Abstract

K

S

, S

S

, K

R

The Therapeutic Usefulness of Ligating

Esophageal Varices with Endoloops in the Primary

and Secondary Prophylaxis of Bleeding from

Esophageal Varices in Patients with Hepatic Cirrhosis

– Three−Year Observation

Ocena przydatności terapeutycznej podwiązywania żylaków przełyku

za pomocą endopętli w profilaktyce pierwotnej i wtórnej

krwawień z żylaków przełyku u pacjentów z marskością wątroby

– obserwacje trzyletnie

Department of Infectious Diseases, Liver Diseases, and Acquired Immune Deficiencies, Silesian Piasts University of Medicine in Wrocław, Poland

Adv Clin Exp Med 2008, 17, 1, 61–67 ISSN 1230−025X

ORIGINAL PAPERS

© Copyright by Silesian Piasts University of Medicine in Wrocław

Abstract

Objectives.The aim of the study is to assess, on the basis of three−year observation, the therapeutic usefulness of ligation of esophageal varices using nylon endoloops in the primary and secondary prophylaxis of bleeding from esophageal varices in patients suffering from hepatic cirrhosis of various etiology and different degrees of progres− sion according to the Child−Pugh score.

Material and Methods.Eighty−seven Caucasian patients were included in a three−year therapeutic program. They were admitted to hospital because they had suffered from or there was a danger of hemorrhage from esophageal varices involving portal hypertension with clinically confirmed hepatic cirrhosis of various etiology. The esopha− geal varices were ligated by means of nylon endoloops (Endominiloop MAJ 339, Olympus, guide−way HX−21L). The ligation procedure was repeated every three months until variceal eradication was achieved. Control endosco− pic examinations were made every 6 months for a minimum in 36 months, applying single endoloops to appearing varices when necessary. The results were statistically analyzed.

Results.During the 36−month observation period, each patient was subjected to an average of 3.62 ligation proce− dures using 15.67 loops with 4.8 loops per procedure. Total eradication of esophageal varices was achieved in 70 (80.46%) of the patients and the time to achieve variceal eradication was 17.5 months. Fourteen (17%) patients had hemorrhage from the esophageal varices. In 11 (12.6%) patients, other complications occurred after the procedu− res, including bleeding from the stomach mucosa, stomach mucosa ulceration, and anal varices, as well as fever, diarrhea, vomiting, and retrosternal pains, but not stenocardial pains. Five patients (5.74%) died. Etiology, degree of progression of hepatic cirrhosis, and hemorrhage from the alimentary tract before and during the treatment had impact on the efficiency and time necessary to achieve eradication of esophageal varicose veins. The quickest va− riceal eradication was achieved in patients with alcoholic cirrhosis of progression degree A on the Child−Pugh score who had not had a hemorrhage before.

Conclusion.Prophylactic endoscopic ligation of esophageal varices by means of nylon endoloops in patients with hepatic cirrhosis of various etiology and different degrees of illness progression decreases the risk of another blee− ding hemorrhage and the risk of death in this group of patients during 36−month observation (Adv Clin Exp Med 2008, 17, 1, 61–67).

Varices of the esophagus and stomach of defi− nitely different localization are a typical manifesta− tion of portal hypertension, which usually leads to complications in the course of hepatic cirrhosis [1–3]. Hemorrhage from esophageal varices is the most serious and, unfortunately, sometimes the first and only life−threatening complication. Hemorrhage is responsible for a high rate of mortality which, according to different statistics, reaches 20–50%. It seems that the latter figure refers to patients who had not undergone primary or secondary prophylaxis of variceal bleeding or those for whom it was too late or it was impossible to apply proper treatment [4, 5]. Moreover, approximately 70% of the patients who survive the first variceal bleeding and are conserva− tively treated experience another hemorrhage, usual− ly within the first six months.

Endoscopic examination is undoubtedly of sig− nificant importance in the detection of varices, assessment of their localization and size, and the risk of bleeding; it makes it possible to monitor the development or regression of varices and their ther− apeutic management (arrest of massive hemor− rhage) as well as prophylactic primary and sec− ondary procedures [6, 7]. However, certain require− ments must be satisfied: a well−equipped endoscopic laboratory and an efficient team includ− ing an endoscopist, an endoscopic nurse, and sometimes an anesthesiologist. The experienced endoscopist easily and with a high degree of prob− ability may find features of the past or future which

