J. Witowski 2006

AM Poznań

Katedra i Zakład Patofizjologii

Akademii Medycznej w Poznaniu

Pathophysiology of diarrhoeal

disorders

J. Witowski 2006

AM Poznań

Diarrhoea

• A condition characterized by increased and

unusual frequency of bowel movements and

significant changes in the volume, the character,

and the consistency of stools

• The volume of stools is usually > 300 g / 24 h

• Diarrhoeal stools may contain blood (desyntery),

mucus, parasites, pus, fat

• It results from disordered water and electrolyte

transport in the small intestine

J. Witowski 2006

AM Poznań

Mean daily fluid balance in the normal gut

Drink 2 L

Saliva 1.5 L

Pancreatic juice 2 L

Gastric juice 1.5 L

Duodenum 8 L

Colon 1.0-1.5 L

Small bowel secretion

2 L

Ileum 4-5 L

Stools 0.15 L

Bile 1 L

Jejunal absorption 5 L (50% efficiency)

Ileal absorption 4 L (75% efficiency)

Colonic absorption 1.0-1.5 L

(>90% efficiency)

J. Witowski 2006

AM Poznań

Osmotic diarrhoea

MECHANISM:

Poorly absorbable, osmotically active substance ingested

CHARACTERISTICS:

• stool volume usually < 1L/day

• subsides with fasting

• stool pH often < 7

• stool ([Na]+[K]) x 2 < Stool osmolality (gap > 40)

EXAMPLES:

• Impaired carbohydrate transport

lactase deficiency

glucose-galactose malabsorption

• Laxative ingestion

magnesium-containing salts

mannitol, lactulose

J. Witowski 2006

AM Poznań

Secretory diarrhoea

MECHANISM:

Abnormal secretion of water and electrolytes into the

small bowel (with or without inhibition of intestinal fluid

absorption)

CHARACTERISTICS:

• stool volume usually > 1L/day

• does not subside with fasting

• stool pH usually ~ 7

• stool ([Na]+[K]) x 2 ~ Stool osmolality (gap < 40)

J. Witowski 2006

AM Poznań

Secretory diarrhoea

EXAMPLES:

• Infection (V.cholerae, enterotoxic E.coli, Salmonella,

Shigella, Staphylococcus, Clostridium, viruses)

• Endocrine mediators (serotonin carcinoid syndrome,

calcitonin medullary cancer of the thyroid, VIP,

gastrin gastrinoma, prostaglandins, methylxanthines)

• Laxative ingestion (Ricinoleic acid)

J. Witowski 2006

AM Poznań

Consequences of diarrhoea

Isotonic dehydration:

• Loss of sodium and water in the same proportion

• Most common

• Serum [Na] normal (130-150 mmol/l)

• Serum osmolality normal (275-295 mOsm/l)

• Loss of skin tugor, hypotension, tachycardia, oliguria

• Life threatening when fluid loss > 10% of body weight

Hypovolaemic shock

J. Witowski 2006

AM Poznań

Consequences of diarrhoea

Metabolic acidosis:

• Loss of bicarbonate in the stool

• If the kidneys function normally bicarbonate is replaced

• In hypovolaemia deterioration of renal function base deficit

• In hypovolaemic shock increased production of lactic acid

• Serum bicarnonate reduced (may be < 10 mmol/l)

• Arterial pH reduced (may be < 7.10)

• Accelerated and deepened breathing, vomiting

Potassium depletion:

• Large faecal losses of potasium

• Acidosis may mask loss of potassium due to the ICF to ECF shift

• Muscular weakness, arrhythmias, paralytic ileus

J. Witowski 2006

AM Poznań

Oral rehydration therapy (ORT)

Principle:

• Intestinal absorption of sodium (and water) is enhanced by

the active absorption of glucose or amino acids

• Absorption continues to function during secretory diarrhoea

WHO-recommended composision of fluids for ORT :

• Osmolality similar to, or less than that of plasma (300 mOsm/L)

• Sodium 30-80 mmol/l (2.0-4.5 g/L)

