3. Epidemiology
Worldwide prevalence of 7-11%
Lovell RM, Ford AC. Global Prevealence of and Risk Factors for Irritable Bowel Syndrome:
a Meta-analysis. Clinical Gastroenterology and Hepatology 2012:10(7); 712-21.
4. Epidemiology and Disease Burden
Prevalence in North America about 7-15%
F:M ratio 1.5-3:1
Over $20 billion in annual direct and indirect costs
Estimated 3.6 million physician visits for IBS in the
U.S. annually
Associated with decreased quality of life
5. Andrews EB , Eaton SC , Hollis KA et al. Prevalence and demographics of irritable bowel
syndrome: results from a large web-based survey. Aliment Pharmacol Ther 2005;22: 935–42.
6. Survey of >31,000 patients
7 % prevalence for IBS
prevalence increased as income decreased
9.0% (CI: 8.1–10.0) among individuals with an annual
income <$20,000 vs. 5.2% (CI: 4.7–5.8) in the highest
income group
Unemployed individuals had a higher prevalence of IBS
(10.0%, CI: 8.9–11.1) than those who were employed
(5.9%; CI: 5.6–6.3)
Andrews EB , Eaton SC , Hollis KA et al. Prevalence and demographics of irritable bowel syndrome:
results from a large web-based survey. Aliment Pharmacol Ther 2005;22: 935–42 .
9. Manning criteria
Pain relieved with defecation
More frequent stools at onset of pain
Looser stools at onset of pain
Visible abdominal distention
Passage of mucus more than 25% of the time
Sensation on incomplete evacuation more than 25% of
the time
10. Kruis score
Kruis W, Thieme C, Weinzierl M, et al. A diagnostic score for the irritable bowel
syndrome. Its value in the exclusion of organic disease. Gastroenterology 1984;87:1–7.
11. Rome III
Recurrent abdominal pain or discomfort at least 3 days
per month in past 3 months and at least 2 other
features:
Improvement with defecation
Onset associated with change in stool frequency
Onset associated with change in stool form
(appearance)
12. Feldman M, Friedman FS, et al. Irritable Bowel Syndrome. Gastroenterology and Liver
Disease Ninth Edition 2010(118)2091-2104.
IBS Classifications
15. Alarm features
Weight loss
Iron deficiency anemia
Rectal bleeding
Nocturnal symptoms
Family history of selected organic diseases including
colorectal cancer, IBD and celiac disease
16. ACG Recommendations (2009)
“Routine diagnostic testing with complete blood count,
serum chemistries, thyroid function studies, stool for
ova and parasites, and abdominal imaging is not
recommended in patients with typical IBS symptoms
and no alarm features because of a low likelihood of
uncovering organic disease.”
“Routine serologic screening for celiac sprue should be
pursued in patients with IBS-D and IBS-M”
Brandt LJ, Chey WD, et al. An Evidence-Based Systematic
Review on the Management of Irritable Bowel Syndrome. The
Am J Gastroenterology 2009; Volume 104 supplement 1.
21. Visceral Hypersensitivity
Balloon distention in intestine
Pain reported at lower volumes in IBS patients; suggests
visceral hypersensitivity
Increased reporting of pain rather than increased
neurosensory sensitivity (Dorn SD. Gut 2007)
Discrimination index: measures neurosensory sensitivity
(physiological) based on ability to discriminate between two
stimuli of similar, yet distinct, intensities.
Report criterion: measure of tendency to label any stimuli as
weak vs intense, independent of the actual stimulus intensity
22. Dorn SD, Palsson OS. Increased colonic pain sensitivity in irritable bowel syndrome is the result of an
increased tendency to report pain rather than increased neurosensory sensitivity. Gut 2007;56:1202–09.
Report criterion (B)
Discrimination index p(A)
23. Brain Imaging and
Visceral Hypersensitivity
Meta-analysis of 16 fMRI or PET studies from 1997-
2010
Brain activation in IBS vs controls during rectal ballon
distention
Inconclusive findings with no significant difference in
any region of the brain
Further studies with standardization of protocol
recommended
Sheehan J, Gaman A, et al. Pooled analysis of brain activity in irritable bowel syndrome and
controls during rectal balloon distension. Neurogastroenterol Motil (2011) 23:336–e158.
