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Home , Autoimmune hepatitis, Coeliac disease

2002;122:881–888

Celiac Disease in Patients With Severe Disease: -Free Diet Reverse Hepatic Failure

KATRI KAUKINEN,* LEENA HALME,‡ PEKKA COLLIN,* MARTTI FA¨RKKILA¨,‡ MARKKU MA¨KI,* PAULA VEHMANEN,§ JUKKA PARTANEN,§ and KRISTER HO¨ CKERSTEDT‡ *Departments of and , Tampere University Hospital, Tampere, and Medical School and Institute of Medical Technology, University of Tampere, Tampere; ‡Division of Transplantation, Department of Surgery, and Department of Internal Medicine, Helsinki University Hospital, Helsinki; and §Department of Tissue Typing Laboratory, Finnish Red Cross Blood Transfusion Service, Helsinki, Finland

Background & Aims: Mild liver abnormalities are com- The mechanisms underlying liver injury in celiac dis- mon in patients with celiac disease and usually resolve ease are poorly understood. is uncommon with a gluten-free diet. We investigated the occurrence today, and the elevation of aminotransferase levels may of celiac disease in patients with severe . be the only presenting feature in patients with celiac Methods: Four patients with untreated celiac disease disease. The increased intestinal mucosal permeability and severe are described. Further, the oc- characteristic of celiac disease may facilitate the entry of currence of celiac disease was studied in 185 adults bacterial toxins and other to the portal system.4 with previous using serum immu- Autoimmune liver diseases and celiac disease often share noglobulin A endomysial and tissue a similar HLA (i.e., HLA DR3-DQ2 or DR4- in . Results: Of the 4 patients with DQ8).11,15,16 severe liver disease and celiac disease, 1 had congenital liver fibrosis, 1 had massive hepatic steatosis, and 2 had Histologically, only minimal hepatic steatosis or reac- progressive without apparent origin. Three tive nonspecific hepatitis can be seen in cases of celiac were even remitted for consideration of liver transplan- disease in which liver levels are slightly in- 1,2,4,5 tation. Hepatic dysfunction reversed in all cases when a creased. The condition is generally viewed as be- gluten-free diet was adopted. In the transplantation nign, because the enzyme levels usually resolve with a group, 8 patients (4.3%) had celiac disease. Six cases gluten-free diet.2–5 The impact of a gluten-free diet on were detected before the operation: 3 had primary bili- the outcome of a concomitant autoimmune liver disease ary , 1 had , 1 had pri- in patients with celiac disease is less clear.2,7,13,17 mary sclerosing cholangitis, and 1 had congenital liver Most patients with celiac disease remain undiagnosed fibrosis. Only 1 patient had maintained a long-term strict today; it may be estimated from population-based gluten-free diet. Screening found 2 cases of celiac dis- screening studies that the frequency of celiac disease is ease, 1 with autoimmune hepatitis and 1 with second- 0.5% to 1.0%,18,19 whereas the reported prevalence fig- ary sclerosing cholangitis. Conclusions: The possible ures in clinical practice are 0.3% to 0.1% or even presence of celiac disease should be investigated in lower.20 It can be hypothesized that untreated celiac patients with severe liver disease. Dietary treatment disease with subclinical hepatic involvement can in some may prevent progression to hepatic failure, even in cases lead with time to a more serious liver disease. This cases in which liver transplantation is considered. would warrant a more aggressive diagnostic workup for celiac disease in the population. In support of such a odest elevation of serum aminotransferase levels is view, here we describe untreated celiac cases with severe Mcommon in untreated celiac disease, occurring in liver disease; some of these patients were even remitted 15%–55% of patients.1–4 On the other hand, in the for consideration of liver transplantation. We further absence of other disorders, celiac disease has been found investigated the frequency of celiac disease in patients in as many as 9% of patients with elevated aminotrans- with previous liver transplantation. ferase levels.5,6 Apart from such nonspecific hepatic dis- turbances, the association between celiac disease and Abbreviations used in this paper: EmA, endomysial ; tTG-ab, autoimmune liver disorders such as primary biliary cir- antibodies. © 7–9 10,11 2002 by the American Gastroenterological Association rhosis, autoimmune hepatitis, and primary scle- 0016-5085/02/$35.00 rosing cholangitis12–14 is well documented. doi:10.1053/gast.2002.32416 882 KAUKINEN ET AL. GASTROENTEROLOGY Vol. 122, No. 4

