“ Dan Setlacec” Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest

Dr. Simona Olimpia Dima

Diabetul zaharat post-rezectie pancreatica, preventie si atitudine

Background

• The number of patients undergoing pancretic surgery is increasing:

– Early diagnosis of premalignant lesions

– Referral of patients affected by surgical pancreatic disease to high-volume centers.1,2

• Life expectancy of patients undergoing pancreatectomy has increased in recent years

• Post-resection diabetes is now atracting attention as a factor influencing quality of life and life expectancy of patients who have undergone this procedure

1Balzano G. Et al. Br. J. Surg.2008;95:357-362; 2Lemmens VE. Et al. Br. J Surg. 2011; 98:1455-1462/ 3Balzano G. Et al. Ann Surg. 2013; 258:210-218

Classification of Diabetes

• Type 1 diabetes

– β-cell destruction

• Type 2 diabetes

– Progressive insulin secretory defect

• Other specific types of diabetes

– Genetic defects in β-cell function, insulin action

– Diseases of the exocrine pancreas

– Drug- or chemical-induced

• Gestational diabetes mellitus (GDM)

ADA. I. Classification and Diagnosis. Diabetes Care 2013;36(suppl 1):S11.

2-3 % of the type 3c DM are patients who underwent pancreatectomy1, 2

1Ewald N et al. Diabetes Met Res Rev. 2011;28: 338-42 2 Hardt PB e al. Diab. Care 2008; 31 Suppl 2: S165-169

Definitions of post-pancreatic resection DM

• postoperative “new-onset DM” :

– FPG>126 mg/dl detected on two or more separate days

– Plasma glucose >200 mg/dl measured in 2 h after a 75 g glucose drink

• “late- onset diabetes” ( later than 3 months after surgery)

Clinical and laboratory charact in type 3c DM

In patients with Type 3c DM due to pancreatectomy was reported a mean of 8,1% HbA1c, which was not statistically significant from the entire diabetic populations.

Ewald N et al. Eur J. Of Internal Medicine. 2013; 24: 203-206

The etiology of Post-resection DM

• Recurrence or progression of underlying disease ( reduction of the islet cell reserve)

• Gland atrophy

• Adjuvant chemotherapy or radiation

• The type of surgery:

– Extend of the resection (volume of resection) – loss of pancreatic parenchyma

– Neurohormonal response after resection

Post-resection DM- incidence ranging from 0% to 50%3

- 4.8 to 38% of patients after DP ( distal pancreatecomy) - 20% of the patients after pancreaticoduodenectomy

1Ewald N et al. Diabetes Met Res Rev. 2011;28: 338-42 2 Hardt PB e al. Diab. Care 2008; 31 Suppl 2: S165-169; 3 Ferrara M et al.cHBP 2013, 15: 170-174.

PRV= ( resected volume of normal pancreas÷ total volume of

normal pancreas) X100

The volume reduction of the pancreatic parenchyma– risk factor for diabetes The mean PRV for the new-onset groupwas 49% vs 32 % for the non-diabetic group PRV >44%- indepedent risk factor for postoperative new onset diabetes Using the PRV – offer specific information about individual risk of the postoperative DM

Human pancreas imaging.

Szczepaniak EW, Malliaras K, Nelson MD, Szczepaniak LS (2013) Measurement of Pancreatic Volume by Abdominal MRI: A Validation Study. PLoS ONE 8(2): e55991. doi:10.1371/journal.pone.0055991 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055991

PANCREATIC CANCER (PDAC) AND DM

Incidence of DM after pancreatic resection in PDAC

1. Distal pancreatectomy

• Between 40% to 80% of the pancreas is removed, depending on the indication for surgery- location of the tumor)1,2

• The rate of new-onset DM after DP in patients with remaining normal parenchyma is low comparative with CP- 5-9%3

1Slezak L.A. Et al. World J. Surg. 2001; 25, 452–460; 2Maeda H, Hanazaki K. Pancreatology 2011; 11:268-276 3Lillemoe KD et al. Ann Surg. 1999; 693-698; King J et al. Ann Surg 2008; 12: 1548-1553

2. Pancreticoduodenectomy (PD)

• The rate of new-onset DM after PD in patients with PDAC

• Amelioration of the diabetes state has been often observed after PD for PDAC

Incidence of DM after pancreatic resection in PDAC

Xiang Yi He et al. suggests that nearly half of newly diagnosed PDAC patients have DM.

71.1 % of these patients have new-onset DM (\2 years) and

65 % of new-onset DM are resolved post-radical resection.

