Fatemeh Rahmani Agenda Definition Prevalence Etiology Pathophysiology Provacative test Risk factors Treatment 54yearold nurse with RYGB 9 y ago no history of DM ID: 932226
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Slide1
Hypoglycemia After Gastric Bypass Surgery
Fatemeh Rahmani
Slide2Agenda
●
Definition
●Prevalence
●Etiology
●Pathophysiology
●Provacative test
●Risk factors
●Treatment
Slide354-year-old nurse with RYGB 9 y ago , no history of DM
began to experience symptoms of hypoglycemia from 4
years ago
occurred within 1 to 2 h after simple carb eating,
initial evaluation : meal test
BS= 34 mg/dL at 105 min after eating
symptoms relieved by drinking juice
Slide4PBH
usually occurs 1y after surgery
Symptoms occur 1-3h after eating
Against the diagnosis
1) 6-12 m in the postoperative period
2)in the fasting state
3) 4 hours after caloric intake
4) with activity& during overnight (2-4am)
Slide51)
history of PP neuroglycopenia occurring 1-3 h
after meals in a patient with history of bariatric surgery at
least 1y before symptom
2)documented hypoglycemia (BS <54 mg/dL) at
time of neuroglycopenic symptoms, and resolution of
symptoms with treatment to raise glucose
3) no hypoglycemia after a prolonged fast of at least 12
hours
Slide6Agenda
●
Definition
●
Prevalence
●Etiology
●Pathophysiology
●Provacative test
●Risk factors
●Treatment
Slide7Slide8inclusion criteria (April 2015- July 2016)
-undergone RYGB surgery 1 y ago
-were operated on by the same surgeon
-had a negative hypoglycemic agent history
-were18 years old
all patients received a standardized solid mixedmeal
energy total :201kcal
carb :34g (49.0%)
fat :8g (32.0%)
protein :3.8g (6.0%)
Slide9tests were performed in the morning after overnight fast
Blood samples were drawn every 30min until 150 min
Patients with pHH underwent a second solid mixed meal
test1-2weeks later,
low carb solid mixed meal consisting of
energy total: 195kcal
carb :9g[18.0%]
fat :5g[22.0%]
protein :26.9g[60.0%]
cutt-off value : Bs <55mg/dL & INS >18pmol/L
Slide10Slide11The purpose : evaluate the frequency of pHH with &w/o symptoms of hypoglycemia
Most current literature considers pHH occurring with a frequency of<1-2%
In our series ,25 expressed typical autonomous symptoms for pHH above 55mg/dL, due to the rapid drop in BS
These patients’ symptomses even w/o severe hypoglycemic episodes suggests that our finding of 1.0% is likely not fully representative of the actual pHH incidence
Slide12Importance
Severe hypoglycemia
●neuroglycopenic symptoms
●syncope
●motor vehicle accidents
●increase morbidity and mortality in DM
●cardiac arrhythmia
●cardiovascular death in post bariatric surgery patients
Slide13Slide14All patients underwent RYGB,SG,or DS at a single center 2002-2015 with postoperative glucose ≤70mg/dL
1)symptoms occurring >1y after surgery
2)normal FBS & insulin levels
3)correlation of symptoms & hypoglycemia
Slide15Slide1683 patients (1.4%)had symptomatichypoglycemia
23 :1episode
60: ≥2episodes
25 were admitted to the hospital for further management
PPH: 32(38%)
Infection :8(10%)
Medication: 8(10%)
Poor oral intake :8(10%)
Unknown :27(32%)
Slide17Slide18rate of symptomatic hypoglycemi & pp hyperinsulinemic hypoglycemia was 1.4%& 5%.
