Alberto Vegetti

Serum Ferritin as a Predictor of Treatment Outcome in Patients With Chronic Hepatitis C

OBJECTIVES:Antiviral treatment in chronic hepatitis C (CHC) involves ribavirin, a hemolytic agent. We planned a prospective study to evaluate whether drug-induced iron perturbation is clinically relevant as it relates to therapeutic outcome.METHODS:Iron variables were sequentially assessed in 206 CHC patients undergoing antiviral therapy and were correlated with pretreatment iron status and histology, hemolysis, and therapeutic outcome.RESULTS:At week 1 of therapy, serum iron (SI), transferrin saturation (TS), and serum ferritin (SF) increased markedly in all patients. All iron parameters correlated with hemolysis up to week 4; this correlation was lost for SF at later time points. SF rise during treatment was inversely related to baseline SF and iron deposits in hepatic mesenchymal/Kupffer cells. Both baseline SF and mesenchymal iron significantly correlated with fibrosis at multivariate analysis (P=0.015 and 0.008, respectively). Interestingly, baseline SF, despite good specificity (89%), had low sensitivity in predicting siderosis (25%). During therapy, SI, TS, and hemolysis parameters did not correlate with sustained virological response (SVR), whereas SF rise became an independent predictor of therapeutic response: a 2.5-fold increase of SF at week 12 associated with higher likelihood of SVR (odds ratio 1.91, P=0.032). Accordingly, lack of mesenchymal iron deposits at the baseline biopsy correlated with SVR (odds ratio 3.02, P=0.043).CONCLUSIONS:In CHC, SF is a useful marker for assessing disease duration and progression before starting treatment and for predicting therapeutic response while on therapy. SF rise during antiviral therapy is largely independent of hemolysis and likely indicates activation of macrophages in response to antivirals.

Hepcidin Expression Does Not Rescue the Iron-Poor Phenotype of Kupffer Cells in Hfe-Null Mice After Liver Transplantation

BACKGROUND & AIMS Hemochromatosis is a common hereditary disease caused by mutations in HFE and characterized by increased absorption of iron in the intestine. However, the intestine does not appear to be the site of mutant HFE activity in the disease; we investigated the role of the liver-the source of the iron regulatory hormone hepcidin-in pathogenesis in mice. METHODS We exchanged livers between Hfe wild-type (+/+) and Hfe null (-/-) mice by orthotopic liver transplantation (OLT) and assessed histopathology, serum and tissue iron parameters, and hepatic hepcidin messenger RNA expression. RESULTS At 6-8 months after OLT, Hfe(-/-) mice that received Hfe(-/-) livers maintained the hemochromatosis phenotype: iron accumulation in hepatocytes but not Kupffer cells (KC), increased transferrin levels, and low levels of iron in the spleen. Hfe(+/+) mice that received Hfe(-/-) livers had increased levels of iron in serum and liver and low levels of iron in spleen. However, they did not develop the iron-poor KCs that characterize hemochromatosis: KCs appeared iron rich, although hepatic hepcidin expression was low. Transplantation of Hfe(+/+) livers into Hfe(-/-) mice prevented hepatic iron accumulation but did not return spleen and plasma levels of iron to normal; KCs still appeared to be iron poor, despite normal hepcidin expression. CONCLUSIONS In Hfe(-/-) mice, transplantation of livers from Hfe(+/+) mice reversed the iron-loading phenotype associated with hemochromatosis (regardless of Hfe expression in intestine). However, KCs still had low levels of iron that were not affected by hepatic hepcidin expression. These findings indicate an independent, iron-modifying effect of HFE in KCs.

