La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco

 
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
La gastroparesi vista dal
        diabetologo:
quali problematiche e quali
         domande?

       Dr.ssa Carla Greco
Università di Modena e Reggio Emilia
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
Disclosure Statement

La dr.ssa Carla Greco dichiara di NON aver ricevuto negli ultimi due anni compensi o
finanziamenti da Aziende Farmaceutiche e/o Diagnostiche.

Dichiara altresì il proprio impegno ad astenersi, nell’ambito dell’evento, dal nominare,
in qualsivoglia modo o forma, aziende farmaceutiche e/o denominazione
commerciale e di non fare pubblicità di qualsiasi tipo relativamente a specifici
prodotti di interesse sanitario (farmaci, strumenti, dispositivi medico-chirurgici, ecc).
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
Agenda

• Definition and epiemiology of diabetic gastroparesis

• Phatophysiology of gastric motor functions

• Diagnostic procedure of gastroparesis in diabetic patient

• Behavioral and pharmacological therapeutic approach
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
X-rays: gastric studies after ingestion of the x-ray meal consisting of 4 ounces of barium sulphate and water.

                                                                       Kassander P. Ann Intern Med 1958; 48(4):797-812.
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
X-rays: gastric studies after ingestion of the x-ray meal consisting of 4 ounces of barium sulphate and water.

                                                                       Kassander P. Ann Intern Med 1958; 48(4):797-812.
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
Diabetic gastroparesis: definition

                                                                                      *
Clinical syndrome characterized by delayed gastric emptying
in the absence of mechanical obstruction of the stomach in
diabetic patient.

                                     Parkman HP et al. Gastroenterology 2004; 127:1589–91.
                                     Camilleri M et al. Am J Gastroenterol 2013; 108:18–37.
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
Community-Based Epidemiologic Studies
                                           of GI Symptoms in DM
     Study                                     Population                                      Upper GI Symptoms

     Dyck et al, 1993                          Residents of Rochester, MN                      Gastroparesis:
                                               DM1 and DM2                                     0% DM1, 1% DM2
     Janatuinen et al, 1993                    Residents in a hospital district                Symptoms of nausea and vomiting were
                                               (481 DM2, 89 DM1 and 635 controls)              not different between cases with DM
                                                                                               and controls
     Maleki et al, 2000                        Samples of Olmsted County residents             No difference in stomach
                                               (217 DM2, 138 DM1 and 388 controls)             symptoms between DM and controls;
                                                                                               less heartburn reported by DM1 patients

     Bytzer et al, 2001                        Sample of people in Sydney, Australia           Vomiting 1.7% vs 11% (OR 2.71)
     Hammer et al, 2003                        (402 DM2, 21 DM1 and 8132 controls)             Upper gut dysmotility (when evaluated)
                                                                                               18.2% vs 15.3% (OR 1.75)
     Choung et al, 2012                        Follow up of samples of Olmsted County          During 10 years, gastroparesis developed
                                               residents, MN                                   in 5.2% DM1, 1% DM2 and 0.2%
                                               (409 DM2, 269 DM1 and 735 controls)             controls.
                                                                                               HR 4.4; 95% CI, 1.1- 17 in DM1 than DM2

     Aleppo et al, 2017                        Multisite study of 7107 patients                Clinical diagnosis of gastroparesis: 4.8%
                                               (>26 years old with DM1 for >2 years)           (women 5.8% vs men 3.5%)

All surveys, with the exception of Aleppo et al., used a mailed questionnaire.   Modifyed by Bharucha AE et al. Endocr Rev 2019; 40(5):1318-1352.
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
Definite Gastroparesis
 Delayed gastric emptying by scintigraphy                                         3604 potential cases
          and typical symptoms                                                      of gastroparesis

        Probable Gastroparesis
  Symptoms as above plus food retention                                                                                      222
    on endoscopy or an upper GI study                     83                              126
           (not scintigraphy)                                                                                              definite
                                                      definite                          definite
                                                                                                                             plus
                                                   gastroparesis                          plus
        Possible Gastroparesis                                                                                            probable/
   Typical symptoms alone or delayed                                                 probable (43)
  gastric emptying by scintigraphy in the         25.3% diabetes                                                         possible (96)
                                                                                     gastroparesis
          absence of GI symptoms.                 82% female                                                             gastroparesis

Incidence Gastroparesis in Olmsted County, 1996–2006                   Prevalence Gastroparesis in Olmsted County, 1996–2006

