Autoimmune Pancreatitis; Causes, Symptoms,Treatment

Autoimmune Pancreatitis

Autoimmune Pancreatitis; Causes, Symptoms,Treatment

Autoimmune Pancreatitis/ Pancreatitis is common and is the leading cause of hospitalization amongst gastrointestinal disorders in the United States. The severity of the disease varies widely, from mild disease needing conservative treatment to severe and complicated disease with high morbidity and mortality. The diagnosis of acute presentation is easy, but the major challenge is predicting the progression of disease course and outcome. This is important to determine the level of care. 

Pancreatitis is a condition characterized by inflammation of the pancreas.[rx] The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones.[rx] There are two main types, acute pancreatitis, and chronic pancreatitis.[rx] Signs and symptoms of pancreatitis include pain in the upper abdomen, nausea, and vomiting.[rx] The pain often goes into the back and is usually severe.[rx] In acute pancreatitis, a fever may occur and symptoms typically resolve in a few days.[rx] In chronic pancreatitis weight loss, fatty stool, and diarrhea may occur.[rx] Complications may include infection, bleeding, diabetes mellitus, or problems with other organs.[rx]

Causes of Autoimmune Pancreatitis

In the majority of cases, alcohol use, gallstones, and hypertriglyceridemia cause acute pancreatitis. The rate of occurrence of each etiology of acute pancreatitis varies across geographic regions and socio-economic strata. Common etiologies of acute pancreatitis are listed below.

  • Alcohol use
  • Gallstones
  • Hypertriglyceridemia
  • Idiopathic
  • Drug-induced pancreatitis
  • Post-procedural (ERCP or abdominal surgery)
  • Ampullary stenosis is formerly known as sphincter of Oddi dysfunction type I
  • Autoimmune pancreatitis, type I (systemic IgG4 disease-related) and type II
  • Viral infection (Coxsackie, Cytomegalovirus, Echovirus, Epstein-Barr virus, Hepatitis A/B/C, HIV, Mumps, Rubella, Varicella)
  • Bacterial infection (Campylobacter jejuni, Legionella, Leptospirosis, Mycobacterium avium, Mycobacterium tuberculosis, Mycoplasma)
  • Trauma
  • Smoking
  • Congenital anomalies (annular pancreas)
  • Genetic disorders (hereditary pancreatitis, cystic fibrosis, alpha 1-antitrypsin deficiency)
  • Hypercalcemia
  • Parasitic infections (Ascaris lumbricoides, Cryptosporidium, Clonorchis sinensis, Microsporidia)
  • Renal disease (Hemodialysis)
  • Toxins (Scorpion bites, organophosphate poisoning)
  • Vasculitis (Polyarteritis nodosa, Systemic lupus erythematosus)

Acute Pancreatitis

There are many potential causes of acute pancreatitis, the two major ones being gallstones and alcohol. The majority of recent studies, detailed in the following section, have employed experimental models of acute pancreatitis to explore the molecular basis of subsequent cellular responses. Recent studies have identified potential mechanisms for several of the common causes of acute pancreatitis.

Bile Acids

  • Exposure of pancreatic acinar cells to bile during biliary acute pancreatitis may contribute to the disease. Many past studies have shown that pathologic increases in acinar cell cytosolic calcium ([Ca2+]i) are linked to the early events in acute pancreatitis.
  • Fischer et al. [] found that bile acids induced pathologic increases in the acinar cell [Ca2+]i through a phosphatidylinositol-3 kinase (PI3K)-dependent mechanism by preventing reuptake of Ca2+ into the endoplasmic reticulum. It was also shown by Barrow et al. [] that bile-mediated Ca2+ responses are enhanced by cellular ATP depletion, suggesting that elevations in bile acids and ischemia may synergize to cause pancreatic injury.

Alcohol

  • Disordered secretion, including inhibition of apical secretion and enhanced basolateral exocytosis, are early features of acute pancreatitis and may be central to disease pathogenesis.
  • Lam et al. [] and Cosen-Binker et al. [,] have now shown that acute ethanol exposure sensitizes the acinar cell to the effects of physiologic concentrations of cholecystokinin (CCK) by causing both inhibitions of apical inhibition and basolateral exocytosis through the same mechanism.

