Renal transplantation in systemic amyloidosis-importance of amyloid fibril type and precursor protein abundance.

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty-nine percent of patients with end-stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A-I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post-RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.

Hereditary lysozyme amyloidosis -- phenotypic heterogeneity and the role of solid organ transplantation.

OBJECTIVES: Lysozyme amyloidosis (ALys) is a form of hereditary systemic non-neuropathic amyloidosis, which is inherited in an autosomal dominant fashion. Lysozyme, which is the amyloidogenic precursor protein in ALys, is a ubiquitous bacteriolytic enzyme synthesized by hepatocytes, polymorphs and macrophages. The aim of this study is to describe the phenotype and outcome of patients with ALys including the role of solid organ transplantation. DESIGN: Retrospective evaluation of patients with ALys. SETTING: UK National Amyloidosis Centre. PATIENTS: All 16 patients with ALys followed at the centre. RESULTS: A family history of amyloidosis was present in every affected individual. Although the phenotype was broadly similar amongst those from the same kindred, there were marked phenotypic differences between kindreds who possessed the same amyloidogenic mutation. Symptomatic gastrointestinal (GI) amyloid was prevalent, and macroscopically visible amyloidotic lesions were present in nine of 10 patients who underwent GI endoscopy. All symptomatic ALys individuals had hepatic amyloid. Four patients received orthotopic liver transplants (OLT), three for spontaneous hepatic rupture and one case, who had extensive hepatic amyloid and a strong family history of hepatic rupture, pre-emptively. All of the liver grafts were functioning at censor 1.7, 5.8, 9.0 and 11.0 years after OLT. Five patients had progressive amyloidotic renal dysfunction culminating in end-stage renal failure, three of whom underwent renal transplantation (RTx). There was no evidence of renal allograft dysfunction at censor 6.6, 1.8 and 0.8 years after RTx. CONCLUSIONS: Lysozyme amyloidosis is a disease of the GI tract, liver and kidneys, which has a slow natural history. There was a clear family history in all cases within this cohort, demonstrating a high clinical penetrance in the presence of an amyloidogenic lysozyme mutation. There is currently no amyloid-specific therapy for the condition which is managed symptomatically. OLT and RTx appear to be successful treatments for patients with liver rupture or end-stage renal disease, respectively, with excellent outcomes in terms of medium-term graft function and patient survival.

Solid organ transplantation in AL amyloidosis.

Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5-year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2-13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients.

Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient.

Oculoleptomeningeal amyloidosis is a rare manifestation of hereditary transthyretin (TTR) amyloidosis. Here, we present the first case of leptomeningeal amyloidosis associated with the TTR variant Leu12Pro mutation in an African patient. A 43-year-old right-handed Nigerian man was referred to our centre with rapidly progressive neurological decline. He presented initially with weight loss, confusion, fatigue, and urinary and erectile dysfunction. He then suffered recurrent episodes of slurred speech with right-sided weakness. He went on to develop hearing difficulties and painless paraesthesia. Neurological examination revealed horizontal gaze-evoked nystagmus, brisk jaw jerk, increased tone, brisk reflexes throughout and bilateral heel-shin ataxia. Magnetic resonance imaging showed extensive leptomeningeal enhancement. Cerebrospinal fluid analysis showed a raised protein of 6.4 g/dl. Nerve conduction studies showed an axonal neuropathy. Echocardiography was characteristic of cardiac amyloid. TTR gene sequencing showed that he was heterozygous for the leucine 12 proline mutation. Meningeal and brain biopsy confirmed widespread amyloid angiopathy. TTR amyloidosis is a rare cause of leptomeningeal enhancement, but should be considered if there is evidence of peripheral or autonomic neuropathy with cardiac or ocular involvement. The relationship between different TTR mutations and clinical phenotype, disease course, and response to treatment remains unclear.

Oncogene expression in cholangiocarcinoma and in normal hepatic development.

