**4. Exocrine pancreatic insufficiency & fat malabsorption**

As previously described, the pancreas functions as the main factory for the digestive enzymes. The gland produces pancreatic juice that consists of a mixture of more than two dozen digestive enzymes in the pre-activated form, called zymogens. Zymogens are produced by acinar cells and mixed with a bicarbonate rich fluid that is produced by pancreatic ducts cells (Whitcomb & Lowe, 2007). Trypsin, chymotrypsin, amylase and lipase are responsible for the majority of the enzyme activity derived from the pancreas (Whitcomb & Lowe, 2007). Lipase is one of the most important enzymes because it plays a leading role in the digestion of fat, which is the highest dietary source of calories.

Pancreatic exocrine insufficiency, partial or complete loss of digestive enzyme synthesis, occurs primarily in disorders directly affecting pancreatic tissue integrity (Table 3).

Table 3. Conditions Causing EPI (adapted from Keller et al., 2009).

Emerging Approaches for the Treatment of

**4.3 Incidence and diagnosis** 

independent of life style factors (Gullo & al., 1996).

Fat Malabsorption due to Exocrine Pancreatic Insufficiency 279

nutrients may lead to tetany, glossitis, cheilosis, and in a more progressive stage, to peripheral neuropathy (Dimagno , 1993). Patients with PEI may exhibit low vitamin D levels and develop osteopathy, i.e. osteopenia, osteoporosis and osteomalacia. There are reports on vitamin A deficiency causing night-blindness, visual impairment and other ocular affections. As a consequence of vitamin E and K deficiencies neurologic symptoms or coagulopathy can occur (Keller & al., 2009). There seems also to be an increased risk for cardiovascular events in PEI,

The prevalence of EPI is increasing with the higher proportion of patients with cystic fibrosis who survive into adult life and the incidence of chronic pancreatitis, which rises in parallel with alcohol consumption. In fact, the incidence of cystic fibrosis is approximately 1 in 2500 live births. The lack of chloride secretion in the pancreatic duct is responsible for severe exocrine pancreatic insufficiency in approximately 85% of CF newborns (Levy, 2011). In case of chronic pancreatitis, an incidence of 8.2 per 100 000 population per year and a prevalence of 26.4 cases per 100 000 along with a 3.6-fold increase in mortality in patients with alcohol-induced chronic pancreatitis compared with a population without chronic pancreatitis has been signaled (Keller & al., 2009). Hence, to avoid malnutrition related

morbidity and mortality, it is pivotal to start treatment as soon as EPI is diagnosed.

**5. Standard approaches for the treatment of fat malabsorption due to** 

The main focus in the management of EPI is to prevent weight loss, EPI related symptoms, vitamin deficiencies, and to improve the patient's nutritional status. Whatever the aetiology, oral pancreatic enzyme supplements are widely used as the first-line approach to treat malabsorption secondary to exocrine pancreatic insufficiency (Breithaupt & al., 2007).

Pancreatic enzyme preparations (PEPs) are typically a mixture of porcine-derived pancreatic enzymes. These preparations, also called pancreatin, contain a variable mixture of protease, lipase and amylase depending on the brand. Various preparations are commercially available. The main formulations are immediate-release, enteric-coated microspheres and minimicrospheres, enteric-coated microtablets and enteric-coated microspheres with a bicarbonate buffer (Table 4). A Comprehensive table of these preparations has been

summarized in other reviews (Krishnamurty & al., 2009, Ferrone & al., 2007).

are not widely established, yet (Dominguez-Munoz & al., 2007).

**exocrine pancreatic insufficiency** 

**5.1 Formulations and galenic properties** 

Several direct and indirect function tests are available for assessment of pancreatic function. Direct invasive function tests like the secretin-caerulein test are still the gold standard with highest sensitivity and specificity. However, their availability is limited to specialized centers, they are costly, time consuming and uncomfortable for the patient (Keller & al., 2009). Determination of fecal elastase is convenient and widely available but its sensitivity is low in mild to moderate cases. Moreover, due to low specificity, it is of limited value for differential diagnosis in patients with diarrhea (Dominguez-Munoz & al., 1995; Stein & al., 1996). Other non-invasive tests such as 13C-breath tests are becoming more important but

It is most frequently due to chronic pancreatitis (in adults) or cystic fibrosis (in children) (Keller & al., 2009). Other pancreatic causes include acute pancreatitis, pancreatic tumors and pancreatic surgery (Table 3).

