• Mechanism: The gut mucosa acts as a semipermeable membrane → allows fluid to enter the bowel when large quantities of non-absorbed hypertonic substances remain in the lumen. 

• Causes: 

  • Ingestion of non-absorbable substance (e.g., a purgative such as magnesium sulphate) 

  • Generalized malabsorption, so that high concentrations of solute (e.g. glucose) remains in the lumen. 

  • Specific absorptive defects (e.g. disaccharidase deficiency of glucose-galactose malabsorption). 

• Characteristics: 

  • The volume of diarrhea produced by these mechanisms is reduced by the absorption of fluid by the ileum and colon. 

  • The diarrhea stops when:

    • The patient stops eating 

    • The malabsorptive substance is discontinued. 

2. Secretory diarrhea: 

• Mechanism:

  •  There is both active intestinal secretion of fluid + electrolytes and decreased absorption.

• Common Causes:

  • Enterotoxins: Cholera, E. coli (thermolabile/thermostable toxin), C. difficile toxin.

  • Hormonal causes: Vasoactive intestinal peptide in Verner–Morrison syndrome.

    • (Verner–Morrison syndrome = is a rare condition caused by a VIPoma, a tumor that secretes vasoactive intestinal peptide (VIP), usually found in the pancreas → causes watery diarrhea)

  • Bile salts & fatty acids: Malabsorption in the colon (e.g., after ileal resection).

  • Laxatives: Docusate sodium.

3. Inflammatory (invasive) diarrhea

• Mechanism:

• Intestinal mucosal damage → inflammation & destruction of epithelial cells

• Loss of fluid, blood, and electrolytes due to disrupted absorption

• Neutrophil infiltration → cytokine release → further tissue damage

• Leads to:

  • Bloody or mucoid diarrhea

  • Fever & abdominal pain (due to inflammation)

• Causes:

  • Infective (Invasive Pathogens)

    • Shigella → Dysentery (Shiga toxin damages intestinal lining)

    • Clostridioides difficile → Pseudomembranous colitis (toxin-mediated)

    • Enterohemorrhagic E. coli (EHEC) → Hemorrhagic colitis, HUS risk

    • Campylobacter jejuni → Gastroenteritis, Guillain-Barré risk

    • Salmonella (non-typhoidal) → Gastroenteritis, systemic spread in immunocompromised

  • Non-Infectious (Inflammatory Conditions)

    • Inflammatory Bowel Disease (IBD)

      • Crohn’s disease → Skip lesions, transmural inflammation

      • Ulcerative colitis → Continuous colonic inflammation, rectal involvement

4. Exudative diarrhea 

• Mechanism:

  • Inflammation, necrosis, and sloughing of colonic mucosa.

  • May include a secretory component due to prostaglandin release from inflammatory cells.

  • Stools contain polymorphonuclear leukocytes (PMNs) and may have occult or gross blood.

• Causes:

  • Bacterial Infections:

    • Campylobacter, Salmonella, Shigella, Yersinia.

    • Invasive or enterotoxigenic E. coli.

    • Vibrio parahaemolyticus.

    • Clostridium difficile colitis (often antibiotic-induced).

  • Parasitic Infections:

    • Entamoeba histolytica (colonic parasite).

  • Inflammatory Conditions:

    • Inflammatory bowel disease (IBD): Crohn’s disease, ulcerative proctocolitis.

    • Idiopathic IBD.

  • Other Causes:

    • Radiation enterocolitis.

    • Cancer chemotherapy.

    • Intestinal ischemia.

5. Fatty (steatorrhea) diarrhea:

A. Malabsorptive

• Impaired nutrient & fat absorption, leading to fatty, foul-smelling stools.

• Causes:

  • Pancreatic insufficiency (e.g., chronic pancreatitis, cystic fibrosis).

  • Celiac disease (gluten intolerance).

  • Small bowel disease (e.g., Crohn’s disease, bacterial overgrowth).

• Key Feature: Fatty, floating stools (steatorrhea).

B. Maldigestive Diarrhea

• Occurs when there is impaired digestion of food, leading to malabsorption and diarrhea. 

• Causes: 

• Pancreatic enzyme deficiency
  → Inadequate secretion of digestive enzymes from the pancreas (amylase, lipase, proteases), leading to poor digestion of fats, proteins, and carbohydrates.

