A woman with improving cholestasis but hepatitis aggravating
Authors: Hao-Chun Yu, Yung-Hsiang Hsu, Chi-Tan Hu
Journal: Hepatology (2011)

A 25-year-old woman from Vietnam presented with 3 weeks of yellowing of the skin. On admission, her alanine aminotransferase (ALT) level was 329 IU/L and her total bilirubin (TBI) level was 5.7 mg/dL. Serological markers for hepatitis A, B, C, and antinuclear and antimitochondrial antibodies were negative, but her anti–smooth muscle antibody (1:20) was weakly positive. Her serum ceruloplasmin level was normal. Corneal Kayser-Fleischer rings were not found. We initiated prednisolone 75 mg/day and made a tentative diagnosis of autoimmune hepatitis. ALT, alanine aminotransferase; ICAH, improved cholestasis but aggravated hepatitis; Ig, immunoglobulin; IHC, immunohistochemistry; PCR, polymerase chain reaction; TBI, total bilirubin. Two weeks later, the patient's ALT level was 91 IU/L, and her TBI level was 1.6 mg/dL. After 3 weeks, her TBI level decreased to 1.0 mg/dL, but her ALT level increased to 360 IU/L. Orientia tsutsugamushi immunoglobulin (Ig) M and polymerase chain reaction (PCR) analyses were negative. A rapid plasma regain test (1:8) and Treponema pallidum hemagglutination assay (1:80) for syphilis were both inconclusive. Leptospira-specific IgG/IgM analysis was positive, but nested Leptospira PCR analysis was negative. A liver biopsy specimen revealed portal lymphocytic infiltration with blurred interface, bilirubinostasis with bile pigment within hepatocytes and Kupffer cells, and canalicular bile plugs (Fig. 1A, hematoxylin and eosin [magnification ×100]). Silver staining demonstrated a one-end hooked wavy spirochete (Fig. 1B, arrowhead [magnification ×400]). A long wavy Leptospira (arrowhead) and other leptospiral forms, including short rods (R), aggregates (Ar), and cocci (arrows), were revealed by way of leptospiral immunohistochemistry (IHC) staining using polyclonal rabbit anti–Leptospira interrogans antiserum (Fig. 1C [magnification ×400]). Initially, improved cholestasis but aggravated hepatitis (ICAH) occurred, during which the patient's TBI level decreased while her ALT level increased (Fig. 1D, dotted circle). Finally, her aspartate aminotransferase and ALT levels decreased gradually to normal within 3 weeks after tapering prednisolone and using doxycycline followed by penicillin G. Leptospirosis is caused by Leptospira species endemic in nonurban areas. The clinical manifestations range from subclinical infection to febrile illness, jaundice, renal failure, and pulmonary hemorrhage.1 The special biochemical pattern ICAH is an important hint for leptospiral hepatitis, as has been shown.1 The diagnosis of leptospirosis is commonly based on serological tests that may have low sensitivity, particularly with early acute-phase specimens.2 In recent years, IHC staining of liver biopsy specimens has been regarded more as a research tool and less as a method of diagnosis.3 Many hepatologists remember that liver biopsy is the gold standard for evaluating complex cases, but they forget to communicate with pathologists to perform leptospiral IHC staining, which veterinarians frequently use for animal leptospirosis.3 In fact, IHC was more sensitive than silver staining and more specific than serodiagnosis in a microscopic agglutination test.4 This difficult and complex case highlights (1) the characteristic biochemical ICAH pattern and (2) the high diagnostic yield of IHC staining for leptospiral hepatitis.