Patients and Methods Statistical Analysis Celiac Disease in Patients With Severe The Fisher exact test was used in cross-tabulations. Ͻ Liver Failure P 0.05 was considered statistically significant. Four patients with severe liver failure who were found Results to have celiac disease are described in detail. These patients were placed on a gluten-free diet, and clinical recovery of the Untreated Celiac Disease in Patients With liver disease was observed. Severe Liver Failure All liver transplantations in Finland, altogether 375 so far, Case 1. In 1984, a 15-year-old white boy was are performed at Helsinki University Hospital. Local specialist examined because of a history of iron deficiency . centers refer patients for consideration when patients seem to He did not have any abdominal symptoms, but his approach end-stage liver disease. Three of 4 patients subse- growth had been slightly retarded at 5 years of age. A quently found to have celiac disease were remitted in such a small bowel mucosal specimen showed villous way; however, during the evaluation process, it was found that with crypt hyperplasia consistent with celiac they did not meet the transplantation criteria. disease. The prescribed gluten-free diet resulted in im- mediate clinical recovery, but for some reason shortly Prospective Study thereafter the patient neglected the diet and surveillance. A prospective screening study was set up to examine Five years later, in 1989, he developed progressive the occurrence of treated or untreated celiac disease in patients and ascites within 1 month, and his liver func- with previous liver transplantation. A total of 185 (118 women tion and overall condition deteriorated to fulmi- and 67 men) such voluntary adults were enrolled; their median nant hepatitis, which was also observed in a age was 52 years (range, 17–72 years). specimen (Table 1 and Figure 1A). He was referred to Serum immunoglobulin (Ig) A-class endomysial antibody the hospital as a possible case for liver transplantation. (EmA)21 and tissue transglutaminase antibodies (tTG-ab)22 There was no relevant family, alcohol, or drug history, were used as screening methods for celiac disease. Sera were and he had never received a blood transfusion. Serum taken before transplantation in 35 patients and thereafter in markers for hepatitis A virus, hepatitis B virus, and 150 patients. EmA was determined by an indirect immu- virus as well as serum antinuclear antibodies, nofluorescence method using human umbilical cord as sub- antibodies, and antimitochondrial anti- strate; the screening dilution was 1:5, and titers 1:Ն5 were bodies were negative, as were antibodies against cyto- considered positive. tTG-ab were investigated by enzyme- megalovirus or Epstein–Barr virus. His hemoglobin level linked immunosorbent assay (Inova Diagnostics, San Diego, was 127 g/L (reference values, 130–180 g/L). CA), and Ն20 U was considered abnormal. Serum IgA In the hospital, the patient was once again placed on levels were measured by laser nephelometry to exclude a gluten-free diet; within 3 weeks, the jaundice and Ͻ selective IgA deficiency ( 0.04 g/L). ascites disappeared, liver function started to recover (Fig- Seropositive patients underwent upper gastrointestinal en- ure 1B), and he was in good condition. Some years later, doscopy, during which biopsy specimens were obtained from however, he evinced signs of ; liver the distal part of the . The specimens were pro- function test results were abnormal (alanine aminotrans- cessed, stained with H&E, and studied under light microscopy. ferase, 51 U/L; , 634 U/L; and bili- Patients found to have subtotal or severe partial small bowel rubin, 29 ␮mol/L [reference values, Ͻ50 U/L, 60–275 villous atrophy with crypt hyperplasia were considered to have U/L, and Ͻ20 ␮mol/L, respectively]), serum albumin celiac disease. Ͼ Serologic identification of HLA-DR antigens was performed level was low (32 g/L; reference values, 40 g/L), and in all patients with a history of liver transplantation. The prothrombin time was slightly prolonged (international presence of HLA-DQ2 and HLA-DQ8 was investigated in normalized ratio, 1.5–1.3; reference values, 0.9–1.2). seropositive patients and in patients with celiac disease as were found on in 1998. described by Karell et al.23 Briefly, the haplotype was deter- During surveillance, compliance with the gluten-free mined using the microsatellite markers DQCAR and DQCA- diet was poor; in 1994, a small bowel biopsy specimen RII, which are situated between the DRB1 and DQB1 genes. showed subtotal villous atrophy, and in February 2001, The control population for HLA-DQ typing comprised 95 he had strongly positive IgA-class tTG-ab (293 U). randomly picked cadaver donors of Finnish origin (32 Simultaneously, his liver disease progressed to end-stage women and 63 men). cirrhosis, and he eventually underwent liver transplanta- All subjects gave informed consent. The study protocol was tion in May 2001, 12 years after the acute fulminant approved by the local ethical committee. episode. April 2002 CELIAC DISEASE AND LIVER FAILURE 883

