Cystic Fibrosis in an Adolescent Being Evaluated for Primary Sclerosing Cholangitis

 

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CASE HISTORY

A 16-year-old white female with a history of hypothyroidism was referred for evaluation of persistent elevation of serum aminotransferases. She initially presented with mild elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which was noted 1 year prior to referral with blood work for a history of hypothyroidism and secondary amenorrhea. Initial AST was 107 U/L (normal, 2 to 35 U/L) and ALT was 93 (normal, 2 to 40 U/L). These abnormalities persisted for the next 18 months (AST, 62 to 107 U/L; ALT, 73 to 93 U/L). There was no history of jaundice, abdominal pain, exposure to viral hepatitis, surgery, transfusion, or liver disease in the family. In addition there was no history of chronic medication use except for levothyroxine. The only notable medical history was the hypothyroidism. Review of systems revealed amenorrhea most likely associated with the hypothyroidism. She continued to be otherwise asymptomatic.

On examination she appeared well with no dysmorphic features. Her weight was between the 50th and 75th percentile and her height was between the 75th and 90th percentile for her age. She had no scleral icterus. Her thyroid was not palpable. Her cardiac and pulmonary examinations were unremarkable. Her abdomen was soft, nontender, and nondistended, with no masses. Her liver was at the costal margin with an unremarkable span and her spleen tip was just palpable. Her neurological exam was normal. She was Tanner stage 5.

At presentation her blood tests revealed white blood cell count (WBC) of 8.1 × 10³/mL, hemoglobin of 14.3 g/dL, and platelet count of 182 × 10³/mL. Her AST was 107 U/L (normal, 2 to 35 U/L) and ALT 93 U/L (normal, 2 to 40 U/L); total bilirubin was 0.6 mg/dL (normal, 0.2 -1.3 mg/dL), alkaline phosphatase was 348 U/L (normal, 60 to 350 U/L); gamma-glutamyltransferase was 84 U/L (normal, 2 to 60 U/L), and hepatitis B surface antibody was reactive; hepatitis B surface antigen was nonreactive; and hepatitis C antibody negative. Tissue transglutaminase was negative, ceruloplasmin was 22 mg/dL (normal, 22 to 50 mg/dL), total serum immunoglobulin G (IgG) was 1980 mg/dL (normal, 694 to 1618 mg/dL); IgA was 131 mg/dL (normal, 81 to 463 mg/dL); IgM was 128 mg/dL (normal, 48 to 271 mg/dL); smooth muscle antibody was positive at a titer of 1:20. Initial antinuclear antibody analysis was equivocal and repeat was negative, liver kidney microsomal antibody was negative, and α-1-antitrysin level was 161 mg/dL (normal, 83 to 199 mg/dL). One and one half years after her initial presentation, her WBC decreased to 4.4 × 10³/mL and her platelets were 143 × 10³/mL

Differential Diagnosis

Persistent elevation of aminotransferases in this 16-year-old patient suggests chronic hepatitis. The presence of splenomegaly and thrombocytopenia also supports a chronic liver disease. Viral etiology was ruled out by the negative serology for hepatitis B and C. Other causes of hepatitis that were considered included Wilson disease, autoimmune hepatitis, and α-1-antitrypsin deficiency. Her ceruloplasmin and α-1-antitrypsin levels were normal. The elevated IgG level and borderline elevation of antismooth muscle antibodies (SMAs) certainly raised the suspicion of an autoimmune etiology or primary sclerosing cholangitis. Drug-induced hepatitis was also considered in this adolescent, but levothyroxine was not typically associated with hepatitis.

An abdominal ultrasound revealed increased echogenicity of the liver and slight prominence of the spleen. The gallbladder was of normal size with no evidence of stones.

A liver biopsy was performed, which revealed findings consistent with biliary cirrhosis (Fig. [1]), most likely secondary to primary sclerosing cholangitis (Fig. [2]). Magnetic resonance cholangiopancreatography (MRCP) failed to confirm the diagnosis of primary sclerosing cholangitis (PSC). It revealed a normal intra- and extrahepatic biliary system (Fig. [3]) and, interestingly, a fatty pancreas (Fig. [4]).

The fatty replacement of the pancreas that was evident on the MRCP was suggestive of cystic fibrosis (CF). The sweat test revealed chloride content of 125 and 127 mEq/L, and confirmed the diagnosis.

Reassessment of her presentation with the knowledge of the elevated sweat chloride revealed a history of four to six pasty stools per day. These were not deemed a problem to the patient and the frequency reduced to once a day with pancreatic enzyme supplementation. Careful examination of her nose revealed a nasal polyp.

Pathologic Findings

The percutaneous liver needle biopsy provided a single 1.0 × 0.2 × 0.2 cm core. At low power the most striking finding was the presence of fibrosis largely expanding the portal tracts, extending with portal-to-portal bridging and focally encircling nodules of hepatic parenchyma, suggestive of cirrhosis (Fig. [1]; trichrome stain, 10×). The portal tracts were also remarkable for the presence of dense collagenous scars, ductular proliferation, mild lymphoplasmacytic inflammation, and damaged interlobular bile ducts. At higher power the damaged ducts showed an irregular lumen profile, focal disruption of the basement membrane continuity, reactive and degenerative biliary epithelium with loss of polarity and infiltrated by occasional lymphocytes and neutrophils. (Fig. [2]; trichrome stain, 40×). Despite the abundant dense collagenous deposition seen in almost all portal tracts, typical concentric lamellar fibrosis (so-called onion skinning) surrounding the bile ducts was not seen. Cholestasis or interface hepatitis was not noted. The lobules showed a mild degree of mixed micro- and macrovesicular steatosis without zonal distribution. Necroinflammatory changes were not present in the lobules. The bile duct lumens did not show presence of dense eosinophilic secretions. Overall, the pathologic findings were interpreted as consistent with biliary cirrhosis. The presence of severely damaged biliary ducts suggested primary sclerosing cholangitis or a biliary obstruction with secondary sclerosing cholangitis.

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Benjamin L ShneiderM.D. 

Mount Sinai School of Medicine, Box 1656

One Gustave L. Levy Place, New York, NY 10029

Email: Benjamin.Shneider@mssm.edu