THE ENDOCRINE PANCREAS

 about 1 million clusters of cells, the islets of Langerhans

 islets have 4 major and 2 minor cell types

The 4 major types:

 The β cells
o produce insulin
 α cells secrete glucagon
o stimulates glycogenolysis in the liver
o increases blood sugar
 δ cells secrete somatostatin
o suppresses both insulin and glucagon release
 PP cells
o secrete pancreatic polypeptide
o stimulation of secretion of gastric and intestinal enzymes
o inhibition of intestinal motility
 They are also scattered in the exocrine pancreas

The two rare cell types:

 D1 cells
o elaborate vasoactive intestinal polypeptide (VIP)
o glycogenolysis and hyperglycemia
o gastrointestinal fluid secretion
o secretory diarrhea
 Enterochromaffin cells
o synthesize serotonin
o carcinoid syndrome
Diabetes Mellitus

 A group of metabolic disorders sharing the common feature of hyperglycemia

 defects in insulin secretion, insulin action, or, most commonly both
 diabetes in U.S
o is the leading cause of end-stage renal disease,
o adultonset blindness
o nontraumatic lower extremity amputations due to atherosclerosis of the arteries
 Diabesity epidemic - sedentary life styles and poor eating habits
Diagnosis of DM

 Normal blood glucose - 70 to 120 mg/dL

 ADA and WHO, diagnostic criteria for diabetes include:
o FBS ≥ 126 mg/dL
o RBS ≥ 200 mg/dL (in a patient with classic hyperglycemic signs)
o 2-hour plasma glucose ≥ 200 mg/dL during (OGTT) with loading dose of 75 gm
o glycated hemoglobin (HbA1C) level ≥ 6.5%
 ALL tests, EXCEPT patient RBS test with classic hyperglycemic signs, need to be repeated and
confirmed on a separate day
 Readout - the result with greater degree of abnormality
 The diagnosis of diabetes requires persistence of hyperglycemia following resolution of the
acute illness
 Impaired glucose tolerance (prediabetes) is defined as:
o FBS 100 - 125 mg/dL
o 2-hour plasma glucose of 140 - 199 mg/dL following a 75-gm glucose OGTT
o glycated hemoglobin (HbA1C) level of 5.7% - 6.4%
 As many as 1/4 of prediabetics will develop overt diabetes over 5 years

Classification of DM

 Type 1 diabetes
o an autoimmune disease
o pancreatic β cell destruction
o absolute deficiency of insulin
o 5% to 10% of all cases
o 20 years old
 Type 2 diabetes
o combination of peripheral resistance to insulin action
o inadequate secretory response by the pancreatic β cells
o relative insulin deficiency
o 90% to 95% of diabetic patients have type 2 diabetes
o Mostly overweight
o classically considered adult-onset
Glucose Homeostasis in DM

 Normal glucose homeostasis is tightly regulated by three interrelated processes:

o glucose production in the liver
o glucose uptake and utilization by peripheral tissues
o actions of insulin and counter-regulatory hormones
 Insulin and glucagon have opposing regulatory effects on glucose homeostasis
 During fasting states
o Low insulin and high glucagon levels
o hepatic gluconeogenesis
o glycogenolysis
o decreased glycogen synthesis
o preventing hypoglycemia
 fasting plasma glucose levels are determined primarily by hepatic glucose output
 Following a meal
o insulin levels rise
o glucagon levels fall in response to the large glucose load
o Insulin promotes glucose uptake and utilization in tissues
 skeletal muscle is the major insulin-responsive site for postprandial glucose utilization
 It is critical for preventing hyperglycemia and maintaining glucose homeostasis

Regulation of Insulin Release

 Insulin
o It is produced in the β cells of the pancreatic islets as a precursor protein
o It is proteolytically cleaved in the Golgi complex
o to generate the mature hormone and a peptide byproduct, C-peptide
o Both insulin and C-peptide are then stored in secretory granules
o secreted in equimolar quantities after physiologic stimulation
o C-peptide levels serve as a surrogate for β-cell function
o C-peptide is decreased with loss of β-cell mass in type 1 diabetes while increased with
type 2
o Glucose – most important stimulus for insulin production
Insulin Action and Insulin Signaling Pathways

1. An increase in blood glucose levels results in glucose uptake into pancreatic β cells
2. glucose uptake is facilitated by an insulin-independent glucose-transporter, GLUT-2
3. β cells express an ATP-sensitive K+ channel on the membrane
4. the membrane comprises two subunits:
o an ATP-sensitive K+ channel
o sulfonylurea receptor - binding site for oral hypoglycemic agents (sulfonylureas)
5. Metabolism of glucose generates ATP
6. ATP will then inhibit the activity of the ATP-sensitive K+ channel
7. membrane depolarization and the influx of Ca2+
8. stimulates secretion of insulin - phase of immediate release of insulin
9. If the secretory stimulus persists, delayed and protracted response follows
10. active synthesis of insulin
 Incretin
o most important hormone for insulin secretion from β cells following feeding
o Two incretins have been identified:
 Glucose-dependent insulinotropic polypeptide (GIP) - K cells in the proximal
small bowel
 Glucagon-like peptide-1 (GLP-1) - L cells in the distal ileum and colon
o Incretin effect - elevation in GIP and GLP-1 levels following oral food intake
o reduce glucagon secretion
o delay gastric emptying
o promotes satiety
o circulating GIP and GLP-1 are degraded in circulation by dipeptidyl peptidase (DPPs),
especially DPP-4
o The “incretin effect” is significantly blunted in patients with type 2 diabetes
o Restoration of incretin function
a) improved glycemic control
 b) loss of weight (through restoration of satiety)

 GLP-1 receptor agonists

o synthetic GLP-1 mimetics
o bind to, and activate the GLP-1 receptor on islet and extrapancreatic sites
 DPP-4 inhibitors
o enhance levels of endogenous incretins by delaying their degradation

Insulin Action and Insulin Signaling Pathways

 Insulin is the most potent anabolic hormone known

 Principal metabolic function of insulin is to increase the rate of glucose transport into certain
cells mainly: striated muscle cells and adipocytes
 Striated muscle cells and adipocytes make up 2/3 of total body weight
 Glucose uptake in other peripheral tissues, most notably the brain, is insulin independent
 Besides promoting lipid synthesis, insulin also inhibits lipid degradation in adipocytes
 It also promote amino acid uptake and protein synthesis, while inhibiting protein degradation
 Anabolic effects of insulin are attributable to increased synthesis and reduced degradation of
glycogen, lipids, and proteins
 Insulin has mitogenic functions
o DNA synthesis in certain cells
o stimulation of their growth and differentiation
 The insulin receptor is a tetrameric protein composed of two α- and two β-subunits
 The β-subunit cytosolic domain possesses tyrosine kinase activity
 The α-subunit extracellular domain activates the β-subunit tyrosine kinase
 Autophosphorylation of the receptor
 Phosphorylation (activation) of several intracellular substrate proteins
o insulin receptor substrates (IRS) - IRS1-IRS4 and GAB1
 PI3K and the MAP kinase pathway activation - metabolic and mitogenic activity
 GLUT-4 transport to the plasma membrane, which promotes glucose uptake
o By AKT signaling - the principal effector of the PI3K pathway
o Independently by the cytoplasmic protein CBL - direct phosphorylation

