Maido Castiglioni

Relationship between low T3 syndrome and NT-proBNP levels in non-cardiac patients

Objectives — A low T3syndrome was described in patients with heart failure (HF), and it appears to be associated with adverse outcome, representing an independent predictor of mortality. However, it is not known if low T3 levels contribute to the pathophysiology of HF. On the other hand, it has been seen that an elevation of brain natriuretic peptides (BNP and NT-proBNP) may represent a warning signal for future cardiovascular disease and may be an early marker of diastolic dysfunction. Therefore we tested the hypothesis that low levels of free-triiodothyronine (FT3) are sufficient to determine an increased concentration of the amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP), as the result of an initial and asymptomatic cardiac impairment. Methods — A total of 52 consecutive non-cardiac patients underwent thyroid function profile evaluation and NT-proBNP determination. On the basis of FT3 values they were divided in two subgroups: a low T3group (19patients) and a normal T3group (33patients). Results — The median NT-proBNP concentration of patients with low T3syndrome was significantly higher than in those with normal FT3 (370 vs. 120 pg/ml, P=0.002). There is a strong and inverse correlation between FT3 and Log NT-proBNP (R = –0.47, P < 0.001); this relation persists in a multivariable regression analysis, after adjustment for other potentially confounding variables (P=0.008). Conclusion — In absence of overt cardiovascular disease, patients with low T3syndrome present an increased concentration of NT-proBNP. These data suggest that low FT3 levels may be a contributing factor for the development of cardiac dysfunction.

Amylase: A disease activity index in multiple myeloma?

This study reports a case of a patient with lambda-light chain multiple myeloma who developed a high hyperamylasaemia of the salivary type during the disease and soon afterwards died. Ectopic production of amylase by myeloma cells has been described in a few cases and demonstrated by tissue culture and immunohistochemical techniques. The common characteristics of these cases were: salivary amylase isoenzyme increase, high tumor mass, extensive extra-medullary spread, extensive bone destruction and poor prognosis. In patients with amylase-producing multiple myeloma, the onset of hyperamylasaemia heralds a rapid disease progression; therefore, in these patients, a simple test such as serum amylase may represent a reliable disease activity index and provide an additional prognostic information.

Rituximab therapy of severe aplastic anemia induced by fludarabine and cyclophosphamide in a patient affected by B-cell chronic lymphocytic leukemia

Aplastic anemia can be the consequence of a direct cytotoxic effect on hematopoietic stem cells from drugs, infections, chemicals or it may result from either cell-mediated or antibody-dependent cytotoxicity [1]. In our department we studied a 68-year-old woman with B-cell chronic lymphocytic leukemia (B-CLL) stage Binet C. The peripherical blood test showed: red cells 3.680.0000/mmc (hematocrit 29.5%, hemoglobin level 9.9 g/dl, platelet count 146.000/mL, white blood cell count 13.710/mL with 72% lymphocytes, 20% neutrophils). The bone marrow biopsy revealed: cellularity of 90%; the infiltrating cells were predominantly small B-CLL lymphocytes. CLL cells were CD 20þ , CD 5þ , CD 23þ, D17, CD 437, Cig7. The patient was treated as first-line therapy, with cyclophosphamide (C: 250mg/m) þ fludarabine (F: 25mg/m) for 3 days. Twenty days later the patient was admitted to hospital because fever and pancytopenia (hematocrit 25.6%, hemoglobin level 8.7 g/dl, reticulocytes count 2.750/mL, platelet count 46.000/mL, white blood cell count 780/mL with 80% lymphocytes, 10% neutrophils) had occurred. Serologic tests for the human immunodeficiency virus, cytomegalovirus (CMV), hepatitis and Epstein-Barr virus (EBV), human B19 parvovirus, human herpes virus-6 were negative. Treatment consisting of antibiotics, granulocyte colony -stimulating factor (G-CSF), supportive care, packed red blood cells leukocyte depleted and irradiated and platelet transfusions were administered. After 5 weeks the patient was treated with highdose corticosteroid for 3 days (methylprednisolone 500 mg iv/d) and intravenous immunoglobulins (IVIG 400mg/kg for 4 days). No response was observed. Two months after infusion with CþF, bone marrow biopsy revealed severe hypocellularity: cellularity less than 30% (50% erythrocytes and 50% lymphoid cells) and fat tissue 70%. Hematologic laboratory data were as follows: hematocrit 17%, hemoglobin level 6.2 g/dl, platelet count 12.000/mL, white blood cell count 550/mL with 89% lymphocytes, 5% neutrophils. Therefore rituximab (anti-CD 20 monoclonal antibody) was given at a dose of 375 mg/m per week for 4 weeks. After rituximab infusion a progressive increase of white blood cells and neutrophils (wbc 230 – 370 – 710 – 2.800/mL, neutrophils 80 – 90 – 450 – 2.360/mL) (Figure 1 and Table I) without evidence of an improvement of the hemoglobin level, reticulocyte count and platelet count was observed. The patient was discharged afebrile without specific constitutional symptoms. During the following 3 months and particularly at 4 and 8 weeks after rituximab infusion, the peripherical blood test showed a good white blood cell and neutrophil count. (see Table I and Figure 1). The patient had several episodes of gastrointestinal bleeding with anemia and persistent thrombocytopenia. The bone marrow cellularity was not greatly increased. A complete cellular recovery was seen after a further 2 months. In fact we observed a good recovery

