Hypoglikemia and Insulinoma

8/22/2019 Hypoglikemia and Insulinoma

http://slidepdf.com/reader/full/hypoglikemia-and-insulinoma 1/77

Learning Objectives

• After completing this activity, participants should beable to:

– Outline patient signs and symptoms that should lead to an

evaluation for NETs

– Describe the diagnostic work-up that can confirm a

suspected diagnosis of NET

– Review current treatment approaches for NETs and

expected patient outcomes

NET = neuroendocrine tumor



EpidemiologySigns and symptoms of NETs

NETs: A Not-So-Rare Disease



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I n c i d e n c e p e r 1 0 0 , 0 0 0 - N E T s

I n c i d e n c e p e r

1 0 0 , 0 0 0 –

A l l m

a l i g n a n t n e o p l a

s m s

All malignant neoplasms

Neuroendocrine tumors

Yao JC et al. J Clin Oncol . 2008;26:3063-3072.

Incidence of NETs Increasing



Colon Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary

0

100

1100

1200

103,312 cases(35/100,000)

C a s e s ( t h o u s a n d s )

29-year limited duration prevalence analysis based on SEER.

Yao JC et al. J Clin Oncol . 2008;26:3063-3072.SEER = Surveillance, Epidemiology, and End Results

NETs Are Second Most Prevalent Gastrointestinal

Tumor

NET Prevalence in the US, 2004

Median survival (1988 – 2004)

• Localized 203 months

• Regional 114 months

• Distant 39 months



Autopsy Studies

• Carcinoid1,2

– 2 studies

• > 15,000 cases each

– 0.7% to 1.2%

• Islet cell3

– > 11,000 cases from

Hong Kong

– 0.1%

1. Berge T, Linell F. Acta Pathol Microbiol Scand . 1976;84:322-330.

2. Moertel CG et al. Cancer . 1961;14:291-293.3. Lam KY, Lo CY. Eur J Surg Oncol . 1997;23:36-42.



Vague abdominal

symptoms

Primary tumor

Flushing

Metastases

Diarrhea

Death

NETs Are Often Diagnosed Late

Time

Vinik A, Moattari AR. Dig Dis Sci . 1989;34[Suppl]:14S-27S.



Missed Symptoms and Late Diagnosis

50%

24%

27%

Localized Regional

Distant

• Flushing – No sweating

– First sip of alcohol

•Diarrhea

– Especially nocturnal

• Wheezing

• Irritable bowel syndrome

• Bloating




Pathologic confirmationAssess disease burden

Assess functional status

Diagnosis and Initial Work-Up



Anatomic Imaging: CT

Std

Venous Delayed

Arterial

Imaging studies property of James Yao, MD. CT: computed tomography.



Anatomic Imaging: MRI

MRI = magnetic resonance imagingImaging studies property of James Yao, MD.



Anatomic CT and Indium-111

Pentetreotide Scintigraphy

Imaging studies property of James Yao, MD.



Tumor Markers

• General NET markers – Chromogranin A

• Affected by somatostatin analogues, proton pump

inhibitors, kidney function, liver function

– Neuron-specific enolase

• Midgut (small bowel, appendix, cecum)

– 5 HIAA (24-hr urine collection)

– Serotonin (blood, more variable)

5-HIAA = 5-hydroxyindoleacetic acid



Other Markers in Functional Tumors

Fasting measurements when possible



Principles of Marker Assessment

• Lots of markers; expression can change over time – Chromogranin B and C, pancreastatin, substance P,

neurotensin, neurokinin A, pancreatic polypeptide

•Take large panel of markers at key points

– Diagnosis or relapse

• Follow a few elevated markers over time

• Not necessary to check every marker at each visit



Somatostatin analogsChemotherapy for pancreatic NETs

Regional therapy approaches

Current Treatment Approaches



Limited Options for Advanced NETs

Octreotide LAR

+ chemotherapy

Chemotherapy

Octreotide LAR

No standard

No standard

Functional

Nonfunctional

Midgut

No syndrome

Non-midgut

No syndrome

pNET

Carcinoid

Carcinoid

syndrome

D i s e a s e p r o g r e

s s i o n

Hepatic artery

embolization

Investigational

agents

(No approved

therapies

available)