Diabetogenic influence of PC

The mechanisms responsible for resolution of DM:

- Surgical resection- associated anatomical changes

Local effects: removal of the:

- diabetogenic factors secreted by the adenocarcinoma cells

- local inflammation due to obstructive lesions ( cause insuline resistance)

Menge BA et al. Diabetologia 2009; 52:306-317/ Ohtsuka T et al. Pancreas 2009; 38: 700-705

Postoperative outcome after pancreatectomy in patients with preoperative DM

The effect of preoperative DM on pancreatic fistula is cntroversial

Mathur et al. – DM offer a protective benefit against pancreatic fistula

- The patients developed pancreatic fistula were less likely to have diabetes. (p<0.05)

1,2 Mathur A. Et al. 2007 Ann Surg.

Postoperative outcome after pancreatectomy in patients with preoperative DM

• Pre-existing DM may have prognostic implications after resection for PDAC1,2

• Patients with preoperative DM – higher risk of any type of pancreatic fistula than those witout DM (10.3% vs 3,7%)

• the risk for ISGPS type B and C is similar (p=0.8)

• No significant difference in the rate of postoperative mortalities between two groups

1,2 Chu CK et al. Ann Surg. Oncol.2010; 17:502-513 / Sperti C. Br J Surg83: 625-631 3Nakata B et al. International Journal of Surgery 2013: 1-5

Pre-operative DM, tumor size > 2 cm, lymph node ratio (LNR)> 0.1, and positive resection margin were associated with a poorer DFS and OS

SOLUTION FOR MANAGEMENT

Management of the

1. Glycemic control

1. Treatment of additional comorbidities (maldigestion, qualitative malnutrition)

Exclusion criteria for TPIAT at University of Minnesota

Why malignancy or concern for malignancy remains a clear exclusion for TPIAT?

• The islet isolation process enriches islets, but does not totally eliminate ductal cells (cell of origin for pancreatic ductal adenocarcinoma)

• Multifocality has been described in pancreatic cancer

Concern for the use of islet preparation contaminated with ductal cells in patients with malignancy

BENIGN AND LOW GRADE MALIGNANT LESIONS AND DM

28

What is chronic pancreatitis ?

• Chronic pancreatitis is a progressive

inflammatory disease implying destroyed

secretory pancreatic parenchyma and

replacement with fibrous tissue, that could

lead to both exocrine and endocrine

insufficiency (i.e. malnutrition and

diabetes)

Braganza JM, Lancet, 2011

29

Treatment goals

• Relieve pain / prevent recurrent attacks

• Manage complications

• Correct metabolic consequences such as

diabetes or malnutrition

30

Whipple procedure - 72 patients

Pylorus preserving PD - 24 patients

Duodenum preserving pancreatic head resections in 10

patients

•Beger procedure - 6 patients

•Frey procedure – 4 patients

Distal pancreatectomy

• with splenectomy - 38 patients

• spleen preserving - 4 patients

Total pancreatectomy - 2 patients

Resection procedures: 150 between 1995 and 2008

DM after pancreatic resection in CP-Distal pancreatectomy

• For patients with CP the incidence of post-resection DM may reflect the underlying disease progression in addition to the effects of resection. 1

• 25-50% of patients with CP have risk of developing DM after DP2

1 Ferrara M et al.cHBP 2013, 15: 170-174

2Maeda H, Hanazaki K. Pancreatology 2011; 11:268-276

Hutchins RR. et al.Ann Surg. 2002;236(5):612-8

32

RESECTION in chronic pancreatitis

DPPHR and PD seem to be equally effective in terms of postoperative pain relief, overall morbidity, and incidence of postoperative endocrine insufficiency. However, the data suggest superiority of DPPHR in the treatment of chronic pancreatitis with regard to several peri and postoperative outcome parameters and quality of life. Further RCTs are eagerly awaited to prove these findings

Diener MK, Ann Surg, 2008

Proximal pancreatectomy

Beger procedure

Specimen of Whipple procedure;

DM after pancreatic resection in CP-proximal pancreatectomy

Proximal pancreatectomy

• Büchler et al. compared endocrine function following pylorus preserving partial pancreaticoduodenectomy or duodenum-preserving pancreatic head resection (DPPHR, or “Beger” procedure) performed for chronic pancreatitis

The observation that the DPPHR (Beger) procedure was superior to pylorus-preserving pancreaticoduodenectomy with respect to glucose metabolism suggests that preservation of the duodenum (or the pancreatic polypeptide- and insulin-containing tissue in the ventral pancreas) was responsible for improved glucose tolerance postoperatively.

