Acute Pancreatitis

Def dan anatomi + histo

Acute pancreatitis(AP) is an inflammatory process of the pancreas that involves peripancreatic tissues and remote organs

Chronic pancreatitis(CP) is an inflammatory disorder that causes anatomic changes, including infiltration of chronic inflammatory cells and fibrosis of the pancreas.

The endocrine and exocrine portions of the pancreas gland are depicted in Figure 1B. The chief endocrine unit is called the Islets of Langerhan where alfa,beta, and ? cells are present and produce insulin, glucagon, and somatostatin, respectively.

Acinar cells make up the exocrine portion of the gland and are where digestive enzymes are produced.The acinar cells are connected to the pancreatic duct by ductules lined by columnar epithelium that secrete a bicarbonate-rich fluid.

fisio

The digestive enzymes are stored in an inactive precursor form inside zymogen granules within the acinar cells to prevent autodigestion of the pancreas.

When neurohumoral factors stimulate the pancreas to secrete digestive enzymes, the zymogen granules fuse with the apical surface of the acinar cell and are secreted into the ductular system of the pancreas.

Under normal circumstances, enterokinase, a brush border enzyme of the duodenal mucosa, partially digests the pancreatic enzyme trypsinogen and releases trypsin, which is responsible for activating most of the other pancreatic enzymes within the lumen of the small bowel.

Other intracellular granules known as lysosomes contain hydrolytic enzymes that help activate the digestive enzymes (dipisah dari zimogin karena sekresi via golgi)

These granules (lysosomes) are maintained separately within the acinar cell to prevent activation of the digestive enzymes within the substance of the pancreas.

Oxidative stress can also cause activation of trypsinogen

Klasifikasi pankreatitis akut

Acute pancreatitis is an inflammatory process of the pancreas that leads to injury to the acinar cells and surrounding tissues of the exocrine pancreas.

Patients usually present with abdominal pain (epigastric radiate to back) and tenderness and serum elevations of pancreatic enzymes.(3x lipat)

Mild acute pancreatitis, which is manifested by interstitial edema of the gland on computed tomography scan, occurs in 80% of patients requiring hospitalization, associated with minimal or no organ dysfunction and an uneventful recovery.

Severe acute pancreatitis occurs in 20% of patients hospitalized forthis disease and is accompanied by organ failure or local complications such as pancreatic necrosis, abscess, pseudocyst, or acute fluid collections.

Sign of organ failure include shock, pulmonary insufficiency,renal insufficiency, and gastrointestinal bleeding

In summary, patients with severe pancreatitis have a higher level of circulating monocytes, lymphocytes, polymorphonuclear leukocytes, and the cytokines compared with those with a milder form of the disease.7 The onset of cytokine production follows immediately after the onset of pancreatitis and peaks after 36 to 48 hours. This provides a potential therapeutic window for cytokine antagonist therapy and has been a topic of interest for many investigators.

Pathophysiology

The key event in the initiation of acute pancreatitis is acinar cell injury and the subsequent activation of trypsinogen to trypsin that leads to autodigestion of the gland.

Acinar Cell Injury

A number of factors have been implicated in causing injury to the pancreatic acinar cells. Alcohol,trauma, viruses, ischemia, and toxins cause primary acinar cell injury.

This disrupts the physiologic harmony between the lysosomes and zymogen granules that store potentially destructive enzymatic products.

The fusion of lysosomes and zymogen granules and the subsequent premature (intra acinar) activation of trypsinogen lead to the phenomena of autodigestion of the pancreas, causing the enzymes to be activated by acid hydrolases within the lysosome and inducing cell death (crinophagy.)

Another important mechanism of injury is obstruction of the pancreatic duct that leads to impaired bile flow with interstitial accumulation of fluid rich in pancreatic lipase, which can cause fat necrosis and local inflammation via stimulation of resident leukocytes and secretion of inflammatory cytokines.

The resulting interstitial edema impairs blood flow and causes ischemic acinar cell injury.

Autodigestion

The proteolytic enzymes secreted by the acinar cells can digest the pancreas itself, but under normalcircumstances, the pancreas is protected from autodigestion by several mechanisms, which are listed in Table 2.

The first line of defense is the production of the digestive enzymes in an inactive precursor form and storage in zymogen granules.

Examples of these proenzymes include trypsinogen, proelastase, and prophospholipase. These enzymes are normally activated in the intestinal lumen byTrypsin (activated by enterokinase from trypsinogen)

The second line of defense is the synthesis of protease inhibitors (Pancreatic secretory trypsin inhibitor ). Normally, a small amount of trypsin is spontaneously activated in the pancreas and is removed by intrapancreatic defense mechanisms.

