Diagnosis

Blood glucose levels normally are maintained in a very narrow range, usually 70 to 120 mg/dL. The diagnosis of diabetes is established by elevation of blood glucose by any one of three criteria:

Derangements in carbohydrate metabolism proceed along a continuum. Persons with serum fasting glucose values less than 110 mg/dL, or less than 140 mg/dL for an OGTT, are considered to be euglycemic. However, those with serum fasting glucose greater than 110 but less than 126 mg/dL, or OGTT values of greater than 140 but less than 200 mg/dL, are considered to have impaired glucose tolerance, also known as prediabetes. Persons with impaired glucose tolerance have a significant risk for progression to overt diabetes over time, with as many as 5% to 10% advancing to full-fledged diabetes mellitus per year. In addition, those with impaired glucose tolerance are at risk for cardiovascular disease, as a consequence of abnormal carbohydrate metabolism and the coexistence of other risk factors (Chapter 9).

Classification

Although all forms of diabetes mellitus share hyperglycemia as a common feature, the underlying causes of hyperglycemia vary widely. The vast majority of cases of diabetes fall into one of two broad classes:

A variety of monogenic and secondary causes make up the remaining cases of diabetes (Table 19–5). An important point is that although the major types of diabetes arise by different pathogenic mechanisms, the long-term complications in kidneys, eyes, nerves, and blood vessels are the same and are the principal causes of morbidity and death.

Table 19–5 Classification of Diabetes Mellitus

Modified from the American Diabetes Association: Position statement from the American Diabetes Association on the diagnosis and classification of diabetes mellitus. Diabetes Care 31(Suppl 1):S55–S60, 2008.

Normal Insulin Physiology and Glucose Homeostasis

Before discussing the pathogenesis of the two major types of diabetes, we briefly review normal insulin physiology and glucose metabolism. Normal glucose homeostasis is tightly regulated by three interrelated processes: (1) glucose production in the liver, (2) glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle, and (3) actions of insulin and counterregulatory hormones (e.g., glucagon).

The principal metabolic function of insulin is to increase the rate of glucose transport into certain cells in the body (Fig. 19–21). These are the striated muscle cells (including myocardial cells) and, to a lesser extent, adipocytes, representing collectively about two thirds of total body weight. Glucose uptake in other peripheral tissues, most notably the brain, is insulin-independent. In muscle cells, glucose is then either stored as glycogen or oxidized to generate adenosine triphosphate (ATP). In adipose tissue, glucose is stored primarily as lipid. Besides promoting lipid synthesis (lipogenesis), insulin also inhibits lipid degradation (lipolysis) in adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis while inhibiting protein degradation. Thus, the metabolic effects of insulin can be summarized as anabolic, with increased synthesis and reduced degradation of glycogen, lipid, and protein. In addition to these metabolic effects, insulin has several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation.

Figure 19–21 Metabolic actions of insulin in striated muscle, adipose tissue, and liver.

Insulin reduces the production of glucose from the liver. Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. After a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. The most important stimulus that triggers insulin release is glucose itself, which initiates insulin synthesis in the pancreatic beta cells. In peripheral tissues (skeletal muscle and adipose tissue), secreted insulin binds to the insulin receptor, triggering a number of intracellular responses that promote glucose uptake and postprandial glucose utilization, thereby maintaining glucose homeostasis. Abnormalities at various points along this complex signaling cascade, from synthesis and release of insulin by beta cells to insulin receptor interactions in peripheral tissues, can result in the diabetic phenotype.

Pathogenesis

Type 1 Diabetes Mellitus

Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous beta cell antigens. Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and progresses with age. Most patients with type 1 diabetes depend on exogenous insulin for survival; without insulin they develop serious metabolic complications such as ketoacidosis and coma.

Although the clinical onset of type 1 diabetes is abrupt, this disease in fact results from a chronic autoimmune attack on beta cells that usually starts many years before the disease becomes evident (Fig. 19–22). The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the beta cells have been destroyed. The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells. This failure of tolerance may be a result of some combination of defective clonal deletion of self-reactive T cells in the thymus, as well as defects in the functions of regulatory T cells or resistance of effector T cells to suppression by regulatory cells. Thus, autoreactive T cells not only survive but are poised to respond to self-antigens. Not surprisingly, autoantibodies against a variety of beta cell antigens, including insulin and the beta cell enzyme glutamic acid decarboxylase, are detected in the blood of 70% to 80% of patients. In the rare cases in which the pancreatic lesions have been examined early in the disease process, the islets show necrosis of beta cells and lymphocytic infiltration (so-called insulitis).

Figure 19–22 Stages in the development of type 1 diabetes mellitus. The stages are listed from left to right, and hypothetical beta cell mass is plotted against age.

(From Eisenbarth GE: Type 1 diabetes—a chronic autoimmune disease. N Engl J Med 314:1360, 1986.)

As with most autoimmune diseases, the pathogenesis of type 1 diabetes involves the interplay of genetic susceptibility and environmental factors. Genome-wide association studies (Chapter 6) have identified over 20 susceptibility loci for type 1 diabetes. Of these, the principal susceptibility locus for type 1 diabetes resides in the chromosomal region that encodes the class II MHC molecules on 6p21 (HLA-D). Between 90% and 95% of white patients with type 1 diabetes have HLA-DR3, or DR4, or both, in contrast with about 40% of normal subjects, and 40% to 50% of patients are DR3/DR4 heterozygotes, in contrast with 5% of normal subjects. Of note, despite the high relative risk in persons with particular class II alleles, most people who inherit these alleles do not develop diabetes. Several non-HLA genes also confer susceptibility to type 1 diabetes, including polymorphisms within the gene encoding insulin itself, as well as CTLA4 and PTPN22. CTLA-4 is an inhibitory receptor of T cells and PTPN-22 is a protein tyrosine phosphatase; both are thought to inhibit T cell responses, so polymorphisms that interfere with their functional activity are expected to set the stage for excessive T cell activation. Polymorphisms in the insulin gene may reduce expression of this protein in the thymus, thus reducing the elimination of T cells reactive with this self protein (Chapter 4). Additional evidence suggests that environmental factors, especially infections, may be involved in type 1 diabetes. It has been proposed that certain viruses (mumps, rubella, and coxsackie B viruses, in particular) may be an initiating trigger, perhaps because some viral antigens are antigenically similar to beta cell antigens (molecular mimicry), leading to bystander damage to the islets, but this idea is not conclusively established.

Type 2 Diabetes Mellitus

Type 2 diabetes is a prototypical complex multifactorial disease. Environmental factors, such as a sedentary life style and dietary habits, unequivocally play a role, as described in the subsequent discussion of the association with obesity. Genetic factors are also involved in the pathogenesis, as evidenced by the disease concordance rate of 35% to 60% in monozygotic twins compared with nearly half that in dizygotic twins. Such concordance is even greater than in type 1 diabetes, suggesting perhaps an even larger genetic component in type 2 diabetes. Additional evidence for a genetic basis has emerged from recent large-scale genome-wide association studies, which have identified more than a dozen susceptibility loci called “diabetogenic” genes. Unlike type 1 diabetes, however, the disease is not linked to genes involved in immune tolerance and regulation (e.g., HLA, CTLA4), and evidence of an autoimmune basis is lacking. The two metabolic defects that characterize type 2 diabetes are (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and (2) beta cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia (Fig. 19–23). Insulin resistance predates the development of hyperglycemia and usually is accompanied by compensatory beta cell hyperfunction and hyperinsulinemia in the early stages of the evolution of diabetes.