24. Abnormal Motility
Present in some patients
Increased frequency/irregularity of intestinal
contractions
(Simren M, et al Dig Dis Sci 2000; Schmidt T, et al Scand J Gastroenterol
1996)
Prolonged transit-time in IBS-C
(Agrawal, A, Houghton LA, et al. Am J Gastro 2009)
Diarrhea may be due to enhanced gastrocolic response, rectal
hypersensitivity, or increased high-amplitude propagated contractions
25. 12 IBS patients
(minimum 4 BM’s
daily with negative
colon biopsies); 10
controls
Exaggerated response
with increased high
amplitude
propogating
contractions to meal
ingestion and to
cholecystokinin
octapeptide in IBS-D.
Chey WY, Jin HO et al. Colonic
motility abnomrality in patients
with irritable bowel syndrome
exhibiting abdominal pain and
diarrhea. Am J Gastroenterol
2001;96:1499-1506.
26. Post-infectious IBS
Associated with bacterial, viral, protozoan and
helminth infections
10-30% incidence of IBS after recovery from proven
bacterial enteritis
Risk factors: younger age, prolonged fever, anxiety,
depression
Bile malabsorption has been reported
Increased seratonin from enteroendocrine
cells/lymphocytes shown after Campylobacter enteritis
27. Findings suggest low-grade
inflammation/immune activation
Findings mostly in IBS-D and post-infectious IBS
Increased lymphocytes in colon and small intestine
Increased mast cells in jejunum, terminal ileum and colon
Proximity to colon neurons correlated with symptoms in one
study
Increased fecal serine-protease levels in IBS-D
Can activate protease-activated receptors (PARs) which may
damage tight junctions and increase intestinal permeability
Increased mRNA levels of pro-inflammatory interleukin-1
β in rectal mucosa after post-infectious IBS
Lower colonic mucosal mRNA expression of anti-
inflammatory cytokine IL-10 in females with IBS
28. Study of 477 cases, 1492 case-relatives, 297
controls, and 936 control-relatives
Saito YA. The Role of Genetics in IBS. Gastroenterol Clin N Am 2011(40):45–67.
29. Genetics
Polymorphisms of the seratonin transporter gene may
be associated with IBS
altered seratonin reuptake efficacy may affect peristalsis
Studies of twins (dizogotic and monozogotic) show
contradictory findings.
30. IL 10 Genotypes Study
230 IBS patients vs 450 controls
Significantly fewer IBS patients with the high producer
(-1082*G/G) genotype (IBS v controls: 21% v 32%;
p=0.003)
Increased proportion of patients being positive for the
A allele, being either the low producer genotype -
1082*A/A or the heterozygous -1082*G/A (IBS v
controls: 79% v 68%; p=0.004).
Gonsalkorale WM, Perrey C. Interleukin 10 genotypes in irritable bowel
syndrome: evidence for an inflammatory component? Gut 2003;52:91–93.
31. Alteration in Fecal Microflora
Both an increase and decrease of variation
have been proposed to characterize the GI microbiota
in IBS
Greater alterations seen in IBS-D than IBS-C
Studies performed with specific quantitative PCR or
with holistic 16S rDNA sequencing
Decreased Clostridium coccoides and some
Bifidobacterium groups
Decrease Lactobacilli has been detected in IBS-D
Salonen A, de Vos WM et al. Gastrointestinal microbiota in irritable bowel
syndrome: present state and perspectives. Microbiology (2010), 156, 3205–15.
32. Molecular analysis of fecal microbiota
of 62 patients with IBS and 46 controls
2-fold decreased
in Bacteroidetes
(P .0001)
1.5-fold reduction
of Bifidobacteria
(P .05)
May produce
active serine
proteinase
inhibitors
5% increased
level of Firmicutes
(P .0001)
Rajilic´-Stojanovic M, Biagi E et al. Global and Deep
Molecular Analysis of Microbiota Signatures in Fecal
Samples From Patients With Irritable Bowel Syndrome.
Gastroenterology 2011;141:1792–1801.
33. Diet
Food Sensitivity--carbohydrate malabsorption
FODMAPs (fermentable oligo-, di-, and
monosaccharides and polyols)
Fermentation in distal small bowel/colon may cause
intestinal permeability and inflammation
Gluten sensitivity
Up to 70% of IBS patients who were HLA DQ2 positive
with negative work up for celiac disease reported
decreased symptoms after a gluten free diet compared
to 20% of HLA DQ2 negative patients
34.
