Endocrine Pathology

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Endocrine Pathology Pancreas
Associate Professor Dr. Alexey Podcheko Spring
2015
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• INTENDED LEARNING OBJECTIVES
• To Know Mechanisms, Clinical and Morphological
  Presentation of
• Diabetes mellitus
• Pancreatic endocrine tumors

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Exocrine Endocrine Islets Alpha Cells
(glucagon) Beta Cells (insulin) Delta Cells
(somatostatin, suppress insulin and
glucagon) Pancreatic Polypeptide (PP) cells
(inhibits motility but increase GI
secretion) Epsilon Cells make gherlin, which
causes hunger D1 cells VIP(similar to
glucagon) Enterochromaffin cells (Serotonin)
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INSULIN

• FAT
• IN-creased glucose uptake
• IN-creased lipogenesis
• DE-creased lipolysis
• MUSCLE
• IN-creased glucose uptake
• IN-creased glycogen synthesis
• IN-creased protein synthesis
• LIVER
• DE-creased gluconeogenesis
• IN-creased glycogen synthesis
• IN-creased lipogenesis

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Insulin synthesis and secretion

1. Intracellular transport of glucose - GLUT-2,
2. Glucose undergoes oxidative metabolism in the ß
   cell to yield ATP.
3. ATP inhibits an inward rectifying K channel
   receptor on the ß-cell surface
4. Inhibition of this receptor leads to membrane
   depolarization, influx of Ca2 ions, and
   release of stored insulin from ß cells.

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Insulin Autocrine LOOP
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Insulin action on a target cell
The metabolic actions of insulin
include -promoting glycogen synthesis by
activating glycogen synthase, -enhancing protein
synthesis and lipogenesis -inhibition of
lipolysis
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Metabolic actions of insulin in striated muscle,
adipose tissue, and liver.
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• A neonate who weighs 4.5 kg (9 lb, 15 oz) is
  found to be hypoglycemic. His mother was treated
  with insulin during the pregnancy after being
  diagnosed with gestational diabetes. The mother
  has a history of depression and drug abuse in the
  past, but she denies using for the past few
  years. Which of the following is the most likely
  cause of this neonates hypoglycemia?
• A. Placental transfer of insulin
• B. Diffuse hyperplasia of the islets
• C. Hypothyroidism
• D. Glycogen storage disease
• E. IGF-2 producing fibrosarcoma

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• Explanation
• Poor glucose control during pregnancy is
  associated with number of birth defects.
  Macrosomia is the classic defect this term
  describes a large infant (larger than 4.0 kg by
  conservative measures). If blood glucose is
  poorly controlled with diet and activity, insulin
  treatment is generally started. High glucose
  levels in the mother enter fetal circulation,
  causing high blood glucose levels to be present
  in the fetus. The fetus responds to this elevated
  blood glucose by increasing insulin. Obviously,
  the amount of insulin generated by these fetuses
  is more than normal, and beta cell hyperplasia
  results. Once free from the mother, the neonate
  continues to over-produce insulin
  (hyperinsulinemia), which can cause the neonate
  to experience severe hypoglycemia. High insulin
  levels are also responsible for the increased fat
  deposition and enhanced fetal growth that results
  in macrosomia.

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DIABETES MELLITUS

• Over 20 Million (7 of population) in the USA
• 1.5 Million/yr new cases
• 50K people die of it per year in the USA

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How to Diagnose Dm

• Random Glucose gt200mg/dL or
• Fasting glucose gt126mg/dL trice or
• Post-prandial glucose gt 200, 2 hrs AFTER standard
  OGTT (Oral Glucose Tolerance Test)

How to Diagnose Pre-Dm

• Fasting glucose concentrations greater than 100
  mg/dL but less than 126 mg/dL or
• Post-prandial glucose greater than 140 mg/dL but
  less than 200 mg/dL 2 hrs AFTER standard OGTT
  (Oral Glucose Tolerance Test)

