GSP M.02 Endocrine System II (Endocrine Pancreas and Adrenal Glands) PDF

PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS o GENERAL AND SYSTEMIC PATHOLOGY LECTURE LECTURER: DR. ARLENE QUITASOL DATE:MARCH 7 2024 Also stimulates gastrointestinal fluid secretion and causes secretory diarrhea. Enterechromaffin Cells synthesize...

PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS o GENERAL AND SYSTEMIC PATHOLOGY LECTURE LECTURER: DR. ARLENE QUITASOL DATE:MARCH 7 2024 Also stimulates gastrointestinal fluid secretion and causes secretory diarrhea. Enterechromaffin Cells synthesize serotonin and are the source of pancreatic tumors that cause the carcinoid syndrome TOPIC OUTLINE I. II. III. ENDOCRINE PANCREAS DIABETES MELLITUS ADRENAL GLANDS ENDOCRINE PANCREAS Consists of about 1 million clusters of cells, the islets of Langerhans, which contain four major and two minor cell types. The four main types are o β (beta) o α (alpha) o δ (gamma) o PP (pancreatic polypeptide) cell β (beta) cells produce INSULIN, which regulates glucose utilization in tissues and reduces blood glucose levels α (alpha) cells secrete GLUCAGON, which stimulates glycogenolysis in the liver and thus increases blood sugar. δ (gamma) cells Secrete SOMATOSTATIN, which suppresses both insulin and glucagon release PP (pancreatic polypeptide) cells Secrete PANCREATIC POLYPEPTIDE, which exerts several gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility. Not only are present in islets but also are scattered throughout the exocrine pancreas Two rare cell types D1 Cells Enterochromafin cells D1 cells Elaborate vasoactive intestinal polypeptide (VIP), o hormone that induces glycogenolysis and hyperglycemia NOTE TAKER: Figure 24.27 Hormone production in pancreatic islet cells. lmmunoperoxidase staining shows insulin in beta cells (A). glucagon in alpha cells (B), and somatostatin in gamma cells (C). (D) Electron micrograph of a beta cell shows the characteristic membrane-bound granules. each containing a dense, often rectangclar core and distinct halo. (E) Portions of an alpha cell (left) and a gamma cell (right) also show granules. but with dosely apportioned membranes. The alpha cell granule shows a dense. round center ENDROCRINE PANCREAS Two main disorders of islet cells o Diabetes Mellitus o Pancreatic Endocrine tumors DIABETES MELLITUS Group of metabolic disorders sharing the common feature of hyperglycemia caused by defects in insulin secretion, insulin action, or most commonly, both. Chronic hyperglycemia and attendant metabolic deregulation may be associated with secondary damage in multiple organ systems, especially the: o Kidneys o Eyes o Nerves o Blood vessels FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 1 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS In the US: leading cause o End-stage renal disease o Adult-onset blindness o Nontraumatic lower extremity amputations IMPAIRED GLUCOSE TOLERANCE OR “PREDIABETES” Elevated blood sugar that does not reach the criterion used for an outright diagnosis of type 2 diabetes (T2D) Individuals with prediabetes are at risk for developing frank T2D DIAGNOSIS Blood glucose is normally maintained in a very narrow range of 70 to 120 mg/dL. According to the ADA and WHO, diagnostic criteria for diabetes include the following: o A fasting plasma glucose ≥126 mg/dL o A random plasma glucose ≥200 mg/dL (in a patient with classic hyperglycemic signs) o A 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test (OGTT) with a loading dose of 75 g o A glycated hemoglobin (HbA1c) level ≥6.5% o All tests, except the random blood glucose test in a patient with classic hyperglycemic signs, need to be repeated and confirmed on a separate day o If there is discordance between two assays, the result with the greatest degreee of abnormality is considered the “readout” PREDIABETES A state of dysglycemia that often precedes development of frank T2D, is defined by one or more of the following: A fasting plasma glucose between 100 and 125 mg/dL (“impaired fasting glucose”) A 2-hour plasma glucose between 140 and 199 mg/dL following a 75-g oral glucose tolerance test (OGTT) (“impaired glucose tolerance”) A glycated hemoglobin (HbA1c) level between 5.7% and 6.4% CLASSIFICATION The vast majority of cases of diabetes fall into one of two broad classes: o TYPE 1 DIABETES (T1D) o TYPE 2 DIABETES (T2D) NOTE TAKER: TYPE 1 DIABETES (T1D) Autoimmune disease characterized by: Most common subtype diagnosed in patients younger than 20 years of age o Pancreatic β-cell destruction o Absolute deficiency of insulin o Accounts for approximately 5% to 10% of diabetes o Most common subtype diagnosed in patients younger than 20 years of age TYPE 2 DIABETES (T2D) Caused by a combination