4. Robbins: Endocrine Pancreas Flashcards
(109 cards)
1
Q
Endocrine pancreas is made up of ________.
A
Islet of langerhans, located in the neck and tail of the pancreas.
2
Q
What cells make up the islet of langerhans?
A
[4 major cell types and 2 minor cell types]
-
4 major cell types
- Alpha cells
- Beta cells
- Delta cells (ς)
- PP cells
-
2 minor cell types
- D1 cells
- Enterochromaffin cells
3
Q
Function of alpha and beta cells
A
- Alpha cells: secrete glucagon => ↑ glycogenolysis in liver => [↑ blood sugar/glucose]
- Beta cells: secrete insulin => [regulates glucose utilization] & [↓ blood sugar/glucose]
4
Q
Function of delta and PP cells
A
- Delta cells: secrete somatostatin => [suppress release of insulin and glucagon_]_
- PP cells: secrete pancreatic polypeptide => [GI effects: ↑ secretion of GI enzymes & inhibits intestinal motility]
5
Q
Function of D1 cells and enterochromaffin cells
A
-
D1 cells: secrete VIP (vasoactive intestinal polypeptide) =>
- [glycogenolysis and hyperglycemia]
- stimulates [GI secretion => diarrhea]
- Enterochromaffin cells: make serotonin & source of pancreatic tumors that cause from carcinoid syndrome.
6
Q
D1 cells of the endocrine pancreas secrete what; what is the effect of this secretory product?
A
- VIP
- Induces glycogenolysis and hyperglycemia
- Stimulates GI secretions –> secretory diarrhea
7
Q
What is the main job of the islet of langerhans?
A
Glucose homeostasis: regulated by
- release of glucose from liver
- utilization of glucose by tissue
- Insulin and glucagon
8
Q
How is insulin release regulated?
A
- GLUT-2 (glucose transporter) to move to takes glucose into B-cells.
- Glucose is metabolized => makes ATP
- ATP inhibits membrane K+ channel
- Membrane is depolarized => Ca2+ influx
- Ca2+ influx => insulin release.
- Insulin causes GLUT-4 to move into the plasma membrane and promote glucose uptake in target cell.
9
Q
How is insulin processed?
A
Proinsulin => cleaved in B-cell to [insulin & C-peptide]
10
Q
How can we measure if insulin was administered by meds or made by the body?
A
Measure C-peptide, a marker of endogenous insulin.
11
Q
Insulin and glucagon effects during fasting vs feeding stages
A
-
Fasting
- [↓ insulin and ↑ glucagon] => hepatic gluconeogenesis and glycogenolysis & ↓ glycogen synthesis => ↑ blood glucose (mainly by liver) prevent hypoglycemia
-
Meal
- ↑ glucose load causes [↑ insulin and ↓ glucagon] => glucose uptake and utilization to prevent hyperglycemia
12
Q
What is the major insulin responsive site for postprandial glucose utilization and critical to prevent hyperglycemia?
A
Skeletal muscle
13
Q
Insulin effects on adipose tissue
A
- ↑ glucose uptake
- ↑ lipogenesis
- ↓ lipolysis
14
Q
Insulin effects on liver
A
- ↑ Glycogen synthesis
- ↑ Lipogenesis
- ↓ Gluconeogenesis
15
Q
Insulin effects on striated muscle
A
- ↑ glucose uptake
- ↑ glycogen synthesis
- ↑ protein synthesis
16
Q
Main job in insulin
A
MOST potent anabolic hormone:
- Growth- promoting effects
- Tell body how to utilize glucose
17
Q
What cell?
A
B-cells (insulin): => dark reaction
18
Q
What cell?
A
D cells (somatostatin)
19
Q
What cell?
A
a cells (glucagon)
20
Q
What cell?
A
EM of B-cell with membrane-bound granules, dense rectangular core and halo.
21
Q
What cell?
A
Left: a-cell with dense, round center
Right: delta cells
22
Q
The most important stimulus for insulin synthesis and release is ______.
A
Glucose
23
Q
What are incretins?
A
Hormones released from cells in GI after a meal (oral glucose) that help to promote insulin release
24
Q
What are 2 incretins?