The third line of defense is the separation of digestive enzymes from lysosomal hydrolases as they pass through the Golgi apparatus.One of these hydrolases is cathepsin B, which , as a result of failure of this mechanism (due to acinar cell injury), comes in contact with trypsinogen and converts it to trypsin (enzyme co-localization).

Oxidative stress can also cause activation of trypsinogen

This premature activation of trypsin is the major factor in the initiation of injury in acute pancreatitis.

Once activated, trypsin leads to activation of other pancreatic enzymes that are usually activated in the lumen of the intestine.

The damaged cells also release lipase that initially causes localized damage but ultimately leaks out in the surrounding tissues, causing peripancreatic fat necrosis.This chain reaction potentiates the process of autodigestion.

Pleural effusions may be unilateral or bilateral and frequently represent a sympathetic responseto the intra-abdominal inflammatory process. In rare cases, massive pleural effusion results from rupture of the pancreatic duct with extravasation of exocrine secretions which track into the pleural cavity or from rupture of a pseudocyst into the pleural cavity. These two types of pleural fluid collections can be differentiated by the amylase content of the pleural fluid

CAVITAS PERITONEAL Dibagi menjadi bagian atas di dalam abdomen (cavum abdomen) dan bagian bawah yg terletak di dalam pelvis (cavum pelvis)

Pada pengumpulan cairan peritoneal pada recessus subprenicus dapat pindah ke pembuluh limfatik diaphragma, menuju pleura

Untuk hambat absorbsi toksin2 dari infeksi intraperitoneal, pasien dirawat dg posisi duduk dan punggu bentuk sudut 45 derajat, cairan peritoneal yg terinfeksi ditarik gravitasi ke bawah cavitas pelvis dan toksi diabsorbsi lambat

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Pancreatic stellate cells(PaSCs or PSCs) aremyofibroblast-like cells that can switch between the quiescent and activated phenotypes, likehepatic stellate cells.[2]PaSCs reside inexocrineareas of thepancreas. When activated (by cytokines from macrophage), PaSCs migrate to the injured location, and participate in tissue repair activities, secretingECMcomponents. PaSCs may play a role in the pathogenesis ofpancreatitisandpancreatic cancer.[1]

Distant Organ DamageDUE TOSystemic Inflammatory Response Syndrome(SIRS)

Acute pancreatitis can progress from an inflammatory process of the pancreas to one that involves multiple organ systems. The progression to a systemic process is related to the balance between proinflammatory (terutama IL1 dan TNF alfa : vasodilate) factors and those that down-regulate these factors. The most common sites of distant organ failure include the cardiovascular system (BP 500 mL/24hr)

The systemic effects of pancreatitis present clinically as fever, tachycardia, tachypnea, hypovolemia, hypoxia, acute respiratory distress syndrome (ARDS), shock, and ultimately multiorgan failurenote : CC chemokine receptor-1 (CCR-1) receptors have been shown to mediate the pulmonary involvement of pancreatitis

One of the most feared and serious complications of acute pancreatitis is acute respiratory distress syndrome (ARDS).

Activation of the CCR-1 receptor by chemokines9 leads to an increase in alveolar capillary permeability and results in interstitial edema.

ARDS tends to occur between the second and seventh day of illness and presents clinically with dyspnea and progressive hypoxemia.2

Other mechanisms contributing to development of ARDS includemicrovascular thrombosis and digestion of lecithin (a major component of surfactant) by phospholipase A.

Pulmonary parenchymal production of IL-1 and TNF-alfa is also involved in the development of ARDS, both in acute pancreatitis and systemic sepsis

Cardiovascular complications of severe pancreatitis can mimic septic shock, even without any infection.This process is most likely caused by the effects of cytokines that are released by the pancreas.11Vasodilation and capillary leak secondary to vasoactive peptides cause shock and myocardial depression.There is speculation that a circulating myocardial depressant factor contributes to the development of hypotension, although it has neverbeen isolated.11,12 TNF-alfa also contributes toward cardiovascular collapse because it has direct myocardial depressant effects.

Renal and gastrointestinal complications of acute pancreatitis are in part the result of cardiovascular instability.

Diminished blood flow to the kidneys results in acute tubular necrosis, and the decreased blood flow to the gastrointestinal tract results in an ileus secondary to decreased intestinal motility.

Inflammatory mediators are also important, especially in patients who develop renal failure.

Finally, local inflammation can also adversely affect the kidneys and gut, resulting in diminution in organ function.

Patients can develop gastrointestinal bleeding as a result of stress gastropathy, splenic vein thrombosis with esophageal and gastric varices, and pseudoaneurysm formation of the splenic vein.

Metabolic Complications of Acute PancreatitisAcute pancreatitis induces a number of metabolic derangements that are more pronounced with greater degrees of pancreatic injury.

