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Prevalence of hypertransaminasemia in adult celiac patients and effect of gluten-free diet
Prevalence of Hypertransaminasemia in Adult Celiac Patients and Effect of Gluten-Free Diet MARIA TERESA BARDELLA, MIRELLA FRAQUELLI, MAURIZIO QUATRINI, NICOLETTA MOLTENI, PAOLO BIANCHI, AND DARIO CONTE
The prevalence of h y p e r t r a n s a m i n a s e m i a and the effect of gluten-free diet (GFD) w e r e evaluated in 158 consecutive adult celiac patients, 127 w o m e n and 31 men, aged 18 to 68 years (mean, 32). At diagnosis, 67 patients (42%) had raised aspartate and/or alanine transaminase levels (AST and ALT; mean, 47 IU/L, range, 30 to 190; and 61 IU/L, range, 25 to 470, respectively), w h e r e a s 91 patients had normal liver function tests (LFT). Patients with and w i t h o u t h y p e r t r a n s a m i n a s e m i a were comparable for epidemiological data, b o d y mass index (18.5 vs. 19.6), and severity of intestinal histological involvement. All patients w e r e g i v e n a strict GFD and were followed for 1 to 10 years (median, 4). At 1 year, a highly significant i m p r o v e m e n t in intestinal histology w a s observed in b o t h groups (P < .0001). In the 67 patients w i t h raised t r a n s a m i n a s e levels b o d y mass index (BMI) also increased significantly (from 18.5 to 21.0, P < .001), and transaminase levels n o r m a l i z e d in 60 (95%). In the other s e v e n cases liver b i o p s y s h o w e d fatty infiltration in t w o and chronic active hepatitis (CAH) in the other five, related to chronic infection with hepatitis B virus in three and hepatitis C virus in one, and to a u t o i m m u n e type in the fifth. We conclude that in adult celiac patients elevated s e r u m transaminases are a frequent finding and normalize in most cases after GFD. When they persist, liver biopsy is m a n d a t o r y to further investigate hepatic involvement, w h i c h in our series was mainly attributable to CAH. (HEPATOLOGY 1995;22:833-836.) A l t e r a t i o n s of liver f u n c t i o n tests (LFT) a n d h e p a t i c d a m a g e such as fatty liver, 1'2 p r i m a r y sclerosing cholangitis, *'4 p r i m a r y biliary cirrhosis, 5 a n d chronic active h e p a t i t i s 6-s h a v e b e e n described in association w i t h or as a p r e s e n t i n g f e a t u r e of celiac s p r u e (CS). However, the incidence v a r i e d d e p e n d i n g on t h e selection criteria a n d p a t i e n t s ' characteristics, a n d the r e p o r t s were of-
Abbreviations: LFT, liver function tests; CS, celiac sprue; GFD, glutenfree diet; BMI,bodymass index; AST, aspartate transaminase; ALT,alanine transaminase; CAH,chronicactive hepatitis. From Cattedra di Gastroenterologia, Istituto di Scienze Mediche, Universit~ degli Studi di Milano, IRCCSOspedale Maggiore,Milano, Italy. ReceivedFebrual:¢21, 1995;acceptedMay 10, 1995. Supported by Associazione Italiana Celiachia (Sezione Lombardia) and AssociazioneAmiciGastroenterologiaGranelli. Address reprint requests to: Maria Teresa Bardella, MD, Istituto di Scienze Mediche, PadiglioneGraneIli, Via F. Sforza, 35-20122Milano, Italy. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2203-002153.00/0
t e n only anecdotal. F u r t h e r m o r e , w h e t h e r a gluten-free diet (GFD) h a s a beneficial effect on the course of hepatic i n v o l v e m e n t is still c o n t r o v e r s i a l . l s For t h e s e reasons we e v a l u a t e d the p r e v a l e n c e of a l t e r e d L F T a t diagnosis a n d a f t e r 1 y e a r of G F D in a large series of I t a l i a n a d u l t celiac patients. PATIENTS AND METHODS One hundred fifty-eight consecutive patients (127 women, 31 men; mean age 32 years; range, 18 to 68) with CS diagnosed on the basis of distal duodenal biopsy between January 1983 and December 1993 were investigated. After diagnosis GFD was started in all patients, and clinical and biochemical follow-up was performed quarterly during the first year and yearly thereafter. The median duration of follow-up was 4 years (range, 1 to 10), and no patient was lost to follow-up. At entry, 122 patients (64%, group A) had chronic symptoms, mainly iron-deficiency anemia, and in two cases hypertransaminasemia was the only presenting manifestation of CS; 35 patients (22%, group B) had classical malabsorption syndrome characterized by diarrhea, weight loss, and weakness, and the remaining 21 (13%, group C) were asymptomatic and investigated as first-degree relatives of celiac patients (15 cases) or because of dermatitis herpetiformis (6 cases). In all patients, alcohol intake, drug use, and exposure to potential hepatic toxins were investigated, and a history of diabetes or associated diseases was sought. Height and weight were