Table 1. Findings Before and After the Introduction of a Gluten-Free Diet in Patients With Severe Liver Failure Subsequently Found to Have Celiac Disease Patient 1 Patient 2 Patient 3 Patient 4

Before After Before After Before After Before After GFD GFD GFD GFD GFD GFD GFD GFD General condition Poor Improved Poor Improved Poor Improved Poor Improved Jaundice ϩϩϩ 0 ϩϮ0000 Ascites ϩϩϩ 0 ϩϩϩ 0 ϩϩϩ 0 ϩϩϩ 0 INR (0.9–1.2) 3.0 1.3 1.5–1.1 1.0 2.1–1.1 1.1 1.1 1.3 Albumin, g/L (Ͼ40 g/L) 18 41 16 38 12 44 29 37 Bilirubin, ␮mol/L (Ͻ20 Ͼ500 25 40 31 13 8 25 24 ␮mol/L) Alkaline phosphatase, 940 735 188 96 358 117 622 835 U/L (60–275 U/L) Alanine aminotransferase, 3390 91 57 25 122 18 41 33–50 U/L (Ͻ50 U/L) Liver histology Acute Improved Increased ND 50% steatosis Improved Early cirrhosis Micronodular hepatitis fibrosis with with mild cirrhosis, lymphocytic chronic proliferation infiltration hepatitis HLA type HLA-DQ2 ND HLA-DQ2 HLA-DQ2

GFD, gluten-free diet; INR, international normalized ratio; ND, not done.

Case 2. In 1977, a 5-year-old boy was examined Case 3. In 1989, a 52-year-old man developed because of liver enlargement, and a subsequent liver severe edema in the legs and tense ascites 2 months later. biopsy specimen was consistent with congenital liver His condition deteriorated rapidly, and he was remitted fibrosis. Esophageal varices were detected 11 years later. to the University Hospital due to severe liver failure. He At 18 years of age, he was evaluated for possible liver experienced muscle wasting but not from or transplantation due to liver failure (Table 1). During the . His height was 170 cm and weight 47 kg. previous 2 years, he had experienced progressive tired- Serum albumin level was low and liver function test ness, muscle atrophy, and peripheral edema and ascites results abnormal (Table 1). There were no signs of viral and was unable to work because of his poor condition. hepatitis or autoimmune liver diseases. He denied alco- Ultrasonography showed a small liver and splenomegaly, hol consumption and was not taking any medication. A endoscopic retrograde cholangiopancreatography showed liver biopsy specimen showed macrovesicular and mi- diffuse irregularity of the intrahepatic bile ducts, and a crovesicular steatosis in 50% of and there liver biopsy specimen gave evidence of increased fibrosis wasnoinflammation, but hemosiderosis and intrahepatic together with proliferation of the bile ducts; all findings were evident (Figure 1C). Hemoglobin level were consistent with the original liver disease. Hemo- was 120 g/L, and serum B12 and folic acid levels globin level was 110 g/L and the anemia normocytic. were within reference values. Further examinations Because there was a slow response to treatment with showed no signs of malignant disease, but a small bowel diuretics and vitamin K, liver transplantation was not biopsy specimen taken on endoscopy showed villous considered necessary, but the patient was kept under atrophy with crypt hyperplasia (Figure 1E). surveillance. Three years later, his overall condition de- A gluten-free diet was introduced, but treatment with teriorated and he developed progressive ascitic fluid re- was also started 2 weeks later because of his tention. His hemoglobin level at this time was 84 g/L; poor condition. Thereafter, recovery occurred rapidly; upper endoscopy showed no visible cause of blood loss, peripheral edema and ascites disappeared within 1 but small bowel villous atrophy with crypt hyperplasia month. A second liver biopsy specimen showed steatosis was found in duodenal biopsy samples. Subsequently, a in only 10% of hepatocytes, and intrahepatic cholestasis gluten-free diet was commenced. Within 6 months, the and hemosiderosis had mostly vanished (Figure 1D). ascites had disappeared and medical treatment was no Treatment with prednisolone could be discontinued longer necessary. In 1998, the follow-up small bowel within 6 months, and the only subsequent treatment was mucosal biopsy specimen was normal; the patient was a gluten-free diet. Fifteen months later, there was a clear feeling well, and there were no signs of active liver improvement in small bowel mucosal villous architecture disease. (Figure 1F ), liver function test results and serum albu- 884 KAUKINEN ET AL. GASTROENTEROLOGY Vol. 122, No. 4

