Liver disease in transfusion dependent thalassaemia major.

AIMS: To study the prevalence and severity of liver diseases of transfusion dependent thalassaemia major patients, and correlate the histological and biochemical changes of iron overload in liver with the peripheral blood markers. METHOD: Liver biopsy was performed to assess the histological changes and liver iron content (LIC). RESULTS: One hundred patients were evaluated (median age 11.7 years, range 1.5-27). A total of 81 liver biopsies were performed in 73 patients; 43 samples were analysed for LIC. Grade 3-4 haemosiderosis and hepatic fibrosis was found in 44% and 30% of patients respectively; both were significantly associated with higher serum ferritin, liver enzymes, and LIC. Very high LIC (>15 mg/g dry weight) was present in 16.3% of patients. CONCLUSION: Severe haemosiderosis and hepatic fibrosis were common in patients with thalassaemia major despite the use of chelation therapy. Liver biopsy provided information on fibrosis and LIC which could not be accurately predicted from peripheral blood markers.     

Liver disease in transfusion dependent thalassaemia major

Aims: To study the prevalence and severity of liver diseases of transfusion dependent thalassaemia major patients, and correlate the histological and biochemical changes of iron overload in liver with the peripheral blood markers. Method: Liver biopsy was performed to assess the histological changes and liver iron content (LIC). Results: One hundred patients were evaluated (median age 11.7 years, range 1.5–27). A total of 81 liver biopsies were performed in 73 patients; 43 samples were analysed for LIC. Grade 3–4 haemosiderosis and hepatic fibrosis was found in 44% and 30% of patients respectively; both were significantly associated with higher serum ferritin, liver enzymes, and LIC. Very high LIC (>15 mg/g dry weight) was present in 16.3% of patients. Conclusion: Severe haemosiderosis and hepatic fibrosis were common in patients with thalassaemia major despite the use of chelation therapy. Liver biopsy provided information on fibrosis and LIC which could not be accurately predicted from peripheral blood markers.     

Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia

PURPOSE: To determine the prevalence of hypoparathyroidism in transfusion-dependent patients with beta-thalassemia. PATIENTS AND METHODS: A total of 28 transfusion-dependent patients with beta-thalassemia were interviewed, and their serum calcium, phosphate, magnesium, and intact parathyroid hormone levels were checked. Serum ferritin levels were measured to monitor the effect of chelation therapy. Blood urea nitrogen, creatinine, total protein, and albumin were measured in patients with undetectable or low intact parathyroid hormone levels. RESULTS: The prevalence of hypoparathyroidism was 10.7% (3/28). Mean age at diagnosis was 18 years. The serum ferritin levels of patients with hypoparathyroidism were 1,032, 2,102, and 7,680 microg/L. Only one patient had clinical symptoms of hypocalcemia. All three of the patients with hypoparathyroidism had hypogonadism, and 66.7% (2/3) of the patients had insulin-dependent diabetes mellitus. CONCLUSIONS: Hypoparathyroidism in transfusion-dependent patients with beta-thalassemia seems to be accompanied by other endocrinopathies. Serum ferritin may not have been a reliable indicator of iron overload in the three patients with hypoparathyroidism. Severe iron overload would easily explain these multiple endocrinopathies. This pattern is commonly seen in iron-overloaded patients with thalassemia elsewhere.     

A case of rhesus hemolytic disease with hemophagocytosis and severe iron overload due to multiple transfusions

BACKGROUND: A newborn with cholestatic hepatic disease and hemophagocytic lymphohistiocytosis due to rhesus hemolytic disease (RHD) is reported. OBSERVATION: A 34 weeks' gestation baby with RHD, who had received multiple intrauterine transfusions (IUT), developed cholestatic hepatic disease and secondary hemophagocytic lymphohistiocytosis (HLH). Her serum ferritin level increased to 5,527 ng/mL, and liver biopsy showed severe iron overload. Treatment with intravenous desferrioxamine resulted in a marked decrease in serum ferritin levels and normalization of liver function CONCLUSION: We suggest that patients who have undergone IUT be evaluated for hyperferritinemia. If hyperferritinemia is noted, chelation therapy should be considered. As another rare finding, HLH can complicate the course of RHD.     

