Fulminant hepatic failure as a presenting paraneoplastic manifestation of Hodgkin's disease.

Malignancies may uncommonly present as fulminant hepatic failure and, due to the rarity of such an occurrence, they may easily be overlooked as one of its possible causes. An unusual case of Hodgkin's disease presenting as a fulminant hepatic failure is reported. A 34-year-old man presented with an acute onset of liver failure characterized by jaundice, ascites, encephalopathy and bleeding diathesis. Chemotherapy was initiated, resulting in a dramatic improvement not only in the patient's level of consciousness, but also in prothrombin time. Unfortunately, he succumbed shortly after to disseminated candidiasis. A post-mortem needle liver sample revealed massive hepatocellular necrosis, but no liver infiltration by the neoplastic disease. We conclude that in Hodgkin's disease, involvement of the liver can be manifested as a syndrome of paraneoplastic fulminant hepatic failure. In such cases, liver transplantation is an absolute contraindication but urgent chemotherapy under antifungal surveillance can be life saving.     

Pulmonary intravascular ultrasound in infants and children with congenital heart disease

A three-layered appearance of the pulmonary arterial wall has only been described by intravascular ultrasound in adults or autopsy studies of patients with pulmonary hypertension. Thus, pulmonary intravascular ultrasound was performed in 11 patients during heart catheterization to test the hypothesis that distinct layers of peripheral pulmonary arteries can be imaged in infants and children with congenital heart disease. A 3.5 Fr 30 MHz ultrasound catheter was used to image proximal pulmonary arteries with an internal diameter of 3 to 6 mm and distal pulmonary arteries with an internal diameter of 1.5 to 2 mm. Three layers were identified in the proximal arteries of 10 patients but could not be identified in the distal arteries of any patient. There was a significant linear correlation between the indexed dimension of the medial echolucent vascular wall layer and pulmonary vascular resistance. We conclude that intravascular ultrasound can identify vascular changes consistent with medial hypertrophy in the branch pulmonary arteries of young patients with corresponding degrees of pulmonary hypertension. Cathet. Cardiovasc. Diagn. 41:395–398, 1997. © 1997 Wiley-Liss, Inc.     

湖南地区肝豆状核变性基因突变热区的序列检测与分析

目的检测湖南地区汉族人群肝豆状核变性患者（WD）ATP7B基因常见突变种类和形式。方法提取22例WD患者外周血基因组DNA，聚合酶链反应（PCR）扩增ATP7B基因第5、8、12及13号外显子并进行DNA直接测序检测，应用在线BLAST软件分析。结果22例患者中共发现15例患者存在基因突变。其中10例患者存在8号外显子2273G→T杂合突变（即Arg778Leu），且均伴有2250C→G多态（即Leu770Leu，均为杂合子），未发现纯合突变。12号外显子中共发现2855G→A多态（即Arg952Lys）7例（杂合突变4例，纯合突变3例），其中1例合并12号外显子2828G→A杂合突变（即Gly943Asp），另3例合并Arg778Leu杂合突变。13号外显子2975C→T杂合突变（即Pro992Leu）1例。5号外显子未发现突变。结论Arg778Leu是湖南地区汉族WD患者的突变热点，5号外显子为非突变热点。     

Prevalence and correlates of growth failure in young African patients with sickle cell disease

Growth failure (GF) in children with sickle cell disease (SCD) tends to decline in high-income countries, but data are lacking in sub-Saharan Africa. We performed a cross-sectional study nested in the CADRE (Cœur, Artères et DREpanocytose) cohort in Mali, Senegal, Cameroon, Gabon and the Ivory Coast. SCD patients and healthy controls aged 5–21 years old were recruited (n = 2583). Frequency of GF, defined as a height, weight or body mass index below the 5th percentile on World health Organization growth charts, was calculated. We assessed associations between GF and SCD phenotypic group, clinical and biological characteristics and history of SCD-related complications. GF was diagnosed in 51% of HbSS, 58% of HbSβ⁰, 44% of HbSC, 38% of HbSβ⁺ patients and 32% of controls. GF in patients was positively associated with parents’ lower education level, male sex, age 12–14 years, lower blood pressure, HbSS or HbSβ⁰ phenotypes, icterus, lower haemoglobin level, higher leucocyte count and microalbuminuria. No association was found between GF and clinical SCD-related complications. In sub-Saharan Africa, GF is still frequent in children with SCD, especially in males and during adolescence. GF is associated with haemolysis and microalbuminuria, but not with the history of SCD-related clinical complications.     

