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Coexistent Primary Biliary Cholangitis with CREST Syndrome (Reynolds Syndrome)

      To the Editor:

      Case Presentation

      A 56-year-old Hispanic woman presented to the Emergency Department with a syncopal episode. Her medical history was significant for primary biliary cholangitis (stage I-II), breast cancer status post lumpectomy and chemoradiation, gastroesophageal reflux disease, and multiple episodes of gastrointestinal bleeding. Her vital signs on admission were normal. On physical examination, the patient had regular heart rate and rhythm, pale conjunctivae with icteric sclera, dry mucosal membrane, mild epigastric abdominal tenderness, firm liver without hepatosplenomegaly, scattered telangiectasia on chest and abdomen, and sclerodactyly on both hands up to the metacarpophalangeal joints. A digital rectal examination was positive for melena. Initial labs showed: hemoglobin: 8.2 (10.8-15.3 g/dL), platelets: 84 (140-393 K/μL), total bilirubin: 3.5 (0.2-1.3 mg/dL), aspartate aminotransferase: 37 (14-36 U/L), alanine aminotransferase: 38 (14-36 U/L), alkaline phosphatase: 196 (38-126 U/L), international normalized ratio: 1.2 (0.9-1.1), and albumin: 3.1 (3.5-5.0 g/dL). Computed tomography scan showed esophageal bleeding without cirrhotic liver morphology or splenomegaly. The patient also reported a history of Raynaud's phenomenon. Considering her history and examination findings, a connective tissue disorder panel was ordered that showed antinuclear antibody: 1:2560 (with anticentromere pattern) and anticentromere antibody: 71 AU/mL (>41 AU/mL is positive). The patient also had low serum complement levels, with C4: 11.8 (14.0-258.0 mg/dL) and C3: 71 (83.0-193.0 mg/dL). C-reactive protein was markedly elevated at 110 mg/L. Anti-Scl 70 antibody, SSA, and SSB antibody were all negative. Thyroid-stimulating hormone and antitransglutaminase antibodies were normal. Transthoracic echocardiogram was not suggestive of heart failure or pulmonary hypertension. The patient was diagnosed with coexistent primary biliary cholangitis and limited cutaneous systemic sclerosis (CREST syndrome), also known as Reynolds syndrome. After controlling the esophageal bleeding, mycophenolate and sucralfate were added to her regimen. She has had no further complications during follow-ups.

      Discussion

      Primary biliary cholangitis is a chronic progressive autoimmune disease affecting intrahepatic bile ducts. The diagnosis of primary biliary cholangitis can be established if 2 of 3 objective criteria are present: serum antimitochondrial antibody at titers ≥1:40, unexplained elevated alkaline phosphatase ≥1.5 times the upper normal value for over 24 weeks, and compatible liver histology, specifically nonsuppurative cholangitis and interlobular bile duct injury.
      • Lindor K.D.
      • Gershwin M.E.
      • Poupon R.
      • et al.
      Primary biliary cirrhosis.
      A distinctive feature of primary biliary cholangitis is its association with autoimmune disorders. Sjögren's syndrome and autoimmune thyroiditis appear to be the most common extrahepatic, and autoimmune hepatitis the most common intrahepatic disorders associated with primary biliary cholangitis.
      • Floreani A.
      • Franceschet I.
      • Cazzagon N.
      Primary biliary cirrhosis: overlaps with other autoimmune disorders.
      Primary biliary cholangitis is reported to be associated with CREST syndrome in 1%-6% of cases.
      • Floreani A.
      • Franceschet I.
      • Cazzagon N.
      Primary biliary cirrhosis: overlaps with other autoimmune disorders.
      The association of primary biliary cholangitis with CREST syndrome was first described by Murray-Lyon et al in 1970.
      • Murray-Lyon I.M.
      • Thompson R.P.H.
      • Ansell I.D.
      • Williams R.
      Scleroderma and primary biliary cirrhosis.
      Galan et al
      • Galan M.F.
      • Rises L.L.
      • Alfonso B.M.J.
      • et al.
      Reynolds' syndrome; primary biliary cirrhosis with CREST syndrome.
      described this entity in a miniseries of 6 patients with other characteristics and thus, it is sometimes called PACK syndrome (primary biliary cirrhosis, anti-centromere antibody, CREST syndrome, and keratoconjunctivitis sicca) or Reynolds syndrome. Tojo et al
      • Tojo J.
      • Ohira H.
      • Suzuki T.
      • et al.
      Clinicolaboratory characteristics of patients with primary biliary cirrhosis associated with CREST symptoms.
      reported that, compared with primary biliary cholangitis alone, patients with coexistent primary biliary cholangitis and CREST syndrome had a higher association of esophageal varices in earlier stages of primary biliary cholangitis, higher titers of anticentromere antibody, lower titers of antimitochondrial antibody, and a higher prevalence of HLA-DR9. Whether primary biliary cholangitis association with other autoimmune disorders changes the characteristics and progression of primary biliary cholangitis is still controversial.
      In summary, it should be remembered that primary biliary cholangitis is commonly associated with extrahepatic autoimmune disorder such as limited cutaneous systemic sclerosis (CREST syndrome). Screening for these autoimmune disorders can prevent further morbidity and keep patients viable candidates for liver transplant.

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