Iron overload and desferrioxamine chelation therapy in β-thalassemia intermedia

This study on serum ferritin levels ind urinary iron excretion after 12h subcutaneous infusion of desferrioxamine in 10 thalassemia intermedia patients shows that even nontransfusion-dependent patients may have positive iron balance resulting in iron overload from 5 years of age. However, the iron overload found in these patients appears to be much lower than in age matched patients with transfusion-dependent thalassemia major. Iron overload increases with advancing age, as shown by increasing serum ferritin levels and desferrioxamine-induced urinary iron elimination. After a six month trial of 12h continuous subcutaneous desferrioxamine administration there was a significant decline in serum ferritin levels.From this study it seems that iron chelation is indicated in thalassemia intermedia patients over 5 years of age in order to prevent iron accumulation. However, the appropriate treatment schedule should be tailored to the individual needs of each patients, established by close monitoring of serum ferritin levels and desferrioxamine-induced urinary iron elimination.This work was supported in part by grants from Assessorato Igiene e Sanità Regione Autonoma della Sardegna, N.I.H. grant number 5 R01 HL-24173-02, C.N.R. subprogetto finalizzato Malattie Ereditarie dell'Eritrocita contract number 80-02252.83     

The effects of deferasirox on renal, cardiac and hepatic iron load in patients with β-thalassemia major: preliminary results

The iron loading related to erythrocyte transfusions is the major cause of morbidities and mortalities in patients with β-thalassemia major (β-TM). Deferasirox, an orally active iron chelator, has been reported to cause serum creatinine increases in addition to acute renal failures in elderly patients with comorbidities. The nefrotoxicities in patients using deferasirox, despite the facts that the drug is minimally excreted from kidneys and its effective chelation of iron from liver and heart, may rise the question of decomparmentalization of iron from these organs to kidneys. Thirteen patients with β-TM were included in the study (mean age 18.5 ± 7.5 years [9-33 years]). The patients received deferasirox in a dose of 34.3 ± 6.5 mg/kg [17-37 mg/kg]. Four patients (31%) exhibited consecutive increases in serum creatinine greater than 33% above baseline twice during the follow-up period. The results indicated that the earliest iron chelation starts in liver in patients receiving deferasirox. Additionally, by the 6th month of deferasirox, the status of cardiac and renal iron in chronically transfused patients with β-TM were preserved. This may indicate that the serum creatinine increases may not be attributed to iron decompartmantalization from other organs to kidneys.     

PATHOLOGY OF LETHAL FETAL GROWTH RETARDATION SYNDROME WITH AMINOACIDURIA, IRON OVERLOAD, AND LACTIC ACIDOSIS (GRACILE)

Autopsy study of 17 newborn infants with lethal autosomal recessive disease presenting as growth retardation with lactic acidosis, Fanconi aminoaciduria, and hepatic hemosiderosis is reported. The patients succumbed between day 1 and 4 months of life; 9 patients died within the first month. All patients showed severe pathologic changes of liver with cholestasis in all livers. Extensive accumulation of stainable iron of the hepatocytes was present in 9/17 autopsy tissues and in two biopsy specimens. Moderate to abundant iron storage in the Kupffer cells was seen in all liver specimens. The amount of hepatocytic iron was high in livers up to 1 month of age and decreased thereafter. The general features and liver findings of this disorder suggest the name Growth Retardation Aminoaciduria Cholestasis Iron Overload, Lactacidosis and Early Death (GRACILE, OMIM 603358). Calcified concrements were seen in the medulla of 13/16 kidney specimens. Pancreas of 13/14 patients showed interstitial fibrosis and exocrine atrophy. Various pathologic findings such as renal tubular dysgenesis, paucity of hepatic bile ducts and iron storage in the macrophages of spleen and pulmonary alveoli were observed in some cases. Previous extensive clinical genetic and laboratory investigations have revealed that the patients had a previously unrecognized genetic disease. It is inherited as an autosomal recessive trait. The gene locus is 2q 33-37. The basic defect of the disease remains unknown.     

Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels

Background:

Chronic transfusions are effective in preventing stroke and other complications of sickle cell disease. The aim of this study was to determine whether serum ferritin levels correlated with liver iron content in sickle cell patients on chronic transfusion.

Procedure:

Forty‐four liver biopsy specimens from 38 patients with homozygous sickle cell anemia (HbSS) and one patient with sickle thalassemia receiving chronic transfusions were studied. Five patients underwent a second liver biopsy for follow up. Three ferritin measurements were used to calculate a mean for each patient. The association between serum ferritin levels and liver iron quantitation was measured using the Spearman rank correlation, and sensitivity and specificity were determined for selected threshold values of serum ferritin.

Results:

Serum ferritin levels ranged from 515 to 6076 ng/ml, liver iron concentration ranged from 1.8 to 67.97 mg/g dry weight. The amount of iron per gram liver dry weight was moderately correlated with serum ferritin values (r = 0.46). The correlation of duration of transfusion with serum ferritin (r = 0.40) and with liver iron content (r = 0.41) also indicated moderate correlation. Liver biopsy results led to changes in the management after 29/44 (66%) of the biopsies. Serum ferritin ≥2500 ng/ml predicted high liver iron content (≥7 mg/g), with a sensitivity of 62.5% and a specificity of 77.8%.

Conclusion:

We found a poor correlation between serum ferritin levels and liver iron content (LIC). Despite being on chelation therapy, many patients on chronic transfusion had high levels of liver iron. Measurement of LIC is highly recommended in these patients. Pediatr Blood Cancer 2008;50:62–65. © 2007 Wiley‐Liss, Inc.     

MRI T2*技术对中、重型β地中海贫血患者心脏及肝脏铁沉积状态的评估

目的：了解中、重型β地中海贫血患者体内铁沉积状况。方法：对39例中、重型β地中海贫血患者的输血、排铁的情况进行统计,检测患者体内铁蛋白水平,并运用MRI T2*技术检测心脏及肝脏铁沉积状况。结果：患者血清铁蛋白水平最低为1500 ng/mL,最高达 11491 ng/mL。肝脏铁重度沉积者15例（38%）,中度沉积者15例（38%）,轻度沉积者7例（18%）,正常者 2例（5%）。 心脏铁重度沉积者7例（18%）,轻度沉积者5例（13%）,正常者27例（69%）。1例出现心律紊乱症状,4例年龄超过20岁者均呈现性腺功能发育不全。大多患者因家庭经济原因未能进行规律输血及排铁治疗,且开始排铁时间较晚。患者血清铁蛋白水平与开始排铁的时间、剂量密切相关。结论：未进行早期规律的输血和排铁治疗的地中海贫血患者,体内铁的沉积发生年龄早,易早期出现重要器官的功能损害而引发相关并发症,应引起临床医师和患者家属的高度重视并制定相应的诊疗措施提高患者的生活质量。     

Correlative study of iron accumulation in liver, myocardium, and pituitary assessed with MRI in young thalassemic patients

