Arhiv 2002

ARCHIVES OF
GASTROENTEROHEPATOLOGY
A QUARTERLY JOURNAL DEVOTED TO CLINICAL AND BASIC STUDIES OF THE DIGESTIVE TRACT AND LIVER PUBLISHED BY THE SERBIAN MEDICAL ASSOCIATION - SECTION FOR GASTROENTEROLOGY TROMESE^NI ÂSOPIS ZA KLINI^KA I BAZI^NA ISTRA@IVANJA DIGESTIVNOG SISTEMA I JETRE IZDAJE SRPSKO LEKARSKO DRU[TVO - GASTROENTEROLO[KA SEKCIJA EDITOR-IN-CHIEF GLAVNI I ODGOVORNI UREDNIK EDITORIAL BOARD URE\IVA^KI ODBOR
Mihajlo Boàni} Ivan Bori~i} Mirko Bulaji} Zoltan Varga Julijana Vojvodi} Tamara Vukavi} Vladimir Vuk~evi} Radivoje Grbi} Sa{a Grgov Branibor Guduri} Branislav Dani~i} Dragan Deli} Du{an \ur|evi} Miodrag @ivanovi} Slobodan Jankovi} Tibor Jesenski Rada Je{i} Julija Kova~evi} Zoran Krivokapi} Miodrag Krsti} Ana Laban Jano{ Lemberger Stojan Luka~evi} Predrag Mijailovi} Jovica Milanovi} Ivanka Mileti} Nikola Milini} Svetlana Milutinovi}-\uri} Ljubomir Muzikravi} Vladislav Nikoli} Predrag Nikoli} Vladimir Obradovi} Andrija Paljm Mirjana Peri{i} Milija Petrovi} Milorad Petrovi} Ljiljana Petronijevi} Milo{ Popovi} Milica Prostran Boìna Radevi} Nedeljko Radlovi} Dragan Sagi} Ranka Samardì} Stojan Sekuli} Ivanka Stamenkovi} Neboj{a Stankovi} Miodrag Stojkovi} Zorica Stoj{i} Tomislav Tasi} Dragan Tomi} Ljiljana Hadna|ev Tihomir [ija~i}
Vojislav N. Peri{i}
De~ija klinika Tir{ova 10 11000 Beograd
INTERNATIONAL ADVISORY BOARD ME\UNARODNI SAVETODAVNI ODBOR

Monica Acalovschi, Cluj-Napoca Mihailo Ali}, San Francisco Athanasios Archimadritis, Athens Constantine Arvanitakis, Thessaloniki Serge Bonfils, France Ian W.Booth, Birmingham Martin C.Carey, Boston Wolfgang F.Caspary, Frankfurt/Main R.Herman Dowling, London M.J.G.Farthing, London Kenneth Hobbs, London Alan F.Hofmann, San Diego Richard H.Hunt, West Hamilton Peter Katelaris, Sydney M.S.Khuroo, Srinagar S.J.Konturek, Krakow Guenter J.Krejs, Graz Anatolij S.Loginov, Moscow Zdenek Maratka, Praha Orestes N.Manousos, Crete Neil McIntyre, London Joseph R.Armengol-Miro, Barcelona J.J.Misiewicz, London Gabriel Nagy, St.Leonards Robert K.Ockner, San Francisco H.Selwyn Odes, Beer Sheva Kunio Okuda, Chiba City G.Bianchi Porro, Milano Jean C.Rambaud, Paris Mario Rizzetto, Turin Rudi Schmid, San Francisco Dame Sheila Sherlock, London J.J.Sidorov, Halifax Marvin H.Sleisenger, Kentfield Howard M.Spiro, New Haven Sandor Szabo, Long Beach B.N.Tandon, New Delhi Aldo Torsoli, Roma Jerry S.Trier, Boston Andreas Tzakis, Miami Michalis Tzivras, Athens Vince Varro, Szeged Christopher B.Williams, London Gordan Vujani}, Cardiff Rodger Williams, London Henrik R.Wulff, Herlev
FOUNDING EDITOR UREDNIK-OSNIVA^
Obren Popovi}
CHAIRPERSON OF EDITORIAL BOARD PREDSEDNIK URE\IVA^KOG ODBORA
Gradimir Golubovi}
DESK EDITOR UREDNIK DESKA

Bojan [timec
TECHNICAL EDITOR TEHNI^KI UREDNIK

Milovan Stevanovi}
ASSOCIATE EDITORS UREDNICI

Radoje ôlovi} Branka Dap~evi} Goran Jankovi} Njegica Joji} Du{an Jovanovi} Miodrag N. Krsti} Nada Kova~evi} Marjan Micev Tomica Milosavljevi} Aleksandar Nagorni \or|ije [aranovi} Neda [virtlih Milenko Uglje{i}
During the spring 1982 by joint effort of a group of enthusiasts, gastroenterohepatologists the Archives of Gastroenterohepatology was created. In memory of these pioneers, Editorial Board of the Archives of Gastroenterohepatology is noticing their names (alphabetically): Milan Andrejevic, Mirko Bulajic, Mihailo Elakovic, Nada Kovacevic, Milenko Lalic, Ljubisa Glisic, Vera Perisic, Obren Popovic, Milentije Petrovic, Jovan Teodorovic.
Reappointed Editor-in-Chief from 2002 to 2006 Dr Vojislav N. Perisic Current appointments: Full Professor of Paediatrics, Faculty of Medicine, Belgrade Vice-Chairmen, Board of Pediatrics, Medical Faculty, Belgrade Head, Department of Hepatology and Section of Digestive Endoscopy, University Children, s Hospital, Belgrade
Reappointed Chairperson of the Editorial Board from 2002 to 2006 Dr Gradimir Golubovic Current appointments: Full Professor of Internal Medicine, Faculty of Medicine, Belgrade Head, Internal Medicine Service, Clinical and Hospital Center Zemun-Belgrade Head, Department of Gastroenterology, Clinical and Hospital Centre, Zemun-Belgrade
INSTRUCTIONS TO AUTHORS AND CHECKLIST

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Alimentary tract and pancreas Alimentarni trakt i pankreas

ARCH GASTROENTEROHEPATOL 2002; 21 (No 1 - 2): 5 - 8
Aleksandar Nagorni, Vuka Katic, Jovica Milanovic, Vesna Zivkovic, Goran Bjelakovic.
The Lynch syndrome: Report on family "S"

Lynch-ov sindrom: Prikaz porodice "S"
( accepted June 20th, 2002 )
Clinic for Gastroenterology and Hepatology and Clinic for Pathology, Clinical Center,Ni{
Key Words: Lynch syndrome, metachronous CRC, stomach cancer
Abstract Lynch syndrome (HNPCC-hereditary non-polyposis colorectal cancer) is an autosomal dominant inherited disorder characterized by early onset of colorectal cancer (CRC), a preponderance of CRC in proximal colon, occurrence of multiple CRC, mucinous and poorly differentiated adenocarcinoma. We report family "S" with 11 (25.5%) affecting members. Metachronous CRC were observed in 27.2% affecting members. In tumour spectrum of Family "S" there were stomach, ovarian and endometrial cancer. Genetic tests are not routinely available in our country, so periodic screening of all family members have to be perform according to recommendation.
Klju~ne re~i: Lynchov sindrom, metahroni KRK, karcinom èluca
Saètak Lynch-ov sindrom (HNPKK- hereditarni ne-polipozni kolorektalni karcinom) je autozomno dominantni nasledni poreme}aj koji se karakteri{e ranim po~etkom kolorektalnog karcinoma (KRK), predispozicijom za proksimalni kolon, pojavom multiplih KRK, mucinozni i slabo diferentovani adenokarcinomi. Saop{tavamo porodicu "S" sa 11 (25.5%) obolelih ~lanova. Metahroni KRK su zapaèni u 27.2% obolelih ~lanova. U tumorskom spektru porodice "S" otkriveni su karcinomi èluca, ovarijuma i endometrijuma. Genetski testovi jos uvek nisu rutinski dostupni u na{oj zemlji, pa periodi~no pra}enje svih ~lanova porodice treba izvoditi u skladu sa preporukama.
INTRODUCTION
Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer deaths in many countries worldwide. In the past few years, advances in the molecular biology and genetics of CRC have not only broadened our understanding of this disease, but have also provided insight into the pathogenesis of both sporadic and hereditary CRC syndromes (1). Hereditary non-polyposis colorectal cancer (HNPCC) firstly was recognized in 1895. Famous pathologist Aldred Warthin then heard from his seamstress who was depressed because she was convinced, based on her family history, that one day she would die of cancer of the female organs or bowels. As she had predicted, she died of endometrial carcinoma at a young age. In 1913 Warthin published Family G with endometrial, colorectal and gastric carciAbbreviations used in this article: CRC,colorectal cancer; HNPCC,hereditary non-polyposis colorectal cancer; ICG HNPCC,International Collaborative Group Hereditary NonPolyposis Colorectal Cancer; MMR,Mismatch Repair.
noma as a predominant malignancy in this kindred (2). In the fame of Henry Lynch who studied this problem in the middle sixties International Collaborative Group Hereditary NonPolyposis Colorectal Cancer (ICG-HNPCC) was named HNPCC as Lynch syndrome. Lynch syndrome is an autosomal dominant inherited cancer syndrome characterized by the development of (CRC) at an early age of onset, a preponderance of cancers in the proximal segments of colon, an excess of multiple CRC, synchronous and metachronous CRC, and poorly differentiated and mucinous CRC (3 - 6). Lynch syndrome is associated with a small number of adenomas that are located predominantly on the right side of the colon (7). ICG-HNPCC proposed the "Amsterdam minimal criteria" in 1990 to facilitate the clinical diagnosis of HNPCC (8). "Minimal" criteria include: 1) the presence of three or more relatives with CRC,
Gastroenterolo{ka sekcija SLD01732, 2002.
Professor: Aleksandar V. Nagorni, MD, PhD, Clinic for gastroenterology and hepatology, Clinical Center Nis, 48 Brace Taskovica St., Yu-18000 Nis, Serbia, Yugoslavia. Fax: +381 18 335 186 E-mail: anagorni@bankerinter.net
one who is a first degree relative of the other two, 2) that the relatives affected by CRC span two or more generations, 3) and at least one relative is affected by CRC before the age of 50 (8). In addition to CRC patients with Lynch syndrome are at risk of developing extracolonic tumours including endometrial, ovarian, ureteral, stomach, renal pelvis, small bowel, hepatobiliary and skin, which are included in the modified Amsterdam criteria (9). The genetic defect underlying Lynch syndrome is a defect in DNA mismatch repair genes. In the presence of normal DNA mismatch repair, abnormally paired nucleotides are excised and replaced with the proper nucleotide base pair. However, if inactivation of mismatch repair system, characteristic of Lynch syndrome, is present, errors in base pairing can accumulate and predispose the cell to malignant progression. This persistent error in base pairing in the DNA from patients with Lynch syndrome has been referred to as the "mutator" phenotype, the "replication error repair" phenotype, or microsatellite instability (1). Six human genes have been identified as participating in the function of mismatch repair. These genes include hMSH2, hMLH1, PMS1, PMS2, hMSH6 and hMSH3 (10-15), although germline mutations in MSH2 and MLH1 account for the majority of Lynch syndrome families (16,17).
involved family members, metachronous CRC were observed 4-23 years after diagnostics of initial CRC. The earliest onset of the disease was diagnosed in the proband (35 years), and in more than a half of involved patients, malignancy was detected before 50 years of age. There were 9 (75%) of right sided, but 3 (25%) of left-sided CRC. In one family member, metachronous sigmoid CRC was small (6 mm) flat lesion revealed four years after surgery for cecal adenocarcinoma. Histology revealed in most of cases mucinous and poorly differentiated adenocarcinoma. The proband is under regular control, without any sign for metachronous growth. The proband is responsible not only for our interest in hereditary cancers, but for the other healthy family members, who follow him and come for regular, determinated gastroenterological and gynecological examinations.
DISCUSSION
Lynch syndrome is an autosomal dominantly inherited disorder of cancer susceptibility with very high penetrance rate of 80-85% (18-21). This syndrome accounts for about 1-2% of all CRC occurrences (22). Mutations of the major mismatch repair (MMR) genes MLH1 and MSH2 are detected in 30-80% of HNPCC kindreds from different ethnic backgrounds (23-26). To date the only known cause is an inherited mutation in one of the following (MMR) genes: hMSH2, hMLH1, PMS1, PMS2, hMSH6, hMSH3 (10-15). ICG-HNPCC at its meeting held in Amsterdam in 1990 was established a set of selection criteria for families with Lynch syndrome to provide a basis for uniformity in collaborative studies. By the time the Amsterdam criteria have also been criticized. Some investigators feel that the criteria exclude some classic Lynch families because they do not take into account the extracolonic cancers that are tumor spectrum of the syndrome (8). It is now concluded that many true HNPCC families would be missed if the criteria are applied to clinical diagnosis, and that families not meeting the criteria might be falsely reassured and excluded from genetic counseling, DNA testing, or surveillance (27). To resolve some of these problems Rodriguez-Bigas et al. developed additional taking into account the molecular and pathologic features of CRC and adenomas in addition to family history (28). Taking into account some new reported data ICG proposed definition of Lynch syndrome (17-21): Familial clustering of colorectal and/or endometrial cancer Associated cancers: cancer of the stomach, ovary, ureter/renal pelvis, brain, small bowel, hepatobiliary tract, and skin (sebaceous tumours) Development of cancer at early age Development of multiple cancers Features of CRC: 1) predilection for proximal colon; 2) improved survival; 3) multiple CRC; 4) increased proportion
REPORT OF A FAMILY
Our interesting for hereditary CRC began in 1989 when a 58year old man (proband) was admitted to the Clinic for gastroenterology and hepatology, Clinical Center of Nis, because of intestinal bleeding and changes in the large bowel movements. First episode was recorded six months before admission. Twenty-three years ago adenocarcinoma of transverse colon was diagnosed and right hemicolectomy was done. In the same time his son was admitted to the Clinic because of liver metastasis of colorectal cancer, two years after surgery for cecal adenocarcinoma. Colonoscopy revealed adenocarcinoma of descending colon at the splenic flexure. Additional analyses: laboratory, abdominal ultrasound and CT are excluded disease spread and left hemicolectomy was done. The proband was followed-up by colonoscopy and ultrasound, but four years after the second operation of metachronous CRC, stomach cancer was diagnosed (adenocarcinoma), and patient was operated. We began to collect family data and pedigree of family "S" was made (Fig. 1). We report the family "S" more than a 10 years after collecting data. In family "S" there are 43 members, but 11 (25.5%) members are involved with a total of 16 malignant tumours. In nine patients there were one or more CRC (metachronous), but in two family members, single stomach and ovarian cancer were detected. Most malignant tumours are CRC, but two stomach cancer and endometrial and ovarian cancer were diagnosed, too (12) . In 3 (27.2%) of
6 Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8
Aleksandar Nagorni
of mucinous tumours, poorly differentiated tumours, and tumours with marked host-lymphocytic infiltration and lymphoid aggregation at the tumor margin Features of colorectal adenoma: 1) the numbers vary from one to a few; 2) increased proportion of adenomas with a villous growth pattern; 3) a high degree of dysplasia, and 4) probably rapid progression from adenoma to carcinoma High frequency of MSI (MSI-H) Immunohistochemistry: loss of MLH1, MSH2, or MSH6 protein expression Germline mutation in MMR genes (MSH2, MLH1, MSH6, PMS1, PMS2). The new set of clinical criteria (Amsterdam criteria II-Revised ICG-HNPCC criteria) was proposed and accepted by the majority of ICG-HNPCC group (27): There should be at least 3 relatives with and HNPCC-associated cancer (CRC, cancer of the endometrium, small bowel ureter, or renal pelvis) One should be a first-degree relative of the other two At least two successive generations should be affected At least one should be diagnosed before age 50 Familial adenomatous polyposis should be excluded in the CRC(s) if any Tumours should be verified by pathological examination. It is important in the discussion of criteria, that criteria aim to provide a common nomenclature for the selection of families for studies and for the comparison of the results of these studies. Criteria are not permanent, they will change as our knowledge of Lynch syndrome advances (27). There are a few forms or variants of HNPCC. Muir-Torre syndrome is characterized by tumor spectrum of Lynch syndrome and skin tumours (6,29-31). "Caf-au-lait spots"(macular, sharply demarcated, evenly oval pigmented spots, present at birth) is another variant of the Lynch syndrome (32), characterized with early onset of CRC, oligopolyposis, glioblastoma and lymphoma. To the best of my known this report is the first in our literature. Reported family "S" fulfills "minimal Amsterdam"(Amsterdam Criteria I) and Revised ICG criteria (Amsterdam Criteria II). More than 25% of family members were affected with malignancy; three
successive generations were involved (11). In 75% of affected members CRC was detected proximal to the splenic flexure and correlate with literature data (33-35). Metachronous CRC were detected 4-23 years after initial CRC in 27.2% of affected family members and this finding correlate with literature data (36,37). In 2 (18.3%) patients stomach cancer was detected. There are conflicting data in literature about inclusion of the stomach cancer in the tumor spectrum of the Lynch syndrome (27,38). Some authors considered that gastric carcinoma is the second most common extra-colonic malignancy associated with Lynch syndrome (39,40). The cumulative risk of carcinoma of the stomach in putative HNPCC gene carriers has been estimated at 19 % (41). The predominance of intestinal type of gastric cancer in Lynch syndrome families (as in our report) was unexpected because the diffuse type usually is associated with familial occurrence (42). It is considered that high prevalence of stomach cancer in some Asian countries may occasionally result in the chance of familial aggregation of CRC and stomach cancer; the inclusion of stomach cancer in the criteria might therefore decrease the certainty that we were dealing with HNPCC (27). Periodic screening of patients with Lynch syndrome and healthy family members of HNPCC families is a secondary prevention of carcinoma and may lead to reduction of morbidity and mortality. Patients should be screened not only for CRC, but also for other malignancy of HNPCC tumor spectrum. The American College of Gastroenterology recommend that a complete colonoscopy be performed in members of a family who meet any of the revised Amsterdam criteria for Lynch syndrome every 1-3 years beginning at the age of 20-25 years when the earliest cases of CRC can occur, until the of 40 years (40,43,44). From 40 years, yearly colonoscopy should then be performed (43,45). Genetic tests are available for the diagnosis of Lynch syndrome in families suspected of having the disease based on the revised criteria (27). Unfortunately these tests are not available routinely in our country. The first test should be perform in the youngest family member with CRC (46). If the mutation is detected in the index patient, then the accuracy of the test in family members approaches 100% since all family members inherit the same mutation. These results are important to decide who needs colonoscopic screening. Genetic tests for HNPCC are far from ideal, so periodical screening of all family members of Lynch syndrome families have to be performed until genetic tests become routinely available.
54 CRC (cecum)
60 CRC (cecum)
60 GCa
35 CRC (transverse) 58 CRC (descending) 62 GCa
60 CRC
50 CRC (transverse) 50 CRC (sigmold)
48 CRC (cecum)
50 ECa 52 CRC (cecum)
39 CRC (cecum)
54 CRC (cecum) 36 OCa 58 CRC (sigmold)
Figure 1. Pedigree of family "S". (CRC - colorectal cancer, GCa - gastric cancer; ECa - endometrial cancer; OCa - ovarian cancer)
Lynch syndrome Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8 7
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17. Han HJ, Maruyama M, Baba S, Park JG, Nakamura Y. Genomic structure of human mismatch repair gene, hMLH1, and its mutation analysis in patients with hereditary non-polyposis colorectal cancer (HNPCC). Hum Mol Genet 1995; 4: 237-42. 18. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993; 104: 1535-49. 19. Marra G, Boland CR. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 1995; 87: 1114-25. 20. Lynch HT, Smyrk T, Lynch J. An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet 1997; 93: 84-99. 21. Jass JR. Diagnosis of hereditary nonpolyposis colorectal cancer. Histopathology 1998; 32: 491-7. 22. Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis coloectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998; 338: 1481-7. 23. Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair gene in hereditary non polyposis colorectal cancer patients. Nat Med 1996; 2: 169-74. 24. Nystrom-Lahti M, Wu Y, Moisio M, et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 1996; 38: 76376. 25. Viel A, Genuardi M, Capozzi E, et al. Characterization of MSH2 and MLH1 mutations in Italian families with hereditary non-polyposis colorectal cancer. Genes Chromosom Cancer 1997; 18: 8-18. 26. Weber TK, Conlon W, Petrelli NJ, et al. Genomic DNA-based hMSH2 and hMLH1 mutation screening in 32 eastern United States hereditary nonpolyposis colorectal cancer pedigrees. Cancer Res 1997; 57: 3798-803. 27. Vasen HFA, Watson P, Mecklin J-P, Lynch HT, and the ICG-HNPCC. New clinical criteria for hereditary Nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999; 116: 1453-6. 28. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute workshop on HNPCC syndrome: meeting hihglights and Bethesda guidelines. J Natl Cancer Inst 1997; 89: 1785-1792. 29. Anderson DE. An inherited form of large bowel cancer: Muir's syndrome. Cancer 1980; 45: 11037. 30. Lynch HT, Lynch PM, Restep J, Fusaro KM. The cancer family syndrome: Rare cutaneous phenotypic linkage of Torre's syndrome. Arch Intern Med 1981; 141: 607-11. 31. Godard V, Coulet F, Bernaudin J-F, Housset M,
Soubrier F. Mutation oh MSH2 gene in MuitTorre syndrome. Ann Dermatol Venereol 1999; 126: 1-4. 32. Trimbath JD, Petersen GM, Erdman SH, Ferre M, Luce MC, Giardiello FM. Caf-au=lait spots and early onset colorectal neoplasia; a variant of HNPCC? Familial Cancer 2001; 1: 101-5. 33. Nagorni A. Hereditary non-polyposis colorectal cancer. Arch Gastroenterohepatol 1996; 15: 11622. 34. Lovett E. Family studies in cancer of the colon and rectum. Br J Surg 1976; 63: 13-8. 35. Lynch PM, Lynch HT, Harris RE. Hereditary proximal colonic cancer. Dis Colon Rectum 1977; 20: 661-8. 36. Mecklin JP, Jrvinen HJ. Clinical features of colorectal carcinoma in cancer family syndrome. Dis Colon Rectum 1986; 29: 160-4. 37. Lynch HT, Watson P, Lanspa SJ, et al. Natural history of colorectal cancer in hereditary nonpolyposis colorectal cancer (Lynch syndrome I and II). Dis Colon Rectum 1988; 31: 439-44. 38. Aarnio M, Salovaara R, Aaltonen LA, Mecklin JP, Jrvinen HJ. Features of gastric cancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer 1997; 74: 551-5. 39. Vasen HFA, Offerhaus GJA, Den Hartog Jager FCA, et al. The tumor spectrum in hereditary nonpolyposis colorectal cancer: a study of 24 kindreds in the Netherlands. Int J Cancer 1990; 46: 31-4. 40. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary non-polyposis colorectal cancer: an updated review. Gastroenterology 1993; 104: 1535-49. 41. Aarnio M, Mecklin J-P, Aaltonen LA, NystromLahti M, Jrvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64: 430-433. 42. Lehtola J. Family study of gastric carcinoma: with special reference to histological types. Scand J Gastroenterol 1978; 13 (suppl. 50): 1-54. 43. Rex DK, Johnson DA, Lieberman DA, Burt RW, Sonnenberg A. Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 2000; 95: 868-77. 44. Terdiman JP, Conrad PG, Sleisenger MH. Genetic testing in hereditary colorectal cancer: indications and procedures. Am J Gastroenterol 1999; 94: 2344-56. 45. Jrvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer (see comments). Gastroenterology 1995; 108: 1405-11. 46. Burt RW. Colon cancer screening. Gastroenterology 2000; 119: 837-53.
Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8
Aleksandar Nagorni

