Pathology of

The Endocrine Pancreas

&
Adrenal Gland
NORMAL PANCREAS
 Staining of immunoperoxidase technique for
insulin insulin containing cells are darkly stained
Secretory Products of Islet Cells and Their Physiologic Actions

Cell Secretory Mol. Physiological Action

Product Wt.
Alpha Glucagon 3500 Catabolic, stimulates glycogenolysis &
gluconeogenesis, raises blood glucose

Beta Insulin 6000 Anabolic, stimulates glycogenesis, lipogenesis,

protein synthesis, lowers blood glucose. Inhibits
secretion of alpha, beta, D1, acinar cells
Delta Somatostatin 1600
D
Delta Vasoactive Intestinal 3800 Same as glucagon, regulates tone & GE tract
Polypeptide (VIP) motility, activates cAMP of intestinal epithelium
D1

PP Human pancreatic 4300 Stimulates gastric enzyme secretion, inhibits

polypeptide (ppp) intestinal motility & bile secretion

EC Serotonin, substance 176 Induce vasodilatation, increases vascular

P (motilin) permeability, stimulates motility of gastric
muscle and tone of lower esophageal sphincter
TYPES OF DM
TYPE I VERSUS TYPE II DM
 DIABETES MELLITUS
Classification and general features
A. Type 1 (insulin-dependent diabetes mellitus / IDDM),
juvenile or ketosis-prone diabetes mellitus
- often begins early in life, before age 30
- is less common than type 2
- is due to failure insulin synthesis by beta cells of the
pancreas islets
- a genetic predisposition complicated by autoimmune
inflammation / insulinitis triggered by a viral infection
or environmental factors. Family history less frequent
than type 2 DM
- Increased incidence with specific point mutation of
HLA- DQ gene, and incidence markedly increased in
HLA-DR3- and HLA-DR4-positive individuals
- marked carbohydrate intolerance with hyperglycemia,
leading polyuria, polydipsia, weight loss despite
increased appetite, ketoacidosis, coma and death
- ketoacidosis keton bodies increased catabolism of
fat
 B. Type 2 DM (non-insulin dependent diabetes
mellitus / NIDDM, adult onset, ketosis-resistant)

More common than type 1 DM

Most often in middle age
due to increased insulin resistance
mediated by decreased cell membrane insulin receptors
or post receptor dysfunction
impaired processing of pro-insulin to insulin
decreased sensing of glucose by beta cells, or
impaired function of intracellular carrier proteins
 Type 2 DM (NIDDM)
(1) Etiologic factors
(a) positive family history more frequent than type 1
(b) most often associated with mild to moderate obesity
(2) Characteristics
(a) plasma insulin concentration normal, often increased,
(b) mild carbohydrate intolerance, most often managed
by oral antidiabetic agents; insulin therapy is not usually
required
(c) ketoacidosis is unsual but does occur, characteris-
tically precipitated by unusual stress such as infection
or surgery
C. Maturity-onset Diabetes Mellitus of
the Young (MODY)

an autosomal dominant syndrome

characterized by mild hyperglycemia and
hyposecretion of insulin, but without loss
of beta cells
onset earlier than type 2 DM
is caused by a diverse group of single
gene defects
 D. Secondary DM
Occurs as a secondary phenomenon in
pancreatic and other endocrine disease
and pregnancy
(a) pancreatic disease
- hereditary hemochromatosis (bronze
diabetes) excess iron absorption and
parenchymal deposition of hemosiderin,
with reactive fibrosis in various organs,
especially pancreas, liver and heart
(b) pancreatitis acute pancreatitis
hyperglycemia, chronic pancreatitis islet
cell destruction and secondary DM
(c) carcinoma of pancreas DM may be the
presenting sign
Other endocrine diseases
Cushing syndrome produces hyperglycemia
as a result of increased gluconeogenesis and
impaired peripheral utilization of glucose
Acromegaly produces hyperglycemia due to
the anti-insulin like effect of GH
Glucagon hypersecretion promotes
glycogenolysis is characteristically caused by an
islet alpha cell tumor (glucagonoma)
Phaeochromocytoma and hyperthyroidism are
sometimes associated with hyperglycemia
 Pregnancy
May associated with transient DM (gestational
diabetes)
Is characteristically associated with increased
fetal birth weight and increased fetal mortality,
notably from neonatal respiratory distress
syndrome (hyaline membrane disease)
When the mother has hyperglycemia can result
in an infant born with hyperplasia of the
pancreatic islets and hypoglycemia
 Pathologic changes in DM

