*2.2.2.1 13C-mixed triglycerides breath test*

The first oral test for fat malabsorption assessment is based on the use of radioactive iodine 131triolein as a substrate. Modern oral tests use non-radioactive substrates the mixed triglyceride test 13C-MTG-breath test, cholesteryl 13C-octanoate, 13C-hyolein and 13C-triolein. Most commonly used and with the most optimal substrate is the only one optimized so far 13C-MTG breath test, which was introduced into clinical practice by Vantrappen et al. in 1989 and develops as a simple alternative to fecal fat quantification. The test directly measures clinically the most significant effect of exocrine pancreatic function: degradation of triglycerides. Following the already explained metabolic pathway of the labeled substrate in oral tests, 13CO2 is released and eliminated together with the exhaled air and measured by near-infrared analysis or mass spectrometry. Patients with PEI have decreased lipase activity, which can be detected by reduced elimination of 13CO2 in the exhaled air. The 13C-MTG breath test sensitivity for PEI verification is higher than 90%. The current mostly adopted and used protocol is the one developed by Domínguez-Muñoz et al. PEI is diagnosed if values are below 29%. The 13C-MTG breath test is an easy, non-invasive and accurate method of PEI diagnosis. The test is easily applicable in clinical practice and can be repeated as often as necessary. It is also used to monitor the enzyme replacement therapy [24, 52–56].

Fecal tests are based on the quantification of pancreatic enzyme concentration (fecal elastase-1) or activity (chymotrypsin) in feces. Enzymes are deactivated and diluted or concentrated during the intestinal passage, which should be taken into account when interpreting the results [24, 35].

#### *2.2.2.2 Fecal chymotrypsin activity*

The test is based on the determination of chymotrypsin activity in a single fecal sample. Fecal chymotrypsin activity lower than 3 U/g is indicative of PEI, but the sensitivity of the test is low. The test is normal in cases of mild CP and in about half of cases with moderate or severe pancreatitis. Significant disadvantages of the test are partial enzyme inactivation during gastrointestinal passage; reduced activity in patients with diarrhea. Quantitative determination of chymotrypsin in feces is an accessible way to assess patient complicity according to the taken replacement therapy as fecal chymotrypsin activity should be significantly increased if oral therapy is administered correctly [24, 35, 57].

**41**

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis*

The protease elastase represents about 6% of the pancreatic enzyme secretion. Determination of Fecal Elastase-1 (FE-1) is the most common PEI screening test as the enzyme is stable during passage through the gastrointestinal tract, its levels correlate with the secreted amount of the pancreas and the direct functional assays. Even though the determination of FE-1 does not offer a significant advantage over other indirect functional tests, its easy conduction makes it a first step pancreatic function screening tool. FE-1 is determined by monoclonal or polyclonal antibodies ELISA tests. The advantage of monoclonal antibody test is its accuracy during enzyme replacement therapy intake. FE-1 concentrations below 200 μg/g feces indicate PEI, and severe PEI is considered if FE-1 is below 100 μg/g (according to some authors below 50 or even 15 μg/g). The specificity of the test is 93%. Diagnostic sensitivity varies between 54 and 63% in mild pancreatic insufficiency and reaches 82–100% in moderate and severe form. Low levels of FE-1 correlate with morphological changes in CP, objectivized by ERCP and MRCP. Determination of FE-1 is very important and useful in children at the age of 2 months with cystic fibrosis. False positive FE-1 results have been reported in the presence of diarrhea, villous atrophy or a strict vegetarian diet prior to testing

The amount of released fat in the feces indirectly reflects the degree of fat digestion and thus the secretion of pancreatic lipase. The steatorrhea-based methods are divided into: qualitative (direct microscopy of Sudan III stained preparations), semiquantitative (steatocrit and semiquantitative determination by Sudan III stain-

A single fecal sample is used for Sudan III staining. The methodology is based on the number and size of fat drops by high-power field (hpf). The accepted normal ranges are the presence of ≤20 fat drops sized 1–4 μm/hpf. Sudan staining has a sensitivity of up to 94% and 95% specificity for the diagnosis of abnormal fat

Steatocrit is a method for semi-quantitative measurement of fats in feces, expressed as a proportion of the fat content of a single centrifuged and homogenized feces sample. The single determination of acid steatocrit (normal values below 10%) has been shown to have 100% sensitivity for steatorrhea detection and

The most reliable and recommended steatorrhea detection method is the 72-h chemical analysis using the van de Kamer method. Many technique modifications have been made so far but still the disadvantages to use large amounts of acids and bases, the manual manipulation of the analysis, the need for additional equipment and specially trained staff remain. However, Near-Infrared Reflectance Analysis (NIRA) methodology, based on the relationship between the intensity of the refractive spectrum of the fecal specimen at a specific wave length and the sample composition, is an alternative, that simplifies and aids application of the study in

The coefficient of fat absorption (CFA) is used for a better steatorrhea characterization. The CFA is calculated by the following equation: CFA (%) = 100 × [(mean fat value − mean fat in feces)/average fat intake]. In healthy people CFA is usually over 80%. The technique has a number of disadvantages, that reduce its everyday applicability—a standard diet containing 80–120 g of fat daily for five consecutive days, collection of entire amount of feces from the last 3 days of the

95% specificity when compared to a 72-h quantitative fat assay [64, 65].