Pathogenesis of Type 1 Diabetes Mellitus

 an autoimmune disease
 islet destruction
 caused primarily by immune effector cells reacting against endogenous β-cell antigens
 most commonly develops in childhood
 all forms of diabetes may be treated with insulin
 most patients with type 1 diabetes require insulin for survival
 without insulin they develop serious metabolic complications such as ketoacidosis and coma
 type 1 diabetes involves an interplay of genetic and environmental factors
Genetic Susceptibility

 most important locus is the HLA gene cluster on chromosome 6p21 - 50%
 95% of Caucasians with this disease have either an HLA-DR3 or HLA-DR4 haplotype
 50% of patients with type 1 diabetes are combined DR3/DR4 heterozygotes
 Individuals who have either DR3 or DR4 concurrently with a DQ8 haplotype demonstrate one of
the highest inherited risks for type 1 diabetes in sibling studies
 polymorphisms in the HLA molecules are located in or adjacent to the peptide binding pockets
 Several non-HLA genes also confer susceptibility to type 1 diabetes
 The first disease-associated non-MHC gene to be identified was insulin
 with variable number of tandem repeats (VNTRs) in the promoter region being associated with
disease susceptibility
 The association between polymorphisms in CTLA4 and PTPN22 and autoimmune thyroiditis

Environmental Factors

 viral infections have been suggested as triggers for development of the disease
  Molecular mimicry - viruses might share epitopes with islet antigens
 infections are also known to be protective against type 1 diabetes

Mechanisms of β Cell Destruction

 clinical onset of type 1 diabetes is often abrupt

 Hyperglycemia and ketosis occur late in its course after more than 90% of the β cells have been
destroyed
 The fundamental immune abnormality in type 1 diabetes is a failure of selftolerance in T cells
specific for islet antigens
 TH1 cells which may secrete cytokines, including IFN-γ and TNF, that injure β cells
 CD8+ CTLs which kill β cells directly
 The islet autoantigens that are the targets of immune attack may include:
o Insulin
o β cell enzyme glutamic acid decarboxylase (GAD)
o islet cell autoantigen 512 (ICA512)
 presence of islet cell antibodies is used as a predictive marker for the disease
 it is not clear if the autoantibodies cause injury or are merely produced as a consequence of islet
injury

Diabetest Mellitus Type 2

Pathogenesis of Type 2 Diabetes Mellitus

 interplay of :
o genetic
o environmental
o proinflammatory state
 no evidence of an autoimmune basis

Genetic Factors

 90% in monozygotic twins

 first-degree relatives have 5- to 10-fold higher risk
  many of the polymorphisms identified are in genes associated with insulin secretion

Environmental Factors

 Obesity - most important environmental risk factor for type 2

 particularly central or visceral obesity
 more than 80% of individuals with type 2 diabetes are obese
 modest weight loss through dietary modifications can reduce insulin resistance and improve
glucose tolerance
 sedentary lifestyle (typified by lack of exercise) is another risk factor for diabetes, independent
of obesity
 Weight loss and exercise usually have additive effects on improving insulin sensitivity
 often the first non-pharmacological measures attempted in patients with milder type 2 diabetes
Metabolic Defects in Diabetes

 2 cardinal metabolic defects that characterize type 2 diabetes:

o Insulin resistance - Decreased response of peripheral tissues
o β-cell dysfunction - Inadequate insulin secretion
 Insulin resistance predates the development of hyperglycemia

Insulin Resistance

 failure of target tissues to respond normally to insulin

 liver, skeletal muscle and adipose tissue are the major tissues where insulin resistance
manifests
 Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver
 Failure of glucose uptake and glycogen synthesis to occur in skeletal muscle following a meal
 Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess circulating free fatty
acids
 reduced tyrosine phosphorylation of the insulin receptor
 exercise can improve insulin sensitivity through increased translocation of GLUT-4 to the
surface of skeletal muscle cells
 obesity is probably the most important
 central obesity (abdominal fat) is more likely to be linked with insulin resistance than are
peripheral (gluteal/ subcutaneous) fat depots

 Obesity can adversely impact insulin sensitivity in numerous ways :

o Free fatty acids (FFAs)
 inverse correlation between fasting plasma FFAs and insulin sensitivity
 Central adipose tissue is more “lipolytic” than peripheral
 Excess FFAs overwhelm the intracellular fatty acid oxidation
 leading to accumulation of cytoplasmic intermediates like diacylglycerol (DAG)
 DAG is a toxic intermediates that can attenuate signaling through the insulin
receptor pathway
 insulin normally inhibits gluconeogenesis by blocking the activity of
phosphoenolpyruvate carboxykinase
 Attenuated insulin signaling allows phosphoenolpyruvate carboxykinase to
“ramp up” gluconeogenesis
 Excess FFAs also compete with glucose for substrate oxidation
 leading to feedback inhibition of glycolytic enzyme
o Adipokines
 Adiponectin levels are reduced in obesity
  Leptin and adiponectin decrease the blood glucose
o Inflammation
 proinflammatory cytokines that are secreted in response to excess nutrients
such as free fatty acid and glucose
 Excess FFAs within macrophages and β cells can activate the inflammasome
 secretion of the cytokine interleukin IL-1β
 IL-1β, in turn, mediates the secretion of additional pro-inflammatory cytokines

β-Cell Dysfunction

 β-cell dysfunction is virtually a requirement for the development of overt diabetes

 β-cell function actually increases early in the disease process in most patients with “sporadic”
type 2 diabetes

Several mechanisms that promotes β-cell dysfunction in type 2 diabetes

 Lipotoxicity
 Glucotoxicity
 Incretin effect
 Amyloid deposition within islets
 Polymorphisms

Monogenic Forms of Diabetes

 primary defect in β-cell function

 defect in insulin receptor signaling

Genetic Defects in β-Cell Function

 1% to 2% of patients with diabetes

 affecting either β-cell mass and/or insulin production
 heterogeneous group of genetic defects
 “maturity onset diabetes of the young” (MODY)
 MODY can result from germline loss- of-function mutations in one of six genes
 Glucokinase (GCK) are the most common
 Glucokinase is a rate limiting step in oxidative glucose metabolism
 Glucokinase is coupled to insulin secretion within islet β cells
 Mutations in genes that code for the two subunits of the ATP-sensitive K+-channel
 defects in mitochondrial DNA
 mutations of the insulin gene itself

Genetic Defects that Impair Tissue Response to Insulin

  receptor synthesis
 insulin binding
 receptor tyrosine kinase activity
 type A insulin resistance
 Acanthosis nigricans - velvety hyperpigmentation of the skin
 Lipoatrophic diabetes - hyperglycemia accompanied by loss of adipose tissue
 Hepatic steatosis

