Amy G. Feldman, Peter F. WhitingtonDepartment of Pediatrics, Feinberg Medical School of Northwestern University, Ann and Robert H. Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Box 57, Chicago, IL 60611-2605, United States 西北大学范伯格医学院儿科,芝加哥 Ann 和 Robert H. Lurie 儿童医院,225 East Chicago Avenue, Box 57, Chicago, IL 60611-2605, 美国
Abstract 抽象
Neonatal hemochromatosis is a clinical condition in which severe liver disease in the newborn is accompanied by extrahepatic siderosis. Gestational alloimmune liver disease (GALD) has been established as the cause of fetal liver injury resulting in nearly all cases of NH. In GALD, a women is exposed to a fetal antigen that she does not recognize as “self” and subsequently begins to produce IgG antibodies that are directed against fetal hepatocytes. These antibodies bind to fetal liver antigen and activate the terminal complement cascade resulting in hepatocyte injury and death. GALD can cause congenital cirrhosis or acute liver failure with and without iron overload and siderosis. Practitioners should consider GALD in cases of fetal demise, stillbirth, and neonatal acute liver failure. Identification of infants with GALD is important as treatment is available and effective for subsequent pregnancies. (J Cun Exp Hepatol 2013;3:313-320) 新生儿血色病是一种临床病症,其中新生儿严重的肝病伴有肝外铁质沉着症。妊娠同种免疫性肝病 (GALD) 已被确定为胎儿肝损伤的原因,导致几乎所有 NH 病例。在 GALD 中,女性暴露于她无法识别为“自身”的胎儿抗原,随后开始产生针对胎儿肝细胞的 IgG 抗体。这些抗体与胎儿肝抗原结合并激活末端补体级联反应,导致肝细胞损伤和死亡。GALD 可引起先天性肝硬化或急性肝衰竭,伴或不伴铁过载和铁质沉着。医生应考虑在胎儿死亡、死产和新生儿急性肝衰竭的情况下使用 GALD。识别患有 GALD 的婴儿很重要,因为治疗是可用的并且对以后的妊娠有效。(J Cun Exp Hepatol 2013;3:313-320)
Neonatal hemochromatosis (NH)(\mathrm{NH}) is a clinical condition in which severe liver disease in the newborn is accompanied by extrahepatic siderosis in the distribution seen with hereditary hemochromatosis. Because it was observed to occur in siblings NH was originally classified as part of the family of hereditary hemochromatosis disorders (OMIM 231100). However, clinical evidence accrued over several decades suggested that NH is not a disease per se, but is the consequence of fetal liver injury. Thus, search for an inherited cause of fetal liver disease capable of producing the NH phenotype ensued. In 2010 it was discovered that the liver in cases of NH showed evidence of complement-mediated hepatocyte injury, which under the circumstances must be initiated by IgG antibody binding to fetal hepatocytes. This finding led to the deduction that gestational alloimmune liver disease (GALD) is the cause of fetal liver injury leading to nearly all cases of NH^(1)\mathrm{NH}^{1} and to the conclusion that while NH is both congenital and familial, it is not hereditable. GALD and NH are not synonymous: GALD is a disease or disease process causing severe fetal liver injury, whereas NH is the phenotypic expression in the neonate of severe liver injury initiated in utero, most commonly by GALD. Moreover, GALD can cause liver disease that is not accompanied by 新生儿血色病 (NH)(\mathrm{NH}) 是一种临床病症,其中新生儿严重的肝病伴有遗传性血色病所见的肝外铁质沉着症分布。由于观察到它发生在兄弟姐妹中,因此 NH 最初被归类为遗传性血色素沉着症家族的一部分 (OMIM 231100)。然而,几十年来积累的临床证据表明,NH 本身不是一种疾病,而是胎儿肝损伤的结果。因此,随后寻找能够产生 NH 表型的胎儿肝病遗传原因。2010 年发现 NH 病例的肝脏显示出补体介导的肝细胞损伤的证据,在这种情况下,这必须由 IgG 抗体与胎儿肝细胞结合引发。这一发现导致推断出妊娠同种免疫性肝病 (GALD) 是胎儿肝损伤的原因,导致几乎所有病例 NH^(1)\mathrm{NH}^{1} 并得出结论,虽然 NH 既是先天性的又是家族性的,但它是不可遗传的。GALD 和 NH 不是同义词:GALD 是导致严重胎儿肝损伤的疾病或疾病过程,而 NH 是在子宫内开始的严重肝损伤在新生儿中的表型表达,最常见的是 GALD。此外,GALD 可导致不伴有
iron overload, including acute liver failure in the fetus and neonate. Therefore, GALD has emerged as a spectrum of diseases with NH as the common but not exclusive phenotype. The discovery of the alloimmune etiology of NH has impacted approaches to its diagnosis, treatment, and prevention. 铁超负荷,包括胎儿和新生儿的急性肝衰竭。因此,GALD 已成为一系列疾病,NH 是常见但并非唯一的表型。NH 同种免疫病因的发现影响了其诊断、治疗和预防方法。
ETIOLOGY OF NEONATAL HEMOCHROMATOSIS 新生儿血色病的病因
Early on, NH was described as a hereditary disorder of iron metabolism. ^(2){ }^{2} Infants with NH were found to be cirrhotic, raising the suspicion for intrauterine liver injury. However, until recently the cause of such injury remained a mystery. Because it was observed to affect siblings, a genetic defect was suspected, but intense investigation uncovered no gene locus. ^(3,4){ }^{3,4} In addition, the recurrence pattern defied genetic explanation. A woman could have multiple unaffected infants prior to having an affected infant; however, after the index case there was a 90%90 \% probability that each subsequent baby born to that mother would be affected. ^(5)NH{ }^{5} \mathrm{NH} would affect maternal half-siblings but not paternal half-siblings. ^(3,6,7){ }^{3,6,7} Female survivors of NH went on to have healthy unaffected infants. Thus, NH appeared to be congenital and familial, but not hereditary. ^(8){ }^{8} This pattern of recurrence led to the theorem that NH is caused by a maternofetal alloimmune disorder. 