  • Conditions:

    • Chronic pancreatitis

    • Cystic fibrosis

    • Pancreatic cancer

• Bile Acid Deficiency
  → Reduced bile production or impaired bile flow affects fat digestion and absorption, causing steatorrhea.

  • Conditions:

    • Liver disease (e.g., cirrhosis, hepatitis).

    • Biliary obstruction (e.g., gallstones, cholestasis).

    • Ileal resection (impairing bile salt reabsorption).

• Lactase Deficiency
  → Inability to digest lactose, leading to osmotic diarrhea due to undigested lactose in the colon.

  • Conditions:

    • Lactose intolerance (congenital or acquired).

• Key Features 

  • Fatty stools (steatorrhea) in cases of pancreatic or bile acid deficiencies.

  • Crampy abdominal pain and bloating due to undigested food.

  • Nutrient deficiencies (e.g., vitamin A, D, E, K, calcium) from malabsorption.

  • Weight loss in chronic cases.

6. Abnormal motility-related diarrhea 

• Rapid intestinal transit prevents adequate absorption.

• Causes:

  • Hyperthyroidism.

  • Irritable bowel syndrome (IBS).

  • Post-vagotomy diarrhea.

  • Diabetes 

• Key Feature: Watery stools with urgency but no infection/malabsorption.

• Symptoms may be exacerbated by small bowel bacterial overgrowth. 

7. Facetious diarrhea 

• Diarrhea that is intentionally or unintentionally induced by the patient, often for psychological reasons → It can occur when a person deliberately causes or exaggerates symptoms in order to seek medical attention, medications, or other benefits.

• Causes:

1. Self-induced by the patient:

   • Laxative abuse (e.g., taking excessive amounts of laxatives to produce diarrhea).

   • Use of other medications that cause diarrhea (e.g., metoclopramide, misoprostol).

   • Enemas or purgatives taken to induce bowel movements.

2. Psychological causes:

   • Munchausen syndrome (factitious disorder) where patients deliberately produce symptoms of illness to seek attention or care from medical professionals.

   • Secondary gain (e.g., attention, medications, avoiding responsibilities).

Definition: Diarrhea lasting <14 days, usually infectious in origin (most commonly viral in children but sometimes bacterial).

Common infectious causes:

• Viral: Norovirus, Rotavirus (more common in children).

• Bacterial:

  • E. coli food poisoning → causes secretory diarrhea.

  • Food poisoning from Salmonella, Campylobacter, Staphylococcus (foodborne).

  • C. difficile (post-antibiotic use).

• Parasitic (contaminated food/water, travel-related):

  • Giardia, Entamoeba histolytica ("traveler’s diarrhea").

    
    

Clinical Features:

• Loose, watery stools (sometimes bloody).

• Fever, abdominal pain, vomiting.

• Risk of dehydration if the diarrhea is severe, especially in young children & elderly.

Key Investigations:

• Patient history! Assess whether they may have been exposed

• Stool samples identify infectious causes by isolating an organism. 

  • Stool microscopy culture sensitivities (MCS) should be sent in all patients.

    • Stool MCS = laboratory test used to identify the cause of infectious diarrhea by analyzing a stool sample:

      • Identifies parasites, ova (eggs), cysts, WBCs (suggests inflammation), RBCs (suggests bleeding), bacterial pathogens 

  • Samples for C. difficile toxin test should be sent in at-risk patients: elderly, nursing home residents, recent antibiotic use.

    • The stool C difficile toxin test detects harmful substances produced by the bacterium Clostridioides difficile (C difficile). This infection is a common cause of diarrhea after antibiotic use. 

  • Stool for ova, cysts, and parasites (OCP):

    • Persistent diarrhea (>14 but <30 days).

    • MSM (men who have sex with men).

    • Immunocompromised patients.

    • Recent travel abroad.

    • Suspected Giardia, Entamoeba histolytica, Cryptosporidium.

Management: focuses on volume repletion

• First-line:

  • Oral rehydration therapy (ORS) → contains water, salts, and sugar.

  • IV fluids for severe dehydration.

• Antibiotics (only if severe):

  • Indications:

    • Severe/prolonged symptoms (>5 days).