Hyperglycemia, the most common metabolic abnormality seen inacute pancreatitis, is caused by inadequate suppression of glucose production because of elevated concentrations of ACTH and cortisol (due to stress + cytokine) = provide energy and an increase in the ratio of glucagon to insulin.

Protein catabolism of lean tissues is increased so that amino acids are released from the muscles for energy production via gluconeogenesis and for the synthesis of acute-phase proteins and leukocytes.

This is beneficial initially, but prolonged protein breakdown can lead to loss of body cell mass and death.15

Abnormal lipid metabolism leads to hypertriglyceridemia and is caused by many of the same humoral changes associated with hyperglycemia.

Elevated triglyceride concentrations are caused by an increase in lipolysis of adipose tissue that provides fatty acids to fuel the hypermetabolic component of the injury response.15

Hypocalcemia seen in acute pancreatitis is the result of several events that include fat necrosis of the pancreas with subsequent calcium-soap formation (Ca + fat = Ca-soap) (a process also referred to as saponification);

Clinical Aspects of acute pancreatitis

Mild and severe forms of acute pancreatitis do not differ in their initial clinical manifestations.The primary symptom is significant pain, which as a rule is in the upper abdominal region (epigastric),and radiates through to the back.

In contrast to simple biliary colic, the pain increases still further in the first few hours and rapidly brings the patient to the hospital.

The pain syndrome is, however, not pathognomonic (characteristic of a disease that it can be used to make a diagnosis) to allow acute pancreatitis to be differentiated from other disorders.

The primary conditions to be ruled out in the differential diagnosis are acute myocardial infarction, a perforated ulcer, mesenteric infarction, and other inflammatory conditions in the abdominal cavity causing peritonitis

In patients in whom the diagnosis is delayed, extrapancreatic complications may predominate with the abdominal pain having largely resolved

The signs and symptoms most frequently accompanying pain in acute pancreatitis are

fever, nausea, vomiting, and adynamic ileus.

fever in the initial stage of acute pancreatitis is not an expression of a bacterial inflammatory process or even of underlying necrotizing pancreatitis but rather of a systemic process and thus does not represent an automatic indication for antibiotic treatment

Clinical Findings

Typically, the patient is agitated, tachycardic, and often looks ill.

The abdomen is very sensitive to touch and palpation usually reveals an abdomen with moderate guarding which, however, is distinguishable from the board-like rigidity ofclassic peritonitis.

The tenderness (pain or discomfort) is usually most marked in the upper abdomen, but it may also bediffuse.

Complication

Depending on the severity of the inflammation and the inflammatory response in both the pancreas and the peripancreatic region, a spectrum of complications can arise in the pancreas itself and in the adjacent structures.

The most serious complication is necrosis of the pancreatic parenchyma as well as extensive fat necrosis in the peripancreatic retroperitoneum which may extend down to the pelvis and rostrally up to the mediastinum.

Chronic Pancreatitis

Chronic pancreatitis starts with pancreatic injury and is characterized by the loss of endocrine and exocrine function because of destruction of the acinar and islet cells and replacement of the gland by fibrous tissue.

Alcohol consumption is the most common etiology in developed countries.The clinical presentation of chronic pancreatitis correlates with the severity of the histologic abnormalities.

Gejala lebih ke loss of endocrine and exocrine function

The loss of exocrine function leads to Gangguan digesti ( enzim kurang) Gangguang absorbsi (dlm btk makro masih) BB turun Malnutrisi SteatorrheaThese symptoms occur when the secretion of pancreatic enzymes falls below 10%.

The loss of endocrine function presents as glucose intolerance. These presentations (loss of endocrine and exocrine) may occur separately or together.However The acinar cells are usually affected before the islet cells.

Pathogenesis of Chronic Pancreatitis

Several mechanisms have been proposed to describe the pathogenic events that lead to the development of chronic pancreatitis. They include the protein plug, toxic-metabolic, necrosis-fibrosis, and the sentinel acute pancreatitis event theories.

1st theory (batu pankreas)

The protein plug theory suggests that the composition of pancreatic secretions changes as a result ofa decrease in the secretion of volume, water, and bicarbonate, and increased enzymatic and nonenzymaticproteins. (perubahan komposisi sekresi , air dan bikarbonat < enzim dan non enzim protein >= bentuk lebih kental, ngedep bentuk batu duktus pancreaticusThis change makes the pancreatic secretions more viscous and prone to form protein plugs in the small ductules of the pancreas. These protein plugs may calcify and form pancreatic duct stones.19 These stones obstruct the small ductules and lead to intraductal hypertension, ischemia, acinar cell damage, and periductular fibrous tissueformation. These stones are seen in chronic alcoholic, tropical, hereditary, and idiopathic pancreatitis.