of peripheral resistance to insulin action and a secretory response by pancreatic β cells that is inadequate to overcome insulin resistance (“RELATIVE INSULIN DEFICIENCY”). Approximately 90% to 95% of diabetes patients have T2D Vast majority of such individuals are overweight Although classically considered “adult-onset,” the prevalence of T2D in children and adolescents has been increasing at an alarming pace due to the increasing rates of obesity in children and young adults GLUCOSE HOMEOSTASIS Tightly regulated by three interrelated processes: o glucose production in the liver o glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle o actions of insulin and counter-regulatory hormones, including glucagon, on glucose uptake and metabolism FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 2 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS DURING FASTING STATES low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Fasting plasma glucose levels are determined primarily by hepatic glucose output. FOLLOWING A MEAL insulin levels rise and glucagon levels fall in response to the large glucose load Insulin promotes glucose uptake and utilization in tissues SKELETAL MUSCLE Major insulin-responsive site for postprandial glucose utilization Critical for preventing hyperglycemia and maintaining glucose homeostasis. BRAIN AND ADIPOSE TISSUES Less dependent on insulin Also extract a significant amount of glucose from the circulation REGULATION OF INSULIN RELEASE Insulin is produced in the β cells of the pancreatic islets as a precursor protein and is proteolytically cleaved in the Golgi complex to generate the mature hormone and a peptide byproduct, C-PEPTIDE. Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation; thus, Cpeptide levels serve as a surrogate for β-cell function, decreasing with loss of β-cell mass in T1D and increasing with insulin resistance–associated hyperinsulinemia. GLUCOSE most important stimulus for insulin synthesis PHASE OF IMMEDIATE INSULIN RELEASE/ FIRST PHASE OF BETA CELL INSULIN SECRETION An increase in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an insulin-independent glucose transporter, GLUT2 Metabolism of glucose generates ATP, which leads to the influx of Ca2+through plasma membrane calcium channels. The resultant increase in intracellular Ca2+ stimulates secretion of insulin,presumably from hormone stored in β-cell granules. First phase of β-cell insulin secretion. NOTE TAKER: Oral intake of food leads to secretion of multiple hormones that play INCRETINS most important class of hormones responsible for promoting insulin secretion from pancreatic β cells following feeding act by binding G-protein–coupled receptors that are expressed on pancreatic β cells Two most important incretins are: o GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (GIP) o GLUCAGON-LIKE PEPTIDE-1 (GLP-1) both secreted by cells in the intestines following oral food intake. Elevation in GIP and GLP-1 levels is known as the “INCRETIN EFFECT.” In addition to increasing insulin secretion from β cells, these hormones reduce glucagon secretion from pancreatic α cells and delay gastric emptying, which promotes satiety. Once released, circulating GIP and GLP-1 are degraded in the circulation by a class of enzymes known as DIPEPTIDYL PEPTIDASES (DPPS), especially DPP-4 The “incretin effect” is significantly blunted in patients with T2D, and efforts to restore incretin function can improve glycemic control and promote weight loss (through restoration of satiety). Two classes of drugs for treating T2D: o GLP-1 RECEPTOR AGONISTS ▪ synthetic GLP-1 mimetics that bind to and activate the GLP-1 receptor on islet and extrapancreatic cells ▪ approved for treatment of obesity o DPP-4 INHIBITORS ▪ enhance levels of endogenous incretins by delaying their degradation. INSULIN ACTION AND INSULIN-SIGNALING PATHWAYS Insulin is the most potent anabolic hormone known The principal metabolic function of insulin is to increase the rate of glucose transport into certain cells in the body The most important targets of insulin action are: o striated muscle cells (including cardiomyocytes) o adipocytes FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 3 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS “BEIGE” ADIPOSE TISSUE o Type of adipose tissue that utilizes the most glucose o Develops with exercise “WHITE” ADIPOSE TISSUE o accumulates in obese individuals. This is one reason why exercise is beneficial and obesity is detrimental to glucose control. In muscle cells, glucose is either stored as glycogen or oxidized to generate ATP. In adipose tissue, glucose is primarily used as a substrate for synthesis of lipids, which are stored as triglycerides OTHER ACTIONS OF