pose the threat of variceal bleeding. These features include rapid growth of varices, their thin−walled character, inflammatory changes of the variceal mucosa, dark−red hyperpigmetations of the mucosa, red spots, and the occurrence of varices of varix. Management of the primary and secondary prophylaxis of esophageal variceal bleeding requires much clinical experience and is an element of an integrated hepatological therapy [8, 9]. The significant constituent elements of the prophylaxis of esophageal variceal hemorrhage include a prop− er diet, pharmacotherapy (beta−blockers, nitrates, and in chronic cases diuretic agents), endoscopic procedures (sclerotherapy, endoscopic variceal lig− ation by means of rubber bands or nylon loops), the creation of transjugular portasystemic anastomosis (TIPS), and surgical methods, including devascu− larization and portasystemic anastomoses [10–16]. The aim of the present study was to make a retrospective assessment of the therapeutic effec− tiveness of the ligation of esophageal varices by means of endoloops in the primary and secondary prophylaxis of bleeding from esophageal varices in patients with hepatic cirrhosis on the basis of three−year observation.

Material and Methods

Seventeen Caucasian patients who had been hospitalized several times were under observation

Streszczenie

Cel pracy.Ocena skuteczności terapeutycznej, w obserwacji 3−letniej, podwiązywania żylaków przełyku za pomo− cą nylonowych endopętli w profilaktyce pierwotnej i wtórnej krwawień żylaków przełyku u pacjentów z marskoś− cią wątroby o różnej etiologii i różnym stopniu zaawansowania według klasyfikacji Childa−Pugha.

Materiał i metody.3−letnim programem terapeutycznym objęto 87 pacjentów rasy kaukaskiej hospitalizowanych z powodu przebytego lub zagrażającego krwotoku żylaków przełyku wikłającego nadciśnienie wrotne, z potwier− dzoną klinicznie marskością wątroby o różnej etiologii. Żylaki przełyku podwiązywano za pomocą nylonowych endopętli (Endominiloop MAJ 339/Olympus, prowadnica do zakładania – HX−21L). Procedurę podwiązywania powtarzano co 3 miesiące aż do uzyskania eradykacji żylaków. Kontrolne badania endoskopowe wykonywano co 6 miesięcy, minimum przez 36−miesięczny okres obserwacji, w razie potrzeby zakładając pojedyncze endopętle (podwiązki) na pojawiające się żylaki. Wyniki poddano analizie statystycznej.

Wyniki.W okresie 36 miesięcy obserwacji u każdego pacjenta: wykonano średnio 3,62 zabiegów podwiązywania żylaków przełyku, wykorzystując 15,67 pętli, w tym 4,8 na jeden zabieg. Całkowitą eradykację żylaków przełyku osiągnięto u 70 (80,46%) leczonych, a łączny czas do uzyskania pełnej eradykacji żylaków wynosił 17,5 miesią− ca. U 14 (17%) pacjentów doszło do ponownego krwotoku z żylaków przełyku. U 11 (12,6%) osób po zabiegach zaobserwowano inne powikłania, w tym: krwawienia ze śluzówki żołądka, z owrzodzenia śluzówki żołądka, z ży− laków odbytu, a także gorączkę, biegunkę, wymioty oraz bóle zamostkowe, niebędące bólami stenokardialnymi. Zmarło 5 (5,74%) pacjentów. Do czynników, które wpłynęły na skuteczność i czas konieczny do uzyskania erady− kacji żylaków należały: etiologia i stopień zaawansowania marskości, przebyte przed i w czasie terapii krwawie− nia z przewodu pokarmowego. Najszybszą eradykację żylaków uzyskano u pacjentów z poalkoholową marskością wątroby, w stopniu zaawansowania A, bez przebytego krwotoku w przeszłości.

Wniosek.Profilaktyczne endoskopowe podwiązywanie żylaków przełyku za pomocą endopętli nylonowych u pac− jentów chorych na marskość wątroby o różnej etiologii i różnym stopniu zaawansowania zmniejsza ryzyko ponow− nego krwawienia i ryzyko zgonu w tej grupie pacjentów, w obserwacji 36−miesięcznej (Adv Clin Exp Med 2008, 17, 1, 61–67).

and examination in the period of 2000–2005 at the Department of Infectious Diseases, Liver Di− seases, and Acquired Immune Deficiencies of Si− lesian Piasts University of Medicine in Wrocław. They were admitted to hospital due to past or pre− sent danger of bleeding from esophageal varices complicating portal hypertension with clinically and, in some cases, histologically confirmed hepatic cirrhosis of various etiology. Hepatic cir− rhosis was diagnosed on the basis of generally accepted clinical and laboratory criteria. The patients who suffered from advanced stomach varices and other causes of portal hypertension with complications of hemorrhage (portal vein thrombosis, Budd−Chiarri syndrome, neoplasms different from HCC which complicate hepatic cir− rhosis, veno−occlusion disease) were excluded from the study. The decision to ligate the esophageal varices of patients who had not suf− fered from bleeding was undertaken after a close assessment of factors regarded as bleeding risk predictors, taking into consideration the rate of growth, size (> 5 mm), extent, and localization of the varices, changes in the variceal wall, which were assessed as symptoms of dangerous bleeding hemorrhage [6, 7], hepatic cirrhosis progression rate (Child−Pugh score), ascites, and coagulation complications which accompany hepatic cirrhosis [8, 9].