LAR = long-acting release; pNET = pancreatic NET



• Median survival

– Carcinoid 43 months

– pNET 27 months

• Carcinoid

– No approved drugs for tumor

control

• pNET – Streptozocin approved but

perceived to be toxic

– No agreed-upon standard

treatment for tumor control

SurvivalPatients with distant NET (1988-2004) Limited Options

Need for Tumor Control Agents Remains High

Carcinoid

Pancreatic NET




Somatostatin receptorPeptide receptor radiotherapy

Angiogenesis

mTOR

Emerging Therapeutic Approaches

mTOR = mammalian target of rapamycin



Targeting NETs

• Somatostatin receptorshighly expressed by NETs

– Targeting SST receptors can

provide symptom and

disease control

• New targets could change

treatment paradigm :

– mTOR, PI3K, VEGF inhibitors

– Other antiangiogenic agents

• High potential for

combinations

PI3K = phosphoinositide 3-kinase; SST = somatostatin; VEGF = vascular endothelial growth factor



No Standard

Potential Management of Advanced NETs

Post-PROMID

Octreotide LAR

+ chemotherapy

Chemotherapy

Octreotide LAR

Consider

octreotide LAR

No standard

Functional

Nonfunctional

Midgut

No syndrome

Non-midgut

No syndrome

pNET

Carcinoid

Carcinoid

syndrome

D

i s e a s e p r o g r e s s i o n

Investigational

agents

(No approved

therapies

available)



• Systemic radiotherapytargeting somatostatin

receptors

• Compounds vary by isotope

and carrier molecule• 177Lu DOTATATE1 and 90Y

DOTATOC2: promising

results in phase 2 studies

Peptide Receptor Radiotherapy (PRRT)111In pentetreotide

DTPA-CO-NH-D-Phe-Cys

S

S

Thr(ol)-Cys

Phe

D-Trp

Lys

Thr

111In

DOTA-CO-NH-D-Phe-Cys

S

S

Thr(ol)-Cys

Tyr

D-Trp

Lys

Thr

90Y DOTATOC

90Y

177Lu DOTATATE

DOTA-CO-NH-D-Phe-Cys

S

S

Thr-Cys

Tyr

D-Trp

Lys

Thr

177Lu

177Lu-DOTATATE:177Lu-1,4,7,10-tetraazacyclododecane- N,N',N'',N''' -tetraacetic acid0 (DOTA), Tyr3-octreotate; 90Y

DOTATOC: [90Y-DOTA]-D-Phe1-Tyr3-octreotide.

1. Kwekkeboom DJ et al. J Clin Oncol. 2008;26:2124-2130.2. Waldherr C et al. Ann Oncol . 2001;12:941-944.



Bevacizumab: Randomized Phase 2 Trial

Stable dose of octreotide

x 2 months

Random assignment

Bevacizumab + PEG interferon α-2b

(+ octreotide)

Protocol

starts here

Bevacizumab

(+ octreotide)

PEG interferon α-2b

(+ octreotide)

18 wks

Bevacizumab

(n = 22)

PEG interferon

(n = 22)

PR(confirmed)

4 0

SD 17 16

PD 1 6

ITT by assignment

P = .019 (2-sided exact)

Additional responses:•1 pt with PD on PEG interferon had PR after addition

of bevacizumab

•1 pt with SD on PEG interferon had PR after addition

of bevacizumab

PR = partial response; SD = stable diseaseYao JC et al. J Clin Oncol . 2008;26:1316-1323.



Sunitinib: Phase 2 Open-Label Study

Carcinoid, n(%) (n = 41)

Islet cell, n(%) (n = 66)

All pts, n(%) (N = 107)

PR (confirmed) 1 (2) 11 (17) 12 (11)

SD 34 (83) 45 (68) 78 (73)

PD 1 (2) 5 (8) 6 (6)

Not evaluable 5 (12) 5 (8) 10 (9)

Kulke MH et al. J Clin Oncol . 2008;26:3403-3410.