Hypertriglyceridemia

  • The mechanism of hypertriglyceridemic pancreatitis may involve the release of free fatty acids (FFA) through the hydrolysis of triglycerides by pancreatic lipase. Pancreatitis-associated ascitic fluid plays a critical role in acute pancreatitis. Gutierrez et al. [] have now shown ascites to contain high concentrations of oxidized FFA, which interferes with the endogenous regulation of inflammation and may promote macrophage activation in acute pancreatitis.

Hemolysis

  • Clinical evidence suggests that acute pancreatitis can arise as a complication of massive hemolysis; a recent study by Saruc et al. [] supports this hypothesis using an experimental model.
  • Hemolysis induced in rats by intraperitoneal (i.p.) injection of acetylphenylhydrazine (APH) caused increased pancreatic cytokine levels and histological signs of acute pancreatitis. Furthermore, free vascular heme seems to act as the signaling molecule for triggering inflammation, though the mechanism remains undetermined.

Experimental Models of Pancreatitis

  • A limiting feature of the commonly used caerulein-hyperstimulation model of acute pancreatitis is that it causes only mild disease. Several new in-vivo mouse models now generate severe acute pancreatitis.
  • This includes mouse models of acute pancreatitis that use retrograde pancreatic duct infusion of the bile salt, sodium taurocholate by Laukkarinen et al. [], and i.p. injection of L-arginine by Dawra et al. []. These models may prove useful for studying therapeutic interventions and examining disease mechanisms in transgenic mice.

Cellular Responses

  • A series of the acinar cell and inflammatory cell responses underlie the pathogenesis of acute pancreatitis. Some of these have been explored in publications during the last year.

Membrane Permeability

  • One of the earliest events in acute pancreatitis may be the disruption of the acinar cell plasma membrane. Muller et al. [] used both caerulein and taurocholate-induced models of acute pancreatitis in rats to demonstrate that endogenous albumin and immunoglobulin G (IgG) entered acinar cell cytosol.
  • Such defects could contribute to pathologic increases in [Ca2+] and allow cytoplasmic proteins to leak from the cell. It will be of interest to determine how these defects occur, whether they might be related to the plasma membrane blebbing that has been observed in acute pancreatitis or to defects in the complex process of membrane resealing and if such defects are found in human acute pancreatitis.

Zymogen Activation

  • Premature intracellular activation of trypsinogen by the lysosomal hydrolase cathepsin B has generally been considered a pivotal event in the initiation of acute pancreatitis. However, using a cathepsin B inhibitor, CA074Me, Van Acker et al. [] showed that enzyme colocalization and other acute pancreatitis events, such as actin redistribution and inflammation, were cathepsin B independent.
  • Other mechanisms, such as those mediated by [Ca2+]and its protein targets, might mediate these responses. The Ca2+-dependent protein phosphatase calcineurin (PP2B) might serve this role. Husain et al. [] showed that the calcineurin inhibitor FK506 or a cell-permeable calcineurin inhibitory peptide reduced zymogen activation without affecting initial elevations in [Ca2+]or enzyme secretion. Thus, PP2B may be down-stream to the pathologic [Ca2+] that typifies acute pancreatitis. The effects of elevating cAMP on acute pancreatitis are complex, but the most important response might be to enhance the secretion of active enzymes.

Inflammation

  • Two recent studies have focused on the neuropeptide, substance P and its role in pancreatic inflammation. Ramnath et al. [] reported that expression of the substance P gene (preprotachykinin-A, PPT-A) and neurokinin-1 receptor (NK-1R), the primary receptor for substance P, were increased in caerulein-treated mouse pancreatic acinar cells. Furthermore, the messenger hydrogen sulphide was shown to provoke inflammation through a substance P, NK-1R related pathway by Tamizhselvi et al. [].

