. A careful search for a nonpituitary cause should be pursued if prolactin is less than 50 ng/ml. Prolactin levels more than 200 ng/ml are usually associated with a prolactinoma and are an indication for MRI scanning of the pituitary.^46,47

Dopaminergic agonists (bromocriptine, cabergoline, and pergolide) are the treatment of choice for prolactinomas, and their use is often associated with both a rapid reduction in the size of the tumor and a reversal of the gonadal effects of hyperprolactinemia.^46,47 Restoration of fertility in previously anovulatory women is common. Although there is an association between valvular heart disease and cabergoline or pergolide used in the treatment of parkinsonism, those individuals receive much higher doses of these medications than those used for prolactinoma. Studies on the long-term safety of cabergoline in treatment of prolactinoma are underway.⁴⁹ Alternatives to dopaminergic agonists are being developed including somatostatin analogs and prolactin receptor antagonists.⁴⁷ In individuals resistant or intolerant to these medications, transsphenoidal surgery and radiotherapy are options.^47,48

Thyrotoxicosis

PATHOPHYSIOLOGY Thyrotoxicosis is a condition that results from any cause of increased levels of circulating TH. The terms thyrotoxicosis and hyperthyroidism are often used interchangeably. The prevalence of hyperthyroidism is estimated to be 1.2% in the United States, of which 0.7% is subclinical.⁵⁰ Thyrotoxicosis has a variety of causes. Identifying the cause is important because the treatment and expected outcome vary accordingly. Primary hyperthyroidism is a form of thyrotoxicosis in which excess TH is synthesized and secreted by the thyroid gland. Specific diseases that can cause primary hyperthyroidism include Graves disease, toxic multinodular goiter, solitary hyperfunctioning nodules, and, very rarely, follicular thyroid carcinoma. Thyrotoxicosis also can occur transiently in subacute thyroiditis (viral, postpartum, painless, or de Quervain thyroiditis) because of the release of preformed TH; however, this is not considered a cause of true hyperthyroidism because an abnormal amount of TH synthesis does not occur, and therefore the thyrotoxicosis is not sustained.⁵⁰ Another cause of thyrotoxicosis is ingestion of excess TH medication, sometimes called thyrotoxicosis factitia (Figure 21-6). Secondary hyperthyroidism is very rare and is caused by TSH-secreting pituitary adenomas. Although each of these conditions is associated with specific pathophysiology and manifestations, all forms of thyrotoxicosis share some common characteristics.

CLINICAL MANIFESTATIONS The clinical features of thyrotoxicosis are attributable to the metabolic effects of increased circulating levels of TH (Figure 21-7). This usually results in an increased metabolic rate with heat intolerance and increased tissue sensitivity to stimulation by the sympathetic division of the autonomic nervous system. The major manifestations are summarized in Table 21-2. Enlargement of the thyroid gland (goiter) is common in hyperthyroid conditions caused by stimulation of TSH receptors.

EVALUATION AND TREATMENT The diagnosis of thyrotoxicosis is based on symptoms of TH excess and documentation of increased circulating thyroid hormone levels. Elevated serum free thyroxine (T₄) and triiodothyronine (T₃) are found in all forms of thyrotoxicosis. In primary hyperthyroidism, TSH is decreased and in secondary hyperthyroidism it is increased. Radioactive iodine uptake (RAIU) can be used in evaluating the etiology of thyrotoxicosis⁵⁰ (Figure 21-8).

Treatment is directed at controlling excessive TH production, secretion, or action. The major types of therapy currently used to achieve these goals include antithyroid drug therapy (methimazole or propylthiouracil), radioactive iodine therapy, and surgery. One of the major complications of both radioactive iodine and surgical treatment of hyperthyroidism is excessive ablation of the gland, resulting in hypothyroidism.

Hyperthyroid Conditions

Hypothyroid Conditions

Type 1 Diabetes Mellitus

Diabetes mellitus is the most common pediatric chronic disease and affects 0.17% of U.S. children.⁹⁹ The common form of type 1 diabetes mellitus is the result of an autoimmune-mediated specific loss of beta cells in the pancreatic islets. The incidence of the condition is increasing in some areas, with other areas showing no change in incidence.⁹⁹ Table 21-6 summarizes the epidemiology of diabetes mellitus.

