Ponad 7000 publikacji medycznych!
Statystyki za 2021 rok:
odsłony: 8 805 378
Artykuły w Czytelni Medycznej o SARS-CoV-2/Covid-19

Poniżej zamieściliśmy fragment artykułu. Informacja nt. dostępu do pełnej treści artykułu tutaj
© Borgis - Postępy Nauk Medycznych 5/2017, s. 250-256
Aneta Pasierbek-Kohutek, *Marek Hartleb
Diagnostic value of serum immunoglobulin G4, immunoglobulin E and anti-lactoferrin antibodies in type 1 autoimmune pancreatitis and immune-associated cholangitis in regular clinical circumstances**
Wartość diagnostyczna stężenia immunoglobuliny G4, immunoglobuliny E i przeciwciał przeciwlaktoferynowych w autoimmunologicznym zapaleniu trzustki typu 1 i immunologicznym zapaleniu dróg żółciowych w typowych uwarunkowaniach klinicznych
Department of Gastroenterology and Hepatology, Medical University of Silesia, School of Medicine in Katowice
Head of Department: Professor Marek Hartleb, MD, PhD
Wstęp. Najczęstszymi manifestacjami klinicznymi choroby IgG4 zależnej są autoimmunologiczne zapalenie trzustki (AIP) i immunologiczne zapalenie dróg żółciowych (IAP), których objawy często naśladują raka trzustki lub dróg żółciowych.
Cel. Ocena znaczenia diagnostycznego stężenia surowiczego IgG4, przeciwciał przeciwlaktoferynowych (ALA) i immunoglobuliny E (IgE) w diagnostyce różnicowej AIP/IAC.
Materiał i metody. Do badania włączono 16 chorych z AIP typu 1 i/lub IAC, 20 ochotników grupy kontrolnej oraz 80 pacjentów z chorobami trzustki lub dróg żółciowych o różnej etiologii wymagającymi różnicowania z chorobą zależną od IgG4. Na podstawie ostatecznego rozpoznania klinicznego wyodrębniono 5 podgrup: AIP lub IAC (AIP/IAC, n = 16), pierwotne stwardniające zapalenie dróg żółciowych (PSC, n = 20), przewlekłe alkoholowe zapalenie trzustki (ChP, n = 20), rak trzustki (PanCa, n = 20) i rak zewnątrzwątrobowych przewodów żółciowych (CCA, n = 20).
Wyniki. W grupie AIP/IAC stężenie IgG4 było zwiększone u 81% chorych i przekraczało dwukrotnie górną granicę wartości referencyjnych u 54% chorych. Odsetek nieprawidłowych wyników IgG4 u chorych z CCA wynosił 35%, z PanCa 30%, a z PSC i ChP po 15%. Na podstawie analizy ROC optymalnym punktem odcięcia dla stężenia IgG4 w różnicowaniu AIP/IAC z innymi chorobami było 127 mg/dl (czułość i swoistość odpowiednio 81% i 90%). Zwiększanie punktu odcięcia dla stężenia IgG4 pozwalało na wykrywanie AIP/IAC z bardzo wysoką swoistością. Stężenia surowicze ALA i IgE nie były pomocne w wykrywaniu i diagnostyce różnicowej AIP/IAC.
Wniosek. Stężenie surowicze IgG4 jest ważnym kryterium diagnostycznym AIP/IAC, lecz należy brać pod uwagę ich wyniki fałszywie pozytywne w chorobach nowotworowych, zwłaszcza raku przewodów żółciowych.
Introduction. Most common presentations of IgG4-related disease are autoimmune pancreatitis (AIP) and IgG4-associated cholangitis (IAC) with clinical images frequently imitating a pancreatic or bile duct cancer.
Aim. To evaluate the diagnostic significance of serum levels of IgG4, antibodies against lactoferrin (ALA) and immunoglobulin E (IgE).
Material and methods. The study involved 16 patients with AIP type 1 and/or IAC, 20 control subjects and 80 patients with pancreatobiliary diseases of different etiology requiring meticulous differentiation with IgG4-related disease. Based on final clinical diagnosis 5 subgroups were identified: AIP type 1 and/or IAC (AIP/IAC, n = 16), primary sclerosing cholangitis (PSC, n = 20), chronic alcoholic pancreatitis (ChP, n = 20), pancreatic cancer (PanCa, n = 20) and cholangiocarcinoma (CCA, n = 20).
Results. In AIP/IAC group the serum level of IgG4 was elevated in 81% of patients, and exceeded doubled limit of upper reference value in 54% of patients. Percentage of abnormal IgG4 results was 35% in CCA, 30% in PanCa, 15% in PSC and 15% in ChP. Based on ROC analysis the optimal cut-off for IgG4 in differentiation of AIP/IAC with other diseases was 127 mg/dl (sensitivity and specificity of 81 and 90%, respectively). Increasing of IgG4 cut-off allowed detection of AIP/IAC with very high specificity. Serum ALA and IgE concentrations were not helpful either in detection or differential diagnosis of AIP/IAC.
Conclusions. Serum IgG4 is important criterion of AIP/IAC but false positive results occurring in malignant diseases, in particular cholangiocarcinoma, should be taken into account.