A rare case of non-Hodgkin lymphoma in a pacemaker pocket

The development of non-Hodgkin lymphomas (NHLs) in pacemaker pockets is an extremely rare event and has been reported only once in the whole international medical literature [1]. Hojo et al. suggested that it is possible to associate lymphomagenesis and chronic inflammatory stimulation. We report the case of a NHL grown in a pacemaker pocket, following an inflammation of a pacemaker pocket that lasted for 5 years. The lymphoma was diagnosed as a ‘large cell lymphoma, null phenotype’, stage I-E, B, international prognostic index (IPI) 2. The case was characterised by a history of long-term inflammation to support the presence of a pathogenic link between chronic phlogosis and NHL. A 68-year-old man, ex-smoker, with a history of hypertension and transient ischemic attack, had a single lead dual-chamber sensing VDDR pacemaker (VDDR) pacemaker implanted, following a syncope, in 2001. Two years later, the patient developed a tumor in the pacemaker lodging pocket and was treated with steroids and antibiotics, with a subsequent complete remission of the tumor. In the years that followed, the tumor reappeared twice until the VDDR pacemaker was replaced with a dual chamber rate adaptive pacemaker (DDDR) pacemaker, in 2007. A clinical examination revealed an elastic, dark red, 6-cm diameter tumor in the VDDR pacemaker pocket site. Lymphadenopathy and hepatosplenomegaly were not detected. The only systemic symptom was fever. An ultrasound scan revealed reactive subcentimetric lymph nodes in the inguinal and axillary areas. The total body computed tomography scan detected a 6-cm diameter mass, with a colliquative-core, situated in the VDDR pacemaker pocket site and a diffused thoracic lymphadenopathy with maximum diameter of 1.2 cm. Laboratory findings showed that enzyme lactate dehydrogenase value was out of range with 496 U/L (normal value 135–214), and a small quantity of M-protein (Ig-A lambda) was also present. Histologic investigation on tissue samples, taken from the VDDR pacemaker pocket during replacement operation, revealed a ‘large cell lymphoma, null cell immunophenotype, CD3, CD20, CD79a negative, CD138 and CD30 positive and CD43 positive in focal way as to indicate a plasmoblastic differentiation’. Bone marrow biopsy was negative. According to Ann Arbor classification this case was rated as NHL, stage I-E, B, IPI 2 (low intermediate risk). The patient received a first cycle of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy and was, then, discharged. Two weeks later, we observed a partial regression of the mass. The total body computed tomography scan, carried out following the fourth chemotherapy cycle, revealed a significant reduction of the mass diameter to 2.5 cm. Other data, compared with data obtained with previous total body computed tomography scans, remained substantially unchanged. The patient completed the sixth chemotherapy cycle in a hospital near his hometown. However, following a pneumonia developed during a period of posttherapy neutropenia, he died.

