Endoscopic submucosal dissection: experience in an Australian tertiary center.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a technique for en bloc resection of superficial tumors of the gastrointestinal tract. In contrast to Japan and other Asian countries, few data are available in Western countries. The objective of the current study was to evaluate the experience of ESD in a single Australian tertiary center. METHODS: The patient features, outcomes and complications of ESD of 20 lesions in 18 patients at a single center between 2008 and 2012, were evaluated retrospectively. RESULTS: Twenty lesions, in 18 patients of median age 69.5 years, were resected with ESD. Ten patients had gastric lesions (of whom two had two synchronous lesions), four patients had rectal lesions, one had a colonic lesion, one had a duodenal lesion and two had esophageal lesions. The median (range) lesion size was 2.5 (0.5-6.5) cm. In the entire cohort, en bloc resection occurred in 80% cases and complete histological resection was achieved in 60% cases. Significant bleeding requiring repeat endoscopy and transfusion occurred in two cases and microscopic perforation occurred in 1 case. Surgery for unsuccessful ESD was pursued without complication in 6 cases. There were two recurrences during follow up of median 36 months, both of which occurred in cases of gastric ESD and one of which (carcinoid) occurred after surgery. CONCLUSIONS: ESD appears feasible in an Australian population. It should however be contemplated in carefully selected patients whilst there is refinement of pre-treatment diagnosis, the ESD technique and the management of its complications.

Senile systemic amyloidosis: clinical features at presentation and outcome.

BACKGROUND: Cardiac amyloidosis is a fatal disease whose prognosis and treatment rely on identification of the amyloid type. In our aging population transthyretin amyloidosis (ATTRwt) is common and must be differentiated from other amyloid types. We report the clinical presentation, natural history, and prognostic features of ATTRwt compared with cardiac-isolated AL amyloidosis and calculate the probability of disease diagnosis of ATTRwt from baseline factors. METHODS AND RESULTS: All patients with biopsy-proven ATTRwt (102 cases) and isolated cardiac AL (36 cases) seen from 2002 to 2011 at the UK National Amyloidosis Center were included. Median survival from the onset of symptoms was 6.07 years in the ATTRwt group and 1.7 years in the AL group. Positive troponin, a pacemaker, and increasing New York Heart Association (NYHA) class were associated with worse survival in ATTRwt patients on univariate analysis. All patients with isolated cardiac AL and 24.1% of patients with ATTRwt had evidence of a plasma cell dyscrasia. Older age and lower N-terminal pro-B-type natriuretic peptide (NT pro-BNP) were factors significantly associated with ATTRwt. Patients aged 70 years and younger with an NT pro-BNP <183 pmol/L were more likely to have ATTRwt, as were patients older than 70 years with an NT pro-BNP <1420 pmol/L. CONCLUSIONS: Factors at baseline associated with a worse outcome in ATTRwt are positive troponin T, a pacemaker, and NYHA class IV symptoms. The age of the patient at diagnosis and NT pro-BNP level can aid in distinguishing ATTRwt from AL amyloidosis.

Inflammatory bowel disease and systemic AA amyloidosis.

BACKGROUND: Systemic AA amyloidosis is a recognised complication of inflammatory bowel disease. AA amyloidosis is a potential cause of end-stage renal failure and mortality but little is known of the natural history of this condition in inflammatory bowel disease. METHODS: We evaluated the clinical phenotype, disease progression and outcome amongst 26 patients with inflammatory bowel disease and AA amyloidosis followed prospectively at a single center between 1989 and 2010. RESULTS: Twenty-two patients had Crohn's disease and four had ulcerative colitis. Fistulae and abscesses occurred in ten cases, all of whom had Crohn's disease. Amyloidotic proteinuric renal dysfunction occurred in all of the cases. It resolved in five patients with well-controlled inflammation, but was progressive in all of the other patients. Fifteen patients reached end-stage renal disease after a median time of 6.3 years from development of renal dysfunction (by Kaplan-Meier estimate), six of whom subsequently proceeded to renal transplantation. There were five functioning grafts at census 0.8, 3.2, 4.2, 20.1 and 24.6 years after transplantation. One graft failed 14.5 years after renal transplantation because of amyloid recurrence in a patient with sustained chronic inflammatory activity. CONCLUSIONS: AA amyloidosis remains a serious complication of both Crohn's disease and ulcerative colitis, and is characterized by proteinuric renal dysfunction that may resolve following suppression of inflammatory activity. Patient and graft survival are excellent in patients who undergo renal transplantation.

A prospective study of nutritional status in immunoglobulin light chain amyloidosis.

Weight loss is common in systemic immunoglobulin light chain amyloidosis but there are limited data on the impact of nutritional status on outcome. Using the Patient-Generated Subjective Global Assessment (PG-SGA) score, we prospectively examined nutritional status in 110 consecutive newly-diagnosed, treatment-naïve patients with immunoglobulin light chain amyloidosis attending the UK National Amyloidosis Centre. At study entry, 72 of 110 (66%) patients had a PG-SGA score of 4 or over, indicating malnutrition requiring specialist nutritional intervention. Number of amyloidotic organs, elevated alkaline phosphatase, presence of autonomic neuropathy and advanced Mayo disease stage were independently associated with poor nutritional status (P<0.05). Quality of life was substantially poorer among those with higher PG-SGA scores (P<0.001). Furthermore, PG-SGA score was a powerful independent predictor of patient survival (P=0.02). Malnutrition is prevalent and is associated with poor quality of life and reduced survival among patients with systemic immunoglobulin light chain amyloidosis. The PG-SGA score would be an appropriate tool to evaluate whether nutritional intervention could improve patient outcomes.