早期,NH 被描述为一种遗传性的铁代谢疾病。 ^(2){ }^{2} 发现患有 NH 的婴儿患有肝硬化,这增加了对宫内肝损伤的怀疑。然而,直到最近,这种伤害的原因仍然是一个谜。因为观察到它会影响兄弟姐妹,所以怀疑存在遗传缺陷,但深入调查没有发现基因位点。 ^(3,4){ }^{3,4} 此外,复发模式与遗传解释相悖。一名女性在生下受影响的婴儿之前可能会有多个未受影响的婴儿;然而,在指示病例之后,该母亲随后所生的每个婴儿 90%90 \% 都有可能受到影响。 ^(5)NH{ }^{5} \mathrm{NH} 会影响同父异母的兄弟姐妹,但不会影响同父异母的兄弟姐妹。 ^(3,6,7){ }^{3,6,7} NH 的女性幸存者继续生下健康未受影响的婴儿。因此,NH 似乎是先天性和家族性的,但不是遗传性的。 ^(8){ }^{8} 这种复发模式导致了 NH 是由母胎同种免疫疾病引起的定理。
PATHOGENESIS 发病机制
GALD, like other maternofetal alloimmune diseases, is mediated by immunoglobulin G (IgG). ^(9){ }^{9} Maternal IgG antibodies are actively transported across the placenta to the fetus starting around the 12 th week of gestation when the neonatal crystallizable fragment receptor (FcRn) is first expressed. ^(10,11){ }^{10,11} These IgG antibodies serve GALD 与其他母胎同种免疫疾病一样,是由免疫球蛋白 G (IgG) 介导的。 ^(9){ }^{9} 母体 IgG 抗体从妊娠第 12 周左右开始主动通过胎盘转运到胎儿,此时新生儿可结晶片段受体 (FcRn) 首次表达。 ^(10,11){ }^{10,11} 这些 IgG 抗体用于
to provide the fetus with humoral immunity as the fetal and newborn adaptive immune system is immature and incapable of warding off infection. Gestational alloimmunity occurs when a women is exposed to a fetal antigen that she does not recognize as “self”. This exposure results in sensitization and production of IgG antibodies against the fetal-derived antigen. Unlike most gestational alloimmune disease such as hydrops fetalis, ABO incompatibility hemolysis, and alloimmune thrombocytopenia in which IgG antibodies are directed against blood elements inherited from the father, in GALD maternal IgG antibodies are directed against fetal hepatocytes. ^(1){ }^{1} The antigen of target appears to be a hepatocyte specific protein that is either uniquely expressed by fetal hepatocytes or is highly sequestered in mature liver. If the antigen is uniquely expressed during fetal development, the mother may have lost tolerance to this self-antigen over time in the absence of central immune tolerance. Alternatively, if the antigen is sequestered in the mature liver, the same could occur in the absence of central tolerance. In either scenario, maternal exposure to this antigen induces an immune response that targets fetal hepatocytes. Non-hepatocyte liver cells and extrahepatic tissue do not appear to be attacked by this primary immune process. It remains unclear how antigen exposure to the maternal circulation occurs. We hypothesize that antigen crosses the placenta either when it becomes trapped in/on an exocytic vesicle, or when soluble protein is spilled during apoptosis during rapid liver development. 为胎儿提供体液免疫,因为胎儿和新生儿的适应性免疫系统不成熟,无法抵御感染。当女性暴露于她无法识别为“自身”的胎儿抗原时,就会发生妊娠同种异体免疫。这种暴露导致针对胎儿来源抗原的 IgG 抗体致敏和产生。与大多数妊娠期同种免疫性疾病(如胎儿水肿、ABO 血型不合溶血和同种免疫性血小板减少症)不同,在这些疾病中,IgG 抗体针对从父亲遗传的血液成分,而在 GALD 中,母体 IgG 抗体针对胎儿肝细胞。 ^(1){ }^{1} 靶标抗原似乎是一种肝细胞特异性蛋白,它要么由胎儿肝细胞独特表达,要么在成熟肝脏中高度隔离。如果抗原在胎儿发育过程中独特表达,则在没有中枢免疫耐受的情况下,母亲可能会随着时间的推移而对这种自身抗原失去耐受性。或者,如果抗原被隔离在成熟肝脏中,则在没有中枢耐受性的情况下也会发生同样的情况。在任何一种情况下,母体暴露于这种抗原都会诱导针对胎儿肝细胞的免疫反应。非肝细胞肝细胞和肝外组织似乎不会受到这种原发性免疫过程的攻击。目前尚不清楚抗原暴露于母体循环是如何发生的。我们假设抗原穿过胎盘,当它被困在胞吐囊泡中/上时,或者在肝脏快速发育期间细胞凋亡期间可溶性蛋白溢出时。
Once sensitization to the fetal antigen has occurred, specific reactive IgG is passed to the fetus where it binds to a hepatocyte antigen and initiates an innate immune response. The terminal complement cascade is activated by the classical pathway resulting in formation of the membrane attack complex. ^(1){ }^{1} Immunohistochemical staining identifies the C5b-9 complex, the neoantigen created during terminal complement cascade activation, in nearly all hepatocytes of infants with GALD. ^(1){ }^{1} Thus, complement-mediated hepatocyte injury has become a defining feature of GALD. 一旦对胎儿抗原致敏,特异性反应性 IgG 就会传递给胎儿,在那里它与肝细胞抗原结合并启动先天免疫反应。末端补体级联反应被经典途径激活,导致膜攻击复合物的形成。 ^(1){ }^{1} 免疫组织化学染色鉴定了 C5b-9 复合物,即终末补体级联激活过程中产生的新抗原,几乎存在于 GALD 婴儿的所有肝细胞中。 ^(1){ }^{1} 因此,补体介导的肝细胞损伤已成为 GALD 的一个决定性特征。
LIVER PATHOLOGY 肝脏病理学
