Liver Affection in Iron Overload Studied with Serum Ferritin and Serum Aminotransferases

ABSTRACT Liver dysfunction as measured by S-ALAT activity was present in 72% of patients over 40 years of age with HLA-related iron overload, mainly detected by laboratory screening. Liver dysfunction was correlated to the amount of iron stored (r=0.54, p<0.001). When iron was removed by phlebotomy, liver function returned to normal. S-ALAT activity was closely correlated to serum ferritin concentration (r=0.73, p<0.001). Even a mild iron excess can affect hepatocytes and result in increased levels of ferritin and aminotransferases in serum. Patients with “transaminitis” should be investigated for iron overload.     

Computed Tomography in Nonalcoholic Fatty Liver Disease

The value and/or limitations of computed tomography (CT) in assessment of hepatosteatosis are not well studied in nonalcoholic fatty liver disease (NAFLD). We prospectively evaluated the accuracy of CT in assessing the amount of hepatosteatosis in NAFLD patients and the impact of demographic and histopathologic variables on CT images. Forty patients with biopsy-proven NAFLD were eligible. Of these, 10 exhibited hepatic iron overload. Liver and spleen attenuation measurements were obtained and spleen-minus-liver attenuation difference (ΔS–LA) was calculated. A good correlation between ΔS–LA and pathological hepatosteatosis was observed (r = 0.837, P < 0.0001). Liver iron overload did not affect this correlation, although the mean ΔS–LA was significantly lower in patients with iron overload. No correlation was detected between ΔS–LA and hepatic inflammation, fibrosis, or body mass index. We conclude that ΔS–LA derived from CT may be a useful tool for predicting the amount of hepatosteatosis in NAFLD patients as it is not affected by various individual factors.     

Screening for Iron Overload Using Transferrin Saturation

ABSTRACT People with parenchymal iron overload exhibit an elevated serum iron concentration and a raised transferrin (TIBC) saturation early in the course of the disease. They can therefore be detected by simple laboratory tests before organ damage has occurred. In this study running for 2 months, 10512 samples from approximately 8750 patients and blood donors were examined in a county hospital in Central Sweden. Abnormal TIBC saturation (>70%) was found in 1.7% of the samples. This abnormality was caused by physiological fluctuations in serum iron in 44%, liver disease in 22%, blood disorder in 10%, iron therapy in 10.5% and parenchymal iron overload in 11.5%. The diagnosis of iron overload was confirmed by measuring the serum ferritin concentration and by performing the desferrioxamine test, liver biopsy, quantitative phlebotomy and family studies including HLA typing. We found a prevalence of iron overload of 0.24%. This figure is almost certainly too low because some affected patients were probably lost because of TIBC desaturation induced by inflammatory conditions.     

慢性肝病中医证型与血清肝纤维化指标及甘胆酸的关系

目的：探讨慢性肝病中医证型与肝纤维化标志物透明质酸（HA）、Ⅳ型胶原（Ⅳ－C）、Ⅲ型前胶原（PCⅢ）及甘胆酸（CG)之间的关系。方法：采用放射免疫法测定120例慢性肝病瘀血阻络、湿热中阻、肝肾阴虚的肝纤维化指标及CG水平,同时与40例正常对照者比较。结果：各中医证型组的肝纤维化3项指标均较对照组升高,以瘀血阻络组的HA、PCⅢ升高最为显著;各中医证型组的CG指标均较对照组升高,以湿热中阻组升高最为显著。结论：上述指标对慢性肝病患者的中医分型有一定的指导意义。     

Hepatic iron in hemochromatosis

Ninety-two families with familial hemochromatosis were reviewed and analyzed in regard to hepatic iron and the value of the hepatic iron index (hepatic iron/age). Hepatic iron was measured in 29 hemochromatosis homozygotes, in 10 hemochromatosis heterozygotes, and in 30 control patients with other liver diseases. Hepatic iron content increased with age in homozygotes. Hepatic iron index differentiated homozygotes from heterozygotes (P<0.05) and heterozygotes from controls (P<0.05). The hepatic iron index is a useful measurement in the diagnosis and management of patients with familial hemochromatosis.The author acknowledges grant support from the Ministry of Health of Ontario and the Medical Research Council of Canada.     

