Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1515_Библиотеки_им_академика_М_И_Перельмана
.pdf
314 R. Margreiter
patient develop epithelial granulomas, which is char-
acteristic of Crohn’s disease. Resection of a bowel
segment became necessary and the graft was eventu-
ally removed 17 months after transplantation. Histol-
ogy revealed recurrent Crohn’s disease and no signs
of chronic or acute rejection [16].
The second case was a 19-year-old male who had
an isolated small-bowel transplant in 1994. Mainte-
nance immunosuppression included tacrolimus, aza-
thioprine, and prednisolone. At 8 years post-trans-
plantation, recurrent Crohn’s disease was diagnosed
that responded to prednisolone [17].
At another center, two patients transplanted for
Crohn’s disease were reported to have a significant
incidence of granulomas in the graft. Both patients
remained asymptomatic for as long as 40 months
after transplantation [14]. Even if there are only few
reports on disease recurrence, it has to be recognized
that Crohn’s disease can recur despite high-level
immunosuppression.
Summary
Improved survival after intestinal transplantation
mainly due to both patient condition at the time of
transplantation and greater center experience, made
small-bowel transplantation an attractive prospect
for patients with complications on TPN and eventu-
ally became an alternative to conservative treatment
of intestinal failure. Patient selection and lifelong
surveillance are crucial to the long-term results.
References
1. The International Intestinal Transplant Registry
(2005) www.intestinaltransplant.org
2. Lillehei RC, Goot B, Miller FA (1959) The physiologi-
cal response of the small bowel of the dog to ischemia
including prolonged in vitro preservation of the bowel
with successful replacement and survival. Ann Surg
150:543–560
3. Lillehei RC, Idezuki Y, Feemster JA et al (1967) Trans-
plantation of stomach, intestine and pancreas: experi-
mental and clinical observation. Surgery 62:721–741
4. Fortner JG, Sichuk G, Litwin SD et al (1972) Immuno-
logical responses to an intestinal allograft with HLA
identical donor-recipient. Transplantation 14:531–535
5. Cohen Z, Silverman RE, Wassef R et al (1986) Small
intestinal transplantation using cyclosporine: report
of a case. Transplantation 42:613–621
6. Deltz E, Schroeder P, Gebhardt H et al (1989) Success-
ful clinical small bowel transplantation: report of a
case. Clin Transplantation 3:89–91
7. Goulet O, Revillon Y, Canioni D et al (1992) Two and
one-half-year follow-up after isolated cadaveric small
bowel transplantation in an infant. Transplant Proc
24:1224–1225
8. Starzl TE, Kaupp HA Jr (1960) Mass homotransplanta-
tions of abdominal organs in dogs. Surg Forum
11:28–29
9. Starzl TE, Rowe MI, Todo S et al (1989) Transplanta-
Table 1. Intestinal transplants for Crohn’s disease (Innsbruck experience)
No. Initials Age Gender Underlying disease Date Immuno- Complication Outcome
suppression
1 T.M. 35 M Crohn’s disease, 14.08.98 ATG 0 Well
short-bowel syndrome TAC 64 months
(after two resections) Aza Good intestinal
P graft function
2 H.S. 37 F Crohn’s disease, 10.04.00 Zenapax Bleeding from Graft loss
short-bowel syndrome, TAC anastomosis (22.04.04)
impaired renal function Aza rejection
P
3 H.S. 37 F Loss of 1st intestinal graft 05.06.02 ATG Recurrent Well
TAC line sepsis Good intestinal
Aza two acute graft function
P rejections 42 months
on dialysis
4 S.H. 6 F Crohn’s disease, 07.07.03 ATG T-cell Intestinal graft
short-bowel + kidney
a
TAC lymphoma removed
syndrome, renal failure Aza intestinal graft 29 months
(pyelonephritis) P Good kidney
function
a
The kidney was transplanted separate from the small bowel
ATG, anti-thymocyte globulin; TAC, tacrolimus; Aza, azathioprine; P, prednisone
Bowel Transplantation for Inflammatory Bowel Disease 315
tion of Multiple Abdominal Viscera. JAMA
261(10):1449–1457
10. Williams JW, Sankary HN, Foster PF et al (1989)
Splanchnic Transplantation. JAMA 261(10):1458–1462
11. Margreiter R, Königsrainer A, Schmid TH et al (1992)
Successful multivisceral transplantation. Transplant
Proc 24:1226–1227
12. Grant D, Wall W, Mimeault R et al (1990) Successful
small-bowel liver transplantation. Lancet 335:181–184
13. Buchman AL, Scolapio J, Fryer J AGA (2003) Technical
review on short bowel syndrome and intestinal trans-
plantation. Gastroenterology 124:1111–1134
14. Fishbein TM, Gondolesi GE, Kaufman SS (2003)
Intestinal transplantation for gut failure. Gastroen-
terology 124:1615–1628
15. Middleton SJ, Jamieson NV (2005) The current status
of small bowel transplantation in the UK and interna-
tionally. Gut 54:1650–1657
16. Sustento-Reodica N, Ruiz P, Rogers A et al (1997)
Recurrent Crohn’s disease in transplanted bowel.