*DOI: http://dx.doi.org/10.5772/intechopen.84738*

*2.2.2.3 Fecal elastase-1*

[24, 35, 57–62].

excretion [35, 63].

clinical practice [24, 66].

*2.2.2.4 Steatorrhea-based methods*

ing) and quantitative (coefficient of fat absorption).

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.84738*

#### *2.2.2.3 Fecal elastase-1*

*Pancreatitis*

classified as oral and fecal tests.

*2.2.2.1 13C-mixed triglycerides breath test*

*2.2.2 Pancreatic exocrine insufficiency assessment by indirect functional tests*

Indirect pancreatic tests are available in clinical practice and are therefore more common. Indirect tests assess pancreatic exocrine function by quantifying pancreatic digestive ability or pancreatic enzyme levels in feces. The sensitivity and specificity of these indirect tests are variable and lower than the direct ones especially in mild and moderate PEI. From a methodological point of view, tests can be

In the oral tests, the substrate is given per os along with test meal. Pancreatic enzymes hydrolyze the substrate in the duodenum, and released metabolites are absorbed from the intestine, metabolized in the liver and therefore they can be measured in serum, urine or exhaled air. Various extrapancreatic causes could limit the accuracy of oral pancreatic tests, mainly by interfering with normal digestion: reduced gastric emptying, biliary secretion and/or intestinal absorption due to intestinal disease. Impaired gastric emptying may be affected by the administration of metoclopramide or another prokinetic (cisapride, domperidone etc.) [24, 35].

The first oral test for fat malabsorption assessment is based on the use of radioactive iodine 131triolein as a substrate. Modern oral tests use non-radioactive substrates the mixed triglyceride test 13C-MTG-breath test, cholesteryl 13C-octanoate, 13C-hyolein and 13C-triolein. Most commonly used and with the most optimal substrate is the only one optimized so far 13C-MTG breath test, which was introduced into clinical practice by Vantrappen et al. in 1989 and develops as a simple alternative to fecal fat quantification. The test directly measures clinically the most significant effect of exocrine pancreatic function: degradation of triglycerides. Following the already explained metabolic pathway of the labeled substrate in oral tests, 13CO2 is released and eliminated together with the exhaled air and measured by near-infrared analysis or mass spectrometry. Patients with PEI have decreased lipase activity, which can be detected by reduced elimination of 13CO2 in the exhaled air. The 13C-MTG breath test sensitivity for PEI verification is higher than 90%. The current mostly adopted and used protocol is the one developed by Domínguez-Muñoz et al. PEI is diagnosed if values are below 29%. The 13C-MTG breath test is an easy, non-invasive and accurate method of PEI diagnosis. The test is easily applicable in clinical practice and can be repeated as often as necessary. It is also

Fecal tests are based on the quantification of pancreatic enzyme concentration (fecal elastase-1) or activity (chymotrypsin) in feces. Enzymes are deactivated and diluted or concentrated during the intestinal passage, which should be taken into

The test is based on the determination of chymotrypsin activity in a single fecal sample. Fecal chymotrypsin activity lower than 3 U/g is indicative of PEI, but the sensitivity of the test is low. The test is normal in cases of mild CP and in about half of cases with moderate or severe pancreatitis. Significant disadvantages of the test are partial enzyme inactivation during gastrointestinal passage; reduced activity in patients with diarrhea. Quantitative determination of chymotrypsin in feces is an accessible way to assess patient complicity according to the taken replacement therapy as fecal chymotrypsin activity should be significantly increased if oral

used to monitor the enzyme replacement therapy [24, 52–56].

account when interpreting the results [24, 35].

therapy is administered correctly [24, 35, 57].

*2.2.2.2 Fecal chymotrypsin activity*

**40**

The protease elastase represents about 6% of the pancreatic enzyme secretion. Determination of Fecal Elastase-1 (FE-1) is the most common PEI screening test as the enzyme is stable during passage through the gastrointestinal tract, its levels correlate with the secreted amount of the pancreas and the direct functional assays. Even though the determination of FE-1 does not offer a significant advantage over other indirect functional tests, its easy conduction makes it a first step pancreatic function screening tool. FE-1 is determined by monoclonal or polyclonal antibodies ELISA tests. The advantage of monoclonal antibody test is its accuracy during enzyme replacement therapy intake. FE-1 concentrations below 200 μg/g feces indicate PEI, and severe PEI is considered if FE-1 is below 100 μg/g (according to some authors below 50 or even 15 μg/g). The specificity of the test is 93%. Diagnostic sensitivity varies between 54 and 63% in mild pancreatic insufficiency and reaches 82–100% in moderate and severe form. Low levels of FE-1 correlate with morphological changes in CP, objectivized by ERCP and MRCP. Determination of FE-1 is very important and useful in children at the age of 2 months with cystic fibrosis. False positive FE-1 results have been reported in the presence of diarrhea, villous atrophy or a strict vegetarian diet prior to testing [24, 35, 57–62].