The expression of the proteins encoded by the ras, myc, and erb B-2 oncogenes was examined in 63 paraffin-embedded human cholangiocarcinomas of Thai and English origin using immunohistochemistry. The observed distributions were compared with oncogene expression in a series of human hepatocellular carcinomas. In an attempt to relate expression of these three oncogenes to specific stages of normal tissue differentiation, tissue sections of normal fetal, infant, and adult human livers were also examined. Of 63 cholangiocarcinomas, 59 (95%) expressed p62 c-myc, 47 (75%) expressed p21 c-ras, and 46 (73%) expressed p190 c-erbB-2. The expression of c-myc and c-ras but not of c-erb B-2 correlated directly with tumor differentiation as judged by morphologic criteria. No difference was observed in oncogene expression between intrahepatic and extrahepatic cholangiocarcinomas. Twelve of 14 hepatocellular carcinomas (86%) stained positively for all three oncoproteins. During normal liver development, expression of c-myc and c-ras was shown to occur from 18 weeks' gestation until 5 years of age, but not thereafter. Expression of c-myc, c-ras, and c-erbB-2 oncogenes may be used as immunohistochemical markers to distinguish cholangiocarcinoma from nonneoplastic biliary tissues, and may provide useful information concerning the cell biology of tumor differentiation.

Unicentric Castleman's disease complicated by systemic AA amyloidosis: a curable disease.

BACKGROUND: Castleman's disease (angiofollicular lymph node hyperplasia) is a group of rare lymphoproliferative disorders sharing characteristic clinical and histological features, and usually accompanied by a marked systemic inflammatory response. All types may be complicated by acquired systemic amyloidosis, usually of AA type, but occasionally of AL type associated with monoclonal gammopathy. DESIGN: Descriptive study of five patients with unicentric Castleman's disease complicated by systemic AA amyloidosis. METHODS: A diagnosis of amyloidosis was confirmed by microscopy and immunohistochemical staining. Serum concentrations of C-reactive protein (CRP) and serum amyloid A protein (SAA) were measured by immunoassays. Radiolabelled serum amyloid P component scintigraphy was used to monitor the progress of amyloid deposition. RESULTS: In four patients the primary diagnosis was made only after years of investigation of systemic symptoms. The tumours were resected in all cases, leading to remission of the systemic inflammatory state. Long-term follow-up in four patients, including scintigraphy, showed regression of amyloid deposits. DISCUSSION: This rare but usually fatal condition can be cured surgically even in advanced cases. Awareness of the diagnosis and its correct management are important in investigation of patients with unexplained systemic symptoms, especially associated with systemic amyloidosis.

Diagnosis of amyloidosis by histological examination of subcutaneous fat sampled at the time of pacemaker implantation.

Atrioventricular conduction disease may occur in a range of conditions. If echocardiography suggests the presence of an infiltrative cardiomyopathy the diagnosis of amyloidosis may be confirmed by subcutaneous fat sampling from the site of pacemaker implantation. This technique requires no additional invasive procedure and confers no extra risk for the patient. Confirmation of amyloidosis provides important prognostic information and may allow specific treatment.

Morphological and immunohistochemical analysis of the human liver in chronic pancreatitis.

Morphological and immunohistological appearances of liver biopsy specimens are described in a personal series of 52 patients undergoing operation for chronic pancreatitis. The findings are compared with those in a series of 10 histologically normal liver biopsy specimens from patients without pancreatitis. Alcohol was the prime aetiological agent in 40 of the 52 patients (77%). No obvious damage to hepatic parenchymal cells or biliary structures was observed but minor morphological changes of alcohol associated liver disease were seen in 42% of specimens. The most consistent finding, present in 48 specimens (92%), was a chronic inflammatory cell infiltration of portal tracts. In all but one case, T lymphocytes predominated, but a few B cells were present. In four biopsy specimens, T cells spilled over into adjacent hepatic parenchyma, but there was no evidence of T cell mediated cytotoxic damage to the parenchymal cells or biliary epithelium. It is suggested that these inflammatory cells are in transit from the pancreas through the liver via the portal circulation and may reflect the underlying pathogenesis of chronic pancreatitis rather than alcoholic liver disease.