Lancet 349:688–691
17. Kaila B, Grant D, Pettigrew N et al (2003) Crohn’s dis-
ease recurrence in a small bowel transplant. Am J Gas-
troenterol 99(1):158–162
Introduction
Primary sclerosing cholangitis (PSC) is a chronic
cholestatic syndrome characterised by diffuse
inflammation and fibrosis of both intra- and extra-
hepatic bile ducts [1]. Although PSC is most likely a
multifactorial disease with genetic predisposition, its
exact aetiology remains unknown. In 75% of cases,
there is comorbidity with inflammatory bowel dis-
ease (IBD) such as ulcerative colitis (UC) and
Crohn’s disease. This underscores the role of
immunological alterations in the pathophysiology of
the disease. Mean age at diagnosis is 40 years, and
men are affected about twice as often as women [2].
PSC lacks a definitive medical therapy. Promising
regimens are high doses of ursodeoxycholic acid
alone or in combination with immunosuppression.
Endoscopic treatment of biliary strictures is fre-
quently needed in the late course of PSC disease.
Repeated stenting may be an option in treating dom-
inant strictures [3]. Occasionally, surgical treatment
of severe extrahepatic strictures is necessary. In gen-
eral, however, most hepatobiliary surgeons are reluc-
tant to perform such procedures, as they may com-
plicate a future liver transplantation (Ltx) and reduce
the chance of long-term survival following Ltx [4].
PSC runs an unpredictable clinical course leading to
liver cirrhosis and terminal liver disease in the
majority of affected individuals.
Primary Sclerosing Cholangitis and Liver
Transplantation
At present, PSC is the fifth most important indication
for liver transplantation in the United States [5].
There are two major difficulties associated with pre-
dicting the course of the disease in each individual
case as well as the increased risk for hepatobiliary
malignancies, primarily cholangiocellular carcinoma
(CCC). The risk for CCC is highest during the first
year of diagnosis and is not linked to the stage of dis-
ease [6, 7]. A PSC patient with cirrhosis and a liver
tumour should also be evaluated for possible hepato-
cellular carcinoma (HCC) and in this case considered
for Ltx if no extrahepatic metastases are detected and
the tumour is within accepted criteria. Liver resec-
tion for HCC is rarely indicated in a PSC patient with
advanced liver disease, as previous hepatobiliary sur-
gery is a negative prognostic factor for transplant
candidates [4].
The problem of identifying PSC patients with a
high risk for developing CCC has not been resolved
so far. No specific tumour markers exist. This has a
great impact because CCC has traditionally been con-
sidered a contraindication to Ltx. Experience with
CCC in patients undergoing Ltx is limited, and treat-
ment guidelines are still lacking. The value of routine
brush cytology obtained during endoscopic retro-
grade cholangiography remains unclear. Patients
with severe dysplasia in cytologic smears should be
considered as running a very high risk for CCC devel-
opment and therefore evaluated to exclude possible
systemic malignant disease. No consensus exists as to
what imaging modality should be preferred in the
management of these patients. Positron emission
tomography (PET) is promising but its exact role
remains unclear [8].
Studies indicate that Ltx results in highly selected
patients with CCC are satisfactory if the patients
undergo multidisciplinary treatment including
chemotherapy and local radiation therapy prior to
Ltx [9, 10]. Due to the fact that the diagnosis of CCC
can be extremely difficult to establish, PSC patients
are usually evaluated for Ltx even when CCC is sus-
pected and the final decision to perform transplanta-
tion is taken during laparotomy. If a limited tumour
without extrahepatic tumour growth is found, the
procedure should be continued and transplantation
performed. Positive lymph nodes contraindicate
transplantation, and the patient is given palliative
therapy. Brandsaeter et al. reported that clinical sus-
picion of cancer, recent diagnosis of PSC and previ-
ous colon cancer are predictors of malignancy, which
was found in 20% of more than 500 patients [11]. Ide-
ally, a PSC patient should be listed for Ltx at the time
Liver Transplantation for Primary Sclerosing Cholangitis
and Inflammatory Bowel Disease
Ingmar Königsrainer, Ruth Ladurner, Claudia Schulz, Wolfgang Steurer,
Alfred Königsrainer
318 I. Königsrainer, R. Ladurner, C. Schulz, W. Steurer, A. Königsrainer
when survival with Ltx supersedes survival without
Ltx. Prognostic models such as the Child-Pugh score
or the model for end-stage liver disease (MELD)
score have been demonstrated to be superior to PSC-
specific prognostic models in predicting posttrans-
plantation survival in PSC patients [12]. Short dura-
tion of PSC, a high bilirubin and an elevated MELD
score are associated with poor outcome [13]. When
assessing a PSC patient for Ltx a colonoscopy is
mandatory. Patients with severe ulcerative colitis or
mucosal dysplasia are candidates for colectomy
before listing them for transplantation. Particular
care is necessary to avoid life-threatening liver
decompensation [14].