Study of autopsy specimens has provided extensive description of the liver pathology in NH. ^(2,12-14){ }^{2,12-14} The liver pathology in NH with proven GALD etiology (GALDNH ) is identical to that described in NH prior to discovery of GALD. Liver tissue of infants with GALDNH displays severe injury with marked loss of hepatocytes (often less than 10% of normal newborn liver). ^(15,16){ }^{15,16} In some cases, no hepatocytes remain. ^(17){ }^{17} Surviving hepatocytes show siderosis, giant-cell or pseudoacinar transformation, and canalicular bile plugs. Unlike the hazy iron staining of normal newborn liver, the hepatocyte siderosis seen in NH is coarsely granular. Severe pan-lobular parenchymal 尸检标本的研究提供了对 NH 肝脏病理学的广泛描述。 ^(2,12-14){ }^{2,12-14} 经证实的 GALD 病因的 NH 肝脏病理学 (GALDNH ) 与发现 GALD 之前 NH 中描述的相同。患有 GALDNH 的婴儿的肝组织表现为严重损伤,肝细胞明显丢失(通常少于正常新生儿肝脏的 10%)。 ^(15,16){ }^{15,16} 在某些情况下,没有肝细胞残留。 ^(17){ }^{17} 存活的肝细胞显示铁质沉着、巨细胞或假腺泡转化和小管胆栓。与正常新生儿肝脏的浑浊铁染色不同,NH 中的肝细胞铁质沉着症是粗颗粒状的。重度全小叶实质
fibrosis is a dominant feature, and regenerative nodules are commonly observed. About 50%50 \% of patients can be said to have cirrhosis. Portal tracts are relatively spared from injury, and inflammation is minimal. Inflammation in the parenchyma consists of macrophages and neutrophils, innate immune cells that may be recruited by C3a and C5a during activation of the terminal complement cascade. Complement-mediated hepatocyte injury can be demonstrated using immunohistochemical staining for C5b-9 to identify accumulations of the membrane attack complex in hepatocytes and giant cells. 纤维化是一个主要特征,通常观察到再生结节。大约 50%50 \% 的患者可以说患有肝硬化。门静脉束相对不受损伤,炎症轻微。实质中的炎症由巨噬细胞和中性粒细胞组成,这些先天免疫细胞可能在末端补体级联反应激活期间被 C3a 和 C5a 募集。使用 C5b-9 免疫组织化学染色可以证明补体介导的肝细胞损伤,以识别肝细胞和巨细胞中膜攻击复合物的积累。
GALD can also cause acute liver injury to the fetal liver resulting in stillbirth or neonatal demise. ^(18){ }^{18} The livers from these infants demonstrate hepatocyte necrosis without collapse, fibrosis or inflammation indicating a hyperacute process. There may not be any siderosis in the liver or other tissues. It remains unclear why certain infants develop this hyperacute liver failure while others present with congenital cirrhosis. GALD 还可导致胎儿肝脏急性肝损伤,导致死产或新生儿死亡。 ^(18){ }^{18} 这些婴儿的肝脏表现出肝细胞坏死,没有塌陷、纤维化或炎症,表明超急性过程。肝脏或其他组织中可能没有任何铁质沉着症。目前尚不清楚为什么某些婴儿会出现这种超急性肝衰竭,而另一些婴儿会出现先天性肝硬化。
EXTRAHEPATIC MANIFESTATIONS OF GESTATIONAL ALLOIMMUNE LIVER DISEASE 妊娠期同种免疫性肝病的肝外表现
Extrahepatic siderosis in NH is most frequently seen in the acinar epithelium of the exocrine pancreas, myocardium, epithelia of thyroid follicles, and the mucosal or minor salivary glands of the oronasopharynx and respiratory tree. ^(12,15,19,20){ }^{12,15,19,20} In a recent cohort of 33 fetuses with NH, thyroid siderosis was more frequent than pancreatic. ^(14){ }^{14} Less frequently affected are the gastric glands, Brunner glands, parathyroid glands, thymus (Hassall corpuscles), renal tubules, pancreatic islets, adenohypophysis, and chondrocytes in hyaline cartilage. The reticuloendothelial system is relatively spared, so spleen, lymph nodes, and bone marrow contain trivial quantities of stainable iron. NH 患者的肝外铁质沉着症最常见于外分泌胰腺的腺泡上皮、心肌、甲状腺滤泡的上皮细胞以及口咽部和呼吸树的粘膜或小唾液腺。 ^(12,15,19,20){ }^{12,15,19,20} 在最近的 33 名患有 NH 的胎儿队列中,甲状腺铁质沉着症比胰腺更常见。 ^(14){ }^{14} 较少受累的是胃腺、Brunner 腺、甲状旁腺、胸腺(Hassall 小体)、肾小管、胰岛、腺垂体和透明软骨中的软骨细胞。网状内皮系统相对较少,因此脾脏、淋巴结和骨髓含有少量的可染色铁。
The mechanisms of iron overload and the specific distribution of siderosis in NH have been carefully examined. The fetus must closely regulate placental iron transport to ensure adequate iron for growth and oxygen carrying capacity while preventing possible toxic iron overload from the mother’s huge iron pool. The fetal liver controls placental iron flux in a manner similar to how the postnatal liver regulates intestinal iron, by sensing iron sufficiency and producing hepcidin as a regulatory feedback molecule. ^(21){ }^{21} In states of iron sufficiency, the liver produces hepcidin, which acts to suppress the cell-surface expression of ferroportin, a transmembrane iron transporter that transfers iron out of cells. Hepcidin binds ferroportin resulting in internalization and proteosomal degradation. This decrease in ferroportin results in decreased iron influx. In fetuses with GALD, liver injury results in significantly decreased production of hepcidin. ^(15){ }^{15} As a result, there is less negative feedback on ferroportin and excess iron is transported from the placenta to the fetal liver. In addition, transferrin gene expression is decreased, 铁过载的机制和 NH 中铁质沉着症的具体分布已被仔细检查。胎儿必须密切调节胎盘铁的运输,以确保足够的铁用于生长和携氧能力,同时防止母亲巨大的铁池可能产生的毒性铁过载。胎儿肝脏通过感应铁充足并产生铁调素作为调节反馈分子,以类似于产后肝脏调节肠道铁的方式控制胎盘铁通量。 ^(21){ }^{21} 在铁充足状态下,肝脏产生铁调素,铁调素的作用是抑制铁转运蛋白的细胞表面表达,铁转运蛋白是一种将铁转移出细胞的跨膜铁转运蛋白。铁调素结合铁转运蛋白,导致内化和蛋白质体降解。铁转运蛋白的减少导致铁内流减少。在患有 GALD 的胎儿中,肝损伤导致铁调素的产生显著减少。 ^(15){ }^{15} 因此,对铁转运蛋白的负反馈较少,过量的铁从胎盘转运到胎儿肝脏。此外,转铁蛋白基因表达降低,