Figure 1. Liver histology of a pa- tient with fulminant hepatitis (pa- tient 1) (A) before and (B) after introduction of a gluten-free diet. Liver and small bowel mucosal his- tology (C and E) before and (D and F ) during a gluten-free diet in a patient (patient 3) with steatosis and severe liver failure. min level were normal, and hemoglobin level was 142 could no longer be found. Antibody to hepatitis g/L. He has returned to work and is in good condition C virus and antinuclear antibodies, smooth muscle anti- today. bodies, and antimitochondrial antibodies were negative. Case 4. A 39-year-old white woman had iron Iron deficiency anemia (hemoglobin level, 75 mg/L) was deficiency anemia for 30 years and had taken occasional again present. A subsequent small bowel mucosal biopsy iron substitution, but no specific diagnosis had been specimen showed villous atrophy with crypt hyperplasia. made. In 1996, she began to experience weakness, and Six months after the introduction of a gluten-free diet, ascites accumulated rapidly within a few months (Table she no longer had ascites and diuretics could be discon- 1). Computed tomography showed a cirrhotic liver with tinued; small bowel villous architecture likewise recov- signs of , but Doppler ultrasonogra- ered. Subsequently, the liver test results remained phy showed portal and hepatic veins to be open. A liver abnormal (alkaline phosphatase, 1428 U/L; alanine ami- biopsy specimen showed early cirrhotic changes with notransferase, 76 U/L; bilirubin, 55 ␮mol/L). In the mild lymphocytic infiltration of unknown etiology. Her second liver biopsy specimen, cirrhotic changes were alcohol consumption was insignificant, and there was no accompanied by lymphocytic inflammation and serum history of blood transfusions or drugs. Antibody to hep- IgG concentration was increased. Autoimmune hepatitis atitis B core antigen was positive, but hepatitis B surface was considered and treatment with prednisolone started. April 2002 CELIAC DISEASE AND LIVER FAILURE 885