Type 1 diabetes mellitus is thought to be the result of a genetic-environmental interaction. Between 10% and 13% of individuals with newly diagnosed type 1 diabetes have a first-degree relative (parent or sibling) with type 1 diabetes. Diagnosis has a seasonal distribution, with more cases reported during autumn and winter in the northern hemisphere. Diagnosis is rare during the first 9 months of life and peaks at 12 years of age.

PATHOPHYSIOLOGY Two distinct types of type 1 diabetes have been identified: autoimmune and nonimmune. In autoimmune-mediated diabetes mellitus, environmental-genetic factors are thought to trigger cell-mediated destruction of pancreatic beta cells. Autoimmune type 1 diabetes is called type 1A. Nonimmune type 1 diabetes is far less common than immune. It occurs secondary to other diseases, such as pancreatitis, or to a more fulminant disorder termed idiopathic (type 1B) diabetes. Type 1B diabetes occurs mostly in people of Asian or African descent and affected individuals have varying degrees of insulin deficiency.¹⁰⁰

Type 2 Diabetes Mellitus

In the United States, type 2 diabetes mellitus affects 10.5% of those ages 45 to 64 years (up from 5.6% in 1985) and 18.4% of those ages 65 to 74 years (up from 10.2% in 1985).⁹⁹ The incidence of diabetes has doubled in all adult age groups in the past two decades. Prevalence varies by ethnic group and gender. Although the increase in overall prevalence of diabetes has increased the most in white men (116% increase since 1980), the condition remains most common in black women with an overall prevalence of 8.8% and a prevalence of 34% in those ages 65 to 74.⁹⁹ There also is an increased prevalence of type 2 diabetes in children, especially in Native American children ages 15 to 19⁹⁹ and in obese children^121–123 (see Table 21-6).

An environmental-genetic interaction appears to be responsible for type 2 diabetes. The most well-recognized risk factors are age, obesity, hypertension, physical inactivity, and family history. The metabolic syndrome is a constellation of disorders (central obesity, dyslipidemia, prehypertension, and a fasting blood glucose more than or equal to 100 mg/dl) that together confer a high risk of developing type 2 diabetes and associated cardiovascular complications (see What’s New? Metabolic Syndrome and Diagnosis). Other novel risk factors being investigated include elevated C-reactive protein, decreased adiponectin, increased leptin, and increased IL-6.¹²⁴ A unique manifestation of insulin resistance in women of reproductive age is polycystic ovary syndrome (PCOS), which is associated with a risk of diabetes seven times the average risk for women without PCOS.

PATHOPHYSIOLOGY Many genes have been identified that are associated with type 2 diabetes, including those that code for beta cell mass, beta cell function (ability to sense

blood glucose levels, insulin synthesis, and insulin secretion), proinsulin and insulin molecular structure, insulin receptors, hepatic synthesis of glucose, glucagon synthesis, and cellular responsiveness to insulin stimulation.^125–128 These genetic abnormalities combined with environmental influences, such as obesity, result in the basic pathophysiologic mechanisms of type 2 diabetes: insulin resistance and decreased insulin secretion by beta cells (Figure 21-14). Both of these mechanisms are essential to the development of type 2 diabetes. Although many individuals with risk factors for type 2 diabetes (including obesity, metabolic syndrome, and hypertension) are insulin resistant, only those individuals who are genetically predisposed to beta cell dysfunction (and therefore a relative deficiency in insulin) will develop type 2 diabetes.^129–130

Insulin resistance is defined as a suboptimal response of insulin-sensitive tissues (especially liver, muscle, and adipose tissue) to insulin. Several mechanisms are involved in abnormalities of the insulin signaling pathway and contribute to insulin resistance. These include an abnormality of the insulin molecule, high amounts of insulin antagonists, down-regulation of the insulin receptor, decreased or abnormal activation of postreceptor kinases, and alteration of glucose transporter (GLUT) proteins.¹³¹ Obesity is present in 60% to 80% of those with type 2 diabetes and is a major contributor to insulin resistance through several important mechanisms:

Compensatory hyperinsulinemia prevents the clinical appearance of diabetes for many years. Eventually, however, beta cell dysfunction develops and leads to a relative deficiency of insulin activity. The islet dysfunction may be caused by a decrease in beta cell mass, abnormal function of the beta cells, or some combination. A progressive decrease in the weight and number of beta cells occurs in type 2 diabetes, and several different mechanisms have been implicated. Beta cells are extremely sensitive to high levels of glucose and free fatty acids, and under these so-called glucolipotoxic conditions, beta cells undergo apoptotic cell death.^{128,130,132,139} The adipokine leptin decreases insulin synthesis in the beta cell. A variety of inflammatory cytokines, including TNF-α and IL-1β, have also been shown to be toxic to beta cells.^{128,130,132,140} Thus many of the obesity-related causes of insulin resistance (elevated free fatty acids [FFA] hyperglycemia, adipokines, and inflammatory cytokines) also promote programmed cell death in B cells. Beta cell “exhaustion” from increased demand for insulin biosynthesis, associated with intracellular oxidative stress and endoplasmic reticulum dysfunction, also has been implicated in beta cell apoptosis.^132,141

Glucagon is a hormone produced by the alpha cells of the pancreas and acts primarily in the liver to increase blood glucose by stimulating glycogenolysis and gluconeogenesis. Glucagon acts as an antagonist to insulin. In healthy individuals, high glucose levels cause glucagon release to be inhibited. In type 2 diabetes, pancreatic alpha cells are less responsive to glucose inhibition resulting in increased glucagon secretion.^142,143 These abnormally high levels of glucagon have long been known to play a role in the increased hepatic production of glucose and resultant hyperglycemia seen in type 2 diabetes.

Amylin is a hormone co-secreted with insulin by the beta cells. A deficiency of amylin in type 1 and type 2 diabetes parallels the reduction in insulin secretion. Amylin inhibits glucagon secretion, and problems with glycemic control may be related to altered glucagon control or assimilation of nutrients in relation to the deficit of amylin. Drugs aimed at improving amylin function are being studied.¹⁴⁴ Amyloid deposition in the pancreas resulting in islet cell destruction also may be related to changes in amylin function.^132,145,146 However, the role of amyloid accumulation in the pathogenesis of type 2 diabetes is unclear.

The incretins are a class of peptides released from the gastrointestinal tract in response to food intake that increase the sensitivity of beta cells to circulating glucose levels, thus improving insulin responsiveness to meals. Glucagon-like peptide 1 (GLP-1) is cleaved from proglucagon in the intestinal mucosa. Another incretin is glucose-dependent insulinotropic polypeptide (GIP), which is synthesized in the duodenum and jejunum. These incretins bind to receptors on beta cells and increase the synthesis and secretion of insulin in response to glucose levels.¹⁴⁷ They are then inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV). Currently one GLP-1 agonist and one DPP-IV inhibitor are approved for use in the United States and others are being evaluated for the treatment of type 2 diabetes^147–150 (see What’s New? Incretin Hormones for Diabetes Mellitus Therapy).

Ghrelin is a peptide produced in the stomach and pancreatic islets that stimulates GH receptors. Decreased levels of circulating ghrelin have been associated with insulin resistance and increased fasting insulin levels; its use as a potential treatment for type 2 diabetes is being investigated.¹⁵¹

CLINICAL MANIFESTATIONS Clinical manifestations of type 2 diabetes are often nonspecific. Although younger people may develop the condition, it generally affects those older than 30 years. The individual often is overweight, dyslipidemic, hyperinsulinemic, and hypertensive. The individual with type 2 diabetes may show some classic symptoms of diabetes, such as polyuria and polydipsia, but more often will have nonspecific symptoms such as fatigue, pruritus, recurrent infections, visual changes, or symptoms of neuropathy (paresthesias or weakness) (Table 21-8).

EVALUATION AND TREATMENT The diagnostic criteria for type 2 diabetes are similar to that of type 1 (see Box 21-1, p. 747). As with type 1 diabetes, the goal of treatment for individuals with type 2 diabetes is the restoration of

near-euglycemia (a normal blood glucose level) and correction of related metabolic disorders.

Dietary measures, including restriction of the total caloric intake, are of primary importance in both the prevention and treatment of type 2 diabetes.^119,121,152 As the obese individual loses weight, the body’s resistance to insulin often diminishes so that weight loss results in improved glucose tolerance. Nonobese individuals with type 2 diabetes should consume calories consistent with their ideal weight and pattern of activity. The emphasis of medical nutrition therapy (MNT) in type 2 diabetes mellitus should be focused on achieving glucose, lipid, and blood pressure goals (see Nutrition & Disease: Medical Nutrition Therapy [MNT] for Prevention and Treatment of Diabetes).