Aleksandar Nagorni, Vuka Katic, Jovica Milanovic, Vesna Zivkovic, Goran Bjelakovic.
The Lynch syndrome: Report on family "S"

Lynch-ov sindrom: Prikaz porodice "S"
( accepted June 20th, 2002 )
Clinic for Gastroenterology and Hepatology and Clinic for Pathology, Clinical Center,Ni{
Key Words: Lynch syndrome, metachronous CRC, stomach cancer
Abstract Lynch syndrome (HNPCC-hereditary non-polyposis colorectal cancer) is an autosomal dominant inherited disorder characterized by early onset of colorectal cancer (CRC), a preponderance of CRC in proximal colon, occurrence of multiple CRC, mucinous and poorly differentiated adenocarcinoma. We report family "S" with 11 (25.5%) affecting members. Metachronous CRC were observed in 27.2% affecting members. In tumour spectrum of Family "S" there were stomach, ovarian and endometrial cancer. Genetic tests are not routinely available in our country, so periodic screening of all family members have to be perform according to recommendation.
Klju~ne re~i: Lynchov sindrom, metahroni KRK, karcinom èluca
Saètak Lynch-ov sindrom (HNPKK- hereditarni ne-polipozni kolorektalni karcinom) je autozomno dominantni nasledni poreme}aj koji se karakteri{e ranim po~etkom kolorektalnog karcinoma (KRK), predispozicijom za proksimalni kolon, pojavom multiplih KRK, mucinozni i slabo diferentovani adenokarcinomi. Saop{tavamo porodicu "S" sa 11 (25.5%) obolelih ~lanova. Metahroni KRK su zapaèni u 27.2% obolelih ~lanova. U tumorskom spektru porodice "S" otkriveni su karcinomi èluca, ovarijuma i endometrijuma. Genetski testovi jos uvek nisu rutinski dostupni u na{oj zemlji, pa periodi~no pra}enje svih ~lanova porodice treba izvoditi u skladu sa preporukama.
UVOD
Kolorektalni karcinom (KRK) je ~etvri naj~e{}i karcinom i drugi vode}i uzrok smrti od karcinoma u mnogim zemljama {irom sveta. U proteklih nekoliko godina, inovacije u molekularnoj biologiji i genetici KRK nisu pro{irili samo na{e razumevanje bolesti, nego su omogu}ili i shvatanje patogeneze sporadi~nog i naslednih sindroma KRK (1). Nasledni ne-polipozni KRK (HNPKK) je prvi put prepoznat 1895 godine. Poznati patolog Aldred Warthin je tada ~uo od svoje {valje, koja je bila depresivna, jer je bila uverena zbog porodi~ne anamneze, da }e jednog dana umreti od karcinoma ènskih organa ili creva. Kao {to je i predpostavila, umrla je u mladosti od karcinoma
Abbreviations used in this article: CRC,colorectal cancer; HNPCC,hereditary non-polyposis colorectal cancer; ICG HNPCC,International Collaborative Group Hereditary NonPolyposis Colorectal Cancer; MMR,Mismatch Repair.
endometrijuma. Warthin je 1913 godine publikovao Porodicu G sa endometrijalnim, kolorektalnim i èluda~nim karcinomom kao predominantnim malignitetima u ovoj porodici (2). U slavu Henrija Lyncha-a, koji je ovaj problem prou~avao sredinom {ezdesetih godina, Internacionalna Kolaborativna Grupa za Nasledni Ne-Polipozni Kolorektalni Karcinom (IKG-HNPKK) nazvala je HNPKK njegovim imenom (Lynch sindrom). Lynchov sindrom je autozomno dominantni sindrom naslednog karcinoma koga karakteri{e razvoj KRK sa po~etkom u ranim godinama, predominacijom karcinoma u proksimalnim segmentima kolona, multiplim KRK, sinhronim i metahronim KRK (3,4), slabo diferentovanim i mucinoznim KRK (5,6). Lynchov sindrom je udruèn sa
Professor: Aleksandar V. Nagorni, MD, PhD, Clinic for gastroenterology and hepatology, Clinical Center Nis, 48 Brace Taskovica St., Yu-18000 Nis, Serbia, Yugoslavia. Fax: +381 18 335 186 E-mail: anagorni@bankerinter.net
malim brojem adenoma koji su predominantno lokalizovani u desnom kolonu (7). IKG-HNPKK je 1990 godine predloìla "Minimalne amsterdamske kriterijume" da bi olaka{ala klini~ku dijagnozu HNPKK (8). "Minimalni" kriterijumi uklju~uju: 1) tri ili vi{e ro|aka sa KRK, jedan je ro|ak prvog kolena srodstva drugoj dvojici, 2) oboleli ro|aci obuhvataju dve ili vi{e generacija, 3) najmanje jedan od ro|aka oboli od KRK pre 50-te godine ìvota (8). Osim KRK, bolesnici sa Lynchovim sindromom imaju rizik da razviju ekstrakoloni~ne tumore uklju~uju}i karcinome endometrijuma, ovarjuma, uretera, èluca, karlice bubrega, tankog creva, hepatobilijarnog trakta i koè, {to je uklju~eno u modifikovane amsterdamske kriterijume (9). Osnovni genetski defekt u Lynchovom sindromu je defekt DNA rasparene popravke gena. U prisustvu normalne DNA rasparene popravke, patolo{ki upareni nukleotidi se isecaju o zamenjuju sa pravim parom nukleotidnih baza. Me|utim, u prisustvu inaktivisanog sistema rasparene popravke, karakteristike Lynchovog sindroma, gre{ke u sparivanju baze se mogu kumulorati i predisponirati }eliju na malignu progresiju. Ova perzistentna gre{ka u sparivanju baza DNA u bolesnika sa Lynchovim sindromom je saop{tena kao "mutator" fenotip, "popravka replikacione gre{ke", ili mikrosatelitna nestabilnost (1). Identifikovano je 6 humanih gena koji u~estvuju u funkciji rasparene popravke. Ovi geni uklju~uju hMSH2, hMLH1, PMS1, PMS2, hMSH6 i hMSH3 (10-15), premda su klicine mutacije u MSH2 i MLH1 obja{njenje za ve}inu porodica sa Lynchovim sindromom (16,17).
bolesnik je operisan. Prikazujemo porodicu "S" posle vi{e od 10 godina prikupljanja podataka. Porodica "S" je brojala 43 ~lana, 11 (25.5%) ~lana su obolela sa ukupno 16 malignih tumora. U 9 bolesnika su otkrivena jedan ili vi{e KRK (metahroni), u dva ~lana porodice otkriveni su po jedan karcinom èluca i ovarijuma. Ve}ina (12) malignih tumora su KRK, tako|e su dijagnstikovana i 2 karcinoma èluca i po jedan karcinom endometrijuma i ovarijuma. U 3 (27.2%) obolelih ~lanova porodice otkriveni su metahroni KRK, 4-23 godine nakon dijagnostikovanja inicijalnog KRK. Najraniji po~etak bolesti je otkriven u probanda (35 godina), u vi{e od polovine obolelih bolesnika malignitet je otkriven pre 50te godine ìvota. Otkriveno je 9 (75%) desno-stranih, i 3 (25%) levostranih KRK. U jednog ~lana porodice metahroni, sigmoidni KRK je bio mali (6 mm) zaravnjena promena otkrivena 4 godine nakon operacije karcinoma cekuma. U ve}ije slu~ajeva histologija je pokazala mucinozni i slabo diferentovani adenokarcinom. Proband se redovno kontroli{e i nema znake za metahroni rast. Proband je zasluàn ne samo za na{e interesovanje za nasledne karcinome, nego i za zdrave ~lanove porodice koji ga slede na redovnim gastroenterolo{kim i ginekolo{kim pregledima.
DISKUSIJA
Lynchov sindrom je nasledni autozomno dominantni poreme}aj osetljivosti na kacinom sa veoma visokom stopom penetracije od 80-85% (18-21). Ovaj sindrom obja{njava oko 1-2% od svih KRK (22). Mutacije glavnih gena rasparene popravke, MLH1 i MSH2 su otkrivene u 30-80% HNPKK srodnika razli~itog etni~kog porekla (2326). Do danas jedini poznati uzrok je nasledna mutacija jednog od slede}ih gena rasparene popravke: hMSH2, hMLH1, PMS1, PMS2, hMSH6, hMSH3 (10-15). IKG-HNPKK na sastanku odrànom 1990 godine u Amsterdamu je utvrdilo grupu selekcionih kriterijuma za porodice sa Lynchovim sindromom da bi obezbedila osnovu za jednolikost u kolaborativnim studijama. Vremenom su amsterdamski kriterijumu kritikovani. Neki istraìva~i su ose}ali da kriterijumi isklju~uju neke klasi~ne poorodice sa Lynchovim sindromom jer ne uzimaju u obzir ekstrakoloni~ne karcinome koji su tumorski spektar ovog sindroma (8). Zaklju~eno je da bi mnoge prave HNPKK porodice nedostajale ako bi se primenili kriterijumi za klini~ku dijagnozu, a da porodica ne ispunjava kriterijume i da bi se pogre{no ponovo uverili i
PRIKAZ PORODICE
Na{e interesovanje za nasledni KRK je zapo~elo 1989 godine kada je 58-godi{nji mu{karaca (proband) primljen na Kliniku za gastroenterologiju i hepatologiju Klini~kog Centra Ni{ zbog intestinalnog krvarenja i promena crevnom motilitetu. Prve tegobe su otpo~ele 6 meseci pre prijema. Trideset godina ranije dijagnostikovan je adenokarcinom transverzalnog kolona i ura|ena je desna hemikolektomija. U isto vreme na Kliniku je primljen njegov sin zbog jetrenih metastaza KRK, dve godine nakon operacije adenokarcinoma cekuma. Kolonoskopija je otkrila adenokarcinom descendentnog kolona na lijenalnoj fleksuri. Dodatne analize: laboratorija, ultrazvuk abdomena, KT su isklju~ile {irenje bolesti i ura|ena je leva hemikolektomija. Zapo~eli smo sa sakupljanjem porodi~nih podataka i sa~injeno je geneolo{ko stablo porodice "S" (Slika 1). Proband je pra}en kolonoskopski i ultrazvu~no i 4 godina nakon druge operacije zbog metahronog KRK, dijagnostikovan je èluda~ni karcinom (adenokarcinom) i
Aleksandar Nagorni
isklju~ili iz genetskog savetovali{ta, DNA testiranja, ili pra}enja (27). Da bi re{ili neke od ovih problema Rodriguez-Bigas i sar. (28) su razvili dodatne kriterijume koji uzimaju u obzir molekularne i patolo{ke osobine CRC i adenoma uz porodi~nu anamnezu. Uzimaju}i u obzir nove saop{tene podatke (17-21) IKG je predloìla definiciju Lynchovog sindroma; ! Porodi~no gomilanje KRK i/ili karcinoma endometrijuma ! Udruèni kacinomi: karcinom èluca, ovarijuma, uretera/bubre`ne karlice, mozga, tankog creva, hepatobilijarnog trakta i koè (tumori lojnih `lezdi) ! Razvoj karcinoma u ranim godinama ! Razvoj multiplih karcinoma ! Osobine KRK: 1) predilekcija za proksimalni kolon; 2) pobolj{ano preìvljavanje; 3) multipli KRK; 4) pove}ana proporcija mucinoznih tumora, slabo diferentovanih tumora, tumori sa zna~ajnom host limfocitnom infiltracijom i limfoidnom agregacijom na ivici tumora ! Osobine kolorektalnog adenoma: 1) broj varira od jednog do nekoliko; 2) pove}ana proporcija adenoma sa viloznim strukturom; 3) visok stepen displazije, and 4) verovatno brza progresija od adenoma do karcinoma ! Visoka u~estalost mikrosatelitne nestabilnosti (MSIH) ! Imunohistohemija: gubitak MLH1, MSH2, ili MSH6 ekspresije proteina ! Klicine mutacijegena rasparene popravke (MSH2, MLH1, MSH6, PMS1, PMS2). Novi klini~ki kriterijumi (Amsterdamski kriterijumi IIPrera|eni IKG-HNPKK kriterijumi) su predloèni i prihva}eni od ve}ine ~lanova IKG-HNPKK (27): ! Najmanje tri ro|aka sa i HNPKK-udruènim karcinomima (KRK, karcinom endometrijuma, tankog creva, uretera ili bubre`ne karlice) ! Jedan je ro|ak drugoj dvojici u prvom kolenu ! Najmanje dve uzastopne generacije su zahva}ene ! Najmanje jedan je dijagnostikovan pre 5o-te godine ! Porodi~na adenomatozna polipoza treba da se isklju~i kod KRK
! Tumore treba verifikovati patolo{kim ispitivanjem. Va`no je u diskusiji kriterijuma, da kriterijumi maju cilj da obezbede zajedni~ku nomenklaturu za selekciju porodica za studije i za upore|enje rezultata ovih studija. Kriterijumi nisu stalni, menja}e se kako na{e znanje o Lynchovom sindromu (27). Postoji nekoliko formi ili varijanti HNPKK. MuirTorreov sindrom (6,29-31) se karakteri{e tumorskim spektrom Lynchovog sindroma i ko`nim. "Caf-au-lait fleke"(makularne, o{tro ograni~ene, glatke, ovalno pigmentisane fleke, prisutne na ro|enju) je druga varijanta Lynchovog sindroma (32), karakteri{e se ranim po~etkom KRK, oligopolipozom, glioblastomom i limfomom. Iz nama dostupne literature ovo je prvi prikaz u na{oj literaturi. Prikazana porodica "S" ispunjava "minimalne amsterdamske (Amsterdamski kriterijumi I) i {rera|ene IKG kriterijume (Amsterdamski kriterijumi II). Vi{e od 25% ~lanova porodice je zahva}eno malignitetima, uklju~ene su tri uzastopne generacije. U 75% zahva}enih ~lanova KRK je otkriven proksimalno od lijenalne fleksure i korelira sa literaturnim podacima (33-35). Metahroni KRK su otkriveni 4-23 godine nakon inicijalnog KRK u 27.2% obolelih ~lanova porodice, ovaj nalaz korelira sa literaturnim podacima (36,37). U 2 (18.3%) bolesnika otkriveni su karcinomi èluca. Postoje dijametralni podaci u literaturi (27,38) o uklju~ivanju karcinoma èluca u tumorski spektar Lynchovog sindroma. Neki autori smatraju da je karcinom èluca drugi naj~e{}i ektrakoloni~ni malignitet udruèn sa Lynchovim sindromom (39,40). Kumulativni rizik karcinoma èluca u predpostavljenih HNPKK nosioca gena je procenjena na 19% (41). Predominacija intestinalnog tipa èluda~nog karcinoma u porodicama sa Lynchovim sindromom (kao i u na{em prikazu) je neo~ekivano jer difuzni tip karcinoma èluca obi~no udruèn sa porodi~nim ispoljavanjem (42). Smatra se da je visoka prevalenca karcinoma èluca u nekim azijskim zemljama moè povremeno rezultirati slu~ajnom porodi~nom agregacijom KRK i karcinoma èluca; uklju~ivanje karcinoma èluca u kriterijume moè stoga da smanji sigurnost da postupamo sa HNPKK (27).
54 CRC (cecum)
60 CRC (cecum)
60 GCa
35 CRC (transverse) 58 CRC (descending) 62 GCa
60 CRC
50 CRC (transverse) 50 CRC (sigmold)
48 CRC (cecum)
50 ECa 52 CRC (cecum)
39 CRC (cecum)
54 CRC (cecum) 36 OCa 58 CRC (sigmold)
Figure 1. Pedigree of family "S". (CRC - colorectal cancer, GCa - gastric cancer; ECa - endometrial cancer; OCa - ovarian cancer)
Lynch syndrome Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8 7
Periodi~no pra}enje bolesnika sa Lynchovim sindromom i zdravih ~lanova porodice je sekundarna prevencija karcinoma i moè da dovede do smanjenja morbiditeta i mortaliteta. Pacijente treba pratitit ne samo za KRK, nego i na druge malignitete tumorskog spektruma HNPKK. Ameri~ki Koled` Gastroenterologa je savetovao da se izvr{i kompletna kolonoskopija u ~lanova porodice koji izpunjavaju neki od prera|enih amsterdamskih kriterijuma za Lynchov sindrom svake 1-3 godine sa po~etkom od 2025 godine kada se najraniji slu~ajevi KRK mogu ispoljiti, sve do 40-te godine (40,43,44). Od 40-te godine, treba izvoditi kolonoskopije jednom godi{nje (43,45).
Za dijagnozu Lynchovog sindroma u sumnjivim porodicama zasnovano na prera|enim kriterijumima dostupni su geneski testovi (27). Na nesre}u ovi testovi nisu rutinski dostupni u na{oj zemlji. Prvi test treba izvr{iti u najmla|eg ~lana porodice sa KRK (46). Kada se otkrije mutacija u indeksnog bolesnika onda ta~nost testa u ~lanova porodice dostiè 100% po{to svi ~lanovi porodice nasle|uju istu mutaciju. Ovi rezultati su va`ni za odluku ko zahteva kolonoskopsko pra}enje. Genetski testovi za HNPKK su daleko od idealnih, tako da periodi~no pra}enje svih ~lanova porodice Lynchovog sindroma treba da se sprovodi sve dok genetski testovi ne postanu rutinski dostupni.
Aleksandar Nagorni

Miodrag N. Krsti}, 2 Gradimir Golubovi}, 1 Marijan Micev, 1 Predrag Dugali}, 1 Dragan Tomi}, 1 Aleksandra Pavlovi}.
1
Case report
Endoscopic ultrasonoghraphy in Mntrier 's disease

Prikaz slu~aja
Institute of Digestive Diseases, Clinical Center of Serbia, Belgrade, 2 Department of Internal Medicine. Clinical Hospital Zemun, Belgrade.
Endoskopska ultrasonorafija u Menetrijerovoj bolesti