When reconstructing the biliary tract during
transplantation two options are available. As experi-
ence with end-to-end biliary anastomosis is limited,
most surgeons prefer a hepaticoenterostomy with a
Roux-en-Y-loop in patients undergoing Ltx for PSC.
There are a few reports that a duct-to-duct anasto-
mosis is associated with a higher recurrence rate.
From the pathophysiological point of view, neither
alternative is logical since a possible source for
malignancy remains untouched in situ. Whether an
obligatory resection of the whole bile duct, meaning
a pancreas head resection, is justified, has not yet
been determined. Heightened attention is needed for
the possibility of growth of malignant tissue infiltrat-
ing the choledochus duct. In this case, a simultane-
ous pancreatic head resection is generally accepted
[15].
From the recipient’s point of view and considering
the development in waiting time in recent years, liv-
ing related liver transplantation is the best option for
PSC, not only in order to reduce waiting time but also
to prevent patients from dropping off the list due to
tumour formation [16]. Patients with PSC in general
have good physical status with low Child-Pugh score
and therefore face a long waiting time. The risk of
developing CCC correlates directly with the length of
time the disease remains untreated.
Outcome after Liver Grafting
Survival rates are comparable with those achieved in
patients with other autoimmune liver diseases, such
as primary biliary cirrhosis and autoimmune hepati-
tis, with 1-year patient survival exceeding 90 % in
recently published series [14]. PSC patients are
reported to have a slightly higher retransplantation
rate without impact on long-term patient survival
[4]. Again, this increased retransplantation rate has
been ascribed to PSC-specific long-term complica-
tions, in particular, biliary strictures [17]. However,
patient survival following Ltx has been shown to be
clearly improved compared with the natural course
of the disease predicted by prognostic models [18].
A number of pretransplantation factors have been
shown to predict poorer posttransplantation sur-
vival, such previous hepatobiliary surgery, elevated
creatinine levels, reduced nutritional status and the
occurrence of hepatobiliary malignancy [4, 18]. Pres-
ence of IBD has also been claimed to affect survival
following Ltx [18]. Other studies failed to identify
IBD as a risk factor [4]. The greatest impact on long-
term outcome is from CCC, which has been consid-
ered poor even in patients with occult tumours [19,
20].
Considering the lack of alternatives and the signif-
icant benefit in patients with small tumours, strict
exclusion from transplantation is not justified. More-
over, improved patient survival has been reported in
smaller series with strictly selected patients [21].
HCC is not observed frequently and has less impact
on patient survival following Ltx in PSC patients [22].
Postoperative Complications
Hepatic artery thrombosis (HAT) with an incidence
of 1–5% following adult Ltx is a feared complication
frequently leading to graft loss and retransplanta-
tion. The reason for the increased incidence of hepat-
ic artery thrombosis in PSC patients is unclear [17].
New immunosuppressive regimens have significant-
ly reduced rejection episodes in liver allograft recipi-
ents. Patients with PSC, PBC or autoimmune hepati-
tis seem to experience more acute rejections com-
pared with patients with alcoholic cirrhosis or chron-
ic viral hepatitis who are thus on a higher level of
immunosuppression [23]. On the other hand, some
centres have also reported fully satisfactory results
after early steroid withdrawal in patients with PSC
[24]. With regard to postoperative infection
episodes, positive bacterial cultures are found in bile
samples from a large portion of PSC patients at the
time of Ltx [25].
Another major concern is recurrent disease. Stric-
tures can be single or multiple, anastomotic or
nonanastomotic, and they can develop early within
the first 3 months or later [26]. Differentiation of
PSC-associated or nonrelated complications can be a
challenge in follow-up. An increased rate of biliary
problems in PSC liver allograft recipients, especially
after duct-to-duct reconstruction of the biliary sys-
tem, was identified by Sheng et al. more than 10 years
ago [27].
Diagnostic criteria, prevalence and prognosis of
PSC recurrence are not established. Cholangiography
has been complicated because it is usually impossible
to perform an endoscopic retrograde cholangiogra-
Liver Transplantation for Primary Sclerosing Cholangitis and Inflammatory Bowel Disease 319
phy in patients in whom a hepaticoenterostomy has
been constructed. However, magnetic resonance
cholangiography (MRC) now permits noninvasive
cholangiography to be performed in these patients.