Clinical complications resulting from unevenly iron accumulation in individual organs of patients with beta-thalassemia major can affect both expectancy and quality of life. Magnetic resonance imaging (MRI) offers a quantitative, noninvasive, accurate method for estimating iron levels in various tissues, not easily accessible with other techniques. The aim of this study was to evaluate and correlate the level of iron accumulation in different organs (anterior pituitary, myocardium, and liver) assessed with MRI, in children and young adults with beta-thalassemia major. Thirty children and young adults (13 female and 17 male patients) with homozygous beta-thalassemia, treated conventionally, were studied with hepatic, myocardial, and hypophyseal MRI. For liver and myocardium, we calculated the natural logarithm of the signal-to-air ratio in flash 2-dimensional sequences with electrocardiogram gating, whereas for anterior pituitary, the signal intensity was measured in sagittal T2 sequences. All scans were performed within 3 months. In 13 patients, data regarding liver iron concentrations (LIC) assessed by percutaneous liver biopsy were available. The mean of serum ferritin concentrations for 1 year before scans was calculated for each patient. MRI values in myocardium and liver showed a significant negative correlation to age (r=-0.73 and -0.69, respectively). For pituitary MRI, a linear regression with age was recorded in patients over 14 years of age (r=-0.67), whereas a relatively increased signal intensity reduction was recorded in pubertal subjects. Mean serum ferritin concentrations ranged from 252 to 5872 mug/L with an average of 1525+/-1047 mug/L. No statistical significant correlation was noted between mean ferritin levels versus liver, pituitary, and cardiac MRI values (r=-0.49, -0.28, and -0.1, respectively). Mean LIC values assessed by percutaneous biopsy were 13.76+/-11.6 mg/g of dry tissue. A statistically significant negative correlation was observed between liver MRI readings and LIC determined by biopsy (r=-0.89). None of the 3 organs studied with MRI were significantly correlated to each other. Pituitary to liver MRI values and liver to myocardial MRI values were moderately correlated (r=0.34 and 0.42, respectively). Pituitary MRI was not correlated at all to myocardial MRI (r=-0.001). In conclusion, iron accumulation in thalassemic patients is a procedure progressing with age, which seems to act independently in different organs. MRI represents a reliable, noninvasive method for assessing iron overload in various tissues, non-easily accessible with other techniques. Regular scanning, to recognize preclinically excessive iron deposits and intensified chelation therapy, can prevent serious and fatal complications.     

Latent chronic cholangitis in congenital hepatic fibrosis

In a five-year-old girl with congenital hepatic fibrosis raised erythrocyte sedimentation rate and serum gammaglobulins were noted for 3 years. Needle liver biopsy showed histological features of cholangitis andKlebsiella oxytoca was cultured from a liver biopsy specimen. Antibiotic treatment resulted in normalization of erythrocyte sedimentation rate and serum gammaglobulins. This suggest that cholangitis can be clinically latent in congenital hepatic fibrosis and should be investigated and treated when unexplained inflammatory signs are present.     

HCV and HGV infection, iron overload and liver disease in multitransfused patients with thalassaemia and persistently normal or abnormal transaminase levels

Prevalence and influence on liver disease of HCV and HGV infections, and HCV genotypes were studied in 28 HCV-Ab positive multitransfused thalassaemia patients with persistently normal ALT levels (group A) matched by sex and age with 28 patients with increased ALT levels (group B). Laboratory and virologic tests (all patients), liver biopsy (28 patients) and LIC by SQUID (30 patients) were performed. In group A, HCV-RNA was positive in 39%, genotype 2a was detected in 91%. In Group B, HCV-RNA was positive in 89%, prevalence of genotype 1b and 2a was 52% and 48% respectively; compared with group A, they had significantly increased values of gammaGT, AF, BA, TP, IgG, IgA, LIC (group B: 2,142 -/+ 1,524 microg/g liver; group A: 1,084 -/+ 610 microg/g liver). Overall prevalence of HGV-RNA was low (12.5%) and not significantly different between groups. Liver biopsies revealed no cirrhosis and severe fibrosis was found in 3 HCV viremic patients in group B. In 14 viremic patients examined both for LIC and liver histology, mild fibrosis was observed in 71%, in which iron overload was below 5 times the normal value. In conclusion, in patients with normal ALT levels, active HCV infection must be excluded by evaluation of HCV-RNA. Liver biopsy is indicated in HCV viremic patients, independent of ALT levels; in non-viremic patients, increased ALT levels may be due to iron overload and LIC measurement is indicated. Our data emphasise the crucial role of chelation therapy to maintain low LIC levels in order to prevent progression of fibrosis to cirrhosis in patients with HCV chronic hepatitis.     

Non-transferrin-bound iron in long-term transfusion in children with congenital anemias

Non-transferrin-bound iron (NTBI), a potentially toxic compound, is increased in the serum of patients with iron overload and fully saturated transferrin. We found markedly elevated NTBI levels in 16 children (including nine with sickle cell disease and five with beta-thalassemia) with iron overload secondary to prolonged transfusion therapy. During iron chelation with subcutaneous desferrioxamine infusion, NTBI levels decreased to normal, but became elevated within 2 to 4 hours after discontinuation of desferrioxamine. NTBI causes hepatic and cardiac toxicity in experimental systems, but our patients lacked sufficient organ dysfunction for this association to be made. The use of continuous 24-hour chelation to maintain NTBI at low levels may prevent progressive iron toxicity in patients who first received chelation therapy at an older age or who already have evidence of cardiac damage.     