Endoplasmic reticulum stress

  • Endoplasmic reticulum stress can lead to accumulation of unfolded proteins, initiation of the unfolded protein response (UPR), inflammation and cell death. Kubisch and Logsdon [] reported that stimulation of rat pancreatic acini with three secretagogues, CCK8, CCK-JVM-180 or bombesin, resulted in distinct UPR responses that included increased chaperone BiP levels, PKR-like endoplasmic reticulum kinase (PERK) phosphorylation, X box-binding protein 1 (XBP1) splicing, and CCAAT/enhancer binding protein homologous protein (CHOP) expression.
  • Treatment with caerulein and lipopolysaccharide (LPS), a more severe model of acute pancreatitis, resulted in less expression of inflammation-associated caspases (caspase-11 and caspase-1) in CHOP−/− mice. These studies indicate a pivotal role for the endoplasmic reticulum stress-CHOP pathway in accelerating pancreatitis through induction of inflammation-linked caspases.

Apoptosis

  • The severity of pancreatitis may depend on the mechanism of cell death; greater levels of apoptosis over necrosis favor milder disease. To examine the mechanisms of apoptosis, Baumgartner et al. [] used the oxidative stressor menadione and identified two independent apoptotic pathways in pancreatic acinar cells.
  • The first is the classical caspase-9-mediated pathway that is Ca2+-dependent, mediated by mitochondria and is rapidly initiated. The second is much slower, mediated by caspase-8, depends on the lysosomal activities of cathepsins and is used when the caspase-9 pathway is disabled.
  • This information might be used to develop strategies for shifting cell death pathways to favor apoptosis during acute pancreatitis.
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Protective Mechanisms

  • A number of protective and restorative mechanisms in acute pancreatitis have been characterized over the past year. Singh et al. [] used protease-activated receptor-2 (PAR-2) deficient mice in a caerulein acute pancreatitis model to demonstrate that PAR-2 stimulation caused exocrine secretion, thus protecting acinar cells from the damaging effects of activated enzymes. The study by Bhagat et al. [] explored the protective role played by heat shock proteins (HSPs), particularly HSP 70, using both caerulein and L-arginine models of acute pancreatitis. Sodium arsenite pretreatment was used to upregulate HSP 70 expression and significantly reduced the severity of pancreatitis in both models.
  • The pancreas is a rich source of the polyamine spermidine, and a study by Hyvonen et al. [] showed that depletion of these polyamines led to acute necrotizing pancreatitis. Replacement of depleted polyamines using methylated polyamine analogs prior to induction of acute pancreatitis prevented the development of the disease, strongly supporting an endogenous protective role for these compounds.

Genetic Factors

  • Two studies from the last year have highlighted the importance of genetic factors in predisposing patients to acute pancreatitis []. Gao et al. [] investigated why some patients are more prone to pancreatic infection during acute pancreatitis. LPS or endotoxin may cross leaky paracellular barriers in the colon or be released into the bloodstream by circulating Gram-negative bacteria during acute pancreatitis.
  • LPS can then bind to Toll-like receptors (TLRs) on the surface of the acinar cell, producing a host defense response. However, in some patients, a polymorphism in TLR-4 led to impaired signaling and lack of a defensive response, rendering them more prone to infection.
  • In another genetic study, Chang et al. [] found that mutations on the cystic fibrosis transmembrane conductance regulator (CFTR) predisposed patients with elevated lipids to developing hypertriglyceridemic pancreatitis. Further studies that use newer genome-wide analysis will likely reveal additional genetic factors that affect the risk of developing acute pancreatitis or its severity.

Miscellaneous Mechanisms

  • Ghrelin is a ligand of the growth hormone secretagogue receptor (GHSR) and has been shown to affect exocrine pancreatic secretion. Previous studies have suggested that ghrelin may modulate the severity of acute pancreatitis and that serum ghrelin levels predict severity in acute pancreatitis.
  • Lai et al. [] reported that both ghrelin and its receptor are present in pancreatic acinar cells and that the receptor was downregulated in acute pancreatitis. The data indicate that a ghrelin-dependent system is present in the exocrine pancreas. However, its function in normal pancreatic physiology and pancreatitis requires further study.