Diabetes and Pregnancy

 when women with preexisting diabetes become pregnant (“pregestational” or overt diabetes)
 gestational diabetes
 Pregnancy is a diabetogenic state
 Women with pregestational diabetes have an increased risk of stillbirth and congenital
malformations in the fetus
 Poorly controlled diabetes that arises later in pregnancy, regardless of prior history, can lead to
macrosomia
 Gestational diabetes typically resolves following delivery
 majority of women with this condition will develop overt diabetes over the next 10 to 20 years

Clinical Features of Diabetes

 Type 1 diabetes
o now known to occur at any age
o honeymoon period - initial 1 or 2 years following the onset of overt type 1 diabetes,
exogenous insulin requirements may be minimal
o transition from impaired glucose tolerance to overt diabetes may be abrupt
 Type 2 diabetes
o older than 40 years
o obese
o unexplained fatigue, dizziness, or blurred vision
o diagnosis of type 2 diabetes is made after routine blood testing in asymptomatic
persons

The Classic Triad of Diabetes

 polyuria, polydipsia, polyphagia

 diabetic ketoacidosis if severe
 insulin deficiency results in a catabolic state
 Unopposed secretion of counterregulatory hormones
o Glucagon
 o growth hormone
o epinephrine
 Glycosuria induces an osmotic diuresis and thus polyuria
 Renal water loss plus hyperosmolarity tends to deplete intracellular water
 triggering the osmoreceptors of the thirst centers of the brain
 Proteolysis follows, releasing gluconeogenic amino acids

Acute Metabolic Complications of Diabetes

 Diabetic ketoacidosis is a severe acute metabolic complication of type 1 diabetes, but may also
occur in type 2 diabetes
 most common precipitating factor is a failure to take insulin
 epinephrine
o blocks any residual insulin action
o stimulates the secretion of glucagon
 insulin deficiency coupled with glucagon excess decreases peripheral utilization of glucose
 increasing gluconeogenesis, severely exacerbating hyperglycemia
 plasma glucose levels are usually in the range of 250 to 600 mg/dL
 Osmotic diuresis and dehydration are characteristics of the ketoacidotic state
 The second major effect of insulin deficiency is activation of the ketogenic machinery
 Insulin deficiency stimulates lipoprotein lipase
 FFA are esterified to fatty acyl coenzyme A
 Oxidation of fatty acyl coenzyme A molecules within the hepatic mitochondria produces ketone
bodies
 acetoacetic acid and β-hydroxybutyric acid
 ketonemia and ketonuria
 metabolic ketoacidosis
 fatigue, nausea and vomiting, severe abdominal pain
 fruity odor, and deep, labored breathing also known as Kussmaul breathing
 depression in cerebral consciousness and coma
 Reversal of ketoacidosis requires insulin, correction of metabolic acidosis, and treatment of the
underlying precipitating factors such as infection
 the frequency of ketoacidosis is significantly lower in type 2 diabetes
 Lower in DM type 2 because higher portal vein insulin levels in these patients, which prevents
unrestricted hepatic fatty acid oxidation
 type 2 diabetics may develop a condition known as hyperosmolar hyperosmotic syndrome
(HHS)
 The hyperglycemia is usually more severe than in diabetic ketoacidosis, in the range of 600 to
  1200 mg/dL
 the most common acute metabolic complication in either type of diabetes is hypoglycemia
 Hypoglycemia due to:
o as a result of having missed a meal
o excessive physical exertion
o an excess insulin administration
o during the phase of dose finding for antidiabetic agents
 hypoglycemia include dizziness, confusion, sweating, palpitations, and tachycardia, and loss of
consciousness
 Reversal of hypoglycemia through oral or intravenous glucose intake prevents the onset of
permanent neurological damage

Chronic Complications of Diabetes

 Diabetic macrovascular disease - damage induced in large and mediumsized muscular arteries
  Microvascular disease are most profound in
o Retina
o Kidneys
o Peripheral nerves
o resulting in diabetic retinopathy, nephropathy, and neuropathy, respectively
 Glucotoxicity seems to be responsible for the long term complications of diabetes
 Assessment of glycemic control in these trials has been based on the percentage of glycated
hemoglobin, also known as HbA1C
 HbA1C is formed by nonenzymatic covalent addition of glucose moieties to hemoglobin in RBC
 HbA1C provides a measure of glycemic control over the lifespan of a red cell (120 days)
 It is recommended that HbA1C be maintained below 7% in diabetic patients
 hyperglycemia is not the only factor responsible for the longterm complications of diabetes

 4 Mechanisms of deleterious effects of persistent hyperglycemia on peripheral tissues

o Formation of Advanced Glycation End Products
o Activation of Protein Kinase C
o Oxidative Stress and Disturbances in Polyol Pathways
o Hexosamine Pathways and Generation of Fructose-6Phosphate
 increased glucose flux through various intracellular metabolic pathways is thought to generate
harmful precursors that contribute to end organ damage

Formation of Advanced Glycation End Products

 Advanced glycation end products (AGEs)

 AGEs are formed from nonenzymatic reactions between intracellular glucose-derived
dicarbonyl precursors (glyoxal, methylglyoxal, and 3-deoxyglucosone) with the amino groups
of both intracellular and extracellular proteins
 The natural rate of AGE formation is greatly accelerated in the presence of hyperglycemia
 AGEs bind to a specific receptor (RAGE) that is expressed on inflammatory cells (macrophages
and T cells), endothelium, and vascular smooth muscle
 Detrimental effects of the AGE-RAGE signaling axis within the vascular compartment:
o cytokines and growth factors
o transforming growth factor β(TGFβ), deposition of excess basement membrane material
o vascular endothelial growth factor (VEGF), implicated in diabetic retinopathy
o reactive oxygen species (ROS) in endothelial cells
o Increased procoagulant activity on endothelial cells and macrophages
o proliferation of vascular smooth muscle cells
o synthesis of extracellular matrix
 Crosslinking of collagen type I molecules in large vessels decreases their elasticity, which may
predispose these vessels to shear stress and endothelial injury
 AGE-induced cross-linking of type IV collagen in basement membrane decreases endothelial
cell adhesion and increases extravasation of fluid
 Proteins cross-linked by AGEs are resistant to proteolytic digestion
  crosslinking decreases protein removal while enhancing protein deposition
 AGE-modified matrix components also trap nonglycated plasma or interstitial proteins
 In large vessels, trapping of LDL
 In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the
glycated basement membrane leading to diabetic microangiopathy

Activation of Protein Kinase C

 Calcium-dependent activation of intracellular protein kinase C (PKC) and second messenger

diacyl glycerol (DAG)
 Intracellular hyperglycemia stimulates the de novo synthesis of DAG from glycolytic
intermediates
 causes excessive PKC activation
 production of VEGF, TGF-β, and procoagulant protein plasminogen activator inhibitor-1 (PAI-1)
by the vascular endothelium

Oxidative Stress and Disturbances in Polyol Pathways

 Tissues that do not require insulin for glucose transport:

o Nerves
o Lenses
o Kidneys
o Blood vessels
 Tissues that don’t need insulin, persistent hyperglycemia leads to an increased intracellular
glucose
 Excess glucose intracellularly is metabolized by the enzyme aldose reductase to sorbitol
 and eventually to fructose in a reaction that uses NADPH (the reduced form of nicotinamide
dinucleotide phosphate) as a cofactor
 NADPH is also required by the enzyme glutathione reductase in a reaction that regenerates
reduced glutathione (GSH)
 progressive depletion of intracellular NADPH by aldol reductase compromises GSH
regeneration
 increasing cellular susceptibility to oxidative stress
 Sorbitol accumulation in the lens contributes to cataract formation

