THE PATHOPHYSIOLOGY OF

GASTROINTESTINAL DISEASES
II
Zoltán Rakonczay MD, PhD, DSc
Zsolt Bagosi MD, PhD

Department of Pathophysiology
Faculty of Medicine
University of Szeged

Reviewed by
Tamás Takács, MD, PhD, DSc
 OVERVIEW

UPPER GI TRACT DISORDERS LOWER GI TRACT DISORDERS

VOMITING MALABSORPTION
DYSPHAGIA DIARRHEA
GASTROESOPHAGEAL REFLUX DISEASE INFLAMMATORY BOWEL DISEASE (IBD)
ACUTE AND CHRONIC GASTRITIS IRRITABLE BOWEL SYNDROME (IBS)
PEPTIC ULCER DISEASE CONSTIPATION
ACUTE AND CHRONIC PANCREATITIS ILEUS
LIVER AND BILIARY TRACT DISORDERS
HYPERBILIRUBINEMIA
JAUNDICE
STEATOSIS
HEPATITIS
CIRRHOSIS
PORTAL HYPERTENSION
LIVER FAILURE
CHOLELITHIASIS
CHOLESTASIS
2
 MALABSORPTION
PHYSIOLOGICAL BACKGROUND

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 3

 MALABSORPTION
DEFINITION
Malabsorbtion includes disorders in which the small intestine is unable to absorb adequate
amount of necessary nutrients (lipids, carbohydrates, proteins, vitamins, minerals and water).

FORMS, CAUSES
1. Defects in digestion (luminal)
A. Disorders of pancreatic enzymes
B. Disorders of bile salts
C. Disorders of stomach (e.g. atrophic gastritis)

2. Defects in absorption (mucosal)

A. Generalized defects: disorders of lipid, carbohydrates and protein absorbtion
B. Specific defects: celiac disease (non-tropical sprue), tropical sprue

3. Defects in nutrient delivery (postmucosal)

A. Decreased nutrient delivery to the intestine
B. Decreased nutrient delivery from the intestine

4
 DEFECTS IN DIGESTION
PHYSIOLOGICAL BACKGROUND

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 5

 DEFECTS IN DIGESTION
DISORDERS OF PANCREATIC ENZYMES

1. With adequate pancreatic enzymes

A. Inappropriate mixing (post-gastrectomy)
B. ↓ pH → ↓ pancreatic lipase activation (Zollinger-Ellison syndrome)

2. With inadequate pancreatic enzymes

A. Rapid gastric emptying → ↓ protein digestion → ↓ CCK → ↓ pancreatic enzyme secretion
B. Chronic pancreatitis, pancreas carcinoma, cystic fibrosis, pancreatic resection →
↓ pancreatic lipase secretion

3. ↓ bicarbonate output (↓ pH)

A. Pancreas resection → loss of functional mass of tissue
B. Chronic pancreatitis, pancreas carcinoma, cystic fibrosis

Lipase deficiency → maldigestion of fat → steatorrhea (>7g fat in stool), bleeding (K

vitamin deficiency), osteomalacia (D vitamin deficiency), weight loss

6
 DEFECTS IN DIGESTION
DISORDERS OF PANCREATIC ENZYMES

Steatorrhea

based on Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 7

 DEFECTS IN DIGESTION
DISORDERS OF BILE SALTS

1. ↓ synthesis of bile salt

Chronic liver disease (liver cirrhosis)

2. ↓ bile salt secretion

A. Intrahepatic biliary obstruction (hepatitis, liver cirrhosis, primary biliary cholangitis)
B. Extrahepatic biliary obstruction (choledocholithiasis, primary sclerosing cholangitis)

3. ↑ deconjugation of bile salt

A. Blind loop
B. Small bowel diverticulum
Anaerobic bacterial overgrowth → bile acid deconjugation → quick reabsorption of the
unconjugated bile acid