recorded, and body mass index was calculated (BMI, body weight in kg/[height in meters]2). Biochemical investigations included a hemogram, kidney and liver function tests, clotting profile, total serum protein and albumin, folic acid and vitamin B12, serum sodium and potassium, plasma calcium and phosphorus, and circulating immunoglobulin A antigliadin antibodies (Pharmacia Gluten IgA EIA). Hepatitis B surface antigen was determined by radioimmunoassay (Abbott Laboratories, Chicago, IL) and antibody to hepatitis C virus by recombinant immunoblot assay II on fresh or frozen serum (Ortho Diagnostic Systems, Milan, Italy). Distal duodenal biopsies were obtained during upper gastrointestinal tract endoscopy at diagnosis and after I year of GFD. The severity of intestinal histological involvement was classified according to Scott and Losowsky.9 Patients with elevated serum transaminases (aspartate aminotransferase, AST, and alanine aminotransferase, ALT, > 40 IU/L) and/or increased serum bilirubin (at least twice the upper normal level of 1.0 mg/dL) and/or raised serum alkaline phosphatase (>170 IU/L) were arbitrarily considered to have possible hepatic involvement. Copper- and ironrelated indexes, alpha-l-antitrypsin levels, and circulating
833
834 BARDELLAET AL
HEPATOLOGYSeptember 1995
antinuclear, smooth muscle, and liver-kidney microsomal antibodies were determined in patients with persistently elevated LFT at 1 year of follow-up. These patients also underwent liver ultrasonography and percutaneous liver biopsy (Tru-Cut, gauge 14, Travenol, IL) and histological findings were evaluated according to accepted criteria. 1°'11 Statistical analysis was performed using the X2 test for differences between groups. Pearson's and Spearman's correlation coefficients were employed to evaluate correlations between transaminases and continuous (age and BMI) and noncontinuous variables (symptoms and histology), respectively. In both groups, differences between the mean values of AST, ALT, and BMI at diagnosis and after GFD were evaluated by Wi]coxon's rank sum test. A P value <.05 was considered as statistically significant. RESULTS
At diagnosis, 67 patients (42%, 54 women and 13 men; m e a n age, 31.5 years; range, 18 to 61) had altered LFT; there was an increase of both ALT and AST in 47, only AST in six, and only ALT in 14. Three patients (aged 31, 42, and 45 years) had a concomitant increase in alkaline phosphatase. Increased serum bilirubin levels were not observed in any instance. Forty patients were in group A, 18 in group B, and nine in group C. Hepatomegaly was present in three patients: two women in group B had liver ultrasound findings compatible with steatosis, and one m a n in group A had chronic iron-deficiency anemia. LFT were within the normal range in the remaining 91 patients (58%, 71 women and 20 men; m e a n age, 32.6 years; range, 18 to 68), of whom 61, 17, and 13 patients were included in groups A, B, and C, respectively. No differences were found in gender, age at diagnosis, symptoms, BMI, and grade of severity in duodenal histological findings in the group of patients with hepatic involvement and the group without. Daily ethanol intake was nil or negligible (<20 g) in all patients, and in no case was there drug abuse or exposure to hepatotoxins. Hepatitis B surface antigen was positive in three subjects with hepatic involvement and one without, and anti-HCV was detected in one and two patients, respectively. In the group with hepatic involvement, AST and ALT levels
TABLE 1. E f f e c t o f O n e - Y e a r G l u t e n - F r e e D i e t (GFD) o n B o d y M a s s I n d e x (BMI), I n t e s t i n a l H i s t o l o g y , a n d A S T a n d A L T L e v e l s i n 67 A d u l t C e l i a c P a t i e n t s W i t h H y p e r t r a n s a m i n a s e m i a at D i a g n o s i s
Mean BMI* Severity of intestinal involvementt Grades I-II (no. of patients) Grades III-IV (no. of patients) Mean AST, IU/L (range) Mean ALT, IU/L (range)
At Diagnosis
After GFD
P
18.5
21.0
<.001
7 60 47 (30-190) 61 (25-470)
60 31 27 (19-275) 29 (19-390)
TABLE 2. C h a r a c t e r i s t i c s a n d H e p a t i c H i s t o l o g i c F i n d i n g s i n S e v e n A d u l t C e l i a c P a t i e n t s W i t h o u t N o r m a l i z a t i o n o f AST and ALT Levels After One Year of Gluten-Free Diet Age Severity of Intestinal Sex (yr) BMI* Involvement (grade)~
F F F
61 43 51
20 21 24
II II I
F F M M
18 49 56 53
19 19 20 28
I II II II
Liver Histology
HBV chronic active hepatitis HBV chronic active hepatitis Fatty liver HCV chronic active hepatitis Chronic active hepatitis$ Fatty liver HBV chronic active hepatitis
* Body mass index, height in cm/(weight in kg) 2. t According to Scott and Losowsky's classification. 9 Concomitant autoimmune thyroiditis.