Figure 19–23 Pathogenesis of type 2 diabetes mellitus. Genetic predisposition and environmental influences converge to cause insulin resistance. Compensatory beta cell hyperplasia can maintain normoglycemia, but eventually beta cell secretory dysfunction sets in, leading to impaired glucose tolerance and, ultimately, frank diabetes. Rare instances of primary beta cell failure can lead directly to type 2 diabetes without an intervening state of insulin resistance.

Insulin Resistance

Insulin resistance is defined as the failure of target tissues to respond normally to insulin. It leads to decreased uptake of glucose in muscle, reduced glycolysis and fatty acid oxidation in the liver, and an inability to suppress hepatic gluconeogenesis. A variety of functional defects have been reported in the insulin signaling pathway in states of insulin resistance (for example, reduced phosphorylation-dependent activation of the insulin receptor and its downstream components), which attenuate signal transduction. Few factors play as important a role in the development of insulin resistance as obesity.

Obesity and Insulin Resistance

The association of obesity with type 2 diabetes has been recognized for decades, with visceral obesity being common in a majority of affected patients. Insulin resistance is present even with simple obesity unaccompanied by hyperglycemia, indicating a fundamental abnormality of insulin signaling in states of fatty excess. In fact, the term metabolic syndrome has been applied to a constellation of findings dominated by visceral obesity, which is accompanied by insulin resistance, glucose intolerance, and cardiovascular risk factors such as hypertension and abnormal lipid profiles (Chapter 7). In the absence of weight loss and lifestyle modifications, persons with metabolic syndrome are at significant risk for the development of frank type 2 diabetes, underscoring the importance of obesity to the pathogenesis of this disease. The risk of diabetes increases as the body mass index (a measure of body fat content) increases, suggesting a dose-response relationship between body fat and insulin resistance. Although many details of the so-called adipo-insulin axis remain to be elucidated, recognition of some of the putative pathways leading to insulin resistance has increased substantially (Fig. 19–24):

• Role of excess free fatty acids (FFAs): Cross-sectional studies have demonstrated an inverse correlation between fasting plasma FFAs and insulin sensitivity. The level of intracellular triglycerides often is markedly increased in muscle and liver tissues in obese persons, presumably because excess circulating FFAs are deposited in these organs. Intracellular triglycerides and products of fatty acid metabolism are potent inhibitors of insulin signaling and result in an acquired insulin resistance state. These lipotoxic effects of FFAs are mediated through a decrease in activity of key insulin-signaling proteins.

• Role of inflammation: Over the past several years, inflammation has emerged as a major player in the pathogenesis of type 2 diabetes. It is now known that a permissive inflammatory milieu (mediated not by an autoimmune process as in type 1 diabetes but rather by pro-inflammatory cytokines that are secreted in response to excess nutrients such as FFAs) results in both peripheral insulin resistance and beta cell dysfunction (see later). Excess FFAs within macrophages and beta cells can engage the inflammasome, a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin IL-1β (Chapter 2). IL-1β, in turn, mediates the secretion of additional pro-inflammatory cytokines from macrophages, islets, and other cells that are released into the circulation and act on the major sites of insulin action to promote insulin resistance. Thus, excess FFAs can impede insulin signaling directly within peripheral tissues, as well as indirectly through the release of pro-inflammatory cytokines. Not surprisingly, there are now several ongoing trials of cytokine antagonists (particularly of IL-1β) in patients with type 2 diabetes.

• Role of adipokines: Adipose tissue is not merely a passive storage depot for fat; it can operate as a functional endocrine organ, releasing so-called adipokines in response to extracellular stimuli or changes in metabolic status. Thus, adipocytes also release IL-1β and other pro-inflammatory cytokines into the circulation in response to excess FFAs, which promote peripheral insulin resistance. By contrast, adiponectin is an adipokine with insulin sensitizing activity, which probably acts by dampening the inflammatory response.

• Peroxisome proliferator-activated receptor-γ (PPARγ): PPARγ is a nuclear receptor and transcription factor expressed in adipose tissue and plays a seminal role in adipocyte differentiation. A class of antidiabetic medications known as thiazolidinediones acts as agonist ligands for PPARγ and improves insulin sensitivity. Activation of PPARγ promotes secretion of antihyperglycemic adipokines such as adiponectin, and shifts the deposition of FFAs toward adipose tissue and away from liver and skeletal muscle.

Figure 19–24 Mechanisms of beta cell dysfunction and insulin resistance in type 2 diabetes. Free fatty acids directly cause beta cell dysfunction and induce insulin resistance in target tissues (such as striated muscle, shown here), and also induce the secretion of pro-inflammatory cytokines that cause more beta cell dysfunction and insulin resistance.

Beta Cell Dysfunction

Beta cell dysfunction in type 2 diabetes reflects the inability of these cells to adapt themselves to the long-term demands of peripheral insulin resistance and increased insulin secretion. In states of insulin resistance, insulin secretion initially is higher for each level of glucose than in controls. This hyperinsulinemic state is a compensation for peripheral resistance and often can maintain normal plasma glucose for years. Eventually, however, beta cell compensation becomes inadequate, and there is progression to hyperglycemia, which is accompanied by an absolute loss in beta cell mass. The molecular mechanisms underlying beta cell dysfunction in type 2 diabetes are multifactorial and in many instances overlap with those implicated in insulin resistance. Thus, excess nutrients such as FFAs and glucose can promote the secretion of pro-inflammatory cytokines from beta cells, which leads to recruitment of mononuclear cells (macrophages and T cells) into the islets, resulting in more local cytokine production. The consequences of this abnormal inflammatory microenvironment are beta cell dysfunction and, ultimately, beta cell death. Amyloid replacement of islets is a characteristic finding in persons with long-standing type 2 diabetes and is present in more than 90% of diabetic islets examined (see later). The islet amyloid polypetide (IAPP), also known as amylin, is secreted by the beta cells in conjunction with insulin, and its abnormal aggregation results in amyloid. IAPP also engages the inflammasome and promotes IL-1β secretion, thus sustaining the inflammatory onslaught on surviving beta cells even late in the disease.

Monogenic Forms of Diabetes

Type 1 and type 2 diabetes are genetically complex, and despite the associations with multiple susceptibility loci, no single-gene defect (mutation) can account for predisposition to these entities. By contrast, monogenic forms of diabetes (Table 19–5) are uncommon examples of the diabetic phenotype occurring as a result of loss-of-function mutations within a single gene. Monogenic causes of diabetes include either a primary defect in beta cell function or a defect in insulin receptor signaling. The largest subgroup of patients in this category traditionally was designated as having maturity-onset diabetes of the young (MODY) because of its superficial resemblance to type 2 diabetes and its occurrence in younger patients; MODY can be the result of inactivating mutations in one of six genes. Other uncommon causes include maternally inherited diabetes and bilateral deafness, secondary to mitochondrial DNA mutations, and mutations within the insulin gene itself, which most commonly manifests with diabetes in the neonatal period. Finally, rare instances of insulin receptor mutations that affect receptor synthesis, insulin binding, or downstream signal transduction can cause severe insulin resistance, accompanied by hyperinsulinemia and diabetes.

