Cardiac [99mTc]Tc-hydroxydiphosphonate uptake on bone scintigraphy in patients with hereditary transthyretin amyloidosis: an early follow-up marker?

PURPOSE: There is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments. METHODS: In this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated. RESULTS: Median heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15-34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer. CONCLUSION: A change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.

Nuclear imaging in cardiac amyloidosis.

Amyloidosis is a disease characterized by depositions of amyloid in organs and tissues. It can be localized (in just one organ) or systemic. Cardiac amyloidosis is a debilitating disease and can lead to arrhythmias, deterioration of heart function and even sudden death. We reviewed PubMed/Medline, without time constraints, on the different nuclear imaging modalities that are used to visualize myocardial amyloid involvement. Several SPECT tracers have been used for this purpose. The results with these tracers in the evaluation of myocardial amyloidosis and their mechanisms of action are described. Most clinical evidence was found for the use of (123)I-MIBG. Myocardial defects in MIBG activity seem to correlate well with impaired cardiac sympathetic nerve endings due to amyloid deposits. (123)I-MIBG is an attractive option for objective evaluation of cardiac sympathetic level and may play an important role in the indirect measurement of the effect of amyloid myocardial infiltration. Other, less sensitive, options are (99m)Tc-aprotinin for imaging amyloid deposits and perhaps (99m)Tc-labelled phosphate derivatives, especially in the differential diagnosis of the aetiology of cardiac amyloidosis. PET tracers, despite the advantage of absolute quantification and higher resolution, are not yet well evaluated for the study of cardiac amyloidosis. Because of these advantages, there is still the need for further research in this field.

[AL-amyloidosis and its treatment by eliminating the precursor protein]. / AL-amyloïdose en de behandeling door eliminatie van het voorlopereiwit.

AL amyloidosis was diagnosed in 2 patients, women aged 61 and 43 respectively. The first patient, who had a nephrotic syndrome, died soon after diagnosis as the disease appeared to be already widespread. The second patient was still alive at the last follow-up, 17 years after diagnosis, because of effective elimination of her light chains by high-dose chemotherapy. AL amyloidosis is a rare, but severe, systemic disease with high mortality. Its aetiology lies in deregulated plasma cells producing excessive numbers of free immunoglobulin light chains. These light chains are the precursor proteins of amyloid fibrils. Amyloid fibrils are deposited extracellularly in tissue leading to organ dysfunction. Symptomatology is diverse, often non-specific, and generally not very well-known. Therefore, the diagnosis is often delayed for a long time. This is unfortunate, as high-dose chemotherapy targeted at elimination of the precursor protein considerably improves prognosis. However, this type of therapy can only be given in patients with limited and moderately progressive disease.

Tumor necrosis factor (TNF) inhibits interleukin (IL)-1 and/or IL-6 stimulated synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes.

Interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) are considered as important mediators for the modulation of liver synthesis of acute phase proteins. However, studies of the direct effect of individual or a combination of these cytokines on the synthesis of acute phase proteins in human hepatocytes are still very limited. In this study, we have examined the synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes exposed to recombinant(r)IL-1 alpha (100 U/ml), rIL-6 (2000 U/ml), rTNF alpha (30 U/ml) and to various combinations of these cytokines in the presence of 1 microM dexamethasone. Monoclonal antibodies to rTNF alpha and monospecific anti-rIL-6 sheep antiserum were also used to investigate the possible endogenous production of TNF or IL-6. The findings indicate: (1) IL-1 and IL-6 are stimulatory cytokines for the liver synthesis of CRP and SAA. Anti IL-6 abolishes the stimulatory effect of IL-1. These findings support the previous observation and indicate that IL-1 exerts its action on the enhanced synthesis of CRP and SAA at least in part via IL-6 production in the liver cell. (2) TNF is an inhibitory cytokine for the liver synthesis of CRP. It inhibits also the stimulatory effect of IL-1 and IL-6 on the synthesis of CRP and SAA. (3) Since anti-TNF enhances the stimulatory effect of IL-6 on the synthesis of CRP and SAA, it seems likely that TNF is also produced by the human hepatocytes. However, further studies for more direct evidence of the liver cell production of TNF, such as the detection of TNF messenger RNA are required.