resulting in reduced iron binding capacity. The result is fetal iron overload and an excess of circulating nontransferrin bound iron (NTBI). 导致铁结合能力降低。结果是胎儿铁过载和循环非转铁蛋白结合铁 (NTBI) 过量。
The tissue distribution of extrahepatic siderosis in the NH phenotype seems to be a function of the ability of various tissues to manage excess circulating NTBI. Tissues affected by siderosis express ZIP14, a known NTBI transporter. ^(15){ }^{15} However, several tissues that express ZIP14 do not develop siderosis in GALD. Tissues that are unaffected by siderosis express ferroportin, which permits iron export. Thus, extrahepatic tissues that are ZIP14 positive and ferroportin negative are uniquely susceptible to siderosis. Reticuloendothelial cells are spared siderosis because they express ferroportin, which in the state of hepcidin paucity is fully active. Hepatocytes express transporters for transferrin bound iron and NTBI, and ferroportin. Accrual of hemosiderin in hepatocytes is likely to be a function of injury and perhaps relatively reduced ferroportin expression or function. NH 表型中肝外铁质沉着症的组织分布似乎是各种组织管理过量循环 NTBI 能力的函数。受铁质沉着症影响的组织表达 ZIP14,一种已知的 NTBI 转运蛋白。 ^(15){ }^{15} 然而,几种表达 ZIP14 的组织在 GALD 中不会发生铁质沉着。不受铁质沉着影响的组织表达铁转运蛋白,从而允许铁输出。因此,ZIP14 阳性和铁转运蛋白阴性的肝外组织特别易患铁质沉着症。网状内皮细胞不受铁质沉着,因为它们表达铁转运蛋白,而铁转运蛋白在铁调素缺乏的状态下是完全活跃的。肝细胞表达转铁蛋白结合的铁和 NTBI 的转运蛋白,以及铁转运蛋白。肝细胞中含铁血黄素的积累可能是损伤的功能,并且可能相对降低铁转运蛋白的表达或功能。
Renal hypoplasia with dysgenesis of proximal tubules and paucity of peripheral glomeruli has been described in infants with NH^(22,23)\mathrm{NH}^{22,23} This pattern of renal abnormality is best explained as a developmental abnormality. Expansion of the proximal tubule and associated glomeruli from the 24th week of gestation onward is dependent upon angiotensinogen, which is synthesized exclusively by the liver. In a study of livers and kidneys from infants with GALD-NH, hepatocyte mass and angiotensinogen gene expression were markedly reduced relative to normal. ^(16){ }^{16} All GALD infants also had some degree of renal proximal tubule paucity, as demonstrated by quantitative immunohistochemistry staining for the proximal tubule marker fumaryl acetoacetic acid hydrolase. Liver expression of angiotensinogen inversely correlated with proximal tubule density. Therefore, it appears that alloimmune liver injury leads to reduced hepatocyte mass, which results in reduced angiotensinogen production, which in turn leads to defective renal development. This pathologic process dates the onset of liver injury in GALD-NH to before the 24th week of gestation. 肾发育不全伴近端肾小管发育不全和外周肾小球缺乏已在婴儿中被描述为这种 NH^(22,23)\mathrm{NH}^{22,23} 肾脏异常模式最好解释为发育异常。从妊娠第 24 周开始,近端肾小管和相关肾小球的扩张取决于血管紧张素原,血管紧张素原完全由肝脏合成。在一项对 GALD-NH 婴儿肝脏和肾脏的研究中,肝细胞质量和血管紧张素原基因表达相对于正常水平显着降低。 ^(16){ }^{16} 所有 GALD 婴儿也存在一定程度的肾近端肾小管缺乏,近端肾小管标志物富马酰乙酰乙酸水解酶的定量免疫组化染色证明了这一点。血管紧张素原的肝脏表达与近端肾小管密度呈负相关。因此,同种免疫性肝损伤似乎会导致肝细胞质量减少,从而导致血管紧张素原产生减少,进而导致肾脏发育缺陷。该病理过程将 GALD-NH 肝损伤的发作日期定为妊娠第 24 周之前。
CAUSES OF NEONATAL HEMOCHROMATOSIS PHENOTYPE OTHER THAN GESTATIONAL ALLOIMMUNE LIVER DISEASE 妊娠期同种免疫性肝病以外的新生儿血色病表型的原因
Occasionally, the NH phenotype can arise from non-GALD diseases including perinatal infection, ^(3,24,25){ }^{3,24,25} trisomy 21, 14,26-28 mitochondrial DNA depletion due to deoxyguanosine kinase deficiency (DGUOK gene mutations), ^(29-31){ }^{29-31} bile acid synthetic defect delta 4-3oxosteroid 5 beta-reductase deficiency (SRD5B1 mutations), ^(32-34){ }^{32-34} GRACILE syndrome (BCS1L mutation), ^(35,36){ }^{35,36} myofibromatosis, ^(14){ }^{14} tricho-hepato-enteric syndrome ^(37,38){ }^{37,38} 有时,NH 表型可由非 GALD 疾病引起,包括围产期感染、 ^(3,24,25){ }^{3,24,25} 脱氧鸟苷激酶缺乏症(DGUOK 基因突变)导致的 21 三体、14、26-28 线粒体 DNA 耗竭、 ^(29-31){ }^{29-31} 胆汁酸合成缺陷 δ 4-3 氧代类固醇 5 β 还原酶缺乏症(SRD5B1 突变)、 ^(32-34){ }^{32-34} GRACILE 综合征(BCS1L 突变)、 ^(35,36){ }^{35,36} 肌纤维瘤病、 ^(14){ }^{14} 毛滴虫肝肠综合征 ^(37,38){ }^{37,38}
and Martinez-Frias syndrome. ^(39){ }^{39} In cases of trisomy 21, transient megakaryocytic leukemia may explain the NH phenotype. For the other diseases, fetal liver injury resulting in impaired regulation of placental iron flux is hypothesized to cause NH. Together, these causes account for no more than 2%2 \% of NH cases. 和 Martinez-Frias 综合征。 ^(39){ }^{39} 在 21 三体综合征病例中,短暂性巨核细胞白血病可以解释 NH 表型。对于其他疾病,假设导致胎盘铁通量调节受损的胎儿肝损伤会导致 NH。这些原因加起来只占 NH 病例 2%2 \% 的数目。
CLINICAL FINDINGS 临床表现