Non-Specific Iron in Patients with Beta-Thalassaemia Trait and Chronic Active Hepatitis

A non-specific iron fraction, not bound to transferrin, has been looked for in the sera of 42 never-transfused patients with beta-thalassaemia trait, 17 of whom had chronic active hepatitis, negative for HBV infection or alcohol abuse. Non-specific iron was found only in the sera of those patients with beta-thalassaemia trait plus chronic active hepatitis who had complete transferrin saturation, high serum ferritin levels and urinary iron excretion and a high degree of hepatic siderosis. In view of the known toxicity of non-transferrin iron, we suggest that this non-transferrin iron fraction may be responsible for the liver damage in these patients. Furthermore, the positive correlation between the presence and the amount of non-transferrin iron and the levels of serum ferritin suggests that this fraction is a sensitive indicator of iron-induced toxicity when severe iron overload slowly develops in patients with beta-thalassaemia trait even in the absence of any iron administration.     

Nonalcoholic fatty liver disease and steatohepatitis in people living with HIV

ABSTRACT

Introduction: The burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing worldwide. This phenomenon poses a potentially dangerous risk of rise in mortalities caused by cirrhosis and liver cancer. Owing to a complex combination of factors, NAFLD and NASH arise in a majority of people living with HIV (PLWH), but accurate estimates of prevalence differ, depending on sample selection, type of analysis, and data interpretation. The wide range of diagnostic tools used to assess liver steatosis and lack of control groups in many studies further contributes to current difficulties in properly assessing prevalence of these conditions.

Areas covered: Thoroughly scrutinizing the current literature, we compared the prevalence of NAFLD and NASH in PLWH to rates found in the general population. We highlighted strengths and limitations of the studies, in order to determine the effective impact of these medical conditions in PLWH.

Expert opinion: The prevalence and progression of NAFLD in human immunodeficiency virus (HIV) infection are reported to be widely variable. HIV infection itself and antiretroviral treatment have been demonstrated to play a role in the development of NAFLD. Larger and more effective studies are needed to evaluate the effects of NASH in PLWH and its progression.     

Iron Overload in a Non-Transfused Patient with Thalassaemia Intermedia

A patient with thalassaemia intermedia and haemosiderosis is reported. This patient did not receive transfusions or iron therapy. The iron absorption and the plasma iron turnover (PIT) were increased. Transfusions were carried out in order to decrease the amount of abnormal erythropoiesis. After that, the erythropoietin and PIT were decreased to normal levels and the iron absorption also returned to normal. The data presented suggest that increased erythropoiesis was responsible for the abnormaly high iron absorption and subsequently for the haemosiderosis of the patient presented.     

Internal Distribution of Excess Iron and Sources of Serum Ferritin in Patients with Thalassaemia

Liver and spleen iron concentrations, serum ferritin level and binding of S-ferritin to concanavalin A (Con A) were measured in 12 patients with thalassaemia major or intermedia at the time of splenectomy. All these subjects had increased liver iron concentration, most of them had hepatic fibrosis but none of them had histological evidence of chronic hepatitis. No patient had ascorbic acid deficiency. Serum ferritin concentration was increased in all cases, ranging from 266 to 5 504 μg/l. In all but 2 subjects most of the protein did not bind to Con A, thus behaving as tissue ferritin. There were highly significant correlations between serum ferritin concentration, amount of blood transfused and liver iron concentration. On the average, iron concentration in the liver was about 3 times that in the spleen. The findings obtained suggest that in patients with thalassaemia major or intermedia most of the iron is deposited in parenchymal tissues and most of the S-ferritin derives by leakage from the cytosol of iron-loaded parenchymal cells. S-ferritin is a valid index of liver iron overload in thalassaemic patients without complications such as viral hepatitis and/or ascorbic acid deficiency.     

