Diseases of the

gastrointestinal tract
Dr. Gábor Kökény

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Institute of Translational Medicine - 2023
 Clinical significance of GI
diseases
• Prevalence:
• 10-11% in total Population
• 35-40% in elderly Patients (age >65 years)

Hospital costs in USA, 2011

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 Gastric diseases
• Gastritis
• Alcoholic
• Viral
• Bacterial (H. Pylori)
• Drug induced
• Ulcer (GERD, NSAID, Zoll.-Ellison sy.)
• Cancer

Common symptoms:
Vomiting, epigastrial pain, hyperacidity (reflux), hypoacidity,
maldigestion, bleeding, vitamin-B12 deficiency
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 Peptic ulcer disease
• Peptic ulcers are defects in the gastrointestinal
mucosa extending through the muscular layer
• Important cause of morbidity and health care costs

Gastric ulcer crater with no

Duodenal ulcer with a small evidence of active bleeding
amount of bleeding 4
 Etiology of peptic ulcer
Peptic ulcer disease (PUD) is associated with:
• Helicobacter pylori infection
• nonsteroidal anti-inflammatory drug (NSAIDs) consumption
(eg. even chronic low-dose /100mg/ Aspirin)
• Viral infections
• Gastrinoma (Zollinger-Ellison sy.)
• Idiopathic

Epidemiology of PUD reflects the changing prevalence of H.

pylori infection with the increasing use of NSAIDs and aging
population.

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 Peptic ulcer disease
• H. pylori tests can be false-negative in at least 10 percent of
patients (use of antibiotics and proton pump inhibitors).
• In developed countries, H. pylori is uncommon in children, 10% at
18-30 years of age, 50% in patients older 60 years.
• Ulcer incidence in H. pylori-infected individuals is 6-10x higher
than in uninfected subjects.

• Chronic NSAID use is a common cause of refractory and

complicated ulcers.
• low-dose aspirin (for prevention of thrombotic events) increases risk
of GI bleeding by 60 percent
• Proton pump inhibitor use reduces the risk of ulceration. It reduces
the rates of ulcer disease in NSAID users at risk

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Helicobacter pylori

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 Urease actibity of H. pylori

Diagnostic procedures:
1) Urease breath test (C-Isotope labeled urea, CO2 assessment)
2) Direct urease test from biopsies
3) Histologic evaluation of biopsies
NSAID in peptic ulcer disease

by Dr Péter Hamar
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 Symptoms and outcome of
peptic ulcer disease
Symptoms:
• Dyspepsia: Epigastric pain or discomfort is the most prominent
in 80% of endoscopically diagnosed ulcer.
• BUT approx. 70% of peptic ulcers are asymptomatic!

Complications:
• In 40-50% gastroesophageal reflux (GERD)
• Bleeding into the GI tract, rarely hematemesis
• In 2-10% perforation of bowel wall: sudden severe, diffuse
abdominal pain
• 6x risk for gastric adenocarcinoma

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 Diseases of the intestines
• Infectious diseases
• Lactose intolerance/malabsorption
• Celiac disease
• Crohn’s disease
• Ulcerative colitis
• Irritable bowel syndrome

Leading symptoms:
abdominal pain, malabsorption,
diarrhea (with or w/o blood)
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Daily flow rates in the intestine

Hammer-McPhee: Pathophysiology of Diseases

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 Lactose intolerance
• Intolerance to lactose-containing foods
• Most common (>70%) intestinal disease worldwide

• Prevalence is low in children <6 years and increases with age

• Newborns and adults with low lactase activity can adapt to
persistent lactose ingestion through bacterial conversion of
lactose to short-chain fatty acids that can be absorbed in the
colon.
Approx. 50g of malabsorbed lactose per day can be used for energy utilization.
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 Lactose intolerance
• Symptoms: abdominal pain, flatulence, and diarrhea
after ingestion of milk or milk-containing products
• >75% of lactose goes unabsorbed toward the colon,
where bacteria ferment it to short-chain fatty acids,
acetate, butyrate, propionate and hydrogen gas

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 Etiology of lactose intolerance
Primary lactose malabsorption:
• Most common cause is acquired primary lactase
deficiency. The majority of the world's populations
develop low intestinal lactase levels at preschool
age.
• Congenital lactase deficiency is a rare autosomal
recessive disorder. Infants have diarrhea from birth.
More frequent in the Finnish population.
• Developmental lactose malabsorption is a
consequence of prematurity (lactase activity
increases in late gestational age />28 wks/).
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Etiology of lactose intolerance 2.
Secondary lactose malabsorption:
• Small intestinal bacterial overgrowth
• Infectious enteritis
• Mucosal injuries
• Celiac disease
• IBD (especially Crohn)
• Drug-induced enteritis
• Irradiation induced enteritis