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a multifaceted systemic disorder that includes various organ manifestations, among which the pancreas and biliary tree are most frequently affected. The predominant involvement of pancreas is known as autoimmune pancreatitis (AIP) and that of biliary tree as IgG4-associated cholangitis (IAC). IgG4-RD responds to corticosteroid treatment when diagnosed early enough, but if it remains untreated may lead to end-stage organ failure such as liver cirrhosis or fatal complications (1, 2). Liver cirrhosis was found in 8% of IAC patients (3).
Because the histology in AIP and IAC patients is often unavailable, the differentiation of these conditions with more common neoplastic and other inflammatory pancreatobiliary diseases can be extremely challenging. There is evidence that significant number of patients with IgG4-RD is falsely diagnosed as cancer and undergoes surgical instead of pharmacological treatment. Erdogan et al. reviewed post-surgery histology of 185 patients operated for biliary cancer, and in 32 patients the diagnosis of cancer was not confirmed, being in 50% of cases compatible with IAC (4). In another study, 25% of 122 patients transplanted for primary sclerosing cholangitis (PSC) showed on explanted hepatic histology moderate or marked IgG4-positive staining (5). These two studies stress the importance of pre-surgery diagnosis, but despite using panels of composite laboratory, radiological and histological parameters the gold standards for diagnosing AIP and IAC are still lacking (6-8).
IgG4-RD is often associated with elevated IgG4 serum level and is characterized by IgG4-positive plasma cells tissue infiltrates. IgG4 is one of the four subtypes of IgG, forming less than 5% of this protein in healthy population. High IgG4 serum level was first reported in patients with AIP and later was also associated with other organ manifestations of IgG4-RD, including IAC. Although elevated IgG4 level is an important diagnostic clue in the current diagnostic panels of AIP and IAC, this parameter presents several flaws such as poorly known reference values, unsatisfactory inter-laboratory reproducibility, and in particular limited specificity for IgG4-RD (9, 10).
Lactoferrin is a multifunctional glycoprotein of the transferrin family that has antimicrobial activity and is part of the innate mucosal defense. This protein is widely represented in various secretory fluids, such as milk, saliva, tears and bile. It is also present in secondary granules of neutrophils and is secreted by pancreatic acinar cells. Lactoferrin may serve as biomarker of inflammation and necrosis (11, 12). Anti-lactoferrin antibodies (ALA) may be found in 75% of patients with AIP (13). These antibodies may also emerge in autoimmune liver and bowel diseases, lupus erythematodes or type 1 diabetes. Moreover, Hardt et al. detected ALA in 21% of patients with non-alcoholic chronic pancreatitis suspected of AIP (14).
Recent studies have shown that patients with AIP demonstrate increased serum levels of IgE (15, 16). In addition, elevated IgE was not associated with allergic reactions and did not correlate with severity of AIP, therefore, it was conceived that this immunoglobulin might be a biomarker of subclinical IgG4-RD when IgG4 level is still normal.
The purpose of this study was to determine the ability of IgG4, ALA and IgE to identify clinically overt AIP and IAC amongst many other pancreatobiliary diseases difficult or impossible to distinguish from IgG4-RD without histology. For this reason we measured serum levels of these biomarkers not only in IgG4-RD but also in patients with wide spectrum of clinically similar diseases.
Material and methods
Ninety six patients with pancreatobiliary diseases consecutively admitted to the tertiary gastro-hepatological center between January 2013 and December 2014 were included to the study. Final clinical diagnosis was based on abdominal imaging methods (ultrasound, computed tomography, magnetic resonance, endoscopic retrograde cholangiopancreatography), histopathological/cytological examination of biopsy samples and serum level of CA19-9, associated with median 17 months clinical follow-up.
