Regenerative nodules in acute or subacute hepatic failure mimic multifocal hepatocellular carcinoma (HCC) on computerized tomographic imaging (CT)

A896 AASLD ABSTRACTS

GASTROENTEROLOGY Vol. 118, No.4

7

9

A MAMMALIAN IRON TRANSPORTING ATPASE: INDUCTION BY IRON. David E. Baranano, Christopher D. Ferris, Johns Hopkins Univ Sch of Medicine, Baltimore, MD. The molecular mechanism of iron entry into cells is well characterized. Transferrin delivers iron to cells. Upon binding to the transferrin receptor, it is endocytosed . Once in the endocytic vesicles, the v-type H-ATPase acidifies the lumen allowing iron to dissociate from transferrin and be cotransported into the cytosol via OCT. In contrast, little is known about how iron is released from cells. Recently, we found that heme oxygenase-I (HO I) expression results in lower cellular iron levels thereby protecting cells from stress-induced death (Nature Cell Biology I: 152-157, 1999). HO-I is an enzyme that catabolizes heme to form CO, biliverdin, and Fe(II). To elucidate the molecular mechanism linking HOI activity to cellular iron efflux, we identified a new iron transporting ATPase that is co-distributed with HOI in tissues and physiologically induced by iron in cells and intact animals. 55Fe transport into microsomal vesicles shows Mg2+, time, and temperature dependence. Non-hydrolyzable nucleotides fail to support iron transport. Ortho-vanadate (100 ILM) inhibits the activity 64.9 ± 2.3 %, suggesting that the Fe-ATPase is a P-type ATPase. The Fe-ATPase and HO-I are both localized in the microsomal membranes by subcellular fractionation and enriched 10-20 fold in the spleen (38± 4 pmol/mg protein) compared to other tissues. HOI-I - mice develop iron overload in the liver and the kidney. We found that the Fe-ATPase activity is increased >400% in the kidney and> 1000% in the liver of HO1+ mice compared to HOI +I-andwild-type. To confirm physiologic induction of the Fe-ATPase by increases in cellular iron, we induced HOI activity in rat kidney by glycerol-induced rhabdomyolysis. Rats were injected with 7.5 ml/kg glycerol into anterior thigh muscles resulting in dramatic induction HOI and Fe-ATPase activity from 6 ± 2 pmol/mg to 36 ± 5 pmol/mg protein. To investigate the molecular mechanism of iron mediated FeATPase induction, we used RAW 264.7 cells which have a basal FeATPase activity of 1.4 ± 0.2 pmol/mg protein. When cultured with 0.5mM FeS04 for 20 h, the activity increases more than 1200% to 28 ± 2 pmol/mg protein. The induction by iron is biphasic with an initial 2-fold induction that occurs within an hour after iron treatment and a delayed induction seen between 18-20 h after exposure to iron. Both cycloheximide and actinomycin 0 block the late phase induction, but not the rapid induction.

REGENERATIVE NODULES IN ACUTE OR SUBACUTE HEPATIC FAILURE MIMIC MULTIFOCAL HEPATOCELLULAR CARCINOMA (HCC) ON COMPUTERIZED TOMOGRAPHIC IMAGING (CT). Richard G. Quist, Rudi F. Thoeni, Timothy 1. Davern, Nathan Bass, Univ of CA, San Francisco, San Francisco, CA. BACKGROUND: Hypodense hepatic nodules are commonly seen on abdominal CT in patients with acute or subacute hepatic failure (AHF or SAHF)I. The frequency and clinical impact of these findings are unknown. PATIENTS: Between 4/98-10/9918 patients with AHF or SAHF (encephalopathy either < or > 8 wks from onset of symptoms) were referred for liver transplantation (OLT). Six were given a diagnosis of multifocal HCC by the referring physician based on dual phase spiral CT. Etiologies were idiosyncratic drug-induced or autoimmune hepatitis (see table) leading to AHF in 3 (A,B,D) and SAHF in 3 (C,E,F). RESULTS: Ultrasound performed as initial imaging in 3 subjects (A,E,F) showed atypical hepatic heterogeneity and led to CT. In 3 patients CT was the initial imaging. In all cases, CT showed multiple hypodense, early phase contrast-enhancing lesions 1.0-4.5 cm in size, either localized (D,F) or diffuse in all segments (A,C,E). CT led to performance of percutaneous (B,D,F) or transjugular (E) biopsy. Complications of biopsy occurred in 4 patients including bacterial peritonitis (F) and bleeding requiring transfusion (E,D,F). Histologic findings in all subjects revealed sub-massive panacinar necrosis with multiple focal regions of regeneration and no dysplasia. Outcomes included successful OLT (A,B,D), death due to infection (C,E) or stable, awaiting OLT (F). CONCLUSIONS: In AHF and SAHF, regenerative nodules commonly appear as multifocal HCC on dual-phase CT. Findings may be coupled with marked AFP elevation, erroneously suggesting a diagnosis of HCC.

