Pancreas Divisum as an indication of Islet transplantation

I. Title
II. Pancreas Divisum as an indication of Islet transplantation 
III. Abstract
IV. Introduction and objective
i. Review cases of pancreas divisum that have been reported in allo- and auto-transplant. 
ii. Normal Pancreas Embryology:
i. Pancreas gland arises during 5th week of gestation from three overgrowths of the primitive duodenum.
a. Dorsal pancreatic: the dorsal pancreas form gut is in the midline and later comes to lie in the cavity of the duodenum.
b. Two caudal ventral buds: the right ventral bud, ventral from gut, develops caudal in association with primitive bile duct to the dorsal and left bud disappear.
c. The ventral rotates at 7th week posteriorly and then left caudal to dorsal bud.
d. The duct system fuse together, the dorsal duct form the main duct of the body and tail while the ventral duct (Wirsung’s duct) becomes the main duct for pancreatic secretion coursing through the head and opening into the major papilla in the duodenum. The dorsal duct drains in the duct of Santorini through minor papilla.
ii. Pancreas Divisum is the most frequent anatomic variation in pancreas. The first description by Joseph Hyrtl (anatomist, 1810-1894).

a. Three types:
i. Type I or Classical divisum: failure of fusion between dorsal and ventral. Without fusion, the main pancreatic duct coming from the tail drains to the small papilla. 70 % of population.
ii. Type II: Dorsal duct (Santorini’s duct) is dominant and the Wirsung’s duct is absent.
iii. Type III or Incomplete Divisum: small communicating branch is present. 15% of population.
iii. Pathophysiology: The cause of pancreatitis in Pancreas divisum is because of the dominant dorsal duct drains to the minor papilla orifice which it is small and consequently excessive high intrapancreatic dorsal ductal pressure occurs during active secretion. This may result in inadequate drainage, ductal distension, and pain. The ducts are so sensitive that even low grade hypertension makes the pancreas more prone to injury from alcohol, trauma, and drugs. 
iv. However, the correlation of pancreatitis with Pancreas divisum is very low [1]. Less than 20 percent of patient with pancreas divisum will develop pancreatitis and most of them are asymptomatic. Therefore, the main issue in pancreas divisum is the physiologic of the valve.
v. [2]Pancreas Divisum diagnosis: MRCP or EU

vi. Indication for Islet transplantation: 
vii. Islet autotransplant eiologies:
i. Minnesota Criteria: Definitions (Must have A, B, or C)
A. Chronic pancreatitis with chronic abdominal pain lasting for > 6 months with features consistent with pancreatitis and objective evidence by having one of the following:

1. Morphological or functional evidence of chronic pancreatitis defined by CT imaging or ERCP evidence of pancreatitis or
2. EUS with 6 of 9 criteria for chronic pancreatitis or
3. At least 2 of the following:
i. T2 weighted MRI with evidence of pancreatic fibrosis, Secretin MRCP or ERCP with findings of chronic pancreatitis
ii. EUS with 4 of 9 criteria positive for pancreatitis
iii. Abnormal exocrine pancreatic function tests as evidence of a peak bicarbonate less than 80or
B. Relapsing acute pancreatitis as defined as both of the following:
1. 3+ episodes of acute pancreatitis with ongoing episodes over 6 months
2. No evidence of gallstone disease or other correctible etiology or
C. Documented hereditary pancreatitis with symptoms
Section II – Indications for TP-IAT A. Chronic pancreatitis or relapsing acute pancreatitis with severe abdominal pain resulting in one of the following:
1. Daily or near daily narcotic dependence for more than 3 months
2. Impaired quality of life as defined as one of the following:
a. Job loss
b. Decreased ability or inability to work or attend school
c. Frequent absences from school
d. Frequent hospitalizations
e. Inability to participate in usual age-appropriate activities
1. Complete evaluation with no reversible cause of chronic pancreatitis or relapsing acute pancreatitis present or untreated
2. Unresponsive to maximal medical therapy and endoscopic therapy
Adequate islet cell function (C-peptide positive non-insulin requiring diabetes or non-diabetic)

Section III - Contraindications 
1. Active alcoholism or recent alcoholism (must be abstinent for 6 month with document therapy)
2. Illegal drug use (must be abstinent for 6 month with documented therapy)
3. Pancreatic cancer
4. End-stage pulmonary disease, liver cirrhosis, or severe coronary artery disease
5. Poorly controlled psychiatric illness
6. Inability to comply with a postoperative regimen
7. Patients with IPMN should not receive islet cell autotransplant outside of clinical trial
ii. Criteria of Islet transplantation in chronic pancreatitis:

1. The primary indication for TP-IAT is to treat intractable pain in patients with  impaired quality of life due to CP or RAP in whom medical, endoscopic, or prior surgical therapy have failed

2. TP-IAT should not be performed in patients with active alcoholism, active illicit substance abuse, or untreated/ uncontrolled psychiatric illness that could be expected to impair the patient’s ability to adhere to a complicated medical management plan…Patients with poor support networks have a relative contraindication due to the cost and complexity of managing diabetes and pancreatic enzyme replacement therapies. Recommendation 2B