Hexosamine Pathways and Generation of Fructose-6Phosphate

 Hyperglycemia-induced flux through the hexosamine pathway

 increases intracellular levels of fructose-6-phosphate
 fructose-6-phosphate is a substrate for glycosylation of proteins
 generation of excess proteoglycans
 abnormal expression of TGFβ or PAI-1

Morphology and Clinical Features of Chronic Complications of Diabetes

Pancreas
 Reduction in the number and size of islets – DM type 1
 Leukocytic infiltrates in the islets (insulitis) – DM type 1; T-cell; infants
 In type 2 diabetes there may be a subtle reduction in islet cell mass
 Amyloid deposition within islets in type 2 diabetes
 An increase in the number and size of islets
 Diabetic Macrovascular Disease
o Endothelial dysfunction
o Accelerated atherosclerosis – hallmark
o Myocardial infarction – most common cause of death
o Gangrene of the lower extremities
o Hyaline arteriolosclerosis

 Diabetic Microangiopathy
o diffuse thickening of basement membranes
o vascular structures of:
 skin
 skeletal muscle
 retina
 renal glomeruli
 renal medulla
o also seen in nonvascular structures:
 renal tubules
 Bowman capsule
 Peripheral nerves
 placenta
o diabetic capillaries are more leaky than normal to plasma proteins
o nephropathy and retinopathy
 Diabetic Nephropathy
o glomerular lesions
o renal vascular lesions – arteriolosclerosis
o pyelonephritis, including necrotizing papillitis
o most important glomerular lesions are:
 capillary basement  membrane thickening
 diffuse mesangial sclerosis
 nodular  glomerulosclerosis
o Pure capillary basement membrane thickening can be detected only by electron
microscopy
o Diffuse Mesangial Sclerosis
o diffuse increase in mesangial matrix
o Matrix depositions are PAS-positive
o Kimmelstiel-Wilson disease
  Nodular Glomerulosclerosis
 Intercapillary glomerulosclerosis
 Ovoid or spherical, often laminated
 Nodules of matrix situated in the periphery of the glomerulus
 Nodules are PAS-positive
 Within mesangial core of the glomerular lobules
 nodules often show features of mesangiolysis
 Capillary microaneurysms
 Uninvolved lobules and glomeruli show diffuse mesangial sclerosis
 Fibrin caps - hyaline material in capillary loops
 Capsular drops – adherent to Bowman capsules
 Both afferent and efferent glomerular hilar arterioles show hyalinosis
 Tubular atrophy and Interstitial fibrosis
 Overall contraction in size
 15% - 30% of long-term diabetics
o Renal atherosclerosis and arteriolosclerosis
o Pyelonephritis
 Both acute and chronic forms are more common in diabetics
 Necrotizing papillitis or papillary necrosis
 Diabetic Ocular Complications
o acquired opacification of the lens
o cataract
o increased intraocular pressure (glaucoma) 
o most profound histopathologic changes of diabetes are seen in the retina
o preproliferative diabetic retinopathy and proliferative diabetic retinopathy 
 Diabetic Neuropathy
o 50% of  diabetics overall have peripheral neuropathy
o 80% of those who have had the disease for more than 15  years
Clinical Manifestations of Chronic Diabetes
 In both types it is the longterm effects of diabetes that are responsible for the majority of the
morbidity and mortality
 Mostly 15 to 20 years after the onset of hyperglycemia do complications occur
 Macrovascular complications - most common causes of mortality
o myocardial infarction
o renal vascular insufficiency
o cerebrovascular accidents
 Diabetics have a 2 – 4 times greater incidence of coronary artery disease
 Fourfold higher risk of dying from cardiovascular complications than nondiabetics
 Myocardial infarction is almost as common in diabetic women
 Diabetic dyslipidemia – from insulin resistance
 Elevated PAI-1, an inhibits fibrinolysis; a procoagulant; formation of atherosclerotic plaques
 Native Americans, Hispanics, and African Americans have a greater risk of developing end-
stage renal disease than do non-Hispanic whites with type 2 diabetes
 Microalbuminuria
o early sign of diabetic nephropathy
o low urine albumin (30 - 300 mg/day)
o marker for greatly increased cardiovascular morbidity and mortality
o should be screened for macrovascular disease
o Without intervention, 80% of type 1 diabetics and 20% to 40% of type 2 diabetics will
develop overt nephropathy with macroalbuminuria (>300 mg) over 10 to 15 years, with
hypertension
 May require dialysis or renal transplantation
 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 administration of antiangiogenic agents
 increased propensity for glaucoma and cataract formation
 Most frequent pattern of involvement is a distal symmetric polyneuropathy of the lower
extremities that affects both motor and sensory function
 “glove and stocking” pattern of polyneuropathy
 autonomic neuropathy, which produces disturbances in bowel and bladder function and
sometimes erectile dysfunction
 diabetic mononeuropathy, which may manifest as sudden footdrop, wristdrop, or isolated
cranial nerve palsies
 enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia, and
pyelonephritis
 decreased neutrophil functions
 impaired cytokine production by macrophages
Pancreatic Neuroendocrine Tumors

 pancreatic neuroendocrine tumors or PanNETs

 2% of all pancreatic neoplasms
 PanNETs can occur anywhere along the length of the pancreas
 resemble their counterparts, carcinoid tumors, found elsewhere in the alimentary tract
 may be single or multiple and benign or malignant
 often elaborate pancreatic hormones, or may be nonfunctional
 90% of insulin producing tumors are benign
 60% to 90% of other functioning and nonfunctioning pancreatic endocrine neoplasms are
malignant
 Insulinomas are the most common subtype of pancreatic endocrine neoplasms

Three major genes or pathways

 MEN1 - familial MEN syndrome, type 1; sporadic neuroendocrine tumors

 PTEN and TSC2
o loss-of-function mutations in tumor suppressor genes
o activation of the oncogenic mammalian TOR (mTOR) signaling pathway
 Alpha-thalassemia/ mental retardation syndrome, X-linked (ATRX) and death domain
associated protein (DAXX)
o Inactivating mutations in two genes
o telomere maintenance
o nearly half of PanNETs have a somatic mutation in either ATRX or DAXX, but not both

Three clinical syndromes with PanNET

 Hyperinsulinism
 Hypergastrinemia and the Zollinger-Ellison syndrome
 Multiple endocrine neoplasia (MEN)
Hyperinsulinism (Insulinoma)