( accepted February 10th, 2002 )
Key Words: Menetrier's disease, large gastric folds, EUS.
Abstract The evaluation of patients with giant gastric rugal folds presents many problems to the gastroenterologist and pathologist. The variety of benign and malignant diseases must be considered in the differential diagnosis and all of them are difficult to separate by means of endoscopy and even biopsy. The unique ability of endoscopic ultrasound ( EUS ) to visualize the all layers of the gut wall makes it very useful in assessing patients with large gastric folds. EUS can precisely define which layers are thickened, characterise the echo pattern of thickness and whether the layer structure is preserved. Mntrier's disease is a prototype disease wich caracterises deep mucosal thickening which can be clear` ly delineated by EUS. Here, we report the very first case of Mntrier's disease which was assessed by EUS in our country. The role of EUS in differential diagnosis of large gastric folds is discussed in detail.
Klju~ne re~i: Menetrierova bolest, uve}ani èluda~ni nabori, endoskopska ultrasonografija.
Saètak Evaluacija pacijenata sa uve}anim èluda~nim naborima je te{ka i za gastroenterologe i za patologe. Veliki broj benignih i malignih stanja mora da se uzeme u razmatranje dok endoskopija, pa ~ak i biopsija naj~e{}e ne mogu da napravi razliku izmedju njih. Endoskopski ultrazvuk je posebno precizan u prikazivanjui slojeva zida digestivnog trakta te se stoga se veoma uspe{no koristi u ispitivanju pacijenata sa velikim èluda~nim naborima. On moè jasno da ukaè koji sloj je zadebljao, kakva je ehogenost zadebljanja i postoji li o~uvan kontinuitet slojeva zida. Menetrierova bolest je tipi~an predstavnik ove grupe obolenja i ona se odlikuje zna~ajnim zadebljanjem dubokog dela mukoze koje se jasno prikazuje na endosonogafiji. U radu je prikazan prvi pacijent sa Menetrierovom bole{}u koji je u na{oj zemlji analiziran endoskopskim ultrazvukom. U radu je takodje detaljno diskutovana uloga EUS-a u diferencijalnoj dijagnozi uve}anih nabora èluca.
Abbreviations used in this article: : LGF, large gastric folds; EUS, endoscopic ultrasound.
Docent Dr Miodrag N. Krstic, Institute of Digestive Diseases, Clinical Center of Serbia, 6 Koste Todorovica St, YU-11000 Belgrade Serbia, Yugoslavia E-mail: miodrag.krstic@kcs.as.yu
Figure 1. Menetrier disease: endoscopic view of large gastric folds in body and fundus.
Figure 2. EUS in Menetrier: thickening of II layer corresponding to deep mucosa.
INTRODUCTION
The evaluation of the patients with giant gastric mucosal usually imposes many problems to the gastroenterologist, the pathologist and even surgeons (1). A large scale of benign and malignant diseases should be considered in the differential diagnosis (2). Standard endoscopic biopsy is oftenly superficial for adequate histological diagnosis. The unique ability of endoscopic ultrasound to visualize the layers of the gut wall makes it very useful in assessing such patients (3). Menetrier's disease is a prototype disease in this category with typical thickening of deep mucosa (4). Here, we report a EUS finding in a patients with Menetrier's disease.
On EUS, extended and diffuse thickening of the second layer corresponding to deep mucosa was clearly demonstrated. A strict preservation of five layer pattern of gastric wall was observed, too. The depth of 3rd (submucosal) and 4th (muscle) layers was not changed. The thickeness of 2nd layer was inhomogenous and more hyperechoic.
DISCUSSION
A broad spectrum of malignant and benign stomach diseases may clinically and endoscopically present with giant mucosal folds (1-7). TABLE 1. Barium X ray studies, CT, MR are of no value in differential diagnosis of this condition. In the majority of cases endoscopic biopsies are not sensitive enough (3). Full-thickeness surgical biopsy used to be the golden standard for diagnosis in past decades. However, EUS is highly accurate in visualisation of the
BE N IGN DISE ASE S Menetrier's disease Zollinger-E llison syndrome Lymphocytic and E osinophylic gastritis Normal hyperrugosity Sarcoidoses and amyloidoses Crohn's disease TB and syphilis H.pyloris; CMV and H.simplex virus MALIGN AN T DISE ASE S Carcinoma Lymphoma Lymphoma of MALT Carcinoid
CASE REPORT
A middle aged man with Menetrier's disease was refeered from Clinical Hospital Zemun for EUS assessment in October 1999. The diagnosis of Menetrier's disease was established on previous hospitalization a couple of months ago. He had typical symptoms: profound weght loss, anorexia, voliting, diarrhoea as well as symetric edema on legs. Biochemical blood tests disclosed iron-defficiency anemia and marked hypoalbuminemia (<25g/l). On endoscopy, the giant mucosal folds (>10mm) were observed in the stomach body and fundus. Histology disclosed foveolar hyperplasia and glandular atrophy without inflammation in lamina propria mucosae. Thus, the diagnosis of advanced Menetrier's disease was confirmed on the basis of typical clinical, laboratory, endoscopical and histology findings.
Table 1. Classification of large gastric folds.
gut wall (3) Echo-endoscopes with 12MHz transducers allows demonstration of the 5-layer gut wall structue which almost completely correlates with anatomic layers of the normal gut wall (I and II layer belongs to the
Miodrag N. Krsti}
10
Figure 3. EUS in Mntriers disease: Thickening of deep mucosa with unchanged submucosa and muscularis propria.
mucosa; III layer ressembles submucosa, IV muscularis propria and V is adventitia or serosa). EUS can accurately disclose the disruption in the continuity of the normal layer pattern which is invariably observed in malignant diseases (4,5). EUS can also determine with high sensitivity which layers are thickened as well as ECHO pattern of such enlargement (6). Infiltrative gastric neoplasms, such as lymphoma or linitis plastica type carcinoma produce diffuse thickening of all layers (6). Thus, EUS can facilitate the differentation of benign from malignant aetiololgies (16). Recent studies confirmed this statement (7-10) Diffuse thickening of all layers or significant enlargement of 4th layer (muscularis propria) was recorded only in malignant conditions (7). Diffuse enlargement of 3 and 4 layer (submucosa and muscularis propria) was present in patients with scihirrous carcinoma (7,8). On the other hand, malignancy did not develop in all patients with gastric wall
Figure 5. EUS in linitis plastica: uniform thickening of mucosa, submucosa and muscularis propria; hypoechoic lamina propria mucosae between black arrowheds; submucosa and muscularis propria between white arrowheds.
thickening limited to layer 2 (deep mucosa) during a mean follow-up period of 35 months (8). When the second layer alone is thickened, Mntrier's disease should be at first considered as possible diagnosis and when third layer alone is abnormally enlarged, anisakiasis might be suspected (8). However, 2 and 3 layer enlargement may be present in healthy subjects with hyperrugosity, but also in patients with lymphoma (8,9). In all malignant conditions, thickening of the second layer was hypoechoic, too (1-9). EUS finding in our patient was typical: isolated, predominantly hyperechoic enlargement of second layer (deep mucosa) with preservation of 5-layer wall structure. These features strongly suggested benign aetiology of giant gastric folds, accoridng to the literature data (4-9). On the
Figure 4. Mntrier disease. Hystology show marked foveolar, ` semicystic hyperplasia of deep mucosa (lamina propria mucosae).
EUS in Mntrier , s disease `
Figure 6. EUS in linitis plastica: Thickening of whole gut wall
11
other hand, EUS finding in Menetrier's disease, although typical is not pathognomonic and diagnosis cannot be made with certainity without histology (8-10). Histologic hallmark of diagnosis is marked elongation and turtuosity of the pits (foveolar hyperplasia), accompanied by a reduction in the number of oxyntric glands. Lamina propria is markedly edematous as well (10). Endoscopic biopsy may not sample the full thickness of the mucosa thus revealing
only the foveolar hyperplasia. This is suggestive of diagnosis, but does not prove it (10). Typical EUS finding in conjuction with foveolar hyperplasia on biopsy diminish the need for surgical biopsy (10). It can provide reassurance that Menetrier's disease is likely or at least that thickened folds are benign (10). In our case this was confirmed too.
REFERENCES:
1. Yasuda K. High-resolution endoluminal sonography of the upper gastrointestinal tract: The radial scanning ultrasound probe. Part II. In: Van Dam J, Sivak MV. Gastrointestinal endosonography. Philadelphia: W.B.Saunders; 1999;95-100. 2. Yasuda K. The handbook of endoscopic ultrasonography in digestive tract. Ied. Oxford.: Blackwell Science; 2000. 3. Dancygier H, Lightdale C, Stevens P. Endoscopic ultrasonography of the upper gastrointestinal tract and colon. In: Dancygier H, Lightdale J. Endosonography in gastroenterology Ied. Stuttgart-New York: Thieme-Verlag; 1999; 13174.
4. Michael B. Kimmey, Peter Vilmann: Endoscopic 9. Manuory V, Klein O, Houcke ML, et al. ultrasonography In. Yamada, et al: Textbook of Endoscopic ultrasonography in the diagnosis of hypertrophic gastropathy (letter). gastroenterology VIed. Philadelphia : Lippnicott Gastroenterology 1994; 106:820. Wiliams and Wilkins; 1999; Chapter 136. 5. Carletti G, Fusaroli P, Bocus P. Endoscopic 10. Okuda M, Iiyuka Y, Oh K, et al. Gastritis cystica Ultrasonography. Digestion 1998; 59: 509-530. profunda presenting as giant gastric mucosal 6. Chak A. Endoscopic Ultrasonography. Endoscopy folds. The role of endoscopic ultrasonography and mucosectomy in the diagnostic work up. 2000; 32: 146-152 7. Mendis RE, Gerdes H, Lightdale C, et al. Large Gastrointestinal Endosc 1994; 40: 640-44. gastric folds: a diagnostic approach using endoscopic ultrasonography. Gastrointestinal Endosc 1994;40:437-441. 8. Songur Y, Okai T, Watanabe H, et al. Endosonographic evaluation of giant gastric folds. Gastrointestinal Endos 1995; 41: 468-474.
12
Miodrag N. Krsti}

Zoran Krivokapic, Radoje Colovic, Nikica Grubor, Marjan Micev
Institute for Digestive Diseases, Clinical Center of Serbia, Belgrade.
Stenosis of the small intestine and entero-enteral fistula due to mesenteric vascular occlusion
Stenoza tankog creva i entero-enteralna fistula prouzrokovani mezentericnom vaskularnom okluzijom
( accepted April 24th, 2002 )
Key Words: mesenteric ischemia, intestinal obstruction, entero-enteral fistula.
Abstract Stenosis of the small bowel due to mesenteric ischemia is rare and, to our best knowledge, a case of the entero-enteral fistula caused by that condition has not been described in literature so far. According to the clinical picture, patological features and localization, small bowel ischemic strictures can be divided into two groups: First, where ischemia goes unnoticed with symptoms only when intestinal stenosis is developed and where a short segment of the bowel is affected, and second, with episodes of acute ischemia followed by asymptomatic periods as well as by symptoms of intestinal obstruction, where the involved segment is longer and usually localized in jejunum. The diagnosis is based on the history, enteroclysis and pathohystological examination. In the differential diagnosis Crohn's disease and others causes of the acquired stenosis of the small bowel have to be considered. The therapy is surgical implying the removal of the stenosed segment of the small bowel with the additional angioplastical operation, when necessary. We present a case of 66-year old patient previously treated for mesenteric vascular occlusion with instillation of Novocain solution in the radix of the mesentery. The diagnosis of intestinal stenosis was established by upper GI series and confirmed itraoperatively. Double jejunal stenosis was found. Segmental resection of the affected intestine and end-to-end anastomosis were performed. Examination of the resected specimen revealed a jejuno-jejunal fistula in the stenotic segments. Crohn's disease was ruled out. The postoperative course was uneventful and the patient was discharged several days later. He is symptom-free three months after surgery.
Professor Dr Zoran Krivokapi} Instut za digestivne bolesti, KCS 6 Koste Todorovica Str, YU-11000 Beograd, Serbia, Yugoslavia. Tel./Fax: +381 11 361 8669 E-mail: scpy@beotel.yu
Klju~ne re~i: mesentrijska ishemija, intstinalna opstrukcija, entero-enteralna fistula.
Saètak Stenoze tankog creva prouzrokovane mezenterijskom sudovnom ishemijom su retke. Prema na{em uvidu u medicinsku literaturu slu~aj entero-enteralne fistule prouzrokovane ovakvim stanjem do sada nije opisan. Zavisno od klini~ke slike, patolo{kih promena i lokalizacije, ishemijske strikture tankog creva mogu da se podele u dve grupe. U prvu grupu spadaju ishemije koje prolaze klini~ki nezapaèno i koje se ispoljavaju tek onda kada nastanu simptomi stenoze tankog creva. U drugoj grupi su slu~ajevi u kojih su epizode crevne ishemije manifestne i iza kojih sledi asimptomski period sve do ispoljavanja simptoma i znakova stenoze tankog creva. Dijagnoza se zasniva na anamneznim podacima, enteroklizi, i patohistolo{kom pregledu reseciranog dela creva. U diferencijalnoj dijagnozi uvek treba da se razmotri Crohn-ova bolest i drugi uzroci ste~enih stenoza tankog creva. Le~enje je hirursko i podrazumeva odstranjenje stenozantnog segmenta sa dodatnom angioplastikom ukoliko je to indicirano. U radu se prikazuje slu~aj pacijenta ìvotne dobi 66 godina koji je prethodno bio le~en od mezenterijske vaskularne okluzije instilacijom Novocaina u radiks mezenterijuma. Dijagnoza intestinalne stenoze je postavljena radioloskim pregledom alimentarnog trakta. Itraoperativno je otkrivena dvostruka stenoza jejunuma. Segmentna resekcija izmenjenog dela creva i termino-terminalna anastomoza je bila na~injena. Pregled reseciranih delova creva je otkrio jejuno-jejunalnu fistulu u stenoticnom segmentu. Crohno-va bolest je bila isklju~ena. Postoperativni tok je bio bez komplikacija i pacijent je otpu{ten desetog dana izle~en.
Ischemic disease of the small intestine is not frequent. In the acute form it is characterized with high mortality (over 50%). To our best knowledge, small bowel stenosis due to mesenterial ischemia is rare, while entero-enteral fistula caused by ischemia has not been described until now.
CASE REPORT
Four months before admission to our institution, the patient, a 66 years old man, undergone emergency explorative laparatomy due to simptoms and signs of mesenteric ischemia. The patient has passed medical history of arterial hypertension for about 30 years. He experienced acute myocardial infarction in 1979, and in 1983 a triple arteriocoronary bypass due to coronary disease. He never used digitalis or potassium chloride medication. At operation mesentery radix was infiltrated with Novocain solution resulting in improvement of bowel perfusion thus making the bowel resection unnecessary. Three months later he became pyrexial. Nausea and protracted diarrhoea appeared as well. During the following month, most of the symptoms abated except abdominal colic, malaise, and progressive weight loss. Physical examination revealed no abnormalities except mild tenderness of the lower abdomen. Laboratory findings were within the normal limits. Plain abdominal x-ray films demonstrated air-fluid levels. Barium enema and sygmoidoscopy were suggestive of
Figure 1. Enteroclysis showing two jejunal stenosis with prestenotic dilatations.

Zoran Krivokapi}
Figure 2. Abdominal aortography and selective visceral angiography showing stenosis of the celiac truncus, occlusion of superior mesenteric artery with rich collateral vascularisation.
dolichocolon. Examination of the small intestine with enteroclysis showed presence of two jejunal stenosis with large prestenotic dilatations. Doppler ultrasonography of portal system did not reveal any pathological findings. There were no signs of thrombosis, decreased flow or presence of collateral venous vessels. Abdominal aortography and selective visceral angiography showed: stenosis of the coeliac trunc up to 60-70%, occlusion of superior mesenteric artery in the middle part with rich collateral vascularisation and an arcus of Riolan that vascularised the coecum with normal features of mesenteric and portal veins. Accordingly, mesenteric ischemia was recognized as the aetiological factor. The patient was operated on 26.07.1999. After the adhesions were removed a subtotal occlusion of the small intestine, 80-100 cm of Treitz and an intestinal jejuno-jejunal fistula was found. Resection of the affected segment of the small intestine was performed in the length of 70 cm with a stapled side-to-side anastomosis. Postoperative recovery was uneventful. The patient was discharged 9 days after the operation and was symptom-free at the time. On the last follow-up examination the patient had no complaints. Histopathological examination of the resected part of the small intestine showed chronic inflammation of the mucosa with ulceration, Crohn's disease-like chronic lymphocytic inflammation of the submucosa without granulomata or other histopathological features of Crohn's disease. This was nonspecific finding that might correspond to the ischemic origin of the changes.
Figure 3. Stenosed jejunal segment with large prestenotic dilatation.
tine thus leading to structural changes. In the acute mesenteric ischemia, ischemic damage may vary from transient impairment of the bowel function to transmural ischemic necrosis resulting in intestinal perforation. Between these two extremes is the so-called "subnecrotizing ischemia", when ischemic lesion does not damage all layers, but the mucosa only, which is the most vulnerable (1). Resistance to ischemic damage rises from the lumen inside out. The level of ischemic damage progression depends on the degree of ischemia and of efficacy of compensatory mechanisms. When ischemic damage reaches the lamina muscularis mucosis, then it leads to formation of fibrous tissue and, subsequently, to retraction and formation of the bowel stenosis (2). Acute mesenteric ischemia usually is so severe that in more than 50% cases of cases it ends lethally (3). All causes of acute mesenteric ischemia belong to
DISCUSSION
Mesenteric ischemia can be chronic, with functional bowel changes (malabsorption), but without impaired intestinal vitality or acute, where ischemic damage of the bowel is so severe that jeopardizes the vitality of the intesEntero-enteral fistula due to mesenteric occulsion
Figure 4. Resected specimen showing stenosis of the small bowel with prestenotic dilatation and jejuno-jejunal communication (fistula).
15
this type of ischemic damage. Thrombosis of the superior mesenteric vein is very rare (4). Embolisation of the superior mesenteric artery (SMA), thrombosis of the SMA, nonocclusive ischemic disease and, especially, focal segmental ischemia are causes of ischemic intestinal strictures ( 5,6,7). In embolisation of the SMA major emboli may be present in 85-90%, usually lodged in the beginning of ileocolic artery and minor emboli, present in 10-15%, in the distal part. The latter are mostly the cause of intestinal stenosis (2). Experimental studies support that opinion. Embolisation of branches of the SMA in dogs with gelatin sponges provoked segmental intestinal stenosis (8). Reasons for focal segmental ischemia of bowel include atheroembolism, strangulated hernias, vasculitis, blunt abdominal trauma, segmental venous thrombosis, radiotherapy, drugs (oral contraceptives, digoxins, NSAID, cocaine) where, due to a range of damage of the intestinal vascular bed, adequate collateral circulation prevents transmural necrosis of small intestine (2,9.10). That is the reason why acute focal segmental ischemia is probably the most common cause of the ischemic bowel stenosis. Clinical manifestations of mesenteric ischemia correlate with the level of ischemic damage of the bowel, and less with the underlying cause (2). Based on histopathological findings, clinical picture and evolution of the disease, we can divide all acquired ischemic strictures of the small bowel into two major types (11): 1) Asymptomatic form of mesenteric ischemia. This clinically manifests with insidously but progressively developing intestinal obstruction. Usually short segment of the small intestine is affected (usually middle or terminal ileum). . 2) Symptomatic form is when symptoms and signs of the acute mesenterial ischemia are present from the beginning. This was followed by asymptomatic period and gradually developing symptoms and signs of the intestinal occlusion thereafter. In this case larger part of the bowel, oftenly jejunum, is affected. It is not always possible to make a clear distinction between these two types of intestinal ischemic strictures, since transitive forms and variations are not rare (5,7,12,13). Our patient, however, fits into to this classification. Kradijan and associates described 6 patients with large ischemic lesions of the small intestine who had an asymptomatic phase followed by clinical picture of ileus and perforation in two cases. The strictures were localized in the ileum and involved short segments up to 3 cm in length, with normal appearance of bowel under stenosis. The confusion is produced by the fact that 5 of 6 patients had enteric-coated potassium chloride in therapy, later found to be the culprit of formation of strictures and bowel
perforation, while the lesions completely matched the lesions accompanying this form of medication, in their appearance (pylorus-like annular and tubular stenoses) and localization (distal ileum) (14). It difficult to determine why ischemic stricturing is more frequent in certain portions of the small intestine. This is partly due to poor vascularisation of the terminal part of the ileum and rich vascularization of the jejunum. That is the reason why larger segment of the jejunum can be involved with ischemic process without causing a perforation, but only stenosis. Macroscopic and radiographic appearance of this type, where stenosis involves long segments of the small bowel, is similar to findings in the Crohn's disease. Therefore, histopathological examination is necessary for differential diagnosis (1,5,11). It is important to distinguish ischemic strictures from nonischemic ones due to Crohn's disease, neoplasm, other inflammatory tumors (for example, acute pancreatitis), use of enteric-coated potassium chloride, and cause of intestinal ischemia: trauma, irradiation, mechanical occlusion, vasculitis, drugs (NSAID's, digitalis, oral contraceptives), embolisation or thrombosis of the mesenteric artery, because further treatment depends on this (7,15). The diagnosis of the intestinal stenosis is simple. Contrast radiography of the small bowel is the diagnostic modality of choice in such a case (16). Ischemic small intestinal lesions may often be the cause of the acquired small bowel stenosis and therefore angiographic examinations are necessary to diagnosed it. The treatment includes resection of strictured segment of the small intestine and end-to-end anastomosis. Also, depending on the cause of ischemia, reconstructive surgery of mesenteric arteries directed towards improvement of perfusion of mesenteric vascular bed is required, as well discontinuation of related drugs. Therefore, depending of the cause of intestinal stenosis the type of treatment is not limited only to resection of stenotic segment. In conclusion, our case of double jejunal stenosis and jejuno-jejunal fistula was caused by mesenteric ischemia, namely SMA thrombosis, which was of limited range due to the localization and previous intraoperative Novocain treatmen. According to these facts and to angiography findings, which showed well developed collateral circulation, the treatment was limited to resection of the stenotic segments. The continuity of digestive tract was established with termino-terminal jejuno-jejunal anastomosis.
Zoran Krivokapi}
REFERENCES:
1. Wayt DM, Helwig EB: Small-bowel ulcerationiatrogenic or multifactorial origin? Amer J Clin Path 1968,49:26-40. 2. Brandt LJ, Smithline AE: Ischemic lesions of the bowel. In Feldman M, Sleisenger MH, Scharschmidt BF (eds): Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management, ed 6. Philadelphia, WB Saunders, 1998, pp 2009-2024. 3. Bastidas JA, Reilly PM, Bulkley GB: Mesenteric vascular insufficiency. In Yamada Y, Alpers DH, Owyang C et al (eds): Texbook of Gastroenterology, ed 2. Philadelphia, JB Lippincott, 1995, pp 2490-2523. 4. Eugene C, Valla D, Wesenfelder L et al. Small intestine stricture complicating superior mesenteric vein thrombosis. A study of three cases. Gut 1995; 37: 292-5. 5. Feurle GE, Haag B. Acute small bowel ischemia without transmural infarction. Z Gastroenterol 1991; 29: 349-52.
6. Thaker P, Weingarten L, Friedman IH. Stenosis of the small intestine due to nonocclusive ischemic disease. Arch Surg 1977; 112: 1216-7. 7. Saegesser F, Borgeaud J, Schnyder P et al. Stenosis of the small intestine of ischemic origin in the adult. Schweiz Med Wochenschr 1976; 106: 367-76. 8. Cho KJ, Schmidt RW, Lenz J. Effects of experimental embolization of superior mesenteric artery branch on the intestine. Invest Radiol 1979; 14: 207-12. 9. Allen JC. Post-traumatic small bowel obstruction. J R Army Med Corps 1994; 140: 47-8. 10. De Backer AI, De Schepper AM, Vaneerdeweg W, Pelckmans P. Intestinal stenosis from mesenteric injury after blunt abdominal trauma. Eur Radiol 1999; 9: 1429-31. 11. Mozes M, Adar R, Tsur N et al. Intestinal obstruction due to mesenteric vascular occlusion. Surg Gynecol Obstet 1971; 133: 583-7. 12. Haraguchi M, Matsushima S, Fujie Y, Sugimachi K: Ischemic stricture of the jejunum-report of a case. Jpn J Surg 1990,20:715-719.
13. Kradjian RM. Ischemic stenosis of small intestine. Arch Surg 1965; 91: 829-34. 14. Grosdidier J, Boissel P, Bresler L, Vidrequin A. Stenosing and perforated ulcers of the small intestine related to potassium chloride in enteric-coated tablets. Apropos of 11 cases. Chirurgie 1989; 115: 163-9. 15. Kato T, Morita T, Fujita M et al. Ischemic stricture of the small intestine associated with acute acute pancreatitis. Int J Pancreatol 1998; 24: 237-42. 16. Ginai AZ, Hussain SM, Hordijk ML, den Hollander JC. Case report: solitary ischaemic small bowel stenosis. Br J Radiol 1994; 67: 405-7. 17. Lietz H, Meissner K. Mysterious segmental stenosis of the small intestine. Dtsch Med Wochenschr 1982; 107: 299-303.
Entero-enteral fistula due to mesenteric occulsion
17

Tamara Vukavi}, M. Stoji}, 2 Ljiljana Savi}, 2 Ivica Stankovi}, 3 M. Peroevi}, 4 K. Ajdànovi}, 5 Lj. Stoli} 6 B. Kaì}.
1 1
Management of acute gastroenteritis in Yugoslavia: Compliance with ESPGHAN recommendations