35. Double blind placebo trial
19 IBS patients on gluten-
free diet despite exclusion
of celiac disease
15 controls
2 slices of bread and a
muffin daily
No difference in HLA-DQ2
or DQ8, fecal lactoferrin,
CRP, intestinal
permeability or celiac
antibodies
P=0.02
P=0.03
P=0.001
Biesiekierski JR, Newnham ED. Gluten Causes
Gastrointestinal Symptoms in Subjects
Without Celiac Disease: A Double-Blind
Randomized Placebo-Controlled Trial. Am J
Gastro 2011;106:508-14.
36. Food Patch Testing in IBS
51 patients with IBS
Most positive was garlic (12)
Stierstorfer MB, Sha CT et al. Food patch testing for irritable bowel syndrome. J Am Acad Dermatology 2012:1-8.
37. Psychosocial Associated Risk
Prospective study of 2456 patients without IBS
Over 15 months 3.5% developed IBS
Independent predictors of IBS onset
Anxiety (OR = 2.0; 95% CI 0.98–4.1)
Sleep problems (OR = 1.6; 95% CI 0.8–3.2)
Somatic symptoms (OR = 1.6; 95% CI 0.8–2.9)
Other studies report association with abuse, anxiety,
depression, and phobias.
Nicholl BI, Halder SL. Psychosocial risk markers for new onset irritable bowel syndrome
– Results of a large prospective population-based study. Pain 2008;137:147–155.
38. Kaptchuk T, Friedlander E, et al. Placebos without Deception: A Randomized
Controlled Trial in Irritable Bowel Syndrome. Plosone 2010:5(12).
Global Improvement Score
(1-7)
1= much worse
4 =no change
7= much better
Symptom Severity Score
(Five 100-point scales)
Pain severity
Pain frequency
Severity of distention
Dissatisfaction with bowel
habits
Interference with quality of
life
Adequate Relief
(over past week: yes/no)
Quality of Life
(34 items, 0-100)
39. Non-pharmacologic Therapies
Fiber may be beneficial in IBS-C
Lactose free, low flatulogenic, gluten-free or
FODMAPs diet
Exercise, stress management (biofeedback, hypnosis,
psychotherapy)
Therapeutic physician-patient relationship
40. Psychosocial Aspect
Treating bowel-related symptoms is important, but
may not be sufficient, to impact overall HRQOL.
Attempt to positively modify the cognitive
interpretation of IBS symptoms (ie, acknowledge and
address the emotional context in which symptoms
occur)
Addressing symptom-related fears/concerns;
reassurance of benign nature of diagnosis
Identifying and eliminating factors contributing to
vital exhaustion
Gauge global symptom severity
41. BEST Questionnaire
“How Bad are your bowel symptoms?”
“Can you still Enjoy the things you used to enjoy?”
“Do you feel like your bowel symptoms mean there’s
something Seriously wrong?”
“Do your bowel symptoms make you feel Tense?”
Scored 0-100
Correlates well with the 34 question IBS-QOL
questionnaire
Spiegel BMR, Naliboff, Mayer E, et al. Development and initial validation of a
concise point-of-care IBS severity index: the 4-item BEST questionnaire.
Gastroenterology 2006;130:S1040
42. Antispasmodics
May help with postprandial pain, gas, bloating and
fecal urgency on a prn basis
Hyoscyamine, Dicyclomine
anticholinergic/antimuscarinic
Pinaverium, Mebeverine
directly relax intestinal smooth muscle
Peppermint oil
may relax smooth muscle
20-40% higher rate for response over placebo
Cimetropium, Trimebutine
43. Antidepressants
May facilitate endogenous endorphin release
Blockade of seratonin
Enhance inhibitory pain pathways via blocking
norepinephrine reuptake
Meta-analysis of 14 studies
# patients % with persistent symptoms
(Treatment vs placebo)
RR for persistence of
symptoms
NNT
TCA 575 41.4 vs 59.8 RR 0.68
(95% CI, 0.56 to 0.83)
4
SSRI 230 44.2 vs 70.9 RR 0.62
(95% CI, 0.45 to 0.87)
3.5
Ford AC, Talley NJ, et al. Efficacy of antidepressants and psychological therapies in
irritable bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367–78
44. Probiotics
Bifidobacterium infantis
Bifidobacterium animalis
Lactobacillus rhamnosus
Lactobacillus plantarum
Lactobacillus reuteri
Bacillus coagulans
Combinations
e.g. VSL#3: Streptococcus thermophilus, B breve, B longum, B
infantis, L acidophilus, L plantarum, L paracasei, L
delbreuckii/bulgaricus
Heterogenous studies, many with end points that are not
clinically applicable or compared with placebo.