correlated with age (r = .34, P < .004 and r = .38, P < .001, respectively), whereas no significant relation was noted between either t r a n s a m i n a s e and BMI. The 91 patients with normal AST and ALT levels at diagnosis showed a clinical and histological improvement and increased BMI after 1 year of GFD; in fact, the number of patients with grades I and II histological abnormalities rose from 9 to 47, and the number with grades III and IV fell from 82 to 44 (X2 35.3, P < .0001). Modifications of the same variables in the 67 patients with h y p e r t r a n s a m i n a s e m i a at diagnosis are reported in Table 1. Transaminase levels normalized at 3 months in 22 and at 6 months in the other 38, including the two patients with hepatomegaly. The remaining seven patients, all symptomatic at entry and including one with hepatomegaly, showed a persistent elevation of AST or ALT values: their characteristics and liver biopsy findings are given in Table 2. The mean initial aminotransferase levels in these patients with liver disease were, respectively, 51 _+ 22 SD IU/L (range, 46 to 108) and 63 _+ 28 SD IU/L (range, 42 to 122) for AST and ALT, whereas in celiac patients whose hypertransaminasemia normalized after GFD mean AST and ALT levels were, respectively, 47 + 46 SD IU/L (range, 30 to 190) and 61 +_ 32 SD IU/L (range, 25 to 470). The three patients with elevated alkaline phosphatase levels had secondary hyperparathyroidism, as indicated by hypocalcemia, increased serum bone alkaline phosphatase isoenzymes and parathyroid hormone, and by decreased bone mineral density. The serum variables, but not bone mineral density, normalized after GFD. DISCUSSION
* Body mass index, height in cm/(weight in kg) 2. t According to Scott and Losowsky's classification2
<.0001 <.001 <.001
In the current series of 158 adult celiac patients, the overall prevalence of increased AST or ALT levels at diagnosis was 42%. This figure is in agreement with the 39% prevalence reported in 74 similar patients by Hagander et a112 and t h a t of 54% found by Bonamico et a113 in a pediatric group. Patients with and without altered LFT were comparable as regards clinical, biochemical, and intestinal histological findings. However, a correlation between serum transaminase levels
HEPATOLOGYVol. 22, No. 3, 1995
and age was found in patients with hepatic involvement. H y p e r t r a n s a m i n a s e m i a in celiac patients could be attributable to various pathogenetic mechanisms, including long-standing malnutrition, which represents a well-known cause of liver damage and could explain the correlation with age. 14 However, 73% of our patients had neither overt malabsorption syndrome nor diarrhea, and BMI at enrollment did not correlate with AST and ALT levels. Secondly, liver damage could be the result of small intestine bacterial overgrowth.15 This possibility can reasonably be ruled out in our patients in view of both clinical findings and normal serum folic acid and vitamin B12 levels. Moreover, a recent series reported a low prevalence (6.4%) of intestinal bacterial overgrowth in celiac patients. 1~ Conversely, based on normalization of AST and ALT levels in 95% of our patients with GFD together with intestinal mucosal improvement, two other hypotheses seem to us of particular interest. The first considers liver damage a consequence of increased intestinal permeability, 1~ resulting in the arrival of toxins or antigens at the liver through the portal circulation. The second suggests that chronic intestinal mucosal inflammation has an important role. In fact, hepatic alterations similar to those reported in celiac patients have recently been described in ulcerative colitis patients, in whom they were related to disease activity and reverted when the underlying disease became quiescent, is In view of the significant improvement in intestinal histology (from III-IV to I-II grade) observed also in our seven patients with persistent hypertransaminasemia at 1 year of GFD, the possibility that small intestine abnormalities are responsible for liver damage is doubtful in these patients. These considerations prompted us to perform liver biopsies. Mild fatty infiltration was found in two patients with normal BMI, alcohol abstainers, and without other known causes of steatosis. Thus, it is difficult to attribute steatosis to CS per se. Moreover, in a Swedish series of asymptomatic subjects investigated for a moderate elevation of AST and ALT, the overall prevalence of fatty liver was 64%, and in a substantial proportion no cause was recognized. ~9 Our other five patients in this subgroup had chronic active hepatitis (CAH), of autoimmune type in one case and related to chronic viral infection in the other four. The prevalence of hepatitis B surface antigen positivity in our series was 2.5%, twice that recently reported in a general population of Northern Italy. 