Celiac sprue presenting as advanced liver disease.

Abstract: This case report describes the complexity of diagnosing celiac sprue in a patient who presented with features predominantly resembling that of advanced liver disease in the absence of diarrhea.

Key Words: celiac sprue, liver disease, small intestine

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Celiac sprue is a lifelong inflammatory condition of the small intestine. The highly variable clinical presentations of celiac sprue make the diagnosis challenging. (1-9) Celiac sprue is generally perceived as a small-bowel disorder, characterized by malabsorption, flatulence, and weight loss. Up to 50% of the patients, however, present without diarrhea, and a small percentage present with extraintestinal manifestations. (10) Studies demonstrate that 11 to 40% of patients with celiac sprue presenting with diarrhea have abnormal liver tests. (11-15)

The diagnosis of celiac sprue remains elusive. Antigliadin antibodies are often the initial screening test; immunoglobulin (Ig)A antibodies being fairly specific and IgG antibodies being fairly sensitive. The combination has a reasonable predictive value but remains suboptimal. Antiendomysial antibodies are directed against a connective tissue protein found in the gastrointestinal tract. IgA endomysial antibody testing is moderately sensitive and highly specific for untreated celiac sprue; the serum levels fall on a gluten-free diet and the test often becomes negative in treated patients. (16-20) HLA-DQ2 is expressed in more than 95% of patients with celiac sprue. The HLA-DQ2 molecule on the antigen-presenting cell presents the gliadin moiety to the mucosal helper T cells, which in turn stimulate plasma cells and lymphocytes. One result is production of antibodies to the enzyme tissue transglutaminase (tTG). (3-5) This has led to the development of the dot-blot test for this anti-tTG antibody, which has a sensitivity of 98% and specificity of 99%. (6-8) ELISA tests for IgA anti-tTG antibodies are now widely available and are easier to perform and less costly than the immunofluorescence assay. Modification of this test with the use of human tTG in immunoassay kits has improved further the diagnostic accuracy. (21) However, small-bowel biopsy remains the gold standard to confirm the diagnosis.

Case Report

A 40-year-old white woman presented with generalized swelling, decreased appetite, and weight loss over a period of 6 months. She was recently diagnosed with end-stage liver disease of unknown etiology at another major medical center. She returned to her hometown and was ultimately referred to us for a second opinion. The medical history included iron-deficiency anemia, which was then presumed to be secondary to menorrhagia. She underwent hysterectomy and was given parenteral iron. She had a remote history of episodic childhood diarrhea, which had not been evaluated. She stated that upper and lower endoscopies had been performed for the evaluation of anemia and were reported normal. She reported no alcohol or illegal substance abuse.

Physical examination revealed anasarca and multiple ecchymotic patches. There were no spider angiomata. Abdominal examination was positive for ascites. Cardiovascular, lung, and nervous system examinations were normal.

Laboratory data are shown in the Table. Urinalysis-was unremarkable. Stool for occult blood was negative. Serum protein electrophoresis confirmed hypoalbuminemia. Abdominal CT was consistent with ascites and a fatty liver. Portal vein Doppler showed normal flow. Serum iron studies showed transferrin saturation of 28%. Serum ceruloplasmin was within normal limits. Serology for hepatitis A, B, and C and HIV were negative. Antimitochondrial antibodies, antinuclear antibodies, and anti-smooth muscle antibodies were undetectable. As part of a workup for malabsorptive disease, because of her childhood diarrhea, IgA antigliadin and antiendomysial antibodies were performed and were significantly elevated. The patient declined liver biopsy. Upper endoscopy with small-bowel biopsy showed flattening of villi and lymphoplasmacytoid infiltration of lamina propria and intraepithelial area (Figs. 1 and 2). This was consistent with the diagnosis of celiac sprue. Our patient was hospitalized and treated with supportive care and total parenteral nutrition. Gluten-free diet was started and continued thereafter. Follow-up visits revealed complete normalization of her liver tests and symptoms.

Discussion

Celiac sprue is classically characterized by malabsorption, diarrhea, flatulence, and weight loss. This case illustrates the complexity involved in diagnosing celiac sprue when a patient does not present with the usual disease manifestations. Our patient had ascites caused by hypoalbuminemia and coagulopathy resulting from vitamin K deficiency, both as a result of malabsorption and possibly hepatic dysfunction. Her abnormal liver tests can be explained by fatty infiltration of liver, secondary to protein-energy malnutrition from celiac sprue. All of these abnormalities were corrected by treating the primary disease process (celiac sprue).