According to final clinical diagnosis the patients were enrolled to one of 5 following subgroups: cholangiocarcinoma (CCA; n = 20), pancreatic cancer (PanCa; n = 20), alcoholic chronic pancreatitis (ChP; n = 20), primary sclerosing cholangitis (PSC; n = 20) and autoimmune pancreatitis and/or IgG4-associated cholangitis (AIP/IAC; n = 16). The control group consisted of 20 patients with functional gastroenterological diseases having neither pancreatobiliary problem nor autoimmune disease.
The initial criterion of recruitment to AIP/IAC group was one of the following: 1) diffusely or segmentally enlarged pancreas, 2) solid tumor of the pancreas that was not diagnosed as cancer in at least two fine-needle aspiration biopsies or post-surgery histology, and 3) common biliary duct stricture at cholangiography (magnetic resonance or endoscopic).
The diagnosis of AIP was based on the criteria established by international consensus from Fukuoka, 2010 (6) and IAC was diagnosed according to latest Japanese criteria (8). Initially, 25 patients were suspected to have AIP/IAC, but ultimately 16 patients were included to this group: 8 patients were diagnosed with AIP-1 and coexisting IAC, 3 with AIP alone, and 5 with IAC alone. Reasons for exclusion of 9 patients were: lack of strong evidence against pancreatic or bile duct malignancy (n = 4), suspicion of genetic background of chronic pancreatitis (n = 2), loss of the patient from the follow-up before final diagnosis could be established (n = 2) and death from other causes (n = 1).
Exclusion criteria from all investigated groups were: type 2 autoimmune pancreatitis, recent acute pancreatitis, serum level of triglycerides > 600 mg/dl, increased serum calcium level, family history of pancreatitis, HIV infection, history of sepsis or hypovolemic shock and liver or kidney transplantation.
Serum samples
Peripheral blood morphology (Sysmex XT-1800i) and serum biochemistry (Olympus AU680) were determined on the day of admission. Serum level of CA19-9 was measured by immunoassay (CMIA Architect i2000SR). Serum levels of γ-globulin, immunoglobulin G and autoantibodies (antinuclear, anti-smooth muscle, antimitochondrial) were determined only in patients with AIP/IAC. Blood samples for non-routine examinations were centrifuged for 15 minutes at 1500 g and immediately stored in small aliquots at -80°C, until further elaboration. Serum level of IgG4 was measured by nephelometry (Minineph Human IgG4 KIT, Binding Site). Anti-lactoferrin antibodies and IgE levels were assayed using a commercially available enzyme-linked immunosorbent kits (Demeditec Diagnostics, Kiel, Germany).
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) and was approved by the Ethics Committee of Silesian Medical University. The informed consent was obtained from all patients.
Statistical analysis
Continuous parameters were reported as a mean ± SD and as a median with interquartile range (IQR 25th-75th percentile). Normality test was performed for all quantitative variables. Non-parametric statistical methods were used for non-normally distributed data. For multiple comparisons Kruskal-Wallis test was used. Testing of significance was carried out using the T-test or Mann-Whitney U test.
Discrete data were summarized as frequencies and percentages. The Chi-Square test was used for comparison of categorical data. Correlations were assessed by Spearman’s test, and the correlation coefficient r was used to measure the strength and the direction of relationship.
Receiver operating characteristic (ROC) curve analysis was carried out and area under the ROC curve (AUROC) was calculated to evaluate accuracy of IgG4, ALA and IgE for diagnosis of AIP/IAC. A two-tailed p < 0.05 was considered significant.