Exercise is an important aspect of prevention and treatment of type 2 diabetes.^119,121 Exercise reduces postprandial blood glucose levels, diminishes insulin requirements, lowers triglyceride and cholesterol levels, and increases the level of high-density lipoprotein (HDL) cholesterol. In addition, exercise is a valuable adjunct to weight loss for the overweight individual. Hypoglycemia may result, however, when the exercising individual receives sulfonylurea or insulin therapy.

In those individuals with morbid obesity unresponsive to diet and exercise interventions, bariatric surgery may be indicated. Recent studies suggest that gastric bypass surgery is associated with a decrease in the incidence of type 2 diabetes and marked improvements in glycemic control in those with established diabetes.^152–155

Although the first approach to treatment of the individual with type 2 diabetes is appropriate meal planning and exercise, medications are usually needed for optimal management. Sulfonylurea, biguanide, thiazolidinediones, DPP-IV inhibitors, and α-glucosidase inhibitors are useful in treating some individuals with type 2 diabetes (Table 21-9). Use of oral hypoglycemic agents requires a pancreas capable of secreting insulin. Sulfonylureas acutely augment beta cell insulin secretion. Biguanides (metformin) inhibit hepatic glucose production and increase the sensitivity of peripheral tissue to insulin. α-Glucosidase inhibitors decrease postprandial hyperglycemia through delaying carbohydrate digestion and absorption. The thiazolidinedione class of insulin-sensitizing compounds activate a nuclear receptor termed the peroxisome proliferator-activated receptor (PPARγ), which in turn regulates cellular carbohydrate and lipid metabolism. As discussed previously, DPP-IV inhibitors increase GLP-1 levels that in turn help augment endogenous insulin secretion. Insulin therapy may be needed in the later stages of type 2 diabetes because of loss of beta cell function.¹⁵⁶ There is some evidence that exogenous insulin may help prevent further beta cell apoptosis.¹⁵⁷ Because the pathogenesis of type 2 diabetes involves a combination of insulin resistance and a relative insulin deficiency, it is common to combine therapeutic agents from different classes of oral agents in order to achieve acceptable glycemic control.

Other Specific Types of Diabetes Mellitus and Gestational Diabetes Mellitus

As described in Table 21-5 (p. 746), the American Diabetes Association (ADA) classification of diabetes mellitus includes not only the most common forms of diabetes (type 1 and type 2) but also “other specific types of diabetes mellitus” and “gestational diabetes mellitus.”⁹⁸ Other specific types of diabetes include genetic defects in beta cell function, genetic defects in insulin action, diseases of the exocrine pancreas, endocrinopathies, drug- or chemical-induced beta cell dysfunction, infections, and other uncommon autoimmune and inherited disorders that are associated with diabetes.

The most well-described of these other specific types of diabetes is termed maturity-onset diabetes of youth (MODY). MODY includes six specific autosomal dominant mutations including genes for hepatocyte nuclear factor-1α (HNF-1α; MODY 3), glucokinase (MODY 2), HNF-4α (MODY 1), insulin promoter factor-1 (IPF-1; MODY 4), HNF-1β (MODY 5), and NeuroD1 (MODY 6).^158–160 Individuals with these genetic defects have a strong family history of diabetes mellitus, are of normal weight, and are usually diagnosed before age 25. MODY was previously classified as a form of type 2 diabetes because insulin levels are often in the normal range yet are inappropriately low for the degree of hyperglycemia. However, weight gain is not a prominent feature of MODY, whereas it is an important contributor to type 2 diabetes. Interestingly, the gene mutations found in MODY are not commonly found in type 2 diabetes.^159–161 Diagnosis and management are similar to type 2 diabetes.

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.⁹⁸ GDM complicates approximately 4% of all pregnancies and represents approximately 90% of pregnancies complicated by diabetes.^98,162 The exact mechanism of GDM is unknown, but insulin resistance and inadequate insulin secretion are contributing factors. Diagnosis of GDM is based on the presence of risk factors (older age, family history, history of glucose intolerance, obesity, membership in certain ethnic or racial group, and history of poor obstetric outcomes, infant weighing greater than 9 pounds), plus the measurement of an elevated fasting or casual FPG. OGTT can also be used to confirm the diagnosis. Often there are no symptoms and careful glucose control prenatally, during pregnancy, and after delivery are essential to both the short- and long-term health of mother and baby.^162–164 There is an increased risk for type-2 diabetes later in life in women who develop gestational diabetes.