4. ↓ ileal resorption of bile salt

A. Inflammatory bowel disease (Crohn’s disease)
B. Surgical resection of the ileum

↓ bile salt deficiency → impaired micelle formation → ↓ lipid absorption → steatorrhea (>7g
fat in stools), bleeding (K vitamin deficiency), osteomalacia (D vitamin deficiency), weight
loss
8
 DEFECTS IN DIGESTION
DISORDERS OF BILE SALTS

Steatorrhea

based on Silbernagl and Lang: Color Atlas of Pathophysiology, 2000

 DEFECTS IN ABSORBTION
DISORDERS OF LIPID ABSORPTION

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 10

 DEFECTS IN ABSORBTION
DISORDERS OF LIPID ABSORPTION

1. Celiac disease (gluten-sensitive enteropathy, non-tropical sprue)

Cause: glutamine-rich α-gliadin from the gluten found in cereals (wheat, barley, rye) → de-
amidated gliadin peptides (DGP) by transglutaminase (TG2) → autoantigens → T-cell-
mediated epithelial damage
Gastrointestinal (GI) manifestations: diarrhea/steatorrhea, secondary lactase deficiency,
abdominal distension, abdominal pain, anorexia, vomiting
Extra-GI manifestations: dermatitis hepetiformis, dental enamel hypoplasia,
osteopenia/osteoporosis, short stature, delayed puberty, iron deficiency, hepatitis, arthritis,
epilepsy

2. Tropical sprue
Cause: probably tropical or subtropical bacteria (e.g. Klebsiella pneumoniae, Enterobacter
cloacae) → epithelial damage
Clinical symptoms: diarrhea, weight loss, nutrient (folate, vitamin B12, and iron) deficiency

11
 CELIAC DISEASE
RISK FACTORS
GENETIC ENVIRONMENTAL
HLA-DQ2 gene polymorphism Consumption of gluten-containing cereals
HLA-DQ8 gene polymorphism Infection in the early years of life
Lower socioeconomical status

Lindfords et al., Nature Reviews Disease Primers, 2019 12

 CELIAC DISEASE
PATHOMECHANISM
INNATE IMMUNE RESPONSE ADAPTIVE IMMUNE RESPONSE

Lindfords et al., Nature Reviews Disease Primers, 2019 13

 CELIAC DISEASE
SYMPTOMS AND SIGNS

Histological Laboratory
findings signs
leletek TG2-Ab
EmA

TG2-Ab = anti-transglutaminase-2 antibodies

EmA = anti-endomysial antibodies
Lindfords et al., Nature Reviews Disease Primers, 2019 14
 CELIAC DISEASE
DIFFERENTIAL DIAGNOSIS

Ghoshal and Gwee, Nature Reviews Gastroenterology & Hepatology, 2017 15

 DEFECTS IN ABSORBTION
DISORDERS OF CARBOHYDRATE ABSORPTION

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 16

 DEFECTS IN ABSORBTION
DISORDERS OF CARBOHYDRATE ABSORPTION

1. Lactase deficiency
A. Primary: congenital
B. Secondary: celiac sprue, infections (e.g. Rotavirus and Giardia), drugs (antibiotics,
chemotherapeutics)
C. Acquired: many individuals acquire lactose intolerance as they get older
Clinical symptoms: abdominal distension and pain, abdominal cramps, flatus, diarrhea, loud
bowel sounds, urgency with bowel movements

2. Glucose/galactose malabsorption (mutation of SLC6A1 gene encoding SLGT1

transporter)
Clinical symptoms: diarrhea and mild glucosuria, no symptoms on fructose ingestion
(fructose is absorbed by GLUT5 transport)

17
 LACTASE DEFICIENCY
RISK FACTORS
GENETIC ENVIRONMENTAL
(PRIMARY) (SECONDARY)
Lactose malabsorption is typically caused by 1. Anxiety disorders
lactase downregulation after infancy due to 2. GI disease (celiac disease, infective
lactase non-persistence which in Caucasians is gastroenteritis, Crohn’s disease)
mediated by the LCT −13’910:C/C genotype. 3. Malabsorption of fermentable
oligosaccharides, disaccharides and
monosaccharides and polyols