45. Bifidobacterium infantis 35624 (Align)
Whorwell PJ, Altringer L, et al. Efficacy of an Encapsulated Probiotic Bifidobacterium
infantis 35624 in Women with Irritable Bowel Syndrome. Am J Gastroenterol 2006;101:1581–1590.
• 362 Women with IBS
• Taken daily for 4
weeks
• Global Assessment
• “Please consider how you
felt in the past week in
regard to your IBS, in
particular your general
well-being, and
symptoms of abdominal
discomfort or pain,
bloating or distension
and altered bowel habit.
Compared to the way
you felt before beginning
the medication, have you
had adequate relief of
your IBS symptoms?”
46. 5-Hydroxytryptamine 3 Receptor
Antangonists
May decreased pain via modulation of visceral afferent
activity
Alosetron, Ondansetron, Granisetron, Cilansetron (FDA
application withdrawn)
Alosetron (Lotronex) developed for IBS
Reduces colonic motility and secretions
Meta-analysis showed improvement in global symptoms
and abdominal pain, mostly in females with IBS-D
Alosetron associated with:
Severe constipation
Idiosyncratic ischemic colitis (2/1000 by 3 months, 3/1000 by
6 months)
Prescription restricted
47. Lubiprostone (Amitiza)
Bicyclic fatty acid derived from prostaglandin E1
Increases chloride transport
ClC-2 chloride channel
CFTR chloride channels via prostanoid receptor EP4?
Approved for women with IBS-C at 8mcg BID (24 mcg
BID for chronic idiopathic constipation)
Pregnancy test recommended in women capable of
becoming pregnant as safety has not been evaluated
48. Lubiprostone (Amitiza)
1154 patients with IBS-C (92% female)
“How would you rate your relief of IBS symptoms (abdominal discomfort/pain,
bowel habits, and other IBS symptoms) over the past week compared to how you
felt before you entered the study?”
Responder if moderately or significantly better (6 or 7 on 7-point balanced scale)
Drossman DA, Chey WD. Clinical trial: Lubiprostone
in patients with constipationassociated irritable
bowel syndrome – results of two randomized,
placebo-controlled studies. Aliment Pharmacol Ther
2009;29:329–341.
• Responders in the lubiprostone
group (17.9%) was significantly higher
than that in the placebo group (10.1%;
P=0.001).
• Follow up study of 522 patients
showed benefits continued at 52
weeks.
49. Linaclotide (Linzess)
Guanylate cyclase activation increases intracellular and extracellular cyclic guanosine
monophosphate
Inhibition of afferent neurons
Activation of Cystic Fibrosis Transmembrane conductance Regulator via phosphorylation by
Protein Kinase II
50. Linaclotide (Linzess)
• 804 IBS-C patients over
26 weeks (90% female)
• FDA approved 290 mcg
daily for IBS-C
Chey WD, Lembo AJ, et al. Linaclotide for Irritable Bowel
Syndrome With Constipation: A 26-Week, Randomized,
Double-blind, Placebo-Controlled Trial to Evaluate Effi
cacy and Safety. Am J Gastro 2012;Vol107:1702-12.
51. Rifaximin (Xifaxan)
Nonabsorbable oral broad spectrum antibiotic
TARGET 1 and 2
1258 patients with IBS-D
550 mg TID for 14 days
Primary end point
Adequate relief of global IBS symptoms for at least 2 of
the first 4 weeks after treatment
52. Rifaximin (Xifaxan)
Adequate relief of global IBS symptoms: 40.7% vs. 31.7%
Decreased bloating: 40% vs 30%
Pimentel M, Lembo A, et al. Rifaximin Therapy for Patients with Irritable
Bowel Syndrome without Constipation. N Engl J Med 2011;364:22-32.