3. TP-IAT should not be performed in patients with specific medical conditions, including: c-peptide negative diabetes, type 1 diabetes, portal vein thrombosis, portal hypertension, significant liver disease, high-risk cardio-pulmonary disease, or known pancreatic cancer. Recommendation D

4. There are no studies that specifically evaluate contraindications to this procedure. However, TP and TP-IAT are major surgical procedures, with potential operative complications, a prolonged surgical recovery, and an intensive post-operative regimen that includes management of diabetes mellitus and lifelong enzyme therapy for pancreatic enzyme insufficiency. Recommendation D

5. The severity, frequency, and duration of pain symptoms, narcotic requirements, disability/impaired quality of life, residual islet function, rate of disease progression, and age of the patient should be considered in timing of the procedure. Recommendation D

6. Patients who meet the inclusion criteria (see above) and who are not excluded should be evaluated by a multi-disciplinary team who will review alternative interventions, assess the likelihood of success in reducing pain and preventing or minimizing diabetes, follow the patient through the procedure and provide guidance for long-term care. Recommendation D.

7. Evaluation should include confirming that pancreatitis is the primary diagnosis, determining that the pain is of pancreatic origin, monitoring the presence of diabetes, assessing beta-cell mass, and assessing the patency of the portal venous system, evaluating for liver disease, and determining immunization status. Recommendation D

8. CP, chronic pancreatitis; RAP, recurrent acute pancreatitis; TP-IAT, Total Pancreatectomy with Islet Autologous Transplant. aMethods of developing consensus based on the Grading of Recommendations, Assessment, Development, and Evaluation Grid. Recommendation D
To be considered for TP-IAT, patients must meet criteria in sections I and II and have no contraindications (section III).75 CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; IPMN, intrapancreatic mucinous neoplasm; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging Tab [ii, iii]

viii. Etiologic risk factors associated with chronic pancreatitis: TIGAR-O classification system

Table 4 Etiologic risk factors associated with chronic pancreatitis: TIGAR-O classification system
Alcoholic: alcohol is considered as cofactor for pancreatitis instead as an absolute cause. 
Tobacco smoking 
Hyperlipidemia (rare and controversial) 
Chronic renal failure 
Phenacetin abuse (possibly from chronic renal insufficiency)  
Organotin compounds (e.g., DBTC)  
Early onset 
Late onset 
Tropical calcific pancreatitis  
Fibrocalculous pancreatic diabetes  
Autosomal dominant 
Cationic trypsinogen (Codon 29 and 122 mutations)  
Autosomal recessive/modifier genes 
CFTR mutations  
SPINK1 mutations  
Cationic trypsinogen (codon 16, 22, 23 mutations)  
α1-Antitrypsin deficiency (possible)  
Isolated autoimmune chronic pancreatitis 
Syndromic autoimmune chronic pancreatitis 
Sjögren syndrome–associated chronic pancreatitis  
Inflammatory bowel disease–associated chronic pancreatitis  
Primary biliary cirrhosis–associated chronic pancreatitis  
Recurrent and severe acute pancreatitis
Postnecrotic (severe acute pancreatitis) 
Recurrent acute pancreatitis 
Vascular diseases/ischemic 
Pancreatic divisum 
Sphincter of Oddi disorders (controversial) 
Duct obstruction (e.g., tumor) 
Preampullary duodenal wall cysts 
Posttraumatic pancreatic duct scars 

ix. According to Melani D. Bellin et al. most common risk factor for patients in children undergoing a TPIAT is the occurrence of predisposing genetic mutations (54%) such as mutations in the trypsinogen gene (PRSSI) which predisposes inappropriate activation of trypsin, loss of trypsin inhibitor function (SPINKI gene mutation), and cystic fibrosis transmembrane (CFTR)gene mutations. Other factors such as pancreas divisum, and idiopathic disease, trauma [3]. 

V. Description /summary

VI. Management and treatment:
VII. Discussion
VIII. Conclusion:
IX. References
i. QUEST L, LOMBARD M, Pancreas divisum: opinio divisa, Gut 2000; 47:317-319.
ii. Bellin MD, Freeman ML, Gelrud A et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: recommendations from PancreasFest. Pancreatology 2014;14:27-35
iii. Jaeschke R, Guyatt GH, Dellinger Pet al.Use of GRADE grid to reach decisions on clinicalpractice guidelines when consensus is elusive.BM 2008;337: a744

1. Muzaffar, A.R., et al., Pancreas divisum in a family with hereditary pancreatitis. Journal of clinical gastroenterology, 1996. 22(1): p. 16-20.
2. Lowes, J., et al., Obstructive pancreatitis: unusual causes of chronic pancreatitis. BJS, 1988. 75(11): p. 1129-1133.
3. Bellin, M.D., et al., Pediatric autologous islet transplantation. Current diabetes reports, 2015. 15(10): p. 67.

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