Liver copper concentration in Wilson''s disease: Effect of treatment with ''anti-copper'' agents

Serial copper determinations have been made on the livers of 10 patients with Wilson's disease. Two were studied before and eight after the start of treatment in order to assess the effect, if any, on the concentration of the metal. In two patients who were receiving no therapy and in one in whom it had been discontinued, the level of copper rose. In the latter patient, resumption of treatment then resulted in a fall in the level of copper in the liver. A similar fall was seen in seven patients on continuous therapy. In one patient, a very poor complier, there was a tendency for the liver copper concentration to rise over a 5-year period. All three therapies investigated--penicillamine, trientine and tetrathiomolybdate--when taken regularly, appear to be effective in reducing liver copper levels. Sixty-nine single determinations of liver copper have been plotted against time on treatment. This shows that the copper concentration falls rapidly in the first year. Thereafter, there is no linear relationship between the duration of treatment and liver copper. Poor compliers have a higher liver copper concentration than do good compliers. Determinations made from different portions of the liver showed that in only one of 19 examples was there an overlap between the near normal and the abnormal range. The principal mechanism of action of 'anti-copper' agents in Wilson's disease appears to be the mobilization of copper from the tissues, but a secondary detoxifying action may come into play later.     

Tissue factor-positive monocytes in children with sickle cell disease: correlation with biomarkers of haemolysis

Tissue Factor (TF) initiates thrombin generation, and whole blood TF (WBTF) is elevated in sickle cell disease (SCD). We sought to identify the presence of TF-positive monocytes in SCD and their relationship with the other coagulation markers including WBTF, microparticle-associated TF, thrombin-antithrombin (TAT) complexes and D-dimer. Whether major SCD-related pathobiological processes, including haemolysis, inflammation and endothelial activation, contribute to the coagulation abnormalities was also studied. The cohort comprised children with SCD (18 HbSS, 12 HbSC, mean age 3·6 years). We demonstrated elevated levels of TF-positive monocytes in HbSS, which correlated with WBTF, TAT and D-dimer (P = 0·02 to P = 0·0003). While TF-positive monocytes, WBTF, TAT and D-dimer correlated with several biomarkers of haemolysis, inflammation and endothelial activation in univariate analyses, in multiple regression models the haemolytic markers (reticulocytes and lactate dehydrogenase) contributed exclusively to the association with all four coagulant markers evaluated. The demonstration that haemolysis is the predominant operative pathology in the associated perturbations of coagulation in HbSS at a young age provides additional evidence for the early use of therapeutic agents, such as hydroxycarbamide to reduce the haemolytic component of this disease.     

肝豆状核变性并发急性溶血及暴发性肝衰竭1例

患者,女性,18岁,学生,因反复肝功能异常3年于2001年8月13日入院,否认肝病家族史。体检:巩膜轻度黄染,角膜KF环( )。未见肝掌、蜘蛛痣、心肺无特殊、肝肋下0.5cm,质中,脾肋下未扪及,腹水征(-),神经系统检查无异常。实验室检查:血清丙氨酸氨基转移酶(ALT)32U/L、天门冬氨酸氨基转移酶(AST)78U/L、碱性磷酸酶(ALP)65U/L、血清胆红素(SB)26μmol/L、白蛋白(ALB)37g/L,各项嗜肝病毒标志阴性,血清铜蓝蛋白60mg/L。入院第5天,尚未开始治疗时无明显诱因下出现寒战、高热,次日出现黄疸,全身皮肤见瘀点瘀斑及中等量腹水,肝脏明显缩小,并有肝性脑病表现,血红蛋白降至56g/L,外周血网织红细胞8％,复查肝     

Substance P is increased in patients with sickle cell disease and associated with haemolysis and hydroxycarbamide use