Chronic Pancreatitis

Chronic pancreatitis is characterized by chronic inflammation, progressive fibrosis, pain and loss of exocrine and endocrine function. The molecular basis of these responses is addressed by many of the studies detailed in the following section.

Inflammation and Fibrosis

  • Pancreatic stellate cells (PSCs) play a key role in pancreatic fibrosis. Masamune et al. [] reported that the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in PSCs generated reactive oxygen species that modulate their activation and the subsequent deposition of extracellular matrix (ECM), leading to pancreatic fibrosis.
  • Coculture experiments with PSCs and peripheral blood mononuclear cells (PBMCs) reported by Michalski et al. [] demonstrated increased fibronectin secretion from the PBMCs as well as increased levels of IL-6, MCP-1, transforming growth factor (TGF)-β, and ECM from the PSCs. Thus, increased infiltration of mononuclear cells, as seen in chronic pancreatitis, might be a trigger for PSCs to initiate fibrosis and inflammation.

Inflammation and Pain

  • They reported that pain levels in patients with chronic pancreatitis correlated with neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) levels. PBMCs from patients with chronic pancreatitis were more responsive to the effects of PACAP. Xu et al. [] reported that pancreatic hyperalgesia is mediated by upregulation of the transient receptor potential vanilloid 1 (TRPV1) in a model of chronic pancreatitis. As pharmacologic TRPV1 inhibition reduced visceral pain responses in this model, this might be a target for pain treatment in chronic pancreatitis.

Alcohol Use and Chronic Pancreatitis

  • Fortunato et al. [] reported that chronic alcohol exposure in rats increased the pancreatic activity of an anti-inflammatory nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ). Although PPARγ activity was associated with the reduced immune cell and inflammatory responses, damage to acinar cell mitochondria and lysosomes and pericellular fibrosis and protease activation occurred. These results could explain how chronic alcohol use might predispose the pancreas to chronic pancreatitis without causing intense inflammation.

Medications

There are seven classes of medications associated with acute pancreatitis

  • Statins,
  • ACE inhibitors
  • Oral contraceptives/hormone replacement therapy (HRT)
  • Diuretics
  • Antiretroviral therapy
  • Valproic acid, and
  • Oral hypoglycemic agents
  • ACE inhibitors cause angioedema of the pancreas through the accumulation of bradykinin.
  • Oral contraceptives/HRT cause arterial thrombosis of the pancreas through the accumulation of fat (hypertriglyceridemia). Diuretics such as furosemide have a direct toxic effect on the pancreas. Meanwhile, thiazide diuretics cause hypertriglyceridemia and hypercalcemia, where the latter is the risk factor for pancreatic stones.
  • HIV infection itself can cause a person to be more likely to get pancreatitis. Meanwhile, antiretroviral drugs may cause metabolic disturbances such as hyperglycemia and hypercholesterolemia, which predisposes to pancreatitis.
  • Valproic acid may have a direct toxic effect on the pancreas.[rx] There are various oral hypoglycemic agents that contribute to pancreatitis including metformin. But, glucagon-like peptide-1 (GLP-1) is more strongly associated with pancreatitis by promoting inflammation.[rx]
  • Atypical antipsychotics such as clozapine, risperidone, and olanzapine can also cause pancreatitis.[rx]

Infection

A number of infectious agents have been recognized as causes of pancreatitis including:[rx][rx]

Viruses

  • Coxsackievirus
  • Cytomegalovirus
  • Hepatitis B
  • Herpes simplex virus
  • Mumps
  • Varicella-zoster virus

