Diagnosis,Pathogenesis, Treatment,and Prognosis of Hereditary Fibrinogen Aα-Chain Amyloidosis

Mutations in the fibrinogen Aα-chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen Aα-chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0–12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.Hereditary non-neuropathic systemic amyloidosis, first described by Ostertag in 1932,¹ is a rare autosomal dominant condition in which progressive amyloid deposition in the viscera, especially the kidneys, frequently leads to organ failure. Mutations in the genes encoding apoAI,^2–12 apoAII,¹³ fibrinogen Aα-chain,^14–17 and lysozyme¹⁸ have been identified as the cause of the disease in different kindreds. The clinical amyloidosis syndromes that accompany the various mutations in these different genes are diverse with respect to age of onset, mode of presentation, pattern of organ distribution, rate of progression, and prognosis.Hereditary fibrinogen amyloidosis (AFib) was first characterized in 1993 in a Peruvian kindred.¹⁴ Patients with AFib present with renal disease and typically progress to ESRD. The natural history and clinical outcome of the disease has been little characterized, previous reports having been only of isolated kindreds, usually in the context of discovery of a novel amyloidogenic fibrinogen mutation.^15–17,19Here we report the clinical presentation, histologic features, molecular basis (including four novel causative fibrinogen Aα-chain gene mutations), and outcome among 71 patients with AFib who were diagnosed and prospectively studied at the U.K. National Amyloidosis Center (NAC) between 1992 and 2007.     

Pathogenesis and mechanisms of pain in chronic pancreatitis

虽然慢性胰腺炎的病理已经十分清楚，但其早期的致病机制尚不明确。慢性胰腺炎的一般特点为纤维化，慢性炎症和胰腺实质的消失，这些特征会随着疾病的发展而逐渐出现，同时还伴有急性胰腺炎的症状。一些专家认为慢性胰腺炎继发于急性胰腺炎。另一些则认为慢性胰腺炎首先发生，急性胰腺炎则在此基础上发生。慢性胰腺炎所引起的疼痛可通过许多机制发生。增高的胰腺压力可干扰神经，影响血流，改变pH值，并引起有毒物质的潴留，激活动作电位。组织的破坏和炎症介质的释放可刺激传入神经。甚至，炎症可直接破坏神经，引起神经性疼痛。掌握疼痛在外周和中枢神经系统中的神经冲动传递路径才能找出减轻胰性疼痛的有效方法。疼痛可以通过内脏、迷走、脊神经和膈神经等外周神经传递。它也可通过脊髓的背侧神经束和脊髓丘脑束中继传递。因此寻找到新的治疗胰性疼痛的方法是可能的。     

Thrombotic Obstruction of the Björk-Shiley Aortic Valve Prosthesis. Report of Four Cases

We present four cases of late thrombotic obstruction of the Björk-Shiley aortic valve prosthesis. The incidence of this complication reported in the literature to vary from 0.7% to 5%. In our experience of a total of 623 Björk-Shiley aortic valve replacements, we observed this complication in only 4 patients (0.6%). Two of them had poorly controlled anticoagulation therapy. The clinical presentation was subacute in all four patients. Surgical treatment, thrombectomy and debridement, was performed in all of them. The diagnosis was made upon abrupt and progressive onset of dyspnoea, physical examination data and echocardiographic and radioscopic findings. Angiocardiographic studies were needed in two patients.     

Pathogenesis of Henoch-Schönlein purpura nephritis

The severity of renal involvement is the major factor determining the long-term outcome of children with Henoch-Schönlein purpura (HSP) nephritis (HSPN). Approximately 40% children with HSP develop nephritis, usually within 4 to 6 weeks after the initial onset of the typical purpuric rashes. Although the pathogenetic mechanisms are still not fully delineated, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of the circulating immune complexes and their mesangial deposition that induce renal injury in HSPN.