    • Systemic infection signs.

    • Extremes of age.

    • Immunocompromised patients.

    • Presence of complications.

    • Bloody/mucoid stools.

• Avoid antimotility agents (e.g., loperamide, codeine phosphate) if possible.

Chronic Diarrhea

Definition: Diarrhea lasting >30 days.

Assessment → a thorough history is important: 

• History: Onset, duration, severity, associated symptoms (bloody stools, abdominal pain, weight loss, steatorrhea), medication/food triggers, full past medical history.

• Physical Examination: Full systemic assessment.

Causes

• IBS

• Microscopic colitis

• IBD

• Colonic cancer

• Medications

• Diet

• Bile acid and diarrhea

• Pancreatic insufficiency

• Celiac disease

• Overflow diarrhea

Initial Investigations:

• Blood tests:

  • Full blood count (FBC).

  • Serum creatinine & electrolytes.

  • Thyroid function tests.

• Coeliac screen:

  • Tissue transglutaminase (TTG) or endomysial antibodies (EMA).

• Stool tests:

  • Faecal calprotectin (marker of intestinal inflammation).

  • Stool microscopy, culture, and sensitivity (MCS).

  • C. difficile toxin test.

Endoscopic Evaluation (if initial tests don't reveal a cause):

• Flexible sigmoidoscopy.

• Full colonoscopy (done under the following circumstances):

  • Iron deficiency anemia.

  • Abnormal faecal calprotectin with suspected IBD.

  • Older patients (to screen for polyps/colorectal cancer).

Further Investigations (if needed):

• Imaging: CT abdomen, MRI small bowel, pancreatic CT.

• Advanced tests (depending on the individual patient’s symptoms): 

  • Video capsule endoscopy (for small bowel evaluation).

  • SeHCAT scan (for bile acid malabsorption).

  • Lactose hydrogen breath test (for lactose intolerance).

Management:

•  Treat the underlying cause based on diagnosis.

Epidemiology: 

• 65-74 year: 15%

• 75-84 year: 25%

• >85: 35%

• More common in elderly individuals → 83% of cases have an identifiable cause.

• Prevalence increases with age due to chronic diseases.

• Size: Based on the mean corpuscular volume (MCV) → average volume of RBCs in a sample

  • 1. Microcytic anemia (<80fl)

    • Iron deficiency = chronic bleeding or inadquate intake 

    • Sideroblastic anemia = dysfunctional heme production (e.g., lead poisoning) 

    • Thalassemia (alpha or beta) = disorder in the genes coding for hemoglobin

      • Severity depends on how many  of the genes are affected

    • Anemia of inflammatory/chronic disease = 

      • During a chronic state of disease/inflammation, there is an increase in hepcidin (marker of inflammation) → it blocks release of iron from macrophages + stops its absorption in the gut so it cannot be used to make hemoglobin. 

      • It tries to prevent the iron being used by microbes to grow and proliferate.

    • Features:

      • Brittle nails, koilonychia, angular stomatitis, glossitis

      • Low serum ferritin, low iron, high total iron-binding capacity (TIBC)

    
    

• 2. Normocytic anemia (80-100fl)

  • Anemia of inflammatory/chronic disease = can present as microcytic or normocytic

  • Hemorrhagic anemia = acute blood loss before iron deficiency develops

  • Hemolytic Anemia = RBC destruction faster than production

  • Malignancies: Bone marrow infiltration (leukemia, lymphoma, metastatic cancer)

  • Features:

• Normal MCV, but low Hb

• Increased inflammatory markers (CRP, ESR) in chronic disease anemia

• Elevated reticulocyte count in hemolysis or blood loss

• 3. Macrocytic anemia (>100fl) 

  • Megaloblastic = problems in DNA synthesis

    • Vitamin B12 deficiency (pernicious anemia, malabsorption, vegan diet)

    • Folate deficiency → caused by diet deficiency, Crohn’s or Celiac’s

  • Non-megaloblastic = no problems in DNA synthesis 

    • Chronic alcohol use

    • Liver disease 

    • Hypothyroidism 

    • Reticulocytosis (an increased circulation of reticulocytes (immature RBCs) → due to hemolysis, blood loss, bone marrow recovery.