Pancreas islets
(1) Type 1 DM islets are small and beta cells are
greatly decreased in number or absent; insulinitis
marked by lymphocytic infiltration is highly specific
early change
(2) Type 2 DM focal islet fibrosis and hyalinization due
to deposit amylin are characteristic but not specific.
Amylin (islet amyloid polypeptide/IAPP) deposition in
pancreatic islet is characteristic of type 2 DM and
thought to interfere either with conversion of proinsulin
to insulin or with the sensing of insulin by beta cells
Amyloid of a pancreatic islet
Hyaline arteriolosclerosis of
afferent arteriolae of kidney
Nodular glomerulosclerosis
Nephrosclerosis in long standing diabetes
Diabetic retinopathy
 ISLET CELL TUMOR
Insulinoma (beta cell tumor)
The most common islet cell tumor
May be benign / malignant
Characterized by greatly increased of insulin
Clinically Whipple triad
1. Episodic hyperinsulinemia and hypoglycemia
2. CNS dysfunction temporally related to hypoglycemia
(confusion, anxiety, stupor, convulsion, coma)
3. Dramatic reversal of CNS abnormalities by glucose
administration
 Insulinoma : ribbon or brown stained cells
resembling those of the normal islet of Langerhans
 ISLET CELL TUMOR

Gastrinoma
- is often a malignant tumor, sometimes
occuring in extrapancreatic sites
- results in gastrin hypersecretion and hyper-
gastrinemia
- is associated with Zollinger-Ellison syndrome
(marked gastric hypersecretion of HCl),
recurrent peptic ulcer disease and hypergas-
trinemia
 ISLET CELL TUMOR
Glucagonoma (alpha cell tumor)
- is a rare tumor
- results in secondary DM and a characteristic skin
lesion called necrolytic migratory erythema
Vipoma
- is a rare tumor
- is marked by secretion of vasoactive intestinal peptide /
VIP
- is associated with Watery Diarrhea, Hypokalemia, and
Achlorhydria (WDHA) syndrome, also known as Verner-
Morrison syndrome or pancreatic cholera
 Pathology of

The Adrenal Glands

Normal adrenal gland
NORMAL CORTEX ADRENAL
 Adrenal glands

CORTEX
- Hypercorticism / Cushing syndrome
- Hyperaldosteronism
- Adrenal virilism
- Hypocorticism
MEDULLA
- Pheochromocytoma
- Medulloblastoma
Normal Adrenal Steroidogenesis
Hydroxylase Deficiency
 ADRENOCORTICAL HYPERPLASIA
The adrenal cortex are yellow, thickened and multinodular
ADRENOCORTICAL ADENOMA
Solitary, circumscribed
ADRENAL CORTICAL ADENOMA
Cells in adrenocortical adenoma
Compact adenoma
Black cortex adenoma in
Cushing syndrome
 Cushing
Syndrome

Red face (flushing)

Major Clinical manifestatons of Cushing Syndrome
 Morphologic changes in adrenal glands
Bilateral hyperplasia of adrenal zona fasciculata occurs
when the syndrome results from ACTH stimulation
Adrenal cortical atrophy is seen when exogenous
glucocorticoid medication is the cause
Adrenal cortical adenoma or carcinoma
- Adenoma is more common
- cannot be supressed by exogenous adrenal steroids in
dexamethasone supression test, in contrast, hyper-
corticism of pituitary origin can usually be supressed
useful diagnosis measures in determining the cause of
hypercorticism.
- ACTH increased in pituitary hypercorticism and in ectopic
ACTH production, and it is low when hypercorticism is of
adrenal origin
 Clinical characteristics of
hypercorticism
Redistribution of body fat with round moon
face, dorsal buffalo hump, often with
relatively thin extremities caused by muscle
wasting; skin atrophy with easy bruishing
and purplish striae, especially over abdomen
, and hirsutism
Muscle weakness, osteoporosis,
amenorrhea, hypertension, hyperglycemia,
and psychiatric dysfunction
 HYPERALDOSTERONISM
Primary aldosteronism ( Conn syndrome)
is caused by primary hyperfunction od adrenal
mineralocorticoids
usually results from an aldosteron-producing
adrenocortical adenoma (aldosteronoma)
can results from hyperplasia of the zona glomerulosa
may rarely caused by adrenocortical carcinoma
is characterized clinically by hypertension, sodium and
water retention, and hypokalemia, often with
hypokalemic alkalosis
demostrates decreased serum renin due to negative
feedback of increased blood pressure on renin secretion
 HYPERALDOSTERONISM
Secondary aldosteronism
is secondary to renal ischemia, renal tumors, and edema
(e.g. cirrhosis, nephrotic syndrome, cardiac failure)
is caused by stimulation of the renin-angiotensin system
demonstates increased serum renin.
In contrast to primary aldosteronism. Renin synthesized
in the juxta glomerular apparatus of the kidney promotes
the conversion of angiotensigen to angiotensin I, which
converted catalytically by angiotensin converting enzyme
(mainly in lung) to AT II. The release of aldosterone is
facilitated by AT II.
 Adrenal virilism
(adrenogenital syndrome)
Causes
a. Congenital enzyme defect result in deminished
corticol production and compensatory increased
ACTH, with resultant adrenal hyperplasia with
androgenic steroid production
(1) 21- hydroxylase deficiency most common
result in salt loss and hypotension
(2) 11- hydroxylase deficiency less common
results in salt retention and hypertension
b. Tumor of the adrenal cortex
Clinical characteristic:
- produces virilism in females and precocious puberty
in males
 HYPOCORTICISM
(adrenal hypofunction)

