Diego Miotto

The Adrenal Vein Sampling International Study (AVIS) for Identifying the Major Subtypes of Primary Aldosteronism

CONTEXT In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky. OBJECTIVE The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers. DESIGN AND SETTINGS The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide. PARTICIPANTS Eligible centers were identified from those that had published on PA and/or AVS in the last decade. MAIN OUTCOME MEASURE The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS. RESULTS Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007). CONCLUSIONS Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

Isolated Hepatocyte Transplantation for Crigler-Najjar Syndrome Type 1:

Crigler-Najjar syndrome type 1 (CN1) is an inherited disorder characterized by the absence of hepatic uridine diphosphoglucuronate glucuronosyltransferase (UDPGT), the enzyme responsible for the conjugation and excretion of bilirubin. We performed allogenic hepatocyte transplantation (AHT) in a child with CN1, aiming to improve bilirubin glucuronidation in this condition. A 9-year-old boy with CN1 was prepared with plasmapheresis and immunosuppression with prednisolone and tacrolimus. When a graft was made available, 7.5 × 109 hepatocytes were isolated and infused into the portal vein percutaneously. After 2 weeks phenobarbitone was added to promote the enzymatic activity of UDPGT of the transplanted hepatocytes. Nocturnal phototherapy was continued throughout the studied period. Total bilirubin was considered a reliable marker of allogenic cell function. There was no significant variation of vital signs nor complications during the infusion. Mean ± SD bilirubin level was 530 ± 38 μmol/L before and 359 ± 46 μmol/L after AHT (t-test, p < 0.001). However, the introduction of phenobarbitone was followed by a drop of tacrolimus level with increase of alanine aminotransferase (ALT) and increase of bilirubin. After standard treatment of cellular rejection bilirubin fell again but from then on it was maintained at a greater level. After discharge the patient experienced a further increase of bilirubin that returned to predischarge levels after readmission to the hospital. This was interpreted as poor compliance with phototherapy. Only partial correction of clinical jaundice and the poor tolerability to nocturnal phototherapy led the parents to refuse further hepatocyte infusions and request an orthotopic liver transplant. After 24 months the child is well, with good liver function on tacrolimus and prednisolone-based immunosuppression. Isolated AHT, though effective and safe, is not sufficient to correct CN1. Maintenance of adequate immunosuppression and family compliance are the main factors hampering the success of this procedure.

Adrenal vein sampling for primary aldosteronism: the assessment of selectivity and lateralization of aldosterone excess baseline and after adrenocorticotropic hormone (ACTH) stimulation.

Background Adrenal vein sampling is crucial for identifying the primary aldosteronism subtypes, but the cutoff values for ascertaining selectivity of catheterization and lateralization of aldosterone secretion remain controversial. Objectives To investigate the safety of adrenal vein sampling, the cutoff values for the selectivity and lateralization indexes, and the effect of adrenocorticotropic hormone stimulation on selectivity index and lateralization index performance. Design We assessed the proportion of selective adrenal vein sampling at different selectivity index cutoff values in 151 consecutive patients with primary aldosteronism undergoing bilaterally simultaneous adrenal vein sampling. Aldosterone-producing adenoma was diagnosed on the basis of the evidence of primary aldosteronism and lateralized aldosterone secretion, adenoma at pathological examination, and normokalemia, and correction of primary aldosteronism and cure or improvement of hypertension at follow-up. In 44 patients with bilaterally selective adrenal vein sampling and unequivocal diagnosis of aldosterone-producing adenoma on the basis of all these criteria, we examined the cutoff values of the lateralization index for assessing the lateralization of aldosterone excess and the effect of adrenocorticotropic hormone stimulation on selectivity index and lateralization index. Results Adrenal vein rupture occurred in one case (0.7%). Bilaterally selective adrenal vein sampling decreased steadily (from 79.9 to 40.2%) with increase in the selectivity index cutoffs from 1.1 to 5.0. Likewise, the proportion of correctly identified aldosterone-producing adenomas decreased (from 95.5 to 43.2%) with increase in lateralization index cutoffs from 1.125 to 5.0. Adrenocorticotropic hormone improved the assessment of selectivity but exerted a confounding effect on lateralization index. Conclusion Adrenal vein sampling is safe; increasing the selectivity index cutoffs lowers the number of usable adrenal vein samplings; higher lateralization index cutoff values lead to missing a proportion of aldosterone-producing adenomas. The improved selectivity rate provided by adrenocorticotropic hormone stimulation should be weighed against the loss of correct lateralization.