GALD can present anytime from 18 weeks gestation to 3 months post-delivery. The majority of infants present with liver failure within hours of birth. NH is one of the most common causes of liver failure in the neonatal period. ^(40){ }^{40} Infants with GALD are often hypoglycemic, coagulopathic, hypoalbuminemic, jaundiced, and edematous. They may have renal involvement and be oliguric. There is frequently a history of intrauterine growth restriction, oligohydramnios, and prematurity. In rarer cases, liver disease may take days to weeks to present. There is a spectrum of disease severity, ranging from acute liver failure to “affected” babies with no clinical disease. Affected twins may have different clinical presentations; with one twin severely affected and the other minimally so. ^(41){ }^{41} Interestingly, infants with NH often have persistent patency of the ductus venosus on ultrasound. ^(2,42){ }^{2,42} This finding is of unclear clinical significance. GALD 可在妊娠 18 周至分娩后 3 个月的任何时间出现。大多数婴儿在出生后数小时内出现肝衰竭。NH 是新生儿期肝衰竭的最常见原因之一。 ^(40){ }^{40} 患有 GALD 的婴儿通常出现低血糖、凝血障碍、低白蛋白血症、黄疸和水肿。他们可能有肾脏受累和少尿。通常有宫内生长受限、羊水过少和早产的病史。在极少数情况下,肝病可能需要数天到数周才能出现。疾病的严重程度有多种范围,从急性肝衰竭到没有临床疾病的“受影响”婴儿。受影响的双胞胎可能有不同的临床表现;一个双胞胎受到严重影响,另一个受到轻微影响。 ^(41){ }^{41} 有趣的是,患有 NH 的婴儿在超声检查中通常有静脉导管持续通畅。 ^(2,42){ }^{2,42} 这一发现的临床意义尚不清楚。
Laboratory evaluation reveals marked hyperbilirubinemia (bilirubin exceeding 30mg//dL30 \mathrm{mg} / \mathrm{dL} ) with elevated conjugated and unconjugated portions. Aminotransferases rarely exceed 100IU//L100 \mathrm{IU} / \mathrm{L}, whereas alpha\alpha-fetoprotein levels are very high (100,000-600,000ng//mL)^(2,7)(100,000-600,000 \mathrm{ng} / \mathrm{mL})^{2,7} Iron studies reveal high serum ferritin levels ( > 800ng//mL>800 \mathrm{ng} / \mathrm{mL} ), low transferrin levels and high iron saturations. ^(15){ }^{15} Serum ferritin levels are a sensitive indicator for NH but are not specific as many liver diseases will show similar elevations. 实验室评估显示显著的高胆红素血症(胆红素超过 30mg//dL30 \mathrm{mg} / \mathrm{dL} ),伴有结合和非结合部分升高。转氨酶很少超过 100IU//L100 \mathrm{IU} / \mathrm{L} ,而 alpha\alpha 胎蛋白水平非常高 (100,000-600,000ng//mL)^(2,7)(100,000-600,000 \mathrm{ng} / \mathrm{mL})^{2,7} 铁研究表明血清铁蛋白水平高 ( > 800ng//mL>800 \mathrm{ng} / \mathrm{mL} ),转铁蛋白水平低,铁饱和度高。 ^(15){ }^{15} 血清铁蛋白水平是 NH 的敏感指标,但不具有特异性,因为许多肝脏疾病会出现类似的升高。
GALD (and GALD-NH) should be at the top of the differential for a neonate presenting in acute liver failure. Other processes that can cause neonatal liver failure include mitochondrial diseases, bile acid synthetic defects, tyrosinemia, hemophagocytic lymphohistiocytosis, ABCB11 gene mutations, hereditary galactosemia, hereditary fructose intolerance, and infection. Clinically, NH infants are unique in that they have evidence of fetal insult and neonatal liver failure. They are extremely coagulopathic, but have low serum aminotransferases (in contrast to infants with virally induced acute liver failure who have extremely high serum aminotransferases). Infants with GALD-NH may be misdiagnosed as having tyrosinemia due to elevated tyrosine levels, but they do not have succinylacetone in the urine. Infants with NH may also be misdiagnosed as having a bile acid defect; however, they will not have the classic pattern of bile metabolites found in serum and urine by mass spectroscopy. Finally, infants with GALD-NH should not have markedly elevated lactate levels as seen in infants with mitochondrial abnormalities. 对于表现为急性肝衰竭的新生儿,GALD(和 GALD-NH)应位于鉴别诊断的首位。其他可导致新生儿肝衰竭的过程包括线粒体疾病、胆汁酸合成缺陷、酪氨酸血症、噬血细胞性淋巴组织细胞增生症、ABCB11 基因突变、遗传性半乳糖血症、遗传性果糖不耐受和感染。在临床上,NH 婴儿的独特之处在于他们有胎儿侮辱和新生儿肝衰竭的证据。他们具有极强的凝血功能,但血清转氨酶水平较低(与病毒诱导的急性肝衰竭婴儿相反,后者的血清转氨酶水平极高)。由于酪氨酸水平升高,患有 GALD-NH 的婴儿可能被误诊为酪氨酸血症,但他们的尿液中没有琥珀酰丙酮。患有 NH 的婴儿也可能被误诊为患有胆汁酸缺陷;然而,它们不会具有质谱法在血清和尿液中发现的胆汁代谢物的典型模式。最后,患有 GALD-NH 的婴儿不应像线粒体异常婴儿那样出现乳酸水平显着升高。
DIAGNOSIS 诊断
GALD should be suspected in infants who manifest liver disease antenatally or in the immediate post birth period. It should also be considered in cases of unexplained stillbirth, neonatal demise, or early infant death. GALD is likely underdiagnosed. In cases of stillbirth or fetal loss, practitioners may not think to look for GALD before the index living case with NH occurs. Likewise, in live infants, symptoms of liver failure may be confused with those of global sepsis and practitioners may have difficulty making a diagnosis of NH with currently available tools. Global knowledge of this disorder and its wide spectrum of presentations may help to increase the number of cases that are accurately diagnosed. 在产前或出生后即刻出现肝病的婴儿应怀疑 GALD。在不明原因的死产、新生儿死亡或婴儿早期死亡的情况下也应考虑 IP。GALD 可能被低估。在死产或胎儿流产的情况下,从业者可能不会考虑在 NH 的指标活体病例发生之前寻找 GALD。同样,在活体婴儿中,肝衰竭的症状可能会与全面脓毒症的症状相混淆,并且从业者可能难以使用当前可用的工具诊断 NH。对这种疾病及其广泛表现的全面了解可能有助于增加准确诊断的病例数。
