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Pathology_Robbins. 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.


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Pathology_Robbins. Type 1 diabetes is an autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous beta cell antigens. Although type 1 diabetes is the most common form of diabetes in childhood, it is important to remember that it can present at any 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, it results from a chronic autoimmune attack on beta cells that usually starts years before the disease becomes evident ( Fig. 20.22 ). The classic manifestations of the disease (such as ketoacidosis) occur late in its course, after more than 90% of the beta cells have been destroyed.


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Pathology_Robbins. As with most autoimmune diseases, the pathogenesis of type 1 diabetes involves genetic susceptibility and environmental factors. Genome-wide association studies have identified over 20 susceptibility loci for type 1 diabetes. Of these, the strongest association is with class II MHC (HLA-DR) genes. 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, however, most individuals who inherit these HLA alleles do not develop diabetes, indicating that these genes contribute to the disease but do not, by themselves, cause it. Several non-HLA genes also increase susceptibility to type 1 diabetes, including polymorphisms within the gene encoding (?) Precipitating event Genetic Overt loss of release insulin release


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Pathology_Robbins. Fig.20.22Stagesinthedevelopmentoftype1diabetesmellitus.Thestagesarelistedfromlefttoright,andhypotheticalβ cellmassisplottedagainstage.(From Eisenbarth GE: Type 1 diabetes—a chronic autoimmune disease. NEnglJMed314:1360, 1986.) insulin itself, as well as CTLA4 and PTPN22. As discussed in Chapter 5, 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 its expression in the thymus, thus reducing the elimination of T cells reactive with this self protein (Chapter 5).


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Pathology_Robbins. Additional evidence suggests that environmental factors, especially infections, are involved in type 1 diabetes. It has been proposed that certain viruses (mumps, rubella, and coxsackie B viruses, in particular) may be initiating triggers, perhaps because some viral antigens mimic beta cell antigens, leading to bystander damage to the islets, but this idea is not conclusively established. More recent advances in elucidating environmental contributions to the pathogenesis of type 1 diabetes have come from studies of the human microbiome. Studies in diabetic children have shown evidence for “intestinal dysbiosis” (change in composition of usual commensal flora), with reduction in diversity of the microbiome, and reduced abundance of certain bacterial species during progression of subclinical to clinical stages of the disease. Whether this is a cause or consequence of hyperglycemia remains unclear.


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Pathology_Robbins. The fundamental immune abnormality in type 1 diabetes is a failure of self-tolerance in T cells specific for beta cell antigens. This failure of tolerance may result from some combination of defective clonal deletion of self-reactive T cells in the thymus and abnormalities of regulatory T cells (Tregs) that normally dampen effector T-cell responses (Chapter 5). One consequence of loss of self tolerance is the production of autoantibodies against a variety of beta cell antigens, including insulin and the beta cell enzyme glutamic acid decarboxylase, which are detected in the blood of 70% to 80% of patients. In the rare cases in which the pancreatic lesions have been examined http://ebooksmedicine.net


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Pathology_Robbins. Fig.20.23Developmentoftype2diabetes.Insulinresistanceassociatedwithobesityisinducedbyadipokines,freefattyacids,andchronicinflammationinadiposetissue.Pancreaticβ cellscompensateforinsulinresistancebyhypersecretionofinsulin.However,atsomepoint,β cellcompensationisfollowedbyβ cellfailure,anddiabetesensues.(Reproduced with permission from Kasuga M: Insulin resistance and pancreatic β-cell failure. JClinInvest116:1756, 2006.) early in the disease process, the islets show necrosis of beta cells and lymphocytic infiltration (so-called “insulitis”, described later).


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Pathology_Robbins. Type 2 diabetes is a heterogeneous and multifactorial complex disease that involves interactions of genetics, environmental risk factors, and inflammation. Unlike type 1 diabetes, however, there is no evidence of an autoimmune basis. The two 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. 20.23 ). 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.


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Pathology_Robbins. Environmental factors, such as a sedentary lifestyle and dietary habits, unequivocally play a role, as described in the subsequent discussion of the association with obesity. Genetic factors also are involved, as evidenced by a concordance rate of 80% to 90% in monozygotic twins, which is even greater than that for type 1 diabetes (approximately 50% concordance rates in twins), 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 dozens of 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). Insulin resistance is defined as the failure of target tissues to respond normally to insulin. The liver, skeletal muscle, and adipose tissue are the major tissues where insulin resistance manifests as follows:


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Pathology_Robbins. Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver, which contributes to high fasting blood glucose levels Abnormally low glucose uptake and glycogen synthesis in skeletal muscle following a meal, which contributes to a high postprandial blood glucose level Failure to inhibit hormone-sensitive lipase in adipose tissue, leading to excess circulating free fatty acids (FFAs), which, as will be discussed, exacerbates the state of insulin resistance


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Pathology_Robbins. Failure to inhibit hormone-sensitive lipase in adipose tissue, leading to excess circulating free fatty acids (FFAs), which, as will be discussed, exacerbates the state of insulin resistance Few factors play as important a role in the development of insulin resistance as obesity. 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 fat excess. The term metabolic syndrome has been applied to a constellation of findings dominated by visceral obesity, accompanied by insulin resistance, glucose intolerance, and cardiovascular risk factors such as hypertension and abnormal lipid profiles. Individuals with metabolic syndrome are at high risk for the development of type 2 diabetes.


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Pathology_Robbins. It is not only the absolute amount but also the distribution of body fat that has an effect on insulin sensitivity: central obesity (abdominal fat) is more likely to be associated with insulin resistance than is peripheral (gluteal/ subcutaneous) obesity. Obesity can adversely impact insulin sensitivity in numerous ways (see Fig. 20.23 Excess 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 in obese individuals, presumably because excess circulating FFAs are taken up into these organs. Central adipose tissue is more “lipolytic” than peripheral adipose tissue, which might explain the particularly deleterious consequences of the central pattern of fat distribution. Intracellular triglycerides and products of fatty acid metabolism are potent inhibitors of insulin signaling and result in an acquired insulin resistance state.


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Pathology_Robbins. Adipokines. Adipose tissue is not merely a passive storage depot for fat; it also is an endocrine organ that releases hormones in response to changes in metabolic status. A variety of proteins secreted into the systemic circulation by adipose tissue have been identified that are known collectively as adipokines (or adipose cytokines). Some of these promote hyperglycemia, and others (such as leptin and adiponectin) decrease blood glucose, in http://ebooksmedicine.net part by increasing the insulin sensitivity of peripheral tissues. Adiponectin levels are decreased in obesity, thus contributing to insulin resistance.


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Pathology_Robbins. • Inflammation. Over the past several years, inflammation has emerged as an important contributor to the pathogenesis of type 2 diabetes. It is now known that a permissive inflammatory milieu (mediated by proinflammatory cytokines that are secreted in response to excess nutrients such as FFAs) results in both peripheral insulin resistance and beta cell dysfunction (discussed later). Excess FFAs within macrophages and beta cells can activate the inflammasome, a multiprotein cytoplasmic complex that leads to secretion of the cytokine interleukin (IL-1β; Chapter 5). IL-1β stimulates the secretion of additional proinflammatory cytokines from macrophages, islets, and other cells, and IL-1 as well as other cytokines promote insulin resistance in peripheral tissues. Thus, excess FFAs can impede insulin signaling directly, as well as indirectly through the release of cytokines.


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Pathology_Robbins. While insulin resistance by itself can lead to impaired glucose tolerance, beta cell dysfunction is an essential component in the development of overt diabetes. Beta cell function actually increases early in the disease process in most patients with type 2 diabetes, mainly as a compensatory measure to counter insulin resistance and maintain euglycemia. Eventually, however, beta cells are unable to adapt to the long-term demands of peripheral insulin resistance, and the hyperinsulinemic state gives way to a state of relative insulin deficiency. Several mechanisms have been implicated in causing beta cell dysfunction in type 2 diabetes, including the following: Abnormal incretin effect, leading to reduced secretion of hormones that promote insulin release (discussed earlier) Amyloid replacement of islets, present in more than 90% of diabetic islets (see ). It is unclear whether the amyloid is a cause or effect of beta cell “burnout.”


Pathology_Robbins

Pathology_Robbins. Amyloid replacement of islets, present in more than 90% of diabetic islets (see ). It is unclear whether the amyloid is a cause or effect of beta cell “burnout.” Polymorphisms associated with an increased lifetime risk for type 2 diabetes in genes that control insulin secretion. 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 diseases. By contrast, monogenic forms of diabetes (see


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Pathology_Robbins. Table 20.5 ) are uncommon examples of the diabetes occurring as a result of loss-of-function mutations within a single gene. Monogenic causes of diabetes include primary defects in beta cell function and insulin receptor signaling. Monogenic diabetes can be classified based on age of onset into congenital early onset diabetes (manifesting in the neonatal period) and maturity onset diabetes of the young (MODY), which develops beyond the neonatal period but usually before 25 years of age. Some of the underlying causes of congenital diabetes include mutations of the insulin gene itself, and mutations in mitochondrial DNA that lead to a syndrome of maternally inherited diabetes and bilateral deafness (the maternal pattern of inheritance being a sine qua non of mitochondrial DNA mutations). Rare instances of insulin receptor mutations that affect receptor synthesis, insulin binding, or downstream signal transduction can cause severe insulin resistance, accompanied by hyperinsulinemia (due


Pathology_Robbins

Pathology_Robbins. instances of insulin receptor mutations that affect receptor synthesis, insulin binding, or downstream signal transduction can cause severe insulin resistance, accompanied by hyperinsulinemia (due to lack of feedback inhibition) and congenital diabetes. In contrast, MODY is caused by mutations in genes encoding factors driving beta cell function (see


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Pathology_Robbins. Table 20.5 ), and at least superficially, tends to resemble usual type 2 diabetes in many of its clinical features. Thus, it is not surprising that the diagnosis of MODY is often missed in individuals who harbor an underlying pathogenic mutation. In addition to Types 1 and 2 and monogenic forms of diabetes, the other broad subtypes include secondary diabetes and pregnancy-induced (“gestational”) diabetes. Secondary diabetes arising as a result of endocrinopathies (for example, Cushing syndrome or growth hormone excess) have been described in relevant portions of this chapter. Here, we will briefly discuss a form of secondary diabetes arising as a result of a variety of chronic exocrine pancreatic diseases (“pancreatogenic” diabetes), and the important subtype known as gestational diabetes.