Even in a graft biopsy, PSC recurrence can be dif-
ficult to identify. In some cases, typical fibrous
cholangitis and/or fibro-obliterative lesions are seen,
supporting the diagnosis of recurrent PSC. About
20–40% of PSC patients will experience recurrent dis-
ease. The Mayo Clinic has defined PSC recurrence as
either cholangiographic changes occurring more
than 90 days after Ltx or characteristic liver biopsy
findings, such as fibrous cholangitis and/or fibro-
obliterative lesions with or without ductopenic bil-
iary fibrosis or cirrhosis, namely in a PSC patient
without HAT or stenosis, ABO incompatibility,
chronic ductopenic rejection, early biliary complica-
tions or biliary strictures [28]. Therefore, the diagno-
sis of recurrent PSC should be made only in patients
with typical cholangiographic findings and/or posi-
tive histology as well as patent arterial circulation.
The improving quality of MRC will probably enable
us to diagnose and characterise PSC recurrence more
precisely in the near future. Pretransplantation colec-
tomy has been claimed to be associated with a lower
rate of recurrence [29]. The impact of different
immunosuppression regimens has not yet been
resolved. Cytomegalovirus (CMV) and donor–recip-
ient gender mismatch have also been proposed as
risk factors for recurrence [30].
The prognosis of PSC recurrence was originally
thought to be favourable, with no cases progressing
to graft failure [20], but more recent reports question
this [28]. To date, no one can propose strategies for
retransplantation.
Management of Inflammatory Bowel Disease
In spite of immunosuppressive medication, a signifi-
cant number of patients undergoing Ltx due to PSC
will experience an exacerbation of IBD following
transplantation, in some cases necessitating colecto-
my. Patients without IBD prior to Ltx have also been
diagnosed with de novo IBD in the posttransplanta-
tion period [31]. Dvorchik et al. described a high inci-
dence of progression of IBD following Ltx [31].
Haagsma et al. found that tacrolimus is more fre-
quently associated with posttransplantation exacer-
bation of IBD and that patients on triple immunosup-
pression (cyclosporine, azathioprine, prednisolone)
have less active bowel disease in follow-up [32]. Dis-
continuation of steroids has also been reported to
increase the risk of IBD exacerbation [33]. Colorectal
cancer in patients with IBD and PSC undergoing Ltx
has been reported in several series [28].
Conclusive evidence that immunosuppression
administered following Ltx may further increase the
risk of colorectal cancer compared with the risk in the
nontransplanted PSC patient with IBD is still lacking
[34, 35]. PSC patients with a diagnosis of IBD and in
whom a colectomy has not been performed should
undergo colonoscopy on a yearly basis. If dysplasia is
detected, colectomy should be considered.
If severe colitis or dysplasia is found during the
waiting period, colectomy can also be performed
during laparotomy for the transplantation provided
the patient’s general condition permits. Indeed, the
ideal time to perform colectomy is not yet known. So
far, it is a matter of local preference and the condi-
tion of the individual patient.
Follow-Up
Due to the risk of PSC-specific complications, it is
advisable that these patients be subjected to further
detailed follow-up controls routinely, including a
cholangiogram. The risk of developing de novo
hepatobiliary malignancy is especially given in
those patients with severe pretransplantation dys-
plasia. Surveillance of the remnant biliary duct
should not be forgotten, and endoscopic ultrasound
examination, including brush cytology, might be
advisable.
Summary
PSC runs an unpredictable clinical course leading to
liver cirrhosis and terminal liver disease in the
majority of affected individuals. The ideal time to
perform colectomy in colitis ulcerosa patients is still
unclear; so far, it is a matter of local preference and
patient condition. The problem of identifying PSC
patients with a particular risk for developing CCC is
multifactorial. Diagnostic features are still lacking.
Living related donor liver transplantation for PSC
could reduce waiting time and thus secondary com-
plications as well as drop-out probability due to
malignancy [16]. Major surgery with simultaneous
pancreatic head resection may be necessary in cases
with extrahepatic duct infiltration in order to achieve
no residual tumour (R0) status [15].
References
1. Sherlock S, Dooley J (2002) Diseases of the liver and
biliary system. Blackwell Science, Oxford
2. Olsson R, Danielsson A, Jarnerot G et al (1991) Preva-
lence of PSC in patients with ulcerative colitis. Gas-
320 I. Königsrainer, R. Ladurner, C. Schulz, W. Steurer, A. Königsrainer
troenterology 100:1319-1323
3. Stiehl A, Rudolph G, Kloters-Plachky P et al (2002)
Development of dominant bile duct stenoses in
patients with PSC treated with ursodeoxycholic acid:
outcome of endoscopic treatment. J Hepatol 36:151-
156
4. Brandsaeter B, Friman S, Broome U et al (2003) Out-
come following liver transplantation for PSC in the
Nordic countries. Scand J Gastroenterol 38:1776-1783
5. Levy C, Lindor KD (2006) Primary sclerosing cholan-
gitis: epidemiology, natural history, and prognosis.