Misselwitz, Gut, 2019 18

LACTASE DEFICIENCY
PATHOMECHANISM

Misselwitz, Gut, 2019 19

 LACTASE DEFICIENCY
SYMPTOMS AND SIGNS
GI manifestations:
1. Abdominal cramps
2. Abdominal pain
3. Bloating
4. Diarrhea

Extra-GI manifestations
1. Headache
2. Vertigo
3. Memory impairment
4. Lethargy
5. Muscle and joint pains
6. Allergy
7. Arrhythmia
8. Mouth ulcers
9. Sore throat
10. Dermatitis herpetiformis

Netter’s Gastroenterology, 2010 20

 LACTASE DEFICIENCY
DIFFERENTIAL DIAGNOSIS

Joseph Feher: Quantitative Human Physiology, 2017 21

 DEFECTS IN ABSORBTION
DISORDERS OF PROTEIN ABSORPTION

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 22

 DEFECTS IN ABSORBTION
DISORDERS OF PROTEIN ABSORPTION

1. Enterokinase deficiency (enterokinase converts trypsinogen to trypsin)

Clinical features: diarrhea, hypoproteinemia, growth retardation

2. Hartnup disease is an autosomal recessive disorder caused by impaired neutral amino

acid transport in the apical brush border membrane of the small intestine and the proximal
tubule of the kidney. Mutation of SLC6A19 gene encoding sodium-dependent and chloride-
independent neutral amino acid transporter → excessive amounts of amino acids, such as
tryptophan, are excreted in the urine → with too little tryptophan in the blood, the body is
unable to synthesize niacinamide
Clinical features: dermatologic and neurologic manifestations: pellagra-like symptoms
(diarrhea, dermatosis, dementia), photosensitivity, psychiatric symptoms (anxiety, emotional
instability, mood changes), ataxia, nystagmus, tremor

23
ENTEROKINASE DEFICIENCY
PATHOMECHANISM

Feher: Quantitative Human Physiology, 2017 24

HARTNUP DISEASE
PATHOMECHANISM

Hartnup
disease

25
Feher: Quantitative Human Physiology, 2017
 DEFECTS IN NUTRIENT DELIVERY
TO THE INTESTINE
1. Congestive heart failure
2. Constrictive pericarditis
3. Mesenteric ischemia (atherosclerosis, thrombosis)

Mesenteric artery

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 26

 DEFECTS IN NUTRIENT DELIVERY
FROM THE INTESTINE
1. Whipple’s disease: gram-positive bacillus Tropheryma whippelii → mucosal damage and
lymphatic obstruction
Clinical manifestations: arthralgia, fever, serositis, diarrhea
2. Lymphatic obstruction: lymphoma, lymphangiectasia
3. Abetalipoproteinema: ß-lipoproteins are required for chylomicron formation
4. Protein-losing enteropathy: celiac disease, ulcerative colitis, Ménétrier’s disease

Clinical manifestations: diarrhea, hypoproteinemia, edema

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 27

 WHIPPLE’S DISEASE
RISK FACTORS
GENETIC ENVIRONMENTAL
HLA-DRB1*13 gene polymorphism Caucasian men
HLA-DQB1*06 gene polymorphism Age of 40-60
IL16 gene polymorphism Frequent contact with with sewage and
wastewater

Netter’s Gastroenterology, 2010 28

WHIPPLE’S DISEASE
PATHOMECHANISM

Marth et al, The Lancet, 2017 29

 WHIPPLE’S DISEASE
SYMPTOMS AND SIGNS

Netter’s Gastroenterology, 2010 30

 MALABSORPTION
CONSEQUENCES
1. Edema
2. Weight loss
3. Muscle wasting
4. Flatulence
5. Watery diarrhea
6. Loss of taste
7. Slow wound healing
8. Acrodermatitis
9. Anemia
10. Glossitis
11. Tetany
12. Paresthesias

