Modified body mass index and time interval between diagnosis and operation affect survival after liver transplantation for hereditary amyloidosis: a single-center analysis.

INTRODUCTION: Familial amyloid polyneuropathy (FAP) is the most common subtype of hereditary amyloidosis. The amyloid protein transthyretin deposits as rigid amyloid fibers in the extracellular matrix of various tissues including peripheral nerves, heart, and gastrointestinal tract. As the mutated amyloid protein is mainly produced in the liver, one form of treatment to halt the progression of disease is liver transplantation (LT). This study was performed to identify risk factors for decreased overall survival. METHODS: Clinical data of 21 transplant patients who underwent LT for FAP between 1996 and 2011 were analyzed retrospectively. RESULTS: The majority of patients had cardiac symptoms (76%), gastrointestinal symptoms (71%), or peripheral polyneuropathy (71%). A conventional operating technique was performed on 11 patients using end-to-end caval anastomoses, while the modified piggyback technique by Belghiti was performed on 10 patients. Overall survival analysis revealed a one-yr survival rate of 74.3% and three- and five-yr survival rates of 60.0% and 52.5%, respectively. Pre-operative modified body mass index (mBMI) <700 kg g/L m² and time interval between diagnosis and operation before LT resulted in significantly lower overall survival (p = 0.0137; p = 0.033). CONCLUSION: The pre-operative nutritional status and time interval between diagnosis and operation before LT influence overall survival after LT for hereditary amyloidosis.

Morphologic patterns of autoimmune pancreatitis in CT and MRI.

BACKGROUND/AIMS: To retrospectively evaluate the morphologic characteristics of autoimmune pancreatitis (AIP) using MRI and CT. METHODS: 86 dynamic contrast-enhanced CT and MRI scans in 36 AIP patients were evaluated regarding: different enlargement types, abnormalities of the main pancreatic duct (MPD), morphology of the parenchyma and other associated findings. RESULTS: 3 types of enlargement were found: (1) a focal type (28%), (2) a diffuse type (involving the entire pancreas, 11%) and (3) a combined type (56%). The MPD was usually dilated together with focal or diffuse narrowing in 67% (24/36). Unenhanced MRI showed AIP area in 56% (mostly T(1) hypo- and T(2) hyperattenuating), and CT in 10% (hypoattenuating). The arterial phase depicted similar patterns for CT and MRI (hypoattenuating in 58 and 52%, respectively). Venous and late venous phase patterns were usually hyperattenuating in MRI (65 and 74%, late enhancement), while CT mostly showed no signal differences (isoattenuating in 57 and 75%), yielding significant differences between CT and MRI for the venous (p < 0.0001) and the late phase (p = 0.025). Miscellaneous findings were: rim sign (25%), pseudocysts (8%) and infiltration of large vessels (11%). CONCLUSIONS: The 'late-enhancement' sign seems to be a key feature and is best detectable with MRI. MRI may be recommended in the diagnostic workup of AIP patients. and IAP.

CT diagnosis of recurrence after pancreatic cancer: is there a pattern?

AIM: To investigate predilection sites of recurrence of pancreatic cancer by computed tomography (CT) in follow-up after surgery. METHODS: Seventy seven patients with recurrence after pancreatic cancer surgery were retrospectively identified. The operative technique, R-status, T-stage and development of tumor markers were evaluated. Two radiologists analyzed CT scans with consensus readings. Location of local recurrence, lymph node recurrence and organ metastases were noted. Surgery and progression of findings on follow-up CT were considered as reference standard. RESULTS: The mean follow-up interval was 3.9 ± 1.8 mo, with a mean relapse-free interval of 12.9 ± 10.4 mo. The predominant site of recurrence was local (65%), followed by lymph node (17%), liver metastasis (11%) and peritoneal carcinosis (7%). Local recurrence emerged at the superior mesenteric artery (n = 28), the hepatic artery (n = 8), in an area defined by the surrounding vessels: celiac trunk, portal vein, inferior vena cava (n = 22), and in a space limited by the mesenteric artery, portal vein and inferior vena cava (n = 17). Lymph node recurrence occurred in the mesenteric root and left lateral to the aorta. Recurrence was confirmed by surgery (n = 22) and follow-up CT (n = 55). Tumor markers [carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA)] increased in accordance with signs of recurrence in most cases (86% CA19-9; 79.2% CEA). CONCLUSION: Specific changes of local and lymph node recurrence can be found in the course of the cardinal peripancreatic vessels. The superior mesenteric artery is the leading structure for recurrence.

Genetic microheterogeneity of human transthyretin detected by IEF.

Mutations of the human transthyretin (TTR) gene have attracted medical interest as a cause of amyloidosis. Recently, we have described in detail an electrophoretic procedure with PAGE followed by IEF in urea gradients for the study of the microheterogeneity of TTR monomers (Altland, K., Winter, P., Sauerborn, M. K., Electrophoresis 1999, 20, 1349-1364). In this paper, we present a study on 49 different mutations of TTR including 33 that result in electrically neutral amino acid substitutions. The aims of the investigation were to test the sensitivity of the procedure to detect TTR variants in patients with TTR amyloidosis and their relatives and to identify some common characteristics that could explain the amyloidogenicity of these variants. We found that all tested amyloidogenic mutations could be detected by our method with the exception of those for which the corresponding variant was absent in plasma samples. Most of the electrically neutral amyloidogenic TTR variants had in common a reduced conformational stability of monomers by the activity of protons and urea. For three variants, e.g. TTR-F64L, TTR-I107V and TTR-V122I, the monomers had a conformational stability close to that of normal monomers but we found experimental and structural arguments for a weakening of the monomer-monomer contact. All types of amyloidogenic mutations affected the stability of TTR tetramers.