Semin Liver Dis 26:22-30
6. Bergquist A, Ekbom A, Olsson R et al (2002) Hepatic
and extrahepatic malignancies in primary sclerosing
cholangitis. J Hepatol 36:321-327
7. Chalasani L, Baluyut A, Ismail A et al (2000) CCC in
patients with primary sclerosing cholangitis: a multi-
center case-control study. Hepatology 31:7-11
8. Keiding S, Hansen SB, Rasmussen HH et al (1998)
Detection of cholangiocarcinoma in primary scleros-
ing cholangitis by positron emission tomography.
Hepatology 28:700-706
9. Sudan D, De Roover A, Chinnakotla S et al (2002)
Radiochemotherapy and transplantation allow long
term survival for non respectable hilar carcinoma. Am
J Transplant 2:774-779
10. Devroede J, Steeres JL, Burch PA et al (2000) Pro-
longed disease free survival after orthotopic liver
transplantation plus adjuvant chemoirradiation for
CCC. Liver Transpl 6:309-316
11. Brandsaeter B, Isoniemi H, Broome U et al (2004)
Liver transplantation for primary sclerosing cholangi-
tis; predictors and consequences of hepatobiliary
malignancy. J Hepatol 40:815-822
12. Talwalkar JA, Seabe E, Kim W, Wiesener RH (2000)
Predicting clinical and economic outcomes after liver
transplantation using the Mayo primary sclerosing
cholangitis model and Child-Pugh score. Liver Transpl
6:753-758
13. Brandsaeter B, Broome U, Isoniemi H et al (2000)
Liver transplantation for primary sclerosing cholangi-
tis in the Nordic countries: outcome after acceptance
on the waiting list. Liver Transpl 9:961-969
14. Adam R, Mc Master P, O’Grady JG et al (2003) Evolu-
tion of liver transplantation in Europe: Report of the
European Liver Transplant Registry. Liver Transpl
9:1231-1243
15. Varotti G, Gondolesi GE, Roayaie S (2003) Combined
adult-to-adult living donor right lobe liver transplan-
tation and pancreatoduodenectomy for distal bile duct
adenocarcinoma in a patient with primary sclerosing
cholangitis. J Am Coll Surg. 197:765-769
16. Oya H, Sato Y, Yamamoto S (2004) Living related
donor liver transplantation for primary sclerosing
cholangitis with hepatocellular carcinoma and Crohn’s
disease: a case report. Transplant Proc 36:2297-2298
17. Wiesner RH (2001) Liver transplantation for primary
sclerosing cholangitis: timing, outcome, impact of
inflammatory bowel disease and recurrence of disease.
Best Pract Res Clin Gastro 15:667-680
18. Neuberger J, Gunson B, Kmolmitt P et al (1999) Pre-
transplant prediction of prognosis after liver trans-
plantation in primary sclerosing cholangitis using a
Cox regression model. Hepatology 29:1375-1379
19. Meyer CG, Penn I, James L (2000) Liver transplanta-
tion for cholangiocarcinoma: results in 207 patients.
Transplantation 69:1633-1637
20. Goss J, Shackleton CR, Farmer DG et al (1997) Ortho-
topic liver transplantation for primary sclerosing
cholangitis: a 12-year single center experience. Ann
Surg 225:472-481
21. Hassoun Z, Gores GJ, Rosen CB (2002) Preliminary
experience with liver transplantation in selected
patients with unresectable cholangiocarcinoma. Surg
Oncol Clin N Am 11:909-921
22. van de Fries W, de Man R, van Buuren HR (2003)
Inflammatory bowel disease and liver transplantation
for primary sclerosing cholangitis. Eur J Gastro Hepa-
tol 15:657-663
23. Neuberger J (1999) Incidence, timing and risk factors
for acute and chronic rejection Liver Transpl Surg
5:30-36
24. Kugelmas M, Spiegelman P, Osgood MJ et al (2003)
Different immunosuppressive regimens and recur-
rence of PSC after liver transplantation. Liver Transpl
9:727-732
25. Olsson R, Bjornsson E, Backman L et al (1998) Bile
duct bacterial isolates in primary sclerosing cholangi-
tis: a study of explanted livers. J Hepatol 28:426-432
26. Feller RB, Waugh RC, Selby WS et al (1996) Biliary
strictures after liver transplantation: clinical picture,
correlates and outcomes. J Gastroenterol Hepatol
11:21-25
27. Sheng R, Zajko AB, Campbell WL, Abu-Elmagd K
(1993) Biliary strictures in hepatic transplants: preva-
lence and type in patients with PSC vs those with other
liver diseases. Am J Roentgenol 161:297-300
28. Graziadei JW, Wiesner RH, Marotta PJ et al (1999)
Long-term results of patients undergoing liver trans-
plantation for primary sclerosing cholangitis. Hepa-
tology 30:1121-1127
29. Vera A, Moledina S, Gunson B et al (2002) Risk factors
for recurrence of primary sclerosing cholangitis of
liver allograft. Lancet 360:1943-1944
30. Jeyarajah DR, Netto GJ, Lee SP et al (1998) Recurrent
PSC after orthotopic liver transplantation: is chronic
rejection part of the disease process? Transplantation
66:1300-1306
31. Dvorchik I, Subotin M, Demetris AJ et al (2002) Effect
of liver transplantation on inflammatory bowel dis-
ease in patients with primary sclerosing cholangitis.