Hypoglycemia

Hypoglycemia is a lowered plasma glucose level. Its causes may be exogenous, endogenous, or functional (Tables 21-10, 21-11, and 21-12 contain summaries of causes). In general, hypoglycemia occurs when blood glucose levels are less than 35 mg/dl in newborns for the first 48 hours of life and less than 45 to 60 mg/dl in children and adults. Some individuals may become symptomatic before glucose levels decrease to 60 mg/dl if the decrease is relatively rapid. Hypoglycemia occurs most often in individuals with diabetes mellitus treated with insulin (see Table 21-10 for a list of both endogenous and exogenous causes of hypoglycemia). It occurs in more than 90% of those with type 1 diabetes (especially in those on multiple daily injections of insulin) and limits the management of the disease.^100,165 Hypoglycemia in diabetes is sometimes called insulin shock or insulin reaction. Individuals with type 2 diabetes are at less risk for hypoglycemia than those with type 1 diabetes because they retain relatively intact glucose counterregulatory mechanisms.¹⁶⁶ However, hypoglycemia does occur in type 2 diabetes when treatment involves insulin secretagogues (e.g., sulfonylureas) or exogenous insulin.^{156,166–168} Hypoglycemia also can occur as a result of many functional causes unrelated to diabetes (see Table 21-11).

Symptoms of hypoglycemia result from either activation of the sympathetic nervous system (adrenergic symptoms) or from an abrupt cessation of glucose delivery to the brain (neuroglycopenic symptoms) or both.⁶⁰ Symptoms commonly vary among individuals but tend to be consistent for each person. Adrenergic reactions occur when the decrease in blood glucose is rapid with tachycardia, palpitations, diaphoresis, tremors, pallor, and arousal anxiety.¹⁶⁹ The response is probably generated when the hypothalamus senses decreased glucose levels. Reduced substrate delivery to the brain (neuroglycopenia) causes changes in neuronal kinase activity and firing rates,¹⁷⁰ thus producing further symptoms including headache, dizziness, irritability, fatigue, poor judgment, confusion, visual changes, hunger, seizures, and coma. Hypoglycemia unawareness is a phenomenon that occurs in individuals without appropriate autonomic warning symptoms before development of neuroglycopenia. These individuals should be advised to raise their glycemic targets to avoid severe hypoglycemia.¹¹⁹ If an individual is receiving a beta-blocking medication, the autonomic symptoms may be blunted, and recovery from hypoglycemia may be delayed because of impaired glycogenolysis and hampered delivery of gluconeogenic substrates to the liver.

When hypoglycemic symptoms are nonspecific, the safest treatment is to provide some form of glucose because failure to provide glucose may precipitate convulsions, coma, and death. The ADA recommends that glucose (15 to 20 g) be given to a conscious patient with hypoglycemia, and that at-risk individuals and caregivers should be instructed in glucagon administration.¹¹⁹ Prevention of hypoglycemia episodes through alternate therapeutic regimens, individualizing target blood glucose levels, frequent self-monitoring of blood glucose, and proper education should be the goal.^{118,166–168,171}

Diabetic Ketoacidosis

Ketoacidosis, a serious complication of diabetes mellitus, is a common cause for hospital admissions. Although average mortality rates throughout the United States are less than 2%, the highest rates of mortality are observed in older adults and those with other severe underlying illnesses.¹⁷² Diabetic ketoacidosis (DKA) develops when there is an absolute or relative deficiency of insulin. This is most common in individuals with type 1 diabetes but can occur in those with type 2 diabetes as well.^60,172–174 In addition, a syndrome called ketosis-prone diabetes (KPD) has been described in which affected individuals do not fit into the traditional ADA categories for diabetes and are more likely to be persons of African, African American, or Hispanic origin.¹⁷⁵ The most common precipitating factor for DKA is intercurrent illness, such as infection, trauma, surgery, or myocardial infarction. Interruption of insulin administration also may result in DKA. In 20% to 30% of cases, no precipitating factors are noted. Emotional factors and stress, particularly in children, are thought to contribute to the development of DKA. The frequency of DKA peaks in adolescence.