53.
54. References
Andrews EB , Eaton SC , Hollis KA et al. Prevalence and demographics of irritable bowel
syndrome: results from a large web-based survey. Aliment Pharmacol Ther 2005;22: 935–42 .
Biesiekierski JR, Newnham ED. Gluten Causes Gastrointestinal Symptoms in Subjects
Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial. Am J Gastro
2011;106:508-14.
Brandt LJ, Chey WD, et al. An Evidence-Based Systematic Review on the Management of
Irritable Bowel Syndrome. The Am J Gastroenterology 2009; Volume 104 supplement 1.
Chey WD, Lembo AJ, et al. Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-
Week, Randomized, Double-blind, Placebo-Controlled Trial to Evaluate Effi cacy and Safety.
Am J Gastro 2012;Vol107:1702-12.
Dorn SD, Palsson OS. Increased colonic pain sensitivity in irritable bowel syndrome is the
result of an increased tendency to report pain rather than increased neurosensory sensitivity.
Gut 2007;56:1202–09
Drossman DA, Chey WD. Clinical trial: Lubiprostone in patients with constipation associated
irritable bowel syndrome – results of two randomized, placebo-controlled studies. Aliment
Pharmacol Ther 2009;29:329–341.
Ford AC, Talley NJ, et al. Efficacy of antidepressants and psychological therapies in irritable
bowel syndrome: systematic review and meta-analysis. Gut 2009;58:367–78
Gonsalkorale WM, Perrey C. Interleukin 10 genotypes in irritable bowel syndrome: evidence
for an inflammatory component? Gut 2003;52:91–93.
Kaptchuk T, Friedland er E, et al. Placebos without Deception: A Randomized Controlled Trial
in Irritable Bowel Syndrome. Plosone 2010:5(12).
Kruis W, Thieme C, Weinzierl M, et al. A diagnostic score for the irritable bowel syndrome. Its
value in the exclusion of organic disease. Gastroenterology 1984;87:1–7.
55. References (continued)
Lovell RM, Ford AC. Global Prevealence of and Risk Factors for Irritable Bowel Syndrome: a
Meta-analysis. Clinical Gastroenterology and Hepatology 2012:10(7); 712-21.
Manning AP, Thompson WG. Towards positive diagnosis of the irritable bowel. BMJ 1978;2:653-
4.
Nicholl BI, Halder SL. Psychosocial risk markers for new onset irritable bowel syndrome –
Results of a large prospective population-based study. Pain 2008;137:147–155.
Pimentel M, Lembo A, et al. Rifaximin Therapy for Patients with Irritable Bowel Syndrome
without Constipation. N Engl J Med 2011;364:22-32.
Rajilic´-Stojanovic M, Biagi E et al. Global and Deep Molecular Analysis of Microbiota
Signatures in Fecal Samples From Patients With Irritable Bowel Syndrome. Gastroenterology
2011;141:1792–1801.
Saito YA. The Role of Genetics in IBS. Gastroenterol Clin N Am 2011(40):45–67.
Salonen A, de Vos WM et al. Gastrointestinal microbiota in irritable bowel syndrome: present
state and perspectives. Microbiology (2010), 156, 3205–15.
Sheehan J, Gaman A et al. Pooled analysis of brain activity in irritable bowel syndrome and
controls during rectal balloon distension. Neurogastroenterol Motil (2011) 23, 336–e158.
Spiegel BMR, Naliboff, Mayer E, et al. Development and initial validation of a concise point-of-
care IBS severity index: the 4-item BEST questionnaire. Gastroenterology 2006;130:S1040
Whorwell PJ, Altringer L, et al. Efficacy of an Encapsulated Probiotic Bifidobacterium
infantis 35624 in Women with Irritable Bowel Syndrome. Am J Gastroenterol 2006;101:1581–
1590.
Some countries, like Africa, had few or zero studies.
domains of the Short-Form 36 QOL survey. Unclear which causes which…do symptoms cause poor QOL or does poor QOL increase symptom perception
Goal is to move from consensus based to evidence based definition
Patients referred to a gastroenterologist for abdominal pain, diarrhea or constipation completed a survey with 15 symptoms prior to initial consultation and then results were compared to final diagnosis.