Hepatology 35:380-384
32. Haagsma H, Van den Berg AP, Kleibeuker JH et al
(2003
) Inflammatory bowel disease after liver trans-
plantation: the effect of different immunosuppressive
regimens. Aliment Pharm Ther 18:33-34
33. Papatheodoridis GV, Hamilton M, Mistry PK (1998)
Ulcerative colitis has an aggressive course after liver
transplantation for primary sclerosing cholangitis.
Gut 43:639-644
34. Higashi H, Yanaga K, Marsh JW et al (1990) Develop-
ment of colon cancer after liver transplantation of pri-
mary sclerosing cholangitis associated with ulcerative
colitis. Hepatology 11:477-480
35. Loftus EV, Aguiar HI, Sandborn WJ et al (1998). Risk of
colorectal neoplasia in patients with primary sclerosing
cholangitis and ulcerative colitis following orthotopic
liver transplantation. Hepatology 27:685-690
SECTION III
Familial Adenomatous Polyposis
Introduction
Although this book is addressed to medical doctors,
in this chapter, we have tried to look at the scientific
literature with the eyes of someone who has an FAP
or has a family member with this disease, in order to
understand, for those who so urgently seek it, what
lies just “around the corner” in terms of breaking
news.
The Disease
Familial adenomatous polyposis (FAP) is a syndrome
affecting 1:10 000 people and accounts for approxi-
mately 1% of colorectal cancer. It is an autosomal
dominant syndrome caused by a germline mutation
of the adenomatous polyposis coli gene (APC) locat-
ed at chromosome 5q21. The disorder is charac-
terised by the development of hundreds of colorectal
adenomas during adolescence. Colorectal cancer will
develop in nearly all affected persons by the sixth
decade of life if prophylactic colectomy is not per-
formed. Most cases begin as benign adenomatous
colonic polyps.
One widely held opinion is that cancer is a genetic
disease that arises from an accumulation of muta-
tions that leads to the selection of cells with increas-
ingly aggressive behaviour. These mutations may
lead either to a gain of function by oncogenes or to a
loss of function by tumour suppressor genes. Most
mutations in cancer are somatic and are found only
in the cancer cells. Most of our information on
human cancer genes has been gained from hereditary
cancers. In the case of hereditary cancers, the indi-
vidual carries a particular germline mutation in every
cell. In the past decade, more than 30 genes for auto-
somal dominant hereditary cancers have been identi-
fied.
Emergent Issues and Trends in Research
The ideal gold standard would be a gene technique
that would allow the removal of the diseased gene and
implant a disease-free gene. At present this is still pure
speculation. Most of the research deals with systems
for screening the germline mutations in the adenoma-
tous polyposis coli (APC) gene that predisposes the
disease susceptibility in familial adenomatous polypo-
sis. Nowadays, there are technical systems that detect
the mutations in APC gene. They might be useful in
the molecular diagnosis of presymptomatic cases in
FAP family. The clinical features of FAP patients may
be related to the genotypes of their APC gene. Howev-
er, there are other interesting ways of approaching the
problem of a presymptomatic carrier risk assessment
in familial adenomatous polyposis such as the com-
bined use of molecular- and biomarkers. Predictive
carrier testing for the inherited disorder of familial
adenomatous polyposis can be conducted using DNA
markers linked to the FAP locus. The presence of
characteristic hypertrophic retinal lesions has been
advocated as useful biomarkers for FAP. Bapat et al.
[1] have compared molecular linkage and retinal
screening techniques by evaluating the presympto-
matic carrier risk of 40 at-risk individuals from 15
FAP families. Linkage analysis was informative in all
the cases as was retinal lesion analysis in 25 cases. For
identification of the at-risk population, predictive
diagnosis by both techniques was completely concor-
dant and identified 15 members at “high” and 10 at
“low” risk of inheriting FAP. Another relevant matter
regarding future trends in FAP research are the bio-
markers for carcinogenesis and the use of drugs to
prevent the evolution to the final stage of cancer.
Progression Markers during the Intestinal
Carcinogenesis:Intermediate Biomarkers
Colon carcinogenesis is a multistep process in which
an accumulation of genetic events within a single cell
Emergent Issues and Future Trends in Familial
Adenomatous Polyposis
Gian Gaetano Delaini, Marco Scaglia, Gianluca Colucci, Tom Öresland
324 G.G. Delaini, M. Scaglia, G. Colucci, T. Öresland
line leads to a progressively dysplastic cellular
appearance, deregulated cell growth, and, finally,
carcinoma. The “adenoma-carcinoma sequence”
occurs through a series of mutations in cancer-caus-
ing genes and usually takes about 11 years. These
genes (oncogenes, tumour suppressor genes, DNA
mismatch repair genes) encode proteins that control
vital cell functions such as growth and survival.