Diagnosis of NH rests upon diagnosing extrahepatic siderosis: the complex of severe liver disease and extrahepatic siderosis defines the condition. Siderosis in the liver alone is not diagnostic as the normal newborn liver can contain quantities of iron that are stainable (though quantitatively different to an experienced pathologist). In addition, pathologic hepatic siderosis can be seen in several neonatal liver diseases. There is no known value of iron content in the liver which can accurately discriminate between NH and other causes of neonatal iron overload. Likewise, absence of liver siderosis does not rule out NH, as some GALD infants may have acute injury without iron overload and other GALD cases are associated with complete hepatocyte destruction, which precludes hepatic siderosis. NH 的诊断取决于肝外铁质沉着症的诊断:严重肝病和肝外铁质沉着症的复合体定义了病情。仅肝脏中的铁质沉着症不能诊断,因为正常的新生儿肝脏可能含有大量可染色的铁(尽管数量与经验丰富的病理学家不同)。此外,病理性肝铁质沉着症可见于几种新生儿肝病。肝脏中铁含量的值尚不清楚,可以准确区分 NH 和其他导致新生儿铁过载的原因。同样,没有肝铁质沉着症并不能排除 NH,因为一些 GALD 婴儿可能有急性损伤而没有铁过载,而其他 GALD 病例与肝细胞完全破坏有关,从而排除了肝铁质沉着症。
Extrahepatic siderosis in live infants is demonstrated by iron staining (Prussian blue, Perl’s stain) of tissues affected by siderosis or by magnetic resonance imaging (MRI) (Figure 1). Glandular tissue containing iron can most easily be obtained from a biopsy of the oral mucosa. ^(43,44){ }^{43,44} The surgery is minimally invasive and when performed by a competent oral surgeon, no complications are seen. Bleeding, which may potentially be made worse by coagulopathy, is controlled by local measures and has not been a serious problem in any case. No fresh frozen plasma or recombinant factor VII is necessary beforehand. One must be sure to obtain a specimen that contains submucosal glands. T2 weighted MRI can also be used to document siderosis as iron-laden tissue has a different magnetic susceptibility than normal tissue, particularly in the liver and pancreas. Although no formal studies have been done, in our experience an adequate oral biopsy or T2 weighted MRI will each demonstrate abnormal iron in 60%60 \% of cases with autopsy proven NH. Together, they have a sensitivity that approaches 80%80 \%. On autopsy, NH can be demonstrated by staining typically affected tissues for iron. 活婴儿肝外铁质沉着症通过受铁质沉着症影响的组织铁染色(普鲁士蓝、Perl 染色)或磁共振成像 (MRI) 来证明(图 1)。含铁的腺体组织最容易从口腔黏膜活检中获得。 ^(43,44){ }^{43,44} 该手术是微创手术,当由称职的口腔外科医生进行时,不会发现并发症。出血可能会因凝血病而恶化,通过局部措施进行控制,在任何情况下都不是一个严重的问题。事先不需要新鲜的冰冻血浆或重组因子 VII。必须确保获得包含粘膜下腺体的标本。T2 加权 MRI 也可用于记录铁质沉着,因为含铁组织的磁化率与正常组织不同,尤其是在肝脏和胰腺中。虽然没有进行正式研究,但根据我们的经验,在尸检证实为 NH 的病例中 60%60 \% ,适当的口腔活检或 T2 加权 MRI 都会显示异常铁。它们共同具有接近 80%80 \% .尸检时,可以通过对通常受影响的组织进行铁染色来证明 NH。
The following diagnostic approach can be utilized to avoid missing cases of NH (Figure 2). In a newborn with liver failure or other suspicious clinical circumstance 可以使用以下诊断方法来避免漏诊 NH 病例(图 2)。在患有肝功能衰竭或其他可疑临床情况的新生儿中
such as nonimmune hydrops, an attempt should be made to identify extrahepatic siderosis by oral biopsy or MRI. It is not necessary to perform both biopsy and MRI simultaneously as either can confirm the diagnosis. One should be performed, and only if that test is negative should the other be performed. If either is positive, the diagnosis of NH is made. Testing for non-GALD causes of NH (bile acid synthesis defect and mitochondrial DNA depletion due to DGUOK mutation) can then be performed as indicated to ensure the NH is secondary to GALD. If extrahepatic siderosis cannot be demonstrated, liver biopsy for C5b-9 staining can be considered. In cases of fetal loss or stillbirth, NH should always be considered and postmortem studies should be performed to look for extrahepatic siderosis. Stillborn liver tissue is often macerated making C5b-9 testing less useful in these cases. 例如非免疫性水肿,应尝试通过口腔活检或 MRI 识别肝外铁质沉着症。没有必要同时进行活检和 MRI,因为两者都可以确认诊断。应该进行一次检查,只有当该测试为阴性时,才应该进行另一种检查。如果其中任何一个呈阳性,则诊断为 NH。然后可以按照指征进行 NH 的非 GALD 原因(胆汁酸合成缺陷和 DGUOK 突变引起的线粒体 DNA 耗竭)的检测,以确保 NH 继发于 GALD。如果不能证明肝外铁质沉着症,可以考虑进行肝活检 C5b-9 染色。在胎儿丢失或死产的情况下,应始终考虑 NH,并应进行尸检以寻找肝外铁质沉着症。死产的肝组织经常被浸渍,这使得 C5b-9 检测在这些情况下不太有用。
TREATMENT 治疗