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Pathology_Robbins. Gestational diabetes. Approximately 5% of pregnancies occurring in the United States are complicated by hyperglycemia. Pregnancy is a “diabetogenic” state in which the prevailing hormonal milieu favors a state of insulin resistance. In some euglycemic pregnant women this can give rise to gestational diabetes. Women with pregestational diabetes (where hyperglycemia is already present in the periconception period) have an increased risk for stillbirth and congenital malformations in the fetus (Chapter 7). Therefore, tight glycemic control is needed early in pregnancy to prevent congenital defects, and through the later trimesters of pregnancy to prevent fetal overgrowth (macrosomia). The latter occurs because maternal hyperglycemia can induce compensatory secretion of insulin-like growth factors in the fetus. Most pregnant women who develop gestational diabetes require insulin for glycemic control. Gestational diabetes typically resolves following delivery; however, there is an elevated


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Pathology_Robbins. in the fetus. Most pregnant women who develop gestational diabetes require insulin for glycemic control. Gestational diabetes typically resolves following delivery; however, there is an elevated risk for developing outright diabetes within the next ten years (highest in the first five years after pregnancy), after which the risk of diabetes reverts to that of women without antecedent gestational diabetes.


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Pathology_Robbins. Pancreatogenic diabetes is defined as hyperglycemia occurring as a result of a disorder of the exocrine pancreas (see Table 20.5 ). Pancreatogenic diabetes is heterogeneous, with underlying causes ranging from cystic fibrosis, to chronic pancreatitis, to pancreatic adenocarcinoma. In fact, evidence suggests that approximately 1% of new-onset diabetes in older adults is actually a manifestation of an occult pancreatic adenocarcinoma. http://ebooksmedicine.net It is difficult to discuss with brevity the diverse clinical presentations of diabetes mellitus. We will discuss the most common initial presentation or mode of diagnosis for each of the two major subtypes, followed by a discussion of acute and chronic complications of diabetes.


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Pathology_Robbins. 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 because of residual insulin secretion, but eventually the beta cell reserve is exhausted and exogenous insulin becomes essential to control hyperglycemia. 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 of diabetes is marked by polyuria, polydipsia, polyphagia (known as the classic triad of diabetes), and in severe cases, ketoacidosis, all resulting from metabolic derangements ( Fig. 20.24 Since insulin is a major anabolic hormone, its deficiency has widespread effects. The assimilation of glucose into Islets of Langerhans Leads to decreased tissue glucose


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Pathology_Robbins. Fig.20.24Sequenceofmetabolicderangementsleadingtodiabeticcomaintype1diabetesmellitus.Anabsoluteinsulindeficiencyleadstoacatabolicstate,eventuatinginketoacidosisandseverevolumedepletion.Thesederangementsbringaboutsufficientcentralnervoussystemcompromisetocausecomaand,eventually,deathifleftuntreated.Adipose tissue Gluconeogenesis Ketogenesis Muscle Liver Kidney Ketonuria Glycosuria Increased lipolysis (free fatty acids) Increased protein catabolism (amino acids) utilization spillover into blood POLYPHAGIA KETOACIDOSIS HYPERGLYCEMIA POLYURIA DIABETIC COMA VOLUME DEPLETION POLYDIPSIA Glucagon excess d muscle and adipose tissue is sharply diminished or abolished. Storage of glycogen in liver and muscle ceases, and reserves are depleted by glycogenolysis. The resultant hyperglycemia exceeds the renal threshold for reabsorption, and glycosuria ensues. The glycosuria induces osmotic diuresis and polyuria, causing the loss of water and electrolytes. The renal water loss combined with


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Pathology_Robbins. the renal threshold for reabsorption, and glycosuria ensues. The glycosuria induces osmotic diuresis and polyuria, causing the loss of water and electrolytes. The renal water loss combined with hyperosmolarity due to increased levels of glucose in the blood depletes intracellular water, triggering osmoreceptors in the brain. This sequence of events generates intense thirst (polydipsia). The deficiency of insulin leads to the catabolism of proteins and fats. Gluconeogenic amino acids produced by proteolysis are taken up and by the liver and used as building blocks for glucose. The catabolism of proteins and fats induces a negative energy balance, which in turn leads to increasing appetite (polyphagia), thus completing the classic triad. Despite the increased appetite, catabolic effects dominate, resulting in weight loss and muscle weakness. The combination of polyphagia and weight loss is paradoxical and should always point to the possibility of diabetes.


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Pathology_Robbins. In patients with type 1 diabetes, significant deviations from normal dietary intake, unusual physical activity, infection, or any other forms of stress may worsen the metabolic imbalance, leading 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 counter-regulatory 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 hormone-sensitive 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., the brain). The rate at which ketones are formed may exceed the rate


Pathology_Robbins

Pathology_Robbins. is an adaptive phenomenon in times of starvation, generating ketones as a source of energy for consumption by vital organs (e.g., the 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 acidosis.


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Pathology_Robbins. Type 2 diabetes also may manifest with polyuria and polydipsia. 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 individuals. 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 individual is an older adult 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.


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Pathology_Robbins. The morbidity associated with long-standing diabetes of any type results from the chronic complications of hyperglycemia, and the resulting damage induced in both largeand medium-sized muscular arteries (diabetic macro-vascular disease) and small-vessels (diabetic microvascular disease). Macrovascular disease causes accelerated atherosclerosis among diabetics, resulting in increased myocardial infarction, stroke, and lower-extremity ischemia. The effects of microvascular disease are most profound in the retina, kidneys, and peripheral nerves, resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively (


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Pathology_Robbins. Fig. 20.25 ). The pathologic findings in these tissues and their clinical consequences are described next. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In individuals with tight control of their diabetes, the onset may be delayed (hence the need for tight control of hyperglycemia). Pathogenesis of Chronic Complications of Diabetes 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.


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Pathology_Robbins. 1. Formation of advanced glycation end products (AGEs). AGEs are formed as a result of nonenzymatic reactions between intracellular glucose-derived precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) and the amino groups of proteins. The rate of AGE formation is greatly accelerated by hyperglycemia. AGEs bind to a specific receptor (RAGE), which is expressed on inflammatory cells (macrophages and T cells), endothelium and vascular smooth muscle. The detrimental effects of AGE-RAGE signaling within the vascular compartment include the following: Release of cytokines and growth factors, including transforming growth factor β (TGFβ), which leads to deposition of excess basement membrane material, and vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy (discussed later) Generation of reactive oxygen species (ROS) in endothelial cells


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Pathology_Robbins. Generation of reactive oxygen species (ROS) in endothelial cells Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix In addition to receptor-mediated effects, AGEs can directly cross-link extracellular matrix proteins. These cross-linked proteins can trap other plasma or interstitial proteins; for example, low-density lipoprotein (LDL) gets trapped within AGE-modified large-vessel walls, accelerating atherosclerosis (Chapter 10), while albumin can be trapped within capillary walls, accounting in part for the basement membrane thickening that is characteristic of diabetic microangiopathy (discussed later). 2. Activation of protein kinase C. Activation of intracellular protein kinase C (PKC) by calcium ions and the second messenger diacylglycerol (DAG) is an important http://ebooksmedicine.net Fig. 20.25 Long-term complications of diabetes.


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Pathology_Robbins. Fig. 20.25 Long-term complications of diabetes. signal transduction pathway in many cellular systems. Intracellular hyperglycemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and hence cause activation of PKC. The downstream effects of PKC activation are numerous and include production of proangiogenic molecules such as vascular endothelial growth factor (VEGF), implicated in the neovascularization seen in diabetic retinopathy, and profibrogenic molecules such as transforming growth factor β, leading to increased deposition of extracellular matrix and basement membrane material.


