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Diarrhea = passage of loose or watery stools more than 3 times in 24h or liquid volume > 200 g/day

A common manifestation of GI disease with many causes

Can range in severity from an acute self-limited episode to a severe, life-threatening illness

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Infective VS. Non-Infectious Causes of Inflammatory Diarrhea

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Infective VS. Non-Infectious Causes of Inflammatory Diarrhea

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1. Osmotic diarrhea:

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).

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The 4 primary mechanisms:

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.

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Diarrhea results from disruptions in the osmotic balance and water transport in the intestine. Normally, the intestine processes 8–9 liters of fluids daily, excreting only 100–200 mL.

However, enteric pathogens disrupt this process by increasing fluid secretion through different mechanisms.

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Acute Diarrhea

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.

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Be able to differentiate clearly!!!

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

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Anemia is defined as a decrease in hemoglobin (Hb) levels below the reference range for age and sex.

Males: <13.5g/dL or <8.1mmol/l

Females: <12g/dL or <7.5mmol/l

Normal hemoglobin values (NL):

Females: 7.5–10 mmol/L

Males: 8.5–11 mmol/L

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.

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1. Nutritional Deficiencies (Impaired RBC Production)

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

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General Symptoms

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

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1. Complete blood count:

Hemoglobin (Hb) → Determines anemia severity

Mean Corpuscular Volume (MCV) → Classifies anemia as  microcytic, normocytic, or macrocytic

Mean Corpuscular Hemoglobin (MCH) → Indicates RBC color (hypochromic vs. normochromic)

Red Cell Distribution Width (RDW) → Measures variation in RBC size

2. Peripheral blood smear

Hypochromic, microcytic RBCs → Iron deficiency

Macro-ovalocytes, hypersegmented neutrophils → Megaloblastic anemia

Spherocytes, sickle cells, schistocytes → Hemolysis

3. Iron studies:

Serum Ferritin → Low in iron deficiency; normal/high in inflammation (anemia of chronic disease)

Serum Iron → Low in iron deficiency and anemia of chronic disease

Total Iron-Binding Capacity (TIBC) → High in iron deficiency; low in anemia of chronic disease

Transferrin Saturation → Low in iron deficiency anemia

4. Vitamin B12, folate levels

5. Hemolysis workup (if hemolytic anemia suspected):

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)

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1. Iron Deficiency Anemia

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)

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Diarrhea is both a sign & symptom.

--> 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.