A
- Glucagon-like-peptide 1 (GLP-1)
- Glucose-dependent insulin-releasing polypeptide (GIP)
25
**MOA** of incretins
1. **GLP-1** and **GIP** act on _B cells_ in pancrease =\> **↑ insulin release**
2. **GLP-1** acts on _a-cells_ and suppresses glucagon release =\> **↓ blood glucose** (↓ glucose release from liver )
3. Inactivated by **DPP-4 (dipeptidyl peptidase-4)**
26
What 2 classes of drugs have been created for pt's with T2DM based on the incretin effect?
1. **- GLP-1 receptor AGO**
2. **- DPP-4 inhibitors** (↓ breakdown of incretins)
27
How is the incretin-effect affect in T2DM?
**Blunted:**
28
**_Diabetes Mellitis_**
* What is it?
* Leading cause of what in the US:
* More common in:
* Lease common in:
* Problem with NL glucose homeostasis =\> **hyperglycemia**
* 1**. Defective insulin secretion**
* **2. Defective insulin effect**
* ESRD, adult-onset blindness, non-traumatic LE amputation due to atherosclerosis
* MC = american indian/alaska native \> Black and hispanic
* LC: Asian and white
29
**NL** blood glucose
**70- 120 mg/dL**
30
Fasting plasma glucose for **DB Diagnosis**
1. **Fasting** plasma glucose **_\>_** **126 mg/dL**
31
Which value of **HbA1C** is considered diagnositc for diabetes?
**_\>_ 6.5 %**
32
A **random** plasma glucose ≥ ______ mg/dL is considered diagnostic for diabetes.
**≥ 200 mg/dL**
33
What are **4 genetic syndromes** associated w/ diabetes?
1. **- Down syndrome**
2. **- Klinefelter syndrome**
3. **- Turner syndrome**
4. **- Prader-Willi syndrome**
34
What are **T1DM** and **T2DM?**
**T1DM**: AI disease that causes immune-mediated destruction of pancreatic B-cells =\> absolute deficiency of insulin.
* T- cells lose self-tolerance against antigens on B- cells
**T2DM**: Caused by combination of resistance to insulin & inadequate secretory response by B-cells =\> relative insulin deficiency.
35
**_T1DM_**
* Onset:
* AutoAB:
* Pathology:
* **Onset**
* Usually _childhood & adolesnce_
* **AutoAB**
1. Anti-insulin ab
2. Anti-GAD ab
3. anti-ICA512 ab
* **Pathology**
1. Insulitis (inflammtory infiltrate of T-cells and MO)
2. B-cell depletion
3. Islet atrophy
36
**_T1DM_**
* **Genetics**:
* **Clinical**:
* Weight
* Insulin levels
* DKA?
* **Genetics**
* MHC class II; HLA-DR3 or DR4 with DQ8.
* **Clinical**
1. NL or WL
2. Progressive ↓ in insulin
3. Severe and w/o insulin therapy: DKA
37
**_T2DM_**
* **Onset:**
* **AutoAB:**
* **Pathology:**
* **Onset**:
* Adult, but increasing incidence in childhood and adolescence
* **AutoAB**:
* None
* **Pathology**:
1. No insulitis
2. Amyloid deposits
3. Mild B-cell deposition
38
**_T2DM_**
* **Genetics:**
* **Clinical:**
* Weight
* Insulin levels
* DKA?
**Genetics**:
* Genetics AND environment are important
* Strong familial predisposition: majority have a 1st degree relative with T2DM
* Obesity (esp central) = major RF
**Clinical**:
* 80% are obese
* Early = ↑ in blood insulin bc of B-cell compensation; Later = NL/moderate ↓ in insulin bc B-cell exhaustion
* Severe =\> hyperglycemic hyperosmotic syndrome (HHS)
39
Pancreas must be ___ destroyed to give overt **T1DM** symptoms (Hyperglycemia + ketosis)
**\>90%**
40
Which type of diabetes (T1DM or T2DM) has a **stronger genetic component?**
**T2DM** ---\> disease concordance \>90% in monozygotic twins
41
What are the **2 cardinal metabolic defects** that characterize **T2DM**?
* **- ↓ response** of peripheral tissues, especially skeletal m., adipose, and liver **to insulin** = **insulin resistance**
* **- Inadequate insulin secretion** in the face of insulin resistance and hyperglycemia = **β-cell dysfunction**
42
What causes **insulin resistance** in **T2DM**?