The endoscopic procedures of esophageal variceal ligation using endoscopic nylon endo− loops (Endominiloop MAJ 339, Olympus, guide− way HX−21L) were performed at the Endoscopic Laboratory of the Gromkowski Memorial Regio− nal Specialists’ Hospital in Wrocław, which is also the Endoscopic Laboratory of the Silesian Piasts University of Medicine in Wrocław Hospital. The procedures were repeated every three months until variceal eradication was achieved. Control endo− scopic examinations were then made every six months for a minimum of 36 months of observa− tion, applying single loops to occurring varices when needed. Apart from the endoscopic proce− dures, the patients were treated with pharmacolog− ical agents due to symptoms (betablockers or isosorbite nitrate under the control of arterial blood pressure and heart action, diuretic agents, inhibitors of the proton pump IPP or H2 blockers) and due to the causes (e.g. nucleoside analogs in HBV patients). A few patients underwent a longer beta−blocker therapy. Apart from many contradic− tions to include the drugs, bad drug tolerance was a problem and it was often the reason to cease administration of the drugs from this group (espe− cially in patients suffering from advanced hepatic cirrhosis) [17–19].

Statistical Analysis

The results are expressed as means. The dif− ference were analyzed for statistical significance using Student’s t−test, variance ANOVA, the chi− squared Pearson’s, and the x2 _{Wald’s tests. The}

0.05 level of probability was used as the criterion of significance.

Results

Demographic results of the patients under observation, disease etiology, progression rate of hepatic cirrhosis, and past hemorrhages of the ali− mentary tract are presented in Table 1. Most patients (mean age: 52.2 years) suffered from postinflammatory hepatic cirrhosis which was

Table 1.Clinical characteristic of the patients before treatment

Tabela 1.Charakterystyka kliniczna pacjentów przed leczeniem

Total number of patients

(Całkowita liczba pacjentów) 87

Race Caucasian

(Rasa)

Gender: female F / male M 39/48 (Płeć: żeńska F / męska M)

Age – range 52.2 (25.7–77.4)

(Wiek – zakres)

Etiology of hepatic cirrhosis (Przyczyny marskości wątroby)

postinflammatory (HBV, HCV) 53 (F−21, M−32) (pozapalna (HBV, HCV))

alcoholic 10 (F−0, M−10)

(alkoholowa)

other 24 (F−18, M−6)

(inne)

Degree of progression according to the Child−Pugh scale

(Stopień zaawansowania w skali Child−Pugha)

A 53

B 27

C 7

Hemorrhage from esophageal varices: 34 (39%) (Krwawienie z żylaków przełyku

przed terapią)

< 12 months before therapy 25 (28.7%) (< 12 miesięcy przed terapią)

12–24 months before therapy 4 (4.6%) (12–24 miesięcy przed terapią)

> 24 months before therapy 5 (5.8%) (> 24 miesięcy przed terapią)

connected with HBV and/or HCV infection (53 patients) and had progression rates according to Child−Pugh score A (53 patients). Thirty−four (39%) had a hemorrhage from the alimentary tract as early as two years before the endoscopic proce− dures were initiated. Table 2 shows the treatment of the esophageal varices with the use of endoloops. In 36−month observation, 315 endo− scopic ligations of esophageal varicose veins were made, with an average of 3.62 procedures on each patient making use of 15.67 loops with an average of 4.8 loops per procedure. Complete eradication of esophageal varices was achieved in 70 (80.46%) patients and the total time to achieve complete eradication of varices was 17.5 months. Only 14 (17%) patients had another hemorrhage from esophageal varices in spite of the applied endoscopic procedures. The significant fact is that the complication occurred only in the first 12 months of observation. Moreover, in 11 (12.6%) patients it was possible to observe other significant complications after the procedures. These occurred directly after the procedure of variceal ligation (none were lethal). There were hemor− rhages from the stomach mucosa, ulceration of the stomach mucosa, and from anal varices as well as fever, diarrhea, vomiting, and retrosternal pains which were not stenocardial pains. In the 36−

month observation only 5 (5.74%) patients died (Table 3). Only in one case did the patient die because it was impossible to suppress hemorrhage from the esophageal varices. This patient suffered from post−alcohol cirrhosis with a B progression rate according to the Child−Pugh scale. In four cases, insufficiency of the liver connected with rapid progression of the illness was the cause of the death; in three cases it was postinflammatory hepatic cirrhosis.