Bacteria

  • Legionella
  • Leptospira
  • Mycoplasma
  • Salmonella

Fungi

  • Aspergillus

Parasites

  • Ascaris
  • Cryptosporidium
  • Toxoplasma

Other

  • Other common causes include trauma, autoimmune disease, high blood calcium, hypothermia, and endoscopic retrograde cholangiopancreatography (ERCP). Pancreas divisum is a common congenital malformation of the pancreas that may underlie some recurrent cases. Diabetes mellitus type 2 is associated with a 2.8-fold higher risk.[rx]
  • Less common causes include pancreatic cancer, pancreatic duct stones,[rx] vasculitis (inflammation of the small blood vessels in the pancreas), and porphyria—particularly acute intermittent porphyria and erythropoietic protoporphyria.
  • There is an inherited form that results in the activation of trypsinogen within the pancreas, leading to autodigestion. Involved genes may include trypsin 1, which codes for trypsinogen, SPINK1, which codes for a trypsin inhibitor, or cystic fibrosis transmembrane conductance regulator.[rx]
  • The mnemonic GETSMASHED is often used to remember the common causes of pancreatitis: G—gallstones, E—ethanol, T—trauma, S—steroids, M—mumps, A—autoimmune pancreatitis, S—scorpion sting, H—hyperlipidemia, hypothermia, hyperparathyroidism, E—endoscopic retrograde cholangiopancreatography, D—drugs (commonly azathioprine, valproic acid, liraglutide)

Symptoms of Autoimmune Pancreatitis

Signs and symptoms of pancreatitis may vary, depending on which type you experience.

Acute pancreatitis signs and symptoms include:

  • Upper abdominal pain
  • Abdominal pain that radiates to your back
  • Abdominal pain that feels worse after eating
  • Upper abdominal pain that radiates into the back; it may be aggravated by eating, especially foods high in fat.
  • Swollen and tender abdomen
  • Nausea and vomiting
  • Fever
  • Increased heart rate
  • Rapid pulse
  • Tenderness when touching the abdomen

Chronic pancreatitis signs and symptoms include

  • Upper abdominal pain
  • Losing weight without trying
  • Oily, smelly stools (steatorrhea)

Diagnosis of Autoimmune Pancreatitis

The differentials for acute pancreatitis include the overall differential for abdominal pain and can often be greatly narrowed with a good history and physical as described above. Differential diagnoses include but is not limited to the following:

  • Peptic ulcer disease
  • Cholangitis
  • Cholecystitis
  • Bowel perforation
  • Bowel obstruction
  • Mesenteric ischemia
  • Acute hepatitis
  • Diabetic ketoacidosis
  • Basilar pneumonia
  • Myocardial infarction
  • Renal colic
  • Aortic dissection

Blood Tests

  • In AP, amylase and lipase are typically elevated, whereas in CP, the serum concentrations of these enzymes are usually normal to mildly elevated due to loss of functional exocrine pancreatic tissue from pancreatic fibrosis [].
  • The white cell count and electrolytes are usually unremarkable, unless diminished intake, vomiting, or digestive insufficiency has occurred. Elevations of serum bilirubin and alkaline phosphatase can occur, which suggests compression of the intrapancreatic portion of the bile duct by edema, fibrosis, or pancreatic cancer [].
  • Transabdominal ultrasound and CT imaging – can be used to detect advanced disease. While ultrasound is relatively inexpensive and free of radiation, its ability to visualize the pancreas is poor compared to other imaging modalities. Multiple echogenic foci representing calcifications are the classic findings seen on ultrasound. These are seen in only up to 40% of patients []. CT imaging has been shown to have sensitivity ranging from 74 to 90% and a specificity of 80–90% in diagnosing advanced CP [].
  • Common findings on CT imaging  – include pancreatic ductal dilatation, parenchymal atrophy, and pancreatic calcifications []. CT imaging is considered to be the best initial imaging test for CP because of its high sensitivity and specificity, and its ability to potentially identify other causes of abdominal pain [].
  • Magnetic resonance cholangiopancreatography (MRCP) and MRI – have also been used to diagnose CP and have the advantage of no radiation exposure. Moreover, MRI has the advantage of detecting both parenchymal and ductal changes []. MRI/MRCP can be combined with hormonal stimulation using intravenous secretin to aid in the diagnosis of early CP with a sensitivity of 77% and specificity of 83% [, ].
  • EUS – has emerged as an important imaging modality to detect early morphologic changes in CP. It can detect mild parenchymal and ductal changes not seen on CT scan and can be used when CT and MR imaging are non-diagnostic [, ].
  • There are nine criteria used in diagnosing CP with EUS – four parenchymal features including hyperechoic foci, hyperechoic strands, lobular contour, and cysts, and five ductal features including main duct dilatation, duct irregularity, hyperechoic margins, visible side branches, and stones [].
  • Endoscopic retrograde cholangiopancreatography (ERCP) – was considered to be the gold standard to detect early changes. However, this procedure is invasive, expensive, and time-consuming. In addition, ERCP can only evaluate for ductal changes. Moreover, given the advent of MRCP and EUS, ERCP has less of a role in diagnosing CP. The most recent guidelines by the American Society for Gastrointestinal Endoscopy (ASGE) in 2006 recommended reserving the use of ERCP for patients in whom the diagnosis is inconclusive despite pancreatic function testing CT/MRI or EUS [].
  • Pancreatic Function Testing – The role of pancreatic function testing is limited based on practicality in comparison with the ease of imaging modalities as previously discussed. However, functional testing can be considered in cases with equivocal morphological imaging []. End-stage CP occurs when more than 90% of exocrine pancreatic function is lost and ultimately leads to pancreatic exocrine insufficiency (PEI) and steatorrhea []. A 72-h quantitative fecal fat determination can be used to diagnose steatorrhea, though it is not specific for CP and can be seen in small bowel mucosal diseases such as celiac disease, Crohn’s disease, and bacterial overgrowth [].
  • Endoscopic transgastric pancreatic necrosectomy – is another alternative that is being increasingly used in select patients with IPN. It involves endoscopic access to the necrotic area through the posterior wall of the stomach. The TENSION trial comparing endoscopic to minimally invasive surgical necrosectomy is currently underway.[] The results of this RCT will determine the role of endoscopic necrosectomy in IPN.
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Treatment of Autoimmune Pancreatitis