Carcinoid: SWOG 0518 Phase 3 Study

Poor prognosis

(N = 283)

Octreotide +interferon

Octreotide +bevacizumab

Supported by CTSU

Endorsed by ECOG, CALGB, NCCTGR

CALGB = Cancer and Leukemia Group B; CTSU = Cancer Trials Support Unit; ECOG = Eastern Oncology CooperativeGroup; NCCTG = North Central Cancer Treatment Group; SWOG = Southwestern Oncology Group



Sunitinib Phase 3 pNET Study

Islet cell w/PD over prior12 months (340 planned,

171 accrued)

Sunitinib 37.5 mgcontinuous dosing

Placebo

Stopped early at unplanned time pointMarch 12, 2009

Investigator-reported PFS:

11.4 mo with sunitinib vs 5.5 mo with placebo

R

PFS = progression-free survivalRaymond E et al. ASCO GI 2010; Abstract 127.



MDACC: Everolimus + Octreotide LARResponse

Per protocolOverallN = 60

Carcinoidn = 30

Islet celln = 30

PR 13 (22%) 5 (17%) 8 (27%)

SD 42 (70%) 24 (80%) 18 (60%)

PD 5 (8%) 1 (3%) 4 (13%)

PFS (median) 60 wks 63 wks 50 wks

ITT RR: 20%

MDACC = M. D. Anderson Cancer Center; RR = response rateYao JC et al. J Clin Oncol . 2008;26:4311-4318.



RADIANT-1: Study Design

• Advanced pancreatic NET with RECIST progression following cytotoxic

chemotherapy

– Stratum 1: No octreotide LAR 60d before enrollment

• Received everolimus 10 mg/d

– Stratum 2: Octreotide LAR ≥ 3mo before enrollment

•Received everolimus 10 mg/d + octreotide LAR ( ≤ 30 mg, q28d)

Treatment until progression; CT or MRI at baseline & q3mo

Primary endpoint• RR stratum 1

Secondary endpoints• RR stratum 2

• Response duration

• Safety

• PFS

• Survival

• PK

Stratum 1

n = 115

SCR

EEN

Stratum 2

n = 45

Everolimus +octreotide LAR

Everolimus

PK = pharmacokinetics; RECIST = Response Evaluation Criteria In Solid TumorsYao JC et al. J Clin Oncol . 2010;28:69-76.



RADIANT-1: Best Change from BaselineCentral Radiology Review

Stratum 1: Everolimus (n = 115)

Stratum 2: Everolimus + Octreotide LAR (n = 45)

Central radiology ITT, n (%)

PR 11 (9.6)

SD 78 (67.8)

Clinical benefit

(PR + SD)

89 (77.4)

PD 16 (13.9)

Unknown 10 (8.7)

Central radiology ITT, n (%)

PR 2 (4.4)

SD 36 (80.0)

Clinical benefit

(PR + SD)38 (84.4)

PD 0 (0.0)

Unknown 7 (15.6)




Octreotide LAR +Everolimus

Octreotide LAR +

placebo

Advanced carcinoidwith syndrome in

progression

(N = 429)

Pivotal Phase 3 Trials with Everolimus in

NETs

R

Accrual completed

Best supportivecare + everolimus*

Best supportivecare + placebo*

Advanced pNET inprogression

(N = 410)

R

Accrual completed

*Octreotide LAR included as best supportive care.



Conclusions

• NETs not that rare• Progress being made

• Somatostatin analogs effective in controlling

hormonal syndrome

• PROMID suggests octreotide LAR controls tumor

growth in midgut carcinoids

• Phase 2: VEGF and mTOR inhibitors have single-

agent activity in NETs• Confirmatory phase 3 studies ongoing



HYPOGLICEMIA

Agus Widiyatmoko



CAUSE OF HYPOGLYCEMIA

1. According to pathogenesis

a) decreased glucose production- lack of contraregulatory hormones

- liver or kidney disease, alcohol

b) increased glucose utilisation- exogenously caused (DM treatment)

- endogenously caused (insulinoma)

2. According to timing of the food ingestion

a) fasting hypoglycemia (!!!)