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Pathology_Robbins. 3. Disturbances in polyol pathways. In some tissues that do not require insulin for glucose transport (e.g., nerves, lens, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by the enzyme aldose reductase to sorbitol, a polyol, and eventually to fructose, in a reaction that uses NADPH (the reduced form of nicotinamide dinucleotide phosphate) as a cofactor. NADPH also is required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH). As described in Chapter 2, GSH is one of the important anti-oxidant mechanisms in the cell, and reductions in GSH increase cellular susceptibility to oxidative stress. In neurons, persistent hyperglycemia appears to be the major underlying cause of diabetic neuropathy (glucose neurotoxicity). The most important morphologic changes are related to the many late systemic complications of diabetes. These changes are seen in both type 1 and type 2 diabetes (see


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Pathology_Robbins. The most important morphologic changes are related to the many late systemic complications of diabetes. These changes are seen in both type 1 and type 2 diabetes (see Fig. 20.25 Pancreas. Lesions in the pancreas are inconstant. One or more of the following alterations may be present: Reduction in the number and size of islets. This changemost often is seen in type 1 diabetes, particularly with rapidly advancing disease. Most of the islets are small, inconspicuous, and not easily detected. Fig. 20.26A ). They are most often seen type 1 diabetes at the time of clinical presentation. Amyloid deposition within islets in type 2 diabetesbegins in and around capillaries and between cells. At advanced stages, the islets may be virtually obliterated (see Fig. 20.26B ); fibrosis also may be observed. Similar lesions may be found in older nondiabetics, apparently as part of normal aging.


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Pathology_Robbins. Fig. 20.26B ); fibrosis also may be observed. Similar lesions may be found in older nondiabetics, apparently as part of normal aging. 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. Diabetic macrovascular disease. The hallmark of diabetic macrovascular disease is accelerated atherosclerosis Fig.20.26(A)Autoimmuneinsulitisinahumanpancreaticexplant.ArrowspointtoinflammationsurroundingisletofLangerhans,whilethesurroundingacinarstructuresareessentiallynormal.(Photograph provided by Dr. Martha Campbell-Thompson, JDRF Network for Pancreatic Organ Donors, University of Florida., Gainesville, Florida.) (B)Amyloidosisofapancreaticisletintype2diabetes.Amyloidosistypicallyisobservedlateinthenaturalhistoryofthisformofdiabetes, withisletinflammationnotedatearlierobservations.


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Pathology_Robbins. Themostimportantglomerularlesionsarecapillarybasementmembranethickening,diffusemesangialsclerosis,andnodularglomerulosclerosis.Theglomerularcapillarybasementmembranesarethickenedalongtheirentirelength.Thischangecanbedetectedbyelectronmicroscopywithinafewyearsoftheonsetofdiabetes,sometimeswithoutanyassociatedchangeinrenalfunction( Fig.20.29 Fig.20.27Severerenalhyalinearteriolosclerosisinaperiodicacid–Schiffstainedspecimen.Notethemarkedlythickened,tortuousafferentarteriole.Theamorphousnatureofthethickenedvascularwallisevident.(Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Science Center, San Antonio,Texas.) http://ebooksmedicine.net Fig.20.28Renalcortexshowingthickeningoftubularbasementmembranesinaspecimenfromadiabeticpatient.(Periodicacid–Schiffstain.)


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Pathology_Robbins. Fig.20.28Renalcortexshowingthickeningoftubularbasementmembranesinaspecimenfromadiabeticpatient.(Periodicacid–Schiffstain.) Diffusemesangialsclerosisreferstoanincreaseinmesangialmatrixassociatedwithmesangialcellproliferationandbasementmembranethickening.Itisfoundinmostindividualswithdiseaseofmorethan10years’duration.Whenglomerulosclerosisissevere,patientsdevelopthenephroticsyndrome,characterizedbyproteinuria,hypoalbuminemia,andedema(Chapter14). Fig.20.30 ).ThesenodulesarePAS-positiveandusuallycontaintrappedmesangialcells.Nodularglomerulosclerosisisencounteredinapproximately15%to30%ofindividualswithlong-termdiabetesandisamajorcontributortorenaldysfunction.Diffuse Fig.20.29Renalglomerulusshowingmarkedlythickenedglomerularbase-mentmembrane(B) inadiabetic.L,Glomerularcapillarylumen;U,urinaryspace.(Courtesy of Dr. Michael Kashgarian, Department of Pathology,Yale Univer-sity School of Medicine, New Haven, Connecticut.)


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Pathology_Robbins. Fig.20.30Nodularglomerulosclerosisinarenalspecimenfromapatientwithlong-standingdiabetes.(Courtesy of Dr. Lisa Yerian, Department of Pathology, University of Chicago, Chicago, Illinois.) mesangialsclerosisalsomaybeseeninassociationwitholdageandhypertension;bycontrast,thenodularformofglomerulosclerosisisvirtuallypathognomonicofdiabetes.Boththediffuseandthenodularformsofglomerulosclerosisinducesufficientischemiatocausescarringofthekidneys,manifestedbyafinelygranular–appearingcorticalsurface( Fig.20.31 Renalatherosclerosisandarteriolosclerosisconstitutepartofthemacrovasculardiseaseseenindiabetics. Thekidneyisoneofthemostfrequentlyandseverelyaffectedorgans;thechangesinthearteriesandarteriolesaresimilartothosefoundthroughoutthebody.Hyalinearteriolosclerosisaffectsnotonlytheafferentbutalsotheefferentarterioles.Suchefferentarteriolosclerosisisrarelyifeverencounteredinindividualswhodonothavediabetes.


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Pathology_Robbins. Fig.20.31Nephrosclerosisinapatientwithlong-standingdiabetes.Thebisectedkidneydemonstratesdiffusegranulartransformationofthesurface(left) andmarkedthinningofthecortex(right). Additionalfeaturesincludesomeirregulardepressions,theresultofpyelonephritis,andanincidentalcorticalcyst(far right). http://ebooksmedicine.net Fig.20.32Characteristicmorphologicchangesofdiabeticretinopathy.Fea-turesincludeadvancedproliferativeretinopathywithretinalhemorrhages,exudates,neovascularization,andtractionalretinaldetachment(lower-right corner). (Courtesy of Dr. Rajendra Apte,Washington University School of Medicine, St. Louis, Missouri.)


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Pathology_Robbins. Clinical Features of Chronic Diabetes As the previous discussion has emphasized, type 1 and type 2 diabetes are distinct pathophysiologic entities with the common manifestation of hyperglycemia. Table 20.6 summarizes some of the clinical, genetic and histopathologic features that distinguish the two diseases. Nonetheless, as previously stated, the long-term sequela of both types 1 and 2 diabetes, arising as a result of uncontrolled Table20.6Type1VersusType2DiabetesMellitus Betacelldepletion,isletMildbetacelldepletionatrophy HLA, Humanleukocyteantigen;MHC, majorhistocompatibilitycomplex. http://ebooksmedicine.net or poorly controlled hyperglycemia, are similar, and are responsible for much of the morbidity and mortality in diabetics. In most instances these complications appear approximately 15 to 20 years after the onset of hyperglycemia. The major chronic complications of the disease are described next.


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Pathology_Robbins. Macrovascular complications, such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents, are the most common causes of mortality in long-standing diabetes. Diabetics have a two to four times greater incidence of coronary artery disease, and a fourfold higher risk of death from cardiovascular complications, than nondiabetics. Diabetes is often accompanied by underlying conditions that favor the development of adverse cardiovascular events, including hypertension and dyslipidemia (see earlier discussion on metabolic syndrome). 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.


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Pathology_Robbins. 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 (>30 but <300 mg/ day). 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 >300 mg/day) over the ensuing 10 to 15 years, usually accompanied by the appearance of hypertension. The progression from overt nephropathy to end-stage renal disease is highly variable and is evidenced by a progressive drop in glomerular filtration rate. By 20 years after diagnosis, more than 75% of individuals 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.


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Pathology_Robbins. Visual impairment, sometimes even total blindness, is one of the more feared consequences of long-standing diabetes. Diabetes 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. The fundamental lesion of retinopathy—neovascularization—is attributable to hypoxia-induced overexpression of VEGF in the retina. Current treatment for this condition includes intravitreous injection of anti-angiogenic agents. 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.


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Pathology_Robbins. Diabetic neuropathy can produce a variety of clinical syndromes, afflicting the central nervous system, peripheral sensorimotor nerves, and autonomic nervous system. The most frequent pattern of nerve involvement is a distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function, particularly the latter (Chapter 22). 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.


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Pathology_Robbins. • Diabetic patients are plagued by an increased susceptibility to infections of the skin, tuberculosis, pneumonia, and pyelonephritis. Infections cause about 5% of diabetes-related deaths. In an individual 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.


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Pathology_Robbins. Several large-scale prospective studies have convincingly demonstrated that the microvascular 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 nonpharmacologic 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 eventually require therapeutic intervention to reduce hyperglycemia. Glycemic control is assessed clinically by measuring the percentage of glycosylated hemoglobin, also known as HbA1C, which is formed by nonenzymatic 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 (2–3 months) and is relatively unaffected by day-to-day variations. The ADA recommends maintenance of HbA1C levels at


Pathology_Robbins

Pathology_Robbins. glucose levels, HbA1C is a measure of glycemic control over long periods of time (2–3 months) and is relatively unaffected by day-to-day variations. The ADA recommends maintenance of HbA1C levels at less than 7% to reduce the risk for long-term complications. In addition, diabetics need to maintain LDL and HDL cholesterol and triglycerides at optimal levels to reduce the risk for macrovascular complications. The adoption of a healthy and active lifestyle remains one of the best defenses against this modern day scourge.