#### *2.2.2.4 Steatorrhea-based methods*

The amount of released fat in the feces indirectly reflects the degree of fat digestion and thus the secretion of pancreatic lipase. The steatorrhea-based methods are divided into: qualitative (direct microscopy of Sudan III stained preparations), semiquantitative (steatocrit and semiquantitative determination by Sudan III staining) and quantitative (coefficient of fat absorption).

A single fecal sample is used for Sudan III staining. The methodology is based on the number and size of fat drops by high-power field (hpf). The accepted normal ranges are the presence of ≤20 fat drops sized 1–4 μm/hpf. Sudan staining has a sensitivity of up to 94% and 95% specificity for the diagnosis of abnormal fat excretion [35, 63].

Steatocrit is a method for semi-quantitative measurement of fats in feces, expressed as a proportion of the fat content of a single centrifuged and homogenized feces sample. The single determination of acid steatocrit (normal values below 10%) has been shown to have 100% sensitivity for steatorrhea detection and 95% specificity when compared to a 72-h quantitative fat assay [64, 65].

The most reliable and recommended steatorrhea detection method is the 72-h chemical analysis using the van de Kamer method. Many technique modifications have been made so far but still the disadvantages to use large amounts of acids and bases, the manual manipulation of the analysis, the need for additional equipment and specially trained staff remain. However, Near-Infrared Reflectance Analysis (NIRA) methodology, based on the relationship between the intensity of the refractive spectrum of the fecal specimen at a specific wave length and the sample composition, is an alternative, that simplifies and aids application of the study in clinical practice [24, 66].

The coefficient of fat absorption (CFA) is used for a better steatorrhea characterization. The CFA is calculated by the following equation: CFA (%) = 100 × [(mean fat value − mean fat in feces)/average fat intake]. In healthy people CFA is usually over 80%. The technique has a number of disadvantages, that reduce its everyday applicability—a standard diet containing 80–120 g of fat daily for five consecutive days, collection of entire amount of feces from the last 3 days of the

diet, inconvenience during feces storing in laboratories, low specificity (any other cause of maldigestion or malabsorption can lead to abnormal fecal fat excretion) [35, 67, 68].

#### *2.2.2.5 Serum trypsin*

The trypsin test is the only currently functional diagnostic test that can be performed in serum. Low concentrations of less than 20 ng/mL are specific for CP, but are only sensitive to advanced stage of disease. Levels ranged from 20 to 29 are intermediate, but in some cases may point to an early CP. The sensitivity of the method varies with mild and severe stages of the disease and is between 33 and 65% while the specificity is high. Another advantage of trypsin is that levels above 150 ng/mL are indicative of pancreatic inflammation even in the case of normal amylase and lipase levels [69].

## *2.2.3 Evaluation of nutritional status as a PEI marker*

Malnutrition is a major clinical consequence of PEI. Lindkvist et al. studied 114 patients with CP (EUS, MRCP), 33% suffered from PEI according to 13C-MTG breath test. Hemoglobin, albumin, prealbumin and retinol-binding protein (RBP) levels below reference limit, magnesium less than 2.05 mg/dL and HbA1C above the upper reference limit are associated with PEI. A normal panel of these serum nutritional markers excludes PEI with a high negative predictive value. In case of an abnormality, these parameters serve as a marker for initiating PERT. Their followup would indicate the need to adjust the dose of PERT [1, 4, 70].

#### *2.2.4 Pancreatic exocrine insufficiency treatment*

Fundamental aspects of PEI treatment, ensuring an optimal therapeutic effect, include pancreatic enzyme replacement therapy (PERT), smoking and alcohol consumption cessation, frequent small meals with a normal fats intake, fat-soluble vitamins and a systemic follow-up with respect to BMI and nutritional markers. The main aim of PEI treatment is, while compensating the lack of endogenous enzyme secretion including lipolysis, to avoid malabsorption and steatorrhea, decrease complications severity, and prevent the associated with malnutrition morbidity and mortality as well as disease progression [1, 7, 18, 20, 26, 71, 72].

Pancreatic enzyme preparations are extracts of porcine pancreas (pancrelipase or pancreatin) with main components: lipase, amylase, trypsin and chymotrypsin. Their alternatives are bovine enzymes, lipase of mushroom origin, bacterial lipase and human lipase. The pancreatic digestive enzymes in PERT are administered orally together with the meal to ensure the mixing of pancreatin with the humus [1, 7, 11, 18, 26, 27, 71, 73, 74].

Currently, the main formulations of the enzyme preparations are with immediate release, enteric-coated microspheres and minimicrospheres, enteric-coated microtablets and enteric-coated microspheres with bicarbonate buffer. The most widely used enzyme preparations are administered as acid-resistant enteric-coated minimicrospheres with a pH-related release. Currently, none of the approved enzyme supplements are specifically designed for use through percutaneous gastrostomy. In infants and patients who cannot swallow large capsules, opening the capsules in a small amount of acidic foods is an acceptable way to administer the drug [1, 2, 12, 75–77].