Carbohydrate-deficient glycoprotein syndrome 1b: a new answer to an old diagnostic dilemma

A patient with carbohydrate-deficient glycoprotein syndrome type 1b (CDGS1b) is reported. The patient presented at 5 months of age with failure to thrive, prolonged diarrhoea, hepatomegaly and elevated serum liver transaminases. Liver biopsy showed steatosis. A low serum albumin and elevated serum liver transaminases persisted throughout childhood during which he had repeated infectious illnesses. From the age of 10 years he had oesophageal and duodenal ulceration together with recurrent bacterial cholangitis. Liver biopsy demonstrated hepatic fibrosis. CDGS1b was suspected, supported by the finding of a protein-losing enteropathy and finally confirmed by showing a reduced phosphomannoseisomerase activity. This case illustrates a rare condition with a wide range of presentations.     

Hyaluronic acid predicts hepatic fibrosis in children with hepatic disease

BACKGROUND: Hyaluronic acid (HA) is removed by the liver via sinusoidal cell adhesion molecules. This is impeded in fibrosis, leading to a rise in serum HA. As a noninvasive marker of fibrosis, HA may obviate the need for liver biopsy. OBJECTIVE: To evaluate HA as a marker of hepatic fibrosis, in unselected children undergoing liver biopsy. METHODS: Ninety-three unselected consecutive children (median age, 7.5 years; range, 0.07-19 years) undergoing a liver biopsy between April 2003 and March 2004 were prospectively recruited. Liver biopsy and fasting HA levels were taken simultaneously. The Ishak score was used to stage fibrosis. Scores of 3 or greater were regarded as significant fibrosis. Hyaluronic acid levels were measured using an enzyme-linked binding protein assay (2002 Corgenix, Inc) (adult reference range, 0-75 ng/mL; pediatric reference range, 0-30 ng/mL). RESULTS: Twenty-three (25%) of 93 biopsies had significant fibrosis, and HA levels in this group were significantly higher than those with mild fibrosis (Ishak score, <3), (median level, 72 ng/mL vs 30 ng/mL; Mann-Whitney U test; P < 0.005). Hyaluronic acid level of 50 ng/mL had a positive predictive value 40% and negative predictive value 86% for significant fibrosis. An HA level 200 ng/mL has a sensitivity of 26% and specificity of 90%. CONCLUSIONS: Hyaluronic Acid is a valid noninvasive predictor of hepatic fibrosis in unselected children with liver disease. An HA level of 200 ng/mL strongly suggests significant fibrosis. Hyaluronic acid level of less than 50 ng/mL accurately identifies those who do not have significant fibrosis.     

An unusual case of intrauterine symptomatic neonatal liver failure

We present an unusual case of neonatal liver failure. Isolated ascites was diagnosed in a female fetus at week 34 gestational age upon routine ultrasound. In the 35th week of gestation a cesarean section was carried out after puncture of fetal ascites. After birth the patient showed symptoms and complications of acute liver failure with portal hypertension. High serum ferritin concentrations, MRI findings compatible with tissue iron overload and no evidence for infectious disease or inborn errors of metabolism suggested possible neonatal hemochromatosis (NH). HFE gene mutation analysis studies of the child and parents were negative. An anti-oxidative and iron chelating therapy was introduced, followed by clinical stabilisation of the newborn and normalisation of liver function. The liver biopsy at 4 month of age showed mild fibrosis with a few iron-loaded hepatocytes and macrophages. At 2 years of age the child was virtually healthy. CONCLUSION: The clinical course of our patient indicates that the pathological changes in the liver being associated with presumptive NH may be reversible when NH is diagnosed early and antioxidative and chelating therapy is immediately initiated.     

Does Rapidly Progressive Iron Overload in a Young Girl with Sideroblastic Anemia Also Signify the Presence of Hereditary Hemochromatosis?