2° The high frequency of CAH in our patients could be merely attributable to a chance association. Because HLA typing was not performed in these patients, we could not evaluate the role of HLA markers in possibly favoring chronicity of hepatitis B virus infection. Furthermore, the overall prevalence of anti-HCV was 1.9%, intermediate between the 1.3% reported in blood donors 21 and the 3.2% in the general population from Northern Italy. 2° Finally, as regards our patient with type 2 CAH, an association between CS and CAH has already been reported and a common pathogenetic mechanism suggested. 22 Histological findings were not consistent with primary
BARDELLA ET AL
835
sclerosing chotangitis or biliary cirrhosis in any of the current series; similarly, we observed no case of CS in 65 patients with primary biliary cirrhosis undergoing intestinal biopsies. 23 The three patients with elevated alkaline phosphatase levels and hyperparathyroidism normalized after GFD. We conclude that increased AST or ALT levels, occasionally as the only presenting feature, occur in a large proportion of untreated adult celiac patients. In most cases these abnormalities normalize with GFD alone. However, the persistence of altered LFT after GFD needs further investigation because the presence of liver damage related to viral infection or systemic autoimmune disease represents a therapeutic problem. REFERENCES
1. Capron JP, Sevenet F, Qu6num C, Doutrellot C, Capron-Chivrac D, Delamarre J. St~atose h~patique massive r~v~latrice d'une maladie coeliaque de l'adulte. Etude d'un cas et revue de la litt~rature. Gastroenterol Clin Biol 1983;7:256-260. 2. Lynch DA, Thornton JR, Axon AT. Acute fatty liver complicating coeliac disease. Eur J Gastroenterol Hepatol 1994; 6:745-747. 3. Hay JE, Wiesner RH, Shorter RG, LaRusso NF, Baldus WP. Primary sclerosing chelangitis and celiac disease: a novel association. Ann Intern Med 1988;109:713-717~ 4. Brazier F, Delcenserie R, Sevestre H, Delamarre J, Capron JP. Primary sclerosing cholangitis and coeliac disease: beneficial effect of gluten-free diet on the liver. Eur J Gastroenterol Hepatol 1994; 6:183-186. 5. Olsson R, Kagevi I, Rydberg L. On the occurrence of primary biliary cirrhosis and intestinal villous atrophy. Scand J Gastroenterol 1982;17:625-628. 6. Maggiore G, De Giacomo C, Scotta MS, Sessa F. Celiac disease presenting as chronic hepatitis in a girl. J Pediatr Gastroenterol Nutr 1986;5:501-503. 7. Leonardi S, Bottaro G, Patan~ R, Musumeci S. Hypertransaminasemia as the first symptom in infant celiac disease. J Pediatr Gastroenterol Nutr 1990;11:404-406. 8. Vairo P, Fontanella A, Mayer M, De Vincenze A, Terracciano LM, D'Armiento M, Vecchione R. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J Pediatr 1993; 122:416-419. 9. Scott BB, Losowsky MS. Patchiness and duodenal-jejunalvariation of the mucosal abnormality in coeliac disease and dermatitis herpetiformis. Gut 1976; 17:984-992. 10. Scheuer PJ, Lefkowitch JH. Liver biopsy interpretation. Major problems in pathology. Vol 31. London: Saunders, 1994. 11. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. HEPATOLOGY1994; 19:1513-1520. 12. Hagander B, Brandt L, Sjolund K, Berg NO, Norden A, Stenstam M. Hepatic injury in celiac disease. Lancet 1977;2:270-272. 13. Bonamico M, Pitzalis G, Culasso F. Hepatic damage during coeliac disease in childhood. Minerva Pediatr 1986; 38:959-962. 14. Sherlock S, Doodley J. Nutritional and metabolic liver diseases. In: Diseases of the liver and biliary system. Ed 9. London: Blackwell Scientific Publications, 1993:408-413. 15. Lichtman SN, Sarter RB, Keku J, Schwab JH. Hepatic inflammation in rats with experimental small intestinal bacterial overgrowth. Gastroenterology 1990;98:414-423. 16. Nunes DP, Kelly CP, Nolan NPM, O'Connor MP, Weir DG. Fasting breath hydrogen, small bacterial overgrowth and intestinal transit in coeliac disease. Eur J Gastroenterol Hepatol 1991;3:313-319. 17. van Elburg RM, Uil JJ, Mulder CJJ, Heymans HSA. Intestinal permeability in patients with coeliac disease and relatives of patients with coeliac disease. Gut 1993;34:354-357. 18. Broom6 U, Glaumann H, Hellers G, Nilsson B, Sorstad J, Hult-