Lecenje akutnog gastroenteritisa u Jugoslaviji: Saglasnost sa peporukama ESPGHANa
Institute of Child and Youth Health Care, Novi Sad; 2 Institute of Mother and Child Health Care, Novi Beograd; 3 Clinical Centre, Podgorica; 4 Health Centre, Ruma; 5 General Hospital, Vrac; 6 General Hospital, Vrbas
Key Words: acute gastroenteritis, treatment, infant, Yugoslavia.
Abstract Oral rehydration is a mainstay of treatment for acute diarrhoea, both, in developing and in industrialized countries. ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) Working Group on Acute Diarrhoea initiated European multicentre survey covering main aspects of the management of water and electrolyte losses and refeeding. Yugoslavia was one of 29 countries participating from Europe. The results showed that physicians often advice oral rehydration solution - ORS (Yugoslavia 70%, others 84%), less frequently ORS with 60 mmol/L sodium (Yugoslavia 62%, others 66%), and seldom practice fast rehydration over 3-4h (Yugoslavia 15%, others 16%). Advice for continued supplementation with ORS for watery stools after initial fast rehydration varies among physicians (Yugoslavia 93%, others 37%). Reintroduction of normal diet after fast rehydration is not in a frequent practice (Yugoslavia 6%, others 21%). Contrary to ESPGHAN recommendations, lactose-free or lactosefree cow's milk protein-free formula is recommend often (Yugoslavia 51% and 24%, others 35% and 19%, respectively). However, breast-feeding is continued at high rate (Yugoslavia 96%, others 77%). Physicians also advise antidiarrhoeal drugs (Yugoslavia 47%, others 25%), antibiotics and probiotics (Yugoslavia 79.6% and 60%).
Klju~ne re~i: akutni gastroenteritis, le~enje, odoj~e, Jugoslavija.
Saètak Oralna rehidracija ~ini osnovu terapije kod akutne dijareje u nerazvijenim i u razvijenim zemljama. Radna grupa za akutnu dijareju Evropskog udruènja za de~iju gastroentrologiju, hepatologiju i ishranu (ESPGHAN), pokrenula je multicentri~nu evropsku studiju za primenu prepopruka za nadoknadu vode i elektrolita i realimentaciju nakon inicijalne rehidracije, u kojoj je Jugoslavija bila jedna 29 zemalja u~esnica zapadne, centralne i isto~ne Evrope. Ispitivanje je pokazalo da lekari ~esto ordiniraju oralnu rehidracionu soluciju - ORS (Jugoslavija 70%, ostali 84%), manje ~esto ORS sa 60 mmol/L natrijuma (Jugoslavia 62%, ostali 66%), a retko retko primenjuju brzu rehidraciju (Jugoslavija 15%, ostali 16%). Nastavljanje nadoknade ORS pri perzistiranju te~nih stolica, posle po~etne rehidracije, razli~ito se praktikuje (Jugoslavija 93%, ostali 37%). Uvo|enje normalne dijete posle po~etne rehidracije primenjuje se retko (Jugoslavija 6%, ostali 21%). Nasuprot ESPGHAN preporukama, preparati kravljeg mleka bez laktoze ili preparati bez laktoze i bela~evina kravljeg mleka ~esto se daju (Jugoslavija 51%, odnosno 24%, ostali 35% odnosno 19%). Me|utim, dojenje se nastavlja u visokom procentu (Jugoslavija 96%, ostali 77%). Lekari tako|e ordiniraju antidijaroi~ne lekove (Jugoslavija 47%, ostali 25%), antibiotike i probiotike (Jugoslavija 79.6% i 60%).
Acknowledgements: The authors wish to thank all participating, 113 physicians from Yugoslavia.
Dr Tamara Vukavic Institute of Child and Youth Health Care Paediatric Clinic 10, Hajduk Veljkova Str YU - 21 000 Novi Sad Serbia, Yugoslavia
Gastroenterolo{ka sekcija SLD, 01729, 2002
INTRODUCTION
Gastroenteritis in children is not only one of the leading causes of morbidity worldwide with around billion episodes of illness, but also of mortality in developing countries with 3-5 millions of deaths annually (1). In industrialized countries, morbidity and mortality from acute diarrhoea are much lower, but still significant. In Europe, they declined sharply over the last decades of the past century - from mid '70 till mid '80, death rates dropped by 20-25% (2, 3). In early '80, acute infectious diarrhoea, was the cause of infant death in of West European countries within the range of 2.3 (Germany) to 72.9 (Portugal) per 100.000 (3). In the USA, a quarter of a million of children, age less than 5 years, are admitted to hospital for acute gastroenteritis, anually. The death rates from diarrhoea and dehydration are between 300 and 500 each year (4, 5). Management of water and electrolyte losses and refeeding is the mainstay of the therapy for diarrhoea. Oral rehydration generally is the treatment of choice for mild to moderate dehydration and also a major approach in preventing complications. Through the activities of the World Health Organization (WHO) and UN Children's Fund, oral rehydration solution (ORS) dramatically reduced mortality from diarrhoeal diseases and became a major weapon in child survival programs. The latest estimated death rate from acute diarrhoea in children and adults, for 1999, fell to 2.2 million annually, as a result of the use of oral rehydration solution (ORS) (6). Working group of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) have issued two sets of recommendations on the treatment of infants with acute gastroenteritis complicated by mild to moderate dehydration. The first one, published in 1992 presented the guidelines for optimal composition of ORS for the use in children of Europe (7). It recommended a glucose based, 60 mmol/L sodium solution, which is hypoosmolar, as more suitable than WHO 90 mmol/L solution designed for treatment of children with cholera diarrhoea in developing countries (8). The second one, published in 1997, as the report of ESPGHAN Working Group on Acute Diarrhoea, recommended that the optimal management of mild to moderately dehydrated children in Europe should consist of oral rehydration over 3-4h and rapid reintroduction of normal feeding thereafter (9). Breast-feeding is to be continued if it is possible. Also, ORS has been recommended after initial rehydration, for replacement of ongoing abnormal losses of water and electrolytes. The Working Group concluded that the use of lactose-free formulae does not
appear to be justified in the vast majority of children. Also in most cases the normal diet can be resumed without restriction of lactose intake. However, if diarrhoea does worsen on the reintroduction of milk, stool pH and/or reducing substances should be checked. Lactose content should be reduced only if the stool is acid and contains > 0,5% reducing substances, suggesting lactose intolerance. Although recommendations on the use of antidiarrhoeal and antimicrobial drugs were not published by the ESPGHAN, there is a general agreement among paediatric gastroenterologists that pharmacological agents should not be used to treat acute gastroenteritis, with only few exceptions (infection with certain pathogenic microorganisms, patients with immune deficiency and some other, specific clinical settings) (10). The recommendations of the ESPGHAN Working Group are in accordance with the recommendations issued by the WHO and American Academy of Pediatrics (AAP) (7,911). In 1992 an analysis was carried out in the USA to assess how their physicians treat infants with acute gastroenteritis (12). It showed that very few primary care physicians followed all aspects of the AAP treatment guidelines for infants with acute diarrhoea complicated by mild to moderate dehydration. In 1998, ESPGHAN Working group on acute diarrhoea initiated a similar study in 29 European countries (13). The purpose of this multicentre study was to determine how closely, physicians treating infants with acute gastroenteritis, complicated by mild to moderate dehydration, follow ESPGHAN recommendations, regarding : 1. type of ORS used (if any) 2. start of oral rehydration (time from diarrhoea onset) 3. duration of oral rehydration 4. timing of refeeding 5. use of cow's milk (CM) protein-free and/or lactosefree formulas 6. use of antidiarrhoeal drugs 7. use of antimicrobial drugs 8. use of other drugs
METHODS
The study was based on questionnaire dealing with the management of hypothetical 6-month old infant with a 3day history of mild to moderate diarrhoea, who was 5% dehydrated, had no fever or vomiting and was fed on cow's milk based lactose-containing formula and solids. The child has not been breast-fed. By all given information the parents of the infant were considered reliable. There were no special indications for hospitalization of this child (13). National coordinators in 29 European countries Arch gastroenterohepatol 2002; 21 (No 1 - 2): 18 - 24 19
Management of acute gastroenteritis in YU
Austria, Belgium, Croatia, Cyprus, Czech, Denmark, Estonia, Finland, France, Georgia, Greece, Hungary, Iceland, Ireland, Israel, Italy, Latvia, Lithuania, Netherlands, Norway, Poland, Portugal, Romania, Russia, Slovakia, Slovenia, Sweden, United Kingdom and Yugoslavia, circulated the questionnaires to randomly selected primary care physicians as well as hospital based registrars and paediatricians. A minimum of 50 completed questionnaires were required from each country. The national data obtained from the questionnaires were collected and analyzed by the coordinators of the working group (13). The study started on October 1, 1998 and was completed by March 31, 1999 (13).
Duration of oral rehydration ESPGHAN guidelines for the use of oral rehydration over 3-4 h was strictly followed by only 14% (14.4% 15/104) of physicians, while majority (49.5% - 50/101) rehydrated their patients over 6-12 h. Not insignificant proportion of physicians - 24% (19.8% - 20/101), stated much longer exclusive oral rehydration. Supplementation with ORS for ongoing loses Supplementary ORS for replacement of ongoing losses from watery diarrhoea after initial rehydration, as recommended by ESPGHAN, was followed by 56% (92.6% 63/68) of physicians. Refeeding after oral rehydration ESPGHAN recommendation to reintroduce rapidly normal diet with solids after initial 3-4 h of oral rehydration was followed by only 12% (5.5% - 6/109), and contrary to guidelines, after 12-24 h (21.1% - 23/109) and even as late as 48 h after fast rehydration, by 36% (37.6% - 41/109) of physicians.
RESULTS
All data quoted in the tables and the text, extracted from the reference 13 for easier comparison, represent a percentage of total response rate of physicians (numbers outside parentheses). Data within parentheses (percentage and actual numbers, concerning Yugoslavia only), represent a percentage of the response rate to individual questions. Response rate The response rate in Yugoslavia, participating with 113/150 returned questionnaires or 3.8% out of total returned from 29 European countries, was 75%. The number of responding physicians varied among cities/towns: Beograd - 60, Herceg Novi - 7, Indija - 4, Nova Pazova 3, Novi Sad - 20, Podgorica - 6, Ruma - 5, Vladicin Han 4, Vrac - 4. Type of solution for oral rehydration The majority of responding physicians, 70% (70.5% 79/112) followed ESPGHAN recommendations for the use of ORS. TABLE 1. The remaining physicians started rehydration with clear fluids such as tea, Coca-Cola, fruit juice, chicken broth or home made ORS. Sodium content of ORS The 60 mmol/L sodium ORS was used by 56% (62.4% - 63/101) of physicians.
Use of special formula Lactose containing formula was adviced after successful oral rehydration by 23% (24.3% - 26/107) of physicians. Contrary to ESPGHAN guidelines, lactose free formula was prescribed by high 49% (51.4% - 55/107) and lactose-free and CM protein-free formula by 23% (24.3% - 26/107). Undiluted formula Only 19% (20.2% - 22/109) of physicians adviced refeeding with full strength formula or cow's milk. Others adviced diluted milk for 2 or 3 days (32.7% - 33/101 or 14.9% - 15/101). High 25% (12.9% - 13/101) of physicians, adviced it for more than 3 days. Continuation of breast-feeding at all times ESPGHAN recommendation to continue breast-feeding was followed by 50% (96.4% - 107/111) of responding physicians.
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Tamara Vukavi}
Medications Antidiarrhoeal drugs were prescribed by 45% (46.8% 51/109) of physicians. Antibacterial drugs were prescribed often (79.6% - 90/113). Probiotics were also prescribed often (60% - 39/65). Smectite is prescribed by 7%, alone (12.3% - 8/65) or combined with probiotic (15.4% 10/65). Homeopathic remedies were prescribed by 5% (3.1% - 2/65). With the exception of only few physicians, greatest majority did not report any use of opiates, loperamide, chlorpromazine or bismuth subsalicylate. Only 18% (18.2% - 20/110) of physicians, usually would not recommend antimicrobial drugs in suggested situation.
DISCUSSION
The survey on the management of acute gastroenteritis in Europe, like any other study based on mailed questionnaires, was in the risk of poor response. However, in Yugoslavia, a good response rate of 75% was achieved, better than in 15 WE, and in 10 CEE countries (13). The response rate was better in only 2 CEE countries Romania (100%) and Slovakia (82%). The reason for low response rate could be either a mere unwillingness to spend time responding in writing or reluctance of physicians to release information on the compliance with ESPGHAN recommendations in their own practice. On the other hand, high response rate, in Yugoslavia, Romania and Slovakia could be the result of good contacts of national survey coordinators with local doctors. The cornerstone in the management of acute gastroenteritis - oral rehydration, is applied in Europe on the whole, by majority of physicians (84%). However, in Yugoslavia, recommendation for the use of ORS is followed by 70% of physicians vs 79% in CEE and 88% in WE. The use of ORS, as shown in this study, is the only ESPGHAN recommendation on the management of acute gastroenteritis generally complied with. This is probably the consequence of its unquestioned success, mirrored in a spectacular fall of mortality from diarrhoea after the introduction of this therapy in developing countries over the past fifteen years. Considering the results on the use of ORS with low sodium concentration Yugoslavia showed a lower score (56%) than CEE (65%) and WE (67%) (13). However, when calculated as a response rate to this particular question, and not on the number of responded questionnaires, this score for Yugoslavia, increased to 62.4%, which is a true result. When duration of exclusive oral rehydration over 3-4h; 3-6h and >12-24h is analyzed, total response rate of
yugoslav physicians are in better accordance with their colleagues in WE than in CEE The true result for Yugoslavia, calculated from the response rate to this particular question, was only half that one calculated from the total response rate of physicians (14.9% vs 31%). It appears that CEE physicians are better followers of the recommendation for fast initial rehydration than others. Still, overall practice of fast initial rehydration is far from routinely practiced, and it is not possible to make any reasonably accurate judgement in this regard about any country, unless the response rate to this particular question was available. The use of ORS for continuing watery stools, advised by only 56% (92.6% - 63/68) of doctors in Yugoslavia, 46% in CEE and 30% in WE are a surprising result. However, it could be the consequence of applied methodology, presenting all results as a percentage of total response rate of physicians and not by the response rate to this particular question, which may give significantly different picture of local practice, as it is obvious from yugoslav data. Eight questions considering refeeding after acute gastroenteritis Revealed even greater differences, not only between European countries, but particularly compared with ESPGHAN recommendations. Early refeeding with full strength formula, introduced immediately after fast initial oral rehydration ( 4h) is practiced at a low rate Rapid reintroduction of previously used normal diet, after initial oral rehydration, was obviously practiced by a minority of interviewed physicians. In 8 European countries (2 WE and 6 CEE), this practice was even less frequent than in Yugoslavia which is sharing the position number 9 with Ireland, also showing 12% rate, calculated from the total response rate of physicians (13 ). However, the true result for Yugoslavia, calculated from the response rate to this particular question, was half that rate (5.5%). The results of very late refeeding (>48h) showed that in Yugoslavia, it is practiced more frequently, than in CEE and in WE (13). It is obvious that more than 60% of doctors in Europe practice refeeding of infants between a wide range of 4h and 48h. Additional questions in the original questionnaire might have revealed true and detailed practice of refeeding. Recent ESPGHAN recommendations, did not persuade clear majority of doctors in Europe that they should not worry too much about secondary lactase intolerance, which may occur in 1-4% of children with acute gastroenteritis (14, 15). This is best mirrored in the answer of physicians on refeeding practice with lactose-containing formula. When advising lactose-free formula, the rate in Yugoslavia was higher and CEE than in WE. Physicians in WE, with 30% positive answers to this question showed, to some extent, a better practice than their colleagues in CEE.
Arch gastroenterohepatol 2002; 21 (No 1 - 2): 18 - 24 21
When CM proteins are considered, there is still a significant caution in the attitudes of physicians in relation to CM protein intolerance. It is greater in CEE than in WE. Lactose-free and CM protein-free formula is advised often in Yugoslavia and CEE and less often in WE. Full strength formula is practiced more in WE (46%) than in other parts of Europe . The practice of the use of lacose-free and lactose-free, CM proteins-free formula in Yugoslavia, certainly was not infrequent and should be abolished, except for selected cases. Prolonged refeeding with diluted formula (>72h) was rather high in Yugoslavia, reaching twice the frequency of CEE and WE (13). This is the sequel of earlier long standing practice of very restrictive diets during and after acute gastroenteritis. But, the true result for Yugoslavia, calculated from the response rate to this particular question was half (12.9%) the one calculated from total response rate of physicians (25%). The practice of continued breast-feeding during acute gastroenteritis, was reported as low 50% for Yugoslavia vs higher 75% in CEE and 78% in WE (13). This is contrary, to all published recommendations. However, the true result for Yugoslavia, calculated from the response rate to this particular question was excellent (96.4% - 107/111), and it revealed how false impresion could emerge when applying certain methodology, i.e. percentage based on total response rate of physicians and not by the response rate to this particular question. In other participating countries, this response rate could maybe represent the percentage of all breast-fed 6-months old infants physicians met in the every-day practice. Nearly one half (47%) of responding physicians in Yugoslavia, reported prescribing antidiarrhoeal drugs, compared with lower rate in CEE and WE. In other 22 European countries, these medications were prescribed by 25% of physicians, and in 6 WEE countries were not at all prescribed. In 5 WEE and 1 CEE, antidiarrhoeal drugs were prescribed by less than 5% of physicians. The answer of physicians to the question whether they use antimicrobial drugs for patients of this age group stated "ALMOST NEVER" was low in Yugoslavia, acceptable in CEE and good in WE. Since the significant number of physicians in Yugoslavia reported prescribing probiotics (60% - 39/65) and 18% stated that almost never prescribed antidiarrhoeal drugs, the assumption would be that a good prescribing practice for acute gastroenteritis in infants run nearly 80%. But, taking into account that the percentage of those who prescribed antibacterial drugs was high (79.6% - 90/113), the conclusion would be that in a clear majority of cases antibacterial drugs were prescribed together with probiotics, as could be judged by the statement that 18% of them
would almost never prescribe antidiarrhoeal drugs. Toxin adsorbing drug - dioctahedral smectite, mostly held a high position in CEE. The only WE country where it was prescribed often was France (44%) (13). Homeopathic drugs are very seldom prescribed in Yugoslavia, CEE and WE. Surprisingly maybe, in Great Britain and in France, where homeopathy is well accepted and practiced, these drugs are not advised (0%) for acute gastroenteritis in infants (13). The suvey, interviewing parents would maybe reveal some different data. Methodology applied in this survey, in calculating results from total response rate of physicians, resulted in false conclusions about physician's practice in Yugoslavia for: 3-6h exclusive rehydration with ORS, ORS supplementation for continuing losses, early refeeding, prolonged refeeding with diluted milk and continuation of breastfeeding in particular (13). The same might also be true for some other participating countries. It is obvious from the survey that a clear majority of responding physicians in Yugoslavia and the rest of Europe do not comply with all ESPGHAN recommendations on the management of acute diarrhoea (13). This survey also imply that additional educational efforts are required in most european countries, including Yugoslavia, in order to introduce fully all ESPGHAN recommendations for the management of acute gastroenteritis in every-day practice. The treatment of acute gastroenteritis and average, true attitudes of physicians in Yugoslavia were not much different from those in the rest of Europe, with few exceptions, some better, others worse, of which the concerning one is a high prescribing rate of antimicrobial drugs.
CONCLUSIONS
1. The use of ORS as the treatment of choice for dehydration is frequently, but still not sufficiently, followed ESPGHAN recommendation. 2. Continuation of breast feeding throughout the whole episode of acute diarrhoea and ORS supplementation for continuing watery stools, are highly followed ESPGHAN recommendations. 3. Fast rehydration over 3-4 hours, with rapid reintroduction of normal feeding are seldom practiced. 4. Very high rate of prescribing antimicrobial drugs call for more re-education of physicians. 5. Frequent use of lactose-free formula, are in discordance with ESPGHAN recommendation.
Tamara Vukavi}
Questions Rehydration with ORS Use of 60 mmol sodium ORS 3-4h exclusive rehydration with ORS 3-6h exclusive rehydration with ORS >12-24h exclusive rehydration with ORS 6. ORS for continuing watery stools
YU 70% (70.5%-79/112) 56% (62.4%-63/101) 14% (14.9%-15/101) 31% (14.4%-15/101) 24% (19.8%-20/101) 56% (92.6%-63/68)
CEE 79% 65% 19% 60% 9% 46%
WE 88% 67% 15% 35% 23% 30%
WE+ CEE 84% 66% 16% 45% 17% 37%
Table 1. The practice of oral rehydration in Yugoslavia (YU), Central and Eastern Europe (CEE) and Western Europe (WE).
Questions Early refeeding (<4h) Late refeeding (>48h) Refeeding with lactose-containing formula Refeeding with lactose-free formula Refeeding with lactose-free and CM protein-free formula Refeeding with full strength formula Prolonged refeeding (>72h) with diluted formula Continuation of breast-feeding
( ) response rate to individual question
YU 12% (5.5%-6/109) 36% (37.6%-41/109) 23% (24.3%-26/107) 49% (51.4%-55/107) 23% (24.3%-26/107) 19% (20.2%-22/109) 25% (12.9%-13/101) 50% (96.4%-107/111)
CEE 19% 26% 23% 42% 28% 38% 14% 75%
WE 22% 17% 45% 30% 12% 46% 12% 78%
WE+ CEE 21% 21% 36% 35% 19% 43% 12% 77%
Table 2. Timing and type of refeeding after initial rehydration in Yugoslavia (YU), Central and Eastern Europe (CEE) and Western Europe (WE)
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Questions 1. Use of antidiarrhoeal drugs 2. Use of smectite 3. Use of homeopathic remedies 4. Almost no use of antimicrobial drugs
YU 45% (46.8%-51/109) 7% (12.3%-8/65) 5% (3.1%-2/65) 18% (18.2%-20/110)
CEE 33% 41% 5% 32%
WE 19% 9% 1% 72%
WE+ CEE 25% 22% 3% 56%
Table 3. Use of antidiarrhoeal drugs in Yugoslavia (YU), Central and Eastern Europe (CEE) and Western Europe (WE)
REFERENCES:
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Hepatology and Nuutrition 2000. A global plan for tis in young children. Pediatrics 1996;97:424-36 the future. ESPGHAN-NASPGN, Boston 12. Bezerra JH, Stathos Th, Duncan B et al. Treatment 2000:129-140. of infants with acute diarrhoea: what's recomPickering LK, Snyder JD. Gastroenteritis. In: mended and what's practice. Pediatrics Behrman RE, Kliegman RM, Arvin A. Textbook of 7. Booth I, Cuhna Ferreira R, Desjeux J-F, et al. Recommendations for composition of oral rehy1992;90:1-4. Pediatrics. W. B. Saunders company; 1996: 721. dration solutions for the children of Europe. 13. Szajewska H, Hoeskstra JH, Sandhu B, et al. World Health Organisation. World Health Report of an ESPGHAN Working group. J Pediatr Management of acute gastroenteritis in Europe Statistics Annual. Geneva 1975. Gastroenterol Nutr 992;14:1135. and the impact of the new recommendations; J World Health Organisation. World Health 8. World Health Organization. A manual for the treatPediatr Gastroenterol Nutr 2000;30(5):522-7 Statistics Annual. Geneva 1987. ment of diarrhoea. WHO/CDD/SER/80.2 Rev .2 14. Brown KH, Peerson JM, Fontaine O. Use of nonAmerican Academy of Pediatrics. Provisional 1990 human milks in the dietary management of Young Committee on Quality Improvement, children with acute diarrhoea: a meta-analysis of Subcommittee on Acute Gastroenteritis. Practice clinical trials. Pediatrics 1994;93:17-27. parameters: the management of Acute gastroen- 9. Walker-Smith JA, Sandhu BK, Isolauri E, et al. Recommendations for feeding on childhood gas- 15. Sandhu BK et al. A muklticentre study on behalf of teritis in young children. Pediatrics 1996;97:424troenteritis. Guidelines prepared by the the European Society of Paediatric 33. ESPGHAN Working Group on Acute Diarrhoea. J Gastroenterology and Nutrition Working Group on Snyder JD. Use and misuse of oral therapy for Pediatr Gastroenterol Nutr 1997;24:619-20 Acute Diarrhoea: Early feeding in Childhood gasdiarrhoea: comparison of US practices with troenteritis. J Pediatr Gastroenterol Nutr American Academy of Pediatrics recommenda- 10. Ashkenazi S, Cleary TG. Antibiotic therapy of bacterial gastroenteritis, Pediatr Infect Dis J 1991; 1997;24:522-27. tions. Pediatrics 1991;87:28-33. 10:140-48. Davidson G, Barnes G, Barsey D et al. Report of the working gropu on infectious diarroea. In: 11. Provisional committee on quality improvement, subcommittee on acute gastroenteritis. Practice Sokol RJ, ed. Report of the working gropus of the parameter; the management of acute gastroenteriWorld Congress of Pediatric Gastroenterology,
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Tamara Vukavi}

Saa Grgov.
Review
Section for Gastroenterology, Department of Internal Medicine, Health Center of Leskovac, Leskovac.
Helicobacter pylori, cardia, and gastroesophageal reflux disease