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Classification

• 1.    Type 1 diabetes (ß-cell destruction,
  usually leading to absolute insulin
  deficiency)  Immune-mediated  Idiopathic  
• 2.    Type 2 diabetes (combination of insulin
  resistance and ß-cell dysfunction)  
• 3.    Genetic defects of ß-cell
  function  Maturity-onset diabetes of the young
  (MODY), caused by mutations in   
• Hepatocyte nuclear factor 4a (HNF4A),
• MODY1  Glucokinase (GCK),
• MODY2  Hepatocyte nuclear factor 1a (HNF1A),
• MODY3  Pancreatic and duodenal homeobox 1 (PDX1),
  
• MODY4  Hepatocyte nuclear factor 1ß (HNF1B),
• MODY5  Neurogenic differentiation factor 1
  (NEUROD1),
• MODY6  Neonatal diabetes (activating mutations in
  KCNJ11 and ABCC8, encoding Kir6.2 and SUR1,
  respectively)  
• Maternally inherited diabetes and deafness (MIDD)
  due to mitochondrial DNA mutations (m.3243A?G)  
• Defects in proinsulin conversion  
• Insulin gene mutations  
• 4.    Genetic defects in insulin action  Type A
  insulin resistance  Lipoatrophic diabetes,
  including mutations in PPARG  
• 5.    Exocrine pancreatic defects  Chronic
  pancreatitis  Pancreatectomy/trauma  Neoplasia  Cy
  stic fibrosis  Hemachromatosis  Fibrocalculous
  pancreatopathy  
• 6.    Endocrinopathies  Acromegaly  Cushing
  syndrome  Hyperthyroidism  Pheochromocytoma  Gluca
  gonoma  
• 7.    Infections  Cytomegalovirus  Coxsackie B
  virus  Congenital rubella  
• 8.    Drugs  Glucocorticoids  Thyroid
  hormone  Interferon-a  Protease
  inhibitors  ß-adrenergic agonists  Thiazides  Nico
  tinic acid  Phenytoin (Dilantin)  Vacor  
• 9.    Genetic syndromes associated with
  diabetes  Down syndrome  Kleinfelter
  syndrome  Turner syndrome  Prader-Willi
  syndrome  

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TWO Types of DM
MODY might be regarded as the third type

• 1
• Genetic
• Autoimmune
• Childhood (juvenile) onset
• Antibodies to beta cells
• Beta cell depletion
• NON-OBESE patients

• 2
• Genetic, but diff. from Type 1
• NOT autoimmune
• Adult, or maturity onset, e.g., 40s, 50s
• Insulin may be low, BUT, peripheral resistance to
  insulin is the main factor
• OBESE patients

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DIABETES

• POLY-URIA
• POLY-DIPSIA
• POLY-PHAGIA

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Pathogenesis of type 1 diabetes

• Genetic Susceptibility.
• Monozygous twins 40 risk of Diabetes Type I if
  one of siblings affected
• HLA HLA-DR3 or HLA-DR4 haplotype- 40 to 50 of
  type 1 diabetics ( 5 of normal subjects)
• Individuals who have either DR3 or DR4
  concurrently with a DQ8 haplotype (which
  corresponds to.
• Non-HLA genes insulin promoter, CTLA4 and PTPN22
  (inhibit T-cell responses), IL2 (CD25)
• Environmental Factors
• Viral infections - (mumps, rubella, coxsackie B,
  or cytomegalovirus, enteroviruses!!!)
• Early introduction of cow's milk protein into an
  infant's diet leads to development of the Type I
  Diabetes

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Stages in the development of type 1 diabetes
mellitus
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PATHOGENESIS OF TYPE 2 DIABETES MELLITUS

• Multifactorial complex disease, multiple factors
  
• 1. Environmental factors -such as a sedentary
  life style and dietary habits,
• 2. Genetic factors
• Concordance in monozygotic twins 60,
• Lifetime risk for type 2 diabetes in an offspring
  is more than double if both parents are affected.
  