PATHOPHYSIOLOGY In a state of relative insulin deficiency there is an increase in insulin counterregulatory hormones including catecholamines, cortisol, glucagon, and GH. Catecholamines, cortisol, glucagon, and GH antagonize insulin by increasing glucose production. In addition, these hormones decrease use of glucose. Profound insulin deficiency results in decreased glucose uptake, increased fat mobilization with release of fatty acids, and accelerated gluconeogenesis and ketogenesis (Figure 21-15). Relatively increased glucagon levels also contribute to activation of the gluconeogenic (glucose-forming) and ketogenic (ketone-forming) pathways in the liver. Because of the insulin deficiency, hepatic overproduction of β-hydroxybutyrate and acetoacetic acids causes increased ketone concentrations.¹⁷³ Ordinarily ketones are used by tissues as an energy source to regenerate bicarbonate. This balances the loss of bicarbonate, which occurs when the ketone is formed. Hyperketonemia (increased blood ketone levels) may be a result of impairment in the use of ketones by peripheral tissue, which permits strong organic acids to circulate freely. Bicarbonate buffering then does not occur, and the individual develops a metabolic acidosis.

CLINICAL MANIFESTATIONS The signs and symptoms of DKA are fairly nonspecific. Polyuria and dehydration result from the osmotic diuresis associated with hyperglycemia. Here the plasma glucose level is higher than the individual’s renal threshold, allowing much glucose to be lost in the urine. Sodium, phosphorus, and magnesium deficits are common. The most important electrolyte disturbance, however, is a marked deficiency in total body potassium. Although the serum potassium may appear normal or elevated because of volume contraction and a shift of potassium out of the cell and into the blood caused by metabolic acidosis, the total body deficiency of potassium may reach 3 to 5 mEq/kg. Symptoms of diabetic ketoacidosis include Kussmaul respirations (hyperventilation in an attempt to compensate for the acidosis), postural dizziness, central nervous system depression, ketonuria, anorexia, nausea, abdominal pain, thirst, and polyuria.

EVALUATION AND TREATMENT The diagnosis of ketoacidosis is suggested when individuals have symptoms of vomiting, abdominal pain, dehydration, an acetone odor on the breath, and change in sensorium. The ADA criteria for diagnosis of DKA include a serum glucose of more than 250 mg/dl, a serum bicarbonate of less than 18 mg/dl, a serum pH of less than 7.30, presence of an anion gap, and presence of urine and serum ketones.¹⁷⁶

Treatment of DKA involves continual administration of low-dose insulin to decrease glucose levels.^60,172 Fluids are administered to replace lost fluid volume, and electrolytes—particularly sodium, potassium, and phosphorus—are administered as needed. Fluids and electrolytes should be monitored closely. Electrolyte deficits become apparent as fluid volume is replaced. After the administration of insulin, the concentration of β-hydroxybutyrate promptly begins to decrease and after a slight increase, acetoacetate also begins to decrease. A persistent ketonuria may be observed for several days after treatment. Continuous monitoring of the individual is essential to ensure an uncomplicated recovery from DKA. Cerebral edema is the most common cause of morbidity and mortality during the first day of treatment for DKA in children. The mechanisms are poorly understood.¹⁷⁷ Health teaching emphasizes predisposing factors and strategies for avoiding DKA.

Hyperosmolar Hyperglycemic Nonketotic Syndrome

Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS) is a life-threatening emergency most often precipitated by infections, medications, nonadherence to diabetes treatment, or coexisting disease.^174,176 HHNKS is more commonly seen with type 2 diabetes. It can also occur in individuals with pancreatic destruction from other causes such as chronic pancreatitis.

PATHOPHYSIOLOGY HHNKS differs from DKA in the degree of insulin deficiency (which is more profound in DKA) and the degree of fluid deficiency (which is more marked in HHNKS) (see Figure 21-15).¹⁷⁶ Levels of free fatty acids in HHNKS are consistently lower than those found in DKA. HHNKS is characterized also by a lack of ketosis. Because the amount of insulin required to inhibit fat breakdown is less than that needed for effective glucose transport, insulin levels are sufficient to prevent excessive lipolysis but not to use glucose properly. Glucose levels are considerably higher in HHNKS than in DKA because of volume depletion.

CLINICAL MANIFESTATIONS The clinical features of HHNKS include a serum glucose of more than 600 mg/dl, a serum pH greater than 7.30, a serum bicarbonate greater than15 mg/dl, a serum osmolarity greater than 320 mOsm/L, and either absent or small ketones in the urine and serum.¹⁷⁶ Glycosuria and polyuria in HHNKS result from the extreme serum glucose elevation. As much as 19 g of glucose per hour may be lost in diuresis, which also causes severe volume depletion, increased serum osmolarity, intracellular dehydration, and loss of electrolytes including potassium. Neurologic changes, such as stupor, correlate with the degree of hyperosmolarity and are more common in HHNKS than in DKA.⁶⁰

