**2. Pathophysiology of malabsorption**

#### **2.1. Electrolyte transport abnormality**

Giardiasis causes malabsorption of glucose, sodium and water and reduces disaccharidase activity due to loss of absorptive surface area [6]. Recent report also suggests that this parasite alters chloride secretory response in human colonic cells in vitro, as well as in murine models [7]. Moreover, study by Troeger et al. proved that in addition to malabsorption, chronic giardiasis may cause chloride hypersecretion in human [8]. Therefore, combinations of malabsorption and electrolyte transport abnormality are responsible for fluid accumulation in the intestinal lumen. The reasons behind these abnormalities remain poorly understood; however, multiple studies and reports suggest that parasite products may break the epithelial barrier. This activated T lymphocyte causing brush border to retract, which in turn leads to the disaccharidase deficiencies and epithelial malabsorption responsible for watery diarrhoea (**Figure 1**) [9, 10]. In fact, epithelial cells dysfunctions and disaccharide deficiencies are medicated by CD8+ T cells, whereas CD4+ T cells contribute to parasite clearance [11, 12]. Moreover, findings that athymic mice infected with *Giardia* do not exhibit microvillus injury and dysfunction despite the presence of live parasites refute the hypothesis that intestinal malfunction solely results from trophozoite attachment or parasite virulence factors [8, 11, 12].

#### **2.2. Role of parasite virulence factors**

Stain-dependent activation of enterocyte apoptosis and epithelial dysfunction induced by *Giardia* may occur in the absence of any other cell types, and small intestinal permeability returns to baseline once *Giardia* is cleared [13]. Virulence factors in *Giardia* and its effect are currently under intensive research. Giardia is thought to express a certain surface glycoprotein able to induce fluid accumulation in the intestine. Moreover, this organism is known to produce variety of potentially toxic substances such as proteinase and lectins that maybe responsible for direct epithelia injury [14, 15]. Much genomic studies are still needed to identify *Giardia's* enterotoxin and ability of *Giardia*'s proteinase to activate host receptors; however, multiple studies have reported that proteinase along with *Giardia* enterotoxins are an important virulence

**Figure 1.** Impaired epithelial tight junctions as a result from attachment of *Giardia*'s trophozoite causing activations of immune response by influx of bacterial products leading to activation of T cells causing injury to brush boarder leading to malabsorption and diarrhoea.

factors in many organisms including *Giardia*. Proteinase-activated receptors are member of class G-protein coupled signalling receptors that can modulate enterocyte apoptosis and increase intestinal permeability [16]. **Table 1** shows example of *Giardia* major virulence factor [17].

## **2.3. Other possible pathophysiology of giardiasis**

as one of the differential diagnosis in patients present with chronic diarrhoea. This is due to

Patients who are infected with *Giardia* intestinalis have symptoms ranging from asymptomatic to severe chronic diarrhoea. The pathogenesis of malabsorption syndrome–related chronic diarrhoea is not fully understood; however, many theories such as epithelial dysfunction, immunologic reactions, altered gut motility and fluid hypersecretion have been postulated. Giardiasis can lead to grown retardation in children and severe malnutrition in adult patients. Patients can also present with protein energy malnutrition, vitamin A deficiency and iron deficiency anaemia. A cross sectional study in Malaysia including 281 children aged 2–15 years showed that 56.5% of the infected children have significantly underweight, while 61.3%

Giardiasis causes malabsorption of glucose, sodium and water and reduces disaccharidase activity due to loss of absorptive surface area [6]. Recent report also suggests that this parasite alters chloride secretory response in human colonic cells in vitro, as well as in murine models [7]. Moreover, study by Troeger et al. proved that in addition to malabsorption, chronic giardiasis may cause chloride hypersecretion in human [8]. Therefore, combinations of malabsorption and electrolyte transport abnormality are responsible for fluid accumulation in the intestinal lumen. The reasons behind these abnormalities remain poorly understood; however, multiple studies and reports suggest that parasite products may break the epithelial barrier. This activated T lymphocyte causing brush border to retract, which in turn leads to the disaccharidase deficiencies and epithelial malabsorption responsible for watery diarrhoea (**Figure 1**) [9, 10]. In fact, epithelial cells dysfunctions and disaccharide deficiencies are medicated by CD8+ T cells, whereas CD4+ T cells contribute to parasite clearance [11, 12]. Moreover, findings that athymic mice infected with *Giardia* do not exhibit microvillus injury and dysfunction despite the presence of live parasites refute the hypothesis that intestinal malfunction solely

Stain-dependent activation of enterocyte apoptosis and epithelial dysfunction induced by *Giardia* may occur in the absence of any other cell types, and small intestinal permeability returns to baseline once *Giardia* is cleared [13]. Virulence factors in *Giardia* and its effect are currently under intensive research. Giardia is thought to express a certain surface glycoprotein able to induce fluid accumulation in the intestine. Moreover, this organism is known to produce variety of potentially toxic substances such as proteinase and lectins that maybe responsible for direct epithelia injury [14, 15]. Much genomic studies are still needed to identify *Giardia's* enterotoxin and ability of *Giardia*'s proteinase to activate host receptors; however, multiple studies have reported that proteinase along with *Giardia* enterotoxins are an important virulence

results from trophozoite attachment or parasite virulence factors [8, 11, 12].

the lack of expertise in many of our public hospitals.

have growth retardations [6].

26 Current Topics in Giardiasis

**2. Pathophysiology of malabsorption**

**2.1. Electrolyte transport abnormality**

**2.2. Role of parasite virulence factors**

As in the case with other enteropathogens, induction of apoptosis in enterocytes by *Giardia* is the key components of the pathophysiology of giardiasis [18, 19]. Enterocytes apoptosis in giardiasis


**Table 1.** The major virulence factors of *Giardia* spp. *Giardia* is a complex organism; they produce complex enterotoxin and proteinase causing epithelial cell damage.

is Caspase 3, Caspase 9 dependent [20]. The reasons behind the activations of these proteins, which play crucial roles in apoptosis, still have not been fully understood. However, it is believed that both host and parasite factors modulate the activation of these proteins, although the exact mechanism is still not known. Interestingly, Giardia's trophozoites may halt enterocytes cell-cycle progression by consumption of arginine and upregulation of cell-cycle inhibitory genes [21].

Other possible key pathophysiology of giardiasis is *Giardia*-induced epithelial bush boarder microvilli shortening. This leads to symptoms of maldigestion and malabsorption such as diarrhoea. The factor contribute to microvilli shortening is still not fully validated; however, it was postulated that parasite's toxins may play a key role in the development of this abnormality. This is very similar to "protease" which was released in patients with bacterial overgrowth causing villi shortening and malabsorption syndrome [22].

*Giardia* infections tend to be self-limiting in immune-competent patient. A recent study in Brazilian children suggests that symptoms are less severe during re-infection. This supports the previous hypothesis that, during the primary infection, the immunity develops leading to less severe symptoms [23]. Patients who are immunodeficiency or have common variable immune deficiency such as Bruton's X-linked agammaglobulinema are prone to chronic giardiasis. This finding confirms the importance of immune system in giardiasis [24].