Helicobacter pylori, kardija, i gastroezofagusna refluksna bolest
Key Words: Helicobacter pylori, gastroesophageal reflux disease, cardia, intestinal metaplasia.
Abstract The relationship between H. pylori, carditis with or without intestinal metaplasia of the cardia, and gastroesophageal reflux disease is not clear enough. There are two divergent opinions about the pathogenesis of carditis and intestinal metaplasia of the cardia. According to one, carditis is the consequence of gastroesophageal reflux disease and represents the histological indicator of reflux disease. According to another, carditis and intestinal metaplasia of the cardia are related with H. pylori infection and are a part of clinical manifestation of multifocal H. pylori gastritis. The latest studies showed that in patients with normally located Z-line, without Barrett's esophagus, intestinal metaplasia of the cardiac mucosa is possibly the consequence of the multifocal atrophic H. pylori gastritis and significantly associated with gastric intestinal metaplasia. By contrast, in the case of endoscopic presence of Barrett's esophagus, intestinal metaplasia of cardiac mucosa is related to gastroesophageal reflux disease, but not with H. pylori infection, and more frequently contains dysplasia. However, further studies are neccessary to prove the low risk of H. pylori-associated cardiac intestinal metaplasia for the development of cardiac carcinoma.
Klju~ne re~i: Helicobacter pylori, gastroezofagusna refluksna bolest, kardija, intestinalna metaplazija.
Saètak Odnosi izme|u H. pylori, karditisa sa ili bez intestinalne metaplazije kardije i gastroezofagusne refluksne bolesti nisu dovoljno jasni. Postoje dva divergentna mi{ljenja o tome {ta je u osnovi karditisa i intestinalne metaplazije kardije. Prema jednom, karditis je posledica gastroezofagusne refluksne bolesti i predstavlja histolo{ki indikator refluksne bolesti. Prema drugom, karditis i intestinalna metaplazija kardije su u vezi sa H. pylori infekcijom i deo su klini~ke manifestacije multifokalnog H. pylori gastritisa. Nedavna ispitivanja su pokazala da u pacijenata sa normalno lokalizovanom Z-linijom, bez Barrett-ovog ezofagusa, intestinalna metaplazija mukoze kardije bi bila posledica multifokalnog atrofi~nog H. pylori gastritisa i signifikantno je bila udruèna sa gastri~nom intestinalnom metaplazijom. Nasuprot tome, u slu~aju endoskopskog prisustva Barrett-ovog ezofagusa, intestinalna metaplazija mukoze kardije je u vezi sa refluksnom bole{}u, ali ne i sa H. pylori infekcijom i sadrì mnogo ~e{}e displaziju. Ipak, dalja istraìvanja su potrebna da bi se potvrdio nizak rizik od razvoja karcinoma kardije kod pacijenata sa intestinalnom metaplazijom kardije povezanom sa H. pylori infekcijom.
Abrevations used in this article: H. pylori, Helicobacter pylori; GERD, gastroesophageal reflux disease; IM, intestinal metaplasia.
Prim. dr sc. med. Saa Grgov Department of Medicine, Health Center of Leskovac, 116 Svetozara Markovica St., Yu- 16000 Leskovac, Serbia, Yugoslavia FAX: + 381 16 247810 E-mail: Grgov@ptt.yu; Grgovs@yahoo.com
In the last twenty years, in the developed countries, the prevalence and incidence of the gastroesophageal reflux disease (GERD), esophageal and cardiac adenocarcinomas increased, while the prevalence of duodenal ulcer and gastric cancer as well as the prevalence of Helicobacter pylori (H. pylori) infection have been decreasing. This observation has imposed many studies about the possible relationship between GERD and H. pylori, as well as researches about the possible role of H. pylori and/or GERD in the pathogenesis of carditis and intestinal metaplasia of the cardia.
H. pylori and GERD - pathogenesis and clinical researches

In GERD patients, the pH of gastric refluxate is the main cause of esophageal mucosal injury. Therefore, the development of GERD is likely to depend on the pattern and severity of H. pylori-associated gastritis. Patients with antral predominant gastritis, such as duodenal ulcer patients, have normal or increased gastric acid secretion and in these people H. pylori can lead to GERD deterioration. If it is a more difficult stage of pangastritis or corpus predominant gastritis, gastric pH is above 3 or 3.5, so in this form of gastritis H. pylori protects from the further development of GERD (1). However, definite conclusions about this matter need further prospective researches. In the majority of patients with GERD, the biggest number of reflux episodes occurs during the transitory relaxations of lower esophageal sphincter. Some studies have shown that GERD patients show increased relaxation of the proximal part of the stomach during meals. This phenomenon can be the starter of transitory relaxation of lower esophageal sphincter and reflux. However, although there is currently no evidence that H. pylori infection can alter gastric wall compliance or postprandial fundic relaxation in dyspeptic subjects, no data are available in GERD patients as yet (2-4). Therefore, according to the recent researches by Zerbib and associates, the frequency of transitory relaxations of lower esophageal sphincter caused by gastric distension, does not differ significantly between H. pylori positive people and the control group of H. pylori negative people (5). Some authors suggested that H. pylori infection might sensitize the gastroesophageal junction to acid, especially in the subgroup of patients with non-erosive GERD. Manes and associates have found an increased prevalence of H. pylori infection in patients with non-erosive GERD (62%) in comparison to healthy persons (40%) and patients with erosive GERD (36%) (6). Dilated intercellular spaces, as the consequence of separation of intercellular junction of epithelium, estimated by electron microscopy, can represent the earliest event in the course of esophageal damage by acid. Latest
studies by Villanacci and associates have shown that the dilated intercellular spaces, as the earliest marker of reflux esophageal damage, can be diagnosed histologically and evaluated semiquantitatively (7). The results of a number of clinical examinations of the relationships between H. pylori and GERD are controversial. Many studies in countries with low H. pylori incidence report little or no difference of H. pylori prevalence in GERD patients versus controls. Thus, for example, the American study by Oberg and his associates, has not established relationship between antral H. pylori presence and the clinical, endoscopical and histological manifestations of GERD (8). Also, in the big Finish study, the relationship between H. pylori and GERD has not been found (9). As opposed to the previous studies, Wu and associates have found, on the population from Hong Kong, that the prevalence of H. pylori is significantly lower (31%) in 106 GERD patients than in 120 controls (61%) (10). Their further researches have shown that H. pylori positive patients with GERD have a milder form of GERD in comparison to H. pylori negative cases (11). Koike and associates reported H. pylori positivity in 33.7% of patients with reflux esophagitis, as compared with 72% in controls. The atrophy score in antrum and body was lower in reflux patients than in controls, and among H. pylori positive patients, atrophic gastritis was milder in patients with reflux esophagitis than in patients without it (12). The virulent strains of H. pylori (cagA positive/iceA1) are significantly less present in GERD patients than non-virulent, and thus, it is believed that these strains can protect from the development of GERD (13). Vicari and associates have found the inverse relation between cagA prevalence and GERD complications: cagA-positive H. pylori prevalence was 42.3% in the control group, 41.2% in non-erosive GERD, 30.8% in erosive GERD, 13.3% in Barrett's esophagus, and 0% in Barrett's esophagus with adenocarcinoma or dysplasia (14).
H. pylori, carditis and intestinal mataplasia of the esophagogastric junction

The gastric cardia represents an area of a few centimetres directly under normally located squamocolumnar junction or the so-called Z-line. Under normal circumstances squamocolumnar junction coincides with the esophagogastric junction. Barrett's esophagus is defined as the presence of columnar type mucosa with specialized intestinal metaplasoa (IM), proximally from esophagogastric junction, 2 (3) cm long (a short segment Barrett's esophagus) or more than 2 (3) cm long (a long segment Barrett's esophagus). Apart from that, IM can exist also in the level of normally located squamoSaa Grgov
columnar junction without Barrett's esophagus (15-17). The techniques of colouring esophagus in methylene blue should increase the possibility of the esophagogastric junction IM and dysplasia detection, with reducing of the socalled sampling error existing in the conventional biopsy techniques. According to certain authors, the sensitivity and specificity of these colouring techniques is 95% and 97%, respectively (18,19). The latest studies by Sharma and associates have shown that colouring esophagus with methylene blue significantly increases the possibility of IM detection with a smaller number of biopsies, in comparison to the randomly taken biopsies, in patients with suspected short segment Barrett's esophagus. However, in patients with irregular Z-lines (< 1 cm of columnar mucosa) the advantage of this method has not been proved (20). According to the results of Wo and associates, methylene blue chromoendoscopy gives exactly the same results as the conventional biopsy in the detection of IM and dysplasia. This method has not shown any advantage in the diagnosis of the short segment Barrett's esophagus (17). The results show that further researches are needed with the aim of standardising the technique of colouring in methylene blue and determining the adequate protocol of taking biopsy samples. The scientific studies of chronic inflammatory changes of cardia (carditis) and IM of the cardia and esophagogastric junction since recently have aroused great interest, because of the hypothesis that these changes can represent precursor lesions for the development of esophageal and cardiac adenocarcinomas. There are two divergent opinions about what is in the basis of carditis and IM of the cardia. According to one, carditis is the consequence of GERD and represents the histological indicator of GERD. According to another, carditis and IM of the cardia are in relation with H. pylori infection and are a part of clinical manifestation of multifocal H. pylori gastritis (21-24). Csendes and associates have examined 500 patients with the aim to establish the relation between carditis and GERD. The prevalence of carditis in patients with reflux disease was 50% whereas in patients without reflux disease was less than 10%. IM was found in over 10% of patients with reflux disease and in only 2% of controls. According to this study, presence of GERD significantly correlates with finding of carditis and/or IM of the cardia, so that carditis represents an objective histological marker for GERD (25). Goldstein and associates have examined 150 patients by endoscopic biopsies from the cardia. Forty-two of these patients were infected with H. pylori. In the H. pylori negative patients cardia inflammation was correlated with the presence of squamous inflammation of the esophagus or GERD. In those infected with H. pylori, cardia inflammation was correlated with antral inflammation and the presence of H. pylori in the carH.pylori, carditis, gastroesophageal reflux
dia. This study has shown that GERD is responsible for carditis in the absence of H. pylori infection (26). Voutilainen and associates have examined the prevalence of carditis in a large population of more than 1000 patients undergoing upper gastrointestinal endoscopy for dyspepsia. In patients with normally located Z-line, carditis was present in 75% of cases, associated in 69% with chronic inflammation in the stomach. In multivariate analyses, only H. pylori infection was associated with carditis in patients with chronic gastritis. By contrast, in patients without chronic gastritis, carditis was significantly associated with erosive esophagitis. These results have shown that carditis may be the consequence of either H. pylori infection when chronic gastritis is present or GERD when inflammation is absent in the stomach (27). Genta and associates have examined the degree of inflammation in the cardia of 42 patients with H. pylori infection. Forty of the 42 (95%) had H. pylori in the cardia. The inflammation in the cardia paralleled that of the antrum, with both being more severe than the gastric body. However, there were fewer lymphoid aggregates in the cardia (28). Golblium and associates found H. pylori infection in 97% of patients with carditis (29). Also, the researches by Pieramico and Zanetti, on 122 patients with GERD and 49 controls, have shown that the inflammation and IM of cardia are in relation with H. pylori infection, and not in relation with GERD (30). Sharma and associates have examined 31 patients with carditis and H. pylori infection. The patients have been monitored after the eradication of H. pylori on average 23.2 months (range: 6-48 months). In patients with successful eradication of H. pylori there was a significant reduction of the degree of inflammation and the inflammatory activity of the cardiac mucosa. The effects of H. pylori eradication on IM and atrophy was not evaluated because of the small number of patients with these lesions. The results indicate that H. pylori is the direct aetiologic factor for carditis, but they do not exclude the presence of other causes of carditis, such as gastric acid (31). IM is commonly found in biopsy specimens obtained from the cardiac mucosa, but the relationships between IM, H. pylori infection and GERD are unclear, especially when erosive esophagitis or Barrett's esophagus are present. Hackelsberger and associates have examined the prevalence of IM in the cardia in relation to the endoscopic aspect of the squamocolumnar junction in 423 patients. In patients with normal squamocolumnar junction, cardiac IM was found with a prevalence of 13.4% and was significantly associated with gastric IM and H. pylori infection. As opposed to this, IM was found in 34.3% of patients with endoscopic features of Barrett's esophagus (including short segments), and associated with erosive esophagitis and male sex, but not with gastric IM and H. pylori infection (32).
According to the results of Voutilainen and associates, prevalence of IM at the gastroesophageal junction was 22.2%, in a large cohort of patients without endoscopic signs of Barrett's esophagus. Complete junctional IM was significantly associated with multifocal atrophic H. pylori gastritis, while incomplete IM was associated with enoscopically detected erosive esophagitis, carditis, but not with H. pylori infection (33). Their further researches have shown that the incomplete IM most likely is not the direct precursor of Barrett's esophagus. In comparison to Barrett's esophagus, dysplasia in incomplete IM without Barrett's esophagus is a rare finding, so that endoscopic monitoring with the aim to prevent junctional adenocarcinoma in these patients is not recommended (15). According to the large study of Hirota and associates, on 889 patients, similar prevalence of short segment Barrett's esophagus (6%) and IM of the esophagogastric junction with normally located Z-line (5.6%) was established, but each entity was 3.5 times more prevalent than the long segment Barrett's esophagus (1.6%). The prevalence of dysplasia was two times larger in the long segment Barrett's esophagus (15%) in comparison to the short segment Barrett's esophagus (8%), and four times larger in comparison to IM of the esophagogastric junction without Barrett's esophagus (4.3%). H. pylori on esophagogastric junction was detected in 21.3% of patients with IM without Barrett's esophagus, and in 4.7% of patients with short segment Barrett's esophagus and in 2.5% of patients with long segment Barrett's esophagus. If monitoring of these patients is applied with the aim of early discovery of junctional adenocarcinoma, the monitoring interval should be shorter in patients with long segment Barrett's esophagus, in comparison to the patients with short segment Barrett's esophagus, but in the patients with IM of the esophagogastric junction without Barrett's esophagus the period should be the longest or the monitoring is even not recommended (16). Based on the results of the up-to-now researches, a conclusion can be drawn that, in patients with normally located Z-line, IM at the esophagogastric junction may be different from IM associated with Barrett's esophagus. In patients with normally located Z-line (without Barrett's), IM of the cardiac mucosa would be the consequence of the multifocal atrophic gastritis related to H. pylori infection. By contrast, when endoscopic features suggestive of Barrett's esophagus are present, IM in cardiac mucosa is related to GERD independently of H. pylori infection, it is predominant in male sex, more frequently contains dysplasia and represents precursor lesion for the development of junctional and esophageal adenocarcinoma. However, further researches are needed to prove the low risk of H. pylori-associated cardiac IM (21).
H. pylori eradication and GERD

The relationships between H. pylori eradication and the development of either GERD symptoms or endoscopic esophagitis are controversial. According to Hamada and associates, eradication of H. pylori increases the frequency of reflux esophagitis in patients with corpus gastritis - incidence of reflux eshophagitis, after three years of monitoring, was 18% in eradicated patients and 0.3% in not treated H. pylori positive patients. The patients who developed reflux esophagitis had significantly higher prevalence of hiatal hernia and severe corpus gastritis before treatment (34). Labenz and associates have shown that the treatment of H. pylori infection can provoke reflux esophagitis, in patients with duodenal ulcer - incidence of reflux esophagitis in three years was 25.8% in eradicated patients and 12.9% in patients with not-treated H. pylori infection. The patients who developed reflux esophagitis after the treatment of H. pylori infection had much more severe corpus gastritis before the treatment, gained in weight, after the treatment, more frequently than others and were predominantly male (35). Also, Fallone and associates have found that reflux esophagitis was significantly more prevalent in eradicated patients with duodenal ulcer (37%) than in non-eradicated (13%), one year after the eradication therapy (36). As opposed to these results, Vakil and associates have not found a significant difference in the frequency of new GERD symptoms, between eradicated (22%) and non-eradicated (15%) duodenal ulcer patients, six months after the eradication therapy (37). Mc Coll and associates, by observing in period from one to three years, 97 patients with duodenal ulcer and/or gastric ulcer, have not found that eradication of H. pylori infection provokes significantly more frequent newly aroused GERD symptoms (38). Also, our prospective study showed that there was not a significant difference in the frequency of the newly occurred reflux esophagitis, one year after the eradication therapy of H. pylori, between eradicated (8.2%) and non-eradicated duodenal ulcer patients (5.9%) (39). The reason for discrepancy in results of the above mentioned studies is not clear. Since ulcer disease and GERD are commonly associated, it has been suggested that reflux symptoms could be unmasked by either withdrawal of acid inhibitory therapy or disappearance of ulcer-associated symptoms (37). In GERD patients, most likely the eradication of H. pylori infection does not have influence on the course of GERD. Tefera and associates have established, by 24-hour esophageal pH-monitoring, that eradication of H. pylori does not cause any kind of changes in gastroesophageal reflux (40). Axon and associates have included in rendomised double-blind study over 250 H. pylori positive patients with a
28
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mild form of GERD. As compared with the control group, H. pylori eradication did not significantly change the course of the disease evaluated by the relapse rate at 1 year and the time to first relapse (41). However, some studies have pointed to the reduction in the efficiency of antisecretory drugs after the eradication of H. pylori, which would point to the mechanism of possible deterioration of GERD after the eradication of H. pylori. Van Herwarrden and associates showed that nocturnal acid breakthrough during proton pump inhibitors treatment occurred more frequently after eradication of H. pylori (42). Katsube and associates showed that nocturnal acid breakthrough occurred more often in H. pylori negative than in H. pylori positive volunteers (43). However, the prevailing attitude is that the minimal fall of the efficiency of the proton pump inhibitors after the eradication of H. pylori, without the practical implications, should not be an argument against the decision of treating the infection in patients with GERD (21). Does the prolonged antisecretory therapy with the proton pump inhibitors in the presence of H. pylori infection in GERD patients favour the development of atrophic gastritis, is the topic of many debates (44). Kuipers and associates examined H. pylori positive patents with GERD, treated with 20-40 mg omeprazole (105 patients) or with fundoplication (72 patients), in the period of 3-8 years. Their examinations showed that treatment with omeprazole increases the risk of development of glandular corpus atrophy in H. pylori positive patients (45). As opposed to this, a three-year long, prospective rendomised study by Lundell and associates, on 155 GERD patients (40 H. pylori positive) treated with omeprazole and 155 GERD patents (53 H. pylori positive) treated with antireflux surgery, showed that in both groups of patients there was a mild progression of inflammation, atrophy and IM, but the incidence of atrophic gastritis was not different in patients treated with omeprazole or treated surgically (46).
These examinations by Lundell and associates were criticised by some European experts. Considering the fact that not much is known about kinetics of atrophic changes during antisecretory therapy, the period of three years of monitoring patients would be too short to see the real effects of therapy, implying that a beta-type statistical error cannot be excluded (47-50). The imposed question is if the eradication therapy of H. pylori can prevent eventual development of atrophic gastritis, during a long-term therapy with proton pump inhibitors, in GERD patients. Some studies show that by eradicating of H. pylori can prevent the development of corpus gastritis during therapy with omeprazole (51), but in order to make definite conclusions large multicentric studies are needed (52, 53). In conclusion, it seems that H. pylori does not have an important role in the pathogenesis of GERD. In the presence of H. pylori infection a short-term increase of the efficiency of antisecretory drugs was noticed, but there are not any proof about a long-term influence of H. pylori on the therapeutic effect of these drugs. Recent data firmly show that a in a certain group of patients long-term use of the proton pump inhibitors may impose an increased risk for the development of hypochlorhydria and gastric cancer. In these cases the benefit of H. pylori eradication can surpass the potential risk of the development of de novo gastroesophageal reflux or the unmasking pre-existing reflux symptoms (21). The latest Maastricht 2 consensus agreed that H. pylori eradication is not associated with the development of GERD and does not exacerbate existing GERD. It considers eradication of H. pylori as advisable in patients who require long-term profound acid suppression with proton pump inhibitors (54).
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27. Voutilainen M, Frkkil M, Mecklin JP, Juhola M, Sipponen P. Chronic inflammation at the gastroesophageal junction (carditis) appears to be a specific finding related to Helicobacter pylori infection and gastroesophageal reflux disease. The Central Finland Endoscopy Study Group. Am J Gastroenterol 1999; 94: 3175-80. 28. Genta RM, Huberman RM, Graham DY. The gastric cardia in Helicobacter pylori infection. Hum Pathol 1994; 25: 915-9. 29. Golblium JR, Vicari JJ, Falk GW, et al. Inflammation and intestinal metaplasia of the gastric cardia: The role of gastroesophageal reflux and H. pylori infection. Gastroenterology 1998; 114: 633-9. 30. Pieramico O, Zanetti MV. Relationship between intestinal metaplasia of the gastro-oesophageal junction, Helicobacter pylori infection and gastrooesophageal reflux disease: a prospective study. Digest Liver Dis 2000; 32: 567-72. 31. Sharma P, Topalovski M, Mayo MS, Samplier RE and Weston AP. Helicobacter pylori eradication dramatically improves inflammation in the gastric cardia. Am J Gastroenterol 2000; 95: 3107-11. 32. Hackelsberger A, Gunther T, Schultze V, et al. Intestinal metaplasia at the gastro-oesophageal junction: Helicobacter pylori gastritis or gastrooesophageal reflux disease? Gut 1998; 43: 17-21. 33. Voutilainen M, Frkkil M, Juhola M, Mecklin JP, Sipponen P. Complete and incomplete intestinal metaplasia at the oesophagogastric junction: prevalences and associations with endoscopic erosive oesophagitis and gastritis. Gut 1999; 45: 6448. 34. Hamada H, Haruma K, Mihara M, et al. High incidence of reflux oesophagitis after eradication therapy for Helicobacter pylori: impacts of hiatal hernia and corpus gastritis. Aliment Pharmacol Ther 2000; 14: 729-35. 35. Labenz J, Blum AL, Bayerdrffer E, Meining A, Stolte M, Brsch G. Curing Helicobacter pylori infection in patients with duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997; 112: 1442-7. 36. Fallone CA, Barkun AN, Friedman G, et al. Is Helicobacter pylori eradication associated with gastroesophageal reflux disease? Am J Gastroenterol 2000; 95: 914-20. 37. Vakil N, Hahn B, Mc Sorley D. Recurrent symptoms and gastro-oesophageal reflux disease in patients with duodenal ulcer treated for Helicobacter pylori infection. Aliment Pharmacol Ther 2000: 14: 45-51. 38. McColl KE, Dickson A, El-Nujumi A, El-Omar E, Kelman A. Symptomatic benefit 1-3 years after H. pylori eradication in ulcer patients: impact of gastroesophageal reflux disease. Am J Gastroenterol 2000; 95: 101-5. 39. Grgov S. Klini~ke, endoskopske i histoloke karakteristike oboljenja gastroduodenuma u pacijenata sa Helicobacter pylori infekcijom. Doktorska disertacija. Univerzitet u Niu, Medicinski fakultet, Ni 2001.
40. Tefera S, Hatlebakk JG, Berstad A. The effect of Helicobacter pylori eradication on gastrooesophageal reflux. Aliment Pharmacol Ther 1999; 13: 915-20. 41. Axon ATR, Bardhan KD, Moayyedi P, Dixon MF, Brown L. Does eradication of Helicobacter pylori influence the recurrence of symptoms in patients with symptomatic gastro-esophageal reflux disease? A randomised double blind study. Gastroenterology 1999; 116: A117. 42. Van Herwarrden MA, Samson M, Smout AJPM. Helicobacter pylori eradication increases nocturnal acid breakthrough. Aliment Pharmacol Ther 2000; 14: 961-2. 43. Katsube T, Adachi K, Kawamura A, et al. Helicobacter pylori infection influences nocturnal acid breakthrough. Aliment Pharmacol Ther 2000; 14: 1049-56. 44. Tytgat GNJ. Review article: long-term use of proton pump inhibitors in GORD-help or hindrance? Aliment Pharmacol Ther 2001: 15 (Suppl 2): 6-9. 45. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux oesophagitis treated with omeprazole or fundoplication. N Engl J Med 1996; 334: 1018-22. 46. Lundell L, Miettinen P, Myrvold HE, et al. Lack of effect of acid suppression therapy on gastric atrophy. Nordic Gerd Study Group. Gastroenterology 1999; 117: 319-26. 47. Pounder RE, Williams MP. Omeprazole and accelerated onset of atrophic gastritis. Gastroenterology 2000; 118: 238-9. 48. McColl KEL, Murray LS, Gillen D. Omeprazole and accelerated onset of atrophic gastritis. Gastroenterology 2000; 118: 239. 49. Kuipers EJ, Klinkenberg-Knol EC, Meuwissen SGM. Omeprazole and accelerated onset of atrophic gastritis. Gastroenterology 2000; 118: 239-40. 50. Stolte M, Meining A. Lack of effect of acid suppression therapy on gastric atrophy. Gastroenterology 2000; 118: 242-3. 51. Schenk BE, Kuipers EJ, Nelis GF, et al. Effect of Helicobacter pylori eradication on chronic gastritis during omeprazole therapy. Gut 2000; 46: 61521. 52. Kuipers EJ, Meuwissen SGM. Long-term proton pump inhibitor therapy accelerates the onset of atrophic gastritis in Helicobacter pylori-positive patients. In: Hunt RH and Tytgat GNJ. Helicobacter pylori - basic mechanisms to clinical cure 2000. Dordrecht. Kluwer Academic 2000: 255-67. 53. Freston JW. Proton pump inhibitors do not accelerate the development of gastric atrophy in Helicobacter pylori gastritis. In: Hunt RH and Tytgat GNJ. Helicobacter pylori - basic mechanisms to clinical cure 2000. Dordrecht. Kluwer Academic 2000: 269-80. 54. Goh K-L. Update on indication for treatment of Helicobacter pylori (including Maastricht 2). Curr Opin Gastroenterol 2001; 17: (Suppl 1): 43-6.
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Liver and biliary tract Jetra i bilijarni trakt