Modulated expression of human leucocyte antigen class I and class II determinants in hyperplastic and malignant human prostatic epithelium.

OBJECTIVES: To determine whether human prostatic carcinoma cells express Class I and/or Class II major histocompatibility complex (MHC) determinants and whether they might thus be immune-competent targets for cell-mediated cytotoxicity. MATERIALS AND METHODS: Immunohistochemistry, performed both before and after neuraminidase digestion, was employed to compare 13 benign prostatic hyperplasias with 42 primary and 44 metastatic prostatic carcinomas obtained from the United Kingdom and from the United States of America. Expression of beta 2-microglobulin was used as the marker of Class I and HLA-DR as the marker of Class II expression. RESULTS: Before desialylation, Class I MHC determinants were expressed in all of the benign hyperplasias, in 26% of primary carcinomas and in 14% of lymph node metastases. Cells expressing Class II determinants were identified in 69% of benign hyperplasias and in 2% of primary carcinomas, but in none of the lymph node metastases. After desialylation. Class I determinants were expressed in 100% of benign hyperplasias. 59% of primary carcinomas and 34% of the lymph node metastases. Class II determinants were expressed in 100% of benign hyperplasias, but only 19% of primary carcinomas and 5% of the lymph node metastases. While more than 50% of epithelial cells in each of the benign hyperplasias expressed MHCs, < 5% of the tumour cell populations in the positive malignant tissues (primary and metastatic) expressed MHCs, even after neuraminidase digestion. No correlation was found between expression of Class I or Class II MHC and Gleason morphological grade. CONCLUSIONS: Failure to express Class I and/or Class II MHC determinants is a common feature of the majority of human prostatic carcinoma cells. Absence of these recognition molecules may be associated with avoidance of immune-surveillance and contribute to the metastatic dissemination of this malignancy.

Expression of major histocompatibility antigens in human chronic pancreatitis.

T-lymphocytic infiltration of the exocrine pancreas and liver in patients with chronic pancreatitis has suggested that cell mediated immune mechanisms may play a part in the pathogenesis of this disease. As expression of major histocompatibility (MHC) antigens is a prerequisite for organ specific autoimmunity, the expression of HLA class I (beta 2-microglobulin) and class II (HLA-DR) determinants have been analysed, together with the presence of T-lymphocytes, in 93 patients (64 men and 29 women, mean age 40.6 years) having an operation for chronic pancreatitis. Ethanol (63 patients), recurrent acute pancreatitis (12), congenital lesions (2), and unknown (16) were suggested to be the causes of the disease. Immunohistochemical staining of formalin fixed and paraffin wax embedded tissue sections used conventional immunohistochemical techniques with specific anti-serum samples. No MHC expression was identified in 10 histologically normal pancreatic control specimens or in four cases of chronic pancreatitis secondary to obstruction by neuroendocrine tumours within the head of the pancreas. beta 2-microglobulin expression by pancreatic exocrine epithelial cells was seen in 76 chronic pancreatitis specimens (82%) while HLA-DR was present in 61 (66%). Simultaneous expression of both class I and II determinants was seen in 53 (57%) of cases. MHC determinant expression was not found in 10 cases (11%) of chronic pancreatitis. In the positive specimens, expression was confined to ductal and ductular (interlobular and intralobular) epithelium with no staining of acinar cells. Staining was not related to the suspected cause of the disease or age. T-lymphocytes were more prominent in chronic pancreatitis mean (SEM) (131 (15) cells per high powered field) than controls (5 (1), p < 0.01). Aberrant MHC expression by exocrine pancreatic epithelial cells occurring in the presence of an appreciable T-cell infiltration confirmed that the appropriate cellular conditions were present for cell mediated cytotoxicity to contribute to the pathogenesis of chronic pancreatitis.