Complications of Diabetes

Diabetes can be a devastating disease because the abnormal glucose metabolism and other metabolic derangements have serious pathologic effects on virtually all the systems of the body. The most significant complications of diabetes are vascular abnormalities, renal damage, and lesions affecting the peripheral nerves and eyes (Fig. 19–25). The pathologic findings in these tissues and their clinical consequences are described below. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In persons with tight control of their diabetes, the onset may be delayed.

The pathogenesis of the long-term complications of diabetes is multifactorial, although persistent hyperglycemia (glucotoxicity) seems to be a key mediator. At least three distinct metabolic pathways seem to be involved in the pathogenesis of long-term complications; it is likely that all of them play a role in a tissue-specific manner.

Morphology

Diabetes and Its Late Complications

Pathologic findings in the diabetic pancreas are variable and not necessarily dramatic. The important morphologic changes are related to the many late systemic complications of diabetes. In most patients, morphologic changes are likely to be found in arteries (macrovascular disease), basement membranes of small vessels (microangiopathy), kidneys (diabetic nephropathy), retina (retinopathy), nerves (neuropathy), and other tissues. These changes are seen in both type 1 and type 2 diabetes (Fig. 19–25).

Figure 19–25 Long-term complications of diabetes.

Pancreas

Lesions in the pancreas are inconstant and rarely of diagnostic value. One or more of the following alterations may be present:

• Reduction in the number and size of islets. This change most often is seen in type 1 diabetes, particularly with rapidly advancing disease. Most of the islets are small, inconspicuous, and not easily detected.

• Leukocytic infiltration of the islets, which are principally composed of mononuclear cells (lymphocytes and macrophages) (Fig. 19–26, A). Of note, both type 1 and type 2 diabetes may demonstrate islet inflammation early in the disease, although it is typically more severe in T1D. In both types inflammation is often absent by the time the disease is clinically evident.

• Amyloid replacement of islets in long-standing type 2 diabetes, appearing as deposition of pink, amorphous material beginning in and around capillaries and between cells. At advanced stages the islets may be virtually obliterated (Fig. 19–26, B); fibrosis also may be observed. While inflammation is observed early in the natural history of type 2 diabetes, amyloid deposition occurs in long-standing cases.

• An increase in the number and size of islets, especially characteristic of nondiabetic newborns of diabetic mothers. Presumably, fetal islets undergo hyperplasia in response to the maternal hyperglycemia.

Figure 19–26 A, Autoimmune insulitis in a rat (BB) model of autoimmune diabetes. This disorder also is seen in type 1 human diabetes. B, Amyloidosis of a pancreatic islet in type 2 diabetes. Amyloidosis typically is observed late in the natural history of this form of diabetes, with islet inflammation noted at earlier observations.

(A, Courtesy of Dr. Arthur Like, University of Massachusetts, Worcester, Massachusetts.)

Diabetic Macrovascular Disease

Diabetes exacts a heavy toll on the vascular system. The hallmark of diabetic macrovascular disease is accelerated atherosclerosis affecting the aorta and large and medium-sized arteries. Except for its greater severity and earlier age at onset, atherosclerosis in diabetics is indistinguishable from that in nondiabetics (Chapter 9). Myocardial infarction, caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics. Significantly, it is almost as common in diabetic women as in diabetic men. By contrast, myocardial infarction is uncommon in nondiabetic women of reproductive age. Gangrene of the lower extremities, as a result of advanced vascular disease, is about 100 times more common in persons with diabetes than in the general population. The larger renal arteries also are subject to severe atherosclerosis, but the most damaging effect of diabetes on the kidneys is exerted at the level of the glomeruli and the microcirculation, as discussed later on.

Hyaline arteriolosclerosis, the vascular lesion associated with hypertension (Chapters 9 and 13), is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly persons who do not suffer from either diabetes or hypertension. It takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen (Fig. 19–27). Not surprisingly, in diabetic patients, its severity is related not only to the duration of the disease but also to the presence or absence of hypertension.

Figure 19–27 Severe renal hyaline arteriolosclerosis in a periodic acid–Schiff stained specimen. Note the markedly thickened, tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is evident.

(Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Science Center, San Antonio, Texas.)

Diabetic Microangiopathy

One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla. However, it also may be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves, and placenta. By both light and electron microscopy, the basal lamina separating parenchymal or endothelial cells from the surrounding tissue is markedly thickened by concentric layers of hyaline material composed predominantly of type IV collagen (Fig. 19–28). Of note, despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy, retinopathy, and some forms of neuropathy. An indistinguishable microangiopathy can be found in aged nondiabetic patients, but rarely to the extent seen in persons with long-standing diabetes.

Figure 19–28 Renal cortex showing thickening of tubular basement membranes in a specimen from a diabetic patient. Periodic acid–Schiff stain.

Diabetic Nephropathy

The kidneys are prime targets of diabetes (see also Chapter 13). Renal failure is second only to myocardial infarction as a cause of death from this disease. Three lesions are encountered: (1) glomerular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3) pyelonephritis, including necrotizing papillitis.

The most important glomerular lesions are capillary basement membrane thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis. The glomerular capillary basement membranes are thickened along their entire length. This change can be detected by electron microscopy within a few years of the onset of diabetes, sometimes without any associated change in renal function (Fig. 19–29).

Figure 19–29 Renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space.

(Courtesy of Dr. Michael Kashgarian, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.)

Diffuse mesangial sclerosis consists of a diffuse increase in mesangial matrix along with mesangial cell proliferation and is always associated with basement membrane thickening. It is found in most individuals with disease of more than 10 years’ duration. When glomerulosclerosis becomes marked, patients manifest the nephrotic syndrome, characterized by proteinuria, hypoalbuminemia, and edema (Chapter 13).

Nodular glomerulosclerosis describes a glomerular lesion made distinctive by ball-like deposits of a laminated matrix situated in the periphery of the glomerulus (Fig. 19–30). These nodules are PAS-positive and usually contain trapped mesangial cells. This distinctive change has been called the Kimmelstiel-Wilson lesion, after the two pathologists who first described it. Nodular glomerulosclerosis is encountered in approximately 15% to 30% of persons with long-term diabetes and is a major contributor to morbidity and mortality. Diffuse mesangial sclerosis also may be seen in association with old age and hypertension; by contrast, the nodular form of glomerulosclerosis, once certain unusual forms of nephropathies have been excluded (Chapter 13), is essentially pathognomonic of diabetes. Both the diffuse and the nodular forms of glomerulosclerosis induce sufficient ischemia to cause scarring of the kidneys, manifested by a finely granular-appearing cortical surface (Fig. 19–31).