  • Analgesics  – are a mainstay of treatment. The WHO method can be used as a guide for pain relief starting with NSAIDs and progressing to strong opioids []. Tricyclic antidepressants such as amitriptyline and nortriptyline can be used with modest efficacy to reduce neuropathic pain []. Pregabalin has been shown to alleviate pain in CP [, ].
  • Pancreatic enzyme replacement therapy (PERT) – can also be used to relieve pain, though the data remain controversial. Those with positive studies used uncoated pancreatic enzymes, which are not readily available [, ] and benefits may be related to the placebo effect. A metaanalysis performed in 1997 showed no significant benefit of PERT to relieve pain []. However, PERT has relatively no side effects and is indicated in patients with exocrine pancreatic insufficiency (EPI) and steatorrhea [].
  • Antioxidant therapy – is another option for the medical management of pain. Braganza et al. proposed that one of the mechanisms of CP is through increased oxidative stress leading to damage of pancreatic and acinar cells []. Current evidence suggests the decreased levels of antioxidants in patients with CP may be due to decrease intake and absorption secondary to pain and malabsorption, respectively []. A recent meta-analysis has shown a reduction in pain symptoms with antioxidants consisting of organic selenium, ascorbic acid, beta-carotene, alpha-tocopherol, and methionine [].
  • Simvastatin and atorvastatin –  were associated with an overall decrease risk in AP. Further subset analysis found a decrease in risk in patients with chronic alcohol abuse, suggesting the possibility of using simvastatin to prevent recurrent pancreatitis and subsequently, CP. A clinical trial is underway to test this possibility entitled “Simvastatin in reducing pancreatitis in patients with recurrent acute or CP” (ClinicalTrials.gov).

Antibiotic Therapy in Acute Pancreatitis

  • Secondary infective complications of acute pancreatitis are associated with increased mortality.
  • The spectrum of microorganisms responsible for infected necrosis is changing. Although Gram-negative aerobic bacteria are commonly yielded in cultures of infected pancreatic necrosis, Gram-positive bacteria, anaerobes, and fungi have also been isolated.
  • Penicillins, first-generation cephalosporins, aminoglycosides, and tetracyclines are ineffective in acute pancreatitis. Antibiotics that are active against Gram-negative bacteria such as imipenem, clindamycin, piperacillin, fluoroquinolones, and metronidazole have adequate tissue penetration and bactericidal properties in infected pancreatic necrosis.
  • Compared with other intravenous antibiotics, carbapenems are associated with a significant reduction in mortality, while the use of imipenem significantly reduced the incidence of infected pancreatic necrosis., Caution should be exercised when interpreting the results of the meta-analyses as the patient numbers are relatively small.,