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 Diagnosis of lactose intolerance
• Presumptive diagnosis: mild symptoms occur within a few hours after
significant lactose ingestion and resolve after five to seven days of
avoidance of lactose-containing foods.
• Hydrogen breath test:
• Simple, noninvasive, and has 80% sensitivity and 98% specificity.
Oral administration of lactose (2g/kg in children, 50g in adults). Hydrogen and
symptom peak occurs at 90-120 min.
• Stool pH:
• Especially in infants, stool pH <6 with clinical symptoms
presumes lactose intolerance
• Lactose tolerance test: Requires repeated blood glucose measure-
ments, has largely been replaced by the lactose breath hydrogen test.
Oral administration of lactose, then blood glucose levels are monitored at 0, 60, and 120
minutes. Low increase (<1.1 mmol/L) in blood glucose plus the development of symptoms is
diagnostic.

• Differential diagnosis:
• Cow's milk allergy (CMA) should be considered in infants and
children with persistent symptoms despite dietary lactose
restriction!
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 Management of
lactose intolerance
Goal: to eliminate symptoms while maintaining calcium and
vitamin-D intake.
• Dietary lactose restriction
• (especially milk and ice cream)

• Enzyme replacement
• Commercially available beta-galactosidases can be
taken orally with lactose-containing food.
• These do not completely hydrolyze all dietary lactose,
thus variable results in each individual.

• Calcium and vitamin-D intake has to be monitored

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Celiac disease: history
First description of a chronic, malabsorptive disorder in
250 AD by Aretaeus from Cappadocia (now Turkey).
He described the disease as „koiliakos” (suffering in the
bowels).

First modern era description and published by

Dr. Samuel Gee (pediatrician, UK) in 1888.

Dutch pediatrician Dr. Willem K. Dicke associated the consumption

of bread and cereals with relapsing diarrhea.
After the II. WW, he linked the disease to gluten, the alcohol-soluble
fraction of wheat protein.
When unrecognized and untreated, celiac disease is associated
with increased mortality!
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 Pathogenesis of celiac disease
• Autoimmune disorder (prevalence: 1:70 - 1:300)
• Occurs primarily in whites of northern European ancestry
• Unrecognized/untreated celiac disease increase mortality
• First-degree relatives of patients have a 10-15% risk of celiac
disease.
• Prevalence correlates with genetic predisposition
(HLA-DQ2>HLA-DQ8) and high wheat consumption.
• HLA DQ2 homozygosity increase the risk for celiac disease and
enteropathy-associated T-cell lymphoma
Serum autoantibodies:
• Serum IgA to gliadin
• Serum IgA to tTG (tissue transglutaminase): 100% specific!
tTG is an intracellular enzyme released by inflammatory cells and fibroblasts in
response to mechanical irritation or inflammation.
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Inducers of celiac disease

GLUTENS

The Lancet 2009 373, 1480-1493DOI: (10.1016/S0140-6736(09)60254-3)

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 Classification of celiac disease
1. Classic disease:
Villous atrophy; symptoms of malabsorption (steatorrhea), weight loss, or
vitamin deficiency. Resolution of the mucosal lesions and symptoms within
few months upon withdrawal of gluten-containing foods. Serum
autoantibody positive.
2. Atypical celiac disease:
Only minor gastrointestinal complaints. May display anemia, osteoporosis,
arthritis, increased transaminases. Mostly with severe mucosal damage
and celiac specific autoantibodies.
3. Asymptomatic (silent) celiac disease:
Incidentally recognized based on antibody screenings. No symptoms.
4. Latent celiac disease:
Normal jejunal mucosa and mild or no symptoms while on a gluten-
containing diet. Mostly in adults who had celiac disease in childhood but
recovered completely. 20% continue asymptomatic in adulthood. Latency
may be transient.
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Pathomechanism of celiac disease

IEL: intraepithelial lymphocyte

MMP: matrix metalloproteinase
The Lancet 2009 373, 1480-1493DOI: (10.1016/S0140-6736(09)60254-3)
tTG: tissue-transglutaminase (TG2)
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 Potential role of microbes in the
pathogenesis of celiac disease

Possible inducers
• Rotavirus in children
• Enterotoxic E. coli
• Campylobacter jejuni

Duodenal dysbacteriosis:
• Increased Bacteroides spp
• Reduced Lactobacillus,
Bifidobacterium spp.

Front Pediatr. 2018; 6: 350.