Can be primary adrenal cause or secondary

to hypothalamic or pituitary hypofunction
Is characterized by deficiency of
glucocorticoid (primary cortisol) , often
associated with mineralocorticoid deficiency
1. ADDISON DISEASE
2. Waterhouse Friderichsen
syndrome
 ADDISON DISEASE
Is most commonly due to idiopathic adrenal
atrophy ( autoimmune lymphocytic adrenalitis)

Can also be caused by tuberculosis, metastatic

tumors and various infections.

Is characterized by hypotension; increased

pigmentation of skin; decreased serum sodium,
chloride, glucose, and bicarbonate; and increase
of serum potasium
 WaterhouseFriderichsen
syndrome
Is catastrophic adrenal insufficiency and
vascular collapse due to hemorrhagic
necrosis of the adrenal cortex
Is often associated with disseminated
intravascular coagulation
Is characteristically due to meningococ-
cemia, most often in association with
meningococcal meningitis
Adrenals in Waterhouse-Friderichsen syndrome
destroyed by hemorrhage
 Tumors of adrenal medulla
1. Pheochromocytoma
Is derived from chromaffin cells of adrenal medulla (
if derived from extra-adrenal chromaffin cells, called
paraganglioma
Most often benign, only 10% malignant
Is characterized by increased urinary excretion of
catecholamines (epinephrine or norepinephrine) and
their metabolites ( metanephrine, normetanephrine,
and vanillymandelic acid (VMA)
Can also cause hyperglycemia
Can be part of MEN IIa or MEN IIb (III)
Can also be associated with bneurofibromatosis or
with von Hippel-Lindau disease
 Pheochromocytoma
the adrenal medulla is expanded by a darked-coloured tumour
with areas of degeneration and hemorrhage
 Pheochromocytoma
left right normal adrenal
Chromaffin cells in
pheochromocytoma
 2. Neuroblastoma
Is highly malignant catecholamine producing
tumor in early childhood. Urinary catecholamine
and cathecolamine metabolites are the same as
in pheochromocytoma
Causes hypertension
Usually originates in the adrenal medulla and
often presents as a large abdominal mass
Occasionally converts into a more differentiated
form termed ganglioneuroma
 2. Neuroblastoma
Is characterized by amplification of the N-myc
oncogene with thousands of gene copies per cell
a. Amplification results in karyotypic changes
homogenous staining regions or double minutes
chromosomes
b. the number of N-myc gene copies is related to
the aggressiveness of the tumor
c. the malignant neuroblastoma sometimes
differentiate into benign cells, and this changes
is reflected by a marked reduction of gene
amplification
Microscopic appearance of neuroblastoma
neurogenic primitive cells
MULTIPLE ENDOCRINE NEOPLASIA
(MEN) SYNDROMES
Are a group of autosomal dominant
syndromes in which more than one
endocrine organ are hyperfunctional
May be associated with hyperplasia
or tumors
MEN I ( Werner syndrome)
MEN IIa (Sipple syndrome)
MEN IIb / III
 MEN I (WERMER SYNDROME)
Includes hyperplasia or tumors of the pituitary,
parathyroid, or pancreatic islets (3Ps)
Additionally may include hyperplasia or tumors
of the thyroid or adrenal cortex
May manifest its pancreatic component by the
Zollinger-Ellison syndrome, hyperinsulinism, or
pancreatic cholera
Is linked to mutations in the MEN I gene
 MEN IIa (Sipple syndrome)

- includes pheochromocytoma, medullary

carcinoma of thyroid, and hyperparathy-
roidism due to hyperplasia or tumor
- is linked to mutations in the ret oncogene
 MEN IIb / III
Includes pheochromocytoma, medullary
carcinoma, and multiple mucocutaneous
neuroma or ganglioneuroma. In contrast to
MEN IIa, does not induce hyperparathy-
roidism.
- is linked to different mutations in the ret
oncogene than is MEN IIa