                Definite          Definite &     Definite & probable                      Definite        Definite &         Definite & probable
              gastroparesis        probable           & possible                        gastroparesis      probable               & possible
                                 gastroparesis      gastroparesis                                        gastroparesis          gastroparesis
Female              9.8              14.2               22.3           Female               37.8             48.9                   70.6
(95% CI)        (7.5-12.1)         (11.4-17)         (18.7-25.9)       (95% CI)          (23.3-52.4)      (32.2-65.7)            (50.6-90.7)
Males               2.4               5.0               11.8           Males                 9.6             15.3                   27.9
(95% CI)         (1.2-3.8)         (3.2-6.9)          (9-14.7)         (95% CI)          (1.8-17.4)       (5.7-24.9)             (14.4-41.4)
Total               6.3               9.8               17.2           Total                24.2             33.4                   50.5
(95%)            (4.9-7.7)        (8.1-11.6)         (14.9-19.5)       (95%)             (15.7-32.6)      (23.3-43.4)            (38.1-62.8)

                                                                                       Jung HK et al. Gastroenterology 2009; 136(4):1225-33.
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
The cumulative proportions developing gastroparesis over a 10-year time period were
5.2% in type 1 DM, 1.0% in type 2 DM, and 0.2% in controls.
The age- and gender-adjusted hazard ratios (HR) for gastroparesis (relative to controls) was 33
(95% CI: 4.0–274) in type 1 DM and 7.5 (95% CI: 0.8–68) in type 2 DM.
The risk of gastroparesis in type 1 DM was significantly greater than in type 2 DM (HR: 4.4 [1.1,
17]).

                                                              Choung RS et al. Am J Gastroenterol 2012; 107(1):82-8.
La gastroparesi vista dal diabetologo: quali problematiche e quali domande? - Dr.ssa Carla Greco
Physiology of gastric motor functions
       Schematic representation of enteric and extrinsic mechanisms that control GI motility

Antegrade peristalsis  proximal contraction mediated by excitatory neurotransmitters,
coordinated with distal relaxation mediated by inhibitory neurotransmitters

The sympathetic neural input can tonically inhibit antegrade peristalsis in the viscus and
stimulates tonic contraction of the sphincters
                                                        Bharucha AE et al. Endocr Rev 2019; 40(5):1318-1352.
Physiology of gastric motor functions

                                     Autonomic Nervous System (ANS)
                                                     Sympathetic nervous system
                                                     Parasympathetic nervous system (vagus)

                                     Enteric Nervous System (ENS)
    GASTRIC PACEMAKER                                Colinergic neurons of myenteric plexus
Interstitial cells of Cajal (ICCs)                   of Auerbach
                                                     Adrenergic neurons of myenteric plexus of
                                                     Auerbach and submucosal plexus of
                                                     Meissner

                                     Interstitial cells of Cajal (ICCs)
                                                     Gastric pacemaker
Phatophysiology of gastric motor functions

Damage to gastric neurons and ICCs in gastric biopsies in diabetic patients.
                                                      Faussone-Pellegrini MS et al. J Cell Mol Med 2012; 16:1573–81.

Alterations neurons and ICCs  lack of fundus relaxation and reduced gastric capacity,
potentially responsible for dyspeptic symptoms        He CL et al. Gastroenterology 2001; 121: 427–34.

Damage to ICCs  tachyarrhythmia  aberrant progression corpus-antrum
                                                                O’Grady G et al. Gastroenterology 2012; 143:589–98.

                                             Yarandi SS et al. Neurogastroenterol Motil 2014; 26(5):611-24 .
                                             Greco C. Published online. Giornale Italiano di Diabete e Metabolismo, 2019.
                                             Modify by Koch KL et al. Gastroenterol Clin North Am 2015; 44(1):39-57.
Autonomic dysfunction and GI motility disorder
Mayo Clinic, Rochester, MN, USA.                                                                   Distribution of gastrointestinal motility scores.
January 1988 - July 1991

                              Pneumohydraulic perfusion manometry.
                              Supine and standing BP  sympathetic adrenergic
                              function.
 113 patients with            HR and BP responses to the Valsalva manoeuvre 
   suspected GI               sympathetic adrenergic function and vagal innervation.
 motility disorders           Sudomotor axon reflex test  cholinergic sympathetic                    Distribution of autonomic function.
                              function.
                              HR responses to deep breathing  vagal cholinergic
                              function.

