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Celiac disease in patients with severe liver disease: gluten-free
diet may reverse hepatic failure
Kaukinen, Katri
2002-04
Kaukinen , K , Halme , L , Collin , P , Färkkilä , M , Mäki , M , Vehmanen , P , Partanen , J &
Höckerstedt , K 2002 , ' Celiac disease in patients with severe liver disease: gluten-free diet
may reverse hepatic failure ' , Gastroenterology , vol. 122 , no. 4 , pp. 881-888 . https://doi.org/10.1053/gast.2002.32416
http://hdl.handle.net/10138/298252
https://doi.org/10.1053/gast.2002.32416
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GASTROENTEROLOGY 2002;122:881–888
Celiac Disease in Patients With Severe Liver Disease:
Gluten-Free Diet May Reverse Hepatic Failure
‡ ¨ ¨ ‡ ¨
KATRI KAUKINEN,* LEENA HALME, PEKKA COLLIN,* MARTTI FARKKILA, MARKKU MAKI,*
§ § ¨ ‡
PAULA VEHMANEN, JUKKA PARTANEN, and KRISTER HOCKERSTEDT
*Departments of Internal Medicine and Pediatrics, 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-
monin patients with celiac disease and usually resolve ease are poorly understood. Malnutrition 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 liver failure. be the only presenting feature in patients with celiac
Methods: Four patients with untreated celiac disease disease. The increased intestinal mucosal permeability
and severe liver disease are described. Further, the oc- characteristic of celiac disease may facilitate the entry of
currence of celiac disease was studied in 185 adults 4
with previous liver transplantation using serum immu- bacterial toxins and other antigens to the portal system.
noglobulin A endomysial and tissue transglutaminase Autoimmune liver diseases and celiac disease often share
antibodies in screening. Results: Of the 4 patients with a similar HLA haplotype (i.e., HLA DR3-DQ2 or DR4-
11,15,16
severeliver disease and celiac disease, 1 had congenital DQ8).
liver fibrosis, 1 had massive hepatic steatosis, and 2 had Histologically, only minimal hepatic steatosis or reac-
progressive hepatitis 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 enzyme 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
2–5
group, 8 patients (4.3%) had celiac disease. Six cases gluten-free diet. 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
2,7,13,17
ary cirrhosis, 1 had autoimmune hepatitis, 1 had pri- in patients with celiac disease is less clear.
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
Mcommoninuntreated celiac disease, occurring in liver disease; some of these patients were even remitted
1–4 for consideration of liver transplantation. We further
15%–55% of patients. On the other hand, in the
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 antibody; tTG-ab,
autoimmune liver disorders such as primary biliary cir- tissue transglutaminase antibodies.
rhosis,7–9 10,11 ©2002bythe American Gastroenterological Association
autoimmune hepatitis, and primary scle- 0016-5085/02/$35.00
12–14
rosing cholangitis 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.
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 Untreated Celiac Disease in Patients With
were placed on a gluten-free diet, and clinical recovery of the Severe Liver Failure
liver disease was observed.
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 anemia.
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 biopsy specimen showed villous
way; however, during the evaluation process, it was found that atrophy 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 jaundice and ascites within 1 month, and his liver func-
withprevious liver transplantation. A total of 185 (118 women tion and overall condition deteriorated to acute fulmi-
and 67 men) such voluntary adults were enrolled; their median nant hepatitis, which was also observed in a liver biopsy
age was 52 years (range, 17–72 years). specimen (Table 1 and Figure 1A). He was referred to
Serumimmunoglobulin(Ig) A-class endomysial antibody the hospital as a possible case for liver transplantation.
21 22 There was no relevant family, alcohol, or drug history,
(EmA) and tissue transglutaminase antibodies (tTG-ab)
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- hepatitis C virus as well as serum antinuclear antibodies,
nofluorescence method using human umbilical cord as sub- smooth muscle antibodies, and antimitochondrial anti-
strate; the screening dilution was 1:5, and titers 1:5 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 20 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
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 chronic liver disease; liver
the distal part of the duodenum. 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; alkaline phosphatase, 634 U/L; and bili-
Patients found to have subtotal or severe partial small bowel rubin, 29 mol/L [reference values, 50 U/L, 60–275
villous atrophy with crypt hyperplasia were considered to have U/L, and 20 mol/L, respectively]), serum albumin
celiac disease. level was low (32 g/L; reference values, 40 g/L), and
Serologic identification of HLA-DR antigens was performed prothrombin time was slightly prolonged (international
in all patients with a history of liver transplantation. The normalized ratio, 1.5–1.3; reference values, 0.9–1.2).
presence of HLA-DQ2 and HLA-DQ8 was investigated in
seropositive patients and in patients with celiac disease as Esophageal varices were found on endoscopy 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 organ 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 0 0000
Ascites 0 0 0 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 (40 g/L) 18 41 16 38 12 44 29 37
Bilirubin, mol/L (20 500 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 (50 U/L)
Liver histology Acute Improved Increased ND 50% steatosis Improved Early cirrhosis Micronodular
hepatitis fibrosis with with mild cirrhosis,
bile duct 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 weight loss or
transplantation due to liver failure (Table 1). During the diarrhea. 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 hepatocytes and there
liver biopsy specimen gave evidence of increased fibrosis wasnoinflammation,buthemosiderosis and intrahepatic
together with proliferation of the bile ducts; all findings cholestasis were evident (Figure 1C). Hemoglobin level
were consistent with the original liver disease. Hemo- was 120 g/L, and serum vitamin B and folic acid levels
12
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- Agluten-free diet was introduced, but treatment with
teriorated and he developed progressive ascitic fluid re- prednisolone 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 improvementinsmallbowelmucosalvillousarchitecture
disease. (Figure 1F), liver function test results and serum albu-
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