EVALUATION AND TREATMENT The serum ketone concentration is normal or only mildly elevated and only minimal acidosis is seen in HHNKS, otherwise DKA and HHNKS show considerable overlap in symptoms and treatment. Insulin infusion should be combined with fluid repletion over 24 hours.^60,176 An important distinction, however, is that the dehydration in HHNKS is far more severe than that in DKA. Thus fluid replacement, with both crystalloids and colloids, is more rapid. Potassium deficits may be so extreme in HHNKS that more than 1 week of potassium repletion may be needed to correct the total body deficits. Phosphorus and sodium also may be needed. HHNKS is a significant risk factor for venous thrombosis and recent studies suggest that anticoagulant prophylaxis should be considered.^60,178 Mortality is also high in HHNKS, and is related to the age of the individual and comorbid conditions including the severity of the precipitating illness (see Table 21-12 for a comparison of the three acute complications described thus far).

Somogyi Effect

The Somogyi effect is a unique combination of hypoglycemia followed by rebound hyperglycemia. The problem is more common in individuals with type 1 diabetes mellitus, particularly in children, and should be investigated whenever fluctuations in blood sugar levels are serious.¹⁷⁹

PATHOPHYSIOLOGY The Somogyi effect occurs when hypoglycemia stimulates glucose counterregulation, including epinephrine, GH, cortisol, and glucagon release.¹⁸⁰ These hormones serve to increase blood glucose by gluconeogenesis (formation of glucose from nonglucose sources) and glycogenolysis (breakdown of glycogen into glucose). They mobilize fatty acids and proteins while inhibiting peripheral glucose use. These hormones may cause insulin resistance for 12 to 48 hours. Commonly, excessive carbohydrate intake may be a major contributor to rebound hyperglycemia. Also hypoglycemia generally occurs during the peak of injected insulin; therefore, as counterregulatory hormones are activated and carbohydrate is consumed by the individual, insulin levels are on the decline, which contributes to the subsequent hyperglycemia.¹⁸⁰ The frequency of this phenomenon is debated, and recent studies suggest that it is much less common than previously reported.

CLINICAL MANIFESTATIONS In addition to fluctuating glucose levels, subtle symptoms of hypoglycemia occur. If an individual has nocturnal hypoglycemia, there may be complaints of nightmares and early morning headaches. Ketonuria may occur if the mobilization of energy sources overshoots the body’s need for glucose and exogenous insulin is depleted.

EVALUATION AND TREATMENT If the individual has nocturnal hypoglycemia, diagnosis involves the measurement of plasma glucose during the night using monitors capable of continuous glucose sensing.¹⁷⁹ Treatment consists of decreasing insulin dosage or changing the time of administration.

Dawn Phenomenon

The dawn phenomenon is an early morning rise in blood glucose concentration with no hypoglycemia during the night. It appears to be related to nocturnal elevations of GH, a counterregulatory hormone that causes hyperglycemia by decreasing peripheral (other than liver) glucose uptake. Increased clearance of plasma insulin also may be involved. Altering the time and dose of insulin manages the problem.¹⁸¹ Treating dawn phenomenon may result in the Somogyi effect and vice versa.

Hyperglycemia and the Polyol Pathway

Tissues that do not require insulin for glucose transport, such as kidney, red blood cells (RBCs), blood vessels, eye lens, and nerves, use an alternate metabolic pathway for glucose metabolism known as the polyol pathway. With hyperglycemia, glucose is shunted to this pathway and is converted to sorbitol (a polyol) by the enzyme aldose reductase. Sorbitol is then slowly converted to fructose by sorbitol dehydrogenase.¹⁸⁵ The accumulation of sorbitol and fructose increases intracellular osmotic pressure and attracts water, leading to cell injury. This is particularly evident in the lens of the eye and leads to swelling with visual changes and cataracts. In nerves, sorbitol interferes with ion pumps, damages Schwann cells, and disrupts nerve conduction. RBCs become swollen and stiff and interfere with perfusion. Aldose reductase inhibitors may slow or prevent some diabetic complications, particularly neuropathies, although their effectiveness has been limited.¹⁸⁶