Sickle cell disease (SCD) pain transitions from acute to chronic for unknown reasons. Chronic elevation of the pain neurotransmitter substance P (SP) sensitizes pain nociceptors. We evaluated SP levels in controls and SCD patients during baseline and acute pain and investigated associations between SP and age, gender, pain history, haemolysis and hydroxycarbamide (also termed hydroxyurea) use. Plasma SP levels were measured using enzyme‐linked immunosorbent assay. Independent samples t‐test compared SP levels between: (i) SCD baseline and controls, and (ii) SCD baseline and acute pain. Multivariate linear regression determined associations between SP and age, gender, pain history and hydroxycarbamide use. Spearman correlation determined an association between SP and haemolysis. We enrolled 35 African American controls, 25 SCD baseline and 12 SCD pain patients. SCD patients were 7‐19 years old. Mean ± standard deviation SP level (pg/ml) in SCD baseline was higher than controls (32·4 ± 11·6 vs. 22·9 ± 7·6, P = 0·0009). SP in SCD pain was higher than baseline (78·1 ± 43·4 vs. 32·4 ± 11·6, P = 0·004). Haemolysis correlated with increased SP: Hb (r = ?0·7, P = 0·0002), reticulocyte count (r = 0·61, P = 0·0016), bilirubin (r = 0·68, P = 0·0216), lactate dehydrogenase (r = 0·62, P = 0·0332), aspartate aminotransferase (r = 0·68, P = 0·003). Patients taking hydroxycarbamide had increased SP (β = 29·2, P = 0·007). SP could be a mediator of or marker for pain sensitization in SCD and a biomarker and/or target for novel pain treatment.     

Significance of intravascular coagulation and fibrinolysis in acute hepatic failure

Twenty-two patients with acute hepatic failure were studied to determine the incidence and magnitude of intravascular coagulation and fibrinolysis and their relation to the severity of bleeding and prognosis. The mean platelet count, Thrombotest, plasminogen activator, and plasminogen were reduced; the reduction in fibrinogen was not statistically significant. Fibrin/fibrinogen degradation products were only moderately increased. Hepatic fibrin deposition was not extensive, being present in 11 of 22 hepatic sections, more in areas of confluent necrosis than in the sinusoids. The combination of increased fibrin/fibrinogen degradation products with decreased plasminogen activator, plasminogen, and thrombocytopenia is consistent with a diagnosis of intravascular coagulation and secondary local fibrinolysis. However, neither of these processes was severe. Severity of bleeding was related only to plasminogen levels and prognosis only to Thrombotest levels. There was no relation between hepatic histological and haematological findings. Heparin therapy is not indicated in the routine management of acute hepatic failure, as intravascular coagulation is not severe and heparin may itself cause massive bleeding.     

Serum lactate dehydrogenase activity as a biomarker in children with sickle cell disease

Serum lactate dehydrogenase (LDH) levels were studied in children with HbSS and HbSC in a single institution, and their relationship to cerebral vasculopathy as assessed by transcranial Doppler scanning (TCD). All children with HbSS ( n  = 97) and HbSC ( n  = 18) who underwent a TCD scan in 2006 were studied. LDH levels were higher in HbSS patients than HbSC (581 IU/l vs. 305 IU/l, P  < 0·001). In children with HbSS, LDH correlated significantly with haemoglobin, reticulocytes, aspartate transaminase and creatinine. LDH also correlated positively and significantly with TCD measurements in the middle and anterior cerebral artery circulations in the children with HbSS.     

Fulminant hepatic failure during perinatal period in a pregnant woman with Wilson’s disease

Wilson’s disease associated with hepatic failure is not common and the underlying mechanism triggering the event is not known at present. We treated a 28-year-old Japanese woman with Wilson’s disease who developed hepatic failure associated with hemolytic crisis just after delivery. She was diagnosed as having Wilson’s disease at 12 years of age, at which time she started taking D-penicillamine. She had previously delivered two children without difficulty. When she found out she was pregnant this time, she stopped taking D-penicillamine in contrast to taking it faithfully during her first two pregnancies. On the day of delivery of her full-term baby, jaundice developed accompanied with severe hemolytic crisis. Plasma exchanges and blood transfusion were performed and D-penicillamine administration was started again. She gradually recovered and apparently was following a good clinical course. However, on day 30 the second hemolytic crisis occurred and subsequent liver failure led her to death on day 50. At autopsy her liver was cirrhotic and showed massive necrosis. Prophylactic oral administration of D-penicillamine and careful observation are therefore recommended to prevent hemolytic crisis during the perinatal period.     