INSULIN Inhibits triglyceride hydrolysis and lipid release by adipocytes Promotes amino acid uptake and protein synthesis, while inhibiting protein degradation Several mitogenic activities, including of DNA synthesis in certain cells and stimulation of their growth and differentiation. Autoimmune disease in which islet destruction is caused primarily by immune effector cells reacting against endogenous β-cell antigens Most commonly develops in childhood, becomes manifest at puberty, and progresses with age. Most patients require insulin for survival; without insulin, they may develop serious metabolic complications such as ketoacidosis and coma. Involves an interplay of genetic and environmental factors GENETIC SUSCEPTIBILITY Epidemiologic studies, such as those demonstrating higher concordance rates in monozygotic versus dizygotic twins, have convincingly established a genetic basis for T1D. Most important locus is the HLA GENE CLUSTER, which according to some estimates contributes as much as 50% of the genetic susceptibility for T1D o HLA-DR3 o HLA-DR4 Non-HLA genes o Also confer susceptibility to T1D o Consisted of variable number of tandem repeats in the promoter region of the insulin gene o Mechanism underlying this association is unknown o Possible that these polymorphisms influence insulin expression by thymic antigenpresenting cells, thus affecting the negative selection of insulin-reactive T cells ENVIRONMENTAL FACTORS Antecedent viral infections have been suggested as triggers Some studies suggest that viruses might share epitopes with islet antigens, and the immune response to the virus results in cross- reactivity and destruction of islet tissues, a phenomenon known as MOLECULAR MIMICRY. MECHANISMS OF β-CELL DESTRUCTION Three distinct stages of TID STAGE 1 (autoimmunity positive, normoglycemia, presymptomatic T1D), individuals have developed two or more islet autoantibodies but are still ormoglycemic STAGE 2 (autoimmunity positive, dysglycemia, presymptomatic T1D) PATHOGENESIS OF TYPE 1 DIABETES NOTE TAKER: FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 4 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS there is increasingly severe loss of glucose tolerance due to progressive loss of β-cell mass, but frank symptoms are absent STAGE 3 (autoimmunity positive, dysglycemia, symptomatic T1D) classic manifestations of the disease (polyuria, polydipsia, polyphagia, ketoacidosis) appear, typically after more than 90% of the β cells have been destroyed. The fundamental immune abnormality in T1D is a failure of self-tolerance in T cells specific for islet antigens. PATHOGENESIS OF TYPE 2 DIABETES Involves the interplay of genetic and environmental factors and a pro- nflammatory state. Unlike T1D, there is no evidence of an autoimmune basis GENETIC FACTORS Disease concordance rate of greater than 90% in monozygotic twins, a rate higher than in T1D. First-degree relatives have 5- to 10-fold higher risk of developing T2D than those without a family history, when matched for age and weight. Atleast 30 gene loci that individually confer a minimal to modest increase in the lifetime risk for T2D Many of these genes are involved in adipose tissue function (through effects on bodily fat distribution [visceral vs. subcutaneous]), islet β- cell function, and obesity ENVIRONMENTAL FACTORS OBESITY o Most important environmental risk factor for T2D o central or visceral obesity SEDENTARY LIFESTYLE o (typified by lack of exercise) is another risk factor o independent of obesity METABOLIC SYNDROME o Obesity o Hyperglycemia o Increased serum cholesterol and triglycerides o Hypertension o Sleep disorders (such as obstructive sleep apnea) and circadian disruption are additional environmental risk factors for T2D. NOTE TAKER: o Circadian disruption ▪ Misalignmnet between the endogenous circadian rhythm and the cycle or rhythm created by individual behaviors ▪ Impairs glucose homeostasis by affecting both insulin secretion and insulin action METABOLIC DEFECTS IN TYPE 2 DIABETES The development of T2D involves two key abnormalities: o INSULIN RESISTANCE: Decreased response of peripheral tissues, especially skeletal muscle, adipose tissue, and liver, to insulin o β-CELL DYSFUNCTION: Inadequate insulin secretion in the face of insulin resistance and 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 gives rise to abnormal glucose tolerance Results in the following: o Failure to inhibit endogenous glucose production (gluconeogenesis) in the liver, which contributes to high fasting blood glucose level o Failure to inhibit activation of “hormonesensitive” lipases in adipose tissue, leading to excess triglyceride breakdown in adipocytes and high levels of circulating free fatty acids (FFAs) OBESITY Most important factor contributing to insulin resistance Risk for diabetes rises as the BMI increases CENTRAL OBESITY (abdominal fat) is more likely to be linked with insulin resistance than is PERIPHERAL (gluteal/ subcutaneous) OBESITY Can adversely impact insulin sensitivity in numerous ways o Free fatty acids (FFAs) ▪ Cross-sectional studies have demonstrated an inverse correlation between fasting plasma FFAs and insulin sensitivity FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 5 | 21 PCC SOM 2026 o GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS ▪ Central adipose tissue is more “lipolytic” than peripheral sites Liver steatosis o High circulating levels of FFAs may result in the accumulation of excess fat (steatosis) in hepatocytes o Nonalcoholic Fatty Liver Disease (NAFLD) ▪ Ranges in severity form hepatic steatosis without evidence of liver injury to nonalcoholic steatohepatitis (NASH) with evidence of inflammation and hepatocyte injury with or without fibrosis o Adipokines o Variety of proteins secreted into the circulation by adipose tissue o Some promote hyperglycemia o Others (leptin and adiponectin) decrease blood glucose, in part by increasing insulin sensitivity in peripheral tissues Inflammation o Emerged as an important factor in the pathogenesis of T2D o Inflammation milieu- mediated not by an autoimmune process, as in T1D, but rather by proinflammatory cytokines that are secreted in response to excess nutrients such as FFAs and glucose-results in both insulin resistance and beta cell dysfunction B-CELL DYSFUNCTION While insulin resistance by itself can lead to impaired glucose tolerance, β-cell dysfunction is a requirement for the development of overt diabetes. Several mechanisms have been implicated in promoting β-cell dysfunction in T2D, including the following: o Excess FFAs that compromise β-cell function and attenuate insulin release (LIPOTOXICITY) o The impact of chronic hyperglycemia (GLUCOTOXICITY) NOTE TAKER: o An abnormal incretin effect, leading to reduced secretion of GIP and GLP-1, hormones that promote insulin release Amyloid deposition within islets. This is a characteristic finding in individuals with longstanding T2D, being present in more than 90% of diabetic islets examined, but it is unclear whether it is a cause or an effect of β-cell “burnout.” MONOGENIC FORMS OF DIABETES Genetically defined causes of diabetes Uncommon Classified separately from type 1 and 2 diabetes Monogenic forms of diabetes result from either a primary defect in β-cell function or a defect in insulin receptor signaling Genetic Defects in β-Cell Function “MATURITY-ONSET DIABETES OF THE YOUNG” (MODY) The largest subgroup of patients in this category Superficial resemblance to T2D and its occurrence in younger patients Result from germline loss-of-function mutations in one of six genes of which mutations of glucokinase (GCK) are the most common. Genetic Defects That Impair Tissue Response to Insulin Rare insulin receptor mutations that affect receptor synthesis, insulin binding, or RTK activity can cause severe insulin resistance, accompanied by hyperinsulinemia and diabetes (type A insulin resistance). Such patients often show a velvety hyperpigmentation of the skin known as ACANTHOSIS NIGRICANS. Females with type A insulin resistance also frequently have polycystic ovaries and elevated androgen levels DIABETES AND PREGNANCY Pregnancy can be complicated by diabetes in one of two settings: o when women with preexisting diabetes become pregnant (“pregestational” or overt diabetes) o women who were previously euglycemic develop impaired glucose tolerance and diabetes for the first time during pregnancy (“GESTATIONAL” DIABETES). Women with pregestational diabetes have an increased risk of stillbirth and congenital malformations in the fetus. FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 6 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS Poorly controlled diabetes that arises later in pregnancy, regardless of prior history, can lead to excessive birth weight in the newborn (macrosomia) and may have long-term sequelae for the child later in life, including an increased risk of obesity and diabetes Clinical Features of Diabtetes T1D May arise at any age HONEYMOON PERIOD o Initial 1 or 2 years following the onset of overt T1D o exogenous insulin requirements may be minimal because of residual endogenous insulin secretion eventually, however, beta cell function declines to a tipping point, and insulin requirements increase dramatically T2D Typically seen in obese patients older than 40 years of age Now being diagnosed in children and adolescents with increasing frequency due to increases in obesity and sedentary lifestyle Medical attention