Development of intermediate markers for chemopre-
vention trials is important. Premalignant lesions are
a potential source of intermediate markers. Monitor-
ing intermediate markers that correlate with a reduc-
tion in cancer incidence would allow a more expedi-
tious evaluation of potentially active chemopreven-
tive agents. If a disappearance of these lesions can be
correlated with a reduction in cancer incidence, then
markers of premalignancy may serve as intermediate
endpoints for chemoprevention trials.
Intermediate biomarkers of abnormal cell growth
and development have recently been used in chemo-
prevention trials in attempts to identify the efficacy
of chemopreventive agents in human subjects. Mea-
surements carried out include those related to cell
proliferation, differentiation, and gene structure and
expression in the colon. Among the modified pat-
terns of cell proliferation identified by microautora-
diographic or immunoperoxidase assays, a charac-
teristic expansion in the size of the proliferative com-
partment has been observed in normal-appearing
colorectal mucosa of human subjects with disease
increasing cancer risk; the same patterns have been
induced by chemical carcinogens in rodents. More-
over, this intermediate biomarker has been modulat-
ed by chemopreventive agents in both rodents and
humans. Newer intermediate biomarkers being stud-
ied for application to human chemopreventive pro-
grams include normal and abnormal patterns of
expression of mucins, intermediate filaments and
cytoskeletal proteins, and the structure and expres-
sion of a variety of genes associated with normal and
abnormal cell development. The application of these
various intermediate biomarkers to chemopreven-
tion studies is increasing the ability of investigators
to analyse the effects of novel chemopreventive
agents in the colon and in other organs.
How to Prevent the Carcinogenic Progression by
Chemical Agents:the Chemoprevention
Cancer chemoprevention, as first defined by Sporn in
1976 [2], uses natural, synthetic, or biological chemi-
cal agents to reverse, suppress, or prevent carcino-
genic progression. It is based on the concepts of mul-
tifocal field carcinogenesis and multistep carcino-
genesis. In field carcinogenesis, diffuse epithelial
injury in tissues such as the aerodigestive tract,
results from generalised carcinogen exposure
throughout the field and clonal proliferation of
mutated cells. Genetic changes exist throughout the
field and increase the likelihood that one or more
premalignant and malignant lesions may develop
within that field. Multistep carcinogenesis describes
a stepwise accumulation of alterations, both geno-
typic and phenotypic. Arresting one or several of the
steps may impede or delay the development of can-
cer. This has been described particularly well in stud-
ies involving precancerous and cancerous lesions of
the head and neck, which focus on oral premalignant
lesions (leukoplakia and erythroplakia) and their
associated increased risk of progression to cancer. In
addition to histologic assessment, intermediate
markers of response are needed to assess the validity
of these therapies in a timely and cost-efficient man-
ner.
Non-steroidal Anti-Inflammatory Agents for Colon
Cancer Prevention
Colon cancer prevention has now focused on novel
targeted therapies, such as non-steroidal anti-inflam-
matory agents (NSAIDs). Aspirin, an inhibitor of
COX-1 and -2, has been studied in several large ran-
domised studies, but the effect on colorectal cancer
prevention is unclear. The US Physician’s Health
Study, which enrolled 22 071 physicians as partici-
pants, reported that aspirin had no effect on the inci-
dence of polyps or colon cancer [3]. However, Baron
et al. conducted the Aspirin/Folate Polyp Prevention
Study, a randomised, double-blind, placebo-con-
trolled trial of daily aspirin (325 mg and 8 mg) and
daily folate (1 mg) in 1121 patients with a recent his-
tory of colon adenomas [4]. This trial demonstrated
that the 81-mg dose of aspirin prevented recurrence
of colorectal adenomas (47% placebo vs. 38% aspirin
81 mg vs. 45% aspirin 325 mg; p=0.04). This translat-
ed into a relative-risk reduction of 19% in the 81-mg
aspirin group and a non-significant reduction of 4%
in the 325-mg aspirin group. This study also report-
ed a relative-risk reduction of 40% in the 81-mg
aspirin group for advanced lesions. In addition, Sandler
et al. [5] reported on the Colorectal Adenoma Pre-
vention Study, which randomised 635 patients with
prior colorectal cancer to 325-mg aspirin or placebo.
Twenty percent of the placebo group developed
recurrent adenomas compared with 17% in the
aspirin arm (p=0.0004), for an adjusted relative risk
of 0.65. Aspirin intervention delayed the develop-
ment of recurrent adenoma and also decreased the
number of recurrent adenomas.