2nd thory (direk injury)

The toxic-metabolic theory is based on the premise that alcohol or one of its by-products causes direct injury to the pancreatic acinar or ductal cells.The toxic-metabolites may also cause an indirect effect by altering the function of the acinar cells, creating an imbalance in the proteolytic and protective secretions, thus causing premature activation of trypsin, leading to destruction and ultimately fibrosis.Cigarette smoke has been shown to have direct toxic effects on the pancreatic acinar cells

3rd theory (makrofag )

The necrosis-fibrosis theory suggests that repeated episodes of acute pancreatitis with cellular necrosis leads to fibrosis and development of chronic pancreatitis, due to SAPE hypothesis, which stands for sentinel acutepancreatitis event. Mononuclear cells (macrophage) that releasevtransforming growth factor-beta_ (TGF- beta_) and other cytokines stimulate the stellate cells to produce collagen that leads to fibrosis of the pancreasOverexpression of phospholipase A2 also occurs and leads to the release of prostaglandins and other inflammatory mediators. These mediators have been shown to play an important role in the development of fibrosis and also diminish vascular elasticity.16 Finally, the immune system participates in the pathogenesis of chronic pancreatitis by decreasing the number ofregulatory CD4 cells and increasing the number of cytotoxic CD8 cells in the pancreas

teori 2 dan 3 bs digabung dan paling bener cakny, tapi teori pertama trgtg hasil usg dapet dag batunyo

Teori Pada pankreatitis senile

Chronic ischemia can lead to chronic pancreatitis, as was shown by an experimental induction of ischemia in a canine model.32

Ischemia may be the underlying mechanism in senile chronic pancreatitis, which is associated with atherosclerotic disease and is manifested as pancreatic insufficiency without pain.27

Reduced blood flow may also play a role in both major causes of chronic pancreatitis, alcohol and obstruction

Alcohol also causes vasoconstriction of splanchnic arteries. As a result of these events, it is believed that ischemic injury contributes to the development of pancreatitis after episodes of heavy alcohol consumption.33

Splanchnic Circulation:is the blood supply to the GI tract, liver, spleen and pancreas. An example of two large capillary networks that are partially in series with each other. The small splanchnic arterial branches supply capillary beds in the GI tract, spleen and pancreas. From these capillary beds the blood flows into the hepatic portal vein which supplies most of the blood to the liver. In addition the hepatic artery feeds the liver.

Maldigestion and Malabsorption in Chronic Pancreatitis

A decrease in the secretion of pancreatic enzymes below 10% of normal is required to cause maldigestionand malabsorption.15,17

The decreased bicarbonate secretion fails to neutralize the acidic environment created by the gastric acid, thus leading to reduced enzyme activity.

The lower levels of bicarbonate lead to precipitation of bile acids and reduced micelle formation, which also impairs fat absorption. Gastric emptying can also be affected.Although fat malabsorption is more prominent, there is concomitant impairment of carbohydrate and, to a lesser degree, protein absorption.

These factors can lead to weight loss and deficiency of fat-soluble vitamins (A, D, E, and K). Vitamin B12 deficiency can occur with severe pancreatic insufficiency because R-proteins are not hydrolyzed from vitamin B12, and R-proteins prevent the binding of intrinsic factor to vitamin B12.

Pathophysiology of Pain in Chronic Pancreatitis

Divides the pain of chronic pancreatitis into pancreatic and extrapancreatic causes

Pancreatic causes of pain include increased ductal pressure, local ischemia, fibrosis, pseudocyst formation, inflammation, nerve stimulation, whereas the extra-pancreatic causes of pain include duodenal obstruction, common bile duct stenosis, and maldigestion

Intraductal/interstitial hypertension theory relates the development of increased pancreatic pressures to tissue ischemia.39 Fibrosis of the pancreas decreases the elasticity of the gland and makes it less compliant to conditions that lead to edema and increase in intertitial pressure

Ductal obstruction secondary to strictures or pancreatic calculi with continued exocrine pancreas secretion lead to intraductal hypertension. Both of these events lead to a compartment syndrome that limits blood flow to the pancreas. This can result in ischemia, necrosis, and the development of pain.

Chronic Pancreatitis and the Risk of Pancreatic Adenocarcinoma

Chronic activation of trypsinogen in chronic pancreatitis leads to activation of matrix metalloproteinasematrilysin-7, which is a part of the early events of pathogenesis of pancreatic carcinoma

Chronic pancreatitis may not be the primary or the only factor responsible for the increased risk of pancreatic cancer. It is only one of several mediators that lead to an increase in genetic mutations and chromosomal changes needed for carcinogenesis.

Other carcinogenic factors likely play a role and include cigarette smoking and alcohol intake.