Serum Leptin Levels in Patients with Liver Cirrhosis and Chronic Viral Hepatitis

Background: The aim of the present study was to investigate serum leptin levels in relation to anthropometric features in patients with liver cirrhosis (LC) and chronic viral hepatitis (CVH), and to determine the effect of the severity and aetiology of the LC on serum leptin levels. Methods: Forty-nine patients with LC, 32 patients with CVH and 69 control subjects were age, body mass index (BMI) and sex-matched and included in the study. Plasma glucose, serum leptin and insulin levels were determined. Insulin resistance was assessed using homoeostasis model assessment (HOMA). Body composition was estimated by skinfold thickness. Results: Female patients with Child-A LC had higher levels of leptin, and female and male patients with Child-A LC had higher absolute leptin (leptin/BFM) levels compared to patients with Child-C LC and control subjects. Serum leptin levels of the patients with alcohol LC were higher than the control subjects, but the absolute leptin levels were comparable. When alcoholic and post-viral hepatitis cirrhotic patients were compared with each other on an aetiologic basis, there was no significant difference between them in leptin and absolute leptin levels. There were significant correlations between leptin and BMI, body fat percentage (BFP), BFM (body fat mass) in all three groups in both sexes. Conclusions: These data suggest that the physiologic correlations among serum leptin level, sex, BMI and BFM were well preserved in patients with chronic liver disease. Patients with alcohol LC had higher leptin levels. In early stages of liver disease, leptin levels and absolute leptin levels are higher than in normal subjects. However, in advanced stages of the disease the significant decline in leptin levels and similar levels of leptin expressed in relation to BFM compared to control subjects predominantly represent the expression of fat mass.     

High Rate of Seropositivity of Chlamydia pneumoniae IgA in Male Patients with Nonalcoholic Steatohepatitis

The aim of this study was to investigate if there was any relationship between nonalcoholic steatohepatitis and the rate of Chlamydia pneumoniae seropositivity in a male population. Fifteen men with nonalcoholic steatohepatitis and 20 healthy men were enrolled in the study. The seropositivity rate of Chlamydia pneumoniae immunoglobulin A in the nonalcoholic steatohepatitis and control groups was 53.3 and 5%, respectively. The rate of Chlamydia pneumoniae immunoglobulin A positivity was significantly higher in the nonalcoholic steatohepatitis group than the controls (P = 0.002), while such a difference did not occur for Chlamydia pneumoniae immunoglobulin G positivity (P > 0.05). There is an association between nonalcoholic steatohepatitis and persistent Chlamydia pneumoniae infection as a probable causative or triggering agent. These findings suggest that further studies are necessary to clarify this association.     

Serial serum ferritin measurements in untreated HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study

Hemochromatosis has often been associated with progressive iron overload, but the natural history of iron accumulation in untreated C282Y homozygotes has been reported infrequently. The Hemochromatosis and Iron Overload Screening (HEIRS) Study screened 101 168 primary care participants for iron overload using transferrin saturation, unbound iron-binding capacity, Serum ferritin (SF), and HFE C282Y and H63D genotyping. SF was measured at initial screening (IS) and again when selected participants returned for a clinical examination (CE). The change in SF over the observation period (defined as ferritin rate of change) was analyzed according to age, gender, initial SF, initial SF/age, transferrin saturation, and iron removed by phlebotomy in C282Y homozygotes. Seventy-four male and 133 female untreated C282Y homozygotes were observed over a median of 112 days (34-924 days) between IS and CE. In men, SF increased in 54% and decreased in 46%. In women, SF increased in 50% and decreased in 50%. The significant variables affecting the SF rate were initial log SF (P = 0.0027) and transferrin saturation (P < 0.0001). Male C282Y homozygotes with higher SF rates (n = 27, upper 50th percentile) had significantly greater iron removed by phlebotomy (mean 4.93 g, range 1.0-17 g) than those with lower SF rates (n = 26, lower 50th percentile) (mean 2.6 g, 0.42-7.1, P < 0.05). SF was as likely to decrease as increase in untreated C282Y homozygotes over this relatively brief observation period. Incremental increases in SF are not inevitable in untreated C282Y homozygotes.     