Although not systematically studied in clinical trials, based on recommendations from different national associations the starting dose of PERT ranges between

**43**

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis*

20,000 to 50,000 IU lipase per main course and half the dose per snacks, which corresponds to about 5–10% of the cumulative lipase activity in the duodenum after normal meal. PERT is well tolerated with no serious adverse events reported. Fibrosing colonopathy is the only serious complication associated with a high PERT dose. Cases of fibrosing colonopathy have been significantly reduced following the recommendation that PERT should not exceed 10,000 IU lipase/kg/day in patients

Of a great importance is to ensure patient's compliance. If the signs or symptoms of maldigestion persist, the dose of PERT may be increased twice or three times. As e next step for optimal pH release of enzymes and to influence the precipitation of bile acids and prevent lipase degradation, proton pump inhibitors/antacids/H2 blockers/prostaglandin analogs can be added. If PERT results are still insufficient, diagnosis revision is required in respect to concomitant and/or alternative causes for maldigestion (small intestine bacterial overgrowth, biliary salt deficiency, gastric resection, therapy with certain medications (nonsteroidal anti-inflammatory drugs, antacids). Up to 40% of PEI patients with CP have concomitant small intestinal bacterial overgrowth. Import of 35 kcal/kg/day is required as protein intake of 1.0–1.5 g/kg/day is usually sufficient. Small frequent meals (4–8 times/day) are generally more tolerable than high-calorie meals due to the more effective mixing of the enzyme preparations with the humus. In the modern nutritional concept of PEI no fat restrictions are advisable to reduce the risk of weight loss and deficiency of fat-soluble vitamins. In addition, studies show that corresponding substance presence increases the half-life of the enzyme activity in small intestine [1, 5, 6, 18,

Oral, enteral and parenteral nutrition are needed in about 10–15, 5 and 1% of patients respectively, usually in case of disease complications (gastric obstruction) prior to surgery or for a short period of time in patients with advanced exocrine

Alcohol and tobacco cessation are of a great importance as they are associated with development of pancreatic cancer, acute and chronic pancreatitis, deterioration of pancreatic exocrine function as shown by endoscopic functional tests in CP cases. Earlier development of calcified pancreatitis and diabetes mellitus are observed in patients with prolonged smoking. Physical activity and a healthy life style along with nutritional therapy should be encouraged for optimal outcome [1, 7, 20, 27, 90]. Most leading researchers recommend a reassessment of symptoms, BMI and serum malnutrition tests with long-term normalization of vitamin status for determining success of PEI treatment. In recent years, studies have shown widespread nutritional deficiencies (fat-soluble vitamins, prealbumin, retinol-binding protein (RBP), and magnesium) in patients with PEI with or without symptoms, which are associated with many risk factors, including malabsorption, diabetes mellitus and alcoholism. Protein markers prealbumin and RBP correlate with age, BMI, morphological changes, fat-soluble vitamins, albumin, hemoglobin, magnesium. According to the United European Gastroenterology evidence based guidelines for the diagnosis and therapy of CP (HaPanEU), PERT should be initiated in patients with PEI in the presence of clinical symptoms or nutritional deficiencies. By PERT optimization in patients with suboptimal dosage an improvement in the nutritional

Deficiency of vitamins A, D, E, K correlates with the severity of steatorrhea in patients with CP and PEI, but can be caused by various mechanisms, including fat malabsorption, suboptimal nutrition, higher losses or requirements, nutrient depletion, antioxidant activity. Vitamin A, D, E and K deficiency are observed in 3, 53, 10 and 63% of patients (Sikkens et al.) with no clinical manifestations of vitamin E deficiency in up to 75% of CP patients. It has been established that the severity

*DOI: http://dx.doi.org/10.5772/intechopen.84738*

since 1994 [6, 18, 20, 25, 78–82].

20, 25, 27, 73, 83–87].

insufficiency [4, 20, 25, 79, 88, 89].

markers is observed [1, 7, 18, 20, 25, 26, 72, 79, 91–95].

#### *Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.84738*

20,000 to 50,000 IU lipase per main course and half the dose per snacks, which corresponds to about 5–10% of the cumulative lipase activity in the duodenum after normal meal. PERT is well tolerated with no serious adverse events reported. Fibrosing colonopathy is the only serious complication associated with a high PERT dose. Cases of fibrosing colonopathy have been significantly reduced following the recommendation that PERT should not exceed 10,000 IU lipase/kg/day in patients since 1994 [6, 18, 20, 25, 78–82].

Of a great importance is to ensure patient's compliance. If the signs or symptoms of maldigestion persist, the dose of PERT may be increased twice or three times. As e next step for optimal pH release of enzymes and to influence the precipitation of bile acids and prevent lipase degradation, proton pump inhibitors/antacids/H2 blockers/prostaglandin analogs can be added. If PERT results are still insufficient, diagnosis revision is required in respect to concomitant and/or alternative causes for maldigestion (small intestine bacterial overgrowth, biliary salt deficiency, gastric resection, therapy with certain medications (nonsteroidal anti-inflammatory drugs, antacids). Up to 40% of PEI patients with CP have concomitant small intestinal bacterial overgrowth. Import of 35 kcal/kg/day is required as protein intake of 1.0–1.5 g/kg/day is usually sufficient. Small frequent meals (4–8 times/day) are generally more tolerable than high-calorie meals due to the more effective mixing of the enzyme preparations with the humus. In the modern nutritional concept of PEI no fat restrictions are advisable to reduce the risk of weight loss and deficiency of fat-soluble vitamins. In addition, studies show that corresponding substance presence increases the half-life of the enzyme activity in small intestine [1, 5, 6, 18, 20, 25, 27, 73, 83–87].