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crantz R. Liver disease in ulcerative colitis: an epidemiological and follow up study in the county of Stockholm. Gut 1994; 35:8489. 19. Hultcrantz R, Glaumann H, Lindberg G, Nilsson LH. Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum aminotransferases. Scand J Gastroenterol 1986;21:109-113. 20. Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, Cristianini G, et al. Prevalence of chronic liver disease in the general population of Northern Italy: the Dionysos study. HEPATOLOGY1994;20:1442-1449.
HEPATOLOGYSeptember 1995 21. Chiaramonte M, Stroffolini T, Caporaso N, Coppola R, Craxi A, Gaeta GB, Sagnelli E, et al. Hepatitis-C virus infection in Italy: a multicentric sero-epidemiological study. Ital J Gastroenterol 1991;23:555-558. 22. Lindberg J, Ahr~n C, Iwarson S. Intestinal villous atrophy in chronic active hepatitis. Scand J Gastroenterol 1979;14:10151018. 23. Bardella MT, Quatrini M, Zuin M, Cesarini L, Velio P, Crosignani A, Podda M, et al. Coeliac disease and intestinal permeability in patients with primary biliary cirrhosis [Abstract]. Ital J Gastroenterol 1993;25:186-187.
The prevalence of h y p e r t r a n s a m i n a s e m i a and the effect of gluten-free diet (GFD) w e r e evaluated in 158 consecutive adult celiac patients, 127 w o m e n and 31 men, aged 18 to 68 years (mean, 32). At diagnosis, 67 patients (42%) had raised aspartate and/or alanine transaminase levels (AST and ALT; mean, 47 IU/L, range, 30 to 190; and 61 IU/L, range, 25 to 470, respectively), w h e r e a s 91 patients had normal liver function tests (LFT). Patients with and w i t h o u t h y p e r t r a n s a m i n a s e m i a were comparable for epidemiological data, b o d y mass index (18.5 vs. 19.6), and severity of intestinal histological involvement. All patients w e r e g i v e n a strict GFD and were followed for 1 to 10 years (median, 4). At 1 year, a highly significant i m p r o v e m e n t in intestinal histology w a s observed in b o t h groups (P < .0001). In the 67 patients w i t h raised t r a n s a m i n a s e levels b o d y mass index (BMI) also increased significantly (from 18.5 to 21.0, P < .001), and transaminase levels n o r m a l i z e d in 60 (95%). In the other s e v e n cases liver b i o p s y s h o w e d fatty infiltration in t w o and chronic active hepatitis (CAH) in the other five, related to chronic infection with hepatitis B virus in three and hepatitis C virus in one, and to a u t o i m m u n e type in the fifth. We conclude that in adult celiac patients elevated s e r u m transaminases are a frequent finding and normalize in most cases after GFD. When they persist, liver biopsy is m a n d a t o r y to further investigate hepatic involvement, w h i c h in our series was mainly attributable to CAH. (HEPATOLOGY 1995;22:833-836.) A l t e r a t i o n s of liver f u n c t i o n tests (LFT) a n d h e p a t i c d a m a g e such as fatty liver, 1'2 p r i m a r y sclerosing cholangitis, *'4 p r i m a r y biliary cirrhosis, 5 a n d chronic active h e p a t i t i s 6-s h a v e b e e n described in association w i t h or as a p r e s e n t i n g f e a t u r e of celiac s p r u e (CS). However, the incidence v a r i e d d e p e n d i n g on t h e selection criteria a n d p a t i e n t s ' characteristics, a n d the r e p o r t s were of-
Abbreviations: LFT, liver function tests; CS, celiac sprue; GFD, glutenfree diet; BMI,bodymass index; AST, aspartate transaminase; ALT,alanine transaminase; CAH,chronicactive hepatitis. From Cattedra di Gastroenterologia, Istituto di Scienze Mediche, Universit~ degli Studi di Milano, IRCCSOspedale Maggiore,Milano, Italy. ReceivedFebrual:¢21, 1995;acceptedMay 10, 1995. Supported by Associazione Italiana Celiachia (Sezione Lombardia) and AssociazioneAmiciGastroenterologiaGranelli. Address reprint requests to: Maria Teresa Bardella, MD, Istituto di Scienze Mediche, PadiglioneGraneIli, Via F. Sforza, 35-20122Milano, Italy. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2203-002153.00/0
