**2.1 Causes and symptoms of chronic pancreatitis**

Chronic Pancreatitis is a fibroinflammatory syndrome of the pancreatic gland histologically characterised by irreversible morphological changes. The evolution towards a picture of Chronic Pancreatitis usually occurs due to recurring episodes of Acute Pancreatitis with permanent organ damage [43, 44]. The use of alcohol and tobacco, as well as the chronic presence of hypercalcaemia and the use of certain drugs, may contribute to the progression of the disease (**Table 12**) [46–49]. Recent studies show the persistence of a chronic inflammation process also in Chronic Pancreatitis (with the involvement of: interleukins 4, 6, 8, 10, 12; tumour necrosis factor


*CFTR, cystic fibrosis transmembrane conductance regulator; CTRC, chymotrypsin C; PRSS1, serine protease 1; PRSS2, serine protease 2; SPINK 1, serine peptidase inhibitor, Kazal type 1; TIGAR-O,Toxic-metabolic, idiopathic, genetic, autoimmune, recurrent, obstructive.*

### **Table 12.**

*Causes of chronic pancreatitis by TIGAR-O classification (LIST 1 - version 2001) [45]).*

[TNF-alfa]; transforming growth factor [TGF-beta]; interferon [IFN-gamma]; macrophage activity; etc.) able to increase the REE [50–52].

The prevailing symptom in over 80% of patients is epigastric pain radiating towards the column or the left upper quadrant of the abdomen [53, 54]. The pain is often postprandial and is accompanied by nausea, vomiting, diarrhoea with or without oily appearance, malodorous faeces and weight loss. However, symptoms may vary and pain might be absent in case the degenerative process affects the nerve endings. On the contrary, persisting pain might manifest in presence of the worst complications of chronic pancreatitis such as fibrosis, diabetes or tumours. A major symptom of this disease is postprandial pain, which induces a progressive reduction of the caloric-protein intake, thus leading to malnutrition, and in severe cases must be treated with opiates. Weight loss could therefore be the combined result of a progressive reduction in food intake and the increase in energy expenditure induced by chronic inflammation. Less frequent causes of chronic pancreatitis are those associated with auto-immune pathologies such as coeliac disease or inflammatory bowel diseases where, however, pain may be absent or masked by intestinal inflammation. In these patients, genetic predisposition to Pancreatitis may be proved, for example, by the presence of variants of the CFTR gene responsible for cystic fibrosis, the Serine Peptidase Inhibitor Kazal Type 1 gene (SPINK1), the Serine Protease 1 gene (PRSS1) and other genes still under study [55].

Another relevant clinical aspect is the delayed gastric emptying, perceived by a high percentage of patients. The causes of this symptom are not clear, especially in patients not undergoing surgery or not taking opioids. In patients undergoing surgery this symptom is believed to be secondary to the resection of the vagus nerve or part of the duodenum [56].

### **2.2 Treatment overview**

The treatment of Chronic Pancreatitis is based on pain control and management of complications. In Chronic Pancreatitis, as well as in Acute Pancreatitis, it is useful to divide the clinical picture into at least three stages: a) clinical picture without complications, caused by recurring episodes of Acute Pancreatitis; b) presence of pain and local complications (pancreatic pseudocysts, calcifications and minimal involvement of adjacent organs); c) end-stage with insufficiency of exocrine and/or endocrine function (**Table 13**).

Typically, these patients will need to implement the enzyme replacement therapy and be gastro-protected with proton pump inhibitors to reduce the denaturation of


### **Table 13.**

*Causes of pancreatic dysfunction.*

pancreatic lipase by stomach acid. The nutritional intervention, which is accompanied by hydro-electrolyte rebalancing, has proved effective not only in the prevention and treatment of malnutrition, but also in reducing the systemic inflammatory process, with reduced complications and improved prognosis of the disease.

## **2.3 Treatment of the endocrine insufficiency**

Over 50% of patients with Chronic Pancreatitis develop Diabetes Mellitus due to mass loss of beta-cells, although Endocrine Insufficiency, which manifests in Chronic Pancreatitis, may have a double aetiology: on the one hand it is secondary to a reduced production of insulin, on the other it could depend on insulin resistance (Pancreatogenic Diabetes, or type 3 Diabetes) [57]. The diagnosis of Diabetes is obviously carried out with the same techniques used in the other types of Diabetes (fasting blood sugar dosage, load curve, C-peptide, dosage of glycosylated haemoglobin). However, the differential diagnosis is carried out by assessing the severity of the pancreatic picture and the the absence of antibodies associated with type 1 diabetes, as well as by detecting pancreatic disease via Imaging. The evaluation of the beta cell reserve function, attained by dosing a fasting C-peptide, is crucial in choosing the best drug. The treatment of patients with Pancreatogenic Diabetes could be more complex than those with type 2 Diabetes due to the concomitant presence of malabsorption, impaired secretion of counter-regulatory hormones and potential lack of compliance in the case of alchol-induced Pancreatopathy. Furthermore, the use of many antidiabetic agents is often contraindicated. There are not randomised clinical trials on hypoglycaemic treatment for diabetes associated with pancreatic disease. In case of preserved beta cell function, metformin is the first choice treatment. Side effects as nausea, weight loss, diarrhoea or the increased risk of lactic acidosis should be carefully assessed and metformin stopped if present. The use of DPP4-inhibitors or GLP1-receptor agonists is not recommended due to the reportedly increased risk of worsening the pancreatic disease.