A severely anemic 3-year-old girl with refractory sideroblastic anemia and fulminant, fatal hemochromatosis is described. The patient had transfusion-dependent anemia with clinical cardiac, liver, and endocrine dysfunction that resulted from iron loading. The patient was minimally transfused, and deferoxamine chelation was started at age 34 months. Despite treatment, the patient died at age 46 months as a result of severe iron overload. Sideroblastic anemia and iron overload in childhood are reviewed, and a pathophysiologic mechanism for the patient's clinical course is postulated.     

Restoration of hematopoiesis after iron chelation therapy with deferasirox in 2 children with severe aplastic anemia

Iron overload is a significant clinical problem in patients with severe aplastic anemia or other transfusion-dependent bone marrow failure diseases. Iron chelation therapy is more readily available owing to the recent introduction of oral iron chelators. We describe 2 cases of children with severe aplastic anemia and related transfusional iron overload who received iron chelation therapy with oral deferasirox. Our patients experienced restoration of trilineage hematopoiesis after the administration of deferasirox along with the reduction in ferritin levels, and subsequently became transfusion-free. Our report raises the possibility of potential benefit on hematopoiesis from iron chelation therapy and warrants furthermore investigations.     

Neonatal intrahepatic cholestasis with hepatic siderosis and steatosis

Abstract Neonatal intrahepatic cholestasis is a heterogeneous disease of undetermined cause. There is an unreported subset of idiopathic neonatal intrahepatic cholestasis with an unusual histological combination of hepatic siderosis and macrovesicular steatosis. The patients were a 34-day-old female and a 39-day-old male with normal birth weights. Their mothers had received oral iron supplement4–6 weeks before delivery. The patients had obstructive jaundice noticed at the well-baby clinic at 1 month of life. They had high levels of serum galactose and tyrosine, hyperferritinemia. Urinary organic acid and bile acid analyses were negative, and galactose-1-phosphate uridyltransferase activity in red cells was normal. Liver biopsies showed diffuse iron deposits and macrovesicular fat. By substituting formula milk with lactose-free milk, the patients responded, and had normal biochemical tests within 5 months of life. Follow-up biopsies, at the age of 12 months, showed mild residual fibrosis without iron or fat deposits. They are both well at 3 and 6 years of age, respectively, without biochemical liver dysfunction and neurologic impairment. Prenatal iron-overload might contribute to the pathogenesis of the disease, but further studies are needed to confirm the assumption.     

Correlation of serum ferritin levels with hepatic MRI T2 and liver iron concentration in nontransfusion beta-thalassemia intermediate patients: A contemporary issue

Background: Beta-thalassemia intermediate is a genetic disease that is milder than beta-thalassemia major. The T2^* magnetic resonance imaging (MRI) technique is currently the gold standard for iron load detection. However, it is expensive and needs an expert radiologist to report findings. Therefore, we conducted this study to determine an optimal cut-off value of ferritin in proportion to T2 MRI of liver and measurement of liver iron concentration for early detection of hepatic iron overload in Beta-thalassemia intermediate patients. Methods: This cross-sectional study was conducted on 108 patients with Beta-thalassemia intermediate who referred to tertiary hospital, Shiraz, Iran. Serum ferritin, hepatic T2 MRI, and liver iron concentration were assessed. Receiver operator characteristic was used to determine the sensitivity and specificity of cut-off value. Results: Serum ferritin levels showed a statistically significant negative correlation with T2 hepatic MRI (r = ?0.290, p value =.003) and positive correlation with liver iron concentration (r = 0.426, p value <.001) in the patients with Beta-thalassemia intermediate. According to the receiver operator characteristic, the best cut-off value for ferritin to show early diagnosis of liver iron overload was 412 ng/mL. Calculated sensitivities and specificities were 0.78 and 0.82 for T2 MRI and 0.76 and 0.86 for liver iron concentration, respectively. Conclusion: Serum ferritin levels of around 450 ng/mL might be considered as a cut-off point to evaluate hepatic iron overload before using expensive, not readily available T2 MRI. This level of serum ferritin could be considered for starting iron chelation therapy in patients with Beta-thalassemia intermediate in areas where T2 MRI is not available.