Figure 19–30 Nodular glomerulosclerosis in a renal specimen from a patient with long-standing diabetes.

(Courtesy of Dr. Lisa Yerian, Department of Pathology, University of Chicago, Chicago, Illinois.)

Figure 19–31 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface (left) and marked thinning of the cortical tissue (right). Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst (far right).

Renal atherosclerosis and arteriolosclerosis constitute part of the macrovascular disease seen in diabetics. The kidney is one of the most frequently and severely affected organs; however, the changes in the arteries and arterioles are similar to those found throughout the body. Hyaline arteriolosclerosis affects not only the afferent but also the efferent arterioles. Such efferent arteriolosclerosis is rarely if ever encountered in persons who do not have diabetes.

Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to involve the tubules. Both the acute and chronic forms of this disease occur in nondiabetics as well as in diabetics but are more common in persons with diabetes than in the general population; once affected, diabetics tend to have more severe involvement. One special pattern of acute pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics.

Ocular Complications of Diabetes

Visual impairment, sometimes even total blindness, is one of the more feared consequences of long-standing diabetes. The ocular involvement may take the form of retinopathy, cataract formation, or glaucoma. Retinopathy, the most common pattern, consists of a constellation of changes that together are considered by many ophthalmologists to be virtually diagnostic of the disease. The lesion in the retina takes two forms: nonproliferative (background) retinopathy and proliferative retinopathy.

Nonproliferative retinopathy includes intraretinal or preretinal hemorrhages, retinal exudates, microaneurysms, venous dilations, edema, and, most importantly, thickening of the retinal capillaries (microangiopathy). The retinal exudates can be either “soft” (microinfarcts) or “hard” (deposits of plasma proteins and lipids) (Fig. 19–32). The microaneurysms are discrete saccular dilations of retinal choroidal capillaries that appear through the ophthalmoscope as small red dots. Dilations tend to occur at focal points of weakening, resulting from loss of pericytes. Retinal edema presumably results from excessive capillary permeability. Underlying all of these changes is the microangiopathy, which is thought to lead to loss of capillary pericytes and hence to focal weakening of capillary structure.

Figure 19–32 Characteristic morphologic changes of diabetic retinopathy. Features include advanced proliferative retinopathy with retinal hemorrhages, exudates, neovascularization, and tractional retinal detachment (lower right corner).

(Courtesy of Dr. Rajendra Apte, Washington University School of Medicine, St. Louis, Missouri.)

The so-called proliferative retinopathy is a process of neovascularization and fibrosis. This lesion leads to serious consequences, including blindness, especially if it involves the macula. Vitreous hemorrhages can result from rupture of newly formed capillaries; the subsequent organization of the hemorrhage can pull the retina off its substratum (retinal detachment).

Diabetic Neuropathy

The central and peripheral nervous systems are not spared by diabetes. The most frequent pattern of involvement is that of a peripheral, symmetric neuropathy of the lower extremities affecting both motor and sensory function, particularly the latter. Other forms include autonomic neuropathy, which produces disturbances in bowel and bladder function and sometimes sexual impotence, and diabetic mononeuropathy, which may manifest as sudden footdrop or wristdrop or isolated cranial nerve palsies. The neurologic changes may be the result of microangiopathy and increased permeability of the capillaries that supply the nerves, as well as direct axonal damage.

Clinical Features

It is difficult to discuss with brevity the diverse clinical presentations of diabetes mellitus. Only a few characteristic patterns are presented here. In the initial 1 or 2 years after manifestation of overt type 1 diabetes (referred to as the “honeymoon period”), exogenous insulin requirements may be minimal to none because of residual ongoing endogenous insulin secretion, but thereafter the beta cell reserve is exhausted and insulin requirements increase dramatically. Although beta cell destruction is a gradual process, the transition from impaired glucose tolerance to overt diabetes may be abrupt, heralded by an event associated with increased insulin requirements such as infection. The onset is marked by polyuria, polydipsia, polyphagia, and in severe cases, ketoacidosis, all resulting from metabolic derangements (Fig. 19–33).

Figure 19–33 Sequence of metabolic derangements leading to diabetic coma in type 1 diabetes mellitus. An absolute insulin deficiency leads to a catabolic state, eventuating in ketoacidosis and severe volume depletion. These derangements bring about sufficient central nervous system compromise to cause coma and, eventually, death if left untreated.

Since insulin is a major anabolic hormone in the body, deficiency of insulin results in a catabolic state that affects not only glucose metabolism but also fat and protein metabolism. The assimilation of glucose into muscle and adipose tissue is sharply diminished or abolished. Not only does storage of glycogen in liver and muscle cease, but also reserves are depleted by glycogenolysis. The resultant hyperglycemia exceeds the renal threshold for reabsorption, and glycosuria ensues. The glycosuria induces an osmotic diuresis and, consequently, polyuria, causing a profound loss of water and electrolytes. The obligatory renal water loss combined with the hyperosmolarity resulting from the increased levels of glucose in the blood tends to deplete intracellular water, triggering the osmoreceptors of the thirst centers of the brain. This sequence of events generates intense thirst (polydipsia). With a deficiency of insulin, the scales swing from insulin-promoted anabolism to catabolism of proteins and fats. Proteolysis follows, and the gluconeogenic amino acids are removed by the liver and used as building blocks for glucose. The catabolism of proteins and fats tends to induce a negative energy balance, which in turn leads to increasing appetite (polyphagia), thus completing the classic triad of diabetes: polyuria, polydipsia, and polyphagia. Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle weakness. The combination of polyphagia and weight loss is paradoxical and should always point to the diagnostic possibility of diabetes.

In patients with type 1 diabetes, deviations from normal dietary intake, unusual physical activity, infection, or any other forms of stress may rapidly influence the treacherously fragile metabolic balance, predisposing the affected person to diabetic ketoacidosis. The plasma glucose usually is in the range of 500 to 700 mg/dL as a result of absolute insulin deficiency and unopposed effects of counterregulatory hormones (epinephrine, glucagon). The marked hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. The second major effect is activation of the ketogenic machinery. Insulin deficiency leads to activation of lipoprotein lipase, with resultant excessive breakdown of adipose stores, giving rise to increased FFAs, which are oxidized by the liver to produce ketones. Ketogenesis is an adaptive phenomenon in times of starvation, generating ketones as a source of energy for consumption by vital organs (e.g., brain). The rate at which ketones are formed may exceed the rate at which they can be used by peripheral tissues, leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by dehydration, the accumulating ketones decrease blood pH, resulting in metabolic ketoacidosis.

Type 2 diabetes mellitus also may manifest with polyuria and polydipsia, but unlike in type 1 diabetes, patients often are older than 40 years and frequently are obese. Unfortunately, with the increase in obesity and sedentary life style in Western society, type 2 diabetes is now seen in children and adolescents with increasing frequency. In some cases, medical attention is sought because of unexplained weakness or weight loss. Most frequently, however, the diagnosis is made after routine blood or urine testing in asymptomatic persons.