 Induce clinically significant hypoglycemia

 blood glucose level falls below 50 mg/dL of serum
 confusion
 stupor
 loss of consciousness
 precipitated by fasting or exercise
 promptly relieved by feeding or parenteral administration of glucose
 generally benign
 Most are solitary
 Bona fide carcinomas are diagnosed based on local invasion and distant metastases
 Insulinoma may arise in ectopic pancreatic tissue
 usually small (often < 2 cm in diameter),  encapsulated
 pale to red-brown nodules
 located anywhere in  the pancreas
 benign tumors look remarkably like giant islets
 preservation of the regular cords of  monotonous cells
 Deposition of amyloid – feature of insulinoma
 focal or diffuse hyperplasia of the islets
 Nesidioblastosis
o islet hyperplasia
o Beckwith-Wiedemann syndrome
o maternal diabetes
o mutations in the β-cell K+-channel protein
o mutations in sulfonylurea receptor
 Surgical removal of the tumor is usually followed by prompt reversal of the hypoglycemia
Zollinger-Ellison Syndrome (Gastrinomas)

 hypersecretion of gastrin
 Gastrinoma triangle - arise in the duodenum and peripancreatic soft tissues as in the pancreas
 severe peptic ulceration
 More than half of gastrin-producing tumors are locally invasive
 as part of the MEN-1  syndrome
 sporadic gastrinomas are usually  single
 duodenal and gastric ulcers are  often multiple
 often  unresponsive  to  therapy
 ulcers may occur in unusual locations such as the jejunum
 intractable jejunal ulcers
 50% of the patients have diarrhea
 Treatment include H+K+-ATPase inhibitors and excision of the neoplasm
 Total resection of the neoplasm, when possible, eliminates the syndrome
 Patients with hepatic metastases have a shortened life expectancy

Other Rare Pancreatic Endocrine Neoplasms

 (Alpha) α-cell tumors (glucagonomas)

o increased serum levels of glucagon
o necrolytic migratory erythema
o anemia
o in perimenopausal and postmenopausal women
 (Delta) δ-cell tumors (somatostatinomas)
o diabetes mellitus
o cholelithiasis
o steatorrhea
o hypochlorhydria
o High plasma somatostatin levels are required for diagnosis
 VIPoma
o WDHA syndrome
 watery diarrhea
 hypokalemia
 achlorhydria
o vasoactive intestinal peptide (VIP) from the tumor
o some are locally invasive and metastatic
o VIP assay should be performed on all patients with severe secretory diarrhea
o Associated with Neural crest tumors
 Neuroblastomas
 Ganglioneuroblastoma and ganglioneuromas
 Pheochromocytomas
 Pancreatic carcinoid tumors
o producing serotonin
 o atypical carcinoid syndrome
 Pancreatic polypeptide-secreting endocrine tumors
o mass lesions
o high plasma levels of this hormone fail to cause symptoms
 Some pancreatic and extra-pancreatic endocrine tumors produce two or more hormones
 May produce ACTH, MSH, ADH, serotonin, and norepinephrine
 Multihormonal tumors are to be distinguished from the MEN syndromes

ADRENAL GLANDS

Adrenal Cortex

 Zona glomerulosa - beneath the capsule; narrow layer

 Zona reticularis - an equally narrow zone abuts the medulla
 Zona fasciculata - intervening zone; 75% of the total cortex
 Three different types of steroids
o Glucocorticoids
 principally cortisol
 zona fasciculata
 lesser in the zona reticularis
o Mineralocorticoids
 Aldosterone
 zona glomerulosa
o Sex steroids
 estrogens and androgens
 zona reticularis
 Adrenal medulla is composed of chromaffin cells for catecholamines

Adrenocortical Hyperfunction (Hyperadrenalism)

 Overproduction of the three major hormones of the adrenal cortex

o Cushing syndrome - characterized by an excess of cortisol
o Hyperaldosteronism - as a result of excessive aldosterone
o Adrenogenital or virilizing syndromes - caused by an excess of androgens
Hypercortisolism (Cushing Syndrome)

 elevated glucocorticoid levels

 broadly divided into exogenous and endogenous causes
 most common cause is exogenous or iatrogenic
 endogenous can be ACTH dependent or ACTH independent
 ACTHsecreting pituitary adenomas account for approximately 70% of hypercortisolism
 Harvey Cushing, the neurosurgeon who first published the full description of this syndrome
 pituitary form is referred to as Cushing disease
 Young adult; Women by 4 times more than men
 Most commonly caused by ACTH-producing pituitary microadenoma
 Rarely by corticotroph cell hyperplasia without a discrete adenoma
 Nodular cortical hyperplasia caused by the elevated levels of ACTH
 The cortical hyperplasia is responsible for hypercortisolism
 Secretion of ectopic ACTH by nonpituitary tumors accounts for about 10% of ACTH-dependent
Cushing syndrome
 Can be caused by small-cell carcinoma of the lung
 Neuroendocrine neoplasm may produce ectopic corticotrophin releasing hormone (CRH) that
causes ACTH secretion and hypercortisolism
 In the pituitary variant, the adrenal glands undergo bilateral cortical hyperplasia
 This variant of Cushing syndrome is more common in older men
 Primary adrenal neoplasms
o Adrenal adenoma - 10% and
o Carcinoma - 5%
o Most common causes for ACTHindependent Cushing syndrome
 Biochemical sine qua non of ACTH-independent Cushing syndrome is elevated serum levels of
cortisol with low levels of ACTH
 Cortical carcinomas have more marked hypercortisolism than adenomas or hyperplasias
 In unilateral neoplasm, the uninvolved adrenal cortex and the cortex in the opposite gland
undergo atrophy because of suppression of ACTH secretion
 Majority of hyperplastic adrenals are ACTH dependent
 Macronodular hyperplasia
o nodules are usually greater than 3 mm in diameter
o sporadic (nonsyndromic) condition observed in adults
o not entirely “autonomous” ACTH independent
o replaced by prominent nodules
 McCuneAlbright syndrome
o somatic mutations that activate GNAS, which encodes a stimulatory Gsα
o causes hyperplasia by increasing intracellular levels of cAMP
 Main lesions of Cushing syndrome are found in pituitary and adrenal glands
 Crooke hyaline change – most common; high levels of glucocorticoids
 Anterior pituitary becomes homogeneous and paler
  Accumulation of intermediate keratin filaments  in the cytoplasm
 Cortical atrophy

Hypercortisolism (Cushing Syndrome) continuation….