Adrenocorticotropic Hormone Stimulation During Adrenal Vein Sampling for Identifying Surgically Curable Subtypes of Primary Aldosteronism. Comparison of 3 Different Protocols

Adrenocorticotropic hormone administration was proposed to overcome the biases associated with pulsatile aldosterone secretion during adrenal venous sampling, but the usefulness of different protocols of stimulation was never systematically assessed. We, therefore, compared the effects of a high dose (HD; 250 &mgr;g IV as a bolus), a very low dose (VLD; 250 pg IV), and an intermediate dose (ID; 50 &mgr;g/h) of adrenocorticotropic hormone on the selectivity index (SI) and the lateralization index in primary aldosteronism patients, using the diagnosis of aldosterone-producing adenoma, based on pathology and follow-up data, as a reference. The HD (n=47) significantly increased plasma cortisol concentration in infrarenal inferior vena cava (+79%) blood and the SI on both sides (SIRIGHT +113% and SILEFT +131%), as compared with baseline values. The ID (n=14) also markedly increased both plasma cortisol concentration inferior vena cava (+93%) and the SI (SIRIGHT +690% and SILEFT +410%); the very low dose (n=6) had no effect on either the plasma cortisol concentration or SI. In the patients with unilateral aldosterone-producing adenoma, the increase of selectivity with the HD and ID was counterbalanced by a confounding effect on the correct identification of the aldosterone-producing adenoma side, which was attributed to the wrong side in 3.0% and 12.5% with HD and ID, respectively. In conclusion, the HD and the ID, but not the very low dose, adrenocorticotropic hormone stimulation protocol facilitated the ascertainment of selectivity of adrenal vein catheterization. However, this favorable effect was overridden by a confounding effect on the identification of lateralized aldosterone excess to the aldosterone-producing adenoma side. Hence, we do not recommend adrenocorticotropic hormone stimulation.

Dynamic testing with high-dose adrenocorticotrophic hormone does not improve lateralization of aldosterone oversecretion in primary aldosteronism patients.

Objective Diagnosing aldosterone-producing adenoma (APA) involves a demonstration of the lateralization of aldosterone oversecretion because adrenal incidentalomas are common in hypertensive individuals and many small-sized APA escape identification with available imaging techniques. However, because of the pulsatile pattern of aldosterone secretion this can be a difficult undertaking. Stimulation of aldosterone secretion before adrenal vein sampling (AVS) can overcome this difficulty, but anecdotal data exist. We, therefore, prospectively investigated the usefulness of AVS with dynamic testing in primary aldosteronism (PA) patients. Methods We enrolled 24 consecutive consenting patients with a biochemical diagnosis of PA from a tertiary referral centre to measure the effects of adrenocorticotrophic hormone (ACTH) on selectivity, the lateralization of aldosterone secretion to the APA side, and adverse effects. After correcting the hypokalemia we performed bilateral AVS. After 3 h supine resting, blood was simultaneously obtained from both sides. A high-dose ACTH (250 μg intravenous) bolus was then administered and AVS was repeated after 30 min. Results AVS was bilaterally selective in 88% of patients; no adverse effects occurred. Of the 21 patients with bilaterally selective AVS, three had idiopathic hyperaldosteronism and 18 an APA that was surgically removed in 12 with an ensuing fall in blood pressure at follow-up. After ACTH patients showed a significant increase (P = 0.007) of aldosterone from contralateral adrenal vein blood, but not from the APA gland. Therefore, lateralization of aldosterone secretion on the APA side did not improve. Conclusion AVS is safe and accurate for identifying APA. However, at a statistical power of 99%, these results do not support the usefulness of high-dose ACTH testing to improve the diagnostic accuracy of AVS.

Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with Child's grade A or B cirrhosis : A multivariate analysis of prognostic factors

We evaluated factors affecting long-term survival after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) complicating cirrhosis. One hundred eighty-two patients with Childs class A or B cirrhosis and an HCC, not amenable to surgery or percutaneous ethanol injection, underwent 346 TACEs (mean 1.9) with epirubicin, iodized oil, and gelatin sponge. Many prognostic factors were subjected to univariate analysis and thereafter, when significant, to the Coxs hazard proportional model. Finally, the significant indices in the Coxs model were used to estimate the accuracy of the probability of death with computation of the area under the receiving operative characteristic (ROC) curve. The cumulative survival rates at 1, 2, 3, and 5 years were 0.83, 0.52, 0.40, and 0.16, respectively. According to Coxs model, the factors associated with significantly worse survival were the presence of ascites (p = 0.0027), elevated bilirubin levels (p = 0.0163), elevated alpha-fetoprotein (alphaFP) values (p = 0.0067), a tumor greater than 5 cm in diameter (p = 0.0001), and the absence of a tumor capsule-like rim (p = 0.0278). According to these parameters, the accuracy of the probability of death estimated with ROC analysis was 0.63. Minor and major complications occurred in 82 patients (45%) and caused death in 2 patients. Long-term prognosis after TACE for HCCs in patients with Childs class A or B cirrhosis depends on the presence of ascites, the bilirubin level, the alphaFP value, the diameter of the tumor, and the presence of a tumor capsule-like rim. However, when considered altogether, these variables are poor predictors to evaluate survival, and other factors should be investigated to identify subjects more responsive to TACE. Complications occur in a high percentage of patients, but they do not affect long-term prognosis.

Impact of the presence and amount of myocardial fibrosis by cardiac magnetic resonance on arrhythmic outcome and sudden cardiac death in nonischemic dilated cardiomyopathy

BACKGROUND Current risk stratification for sudden cardiac death (SCD) in nonischemic dilated cardiomyopathy (NIDC) relies on left ventricular (LV) dysfunction, a poor marker of ventricular electrical instability. Contrast-enhanced cardiac magnetic resonance has the ability to accurately identify and quantify ventricular myocardial fibrosis (late gadolinium enhancement [LGE]). OBJECTIVE To evaluate the impact of the presence and amount of myocardial fibrosis on arrhythmogenic risk prediction in NIDC. METHODS One hundred thirty-seven consecutive patients with angiographically proven NIDC were enrolled for this study. All patients were followed up for a combined arrhythmic end point including sustained ventricular tachycardia (VT), appropriate implantable cardioverter-defibrillator (ICD) intervention, ventricular fibrillation (VF), and SCD. RESULTS LV-LGE was identified in 76 (55.5%) patients. During a median follow-up of 3 years, the combined arrhythmic end point occurred in 22 (16.1%) patients: 8 (5.8%) sustained VT, 9 (6.6%) appropriate ICD intervention, either against VF (n = 5; 3.6%) or VT (n = 4; 2.9%), 3 (2.2%) aborted SCD, and 2 (1.5%) died suddenly. Kaplan-Meier analysis revealed a significant correlation between the LV-LGE presence (not the amount and distribution) and malignant arrhythmic events (P < .001). In univariate Cox regression analysis, LV-LGE (hazard ratio [HR] 4.17; 95% confidence interval [CI] 1.56-11.2; P = .005) and left bundle branch block (HR 2.43; 95% CI 1.01-5.41; P = .048) were found to be associated with arrhythmias. In multivariable analysis, the presence of LGE was the only independent predictor of arrhythmias (HR 3.8; 95% CI 1.3-10.4; P = .01). CONCLUSIONS LV-LGE is a powerful and independent predictor of malignant arrhythmic prognosis, while its amount and distribution do not provide additional prognostic value. Contrast-enhanced cardiac magnetic resonance may contribute to identify candidates for ICD therapy not fulfilling the current criteria based on left ventricular ejection fraction.

Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study.