Table 2. Liver Diseases and HLA Status of 185 Adults With Prospective Study Previous Liver Transplantation The liver diseases and HLA status of 185 patients No. of HLA DR3 DQ2– or No. of DR4 DQ8–positive who underwent transplantation are shown in Table 2; Liver diseases patients (%) patients (%) these cases represent one half of the Finnish adult liver Primary biliary cirrhosis 61 (33) 22/56 (39) transplantation population. Altogether, 8 patients (4.3%) 29 (16) 15/27 (56) were found to have biopsy-proven celiac disease (Table Primary sclerosing cholangitis 21 (11) 11/19 (58) 3). In 6 patients, the disease had been detected earlier; in Cirrhosis of unknown origin 20 (11) 8/20 (40) Alcohol cirrhosis 15 (8) 3/15 (20) 2 patients diarrhea and were symptoms Budd–Chiari syndrome 9 (5) 3/9 (33) leading to the diagnosis, 2 patients had iron deficiency Hepatic malignancies 6 (3) 3/6 (50) anemia, and in 2 patients a small bowel mucosal biopsy Autoimmune hepatitis 5 (3) 3/4 (75) Hepatitis C 5 (3) 2/5 (40) specimen was taken in conjunction with endoscopy per- Toxic damage 4 (2) 3/4 (75) formed to examine esophageal varices. Two cases of celiac Miscellaneousa 10 (5) 4/10 (40) disease were found by current screening. Patient 1 (Table b Controls 93 37/95 (39) 3) had rheumatoid , patient 5 had ulcerative aSecondary sclerosing cholangitis in 4, hepatitis B in 2, hemochro- , and patient 8 had IgA nephropathy; the remain- matosis in 1, postoperative hepatic in 1, congenital liver ing 5 patients with celiac disease did not have any fibrosis in 1, and Wilson’s disease in 1. bDifferences between controls and patients with various liver dis- associated diseases. eases were not statistically significant. In the previously detected cases of celiac disease, 3 patients had primary biliary cirrhosis, rapidly progress- ing in 2 (patients 2 and 4, Table 3), 1 had acute In recent months, no clear recovery of the liver disease autoimmune hepatitis unresponsive to immunosuppres- has been observed. However, her compliance with the sive therapy, 1 had primary sclerosing cholangitis, and 1 steroid treatment has been poor; moreover, she does had congenital liver fibrosis. In 5 patients, the liver not follow a strict gluten-free diet, and a recent small disorder had developed when celiac disease was still bowel biopsy specimen again showed mucosal villous undiagnosed. At the time of transplantation, only 1 atrophy. patient had adhered to a long-term strict gluten-free diet

Table 3. Celiac Disease in Patients With Previous Liver Transplantation Duration of Age at diagnosis Age at Symptoms and liver disease Duration of CD Sex/age of liver disease diagnosis signs leading to before before Adherence to No. (yr) Liver disease (yr) of CD diagnosis of CD transplantation transplantation gluten-free diet 1 F/63 AIH (acute) 56 56 yr No symptoms 9 mo 9 mo Strict Iron deficiency anemia 2 F/59 PBC 48 49 yr Loose stools 1 yr 8 mo Strict Iron deficiency anemia 3 F/66 PBC 39 46 yr No symptoms 8 yr 2 mo Strict Anemia 4 M/61 Steatosis, 48 49 yr Loss of weight 3 yr 3 yr Frequent PBC Diarrhea dietary suspicion lapses 5 M/46 PSC 20 6 mo Diarrhea 20 yr 39 yr Frequent Protruding dietary lapses 6 F/22 Congenital Ͻ1 11 yr Variceal bleeding 22 yr 11 yr Strict liver fibrosis (routine duodenal biopsy) No malabsorption 7 F/54 Chronic active 25 54 yr No symptoms 16 yr 0a No diet hepatitis No malabsorption 8 M/34 Secondary 27 34 yr No symptoms 4yr 0a No diet sclerosing No malabsorption cholangitis

CD, celiac disease; AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis. aCeliac disease detected in prospective screening study. 886 KAUKINEN ET AL. GASTROENTEROLOGY Vol. 122, No. 4