Oral, enteral and parenteral nutrition are needed in about 10–15, 5 and 1% of patients respectively, usually in case of disease complications (gastric obstruction) prior to surgery or for a short period of time in patients with advanced exocrine insufficiency [4, 20, 25, 79, 88, 89].

Alcohol and tobacco cessation are of a great importance as they are associated with development of pancreatic cancer, acute and chronic pancreatitis, deterioration of pancreatic exocrine function as shown by endoscopic functional tests in CP cases. Earlier development of calcified pancreatitis and diabetes mellitus are observed in patients with prolonged smoking. Physical activity and a healthy life style along with nutritional therapy should be encouraged for optimal outcome [1, 7, 20, 27, 90].

Most leading researchers recommend a reassessment of symptoms, BMI and serum malnutrition tests with long-term normalization of vitamin status for determining success of PEI treatment. In recent years, studies have shown widespread nutritional deficiencies (fat-soluble vitamins, prealbumin, retinol-binding protein (RBP), and magnesium) in patients with PEI with or without symptoms, which are associated with many risk factors, including malabsorption, diabetes mellitus and alcoholism. Protein markers prealbumin and RBP correlate with age, BMI, morphological changes, fat-soluble vitamins, albumin, hemoglobin, magnesium. According to the United European Gastroenterology evidence based guidelines for the diagnosis and therapy of CP (HaPanEU), PERT should be initiated in patients with PEI in the presence of clinical symptoms or nutritional deficiencies. By PERT optimization in patients with suboptimal dosage an improvement in the nutritional markers is observed [1, 7, 18, 20, 25, 26, 72, 79, 91–95].

Deficiency of vitamins A, D, E, K correlates with the severity of steatorrhea in patients with CP and PEI, but can be caused by various mechanisms, including fat malabsorption, suboptimal nutrition, higher losses or requirements, nutrient depletion, antioxidant activity. Vitamin A, D, E and K deficiency are observed in 3, 53, 10 and 63% of patients (Sikkens et al.) with no clinical manifestations of vitamin E deficiency in up to 75% of CP patients. It has been established that the severity

*Pancreatitis*

[35, 67, 68].

*2.2.2.5 Serum trypsin*

amylase and lipase levels [69].

[1, 7, 11, 18, 26, 27, 71, 73, 74].

drug [1, 2, 12, 75–77].

*2.2.3 Evaluation of nutritional status as a PEI marker*

*2.2.4 Pancreatic exocrine insufficiency treatment*

up would indicate the need to adjust the dose of PERT [1, 4, 70].

mortality as well as disease progression [1, 7, 18, 20, 26, 71, 72].

diet, inconvenience during feces storing in laboratories, low specificity (any other cause of maldigestion or malabsorption can lead to abnormal fecal fat excretion)

The trypsin test is the only currently functional diagnostic test that can be performed in serum. Low concentrations of less than 20 ng/mL are specific for CP, but are only sensitive to advanced stage of disease. Levels ranged from 20 to 29 are intermediate, but in some cases may point to an early CP. The sensitivity of the method varies with mild and severe stages of the disease and is between 33 and 65% while the specificity is high. Another advantage of trypsin is that levels above 150 ng/mL are indicative of pancreatic inflammation even in the case of normal

Malnutrition is a major clinical consequence of PEI. Lindkvist et al. studied 114 patients with CP (EUS, MRCP), 33% suffered from PEI according to 13C-MTG breath test. Hemoglobin, albumin, prealbumin and retinol-binding protein (RBP) levels below reference limit, magnesium less than 2.05 mg/dL and HbA1C above the upper reference limit are associated with PEI. A normal panel of these serum nutritional markers excludes PEI with a high negative predictive value. In case of an abnormality, these parameters serve as a marker for initiating PERT. Their follow-

Fundamental aspects of PEI treatment, ensuring an optimal therapeutic effect, include pancreatic enzyme replacement therapy (PERT), smoking and alcohol consumption cessation, frequent small meals with a normal fats intake, fat-soluble vitamins and a systemic follow-up with respect to BMI and nutritional markers. The main aim of PEI treatment is, while compensating the lack of endogenous enzyme secretion including lipolysis, to avoid malabsorption and steatorrhea, decrease complications severity, and prevent the associated with malnutrition morbidity and

Pancreatic enzyme preparations are extracts of porcine pancreas (pancrelipase or pancreatin) with main components: lipase, amylase, trypsin and chymotrypsin. Their alternatives are bovine enzymes, lipase of mushroom origin, bacterial lipase and human lipase. The pancreatic digestive enzymes in PERT are administered orally together with the meal to ensure the mixing of pancreatin with the humus

Currently, the main formulations of the enzyme preparations are with immediate release, enteric-coated microspheres and minimicrospheres, enteric-coated microtablets and enteric-coated microspheres with bicarbonate buffer. The most widely used enzyme preparations are administered as acid-resistant enteric-coated minimicrospheres with a pH-related release. Currently, none of the approved enzyme supplements are specifically designed for use through percutaneous gastrostomy. In infants and patients who cannot swallow large capsules, opening the capsules in a small amount of acidic foods is an acceptable way to administer the