Kinetic studies with iodine-123-labeled serum amyloid P component in patients with systemic AA and AL amyloidosis and assessment of clinical value.

UNLABELLED: In systemic amyloidosis, widespread amyloid deposition interferes with organ function, frequently with fatal consequences. Diagnosis rests on demonstrating amyloid deposits in the tissues, traditionally with histology although scintigraphic imaging with radiolabeled serum amyloid P component (SAP) has lately been developed as a specific noninvasive alternative. We report a detailed analysis of the abnormal turnover of SAP in patients with systemic amyloidosis and an assessment of its clinical value. METHODS: Iodine-123-labeled human SAP (200 MBq) SAP was injected intravenously into 49 patients with histologically proven systemic AA- or AL- amyloidosis and in 7 control subjects. Plasma clearance and whole-body retention of labeled SAP were analyzed over 48 hr using plasma sampling, whole-body gamma camera imaging and measurement of radioactivity in the urine. The rate of SAP synthesis and interstitial exchange were determined, and the size of the amyloid compartment was compared with clinical estimates of whole-body amyloid load and patient survival. RESULTS: All plasma time-activity curves were biphasic. In comparison with control subjects, patients with amyloidosis showed significantly faster plasma disappearance [4-hr value: AA 48% +/- 18%, AL 45% +/- 15% versus 65% +/- 8% (p < 0.05)], higher total-body retention 48 hr p.i. [AA 74% +/- 14%, AL 73% +/- 17% versus 46% +/- 15% (p < 0.01)] and especially higher extravascular retention 48 hr p.i. [AA 59% +/- 16%, AL 58% +/- 19% versus 30% +/- 14% (p < 0.01)]. Extravascular retention correlated with clinical estimation of the amyloid load. If extravascular retention values in patients with AL amyloidosis were over 60%, survival was decreased (median 4 versus 23 mo, p < 0.001). Markedly increased interstitial exchange rates were present in amyloidosis (AA 64 +/- 61, AL 50 +/- 37 versus 18 +/- 8 mg/hr), whereas the SAP synthesis rate did not differ from the control values (AA 5.0 +/- 3.0, AL 5.5 +/- 3.2 versus 4.5 +/- 1.4 mg/hr). CONCLUSION: The presence of systemic amyloidosis is characterized by accelerated initial clearance of 123I-SAP from the plasma and increased interstitial exchange rate and extravascular retention. These findings reflect reversible binding of radiolabeled SAP to amyloid deposits and provide clinically useful information for diagnosis, monitoring of therapy and prognosis in patients with systemic amyloidosis.

Omeprazole (20 mg o.m.) versus ranitidine (150 mg b.d.) in duodenal ulcer healing and pain relief.

The object of this double-blind, multicentre study was to compare duodenal ulcer healing rates after 2 to 4 weeks of treatment with either 20 mg omeprazole o.m. or 150 mg ranitidine b.d. One hundred and eighty-one patients were randomized: 91 received omeprazole and 90 received ranitidine. In a per protocol analysis at 2 weeks, 63% of the patients were healed on omeprazole and 65% of the patients were healed on ranitidine (N.S.); at 4 weeks 91% were healed in the omeprazole group and 96% were healed in the ranitidine group. There were no differences in ulcer symptom relief between the two groups. There were no significant changes in laboratory values in either of the groups. Adverse events were few and mainly mild and transient. We conclude that both omeprazole (20 mg o.m.) and ranitidine (150 mg b.d.) result in rapid, ulcer healing rates.

Transthyretin Val71Ala mutation in a Dutch family with familial amyloidotic polyneuropathy.

A Dutch family with familial amyloidotic polyneuropathy associated with the transthyretin mutation Val71Ala is described. This is the third reported family with this mutation, causing at the protein level an unstable TTR monomer and at the clinical level progressive wasting, polyneuropathy, autonomic dysfunction and vitreous opacities.

The assessment of autonomic function in patients with systemic amyloidosis: methodological considerations.

