La Stipsi severa: attualità

terapeutiche Verona, 14-15 giugno 2012

Eziopatogenesi e clinica

Fabrizio Bonfante

Chronic constipation

Constipation is divided, with considerable

overlap, into issues of stool consistency

(hard, painful stools) and issues of

defecatory behavior (infrequency,

difficulty in evacuation, straining during

defecation)

Rome III Definition of Chronic Constipation

Must include 2 or more of the following:

a. Straining during at least 25% of defecations

b. Lumpy or hard stools in at least 25% of defecations

c. Sensation of incomplete evacuation for at least 25% of

defecations

d. Sensation of ano-rectal obstruction for at least 25% of

defecations

e. Manual maneuvers to facilitate at least 25% of defecations

f. Fewer than 3 defecations per week

• Loose stools are rarely present without the use of laxatives • There are insufficient criteria for IBS Longstreth et al., Gastroenterology 2006; 130(5):1480-91

Functional Bowel Disorders

Longstreth G et al, Gastroenterology 2006

Constipation Symptoms in a Patient Perspective Survey

%

n= 557

Johanson JF & Kralstein J. APT 2007;25:599-608

%

“Easy“ Chronic constipation

Myths and misconceptions in Constipation

Constipation is caused by inadequate dietary fiber intake

Increased dietary fiber relieves symptoms

Constipation is caused by inadequate fluid intake

Increased fluid intake is a helpful treatment

Constipation is caused by inadequate psysical exercise

Constipation is caused by a long colon

Laxatives cause enteric neural damage

Muller-Lissner SA et al, Am J gastroenterol 2005

Non tutte le stipsi sono uguali…

Severe chronic constipation

What mean “severe constipation” ?

• Impairment of work (69%), and social and personal life (73%)

• Almost half (47%) unsatisfied with current treatment

– For the majority (82%), due to lack of efficacy

Johanson et al. Aliment Pharmacol Ther 2007; 25: 599

80

79

66

50

52

75

50

50

67

71

60

44

Ineffective relief of bloating

Lack of predictability

Ineffective relief of multiple symptoms

Ineffective relief of constipation

OTC laxatives (n=146) Prescription laxatives (n=42) Fibre (n=68)

Patients (%)

557 eligible participants:

243 men and 314 women,

≥18 years old;

Rome II criteria;

45-question survey

Wald et al., APT 2007;26:227-36

* P<0.05 in constipated vs not constipated

Effect of constipation on QoL - 13.875 adults in 7 Countries -

Physical Scale

SF-36 Score

*

*

*

*

*

35 40 45 50 55

MSC

MH

RE

SF

VI

Mental Scale

SF-36 Score

*

*

*

*

*

• PF = Physical

functioning

• RP = Role Physical

• BP = Bodily Pain

• GH = General Health

• VT = Vitality

• SF = Social

functioning

• RE = Role Emotional

• MH = Mental Health

Constipated

Not Constipated

effect on QoL osteoarthritis, chronic allergies, diabetes, GERD, heart disease, depression

Chronic constipation

Primary constipation

Secondary constipation

Secondary constipation

Organic lesions

Medication

Neurologic Disorders

Endocrinologic or metabolic disorders

Connective tissue disorders

Muscolar disorders

Psychological issue e/o eating disorders

Medication

Antidepressants

Psychotropic drugs

Anticholinergics

Opioids

Calcium channel blockers

NSAIDs

Neurological disorders

Stroke

Hirschprung disease

Parkinson disease

Multiple sclerosis

Diabetic autonomic neuropathy

Spinal cord lesion

Chagas disease

Endocrinological or metabolic

disorders

Hypercalcemia

Hyperparathyroidism

Hypokaliemia

Hypothiroidism

Addison disease

Porphyria

Diabetes mellitus

Primary and Secondary Forms of Chronic Constipation

Iantorno et al. Dig Dis Sci. 2007;52:317–320

466 patients* with chronic constipation† referred to a gastroenterology referral unit

54% secondary

Including:

• Pharmacology (27%)

• Endocrine disorders (16%)