Clinical Findings atPresentation inSix patients with Subacute Hepatic Failure SUbject

OLT 4 18

I. Acetaminophen King's criteria Clichycriteria

Sensitivity %

Specificitv(%

71 86

78 56

71 60

75 69

100 100

100 100

81

II. non-Acetaminophen King's criteria % Clichvcriteria 80 '" P.P.V., Positive predictivevalue

·P.P.V %

ACCUIllC)(%

%

Jaundice

T.BiII

AST

PT

Albumin

AFP

6.4 12.7 19.8 40.2 23.3 137

893 264 89 291 82 1272

21 20 32 20 31 22

3.4 3.1 1.6 2.6 2.0 2.5

10.5

(wks)

A B C 0

8 COMPARISON OF THE APPLICABILITY OF TWO PROGNOSTIC INDICATOR SCORES IN PATIENTS WITH FULMINANT HEPATIC FAILURE. Won-Choong Choi, Walid S. Arnaout, Federico G. Villamil, Achilles A. Demetriou, John M. Vierling, Cedars-Sinai Med Ctr, Los Angeles, CA. Medical management of patients with fulminant hepatic failure (FHF) remains ineffective with poor survival. Liver transplantation (LT) remains the treatment of choice. Optimal outcome depends on assessment of the severity of liver injury and early referral for LT. Prognostic indicator scoring systems to assess severity of FHF have been developed; however, they have not been validated in a large cohort of patients (pts) in the US. Aim: To compare the prognostic predictability of the two systems currently in use: King s college and Clichy (Factor V). Methods: We accessed both prognostic scoring systems in 43 pts (15M128F; age37±16yrs) admitted to our Center between Nov 91 and March 99 with FHF according to the definition of Trey and Davidson. Admission data were used to determine the prognosis based on King s college and Clichy criteria. Sixteen pts had FHF due to acetaminophen (ACM) toxicity and the remaining 27 pts had other etiologies (viral, indeterminate etc.). All pts received ICU care, in addition 18/43 pts (8ACM, IOnon-ACM) underwent Bioartificial Liver support. We examined survival or death with medical therapy alone or need for LT. A true positive outcome: pts met the criteria and died with medical therapy or underwent LT; true negative outcome: pts did not meet criteria and survived with medical therapy. Results: Neither King s nor Clichy prognostic criteria were accurate outcome-predictive in pts with ACM toxicity. In contrast, in the non-ACM group, the King s prognostic index was superior with respect to sensitivity and accuracy to that of Clichy. These findings indicate that at our Center more pts with ACM toxicity survive than predicted by both prognostic indicators probably due to superior intensive therapy and Bioartifial Liver support. In contrast, pts with non-ACM FHF who meet King s criteria are more likely to require LT.

Etiology

E F

Nitrofurantoin Troglitizone Autoimmune Hep Zafirlucast Autoimmune Hep Autoimmune Hep

6 8 8 7 4 9

13 2.4 479 2.3 18.4

11tai Y, etal. Radiology 1997202:379-82.

10 CHOLEDOCHAL CYSTS IN ADULTS: ANALYSIS OF PRESENTATION, TREATMENT AND COMPLICATIONS. Clarence KW Wong, Juanita Gamarra, Norman M. Kneteman, Gord M. Lees, Garth Warnock, Vincent G. Bain, Univ of Alberta, Edmonton, AB, Canada. Background: Choledochal cysts are rare, cystic dilatations of the biliary tract. Although they generally present in childhood, diagnosis is delayed to adulthood in 20-30%. They are significant due to potential hepatobiliary and pancreatic complications, as well as the lifetime risk for malignancy (8-26%). Aim: To describe the presentation, treatment and complications of adult patients diagnosed with choledochal cysts over the last 15 years. Methods: A retrospective analysis of adult patients (=::18years) diagnosed with choledochal cysts between 1985 and 1998 was conducted. Hospital and clinic records of gastroenterologists/surgeons were reviewed, with data collected on age, sex, past medical history, clinical, lab and radiological findings at the time of diagnosis. Cholangiograms, surgical interventions, complications and followup were also recorded. Results: Seventeen patients were reviewed, with fourteen meeting inclusion criteria. There were nine female and five male patients, with a mean age of 47.0 years (range 19 to 73 years). Abdominal pain was the presenting complaint in 86% (12/14), jaundice in 50% (7/14) and the classic triad of abdominal pain, abdominal mass and jaundice was only found in two (14%) patients. One patient presented acutely with cholangitis. Duration of symptoms ranged from acute to fifteen years. Whereas abnormal liver function tests were found in 71% (10/14), only 14% (2/14) had an elevated WBC. ERCP was attempted in all patients, with 85.7% success. Common channel length was abnormal (> 15mm) in three patients. Nine choledochal cysts were Type I, two were Type II, two were Type IVa and there was one Type V cyst. One patient developed an adenocarcinoma of the common bile duct and died from this, despite having choledochal cyst excision with unremarkable histology. Two patients had recurrent cholangitis and one had a postoperative leak with abscess formation. Conclusion: Choledochal cysts can present in adulthood with significant sequelae. Complications such as cholangiocarcinoma and recurrent cholangitis occur despite currently accepted medical and surgical management. However, early diagnosis with techniques such as ERCP and surgical excision can lead to symptom relief and prolonged survival in most patients.