Autoimmune Pancreatitis – Causes, Symptoms, Treatment

Autoimmune pancreatitis (AIP) is a distinct, infrequent, progressive inflammatory, gastrointestinal disorders that lead to irreversible destruction of exocrine and endocrine pancreatic parenchyma caused by atrophy and/ or replacement with fibrotic tissue with a form of pancreatitis in children with a poorly understood pathophysiology with a systemic autoimmune condition that involves not only the pancreas but also a variety of other organs such as the bile duct[], the retroperitoneum[], and lymph nodes[]. AIP is also known by other names including lymphoplasmacytic sclerosing pancreatitis with cholangitis, idiopathic duct destructive pancreatitis, primary inflammatory pancreatitis, non-alcoholic duct destructive chronic pancreatitis, tumefactive pancreatitis, and destructive pancreatitis depending on the specific tissue changes found on biopsy or the predominant and accompanying symptoms.

Autoimmune pancreatitis (AIP) is a chronic inflammation identified by a distributed abnormal contraction of the main pancreatic duct, distributed expansion of the pancreas, antibodies, raised levels of serum gamma globulin or IgG, pancreas fibrosis, and critical lymphoplasmacytic infiltration [rxrx].

Types of Autoimmune Pancreatitis

  • Type 1[lymphoplasmacytic sclerosing pancreatitis (LPSP)] and
  • Type 2 [idiopathic duct-centric pancreatitis (IDCP) or AIP with a granulocytic epithelial lesion (GEL)].

Causes of Autoimmune Pancreatitis

Causes of chronic pancreatitis include alcohol abuse, ductal obstruction (malignancy, stones, trauma), genetics (cystic fibrosis, hereditary pancreatitis), chemotherapy, and autoimmune diseases such as systemic lupus erythematosus (SLE) or autoimmune pancreatitis. New studies are finding that deficiencies in certain vitamins and antioxidants may be linked to the disease.

The most common cause is alcohol consumption. The alcohol increase secretion of proteins from acinar cells, causing the fluid to become viscous, leading to ductal obstruction, acinar fibrosis, and atrophy. Fortunately, less than 10% of alcoholics develop. In chronic pancreatitis, suggesting that other mechanisms play a role in the pathology.

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
  • Peptic ulcer disease
  • Cholangitis
  • Cholecystitis
  • Bowel perforation
  • Bowel obstruction
  • Mesenteric ischemia
  • Acute hepatitis
  • Diabetic ketoacidosis
  • Basilar pneumonia
  • Myocardial infarction
  • Renal colic
  • Aortic dissection
  • 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)
  • Hypercalcemia
  • Hyperlipidemia (usually types 1 and V)
  • Nutrition
  • Obstruction of the duct (either congenital or acquired)
  • Medications

Symptoms of Autoimmune Pancreatitis

  • Jaundice (>60%)
  • Abdominal Pain (>30%)
  • Dark urine
  • Pale stools or stools that float in the toilet
  • Yellow skin and eyes (jaundice)
  • Pain in your upper abdomen or middle part of your back
  • Nausea and vomiting
  • Weakness or extreme tiredness
  • Loss of appetite or feelings of fullness
  • Weight loss for no known reason
  • Prolonged abdominal pain with intermittent pain-free periods,
  • Weight loss, and relief of abdominal pain when leaning forward.
  • Nausea, vomiting, and steatorrhea or greasy, foul-smelling, difficult-to-flush stools can also occur.

AIP is characterized by the following features

  • Scleral Icterus (yellow eyes), jaundice (yellow skin) which is usually painless, usually without acute attacks of pancreatitis.
  • Relatively mild symptoms, such as minimal weight loss or nausea.
  • Increased serum levels of gamma globulins, immunoglobulin G (IgG) or IgG4.
  • The presence of serum autoantibodies such as anti-nuclear antibody (ANA), anti-lactoferrin antibody, anti-carbonic anhydrase II antibody, and rheumatoid factor (RF).
  • Contrast-enhanced CT demonstrates a diffusely enlarged (sausage-shaped) pancreas.
  • Diffuse irregular narrowing of the main pancreatic duct, and stenosis of the intrapancreatic bile duct on endoscopic retrograde cholangiopancreatography (ERCP).
  • Rare pancreatic calcification or cyst formation.
  • Marked responsiveness to treatment with corticosteroids.

Diagnosis of Autoimmune Pancreatitis

Basic lab studies for chronic pancreatitis can include a CBC, BMP, LFTs, lipase, amylase, lipid panel, and a fecal-elastase-1 value. Lipase and amylase levels can be elevated, but they are usually normal secondary to significant pancreatic scarring and fibrosis. Of note, amylase and lipase values should not be considered diagnostic nor prognostic.