Autonomic neuropathy is a well-known and prognostically important feature of systemic amyloidosis. In other conditions, autonomic function is commonly assessed by cardiovascular reflex tests, described by Ewing, but the feasibility of these tests has not been investigated in patients with systemic amyloidosis. We studied autonomic function in amyloidotic patients using cardiovascular tests and assessed their feasibility. Patients with AA, AL and ATTR amyloidosis participated. In all patients, cardiovascular reflex testing (mental arithmetic stress test and head-up tilting, besides the Ewing-tests) was performed. Of the 46 patients included, only 28 patients could perform all 4 Ewing-tests. In particular, patients with AA amyloidosis secondary to rheumatoid arthritis could not perform standing up and the isometric handgrip test. However, when the mental stress test replaced the handgrip test and head-up tilting replaced standing up, in 45 of the 46 patients, autonomic function could be assessed with cardiovascular reflex tests. Half of the patients with AA amyloidosis had signs of autonomic neuropathy--which was more than expected. We propose to replace the isometric handgrip test with the mental arithmetic stress test and standing up with head-up tilting if a patient is not able to perform these tests.

Prevention of relapse in reflux esophagitis: a placebo controlled study of ranitidine 150 mg bid and 300 mg bid.

OBJECTIVE: To compare the efficacy and safety of long term use of ranitidine 150 mg bid, 300 mg bid and placebo in prevention of endoscopic and symptomatic relapse of reflux esophagitis in an international, double-blind, placebo controlled, parallel group study. PATIENTS AND METHODS: A total of 279 patients at least 18 years old from hospital out-patient departments with healed esophagitis (grade 0) with no or mild symptoms entered the study. Patients were randomly allocated to receive ranitidine 150 mg, 300 mg placebo twice daily for 48 weeks. Patients returned for symptom assessments at eight-week intervals and for re-endoscopy every 16 weeks. RESULTS: Both ranitidine regimens were significantly more effective than placebo in preventing endoscopic and symptomatic relapse of reflux esphagitis (p = 0.003 for ranitidine 150 mg bid; P < 0.001 for ranitidine 300 mg bid). No statistically significant differences were observed in relapse rates between the two ranitidine regiments. The percentage of patients with endoscopic relapse (grade 2) after 48 weeks were 60%, 37% and 27% for placebo, ranitidine 150 mg bid and ranitidine 300 mg bid, respectively (P = 0.002 for ranitidine 150 mg bid versus placebo; P < 0.001 for ranitidine 300 mg bid versus placebo). Ranitidine was well tolerated. CONCLUSIONS: Ranitidine 150 mg bid and 300 mg bid are safe and effective treatments in the prevention of reflux esophagitis relapse.

Weil's disease as a cause of jaundice.

Two patients are described with Weil's disease as a rare cause of jaundice. We discuss some features that can lead to early diagnosis. This concerns the apparently aspecific flu-like syndrome that precedes the icteric phase of the disease, as well as the typical pattern of liver function tests in the jaundiced patient: serum bilirubin is markedly elevated as compared with the liver enzymes. Another clue to the diagnosis can be obtained by enquiring not only about the patient's profession, but also about his leisure activities, since both patients acquired the disease in their leisure time.

Therapeutic options in systemic AL amyloidosis.

Systemic amyloid light chain (AL) amyloidosis is a severe disease with unfavourable prognosis. Since the late 1970s different therapeutic modalities in AL amyloidosis have been investigated, trying to prolong survival. This review deals with the therapeutic modalities in AL amyloidosis to date, and highlights future perspectives.

Nizatidine versus ranitidine in the treatment of peptic ulcer disease: report on the Dutch investigation as part of a European multicentre trial.

The efficacy and safety of nizatidine was evaluated in comparison with ranitidine in 230 patients with endoscopically documented gastric (71) or duodenal (159) ulcers. Gastric ulcer patients who satisfied all criteria for inclusion and exclusion were randomly allocated to nizatidine 300 mg nocte, 150 mg b.d. or ranitidine 150 mg b.d., duodenal ulcer patients to nizatidine 300 mg nocte or ranitidine 300 mg nocte. Endoscopic healing was defined as complete epithelialisation of all mucosal lesions. Endoscopy was performed at 4 and, if not healed, at 8 weeks. Healing rates were shown to be comparable for all treatment regimens. In both duodenal ulcer treatment groups, and with both drugs, healing was negatively influenced by ulcer size, ulcer number, smoking habits and a disease duration of 5 years or more. Few side effects were noted. Nizatidine, administered as a 300 mg nocte and as a 150 mg b.d. dose appeared to be a safe H2 antagonist and was as effective as ranitidine in the treatment of duodenal and gastric ulceration.