t e n only anecdotal. F u r t h e r m o r e , w h e t h e r a gluten-free diet (GFD) h a s a beneficial effect on the course of hepatic i n v o l v e m e n t is still c o n t r o v e r s i a l . l s For t h e s e reasons we e v a l u a t e d the p r e v a l e n c e of a l t e r e d L F T a t diagnosis a n d a f t e r 1 y e a r of G F D in a large series of I t a l i a n a d u l t celiac patients. PATIENTS AND METHODS One hundred fifty-eight consecutive patients (127 women, 31 men; mean age 32 years; range, 18 to 68) with CS diagnosed on the basis of distal duodenal biopsy between January 1983 and December 1993 were investigated. After diagnosis GFD was started in all patients, and clinical and biochemical follow-up was performed quarterly during the first year and yearly thereafter. The median duration of follow-up was 4 years (range, 1 to 10), and no patient was lost to follow-up. At entry, 122 patients (64%, group A) had chronic symptoms, mainly iron-deficiency anemia, and in two cases hypertransaminasemia was the only presenting manifestation of CS; 35 patients (22%, group B) had classical malabsorption syndrome characterized by diarrhea, weight loss, and weakness, and the remaining 21 (13%, group C) were asymptomatic and investigated as first-degree relatives of celiac patients (15 cases) or because of dermatitis herpetiformis (6 cases). In all patients, alcohol intake, drug use, and exposure to potential hepatic toxins were investigated, and a history of diabetes or associated diseases was sought. Height and weight were recorded, and body mass index was calculated (BMI, body weight in kg/[height in meters]2). Biochemical investigations included a hemogram, kidney and liver function tests, clotting profile, total serum protein and albumin, folic acid and vitamin B12, serum sodium and potassium, plasma calcium and phosphorus, and circulating immunoglobulin A antigliadin antibodies (Pharmacia Gluten IgA EIA). Hepatitis B surface antigen was determined by radioimmunoassay (Abbott Laboratories, Chicago, IL) and antibody to hepatitis C virus by recombinant immunoblot assay II on fresh or frozen serum (Ortho Diagnostic Systems, Milan, Italy). Distal duodenal biopsies were obtained during upper gastrointestinal tract endoscopy at diagnosis and after I year of GFD. The severity of intestinal histological involvement was classified according to Scott and Losowsky.9 Patients with elevated serum transaminases (aspartate aminotransferase, AST, and alanine aminotransferase, ALT, > 40 IU/L) and/or increased serum bilirubin (at least twice the upper normal level of 1.0 mg/dL) and/or raised serum alkaline phosphatase (>170 IU/L) were arbitrarily considered to have possible hepatic involvement. Copper- and ironrelated indexes, alpha-l-antitrypsin levels, and circulating
833
834 BARDELLAET AL
HEPATOLOGYSeptember 1995
antinuclear, smooth muscle, and liver-kidney microsomal antibodies were determined in patients with persistently elevated LFT at 1 year of follow-up. These patients also underwent liver ultrasonography and percutaneous liver biopsy (Tru-Cut, gauge 14, Travenol, IL) and histological findings were evaluated according to accepted criteria. 1°'11 Statistical analysis was performed using the X2 test for differences between groups. Pearson's and Spearman's correlation coefficients were employed to evaluate correlations between transaminases and continuous (age and BMI) and noncontinuous variables (symptoms and histology), respectively. In both groups, differences between the mean values of AST, ALT, and BMI at diagnosis and after GFD were evaluated by Wi]coxon's rank sum test. A P value <.05 was considered as statistically significant. RESULTS
At diagnosis, 67 patients (42%, 54 women and 13 men; m e a n age, 31.5 years; range, 18 to 61) had altered LFT; there was an increase of both ALT and AST in 47, only AST in six, and only ALT in 14. Three patients (aged 31, 42, and 45 years) had a concomitant increase in alkaline phosphatase. Increased serum bilirubin levels were not observed in any instance. Forty patients were in group A, 18 in group B, and nine in group C. Hepatomegaly was present in three patients: two women in group B had liver ultrasound findings compatible with steatosis, and one m a n in group A had chronic iron-deficiency anemia. LFT were within the normal range in the remaining 91 patients (58%, 71 women and 20 men; m e a n age, 32.6 years; range, 18 to 68), of whom 61, 17, and 13 patients were included in groups A, B, and C, respectively. No differences were found in gender, age at diagnosis, symptoms, BMI, and grade of severity in duodenal histological findings in the group of patients with hepatic involvement and the group without. Daily ethanol intake was nil or negligible (<20 g) in all patients, and in no case was there drug abuse or exposure to hepatotoxins. Hepatitis B surface antigen was positive in three subjects with hepatic involvement and one without, and anti-HCV was detected in one and two patients, respectively. In the group with hepatic involvement, AST and ALT levels