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 31

 DEFECATION
PHYSIOLOGICAL BACKGROUND
Normal stools/feces
1. color: brown
2. shape: sausage
3. amount: 200 g/day
4. water content: 75%
5. consistency: formed, semisolid
6. frequency: from 3 times a day to 3 times a week

Netter’s Gastroenterology, 2010

 DIARRHEA
PHYSIOLOGICAL BACKGROUND

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013

 DIARRHEA
DEFINITION
Diarrhea is increase in daily frequency (more than 3/day) and/or fluidity (>90%) and/or
amount of stool (above 200 g).
FORMS
Acute diarrhea < 2 weeks
Persistent diarrhea 2-4 weeks
Chronic diarrhea > 4 weeks

34
 ACUTE DIARRHEA
INFECTIOUS, NON-INFLAMMATORY DIARRHEA
1. Toxin-producing bacteria: enterotoxigenic E. coli, Vibrio cholerae
2.Viruses: calicivirus, rotavirus
3. Parasites: Giardia lamblia, Entamoeba histolytica, Cryptosporidium, Strongyloides
4. Traveler’s diarrhea: enterotoxigenic E. coli (40-75%), rotavirus, Giardia lamblia

Clinical features: abdominal pain, watery, non-bloody diarrhea, periumbilical cramps,

bloating, nausea or vomiting, no fecal leukocytes are present

35
 ACUTE DIARRHEA
INFECTIOUS, NON-INFLAMMATORY DIARRHEA

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 36

 ACUTE DIARRHEA
INFECTIOUS, INFLAMMATORY DIARRHEA
1. Invasive bacteria: Shigella, Salmonella, Campylobacter, Yersinia

2. Toxin-producing bacteria: Clostridium, enterohemorrhagic E. coli

Clinical features: abdominal pain, fever and bloody diarrhea (dysentery), fecal leukocytes
are present

37
 ACUTE DIARRHEA
INFECTIOUS, INFLAMMATORY DIARRHEA

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 38

 ACUTE DIARRHEA
NON-INFECTIOUS DIARRHEA
1. Diet: non-absorbable sugar substitutes (sorbitol), food allergies, spicy foods, excessive
caffeine

2. Drugs: antibiotics, laxatives, antacids, colchicine, cholinergic agents, lactulose, quinidine,

NSAIDs

3. Inflammation: colitis, appendicitis, diverticulitis, GI hemorrhage, fecal impaction

39
 ACUTE DIARRHEA
NON-INFECTIOUS DIARRHEA

Netter’s Gastroenterology, 2010 40

 CHRONIC DIARRHEA
OSMOTIC DIARRHEA
1. Lactase deficiency
2. Ingestion of fruits (prunes, figs, and
grapes)
3. Corn syrup
4. Poorly absorbed carbohydrates (mannitol,
sorbitol, lactulose)
5. Magnesium or phosphate containing
compounds (osmotic laxatives, antacids)

Clinical features: stool osmotic gap > 50;

stool volume decreases with fasting

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 41

 CHRONIC DIARRHEA
SECRETORY DIARRHEA
1. Endocrine tumors (VIP, gastrin, glucagon)
2. Carcinoid tumors (serotonin)
3. Villous adenoma
4. Bile salt malabsorption after terminal ileum resection
5. Laxatives (senna, ricinoleic acid)

Clinical features: large, watery stools (1-10 l/day); little

change with fasting

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 42

 CHRONIC DIARRHEA
STEATORRHEA
1. Chronic pancreatitis
2. Cystic fibrosis
3. Pancreatic duct obstruction (e.g. cancer)
4. Pancreatic resection
5. Blind loop
6. Small bowel diverticulum
7. Liver cirrhosis
8. Biliary obstruction
9. Celiac disease
10. Tropical sprue
11. Lymphatic obstruction: Whipple’s
disease, trauma, infection, congenital
lymphangiectasia