Pathology_Robbins

Pathology_Robbins. Pancreatic neuroendocrine tumors (PanNETs), also known as islet cell tumors, are rare in comparison with tumors of the exocrine pancreas, accounting for only 2% of all pancreatic neoplasms. PanNETs are most common in adults and may be single or multifocal; when they are malignant, the liver is the most common site of metastases. These tumors have a propensity to elaborate pancreatic hormones, but some are nonfunctional. The latter typically are larger at the time of diagnosis, since they come to clinical attention later in their natural history than functional PanNETs, which often present with symptoms related to excessive hormone production. All PanNETs, with the exception of insulinomas (see later), are regarded as having malignant potential, and in fact, 60% to 90% of PanNETs manifest with overtly malignant features of biologic aggressiveness, such as invasion into local tissues or distant metastases. The tumors frequently have mutations in tumor suppressor genes MEN1 and PTEN, or


Pathology_Robbins

Pathology_Robbins. with overtly malignant features of biologic aggressiveness, such as invasion into local tissues or distant metastases. The tumors frequently have mutations in tumor suppressor genes MEN1 and PTEN, or inactivating mutations in genes (e.g. ATRX) whose products maintain telomere length.


Pathology_Robbins

Pathology_Robbins. Beta cell tumors (insulinomas) are the most common type of PanNET and elaborate sufficient insulin to induce attacks of hypoglycemia when blood glucose levels fall below 50 mg/dL. These attacks manifest 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.


Pathology_Robbins

Pathology_Robbins. 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”). The Zollinger-Ellison syndrome refers to the association of pancreatic islet cell lesions with hypersecretion of gastric acid and severe peptic ulceration, present in 90% to 95% of patients with gastrinomas. 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 one-half of affected patients have diarrhea; in 30%, it is the


Pathology_Robbins

Pathology_Robbins. locations such as the jejunum; when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered. More than one-half of affected patients have diarrhea; in 30%, it is the presenting manifestation.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYGastrinomasmayariseinthepancreas,theperipancreaticregion,orthewalloftheduodenum.Overone-halfofgastrin-producingtumorsarelocallyinvasiveorhavealreadymetastasizedatthetimeofdiagnosis.Inapproximately25%ofpatients,gastrinomasariseinconjunctionwithotherendocrinetumors,thusconformingtotheMEN-1syndrome(discussedlater);MEN-1–associatedgastrinomasfrequentlyaremultifocal,whilesporadicgastrinomasusuallyaresingle.Aswithinsulin-secretingtumorsofthepancreas,gastrin-producingtumorsarehistologicallyblandandrarelyexhibitmarkedanaplasia. The adrenal glands are paired endocrine organs consist-consists of three layers of distinct cell types. Beneath the ing of two regions, the cortex and medulla, which differ capsule of the adrenal gland is the narrow layer of zona in their development, structure, and function. The cortex glomerulosa. An equally narrow zona reticularis abuts the http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Adrenocortical Hyperfunction: Hyperadrenalism785 medulla. Intervening is the broad zona fasciculata, which makes up about 75% of the total cortex. The adrenal cortex synthesizes three different types of steroids: Glucocorticoids (principally cortisol), synthesized primarily in the zona fasciculata, with a small contribution from the zona reticularis Mineralocorticoids, the most important being aldosterone, generated in the zona glomerulosa Sex steroids (estrogens and androgens), produced largely in the zona reticularis The adrenal medulla is composed of chromaffin cells, which synthesize and secrete catecholamines, mainly epinephrine. This section deals first with disorders of the adrenal cortex and then of the medulla. Diseases of the adrenal cortex can be conveniently divided into those associated with cortical hyperfunction or hypofunction. ADRENOCORTICAL HYPERFUNCTION: HYPERADRENALISM


Pathology_Robbins

Pathology_Robbins. ADRENOCORTICAL HYPERFUNCTION: HYPERADRENALISM There are three distinctive hyperadrenal clinical syndromes, each caused by abnormal production of one or more of the hormones produced by the three layers of the cortex: Cushing syndrome, characterized by an excess of cortisol Hyperaldosteronism, caused by an excess of mineralocorticoid Adrenogenital or virilizing syndromes, caused by an excess of androgens The clinical features of some of these syndromes show some similarities because of the shared functions of adrenal steroids. Hypercortisolism: Cushing Syndrome Hypercortisolism (Cushing syndrome) is caused by elevated 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 disorders are as follows ( Fig. 20.34 Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH


Pathology_Robbins

Pathology_Robbins. Fig. 20.34 Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH Secretion of ectopic ACTH by nonpituitary neoplasms Primary adrenocortical neoplasms (adenoma or carcinoma) and, rarely, primary cortical hyperplasia Primary hypothalamic-pituitary disease associated with hypersecretion of ACTH, also known as Cushing disease, Fig. 20.34 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.


Pathology_Robbins

Pathology_Robbins. 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 twenties and thirties). In the vast majority of cases, the pituitary gland contains an ACTH-producing microadenoma that does not produce mass effects in the brain. In some cases there is a microadenoma and rarely, 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 corticotropinreleasing hormone (CRH)–producing tumor. The adrenal glands in patients with Cushing disease show variable degrees of bilateral nodular cortical hyperplasia (discussed later), secondary to the elevated levels of ACTH (“ACTHdependent” Cushing syndrome). The cortical hyperplasia is, in turn, responsible for the


Pathology_Robbins

Pathology_Robbins. of bilateral nodular cortical hyperplasia (discussed later), secondary to the elevated levels of ACTH (“ACTHdependent” Cushing syndrome). The cortical hyperplasia is, in turn, responsible for the hypercortisolism.


Pathology_Robbins

Pathology_Robbins. 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, occasional neuroendocrine neoplasms produce 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.


Pathology_Robbins

Pathology_Robbins. 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, also designated ACTH-independent Cushing syndrome, because the adrenals function autonomously. The biochemical hallmark of adrenal Cushing syndrome is elevated levels of cortisol and low serum levels of ACTH. In most cases, adrenal Cushing syndrome is caused by a unilateral adrenocortical neoplasm, which may be benign (adenoma) or malignant (carcinoma). 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 (typically less than 3 cm in diameter) and the second as micronodules (1–3 mm).


Pathology_Robbins


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Pathology_Robbins. Fig.20.37B ).ThecarcinomasassociatedwithCushingsyndrome,bycontrast,tendtobelargerthantheadenomas. http://ebooksmedicine.net Fig.20.36(A)Primarypigmentednodularadrenocorticalhyperplasiashowingprominentpigmentednodulesintheadrenalgland.(B)Onhistologicexamination,thenodulesarecomposedofcellscontaininglipofuscinpigment,seenintherightpartofthefield.(Photographs courtesy of Dr. Aidan Carney, Department of Medicine, Mayo Clinic, Rochester, Minnesota.) Thesetumorsarenonencapsulatedmassesfrequentlyexceeding200to300ginweight,havingalloftheanaplasticcharacteristicsofcancer,asdetailedlater.Withfunctioningtumors,bothbenignandmalignant,theadjacentadrenalcortexandthatofthecontralateraladrenalglandareatrophic,asaresultofsuppressionofendogenousACTHbyhighcortisollevels.


Pathology_Robbins

Pathology_Robbins. 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 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 redistribution of adipose tissue becomes apparent, with resultant truncal obesity, “moon facies,” and accumulation of fat in the posterior neck and back (“buffalo hump”). 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, resulting in


Pathology_Robbins

Pathology_Robbins. 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, resulting in secondary diabetes with its attendant hyperglycemia, glucosuria, and polydipsia. The catabolic effects of insulin resistance on proteins cause loss of collagen. Thus, the skin is thin, fragile, and easily bruised; cutaneous striae are particularly common in the abdominal area (


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Pathology_Robbins. Fig. 20.38 ). Cortisol also has diverse effects on calcium metabolism that lead to resorption of bone, which 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 psychiatric symptoms 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.


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Pathology_Robbins. Fig.20.37Adrenocorticaladenoma.(A)Theadenomaisdistinguishedfromnodularhyperplasiabyitssolitary,circumscribednature.Thefunctionalstatusofanadrenocorticaladenomacannotbepredictedfromitsgrossormicroscopicappearance.(B)Histologicfeaturesofanadrenalcorticaladenoma.Theneoplasticcellsarevacuolatedbecauseofthepresenceofintracytoplasmiclipid.Thereismildnuclearpleomorphism.Mitoticactivityandnecrosisarenotseen. http://ebooksmedicine.net Fig.20.38ApatientwithCushingsyndrome.Characteristicfeaturesincludecentralobesity,“moonfacies,”andabdominalstriae.(Reproduced with permis-sion from Lloyd RV, et al: Atlasofnontumorpathology:endocrinediseases.Washington, DC, American Registry of Pathology, 2002.) In pituitary and ectopic Cushing syndrome, ACTH levels are elevated and the urine is characterized by high levels of excreted corticosteroids. In contrast, ACTH levels are low in Cushing syndrome secondary to adrenal tumors. Themostcommoncauseofhypercortisolismisexogenousadministrationofsteroids.