TABLE 1. E f f e c t o f O n e - Y e a r G l u t e n - F r e e D i e t (GFD) o n B o d y M a s s I n d e x (BMI), I n t e s t i n a l H i s t o l o g y , a n d A S T a n d A L T L e v e l s i n 67 A d u l t C e l i a c P a t i e n t s W i t h H y p e r t r a n s a m i n a s e m i a at D i a g n o s i s
Mean BMI* Severity of intestinal involvementt Grades I-II (no. of patients) Grades III-IV (no. of patients) Mean AST, IU/L (range) Mean ALT, IU/L (range)
At Diagnosis
After GFD
P
18.5
21.0
<.001
7 60 47 (30-190) 61 (25-470)
60 31 27 (19-275) 29 (19-390)
TABLE 2. C h a r a c t e r i s t i c s a n d H e p a t i c H i s t o l o g i c F i n d i n g s i n S e v e n A d u l t C e l i a c P a t i e n t s W i t h o u t N o r m a l i z a t i o n o f AST and ALT Levels After One Year of Gluten-Free Diet Age Severity of Intestinal Sex (yr) BMI* Involvement (grade)~
F F F
61 43 51
20 21 24
II II I
F F M M
18 49 56 53
19 19 20 28
I II II II
Liver Histology
HBV chronic active hepatitis HBV chronic active hepatitis Fatty liver HCV chronic active hepatitis Chronic active hepatitis$ Fatty liver HBV chronic active hepatitis
* Body mass index, height in cm/(weight in kg) 2. t According to Scott and Losowsky's classification. 9 Concomitant autoimmune thyroiditis.
correlated with age (r = .34, P < .004 and r = .38, P < .001, respectively), whereas no significant relation was noted between either t r a n s a m i n a s e and BMI. The 91 patients with normal AST and ALT levels at diagnosis showed a clinical and histological improvement and increased BMI after 1 year of GFD; in fact, the number of patients with grades I and II histological abnormalities rose from 9 to 47, and the number with grades III and IV fell from 82 to 44 (X2 35.3, P < .0001). Modifications of the same variables in the 67 patients with h y p e r t r a n s a m i n a s e m i a at diagnosis are reported in Table 1. Transaminase levels normalized at 3 months in 22 and at 6 months in the other 38, including the two patients with hepatomegaly. The remaining seven patients, all symptomatic at entry and including one with hepatomegaly, showed a persistent elevation of AST or ALT values: their characteristics and liver biopsy findings are given in Table 2. The mean initial aminotransferase levels in these patients with liver disease were, respectively, 51 _+ 22 SD IU/L (range, 46 to 108) and 63 _+ 28 SD IU/L (range, 42 to 122) for AST and ALT, whereas in celiac patients whose hypertransaminasemia normalized after GFD mean AST and ALT levels were, respectively, 47 + 46 SD IU/L (range, 30 to 190) and 61 +_ 32 SD IU/L (range, 25 to 470). The three patients with elevated alkaline phosphatase levels had secondary hyperparathyroidism, as indicated by hypocalcemia, increased serum bone alkaline phosphatase isoenzymes and parathyroid hormone, and by decreased bone mineral density. The serum variables, but not bone mineral density, normalized after GFD. DISCUSSION
* Body mass index, height in cm/(weight in kg) 2. t According to Scott and Losowsky's classification2
<.0001 <.001 <.001
In the current series of 158 adult celiac patients, the overall prevalence of increased AST or ALT levels at diagnosis was 42%. This figure is in agreement with the 39% prevalence reported in 74 similar patients by Hagander et a112 and t h a t of 54% found by Bonamico et a113 in a pediatric group. Patients with and without altered LFT were comparable as regards clinical, biochemical, and intestinal histological findings. However, a correlation between serum transaminase levels
HEPATOLOGYVol. 22, No. 3, 1995