• Mutations in TCF7L2 - factor in the WNT signaling
  pathway
• No link to HLA genes regulating immunity

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PATHOGENESIS OF TYPE 2 DIABETES MELLITUS

• Metabolic defects in T2D
• (1) peripheral tissues insulin resistance, high
  level of NEFA in the serum
• (2) ß-cell dysfunction and death (lipotoxicity,
  Amyloidosis of islets)

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PATHOGENESIS

• 1
• T-Lymphocytes reacting against poorly defined
  beta cell antigens
• Inflammatory inflitrate, chronic, i.e.,
  INSULITIS

• 2
• Diet
• Life Style
• Obesity
• INSULIN RESISTANCE
• Beta cells UN-able to adapt to the long term
  demands of insulin resistance

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MONOGENIC FORMS OF DIABETES

• MODY (Maturity Onset Diabetes of the Young)
• Multiple types
• 2-5 of diabetics
• Primary defects in gene regulating beta-cell
  growth, survival and function
• Most common mutations of GLUCOKINASE gene

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Insulin Autocrine LOOP
Glucokinase- is the main glucose sensor in the
beta-cells!
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PANCREAS in Type I Diabetes
INSULITIS mononuclear infiltration of islets
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PANCREAS in Type 2 Diabetes
Which islet is normal and which one is filled
with amyloid?
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PATHOGENESIS OF THE COMPLICATIONS OF DIABETES

• MACRO-VASCULAR disease, accelerated
  atherosclerosis
• MICRO-VASCULAR disease, kidneys, retina, nerves -
  diabetic retinopathy, nephropathy, and neuropathy
  
• IMMUNE related problems, INFECTIONS, e.g., TB,
  pneumonia, pyelonephritis, candida, etc.

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PATHOGENESIS OF THE COMPLICATIONS OF DIABETES

• Formation of Advanced Glycation End Products
  AGE, e.g. collagen, laminin, polypeptides, GBM
  (glomerular basement membrane), Hgb1c
• AGEs activate macrophages with Receptors for AGE

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PATHOGENESIS OF THE COMPLICATIONS OF DIABETES

• ACTIVATION of PROTEIN KINASE C, VEGF,
  endothelin-1, increased ECM, decreased
  fibrinolysis, inflam. cytokines
• Intracellular Hyperglycemia and Disturbances in
  Polyol Pathways - accumulation of sorbitol and
  depletion of GSH as a result cell edema,
  increased level of free radicals (neurons, retina)

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MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS
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ATHEROSCLEROSIS
Myocardial infarction, caused by atherosclerosis
of the coronary arteries, is the most common
cause of death in diabetics, and an elevated risk
for cardiovascular disease is even observed in
pre-diabetics
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ATHEROSCLEROSIS
Gangrene of the lower extremities, as a result of
advanced vascular disease, is about 100 times
more common in diabetics than in the general
population In pathology, you almost assume if
you get an amputation specimen, it is from a
diabetic.
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• A 53-year-old woman presents to your office for
  routine check-up. She has no present complaints.
  Her past medical history is significant for
  osteoarthritis of the right knee. Her mother
  suffered from hypertension and was diagnosed with
  breast cancer at 68 years old, which caused the
  womans death four years later. The patients
  father had diabetes mellitus and died in a motor
  accident. Todays blood pressure is 140/85 mmHg,
  and heart rate is 80/mm. Physical examination,
  including breast examination is normal.
  Laboratory testing is significant for a blood
  glucose level of 160 mg/dL. This patient will
  most likely die of which of the following causes?
  