Powyżej zamieściliśmy fragment artykułu, do którego możesz uzyskać pełny dostęp.
Mam kod dostępu
  • Aby uzyskać płatny dostęp do pełnej treści powyższego artykułu albo wszystkich artykułów (w zależności od wybranej opcji), należy wprowadzić kod.
  • Wprowadzając kod, akceptują Państwo treść Regulaminu oraz potwierdzają zapoznanie się z nim.
  • Aby kupić kod proszę skorzystać z jednej z poniższych opcji.

Opcja #1


  • dostęp do tego artykułu
  • dostęp na 7 dni

uzyskany kod musi być wprowadzony na stronie artykułu, do którego został wykupiony

Opcja #2


  • dostęp do tego i pozostałych ponad 7000 artykułów
  • dostęp na 30 dni
  • najpopularniejsza opcja

Opcja #3


  • dostęp do tego i pozostałych ponad 7000 artykułów
  • dostęp na 90 dni
  • oszczędzasz 28 zł
1. Sah RP, Chari ST: Autoimmune pancreatitis: an update on classification, diagnosis, natural history and management. Curr Gastroenterol Rep 2012; 14: 95-105.
2. Huggett MT, Culver EL, Kumar M et al.: Type 1 Autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol 2014; 109: 1675-1683.
3. Webster G, Pereira S, Chapman R: Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis – overlapping or separate diseases? J Hapatol 2009; 51: 398-402.
4. Erdogan D, Kloek JJ, ten Kate FJ et al.: Immunoglobulin G4-related scleroting cholangitis in patients resected for presumed malignant bile duct strictures. Br J Surg 2008; 95: 727-734.
5. Fischer S, Trivedi PJ, Ward S et al.: Frequency and significance of IgG4 immunohistochemical staining in liver explants from patients with primary sclerosing cholangitis. Int J Exp Pathol 2014; 95(3): 209-215.
6. Shimosegawa T, Chari ST, Frulloni L et al.: International Association of Pancreatology. International consensus diagnostic criteria for autoimmune pancreatitis: Guidelines of the International Association of Pancreatology. Pancreas 2011; 40: 352-358.
7. Tabata T, Kamisawa T, Kuruma S et al.: Capability and limitations of recent diagnostic criteria for autoimmune pancreatitis. Int J Rheumatol 2013; 2013: 465428. DOI: 10.1155/2013/465428.
8. Ohara H, Okazaki K, Tsubouchi H: Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci 2012; 19: 536-542.
9. Kawa S, Ito T, Watanabe T et al.: The utility of serum IgG4 concentration as a biomarker. Int J Rheumatol 2012; 2012: 198314. DOI: 10.1155/2012/198314.
10. Okazaki K, Kazushige U, Ikeura T, Takaoka M: Current concept and diagnosis of IgG4-related disease in the hepato-bilio-pancreatic system. J Gastroenterol 2013; 48: 303-314.
11. Hayakawa T, Jin ChX, Ko S et al.: Lactoferrin in gastrointestinal disease. Inter Med 2009; 48: 1251-1254.
12. Jin CH, Hayakawa T, Kitagawa M, Ishiguro H: Lactoferrin in chronic pancreatitis. JOP J Pancreas 2009; 10: 237-241.
13. Okazaki K: Autoimmune pancreatitis: etiology, pathogenesis, clinical findings and treatment. The Japanese experience. JOP 2005 Jan 13; 6 (1 suppl.): 89-96.