Applications of intravascular scanning and transesophageal echocardiography in congenital heart disease: tradeoffs and the merging of technologies

This chapter will review the evolving role of intravascular ultrasound imaging and transesophageal echo in the care of children, infants and adults with congenital heart disease. The technologies relevant to congenital heart disease applications differ from those involving coronary disease since the intravascular structures imaged often involve visualization of large vessels and cardiac chambers. On the other hand, the requirements for transesophageal echo in children with congenital heart disease involve intraoperative (surgical) and imaging procedures in the catheterization laboratory which are performed for monitoring interventional catheterization therapy. As such, whereas the intravascular devices needed for pediatric cases involve lower frequency and sometimes larger catheters, the requirements for transesophageal echocardiography require higher frequency and smaller esophagoscopes. Applications of intravascular imaging including sizing of congenital stenoses, dilation of coarctation and valvular stenoses, imaging of intrapulmonary thrombi and monitoring of placement of ASD button devices in the heart will be reviewed. The intraoperative transesophageal uses for monitoring infant surgery include procedures for tetralogy repair, transposition repair and repair of AV septal defects and other complex congenital heart disorders. Both of these invasive methods of echocardiography have an important and evolving role in the management of congenital heart disease in children and infants.     

Intensive liver care and management of acute hepatic failure

In describing acute liver failure, the term fulminant hepatic failure (FHF) is used to denote patients with the most rapid progression, normally defined as the onset of encephalopathy within eight weeks of the onset of symptoms. For patients with a slower onset of encephalopathy, ranging from eight weeks to six months after the onset of symptoms, late-onset hepatic failure is the term used to reflect the overlap in clinical features with some patients with FHF. The importance of accurately determining the type of acute liver failure results from increasing evidence of an inverse relationship between the tempo of disease progression and the chances of recovery. Prognosis is also dependent on the underlying etiology. Principles of management are as follows: (1) an accurate recognition of the tempo of the hepatic failure—fulminant, late onset, acute on chronic—and the establishment of a likely etiology; (2) early detection and treatment of complications, particularly metabolic acidosis (early), renal failure, cerebral edema, and infection (late); (3) optimization of conditions for regeneration by maintenance of a near normal metabolic milieu (with removal of toxins by various methods of artificial liver support if necessary); and (4) early consideration of an orthotopic liver transplant for those patients in the poor prognosis group. Variations in the natural history and clinical features of acute liver failure (ALF) have led to a number of different classifications and subgroupings. Knowledge of these is important in relation to the assessment of prognosis and is even more important now that transplantation is a therapeutic option. Fulminant hepatic failure (FHF) is the term used to denote the subgroup where the tempo is greatest and is variously defined as the onset of encephalopathy within four weeks (1), six weeks (EASL, 1979) and eight weeks [as described by Trey and Davidson (2)] of the onset of symptoms, or within two weeks of the onset of jaundice (3). The patients with a more protracted course are designated by the terms subacute or late-onset hepatic failure (LOHF) (4) or subfulminant hepatic failure (3). The etiology of the hepatic failure also has a major influence on the likely prognosis.Presented at the Proceedings of International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Fulminant liver failure from acute autochthonous hepatitis E in France: description of seven patients with acute hepatitis E and encephalopathy

Fulminant hepatitis E has not been well characterized in industrialized countries. The aim of this study was to prospectively describe patients with acute hepatitis E presenting as fulminant hepatic failure, i.e. with encephalopathy and prothrombin index <50%. Between February 1997 and April 2005, seven patients with encephalopathy were diagnosed with acute hepatitis E using viral RNA detection. These patients were compared with 33 patients diagnosed with a mild form (absence of encephalopathy) of acute hepatitis E during the same time period. Patients were 65 +/- 11 years old. Five were active drinkers and six had chronic liver disease. All hepatitis E virus sequences evaluated (5/7) were of genotype 3. All patients but two died (71%). Four patients had no travel history. When compared with patients with a mild form of acute hepatitis E, active alcohol abuse and chronic liver disease were more frequent in patients with the severe form. Duration of hospitalization was longer. Aspartate transferase and bilirubin levels were significantly higher. Prothrombin index and accelerin levels were lower and death was more frequent. Acute nontravel-associated hepatitis E can appear as fulminant hepatitis with encephalopathy and coagulation disorders. Prognosis is severe and this may be due to the age at which it occurs and frequent underlying chronic liver disease.     