b) random hypoglycemia during the day

- reactive (functional), postoperative



Hypoglycemia and activation of

contraregulatory hormones

Glucose Hormone

3,8-3,6 mmol/l glucagon 3,5-3,2 mmol/l catecholamines

3,1-2,7 mmol/l growth hormone

2,8-2,6 mmol/l cortisol

neurogenic

symptoms

neuroglycopenic

symptoms



HYPOGLYCEMIC SYMPTOMS

1) neurogenic: sweatting, palpitations, tachycardia,

(adrenergic) anxiety, tremor

2) neuroglycopenic:

a) neurologic: confusion,headache, blurred vision,diplopy, dysarthria, decreased abbility

to concentrate, impaired speech and

consciousness, cramps, epilepsy

b) psychiatric: unusual hesitation, temper changes

(depression, euphory)

impaired thinking



INSULINOMA



INSULINOMA

• Epidemiology

•Pathophysiology & Symptoms

•Dignosis & Locallization

•Management

• Anaesthetic considerations



Epidemiology

• First described by Harris in JAMA 1924

• Commonest hormone producing Neuro Endocrine

Tumors of GIT

• 99% of pancreatic origin

• 90% solitary, 90% < 2cm, 90% benign

• 8% ass. with Multiple Endocrine Neoplasia type I

(multiple, malignant in 25%)

• Median age at presentation is 47yrs• F to M ratio 1.4:1

P h h i l



Pathophysiology

Hypoglycemia

↑glucagon(glycemic threshold 65-70mg/dl)

↑catecholamines

↑cortisol & GH

Neuroglucopenic symptoms(<50mg/dl)



Pathophysiology

• Reduced epinephrine response in

response to chronic hypoglycemia

(hypoglycemia unawareness)

• Present with neuroglucopenic symptoms

• Nonspecific & episodic in nature



Symptoms

• Neuroglucopenic symptoms

– Headache

– Visual disurbances

– Lethargy,lassitude,confusion

– Difficulty in speech, thinking

– Personality changes

– Convulsions, coma

S t



Symptoms• Neurogenic

– Cholinergic symtoms• Hunger

• Sweating

• Parasthesia

– Adrenergic symptoms• Anxiety, nervousness

• Tremors

• Tachycardia, palpitations

• hypertension

• Weight gain in 20-30%• Appear in early morning, after fasting

• Aggravated by exercise

Diagnosis



Diagnosis

• Whipples triad – Hypoglycemic symptoms brought about by

fasting or exercise

– ↓Blood Sugar during symptoms

– Relief on administration of glucose

• ↑ C peptide level

• ↑ plasma insulin

• Absence of sulfonylurea

Diagnostic testing



Diagnostic testing

• 72 hrs fast(gold standard) – Plasma glucose ≤2.5 mmol/l

– Plasma insulin ≥6 μunits/ml (43 pmol/l)

– Plasma C-peptide ≥0.2 nmol/l

– Plasma proinsulin ≥0.5 nmol/l

– Plasma sulphonylurea Negative

– Plasma β-hydroxybutyrate <2.7 mmol/l

– Change in glucose with 1 mg glucagon ≥25 mg/dl at 30 min

– symptoms develop in 35 %of patients within 12 h, 75 % within 24

h, 92 % within 48 h and 99 % within 72 h• C peptide suppression test

• Stimulation tests with glucagon, Calsium, tolbutamide



Locallization

• CT, MRI

• Transabdominal USG,

Endoscopy US

• Intraop US

• Somatostatin receptor

scintigraphy

• Angiography

• Selective intra-arterialCalsium injection

stimulation with hepatic

venous sampling







Octreoscan





TREATMENT

a) surgical

- by laparotomy

- by laparoscopy

b) conservative

- regimen (diet, activity)

- pharmacological(diazoxide, octreotide)

Management



Management

• Medical

– When awaiting surgery

– Metastatic disease

– Failed surgery

• Dietary• Diazoxide (with hydrochlorthiazide)

• CCBs, Verapamil, Nifedipine

• Somatostatin analogues, Octeotride

• CT- Streptozocin, 5FU, Doxarubicin

• Hepatic art. embolization

M t



Management

• Surgical

– Resection is the treatment of choice

– Specialized units

– Enecluation in most cases

– Distal pacreatectomy/ whipples’s procedure in

a few

– Blind resection shouldn’t be performed



Enucleation

Resection (hemipancreatectomy)