[FIGURE 1 OMITTED]

The association between celiac sprue and liver disease other than primary biliary cirrhosis, autoimmune hepatitis, or primary sclerosing cholangitis is not generally recognized. (11) Jacobsen et al (12) reported that 36% of patients with celiac sprue who presented with diarrhea had elevated aminotransferase levels and only 11% had elevated alkaline phosphatase levels. In a group of 74 newly diagnosed adults with celiac sprue, Maggiore and Caprai (13) found that 40% had an elevation of serum aminotransferase activity that normalized in most cases during treatment with a gluten-free diet. Retrospective studies in adults suggested that as many as 9% of patients with persistent and cryptogenic elevation of serum aminotransferases may be affected by asymptomatic celiac sprue. (14) All of the subjects had normal bilirubin and GGT ([gamma]-glutamyl transferase) levels, which made our case very unusual. Several investigators have reported that liver biopsy specimens in similar patients ranged from normal to microvesicular and macrovesicular steatosis. (13) The current recommendation in patients with celiac sprue and abnormal liver tests is that liver biopsy is recommended only if there is no improvement with a gluten-free diet. Literature search has revealed fewer than 10 case reports of celiac sprue presenting with features of end-stage liver disease as the major manifestation. (16-19) However rare, the diagnosis becomes crucial to prevent the progression of reversible liver failure.

[FIGURE 2 OMITTED]

Conclusion

An awareness of the varied presentations of celiac sprue can help raise the clinical suspicion of a primary care physician who probably will make the first patient contact in the evaluation of this complex disease. Approximately 50% of adults with celiac sprue do not have clinically significant diarrhea. The diagnosis of celiac sprue is challenging when the only manifestations are those of isolated liver test abnormalities, as in our patient. It is precisely in these circumstances that the diagnosis is most crucial, because celiac sprue represents a potentially reversible cause of liver disease.

Table. Laboratory data

Name of test                  At time of presentation  One year later

Serum potassium                 2.5 mEq/L                4.1 mEq/L
Serum magnesium                 1.5 mEq/L                2.4 mEq/L
Serum albumin                   1.3 g/dL                 4.0 g/dL
Aspartate aminotransferase    202 [mu]/L                32 [mu]/L
Alanine aminotransferase      198 [mu]/L                30 [mu]/L
Alkaline phosphatase          541 [mu]/L               110 [mu]/L
[gamma]-Glutamyl transferase  409 [mu]/L                62 [mu]/L
Prothrombin time               25 seconds               11 seconds
Total bilirubin                 2.5 mg/dL                0.8 mg/dL
Hemoglobin                     11.2 g/dL                13.6 g/dL
Platelet count                230 k/UL                 300 k/UL
Serum folate level              3.4 ng/mL                6 ng/mL
Serum [B.sub.12] level        300 pg/mL                500 pg/mL
Mean corpuscular volume        91 fL                    90 fL

Name of test                  Normal values

Serum potassium                 3.5-5.0 mEq/L
Serum magnesium                 1.8-2.6 mEq/L
Serum albumin                   3.8-5.8 g/dL
Aspartate aminotransferase     10-35 [mu]/L
Alanine aminotransferase       12-35 [mu]/L
Alkaline phosphatase           30-120 [mu]/L
[gamma]-Glutamyl transferase    8-78 [mu]/L
Prothrombin time               10-12 seconds
Total bilirubin                 0-1 mg/dL
Hemoglobin                     13-17 g/dL
Platelet count                140-400 k/UL
Serum folate level              3.1-18 ng/mL
Serum [B.sub.12] level        200-1,100 pg/mL
Mean corpuscular volume        80.8-98.0 fL

Accepted October 19, 2004.

References

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RELATED ARTICLE: Key Points

* Highly variable clinical presentations make the diagnosis of celiac sprue challenging.

* The association between celiac sprue and liver disease other than primary biliary cirrhosis, autoimmune hepatitis, or primary sclerosing cholangitis is not generally recognized.

* In a patient with celiac sprue, liver biopsy for abnormal liver tests is recommended only if there is no improvement with gluten-free diet.

* The differential diagnosis of unexplained advanced liver disease should include celiac sprue.

Kiran Tiriveedhi, MD, and Stephen P. Kelleher, MD

From Texas Tech University Health Sciences Center, Amarillo, TX.

Reprint requests to Dr. Kiran Tiriveedhi, 5602 York Avenue, Lubbock, TX 79414. Email: [e-mail]