Disease progression and liver cancer in the ferroportin disease

Ferroportin-associated iron overload (also known as the ferroportin disease) was clinically recognised in 1999,1 and linked in 2001 to the A77D mutation of ferroportin (FPN).2 Owing to the mild clinical expressivity reported in the literature, doubts have been raised on the penetrance of the genetic defect and the rationale for iron-removal therapy.3 However, so far, no prospective data have been collected pertaining to this disorder. We have had the opportunity to study six members of a pedigree carrying the A77D mutation of FPN for 11–24 years in whom the disease was first described.1,2 The proband (subject V13, table 1) was diagnosed at the age 59 years. After being on weekly phlebotomy for 2 years, he was on a maintenance programme for 18 years (one phlebotomy every 3 months). At the age of 79 years, he refused to continue on phlebotomy. In 2006, at the …

An unfortunate case of post-ERCP complications

A 47-year-old woman was admitted to our internal medicine unit with a 1-week history of recurrent abdominal pain, without nausea, vomit, fever or itching. Physical examination revealed a positive Murphy’s sign, and laboratory tests were compatible with cholestasis and mild hepatitis (total bilirubin 1.24 mg/dL, direct bilirubin 0.5 mg/dL), AST 103 U/L, ALT 231 U/L, Y-GT 635 U/L, alkaline phosphatase 269 U/L, bile acids 10.9 lmol/L, amylase 64 U/L, lipase 33 U/L. Abdominal ultrasound showed a dilatation of the intrahepatic/extrahepatic bile ducts and gallbladder sludge. She was diagnosed with three small common bile duct stones by magnetic resonance cholangiopancreatography (Fig. 1a, b): an endoscopic biliary sphincterotomy was performed via ERCP, and the stones were successfully extracted with a Fogarty catheter without apparent complications. A nasobiliary tube (NBT) was left in place to allow future controls and in preparation for a cholecystectomy. Eight hours post-procedure, the patient suddenly presented a severe upper quadrant abdominal pain, without tenderness or signs of peritonitis, with intermittent fever (up to 39 C) and chills. There were no signs of hemodynamic instability. Serum biochemistry demonstrated a rise of pancreatic enzymes and inflammatory markers: amylase 1395 U/L, lipase 2837 U/L, white blood cells 10.99 9 10/ L, serum C-reactive protein 1.3 mg/dL. Samples for blood cultures were collected. Suspecting an infected acute necrotizing hemorrhagic pancreatitis, total parenteral nutrition regimen was started, and intravenous ciprofloxacin was administered together with omeprazole. On day 1, despite the treatment, abdominal pain worsened so intravenous paracetamol and tramadol were dispensed as analgesics providing only poor pain control. A computed tomography (CT) was performed: acute interstitial edematous pancreatitis and a subcapsular hepatic lesion (Ø 4.5 cm) in the second liver segment, which, according to the radiologist, was compatible with a biloma (Fig. 1c, d), were documented. On day 2, amylase and lipase levels rapidly declined, which suggested recovery from the acute pancreatitis, a common complication of ERCP. However, fever with chills and particularly abdominal pain persisted even after 48 h of treatment with ciprofloxacin. There was an increase of inflammatory markers (white blood cells 17.78 9 10/L, serum C-reactive protein 24.4 mg/dL). Blood and urine culture samples were persistently negative, as chest X-ray study, serum b-D-glucan and galactomannan assessment. The patient underwent a second (piperacillin/tazobactam) and a third line (meropenem) broad-spectrum antibiotic therapy, without benefit. Therefore, on day 6, a trans-cutaneous drainage under ultrasound guidance of the hepatic lesion was planned: neither bile nor purulent material were drained, but only a small amount of sterile clotted blood, indicating a subcapsular hepatic hematoma. On the same day the NBT placed during ERCP was removed. The subsequent NBT tip microbiological assays revealed a colonization by Candida glabrata, Candida albicans and methicillin-resistant Staphylococcus aureus. An antibiogram/antimicogram-guided therapy with teicoplanin and fluconazole was started: defervescence finally occurred within 48 h. The observed clinical evolution suggested that a second most common complication of ERCP, cholangitis, was successfully treated. Yet, abdominal pain persisted in & Massimo Fiorini massimo.fiorini.88@hotmail.it