 Clinical manifestations of
celiac disease
• Typical age of onset: 10 - 40 years

Classic symptoms:
• Gastrointestinal manifestations (diarrhea, abdominal pain)
• Growth failure in children, weight loss in adults
• High temperature
• Severe anemia
• Neurologic disorders from deficiencies of B vitamins
• Osteopenia from deficiency of vitamin D and calcium

Subclinical disease: unspecific symptoms

• Fatigue
• Borderline iron deficiency
• Unexplained elevations in serum AST, ALT
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 Clinical manifestations of
celiac disease 2.
Non-gastrointestinal manifestations:
• Arthritis
• Iron deficiency (celiac disease may be a frequent cause of iron
deficiency anemia)
• Metabolic bone disease (common in celiac disease and can
occur in patients without gastrointestinal symptoms)
• Kidney disease: glomerular IgA deposition in 33% of patients

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 Endoscopy and histology of
celiac disease

Markedly reduced (A) and scalloped configuration of folds (B, arrow) in active coeliac disease.

Representative histology of low grade (A), medium grade (B) and high grade (C) celiac disease.

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The Lancet 2009 373, 1480-1493DOI: (10.1016/S0140-6736(09)60254-3)
 Celiac disease associated conditions
• Dermatitis herpetiformis:
• autoantibodies against epidermal transglutaminase
(homologue to tTG).
• Responds to gluten withdrawal

• Selective IgA deficiency: celiac disease in 8% of IgA deficiency patients

• Down syndrome patients have 20-fold increased risk for celiac disease
• Type 1 DM: share common genetic risk regions (HLA-DQ)
• Liver disease: nonspecific mild chronic elevation in serum aminotransferase
levels is often. Also associated with advanced liver disease.
• Thyroid disease: increased incidence of autoimmune thyroiditis (Hashimoto
is more frequent)
• Inflammatory bowel disease: risk of IBD is 10-fold higher

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Consequences of celiac disease

• Leads to a significant absolute increase in mortality

• Population-based studies associated celiac disease

to increased risk for lymphoma and gastrointestinal
cancer.

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 Celiac disease: novel treatments

The Lancet 2009 373, 1480-1493DOI: (10.1016/S0140-6736(09)60254-3)

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 Inflammatory bowel diseases
(IBD)
Relative frequent autoimmune disorders of the GI tract:

• Ulcerative colitis

• Crohn’s disease

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 Global IBD prevalence (2015)

Kaplan, G. G. (2015) Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2015.150

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Pathogenesis model of IBD

Environmental
factors

Genetic
Autoimmunity IBD factors

Intestinal
microbiom

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 Microbiom and IBD

AMP: antimicrobial peptides; NOD2: nucleotide-binding oligomerization domain-2; SIgA: secretory IgA
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 Salt load changes the intestinal
bacterial population – role of IL-17

(approx. 14g/day NaCl intake for 2 weeks)

(average intake in adults: 8-10g/day)

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 The role of IL-17 in IBD
Control Ischaemia

Ulcerative colitis 100x Ulcerative colitis 200x

Crohn’s disease 100x Crohn’s disease 200x

UC: ulcerative colitis

CD: Crohn’s disease
! !
S Fujino et al. Gut 2003;52:65-70

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 Ulcerative colitis

• Recurring episodes of inflammation limited to the

mucosal layer of the colon
• Commonly involves the rectum
• Attacks of bloody diarrhea that last for weeks
• Intermittent exacerbations alternating with long
periods of complete symptomatic remission

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 Ulcerative colitis:
Clinical manifestation
• Diarrhea, usually associated with blood
• Colicky abdominal pain, urgency, tenesmus, and incontinence.
• Frequent discharge of blood and mucus.
• Systemic symptoms: fever, fatigue, weight loss
• Disease severity: mild, moderate or severe
(clinical management and predicts long-term outcome).

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 Ulcerative colitis:
Extraintestinal manifestations
• Arthritis (most frequent)
• Ocular lesions (uveitis and episcleritis)
• Skin lesions
• Hepatobiliary:
• primary sclerosing cholangitis,
• fatty liver,
• autoimmune liver disease
• Venous and arterial thromboembolism
• Autoimmune hemolytic anemia
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 Ulcerative colitis:
Diagnosis
• Presence of chronic diarrhea for more than 4 weeks
• Active inflammation on endoscopy
• Chronic changes on biopsy
• crypt abscesses, atrophy,
• increased lamina propria leukocytes, plasmacytosis,
lymphoid aggregates, and eosinophils.

• Laboratory findings
• Anemia,
• ESR ≥30 mm/hour,
• Low albumin,
• Electrolyte abnormalities due to diarrhea and dehydration.
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 Ulcerative colitis:
Acute complications
• Severe bleeding in up to 10% of patients.
• Fulminant colitis: >10 stools per day, continuous
bleeding, abdominal pain, distension, and acute,
severe toxic symptoms with fever and anorexia.
• Toxic megacolon: colonic diameter ≥6 cm or cecal
diameter >9 cm and the presence of systemic toxicity
• Perforation of the colon most commonly occurs as a
consequence of toxic megacolon, peritonitis has a
50% mortality.
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 Ulcerative colitis:
Chronic complications

• Benign strictures in the rectosigmoid colon can occur

in approx. 10% of UC, and may cause obstruction.
• Increased risk for colorectal cancer.
Important risk factors are the extent and duration of
colitis.