                                                                        Significant (p
Gastrointestinal vagal dysfunction

A subnormal plasma pancreatic polypeptide response during sham
feeding is associated with cardiovascular vagal dysfunction.
                                   Glasbrenner B et al. Diabetes Res ClinPract 1995; 30(2):117–123.
                                   Krishnasamy S et al. Diabetes Ther 2018; 9:1-42.
Hyperglycemia and gastric emptying

                                                        Effect of hyperglycemia on plasma motilin concentration

                                                         Effect of hyperglycemia on antral phase III activity.

Acute hyperglycemia delays gastric emptying.

In contrast, insulin-induced hypoglycaemia accelerates gastric emptying even in diabetic
patients with gastroparesis.

Conflicting relationship between HbA1cand gastric symptoms among diabetic people.
                                                 Halland M et al. Clin Gastroenterol Hepatol 2016; 14(7):929-36.
                                                 Barnett JL et al. Gastroenterology 1988; 95(1):262.
                                                 Bharucha AE et al. Endocr Rev. 2019; 40(5):1318-1352.
Glycemia and gastric emptying

    42 T1DM patients without chronic complications and 31 controls evaluated by 13C-octanoate breath test.

T1DM patients showed a significantly slower GE T1/2          T1DM patients with delayed GE time showed a mean time-
value (113+34 min) than controls (89+17 min; P < 0.001).     to-peak glucose significantly longer than that in patients
36% T1DM showed a delayed GE (T1/2>120 min), whereas         with normal GE time (108+19 min in T1DM T1/2 > 120 min
all controls showed a normal GE (T1/2 < 120 min).            vs 81+36 min in T1DM T1/2 > 120 min; P = 0.004).

Time-to-peak glucose directly related to the GE T1/2 (r = 0.424; P = 0.009).
After adjustment, GE T1/2 independent predictor of time-to-peak glucose (β = 0.329; P = 0.025), and GE T1/2
> 120 minutes independently associated with time-to-peak glucose > 120 minutes (OR 5.33; 95% CI, 1.16-
24.5; P = 0.031).
In the ROC analysis, time-to-peak glucose > 120 minutes identified 73% of patients with GE T1/2 > 120 min.

                                                                                   Lupoli R et al. JCEM 2018; 103:2269-2276.
Clinical evaluation of gastric symptoms

When to start screening?...

   Characteristic symptoms      nausea/vomiting
                                 gastric fullness and early satiety
                                 bloating

   Hypoglycemia-hyperglycemia   blood glucose oscillations due to
                                 incoordination between the
                                 absorption of sugars and exogenous
                                 insulin action or other antidiabetic

   Ketoacidosis
Clinical evaluation of gastric symptoms

                Gastroparesis Cardinal Symptom Index (GCSI)

3 sub-scales:
• post-prandial fullness/early satiety (4 items)
• nausea/vomiting (3 items)
• bloating (2 items).
                                                   Revicki DA et al. Aliment Pharmacol Ther 2003; 18(1):141-50.
                                                   Revicki DA et al. Qual Life Res 2004; 13(4):833-44.
Clinical evaluation of gastric symptoms

6 domains (31 items):
• Orthostatic intolerance                            Nell’ultimo anno ha notato dei cambiamenti nella comparsa del senso
                                                     di sazietà (sentirsi pieno) quando consuma un pasto?
• Vasomotor
                                                     Nell’ultimo anno le è capitato di sentirsi troppo pieno o pieno più a
• Secretomotor                                       lungo (sensazione di gonfiore) dopo un pasto?

• Gastrointestinal                                   Nell’ultimo anno le è capitato di vomitare dopo un pasto?

• Bladder
                                                     Nell’ultimo anno le è capitato di avere un dolore addominale come un
• Pupillomotor                                       crampo o una colica?
                                                                                                             Italian version
(six domain scores and a total score (range 0–100)
after appropriate weighting)

                                                                           Sletten DM et al. Mayo Clin Proc 2012; 87: 1196–1201.
                                                                           Pierangeli G et al. Neurol Sci 2015; 36(10):1897-902.
                                                                           Greco C et al. Diabet Med 2017; 34(6):834-838.
Evaluation of gastroparesis

    Proposal diagnostic procedure of gastroparesis in diabetic patient

Clinical suspicion                           Characteristic symptoms
                                             Hypoglycemia-hyperglycemia
Evaluation autonomic neuropathy              Cardiovascolar tests
Exclude mechanical obstruction               EGDS
Ex adiuvantibus therapy                      Prokinetic drugs for 4 weeks
Evaluation                                   Gastric scintigraphy
                                             Electrogastrography
                                             Wireless capsule
                                             13C-octanoic and –spirulina breath test

                            Modify by Greco C. Published online. Giornale Italiano di Diabete e Metabolismo, 2019.
Instrumental evaluation
    Gastric scintigraphy

                99m Tc-radiolabeled EggBeaters (meal
                with jam, toast and water) to perform
                solid-phase.

