Toshikuni Takikawa

Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C

OBJECTIVE:There is considerable evidence that iron is a risk factor for liver injury in chronic hepatitis C. Known as iron reduction therapy, phlebotomy reduces serum ALT activity. This effect might continue with maintenance phlebotomy and result in slower progression of liver fibrosis.METHODS:We examined the biochemical parameters and liver histology of patients with chronic hepatitis C treated by maintenance phlebotomy. For biochemical evaluation, 25 patients were treated by initial phlebotomy to reduce serum ferritin levels to 10 ng/ml or less and then observed for 5 yr with maintenance phlebotomy to maintain the iron-deficient state. For histological evaluation, liver biopsies were performed before and after the study period in 13 of the patients. Thirteen patients who were virological nonresponders to interferon alone and had undergone second liver biopsies after more than 3 yr served as histological controls.RESULTS:Serum aminotransferase levels were decreased significantly by initial phlebotomy and remained at the same levels during the study period (p < 0.05). The grading scores were improved significantly in the study group (p < 0.05) and unchanged in the controls. The staging scores remained unchanged in the study group but were increased in the controls (p < 0.005). Disease progression was significantly different between the two groups (p < 0.05).CONCLUSIONS:These results suggest that phlebotomy with maintenance lowers serum aminotransferase levels, improves liver inflammation, and suppresses the progression of liver fibrosis in chronic hepatitis C.

Iron accumulation in the liver of male patients with Wilson's disease

OBJECTIVES:There is accumulating evidence that ceruloplasmin, a copper protein with ferroxidase activity, plays an important role in iron metabolism. The genetic disorder, aceruloplasminemia, can lead to tissue storage of iron as in hemochromatosis. Because most patients with Wilsons disease, a genetic copper toxicosis, have hypoceruloplasminemia, some could be affected by iron overload.METHODS:Four male patients with Wilsons disease were enrolled in this study of pre- and post-treatment iron metabolism.RESULTS:Pretreatment copper contents of the liver were high in all four male patients studied as diagnostic of Wilsons disease. Genetic analysis supported their clinical diagnosis of Wilsons disease without a background of hemochromatosis. Pretreatment serum ceruloplasmin levels were <20 mg/dl in all four patients. A standard penicillamine treatment for 3–8.5 yr further decreased their serum ceruloplasmin levels. Post-treatment serum ferroxidase activity was low as was the serum ceruloplasmin protein. Copper contents in the liver decreased after treatment in all subjects. In contrast, nonheme iron in the liver increased during treatment. Pretreatment liver specimens were positive for histochemical iron in two patients, and post-treatment specimens were positive in all four patients. In two patients, serum aminotransferase levels rebounded with elevation of serum ferritin concentration during the treatment period. Subsequent iron reduction by phlebotomy ameliorated their biochemical liver damage.CONCLUSION:Iron overload related to hypoceruloplasminemia may be clinically important, particularly in male patients with Wilsons disease.

Serum aminotransferase levels as an indicator of the effectiveness of venesection for chronic hepatitis C

BACKGROUND/AIMS Iron cytotoxicity may play an important role in chronic hepatitis C. The effects of venesection suggest that a slight iron overload contributes to hepatic injury in subjects infected with hepatitis C virus. A better indication of the efficacy of venesection was studied in patients with and without overt iron overloading. METHODS All 40 patients had chronic hepatitis C but none had hemochromatosis of a known etiology. A serum ferritin level of 10 ng/ml or less was chosen as the treatment goal. A mean blood volume of 2400 +/- 1100 ml was removed during treatments lasting 5 +/- 3 months. RESULTS Treatment significantly reduced the mean serum levels of alanine aminotransferase activity from 128 +/- 74 to 63 +/- 28 IU/l (p < 0.01). The baseline enzyme activity was highly correlated with reduction in activity after treatment (r = 0.94, p < 0.01), but the baseline levels of ferritin and histochemistry for iron showed poor correlations with the reduction in enzyme activity (r = 0.63 with p < 0.01 and r = 0.38 with p < 0.05, respectively). CONCLUSIONS Thus, serum levels of aminotransferases were a more important indicator for venesection than conventional indices of iron overload, probably because cytotoxic iron includes some reactive iron species rather than stored iron alone.

Correlation between serum levels of alanine aminotransferase and ferritin in male blood donors with antibody to hepatitis C virus

Chronic hepatitis C has been demonstrated to be associated with hepatic iron overload, and the hypothesis that the disease activity of hepatitis C is associated with iron cytotoxicity was tested in male volunteer blood donors. Sera with either antibody to hepatitis C virus or hepatitis B surface antigen were selected for determination of ferritin concentration and alanine aminotransferase activity. A correlation between serum ferritin concentration (Y; μg/l) and alanine aminotransferase activity (X; IU/l) was found in donors with antibody to hepatitis C (logY=0.65 × logX+0.98,r=0.53, andP<0.01). The correlation was lower in donors with hepatitis B surface antigen (r=0.37;P<0.01). Hepatitis C virus infection probably induces time-dependent iron accumulation associated with the progression of disease activity, while hepatitis B virus infection results in a variety of iron loads with different clinical features. The high disease activity related to hyperferritinemia suggests the presence of iron-induced liver damage in donors with hepatitis C.

Combined phlebotomy and ursodeoxycholic acid treatment in the patients with chronic hepatitis C

As an option to interferon, either iron removal by phlebotomy or ursodeoxycholic acid administration has been recommended for patients with chronic hepatitis C. Some patients, however, show only partial responses to such monotherapy. In the present study, we investigated the effects of a combination of phlebotomy and ursodeoxycholic acid in the patients who did not show normalization of serum alanine aminotransferase levels by either phlebotomy or ursodeoxycholic acid monotherapy. The combination of these therapies in any order additively improved the biochemical parameter to the upper normal range. There were no statistically significant differences between the results of the two combination treatments. The combination treatment was also effective in decreasing serum alpha fetoprotein levels.

Hepatotoxic iron storage in patients with chronic hepatitis C but no hepatic iron detectable histochemically

The accumulation of iron plays a role in the pathogenesis of chronic hepatitis C. Therefore, even slight excesses of iron should be measured if possible. Eight patients were entered in this study who were negative for histochemical tests for iron in the liver. X-ray microanalysis showed that all eight patients had iron stored as scattered hepatocyte hemosiderin. Hemosiderin iron index expressed as the Fe X-ray count was correlated with serum ferritin levels. Phlebotomy reduced serum aminotransferase levels. Thus, the serum ferritin level is an index of excess iron that potentiates viral-induced hepatotoxicity in chronic hepatitis C.

Electron microscopic findings of the liver of a patient with Dubin–Johnson syndrome complicated by chronic hepatitis C and iron overload

A patient was first found to have Dubin–Johnson syndrome and chronic hepatitis at the age of 25 years. Two years later, he underwent gastrectomy because of massive bleeding from duodenal ulcer, followed by posttransfusion self-limited biochemical liver damage. Twenty-five years later, his jaundice worsened to a serum bilirubin level of 10 mg/dl. The test for circulating hepatitis C virus RNA was highly positive, and liver histology showed cirrhosis with brown pigment granules in small numbers of hepatocytes. Some pigment granules were positive for histochemical iron stain. Ultrastructural study on the liver showed (1) the presence of iron-specific X-ray-positive pigment granules, and (2) large numbers of myelin-like bodies throughout the hepatocyte cytoplasm. Histologically advanced hepatic lesions of hepatitis C virus infection and posttransfu-sion iron overload may exacerbate bilirubin transport dysfunction of the syndrome.