In cases where chronic autoimmune pancreatitis is suspected, inflammatory markers including ESR, CRP as well as ANA, RF, antibodies, and immunoglobulins can be obtained. To workup steatorrhea, a 72-hour quantitative fecal fat is the gold standard (whereby values greater than 7 gm per day is confirmatory). As an alternative, a fecal elastase-1 level can be obtained from a single random stool sample to help evaluate pancreatic insufficiency. This is the most sensitive and specific alternative to the qualitative fecal fat test available.

The MRCP is the premier diagnostic imaging study because it can reveal calcifications (hallmark sign), pancreatic enlargement, ductal obstruction, or dilation. MRCP has higher sensitivity and specificity for chronic pancreatitis than does the transabdominal ultrasound or plain films (though both can reveal calcifications). Management could also include a CT scan of the abdomen as an alternative.

ERCP has been the traditional test of choice in diagnosing chronic pancreatitis. It is used when there is no steatorrhea or when plain films do not reveal calcifications. However, currently, many hospitals are trending towards using MRCPs instead and are relying on ERCP only when therapeutic intervention is needed. Endoscopic ultrasound is another imaging modality that can be used to diagnose the disease.

Specific tests may include

  • Laboratory – work ordered on admission should include a complete metabolic panel, complete blood count, serum lipase, lactate, serum triglycerides, and C-reactive protein (CRP) levels. The best assessment of evolvement of acute pancreatitis can be made using a rising blood urea nitrogen (BUN) level or a rising hematocrit level. Systemic inflammatory response syndrome (SIRS) criteria can also be used to assess the clinical status of the patient.
  • Imaging tests – Tests of your pancreas and other organs may include CT, MRI, endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP).
  • Blood tests – You will be tested for elevated levels of an immunoglobulin called IgG4, produced by your immune system. People with type 1 AIP, but usually not with type 2 AIP, will have highly elevated blood levels of IgG4. However, a positive test doesn’t necessarily mean that you have the disease. A small number of people who don’t have autoimmune pancreatitis, including some with pancreatic cancer, also have high blood levels of IgG4.
  • Endoscopic core biopsy – In this test, pathologists analyze a sample of pancreatic tissue in the laboratory. AIP has a distinctive appearance that can be easily recognized under a microscope by an expert pathologist. Doctors insert a small tube (endoscope) through the mouth into the stomach and, guided by ultrasound, remove some tissue from the pancreas using a special needle. The challenge is obtaining a sample of tissue large enough to analyze, rather than just a few cells. This procedure is not widely available, and the results may not be conclusive.
  • Steroid trial – Autoimmune pancreatitis generally responds to steroids; doctors sometimes use a trial course of this drug to confirm a diagnosis. However, this strategy should ideally be under expert guidance, be used sparingly, and only be done when there is strong evidence to support a diagnosis of autoimmune pancreatitis. Response to corticosteroids is measured by CT and improvement in serum IgG4 levels.
  • Tests to assess the pancreas – Tests to assess pancreatic function are sensitive but need to be done early. Duodenal aspirates can help determine the output of amylase, pancreatic bicarbonate, and lipase. The pancreatic duct can be cannulated during ERCP and the pancreatic juice can be assessed for the same parameters.
  • Computed tomography (CT scan) – The introduction of CT scan realized a revolution in the prognostic evaluation of acute pancreatitis. Ranson and Balthazar described two scoring systems. The first one was based on the presence of extra-pancreatic collections and the second associated both extra-pancreatic collections and non-enhancement of the pancreas on angioscanner ().
  • Ultrasonography – Ultrasonography gives less precise pieces of information on pancreatic and peri-pancreatic lesions than CT-scan but is necessary for the search of gallstones. It may be helpful to guide percutaneous fine-needle aspiration of collections or insert drains.
  • Magnetic Resonance Imaging – MRI gives information equivalent to that of a CT scan but its prognostic value is not yet thoroughly evaluated in acute pancreatitis

Current Guidelines

  • CT is the ideal test to image the abdomen and assess pancreas morphology
  • CT scan can also help exclude other pathologies
  • MRCP is indicated when the CT is normal
  • Secretin stimulated MRCP can define subtle changes in the ducts, and also helps assessment of ductal compliance and exocrine function.
  • Endoscopic ultrasound can be used to assess ductal and parenchymal changes early in the course of the disease.

In 2002, the Japanese Pancreas Society proposed the following diagnostic criteria for autoimmune pancreatitis

  • I. Pancreatic imaging studies show diffuse narrowing of the main pancreatic duct with an irregular wall (more than 1/3 of the length of the entire pancreas).
  • II. Laboratory data demonstrate abnormally elevated levels of serum gamma globulin and/or IgG or the presence of autoantibodies.
  • III. Histopathologic examination of the pancreas shows fibrotic changes with lymphocyte and plasma cell infiltrate.