                Labeling of solid and liquid phases may
                also be performed.

                Gastric emptying is considered
                delayed if there is greater than 60%
                retention at 2 h or 10% retention at 4 h.

                     Camilleri M et al. Am J Gastroenterol 2013; 108:18–37.
                     Shin AS et al. Diabetes 2013; 62:2667–73.
                     Krishnasamy S et al. Diabetes Ther 2018; 9:1-42.
Instrumental evaluation
                           Electrogastrography (EGG)

High-resolution electrogastrogram is a
research tool that reveals abnormal
initiation and/or propagation of gastric
electrical activity.

                                             Murakami H et al. J Smooth Muscle Res 2013; 49:78-88.
Instrumental evaluation
       13C-Octanoic breath test                           13C-Spirulina breath test

       Methods for GE assessment by breath test (T1/2B) and scintigraphy (T1/2S), and
       corresponding correlation of T1/2 in erythromycin, control and atropine groups
       showing a significant correlation between estimates (r = 0.88, P < 0.0001) based on
       the multiple linear regression model.
                                                 Ziegler D et al. Diabetologia 1996; 39: 823–830.
                                                 Viramontes BE et al. Neurogastroenterol Motil 2001; 13(6):567-74.
                                                 Szarka LA et al. Clin Gastroenterol Hepatol 2008; 6:635-643.
GEBT, Gastric Emptying Breath Test               Shin AS et al. Diabetes 2013; 62:2667–73.
Instrumental evaluation
                        Wireless Motility Capsule (WMC)

Ingestion of non-digestible capsule capable
of measuring temperature, pH and the
pressure of its immediate surroundings
allows for the measurement of gastric,
small bowel, and colonic transit times in an
ambulatory setting.

WMC is a useful clinical tool in assessment
and management of diabetic patient with
motility impairment.

                                               Saad RJ. Curr Gastroenterol Rep 2016; 18(3):14.
                                               Rouphael C et al. Neurogastroenterol Motil 2017; 29(9).
Therapeutic approach

What therapeutic approach?...

 improving glycemic control      GLP-1 analogs delay gastric emptying
                                  DPP-IV inhibitors do not delay
                                  CSII

 diet and nutritional support    small meals that are low in fat and fiber
                                  small particle size diet
                                  multivitamin support
                                  enteral/parenteral nutrition

 behavioral approach             reduce carbonated beverages
                                  avoide alcohol and tobacco smoking

 ex adiuvantibus therapy         …

                                 Camilleri M et al. Am J Gastroenterol 2013; 108:18–37.
                                 Olausson EA et al. Am J Gastroenterol 2014; 109(3):375-85.
Ex adiuvantibus therapy

Classe                  Meccanismo d’azione    Molecola                  Posologia                 Principali eventi avversi
Farmacologica
Procinetici             Antagonista D2 e       Metoclopramide                  10-20 mg x 4        Sintomi extrapriramidali
                        agonista 5-HT3/5-HT4                                                       Iperprolattinemia
                                                                                                   Tachifiassi

Procinetici             Antagonista D2         Domperidone                     10-20 mg x 4        Iperprolattinemia

Antibiotici macrolidi   Agonista motilina      Eritromicina                    40-250 mg x 3       Dolori addominali
                                                                                                   Allungamento QT

Antibiotici macrolidi   Agonista motilina      Azitromicina                       500 mg           Allungamento QT

Procinetici             Antagonista D2         Levosulpiride                     25 mg x 3         Iperprolattinemia
Antiemetici             Agonista 5-HT4                                                             Allungamento QT

Antiemetici             Antagonista 5-HT3      Ondansetron                      4-8 mxg x 2        Allungamento QT
                                               Granisetron                        1-3 mg
Antidepressivi          Antagonista 5-HT3      Mirtazapina                        30 mg            Vertigini
noradrenergici                                                                                     Ipotensione ortostatica
serotoninergici

                                               Greco C. Published online. Giornale Italiano di Diabete e Metabolismo, 2019.
Conclusion

             …
Grazie per l’attenzione
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