(patient 6, Table 3). In 3 patients, the gluten-free diet On the other hand, 8 (4.3%) of 185 patients who had had lasted only a short time (patients 1–3, Table 3); 2 undergone liver transplantation were found to have celiac patients had frequent dietary transgressions, and in these disease; the figure is 4–10 times higher than that found patients small bowel mucosal partial villous atrophy was in population screening studies performed in our country still found 3 and 25 years after the introduction of the and elsewhere.24 Of these 8 patients, only 1 had adopted diet (patients 4 and 5, Table 3). an adequate long-term gluten-free diet before liver trans- In the screening study, 1 patient with chronic active plantation. This suggests, albeit indirectly, that a glu- hepatitis was found to be serum EmA- and tTG-ab– ten-free diet may be of benefit in the prevention of positive, and a small bowel mucosal biopsy specimen end-stage liver disease in patients with gluten intoler- showed subtotal villous atrophy with crypt hyperplasia ance. Similarly, there may be a risk that the underlying (patient 7, Table 3). In fact, 5 years before liver trans- liver disease may proceed in the liver transplant if pa- plantation, she had been suspected to have celiac disease tients with celiac disease have persistent villous atrophy by reason of iron deficiency anemia and low serum B12 due to continuous ingestion of gluten. This again justi- vitamin level. For some reason, an experimental gluten- fies active screening for celiac disease in patients who free diet had been advocated instead of a diagnostic small have undergone liver transplantation. Moreover, an es- bowel biopsy, but she soon gave up this diet. One patient sential part in the course of surveillance after transplan- with postoperative sclerosing cholangitis had positive tation is to see that a strict gluten-free diet is followed in tTG-ab but negative EmA. His biopsy specimen showed patients with biopsy-proven celiac disease. patchy partial villous atrophy. He had also had an itch- Interestingly, not all of our patients with severe liver ing papulovesicular for many years. Now, a skin failure and celiac disease had apparent symptoms com- biopsy specimen showed granular IgA deposition, con- patible with celiac disease, suggesting that the celiac firming the diagnosis of celiac disease and disease–related liver involvement was not necessarily a herpetiformis. complication of malabsorption. Rather, it may well be a All other serologically screened patients were EmA gluten-dependent immunologically induced extraintesti- negative, but 10 were tTG-ab positive, including the nal manifestation of celiac disease. Similar examples can patient with partial villous atrophy. Of the remaining 9 already be found in the literature. In the study by tTG-ab–positive patients, 3 had primary sclerosing Hadjivassiliou et al.,25 silent celiac disease was found in cholangitis, 2 had primary biliary cirrhosis, 2 had cir- 16% of patients with neurologic disorders of unknown rhosis of unknown origin, 1 had toxic hepatic damage, origin. They subsequently observed that patients with and 1 had hepatitis C. Five consented to small bowel celiac-related may improve with a gluten-free mucosal biopsy, and the villous morphology was found diet.26 Recently, Ventura et al.27 showed that prolonged to be normal in all. Three patients had selective IgA exposure to gluten in patients with celiac disease con- deficiency. One had earlier detected celiac disease (pa- tributes to the development of other autoimmune dis- tient 5, Table 3). The remaining 2 patients had earlier eases such as diabetes mellitus or autoimmune undergone a small bowel biopsy for clinical reasons, and disorders. By the same token, it may be hypothesized the mucosal histology was normal. that ingestion of gluten can sometimes even result in HLA-DQ2 was observed in all patients with celiac disease. Six patients without celiac disease but with liver damage in patients with celiac disease. Such hepatic positive tTG-ab and negative EmA had no HLA-DQ2 or involvement is usually considered to be mild, but our HLA-DQ8. findings suggest that in some cases it may eventually lead to an end-stage liver disorder. There is one earlier anec- dotal report in which a gluten-free diet was shown to Discussion reverse severe liver failure in 2 patients with celiac dis- Here we describe 4 patients with advanced liver ease and primary biliary cirrhosis, and liver transplanta- disease who were found to have celiac disease. Three of tion was no longer needed.28 these patients were remitted as possible candidates for In our patients with severe liver disease, celiac disease liver transplantation. It is impossible in retrospect to was mainly associated with autoimmune liver disorders. envisage the possible outcome of liver disease in the It is of note that the course of the liver condition was absence of a gluten-free diet. Nevertheless, the liver rapidly progressive in some individuals. For instance, in disease improved significantly in every case after adop- 2 patients with primary biliary cirrhosis and celiac dis- tion of the diet, and the favorable effect was sustained in ease, end-stage liver failure developed rapidly within 1 the 2 patients who continued on a strict diet. and 3 years (Table 3), whereas primary biliary cirrhosis April 2002 CELIAC DISEASE AND LIVER FAILURE 887