Fluid Therapy in Acute Pancreatitis

  • The initial management of acute pancreatitis is largely supportive, with fluid replacement and optimization of electrolyte balance, providing adequate caloric support, and preventing or identifying and treating local and systemic complications.
  • The local and systemic inflammatory response in acute pancreatitis results in fluid depletion in the form of vomiting, reduced oral fluid intake, third-space fluid loss, and increased insensible losses in sweat and respiration.
  • Fluid replacement in acute pancreatitis can be undertaken using crystalloid, colloid, or a combination of both. Ringer’s lactate is the preferred crystalloid fluid, but caution should be exercised in hypercalcemic patients. The literary evidence for recommendations for fluid resuscitation has been summarized previously. However, to date, there is no clear agreed consensus regarding the ideal fluid type and regimen for fluid resuscitation.,

Fluid Resuscitation

  • The disease process leads to acinar cell injury and the consequent proinflammatory cytokine cascade leads to microvascular permeability, interstitial edema, vasoconstriction, and eventually decreased capillary perfusion in animal models. Pancreatitis also causes hypovolemia by inducing poor oral intake, insensible losses, third-spacing of fluids, and emesis. Therefore, fluid resuscitation has become the cornerstone of conservative treatment [].
  • In the absence of cardiac, pulmonary, or renal contraindications, various recommendations on the initial fluid resuscitation regimen have varied from 250–500 cc/hr with or without bolus to achieve hemodynamic stability, targeting a mean arterial pressure > 60 or simply targeting a urine output > 0.5 cc/kg/hr [–].
  • While no specific targets are currently recommended, hemodilution (decreased hematocrit), reduced uremia (indicating adequate kidney perfusion), and normalization or maintenance of normal creatinine have been proposed. A practical, evidence-based approach to fluid resuscitation is needed [–].
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Nutrition

  • Current data support the early resumption of a low-fat solid diet with mild acute pancreatitis. While it does not lead to a shorter length of hospital stay or decreased 30-day readmission rate, a randomized trial evaluating the tolerance of a low fat solid meal versus a liquid diet showed no increased adverse events (pain/nausea necessitating cessation) and led to increased caloric intake [].

Role of Endoscopic Retrograde Cholangiopancreatography (ERCP)

  • The role of ERCP in patients with AP is generally reserved for acute biliary pancreatitis secondary to choledocholithiasis. While many scoring systems and algorithms have been developed, the proposed strategy to assign the risk of choledocholithiasis proposed by the American Society for Gastrointestinal Endoscopy is the most widely used.
  • It stratifies predictors of choledocholithiasis into very strong (observed on US, cholangitis or total bilirubin > 4 mg/dL), strong (CBD > 6 mm with gallbladder in situ or total bilirubin between 1.8 and 4 mg/dL), and moderate (abnormal AST/ALT or alkaline phosphatase, clinical gallstone pancreatitis, or age > 55). When a patient has one very strong predictor or two strong predictors, the risk of choledocholithiasis is high. All other predictors are considered intermediate and no qualifying predictors is considered low risk [, ].
  • In patients with mild biliary pancreatitis with improving signs and symptoms, ERCP preceding cholecystectomy has limited value and may be harmful. In these cases, magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) can be used for diagnostic purposes [].

Cholecystectomy

  • Cholecystectomy should be performed on initial hospitalization in patients with acute biliary pancreatitis. A systematic review of 9 studies involving 998 patients with mild biliary pancreatitis showed that early cholecystectomy in the setting of gallstone pancreatitis (i.e., during the index admission) reduced the incidence of recurrent admissions for repeat biliary-related events including pancreatitis, cholecystitis, and biliary colic. Early cholecystectomy was not associated with increased adverse events including mortality nor conversion from a laparoscopic procedure to an open procedure [].