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 Crohn’s disease
A disorder of uncertain etiology, characterized by
transmural inflammation of the gastrointestinal tract:
• Approx. 80% of patients have distal ileum involvement.
• Approx. 50% of patients have involvement of both the ileum
and colon (ileocolitis).
• Approx. 33% of patients have perianal disease.
• Approx. 20% have disease limited to the colon, rectal
involvement is less common than in UC.

Prognosis
The typical course shows intermittent exacerbations of
symptoms followed by periods of remission.
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Crohn’s disease: Pathogenesis
An interplay between genetic susceptibility, environmental factors
and intestinal microbiome leads to altered mucosal immune
response and reduced epithelial barrier function.
• Genetic factors: approx. 39 genes identified in Crohn patients,
mostly participating in JAK2, HLA, STAT3, NOD2 or Th-17
signaling pathways.
• Environmental factors:
• Smoking (2x risk)
• Antibiotics in childhood (1.74x risk)
• Oral contraceptives, NSAID, low fiber intake

• Bacterial dysbiosis: leads to intestinal TNF-α production

• ↑ Gammaproteobacteria (Enterobacter, Escherichia, Klebsiella, Proteus,
Salmonella, Shigella, Yersinia)
• Mucosa-associated invasive E. coli – in 30% of patients
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 Crohn’s disease: symptoms
• Clinical manifestations are more variable
than those of UC.
• Hallmarks:
• Fatigue,
• Prolonged diarrhea with crampy abdominal pain,
• (A disease limited to the distal ileum frequently presents with
right lower quadrant pain)
• Weight loss and malabsorption (steatorrhea),
• Fever,
• Occult bleeding (gross bleeding is unfrequent).

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 Crohn’s disease: Diagnosis I.
Diagnosis established with endoscopy or imaging (gold standard).
Endoscopy:
• Colonoscopy — Standard method for ileocolonic CD. Features:
focal ulcerations, polypoid mucosal changes (cobblestone
appearance).
• Wireless capsule endoscopy — Used increasingly for the
evaluation of suspected and established small bowel CD.
Capsule endoscopy
showing focal ulcerations

Imaging:
• Magnetic resonance
enterography (MRE)

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 Crohn’s disease: Diagnosis II.
Routine laboratory tests
• Anemia with iron deficiency and/or B12 deficiency
• Elevated WBC
• Elevated ESR or CRP
• Hypalbuminaemia
• Stool calprotectin, lactoferrin: screening and follow-up
• Correlation with neutrophil infiltration
• Sensitive marker for intestinal inflammation in IBD

Serologic markers
(accuracy and predictive value still undetermined)
• Antineutrophil cytoplasmic antibodies (pANCA)
• Anti-OmpC antibody (OmpC: outer membrane porin of E. coli)
• Elevated C-reactive protein (higher levels than in ulcerative colitis)

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 Crohn’s disease:
Differential diagnosis
• Irritable bowel syndrome (IBS):
chronic abdominal pain and altered stool habits in the absence
of an organic cause
• Lactose intolerance:
diarrhea, abdominal pain, and flatulence after ingestion dairy
products.
• Infectious colitis:
Shigella, Salmonella, Campylobacter, Escherichia coli O157:H
etc. C. difficile after broad spectrum antibiotics treatment.
• Ulcerative colitis:
rectal involvement, gross bleeding, sparing of the small
intestine
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 Therapy of Crohn’s disease

• Corticosteroids (systemic) – side effects!

• Metothrexate (can lead to melanoma, lymphoma)
• Biological therapies:
• Vedolizumab
Monoclonal antibody against α4β7-Integrin → Selective intestinal anti-inflammatory effect

• Anti-TNF drugs (infliximab, adalimumab, etc):

given only at steroid/metothrexate resistence, still anti-TNF are the most potent
medications for Crohn

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Crohn’s disease: background of
biological therapies

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Lancet, 2017: 389; 10066, page 226
 Irritable bowel syndrome (IBS)
• Functional disorder of the gastrointestinal tract
• Chronic abdominal pain:
Mild to severe cramping abdominal pain with variable
intensity and periodic exacerbations.
• Altered bowel habits:
Diarrhea, constipation, alternating diarrhea and constipation, or normal
bowel habits alternating with either diarrhea and/or constipation.
• Does not lead to alteration in bowel wall structure
• Does not increase the risk of CRC (!)
• Significant health care cost
• 25-50% of all referrals to gastrenterologists (USA)
• Diagnosis: exclusion of other GI diseases! (IBD, celiac disease,etc). No
specific diagnostic tests for IBS.

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Thank you
for your
attention!

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© by Gábor Kökény