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Endocrine Pathology

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Title: Endocrine Pathology


1
Endocrine Pathology Pancreas
Associate Professor Dr. Alexey Podcheko Spring
2015
2
  • INTENDED LEARNING OBJECTIVES
  • To Know Mechanisms, Clinical and Morphological
    Presentation of
  • Diabetes mellitus
  • Pancreatic endocrine tumors

3
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)
4
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

5
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.

6
Insulin Autocrine LOOP
7
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
8
Metabolic actions of insulin in striated muscle,
adipose tissue, and liver.
9
  • 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

10
  • 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.

11
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

12
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13
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)

14
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  

15
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

16
DIABETES
  • POLY-URIA
  • POLY-DIPSIA
  • POLY-PHAGIA

17
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

18
Stages in the development of type 1 diabetes
mellitus
19
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

20
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)

21
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

22
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

23
Insulin Autocrine LOOP
Glucokinase- is the main glucose sensor in the
beta-cells!
24
PANCREAS in Type I Diabetes
INSULITIS mononuclear infiltration of islets
25
PANCREAS in Type 2 Diabetes
Which islet is normal and which one is filled
with amyloid?
26
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.

27
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

28
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)

29
MORPHOLOGY OF DIABETES AND ITS LATE COMPLICATIONS
30
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
31
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.
32
  • 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

33
  • 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.

34
RETINOPATHY in Dm
Shows microaneurysms, areas of hemorrhage, cotton
wool spots, hard exudates, venous beading,
neovascularization, retinal detachment, vitreous
detachment, pre retinal hemorrhage
35
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

36
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.

37
NEPHROPATHY
Kimmelstiel-Wilson (KW) Kidneys Is Nodular
glomerulosclerosis
38
NEPHROPATHY
NEPHROSCLEROSIS
39
NEPHROPATHY
GBM thickening
40
NEPHROPATHY
Diffuse Mesangial Sclerosis
Diffuse mesangial sclerosis. Note the sclerotic
part, or fibrosis, is stained blue by the
trichrome stain.
41
INFECTIONS in Dm
  • SKIN
  • TUBERCULOSIS
  • PNEUMONIA
  • PYELONEPHRITIS
  • CANDIDA

42
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

43
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

44
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

45
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

46
Syndromes associated with pancreatic
neuroendocrine tumor
47
  • 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

48
Insulinoma. Nests of tumor cells are surrounded
by numerous capillaries
49
  • 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

50
  • 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.

51
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52
  • 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

53
  • 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.
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