Although not systematically studied in clinical trials, based on recommendations from different national associations the starting dose of PERT ranges between

**42**

of CP (according to the Cambridge classification) correlates with the bone mineral density of the spine and the femoral neck. Patients with CP regardless their exocrine status have more often than expected reduced bone mineral density as shown in a recent meta-analysis: 1 in 4 patients were diagnosed with osteoporosis and 2/3 with osteopathy. Risk factors for fractures include female gender, older patients (the relative risk is higher in younger patients), smoking, alcohol consumption (60–150% greater risk than non-alcoholic CP patients), chronic inflammation, low BMI regardless of bone mineral density. The incidence of fractures after minimal trauma among CP patients is comparable and even higher than in patients with high-risk gastrointestinal diseases (Crohn's disease, cirrhosis, celiac disease, after gastrectomy), for which guidelines for osteoporosis screening exists. The treatment of osteopathy should be carried out in accordance with up-to-date guidelines on the treatment of metabolic bone disease in the general population [2, 14, 16, 27, 28, 59, 65, 96–103].

In addition to bone metabolism, vitamin D is a factor in the development of pancreatic fibrosis and atrophy, cardiovascular and autoimmune diseases, type 1 and 2 diabetes mellitus, and contributes to an increased overall mortality [104, 105].

Due to insufficient protease secretion from the pancreas, vitamin B12 deficiency may occur. Micronutrient deficiencies have been reported as well: zinc (especially in diabetes mellitus), calcium (normal levels in patients receiving PERT), magnesium, thiamine and folic acid, riboflavin, choline, manganese, sulfur, copper and others [106–108].

The assessment of fat-soluble vitamins, minerals and trace elements and bone density should be monitored 1–2 times a year [109].

#### *2.2.5 Cardiovascular risk evaluation*

A recent study observed increased mortality in patients with PEI. Patients who died used to have a worse nutritional status. However, an optimal PERT is essential to reduce morbidity and mortality associated with CP. Maldigestion is associated with life-threatening complications such as cardiovascular, cachexia, which are related to low plasma levels of the cardioprotective HDL, apolipoprotein (apo) A-I and lipoprotein A (2). In a recent study in patients with CP who had not received PERT, mean triglyceride levels were found to be significantly higher in patients with PEI than those without PEI. According to randomized clinical trials, mean levels of cholesterol, HDL, LDL and triglycerides in patients with CP and PEI receiving PERT have been reported in reference ranges. Based on American, European and Canadian guidelines, a complex approach, including screening systems, lipid profile, apolipoproteins, is needed to properly assess cardiovascular risk. Apolipoprotein B as part of all atherogenic or potentially atherogenic particles including LDL, VLDL, IDL, lipoprotein (a) (each particle contains 1 molecule of apo B) provides direct measurement of all atherogenic lipoprotein particles in the circulation, which makes apo B more reliable indicator of cardiovascular risk than LDL. Clinical and epidemiological studies confirm that apo B and Apo B/ Apo A-I ratio are associated with a worse outcome in patients with cardiovascular diseases and are supposed to predict cardiovascular incidents more accurately than the routinely tested cholesterol, LDL, TC/HDL, non-HDL. The proposed cut-off values for Apo B/ApoA-I ratio predicting high cardiovascular risk (acute myocardial infarction) are 0.9 for men and 0.8 for women. In patients with Apo B/ApoA-I ratio higher than 0.9, higher triglyceride levels and plasma atherogenic index and lower apo E were found. A study demonstrates an increased risk of myocardial infarction using Apo B/Apo A-I ratio in patients with CP [1, 5, 7, 79, 89, 110–131].

**45**

132–137].

*Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis*

In respect to its etiology, the diabetes mellitus (DM), which is caused by pancreatic diseases, is defined by the American Diabetes Association (ADA) and World Health Organization as pancreatogenic diabetes or Type 3c DM and is included in "other specific forms of diabetes" (ADA). About 5–10% of all diabetic patients in Western populations fulfill the criteria for pancreatogenic DM, of which circa 80% have underlying CP. The prevalence and clinical significance of DM secondary to CP has been recently underestimated. The median survival is 8.7 years after diagnosing type 3c DM. Chronic pancreatitis and DM are independent risk factors for pancreatic cancer development. While the presence of anti-insulin antibodies and clinical or biochemical data on insulin resistance are associated with type 1 and 2 DM respectively, the pathogenesis of type 3c DM is very complex. According to the recommendations of Rickels MR et al. from the Pancreas Fest 2012, the following criteria for the diagnosis of type 3c DM were proposed. Major criteria (all must be fulfilled): (1) Pancreatic exocrine insufficiency. (2) Pathological pancreas imaging (EUS, MRI, CT). (3) Lack of type 1 DM associated with the presence of autoantibodies. Minor criteria: (1) Impaired beta-cell function (HOMA-B, C-peptide/glucose ratio). (2) Lack of insulin resistance (HOMA-IR). (3) Invasive secretion disorder (GLP-1, pancreatic polypeptide). (4) Low levels of serum fat-soluble vitamins (A, D, E, K). Because of loss of glucagon response to hypoglycemia and low carbohydrate levels (malabsorption; inadequate food intake due to pain, nausea and/or chronic alcohol abuse), patients with type 3c DM may experience frequent episodes of hypoglycemia, making the glucose control challenging. The course of the disease is further complicated by the presence of comorbidities such as maldigestion and accompanying malnutrition. Metformin, which is recommend as first-line treatment for type 2 DM by ADA and EASD, has been shown to reduce the risk of pancreatic cancer by 70% and the associated mortality, making metformin suitable therapeutic option for type 3c DM patients. The associated with an increased risk of developing pancreatitis as well as numerous gastrointestinal side effects (nausea, delayed gastric emptying, weight loss) GLP-1 analogues and DPP4-inhibitors should be avoided as long as their safety and benefits are proven. Impaired incretin hormone secretion can be normalized by supplementation with pancreatic enzymes, which is reflected

