Usefulness and limitations of laboratory and hepatic imaging studies in iron-storage disease

Liver biopsy with measurement of hepatic iron concentration is the most certain procedure for evaluation of iron-storage disease, although use of computed tomography and magnetic resonance imaging procedures recently have been proposed as alternative, noninvasive methods for estimating the degree of iron overload. The results of these imaging procedures were compared with those of other noninvasive techniques and liver biopsies in 48 patients. Final diagnoses, based on synthesis of clinical and laboratory data, included (a) primary hemochromatosis (n = 25; 19 homozygous, 6 heterozygous); (b) secondary hemochromatosis (n = 7); (c) alcoholic liver disease (n = 11); (d) chronic active hepatitis (n = 3); and (e) other (n = 2). Serum ferritin and computed tomography or magnetic resonance scanning had 100% sensitivity in detecting hepatic iron overload more than fivefold above the upper limit of normal (greater than 10.7 mumol Fe/100 mg dry liver) but did not detect lesser degrees of iron overload reliably, including those found in 6 of 13 patients with untreated homozygous primary hemochromatosis and 3 of 7 with secondary hemochromatosis. Computed tomography and magnetic resonance imaging were more specific than ferritin (64% and 92% vs. 21%) in the detection of iron excess, more than five times the upper limit of normal. Among magnetic resonance imaging measures, the ratio of the second echo signal intensities of liver to paraspinous muscle was the most sensitive and most specific for detection of this degree of iron overload. The degree of correlation between hepatic iron concentration and results of noninvasive laboratory or imaging studies were insufficient to permit prediction of hepatic iron content by noninvasive studies alone. It is concluded that computed tomography or magnetic resonance scanning as currently usually used is not cost-effective in routine evaluation of iron overload, although these imaging procedures may play a role in patients in whom liver biopsy is contraindicated. Because of their low cost and ready availability, serum ferritin and transferrin saturation tests remain the preferred screening studies for iron overload. Liver biopsy with quantitative iron measurement remains the study of choice for the definitive diagnosis of hemochromatosis.     

Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C

BACKGROUND & AIMS: Reducing the dose of peginterferon and/or ribavirin to <80% when treating chronic hepatitis C virus has been associated with a reduction in sustained virologic response (SVR). However, prior studies did not assess the impact of reducing the dose of peginterferon independent of ribavirin or differentiate between dose reduction or interrupting or prematurely discontinuing treatment. METHODS: Nine hundred thirty-six patients with chronic hepatitis C genotype 1, advanced fibrosis, or cirrhosis (Ishak 3-6) and prior nonresponse to standard interferon +/- ribavirin were retreated with peginterferon alfa-2a (180 microg/wk) and ribavirin (1000-1200 mg/day) during the lead-in phase of the HALT-C trial. The percentage of each medication actually taken during treatment was calculated. RESULTS: Reducing the total cumulative dose of peginterferon received during the first 20 weeks of treatment from full dose (> or =98%) to < or =60% reduced week 20 virologic response (W20 VR) from 35% to 12% and SVR from 17% to 5%. Reducing the dose of ribavirin from full dose (> or =98%) to < or =60% did not affect either W20 VR or SVR as long as ribavirin dosing was not interrupted for more than 7 consecutive days. Prematurely discontinuing ribavirin, even at full-dose peginterferon, reduced W20 VR to < or =19% and SVR to < or =4%. CONCLUSIONS: Reducing the peginterferon dose during the first 20 weeks of treatment reduced viral clearance and SVR. In contrast, reducing ribavirin did not affect either W20 VR or SVR as long as patients remained on full-dose peginterferon. Discontinuing ribavirin prematurely was associated with a marked decline in both VR and SVR.     

Reciprocal effects of micro-RNA-122 on expression of heme oxygenase-1 and hepatitis C virus genes in human hepatocytes

BACKGROUND & AIMS: Heme oxygenase-1 (HO-1) is an antioxidant defense and key cytoprotective enzyme, which is repressed by Bach1. Micro-RNA-122 (miR-122) is specifically expressed and highly abundant in human liver and required for replication of hepatitis C virus (HCV) RNA. This study was to assess whether a specific miR-122 antagomir down-regulates HCV protein replication and up-regulates HO-1. METHODS: We transfected antagomir of miR-122, 2'-O-methyl-mimic miR-122, or nonspecific control antagomir, into wild-type (WT) Huh-7 cells or Huh-7 stably replicating HCV subgenomic protein core through nonstructural protein 3 of HCV (NS3) (CNS3 replicon cells) or NS3-5B (9-13 replicon cells). RESULTS: Antagomir of miR-122 reduced the abundance of HCV RNA by 64% in CNS3 and by 84% in 9-13 cells. Transfection with 2'-O-methlyl-mimic miR-122 increased HCV levels up to 2.5-fold. Antagomir of miR-122 also decreased Bach1 and increased HO-1 mRNA levels in CNS3, 9-13, and WT Huh-7 cells. Increasing HO-1 by silencing Bach1 with 50 nmol/L Bach1-short interfering RNA or by treatment with 5 mumol/L cobalt protoporphyrin or heme (known inducers of HO-1) decreased HCV RNA and protein by 50% in HCV replicon cells. CONCLUSIONS: Down-regulation of HCV replication using an antagomir targeted to miR-122 is effective, specific, and selective. Increasing HO-1, by silencing the Bach1 gene or by treatment with cobalt protoporphyrin or heme, decreases HCV replication. Thus, miR-122 plays an important role in the regulation of HCV replication and HO-1/Bach1 expression in hepatocytes. Down-regulation of miR-122 and up-regulation of HO-1 may be new strategies for anti-HCV intervention and cytoprotection.     

Recommendations for the diagnosis and treatment of the acute porphyrias

The acute porphyrias, 4 inherited disorders of heme biosynthesis, cause life-threatening attacks of neurovisceral symptoms that mimic many other acute medical and psychiatric conditions. Lack of clinical recognition often delays effective treatment, and inappropriate diagnostic tests may lead to misdiagnosis and inappropriate treatment. We review the clinical manifestations, pathophysiology, and genetics of the acute porphyrias and provide recommendations for diagnosis and treatment on the basis of reviews of the literature and clinical experience. An acute porphyria should be considered in many patients with unexplained abdominal pain or other characteristic symptoms. The diagnosis can be rapidly confirmed by demonstration of a markedly increased urinary porphobilinogen level by using a single-void urine specimen. This specimen should also be saved for quantitative measurement of porphobilinogen, 5-aminolevulinic acid, and total porphyrin levels. Intravenous hemin therapy, started as soon as possible, is the most effective treatment. Intravenous glucose alone is appropriate only for mild attacks (mild pain, no paresis or hyponatremia) or until hemin is available. Precipitating factors should be eliminated, and appropriate supportive and symptomatic therapy should be initiated. Prompt diagnosis and treatment greatly improve prognosis and may prevent development of severe or chronic neuropathic symptoms. We recommend identification of at-risk relatives through enzymatic or gene studies.