is sought because of unexplained fatique, dizziness or blurred vision In the US, routine blood glucose testing is recommended for everyone older than 45 years of age and in younger individuals with obesity, family history, or the presence of the metabolic syndrome. CLASSIC TRIAD OF DIABETES POLYURIA POLYDIPSIA POLYPHAGIA GLYCOSURIA-When severe, diabetic ketoacidosis, all resulting from metabolic derangements o The resultant hyperglycemia leads to filtration of so much glucose in the kidney that the renal tubular threshold for reabsorption is exceeded. o This leads TO GLYCOSURIA, which induces an osmotic diuresis and thus polyuria, causing a profound loss of water and electrolytes The renal water loss combined with the hyperosmolarity owing to increased levels of glucose in the blood depletes intracellular water, triggering NOTE TAKER: the osmoreceptors of the thirst centers of the brain. Thus, intense thirst (POLYDIPSIA) appear The catabolism of proteins and fats tends to induce a negative energy balance, which in turn leads to increasing appetite (POLYPHAGIA) Acute Metabolic Complications of Diabetes DIABETIC KETOACIDOSIS o Severe acute metabolic complication of T1D o The most frequent precipitating factor is a failure to take insulin o Plasma glucose levels are usually in the range of 250 to 600 mg/dL o The hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. o Not as common or severe in T2D o Most Frequent precipitating factor is failure to take insulin The insulin deficiency coupled with glucagon excess decreases peripheral utilization of glucose while increasing gluconeogenesis, severely exacerbating hyperglycemia A second major effect of insulin deficiency is increased synthesis of ketone bodies leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by dehydration, the result is a systemic metabolic ketoacidosis. The clinical manifestations of diabetic ketoacidosis: o Fatigue o nausea and vomiting o severe abdominal pain o characteristic fruity odor, and deep labored breathing (also known as Kussmaul breathing). Persistence of the ketotic state eventually leads to depressed consciousness and coma HYPEROSMOLAR HYPERGLYCEMIC STATE patients with T2D may develop this condition due to severe dehydration resulting from sustained osmotic diuresis (particularly in patients who do not drink enough water to compensate for urinary losses from chronic hyperglycemia) Occurs in an older patient who has diabetes and is disabled by a stroke or an infection and thus unable to maintain adequate water intake. FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 7 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS HYPOGLYCEMIA Once treatment commences, ironically, the most common acute metabolic complication in either type of diabetes I Causes include: o missing a meal o excessive physical exertion o excessive insulin administration o “misdosing” during the phase of dose finding for antidiabetic agents such as sulfonylureas Chronic Complications of Diabetes The morbidity associated with long-standing diabetes of either type is due to damage induced in large- and medium-sized muscular arteries (DIABETIC MACROVASCULAR DISEASE) and in small vessels (DIABETIC MICROVASCULAR DISEASE) by chronic hyperglycemia Macrovascular disease causes accelerated atherosclerosis among patients with diabetes, resulting in increased risk of o myocardial infarction o stroke o 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 HbA1c formed by nonenzymatic covalent addition of glucose moieties to hemoglobinin red cells provides a measure of glycemic control over the lifespan of a red cell (120 days) affected little by day-to-day variation in glucose levels It is recommended that HbA1c be maintained below 7% in patients with diabetes. At least four distinct mechanisms have been implicated in the 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-6-phosphate NOTE TAKER: MORPHOLOGY (PANCREAS) Reduction in the number and size of islets (> T1D) Leukocytic infiltrates in the islets (insulitis) Tlymphocytes In T2D there may be a subtle reduction in islet cell mass Amyloid deposition within islets in T2D begins in and around capillaries and between cells An increase in the number and size of islets is especially characteristicof nondiabetic newborns of mothers with diabetes. Diabetic Macrovascular Disease Hallmark: accelerated atherosclerosis involving the aorta and large- and medium-sized arteries. MYOCARDIAL INFARCTION o caused by atherosclerosis of the coronary arteries o most common cause of death in diabetes. Gangrene of the lower extremities, as a result of advanced vascular disease, is about 100 times more common in diabetes patients than in the general population. Diabetic Microangiopathy