新生儿血色病-妊娠同族免疫性肝病临床病理分析并文献回顾

Clinopathological analysis of neonatal hemochromatosis-gestational alloimmune liver disease with literature review

目的探讨新生儿血色病-妊娠同族免疫性肝病(NH-GALD)的临床病理特征。方法收集广州市妇女儿童医疗中心2018年9月至2021年3月3例NH-GALD的临床资料,尸体解剖检查内脏及脑组织,各脏器常规取材并行HE染色观察各脏器形态学改变,行普鲁士蓝染色观察铁沉积情况,应用免疫组化染色检测肝脏组织肝细胞膜复合攻击物C5b-9的表达。病例1由于病情危重死亡未做基因检测,病例2及病例3两例均行全外显子高通量测序。同时进行相关文献回顾。结果 3例NH-GALD均为男性,死亡年龄分别为9、58、50 d。病例1及病例2母孕期无异常,均为G1P1,胎龄分别为36+4 W、33+6 W。病例1出生时羊水少,出生体质量2300 g。病例2为胎龄双胎之大,出生体质量1450 g。病例3母妊娠期糖尿病,G2P2,胎龄37+3 W,出生体质量2900 g。3例均无窒息抢救病史。3例临床均表现为急性肝衰竭及多脏器损害,包括凝血功能障碍、黄疸、水肿、新生儿肺炎等。实验室检查3例均提示贫血、血糖降低、严重的凝血障碍、直接及间接胆红素均增高、转氨酶正常或增高后降至正常、铁蛋白增高;2例AFP增高。3例尸体解剖主要病症均为NH-GALD,急性重型肝坏死并肝纤维化(或肝硬化),其他诊断包括肺出血、肺水肿、间质性肺炎、淤血性脾肿大、脑水肿及急性胸腺退化等。尸体解剖时大体观察3例肝脏重41.1~73.1 g(均低于同龄儿平均值),病例1及2肝脏表面细颗粒状,切面灰黄或暗红,病例3表面及切面可见大小不等暗红或墨绿色结节。镜下,3例肝脏均可见肝小叶结构破坏,肝细胞大片坏死,病例1及2见残留肝细胞呈梁索状或假腺样散在分布于疏松纤维间质中,胞质内含色素颗粒,可见少量多核肝巨细胞,微胆栓形成,小胆管相对增生。病例3肝组织见大小不等呈结节状分布的假小叶,结节内肝细胞大片坏死,周边残留多少不等的肝细胞。普鲁士蓝染色3例肝脏、胰腺及甲状腺均可见弥漫铁沉积;其他铁沉积组织包括肾上腺皮质(病例1和2),心肌和颌下腺(病例2和3),口腔黏膜涎腺、喉和支气管黏膜涎腺和小肠黏膜上皮(病例3)。免疫组化染色3例肝细胞膜复合攻击物C5b-9均弥漫阳性。2例全外显子高通量测序,均未检测到与肝脏遗传代谢性及胆汁淤积性疾病相关基因改变。结论新生儿急性肝衰竭时需要考虑到罕见的NH-GALD的可能,肝外器官铁沉积是其特征性改变,明确病理诊断对于患儿治疗及孕母再次妊娠预防性干预的意义重大。

Objective To explore clinical and pathological features of neonatal hemochromatosis-gestational alloimmune liver disease(NH-GALD).Methods The clinical data of 3 autopsy cases of NH-GALD were collected from September 2018 to March 2021 in Guangzhou Women and Children’s Medical Center.The tissues of visceral organs and brain were examined by autopsy,and routine sampling and HE staining were performed to observe morphological changes.The siderosis were observed in internal organs using prussian blue staining.Immunohistochemical staining were performed in liver to detect the expression of membrane attack complex C5b-9.Case 1 died due to critical illness and did not undergo genetic testing.Both Case 2 and Case 3 underwent full exon high-throughput whole exon sequencing.Meanwhile the related literatures were reviewed.Results 3 cases of NH-GALD were all male,and the death age was 9 days,58 days and 50 days respectively.The maternal gestation history of case 1 and case 2 was unremarkable,both G1P1,and the gestational age was 36+4Wand 33+6W respectively.Case 1 with oligohydramnios at birth,and birth weight was 2300 g.Case 2 was the older baby of the twin,and birth weight was 1450 g.The mother of case 3 had gestational diabetes,G2P2,and the gestational age was 37+3W,and birth weight was 2900 g.3 cases all had no history of suffocation rescue.The clinical presentation of 3 cases was acute liver failure and multi-organ damage,including coagulation dysfunction,jaundice,edema,neonatal pneumonia,etc.Laboratory tests showed anemia,hypoglycemia,severe coagulation disorder,increased direct and indirect bilirubin,normal serum transaminases or increased firstly then decreased to normal level,and increased ferritin in 3 cases,and increased AFP in 2 cases.The main diseases of 3 autopsy cases were NH-GALD with acute severe liver necrosis and liver fibrosis(or cirrhosis),other diagnosis including pulmonary hemorrhage,pulmonary edema,interstitial pneumonia,congestive splenomegaly,cerebral edema and acute thymic degeneration.Postmortem examinations showed the liver weight was 41.1-73.1 g(lower than the average weight of the same age),and the liver surface is finely granular with the cut surface is grayish yellow or dark red in case1 and case 2.Dark red or dark green nodules of varying sizes can be seen on the surface and section in case 3.Microscopically,liver architecture was severely disturbed and sheets of necrosis of liver cells were seen in 3 cases.Case 1 and 2 showed residual hepatocytes are scattered in the loose fibrous stroma arranging tribacular or pseudoglandular pattern,with pigment granules in the cytoplasm,multinucleated liver giant cells,the formation of microbiliary plugs,and the relative proliferation of small bile ducts.Case 3 displayed nodular pseudolobules of different sizes,with central sheets of hepatic necrosis,and peripheral residual hepatocytes.Prussian blue staining highlighted diffuse siderosis in liver,pancreas and thyroid tissues.Other tissues with siderosis including adrenal cortex(case 1 and 2),myocardium and submandibular glands(cases 2 and 3),salivary glands of oral mucosa,salivary glands of laryngeal and bronchial mucosa,and epithelium of small intestinal mucosa(case 3).Immunoreactivity of membrane attack complex C5b-9 was detected in hepatocytes of 3 cases.The gene changes related to liver genetic metabolic and cholestasis diseases were not detected by whole exon high-throughput sequencing in two cases.Conclusions The possibility of rare NH-GALD needs to be considered for neonatal acute liver failure.The histopathological feature is hepatic and extrahepatic siderosis.It is of great significance to make a clear pathological diagnosis for the treatment and preventive intervention for re-pregnancy.