**Obesity** and **excess adipocytes** cause:
1. ↑ in bad **adipokines** =\> promote hyperglucemia and
2. ↓ in toxic **FFA** =\> release cytoines =\> + inflammasome =\> secretion of IL-1β =\> release of pro-inflammatory cytokines =\>
3. **Inflammation:** damages B cells and end organs =\> ↓ response to insulin
43
**Insulin resistance** in **T2DM** results in what?
1. Liver = no gluconeogenesis: _high fasting blood glucose levels_
2. Skeletal muscle = failure of glucose uptake and glycogen synthesis after a meal =\> _high post-prandial blood glucose levels_
3. Adipose tissue = activation of "hormone-sensitive" lipase is NOT inhibited =\> _excess TAG breakdown and FFA._
44
What is required for the development of overt T2DM?
**B-cell dysfunction**
45
Causes of ***B-cell dysfunction*** that cause exhaustion:
1. ◦ **Lipotoxicity** to B cells from FFA
2. ◦ **Glucose toxicity**
3. ◦ **Decreased incretin/incretin effect**
4. ◦ **Amyloid deposition** (cause or effect?)
5. ◦ **Genetics**!
46
**Monogenic forms** of DB are due to either a [primary defect in B-cell or defect in insulin receptor signaling].
What are the 2 types?
1. MODY (Maturity-onset DB of the young)
2. Insulin receptor mutations
47
What is **Maturity-Onset DB of the Young (MODY)?**
* DB that **resembles T2DM clinically, but occurs in youth**
1. ↑ blood insulin
2. No autoAB
3. Non-ketotic
* Caused by: **LOF mutation of _Glucokinase**_ =\> primary defect in B-cell function that occurs _**without_** loss of B-cells, affecting B-cell mass and/or insulin production.
48
**_Insulin receptor mutations_**
Affect what:
Cause:
* Receptor synthesis, insulin binding or RTK activity
* **Severe insulin resistance** + **hyperinsulinemia** + **DB (type A)**
* Pts have: acanthosis nigracans polycytic ovaries, high androgen levels and lipoatrophic DB (hyperglycemia + loss of adipose tissue).
49
What is the difference between **gestational DB** and **pre-gestational/overt DB**?
* **Gestational DB:** previously euglycemic develop impaired glucose tolerance and DB for the first time during PG.
* due to: genetics/env
* **Pregestational DB:** W with _pre-existing DB_ become PG.
50
How does **pregnancy** affect **insulin processing?**
**Pregnancy** = "diabetogenic" state that **favors insulin resistance.**
51
Gestational/pre-gestation DB **risks** to mom and fetus
* **Mom**
* C-section
* **Fetus** (used to a hyperglycemic environment)
1. Neonatal hypoglycemia =\> seizures =\> brain damage
2. Macrosomnia = big ass bb
3. Congenital malformations
4. Stillbirth
52
How is the diagnosis of **T2DM** typically made?
**After routine blood testing in asymptomatic people.**
53
* **Insulin** =\> catabolic/anabolic.
* **Insulin deficient** =\> catabolic/anabolic state
* Insulin =\> **anabolic** hormone
* **When deficient** =\> _catabolic_ state
54
Classic Triad of **T1DM**
* If severe =\> \_\_\_\_
* Combination of what sx should suggest T1DM?
1. **Polyphagia** (increase appetite), but WL/ muscle loss!
2. **Polyuria** (water/electrolyte loss)
3. **Polydipsia** (intense thirst)
When severe =\> **DKA**
**WL** (bc insulin deficient = catabolic state) & **increased appetite.**
55
**Severe** T1DM and T2DM causes =\> \_\_\_\_\_\_\_\_
* **Severe T1DM** = DKA (occurs less often in T2DM)
* **Severe T2DM =** Hyperglycemic hyperosmotic syndrome (HHS)
56
**_DKA_**
## Footnote
* Occurs in T1DM/T2DM?