Clinical features: steatorrhea: stool fat > 7

g/day

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 43

 CHRONIC DIARRHEA
INFLAMMATORY DIARRHEA
1. Inflammatory bowel diseases: ulcerative
colitis, Crohn’s disease
2. Primary or secondary immunodeficiencies
3. Radiation enterocolitis

Clinical features: fever, hematochezia,

abdominal pain

Dickman et al., Digestive Diseases and Sciences, 2015

Kumagai et al., Nutrients, 2018 44

 CHRONIC DIARRHEA
DIARRHEA CAUSED BY HYPERMOTILITY
1. Irritable bowel syndrome (IBS)
2. Hyperthyroidism
3. Carcinoid syndrome
4. Dumping syndrome
(after gastrectomy or truncal vagotomy)

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 45

 DIARRHEA
CONSEQUENCES

1. Dysbiosis
2. Dehydration
3. Metabolic acidosis
4. Hypokalemia
5. Death

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 46

 INFLAMMATORY BOWEL DISEASE (IBD)
DEFINITION
IBD is a group of chronic idiopathic inflammatory conditions affecting the colon and small
intestine. The two major types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD).
RISK FACTORS

Neurath, Nature Reviews Immunology, 2016 47

 INFLAMMATORY BOWEL DISEASE (IBD)
PATHOMECHANISM
INNATE IMMUNE RESPONSE ADAPTIVE IMMUNE RESPONSE

Neurath, Nature Reviews Gastroenterology & Hepatology, 2017 48

INFLAMMATORY BOWEL DISEASE (IBD)
SYMPTOMS
GI manifestations Extra-GI manifestations

crypt abscess

https://www.hopkinsmedicine.org/gastroenterology_hepatology/ 49
 INFLAMMATORY BOWEL DISEASE (IBD)
DIFFERENTIAL DIAGNOSIS
ULCERATIVE COLITIS CROHN’S DISEASE
1. Incidence: 2-19/100,000 individuals per 1. Incidence: 3-20/100,000 individuals per
year year
2. Risk factors: genotype and environment 2. Risk factors: genotype and environment
(smoking is a protective factor) (smoking is an aggressive factor)
3. Onset: between 15 and 40 years 3. Onset: between 15 and 40 years
4. Location: inflammation affects the colon 4. Location: inflammation frequently
only affects distal ileum and colon
5. Pathology: continuous inflammation 5. Pathology: discontinuous, patchy gut
from the rectum to proximal parts of the inflammation with skip lesions of the
colon distal ileum and colon
6. Histology: superficial inflammation 6. Histology: transmural inflammation (all
(mucosa and submucosa) layers of the bowel wall)
7. GI-related manifestations: diarrhoea 7. GI-related manifestations: diarrhoea,
(bloody), abdominal cramping, anaemia, abdominal cramping, fever, anaemia,
weight loss and fatigue weight loss and fatigue
8. Extra-GI manifestations: joints, skin, 8. Extra-GI manifestations: joints, skin,
liver (PSC), eye, mouth, blood liver, eye, mouth, blood (coagulation)
(coagulation) 9. Complications: stenosis, abscess
9. Complications: severe bleeding, toxic formation, fistulas and colon cancer
megacolon, rupture of the bowel and
colon cancer 50
 IRRITABLE BOWEL SYNDROME (IBS)
DEFINITION
IBS is a common chronic functional disorder of the colon including psychosocial factors,
altered bowel motility, visceral hypersensitivity, neurotransmitter imbalance, and infection