One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla Microangiopathy includes: o Diabetic nephropathy o Retinopathy o Neuropathy DIABETIC NEPHROPATHY Kidneys are prime targets of diabetes Renal failure is second only to myocardial infarction as a cause of death Three lesions are encountered: (1) glomerular lesions (2) renal vascular lesions, principally arteriolosclerosis (3) pyelonephritis, including necrotizing papillitis Most important glomerular lesions are: o capillary basement membrane thickening o diffuse mesangial sclerosis o nodular glomerulosclerosis FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 8 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS Capillary Basement Membrane Thickening Widespread thickening of the glomerular capillary basement membrane (GBM) Capillary basement membrane thickening is best appreciated by electron microscopy Morphometric studies demonstrate that thickening begins as early as 2 years after the onset of T1D and by 5 years amounts to about a 30% increase. These progressive changes in the GBM are usually accompanied by mesangial widening and thickening of the tubular basement membranes Diffuse Mesangial Sclerosis Consists of diffuse increase in mesangial matrix Matrix depositions are PAS-positive As the disease progresses, the mesangial matrix deposits may take on a nodular appearance. Nodular Glomerulosclerosis Also known as INTERCAPILLARY GLOMERULOSCLEROSIS OR KIMMELSTIEL-WILSON DISEASE Glomerular lesions take the form of ovoid or spherical, often laminated, PAS- positive nodules of matrix situated in the periphery of the glomerulus. They lie within the mesangial core of the glomerular lobules and may be surrounded by patent peripheral capillary loops or loops that are markedly dilated. The nodular lesions are frequently accompanied by prominent accumulations of hyaline material in capillary loops (“FIBRIN CAPS”) or adherent to Bowman capsules (“CAPSULAR DROPS”) NOTE TAKER: Diabetic Ocular Complications CATARACT Diabetes-induced hyperglycemia leads to acquired opacification of the lens. GLAUCOMA o Increased intraocular pressure resulting damage to the optic nerve The most profound ocular changes of diabetes are seen in the retina. The retinal vasculopathy of diabetes mellitus can be classified into background (preproliferative) diabetic retinopathy and proliferative diabetic retinopathy Clinical Manifestations of Chronic Diabtetes Macrovascular complications such as myocardial infarction, renal vascular insufficiency, and cerebrovascular accidents are the most common causes of mortality in long-standing diabetes o Patients with diabetes have a two to four times greater incidence of coronary artery disease and a fourfold higher risk of dying from cardiovascular complications than agematched individuals without diabetes Hypertension is found in approximately 75% of individuals with T2D and potentiates the effects of hyperglycemia and insulin resistance on endothelial dysfunction and atherosclerosis. Another cardiovascular risk frequently seen in diabetes patients is dyslipidemia, which includes both increased triglycerides and LDL levels and decreased levels of the “protective” lipoprotein, high-density lipoprotein Diabetic nephropathy is a leading cause of end-stage renal disease in the United States. FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 9 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS o Earliest manifestation of diabetic nephropathy is the appearance of low amounts of albumin (microalbuminuria) in the urine (>30 mg and 300 mg/day of urinary albumin) over 10 to 15 years, usually accompanied by the appearance of hypertension Visual impairment, including total blindness, is one of the more feared consequences of long-standing diabetes. o Fundamental lesion of retinopathy— neovascularization—is attributable to hypoxia-induced expression of VEGF in the retina. Diabetic neuropathy can result in damage to the central nervous system, peripheral sensorimotor nerves, and the autonomic nervous system. o It most frequently takes the form of a distal symmetric polyneuropathy of the lower extremities that affects both motor and sensory function. o Over time, the upper extremities may be involved as well, thus approximating a “glove-and-stocking” pattern Patients with diabetes are plagued by enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia, and pyelonephritis o Basis of enhanced susceptibility is multifactorial and includes decreased neutrophil function (chemotaxis, adherence to the endothelium, phagocytosis, and microbicidal activity) and impaired cytokine production by macrophages. o Vascular compromise also impairs the delivery of immune cells and molecules to sites of infection. PANCREATIC NEUROENDOCRINE TUMORS