特殊人群肝豆状核变性诊治进展*

肝豆状核变性的临床表现具有异质性,早期诊断较难,容易漏诊。尽管肝豆状核变性是一种遗传代谢性疾病,但若能早期诊断,根据患者的临床特点制定治疗方案,治疗效果较佳,长期预后较好。妊娠、儿童、急性肝衰竭等特殊人群的治疗仍是临床医生关注的热点问题。     

A new variant deletion of a copper-transporting P-type ATPase gene found in patients with Wilson's disease presenting with fulminant hepatic failure

A candidate gene (ATP7B) for Wilson's disease, an autosomal recessive disorder of copper transport, has recently been identified. We examined the ATP7B gene in two Japanese sisters with Wilson's disease presenting with fulminant hepatic failure but who did not exhibit Kayser-Fleischer rings or abnormal neurological findings. Genomic DNA was isolated from the whole blood of the patients and their family. Entire exons of ATP7B, and their associated splice junctions, were amplified by polymerase chain reaction. The sequencing of all exons was performed by a non-radioactive sequencing method. The sequencing of exon 12 of ATP7B revealed a 9-bp deletion. The mutation deleted 922Gly, 923Tyr, and 924Phe, and three residues conserved in the Menkes gene, ATP7A, located in the fifth transmembrane region. Of the 14 family members tested, 7 were normal and 7 were heterozygous for the deletion. Mean serum copper and cerulopasmin levels were significantly lower in the family members who were heterozygous for the deletion than in the normal family members, and two heterozygous family members showed abnormally low ceruloplasmin levels; however, there were no differences in mean aspartate aminotransferase or alanine aminotransferase levels between the two groups. Received: February 13, 1999 / Accepted: October 22, 1999     

Association between oxidative stress and vascular reactivity in children with sickle cell anaemia and sickle haemoglobin C disease

Oxidative stress and haemolysis‐associated nitric oxide (NO) depletion plays a crucial role in the development of vasculopathy in sickle cell anaemia (SS). However it remains unknown whether oxidative stress and haemolysis levels influence vascular function in patients with sickle haemoglobin C disease (SC). Microvascular response to heat (using Laser Doppler flowmetry on finger), oxidative stress biomarkers, NO metabolites, endothelin‐1 and haematological parameters were compared between patients with SS and SC. Vascular function, oxidative and nitrosative markers were also measured in healthy (AA) children. SS and SC had increased plasma advanced oxidation protein products (AOPP), malondialdehyde, plasma antioxidant activities and NO end products, compared to AA. SC had lower catalase activity compared to AA and SS. Haemolytic rate, glutathione peroxidase and nitrotyrosine concentrations were significantly increased in children with SS compared to SC and AA. SS and SC had impaired microvascular reactivity compared to AA. In SS, the plateau phase of the response to local thermal heating was negatively associated with nitrotyrosine and AOPP. No association between vascular function parameters and oxidative stress markers was observed in SC. Mild haemolysis in SC, compared to SS, may limit oxidative and nitrosative stress and could explain the better preserved microvascular function in this group.     

肝损害为主的肝豆状核变性临床及超微结构特点

目的探讨超微结构特点用作临床肝豆状核变性早期诊断指标的可行性。方法对l5例以肝损害为主要临床表现的肝豆状核变性病例进行临床、组织学、超微结构观察与X线能谱分析。结果在同一标本中可以见肝细胞不同阶段的病变，分别为：早期的脂肪变性、线粒体病变、毛细胆管内胆汁淤积；中期的细胞核损伤、细胞内浆网损伤、溶酶体和残余小体出现；晚期的细胞完全破坏、高电子密度的残余体、胶原纤维增生；炎症细胞极少。x线能谱分析表现为铜离子沉积。结论细胞内大块高电子密度的残余体、胶原纤维增生和炎症细胞极少是该病的超微结构和组织学特征，具有诊断意义；X线能谱分析显示铜离子含量增多具有确诊意义。