• Psychiatric disorders (13%)

46% primary

*382 women, 82 men; age range, 18–83 years, referred over a 10-year period to a centre in Buenos Aires, Argentina

† Defined using Rome I criteria

76,3%

8,4%

10,7%

4,7% Pelvic floor disorder

Slow transit constipation

IBS-C (normal transit)

Normal transitconstipation

Primary chronic constipation

Classification

Normal transit constipation

Slow transit constipation

Pelvic floor dysfunction or outlet

obstruction

Normal transit

Stool passage in colon at a normal rate

Overlap with IBS – constipation

Difficult evacuation :

– Bloating

– Straining

– Hard stools

Outlet obstruction

Anorectal manometry

Outlet obstruction

Dysfunction of the pelvic floor or anal sphinter

Defecation disorders

Impaired rectal contraction

Paradoxical anal contraction

Inadequate anal relaxation

Lack of coordination (or dyssynergia)

Impaired rectal sensation

Structural abnormalities

Structural abnormalities

Rectal prolapse and or intussusceptions

Rectocele

Excessive perineal descent

Slow transit constipation (STC)

Impaired phasic colonic motor activity

Infrequent bowel movements

Lack of an increase in motor activity after :

– meal

– cholinergic agents

– awakening in the morning

No answer to rectal balloon distension

Dinning PG et al., WJG 2010;116:5162-72

High Amplitude Propagated Contractions

in Healthy Controls

24-hr Spatiotemporal Maps of Colonic Propagating Sequences

Dinning PG et al., WJG 2010;116:5162-72

Enteric nervous system

(the brain of the gut)

– Bowel movement

– Fluid secretion

– Blood flow

Linden & Farrugia, 2008

GI Control Mechanisms

Enteric neurons

Inter. Cajal cells Enteric glia cells Smooth muscle

changes ?

and Related Abnormalities in STC

Reviewed by Di Nardo & De Giorgio, et al. Aliment Pharmacol Ther, 2008;28:25-42

Serotonin (5-HT)

95% of serotonin in the

human body is found in

the digestive tract

Necessary for

communication between

brain and the gut

Peristalsis & Related Neuronal Circuitries

modified from Tonini et al. Neuroscience 1996;73:287-97

Ascending reflex contraction

Descending reflex relaxation

Excitatory motor neuron

Inhibitory motor neuron

Sensory neuron

ACh/TK NO/VIP/(ATP)

ACh/TK ACh/TK

Intraluminal content

Fibre colinergiche

Fibre adrenergiche

5-HT signaling

Dysfunction of the 5-HT signaling

• 5-HT availability

• 5-HT reuptake

• 5-HT receptor mechanisms e/o density

5-HT4 receptor agonists

stimulate acetylcholine secretion, thus display prokinetic activity (as tegaserod and prucalopride).

Impaired motility in

slow transit constipation

HAPCs are decreased in amplitude and

frequency • Abnormalities of the myenteric plexus

• Reduction of argyrophilic neurons and axons

• Increase in the number of variably sized nuclei within ganglia

Reduced volume of interstizial cells of Cajal

Reduced number of enteric glial cells

Dysfunction of the 5-HT signaling

Vi ringrazio per l’attenzione

Enteric glial cells (EGC)

Mechanical supporters

Promoting synaptic communication by neurotrophic factor release

Involving in enteric neurotransmission

– Glutamatergic signaling

– Nitrergic neurotransmission

Outlet obstruction

Dysfunction of the pelvic floor or anal sphinter

Defecation disorders

Impaired rectal contraction

Paradoxical anal contraction

Inadequate anal relaxation

Lack of coordination (or dyssynergia)

Impaired rectal sensation

Structural abnormalities

Neurotransmitters

The functions of enteric and extrinsic neurons are regulated by these neurotransmitters:

– noradrenalin

– acetylcholine

– opioids

– serotonin

– somatostatin

– CCK

– substance-P

– VIP

– neuropeptide-Y

Structural abnormalities

Rectal prolapse and or intussusceptions

Rectocele

Excessive perineal descent

Non tutte le stipsi sono uguali….