Büchler et al. Am. J. Surg. 169:65, 1995; Slezak L.A. Et al. World J. Surg. 2001;

DM after pancreatic resection in CP-Distal pancreatectomy

34

Total / near-total pancreatectomy

• Extensive / demanding surgery

• Severe metabolic consequences - IDDM

Pancreatogenic diabetes

Chronic pancreatitis (up to 83% within 25 years of the clinical onset)

Cui YF, Pancreatology, 2011; Maeda H, Pancreatology, 2011; Parsaik AK, Clinical Endocrinology, 2010

•Frequently hypoglycemic attacks – severe 41% •Hospitalization •Central nervous system damage / death

•Glycemic control - challenging

Total pancreatectomy

Specialized and distinct management

Pancreatic enzymes – 97% Severe diarrhoea – 18% Microvascular complication – 23%

35

Total pancreatectomy

Total pancreatectomy should no longer be generally avoided, because it is

a viable option in selected patients.

Mortality decreased from 22% to 3%, but hypoglycemia continues to be a problem

Parsaik AK, Clinical Endocrinology, 2010

36 Alexakis N, Br J Surg, 2003

37

DC, 29 yrs old, idiopathic chronic pancreatitis progressively affecting the whole pancreas (2001) Resistant pain to medical and non-resectional surgical treatment (left thoracoscopic splanchnicectomy (April 2007) CA 19-9 tumor marker reaches values over 100 U/mL.

Follow-up- good regarding pain control diabetes control - 32 UI Insulin

Stroescu C, Ivanov B, Dima S, Scarlat A, Popescu I. Chirurgia (Bucur). 2009 Sep-Oct;104(5):601-6.

Chronic pancreatitis involving the whole pancreas

Dec 2007

SOLUTION FOR MANAGEMENT

-Parenchyma sparing procedures -Islet autotransplantation

Central pancreatectomy

Parenchyma sparing surgery

CP removes only central lesions and preserves a greater volume of pancreatic tissue

The incidence of the endocrine failure was 5.5% after CP and 23,6% after DP

42

Chronic pancreatitis - total pancreatectomy and autologus islet transplants

PAIN IDDM

TOTAL PANCREATECTOMY

AUTOLOGUS ISLET TRANSPLANTS

Management of the

1. Glycemic control

2. Treatment of additional comorbidities (maldigestion, qualitative malnutrition)

- risk of vitamin D deficiency( risk of

osteoporosis)

- risk of impaired incretin secretion (pancreatic enzyme replacement)

3. Cancer risk

– Use of the Metformin may be beneficial

• CP and T3c DM are risk factors for the development of pancreatic cancer

44 Marquez S, Pancreas, 2010

Islet autotransplantation

46

Total pancreatectomy technique

Islet cells – reduced warm ischemia – preserve blood supply – increase islet yield

Desai CS, J Am Coll Surg, 2011

Alexakis N, Br J Surg, 2003

47

Duodenum and spleen preserving

total pancreatectomy and islet autotransplantation

5.07.2011

MJ, 53 yrs old, chronic pancreatitis

affecting the whole pancreas

48

Islet cells infusion

3 techniques:

• Patient with open abdomen in OR – The most common method

• PO percutaneous transhepatic approach – Safe and more cost-effective

(Morgan KA, HPB, 2011)

• IOP placement of a catheter

Farnell MB, HPB, 2011 Nath DS, J Am Coll Surg, 2004

49

Results of total pancreatectomy and autoislet

transplant

• Complications: 6% to 42% • Ris F, Transplantation, 2011; Morgan KA, HPB, 2011; Desai CS, J Am Coll Surg, 2011

• Insulin independence: – at 1 year: 47% - 95%

• Ris F, Transplantation, 2011; Sutherland DER, Transplantation, 2008; Wahoff SC, Ann Surg, 1995

– at 10 year: 76% • Sutherland DER, Transplantation, 2008

• Pain relief in chronic pancreatitis: 82% • White SA, Am J Surg, 2000

50

Islet cells processing

The pancreas was distended with

enzymatic solution containing: 20 U/ g

pancreas GMP grade NB1 colagenase

(Serva, USA) and 0.6U/ g pancreas neutral

protease (Serva, USA)

The pancreas was cannulated

for enzymatic infusion

Pancreas distension by

using Perfusion Apparatus

51

Islet cells processing

Islet digestion using Ricordi®Islet

Isolator - automatic method Islet collection for centrifugation

52

Islet cells infusion

Islets infused via an inferior

mesenteric vein catheter into the

portal system

Portal pressure was monitoring during infusion in

ICU

4700 islet

equivalent/kilogram

(IEQ/kg)

Today- free of Insulin

Conclusions

53

- the postoperative incidence of diabetes is directly

related to the extent of the pancreatic resection

- those patients who require only distal pancreatectomy or

limited excavation of the pancreatic head develop diabetes

far less frequently than those who require

pancreaticoduodenectomy or near-total or total

pancreatectomy