A patient with a variant form of hairy cell leukaemia.

A 57-year-old woman was admitted because of weakness, fatigue, abdominal discomfort, easy bruising and splenomegaly. A highly elevated leukocyte count with hairy-cell-like cells was found, the cells being positive for the monoclonal antibodies CD19, FMC7, CD11c and B-ly-7 and negative for CD24 and CD25. Blood and bone marrow were investigated not only in our own laboratory but also in several other laboratories resulting in a variety of possible diagnoses. Only after combining all data could a definitive diagnosis of variant hairy cell leukaemia be made. The patient was treated initially with a splenectomy and later on with interferon-alpha-2b, resulting in a steady decrease in the leukocyte count. After a follow-up of 2 years a nearly complete remission was obtained with a good quality of life. The differential diagnosis of this rare disorder is discussed with emphasis on the relative contribution of different diagnostic procedures.

A homozygous M694V mutation of the MEFV gene in a patient with periodic fever and thoracic pain.

A Turkish patient with episodic fever and thoracic pain is described in whom a homozygous M694V mutation of the MEFV gene confirmed the clinical diagnosis of familial Mediterranean fever. The role of DNA analysis is discussed with respect to understanding the pathogenesis of the fever and assessing the risk of amyloidosis in specific mutations of the MEFV gene.

Diagnostic and therapeutic approach of systemic amyloidosis.

Amyloidosis is a group of diseases, all characterised by deposition of protein fibrils with a beta-sheet structure. This structure generates affinity of amyloid for Congo red dye and is resistant to proteolysis. Three types of systemic amyloidosis are important for the clinician: AA (related to underlying chronic inflammation), AL (related to underlying monoclonal light chain production) and ATTR amyloidosis (related to old age or underlying hereditary mutations of transthyretin). Signs and symptoms vary considerably among the three types and the choice of treatment differs completely. A stepwise approach in diagnosis and therapy is presented. When amyloidosis is suspected the first step is histological proof of amyloid and the second is proof of systemic involvement. The next two steps are determination of the type of amyloid followed by detection of the precursor protein. The fifth step is a thoughtful clinical evaluation, necessary for assessment of prognosis and therapy. Subsequently, the choice of therapy is based on the 'precursor-product' concept. In the final step, the effects of therapy on the underlying disease as well as on the amyloidosis are assessed during follow-up. In this evaluation serum amyloid P component (SAP) scintigraphy helps to show organ involvement and therapy response.

[Hematopoietic growth factors as supportive treatment in drug-induced agranulocytosis]. / Hematopoëtische groeifactoren als ondersteunende behandeling bij agranulocytose als gevolg van gebruik van geneesmiddelen.

This article describes the use of granulocyte macrophage colony stimulating factor and granulocyte colony stimulating factor in two patients with drug induced granulocytopenia. A granulocyte count > 1 x 10(9)/l was obtained after 7 days' treatment. These results suggest that the haematopoietic growth factors shortened the period of agranulocytosis and subsequently may improve the survival of these patients.

[Amyloidosis as cause of severe abdominal symptoms in a young Somali immigrant?]. / Amyloidosis als oorzaak van ernstige buikklachten bij een jonge Somalische immigrante?

Extensive deposition of amyloid was detected in the digestive tract of a Somali woman aged 20 yr with abdominal pain, diarrhoea and cachexia. Immunohistochemical characterisation showed that the amyloid protein involved was of the AA type. Elevated levels were also found for serum amyloid A (SAA), an acute-phase protein which is the precursor of AA amyloid. The underlying inflammatory disease was peritoneal tuberculosis. The normalisation of the SAA levels and the recovery of the small intestine during tuberculostatic therapy showed that the tuberculosis was the cause of the enteropathy. This case report highlights the importance of early detection and effective treatment of the underlying inflammatory disease in case of AA amyloidosis.