Apolipoprotein A, which is the main apolipoprotein associated with HDL, has two forms—apo A-I and apo A-II. The levels of apolipoprotein A-I are strongly related to those of HDL and can serve for plasma HDL level determination. In a recent study, an impaired nutritional status with decreased prealbumin, RBP, hemoglobin, magnesium has been found to significantly relate to low apoA-I and apoA-II levels with a tendency of increased apo B/apo A-I ratio, which does not reach a significant value. Apolipoprotein C-III inhibits the lipolysis of triglyceriderich lipoproteins and complicates their elimination from the bloodstream. High levels of apolipoprotein C-III are associated with an increased risk of cardiovascular events and atherogenesis. Lower apolipoprotein C-III levels are observed by morphological changes worsening in CP. The metabolic and inflammatory status in patients with CP can be traced with great accuracy by examining a protein panel of retinol binding protein, serum amyloid-alpha, Apo A-II, Apo A-I, Apo C-I, Apo C-II, Apo C-III and prealbumin, which are significantly more reduced than the controls (Hartmann et al.). The observed changes may be associated with underlying malnutrition/cachexia, which phenomena are known in the modulation of the synthesis of acute phase proteins in acute or chronic disease [112, 119, 127, 128, 130,

*DOI: http://dx.doi.org/10.5772/intechopen.84738*

**2.3 Pancreatic endocrine insufficiency**

#### *Up-To-Date View on the Clinical Manifestations and Complications of Chronic Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.84738*

Apolipoprotein A, which is the main apolipoprotein associated with HDL, has two forms—apo A-I and apo A-II. The levels of apolipoprotein A-I are strongly related to those of HDL and can serve for plasma HDL level determination. In a recent study, an impaired nutritional status with decreased prealbumin, RBP, hemoglobin, magnesium has been found to significantly relate to low apoA-I and apoA-II levels with a tendency of increased apo B/apo A-I ratio, which does not reach a significant value. Apolipoprotein C-III inhibits the lipolysis of triglyceriderich lipoproteins and complicates their elimination from the bloodstream. High levels of apolipoprotein C-III are associated with an increased risk of cardiovascular events and atherogenesis. Lower apolipoprotein C-III levels are observed by morphological changes worsening in CP. The metabolic and inflammatory status in patients with CP can be traced with great accuracy by examining a protein panel of retinol binding protein, serum amyloid-alpha, Apo A-II, Apo A-I, Apo C-I, Apo C-II, Apo C-III and prealbumin, which are significantly more reduced than the controls (Hartmann et al.). The observed changes may be associated with underlying malnutrition/cachexia, which phenomena are known in the modulation of the synthesis of acute phase proteins in acute or chronic disease [112, 119, 127, 128, 130, 132–137].

### **2.3 Pancreatic endocrine insufficiency**

*Pancreatitis*

65, 96–103].

[106–108].

of CP (according to the Cambridge classification) correlates with the bone mineral density of the spine and the femoral neck. Patients with CP regardless their exocrine status have more often than expected reduced bone mineral density as shown in a recent meta-analysis: 1 in 4 patients were diagnosed with osteoporosis and 2/3 with osteopathy. Risk factors for fractures include female gender, older patients (the relative risk is higher in younger patients), smoking, alcohol consumption (60–150% greater risk than non-alcoholic CP patients), chronic inflammation, low BMI regardless of bone mineral density. The incidence of fractures after minimal trauma among CP patients is comparable and even higher than in patients with high-risk gastrointestinal diseases (Crohn's disease, cirrhosis, celiac disease, after gastrectomy), for which guidelines for osteoporosis screening exists. The treatment of osteopathy should be carried out in accordance with up-to-date guidelines on the treatment of metabolic bone disease in the general population [2, 14, 16, 27, 28, 59,

In addition to bone metabolism, vitamin D is a factor in the development of pancreatic fibrosis and atrophy, cardiovascular and autoimmune diseases, type 1 and 2 diabetes mellitus, and contributes to an increased overall mortality [104, 105]. Due to insufficient protease secretion from the pancreas, vitamin B12 deficiency may occur. Micronutrient deficiencies have been reported as well: zinc (especially in diabetes mellitus), calcium (normal levels in patients receiving PERT), magnesium, thiamine and folic acid, riboflavin, choline, manganese, sulfur, copper and others