Selected factors which could have impact on the efficiency of esophageal variceal eradication were also analyzed (Table 4). Statistically signifi− cant factors which, in the present examinations, had impact on the duration of treatment necessary to achieve complete eradication included etiology and progression rate of the hepatic cirrhosis as well as past hemorrhages from the alimentary tract or those in the course of treatment. The quickest eradication of varices was obtained in patients suf− fering from post−alcoholic hepatic cirrhosis with progression rate A who had not had hemorrhage in the past. Gender and age of the patients had no influence on the duration of variceal ligation pro− cedures. Hemorrhage before or during the 36− month observation influenced the number of pro− cedures which were necessary to achieve variceal eradication and the number of loops used.

Table 2.Result of therapy of esophageal varices by means of endoloops: 36−month observation

Tabela 2.Wyniki leczenia żylaków przełyku za pomocą endopętli w czasie 36−miesięcznej obserwacji

Total number of ligation procedures 315

(Całkowita liczba procedur ligatyzacji)

Average number of ligation procedures per patient 3.62 (Średnia liczba procedur ligatyzacji u pacjenta)

Complete eradication of esophageal varices achieved 70 (80.5%) (Uzyskanie całkowitej eradykacji żylaków przełyku)

Average number of loops per patient 15.67

(Średnia liczba pętli u pacjenta)

Average number of loops per procedure 4.8

(Średnia liczba pętli na zabieg ligatyzacji)

Average time to achieve variceal eradication 17.5

(Średni czas do osiągnięcia eradykacji żylaków przełyku)

Secondary hemorrhage in the period of observation – treatment 14 (17%) (Wtórne krwawienie w okresie obserwacji – leczenia)

≤ 12 months 14

(do 12 miesiecy)

> 12 months 0

(> 12 miesięcy)

Essential complications of ligation 11 (12.6%)

(Istotne powikłania po ligatyzacji)

Discussion

Ligation of esophageal varices is undoubtedly more effective (it requires fewer endoscopic pro− cedures do achieve variceal eradication) and safer

(especially in coexisting disorders of coagulation, which are usually observed in advanced hepatic cirrhosis) than the traditional sclerotherapy in the prophylaxis of esophageal variceal bleeding. This results from the present authors’ many years of experience as well as data from specialist literature [20–23], although the present authors did not con− duct such observations directly in the group of the patients in question. However, ligature as well as sclerotherapy are, unfortunately, ultimately almost ineffective in the inhibition and prophylaxis of hemorrhages from stomach varices [21–26]. Therefore, only patients with esophageal varices, who are technically “easier” for treatment with the endoscopic method, were included in the analysis. The present authors prefer the technique of esophageal variceal ligation by means of nylon endoloops, i.e. the “endominiloop” (they can also be applied at the base of polyps) and regard them at least as efficient as, though technically more dif− ficult than, rubber−band “O−rings”. This opinion is consistent with data presented by other authors [12–22]. Finally, ligation of esophageal varices by means of nylon endoloops is a cheaper procedure than the application of rubber bands (put on the endoscope in special disposable compact sets), which is of significance in the light of the current situation of health service in Poland. The endoloops are applied one by one in the number

Table 3.Mortality during treatment in the 36−month period

Tabela 3.Śmiertelność w czasie leczenia żylaków przełyku za pomocą endopętli w okresie 36−miesięcznej obserwacji

Total number of deceased 5 (5.74%) (Całkowita liczba zgonów)

Cause of death: secondary hemorrhage 1 (Przyczyny zgonów: wtórny krwotok)

hepatic insufficiency 4

(niewydolność wątroby)

Distribution regarding etiology 3 (Podział ze względu na etiologię)

postinflammatory HBV, HCV 1 (pozapalna HBV, HC)

alcoholic (alkoholowa) 1

other (inne)

Degree of progression according to the Child−Pugh scale (initial/final) (Stopień zaawansowania w skali Child− −Pugha (początkowy/końcowy))

A 0/0

B 5/1

C 0/4

Table 4. Factors which could have impact on the efficiency of esophageal variceal eradication

Tabela 4. Czynniki wpływające na skuteczność eradykacji żylaków przełyku za pomocą endopętli