Relationship between serum uric acid levels and urinary albumin excretion in patients with heart failure

Objectives — Hyperuricaemia is a constant finding in patients with heart failure (HF). Upregulated xanthine-oxidase activity seems to contribute to progression of the disease through the production of oxidative stress and the development of vascular and endothelial dysfunction. On this basis we speculated that in HF serum uric acid levels correlated with a reliable marker of endothelial dysfunction as urinary albumin excretion. Methods — Fifty-three patients with HF underwent assessment of serum uric acid, N-terminal probrain natriuretic peptide (NT-proBNP), glomerular filtration rate (GFR), other metabolic parameters and determination of urinary albumin concentration (UAC) in a morning urine sample. Results — In univariate analysis there is a direct correlation between serum uric acid levels and log UAC (r = 0.43, P < 0.01); uric acid correlates also positively with log NT-proBNP (r = 0.31, P < 0.05) and negatively with log-GFR (r= –0.38, P< 0.01). In stepwise regression analysis serum uric acid emerged as the only predictor of increased UAC (standardized coefficient= 0.42, P = 0.001) independent of other clinical determinants and metabolic factors. Conclusion — Serum uric acid represents the strongest predictor of elevated UAC in HF. Regression of albuminuria may be a simple target to verify the efficacy of xanthine-oxidase inhibition in these patients.

Antimitochondrial antibodies and non-Hodgkin lymphoma presenting as hepatobiliary disease

This short report describes a case of positive antimitochondrial antibodies (AMA) in a patient with signs and symptoms mimicking a liver disease who, after evaluation of the condition, was found to have splenic lymphoma with villous lymphocites (SLVL). The AMA are the immunological marker of Primary Biliary Cirrhosis (PBC) and they are rarely found in other forms of liver disease [1]. Patients with lymphoproliferative disorders can present with features suggesting hepatobiliary disease [2] and have a variety of autoantibodies [3]. However, in these patients, to the best of our knowledge, the presence of AMA, in the absence of PBC, was never reported in the literature. An 80-year old woman was admitted to our department with itching, fatigue and elevated levels of alkaline phosphatase (ALP) and g-glutamiltranspeptidase (g-GT). Six months before, the hepatobiliary function tests were all normal. On physical examination there was hepatosplenomegaly without palpable lymphadenopathy. Her laboratory tests showed increased levels of ALP at 798 U L (normal range 90 – 260 U L) and g-GT at 319 U L (normal range 10 – 66 U L); alanine aminotransferase, aspartate aminotransferase and bilirubin were normal, serologic tests for hepatitis B and C viruses were negative. There were not monoclonal spikes in the serum or urine electrophoresis. The AMA were positive as determinated by indirect immunofluorescence in a titer of 1:320, while the antinuclear antibodies and the other autoantibodies were all negative. On the basis of the clinical presentation and laboratory abnormalities PBC appeared to be the most likely diagnosis; however, a hepatic biopsy showed an infiltration by small-sized lymphoid cells consistent with a chronic lymphoproliferative disease in absence of histologic findings compatible with PBC. Afterwards a total-body computed tomography (CT) revealed intra-abdominal lymphadenopathy and confirmed a moderate splenomegaly. Finally, a bone-marrow biopsy and an immunohistochemical study allowed the diagnosis of SLVL. A therapy with chlorambucil (0.2 mg Kg per day on days 1 – 4, every 4 weeks for 12 cycles) was given and, 1 year after our diagnosis, clinically she is well, the itching is improved and the illness appears stable. A CT scan showed no increase of abdominal lymphadenopathy and mild reduction of the splenomegaly. The value of ALP is still elevated to about twice the normal values; the AMA persist positive (1:160), whereas the other autoantibodies are negative. A relationship between PBC and primary hepatic lymphoma [4] or, more unusually, systemic lymphoma [5] has previously been described, but our case results the first one suggesting a possible direct association between AMA and lymphoproliferative diseases. What role might these autoantibodies play in patients with lymphoma? A prolonged activation of the immune system appears to contribute to lymphomagenesis. Therefore, the AMA might reflect a marker of immunogenic stimulation in those subjects that will develop a severe and prevalent liver involvement by lymphoma. Alternatively, a massive lymphomatous infiltration of hepatic parenchyma might induce a release of mitochondrial antigens by biliary cells and the consequent formation of AMA.

Systemic amyloidosis: a clinical challenge.

This study reports a case of an 82-year-old white woman with a history of congestive heart failure refractory to diuretic therapy who was found to have systemic amyloidosis, confirmed by a rectal biopsy. Cardiac involvement by amyloid should be considered in the differential diagnosis of any patient with heart failure with preserved ventricular systolic function, who does not have evidence of ischaemic heart disease or hypertension. However, the rarity of this disease and the various involvement of different organs and tissues are often responsible for missed or delayed diagnosis. Systemic amyloidosis is a life-threatening disease but an early diagnosis may modify its course; therefore it is important to maintain a high clinical suspicion and to increase the awareness of this overlooked condition among clinicians.