• The molar ratio of glucose to sodium should be at least 1:1

(but total osmolality should not be > 300 mOsm/L)

• The source of glucose may be a food starch (cooked cereal, rice

gruel, starchy vegetable) or sucrose

• If needed: potassium 20 mmol/L and bicarbonate 30 mmol/L

J. Witowski 2006

AM Poznań

A clinical syndrome characterized by:

• Diarrhoea

• Systemic effects of deficiency of certain nutrients

Patients with malabsorptive disorders may present with:

• Gross evidence of malabsorption and typical symptoms

• Isolated findings, which alone may not suggest the

diagnosis

Signs and symptoms of malabsorption result from

• Deficiency of dietary nutrients

• Abnormal contents in the intestine

Malabsorption syndrome

J. Witowski 2006

AM Poznań

Basis for the effects of malabsorption

Diarrhoea:

• undigested and unabsorbed contents in the intestinal lumen

• bacterial activity hydroxy fatty acids production from

undigested fat increase in intestinal secretion and motility

Steatorrhoea:

• malabsorption of fat 6 g of fat in the stools / 24 hrs

bulky malodorous stools, droplets of fat, difficult to flush

Weight loss:

• malabsorption of protein, carbohydrates, and fat

• loss of calories

Flatulence:

• bacterial activity release of gaseous metabolites (CH4, H2)

from undigested food abdominal distension, cramps

J. Witowski 2006

AM Poznań

Basis for the effects of malabsorption

Oedema:

• malabsorption of protein hypoproteinemia peripheral

oedema, ascites

Anaemia:

• malabsorption of iron, folate, vitamin B12

Weakness and fatigue:

• anaemia

• electrolyte depletion due to diarrhoea hypopotassemia,

hypomagnesemia

Nocturia:

• delayed absorption and excretion of water (may be pooled in

the gut during the day)

Night blindness:

• malabsorption of vitamin A

J. Witowski 2006

AM Poznań

Basis for the effects of malabsorption

Bleeding tendency:

• malabsorption of vitamin K impaired synthesis of

prothrombin

Bone pain and pathological fractures:

• malabsorption of vitamin D malabsorption of calcium

osteomalacia and osteoporosis

Tetany:

• malabsorption of calcium and /or magnesium

hypocalcemia, hypomagnesemia

Paresthesias and peripheral neuropathy:

• malabsorption of vitamin B1 and B12

Glossitis and cheilosis:

• malabsorption of iron

J. Witowski 2006

AM Poznań

Causes of malabsorption

Classification according to phases of absorption:

1. Luminal phase

digestion of food materials by enzymes and bile

2. Mucosal phase

transport of the digested products from the gut

lumen to intestinal epithelial cells

3. Postabsorptive phase

transport of nutrients from intestinal epithelial

cells via lymphatics and portal vein circulation

J. Witowski 2006

AM Poznań

Causes of malabsorption

Luminal phase

Impaired nutrient hydrolysis

• following gastric resection

• exocrine pancreatic insufficiency (chronic

pancreatitis, pancreatic resection, pancreatic

cancer, cystic fibrosis)

• inactivation of pancreatic enzymes by gastric

hypersecretion (Zollinger-Ellison syndrome)

• inadequate mixing of nutrient, enzymes and bile

(increased intestinal motility, gastrojejunostomy)

J. Witowski 2006

AM Poznań

Luminal phase

Impaired micelle formation

• decrease bile salt synthesis (liver disease)

• impaired bile secretion (biliary tract obstruction)

• impaired enterohepatic bile circulation (regional

enteritis, ileal resection)

• bile salt deconjugation (bacterial overgrowth)

• bacterial overgrowth

• stasis of intestinal contetnts (strictures, blind

loops, diverticula)

• decreased intestinal motility (scleroderma,

diabetic neuropathy, obstruction)

Causes of malabsorption

J. Witowski 2006

AM Poznań

Mucosal phase

Inadequate absorptive surface area

• intestinal resection

Damage to absorptive surface

• inflammation (celiac sprue, inflammatory bowel

disease, AIDS enteropathy, bacterial infection,

irradiation, chemotherapy)