Pathology_Robbins

Pathology_Robbins. Themostcommoncauseofhypercortisolismisexogenousadministrationofsteroids. EndogenoushypercortisolismmostoftenissecondarytoanACTH-producingpituitarymicroadenoma(Cushing disease), followedbyprimaryadrenalneoplasms(ACTH-independent hypercortisolism)andparaneoplasticACTHproductionbytumors(e.g.,small-celllungcancer). Themorphologicfeaturesintheadrenalincludebilateralcorticalatrophy(inexogenoussteroid-induceddisease),bilateraldiffuseornodularhyperplasia(mostcommonfindinginendogenousCushingsyndrome),oranadrenocorticalneoplasm. 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. Primary hyperaldosteronism refers to autonomous overproduction of aldosterone with resultant suppression of the renin-angiotensin system and decreased plasma renin activity. The causes of primary hyperaldosteronism are as follows ( Fig. 20.39


Pathology_Robbins

Pathology_Robbins. Fig. 20.39 Bilateral idiopathic hyperaldosteronism, characterized by bilateral nodular hyperplasia of the adrenal glands. This is the most common underlying cause of primary hyperaldosteronism, accounting for about 60% of cases. The pathogenesis of idiopathic hyperaldosteronism is unclear, although a subset harbors germ line mutations in the KCNJ5 gene, which encodes a potassium channel protein that is expressed in the adrenal gland. Adrenocortical neoplasm, either an aldosterone-producing adenoma (the most common cause) or, rarely, an adrenocortical carcinoma. In approximately 35% of cases, primary hyperaldosteronism is caused by a solitary aldosterone-secreting adenoma, a condition referred to as Conn syndrome. Somatic mutations of KCNJ5 (see earlier) are also present in a subset of aldosteronesecreting adenomas. Rarely, familial hyperaldosteronism may result from a genetic defect that leads to overactivity of the aldosterone synthase gene, CYP11B2.


Pathology_Robbins

Pathology_Robbins. Rarely, familial hyperaldosteronism may result from a genetic defect that leads to overactivity of the aldosterone synthase gene, CYP11B2. Na is reabsorbed from tubular urine back into bloodstream K moves from bloodstream into tubule and is excreted Fig.20.39Themajorcausesofprimaryhyperaldosteronismanditsprincipaleffectsonthekidney. http://ebooksmedicine.net 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 the following: Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome)


Pathology_Robbins

Pathology_Robbins. The most important clinical consequence of hyperaldosteronism is hypertension. With an estimated prevalence rate of 5% to 10% among unselected hypertensive patients, primary hyperaldosteronism may be the most common cause of secondary hypertension (i.e., hypertension secondary to an identifiable cause). The long-term effects of hyperaldosteronism-induced hypertension are cardiovascular compromise (e.g., left ventricular hypertrophy and reduced diastolic volumes) and an increase in the prevalence of adverse events such as stroke and myocardial infarction. Hypokalemia results from renal potassium wasting and, when present, can cause a variety of neuromuscular manifestations, including weakness, paresthesias, visual disturbances, and occasionally frank tetany. Hypokalemia was considered a mandatory feature of primary hyperaldosteronism, but almost 50% of normokalemic patients are now being diagnosed largely due to early detection.


Pathology_Robbins

Pathology_Robbins. In primary hyperaldosteronism, the therapy varies according to cause. Adenomas are amenable to surgical excision. By contrast, surgical intervention is not very beneficial in patients with primary hyperaldosteronism due to bilateral hyperplasia, which often occurs in children and young adults. These patients are best managed medically with an aldosterone antagonist such as spironolactone. The treatment of secondary hyperaldosteronism rests on correcting the underlying cause of the renin-angiotensin system hyperstimulation.


Pathology_Robbins

Pathology_Robbins. Adrenogenital syndromes refer to a group of disorders caused by androgen excess, which may stem from a number of etiologies, 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.


Pathology_Robbins

Pathology_Robbins. 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. In the adrenal glands cortisol, aldosterone and sex steroids are synthesized from cholesterol through various intermediates. 21-hydroxylase is required


Pathology_Robbins

Pathology_Robbins. on the nature of the underlying mutation. In the adrenal glands cortisol, aldosterone and sex steroids are synthesized from cholesterol through various intermediates. 21-hydroxylase is required for synthesis of cortisol and aldosterone but not sex steroids. Thus, a deficiency of this enzyme reduces cortisol and aldosterone synthesis and shunts the common precursors into the sex steroid pathway.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInallcasesofCAH,theadrenalsarehyperplasticbilaterally,sometimesexpandingto10to15timestheirnormalweights.Theadrenalcortexisthickenedandnodular,andoncutsection,thewidenedcortexappearsbrownasaresultofdepletionoflipid.Theproliferatingcellsmostlyarecompact,eosinophiliccellsintermixedwithlipid-ladenclearcells.Hyperplasiaofcorticotroph(ACTH-producing)cellsispresentintheanteriorpituitaryinmostpatients. The clinical manifestations of CAH are determined by the specific enzyme deficiency and include abnormalities related to androgen excess, with or without aldosterone and glucocorticoid deficiency. Depending on the nature and severity of the enzymatic defect, the onset of clinical symptoms may occur in the perinatal period, later childhood, or (less commonly) adulthood. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net In 21-hydroxylase deficiency, excessive androgenic activity causes signs of masculinization in females, ranging from clitoral hypertrophy and pseudohermaphroditism in infants to oligomenorrhea, hirsutism, and acne in postpubertal girls. In males, androgen excess is associated with enlargement of the external genitalia and other evidence of precocious puberty in young patients. Most men with CAH are fertile but some have failure of Leydig cell development and oligospermia. In approximately one-third of individuals with 21-hydroxylase deficiency, the enzymatic defect is severe enough to produce aldosterone deficiency, with resultant salt (sodium) wasting. Concomitant cortisol deficiency places individuals with CAH at risk for acute adrenal insufficiency (discussed later).


Pathology_Robbins

Pathology_Robbins. CAH should be suspected in any neonate with ambiguous genitalia. Severe enzyme deficiency in infancy can be a life-threatening condition, with vomiting, dehydration, and salt wasting. In the milder variants, women may present with delayed menarche, oligomenorrhea, or hirsutism. In all cases, an androgen-producing ovarian neoplasm must be excluded. Treatment of CAH is with exogenous glucocorticoids, which, in addition to providing adequate levels of glucocorticoids, also suppress ACTH levels, thereby decreasing the excessive synthesis of the steroid hormones responsible for many of the clinical abnormalities. Mineralocorticoid supplementation is required in the salt-wasting variants of CAH. Theadrenalcortexcansecreteexcessandrogensineitheroftwosettings:adrenocorticalneoplasms(usuallyvirilizing carcinomas)orcongenitaladrenalhyperplasia(CAH).


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Bilateralhyperplasiaoftheadrenalcortexischaracteristic. Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals resulting from ACTH deficiency (secondary hypoadrenalism). Primary adrenocortical insufficiency may be acute (called adrenal crisis), or chronic (Addison disease). Table20.7CausesofAdrenalInsufficiency APS1, APS2, Autoimmunepolyendocrinesyndrometypes1and2;AIRE, autoimmuneregulatorgene. Acute adrenocortical insufficiency occurs most commonly in the clinical settings listed in


Pathology_Robbins

Pathology_Robbins. Acute adrenocortical insufficiency occurs most commonly in the clinical settings listed in Table 20.7 . Individuals 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 anti-coagulant therapy, in postoperative patients who develop disseminated intravascular coagulation, during pregnancy, and in patients suffering from overwhelming sepsis; in the latter setting, it is known as the Waterhouse-Friderichsen syndrome (


Pathology_Robbins

Pathology_Robbins. Fig. 20.40 ). This catastrophic syndrome is classically associated with Neisseria meningitidis septicemia but can also be caused by other organisms. Waterhouse-Friderichsen syndrome can occur at any age but is somewhat more common in children. The basis for the adrenal hemorrhage is uncertain but may be attributable to direct bacterial seeding of small vessels in the adrenal, the development of disseminated intravascular coagulation (Chapter 4), endotoxin-induced vasculitis, or some form of hypersensitivity vasculitis. ChronicAdrenocorticalInsufficiency:AddisonDisease 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 (see


Pathology_Robbins

Pathology_Robbins. Table 20.7 • Autoimmune adrenalitis accounts for 60% to 70% of cases and is by far the most common cause of primary adrenal insufficiency in countries where infectious causes are uncommon. As the name implies, there is autoimmune destruction of steroid-producing cells, and autoantibodies to several key steroidogenic enzymes have been detected in affected patients. Autoimmune adrenalitis may occur in association with several distinct autoimmune polyendocrine syndromes (APS). The best characterized of these is APS1, which is caused by mutations in the autoimmune regulator (AIRE) gene on chromosome http://ebooksmedicine.net Fig.20.40Waterhouse-Friderichsensyndrome.Bilateraladrenalhemor-rhageinaninfantwithoverwhelmingsepsis,resultinginacuteadrenalinsuf-ficiency.Atautopsy,theadrenalglandsweregrosslyhemorrhagicandshrunken;inthisphotomicrograph,littleresidualcorticalarchitectureisdiscernible.


Pathology_Robbins

Pathology_Robbins. 21. It is characterized by mucocutaneous candidiasis and abnormalities of skin, dental enamel, and nails (ectodermal dystrophy) occurring in association with a combination of organ-specific autoimmune disorders that result in destruction of target organs. The AIRE protein is involved in the expression of tissue antigens in the thymus and the elimination of T cells specific for these antigens (Chapter 5). Individuals with APS1 develop autoantibodies against IL-17 and IL-22, which are the principal effector cytokines secreted by TH17 T cells (Chapter 5). Because these two TH17-derived cytokines are crucial for defense against fungal infections, affected patients develop chronic mucocutaneous candidiasis.