The assessment of fat-soluble vitamins, minerals and trace elements and bone

A recent study observed increased mortality in patients with PEI. Patients who died used to have a worse nutritional status. However, an optimal PERT is essential to reduce morbidity and mortality associated with CP. Maldigestion is associated with life-threatening complications such as cardiovascular, cachexia, which are related to low plasma levels of the cardioprotective HDL, apolipoprotein (apo) A-I and lipoprotein A (2). In a recent study in patients with CP who had not received PERT, mean triglyceride levels were found to be significantly higher in patients with PEI than those without PEI. According to randomized clinical trials, mean levels of cholesterol, HDL, LDL and triglycerides in patients with CP and PEI receiving PERT have been reported in reference ranges. Based on American, European and Canadian guidelines, a complex approach, including screening systems, lipid profile, apolipoproteins, is needed to properly assess cardiovascular risk. Apolipoprotein B as part of all atherogenic or potentially atherogenic particles including LDL, VLDL, IDL, lipoprotein (a) (each particle contains 1 molecule of apo B) provides direct measurement of all atherogenic lipoprotein particles in the circulation, which makes apo B more reliable indicator of cardiovascular risk than LDL. Clinical and epidemiological studies confirm that apo B and Apo B/ Apo A-I ratio are associated with a worse outcome in patients with cardiovascular diseases and are supposed to predict cardiovascular incidents more accurately than the routinely tested cholesterol, LDL, TC/HDL, non-HDL. The proposed cut-off values for Apo B/ApoA-I ratio predicting high cardiovascular risk (acute myocardial infarction) are 0.9 for men and 0.8 for women. In patients with Apo B/ApoA-I ratio higher than 0.9, higher triglyceride levels and plasma atherogenic index and lower apo E were found. A study demonstrates an increased risk of myocardial infarction using Apo B/Apo A-I ratio in patients with CP [1, 5, 7, 79,

density should be monitored 1–2 times a year [109].

*2.2.5 Cardiovascular risk evaluation*

**44**

89, 110–131].

In respect to its etiology, the diabetes mellitus (DM), which is caused by pancreatic diseases, is defined by the American Diabetes Association (ADA) and World Health Organization as pancreatogenic diabetes or Type 3c DM and is included in "other specific forms of diabetes" (ADA). About 5–10% of all diabetic patients in Western populations fulfill the criteria for pancreatogenic DM, of which circa 80% have underlying CP. The prevalence and clinical significance of DM secondary to CP has been recently underestimated. The median survival is 8.7 years after diagnosing type 3c DM. Chronic pancreatitis and DM are independent risk factors for pancreatic cancer development. While the presence of anti-insulin antibodies and clinical or biochemical data on insulin resistance are associated with type 1 and 2 DM respectively, the pathogenesis of type 3c DM is very complex. According to the recommendations of Rickels MR et al. from the Pancreas Fest 2012, the following criteria for the diagnosis of type 3c DM were proposed. Major criteria (all must be fulfilled): (1) Pancreatic exocrine insufficiency. (2) Pathological pancreas imaging (EUS, MRI, CT). (3) Lack of type 1 DM associated with the presence of autoantibodies. Minor criteria: (1) Impaired beta-cell function (HOMA-B, C-peptide/glucose ratio). (2) Lack of insulin resistance (HOMA-IR). (3) Invasive secretion disorder (GLP-1, pancreatic polypeptide). (4) Low levels of serum fat-soluble vitamins (A, D, E, K). Because of loss of glucagon response to hypoglycemia and low carbohydrate levels (malabsorption; inadequate food intake due to pain, nausea and/or chronic alcohol abuse), patients with type 3c DM may experience frequent episodes of hypoglycemia, making the glucose control challenging. The course of the disease is further complicated by the presence of comorbidities such as maldigestion and accompanying malnutrition. Metformin, which is recommend as first-line treatment for type 2 DM by ADA and EASD, has been shown to reduce the risk of pancreatic cancer by 70% and the associated mortality, making metformin suitable therapeutic option for type 3c DM patients. The associated with an increased risk of developing pancreatitis as well as numerous gastrointestinal side effects (nausea, delayed gastric emptying, weight loss) GLP-1 analogues and DPP4-inhibitors should be avoided as long as their safety and benefits are proven. Impaired incretin hormone secretion can be normalized by supplementation with pancreatic enzymes, which is reflected

#### *Pancreatitis*

in improved insulin secretion and glucose tolerance during meals. Adequate oral enzyme replacement affects steatorrhea, prevents malnutrition and metabolic complications. In patients with severe malnutrition, insulin therapy is a first-line of choice because of the anabolic effect of insulin. The association of low levels of vitamin D and poor glycemic control draws attention to the need to normalize vitamin status in patients with type 3c DM. Diagnosis and monitoring of DM should be consistent with the endocrinology societies guidelines. Annually screening for type 3c DM by fasting glucose and HbA1c is of a great importance in patients with CP regardless the grade of pathological structural changes [18, 20, 25, 31, 32, 122, 138–143].