In the decompensated state, patients with type 2 diabetes may develop hyperosmolar nonketotic coma. This syndrome is engendered by severe dehydration resulting from sustained osmotic diuresis and urinary fluid loss due to chronic hyperglycemia. Typically, the affected person is an elderly diabetic who is disabled by a stroke or an infection and is unable to maintain adequate water intake. The absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays recognition of the seriousness of the situation until the onset of severe dehydration and coma. Table 19–6 summarizes some of the pertinent clinical, genetic, and histopathologic features that distinguish between type 1 and type 2 diabetes.

Table 19–6 Type 1 Versus Type 2 Diabetes Mellitus

Type 1 Diabetes Mellitus	Type 2 Diabetes Mellitus
Clinical
Onset usually in childhood and adolescence	Onset usually in adulthood; increasing incidence in childhood and adolescence
Normal weight or weight loss preceding diagnosis	Vast majority of patients are obese (80%)
Progressive decrease in insulin levels	Increased blood insulin (early); normal or moderate decrease in insulin (late)
Circulating islet autoantibodies	No islet autoantibodies
Diabetic ketoacidosis in absence of insulin therapy	Nonketotic hyperosmolar coma
Genetics
Major linkage to MHC class I and II genes; also linked to polymorphisms in CTLA4 and PTPN22	No HLA linkage; linkage to candidate diabetogenic and obesity-related genes
Pathogenesis
Dysfunction in regulatory T cells (Tregs) leading to breakdown in self-tolerance to islet autoantigens	Insulin resistance in peripheral tissues, failure of compensation by beta cells
	Multiple obesity-associated factors (circulating nonesterified fatty acids, inflammatory mediators, adipocytokines) linked to pathogenesis of insulin resistance
Pathology
Autoimmune “insulitis”	Early: inflammation; late: amyloid deposition in islets
Beta cell depletion, islet atrophy	Mild beta cell depletion

HLA, human leukocyte antigen; MHC, major histocompatibility complex.

As previously discussed, it is the long-term effects of diabetes, more than the acute metabolic complications, which are responsible for the overwhelming preponderance of morbidity and mortality attributable to this disease. In most instances, these complications appear approximately 15 to 20 years after the onset of hyperglycemia.

• In both forms of long-standing diabetes, cardiovascular events such as myocardial infarction, renal vascular insufficiency, and stroke (cerebrovascular accident) are the most common contributors to mortality. The impact of cardiovascular disease can be gauged by its involvement in as many as 80% of deaths among persons with type 2 diabetes; in fact, diabetics have a 3 to 7.5 times greater incidence of death from cardiovascular causes than nondiabetic populations. The hallmark of cardiovascular disease is accelerated atherosclerosis of the large and medium-sized arteries (i.e., macrovascular disease). The importance of obesity in the pathogenesis of insulin resistance has already been discussed, but it also is an independent risk factor for development of atherosclerosis.

• Diabetic nephropathy is a leading cause of end-stage renal disease in the United States. The earliest manifestation of diabetic nephropathy is the appearance of small amounts of albumin in the urine (greater than 30 but less than 300 mg/day—i.e., microalbuminuria). Without specific interventions, approximately 80% of patients with type 1 diabetes and 20% to 40% of those with type 2 diabetes will develop overt nephropathy with macroalbuminuria (excretion of more than 300 mg/day) over the succeeding 10 to 15 years, usually accompanied by the appearance of hypertension. The progression from overt nephropathy to end-stage renal disease can be highly variable and is evidenced by a progressive drop in glomerular filtration rate. By 20 years after diagnosis, more than 75% of persons with type 1 diabetes and about 20% of those with type 2 diabetes with overt nephropathy will develop end-stage renal disease, necessitating dialysis or renal transplantation.

• Visual impairment, sometimes even total blindness, is one of the more feared consequences of long-standing diabetes. This disease currently is the fourth leading cause of acquired blindness in the United States. Approximately 60% to 80% of patients develop some form of diabetic retinopathy approximately 15 to 20 years after diagnosis. In addition to retinopathy, diabetic patients also have an increased propensity for glaucoma and cataract formation, both of which contribute to visual impairment in diabetes.

• Diabetic neuropathy can elicit a variety of clinical syndromes, afflicting the central nervous system, peripheral sensorimotor nerves, and autonomic nervous system. The most frequent pattern of involvement is a distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function, particularly the latter (Chapter 21). Over time, the upper extremities may be involved as well, thus approximating a “glove and stocking” pattern of polyneuropathy. Other forms include autonomic neuropathy, which produces disturbances in bowel and bladder function and sometimes sexual impotence, and diabetic mononeuropathy, which may manifest as sudden footdrop, wristdrop, or isolated cranial nerve palsies.

• Diabetic patients are plagued by an enhanced susceptibility to infections of the skin, as well as to tuberculosis, pneumonia, and pyelonephritis. Such infections cause about 5% of diabetes-related deaths. In a person with diabetic neuropathy, a trivial infection in a toe may be the first event in a long succession of complications (gangrene, bacteremia, pneumonia) that may ultimately lead to death.

Several large-scale prospective studies have convincingly demonstrated that the long-term complications, and the associated morbidity and mortality, from diabetes are attenuated by strict glycemic control. For patients with type 1 diabetes, insulin replacement therapy is the mainstay of treatment, while non-pharmacologic approaches such as dietary restrictions and exercise (which improves insulin sensitivity) are often the “first line of defense” for type 2 diabetes. Most patients with type 2 diabetes will eventually require therapeutic intervention to reduce hyperglycemia, which can be achieved by administration of a number of agents that lower glucose levels through several distinct mechanisms of action. Glycemic control is assessed clinically by measuring the percentage of glycosylated hemoglobin, also known as HbA1C, which is formed by non-enzymatic addition of glucose moieties to hemoglobin in red cells. Unlike blood glucose levels, HbA1C is a measure of glycemic control over long periods of time (2 to 3 months) and is relatively unaffected by day-to-day variations. An HbA1C below 7% is taken as evidence of tight glycemic control, but patients with HbA1C levels in this range also have an increased risk of potentially life-threatening episodes of therapy-related hypoglycemia, and “optimal” control of glucose levels in diabetic patients remains an unsettled area of clinical investigation.

Summary

Diabetes Mellitus: Pathogenesis and Long-Term Complications

• Type 1 diabetes is an autoimmune disease characterized by progressive destruction of islet beta cells, leading to absolute insulin deficiency. Both autoreactive T cells and autoantibodies are involved.

• Type 2 diabetes is caused by insulin resistance and beta cell dysfunction, resulting in relative insulin deficiency. Autoimmunity is not involved.

• Obesity has an important relationship with insulin resistance (and hence type 2 diabetes), probably mediated by cytokines released from adipose tissues (adipocytokines). Other players in the adipo-insulin axis include FFAs (which may cause lipotoxicity) and the PPARγ receptor, which modulates adipocytokine levels.

• Monogenic forms of diabetes are uncommon and are caused by single-gene defects that result in primary beta cell dysfunction (e.g., glucokinase mutation) or lead to abnormalities of insulin–insulin receptor signaling (e.g., insulin receptor gene mutations).

• The long-term complications of diabetes are similar in both types and affect mainly blood vessels, and the kidneys, nerves and eyes. The development of these complications is attributed to three underlying mechanisms: formation of AGEs, activation of PKC, and disturbances in polyol pathways leading to oxidative stress.