Both conditions were most commonly seen after RYGB
1/3 required hospitalization
38% referred to endocrinologists for more evaluation
9 patients required nutritional intervention in the form of
feeding tube placement or parenteral nutrition
Slide19Rate of hypoglycemia is less after SG compared with RYGB
In our cohort ,hypoglycemia occurred more frequently
●post-RYGB(88%)
● nondiabetic patients(54%)
●with a median of 781d between surgery & hypoglycemia
Slide20What glucose threshold should be used
Typical patterns of glycemia in a post-bypass patient
▪normal fasting glucose
▪exaggerated postprandial excursions compared with
those without GI surgery
▪rapid rise in glucose shortly after food intake and a fast
decline thereafter
Glucose alone can not be used to define hypoglycemia
(integration with symptoms)
Slide21Slide22Agenda
●
Definition
●Prevalence
●
Etiology
●Pathophysiology
●Provacative test
●Risk factors
●Treatment
Slide23Slide24The primary etiologies of PPHH
■
Dumping syndrome
■factitious insulin/sulfonylurea administration
■nesidioblastosis
■Noninsulinoma pancreatogenous hypoglycemia –
syndrome (NIPHS)
■Insulinoma
Slide25Slide26Slide27Slide28Diagnosis of nesidioblastosis is 1 of exclusion
-biochemical
-provocative
-radiologic testing
-pancreatic resection
- pathologic confirmation
Slide29imaging is necessary to distinguish nesidioblastosis and insulinoma after the biochemical evaluation.
Insulinoma can be identied in CT , Sono ,MRI. indium-111 pentetreotide (GLP-1) scan is the most sensitive for detecting occult insulinoma by highlighting somatostatin
receptorpositive tumors
Calcium stimulated selective mesenteric arteriography
invasive , selectively sample insulin secretion from the pancreas ,useful in localizing the B-cell mass in cases of nesidioblastosis
Slide30recurrent nesidioblastosis after distal pancreatectomy has been described in surgical therapy failure.
Several series of open distal pancreatectomy in children for nesidioblastosis found that 100(52%)of 193 patients had recurrent symptoms after resection
61 (32%) required an additional resection to ameliorate their symptoms
Adults could differ from children in that the former has diffuse nesidioblastosis instead of focal and recurrent hypoglycemia in the initial postoperative period are commonly not transiently
Slide31NIPHS
rare syndrome characterized by endogenous HH in adults that is not caused by an insulinoma
Pancrease show similar pathological feature of nesidioblastosis
Service et al. In 1999 in 5 adults found symptoms of PP neuroglycopenia secondary to hyperinsulinemic hypoglycemia due to excessivebeta –cell growt
these patients had negativeimaging studies, negative 72 h fasts, and positive selective arterial calcium stimulation tests indicative of pancreatic beta-cell hyperfunction
Slide32Another possible but rare cause of hypoglycemiain post-RYGB patients is insulinoma
The persistence of hypoglycemic episodes after dietary adjustments led to consideration of an autonomous source of hyperinsulinemia, and MRI and CT iden-tified an insulinoma.
Insulinoma can present with hypoglycemia in both fasting and postprandialstates (rarely)
Slide33Which patients with hypoglycemia after bariatric surgery require a prolonged fasting test and imaging
Slide34For patients with typical PPH and no fasting hypoglycemia, don’t need prolonged fasting tests.
In patients with fasting hypoglycemia who do not appear well, additional diagnostic testing (AI, critical illnes, malnutrition associated with excessive weight loss or food aversion) should be considered
Imaging studies should not be performed unless the history and biochemical testing demonstrate that fasting hypoglycemia is present and is caused by excessive insulin secretion, or other atypical clinical features raise suspicion for other pathology
Slide35Agenda
●
Definition
●Prevalence
●Etiology
●
Pathophysiology
●Provacative test
●Risk factors
● Treatment
Slide36PPHH ( late dumping syndrom )is seen mainly after RYGB.