• infiltrating disease (lymphoma, amyloidosis)

Impaired brush-border enzymatic activity

• Dissacharidase deficiency (primary and secondary

lactose deficiency)

Causes of malabsorption

J. Witowski 2006

AM Poznań

Postabsorptive phase

Obstruction of the lymphatic system

• Whipple disease,

• malignancy (lymphoma)

• infection (tuberculosis)

Cardiovascular disorders

• Congestive heart failure

Causes of malabsorption

J. Witowski 2006

AM Poznań

Celiac sprue

Celiac sprue = gluten-sensitive enteropathy

food hypersensitivity disorder caused by

an inflammatory response to wheat gluten

and similar proteins of barley and rye

GLUTEN Wheat gluten remains after washing dough and consists of a complex mixture of many gliadin and glutenin polypeptides; gluten-like proteins are also found in rye and barley

Kagnoff M, Gastroenterology 2005, 128, S10

Lesions in the small intestine:

• flattened mucosa,

• loss of villi,

• hyperplasia of crypts,

• lymphocytic infiltrates

Normal Celiac disease

J. Witowski 2006

AM Poznań

Rewers M, Gastroenterology 2005, 128, S47

Celiac sprue

• Prevalence ~1%

• Most commonly occurs in childhood

• Magnitude of exposure to gluten

important

• The pattern of incidence is changing

increasing number of cases in

adulthood

• Untreated may lead to severe

malabsorption and increased mortality

(enteropathy associated T-cell

lymphoma)

J. Witowski 2006

AM Poznań

Kagnoff M, Gastroenterology 2005, 128, S10

Genetic background for celiac sprue

Gluten peptide binding in the peptide binding groove of DQ2

J. Witowski 2006

AM Poznań

Immune response in celiac sprue

Kagnoff M, Gastroenterology 2005, 128, S10

DEAMIDATION The modification of glutamine residues in peptides and proteins to glutamate, or asparagine residues to aspartate

TISSUE TRANSGLUTAMINASE An enzyme responsible for modifying proteins by deamidation of specific glutamine residues; patients with celiac disease have IgA and IgG antibodies against TG

J. Witowski 2006

AM Poznań

Diagnosis: 1. Evidence of malabsorption 2. IgA and/or IgG antibodies

against: • gliadin • reticulin • endomysium (TG)

3. Abnormal small bowel biopsy

4. Response to gluten-free diet

Rewers M, Gastroenterology 2005, 128, S47

Clinical features of celiac sprue

J. Witowski 2006

AM Poznań

Lactose intolerance

Congenital lactase deficiency

• Extremely rare

Primary lactase deficiency

• Very common

• Reduced lactase activity in the brush border (decreases with age)

• Child-onset and adult-onset

Secondary lactase deficiency

• gastroenteritis

• parasite infestation

• celiac sprue

• irradiation

• Whipple syndrome

• HIV enteropathy

• chemotherapy

• gastrinoma

J. Witowski 2006

AM Poznań

Lactose intolerance

LACTASE DEFICIENCY

DIARRHOEA

Unhydrolyzed lactose

Fermentation

of lactose

Irritation of

the colonic mucosa

Increased

colon motility

Osmotic effect

Insorption of

fluid into

the lumen

• Abdominal pain and diarrhoea

after ingestion of milk

• Lactose load (tolerance test):

• Induction of symptoms

• No increase in blood

glucose

• Decreased lactase activity in

the jejunal biopsy

• Amelioration of symptoms on

milk-free diet

• Stool pH < 6

(fermentation of sugar)

• Increased excretion of lactic

acid

J. Witowski 2006

AM Poznań

Acute pancreatitis

Mechanisms protecting the pancreas against autodigestion:

• Pancreatic enzymes are synthesized as inactive proenzymes

• Digestive enzymes and lysosomal enzymes are packed into

separate subcelluar compartments

• The digestive proenzymes are packaged together with protease

inhibitors

• Zymogen granules have an acidic pH and low Ca++ concentration

Cellular events in acute pancreatitis:

• Fusion of lysosomal and zymogen granules activation of

trypsinogen

• Activated trypsin activation of all zymogen enzymes cascades

• Release of secretory vesicles into interstitium activation of

inflammatory reaction

• Chemoattraction of neutrophils further exacerbation of

inflammation

J. Witowski 2006

AM Poznań

Acute pancreatitis

Causes of pancreatitis:

• Biliary tract disease ~ 40%

• Alcohol ~ 40%

• Post-surgery / ERCP ~ 5%

• Idiopathic ~ 10%

• Other ~ 5%

• Trauma

• Drugs (azathioprine, furosemide, oestrogens,

corticosteroids, ACE inhibitors)

• Infection (mumps, EBV, CMV, Coxsackie)

• Parasites (Ascaris lumbricoides)

• Penetrating peptic ulcer

• Hypercalcemia (hyperparathyiroidism)

• Hypetrigliceridemia

• Tumour

• Toxins (insecticides, scorpion bite)

• Anatomical abnormalities

J. Witowski 2006

AM Poznań

Acute pancreatitis

Mortality is 10-30%, but may reach 70% in severe cases;

most deaths due to multiorgan failure

Biliary microlithiasis is increasingly recognised as a cause of “idiopathic” pancreatitis

Beckingham et al, Br Med J 2001, 332, 595

J. Witowski 2006

AM Poznań

INSULT

ACINAR CELL INJURY

PANCREATIC DUCT OBSTRUCTION

DERANGED TRANSPORT OF ZYMOGEN AND LYSOSOMAL ENZYMES

Plasmin Trypsin Chymotrypsin

Proteolysis Oedema Necrosis

Haemorrhage

Kinins

Pain Oedema Vascular

permeability

Elastase

Elastolysis Vascular damage

Haemorrhage

ACTIVATION OF TRYPSIN LEUKOCYTE

INFILTRATION

Release of cytokines

Release of enzymes

Leakage of enzymes from ductules

Activation of enzymes

Phospholipase Lipase

Fat necrosis

TISSUE DESTRUCTION

Consumption of clotting factors and platelets

Activation of coagulation pathway

Release of tissue

thromboplastin BLEEDING

Acute pancreatitis

Breakdown of fibrin

Fibrin degradation products

Inhibition of thrombin,

platelet aggregation, and fibrin formation

J. Witowski 2006

AM Poznań

Local complications of acute pancreatitis

Beckingham et al, Br Med J 2001, 332, 595

• Pancreatic necrosis

• Pancreatic abscess

• Pancreatic pseudocyst

• Oedema and obstructive jaundice

J. Witowski 2006

AM Poznań

Systemic complications of acute pancreatitis

Beckingham et al, Br Med J 2001, 332, 595

CARDIOVASCULAR:

• Hypotension

• Shock

• Pericardial effusion

• Disseminated intravascular coagulation

RENAL:

• Acute renal failure

• Renal vein thrombosis

PULMONARY:

• Pleural effusion

• Respiratory distress syndrome

CENTRAL NERVOUS SYSTEM:

• Fat emboli

J. Witowski 2006

AM Poznań

Beckingham et al, Br Med J 2001, 332, 595

GASTROINTESTINAL:

• Haemorrhage from eroded blood vessels

• Haemoperitoneum

• Ileus

FAT NECROSIS:

• Subcutaneus tissue

• Bone

• Retroperitoneal tissue

• Mediastinal tissue

METABOLIC:

• Hyperglycaemia

• Hyperlipaemia

• Hypocalcaemia

The Cullen sign

The Grey-Turner sign

Systemic complications of acute pancreatitis

J. Witowski 2006

AM Poznań

Chronic pancreatitis

Whitcomb DC, Nat Clin Pract Gastroenterol Hepatol 2004; 1: 46.

Significant pancreatic destruction

associated with inflammation,

fibrosis, acinar and islet cell loss,

calcifications, and severe

pancreatic dysfunction

Recurrent injury

Sustained immune activation and persistent inflammation

Fibrosis