Insulinomas

Beta cell tumors (insulinomas) are the most common type of PanNET and may be responsible for the elaboration of sufficient insulin to induce clinically significant hypoglycemia. The characteristic clinical picture is dominated by attacks of hypoglycemia, which occur when plasma blood glucose levels fall below 50 mg/dL. The attacks consist principally of such central nervous system manifestations as confusion, stupor, and loss of consciousness. They are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose. Most insulinomas are cured by surgical resection.

Morphology

Insulinomas exhibit favorable biologic behavior, possibly because the vast majority are identified while they are small (less than 2 cm in diameter) and localized to the pancreas. Most are solitary lesions, although multifocal tumors or tumors ectopic to the pancreas may be encountered. Malignancy in insulinomas, constituting less than 10% of cases, is diagnosed on the basis of local invasion or metastases. On histologic examination, these benign tumors look remarkably like giant islets, with preservation of the regular cords of monotonous cells and their orientation to the vasculature. Not even malignant lesions present much evidence of anaplasia, and they may be deceptively encapsulated. Deposition of amyloid in the extracellular tissue is a characteristic feature of many insulinomas (Fig. 19–34, A). Under the electron microscope, neoplastic beta cells, like their normal counterparts, display distinctive round granules (Fig. 19–34, B).

Figure 19–34 Pancreatic neuroendocrine tumor (PanNET), also called islet cell tumor. A, The neoplastic cells are monotonous in appearance and demonstrate minimal pleomorphism or mitotic activity. There is abundant amyloid deposition, characteristic of an insulinoma. On clinical evaluation, the patient had episodic hypoglycemia. B, Electron micrograph of a normal beta cell shows the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. Insulinomas contain comparable granules.

Gastrinomas

Marked hypersecretion of gastrin usually has its origin in gastrin-producing tumors (gastrinomas), which are just as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas (the so-called gastrinoma triangle). Zollinger and Ellison first called attention to the association of pancreatic islet cell lesions with hypersecretion of gastric acid and severe peptic ulceration, which are present in 90% to 95% of patients with gastrinomas—the clinical hallmark of Zollinger-Ellison syndrome. In this condition, hypergastrinemia from a pancreatic or duodenal tumor stimulates extreme gastric acid secretion, which in turn causes peptic ulceration. The duodenal and gastric ulcers often are multiple; although they are identical to those found in the general population, they often are unresponsive to usual therapy. In addition, ulcers may occur in unusual locations such as the jejunum; when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered. More than half of the affected patients have diarrhea; in 30%, it is the presenting manifestation.

Hypercortisolism and Cushing Syndrome

Hypercortisolism, typically manifested as Cushing syndrome, is caused by any condition that produces an elevation in glucocorticoid levels. In clinical practice, the vast majority of cases of Cushing syndrome are the result of administration of exogenous glucocorticoids (iatrogenic). The remaining cases are endogenous, and the three most common etiologic disorders are (Fig. 19–35):

Figure 19–35 Schematic representation of the various forms of Cushing syndrome: The three endogenous forms, as well as the more common exogenous (iatrogenic) form. ACTH, adrenocorticotropic hormone.

Primary hypothalamic-pituitary disease associated with hypersecretion of ACTH, also known as Cushing disease, accounts for approximately 70% of cases of spontaneous, endogenous Cushing syndrome. The prevalence of this disorder is about four times higher among women than among men, and it occurs most frequently during young adulthood (the 20s and 30s). In the vast majority of cases, the pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain; some corticotroph tumors qualify as macroadenomas (larger than 10 mm across). In the remaining patients, the anterior pituitary contains areas of corticotroph cell hyperplasia without a discrete adenoma. Corticotroph cell hyperplasia may be primary or, much less commonly, secondary to excessive ACTH release by a hypothalamic corticotropin-releasing hormone (CRH)–producing tumor. The adrenal glands in patients with Cushing disease are characterized by a variable degree of bilateral nodular cortical hyperplasia (discussed later), secondary to the elevated levels of ACTH (“ACTH-dependent” Cushing syndrome). The cortical hyperplasia is in turn responsible for the hypercortisolism.

Secretion of ectopic ACTH by nonpituitary tumors accounts for about 10% of cases of Cushing syndrome. In many instances the responsible tumor is a small cell carcinoma of the lung, although other neoplasms, including carcinoids, medullary carcinomas of the thyroid, and PanNETs, have been associated with the syndrome. In addition to tumors that elaborate ectopic ACTH, an occasional neuroendocrine neoplasm produces ectopic CRH, which in turn causes ACTH secretion and hypercortisolism. As in the pituitary variant, the adrenal glands undergo bilateral cortical hyperplasia secondary to elevated ACTH, but the rapid downhill course of patients with these cancers often cuts short the adrenal enlargement.

Primary adrenal neoplasms, such as adrenal adenoma and carcinoma, and rarely, primary cortical hyperplasia, are responsible for about 15% to 20% of cases of endogenous Cushing syndrome. This form of Cushing syndrome is also designated ACTH-independent Cushing syndrome, or adrenal Cushing syndrome, because the adrenals function autonomously. The biochemical hallmark of adrenal Cushing syndrome is elevated levels of cortisol with low serum levels of ACTH. In most cases, adrenal Cushing syndrome is caused by a unilateral adrenocortical neoplasm, which may be either benign (adenoma) or malignant (carcinoma). The overwhelming majority of hyperplastic adrenals are ACTH-dependent, and primary cortical hyperplasia of the adrenal cortices is a rare cause of Cushing syndrome. There are two variants of this entity; the first presents as macronodules of varying sizes (3 cm or greater in diameter) and the second as micronodules (1 to 3 mm).

Morphology

The main lesions of Cushing syndrome are found in the pituitary and adrenal glands. The pituitary in Cushing syndrome shows changes that vary with different causes. The most common alteration, resulting from high levels of endogenous or exogenous glucocorticoids, is termed Crooke hyaline change. In this condition, the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary is replaced by homogeneous, lightly basophilic material. This alteration is the result of the accumulation of intermediate keratin filaments in the cytoplasm.

Morphologic changes in the adrenal glands also depend on the cause of the hypercortisolism and include: (1) cortical atrophy, (2) diffuse hyperplasia, (3) macronodular or micronodular hyperplasia, or (4) an adenoma or a carcinoma.

In patients in whom the syndrome results from exogenous glucocorticoids, suppression of endogenous ACTH results in bilateral cortical atrophy, due to a lack of stimulation of the zona fasciculata and zona reticularis by ACTH. The zona glomerulosa is of normal thickness in such cases, because this portion of the cortex functions independently of ACTH. In cases of endogenous hypercortisolism, by contrast, the adrenals either are hyperplastic or contain a cortical neoplasm. Diffuse hyperplasia is found in patients with ACTH-dependent Cushing syndrome (Fig. 19–36). Both glands are enlarged, either subtly or markedly, each weighing up to 30 g. The adrenal cortex is diffusely thickened and variably nodular, although the latter is not as pronounced as in cases of ACTH-independent nodular hyperplasia. The yellow color of diffusely hyperplastic glands derives from presence of lipid-rich cells, which appear vacuolated under the microscope. In primary cortical hyperplasia, the cortex is replaced almost entirely by macro- or micronodules, with the latter composed of 1- to 3-mm darkly pigmented nodules. The pigment is believed to be lipofuscin, a wear-and-tear pigment (Chapter 1).