The pathophysiology of this is not well understood
it is believed to be due to alterations in
▪glucose regulatory mechanism
▪incretin hormones
▪INS sensitivity
▪increased
β-
cell hyperplasia/ activity/ sensitivity
PPHH usually occurs 1 y after bariatric surgery, with normal glucose and insulin levels in the fasting state
Slide37e
arly dumping:typically occurred within 1h of eating due to concentrated nutrients and carb rapidly entering the small bowel and occurred in 1/3 gastrectomy patients.(9-21%)
late dumping: typically occurred 2–3 h after eating, associated with hypoglycemia and generally developed later in the post-operative course, but with an etiology that was less clear(1-6%)
Slide38Slide39Several factors implicated ,including increase in incretins
Incretins are gut-derived hormones that are released into
the blood post-prandially, and stimulate insulin release
from the beta cells of the islets of Langerhans
2 incretins that are most often implicated are:
a) Glucagon-like peptide-1(GLP-1)
b) Gastric inhibitory peptide (GIP;also known as
glucose-dependent insulinotropic polypeptide)
Slide40levels of GLP-1 increase after bariatric surgery, due to the rapid transit of unabsorbed nutrients to the jejunum &ileum, the distal portion of which is the site of Lcells, the source of GLP-1
Rabiee et al. in 2011 studied 4 post-RYGB patients and reported 3-4 fold increase in GLP-1 levels 1y after surgery & 2 fold increase in GIP level
Goldfine et al. in 2007 found incretin levels to be 5-10 fold higher in post-RYGB patients compared to controls
Slide41GLP-1 has been
▪increase beta cell mass in prolieration
▪decreasing- beta cell apoptosis
▪induce hypertrophy of pancreatic cells
other possible mechanisms:
-lack of reduction of b-cell mass which was increased
during the preoperative obese state
-increased insulin sensitivity following weight loss
-inappropriate beta cell secretion following early
entry of ingested nutrients into the small intestine
-abnormal counter-regulatory hormonal (glucagon)
responses
Slide42GLP-1 has 2 functions:
▪antihyperglycemic hormone increasing B-cell sensitivity
to glucose to induce glu-dependent insulin secretion
with inhibition of glucagon secretion
▪initiator of the “ileal brake” to slow small bowel motility in
response to the rapid delivery of food into bowel
resulting in the activation of the “ileal brake” at the
consequence of profound insulin secretion and
subsequent hypoglycemia
Slide43Plasma GIP levels andGLP-1levels in four patients with neuroglycopenia occurring 2–3 years after Roux-en-Y gastric bypass (colored symbols, cases 1–4) and in five asymptomatic patients 1 year after Roux-en-Y gastric bypass (controls—open circles) following a standardized test meal
Slide44Loss of pylorus in RYGB causes faster GI transit and absorption of simple sugars that evoke a stronger GLP1 response resulting in higher insulin level called Postprandial hyperinsulinemic hypoglycemia
Slide45In patients with post-RYGB hypoglycemia, elevation of GIP &GLP-1 persist for years after surgery with hypersecretion of INS in setting of normal BS
INS sensitivity as well as b-cell GLP-1 receptor availability, sensitivity to GLP-1, and sensitivity to glucose are normal in patients with post-RYGB hypoglycemia
so an inappropriately exuberant INS response with subsequent hypoglycemia is due to excessive secretion of GLP-1 after oral nutrients
Slide46Agenda
●
Definition
●Prevalence
●Etiology
●Pathophysiology
●
Provacative test
●Risk factors
●Treatment
Slide47provocative tests
GTT is not well tolerated in previous history of UGI
- hyperosmolar liquid provokes dumping syndrom
-10% of healthy people have glucose <50 mg/dL in 180
min of the challenge, without neuroglycopenia.