Sensitivity 78%, Specificity 72%
No number specified, but presence of at least 3 usually used
Score over 44 equates to PPV of 94%
So any of the negative predictors (besides for just ESR) reduces total score to less than 44.
Some may warrant evaluation for an organic abnormality.
Celiac disease up to 4 times more common but other studies suggest not increased beyond control
Lactose intolerance is common and symptoms may be worse with concomitant IBS
Rectal bleeding and nocturnal pain specificity not great for organic diseases.
Anemia and weight loss have poor sensitivity for organic diseases but offer very good specificity.
Celiac disease prevalence in those with IBS complaints reported to be up to 4 fold increased, but from other studies it may be same as in controls (uptodate). Still “routine serologic screening for celiac sprue should be pursued in
patients with IBS-D and IBS-M” per ACG guidelines
Discrimination index p(A): measures neurosensory sensitivity (physiological) based on ability to discriminate between two stimuli of similar, yet distinct, intensities.
Report criterion (B): measure of tendency to label any stimuli as weak vs intense, independent of the actual stimulus intensity
Mostly small studies
-Mast cells in proximity to colon nerves correlated with symptoms in once study, but in other studies number was not increased
-Serine proteases: signalling molecules that activate protease-activated receptors (PARs), including PAR-2 which is highly expressed on intestinal epithelial cells, particularly at the apical side
-Mostly shown in IBS-D and PI-IBS, and only small studies
Increased incidence among relatives of patients with IBS vs relatives of controls, odds ratio 2.75.
Bifidobacterium spp may produce active serine proteinase inhibitors belonging to the SERPIN family
FODMAPs
IBS-GIS = Global improvement score (compared to prior eval how feeling: 1 worse, 4 no change, 7 best)
IBS-AR = Over the past week have you had Adequate Relief (yes/no) 59% response higher than usual 30-40% for placebo in IBS studies
IBS-SSS = Symptom severity score five 100-point scales, assess pain severity, pain frequency, the severity of distention, dissatisfaction with bowel habits, and interference with quality of life
IBS-QoL = Quality of life, 34-item measure assessing degree of interference with QOL. Each is rated on a 5-point scale, summed range 0-100, higher score indicating better QOL.
Scored 0-100. Correlates well with the 34 question IBS-QOL questionnaire
TCA’s tend to cause constipation, start low at 10 mg
SSRI’s tend to cause diarrhea and help with anxiety
10 to the 10 preparation had formulation/preparation difficulties (capsule did not dissolve normally)
5-HT4 receptor agonist Tegaserod (Zelnorm) increases colonic motility and was approved but was removed from market due to cardiovascular risk
ITT= Intention to Treat. LOCF=last observation carried forward
cGMP can exit the epithelial cells to block pain signaling by inhibiting the pain-sensing neurons that carry signals from the gastrointestinal tract to the central nervous system (afferent pain fibers). Second, cGMP can remain inside the epithelial cell to activate protein kinase GII, or PKGII, which activates the protein Cystic Fibrosis Transmembrane conductance Regulator, or CFTR, by phosphorylation, or P, to stimulate electrolyte (Na + = sodium, Cl - = chloride, and HCO 3 - = bicarbonate) and fluid (H 2 O = water) secretion into the intestinal lumen. The resulting increase in intestinal fluid volume accelerates intestinal transit.
http://google.brand.edgar-online.com/EFX_dll/EDGARpro.dll?FetchFilingHtmlSection1?SectionID=7027331-335942-474039&SessionID=9MGJHH_6_ct7G_7
CSBM=complete spontaneous bowel movement
90% female
Combined responder (above plus 3 or more CSBM in the same week) 12.7% vs 3.0% for placebo (95% CI for difference 9.7% [6.1%-13.4%])
Rated average daily abdominal pain and bloating as somewhat to a good/great deal (score of 2 to 4.5 on a 7-point scale)
7-point Likert scoring system with 0 indicating not at all; 1, hardly; 2, somewhat; 3, moderately; 4, a good deal; 5, a great deal; and 6, a very great deal.
Rated average daily stool consistency at least formed to loose (3.5 or more on a 5-point scale) over the course of at least 7 days. 5-point scale for stool consistency (with 1 indicating very hard; 2, hard; 3, formed; 4, loose; and 5, watery