Tumors of the pancreatic islet cells (“islet cell tumors”) Resemble their counterparts, carcinoid tumors, found elsewhere in the alimentary tract Rare Can occur anywhere within the pancreas or in the immediate peripancreatic tissues. May be single or multiple and benign or malignant Often elaborate pancreatic hormones, but are sometimes nonfunctional NOTE TAKER: Three most common and distinctive clinical syndromes associated with functional pancreatic endocrine neoplasms are: o (1) Hyperinsulinism o (2) Hypergastrinemia and the ZollingerEllison syndrome o (3) MEN Tumors with a higher proliferation index (measured as 3% or more neoplastic nuclei expressing Ki-67) can have an aggressive biological potential Pathogenesis Genome of sporadic PanNETs recently has been sequenced, with identification of recurrent somatic alterations in three major genes or pathways: MEN1 Loss-of-function mutations in tumor suppressor genes such PTEN and TSC2 Inactivating mutations in two genes, alphathalassemia/ mental retardation syndrome, X-linked (ATRX) and death-domain–associated protein (DAXX) HYPERINSULINISM (INSULINOMA) β-cell tumors (INSULINOMAS) Most common pancreatic endocrine neoplasms and often produce sufficient insulin to induce clinically significant hypoglycemia Characteristic clinical picture is dominated by hypoglycemic episodes, which occur when the blood glucose level falls below 50 mg/dL Clinical manifestations include confusion, stupor, and loss of consciousness MORPHOLOGY Found within the pancreas and are usually benign Most are solitary, although multiple tumors may be encountered. Bona fide carcinomas, making up only about 10% of cases, are diagnosed on the basis of local invasion and distant metastases Solitary tumors are usually small Deposition of amyloid is a characteristic feature of many insulinomas May also be caused by focal or diffuse hyperplasia of the islets. FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 10 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS CLINICAL FEATURES While up to 80% of islet cell tumors demonstrate excessive insulin secretion, the hypoglycemia is mild in all but about 20%, and many cases never become clinically symptomatic. Critical laboratory findings in insulinomas are high circulating levels of insulin and a high insulin-toglucose ratio. Surgical removal of the tumor is usually followed by prompt reversal of the hypoglycemia. ZOLLINGER-ELLISON SYNDROME (GASTRINOMA) Marked hypersecretion of gastrin Likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas (so-called gastrinoma triangle) Hypergastrinemia gives rise to excessive gastric acid secretion, which in turn causes peptic ulceration α-CELL TUMORS (GLUCAGONOMAS) Associated with increased serum levels of glucagon and a syndrome consisting of mild diabetes mellitus, a characteristic skin rash (necrolytic migratory erythema), and anemia They occur most frequently in perimenopausal and postmenopausal women and are characterized by extremely high plasma glucagon levels δ-CELL TUMORS (SOMATOSTATINOMAS) Associated with diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria. They may be very difficult to localize preoperatively. High plasma somatostatin levels are required for diagnosis VIPoma Induces a characteristic syndrome: o watery diarrhea o Hypokalemia o achlorhydria o or WDHA syndrome that is caused by release of vasoactive intestinal peptide (VIP) from the tumor o Locally invasive and metastatic ADRENAL GLANDS ADRENAL GLANDS Paired endocrine organs consisting of: o CORTEX o MEDULLA Adrenal cortex has 3 zones: NOTE TAKER: ZONA GLOMERULOSA – beneath the capsule ZONA FASCICULATA - makes up about 75% of the total cortex ZONA RETICULARIS – abuts the medulla The adrenal cortex synthesizes three different types of steroids: GLUCOCORTICOIDS (principally cortisol) o Synthesized primarily in the zona fasciculata and to a lesser degree in the zona reticularis MINERALOCORTICOIDS o Most important being aldosterone o Generated in the zona glomerulosa SEX STEROIDS (ESTROGENS AND ANDROGENS) o produced largely in the zona reticularis ADRENAL MEDULLA o composed of chromaffin cells, which synthesize and secrete catecholamines, mainly epinephrine ADRENAL CORTEX Diseases of the adrenal cortex can be conveniently divided into those associated with hyperfunction and those associated with hypofunction ADRENOCORTICAL HYPERFUNCTION (HYPERADRENALISM) Syndromes of adrenal hyperfunction are caused by overproduction of the three major hormones of the adrenal cortex (1) CUSHING SYNDROME, characterized by an excess of cortisol (2) HYPERALDOSTERONISM as a result of excessive aldosterone (3) ADRENOGENITAL OR VIRILIZING SYNDROMES caused by an excess of androgens HYPERCORTISOLISM (CUSHING SYNDROME) Pathogenesis