an oral GTT should play no role in the evaluation of meal-induced hypoglycemia particularly in individuals after GI surgery and dumping syndrome
Slide48provocative testing
mixed meal (protein,carbohydrates ,fat)
-no currently accepted standard for meal testing;
- solid& liquid mixed meal are used with carb 40-75g
some believe liquid meal has no place in the evaluation of patients with accelerated& unregulated transit of calories into the proximal small intestine but others believe it provides reproducible stimulus
Slide49Agenda
●
Definition
●Prevalence
●Etiology
●Pathophysiology
●Provacative test
●
Risk factors
● Treatment
Slide50Slide51questionnaire-based survey was conducted in bariatric surgery patients between Aug2013- Feb 2014 to obtain data on new-onset symptoms of hypoglycemia included (sweating,palpitations ,shaking ,hunger ,confusion ,drowsiness ,odd behavior ,speech difficulty ,incoordination ,nausea ,headache)
We asked the participant about the presence of any of these symptoms before and after bariatric surgery
Slide52Exclusion criteria
▪ ≥3 preoperative symptoms of postprandial hypoglycemia
▪preoperative history of requiring assistance for symptoms ▪medical diagnosis of hypoglycemia
remaining patients(N=341)into low or high suspicion group
low suspicion: 2 PP symptomatic hypoglycemia
High suspicious:>3 PP symptomatic hypoglycemia
Slide53Slide54Slide55High suspicion group was more likely to be
female(90.9%versus74.4%)
younger (48.4versus51.1)
nondiabetic (17.2%versus34.3%)
undergoneRYGB (91.9%versus72.3%)
longer time since surgery (6.6versus6.2y)
Indipendent risk factor
▪female sex
▪RYGB
▪absence of preexisting DM
Slide56Protective role of diabetes
▪decreased functional beta -cell mass
▪increased peripheral resistance
▪both
Individuals with diabetes are less susceptible to incretin
effects and they may require a longer time interval to
develop excess islet mass and manifest significant
hypoglycemia
Slide57Slide58Agenda
●
Definition
●Prevalence
●Etiology
● Pathophysiology
●Provacative test
●Risk factors
●
Treatment
Slide59Slide60Medical nutrition therapy
Diet is the cornerstone of therapy
Ingested carb(rapidly/ simple/high glycemic index carb)
▪rapidly increase plasma glucose
▪stimulates insulin secretion
▪increases the risk of subsequent hypoglycemia
Slide61Slide62Carb ingestion stimulus rising BS and insulin secretion
Some patients with PBH are more sensitive to carb
due to excessive intestinal glucose absorption
limiting carb reduces the PPHH rise and INS secretion
Slide63Slide6414 patients with PPHH
mixed meal ( H.carb on day 1 & L.carb on day 2)
The plasma glucose & INS levels were measured
fasting , 30, 60, 90, 120, 150, 180 minutes after the meal.
After Hcarb ,12 of 14 become hyperglycemic with hyperinsulinemia at 30 min & hypoglycemic while INS corrected
Slide65After reaching a nadir at 120 min,the Bs corrected
spontaneously
The postprandial peak serum INS occurred at 30-90 min in all patients
The nadir of the plasma glucose occurred at 90-120 min in all patients
Slide66H carb(80 g),low protein (10 g) meal
led to significant hyperinsulinemia and hypoglycemia
isocaloric very L. carb (2 g), high protein(25 g)
prevented excessive INS secretion or PPH
study in 10 patients with PBH showed H.carb containing
sucrose provoked PPHH
H.carb composed of fructose was associated with lower
glycemic peak, lower INS secretion, no induction of
hypoglycemia
Slide67Mean BS(red) & INS (blue)responses to(A)high-carb (B)low-carb
High-carb induced closely coupled glucose and INS response
After initial INS response ,patients became hypoglycemic while serum insulin was rapidly declining .After reaching a nadir at 120 min ,BS corrected spontaneously. B)After low-carb ,patients show little change in BS & modest increase Ins
Slide68Response to low-carbohydrate diet
Of 12 patients:
10 (83%) improved in symptoms
3 (25%) reported complete symptom resolution
3(25%) reported major symptom improvement
4 (33%) reported minor symptom improvement
2 (17%) reported no improvement.
2 patients(1 reporting minor &1 reporting no improvement) were unable to fully comply with the lowcar diet
2 patients refractory to the low-carb treated with Acarbose
Slide6930-g carb increase glucose by 100 mg/dL, and a 15 g carb may increase glucose by ~100 mg/dL.