• A. Stroke
• B. Myocardial infarction
• C. Breast cancer
• D. Hyperosmolar nonketotic coma
• E. Renal failure

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• Explanation
• Cardiovascular mortality is increased by two to
  three-fold in patients with diabetes mellitus.
  Several studies have shown that diabetes is the
  strongest risk factor for coronary heart disease.
  Approximately 40-50 of patients with diabetes
  mellitus die secondary to coronary artery
  disease. For a person with diabetes the risk of
  dying from ischemic heart disease exceeds the
  risk of dying from any of the other causes
  listed. Even in the absence of other major risk
  factors for ischemic heart diseasehypertension
  hypercholesterolemia, and smokingthe relative
  risk of ischemic heart disease in diabetes is
  elevated.
• Educational Objective
• Myocardial infarction is the most common cause of
  death in patients with diabetes.

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RETINOPATHY in Dm
Shows microaneurysms, areas of hemorrhage, cotton
wool spots, hard exudates, venous beading,
neovascularization, retinal detachment, vitreous
detachment, pre retinal hemorrhage
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Hypertensive Retinopathy
Diabetic Retinopathy

• Retinal examination
• dot-blot retinal hemorrhages
• microaneurysms (non-proliferative)
• neovascularization (proliferative)

• Retinal examination
• copper wiring (blood is still passing thorugh)
• silver wiring (the vessel is obliterated)
• cotton wool exudates (microinfarction)
• AV nicking (arterioles that cross over veins)
• Papilledema

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Kidneys and Diabetes

• Three lesions are encountered
• (1) glomerular lesions (capillary basement
  membrane thickening, diffuse mesangial sclerosis,
  and nodular glomerulosclerosis )
• (2) renal vascular lesions, principally
  arteriolosclerosis (hyaline changes)
• (3) pyelonephritis, including necrotizing
  papillitis.

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NEPHROPATHY
Kimmelstiel-Wilson (KW) Kidneys Is Nodular
glomerulosclerosis
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NEPHROPATHY
NEPHROSCLEROSIS
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NEPHROPATHY
GBM thickening
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NEPHROPATHY
Diffuse Mesangial Sclerosis
Diffuse mesangial sclerosis. Note the sclerotic
part, or fibrosis, is stained blue by the
trichrome stain.
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INFECTIONS in Dm

• SKIN
• TUBERCULOSIS
• PNEUMONIA
• PYELONEPHRITIS
• CANDIDA

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Pancreatic Neuroendocrine Tumors
Islets of Langerhans contain following types of
the cells

1. Alpha cells - 15-20 of all cells in the islet,
   synthesize glucagon and are found at the
   periphery of islet lobules
2. Beta cells comprise 60 to 70 of islet cells and
   produce insulin. They are found toward the
   centers of islets.
3. Delta cells secrete somatostatin. SS inhibits
   pituitary release of growth hormone secretion by
   alpha, beta and acinar cells of the pancreas and
   certain hormone-secreting cells in the
   gastrointestinal tract)
4. Pancreatic polypeptide-secreting cells (PP)
   stimulates enzymes secretion by the gastric
   mucosa and inhibiting smooth muscle contraction
5. Gastrin producing G-cells - stimulates secretion
   of gastric acid (HCl) by the parietal cells and
   aids in gastric motility
6. Vasoactive Intestinal Peptide secreting cells
   (VIP)- stimulate secretion of water and
   electrolytes as well as stimulating contraction
   of enteric smooth muscle, stimulating
   pancreatic bicarbonate secretion, increase bowels
   motility

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NEOPLASMS of the Endocrine Pancreas

• Islet cell tumors
• Beta cells? INSULINOMAS (MC)
• Alpha cells? GLUCAGONOMAS (rare)
• Delta cells? SOMATOSTATINOMAS (rare)
• GASTRINOMAS, producing ZOLLINGER-ELLISON
  SYNDROME, consisting of increased acid and ulcers

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Pancreatic neuroendocrine tumors (PanNETs)