Although the role of aspirin remains debated, the
Emergent Issues and Future Trends in Familial Adenomatous Polyposis 325
benefit of NSAIDs in chemoprevention has clearly
been defined in certain high-risk subgroups [6]. In
clinical trials of patients with FAP, sulindac (150 mg
twice a day for 9 months) was shown to decrease the
number of polyps by 44% and decrease the diameter
of the polyps by 35% (p=0.014 and p<0.001, respec-
tively) [7]. In a study, 77 patients with FAP (more
than 5 polyps 2 mm in size) were randomised to
receive placebo, 100 mg, or 400 mg of celecoxib twice
daily [8]. Celecoxib is a selective COX-2 inhibitor.
Response to treatment was reported as the mean per-
cent change from baseline. After 6 months, the 30
patients assigned to 400 mg of celecoxib had a 28%
reduction in the mean number of colorectal polyps
(p=0.003) and a 30.7% reduction in the polyp burden
(p=0.001) compared with 4.5 and 4.9% in the placebo
group, respectively. This positive result led to the
FDAs approval of celecoxib in the treatment of
patients with FAP.
Other Agents under Trial
Other agents under investigation in colorectal
chemoprevention include difluoromethylornithine
(DFMO), which irreversibly inhibits ornithine decar-
boxylase and blocks cell proliferation. Ursodeoxy-
cholic acid reduces the concentration of the second-
ary bile acid deoxycholic acid in the colon and affects
arachidonic acid metabolism [9–11]. 3-hydroxy-3-
methylglutaryl Coenzyme A reductase inhibitors are
usually used in the setting of lowering cholesterol but
also have antioxidant anti-inflammatory properties
and inhibit cell proliferation [12]. Preclinical work in
mutant APC murine models have shown that sulin-
dac in combination with EGFR inhibitor EKI-785 can
decrease intestinal polyps [13]. Almost one-half the
mice treated with the combination agents did not
develop polyps. With the recent success of beva-
cizumab, an antibody to the VEGF-receptor in
metastatic colorectal cancer, and cetuximab, an anti-
body to EGFR, further strategies will be applied to
prevention.
The continued study of immunology, tumour
biology and natural history through controlled trials
focusing not only on efficacy endpoints but also on
biological markers in tissue and serum will help
develop detailed risk models. Chemopreventive
agents appear thus far to have efficacy in several
tumour types, and we hope to define their future role
in treating and preventing other cancers in high-risk
individuals.
Advances in delaying the development of colorec-
tal carcinoma have been shown in patients with FAP
with celecoxib treatment. Current and future trials
using celecoxib alone or in combination with
chemotherapy and other biological therapies are tar-
geting several cohorts including children with APC
mutations, patients with FAP, HNPCC, prior colorec-
tal adenoma, or prior history of sporadic adenomas
[14]. The use of celecoxib in the prevention of polyps
has resulted in continued efforts to define a high-risk
population and to implement a chemopreventive
agent in the treatment of cancer. With regard to
aspirin use in the prevention of colon adenomas, two
large randomised, placebo-controlled trials showed
benefit. However, although the Aspirin/Folate Polyp
Prevention Study and the Colorectal Adenoma Pre-
vention Study reported positive results, a certain per-
centage of patients receiving aspirin intervention still
developed colon adenomas. This suggests that
aspirin use cannot be a substitute for colon surveil-
lance and that further studies are necessary for effec-
tive colon cancer chemoprevention.
Surgical Prevention of Colorectal Cancer in FAP
Familial adenomatous polyposis coli (FAP) may not
be considered a single disease entity with standard-
ised guidelines for operative treatment. However,
prophylactic colectomy after the manifestation of
polyps but prior to the development of colorectal
cancer remains the most effective prevention of col-
orectal cancer in FAP. The optimal timing of prophy-
lactic surgery remains a clinical decision taken inde-
pendently of mutation analysis. In the case of the
classic FAP phenotype, restorative proctocolectomy
and ileal pouch-anal anastomosis might be the pro-
cedure of choice. The development of reliable guide-
lines for attenuated FAP variants requires further
evidence from clinical studies on surgical strategy
and the advantages of prophylactic surgery over reg-
ular endoscopic screening with removal of polyps. A
study by Winde et al. [15] has shown that low-dose
rectal sulindac maintenance therapy is highly effec-
tive in achieving complete adenoma reversion with-
out relapse in 87% of patients after 33 months. Rectal
FAP phenotype should be crucial in the surgical deci-
sion. Colectomy with ileo-rectal anastomosis and
regular chemoprevention might proceed to be a
promising alternative to pouch procedures. Chemo-
prevention with lower incidence of FAP-related
tumours via dysplasia reversion might be possible in
the future.
The Aftermath of Prophylactic Colectomy
A patient after a proctocolectomy is cleared from col-
orectal cancer, but he is not entirely free from trou-
bles. Duodenal adenomas might be the next problem,
Соседние файлы в папке Библиотека им академика М.И. Перельмана