There is substantial variability in glucose “spikes” between individuals, and even from day to day, potentially related to rate of delivery of foods to the intestine, rates of glucose absorption by the proximal intestine, time of day, and other metabolic factors
Slide702.low glycemic index carbohydrates
Slide713. Avoid high glycemic index carbohydrates
Slide72Emphasize adequate protein intake
30 g of protein at each meal or 0.9 g/kg actual weight
meat, chicken,egg whites, fish, milk
high quality non-animal proteins such as soy
Excessive protein intake is not desirable, it may displace other nutrients in the diet.
In some patients, excessive liquid protein intake may cause
hypoglycemia, as proteins also robustly stimulate insulin
secretion
Slide73Avoid consuming liquids with meals and chew foods slowly
hormonal responses in “dumping” are similar to those in patients with severe PPHH (rapid surges in glu,incretin , INS secretion)
Dietary management of the dumping includes :
avoiding ingesting liquids with meals
to attenuate rapid delivery of nutrients to the intestine glucose absorption
increased insulin secretion
Slide74Slide75Pharmacotherapy
▪
Acarbose
:
delays & reduces absorption of glucose by inhibition of
intestinal alfa-glucosidase which is required to break down luminal carb into monosaccharides&
reducing postprandial glycemic excursions
-abdominal cramping
- low doses (25mg before meal)
-slow escalation to the max tolerated dose
Slide76▪
Diazoxide
:
reduces INS secretion by inhibition of b-cell ATP-sensitive K
channels
used in persistent HH of infancy, insulinoma,
noninsulinoma pancreatogen syndrome
Case reports in PBH show efficacy of 50-100 BID
fluid retention, edema, N/V, hypotension, headache
Slide77▪
Octreotide (somatostatin)
slowing small bowel motility
inhibition of insulin secretion
inhibition of PP splanchnic vasodilation
Both short& long-acting octreotide have been used and
have a benecial effect on symptoms
the short-acting form was better tolerated and more efcacious for the treatment of symptoms
Slide78Surgical therapy
When diet, CGM, and pharmacotherapy fail
The placement of the feeding gastrostomy tube (G-tube) into the remnant stomach (bypassed portion) allows liquid nutrients to foregut through the duodenum and jejunum
normalizing glucose, insulin, and incretin responses
Feeds via this route can be bolus, overnight, or continuous
Slide79Rare patients continue to have mild episodic hypoglycemia despite continuous G-tube feeding,
improveing with addition of carb to tube-feeding formula
More invasive options :
▪partial pancreatectomy
▪Surgical reversal of bariatric surger
persistenthypoglycemia
weight regain
persistant N/V
▪Placement of an adjustable gastric band
Slide80Experimental approaches
Exendin 9-39
competitively binds the GLP-1 receptor, reducing GLP-1
action
human studies demonstrate efficacy of Iv and SQ
exendin 9-39 in preventing hypoglycemia by reducing
postload insulin secretion
Slide818 patients with confirmed PBH were assigned to IV infusion of the GLP-1 receptor antagonist. Exendin(9-39),placebo for OGTT in 2 days
Ex-9 decreas time to peak GLU ,rate of GLU decline during
OGTT,prevent HH in all PBH
INS secretion rate decreased 71%,PP ins was normalised Autonomic &neuroglycopenic symptoms were significantly reduced during Ex-9 infusion
Slide82Glucagon
delivery from a pump triggered by CGM sensor glucose data
Meal tolerance testing was performed in 7 participants with PPH and history of neuroglycopenia.
Glucagon administered when hypoglycemia was predicted
These modifications, with rescue carbohydrates contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL)
Slide83antibody-mediated blockade of the insulin receptor,
decreasing INS signaling, prevent hypoglycemia
may modify glucose patterns in pilot human studies
Until further clinical studies are performed, the role of these
potential therapies remains uncertain
Slide84Thanks for attention