The electrocardiographic features associated with cardiac amyloidosis of variant transthyretin isoleucine 122 type in Afro-Caribbean patients.

BACKGROUND: About 4% of African Americans possess the isoleucine 122 (V122I) variant of transthyretin, associated with cardiac amyloidosis beyond ages of 55 to 60 years. Transthyretin amyloidosis associated with variant V122I (ATTR V122I) is likely to be an important cause of heart failure in Afro-Caribbean populations, but the high prevalence of left ventricular hypertrophy (LVH) and lack of awareness of this genetic disorder pose diagnostic hurdles. We report the electrocardiographic (ECG) features of ATTR V122I in the largest clinical series to date. METHODS: Patients with ATTR V122I were identified in collaboration with the UK National Amyloidosis Centre. The ECG at presentation was assessed for cardiac rhythm, axis, and voltage complex size. RESULTS: We include 64 patients with ATTR V122I, with a median age of 74 years (range, 57-88 years). Normal or increased ECG voltage was present in 44.3% of patients, and overall 25% met the criteria for LVH. A significant negative correlation between voltage complex size and duration of illness was seen (P < .05). First-degree heart block was evident in 56% of patients in sinus rhythm. During follow-up (n = 17; median, 28 months), 50% of patients with initial first-degree heart block required pacing. CONCLUSION: Electrocardiographic voltages meet the criteria for LVH in one quarter of patients with ATTR V122I cardiac amyloidosis. The widely held belief that cardiac amyloidosis is associated with low-voltage complexes is likely to contribute to underdiagnosis of ATTR V122I. First-degree heart block is common at diagnosis and identifies patients at high risk for subsequent pacing requirement.

Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant.

AIMS: Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. METHODS AND RESULTS: Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45-78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. CONCLUSION: Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I.

The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Laser microdissection and tandem mass spectrometry-based proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease.

Outcome in renal Al amyloidosis after chemotherapy.

PURPOSE: Chemotherapy in AL (primary or light chain) amyloidosis is associated with improved survival, but its effect on renal outcome has not been examined systematically. The purpose of this study was to evaluate the effect of chemotherapy on clinical outcome among patients with renal AL amyloidosis. PATIENTS AND METHODS: We evaluated factors influencing survival among 923 patients with renal AL amyloidosis observed during a 21-year period, including 221 patients who became dialysis dependent. Factors associated with renal outcome were analyzed, including serum free light chain (FLC) response to chemotherapy using a simple subtraction formula applicable to all stages of chronic kidney disease. Patient survival and graft survival were analyzed in 21 renal transplantation recipients. RESULTS: Median survival from diagnosis for the whole cohort was 35.2 months. Magnitude of FLC response with chemotherapy was strongly and independently associated with overall survival (P < .001) and renal outcome. Evaluable patients achieving more than 90% FLC response had a significantly higher rate of renal responses and lower rate of renal progression compared with patients achieving a 50% to 90% response, whose renal outcomes were, in turn, better than patients achieving less than 50% FLC response (P < .001). Median survival from dialysis dependence was 39.0 months, and median survival from renal transplantation was 89.0 months. CONCLUSION: Renal outcome and overall outcome in AL amyloidosis are strongly associated with FLC response to chemotherapy and are best among patients achieving more than 90% suppression of the amyloidogenic monoclonal component. Survival on dialysis was substantially superior to that previously reported, and renal transplantation should be considered in selected patients with AL amyloidosis with end-stage renal disease.

Amyloid and the GI tract.

Amyloidosis is characterized by the extracellular deposition of an abnormal fibrillar protein, which disrupts tissue structure and function. Amyloid may be localized to a single organ, such as the GI tract, or be systemic where the amyloid type is defined by the respective fibril precursor protein. Among patients with systemic amyloidosis, histological involvement of the gastrointestinal (GI) tract is very common but often subclinical. The presence and pattern of GI symptoms varies substantially, not only between the different amyloid types but also within them. GI presentations are frequently nonspecific and include macroglossia, dyspepsia, hemorrhage, a change in bowel habit and malabsorption. Endoscopic and radiological features of amyloidosis are also nonspecific, with the small intestine most commonly affected. In the absence of specific treatments for GI amyloidosis, therapy is aimed at reducing or eliminating the supply of the respective fibril precursor protein. Supportive measures such as nutritional support and antidiarrheal agents should be instigated while awaiting the clinical improvement associated with a successful reduction in the abundance of the fibril precursor protein. GI tract surgery should be performed only if the benefits clearly outweigh the risks, as there is a risk of decompensation of organs affected by amyloid.

Systemic amyloidosis and the gastrointestinal tract.

Systemic amyloidosis is characterized by the extracellular deposition of protein in an abnormal fibrillar form. Several different types of amyloidosis exist, each defined by the identity of their respective fibril precursor protein. Among patients with systemic amyloidosis, histological involvement of the gastrointestinal tract is very common but is often subclinical. Conversely, primary diseases of the gastrointestinal tract can cause systemic amyloidosis; for example, AA amyloidosis can occur secondary to IBD. The presence and pattern of gastrointestinal symptoms varies substantially, not only between the different types of amyloidosis but also within them. Typical clinical presentations, most of which are nonspecific, include macroglossia, hemorrhage, motility disorders, disturbance of bowel habit and malabsorption. Endoscopic and radiological features are also nonspecific, with the small intestine most commonly affected. Currently, the aim of therapy for amyloidosis is to slow amyloid formation by reducing the abundance of the fibril precursor protein. No specific treatments for the gastrointestinal symptoms of systemic amyloidosis are available; however, case reports and small published series encourage nutritional support for patients with motility disorders and pharmacological agents for treatment of diarrhea. Surgical procedures should be contemplated only in an emergency setting because of the risk of decompensation of organs affected by amyloid deposition.