Figure 19–36 Diffuse hyperplasia of the adrenal (bottom) contrasted with normal adrenal gland (top). In cross-section, the adrenal cortex is yellow and thickened, and a subtle nodularity is evident. The abnormal gland was from a patient with ACTH-dependent Cushing syndrome, in whom both adrenals were diffusely hyperplastic. ACTH, adrenocorticotropic hormone.

Functional adenomas or carcinomas of the adrenal cortex as the source of cortisol are not morphologically distinct from nonfunctioning adrenal neoplasms (described later). Both the benign and the malignant lesions are more common in women in their 30s to 50s. Adrenocortical adenomas are yellow tumors surrounded by thin or well-developed capsules, and most weigh less than 30 g (Fig. 19–37, A). On microscopic examination, they are composed of cells similar to those encountered in the normal zona fasciculata (Fig. 19–37, B). The carcinomas associated with Cushing syndrome, by contrast, tend to be larger than the adenomas. These tumors are nonencapsulated masses frequently exceeding 200 to 300 g in weight, having all of the anaplastic characteristics of cancer, as detailed later on. With functioning tumors, both benign and malignant, the adjacent adrenal cortex and that of the contralateral adrenal gland are atrophic, as a result of suppression of endogenous ACTH by high cortisol levels.

Figure 19–37 Adrenocortical adenoma. A, The adenoma is distinguished from nodular hyperplasia by its solitary, circumscribed nature. The functional status of an adrenocortical adenoma cannot be predicted from its gross or microscopic appearance. B, Histologic features of an adrenal cortical adenoma. The neoplastic cells are vacuolated because of the presence of intracytoplasmic lipid. There is mild nuclear pleomorphism. Mitotic activity and necrosis are not seen.

Clinical Features

The signs and symptoms of Cushing syndrome represent an exaggeration of the known actions of glucocorticoids. Cushing syndrome usually develops gradually and, like many other endocrine abnormalities, may be quite subtle in its early stages. A major exception to this insidious onset is with Cushing syndrome associated with small cell carcinomas of the lung, when the rapid course of the underlying disease precludes development of many of the characteristic features. Early manifestations of Cushing syndrome include hypertension and weight gain. With time, the more characteristic centripetal distribution of adipose tissue becomes apparent, with resultant truncal obesity, “moon facies,” and accumulation of fat in the posterior neck and back (“buffalo hump”) (Fig. 19–38). Hypercortisolism causes selective atrophy of fast-twitch (type II) myofibers, with resultant decreased muscle mass and proximal limb weakness. Glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells, with resultant hyperglycemia, glucosuria, and polydipsia, mimicking diabetes mellitus. The catabolic effects on proteins cause loss of collagen and resorption of bone. Thus, the skin is thin, fragile, and easily bruised; cutaneous striae are particularly common in the abdominal area. Bone resorption results in the development of osteoporosis, with consequent increased susceptibility to fractures. Because glucocorticoids suppress the immune response, patients with Cushing syndrome also are at increased risk for a variety of infections. Additional manifestations include hirsutism and menstrual abnormalities, as well as a number of mental disturbances, including mood swings, depression, and frank psychosis. Extraadrenal Cushing syndrome caused by pituitary or ectopic ACTH secretion usually is associated with increased skin pigmentation secondary to melanocyte-stimulating activity in the ACTH precursor molecule.

Figure 19–38 A patient with Cushing syndrome. Characteristic features include central obesity, “moon facies,” and abdominal striae.

(Reproduced with permission from Lloyd RV, et al: Atlas of Nontumor Pathology: Endocrine Diseases. Washington, DC, American Registry of Pathology, 2002.)

Summary

Hypercortisolism (Cushing Syndrome)

• The most common cause of hypercortisolism is exogenous administration of steroids.

• Endogenous hypercortisolism most often is secondary to an ACTH-producing pituitary microadenoma (Cushing disease), followed by primary adrenal neoplasms (ACTH-independent hypercortisolism) and paraneoplastic ACTH production by tumors (e.g., small cell lung cancer).

• The morphologic features in the adrenal include bilateral cortical atrophy (in exogenous steroid-induced disease), bilateral diffuse or nodular hyperplasia (most common finding in endogenous Cushing syndrome), or an adrenocortical neoplasm.

Hyperaldosteronism

Hyperaldosteronism is the generic term for a group of closely related conditions characterized by chronic excess aldosterone secretion. Hyperaldosteronism may be primary, or it may be secondary to an extraadrenal cause. In secondary hyperaldosteronism, aldosterone release occurs in response to activation of the renin-angiotensin system. This condition is characterized by increased levels of plasma renin and is encountered in association with

Primary hyperaldosteronism, by contrast, indicates a primary, autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity. The potential causes of primary hyperaldosteronism are:

Adrenogenital Syndromes

Excess of androgens may be caused by a number of diseases, including primary gonadal disorders and several primary adrenal disorders. The adrenal cortex secretes two compounds—dehydroepiandrosterone and androstenedione—which require conversion to testosterone in peripheral tissues for their androgenic effects. Unlike gonadal androgens, adrenal androgen formation is regulated by ACTH; thus, excessive secretion can present as an isolated syndrome or in combination with features of Cushing disease. The adrenal causes of androgen excess include adrenocortical neoplasms and an uncommon group of disorders collectively designated congenital adrenal hyperplasia (CAH). Adrenocortical neoplasms associated with symptoms of androgen excess (virilization) are more likely to be carcinomas than adenomas. They are morphologically identical to other functional or nonfunctional cortical neoplasms.

CAH represents a group of autosomal recessive disorders, each characterized by a hereditary defect in an enzyme involved in adrenal steroid biosynthesis, particularly cortisol. In these conditions, decreased cortisol production results in a compensatory increase in ACTH secretion due to absence of feedback inhibition. The resultant adrenal hyperplasia causes increased production of cortisol precursor steroids, which are then channeled into synthesis of androgens with virilizing activity. Certain enzyme defects also may impair aldosterone secretion, adding salt loss to the virilizing syndrome. The most common enzymatic defect in CAH is 21-hydroxylase deficiency, which accounts for more than 90% of cases. 21-Hydroxylase deficiency may range in degree from a total lack to a mild loss, depending on the nature of the underlying mutation involving the CYP21A2 gene, which encodes this enzyme.