  • Features:

    • Hypersegmented neutrophils on blood smear

    • Neurological deficits in B12 deficiency (subacute combined degeneration of the spinal cord)

    • Elevated serum methylmalonic acid and homocysteine in B12 deficiency

• 4. Hemolytic (increased RBC destruction) 

  Extravascular hemolysis (in spleen, liver)

• Mechanism: RBCs are removed by macrophages in the spleen & liver

• Causes:

  • Membrane Defects: Hereditary Spherocytosis, Hereditary Elliptocytosis

  • Enzyme Deficiencies: G6PD Deficiency, Pyruvate Kinase Deficiency

  • Hemoglobinopathies: Sickle Cell Disease, Thalassemia

  
  

  Intravascular hemolysis (within circulation)

• Mechanism: RBCs are destroyed directly in blood vessels

• Causes:

• Autoimmune Hemolytic Anemia (AIHA)

• Mechanical Hemolysis: Prosthetic heart valves, mechanical trauma

• Microangiopathic Hemolytic Anemia (MAHA): TTP, HUS, DIC

• External Toxins: Snake bites, infections, transfusion reactions

• Intrinsic (Inherited):

• Paroxysmal Nocturnal Hemoglobinuria (PNH): RBCs lack protective proteins → complement-mediated destruction

• G6PD Deficiency: RBCs susceptible to oxidative stress (triggered by infections, fava beans, certain drugs)

  • Glucose-6-phosphate dehydrogenase protects RBCs from substances in the blood that could harm them. 

• Hereditary Spherocytosis: RBC membrane defect → spherical RBCs destroyed in the spleen

• Extrinsic (Acquired):

•  Autoimmune hemolytic anemia → antibodies attack RBCs (Coombs positive) 

• Mechanical trauma to RBCs:

  • Mechanical hemolysis (e.g., prosthetic heart valves)

  • Microangiopathic hemolytic anemia 

• External toxins + infections:

  • Snake bites, infections, transfusion reactions

• Features: 

• Jaundice, splenomegaly, dark urine, elevated LDH, low haptoglobin

• Positive Coombs test in autoimmune hemolysis

  
  

• CHeck hematopoiesis

• Iron Deficiency → Chronic blood loss (e.g., GI bleeding, menstruation), inadequate dietary intake

• Vitamin B12 Deficiency → Malabsorption (pernicious anemia, gastrectomy, Crohn’s), vegan diet

• Folate Deficiency → Poor diet, malabsorption (Celiac, Crohn’s), alcoholism, pregnancy

2. Chronic Diseases & Inflammation

• Inflammatory Diseases (e.g., rheumatoid arthritis, inflammatory bowel disease)

• Chronic Kidney Disease (CKD) → ↓ Erythropoietin (EPO) production

• Liver Disease → Impaired metabolism, decreased clotting factors, altered RBC survival

3. Bone Marrow Disorders (Reduced RBC Production)

• Aplastic Anemia → Bone marrow failure → ↓ RBC, WBC, and platelet production

• Myelodysplastic Syndromes (MDS) → Abnormal bone marrow cell development → Ineffective hematopoiesis

• Leukemia → Cancer of blood-forming tissues → Crowding out normal RBC production

4. Hemolysis (Increased RBC Destruction)

• Hemoglobinopathies →

  • Sickle Cell Disease → Abnormal hemoglobin leads to RBC destruction

  • Thalassemia → Defective globin chain synthesis leads to ineffective erythropoiesis

• Enzyme Deficiencies →

  • G6PD Deficiency → RBCs vulnerable to oxidative damage → hemolysis

  • Pyruvate Kinase Deficiency → ATP depletion → RBC membrane instability

• Membrane Defects →

  • Hereditary Spherocytosis → Defective RBC membrane proteins → RBC destruction in the spleen

  • Hereditary Elliptocytosis → RBCs more prone to hemolysis

5. Blood Loss (RBC Depletion)

• Gastrointestinal Bleeding → Ulcers, colorectal cancer, inflammatory diseases

• Menstrual Bleeding → Heavy/prolonged menstruation (menorrhagia)

• Post-Surgical Blood Loss → Significant hemorrhage after surgery

Additional Factors Affecting Hemoglobin Levels

• Plasma Volume Changes:

  • Decreased plasma volume → Spurious high Hb (e.g., dehydration, apparent polycythemia)

  • Increased plasma volume → Spurious anemia (e.g., pregnancy, fluid overload)

• Altitude (Elevation):

  • Hb levels naturally vary with altitude → No fixed universal "normal" value

• Fatigue

• Shortness of breath (dyspnea)

• Dizziness/fainting

• Palpitations

• Headaches

• Exacerbation of pre-existing heart/lung disease

General Signs

• Pallor (pale skin, mucous membranes, conjunctivae)

• Tachycardia

• Systolic flow murmur

• Cardiac failure (in severe cases)

Specific Signs Based on Type of Anemia

• Iron deficiency → Koilonychia (spoon-shaped nails), brittle nails, hair loss, glossitis, angular stomatitis

• Hemolytic anemia → Jaundice, splenomegaly, dark urine

• Thalassemia major → Frontal bossing, maxillary overgrowth (bone deformities)

• Sickle cell disease → Leg ulcers, dactylitis (hand-foot syndrome), pain crises

• Vitamin B12 deficiency → Neurological symptoms (paresthesia, ataxia, cognitive impairment)

• PICA (craving for non-nutritive substances like ice, clay, dirt) → Common in iron deficiency

• Lactate Dehydrogenase (LDH) → Elevated in hemolysis

• Indirect Bilirubin → Increased in hemolysis (unconjugated hyperbilirubinemia)

• Haptoglobin → Decreased (as it binds free hemoglobin in hemolysis)

• Coombs Test (Direct Antiglobulin Test) → Detects immune-mediated hemolysis (autoimmune hemolytic anemia)

6. Bone marrow biopsy (if marrow failure suspected)

• Treat underlying cause (e.g., GI bleeding, dietary deficiency)

• Oral iron supplementation (ferrous sulfate 200 mg daily)

• IV iron if severe or malabsorption present

2. Vitamin B12 & Folate Deficiency

• B12 deficiency: Intramuscular hydroxocobalamin or oral cyanocobalamin

• Folate deficiency: Oral folic acid 5 mg/day

3. Anemia of Chronic Disease

• Treat underlying disease

• Consider erythropoiesis-stimulating agents (ESAs) in CKD

4. Hemolytic Anemia

• Steroids, immunosuppressants (if autoimmune)

• Folic acid supplementation

• Splenectomy (for hereditary spherocytosis)

1. Alteration in Ion Transport (Secretory Diarrhea)

• Caused by: Vibrio cholerae, enteropathogenic E. coli (EPEC), Clostridium difficile

• Mechanism: These pathogens disrupt ion transporters, leading to excessive chloride secretion and impaired sodium absorption. This results in an osmotic imbalance, drawing water into the intestinal lumen and causing watery diarrhea.

  • Know which part of the channel (cAMP)

2. Depletion of Absorptive Surface

• Caused by: Vibrio cholerae, EPEC, Clostridium difficile, Giardia, Rotavirus enteritis

• Mechanism: These pathogens damage or destroy microvilli in the intestinal epithelium, reducing the surface available for nutrient and water absorption.

3. Inflammation (Inflammatory/Invasive Diarrhea)

• Caused by: Salmonella spp., Shigella spp., Clostridium difficile, Yersinia spp., Campylobacter spp., Entamoeba histolytica

• Mechanism: These pathogens invade the intestinal mucosa, triggering immune responses and cytokine release. This increases permeability, leading to exudative diarrhea with blood and mucus.

4. Activation by Neuropeptides

• Caused by: Rotavirus, Clostridium difficile

• Mechanism: Some pathogens stimulate the enteric nervous system, releasing neuropeptides that promote fluid secretion and motility, exacerbating diarrhea.

--> Symptom of various diseases

--> Sign that points to other diseases based on severity & duration

Use flowchart:

(be able to identify difference in causes for each type of diarrhea and the different mechanisms)

1. Acute or chronic

2. If acute possible causes are:

   1. Virus

   2. Bacteria

   3. Parasite

3. If chronic possible causes are:

   1. IBD

   2. Liver

   3. Pancreas

   4. Celiac

      
      

Most important management: volume repletion!

--> They are dehydrated is skin is turgor, pale, mucous membranes, etc.