Pathophysiology models of irritable bowel disorder

Question

Describe the pathophysiology of DKA (Diabetic Ketoacidosis) and HHNS (Hyperglycemic Hyperosmolar non-Ketotic Syndrome)

DKA is a diabetes-related complication that disproportionately affects patients with Type 1 diabetes (Elendu et al., 2023). It is characterized by absolute or relative deficiency in insulin and a surge in hormones that trigger insulin resistance, such as catecholamines, growth hormone, and glucagon, leading to electrolyte imbalance, ketosis, dehydration, and hyperglycemia (Elendu et al., 2023). The precipitating event of DKA is often insulin deficiency resulting from infections, improper insulin administration, or missed doses, which inhibits the intracellular transportation of glucose (Elendu et al., 2023). This triggers intracellular starvation and hunger as cells lack sufficient glucose for energy generation. As a result, cells begin to use free fatty acids (FFA) to generate energy. The low levels of insulin limit effective adipocytes lipolysis, leading to increased concentrations of FFA in the bloodstream, which are then transported to the mitochondria in the liver for oxidation, leading to the formation of ketone bodies (Elendu et al., 2023). Since insulin levels are not sufficient to effectively regulate biochemical processes, ketone bodies are produced in excessive amounts, overwhelming the body and leading to ketosis (Elendu et al., 2023).

In the second pathophysiology model, insulin deficiency may trigger the release of cortisol, catecholamine, glucagon, and growth hormone. These lead to accelerated glycogenolysis and increased gluconeogenesis, both of which increase hepatic production of glucose, and decreased uptake by tissues, triggering hyperglycemia (Elendu et al., 2023). If not accompanied by adequate fluid intake, hyperglycemia leads to electrolyte loss, hyperosmolarity, dehydration, and reduced glomerular filtration (reduced renal action). Reduced renal action worsens hyperosmolarity, diminishing intracellular potassium utilization and causing high potassium deficiency (Elendu et al., 2023), which is why DKA patients present with low serum potassium concentrations.

The pathophysiology of HHS is similar to that of DKA, with only mild differences. As with DKA, HHS is precipitated by insulin deficiency that decreases intercellular glucose utilization, leading to hyperglycemia (Ortowska et al., 2024). Hyperglycemia triggers hyperosmolarity, (Ortowska et al., 2024). It increases the osmotic gradient, leading free water to be drawn out of the intracellular space, and excreted via urinary excretion, causing dehydration that is often more severe than that caused by DKA (Ortowska et al., 2024). The risk of cardiovascular failure is also higher in HHS due to the severe dehydration (Ortowska et al., 2024). Differently from DKA, however, HHS is characterized by less production of ketone bodies and hence, a lower risk of ketosis (Ortowska et al., 2024). This is because with HHS, beta cells in the pancreas continue to produce insulin, which inhibits ketogenesis. Thus, compared to DKA, HHS is associated with lower glucagon levels and higher insulin levels, leading to mild (if any) ketosis. Thus, HHS is often indicated by absence of ketoacidosis, osmolarity in excess of 320 mOsm/L and blood glucose levels above 600mg/dL (Ortowska et al., 2024).

Question 2

Describe in detail the pathophysiology models of irritable bowel disorder (IBS)

IBS is a bowel disorder characterized by changes in bowel habits and recurrent or chronic abdominal pain (Tang et al., 2021). The pathophysiology of IBS is uncertain. However, sources identify several possible pathophysiology models involving brain-gut interactions, visceral sensation, motility changes, and psychosocial distress (Tang et al., 2021).

The first pathophysiology model involves changes in gut microbiota, which are responsible for protecting the gut’s integrity and immunity (Tang et al., 2021). The mucosal epithelium is responsible for restricting microbes to the intestinal lumen or gut surface, thus maintaining a homeostatic balance to support commensal bacteria (Tang et al., 2021). This ensures the bacteria effectively carry out symbiotic functions and colonize the intestines (Chong et al., 2019). However, attacks by pathogens and other inflammatory mediators on the mucosal epithelium cells compromise the barrier, causing changes in the intestinal environment, which subsequently triggers changes in the composition of gut microbiota (Chong et al., 2019). Alterations in gut microbiota alter the gut’s immunity and integrity, leading to IBS pathogenesis (Chong et al., 2019).

Another pathophysiology model involves changes in gut motility as a result of changes in the structure of gut microbiota. The vagus nerve links the gut to the brain via the gut-brain axis. Altered gut microbiota affect the signals that the gut sends out to the brain, leading to alterations in immune function, microbial balance, nutrient delivery, motility, and secretions (Tang et al., 2021). Ultimately, these alterations lead to IBS symptoms (Tang et al., 2021).

Sources also attribute the pathophysiology of IBS to psychological stress (Tang et al., 2021). Stress stimulates the brain to secrete pro-inflammatory cytokines (Tang et al., 2021). These, in turn, activate the hypothalamic autonomic nervous system (ANS) axes and the hypothalamo-pituitary- adrenal (HPA) axis. This action triggers the release of cortisol, which affects the homeostasis of the gut by stimulating intestinal cells, subsequently giving rise to IBS symptoms (Tang et al., 2021).