Safety and effectiveness of 100 mg/kg/day deferiprone in patients with thalassemia major: a two-year study.

Deferiprone at a dose of 75 mg/kg/day is not sufficiently effective to maintain iron stores at a level which has been considered safe in all patients with iron overload. Our main aim was to determine the safety of long-term therapy with high-dose (100 mg/kg/day) deferiprone. A secondary aim was to determine the efficacy of this high dose. Twelve thalassemia major patients received deferiprone at a dose of 100 mg/kg/day over 2 years. Transient aspartate aminotransferase increase (8 patients), gastrointestinal discomfort (3 patients) and arthralgia (2 patients) were the most commonly reported side effects. None of the patients discontinued therapy. The mean serum ferritin level fell from 3,901 +/- 3,618 to 1,790 +/- 2,205 microg/l after 2 years (p < 0.05). Five of the 12 patients continued to receive deferiprone for an additional 3 years. No new side effects were encountered. The mean serum ferritin level in this subgroup was initially 2,510 +/- 332 microg/l and dropped to 1,511 +/- 664 microg/l after 5 years (p < 0.05). Liver iron levels at the end of the 2-year study ranged from 1.0 to 30.9 mg/g dry weight, 3 of the patients having levels above 15 mg/g.

Five-year trial of deferiprone chelation therapy in thalassaemia major patients.

Twelve thalassaemia major patients have been given deferiprone 75 mg/kg body weight daily as iron chelation therapy for 5 years. Their ages ranged from 18 to 34 years (mean 24.2) at the end of the study. Two patients were hepatitis C virus (HCV) mRNA positive and a further 5 were positive for HCV antibody. The mean serum ferritin level fell significantly from 4,302 +/- 2,245 microg/l SD at baseline to 3,032 +/- 1,155 microg/l at 2 years (p = 0.037) and 2,229 +/- 1,070 microg/l (p = 0.007) at 5 years. At the end of the study, liver iron ranged from 3.59 to 23.7 mg/g dry weight (mean 11.9 +/- 5.4), 3 patients having levels >15 mg/g. There was no significant change in serum AST levels, but ALT levels fell significantly at 2 years (p = 0.019) and 5 years (p = 0.001). Liver biopsy at the end of the study showed no evidence of hepatic fibrosis caused by deferiprone. Cardiac studies showed no overall change in left ventricular ejection fraction but a significant improvement in isovolumic relaxation time (p = 0.045). We conclude that in this albeit small group of thalassaemia major patients, deferiprone was a safe long-term method of iron chelation. In a minority, higher doses of deferiprone or a combination with desferrioxamine would be needed to lower liver iron below 15 mg/g.

Small hepatocellular carcinomas in cirrhotic explant livers: identification by macroscopic examination and lipiodol localization.

Small hepatocellular carcinomas (HCCs) in cirrhotic livers are difficult to detect. This study aimed to assess if small HCCs can be better identified using specific macroscopic sampling criteria and Lipiodol (iodized oil) localization on radiographs, and to evaluate thereby their incidence and morphology. Prospective cirrhotic recipients of orthotopic liver transplantation (OLT) were administered hepatic arterial Lipiodol at angiography. Posttransplantation, the explant livers were sliced and inspected as per routine for unusual nodules. If unusual nodules were found or HCC clinically suspected, the slices underwent soft-tissue radiography. Tissue samples were then taken as per protocol from all nodules with diameter > or =1 cm/unusual appearance/exophytic bulge, and from foci of radiographic Lipiodol uptake or high soft-tissue density. One hundred three lesions were assessed and classified histologically as HCC (n = 55) or regenerative nodule (n = 39) or borderline (n = 9). Sampling according to predetermined macroscopic criteria proved an effective method for identifying small HCCs: 44 cancers were detected, most <5 mm in diameter, additional to those picked up on routine assessment. Green nodules were more likely to be HCC (P < .0001). The cancers were all multifocal, and had characteristic histological features of HCC except for 12 unusual fibrotic cancers in livers with alcoholic cirrhosis. Lipiodolization alone identified one additional HCC. Lipiodol retention on x-ray is fairly specific for HCC (83%), and can even identify lesions 2 mm in diameter. But its sensitivity is poor (45%), and its routine use to identify HCCs in explant livers is not recommended.

Detection of small hepatocellular carcinomas in cirrhotic livers using iodised oil computed tomography.

BACKGROUND: The detection of hepatocellular cancers (HCC) is a major role of preoperative imaging in patients with end stage liver disease being considered for orthotopic liver transplantation (OLT). AIMS: To assess the sensitivity of iodised oil computed tomography (IOCT). PATIENTS AND METHODS: A prospective evaluation in 50 consecutive patients undergoing OLT included ultrasound scan, contrast enhanced CT, angiography (with intra-arterial injection of iodised oil), and a second CT (IOCT) 10 days later. Following transplantation the explant liver was serially sectioned for pathological evaluation. Soft tissue radiographs of the liver slices were used to match histological lesions with CT findings. RESULTS: Eleven patients were excluded due to protocol violations. Of the remaining 39, histological evaluation revealed no cancers in 33 explant livers, in keeping with negative preoperative imaging. Six explant livers contained 55 HCCs, 84% of which were less than 1 cm in diameter. Pretransplant IOCT detected 3/6 patients with cancer (50%) but only 7% of cancerous lesions. Ultrasound, contrast CT, and angiography each detected 2/6 patients with cancer and 4% of cancerous lesions. CONCLUSION: IOCT is an insensitive method for the detection of small HCCs in livers with advanced cirrhosis but in this study was slightly superior to ultrasound, CT, and angiography.

Human liver cancer cells and endothelial cells incorporate iodised oil.

Iodised oil (lipiodol) administered via the hepatic artery localises selectively in primary liver cell cancers (hepatocellular carcinomas or HCCs) for prolonged periods and has been used as a vehicle for cytotoxic agents. Despite clinical use, the mechanism of lipiodol retention by tumours has remained unclear, embolisation of oil droplets in the tumour vasculature being the prevailing hypothesis. We have investigated the role of tumour and endothelial cells in lipiodol retention. Human liver tumour (Hep G2) cells and human umbilical vein endothelial cells in culture were exposed to lipiodol. Light microscopy using selective silver impregnation stains and transmission electron microscopy revealed lipiodol incorporation by both cell types, probably by pinocytosis. This was not associated with cellular injury in terms of cell lysis, cell replication or radio-labelled leucine uptake. Histological analysis of 24 HCCs either surgically resected or discovered incidentally at liver transplantation (with prior arterial injection of lipiodol) revealed vesicles of lipiodol in the cytoplasm of tumour cells and endothelial cells lining tumour vessels. Thus, lipiodol is likely to deliver cytotoxic agents directly into tumour cells and endothelial cells, both in vitro and in vivo. This may also apply to other lipids and to other human tumours. These findings have significant therapeutic implications.