The use of sulfonylureas as a front-line therapy is not recommended due to both the increased risk of hypoglycaemia and the dependence of intact islet cell function. Also the use of thiazolidinediones is discouraged because of their side effects (weight gain, fluid retention) and their role in increasing the risk of osteoporosis, especially in patients with calcium malabsorption. Given the progressive impairment of insulin secretion, insulin therapy with rapid and basal analogues is frequently required. Insulin therapy should be initiated without delay in case of: symptomatic hyperglycaemia (>180 mg/dl), catabolic state secondary to uncontrolled diabetes, history of diabetic keto-acidosis, hospitalisation for uncontrolled diabetes. Special attention must be paid to the management of hypoglycaemia and the gradual adjustment of insulin dose, as these patients are more likely to be insulin sensitive and to present a loss of counter regulatory hormones. Other important factors are hepatic glycogen storage deficit, carbohydrate malabsorption and malnutrition, inconsistent eating patterns due to pain or nausea, and possibly underlying alcoholic liver disease and enhanced peripheral insulin sensitivity. Diabetic education or glucose self-monitoring and glucagon utilisation should be provided to all patients. A valid alternative to capillary glycaemic control is the use of continuous or flash glucose monitoring. There are currently no studies available comparing glycaemic control in patients with pancreatic disease using self glucose blood monitoring and flash/continuous glucose monitoring. Lifestyle modifications, such as stopping smoking and drinking alcohol, are essential to reduce the risk of recurrence, since alcohol and tobacco smoking contribute to keeping the inflammatory process high, thus favouring the risk of pancreatic cancer and diabetes [58].

### **2.4 Nutritional assessment in chronic pancreatitis**

A reduced exocrine function, especially if under-diagnosed, may on its own induce a state of hypo- or malnutrition, possibly secondary to a malabsorption of macro and micro-nutrients [59]. It is estimated that a picture of pancreatic dysfunction develops in about ten years in patients with potus and in about 20 years in those with idiopathic aetiology and that it is extremely frequent in people with autoimmune diseases. Enteric symptoms (malabsorption, bloating, diarrhoea, steatorrhea, weight loss, abdominal discomfort) are usually present when enzymatic secretion is 10% lower than normal. Since this situation is mainly linked to inadequate lipid digestion, it may result in a malabsorption of fat-soluble vitamins (vit. A: 1–16% of cases; vit. D: 33–87%; vit. E: 2–27%; vit. K: 13–63%), with loss of micro-nutrients and reduction of circulating lipoproteins (**Table 14**) [60]. In Severe Chronic Pancreatitis, the use of parenteral fat-soluble vitamins is absolutely indicated. Much less frequent is the lack of hydro-soluble vitamins with the exception of thiamine (vit. B1), which is often deficient in alcoholics. A shortage of zinc, copper and selenium has also been observed in patients who do not consume alcohol, so the use of specific supplements is recommended by a number of scholars.

The state of chronic inflammation, also variably present in Chronic Pancreatitis, can interfere with the protein synthesis and catabolism by the body. Insufficient levels of pancreatic protease may lead to protein malnutrition and be a cause of vitamin B12 deficiency. The absorption of vitamin D, calcium and folic acid, whose deficiency causes significant changes in the clinical picture, requires a separate discussion. In fact, a picture of osteopathy (osteoporosis, osteomalacia, osteopenia) is present in about a quarter of patients with Chronic Pancreatitis. Vitamin D deficiency, which is often underestimated, may present itself with not clearly defined bone pain and may trigger other diseases (**Table 15**) [61]. However, hyper-secretion of the parathyroid hormone (PTH) may be one of the first signs of vitamin D deficiency. Densitometric studies (dual-energy x-ray absorptiometry) should always be implemented to prevent or monitor any skeletal damage. Exocrine pancreas dysfunction requires a change in lifestyle (e.g. no smoking, no alcohol) and the intake of pancreatic enzymes during meals in order to reduce the effects of malabsorption-induced malnutrition. A supplementation of protein or macro-nutrients should be recommended particularly to patients who reduce their food intake or undertake unbalanced low-calorie and low-protein diets because of pain or fear of pain. Early enzymatic and vitamin supplementation should be associated with careful clinical evaluation over time.


### **Table 14.**

*Dietary sources and functions of fat-soluble vitamins.*


**Table 15.**

*Diseases secondary to vitamin D deficiency.*

**Figure 7** summarises the essential components of an adequate nutritional assessment [62]. If malnutrition develops, the symptoms described in **Table 5**, often blurred, or simply vitamin deficiency signs may be present. Although sarcopenia has been poorly studied in patients with Chronic Pancreatitis, it may, as in neoplastic patients, increase the risk of complications and hospitalisation. An accurate nutritional assessment is therefore always appropriate in patients with Chronic Pancreatitis.