and age was found in patients with hepatic involvement. H y p e r t r a n s a m i n a s e m i a in celiac patients could be attributable to various pathogenetic mechanisms, including long-standing malnutrition, which represents a well-known cause of liver damage and could explain the correlation with age. 14 However, 73% of our patients had neither overt malabsorption syndrome nor diarrhea, and BMI at enrollment did not correlate with AST and ALT levels. Secondly, liver damage could be the result of small intestine bacterial overgrowth.15 This possibility can reasonably be ruled out in our patients in view of both clinical findings and normal serum folic acid and vitamin B12 levels. Moreover, a recent series reported a low prevalence (6.4%) of intestinal bacterial overgrowth in celiac patients. 1~ Conversely, based on normalization of AST and ALT levels in 95% of our patients with GFD together with intestinal mucosal improvement, two other hypotheses seem to us of particular interest. The first considers liver damage a consequence of increased intestinal permeability, 1~ resulting in the arrival of toxins or antigens at the liver through the portal circulation. The second suggests that chronic intestinal mucosal inflammation has an important role. In fact, hepatic alterations similar to those reported in celiac patients have recently been described in ulcerative colitis patients, in whom they were related to disease activity and reverted when the underlying disease became quiescent, is In view of the significant improvement in intestinal histology (from III-IV to I-II grade) observed also in our seven patients with persistent hypertransaminasemia at 1 year of GFD, the possibility that small intestine abnormalities are responsible for liver damage is doubtful in these patients. These considerations prompted us to perform liver biopsies. Mild fatty infiltration was found in two patients with normal BMI, alcohol abstainers, and without other known causes of steatosis. Thus, it is difficult to attribute steatosis to CS per se. Moreover, in a Swedish series of asymptomatic subjects investigated for a moderate elevation of AST and ALT, the overall prevalence of fatty liver was 64%, and in a substantial proportion no cause was recognized. ~9 Our other five patients in this subgroup had chronic active hepatitis (CAH), of autoimmune type in one case and related to chronic viral infection in the other four. The prevalence of hepatitis B surface antigen positivity in our series was 2.5%, twice that recently reported in a general population of Northern Italy. 2° The high frequency of CAH in our patients could be merely attributable to a chance association. Because HLA typing was not performed in these patients, we could not evaluate the role of HLA markers in possibly favoring chronicity of hepatitis B virus infection. Furthermore, the overall prevalence of anti-HCV was 1.9%, intermediate between the 1.3% reported in blood donors 21 and the 3.2% in the general population from Northern Italy. 2° Finally, as regards our patient with type 2 CAH, an association between CS and CAH has already been reported and a common pathogenetic mechanism suggested. 22 Histological findings were not consistent with primary
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sclerosing chotangitis or biliary cirrhosis in any of the current series; similarly, we observed no case of CS in 65 patients with primary biliary cirrhosis undergoing intestinal biopsies. 23 The three patients with elevated alkaline phosphatase levels and hyperparathyroidism normalized after GFD. We conclude that increased AST or ALT levels, occasionally as the only presenting feature, occur in a large proportion of untreated adult celiac patients. In most cases these abnormalities normalize with GFD alone. However, the persistence of altered LFT after GFD needs further investigation because the presence of liver damage related to viral infection or systemic autoimmune disease represents a therapeutic problem. REFERENCES
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HEPATOLOGYSeptember 1995 21. Chiaramonte M, Stroffolini T, Caporaso N, Coppola R, Craxi A, Gaeta GB, Sagnelli E, et al. Hepatitis-C virus infection in Italy: a multicentric sero-epidemiological study. Ital J Gastroenterol 1991;23:555-558. 22. Lindberg J, Ahr~n C, Iwarson S. Intestinal villous atrophy in chronic active hepatitis. Scand J Gastroenterol 1979;14:10151018. 23. Bardella MT, Quatrini M, Zuin M, Cesarini L, Velio P, Crosignani A, Podda M, et al. Coeliac disease and intestinal permeability in patients with primary biliary cirrhosis [Abstract]. Ital J Gastroenterol 1993;25:186-187.