 Diffuse hyperplasia
 Macronodular or micronodular hyperplasia
 Adenoma or carcinoma
 Exogenous glucocorticoids
o Suppression of endogenous ACTH results in bilateral cortical atrophy
o Due to lack of stimulation of the zona fasciculata and reticularis by ACTH
 Zona glomerulosa is of normal thickness; because it is independent from ACTH
 Diffuse hyperplasia is found in ACTH-dependent Cushing syndrome
 Hyperplastic cortex demonstrates an expanded lipid-poor zona reticularis
 surrounded  by  an  outer  zone  of  vacuolated  “lipid-rich”  cells
 Micronodular hyperplasia – composed of 1-3-mm darkly pigmented (brown to black)
micronodules
 Pigment  is  believed to be lipofuscin, a wear-and-tear pigment
 Adrenocortical adenomas – yellow tumors surrounded by thin or well-developed capsules
 Carcinomas - are unencapsulated masses and larger than adenomas
 Hypertension
 Weight gain
 Truncal obesity
 Moon facies
 Buffalo hump
 Selective atrophy of fast-twitch (type 2) myofibers
 Decreased muscle mass and proximal limb weakness
 Secondary diabetes - hyperglycemia, glucosuria and polydipsia
 Loss of collagen
 Bone resorption
 Fragile skin
 Poor wound healing
 Abdominal cutaneous striae
 Infection risk - because glucocorticoids suppress the immune response
 Mood swings, depression, and frank psychosis
 Hirsutism and menstrual abnormalities
Basis of laboratory diagnosis of Cushing syndrome

 increased 24-hour urine free-cortisol concentration

 loss of normal diurnal pattern of cortisol secretion
Test results fall into three general patterns:

1. Pituitary Cushing syndrome

 Cannot be suppressed by the administration of a low dose of dexamethasone

 No reduction in urinary excretion of 17-hydroxycorticosteroids
 Pituitary responds by reducing ACTH secretion seen in urinary steroid
 Ectopic ACTH secretion results in an elevated level of ACTH
 Secretion is completely insensitive to low or high doses of exogenous dexamethasone

2. Adrenal tumor Cushing syndrome

 ACTH level is quite low because of feedback inhibition of the pituitary

 Both low-dose and high-dose dexamethasone fail to suppress cortisol excretion

3. Primary Hyperaldosteronism

 chronic excess aldosterone secretion

 from an autonomous overproduction of aldosterone
 suppression of the reninangiotensin system
 decreased plasma renin activity
 Blood pressure elevation is the most common manifestation
o Bilateral idiopathic hyperaldosteronism
 bilateral nodular hyperplasia of the adrenal glands
 most common cause of primary
 Germline mutations of KCNJ5, encoding a potassium channel
 in older people
o Adrenocortical neoplasm
 Conn syndrome
 adult middle life
 women
 Somatic mutations of KCNJ5
o Glucocorticoid-remediable hyperaldosteronism
 rearrangement involving chromosome 8
 CYP11B2 (the gene that encodes aldosterone synthase) under the control of the
ACTH responsive CYP11B1 gene promoter
 ACTH thus stimulates the production of aldosterone synthase
 aldosterone production is under the control of ACTH
 suppressible by dexamethasone
Secondary hyperaldosteronism

 aldosterone release from reninangiotensin system

 increased levels of plasma renin
 Decreased renal perfusion
 Arterial hypovolemia and edema
 Pregnancy – from estrogen-induced increases in plasma renin substrate
Aldosterone-producing adenomas

 Solitary
 well-circumscribed  lesions
 more often found on the left
 in the 30s and 40s, and in women
 buried within the gland
 do not produce  visible enlargement
 bright yellow on cut  section
 composed of lipid-laden cortical  cells
 uniform in size and shape
 Spironolactone bodies – characteristic feature; eosinophilic, laminated cytoplasmic inclusions
 Adjacent adrenal cortex and contralateral gland are not atrophic
 Resemble zona fasciculata cells
 Bilateral idiopathic hyperplasia
o diffuse and  focal hyperplasia of cells
o Resemble zona glomerulosa cells
o wedge-shaped
o from the periphery toward the center of the gland
 Hypertension - most important clinical consequence of hyperaldosteronism
 Prevalence of hyperaldosteronism increases with the severity of hypertension
 20% are treatment-resistant hypertension
 Hypokalemia was considered a mandatory feature of primary hyperaldosteronism
 Screening test is ratios of plasma aldosterone concentration to plasma renin activity
 If this screening is positive, a confirmatory aldosterone suppression test must be performed
 Adenomas are amenable to surgical excision
 No surgery recommended for primary hyperaldosteronism due to bilateral hyperplasia
 Aldosterone antagonist such as spironolactone

Adrenogenital Syndromes

 Disorders of sexual differentiation

 virilization or feminization
 caused by primary gonadal disorders
 Adrenal cortex secretes two compounds:
o Dehydroepiandrosterone
o Androstenedione - converted to testosterone in peripheral tissues
 ACTH regulates adrenal androgen formation
 Excess secretion can occur either as a pure syndrome or as a component of Cushing
 Androgen excess include adrenocortical neoplasms and congenital adrenal hyperplasia (CAH)
 Virilization are more likely to be androgen-secreting adrenal carcinomas than adenomas
Congenital adrenal hyperplasia

 Autosomal recessive, inherited metabolic errors

 deficiency or total lack of a particular enzyme involved in the biosynthesis of cortical steroids,
particularly cortisol
 Steroid precursors that build behind the defective step are channeled into other pathways
 Increased production of androgens
 Virilization
 Simultaneously, the deficiency of cortisol leads to increased secretion of ACTH

21-hydroxylase deficiency

 mutations of CYP21A2
 most common
 Classic - salt-wasting adrenogenitalism
 Non-classic adrenogenitalism
 simple virilizing adrenogenitalism
 Salt-wasting syndrome
o from an inability to convert progesterone into deoxycorticosterone
o total lack of the hydroxylase
o virtually no synthesis of mineralocorticoids
o block in the conversion of hydroxyprogesterone into deoxycortisol
o deficient cortisol synthesis
o after birth; because electrolytes and fluids can be maintained by the maternal kidneys
o hyponatremia
o hyperkalemia
o acidosis
o hypotension
o cardiovascular collapse
o virilization
o Males clinical attention 5 to 15 days later after birth
 Simple virilizing adrenogenital syndrome without salt wasting
o genital ambiguity
o 1/3 of patients with 21-hydroxylase deficiency
o sufficient mineralocorticoid to prevent a salt-wasting “crisis”
o failure of feedback inhibition of ACTH secretion
o level of testosterone is increased
o progressive virilization
 Nonclassic or late-onset adrenal virilism
o more common than the classic patterns
o mild manifestations
o hirsutism
o acne
o menstrual irregularities
o diagnosis by biosynthetic defects in steroidogenesis
Congenital adrenal hyperplasia (CAH)

 Adrenals are bilaterally hyperplastic
 increasing to 10 to 15 times their normal weights
 adrenal cortex  is  thickened  and  nodular
 brown, because of total depletion of all lipid
 Hyperplasia of corticotroph (ACTH-producing) cells is present in anterior pituitary in most
persons with CAH
 CAH also affects the products synthesized in the medulla
 High levels of intra-adrenal glucocorticoids are required to facilitate medullary catecholamine
 Severe salt-wasting 21-hydroxylase deficiency
o low cortisol levels and developmental defects of the medulla
o predispose to hypotension and circulatory collapse
 Masculinization in females – excessive androgenic activity
 Clitoral hypertrophy
 Pseudohermaphroditism in infants
 Oligomenorrhea
 Hirsutism
 Acne in postpubertal females
 Enlargement of the external genitalia
 CAH should be suspected in any neonate with ambiguous genitalia
 CAH are treated with exogenous glucocorticoids
 Mineralocorticoid supplementation is required in the salt-wasting variants of CAH

Adrenocortical Insufficiency

 caused by either primary adrenal disease (primary hypoadrenalism)

 or decreased stimulation of the adrenals due to a deficiency of ACTH (secondary
hypoadrenalism)
 Patterns
o Adrenal crisis
o Addison disease - primary chronic
o Secondary adrenocortical insufficiency