Parameters Yes / No p < 0.05

(Czynniki) (Tak/Nie)

1. Influence on the duration of treatment necessary to achieve complete eradication: (1. Wpływ czasu trwania leczenia koniecznego do uzyskania pełnej eradykacji)

gender (płeć) No

age (wiek) No

hemorrhage before or during treatment (krwawienie przed lub w czasie terapii) Yes = 0.000

etiology (etiologia) Yes = 0.000

progression rate of hepatic cirrhosis (Ch−P) (stopień progresji marskości wątroby (Ch−P) Yes = 0.000 2. Influence on the number of loops necessary to achieve complete eradication:

(2. Wpływ liczby pętli koniecznych do uzyskania pełnej eradykacji)

gender (płeć) No

age (wiek) No

hemorrhage before or during treatment (krwawienie przed lub w czasie terapii) Yes 0.0314

etiology (etiologia) No

progression rate of hepatic cirrhosis (Ch−P) (stopień progresji marskości wątroby (Ch−P) No 3. Influence on the number of ligation procedure necessary to achieve complete eradication: (3. Wpływ liczby zabiegów ligatyzacji koniecznych do uzyskania pełnej eradykacji)

gender (płeć) No

age (wiek) Yes

hemorrhage before or during treatment (krwawienie przed lub w czasie terapii) No 0.0077

etiology (etiologia) No

progression rate of hepatic cirrhosis (Ch−P) (stopień progresji marskości wątroby (Ch−P) No p– level of significance.

corresponding to the required clinical situation. In the present authors’ opinion it is a safer procedure for the patient as the degree of variceal tightening depends mainly on the skill of the endoscopist or the assisting nurse. Moreover, in case of a sudden hemorrhage from the varices when ligature is applied (ligation and the application of a rubber band are technically more difficult during hemor− rhage) and variceal sclerotherapy is necessary in order to obtain a field of visual area [23–25], it is necessary to remove only the guide−way and not the whole endoscope (to remove the instrument for the application of rubber ligatures). This makes it possible to continue variceal ligation without the necessity of removing the endoscope.

The primary and secondary endoscopic proce− dures of esophageal variceal ligation conducted undoubtedly had impact on the decrease in other hemorrhages and, consequently, the death rate in the group of patients under 36−month observation of the present study (irrespective of the initial cause of hepatic cirrhosis) when these results are compared with data presented in specialized liter− ature which evaluate the natural course of hepatic cirrhosis and the fate of patients who survived their first hemorrhage from esophageal varicose veins [4, 5, 8, 9, 12, 14, 16, 24, 26–28]. The num− ber of endoscopic failures which require surgical procedures or deaths brought about by causes other than another hemorrhage from esophageal varices was evaluated in the examined group of patients. The application of endoloops was bur− dened with a small number of local complications and was well tolerated by the patients. Nevertheless, so far only a few recently published studies have explicitly confirmed a positive influ− ence of prophylactic esophageal variceal ligation on longer survival of patients suffering from

hepatic cirrhosis [4, 5, 8, 27]. An assessment of the authors’ results as well as those presented in spe− cialized literature is very difficult in this respect as there is a lack of large multicenter randomized clinical studies on comparable groups of patients and long−term clinical observations. Apart from that, leaving patients with advanced varices (a con− trol group) without endoscopic protection is uneth− ical. The assessment is also complicated by the fact that at the same time there is enormous progress both in the causal treatment and sympto− matic treatment of hepatic cirrhosis, which can also inhibit the progression of the disease and influence the longevity of the patients. Examples of this are nucleoside analogs, e.g. lamivudine, adefovir dipivoxil, and entecavir, which inhibit HBV replication, long−term therapy with small doses of IFN−alpha suppressing a fibrous process and HCV replication, efficient elimination of cop− per in patients suffering from Wilson’s disease or iron in hemochromatosis, as well as efficient, in some cases, pharmacotherapy of portal hyperten− sion [5, 6, 12, 14, 17–19, 29].

Conclusions

Prophylactic endoscopic ligation of esophageal varices by means of nylon endoloops in patients with hepatic cirrhosis of various etiology and dif− ferent degrees of disease progression decreases the risk of another bleeding and the risk of death in this group of patients during 36−month observa− tion. The ligation procedure of esophageal varices by means of endoloops is well tolerated by patients and is characterized by a small number of significant clinical complications.

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Address for correspondence:

Sylwia Serafińska

Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies Silesian Piasts University of Medicine

Koszarowa 5 51−149 Wrocław Poland

Tel.: +48 604 987 041

E−mail: [email protected]

Conflict of interest: None declared