Rada Jesic, 1 Ivan Boricic, Miodrag N. Krstic, Branka Nikolic, Dragan Tomic, Aleksandra Pavlovic, Djordje Culafic, Vladislava Bulat, Tatjana Cvejic, Radmila Kovac
Clinic for Gastroenterology and Hepatology, Institute of Digestive Diseases, Clinical Centre of Serbia, Belgrade, 1 Institute of Pathology, School of Medicine, University of Belgrade.
Autoimmune cholangitis - AMA-negative syndrome

Autoimuni holangitis - AMA negativni sindrom
( accepted May 17th, 2002 )
Key Words: overlapping syndrome, autoimmune cholangitis.
Abstract Six females and one male patient (mean age: 51 years; range, 27-67 years). with clinical and laboratory signs of both primary biliary cirrhosis and autoimmune hepatitis were reported. Mean follow-up was 34 months (range: 9-47 months). All but one has been having overlap syndrome at presentation; one patient with PBC subsequently developed AIH. All cases had clinical and laboratory evidence of cholestatic liver disease. Liver biopsy demonstrated cirrhosis with significant bile ductular changes of mixed type. In all patients ANA or ASMA, or both ANA and ASMA, were positive. The treatment protocol consisted of prednisolone and/or prednisolone and ursodeoxycholic acid. Follow-up liver function tests demonstrated improvement of aminotransferases level. We conclude that our group of patient may be classified as having overlapping syndrome or autoimmune cholangitis, since they manifested with clinical, biochemical, immunological, and histological characteristics of primary biliary cirrhosis and autoimmune hepatitis type-1.
Klju~ne re~i: overlap sindrom, autoimuni holangitis.
Saètak U ovoj studiji je prikazano 7 pacijenata sa autoimunim holangitisom (AIC)-PBC i AIH. Prose~na starosna dob je bila 51 godina (27-67godina). Prose~no vreme pra}enje bolesnika je bilo 34 meseca (9-47 meseci). [est pacijenata je imalo AIC - overlap sindrom. Na po~etku pra}enja jedan pacijent je imao PBC da bi docnije razvio AIH. Laboratorijski i klini~ki pokazatelji su ukazivali na holestatsku bolest jetre u svih pacijenta. Biopsijske promene na jetri su pokazale cirozu sa zna~ajnim o{te}enjima ù~nih vodova (pome{ane dve slike, neke od njih su pokazivale vi{e sliku AIH, dok je kod drugih bila manifestnija PBC). U na{ih pacijenata ANA i ASMA su bila pozitivna. Pacijenti su le~eni prednisolonom ili prednisolonom i ursodeoksiholnom kiselinom (UDCA). Prate}i terapijske efekte uo~eno je podolj{anje jetrinih funkcije u svih bolesnika. S obzirom na klini~ke, biohemijske, imunolo{ke i histopatolo{ke karakteristike primarne bilijarne ciroze i autoimunog hepatitisa tip-1 zaklju~ili smo da su na{i pacijenti imali ima overlap sindrom ili autoimuni holangitis.
Professor Dr Rada Jesic Institute of Digestive Diseases, Clinical Centre of Serbia, 6 Koste Todorovica Str, YU-11000 Belgrade, Serbia, Yugoslavia.
INTRODUCTION
Autoimmune cholangitis (AIC) is an idiopathic disorder with mixed hepatocellular and cholestatic liver changes, lacking uniform diagnostic criteria. At present this entity usually denotes overlap between AIH with AMA-negative bile ductular lesions by histology (1). Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are two major autoimmune liver diseases. Generally, they can be easily separated on the basis of clinical, biochemical, serological, and histological findings. Occasionally, otherwise distinctive features of both entities may overlap in the individual case. First series of such patients with PBC -AIH overlap syndrome was reported in 1970 (1-3). In some cases the diagnosis of autoimmune hepatitis (AIH) or primary biliary cirrhosis (PBC) is difficult because some patients may have characteristics common to PBC and AIH. This may account for 5 - 10% of all cases of AIH (3). Until recently this AMA-negative syndromes has been classified as autoimmune cholangitis/cholangiopathy (3). The diagnosis of autoimmune cholangitis/cholangiopathy (AIC) is based on the clinical and biochemical evidence of chronic cholestatic liver disease, histological changes of chronic non-suppurative cholangitis, positivity of antibodies other than AMA, and elevation of gammaglobulin (4). Liver biopsy usually demonstrates mixed microscopic changes, some typical for AIH and others of PBC. In some cases typical changes of PBC and AIH were present in the same biopsy specimen (5). Generally, response to steroid therapy helps to distinguish one from another disease. The diagnosis of AIC is often confirmed by ALT/AST decrease after the initiation of steroid treatment, what is found in almost 80% of AIH patients. There is evidence that AIC resistance to steroids or UDCA acid may occur (1). The objectives of this study were to describe the clinical features of our group of patients with AMA-negative AIC overlap syndrome and to analyze its response to therapy: immunosuppressive medication and UDCA.
months). Six patients had overlap syndrome at presentation. One patient initially diagnosed as having PBC subsequently developed AIH. The criteria for diagnosis of AIC were: 1) laboratory evidence of autoimmunity, including ANA and/or SMA seropositivity and/or hypergammaglobulinemia, 2) absence of AMA, 3) clinical, laboratory and/or histological changes of chronic cholestatic liver disease in addition to biochemical features of active hepatocellular inflammation, 4) negativity to HBV and HCV infection, 5) an absence of other aetiologies of chronic liver disease. All patients underwent liver and biliary tract ultrasonography and ERCP. The signs of biliary obstruction and biliary tract disease were absent in any case.
RESULTS
In this series the main patient, s complaint was fatigue. Three cases had jaundice and 2 pruritus. Moderate hepatosplenomegaly was documented in 4 cases. Four patients (1,2,5,7) had extrahepatic disorders (Sjgren's syndrome, Raynaud's phenomenon, and arthropathies). Normal serum albumin, PT, and PTT time had all patients except Case 5. One had positive AMA (ASMA appeared later on, while AMA became negative). Five patients had positive ASMA, while positive ANA were found in 4. Liver biopsies in all 7 patients demonstrated cholestatic changes in general. But there were some differences in microscopic changes in the studied group. The portal tracts were enlarged with slight periportal fibrosis in 3 cases, porto-portal fibrous septa in 3, and biliary cirrhosis in 1 case. Lymphocyte piece-meal necroses were seen in 1 case, as were biliary ones. Bile ductules were increased in number in 4 cases. More or less pronounced disappearance (vanishing) of biliary ducts was present in 4 cases. Larger interlobular bile duct demonstrated damage to their lining cells in 1 case. In the liver parenchyma, single cell necrosis and acidophil bodies were found in 3 cases. Slight periportal cellular and canalicular cholestasis was noticeable in 4 cases. In one patient small, round megamitochondriae were seen. The deposits of copper binding protein and copper were found in periportal hepatocytes in one case. Haemosiderin was present (grade 1) in periportal hepatocytes in one case. The number of Kupffer cells was increased in all 7 cases and in 1 patient the cytoplasm of the macrophages contains biliary pigment. All patients were treated with UDCA (10 mg/kg/24h) and prednisolone (30 mg/24h). After 6-12 months of such treatment prednisolone maintenance dose of 10mg/kg was instituted.
Rada Je{i}
PATIENTS AND METHODS

From February 1996 to February 2002, 7 patients (6 females and 1 male) with PBC-AIH overlap syndrome and AIC were treated at the Clinic for Gastroenterology and Hepatology, Institute of Digestive Diseases, Clinical Centre of Serbia, Belgrade. Their mean age was 51 years (range: 27-67 years). All met criteria for PBC-AIH overlap syndrome and AIC. Mean follow-up was 34 months (9-47
Patiens
Age
Sex
Pruritus/ Jaundice
bilirubin mol/l 19 15 47 187 16 20 14
AF IU/L 165 283 372 198 325 236 256
GGT IU/L 254 378 486 285 753 564 587
ALT IU/L 95 87 254 202 187 98 137
AST IU/L 58 69 203 176 196 48 78
IgG g/L 22,3 19,6 28,2 31,2 25,6 34,5 34
IgM g/L 5,8 3,0 4,9 3,1 2,1 7,4 6,7
AMA/ ASMA /ANA
1 2 3 4 5 6 7
31 27 42 67 34 52 61
F F F F M F F
+/-/+ /+ +/+ -/-/+ - /-
-/ + /-/ +/-/- /+ -/ +/ -/ + / + - / -/+ +/ + /+
Table 1. The initial characteristics of 7 patients with PBC-AIH overlap syndrome
DISCUSSION
Differential diagnosis between AIH and other chronic autoimmune liver diseases of different aetiology is of particular interest. Their management strategy differs significantly. It is considered that about 20% of AIH patients initially present with biochemical evidence of cholestasis, 20% are or may become AMA-positive during disease course, and some AIH patients may have significant histological evidence of small bile ducts damage (3). Therefore cholestatic syndromes overlapping with AIH may occur in the individual patients. The most common overlaps are AIH/PBC, AMA-negative PBC, AMA- positive AIH, cholestatic AIH, and AIH/PSC (24). AIC is used to determine overlap between AIH and AMA-negative bile ductular changes by histology. Typically this AMA-negative patients are ANA and/or ASMA positive with clinical, laboratory, and/or histological cholestatic hepatic changes, and normal biliary tree by cholangiography. On the contrary to PBC, patients with AIC have higher AST and lower serum IgM. They are also characterized by the presence of antibodies to carbonic anhydrase. HLA risk factors are different from PBC with clonal expansion of liver-infiltrating lymphocytes expressing V 5.1 T-cell receptor (2). Overlap between AIH with AMA-negative bile ductular changes by histology, AIC is sometimes called AMA-negative PBC (6,24). Recently, Czaja and associates considered this disease as variant of PBC or AIH, hybrid of both conditions, or separated entity (6). They suggested that AIC is the most probably the heterogeneous condition with features of atypical PBC, small-duct PSC, or transitory disease. In fact, this syndrome may represent different stages of the same process, variant expression of established diverse autoimmune diseases, transitory state between one
autoimmune disease to another, or a single disorder with varying manifestations (1,2). Alternatively, it may be a separate disease entity with different histological manifestations of PBC, PSC or AIH (1,2,7,8). On the contrary, there is evidence that there are no substantial differences in the clinical spectrum or disease course between AMA-positive PBC and AMA-negative PBC (9,10). Further on, some patients with so-called AMA-negative PBC are in fact AMA positive when rigorously tested for a series of mitochondria antigens reacting with each of three main immunoglobulin isotypes (11). If one consider that AMA positivity (and particularly M2 subtype that reacts with 2oxo acid dehydrogenase complexes) is pathognomonic for PBC and that, accordingly, patients with AMA are not considered to have AIH, then "AMA-positive AIH" is a contradictory term. Therefore it seems likely that some patients suffer from PBC and that failure to find histological evidence of PBC is due to an early stage of the disease and/or liver biopsy sampling error. There is group of hepatologist who argue about the possibility of simultaneous occurrence of AIH and PBC (14). They suggest that in some patients differentiation between AIH and PBC is not easy because in 5-10% PBC of cases are AMA-negative and their liver biopsy demonstrate piece-meal necrosis. In these patients ANA and SMA can be positive but their titers are low. Patients with AIH type-1 share some features with PBC such as female preponderance and age of presentation (fifth decade). Their biochemical indices of hepatocellular necrosis, AST and ALT increase, are more pronounced than in PBC. They also usually have higher SMA and/or ANA titers. Commonly, liver biopsy reveals more intense piece-meal necrosis and interacinar focal inflammation than in PBC. Clinical and biochemical response to steroids is generally good, though somewhat different to that in PBC cases (15).
Autoimmune cholangitis - AMA- negative syndrome
To distinguish AIH from PBC, pANCA, antibody assay may help because pANCA, which are frequently positive in AIH, are relatively rare in PBC. Therefore, this autoantibody may be useful to differentiate between the genuine cases of AIH and PBC patients with features overlapping AIH. Some studies have documented the improvement of parenchymal inflammation indices with steroid therapy in patients with AMA-negative PBC (although the biliary damage persisted), but others found that steroids are ineffective (12). In some patients the characteristics seem to change over the years. Colombato reported a case of AMA positive PBC patient, who had had a good response to UDCA and subsequently developed a clinical picture of AIH with negative AMA (13). "Cholestatic AIH" is a term that has been used to describe approximately 10% of AIH patients manifesting markedly elevated serum ALP and -glutamyl transferase (GGT) but without histological evidence of biliary tract disease (16,17). Our two female patients with such biochemical and histological characteristics responded well to combined therapy prednisolone and UDCA. Overlap between AIH and PSC are well recognized, particularly in children. The comprehensive study of PSC in adults by Boberg et al. demonstrated that in adult patients with AIH, features of PSC: hyper-IgG and indefinite hepatitis liver histology may occur frequently. But very few patients have combination of these laboratory and microscopic changes of sufficient severity to qualify them as having definite AIH (18). Their differential diagnosis from AIH can be difficult in the presence of histological evidence of biliary changes and in the absence of cholangiographic changes of PSC especially because the serum ALP in PSC is not oftenly markedly elevated. However, due to the fact that very few series of such cases are described, an optimal clinical management is still undefined. Several case reports have documented a good response to steroids in terms of improved parenchymal necroinflamatory indices and normalization of serum aminotransferases but others have noted less marked posi-
tive response. Gohlke and colleagues suggested the treatment protocol, which combined steroids, azathioprine, and UDCA. The efficacy of such regimen has to be determined yet (19). This syndrome may represent an important and unrecognized cause of resistance to UDCA in patients with PBC (18). The recognition of autoimmune overlap syndrome AIC is not only important from classification point of view, but it may have important therapeutic implications. Late Dame S.Sherlock suggests that AIC may represent a subgroup of AIH, ANA positive/AMA negative cholestatic autoimmune liver disease with significant small bile ductular changes. She suggested elective therapy with steroids (20,23). UDCA is also recommended although this drug is less efficient in PBC (20,21). On the contrary Ishak considered AIC as variant of PBC without indication for steroid treatment (16). Masumoto et al indicated that the type of response to steroids indicates the final diagnosis in AIC (22). Czaja et al found no positive responses to the same therapy in his series of patients (1). In conclusion, we presented our 7 patients with AMAnegative overlap syndrome with bile ductular changes of so-called AIC. In spite of verified liver cirrhosis at the beginning of therapy, after the initiation of combined steroid-UDCA therapy the clinical course in 4 patients was favorable, without any episode of further decompensation of liver function tests. The similar situation occurred with our female patient, who initially presented with clinical picture of PBC, and subsequently developed AIH verified by repeated liver biopsy. After 3 years, ASMA appeared, while test to AMA turned to be negative. Prednisolone was introduced in the therapy and the remission occurred in this patient too.
34
Rada Je{i}
REFERENCES:
1. Czaja A, Carpenter H, Santrach P, Moore B. Autoimmune cholangitis within the spectrum of autoimmune liver disease. Hepatology 2000; 31:1231-9. 2. Kloppel G, Seifert G, Lindner H, Dammermann R. Histopathological features in mixed types of chronic aggressive hepatitis and primary biliary cirrhosis. Arch Pathol Anat Histopatol 1977;373:143-60. 3. Shouval D, Levi IS, Eliakim M. Chronic active hepatitis with cholestatic features Am J Gastroenterol 1979;72:542-50. 4. Michieletti P, Wanless JR, Katz A, Scheuer PJ. Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis. Gut 1994;35:260-5. 5. Marinho R, Grace H, Ramalho F. Autoimmune cholangitis. Case report. HepatoGastroenterology 1999;46:1949-52. 6. Kenny RP, Czaja AJ, Ludwig J, Dickson ER. Frequency and significance of antimitochondrial antibodies in severe chronic active hepatitis. Dig Dig Sci 1986;31:705-11. 7. Vyberg M. The hepatitis -associated bile duct lesion. Liver 1993;13:289-301. 8. Chazouilleres O, Wendum D, Serfaty L. Primary biliary cirrhosis -autoimmune hepatitis overal syndrome: clinical features and response to therapy.Hepatology 1998;28:296-301.
9. Inverizzi P, Crosignani A, Battezzati PM, Covini G. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and negative primary bliary cirrhosis. Hepatology 1997;25:1090-5. 10. Kim WR, Poterucha JJ, Jorgesen RA, Batts KP. Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Hepatology 1997;26:22-6. 11. Kinoshita H, Omagari K, Whittigham S, Kato Y. Autoimmune cholangitis and primary biliary cirrhosis - an autoimmune enigma. Liver 1999;19:122-8. 12. Neuberger J, Thomson R. PBC and AMA -what is the connection ? Hepatology 1999; 29:271-2 13. Colombato L, Alvarez F, Cote J. Autoimmune cholangiopathy : The result of consecutive primary biliary cirrhosis and autoimmune hepatitis? Gastroenterolology 1994;107:1839-43 14. Ben-Ari Z, Dhillon AP, Sherlock S. Autoimmune cholangiopathy: part of the spectrum of autoimmune chronic hepatitis. Hepatology 1993;18:10-5. 15. Lohse AW, Meyer GVM, Buschenfelde KH. Characterisation of the overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis:evidence for it being a hepatic form of PBC in genetically susceptible individuals. Hepatology 1999;29:1078-80. 16. International Autoimmune Hepatitis Group. Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatology 1999;31:929-30.
17. Porayko MK, Wiesner RH, LaRussoNF et al. Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease. Gastroenterology 1990;98:1594-6. 18. Bogerg KM, Fausa O, Haaland T, Holter E, Mellbye OJ. Features of autoimmune hepatitis in promary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology 1996; 23:1369-76 19. Gohlke F, Lohse AW, Dienes HP et al: Evidence for on overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis. J Hepatol 1996;24:699-705. 20. Sherlock S. Overview of chronic cholestasis conditions in adults. Terminology and definitions. Clin Liver Dis 1998;2:217. 21. Sherlock S. Autoimmune cholangitis: a unique entity ? Mayo Clin. Proc. 1998;73:184. 22. Masumoto T, Ninomiya T, Michitaka K et al. Three patients with autoimmune cholangiopathy treated with prednisolone. J Gastroentrology 1998;33:909. 23. Ben-Ari Z, Dhillon AP, Sherlock S. Autoimmune cholangiopathy: part of the spectrum of autoimmune chronic active hepatitis. Hepatology 1993;21:18-20. 24. Svirtlih N. Criteria for diagnosis of autoimmune hepatitis are revised: Report of the international autoimmune hepatitis group. Arch Gastroenterohepatol 2000; 19: 59-64.
Autoimmune cholangitis - AMA- negative syndrome
35

\orde ]ulafi}
Clinic for Gastroenterology and Hepatology, Institute of Digestive Diseases, Clinical Center of Serbia, Belgrade.
Hepatopulmonary syndrome: Experience from one centre