* MC occurs due to:
* Pathology:
**_DKA_**
* **Severe T1DM**, but occasionally occurs in T2DM
* **MC due to factors that increase EPI.**
* 1. Failure to take insulin
* 2. Precursor infections: pneumonia and UTI
* Pathology
* [↑ EPI release] =\> [blocks insulin action =\> cant process glucose & ↑ glucagon secretion] =\>
* [w/o insulin and glucose for NRG] =\>
* Body breaks down fat via lipase=\> FFA are released from adipose tissue =\> making ketones in liver =\> ketonemia and ketoneuria (go into urine) =\> kidneys dump glucose and ketones via osmotic diuresis
* ↓ peripheral utilization of glucose while glucagon secretion ↑ gluconeogenesis in liver =\> exacerbating hyperglycemia (250 - 600 mg/dL)
* **=\> ketoacidotic state** (osmotic diuresis and dehydration =\> shock and ↑ EPI)
57
**DKA**
* Names of 2 ketone bodies
* Diagnose:
* Clinical manifestations
* **Ketone bodies:** acetoacetic acid and Beta-hydoxybutyrate
* **Dx**: test for ketone bodies
* **Clinical manifestations**: fatigue, N/V, abdominal pain, fruity odor, Kassmaul breathing (deep, labored breathing)
58
In patients with **DKA**, when does **metabolic ketoacidosis**?
When **urinary excretion of ketones is compromised by dehydration** =\> metabolic ketoacidosis
59
**_DKA_**
* Triad of symptoms:
* Resulting in:
* Presnting signs/sx
* **Hyperglycemia**, **ketonemia**, **metabolic acidosis**
* _Dehydration_, _polydipsia_, _polyuria/ketonuria_
* N/V, tachycardia, kassmaul respirations (respiratory alkalosis d/t metabolic acidosis)
60
What causes **Kassmaul respirations?**
**Compensatory respiratory alkalosis** due to metabolic acidosis seen in DKA
61
How is **DKA** treated?
1. **Insulin**
2. **Hydration**
3. **Potassium**
62
Autoantibodies associated with **T1DM** are present more often in which ethnicity, therefore are more reliable indicators of disease?
\>90% of **Caucasians**
63
What is **Hyperglycemic Hyperosmotic Syndrome (HHS)?**
Most common in whom?
* **Acute crisis in T2DM** where [chronic hyperglycemic state] causes severe dehydration due a to chronic osmotic diuiresis, MC occuring in older people who do not rehydrate after polyruria.
* Hyperglycemic state occurs dt:
* prolonged insulin deficiency,
* ↑ gluconeogeniesis
* ↓ glucose uptake]
64
How does **HHS** differ from **DKA**?
1. **More severe HYPERglycemia** (600-1200 mg/dL)
2. **HYPERosmolality** (\>350 mOsm/L) =\> obtundation and coma
3. **NO ketones,** ketonemia and ketonuria
4. **Severe dehydration** and **impaired kidney function**
65
How do patients with **HHS** first typically present?
**Older** with **AMS**, because (-) ketoacidosis and its symptoms delay medical attention until severe dehydration and AMS occur.
66
What is the **most common acute metabolic complication** in both T1DM and T2DM; how does it present clinically?
* - **HYPOglycemia** from either missing a meal, excessive exertion, or too much insulin administration
* - Presents as: dizziness + confusion + sweating + palpitations + tachycardia
67
Morbitidty associated with **chronic DB** is due to what?
* Damage to large/medium muscular arteries (**diabetic macrovascular disease)**
* Damage to small vessels (**diabetic microvascular disease**)
68
**Chronic DB =\> diabetic **_macro_**vascular disease.**
What is the hallmark?
1. \*\*\* Accelerated **atherosclerosis** of aorta and large/medium arteries =\> **MI**, **stroke**, **LE gangrene** (100x more common in DB than non)
2. **Hyaline arteriolosclerosis** =\> amorphous hyaline thickening of wall of arterioles, narrowing the lumen and causing **HTN**
69
**Chronic** **DB** =\> **diabetic **_micro_**vascular disease** causes what?
* **DB retinopathy**, **nephropathy** and **neuropathy**.
70
MC cause of death in DB?
**MI**
71
What is a **good measure of glycemic control** and why?
* **HbA1C levels:** glucose becomes irreversibly bound to Hb tetramer, providing a measure of glycemic control over the lifespan of a RBC (120 days) and is affected little by day-day variations.
* **Target A1C levels:** below 6.5 - 7
72
How does **hyperglycemia** damage peripheral tissue?