Pathology_Robbins

Pathology_Robbins. • Infections, particularly tuberculosis and those produced by fungi, also may cause primary chronic adrenocortical insufficiency. Tuberculous adrenalitis, which once accounted for as many as 90% of cases of Addison disease, has become less common with improved anti-tuberculosis therapy. With the resurgence of tuberculosis mainly because of HIV infection and immunodeficiency, this cause of adrenal deficiency must be borne in mind. When present, tuberculous adrenalitis usually is associated with active infection in other sites, particularly the lungs and genitourinary tract. Among fungi, disseminated infections caused by Histoplasma capsulatum and Coccidioides immitis also may result in chronic adrenocortical insufficiency. Patients with AIDS are at risk for the development of adrenal insufficiency from several other infectious (cytomegalovirus, Mycobacterium avium-intracellulare) and noninfectious (Kaposi sarcoma) complications of their disease.


Pathology_Robbins

Pathology_Robbins. • Metastatic neoplasms involving the adrenals are another potential cause of adrenal insufficiency. The adrenals are a fairly common site for metastases in patients with disseminated carcinomas, which sometimes destroy sufficient adrenal cortex to produce a degree of adrenal insufficiency. Carcinomas of the lung and breast are the source of a majority of metastases in the adrenals.


Pathology_Robbins

Pathology_Robbins. Any disorder of the hypothalamus and pituitary that reduces the output of ACTH, such as metastatic cancer, infection, infarction, or irradiation, leads to a syndrome of hypoadrenalism having many similarities to Addison disease. ACTH deficiency may occur alone, but in some instances, it is only one part of panhypopituitarism, associated with multiple pituitary hormone deficiencies. In patients with primary disease, the destruction of the adrenal cortex prevents 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.


Pathology_Robbins

Pathology_Robbins. In general, clinical manifestations of adrenocortical insufficiency do not appear until at least 90% of the adrenal cortex has been compromised. The initial manifestations often include progressive weakness and easy fatigability, which may be dismissed as nonspecific complaints. Gastrointestinal disturbances are common and include anorexia, nausea, vomiting, weight loss, and diarrhea. In patients with primary adrenal disease, increased levels of ACTH precursor hormone stimulate melanocytes, with resultant hyperpigmentation of the skin and mucosal surfaces. The face, axillae, nipples, areolae, and perineum are particularly common sites of hyperpigmentation. By contrast, hyperpigmentation is not seen in patients with secondary adrenocortical insufficiency because melanotropic hormone levels are not increased. Decreased mineralocorticoid (aldosterone) activity in patients with primary adrenal insufficiency results in potassium retention and sodium loss, with consequent hyperkalemia,


Pathology_Robbins

Pathology_Robbins. are not increased. Decreased mineralocorticoid (aldosterone) activity in patients with primary adrenal insufficiency results in potassium retention and sodium loss, with consequent hyperkalemia, hyponatremia, volume depletion, and hypotension, whereas secondary hypoadrenalism is characterized by deficient cortisol and androgen output but normal or near-normal aldosterone synthesis. Hypoglycemia occasionally may occur as a result of glucocorticoid deficiency and impaired gluconeogenesis. It is more common in infants and children than adults. Stresses such as infections, trauma, or surgical procedures in affected patients may precipitate an acute adrenal crisis, manifested by intractable vomiting, abdominal pain, hypotension, coma, and vascular collapse. Death follows rapidly unless corticosteroids are replaced immediately.


Pathology_Robbins

Pathology_Robbins. Patientstypicallypresentwithfatigue,weakness,andgastrointestinaldisturbances.PrimaryadrenocorticalinsufficiencyalsoischaracterizedbyhighACTHlevelswithassociatedskinpigmentation. It should be evident from the discussion of adrenocortical hyperfunction that functional adrenal neoplasms may be responsible for any of the various forms of hyperadrenalism. While functional adenomas are most commonly associated with hyperaldosteronism and with Cushing syndrome, a virilizing neoplasm is more likely to be a carcinoma. Not all adrenocortical neoplasms, however, elaborate steroid hormones. Determination of whether a cortical neoplasm is functional or not is based on clinical evaluation and measurement of the hormone or its metabolites in the laboratory.


Pathology_Robbins

Pathology_Robbins. Fig.20.42Adrenalcarcinoma.Thetumordwarfsthekidneyandcom-pressestheupperpole.Itislargelyhemorrhagicandnecrotic. http://ebooksmedicine.net The adrenal medulla is embryologically, functionally, and structurally distinct from the adrenal cortex. It is populated by cells derived from the neural crest (chromaffin cells) and their supporting (sustentacular) cells. The chromaffin cells are so named because of their brown-black color after exposure to potassium dichromate. They synthesize and secrete catecholamines in response to signals from preganglionic nerve fibers in the sympathetic nervous system. Similar collections of cells are distributed throughout the body in the extraadrenal paraganglion system. The most important diseases of the adrenal medulla are neoplasms, which include both neuronal neoplasms (including neuroblastomas and more mature ganglion cell tumors) and neoplasms composed of chromaffin cells (pheochromocytomas).


Pathology_Robbins

Pathology_Robbins. Pheochromocytomas are neoplasms composed of chromaffin cells, which, like their nonneoplastic 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”: 10% of pheochromocytomas are extraadrenal, occurring in sites such as the organ of Zuckerkandl and the carotid body, where they usually are called paragangliomas, rather than pheochromocytomas. 10% of adrenal pheochromocytomas are bilateral; this proportion may rise to 50% in cases that are associated with familial syndromes. 10% of adrenal pheochromocytomas are malignant, although the associated hypertension represents a serious and potentially lethal complication of even benign tumors. Fig.20.43Adrenalcarcinomawithmarkedanaplasia.


Pathology_Robbins

Pathology_Robbins. Fig.20.43Adrenalcarcinomawithmarkedanaplasia. Frank malignancy is somewhat more common in tumors arising in extraadrenal sites. • 10% of adrenal pheochromocytomas are not associated with hypertension. Of the 90% that present with hypertension, approximately two-thirds have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations, which can, on occasion, be fatal.


Pathology_Robbins

Pathology_Robbins. One “traditional” 10% rule that has since been modified pertains to familial cases. It is now recognized that as many as 25% of individuals with pheochromocytomas and paragangliomas harbor a germ line mutation in one of at least six known genes, including RET, which causes type 2 MEN syndromes (described later); NF1, which causes type 1 neurofibromatosis (Chapter 22); VHL, which causes von Hippel-Lindau disease (Chapters 14 and 23); and three genes encoding subunits within the succinate dehydrogenase complex (SDHB, SDHC, and SDHD), which is involved in mitochondrial electron transport and oxygen sensing. It is postulated that loss of function in one or more of these subunits leads to stabilization of the transcription factor hypoxia-inducible factor 1α (HIF-1α), promoting tumorigenesis.


Pathology_Robbins

Pathology_Robbins. The dominant clinical manifestation of pheochromocytoma is hypertension, observed in 90% of patients. Approximately two-thirds of patients with hypertension demonstrate paroxysmal episodes, which are described as an abrupt, precipitous elevation in blood pressure, associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension. These episodes may also be associated with pain in the abdomen or chest, nausea, and vomiting. Isolated paroxysmal episodes of hypertension occur in fewer than half of patients; more commonly, patients demonstrate a chronic, sustained elevation in blood pressure punctuated by the aforementioned paroxysms. The elevations of blood pressure are induced by the sudden release of catecholamines that may acutely precipitate congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation, and cerebrovascular accidents. The cardiac complications have been attributed to what has been called catecholamine


Pathology_Robbins

Pathology_Robbins. heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation, and cerebrovascular accidents. The cardiac complications have been attributed to what has been called catecholamine cardiomyopathy, or catecholamine-induced myocardial instability and ventricular arrhythmias. In some cases, pheochromocytomas secrete other hormones such as ACTH and somatostatin and may therefore be associated with clinical features related to the effects of these and other peptide hormones. The laboratory diagnosis is based on demonstration of increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines. Isolated benign pheochromocytomas are treated with surgical excision. With multifocal lesions, long-term medical treatment for hypertension may be required.


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Pathology_Robbins. 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 7, along with other pediatric neoplasms. Fig.20.45Photomicrographofpheochromocytoma,demonstratingcharac-teristicnestsofcellswithabundantcytoplasm.Granulescontainingcate-cholaminearenotvisibleinthispreparation.Itisnotuncommontofindbizarrecells(suchastheoneinthecenterofthisimage),eveninpheochro-mocytomasthatarebenign. http://ebooksmedicine.net


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Pathology_Robbins. http://ebooksmedicine.net The MEN syndromes are a group of inherited diseases caused by proliferative lesions (hyperplasias, adenomas, and carcinomas) of multiple endocrine organs. Like other inherited cancer disorders (Chapter 6), endocrine tumors arising in the context of MEN syndromes have certain distinctive features that are not shared with their sporadic counterparts: These tumors occur at a younger age than that typical for sporadic cancers. They arise in multiple endocrine organs, either synchronously (at the same time) or metachronously (at different times). Even in one organ, the tumors often are multifocal. The tumors usually are preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin of the tumor (e.g., patients with MEN-2 almost universally demonstrate C cell hyperplasia in the thyroid parenchyma adjacent to medullary thyroid carcinomas).