Acute Adrenocortical Insufficiency

Acute adrenocortical insufficiency occurs most commonly in the clinical settings listed in Table 19–7. Persons with chronic adrenocortical insufficiency may develop an acute crisis after any stress that taxes their limited physiologic reserves. In patients maintained on exogenous corticosteroids, rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress may precipitate a similar adrenal crisis, because of the inability of the atrophic adrenals to produce glucocorticoid hormones. Massive adrenal hemorrhage may destroy enough of the adrenal cortex to cause acute adrenocortical insufficiency. This condition may occur in patients maintained on anticoagulant therapy, in postoperative patients who develop disseminated intravascular coagulation, during pregnancy, and in patients suffering from overwhelming sepsis; in this last setting it is known as the Waterhouse-Friderichsen syndrome (Fig. 19–39). This catastrophic syndrome is classically associated with Neisseria meningitidis septicemia but can also be caused by other organisms, including Pseudomonas spp., pneumococci, and Haemophilus influenzae. The pathogenesis of the Waterhouse-Friderichsen syndrome remains unclear but probably involves endotoxin-induced vascular injury with associated disseminated intravascular coagulation (Chapter 3).

Table 19–7 Causes of Adrenal Insufficiency

APS1, APS2, autoimmune polyendocrine syndrome types 1 and 2.

Figure 19–39 Waterhouse-Friderichsen syndrome. Bilateral adrenal hemorrhage in an infant with overwhelming sepsis, resulting in acute adrenal insufficiency. At autopsy, the adrenals were grossly hemorrhagic and shrunken; in this photomicrograph, little residual cortical architecture is discernible.

Chronic Adrenocortical Insufficiency: Addison Disease

Addison disease, or chronic adrenocortical insufficiency, is an uncommon disorder resulting from progressive destruction of the adrenal cortex. More than 90% of all cases are attributable to one of four disorders: autoimmune adrenalitis, tuberculosis, the acquired immune deficiency syndrome (AIDS), or metastatic cancer (Table 19–7).

Secondary Adrenocortical Insufficiency

Any disorder of the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or irradiation, that reduces the output of ACTH leads to a syndrome of hypoadrenalism having many similarities to Addison disease. With secondary disease, the hyperpigmentation of primary Addison disease is lacking because melanotropic hormone levels are low (discussed later). ACTH deficiency may occur alone, but in some instances, it is only one part of panhypopituitarism, associated with multiple tropic hormone deficiencies. In patients with primary disease, serum ACTH levels may be normal, but the destruction of the adrenal cortex does not permit a response to exogenously administered ACTH in the form of increased plasma levels of cortisol. By contrast, secondary adrenocortical insufficiency is characterized by low serum ACTH and a prompt rise in plasma cortisol levels in response to ACTH administration.

Morphology

The appearance of the adrenal glands varies with the cause of the adrenocortical insufficiency. In secondary hypoadrenalism the adrenals are reduced to small, flattened structures that usually retain their yellow color because of a small amount of residual lipid. A uniform, thin rim of atrophic yellow cortex surrounds a central, intact medulla. Histologic evaluation reveals atrophy of cortical cells with loss of cytoplasmic lipid, particularly in the zona fasciculata and zona reticularis. Primary autoimmune adrenalitis is characterized by irregularly shrunken glands, which may be exceedingly difficult to identify within the suprarenal adipose tissue. On histologic examination, the cortex contains only scattered residual cortical cells in a collapsed network of connective tissue. A variable lymphoid infiltrate is present in the cortex and may extend into the subjacent medulla (Fig. 19–40). The medulla is otherwise preserved. In tuberculosis or fungal diseases, the adrenal architecture may be effaced by a granulomatous inflammatory reaction identical to that encountered in other sites of infection. When hypoadrenalism is caused by metastatic carcinoma, the adrenals are enlarged, and their normal architecture is obscured by the infiltrating neoplasm.

Figure 19–40 Autoimmune adrenalitis. In addition to loss of all but a subcapsular rim of cortical cells, there is an extensive mononuclear cell infiltrate.

Pheochromocytoma

Pheochromocytomas are neoplasms composed of chromaffin cells, which, like their non-neoplastic counterparts, synthesize and release catecholamines and, in some cases, other peptide hormones. These tumors are of special importance because although uncommon, they (like aldosterone-secreting adenomas) give rise to a surgically correctable form of hypertension.

Pheochromocytomas usually subscribe to a convenient “rule of 10s”:

Morphology

Pheochromocytomas range in size from small, circumscribed lesions confined to the adrenal to large, hemorrhagic masses weighing several kilograms. On cut surface, smaller pheochromocytomas are yellow-tan, well-defined lesions that compress the adjacent adrenal (Fig. 19–43). Larger lesions tend to be hemorrhagic, necrotic, and cystic and typically efface the adrenal gland. Incubation of the fresh tissue with potassium dichromate solutions turns the tumor dark brown, as noted previously.

Figure 19–43 Pheochromocytoma. The tumor is enclosed within an attenuated cortex and demonstrates areas of hemorrhage. The comma-shaped residual adrenal is seen below.

On microscopic examination, pheochromocytomas are composed of polygonal to spindle-shaped chromaffin cells and their supporting cells, compartmentalized into small nests, or Zellballen, by a rich vascular network (Fig. 19–44). The cytoplasm of the neoplastic cells often has a finely granular appearance, highlighted by a variety of silver stains, because of the presence of granules containing catecholamines. Electron microscopy reveals variable numbers of membrane-bound, electron-dense granules, representing catecholamines and sometimes other peptides. The nuclei of the neoplastic cells are often quite pleomorphic. Both capsular and vascular invasion may be encountered in benign lesions, and the mere presence of mitotic figures does not imply malignancy. Therefore, the definitive diagnosis of malignancy in pheochromocytomas is based exclusively on the presence of metastases. These may involve regional lymph nodes as well as more distant sites, including liver, lung, and bone.

Figure 19–44 Photomicrograph of pheochromocytoma, demonstrating characteristic nests of cells (Zellballen) with abundant cytoplasm. Granules containing catecholamine are not visible in this preparation. It is not uncommon to find bizarre cells even in pheochromocytomas that are biologically benign, and this criterion by itself should not be used to diagnose malignancy.

Neuroblastoma and Other Neuronal Neoplasms

Neuroblastoma is the most common extracranial solid tumor of childhood. These neoplasms occur most commonly during the first 5 years of life and may arise during infancy. Neuroblastomas may occur anywhere in the sympathetic nervous system and occasionally within the brain, but they are most common in the abdomen; a majority of these tumors arise in either the adrenal medulla or the retroperitoneal sympathetic ganglia. Most neuroblastomas are sporadic, although familial cases also have been described. These tumors are discussed in Chapter 6, along with other pediatric neoplasms.

Multiple Endocrine Neoplasia Type 1

MEN type 1 is inherited in an autosomal dominant pattern. The gene (MEN1) is located at 11q13 and is a tumor suppressor gene; thus, inactivation of both alleles of the gene is believed to be the basis for tumorigenesis. Organs most commonly involved are the parathyroid, the pancreas, and the pituitary—the “3 Ps.”

Multiple Endocrine Neoplasia Type 2

MEN type 2 actually comprises two distinct groups of disorders that are unified by the occurrence of activating (i.e., gain-of-function) mutations of the RET proto-oncogene at chromosomal locus 10q11.2. A strong genotype-phenotype correlation has been recognized for the MEN-2 syndromes, and differences in mutation patterns account for the variable features in the two subtypes. MEN-2 is inherited in an autosomal dominant pattern.