The effect of desferrioxamine on iron metabolism and lipid peroxidation in hepatocytes of C57BL/10 mice in experimental uroporphyria.

The effects of the iron chelator desferrioxamine (DFx) on liver iron accumulation, malondialdehyde (MDA) production, porphyrin accumulation and uroporphyrinogen decarboxylase (URO-D; EC 4.1.1.37) activity were investigated over a period of 14 weeks in C57BL/10 mice, made porphyric by the administration of hexachlorobenzene (HCB) and iron-dextran (Imferon, IMF) or IMF alone. In addition, we measured the amount of low molecular weight (LMW) iron in liver tissue to determine a possible correlation with MDA production. These experiments showed that combined treatment with HCB + IMF, as well as IMF alone, resulted in porphyrin accumulation, increased MDA production and reduced URO-D activity, whereas HCB alone had no effect. DFx caused a reduction in hepatic porphyrins, this reduction being more distinct in the IMF group than in the HCB + IMF group. The effect of DFx on MDA production and URO-D activity was in agreement with the results on porphyrin accumulation. LMW iron pool measurements at 11 weeks correlated well with data on MDA production in all treated groups in that period (r2 = 0.84), suggesting both variables are interdependent. In conclusion, these results suggest an important role for iron in porphyrin accumulation, probably through its catalytic role in the generation of oxygen-related free radicals, resulting in direct damage to URO-D. The effectiveness of DFx in reducing porphyrin accumulation is probably the result of a reduction in LMW iron, thus diminishing the amount of iron available for a catalytic role in the generation of oxygen-related free radicals.

Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia.

Nine patients with heterozygous familial hypercholesterolaemia were treated for eight weeks with either 40 mg pravastatin or placebo under double blind conditions. Six patients received pravastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Treatment with pravastatin resulted in a significant decrease in plasma cholesterol caused by a decrease in low density lipoprotein cholesterol (LDL-c) of 30% (p less than 0.005). We determined the effect of this medication on the lithogenicity of bile. Cholesterol saturation index of fasting gall bladder bile decreased with 23% (p less than 0.01) from 1.06 to 0.75 during treatment with pravastatin. A reduction of 24% (p less than 0.01) in molar percentage of biliary cholesterol was seen. After treatment the total bile acid excretion in faeces and the molar percentage of biliary bile acids were not significantly changed, suggesting that pravastatin does not influence bile acid biosynthesis to a significant extent. These findings indicate that treatment with pravastatin can decrease the incidence and complications of cholesterol gall stones.

Serum IgM in primary biliary cirrhosis.

Serum IgM concentrations were measured in 25 patients with primary biliary cirrhosis (PBC) and 25 age- and sex-matched controls by the classical Mancini technique and by a modified method, which included reduction to 7 S monomers. Standards calibrated against the WHO standard, as well as a serum standard with an absolute value calibrated by immunological and non-immunological techniques, were used. All patients had an elevated IgM level; measurement of serum IgM is therefore a simple and sensitive screening test for patients with cholestasis. When measured with the standard calibrated against the WHO standard, the average IgM levels for PBC patients and controls agreed with results previously reported; the average IgM levels were much lower when a serum standard with an absolute IgM value was used; further standardization in needed. The differences in the ratio of the IgM measured by the classical method (pentameric IgM) to that measured by the alternative method (monomeric IgM) support the existence of different IgM subgroups or the in vivo presence of monomeric IgM in some patients with PBC.