Primary Acute Adrenocortical Insufficiency

 As a crisis precipitated by any form of stress that requires increased in steroid output
 Rapid withdrawal of steroids or failure to increase steroid doses in response to an acute stress
 Massive adrenal hemorrhage which affects adrenal cortex
Waterhouse-Friderichsen Syndrome

 Bacterial infection - Neisseria meningitides

 Rapidly progressive hypotension leading to shock
 DIC with purpura
 Massive bilateral adrenal hemorrhage
 more common in children
 Adrenals are converted to sacs of clotted blood
 Hemorrhage starts within medulla near thin-walled venous sinusoids
 suffuses peripherally into the cortex
 Islands of recognizable cortical cells
 Death follows within hours to a few days
Primary Chronic Adrenocortical Insufficiency (Addison Disease)

 Thomas Addison
 General languor
 Debility
 Feebleness of the heart’s action
 Peculiar change in the color of the skin
 Suprarenal capsules – the adrenal glands
 Adrenocortical insufficiency do not appear until at least 90% of the adrenal cortex has been
compromised
 Autoimmune adrenalitis
o more common in whites; women
o 60% to 70% of cases
o destruction of steroidogenic cells
o autoantibodies to steroidogenic enzymes (21-hydroxylase, 17-hydroxylase)
o Autoimmune polyendocrine syndrome type 1 (APS1) - autoimmune polyendocrinopathy
 chronic mucocutaneous candidiasis
 ectodermal dystrophy
 pernicious anemia
 mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22
 AIRE is expressed primarily in the thymus
 In the absence of AIRE function, central T-cell tolerance to peripheral tissue
antigens is compromised, promoting autoimmunity
 autoantibodies against IL-17 and IL-22 of TH17 T-cells
 IL-17 and IL-22 are for fungal infections
o Autoimmune polyendocrine syndrome type 2 (APS2)
 early adulthood
 with autoimmune thyroiditis or type 1 diabetes
 NO ectodermal dysplasia and autoimmune hypoparathyroidism
 Infections, particularly tuberculosis
 Tuberculous adrenalitis - 90% of cases of Addison disease
 Fungal - Histoplasma capsulatum and Coccidioides immitis
 noninfectious (Kaposi sarcoma) complications
 Metastatic neoplasms involving the adrenals
 Genetic causes of adrenal insufficiency
o Congenital adrenal hypoplasia – is a X-linked disease
o Adrenoleukodystrophy
Primary autoimmune adrenalitis

 irregularly shrunken glands
 scattered residual cortical cells in a collapsed network of connective tissue
 medulla is otherwise preserved

Tuberculous and fungal disease

 adrenal architecture is effaced by a granulomatous inflammatory  reaction
 adrenals are enlarged in metastatic carcinoma
 initial manifestations include progressive weakness and easy fatigability
 anorexia, nausea, vomiting, weight loss, and diarrhea
 hyperpigmentation of the skin - neck, elbows, knees, and knuckles
 elevated levels of pro-opiomelanocortin (POMC)
 POMC
o from the anterior pituitary
o precursor of both ACTH and melanocyte stimulating hormone (MSH)
 primary pituitary or hypothalamic disease has no hyperpigmentation
 Decreased mineralocorticoid activity results in potassium retention and sodium loss
 Hyperkalemia
 hyponatremia
 volume depletion
 hypotension
 Hypoglycemia from impaired gluconeogenesis
 Death occurs rapidly unless corticosteroid therapy begins immediately
Secondary Adrenocortical Insufficiency

 Any disorder of the hypothalamus and pituitary

 prolonged administration of exogenous glucocorticoids suppresses the output of ACTH
 No hyperpigmentation
 because levels of melanocyte-stimulating hormone are not elevated
 deficient cortisol and androgen output
 Normal aldosterone synthesis
 NO hyponatremia and hyperkalemia
 with secondary hypofunction there is a prompt rise in plasma cortisol levels
 Adrenals may be moderately to markedly decreased in size
 Small, flattened glands usually retain yellow color as a result of small amount of residual lipid
 Cortex may be reduced to a thin ribbon composed largely of zona glomerulosa
 Medulla is unaffected

Adrenocortical Neoplasms

 most cortical neoplasms are sporadic

 Li-Fraumeni syndrome and BeckwithWiedemann syndrome have predisposition for
adrenocortical carcinomas
 Li-Fraumeni syndrome - TP53 mutations
 BeckwithWiedemann syndrome - disorder of epigenetic imprinting
 Functional adenomas are associated with hyperaldosteronism and Cushing syndrome
 Virilizing neoplasm is more likely to be a carcinoma
 Not all adrenocortical neoplasms elaborate steroid hormones
 Functional and nonfunctional adrenocortical neoplasms cannot be distinguished on the basis of
morphologic features
 Determination of functionality is based on
o clinical evaluation
o hormones or hormone metabolites in the blood
 Adrenocortical adenomas are clinically silent mostly
 well circumscribed and nodular
 Cortex adjacent to nonfunctional adenomas is normal
 Adenomas – yellow to yellow brown because of the presence of lipid
 Endocrine atypia
 Cytoplasm of the neoplastic cells ranges from eosinophilic to  vacuolated
Adrenocortical carcinomas

 occur at any age, including childhood
 more likely to  be functional than adenomas
 often associated with  virilism
 large,  invasive  lesions
 variegated
 poorly demarcated lesions containing areas of necrosis, hemorrhage, and cystic change
 strong tendency to invade the adrenal vein, vena cava, and lymphatics
 Metastases to regional and periaortic nodes
 median patient survival is about  2 years
 Adrenocortical carcinomas  may  be  composed of well-differentiated cells
 or bizarre, monstrous giant cells
Other Adrenal Lesions

 Adrenal cysts may produce an abdominal mass and flank pain

 Nonfunctional cysts
 Adrenal myelolipomas
o Benign
o composed of mature fat and hematopoietic cells
 Adrenal incidentaloma
o adrenal masses in asymptomatic individuals
o complaint is not directly related to the adrenal gland
o age-dependent increase in prevalence
o mostly small nonsecreting cortical adenomas of no clinical importance
Adrenal Medulla

 developmentally, functionally, and structurally distinct from the adrenal cortex

 composed of :
o specialized neural crest (neuroendocrine) cells, termed chromaffin cells
o supporting (sustentacular) cells
 major source of catecholamines (epinephrine, norepinephrine)
 Neuroendocrine cells are widely dispersed in an extra-adrenal system; clusters and nodules
 Paraganglion system - neuroendocrine cells plus adrenal medulla
 Extra-adrenal paraganglia are closely associated with the autonomic nervous system
 Paraganglion system three groups based on their anatomic distribution
o Branchiomeric
o Intravagal
o Aorticosympathetic
 The branchiomeric and intravagal paraganglia associated with the parasympathetic system
 They are also located close to the major arteries and cranial nerves of the head and neck and
include the carotid bodies
 The intravagal paraganglia are distributed along the vagus nerve
 The aorticosympathetic chain
o found with segmental ganglia of the sympathetic system
o distributed mainly alongside of the abdominal aorta
o organs of Zuckerkandl is close to the aortic bifurcation