Risk stratification in cardiac amyloidosis: novel approaches.

Amyloidosis is a term for diseases with extracellular deposition of insoluble beta-fibrillar proteins in different organs. The heart is primarily involved in more than half of patients with immunoglobulin light-chain amyloidosis or hereditary amyloidosis and associated with poor prognosis. Different traditional diagnostic tools that have been described for risk stratification lack of sufficient sensitivity and specificity for patient survival. Until November 2004 in 50 consecutive patients with light chain amyloidosis and 15 patients with hereditary amyloidosis electrocardiography, echocardiography, Holter monitoring, cardiopulmonary exercise test, lung function testing, tilt-test, and laboratory investigations have been performed at our department. Cardiac amyloidosis was found in 32 patients. Interventricular septum (14.3+/-0.5 mm vs. 12.3+/-0.7 mm, P<0.05), plasma NT-proBNP (7154+/-2122 ng/l vs. 380+/-113 ng/l; P<0.01), cardiac Troponin T (0.105+/-0.030 vs. 0.019+/-0.010 microg/l; P<0.05) were increased in patients with cardiac amyloidosis as compared to patients light chain amyloidosis but no cardiac involvement. Maximal inspiratory (Pimax) and expiratory (Pemax) mouth pressure were decreased with CA compared to controls. Correlation of NT-proBNP and interventricular septum thickness (r=0.53, P=0.029) as well as and Pimax (r=0.72, P<0.01) or Pemax (r=0.69; P<0.01) was noticed. A correlation of grade of arrhythmias in Holter monitoring and syncopes was not observed. Cardiac involvement of amyloid disease carries a poor prognosis and is not well characterized by classic heart failure determinants. Heart transplantation based on novel risk markers including NT-proBNP might be a suitable therapeutic approach for patients with manifest cardiac amyloidosis, but will require alternative patient selection and listing criteria.

Indications for liver transplantation in patients with amyloidosis: a single-center experience with 11 cases.

Familial amyloidotic polyneuropathy (FAP) is an inherited disorder with the systemic deposition of amyloid fibrils containing mutant transthyretin variants. The mutant form of transthyretin amyloidosis is produced mainly in the liver. Successful liver transplantation (LTx) could eliminate the source of the variant transthyretin molecule, and is now the only known curative treatment. The aim of this study is to evaluate the results of LTx for FAP at the University of Heidelberg. Eleven patients who underwent LTx between 1985 and 2004 with the diagnosis of FAP were evaluated. Of 11 patients, seven (64%) were male and four (36%) were female. The mean age was 49.5 years (range 27-70). Met 30 (n=5) was the most common type of amyloidosis followed by Arg 50 (n=3), Val 107 (n=2), and Phe 33 (n=1). All of the patients were selected for LTx and Domino LTx was performed in six patients. The majority (80%) of the patients with type Met 30 amyloidosis are alive, whereas in other types of amyloidosis only 33% are living. This finding emphasizes better prognosis of Met 30 variant of FAP in comparison to other variants such as Arg 50, Val 107, and Phe 33. After LTx, improvement of clinical symptoms (completely or partially) was observed in six patients (55%). In conclusion, LTx is considered as the only therapeutic alternative in patients with amyloidosis accompanied by hepatic synthesis of the amyloid protein. The most important risk factors for LTx can be predicted by assessing the nutritional condition of the patient, the duration of the disease, and the amyloid variant. Therefore, precise diagnostic measures are required before listing a patient for LTx. Domino LTx is an acceptable form of LTx that can preserve the pool of organ donors. In order to stop the progression of FAP, LTx would be justified in a subgroup of patients with amyloidosis. Based on our results, we support the idea that the effectiveness of extended preoperative period before LTx or the transplantation of other transthyretin variants other than Met 30 is questionable.

Indications for high-dose chemotherapy with autologous stem cell support in patients with systemic amyloid light chain amyloidosis.

Systemic amyloid light chain amyloidosis is a protein conformation disorder caused by a clonal plasma cell dyscrasia. Symptoms result from fibrillar extracellular deposits in kidney, heart, liver, gut, peripheral nervous system and other tissues. The deposits disrupt organ function and ultimately lead to death. The prognosis of systemic amyloid light chain (AL) amyloidosis is poor; less than 5% of all patients survive 10 years or longer. Using conventional chemotherapy, the median survival could be prolonged by 4 months. Treatment with high-dose melphalm (HDM) and autologous stem cell transplantation (ASCT) of selected patients has been shown to arrest and even to reverse the disease course. This procedure however remains controversial because treatment related mortality (TRM) in AL amyloidosis is substantially higher (15-40%) than in multiple myeloma (<5%). Here we review recent results of ASCT, eligibility criteria for HDM and report our own treatment results in 41 patients.