Hepatopulmonalni sindrom: Iskustvo jednog centra
( accepted January 30th, 2002 )
Key Words: hepatopulmonary syndrome.
Abstract Hepatopulmonary syndrome is defined by hypoxemia, an increase of alveolo-arterial gradient during inhalation of room air, and intrapulmonary vascular dilatation in the presence of hepatocelullar insufficiency. Pathoanatomic substrate of hepatopulmonary syndrome is intrapulmonary vascular dilatation due to dilated precapillaries, direct arterio-venous communications, and engorged pleural blood vessels. During 1998, 50 consecutive patients with liver cirrhosis enrolled this prospective study. After hepatological examinations, the morphological and pulmonary function tests were performed. Arterial blood gas analyses were performed in both supine and sitting positions while inhaling room air, and after 15 minutes of hyperoxic mixture exposure. Hypoxemia was documented in 25 (50%) patients. Further functional and morphological studies established the diagnosis of hepatopulmonary syndrome in 9 (18%) patients. Orthodeoxia was confirmed in all patients with hepatopulmonary syndrome and in 3 patients with subclinical intrapulmonary arterio-venous shunts. Radioisotope marker 99mTc-MAA skipped intrapulmonary circulation, being accumulated in the brain and kidneys in 9 patients with hepatopulmonary syndrome, and in 3 patients with subclinical intrapulmonary shunts, what correlated with functional findings. Precapillary dilatation, subclinical intrapulmonary shunts and true anatomic shunts indicate that changes of pulmonary blood vessels may evolve, defining the degree of hypoxemia. After liver transplantation, the reversion of vascular abnormalities and the improvement of oxygenation are possible in patients with subclinical intrapulmonary shunts and mild precapillary dilatation. Regression of vascular abnormalities is not expected in patients with true anatomic shunts and marked praecapillary dilatation documented by incomplete oxygenation response to 100% oxygen exposure.
Dr \orde ]ulafi} 49 Mirjevski Venac Str, YU - 11160 Belgrade, Serbia, Yugoslavia dculafic@EUnet.yu
Gastroenterolo{ka sekcija SLD, 01725, 2002.
Klju~ne re~i: hepatopulonalni sindrom.
Saètak Hepatopulmonalni sindrom je definisan hepatocelularnim o{te}enjem jetre, hipoksemijom, pove}anjem alveolno-arterijskog gradijenta tokom udisanja atmosferskog vazduha i intrapulmonalnom vaskularnom dilatacijom. Patoanatomski supstrat intrapulmonalne vaskularne dilatacije cine: dilatirani prekapilari, direktne arterio-venske komunikacije i dilatirani pleuralni krvni sudovi. U prospektivnoj studiji sprovedenoj tokom 1998. godine ispitali smo 50 pacijenta sa cirozom jetre. Nakon hepatolokih, izvrena su morfoloka i funkcionalna ispitivanja plu}a. Arterijske gasne analize smo uzimali u leè}em i sede}em poloàju, pri udisanju sobnog vazduha i posle 15 minuta udisanja hiperoksicne sme{e. Hipoksemija je imalo 25 (50%) pacijenata, me|utim, morfolokim i funkcionalnim ispitivanjem plu}a hepatopulmonalni sindrom je dijagnostikovan kod 9 (18%). Ortodeoksija je potvr|ena kod svih pacijenata sa hepatopulmonalnm sindromom, ali i kod 3 pacijanata sa sa subklini~kim intrapulmonalnim antom. Perfuzionom scintigrafijom sa 99mTc-MAA, detaktovana je akumulacija radiofarmaka u mozgu i bubrezima kod svih pacijenata sa hepatopulmonalnm sindromom i subklini~kim intrapulmonalnim antovima, to je korelisalo sa nalazom funkcionalnih testova. Prekapilarna dilatacija, subklini~ki intrapulmonalni antovi i pravi anatomski antovi ukazuju da promene u plu}nim krvnim sudovima evoluiraju, to odre|uje stepen hipoksemije. Posle transplantacije jetre, reverzija vaskularnih abnormalnosti i poboljanje oksigenacije je mogu}a kod pacijenata sa subklini~kim intrapulmonalnim antovima i blagom prekapilarnom dilatacijom. Regresija vaskularnih poreme}aja se ne o~ekuje kod pacijenata sa pravim anatomskim antom i izraènom prekapilarnom dilatacijom, koje karakterie nepotpun oksigenacioni odgovor na udisanje 100% kiseonika.
INTRODUCTION
Kennedy and Knudson in 1977 introduced the term hepatopulmonary syndrome (HPS) describing an association between hepatocellular insufficiency with severe hypoxemia due to "dilatation of pulmonary blood vessels" (intrapulmonary vascular dilatation) and intrapulmonary arterio-venous shunts (1). By definition, this syndrome characterised advanced liver disease accompanied with hypoxemia, an increase of alveolo-arterial gradient during inhalation of room air, and intrapulmonary vascular dilatation (IPVD). Pathoanatomic substrate of intrapulmonary vascular dilatation consists of: dilated praecapillaries, direct arterio-venous communications, and dilated pleural blood vessels. Dilated pleural blood vessels resemble the cutaneous (spider-like) nevi, and therefore, they are denoted as pleural spiders. Hypoxemia with partial oxygen pressure ( PaO2 ) less than 8 kPa in patients with liver cirrhosis in the absence of other cardiorespiratory diseases suggests the presence of intrapulmonary vascular dilatation. Severe hypoxemia with PaO2 below 6.6 kPa indicates the diagnosis of HPS (2-4). The most common pulmonary symptom in HPS is dyspnea, affecting almost 40% of patients with HPS. Another characteristic manifestation of intrapulmonary vascular dilatation in cirrhosis is platypnea, specifying that dyspnea is more pronounced in the upright and sitting position than in a recumbent one (5). Orthodeoxia is another significant clinical sing in HPS, representing the decrease of partial oxygen pressure more than 10% when patient is changing the position from a recumbent to a sitting one. It is preHepatopulmonary syndrome
sumed that the partial oxygen pressure decrease, occurring during the recumbent-to-sitting position change, is caused an increase of blood flow via dilated basal pulmonary blood vessels by gravitation. Platypnea and orthodeoxia conclusively indicate the presence of intrapulmonary vascular dilatation (6).
MATERIAL AND METHODS

During 1998, we prospectively studied 50 consecutive patients with liver cirrhosis, diagnosed at the Institute of Digestive Diseases and Institute of Pulmonary Diseases, Clinical Center of Serbia. The initially performed hepatological examinations were based on: medical history, physical examination, liver function tests, specific test for aetiological diagnosis such as serum ceruloplasmin, afla-1 antitiripsin , serum feritin, transferin saturation, viral markers, and percutaneous liver biopsy. The degree of liver insufficiency was made according to the Child classification. After throughout hepatologic investigations, morphological and pulmonary function tests were performed. Two groups of pulmonary function tests were made: arterial blood gases measurement and ventilation tests (spirometry, flow-volume curve and body plethysmography). Gas analyses were carried out using Blood Gas Manager 1312 equipment, while predicted values for the partial oxygen pressure were calculated using Sorbini equation (PaO2 =103,5 - 0,42 x years) (7). Arterial blood gases analysis was performed in both supine and sitting positions while
exposed to the room air and after 15 minutes of breathing of hyperoxic mixture using a direct method, which includes arterial blood sampling with a heparinized syringe. Spirometry was used for the determination of the statical, dynamic pulmonary volumes and capacities: vital capacity (VC), forced vital capacity (FVC) and forced expiratory volume during the first second (FEV1). These tests were performed using Pneumoscreen II spirometer. Body plethysmography was used to measure of total lung capacity (TLC), thoracic gas volume (TGV), residual volume (RV), and airflow resistance in the airways (RaW). The measurements were performed using Bodyscreen II. In our study, the alveolo-arterial gradient of oxygen pressure (P(A-a)O2=PAO2-PaO2) was calculated in the way usually used in practice. The oxygen pressure in the alveolar gas is calculated on the basis of the measured atmospheric pressure and CO2 in the exhaled air, while PaO2 is measured directly in the arterial blood (8). Given to the variations of respiration changes in cirrhotics while assuming different body positions, arterial blood changes occurred; the change of P(A-a),O2 for at least 0.66 kPa is a sign of significant alteration of alveolocapilary exchange with the assumption of different body positions (9). In our study standard chest radiography and perfusion pulmonary scintigraphy was routinely performed. With the patient in a supine position, albumin macroaggregates labelled with radioactive technetium (99mTc-MAA) were injected. Following the contrast medium injection, the patient was placed in a sitting position with his back turned toward the gamma camera (Siemens Gammasonics ZLC 3700) connected with the PC (Microdelta computer RT-11, Clinic Menu V 87A). The visualization was performed in six standard planes - gamma camera positions: anterior, posterior, left lateral, right lateral, left lateral oblique and right lateral oblique until 500 000 impulses per projection was accumulated in the PC matrix 64 x 64. The scanning of extra thoracic organs was used for the measurement of the total number of the brain and kidney impulses in order to confirm intrapulmonary arterio-venous shunting.
Hypoxemia caused by ventilation-perfusion mismatching (Va/Q) in supine position was evidenced in 18 (36%) patients. Mean PaO2 was 9.68 kPa (MD=1.10), while hypoxemia in the sitting position was evidenced in the additional 12 (24%) patients due to ascites. The mean PaO2 value was 10.37 kPa (MD=1.09). No statistically significant difference between a supine and sitting position was found (p=0.102, t-test). Hypoxemia caused by HPS detectable in a supine position was evidenced in 7 (14%) patients. The mean PaO2 value was 8.72 kPa (MD=1.02). Hypoxemia caused by HPS detectable in a sitting position was evidenced in 9 (18%). The mean PaO2 value was 7.41 kPa (MD = 1.81). When compared to the HPS-free group, the patients with HPS had more severe hypoxemia in a sitting position. When measured in a sitting position, the difference in PaO2 values in patients with and without HPS was highly significant (p=0.001, t- test ). Orthodeoxia was recorded in all patients with HPS, and in 3 patients with subclinical intrapulmonary arteriovenous shunts. When exposed to the room air, the average PaO2 value in a supine position was 10.49 kPa (MD=2.14), while in a sitting position this was 8.34 kPa (MD=2.31). When exposed to 100% oxygen, in supine position the average PaO2 value was 32.64 kPa (MD=13.64), while in the sitting position this was 19.19 kPa (MD=9.94). The perfusion lung scintigraphy in normal conditions, after intravenous injection 99mTc-MAA, usually demonstrated that more than 95 % of injected material is trapped within pulmonary capillaries, whose diameter is 7 m. When intrapulmonary arterio-venous shunts are present, Radionucleide labelled particles of 20-100 m in diameter pass into a systemic circulation and are detected in the brain and the kidneys. In our study, the radioisotope marker 99mTc-MAA skipped intrapulmonary circulation, being accumulated in the brain and kidneys in 9 patients with HPS and in 3 patients with subclinical intrapulmonary arterio-venous shunts, what absolutely correlated with functional findings.
RESULTS
The patients were classified according to Child's score system. Class A included 16 (32%), class B 20 (40%) and class C 14 (28%) patients. Hypoxemia was documented in 25 (50%) patients; however, based on functional and morphological investigations the diagnosis of HPS was made in 9 (18%) patients with liver cirrhosis. The majority of the HPS patients (6) belonged to the Child C group, while 3 patients were categorised as Child B.
DISCUSSION
Disorders of oxygenation with consequent arterial hypoxemia is frequently seen in patients with impaired liver function. Between 12% and 30% patients with cirrhosis demonstrate moderate hypoxemia, small percentage of them have gross hypoxia (10). Approximately 50% of patients planned for liver transplantation have some degree of arterial oxygenation impairment, while 13% to 47% of
\orde ]ulafi}
these cases may have eventually HPS (11). There is evidence that in advanced liver diseases ventilation-perfusion (Va/Q) defect is an important cause of hypoxemia (12,13). When liver disease, s associated mild hypoxemia, HPS (intrapulmonary arterio-venous shunting) is absent, in such cases Va/Q mismatch is primarily responsible for impaired oxygenation. The genesis of Va/Q disorder in liver disease is multifactorial and may be caused by: ascites, pleural effusion, reduced pulmonary vasoconstrictive response, and an increase of the closing volume. During normal breathing. the premature airway closure is result of the mechanical airway compression or interstitial pulmonary oedema caused by salt retention, low serum albumin, capillary permeability increase, hormone dependent water retention, and reduced pulmonary lymph drainage. Microatelectases may lead to perfusion of the unventilated pulmonary area (14). In patients with liver cirrhosis and prominent hypoxemia, intrapulmonary right-to-left shunts represent the major pathogenetic mechanism in the development of severe respiratory disorders, in spite of accompanied Va/Q disorder (15-17). In our series, 18 (36%) patients had hypoxemia, but without intrapulmonary shunts. However, all patients had only mild oxygenation disorders, with the average PaO2 value of 9.68 kPa. Hypoxemia caused by intrapulmonary arterio-venous shunts was documented in 9 (18 %) patients with the average PaO2 value of 7.41 kPa. Severe hypoxemia was observed in patients with shunting in a sitting position, and this was statistically significant when compared to the group without shunts. An important functional index of intrapulmonary vascular shunting is the fall of partial oxygen pressure when body position is changed to supine one. In liver cirrhosis, deoxygenation phenomenon associated with body position change, called orthodeoxia, is highly sensitive and specific (18). In this study we confirmed the sensitivity of orthodeoxia phenomenon, which was diagnosed in all patients with HPS, and in 3 patients with subclinical intrapulmonary arterio-venous shunts. The determination of alveolo-arterial gradient of oxygen pressure, P(A-a)O2 = PAO2-PaO2, is the simplest method to assess the ratio of ventilation and perfusion of the lungs. It is postulated that P(A-a)O2 2 kPa with or without hypoxemia indicates the intrapulmonary vascular dilatation (19). Frequently, the hyperventilation of patients with liver cirrhosis may increase P(A-a)O2 values even in the case of normoxemia. Therefore, alveolo-arterial gradient is sensitive parameter of pulmonary gas exchange disorder. High diagnostic significance of these tests has been corroborated by finding of the unchanged basal partial oxygen pressure in the presence of subclinical intrapulHepatopulmonary syndrome
monary shunts, in spite of the increase of alveolo-arterial gradient of oxygen pressure (20). Subclinical intrapulmonary shunts, as specific entity, and present the transitory phase in the development of HPS. In spite of intrapulmonary vascular dilatation and the increased alveolo-arterial gradient, the partial arterial oxygen pressure may stay unchanged for a long period of time. This is caused by alveolar hyperventilation, hyperdynamic circulation, and an increase of cardiac output characteristic for cirrhotics (21,22). Subclinical lung vasculature vasodilatation, with concomitant normoxemia may be found in the incipient liver cirrhosis. With the progression of pulmonary changes, the hypoxemia becomes increasingly manifested. During the course of the disease, the oxygenation may be intensified even without the aggravation of liver function (23). On the basis of response to exposssure to 100% oxygen, two types of vascular abnormalities in patients with hepatocellular insufficiency have been described. HPS type-1 is characterized by diffuse vascular dilatation at praecapillary level, while HPS type-2 is defined by true anatomic pulmonary arterio-venous shunting. The application of 100% oxygen leads to significant increase of partial oxygen pressure in the HPS of type-1, while the effect is minimal in the type-2 (4). In cirrhosis various types of pulmonary vascular abnormalities have been described by angiography: minimal spider-like dilatations, diffuse spongiotic dilatations, and discrete arterio-venous communications. It has been observed that the patients with significant hypoxemia and excellent response to inhalation of 100% oxygen (PaO2 > 53.3 kPa) usually have normal pulmonary angiogram, because their vascular abnormalities is microscopic. The patients with severe hypoxemia (PaO2 < 8 kPa) and poor response to 100% oxygen exposure, usually have fixed arterio-venous communications or advanced diffuse spongiotic dilatation (24). In order to confirm the diagnosis of pulmonary vascular changes in liver cirrhosis the visualisation of the intrapulmonary vascular dilatation is necessary. In his series of 135 paediatric cases with chronic liver diseases of various aetiology and candidates for liver transplantation Grimmon recorded significant hypoxemia in 26 patients. In his study perfusion pulmonary scintigraphy was sensitive and specific method to detect intrapulmonary shunts, particularly when hypoxemia was insignificant (25). Great diagnostic significance of perfusion pulmonary scintigraphy using 99mTc-MAA was also confirmed by the fact that when subclinical intrapulmonary arterio-venous shunts were present, partial oxygen pressure remained unchanged in spite of the increase of alveolar-arterial oxygen gradient (20).
In our study, perfusion pulmonary scintigraphy enabled us to diagnose pulmonary arterio-venous shunts in 9 (18%) patients with HPS and in 3 patients with subclinical intrapulmonary arterio-venous shunts. This method significantly correlated with pulmonary function tests, primarily based on the phenomenon of orthodeoxia. In 1998, Abrams et al. reported that to diagnose intrapulmonary arterio-venous shunts, the contrast two-dimensional echocardiography was far more sensitive than perfusion scintigraphy with 99mTc-MAA (26). In 1999, Aller et al tested the specificity of transesophageal contrast echocardiography in diagnosing intrapulmonary vascular abnormalities in 71 patients with liver cirrhosis. They found that transesophageal contrast echocardiography was the most sensitive diagnostic method, which, as pulmonary angiography, should be included in the liver pretransplant assessment programme (27). In the pretransplantation assessment, it is important to diagnose and differentiate the vascular pulmonary abnormalities including search for probable intracardiac shunt, pulmonary embolism, and pulmonary hypertension. The patients with PaO2 < 9.3 kPa require a special preoperative staging, in order to assess whether adequate oxygenation may be provided during their operative and postoperative periods (28). In 1994, Hobeika et al. concluded that partial oxygen pressure below 8 kPa makes liver transplantation hazardous. In their series of 9 transplanted patients with HPS, there was 4 death. All had PaO2 < 8 kPa, while
among 5 cases with PaO2 > 8 kPa, only 1 patient died (29). Praecapillary dilatation, subclinical intrapulmonary shunts evolving to the true anatomic shunts indicate that changes of pulmonary blood vessels may undergo evolution, thus worsening the degree of hypoxemia. At the onset of the disease, mild hypoxemia correlates with the decrease of Va/Q ratio, while severe hypoxemia is the sequel of marked precapillary dilatation and anatomic intrapulmonary microvascular right-to-left shunts. The progression of vascular pulmonary dilatation leads to deterioration of arterial oxygenation, indicating fairly poor transplant prognosis (4,30). Therefore HPS with good oxygenation response to inhalation of 100% oxygen is a new indication for liver transplantation. The reversion of vascular abnormalities and the improvement of oxygenation after liver transplantation is possible in patients with subclinical intrapulmonary shunts and mild praecapillary dilatation characterised by complete oxygenation response to 100% oxygen as well as angiographic findings of minimal spider-like dilatation. Regression of vascular abnormalities does not occur in patients with true anatomic shunts and marked. praecapillary dilatation characterised by incomplete oxygenation response to 100% oxygen and angiographic finding of diffuse spongiotic dilatation and/or discrete arterio-venous communications (31).
REFERENCES:
1. Kennedy TC, Knudson RJ. Exercise-aggravated hypoxaemia and orthodeoxia in cirrhosis. Chest 1977; 72: 305-9. 2. Krowka MJ, Cortese DA. Pulmonary aspects of chronic liver disease and liver transplantation. Mayo Clin Proc 1985; 60: 407-18. 3. Rodriguez-Roisin R. The hepatopulmonary syndrome: new name, old complexities. Thorax 1992; 47: 897-902. 4. Krowka MJ, Cortese DA. Hepatopulmonary syndrome: Current concepts in diagnostic and therapeutic considerations. Chest 1994; 105: 1528-37. 5. Robin ED, Laman D, Horn BR, Theodore J. Platypnea related to ortodeoxia caused by true vascular lung shunts. N Engl J Med 1976; 294: 941-3. 6. Krowka MJ, Cortese DA. Severe hypoxaemia associated with liver disease: Mayo Clinic experience and the experimental use of almitrine bismesylate. Mayo Clinic Proc 1987; 62: 164-73. 7. Sorbini CA, Grassi V, Solinas E, Muiesan G. Arterial oxygen tension in relation to age in healthy subjects. Respiration 1968; 25: 3-13. 40
8. Rebic P. Merenje odnosa ventilacije i perfuzije u plucima. U: Sekulic S, ed. Plucne bolesti. Elit Medica. Beograd 2000; 79-81. 9. Hourani JM, Bellamy PE, Tashkin DP, Batra P, Simmons MS. Pulmonary dysfunction in advanced liver disease: frequent occurrence of an abnormal diffusing capacity. Am J Med 1991; 90 : 693-700. 10. Sherlock S. Vasodilatation associated with hepatocellular disease: relation to functional organ failure. Gut 1990; 31: 365- 71. 11. Hopkins WE, Waggoner AD, Barazilai B. Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease. Am J Cardiol 1992; 70: 516-9. 12. Melot C, Naeije R, Dechamps P, Hallemans R, Lejeune P. Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis. Am Rev Respir Dis 1989; 139: 632-40. 13. Agusti AG, Roca J, Bosch J, Rodriguez-Roisin R. The lung in patients with cirrhosis. J Hepatol 1990; 10: 251-7. 14. Ruff F, Hughes JM, Stanley N, et al. Regional lung function in patients with hepatic cirrhosis. J Clin Invest 1971 ; 50: 2403-13.
15. Edell ES, Cortese DA, Krowka MJ, Rehder K. Severe hypoxemia and liver disease. Am Rev Respir Dis 1989 ; 140: 1631-5. 16. Andrivet P, Cadranel J, Housset B, Herigault R, Harf A, Adnot S. Mechanisms of impaired arterial oxygenation in patients with liver cirrhosis and severe respiratory insufficiency. Effects of indomethacin. Chest 1993; 103 : 500-7. 17. Robert V, Chabot F, Vial B, Guito P, Poussel JF, Polu JM. Hepatopulmonary syndrome: physiopathology of impaired gas exchange. Rev Mal Respir 1999; 16:769- 79. 18. Thorens JB, Junod AF. Hypoxemia and liver cirrhosis: a new argument in favor of a "diffusionperfusion" defect. Eur Respir J 1992 ; 5 : 754-6. 19. Rodriguez-Roisin R. The hepatopulmonary syndrome: new name, old complexities. Thorax 1992; 47: 897-902.
\orde ]ulafi}

Nafiye Urganci, Fgen ullu, 2 Bayram Kiran, 1 Tlay Erkan, 1 Tufan Kutlu, 1 Gngr Tmay, 3 Glsen zbay,
1 1
Plasma endothelin-1 level in children with cholestatic liver diseases