Literature suggests that the prognosis for severe NH without intervention is very poor. In the past, a cocktail of antioxidants and an iron chelator was used based on the hypothesis that liver injury was secondary to oxidative injury caused by iron overload. Survival rates with this treatment regimen were dismal with rates as low as 10-20%.^(45-47)10-20 \% .{ }^{45-47} After the discovery that NH was caused by GALD, a new treatment regimen was initiated utilizing the combination of double-volume exchange transfusion to remove existing reactive antibody followed immediately by administration of high-dose intravenous immunoglobulin (IVIG) (1 g/kg) to block antibody induced complement activation. The published experience with this treatment regimen shows marked improvement in survival compared to historical controls. ^(48){ }^{48} Of 16 infants treated, twelve subjects ( 75%75 \% ) survived without a liver transplantation compared to 17%17 \% of historical control patients (P < 0.001)(P<0.001). The remaining four infants died, two without a liver transplant and two after liver transplantation. Unpublished experience (data collected in our center) includes over 50 infants treated with IVIG with or without exchange transfusion. Survival of these cases exceeds 80%80 \% without liver transplant. Thus, this new therapy appears to offer significant survival benefit in treating NH. It can be utilized in less than sophisticated medical environments. Sepsis and other catastrophic events that intervene are the major cause of treatment failure in 20%20 \% of patients. 文献表明,不进行干预的重度 NH 预后非常差。过去,使用抗氧化剂和铁螯合剂的混合物是基于肝损伤继发于铁过载引起的氧化损伤的假设。这种治疗方案的生存率很低,存活率低至 10-20%.^(45-47)10-20 \% .{ }^{45-47} 在发现 NH 是由 GALD 引起的后,启动了一种新的治疗方案,利用双倍体积交换输血的组合来去除现有的反应性抗体,然后立即给予大剂量静脉注射免疫球蛋白 (IVIG) (1 g/kg) 以阻断抗体诱导的补体激活。已发表的这种治疗方案的经验显示,与历史对照相比,生存率有显着改善。 ^(48){ }^{48} 在接受治疗的 16 名婴儿中,与历史对照患者 (P < 0.001)(P<0.001) 相比 17%17 \% ,12 名受试者 ( 75%75 \% ) 在没有肝移植的情况下存活下来。其余 4 名婴儿死亡,其中 2 名未接受肝移植,2 名在肝移植后死亡。未发表的经验(我们中心收集的数据)包括 50 多名接受 IVIG 治疗联合或不联合换血疗法的婴儿。这些病例的存活率超过 80%80 \% 了没有肝移植的情况下。因此,这种新疗法似乎在治疗 NH 方面提供了显着的生存益处。它可以在不太复杂的医疗环境中使用。脓毒症和其他干预的灾难性事件是患者治疗失败 20%20 \% 的主要原因。
It is our recommendation that any infant in liver failure should be given one dose of IVIG while NH is being considered. The medication is benign and a single dose poses little risk to the newborn, regardless of disease etiology. If NH is proven, and the infant has not improved, an exchange transfusion should be performed followed by administration of a second dose of IVIG. Normalization of the international normalized ratio (INR) may take 4-6 weeks as this 我们建议,在考虑 NH 期间,任何肝功能衰竭的婴儿都应给予一剂 IVIG。该药物是良性的,无论疾病病因如何,单剂量对新生儿的风险都很小。如果证实 NH 且婴儿没有改善,则应进行换血疗法,然后给予第二剂 IVIG。国际标准化比值 (INR) 的标准化可能需要 4-6 周,因为
Historically, NH is a frequent indication for liver transplantation in the first 3 months of life. ^(46){ }^{46} However, transplantation is extremely challenging in these patients given their frequent history of prematurity, small size, and multiorgan failure. ^(49){ }^{49} The overall survival of infants receiving a liver transplant for the indication of NH is approximately 35%^(48)35 \%{ }^{48} The timing of liver transplantation in these patients is difficult. Transplant is often considered 从历史上看,NH 是出生后前 3 个月肝移植的常见适应症。 ^(46){ }^{46} 然而,鉴于这些患者经常有早产、体积小和多器官衰竭的病史,移植对他们来说极具挑战性。 ^(49){ }^{49} 接受肝移植以适应 NH 的婴儿的总生存期约为 35%^(48)35 \%{ }^{48} 这些患者进行肝移植的时机很困难。通常考虑移植
when medical management appears to be failing. However, medical management most often fails during settings that would also preclude transplant (concurrent infection, intracranial hemorrhage, multiorgan failure). If liver transplant is performed, it is impossible to know whether medical treatment would truly have failed. Therefore, caution must be used when considering liver transplantation. 当医疗管理似乎失败时。然而,在也会排除移植的情况下(并发感染、颅内出血、多器官衰竭),药物治疗最常失败。如果进行肝移植,则无法知道药物治疗是否真的会失败。因此,在考虑肝移植时必须谨慎。
There are limited published studies on long-term outcome of babies who receive medical treatment for NH. In our experience, infants recover sufficiently to go 关于接受 NH 药物治疗的婴儿的长期结局的已发表研究有限。根据我们的经验,婴儿恢复得足够好,可以走
Figure 2 Diagnostic algorithm for neonatal hemochromatosis (NH). In newborns with liver failure or other clinical circumstance suspicious for NH , the infant should be given one dose of intravenous immunoglobulin (IVIG). An attempt should be made to identify extrahepatic siderosis by MRI or buccal biopsy. If either demonstrates iron overload, the diagnosis of NH is made. If both are negative, a liver biopsy for C5b-9 staining should be considered. GALD, gestational alloimmune liver disease. 图 2 新生儿血色病 (NH) 的诊断流程。对于患有肝功能衰竭或其他临床情况疑似 NH 的新生儿,应给予婴儿一剂静脉注射免疫球蛋白 (IVIG)。应尝试通过 MRI 或颊部活检识别肝外铁质沉着症。如果其中任何一方显示铁超负荷,则诊断为 NH。如果两者都是阴性的,应考虑进行 C5b-9 染色的肝活检。GALD,妊娠同种免疫性肝病。
home in 1-4 months. However, it may take 2-4 years for the liver to fully recover. In two isolated cases, liver biopsies showed reversal of cirrhosis suggesting that the neonatal liver is able to recover even from severe injury. 1-4 个月回家。但是,肝脏可能需要 2-4 年才能完全恢复。在两个孤立的病例中,肝活检显示肝硬化逆转,表明新生儿肝脏即使从严重损伤中也能恢复。