Glucose breaksdown and forms **AGEs** (advanced glycated end-products) =\> **bind to RAGE receptor** on inflammatory cells =\> **AGE-RAGE signaling** causes:
1. **↑ release cytokines + GF's** --\> **TGF-β** ( =\> deposits excess BM) and **VEGF** ( =\> causes diabetic retinopathy)
2. Generation of **ROS's**
3. **Procoagulant** activity
4. **Proliferation of vascular smooth m.** and synthesis of **ECM** (=\> proatherogenic)
73
**Morphological Changes** in the Pancreas in **T1DM**
1. ↓ in the number and size of islets in T1DM
2. Leukocytic infiltrates in the islet (insulitis) in T1DM
74
How does the **size** of the islet cell change in **T2DM**?
1. **Subtle reduction**
75
An **increase** in the **number** and **size** of the **pancreatic islets** is a characteristic morphological feature in which pt's?
**NON-diabetic newborns of diabetic mothers:** fetal islets undergo hyperplasia due to maternal hyperglycemia
76
Chronic DB =\> **Diabetic Microangiopathy**
1. **DB Retinopathy**
2. **DB Nephropathy**
3. **DB Neuropathy**
77
What 3 lesions are encountered in **DB Nephropathy?**
* **1. Glomerular lesions (MC)**
* Thick BM
* Disruption of the protein cross-linkages that make the membrane a effective filter =\> DB capillaries are more leaky than NL to plasma proteins.
* **2. Renal vascular lesions**, mainly arteriolosclerosis
* 3. **Pyelonephritis**, including necrotizing papillitis
78
What are the 3 most important glomerular lesions encountered in **diabetic nephropathy?**
* **1. Thickening of glomerular capillary BM** = (in almost cases)
* **2. Diffuse mesangial sclerosis** due to diffuse ↑ in mesangial MATRIX
* Occurs concurrently with thickening of GBM
* **3. Nodular glomerulosclerosis (Kimmelstiel-Wilson disease)**
79
_Matrix depositions_ in **DB nephropathy** stain (+) for \_\_\_\_
**(+) PAS**
80
What is **nodular glomerulosclerosis** that occurs in **DB nephropathy?**
Glomerular lesions become **PAS + nodules,** often **located in periphery** of the glomerulus.
81
**Grossly**, what will the **kidney** look like in **chronic diabetes** leading to nephrosclerosis?
1. - **Diffuse granular transformation of the surface**
2. - **Cortex thins**
3. **- Contracts (gets smaller)**
82
Which arterioles of the kidney (afferent or efferent) are affected by **hyaline arteriolosclerosis** in long-standing diabetic nephropathy?
**BOTH** afferent and efferent arterioles.
83
**Diabetic nephropathy** is the leading cause of _____ in the US.
**ESRD**
84
How do we screen for **diabetic nephropathy?**
**Urine [Albumin: Cr] Ratio** (**UACR**) = gold standard for urine albumin testing.
85
What is **Diabetic Retinopathy?**
* Caused by:
* Results in:
DB causes retinopathy **neovascularization** due **hypoxia**-induced expression of **VEGF** =\>
1. **Hemorrhage**
2. **Blindness**
3. **Cataracts** (d/t hyperglycemia) and **glaucoma** (d/t increase intraocular pressure)
86
What is the most frequent pattern of involvement seen with **diabetic neuropathy**?
**Distal symmetric polyneuropathy** of the **LE's** that affects BOTH **motor** and **sensory** function
87
**_Diabetic Nephropathy_**
1. ESRD in most common in who:
2. Earliest manifestation:
1. **NA, Hispanics** and **AA** than whites with **T2DM**.
2. **Microalbuminuria**: Low amounts of albumin in the urine (30-300 mg/day)
88
Besides diabetic nephropathy, **microalbuminuria** is also a marker for what?
What measures should be taken?
Comorbid **CV disease** in T1DM/T2DM.
**Screen** all patients with microalbuminuria **for macrovascular disease** and **aggressive intervention** to reduce RF.
89
Without intervention, which (T1DM/T2DM) is more likely to cause **overt nephropathy with with macroalbuminuria** ( \> 300mg of urinary albumin) in 10-15 years?
* **80% T1DM =**
* 20-40% of T2DM
90
**Diabetics** have increased susceptibility to what type of infections?
1. **- Skin i.e., cellulitis**
2. **- Tuberculosis**
3. **- Pneumonia**
4. **- Pyelonephritis**
91
Tumors that occur in the pancreatic islet cells are called what?