For diagnosis, criterion I (pancreatic imaging) must be present with criterion II (laboratory data) and/or III (histopathologic findings).[dx]

Treatment of Autoimmune Pancreatitis

  • Lactated Ringer’s solution – Management for acute pancreatitis remains early aggressive fluid resuscitation. Lactated Ringer’s solution is the recommended fluid with an initial bolus of 15 to 20 mL/kg and following rates of 3 mL/kg per hour (usually approximately 250 to 500 mL per hour) for the first 24 hours if no other contraindications are present. The fluid resuscitation is monitored with a combination of blood urea nitrogen, hematocrit, and urine output, monitoring every 4 to 6 hours in the first 24 hours of resuscitation to adjust the fluid rate. Continued non-response indicates a high likelihood of ensuing MODS and is grounds for upgrading the level of care.
  • NSAIDs – In cases where pain relief is not achieved with enzyme replacement treatment and dietary modification, non-opioid regimens should be utilized (TCA, NSAIDs, pregabalin) initially before starting a trial of opioids. Studies regarding the benefit of antioxidants are unconfirmed. New studies show some benefits of using medium-chain triglycerides. Surgery should be considered in patients who fail medical therapy and continue to have pain.
  • Prophylactic antibiotics – If the infection is suspected, empirical antibiotics are appropriate until culture results are back. Indication for antibiotics is limited to the presence of infected necrosis. The preferred antibiotic regimen includes a carbapenem alone, or a combination of quinolone, ceftazidime, or cefepime with metronidazole. Antibiotics are continued for 4 to 6 weeks.[rx]
  • Corticosteroids – Prednisone is usually initiated at a dose of 0.4-0.6 mg/kg per day for a period of months. Although a detailed steroid schedule has not yet been fully defined, most patients are usually treated for a period of 2-3 mo, with a tapering schedule of 5 mg every 1-2 wk. Prednisone is relatively low, about 0.5–0.6 mg/kg/day. Others initiate the treatment with 40 mg prednisone/day. After 3–4 weeks with this treatment, the steroid dose is tapered, reducing it 5 mg/day every 2 weeks.
  • Immunosuppressants and immunomodulators – steroid-sparing agent, azathioprine (1.0–1.5 mg/kg/day) or mycophenolate (2 to 3 g/day) for several years. If these treatments fail, rituximab has been shown effective in the treatment of the first episode of the disease and also in its recurrence include mycophenolate (CellCept), mercaptopurine (Purinethol, Puritan), azathioprine (Imuran, Azasan), and rituximab (Rituxan). In our experience, steroid treatment with or without steroid-sparing agents was effective in all but one case; we recently used rituximab 1000 mg repeated in 15 days, i.e., 2000 mg as total dose, in one exceptional patient, with a good initial result. The Mayo Clinic experience [rx] is in favor to repeat rituximab 1000 mg every 2–6 months and use it as maintenance treatment. [rx]
  • Pancreatic enzymes – are usually taken with a meal and help lower the pain. However, the benefits of pancreatic enzymes still remain questionable.
  • Monitoring of other organ involvement – Type 1 AIP often is associated with other organ involvement, including enlarged lymph nodes and salivary glands, scarring of the bile ducts, liver inflammation, and kidney disease. Although these signs may lessen or disappear completely with steroid therapy, your doctor will continue to monitor you

Surgery is required for

  • Pancreatic abscess, fistula, or pseudocyst
  • Pancreatic ascites
  • Mechanical obstruction of the common bile duct
  • Stenosis of the duodenum leading to gastric outlet obstruction
  • Variceal bleeding due to splenic vein thrombosis

Surgery to resect the pancreas can produce good results in the hands of experienced surgeons, but the operative mortality can exceed 10% and the quality of life is impaired without a functioning pancreas.

Today, interventional radiology can be used to manage most complications including drainage and stent placement.

Celiac ganglion blockade can be performed to decrease pain but this is an invasive procedure with a risk of paralysis due to transverse myelopathy. Endoscopic methods of celiac nerve blocks have not been beneficial. Endoscopy is often used to relieve obstruction in the pancreatic duct but only works in 60% of patients.

Complications

Complications of acute pancreatitis can be divided into local and systemic. Local complications include the following:

  • Pancreatic pseudocyst
  • Walled-off necrosis
  • Peri-pancreatic fluid collection
  • Acute necrotic collection

Peripancreatic fluid collections usually develop in less than 4 weeks after the initial presentation of pancreatitis whereas a pseudocyst and walled-off necrosis more than 4 weeks after the onset of acute pancreatitis.

Systemic complications include the following:

  • Acute respiratory distress syndrome (ARDS)
  • Compartment syndrome
  • Acute kidney injury (AKI)
  • Disseminated intravascular coagulation(DIC)

Chronic pancreatitis has several complications including

  • Formation of pseudocysts
  • Diabetes
  • Pseudoaneurysms
  • Splenic vein thrombosis
  • Recurrent acute pancreatitis
  • Risk of progression to pancreatic cancer

Reference

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