Protein Kinase C

Protein kinase C (PKC) is an enzyme that is inappropriately activated in different tissues by hyperglycemia, particularly the diacylglycerol (DAG)-PKC pathway. Various consequences have been observed, including insulin resistance, production of extracellular matrix and cytokines, vascular cell proliferation, enhanced contractility, and increased permeability.¹⁸⁷ These effects may contribute to the macrovascular, microvascular, and neurologic complications of diabetes. Specific PKC inhibitors are under investigation and have shown some promise in stabilizing or preventing retinopathy, nephropathy, and neuropathy.¹⁸⁸

Hyperglycemia and Nonenzymatic Glycosylation

Nonenzymatic glycosylation is the reversible attachment of glucose to proteins, lipids, and nucleic acids without the action of enzymes. With recurrent or persistent hyperglycemia, glucose becomes irreversibly bound to collagen and other proteins in red blood cells (e.g., glycated hemoglobin), blood vessel walls, and interstitial tissue. The products of this binding are known as advanced glycosylation end product (AGE) and their receptor (RAGE) have a number of properties that may cause tissue injury or pathologic conditions associated with diabetes^189–192:

Pharmacologic agents that inhibit AGE formation or block their receptor (RAGE) are being evaluated.¹⁸⁹

Hyperglycemia and Oxidative Stress

Chronic hyperglycemia increases the production of reactive oxygen species (ROS) and the detrimental effects of oxidative stress. AGEs, defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase generate ROS, which damage large and small vessels and contribute to atherogenesis, cardiovascular disease, nephropathy, and neuropathy. Direct cellular injury, as well as the formation of gene products that cause cellular injury, contribute to these late complications of diabetes mellitus.^193,194

Hyperglycemia and the Hexosamine Pathway

Chronic hyperglycemia causes shunting of excess intracellular glucose into the hexosamine pathway and leads to O-linked glycosylation of several enzymes and proteins with alteration in signal transduction pathways and oxidative stress. The O-linked attachment of N-acetylglucosamine (O-GlcNAc) on serine and threonine residues of nuclear and cytoplasmic proteins is associated with insulin resistance and cardiovascular complications of diabetes mellitus.^195,196

Microvascular Disease

Diabetic microvascular complications are a leading cause of blindness, end-stage renal failure, and various neuropathies.¹⁹⁷ Thickening of the capillary basement membrane, endothelial cell hyperplasia, thrombosis, and pericyte degeneration are characteristic of diabetic microangiopathy and emerges over a period of 1 to 2 years. The thickening eventually results in decreased tissue perfusion. Hyperglycemia is a prerequisite for these microvascular changes and may be related to glycation of structural proteins, which results in the accumulation of AGEs. The frequency of the lesions appears to be proportional to the duration of the disease and blood glucose levels. In the DCCT study, individuals with tightly controlled blood glucose were half as likely to have renal and eye complications as those who received standard treatment.¹⁹⁸ Hypoxia and ischemia of various organs may result from microangiopathy. Three areas often affected are the retina, the kidney, and nerves.

Macrovascular Disease

Macrovascular disease is a major cause of morbidity and mortality, particularly among individuals with type 2 diabetes mellitus. Children with poorly controlled type 2 diabetes have high risk for macrovascular disease within one or two decades.²²⁸ The premature atherosclerosis of diabetes has many contributing factors, including hyperinsulinemia (insulin resistance), hyperglycemia, hypertriglyceridemia, low HDL, high LDL, lipoprotein oxidation, inflammation, vascular consequences of AGEs and their endothelial receptors (RAGEs), and altered endothelial function. The fibrous plaques of atherosclerosis are associated with the proliferation of subendothelial smooth muscle in the arterial wall. Other factors in the serum of individuals with diabetes also stimulate this proliferation (Figure 21-19).

In addition, deposition of lipids in vascular lesions may be facilitated in individuals with diabetes. Triglyceride elevations with low levels of the protective HDL cholesterol are common in individuals with type 2 diabetes mellitus in association with increased quantities of small, dense (very atherogenic) LDL cholesterol and endothelial cell and platelet abnormalities.²²⁹ Increased levels of the atherogenic oxidized LDL also are seen in hyperglycemic individuals. Hypertension can increase capillary wall pressure, damage endothelium, increase capillary permeability, decrease nitric oxide synthesis, and decrease autoregulation of blood flow.^230,231 Further work is needed to clarify the complexities of macrovascular complications.

Infection

Increased morbidity and mortality from infectious agents have been documented in those with diabetes.²⁴¹ The individual with diabetes is at increased risk for infection throughout the body for several reasons:

The risk of infection is especially high for individuals undergoing surgery and for those taking immunosuppressant medications.^242,243