Up-regulation of Transferrin Receptor Expression in Hepatocytes by Habitual Alcohol Drinking Is Implicated in Hepatic Iron Overload in Alcoholic Liver Disease

Background Hepatic iron overload is often seen in alcoholic liver disease (ALD). We previously reported that the expression of 4-hydroxy-2-nonenal-protein adducts, which is a lipid peroxidative product and can be used as a marker of radical-mediated cellular damage, was increased in iron-overloaded hepatocytes with ALD. However, the mechanism of hepatic iron overload in ALD has not been clarified. In this study, to elucidate the mechanism of hepatic iron overload in ALD, we immunohistochemically investigated the expression of transferrin receptor (TfR), which mainly acts for cellular iron uptake.
Methods Hepatic tissues were obtained from 31 patients with ALD and 5 normal livers by percutaneous needle biopsy under laparoscopy or ultrasound guidance. Chemical detection of hepatic iron accumulation was performed by Perls' Prussian blue stain. Immunohistochemical detection of TfR expression was done using human monoclonal anti-TfR antibody (TR104) according to the avidin-biotin complex method with alkaline phosphatase.
Results Excess iron accumulation was found in 22 hepatic tissues with ALD but not in any normal hepatic tissues. TfR expression was increased in hepatocytes of 18 hepatic tissues with ALD but was not detected in any normal hepatic tissues. The mean duration of abstinence of patients who demonstrated positive TfR expression in hepatocytes was significantly shorter than that of patients who demonstrated negative TfR expression (positive: 14 days; negative: 30 days). However, total ethanol consumption, daily ethanol intake, and serum aspartate aminotransferase and γ-glutamyl transpeptidase values on admission were not significantly correlated with TfR expression in hepatocytes.
Conclusions The up-regulation of TfR expression in hepatocytes is implicated in hepatic iron overload in ALD, and habitual alcohol drinking is an important factor for the induction of TfR expression.     

Improvement of Serum Aminotransferase Levels after Phlebotomy in Patients with Chronic Active Hepatitis C and Excess Hepatic Iron

Objectives: Iron metabolism may be altered in patients with chronic active hepatitis C. In an attempt to evaluate whether excess iron contributes to liver injury, we used phlebotomy for removal of iron from patients with chronic hepatitis C. Methods: All 10 patients had histochemically detectable iron In the liver and underwent an initial period of weekly or monthly phlebotomy of 200 or 400 ml. A serum ferritin level of 10 ng/ml or less was chosen as the endpoint, and maintenance phlebotomy was performed if the level rebounded. Results: The treatment reduced mean serum alanine aminotransferase activity from 152 ± 49 to 55 ± 32 IU/L; this level became normal in five of the 10 patients. Anti-HCV antibodies could be detected in all patients throughout the study. Histologic abnormalities of the liver were unchanged except for disappearance of iron deposits from seven of the patients studied. Conclusions: Our findings suggest that iron removal may be beneflcial for patients with chronic active hepatitis C and histochemical iron in the liver.     

Serum procollagen III peptide concentration in iron overload

Abstract: Patients with severe iron overload may develop hepatic fibrosis due to iron toxicity. Unfortunately, the follow-up of the fibrogenic activity during treatment by histological examination of tissue biopsies carries potential side effects, and may therefore not be justified ethically. Recently, the serum concentration of procollagen type III peptide (S-PIIINP) has been shown to be a valid serum marker of the activity of collagen metabolism in conditions with hepatic fibrosis unrelated to iron overload. In order to evaluate the potential usefulness of this test in patients with fibrosis due to iron overload, we investigated the relationship between the PIIINP serum concentration and the size of iron overload in 18 patients with hereditary haemochromatosis (HH) and in 14 patients with transfusional iron overload. A close correlation was found between S-ferritin and S-PIIINP (r=0.73, p<0.0001). Follow-up of 6 patients during iron depletion treatment revealed a normalization of the serum aminotransferase concentration before normalization of S-PIIINP was found. This may indicate that excess iron directly induces an increase in fibrogenesis rather than the increased fibrogenesis is secondary to hepatocellular injury caused by iron excess. Thus, serial measurements S-PIIINP may be useful in follow-up of the fibrogenic process due to iron overload.