Nivo endotelina-1 u plazmi dece sa holestatskim bolestima jetre
( accepted May 17th, 2002. )
Department of Pediatric Gastroenterology, Cerrahpasa Faculty of Medicine, University of Istambul, Istambul, 2 DETAM Research Institute, Istambul, 3 Department of Pathology, Cerrahpasa Faculty of Medicine, University of Istanbul, Istambul, Turkey.
Key Words: Children, cholestasis, endothelin-1.
Abstract Cholestatic paeditric liver diseases are prevaling during infancy and early childhood. They frequently lead to early biliary cirrhosis and portal hypertension. This study was planned to determine the relationship between the endothelin-1 level and the prognosis of cholestatic liver disease in early childhood. Nine cases of Biliary Atresia (BA), 4 cases of progressive intrahepatic cholestasis (PFIC), and one case of Alagille syndrome (AS), who were followed in the Pediatric Clinic of Cerrahpasa Faculty of Medicine, were included in the study. Nine were male and 5 were female; mean age: 2.5 2.4 years. The control group consisted of 10 healthy male children; mean age of 9.2 6 years. Plasma endothelin-1 level was studied in DETAM Research Institute, Istambul with RIA method. The patients were separated in two groups according to the presence of cholestasis ( gamma glutamyl transpeptidase (GGT) > 40 IU, total bilirubin (TB) > 1.5 mg/dl . Group-1 consisted of 9 children, 5 with portal hypertension (PH) (PFIC, n= 4, BA, n= 1) and 4 without PH (AS, n= 1, BA, n=3). Group- 2 (non cholestatic) included 5 children (BA, n=5) without PH. At the time of the study none of these patients had ascites or hepatorenal syndrome. Plasma endothelin-1 level did not differ between Group-1 and Group-2I, but it was higher than the control group ( p<0.0001, p<.00007 respectively ). Althought not statistically significant, plasma endothelin1 level increase was higher in children with cholestasis with PH than those without PH ( p>0.05 ).
Klju~ne re~i: deca, holestaza, endotelin-1.
Saètak U periodu odojceta i malog deteta holestatske bolesti jetre cu ~este. Ciroza i portna hipertenzija mogu da se jave relativno rano u toku bolesti. Ova studija je planirana da bi se ispitao odnos izmedju nivoa endotelina-1 u plazmi i prognoze holestatskih bolesti jetre dece. Devetoro dece sa bilijarnom atrezijom ( BA), 4 sa progresivnom familijarnom intrahepaticnom holestazom ( PFIC ), i 1 sa Alagille-ovim sindromom koja su pracena u Decijoj Klinici, Carrahpasa Medicinskog Fakulteta, Instambul, Turska je bilo ukljuceno ovo ispitivanje. Ona su bila procesne dobi 2.5 2.4 godine. Kontrolnu grupu je sacinjavalo 10 zdrave muske dece prosecne dobi 9.2 6 godina. Plazma endotelin-1 je odredjivan u DATEM Istrazivackom Institutu, Istambul, Turska RIA metodom. Zavisno od prisutnosti holestaze ( GGT > 40 IU/L, ukupni bilirubin > 1.5 mg/dl ) deca su podeljena u dve grupe: Grupa 1- 9 dece sa holestaznom bolesti jetre koja je bila komplikovana portnom hipertenzijom ( PH ) ( PFIC 4, BA 1 ) odnosno koja nije bila komplikovana sa PH. Grupu-2 ( deca bez holestaze ) je sacinjavalo 5 dece ( BA, 5) cija bolest nije bila komplikovana sa PH. Ni jedno od ispitivane dece nije imalo ascitni izliv odnosno hepatorenalni sindrom. Nivo plazma endotelina-1 se nije statisti~ki razlikovao izmedju Grupa 1 i 2, medjutim bio je visi nego u kontrolnoj grupi ( p<0.0001, p<0.0007 retrospektivno ). Premda statisti~ki nesignifikantno, nivo endotelina-1 u plazmi dece sa holestaznim bolestima i PH je bio visi nego u dece sa holestaznim bolestima ali bez PH ( p>0.05 ).
Professor Dr Nafiye Urganci Dereboyu caddesi, Cudi Efendi sok. Pinyal apt. No: 3/6 80840 Ortaky - Istanbul / Turkey FAX:: +90 216 5222222 E-mail: aurganci@netas.com.tr
INTRODUCTION
Cholestatic liver diseases frequently start during the neonatal period and may rapidly progress to cirrhosis and portal hypertension ( PH ). Among them, the most freqeuent is congenital biliary atresia (BA) which is due to progressive destructive inflammatory process involving intra and/or extrahepatic bile duct (1,2). Endothelins are a group of peptides made of 21 aminoacid which are synthetised by endothelial cells. They have powerful vasoconstrictor activity, ten times higher than angiotensin (3). It was shown that in chronic liver disease with cirrhosis with or without ascites, plasma endothelin-1 (ET-1) level is increased (4,5,6,7). However, paediatric literature date about the relationship between cholestasis and ET-1 are rare. In this study we investigated plasma ET-1 level in variety of cholestatic liver diseases and explored its prognostic value.
University Medical Faculty, DETAM Research Institute, with RIA ( Euro-Diagnostica, Sweden). Endothelin-1 from plasma samples kept in Eppendorf tubes were let to settle at -20 C the colons of Sep-Pak C18 (Waters, Millipore intertech corporation, P.O BOX 225, Bedford MM USA). One mililiter serum was used for the analysis Statistical Evaluation: The Kruskal Wallis test and the Mann-Whitney-U test were used for the statistical analysis between groups. Graphics were placed on windows metafile . Ethical Considerations: The study was approved by Pediatric Gastroenterology Department of Cerrahpasa Faculty of Medicine. Informed consent was obtained from the parents of all children the analysis of sera .
RESULTS MATERIAL
This study enrolled 9 children with BA, 4 with PFIC, and 1 with Alagille syndrome (AS) who were followed in the Paediatric clinics, Cerrahpasa Faculty of Medicine, Istambul, Turkey. Nine children were males, 5 females; mean age: 2.5 2.4 years. Ten healthy male children served as control group; mean age: 9.2 6 years. None of the patients presented had ascites or hepatorenal syndrome at the time of the study. The patients were separated in two groups according to liver function tests, and the presence of jaundice and PH. . Group-1 consisted of 9 children with cholestatic liver diseases. Five were diagnosed as having PH ( 4 PFIC, 1 BA ). The remainder 4 without PH included one case AS ( syndromic congenital biliary hypoplasia ), and 3 operated patients of BA which were cholestatic but without evidence of PH. . All children had GGT> 40 IU/L, and total serum bilirubin (TB) > 1.5 mg/dl . Group-2 included 5 cases operated of BA with good postoperative biliary flow whith GGT<40 IU/L, and TB<1.5 mg/dl. They had no evidence of PH. Group-1 and Grup-2 plasma ET-1 levels were found to be higher than in the controls; 21.8 5.4, 16.96 2.3, and 9.61 0.67 pmol/l respectively ( p<0.0001, p<0.0007 respectively ). The plasma ET-1 level between Group-1 and Group-2 did not differ statistically (p>0.08). In Group1, plasma ET-1 level in children with PH was higher than in those who were not PH ( respectively 24.202.5, 18.972.3 pmol/1 respectively; p>0.05 ). However, the difference was not found to be statistically significant.
DISCUSSION
There is plenty of evidence that endothelins have an important in the pathogenesis of essential arterial hypertension, acute and chronic kidney failure, acute myocardial infarction, pulmonary hypertension and systemic sclerosis (8-10). Beside endothelial cells, endothelins are made by neurons, heart, lung, pancreas, kidney, and smooth-muscle cells (11,12). They exert powerful mytogenic activity acting on vascular smooth -muscle cells, fibroblast, and glomeruler mesenchemical cells (13,14). Endothelins have an important role in regulating hepatic stellate cell contraction which control sinusoidal blood flow. In stellate cells endothelins are released by transforming growth factor stimulus. In a case of active liver damage, ET-1 increases number of stellate cells, contract them, and change them structurally and functionally, causing hepatic fibrosis eventually. As a result, intrahepatic blood flow is further impaired (15). In recent years, several animal and human studies demonstrated casual connection between plasma ET-1 level and PH development in patients with
Nafiye Urganci
METHOD
Ten mililiter of blood was taken from each child and placed into tubes with EDTA. They were centrifuged at +2 C, 2000 cycles for 15 minutes. Serum specimens were then put in Eppendorf tubes and kept at -20 C until they were analyzed. The endothelin-1 analysis was done in Istanbul
42
cirrhosis (4-7). In 1995, Nozue reported that the plasma ET-1 concentration is near normal in children with BA after succesfull portoenterostomy (hepatico-jejunostomy according to Kasai), whereas in PFIC ET-1 tends to be higher (16). Kabayoski et al. found higher plasma ET-1 level in children with portoenterostomy presenting with cirrhosis and PH, than in children without cirrhosis and PH (17). They stated that increased ET-1 level is possibly due to deterioration of liver function and ET-1 monitoring can be helpful in the assessment of liver fibrosis progression and the development of PH. In our study, we found that in children with chronic cholestatic liver diseases plasma ET-1 level is higher than in the control group. In children with more severe liver damage, plasma ET-1 is higher than in the group with more
Group I ET-1 21.85.4 Group II Control
or less preserved liver functions and less severe liver damage. In our study, the absence of relationship between ETI and prognosis of liver disease could be explained by the fact that most of our patients with cholestasis were infants whose portoenterostomies (hepatico-jejunostomies according to Kasai) were not provided adequate biliary flow. In conclusion, this very preliminary study demonstrates that increased plasma ET-1 concentration reflects very early liver damage in infants and small children with cholestatic liver diseases. ET-1 plasma concentration tends to be higher in portal hypertensive children reflecting advanced liver fibrogenesis. Further studies are necessary to determine the prognosic role of ET-1 in the development of PH and cirrhosis in paediatric liver diseases.
p Group I-II Group I -Control 0.0001* Group II -Control 0.007*
16.962.3 9.610.67 0.08
P*<0.005
Table 1. Plasma endothelin-1 concentrations in patients with cholestasis
24 22 20 18 ET-1 16 14 12 10 8
Group 1 (n=9) Group 2 (n=5)
25
21.8 5.4
20
21.8 5.4 16.96 2.3
15 16.96 2.3 ET-1 10
5 9.61 0.67 0
Control subjects (n=10) PH(+) n=5 PH(-) n=4
Figure 1. Plasma endothelin-1(ET-1) concentrations in patients with cholestasis.
Figure 2. Plasma endothelin-1 (ET-1) concentrations according to the precence of portal hypertension in patients with cholestasis (Group-1).
Endothelin-1 in cholestatic liver diseases
43
REFERENCES:
1. Roy CC, Silverman .A, Alagille D Pediatric Clinical Gastroenterology 4 th ed. 1995; Mosby -Year book 2. Peter FW. Chronic cholestasis of infancy. In:Lebenthal E (ed). Pediatr Clin North Am 1996; 43: 1-26 3. Yanagisawa M, Kuihara S, Kimura S, Tomobe Y, Kobayashi M, Mitui Y, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1998;332: 411-5 4. Uchihara M, Izumi N, Sato C, Marumo F. Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis. Hepatology 1992; 16: 95-9 5. Asbert M, Gines A, Gines P, Jimenes W, Claria J, Salo J, et al. Circulating levels of endothelin in cirrhosis. Gastroenterology 1993; 104: 148591 6. Lerman A, Click LR, Narr JB, Wiesner HR, Krom RAF, Textor SC, et al. Elevation of plasma endothelin associated with systemic hypertension in humans following orthotopic liver transplantation. Transplantation 1991; 51: 46-50
7. Veglio F, Pinna G, Melchio R, Rabbia F, Panarelli M, Gagliardi B, et al. Plasma endothelin levels in cirrhotic subjects. J Hepatol 1992; 15:85-7 8. Shichiri M, Hirata Y, Ando K, Emori T, Ohta K, Kimota S, et al. Plasma endothelin levels in hypertension and chronic renal failure. Hypertension 1990; 15: 493-96 9. Cernacek P, Steward JD. Immunoreactive endothelin in human plasma. Marked elevations in patients in cardiogenic shock. Biochem Biophys Res Commun 1989; 161 : 562-7 10. Morelli S, Ferri C, Francesco DL, Baldoncini R, Carlesimo M, Bottoni U, et al. Plasma endothelin-1 levels in patients with systemic sclerosis : Influence of pulmonary or systemic arterial hypertension. Ann Rheumatic Dis 1995; 54: 730-4 11. Masaki T. Endothelins : Homeostatic and compensatory actions in the circulatory and endocrine systems. Endocrine Reviews 1993; 14 : 256-267 12. Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors. Tips 1992; 13: 103-8
13. Mallat A, Fouassier L, Preaux MA, Gal CSL, Raufaste D, Rosenbaum J, et al. Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. J Clin Invest 1995; 96: 42-49 14. Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin and nitric oxide. Hepatology 1997; 25: 2-5 15. Rockey D, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, et al. Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998; 27: 472-80 16. Nozue T, Kobayashi A, Uemasu F, Takagi Y, Endoh H, Sako A. Plasma endothelin-1 levels of children with cirrhosis. J Pediatr Gastroenterol Nutr 1995; 21: 220-3 17. Kobayashi A, Miyano T, Horikoshi K, Orihata S, Watanabe S, Fugawata S. Clinical significance of plasma endothelin levels in patients with biliary atresia. Pediatr Surg Int 1998; 13: 491-3
44
Nafiye Urganci
Gastroenterohepatologic iconography Gastroenterohepatolo{ka ikonografija

Mira Petrovic Vojislav N. Perisic, 2 Miodrag N. Krstic, 3 Dejan Opric, 1 Sasa Milicevic.
1 1
Eosinophilic ascites
Eozinofilni ascites
( accepted May 20th, 2002. )
1 2
University Children , s Hospital, Belgrade, Clinic for Gastroenterohepatology, Institute of Digestive Diseases, Clinical Center of Serbia, Belgrade, 3 Institute of Pathology, School of Medicine, University of Belgrade.
A 14-year old by was referred for further evaluation of his tense ascites and dull abdominal pain. This child developed insidious but progressive abdominal distension accompanied with dull abdominal pain few weeks before admission. He had past medical history of well-controlled bronchial asthma. At admission, beside tense ascitic peritoneal fluid effusion this patient, s clinical finding was normal. Blood pressure was normal. Immediately performed chest x - ray and ECG were normal as well. Laboratory investigations demonstrated haematological abnormality of pronounced eosinophilia. Total white blood cell count was 17.1 with increased number of eosinophils (20%, total number 3400; normal < 500). ESR, hemoglobin, RBC, and trombocyte
counts were within reference range. Urinalysis was negative. Stools for ova and parasites were repeatedly negative. Blood biochemistry including blood sugar, BUN, serum creatinine, liver function tests, total serum proteins, albumin, serum electrolytes, serum and urinary amylases, and serum lipase were normal. IgA, IgM, and IgG were within normal limits. Serum IgE was increased 800 u/ml (normal: 0-200). Abdominal ultrasound scan revealed normal liver, spleen, and kidneys. No abdominal masses were detected. Ascitic fluid effusion with floating small bowel loops was seen. Diagnostic abdominal paracentesis was performed. Twenty milliliters of clear ascitic fluid was removed. Its biochemistry including glucose concentrations and amylase titer was normal except protein concentration of 3.5g/l. After centrifugation, microscopic examination of ascitic fluid sediment was made. Eight thousand cells, exclusively eosinophils per 1 ml of ascitic fluid were found.
Figure 1. Note peritoneal effusion. Aspiration needle is visible (arrow).
Figure 2. Eosinophils in the ascitic fluid.
Professor Dr VN.Perisic University Children, s Hospital 10 Tirsova St. Yu-11000 Belgrade, Serbia, Yugoslavia
Two weeks of methyl prednisolone treatment (30mg/day) led to quick and full amelioration of peritoneal effusion which almost disappeared, normalisation of peripheral blood eosinophilia, and reduction of serum IgE (350 u/ml). Six-month follow up was uneventful, no peritoneal effusion recurred, and peripheral blood eospnophil count was normal. Abdominal ultrasound examination was normal. Comment: Eosinophilic gastroenteropathy may be protein sensitive and idiopathic. Protein-sensitive forms of eosinophilic gastroenteropathy occur in infants and children below the age of 2 years and most commonly result from allergic reaction to cow, s milk or soy protein or, infrequently, breast milk (1). The idiopathic form presents with a highly variable clinical picture, depending on the anatomic and histologic distribution of the eosinophilic tissue infiltration. Tissue eosinophilia can be mucosal, muscular, or serosal and has been described to affect the oeosphagus, stomach, intestine, or colon alone or in combination (2). The most commonly encountered presentation results from mucosal involvement of the small intestine and stomach (1,2,3). This usually presents with chronic diarrhoea weight loss, malabsorption, and protein loosing enteropathy when small intestinal mucosal infiltration with eosinophils occur. Eosinophilic gastritis presents with epigastric pain, nausea, and vomiting. Patients with predominant muscle layer disease (eosinophilic infiltration of tunica muscularis) manifest with pyloric, intestinal obstruction, or/and achalasia-like picture (1,2,3).
The rarest form is serosal layer disease, which typically present with eosinophilic ascites (4). Serosal eosinophilic infiltration led to weeping of fluid in the peritoneal cavity. An associated pleural effusion may be present. The fluid is usually a sterile exudate that contains a high eosinophil count. In eosinophilic gastroenteropathy laboratory studies usually indicate peripheral eosinophilia and increased serum IgE, particularly in children. In all cases, stool studies must be done to rule out parasitic infestation. The radiographic changes are found in mucosal and muscle layer disease. This are enlarged gastric mucosal folds, pronounced antral and corporal nodularity, small intestinal thickening of the folds with or without nodules (3). The small intestine is dilated. Antro-pyloric obstruction, segmental small intestinal obstruction, and achlasia-like x-ray picture are signs of muscle layer disease. In serosal disease abdominal ultrasound demonstrates peritoneal effusion. Endoscopic mucosal biopsies, laparoscopic muscle layer and serosal biopsies indicating pure tissue eosinophilic infiltration and abdominal paracentesis with cytology are important diagnostic methods. Steroids are the mainstay of therapy in particular in obstructive symptoms and eosinophilic ascites. This disease tends to respond quickly. Occasionally low dose maintenance steroids are needed to keep symptoms under control. In severe disease additional immunosuppressive therapy using cyclosporine, azathioprine and cyclophosphamide may be considered
46
Mira Petrovi}
REFERENCES:
1. Proujansky R. Eosinophlic gastroenteritis. In: Pediatric gastrointestinal disease, Wyllie R, Hyams JS, eds. Philadelphia: WB Saunders, 1993;566-71. 2. Steffen RM, Wylie R, Petras RE, et al. The spectrum of eosinophilic gastroenteritis. Report of six pediatric cases and review of the literature. Clin Ped 1991; 30: 404-11.
3. Talley NJ. Eosinophilic gastroenteritis. In: Sleisenger and Fordtran, s Gastrointestinal and liver disease, Feldman M, Scharschmidt BF, Sleisenger M, eds. Philadelphia: WB Saunders, 1998; 1679-88. 4. Talley NJ, Shorter RG, Philips SF, et al. Eosinophilic gastroenteritis. A clinicopathological study of patients with disease of the mucosae, muscle layer, and subserosal tissue. Gut 1990; 299-303.
Eosinophilic ascites
47
ARCHIVES OF
130th Aniversary of Serbian Medical Association
CONTENTS
ALIMENTARY TRACT AND PANCREAS 5 The Lynch syndrome: Report on family "S" Aleksandar Nagorni,Vuka Katic,Jovica Milanovic, Vesna Zivkovic,Goran Bjelakovic. Endoscopic ` ultrasonoghraphy in Mntrier 's disease Miodrag N. Krsti}, Gradimir Golubovi}, Marijan Micev, Predrag Dugali}, Dragan Tomi}, Aleksandra Pavlovi}. Stenosis of the small intestine and entero-enteral fistula due to mesenteric vascular occlusion Zoran Krivokapic, Radoje Colovic, Nikica Grubor, Marjan Micev Management of acute gastroenteritis in Yugoslavia: Compliance with ESPGHAN recommendations Tamara Vukavi}, M. Stoji}, Ljiljana Savi}, Ivica Stankovi}, M. Peroevi}, K. Ajdànovi}, Lj. Stoli} B. Kaì}. Review Helicobacter pylori, cardia, and gastroesophageal reflux disease Saa Grgov. 31 LIVER AND BILIRY TRACT Autoimmune cholangitis - AMA-negative syndrome Rada Jesic, Ivan Boricic, Miodrag N. Krstic, Branka Nikolic, Dragan Tomic, Aleksandra Pavlovic, Djordje Culafic, Vladislava Bulat, Tatjana Cvejic, Radmila Kovac Hepatopulmonary syndrome: Experience from one centre \orde ]ulafi} Plasma endothelin-1 level in children with cholestatic liver diseases Nafiye Urganci, Fgen ullu, Bayram Kiran, Tlay Erkan, Tufan Kutlu, Gngr Tmay, Glsen zbay, GASTROENTEROHEPATOLOGIC ICONOGRAPHY 45 Eosinophilic ascites Mira Petrovic, Vojislav N. Perisic, Miodrag N. Krstic, Dejan Opric, Sasa Milicevic.
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Arhiv 2002

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ARCHIVES OF

INTERNATIONAL ADVISORY BOARD ME\UNARODNI SAVETODAVNI ODBOR

FOUNDING EDITOR UREDNIK-OSNIVA^

DESK EDITOR UREDNIK DESKA

TECHNICAL EDITOR TEHNI^KI UREDNIK

ASSOCIATE EDITORS UREDNICI

INSTRUCTIONS TO AUTHORS AND CHECKLIST

Alimentary tract and pancreas Alimentarni trakt i pankreas

The Lynch syndrome: Report on family "S"

Key Words: Lynch syndrome, metachronous CRC, stomach cancer

Klju~ne re~i: Lynchov sindrom, metahroni KRK, karcinom `eluca

35 CRC (transverse) 58 CRC (descending) 62 GCa

50 CRC (transverse) 50 CRC (sigmold)

50 ECa 52 CRC (cecum)

54 CRC (cecum) 36 OCa 58 CRC (sigmold)

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8

Alimentary tract and pancreas Alimentarni trakt i pankreas

The Lynch syndrome: Report on family "S"

Key Words: Lynch syndrome, metachronous CRC, stomach cancer

Klju~ne re~i: Lynchov sindrom, metahroni KRK, karcinom `eluca

35 CRC (transverse) 58 CRC (descending) 62 GCa

50 CRC (transverse) 50 CRC (sigmold)

50 ECa 52 CRC (cecum)

54 CRC (cecum) 36 OCa 58 CRC (sigmold)

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 5 - 8

Alimentary tract and pancreas Alimentarni trakt i pankreas

Endoscopic ultrasonoghraphy in Mntrier 's disease

Endoskopska ultrasonorafija u Menetrijerovoj bolesti

Key Words: Menetrier's disease, large gastric folds, EUS.

Klju~ne re~i: Menetrierova bolest, uve}ani `eluda~ni nabori, endoskopska ultrasonografija.

Gastroenterolo{ka sekcija SLD01730, 2002.

Figure 2. EUS in Menetrier: thickening of II layer corresponding to deep mucosa.

Table 1. Classification of large gastric folds.

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 9 - 12

Figure 6. EUS in linitis plastica: Thickening of whole gut wall

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 9 - 12

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 9 - 12

Alimentary tract and pancreas Alimentarni trakt i pankreas

Zoran Krivokapic, Radoje Colovic, Nikica Grubor, Marjan Micev

Institute for Digestive Diseases, Clinical Center of Serbia, Belgrade.

Key Words: mesenteric ischemia, intestinal obstruction, entero-enteral fistula.

Gastroenterolo{ka sekcija SLD01728, 2002.

Klju~ne re~i: mesentrijska ishemija, intstinalna opstrukcija, entero-enteralna fistula.

Figure 1. Enteroclysis showing two jejunal stenosis with prestenotic dilatations.

Figure 3. Stenosed jejunal segment with large prestenotic dilatation.

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 13 - 17

Entero-enteral fistula due to mesenteric occulsion

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 13 - 17

Alimentary tract and pancreas Alimentarni trakt i pankreas

Management of acute gastroenteritis in Yugoslavia: Compliance with ESPGHAN recommendations

Key Words: acute gastroenteritis, treatment, infant, Yugoslavia.

Klju~ne re~i: akutni gastroenteritis, le~enje, odoj~e, Jugoslavija.

Gastroenterolo{ka sekcija SLD, 01729, 2002

Management of acute gastroenteritis in YU

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 18 - 24

CEE 79% 65% 19% 60% 9% 46%

WE 88% 67% 15% 35% 23% 30%

WE+ CEE 84% 66% 16% 45% 17% 37%

CEE 19% 26% 23% 42% 28% 38% 14% 75%

WE 22% 17% 45% 30% 12% 46% 12% 78%

Management of acute gastroenteritis in YU

Arch gastroenterohepatol 2002; 21 (No 1 - 2): 18 - 24