Resection (hemipancreatectomy)



Surgical and histological finding

a) localization (n=115)Head: 30 %

Body: 28 %

Tail: 42 %

b) histology

Benign adenoma: 103

Malign carcinoma: 4

Uncertain biological activity: 5

Multiple microadenomatosis: 3

Al ith f di i i i h i li i



Algorithm of diagnosis in organic hyperinsulinism Clinical suspition

Biochemical examination

Diagnosis confirmed Diagnosis unconfirmed

Topographic localisation

CT Ang iography Endosonography

Localisation confirmed Localisation unconfirmed

Surgery

Insulinoma removed Insulinoma unremoved

Conservative treatment

T R E A T M E N T

D I A G N O S I S



In differential diagnosis:

HYPOGLYCEMIA FACTITIA



HYPOGLYCEMIA FACTITIA

Characteristic signs:

- suspicion on insulinoma

- uncertainty from clinical picture- uncertainty from laboratory findings

- frequent relationship of the patient to

health care providers

Attention: IATROGENIC HYPOGLYCEMIA



Insulinoma vs hypoglycemia factitia

Laboratory

variable

Insulinoma Hypoglycemia

factitia

caused by insulin

Hypoglycemia

factitia

caused

by sulphonylurea

Plasma glucose ↓↓↓ ↓↓↓ ↓↓↓

Plasma insulin ↑ - ↑↑↑ ↑↑↑ ↑↑↑

Serum C-

peptide

↑ - ↑↑ ↓ - ↓↓ ↑ - ↑↑

Plasma

proinsulin

↑ - ↑↑ ↔ ↔

Sulphonylurea

(urine)

negative negative positive



DIABETES HYPOGLICEMIA



Hypoglycemia in Diabetes Checklist

RECOGNIZE hypoglycemia and CONFIRM

DIFFERENTIATE mild-moderate vs. severe

TREAT hypoglycemia but AVOID overtreatment

AVOID hypoglycemia in the future

2013



1. Development of neurogenic or neuroglycopenic symptoms

2. Low blood glucose (<4 mmol/L if on insulin or

secretagogue)

3. Response to carbohydrate load

Neurogenic

(autonomic)

Neuroglycopenic

Trembling Difficulty Concentrating

Palpitations Confusion

Sweating Weakness

Anxiety Drowsiness

Hunger Vision Changes

Nausea Difficulty Speaking

Dizziness

Definition of Hypoglycemia



• Mild – Autonomic symptoms present

– Individual is able to self-treat

• Moderate

– Autonomic and neuroglycopenic symptoms

– Individual is able to self-treat

• Severe

– Requires the assistance of another person

– Unconsciousness may occur

– Plasma glucose is typically <2.8 mmol/L

Severity of Hypoglycemia



• Can result in significant morbidity and mortality

• Serious obstacle to meet glycemic targets

• Counsel patients who drive on insulin or

secretagogues re: self-monitoring of blood glucose

and taking appropriate precautions

Drug Induced Hypoglycemia



Steps to Address Hypoglycemia

1. Recognize autonomic or neuroglycopenic symptoms

2. Confirm if possible (blood glucose <4.0 mmol/L)

3. Treat with “fast sugar” (simple carbohydrate) (15 g) torelieve symptoms

4. Retest in 15 minutes to ensure the BG >4.0 mmol/L and

retreat (see above) if needed

5. Eat usual snack or meal due at that time of day or a

snack with 15 g carbohydrate plus protein



• 15 g of glucose in the form of glucose

tablets

• 15 mL (3 teaspoons) or 3 packets of sugar

dissolved in water

• 175 mL (3/4 cup) of juice or regular soft

drink

• 6 Lifesavers (1=2.5 g of carbohydrate)