RISK FACTORS

Spiller and Major, Nature Reviews Gastroenterology & Hepatology, 2016 51

IRRITABLE BOWEL SYNDROME (IBS)
PATHOMECHANISM

Enck et al., Nature Reviews Disease Primers, 2016 52

 IRRITABLE BOWEL SYNDROME (IBS)
SYMPTOMS
GI MANIFESTATIONS EXTRA GI MANIFESTATIONS
Recurrent abdominal pain or discomfort
at least 3 days per month in the past 3
months associated with two or more of the
following:
1. Improvement with defecation
2. Onset associated with a change in the
frequency of stool
3. Onset associated with a change in the
form (appearance) of stool
IBS with constipation (IBS-C)
IBS with diarrhoea (IBS-D)
Mixed-type IBS (IBS-M)
Unsubtyped IBS (IBS-U)

Enck et al., Nature Reviews Disease Primers, 2016 53

IRRITABLE BOWEL SYNDROME (IBS)
DIFFERENTIAL DIAGNOSIS

Enck et al., Nature Reviews Disease Primers, 2016 54

 CONSTIPATION
PHYSIOLOGICAL BACKGROUND

Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 55

 CONSTIPATION
DEFINITION
Constipation is less than three bowel movements per week or difficulty passing the stool
in a person who is ingesting a normal diet.

FORMS, CAUSES
1. Habitual: 4. Systemic diseases
A. Lack of fibers A. Diabetes mellitus (DM)
B. Lack of hydration B. Hypothyroidism
C. Lack of exercise C. Neuromuscular diseases
D. Multiple sclerosis (MS)
2. Dyshigienic E. Scleroderma (SD)
A. Faulty habits F. Low spinal injury
B. Suppression of normal urge

3. Idiopathic: 5. Drug-induced/iatrogenic
A. With normal colonic transit: irritable A. Opiates
bowel syndrome (IBS) B. Phenothiazines
B. With delayed colonic transit: colonic C. Post-diarrheal (laxatives)
inertia (mainly in females), pelvic floor
dysfunction or obstruction

56
 CONSTIPATION
PATHOMECHANISM

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 57

 CONSTIPATION
CONSEQUENCES
1. Ischemia of the
intestinal wall → necrosis
2. Inflammation of the
intestinal wall → edema
→ hypovolemia
3. Increased intestinal
permeability →
bacteremia → septicemia
→ septic shock
4. Distension of colon →
megacolon
5. Inflammation or
infection of the peritoenum
→ peritonitis
6. Paradoxical diarrhea →
dehydration
7. Fecal vomiting
(miserere)

Netter’s Gastroenterology, 2010 58

 ILEUS
PHYSIOLOGICAL BACKGROUND

Hammer and McPhee: Pathophysiology of Disease, 2019

 ILEUS
DEFINITION
Ileus is the restriction or blockage of movement of chyme along the GI tract.
FORMS, CAUSES
MECHANICAL PARALYTIC
1. Simple obstruction (foreign bodies, 1. GI tract surgery
gallstones, neoplasms, inflammation, 2. Infections (peritonitis, appendicitis)
radiation, cystic fibrosis, hematoma) 3. Hemorrhage
2. Adhesions 4. Acute pancreatitis
3. Strangulation 5. Anoxic injury
4. Volvulus 6. Drugs: anticholinergic drugs, narcotics
5. Intussusception 7. Vertebral or spinal cord injuries
6. Herniation (external: inguinal canal, 8. Renal colic pain
umbilical, or internal: into the obturator 9. Chronic renal failure (uremia)
foramen, foramen epiploicum) 10. DM (ketoacidosis, autonomic neuropathy)
VASCULAR 11. Electrolyte abnormalities (hypokalemia,
Thrombosis/compression of the mesenteric hypocalcemia)
vessels

60
 ILEUS
PATHOMECHANISM

Silbernagl and Lang: Color Atlas of Pathophysiology, 2000 61

 ILEUS
CONSEQUENCES

1. Pain
2. Vomiting
3. Hypovolemia
4. Megacolon
Keshav and Bailey: The Gastrointestinal System at a Glance, 2013 62