Caused by conditions that produce elevated glucocorticoid levels. Broadly divided into: o EXOGENOUS o ENDOGENOUS The vast majority of cases of Cushing syndrome are the result of the administration of exogenous glucocorticoids (iatrogenic Cushing syndrome). Endogenous causes can be divided into: o ACTH dependent o ACTH independent FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 11 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS ACTH SECRETING PITUITARY ADENOMAS Account for 60% to 70% of cases of endogenous hypercortisolism Pituitary form of this syndrome is referred to as CUSHING DISEASE. The disorder affects women about four times more frequently than men and occurs most frequently in young adults Majority caused by an ACTH-producing pituitary microadenoma In some cases o Macroadenoma o Corticotroph cell hyperplasia without a discrete adenoma ▪ May be primary or arise secondarily from excessive stimulation of ACTH release by a hypothalamic corticotrophin-releasing hormone (CRH)-producing tumor o Secretion of ectopic ACTH by nonpituitary tumors accounts for about 5% to 10% of ACTH-dependent Cushing syndrome cases ▪ Small-cell carcinoma of the lung ▪ Carcinoids ▪ Medullary carcinomas of the thyroid ▪ PanNETs Primary adrenal neoplasms, such as adrenal adenoma (~10% to 20%) and carcinoma (~5% to 7%) are the most common underlying causes of ACTHindependent Cushing syndrome. The biochemical sine qua non of ACTH-independent Cushing syndrome is elevated serum levels of cortisol with low levels of ACTH. Cortical carcinomas tend to produce more marked hypercortisolism than adenomas or hyperplasias PRIMARY CORTICAL HYPERPLASIA (ACTH-INDEPENDENT HYPERPLASIA) Much less common than ACTH-dependent adrenal cortical hyperplasia Bilateral macronodular adrenal hyperplasia (BMAH) o Nodules are usually greater than 10 mm in diameter MCCUNE-ALBRIGHT SYNDROME Subset of BMAH arises in this setting Multisystemic disease characterized by germline mutations that activate GNAS, which encodes a stimulatory gsα NOTE TAKER: Gsα mutation causes hyperplasia by increasing intracellular levels of CAMP, an important second messenger in many endocrine cell types ACTH-independent bilateral hyperplasia can also be micronodular(commonly associated with mutations of the regulatory subunit of cAMP-dependent protein kinase (encoded by the PRKAR1A gene), which, like activating GNAS mutations, act by increasing intracellular cAMP levels HYPERCORTISOLISM MORPHOLOGY: Main lesions found in the pituitary and adrenal glands Most common alteration, resulting from high levels of endogenous or exogenous glucocorticoids, is termed CROOKE HYALINE CHANGE. In this condition, the normal granular, basophilic cytoplasm of the ACTH-producing cells in the anterior pituitary becomes homogeneous and paler. This alteration is the result of the accumulation of intermediate keratin filaments in the cytoplasm, a finding that is also seen in “Crooke cell” corticotroph adenoma Depending on the cause of the hypercortisolism, the adrenals show one of the following abnormalities: (1) cortical atrophy (2) diffuse hyperplasia (3) macronodular or micronodular hyperplasia (4) adenoma or carcinoma In patients in whom the syndrome results from exogenous glucocorticoids, suppression of endogenous ACTH results in BILATERAL CORTICAL ATROPHY, due to a lack of stimulation of the zonae fasciculata and reticularis by ACTH. DIFFUSE HYPERPLASIA Found in individuals with ACTH-dependent Cushing syndrome Both glands are enlarged, either subtly or markedly, weighing up to 30 g. Adrenal cortex is diffusely thickened and variably nodular Microscopically, the hyperplastic cortex demonstrates an expanded “lipid-poor” zona reticularis, comprising compact, eosinophilic cells, surrounded by an outer zone of vacuolated “lipidrich” cells, resembling those seen in the zona fasciculata FERRER, NAMUHMUH, OLARTE, SANTIAGO Page 12 | 21 PCC SOM 2026 GENERAL AND SYSTEMIC PATHOLOGY M.02 ENDOCRINE SYSTEM II: PANCREAS AND ADRENAL GLANDS o o moon facies accumulation of fat in the posterior neck and back (buffalo hump) Hypercortisolism causes selective atrophy of fasttwitch (type 2) myofibers, resulting in decreased muscle mass and proximal limb weakness. Secondary diabetes Skin is thin, fragile, and easily bruised; wound healing is poor; Cutaneous striae are particularly common in the abdominal area Osteoporosis MACRONODULAR HYPERPLASIA Adrenals are almost entirely replaced by prominent nodules of varying sizes (10 to 30 mm), which contain an admixture of lipid-poor and lipid-rich cells. Unlike diffuse hyperplasia, the areas between the macroscopic nodules also demonstrate evidence of microscopic nodularity MICRONODULAR HYPERPLASIA Composed of 1- to 3-mm (typically