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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 for
this 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 <colocalization> (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 normal
circumstances, 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 by
Trypsin (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


response
to 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

Pancreatic stellate cells (PaSCs or PSCs) are myofibroblast-like cells that can switch between
the quiescent and activated phenotypes, like hepatic stellate cells.[2] PaSCs reside
in exocrine areas of the pancreas. When activated (by cytokines from macrophage), PaSCs
migrate to the injured location, and participate in tissue repair activities,
secreting ECMcomponents. PaSCs may play a role in the pathogenesis
of pancreatitis and pancreatic cancer.[1]

Distant Organ Damage


DUE TO
Systemic 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 downregulate these factors.

The most common sites of distant organ failure include


the cardiovascular system (BP <90),lungs (PO2 <60),
kidneys (creatinin >5), and the gastrointestinal tract
(bleeding > 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 failure
note : 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 include
microvascular thrombosis and digestion of lecithin (a
major component of surfactant) by phospholipase A.
Pulmonary parenchymal production of IL-1 and TNFalfa 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.11
Vasodilation 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 never
been 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 Pancreatitis


Acute pancreatitis induces a number of metabolic
derangements that are more pronounced with greater
degrees of pancreatic injury.
Hyperglycemia, the most common metabolic
abnormality seen in
acute 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 of
classic peritonitis.
The tenderness (pain or discomfort) is usually most marked in the upper abdomen, but it may
also be
diffuse.

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
- Steatorrhea
These 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 of
a decrease in the secretion of volume, water, and bicarbonate, and
increased enzymatic and nonenzymatic
proteins. (perubahan komposisi sekresi , air dan bikarbonat <
enzim dan non enzim protein >= bentuk lebih kental, ngedep
bentuk batu duktus pancreaticus
This 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
tissue
formation. 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
acute
pancreatitis 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 pancreas
Overexpression 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 of
regulatory 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 maldigestion
and 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 metalloproteinase
matrilysin-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.