Vitamin K (vitamin K1 or phylloquinone and vitamin K2, a series of menaquinones [MKs]) is involved in the production of bone and matrix amino acid γ‐carboxy‐glutamic acid (Gla) proteins, regulating bone and vascular calcification. Low vitamin K concentrations are associated with increased risks of fractures and vascular calcification, and frequent complications in hemodialysis patients. We carried out an observational study to establish the prevalence of vitamin K deficiency and to assess the relationship between vitamin K status, vertebral fractures, vascular calcification, and survival in 387 patients on hemodialysis for ≥1 year. We determined plasma levels of vitamin K compound, bone‐Gla‐protein, matrix‐Gla‐protein, and routine biochemistry. Vertebral fractures (reduction in vertebral body height by ≥20%) and aortic and iliac calcifications were also investigated in a spine (D5–L4) radiograph. Three‐year patient survival was analyzed. Important proportions of patients had deficiency of MK7 (35.4%), vitamin K1 (23.5%), and MK4 (14.5%). A total of 55.3% of patients had vertebral fractures, 80.6% had abdominal aorta calcification, and 56.1% had iliac calcification. Vitamin K1 deficiency was the strongest predictor of vertebral fractures (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.38–6.26). MK4 deficiency was a predictor of aortic calcification (OR, 2.82; 95% CI, 1.14–7.01), whereas MK5 deficiency actually protected against it (OR, 0.38; 95% CI, 0.15–0.95). MK7 deficiency was a predictor of iliac calcification (OR, 1.64; 95% CI, 1.03–2.60). The presence of vertebral fractures was also a predictor of vascular calcifications (OR, 1.76; 95% CI, 1.00–3.08). Increased alkaline phosphatase and C reactive protein (CRP), age, and cerebrovascular events were predictors of mortality. Our study suggests that the vitamin K system may be important for preserving bone mass and avoiding vascular calcification in hemodialysis patients, pointing out a possible role of vitamin K in bone and vascular health. Based on our results, we suggest that the general population should also be studied for vitamin K deficiency as a possible cause of both vertebral fractures and vascular calcification.

Arterial complications of pancreatitis : diagnostic and therapeutic role of radiology

Hemorrhage from pseudoaneurysm complicating pancreatitis is an infrequent but very severe condition. In most cases, acute, massive gastrointestinal bleeding is typical at onset, and prognosis of these cases is usually poor. Nine cases of arterial lesions secondary to pancreatic inflammation are presented, eight related to chronic pancreatitis and one to acute postoperative pancreatitis. Five patients were evaluated during emergency episodes because of acutely gastrointestinal bleeding (four cases), and pseudocyst acute bleeding (one case). Four patients were selectively evaluated: three had a history of self-limiting gastrointestinal hemorrhage, whereas one had experienced no episodes of gastrointestinal hemorrhage. Angiography was performed in all cases and was always diagnostic, even in the two cases of very small pseudoaneurysms. Transcatheter arterial blockade was attempted in five patients and failed to control the hemorrhage in one acutely bleeding patient because of irreversible shock. Two cases of pancreatic hemorrhage not related to a pseudocyst were effectively and permanently treated by embolization. A case of a pseudoaneurysm associated with a pseudocyst required surgery in addition to embolization for a definitive treatment. Nevertheless, when a pseudoaneurysm or a pseudocyst hemorrhages acutely, transcatheter arterial blockade can control the hemorrhage and improve the hemodynamic status of the patient before surgery.

Impact of Accessory Hepatic Veins on Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism

Adrenal vein sampling is the gold standard for identification of surgically curable primary aldosteronism, but its accuracy might be hindered by blood dilution from accessory vein blood. We prospectively investigated the presence of accessory veins draining into adrenal veins and their effect on the selectivity index (SI) in 74 consecutive patients undergoing adrenal vein sampling. On the right side, the venous anatomic pattern could be conclusively determined in 91.8% of the cases: we detected hepatic accessory veins in 12.1%, no accessory veins in 42.4%, and renal capsular veins in 45.5%. On the left side there was a phrenico-adrenal trunk in 89.4% and renal capsular accessory veins in 10.6% of the cases. On both sides, renal capsular and phrenic accessory veins did not affect the SI. At variance, on the right side, hepatic accessory veins were associated with SI values ≈3-fold lower than that found when such accessory veins were absent (median: 3.10 [range: 0.80 to 84.2] versus median: 1.10 [range: 0.70 to 2.20]; P=0.01). However, superselective adrenal catheterization resulted into higher SI values (median: 23.88; range: 4.80 to 84.20) in these cases. Thus, hepatic accessory veins sharing egress into the inferior vena cava with the right adrenal vein occurred in ≈12% of the patients and imply a low SI, likely because of adrenal blood dilution by hepatic blood carrying a low cortisol concentration. In the presence of this anatomic variation, superselective catheterization of the right adrenal vein should be undertaken to determine the lateralization of aldosterone secretion.