PREVENTION 预防
Once a woman has delivered an infant with NH, the probability that the next pregnancy will be lethally affected is greater than 90%^(5)90 \%{ }^{5} However, recurrence of severe NH can be prevented by treatment with IVIG during gestation. ^(5,7){ }^{5,7} Our current recommendation is that subsequent pregnancies be treated with 1g//kg1 \mathrm{~g} / \mathrm{kg} body weight (maximum 60 g ) of IVIG at 14 weeks, 16 weeks, and then weekly from the 18th week of pregnancy until the end of gestation. Records of 140 pregnancies treated under these guidelines have been collected at our center, with good outcome in 99%99 \% of cases. One pregnancy was lost at 22 weeks due to severe acute GALD (treatment for this woman was started at 18 weeks under an old protocol). Two infants were born prematurely at 26 and 32 weeks and both survived intact. All other infants were born full term with no signs of fetal distress or liver disease. Five infants experienced clinical liver disease during childhood. Four of these children had full recoveries, whereas one died at 2 months of age secondary to post viral 一旦妇女生下患有 NH 的婴儿,下一次怀孕受到致命影响的可能性大于 90%^(5)90 \%{ }^{5} 然而,在妊娠期间使用 IVIG 治疗可以防止严重 NH 的复发。 ^(5,7){ }^{5,7} 我们目前的建议是,后续妊娠应在妊娠 14 周、16 周时用 1g//kg1 \mathrm{~g} / \mathrm{kg} 体重(最大 60 克)的 IVIG 治疗,然后从妊娠第 18 周开始每周一次,直至妊娠结束。我们中心收集了 140 例根据这些指南治疗的妊娠记录, 99%99 \% 其中 1 例结果良好。由于严重的急性 GALD,1 例妊娠在 22 周时丢失(根据旧方案,该妇女的治疗在 18 周开始)。两名婴儿在 26 周和 32 周时早产,均完好无损地存活下来。所有其他婴儿都是足月出生的,没有胎儿窘迫或肝病的迹象。5 名婴儿在儿童期患有临床肝病。其中 4 名儿童完全康复,而 1 名儿童在 2 个月大时继发于病毒后感染而死亡
encephalomyelitis. Others have reported similar success with this approach. ^(50-53){ }^{50-53} The success of this preventative therapy provides the impetus to make a diagnosis in any affected infant and stillbirth, so the family can have a healthy baby in the future. 脑脊髓炎。其他人报告了这种方法取得类似的成功。 ^(50-53){ }^{50-53} 这种预防性疗法的成功为任何受影响的婴儿和死产提供了诊断的动力,因此家庭将来可以拥有一个健康的婴儿。
CONCLUSIONS AND FUTURE RESEARCH 结论和未来研究
GALD is the most common cause of neonatal acute liver and should be considered in all cases of severe fetal liver injury as well as in cases of stillbirth, fetal demise, and early postnatal death. It is likely underdiagnosed. Diagnosis rests upon demonstrating extrahepatic siderosis for identifying NH, which is almost always due to GALD. Once a mother has given birth to an NH infant, the risk for recurrence in subsequent offspring is very high, so IVIG should be used in future pregnancies. Although much has been learned about NH in the past five years, there remain many unanswered questions. How does fetal antigen gain exposure to maternal circulation? Why is there such a spectrum of disease ranging from stillbirth and gestational loss, to acute liver failure at birth, to congenital cirrhosis? Why do some affected infants experience only liver siderosis while others have extensive extrahepatic siderosis? Development of a suitable animal model is necessary to further study this disease, allowing for manipulation of genetic and environmental susceptibility factors. GALD 是新生儿急性肝病的最常见原因,所有严重胎儿肝损伤病例以及死产、胎儿死亡和产后早期死亡病例都应考虑 GALD。它可能被低估了。诊断依据肝外铁质沉着症来识别 NH,这几乎总是由 GALD 引起。一旦母亲生下 NH 婴儿,后续后代复发的风险非常高,因此应在未来的怀孕中使用 IVIG。尽管在过去五年中对 NH 了解了很多,但仍有许多未解之谜。胎儿抗原如何接触母体循环?为什么有如此一系列的疾病,从死产和妊娠丢失,到出生时的急性肝衰竭,再到先天性肝硬化?为什么一些受影响的婴儿只出现肝铁质沉着症,而另一些婴儿则患有广泛的肝外铁质沉着症?开发合适的动物模型对于进一步研究这种疾病是必要的,允许操纵遗传和环境易感因素。
JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY 临床和实验肝病学杂志
CONFLICTS OF INTEREST 利益冲突
All authors have none to declare. 所有作者都无需声明。
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Keywords: acute liver failure, complement, gestational alloimmune liver disease, immunoglobulin 关键词:急性肝衰竭, 补体, 妊娠同种免疫性肝病, 免疫球蛋白
Received: 26.9.2013; Accepted: 27.10.2013; Available online: 27.11 .2013 收稿日期: 2013 年 9 月 26 日;接受日期: 2013 年 10 月 27 日;网络出版日期: 27.11 .2013
Address for correspondence. Amy G. Feldman, MD, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 East Chicago Avenue, Box 57, Chicago, IL 60611-2605, United States. Tel.: +1 312227 7600; fax: +1 312 2279645 通信地址。Amy G. Feldman,医学博士,Ann & Robert H. Lurie芝加哥儿童医院,225 East Chicago Avenue, Box 57, Chicago, IL 60611-2605, 美国。电话:+1 312227 7600;传真:+1 312 2279645
E-mail: afeldman@luriechildrens.org 电子邮件: afeldman@luriechildrens.org
Abbreviations: GALD: gestational alloimmune liver disease; FcRn: fragment receptor; IgG: immunoglobulin G; IVIG: intravenous immunoglobulin; NH: neonatal hemochromatosis; NTBI: non-transferrin bound iron http://dx.doi.org/10.1016/j.jceh.2013.10.004