• 5 of all pancreatic tumors
• Derived most likely from progenitors of normal
  islet cells
• Previously known as islet cell tumors
• PanNETs may secrete hormones that cause dramatic
  paraneoplastic syndromes, or they may be
  nonfunctioning.
• Functioning PanNETs include insulinoma,
  glucagonoma, somatostatinoma, gastrinoma, VIPoma
• insulinomas are most common

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Pancreatic neuroendocrine tumors (PanNETs)

• most occur between 40 and 60 years
• M/F1
• Nonfunctioning PanNETs are detected incidentally
  by imaging studies and commonly provide
  metastases into liver

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Syndromes associated with pancreatic
neuroendocrine tumor
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• A 40-year-old woman comes lo the physician with a
  6-week history of episodic hunger and fainting
  spells. She is currently seeing a psychiatrist
  because she is irritable and quarreling with her
  family. Laboratory studies show a serum glucose
  concentration of 35 mg/dL. A CT scan of the
  abdomen demonstrates a 1.5cm mass in the
  pancreas. The gross appearance of the bisected
  tumor is shown What is the most likely diagnosis?
• (A) Adenocarcinoma
• (B) Gasirinoma
• (C) Glucagonoma
• (D) Insulinoma
• (E) Somatostatinoma

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Insulinoma. Nests of tumor cells are surrounded
by numerous capillaries
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• A 46-year-old female develops a painful rash over
  her lower extremities. On physical examination,
  there are erythematous indurated lesions with
  crusting and scaling. Biopsy of the lesions shows
  superficial necrolysis. The patients past
  medical history is significant for diabetes
  mellitus diagnosed six months ago and anemia
  diagnosed one month ago. Which of the following
  hormones is most likely to be elevated in this
  patient?
• A. Gastrin
• B. Insulin
• C. Glucagon
• D. VIP
• E. Somatostatin
• F. PTHrP
• G. ACTH

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• Explanation
• The patient in the vignette presents with a
  constellation of symptoms highly suggestive of a
  glucagonoma. Glucagonomas are rare pancreatic
  tumors that characteristically present with
  necrolytic migratory erythema, an elevated
  erythematous rash typically affecting the groin
  area. Other clinical features of glucagonomas
  include hyperglycemia, stomatitis, cheilosis,
  and abdominal pain. Diagnosis is made by the
  measurement of serum glucagon levels.
• Glucagon is a hormone secreted by the alpha-cells
  of the pancreatic islets of Langerhans. The three
  other types of pancreatic endocrine cells in the
  islets include insulin-secreting beta-cells,
  somatostatin-secreting delta-cells, and
  pancreatic polypeptide-secreting PP-cells.
• Educational Objective
• Diabetes mellitus, necrolytic erythema and anemia
  comprise the typical clinical picture of a
  glucagonoma.

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• A 40-year-old male presented to the physician
  with a thyroid nodule. Physical examination
  reveals a 2-cm thyroid nodule and mucosal
  neuromas of the lips and tongue. Upon further
  investigation, this patients arm span is noted
  to exceed his height, and he has long fingers.
  Serum calcitonin levels are elevated. This
  patient will most likely also have?
• A. Hypercalcemia
• B. Visual filed defects
• C. Episodic headache
• D. Recurrent peptic ulcers
• E. Hypoglycemic episodes

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• Explanation
• The mucosal neuromas, thyroid nodule, and
  Marfanoid habitus of this man indicate MEN type
  2B. (Although pheochromocytomas are also a
  feature of MEN 2B, not all features have to be
  present to suggest a MEN syndrome.) The thyroid
  nodule described most likely represents medullary
  thyroid cancer. Even without the mucosal
  neuromas, one would suspect a MEN syndrome as
  about 20 of medullary thyroid cancers are
  familial. Episodic secretion of catecholamines by
  pheochromocytomas causes episodic increases in
  blood pressure, flushing, diaphoresis, and
  headaches.
• !!! All patients with medullary thyroid cancer
  should be screened for pheochromocytoma by
  clinical and biochemical assessment.