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Pathology_Robbins. These tumors are usually more aggressive and recur in a higher proportion of cases than similar endocrine tumors that occur sporadically. MEN-1 syndrome is caused by germ line mutations in the MEN1 tumor suppressor gene, which encodes a protein called Menin. Menin is a component of several different transcription factor complexes, and loss of Menin function leads to deregulation of the corresponding binding partners, promoting endocrine neoplasia. Organs most commonly involved are the parathyroid, the pancreas, and the pituitary—the “3 Ps.” Parathyroid. Primary hyperparathyroidism is the most common manifestation of MEN-1 (80%–95% of patients) and is the initial manifestation of the disorder in most patients, appearing in almost all by 40 to 50 years of age. Parathyroid abnormalities include hyperplasia and adenomas.


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Pathology_Robbins. Pancreas. Endocrine tumors of the pancreas are the leading cause of death in MEN-1. These tumors usually are aggressive and present with metastatic disease. Pancreatic endocrine tumors often are functional (i.e., secrete hormones). Zollinger-Ellison syndrome, associated with gastrinomas, and hypoglycemia, associated with insulinomas, are common endocrine manifestations. Pituitary. The most frequent pituitary tumor in patients with MEN-1 syndrome is a prolactin-secreting macroadenoma. In some cases, acromegaly develops in association with somatotropin-secreting tumors.


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Pathology_Robbins. MEN-2 syndrome 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. Organs commonly involved in MEN-2A include the following:


Pathology_Robbins

Pathology_Robbins. Organs commonly involved in MEN-2A include the following: Thyroid: Medullary carcinoma of the thyroid develops in virtually all untreated cases, and the tumors usually occur in the first 2 decades of life. The tumors commonly are multifocal, and foci of C cell hyperplasia can be found in the adjacent thyroid. Familial medullary thyroid cancer is seen in a variant of MEN-2A, without the other characteristic manifestations listed here. In comparison with MEN-2, familial medullary carcinoma typically occurs at an older age and follows a more indolent course. Adrenal medulla: Adrenal pheochromocytomas develop in 50% of the patients; fortunately, no more than 10% of these tumors are malignant. Parathyroid: Approximately 10% to 20% of patients develop parathyroid gland hyperplasia with manifestations of primary hyperparathyroidism.


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Pathology_Robbins. Parathyroid: Approximately 10% to 20% of patients develop parathyroid gland hyperplasia with manifestations of primary hyperparathyroidism. A single amino acid change in RET, distinct from the mutations that are seen in MEN-2A, seems to be responsible for virtually all cases of MEN-2B. Patients develop medullary thyroid carcinomas, which are usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas. MEN-2B has the following distinctive features: Primary hyperparathyroidism does not develop in patients with MEN-2B. Extraendocrine manifestations are characteristic in patients with MEN-2B. These include ganglioneuromas of mucosal sites (gastrointestinal tract, lips, tongue) and a marfanoid habitus, in which overly long bones of the axial skeleton give an appearance resembling that in Marfan syndrome (Chapter 7).


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Pathology_Robbins. Before the advent of genetic testing, relatives of patients with the MEN-2 syndrome were screened with annual biochemical tests, which often lacked sensitivity. Now, routine genetic testing identifies RET mutation carriers earlier and more reliably in MEN-2 kindreds. All individuals carrying germ line RET mutations are advised to have prophylactic thyroidectomy to prevent the inevitable development of medullary carcinomas. Andersen DK, Andren-Sandberg A, Duell EJ, et al: Pancreatitisdiabetes-pancreatic cancer: summary of a NCI-NIDDK workshop, Pancreas 42:1227–1237, 2013. [This workshop summary discusses the complex relationship between diabetes and pancreatic cancer, as well as http://ebooksmedicine.net the recent emergence of the entity known as type 3c or pancreatogenic diabetes. One of the causes of type 3c diabetes is pancreatic cancer.]


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Pathology_Robbins. Asa SL, Ezzat S: Genomic approaches to problems in pituitary neoplasia, Endocr Pathol 25:209–213, 2014. [A review on genomics of pituitary neoplasia from two of the best recognized authorities on these tumors.] Bancos I, Hahner S, Tomlinson J, et al: Diagnosis and management of adrenal insufficiency, Lancet Diabetes Endocrinol 3:216–226, 2015. [A clinically oriented review on the etiology of acute and chronic adrenal insufficiency.] Bilezikian JP, Cusano NE, Khan AA, et al: Primary hyperparathyroidism, Nat Rev Dis Primers 2:16033, 2016. [This review follows the format of other reviews in this journal that is heavy on summary figures and overviews written for a broad audience. The reader is encouraged to periodically browse the journal for discussions of other pertinent diseases.]


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Pathology_Robbins. Burman KD, Wartofsky L: Clinical practice. Thyroid nodules, N Engl J Med 373:2347–2356, 2015. [An authoritative review on etiology and management of thyroid nodules. Useful supplement to the chapter discussion.] DeFronzo RA, Ferrannini E, Groop L, et al: Type 2 diabetes mellitus, Nat Rev Dis Primers 1:15019, 2015. [An excellent overview of type 2 diabetes, again with overview figures on pathophysiology and complications. The level of discussion is beyond the scope of the chapter, so readers can use this review to supplement their knowledge.] De Leo S, Lee SY, Braverman LE: Hyperthyroidism, Lancet 388:906– 918, 2016. [An excellent and clinically oriented recent review on etiology of hyperthyroidism, including common and uncommon causes.]


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Pathology_Robbins. De Leo S, Lee SY, Braverman LE: Hyperthyroidism, Lancet 388:906– 918, 2016. [An excellent and clinically oriented recent review on etiology of hyperthyroidism, including common and uncommon causes.] Dralle H, Machens A, Basa J, et al: Follicular cell-derived thyroid cancer, Nat Rev Dis Primers 1:15077, 2015. [A timely review of thyroid cancers, including follicular and papillary neoplasms. As with reviews in this journal, the text spans genetics, symptoms, diagnosis, and management and can be a very useful supplement to the text for the curious reader.] Faillot S, Assie G: Endocrine tumors: the genomics of adrenocortical tumors, Eur J Endocrinol 174:R249–R265, 2016. [In contrast to the TCGA paper below that is focused on adrenocortical cancers, this review also encompasses genetics of other adrenal pathologies, including adenomas and primary hyperplasia.]


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Pathology_Robbins. Higham CE, Johannsson G, Shalet SM: Hypopituitarism, Lancet 388:2403–2415, 2016. [A current review on hypopituitarism including etiology and management.] Lacroix A, Feelders RA, Stratakis CA, et al: Cushing’s syndrome, Lancet 386:913–927, 2015. [A definitive review on Cushing syndrome, including genetics, pathophysiology, laboratory diagnosis, symptoms, and management. The text is exhaustive and can be used by the discerning for supplementing the text.]


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Pathology_Robbins. Nikiforov YE, Seethala RR, Tallini G, et al: Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors, JAMA Oncol 2:1023–1029, 2016. [The defining paper that led to changing the nomenclature for the erstwhile entity known as encapsulated follicular variant of papillary thyroid carcinoma. This paper is also important to understand the concept of “overdiagnosis,” which is increasingly becoming a factor due to increasing use of imaging modalities in patients.] Pociot F, Lernmark A: Genetic risk factors for type 1 diabetes, Lancet 387:2331–2339, 2016. [A recent review on the complex genetics of type 1 diabetes, especially the HLA alleles, and how these might interface with the environment.]


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Pathology_Robbins. Tuomi T, Santoro N, Caprio S, et al: The many faces of diabetes: a disease with increasing heterogeneity, Lancet 383:1084–1094, 2014. [An excellent review underscoring the etiologic heterogeneity of the entity that we know as “diabetes”—and how so many diverse genetic and environmental factors contribute to the phenotype of hyperglycemia.] Zheng S, Cherniack AD, Dewal N, et al: Comprehensive pan-genomic characterization of adrenocortical carcinoma, Cancer Cell 29:723– 736, 2016. [The definitive study from The Cancer Genome Atlas (TCGA] on genomics of adrenocortical cancers.] http://ebooksmedicine.net studentconsult.com Bones, Joints, and Soft Healing of Fractures Tumors of Unknown Origin


Pathology_Robbins

Pathology_Robbins. Bones, Joints, and Soft Healing of Fractures Tumors of Unknown Origin The functions of bone include mechanical support, transmission of forces generated by muscles, protection of viscera, mineral homeostasis, and providing a niche for the production of blood cells. The constituents of bone include an extracellular matrix and specialized cells responsible for production and maintenance of the matrix.