**Pancreatic Neuroendocrine Tumors (PanNETS)**
92
**PanNETs** all look the same.
What are the **unifying features (gross, histology, on EM)?**
* Most commonly occur in **neck** and **tail** and pancreas
* **Gross:** Solid; tan- yellow
* **Histo**: Well-differentiated small, round blue cell tumors (NE tumors)
* **EM**: have secretory granules.
93
Mutations in **sporadic** pancreatic neuroendocrine tumors:
1. **MEN1**
2. **LOF** mutations in **PTEN and TSC2** ---\> **↑ mTOR signaling pathway**
3. **Inactivating mutations** of **ATRX** (alpha-thallasemia/mental-retardation syndrome, X- linked) and **DAXX** (death-domain associated protein)
94
4 Functional **Pancreative Endocrine Neoplasms**: which is the MC?
1. Insulinoma \*\*\*
2. Gastrinoma
3. Somatstatinoma
4. Glucagonoma
5. VIPoma
95
**Deposition of amyloid** is a characteristic histologic feature of which type of pancreatic neuroendocrine tumor?
**Insulinoma**
96
**_Insulinoma_**
1. What are they?
2. Symptoms
3. Common histological finding:
4. Diagnosis is made measuring \_\_\_\_\_\_\_.
* **Solitary, small encapsulated tumors (\< 2cm)** of B-cells that secrete insulin and cause episodes of **symptomatic hypoglycemia (\< 50 mg/dL)**
* =\> [Confusion, LOC, stupor] that occurs after fasting/exercise (relieved after giving glucose)
* **Amyloid**
* **C-peptide levels**
97
Which type of pancreatic neuroendocrine tumor is **generally benign** and is associated with the **lowest rate of metastasis (10%)**?
**Insulinoma**
98
**Triad of _Gastrinoma_**
1. **Islet cell tumor**
2. **Gastric acid hypersecretion**
3. **Peptic ulceration\***
\*GA hypersecretion and peptic ulcers =\> **Zolinger-Ellison Syndrome**
99
How are the **ulcers** produced by **Gastrinomas** different from those found in general population?
1. **Unresponsive** to **regular therapy.**
2. Occur in the **jejunum** (in addition to dudodenum and stomach)
* (peptic ulcers in jejunum = assume ZE syndrome)
100
How do **MEN-1-associated gastrinomas** differ morphologically from **sporadic gastrinomas**?
* - **MEN-1-associated** are often **multifocal**
* - **Sporadic** are usually **single**
101
**Metastasis in Gastrinomas**
**More than 1/2** of gastrinomas are **locally invasive** or have **already metastasized** when diagnosed
102
If peptic ulcers are found in jejunum =\> assume \_\_\_\_\_\_\_
**ZE Syndrome**
103
Patients with **Zollinger-Ellison syndrome** with metastasis **where** have a shortened life expectancy?
**Liver**; progressive tumor growth causes liver failure within 10 years
104
What are the 4 D's of **Glucagonomas**?
1. **Diabetes** (mild)
2. **Dermatitis** (necrolytic migratory erythema = pathognomic rash) in groin and LE
3. **Depression**
4. **DVT's**
105
What is **necrolytic migratory erythema?**
**Pathogneumonic rash** caused by glucagonma, causing [erythema, superificial areas of epidermal necrosis =\> shed, form bullae and crust].
106
**δ-cell tumors (somatostatinomas)** are associated with what 4 clinical manifestations?
* Symptoms often **subtle** = hard to diagnose
* Clinical manifestations:
* **1. Diabetes**
* **2. Cholelithiasis (gallstones)**
* **3. Steatorrhea**
* **4. HYPOchlorhydria**
107
**_Somatostatinoma_**
## Footnote
Since **somatostatin** functions as a paracrine regulator, what 3 things are reduced when somatostatin levels are high?
1. ↓ insulin
2. ↓ gallbladder motility
3. ↓ exocrine pancreatic secretions
108
**VIPomas** are associated with what syndrome and what are the clinical manifestations?
* Increase VIP (vasoactive intestinal peptide) secretion by D1 cells =\> intestinal fluid secretion =\>
* **WDHA** syndrome
* - **Watery diarrhea**
* **- HYPOkalemia**
* **- Achlorhydria**
109
**20%** of patients with **VIPomas** will also have what presenting sx?
* What else gives you this symptoms?
* Metastatic rate?
**- Flushing**
**- Carcinoma tumors**
**- 80% metastatic rate**