Pheochromocytoma

 neoplasms composed of chromaffin cells

 synthesize and release catecholamines and sometimes peptide hormones
 surgically correctable hypertension
 Traditional rule of 10s
o 10% are extra-adrenal - paragangliomas; organs of Zuckerkandl and the carotid body
o 10% of sporadic are bilateral
o 10% are malignant
o 10% have no hypertension
 Now, 25% of individuals with pheochromocytomas and paragangliomas harbor a germline
mutation in one of at least six known genes
 Affected genes fall into two broad classes:
o those that enhance growth factor receptor pathway signaling (e.g., RET, NF1)
o those that increase the activity of the transcription factor HIF-1α
 VHL gene encodes a tumor suppressor protein that is needed for the oxygen-dependent
degradation of HIF-1α
 Other mutations include germline mutations in genes encoding components of the succinate
dehydrogenase complex (SDHB, SDHC, and SDHD)
 This complex is involved in mitochondrial electron transport and oxygen sensing
 Pheochromocytomas range from small, circumscribed lesions  confined  to 
the  adrenal to  large  hemorrhagic  masses
 average weight of a pheochromocytoma is 100 gm
 The larger tumors are well  demarcated by either connective tissue or 
compressed cortical  or  medullary  tissue
 lobular pattern
 yellow-tan
 Larger lesions  tend to be hemorrhagic, necrotic, and cystic and typically 
efface the adrenal gland
 Chromaffin – incubation of fresh tissue with potassium dichromate solution turns tumor into
a  dark brown color
 Polygonal to spindle shaped chromaffin cells or chief cells surrounded by supporting
sustentacular cells
 Zellballen – small nests or alveoli;  supplied by a rich vascular network
 cytoplasm has a finely granular appearance;  containing  catecholamines
 nuclei are usually round to ovoid, with a  stippled “salt and pepper” chromatin
 membrane-bound, electron-dense secretory granules
 chromogranin and synaptophysin is seen in the chief cells
 peripheral sustentacular cells stain with antibodies  against S-100
 S-100 is a calcium-binding protein expressed by a variety  of mesenchymal 
cell types
 There is no histologic feature that reliably predicts clinical behavior
 Tumors  with  “benign”  histologic  features  may  metastasize
 while  bizarrely  pleomorphic  tumors  may  remain  confined  to    the 
adrenal gland
 cellular and nuclear pleomorphism,  including  the  presence  of  giant  cells, 
and  mitotic  figures    are often seen in benign pheochromocytomas
 monotony  is  paradoxically  associated  with  an  aggressive  behavior
 Even capsular and vascular invasion may be encountered in benign lesions
 definitive diagnosis of malignancy is based exclusively on the presence of metastases
 2/3 of patients with hypertension demonstrate paroxysmal episodes
 abrupt, precipitous elevation in blood pressure
 with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension
 may also be associated with pain in the abdomen or chest, nausea, and vomiting
 paroxysms may be precipitated by emotional stress, exercise, changes in posture, and
palpation in the region of the tumor
 urinary bladder paragangliomas occasionally precipitate paroxysm during micturition
 catecholamine cardiomyopathy
 or catecholamine-induced myocardial instability and ventricular arrhythmias
 some cases pheochromocytomas secrete other hormones, such as ACTH and somatostatin
 laboratory diagnosis of pheochromocytoma is based on the demonstration of increased urinary
excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and
metanephrines
 Multifocal lesions require long-term medical treatment for hypertension
 MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

 MEN syndromes are a group of inherited diseases resulting in proliferative lesions

 Tumors occur at a younger age than sporadic tumors
 arise in multiple endocrine organs, synchronously or metachronously (at different times)
 tumors are often multifocal
 preceded by an asymptomatic stage of hyperplasia
 MEN-2 have C-cell hyperplasia in the thyroid parenchyma adjacent to medullary thyroid
carcinomas
 More aggressive and recur in a higher proportion of cases than sporadic endocrine tumors

Multiple Endocrine Neoplasia, Type 1

 Wermer syndrome
 2 per 100,000
 the 3Ps: with additional
o Parathyroid: Primary hyperparathyroidism is the most common sign of MEN-1
o Pancreas: Endocrine tumors of the pancreas are a leading cause of morbidity and
mortality
o Pituitary: Prolactinoma; most frequent anterior pituitary tumor in MEN-1; acromegaly
o Duodenum is the most common site of gastrinomas in individuals with MEN-1
 germline mutations in the MEN1 tumor suppressor gene
 which encodes a protein called menin
 Menin may either promote or inhibit tumorigenesis
o factors—JunD - multiple endocrine neoplasia
o mixed lineage leukemia (MLL) protein - leukemia
 dominant clinical manifestations of MEN-1 is from the peptide hormones
o recurrent hypoglycemia due to insulinomas
o intractable peptic ulcers in persons with Zollinger-Ellison syndrome
o nephrolithiasis caused by PTH-induced hypercalcemia
o symptoms of prolactin excess from a pituitary tumor
Multiple Endocrine Neoplasia, Type 2

 three distinct syndromes:

o MEN-2A, or Sipple syndrome
 Pheochromocytoma
 Medullary carcinoma of the thyroid – 100% of patients; aggressive; calcitonin
 Parathyroid hyperplasia - hypercalcemia or renal stones
 MEN2A is clinically and genetically distinct from MEN1
 germline gainoffunction mutations in the RET protooncogene on chromosome
10q11.2
 RET proto-oncogene encodes a receptor tyrosine kinase that binds glial-derived
neurotrophic factor (GDNF)
 On the opposite, loss-of-function mutations in RET result in intestinal
aganglionosis and Hirschsprung disease
o MEN-2B has significant clinical overlap with MEN-2A
 No primary hyperparathyroidism
 neuromas or ganglioneuromas
 skin
 oral mucosa
 eyes
 respiratory tract
 gastrointestinal tract
 Marfanoid habitus - long axial skeletal features and hyperextensible joints
o Familial medullary thyroid cancer
 strong predisposition to medullary thyroid cancer but not the other clinical
manifestations of MEN-2A or MEN-2B
PINEAL GLAND

 minute, pinecone-shaped organ

 weighing 100 to 180 mg
 lying between the superior colliculi at the base of the brain
 composed of a loose, neuroglial stroma enclosing nests of epithelial-appearing pineocytes
 cells with photosensory and neuroendocrine functions (hence the designation of the pineal
gland as the “third eye”)
 cells have long, slender processes reminiscent of primitive neuronal precursors intermixed
with the processes of astrocytic cells
 Melatonin
o principal secretory product of the pineal gland
o control of circadian rhythms
o sleep-wake cycle
o treatment of jet lag
 Tumors arise from sequestered embryonic germ cells
 Germinomas, resembling testicular seminoma or ovarian dysgerminoma
 Germ cell differentiation include:
o Mixtures of germinoma
o Embryonal carcinoma
o Choriocarcinoma
o Teratomas (usually benign)