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Pathology_Robbins. Bone matrix is composed of an organic component known as osteoid (35%) and a mineral component (65%). Embedded within the bone matrix are a variety of bone cells including osteocytes that lay down bone and osteoclasts that reabsorb bone. These two cells types maintain bone homeostasis. Osteoid is made up predominantly of type I collagen with smaller amounts of glycosaminoglycans and other proteins. The unique feature of bone matrix, its hardness, is imparted by the inorganic moiety hydroxyapatite (Ca10[PO4]6[OH]2). The bone matrix is synthesized in one of two histologic forms, woven or lamellar (Fig. 21.1 ). Woven bone is produced rapidly, such as during fetal development orfracturerepair,butthehaphazardarrangementofcollagen fibers imparts less structural integrity than the parallel collagen fibers in slowly produced lamellar bone. In an adult, the presence of woven bone is always abnormal, but it is not specific for any particular bone disease. A cross section of a typical long bone


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Pathology_Robbins. fibers in slowly produced lamellar bone. In an adult, the presence of woven bone is always abnormal, but it is not specific for any particular bone disease. A cross section of a typical long bone shows a dense outer cortex and a central medulla composed of bony trabeculae separated by marrow.


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Pathology_Robbins. Bone contains three major cell types: • Osteoblasts, located on the surface of the matrix, synthesize, transport and assemble bone matrix and regulate its mineralization ( Fig. 21.2A ). They are derived from mesenchymal stem cells that are located under the periosteum in the developing bone and additionally in the medullary space later in life. http://ebooksmedicine.net Fig.21.1Wovenbone(A)ismorecellularanddisorganizedthanlamellarbone(B). Fig.21.2(A)Activeosteoblastssynthesizingbonematrix.Thesurroundingspindlecellsrepresentosteoprogenitorcells.(B)Twoosteoclastsresorbingbone. Osteocytes, located within the bone, are interconnected by an intricate network of cytoplasmic processes through tunnels known as canaliculi. Osteocytes help to control calcium and phosphate levels, detect mechanical forces, and translate them into biologic activity—a process called mechanotransduction.


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Pathology_Robbins. Osteoclasts, located on the surface of bone, are specialized multinucleated macrophages, derived from circulating monocytes, which are responsible for bone resorption ( Fig. 21.2B ). By means of cell surface integrins, osteoclasts attach to bone matrix and create a sealed extracellular trench (resorption pit). The cells secrete acid and neutral proteases (predominantly matrix metalloproteases [MMPs]) into the pit, and these enzymes resorb the bone. During embryogenesis, long bones develop from a cartilage mold by the process of endochondral ossification.


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Pathology_Robbins. During embryogenesis, long bones develop from a cartilage mold by the process of endochondral ossification. A cartilage mold (anlagen) is synthesized by mesenchymal precursor cells. At approximately 8 weeks’ gestation, the central portion of the anlagen is resorbed, creating the medullary canal. Simultaneously, at midshaft (diaphysis), osteoblasts begin to deposit the cortex beneath the periosteum producing the primary center of ossification and growing the bone radially. At each longitudinal end (epiphysis), endochondral ossification proceeds in a centrifugal fashion (secondary center of ossification). Eventually, a plate of the cartilage becomes entrapped between the two expanding centers of ossification, forming the physis or growth plate (


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Pathology_Robbins. Fig. 21.3 ). The chondrocytes within the growth plate undergo sequential proliferation, hypertrophy, and apoptosis. In the region of apoptosis the matrix mineralizes and is invaded by capillaries, providing the nutrients for osteoblasts, which synthesize osteoid. This process produces longitudinal bone growth. Intramembranous ossification, by contrast, is responsible for the development of flat bones. Bones of the cranium, for example, are formed by osteoblasts directly http://ebooksmedicine.net Fig.21.3Activegrowthplatewithongoingendochondralossification.1,Reservezone.2,Zoneofproliferation.3,Zoneofhypertrophy.4,Zoneofmineralization.5,Primaryspongiosa. from a fibrous layer of tissue, without cartilage anlagen. The enlargement of flat bones is achieved by deposition of new bone on a preexisting surface.


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Pathology_Robbins. from a fibrous layer of tissue, without cartilage anlagen. The enlargement of flat bones is achieved by deposition of new bone on a preexisting surface. The adult skeleton appears static but is actually constantly turning over in a tightly regulated process known as remodeling. Remodeling takes place at a microscopic locus known as the bone (or basic) multicellular unit (BMU), which consists of a unit of coupled osteoblast and osteoclast activity on the bone surface. The events at the BMU are regulated by cell–cell interactions and cytokines (


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Pathology_Robbins. Fig. 21.4 ). An important signaling pathway that controls remodeling involves three factors: (1) the transmembrane receptor activator of NF-κB (RANK), which is expressed on osteoclast precursors; (2) RANK ligand (RANKL), which is expressed on osteoblasts and marrow stromal cells; and (3) osteoprotegerin (OPG), a secreted “decoy” receptor made by osteoblasts that can block RANK interaction with RANKL. RANK signaling activates the transcription factor NF-κB, which is essential for the generation and survival of osteoclasts. Other important pathways include monocyte-colony stimulating factor (M-CSF), produced by osteoblasts. WNT proteins produced by various cells bind to the LRP5 and LRP6 receptors on osteoblasts and trigger the production of OPG. The importance of these pathways is proven by rare but informative germline mutations in the OPG, RANK, RANKL, and LRP5 genes, which cause severe disturbances of bone metabolism (described later).


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Pathology_Robbins. Bone resorption or bone formation can be favored by tipping the RANK-to-OPG ratio. Systemic factors that affect this balance include hormones, vitamin D, inflammatory cytokines (e.g., IL-1), and growth factors (e.g., bone morphogenetic factors). The mechanisms are complex, but parathyroid hormone (PTH), IL-1, and glucocorticoids promote osteoclast differentiation and bone turnover. In contrast, BMPs and sex hormones (estrogen, testosterone) generally block osteoclast differentiation or activity by favoring OPG expression. Peak bone mass is achieved in early adulthood after the cessation of skeletal growth. This set point is determined by many factors, including polymorphisms in the vitamin D and LRP5/6 receptors, nutrition, and physical activity. Beginning in the fourth decade, resorption exceeds formation, resulting in a decline in skeletal mass. Congenital abnormalities of the skeleton frequently result from inherited mutations and first become manifest


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Pathology_Robbins. Congenital abnormalities of the skeleton frequently result from inherited mutations and first become manifest Fig.21.4Paracrinemolecularmechanismsthatregulateosteoclastformationandfunction.Osteoclastsarederivedfromthesamemononuclearcellsthatdifferentiateintomacrophages.Osteoblast/stromalcellmembrane-associatedRANKLbindstoitsreceptorRANKlocatedonthecellsurfaceofosteoclastprecursors.Thisinteractioninthebackgroundofmacrophagecolony-stimulatingfactor(M-CSF)causestheprecursorcellstoproducefunctionalosteoclasts.Stromalcellsalsosecreteosteoprotegerin(OPG),whichactsasa“decoy”receptorforRANKL,preventingitfrombindingtheRANKreceptoronosteoclastprecursors.Consequently,OPGpreventsboneresorptionbyinhibitingosteoclastdifferentiation. http://ebooksmedicine.net during the early stages of bone formation. The spectrum of developmental disorders of bone is broad, and the classification system is not standardized. Here we will categorize the major diseases according to their perceived pathogenesis.


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Pathology_Robbins. Congenital anomalies can result from localized abnormalities in the migration and condensation of mesenchyme (dysostosis) or global disorganization of bone and/ or cartilage (dysplasia). Dysostoses result from defects in the formation of mesenchymal condensations and their differentiation into the cartilage anlage. The most common forms include the complete absence of a bone or a digit (aplasia), extra bones or digits (supernumerary digit), and abnormal fusion of bones (e.g., syndactyly, craniosynostosis). Genetic alterations that affect homeobox genes, cytokines, and cytokine receptors are especially common among the dysostoses. In contrast, dysplasias arise from mutations in genes that control development or remodeling of the entire skeleton. It is important to note that, as for developmental anomalies in other tissues, the term dysplasia implies abnormal growth rather than a premalignant lesion as used in the context of neoplasia (Chapter 6).


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Pathology_Robbins. More than 350 skeletal dysostoses and dysplasias, most of them extremely rare, have been described. Examples of diseases with defined genetic abnormalities are discussed below. Note that various point mutations in a single gene (e.g., COL2A1) can result in different phenotypes, whereas mutations in diverse genes (e.g., LRP5, RANKL) can give rise to similar clinical phenotypes.


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Pathology_Robbins. Achondroplasia, the most common skeletal dysplasia and a major cause of dwarfism, is an autosomal dominant disorder resulting from retarded cartilage growth. The disease is caused by gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Normally, FGF inhibits endochondral growth. FGFR3 mutation results in a constitutively active receptor, thereby exaggerating this effect and suppressing growth. Approximately 90% of cases stem from new mutations, almost all of which occur in the paternal allele. Affected individuals have shortened proximal extremities, a trunk of relatively normal length, and an enlarged head with bulging forehead and conspicuous depression of the root of the nose. The skeletal abnormalities are usually not associated with changes in longevity, intelligence, or reproductive status.


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Pathology_Robbins. Thanatophoric dysplasia, the most common lethal form of dwarfism, results from diminished proliferation of chondrocytes and disorganization in the zone of proliferation. It also is caused by gain-of-function mutations in FGFR3, albeit ones that are distinct from those that cause achondroplasia. It occurs in about 1 of every 20,000 live births. Affected individuals have micromelic shortening of the limbs, frontal bossing, relative macrocephaly, a small chest cavity, and a bell-shaped abdomen. The underdeveloped thoracic cavity leads to respiratory insufficiency, and these individuals usually die at birth or soon thereafter.