• 15 mL (1 tablespoon) of honey

Examples of 15 g Simple Carbohydrate



Recognize Risk Factors for Severe

Hypoglycemia

Risk factors in Type 1 DM

patients

Risk factors in Type 2 DM

patients

Adolescence Elderly

Children unable to detect and/ortreat mild hypoglycemia

Poor health literacy, Foodinsecurity

A1C <6.0% Increased A1C

Long duration of diabetes Duration of insulin therapy

Prior episode of severehypoglycemia

Severe cognitive impairment

Hypoglycemia unawareness Renal impairment

Autonomic neuropathy Neuropathy



Treatment of SEVERE Hypoglycemia in

Conscious Person

1. Treat with oral “fast sugar” (simple carbohydrate)

(20 g) to relieve symptoms

2. Retest in 15 minutes to ensure the BG> 4.0mmol/L and retreat with a further 15 g of

carbohydrate if needed

3. Eat usual snack or meal due at that time of day ora snack with 15 g carbohydrate plus protein




Unconscious Person with no IV Access

1. Treat with 1 mg of glucagon subcutaneously or

intramuscularly

2. Call 911

3. Discuss with diabetes healthcare team




Unconscious Person with IV Access

1. Treat with 10-25 g (20-50 cc of D50W) of glucose

intravenously over 1-3 minutes

2. Retest in 15 minutes to ensure the BG >4.0 mmol/Land retreat with a further 15 g of carbohydrate if

needed

3. Once conscious, eat usual snack or meal due at thattime of day or a snack with 15 g carbohydrate plus

protein



Hypoglycemia and Driving

• If BG <5.0 mmol/L prior to driving:

– Take 15 g carbohydrate

– Re-check in 15 minutes

– When BG >5 mmol/L for at least 45 minutes safe to drive

• Need to re-check BG every 4 hours of continuousdriving and carry simple carbohydrate snacks

Iain S. Begg et al . Canadian Journ al of Diabetes . 2003;27(2):128-140.

Safe blood glucose

(BG) prior to drivingBG ≥ 5.0 mmol/L



Recommendation 1

1. Mild to moderate hypoglycemia should be treated

by oral ingestion of 15 g carbohydrate; glucose or

sucrose tablets/solutions are preferable to orange

juice and glucose gels [Grade B, Level 2]

Patients should retest blood sugar in 15 minutes

and retreat with another 15 g of carbohydrates if BG

remains <4.0 mmol/L [Grade D, Consensus]



Recommendation 2

2. Severe hypoglycemia in a conscious person

should be treated by oral ingestion of 20 g of

carbohydrate, preferable as glucose tablets or

equivalent.

Blood sugar should be retested in 15 minutes, and

then retreated with a further 15 g of glucose if BG

remains <4.0 mmol/L [Grade D, Consensus]



3. Severe hypoglycemia in an unconsciousindividual:

– No IV access: 1 mg of glucagon should be

administered subcutaneously or intramuscularly.

Caregivers or support persons should call for

emergency services and the episode should be

discussed with the diabetes healthcare team as

soon as possible [Grade D, Consensus]

– With IV access: 10-25 g (20-50 cc of D50W) of

glucose should be given intravenously over 1-3

minutes [Grade D, Consensus]

Recommendation 3



4. For individuals at risk of severe hypoglycemia,

support persons should be taught how to

administer glucagon by injection [Grade D, Consensus]

Recommendation 4



Recommendation 5

5. Once the hypoglycemia has been reversed, the

person should have the usual meal or snack that

is due at that time of the day to prevent repeated

hypoglycemia [Grade D, Consensus].

If a meal is > 1 hour away, a snack

(including 15 g of carbohydrate and

protein source) should be consumed[Grade D, Consensus]



Recommendation 6

6. Patients receiving antihyperglycemic agents that

may cause hypoglycemia should be counseled

about strategies for prevention, recognition and

treatment of hypoglycemia related to driving [Grade

D, consensus]

2013



Conclusions for clinical practice

• to analyse symptoms (history !)

• to confirm hypoglycemia

• to elucidate cause of hypoglycemia(confirm diagnosis)

• to realize reliable treatment strategyremoving hypoglycemia(related to diagnosis and clinical state ofthe patient)

Hypoglycemia is deleterious for organismand is life threatening

Documents

Hypoglikemia and Insulinoma