commonly follows a course extending over a 10–20-year Celiac disease has been found in 0%–7% of patients period. Interestingly, it has been shown that chronic with primary biliary cirrhosis8,11,35,36 and in 2.8% of active hepatitis may have a more serious outcome in those with autoimmune hepatitis.11 There are some case patients with concomitant celiac disease than in those reports on an association between celiac disease and with normal small bowel villous architecture.17 primary sclerosing cholangitis12–14 or hepatic steato- It is now widely accepted that immunologic mecha- sis.37–39 In some cases, a gluten-free diet has had a nisms are implicated in the development of the mucosal beneficial effect. Such evidence notwithstanding, we con- damage in patients with celiac disease. The major single sider that celiac disease is still overlooked in patients environmental trigger is ingested gluten. Tissue trans- with severe liver disease. glutaminase seems to play a critical role in controlling Our prevalence figure for celiac disease may well be an cell homeostasis regulating the cell cycle through its underestimate. First, in one half of the patients, sera were involvement in proliferation, differentiation, and apopto- collected after liver transplantation. Immunosuppressive treatment may heal a celiac small bowel mucosal lesion,40 sis. This enzyme is now shown to be the predominant and thus there may be both false-negative antibody autoantigen for celiac disease.29 It can generate new results and patients with celiac disease with normal antigenic neoepitopes by cross-link formation or deami- villous architecture. Second, IgA-class antibodies are not dation of . In genetically predisposed individuals positive in all untreated individuals with celiac disease.41 (i.e., HLA-DQ2– or HLA-DQ8–positive), gluten-spe- To further increase the value of the screening, we used 2 30 cific T cells are present in the celiac mucosal lesion. sensitive antibody assays and examined all sera for selec- Through of gliadin, the enzyme facilitates tive IgA deficiency. In addition, we recommend taking a the binding of gliadin to HLA-DQ2 and HLA- small bowel biopsy specimen in patients with liver dis- DQ8 molecules.31,32 Antigen-presenting cells in the lam- ease whenever upper endoscopy is performed for clinical ϩ ina propria present digested gluten to CD4 T reasons. cells. Stimulated T cells secrete Th1 cytokines, which can Patient 8 in Table 3 had sclerosing cholangitis as a damage the small bowel mucosa, and the simultaneous complication of cholecystectomy. He definitely did not Th2 response results in the formation of . seem to run any increased risk of celiac disease. On the Autoantibodies against tissue transglutaminase may have other hand, based on the postulated prevalence figures for a direct pathogenetic role in the pathogenesis of enter- celiac disease, it is not surprising to find 1 patient with opathy by disturbing epithelial differentiation on the celiac disease without any apparent risk among 185 crypt-villous axis.33 subjects. It is possible that, apart from gliadin, tissue transglu- In conclusion, celiac disease may occur in patients taminase can also modify other external or self antigens with severe liver disease and in those who have under- and generate different neoantigens. Analogously to celiac gone liver transplantation. Moreover, celiac disease disease, these antigens and antibody production can in- should be rigorously investigated in all patients with duce various autoimmune phenomena outside the intes- autoimmune hepatitis or hepatitis of unknown etiology. tine.34 The increased permeability in may In some cases, early detection and treatment of celiac further facilitate external antigens such as food proteins, disease may prevent progression to end-stage liver fail- bacterial products, and endotoxins to enter into the ure. intestinal lamina propria, portal circulation, and liver.4 These mechanisms might explain how ingested gluten References could exacerbate various autoimmune liver diseases in 1. Hagander B, Berg N, Brandt L, Norden Å, Sjo¨lund K, Stenstam M. Hepatic injury in adult . Lancet 1977;1:270–272. genetically susceptible individuals. This hypothesis can 2. Jacobsen MB, Fausa O, Elgjo K, Schrumpf E. 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Does cryptic gluten sensitivity play a part Hospital, the Emil Aaltonen Foundation, the Sigrid Juselius Foundation, in neurological illness? Lancet 1996;347:369–371. the Medical Research Fund of Finnish Red Cross Blood Transfusion 26. Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies- Service, and the Academy of Finland (grant 51547 to K.K.).