14. Hardt PD, Ewald N, Bröckling K et al.: Distinct autoantibodies against exocrine pancreatic antigens in European patients with type 1 diabetes mellitus and non-alcoholic chronic pancreatitis. JOP 2008; 9: 683-689.
15. Hirano K, Tada M, Isayama H et al.: Clinical analysis of high serum IgE in autoimmune pancreatitis. World J Gastroenterol 2010; 16: 5241-5246.
16. Kuruma S, Kamisawa T, Tabata T et al.: Allergen-specific IgE antibody serologic assays in patients with autoimmune pancreatitis. Intern Med 2014; 53: 541-543.
17. Okazaki K, Uchida K, Fukui T: Recent advances in autoimmune pancreatitis: concept, diagnosis and pathogenesis. J Gastroenterol 2008; 43: 409-418.
18. Ketwaroo GA, Sheth S: Autoimmune pancreatitis. Gastroenterol Rep 2013; 1: 27-32.
19. Zhang X, Zhang X, Li W et al.: Clinical analysis of 36 cases of autoimmune pancreatitis in China. Plos One 2012; 7(9): e44808.
20. Zen Y, Nakanuma Y: IgG4 cholangiopathy. Int J Hepatol 2012; 2012. DOI: 10.1155/2012/472376.
21. Graham RP, Smyrk TC, Chari ST et al.: Isolated IgG4-related sclerosing cholangitis: a report of 9 cases. Hum Pathol 2014; 45: 1722-1729.
22. Hamano H, Kawa S, Horiuchi A et al.: High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001; 344: 732-738.
23. O’Reilly DA, Malde DJ, Duncan T et al.: Review of the diagnosis, classification and management of autoimmune pancreatitis. World J Gastrointest Pathophysiol 2014; 5: 71-81.
24. Oseini A, Chaiteerakij R, Shire A et al.: The utility of serum immunoglobulin G4 in distinguishing immunoglobulin G4-associated cholangitis from cholangiocarcinoma. Hepatology 2011; 54: 940-948.
25. Kamisawa T, Takuma K, Tabata T et al.: Serum IgG4-negative autoimmune pancreatitis. Gastroenterol 2011; 46: 108-116.
26. Tabata T, Kamisawa T, Takuma K et al.: Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease. Intern Med 2011; 50: 69-75.
27. Taghavi SA, Majd SK, Sianati M, Sepehrimanesh M: Prevalence of IgG-4-associated cholangiopathy based on serum IgG-4 levels in patients with primary sclerosing cholangitis and its relationship with inflammatory bowel disease. Turk J Gastroenterol 2016; 27: 547-552.
28. Beyer G, Schwaiger T, Lerch M, Mayerle J: IgG4-related disease: a new kid on the block or an old acquaintance? United European Gastroenterol J 2014; 2: 165-172.
29. Okazaki K, Uchida K, Koyabu M et al.: IgG4 cholangiopathy – current concept, diagnosis, and pathogenesis. J Hepatol 2014; 61: 690-695.
otrzymano: 2017-04-06
zaakceptowano do druku: 2017-04-27

Adres do korespondencji:
*Marek Hartleb
Klinika Gastroenterologii i Hepatologii Śląski Uniwersytet Medyczny w Katowicach
ul. Medyków 14, 40-752 Katowice
tel. +48 (32) 789-44-01

Postępy Nauk Medycznych 5/2017
Strona internetowa czasopisma Postępy Nauk Medycznych