Management of Persistent Fluid Collections or Infected Necrosis

  • We intervene upon pancreatic fluid collection or infected necrosis only when there are significant symptoms present, including persistent abdominal pain, gastric outlet obstruction, fluid leakage due to disconnected pancreatic duct, and infection [].
  • It is crucial to classify fluid collections as either pseudocyst or walled-off pancreatic necrosis because of the differences in prognosis and treatment. CT imaging can underestimate the existence of necrotic debris; therefore, MRI  and endoscopic ultrasound (EUS) are better for assessment [].

 Open Surgical Drainage

  • Open necrosectomy is performed via laparotomy through a subcostal incision, where blunt removal of all necrotic tissue is done []. Early conservative management with late surgical intervention is superior to early necrosectomy []. Surgery is delayed preferably four weeks after onset of disease, as this is thought to allow for time for the acute necrotic collection to mature and demarcate, hereby facilitating necrosectomy [].
  • In a recent randomized control trial, open necrosectomy had a high rate of complications or death (69%) []. Those undergoing open necrosectomy also had a higher rate of long-term complications, including incisional hernias (24%), new onset diabetes (38%), and use of pancreatic enzymes (33%).
  • Therefore, therapy has shifted toward a minimally invasive “step-up” approach. This approach starts with more conservative techniques (percutaneous, laparoscopic, and endoscopic) first and then reserving surgery for cases of salvage therapy [].

Minimally Invasive Techniques

  • There are several different types of noninvasive techniques to drain and debride persistent fluid collections or infected pancreatic necrosis, including image-guided percutaneous drainage, laparoscopy, and retroperitoneoscopy [].
  • Using ultrasound or CT guidance – percutaneous drain placement allows for external access to the area of necrosis to be obtained []. A considerable number of patients can be treated with percutaneous drain (PCD) alone without the need for surgical necrosectomy []. The PANTER trial found that 35% of their patient population undergoing drainage did not need further surgery [].
  • A systematic review by van Baal et al. showed that percutaneous drainage alone was successful in 56% of cases []. In the patients who did need surgery, drain placement delayed operative management for several weeks, by allowing for sepsis control [].
  • Complications of percutaneous drain placement are pancreatic cutaneous and pancreaticoenteric fistulas (most common), as well as procedure-related complications (i.e., bleeding, colonic perforation, abdominal pain, pneumothorax, or catheter dislodgment) [].
  • Transperitoneal laparoscopy is generally not supported because of the technical difficulty and risk of contamination of the peritoneal cavity [].

Endoscopic Techniques in the Management of Persistent Fluid Collections or Infected Necrosis

  • Over the last two decades, endoscopic ultrasound- (EUS-) guided intervention of PFCs and infected necrosis has significantly evolved. There are multiple techniques for the drainage of PFCs including lumen-apposing metal stents (LAMS), direct endoscopic necrosectomy (DEN), and a double-pigtail plastic stent []. The TENSION trial is currently underway and will compare the surgical step-up approach versus an endoscopic step-up approach [].
  • While there are no absolute size guidelines as to when to intervene, encapsulated areas less than 3 cm do not allow placement of a stent for drainage [].

Surgical treatment modalities in necrotizing pancreatitis[]

Surgical treatment modalities
  • Open necrosectomy with open packing – after necrosectomy, the abdomen maybe left open and repeatedly debrided until there is no residual necrosis, and is allowed to close by secondary intention
  • Open necrosectomy with closed packing – after the removal of necrotic tissue, the abdomen is closed, packing with external drains left in place. The drains are removed singly every other day, starting 5-7 d postoperatively
  • Open necrosectomy with continous postoperative lavage – the procedure is based on the insertion of 2 or more double lumen catheters. Repeated open necrosectomy is performed and the packing is removed when there is no residual necrosis. The smaller lumen of the drains is used for the inflow of the lavage, and the larger lumen is used for the outflow. The drains can be removed after 2-3 wk
  • Programmed open necrosectomy – necrosectomy of necrotic tissue is performed using multiple procedures. After necrosectomy, the pancreatic bed is packed with sponges and soft drains are placed on the top of the packs. The abdomen is closed using a zipper

References

Autoimmune Pancreatitis

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