While protein and starch digestion are usually maintained at a normal physiological level even in severe cases of pancreatic insufficiency, lipid malabsorption becomes the overriding problem and causes many of the clinical symptoms and nutritional deficiencies.

#### **4.1 Pathophysiology**

Clinically evident EPI occurs only when 90% of the function is lost and the secretion of pancreatic enzymes is less than 10% of normal (Lankisch & al., 1986; Layer & al., 1986). In chronic pancreatitis, an earlier decrease of lipase secretion is observed in comparison with amylase and protease. This is due to higher susceptibility of lipase to acidic pH caused by concomitant impairment of bicarbonate secretion, higher susceptibility of lipase to proteolytic destruction during small intestinal transit, additional acidic denaturation of bile acids and marked inhibition of bile acid secretion in malabsorptive states (Keller & Layer, 2005). Hence, in case of EPI, fat malabsorption precedes malabsorption of proteins and carbohydrates and is clinically more apparent. Additionally, due to the low bicarbonate secretion, the intraduodenal pH may drop below 4 late postprandially, bile salts may precipitate which leads to a decrease in post- prandial duodenal lipid solubilisation and contribute to impaired lipolysis (Zentler-Munro & al., 1984). The increased presence of lipids and other nutrients in the distal small bowel causes significant alterations in gut motility leading to accelerated gastric emptying and intestinal transit. This results in a marked decrease in the time available for digestion and absorption of nutrients, which also contributes to the malabsorption (Layer & al. 1997). However, more than 80% of carbohydrates can be digested and absorbed in the absence of pancreatic amylase activity and the colonic flora can further metabolizes malabsorbed carbohydrates (Layer & al., 1986). By contrast, gastric lipase, the only extrapancreatic source of lipolytic activity in humans, does not compensate efficiently for pancreatic lipase deficiency although it may be elevated in patients with chronic pancreatitis compared to healthy individuals (Carrière & al., 1993b). That's why fat malabsorption remains the first problem to be considered when treating EPI.

#### **4.2 Clinical symptoms and complications**

Maldigestion of fat results in steatorrhoea. In western countries steatorrhoea is diagnosed when daily stool fat content exceeds 7 g during ingestion of a diet containing 100 g fat per day. This corresponds to a decrease of the enteral absorption rate to less than 93% (Dimagno & al., 1973). Steatorrhoea causes symptoms such as foul-smelling, voluminous, greyish, fatty stools, abdominal cramps, bloating and chronic abdominal pain (Pasquali & al., 1996). It may also cause weight loss due to the loss of the highest dietary source of calories (fat contains 38 kJ/g, carbohydrates and protein contain 17 kJ/g) (Rosenlund & al., 1974). Steatorrhoea and weight loss are the overt clinical symptoms of EPI. They usually only occur if pancreatic enzyme secretion falls below 5–10% of normal levels (Keller & al., 2009).

Due to fat malabsorption fat-soluble vitamins (A, D, E and K), magnesium, calcium and essential fatty and amino–acids are insufficiently resorbed (Dutta & al., 1982; Keller & al., 2009) which results in a variety of associated complications. Deficiencies in these vitamins and nutrients may lead to tetany, glossitis, cheilosis, and in a more progressive stage, to peripheral neuropathy (Dimagno , 1993). Patients with PEI may exhibit low vitamin D levels and develop osteopathy, i.e. osteopenia, osteoporosis and osteomalacia. There are reports on vitamin A deficiency causing night-blindness, visual impairment and other ocular affections. As a consequence of vitamin E and K deficiencies neurologic symptoms or coagulopathy can occur (Keller & al., 2009). There seems also to be an increased risk for cardiovascular events in PEI, independent of life style factors (Gullo & al., 1996).
