Pulmonary hypertension is a common complication of sickle cell disease (SCD) and a risk factor for early death. Hemolysis may participate in its pathogenesis by limiting nitric oxide (NO) bioavailability and producing vasculopathy. We hypothesized that hemoglobin mutations that diminish hemolysis in SCD would influence pulmonary hypertension susceptibility. Surprisingly, coincident a-thalassemia (Odds Ratio [OR] 5 0.95, 95% CI 5 0.46-1.94, P 5 NS) was not associated with pulmonary hypertension susceptibility in homozygous SCD. However, pulmonary hypertension cases were less likely to have hemoglobin SC (OR 5 0.18, 95% confidence interval [CI] 5 0.06-0.51, P 5 0.0005) or Sb 1 thalassemia (OR 5 0.25, 95% CI 5 0.06-1.16, P 5 0.10). These compound heterozygotes may be protected from pulmonary hypertension because of reduced levels of intravascular hemolysis, but develop this complication at a lower rate possibly due to the presence of non-hemolytic risk factors such as renal dysfunction, iron overload and advancing age. Despite this protective association, patients with SC who did develop pulmonary hypertension remained at significant risk for death during 49 months of followup (Hazard Ratio 5 8.20, P 5 0.0057). Am.
Introduction: Transient Central Diabetes Insipidus (tCDI) induced by vasopressin withdrawal is a rare condition which is possibly under recognized. It occurs in very sick, often critically ill patients and usually complicates an already complex clinical picture, so early recognition and treatment are critical to reduce morbidity. Case Description: A 47-y/o male with a PMH of Coffin Lowry syndrome, atrial fibrillation, and GERD presented with abdominal pain and flu like symptoms. His home medications were metoprolol, loratadine and colestipol. Work up revealed bowel perforation for which he was taken to the OR for repair. Intraoperatively he developed septic shock requiring pressor support with norepinephrine and vasopressin. He was weaned off norepinephrine on post-op day (POD)1, and vasopressin on POD 2. Approximately three hours after withdrawal of vasopressin support his urine output increased dramatically up to a peak of 350 cc/hour with a recorded 24hr urine volume of >5L. Concurrently, his serum sodium was found to have increased from 147 mmol/L to 173 mmol/L (n 135-145) over the course of 13 hours. Clinically, he became increasingly lethargic with abnormal eye movements. His sodium did not improve with fluid management with D5W. His other laboratory values included a urine osmolality of 141 mOsm/kg, urine sodium of 60 mmol/L and a peak serum sodium of 177mmol/L. He was administered 1mcg desmopressin and his D5W rate was increased. His urine output dropped gradually to ~150cc/hr, his serum sodium level started to trend down to 168 mmol/L and his urine osmolality increased to 439 mOsm/kg five hours after desmopressin administration, with improvement in mental status. The patient received a total of two doses of desmopressin and continued support with IV fluids. His sodium eventually normalized, and his polyuria did not return. Discussion: This patient’s clinical picture is consistent with tCDI secondary to discontinuation of vasopressin. Transient Central diabetes insipidus due to vasopressin withdrawal is a phenomenon that is not well understood, but there is a strong male preponderance, and it tends to occur more commonly in patients with underlying neurological conditions, as did our patient. Current proposed mechanisms include decreased production and release of exogenous ADH due to negative feedback, down regulation of the V2 receptors, and hypoperfusion to the posterior pituitary. This condition deserves more investigation to better understand the incidence, risk factors and pathophysiological mechanisms.
Pulmonary hypertension (PH) is an increasingly recognized phenotypic manifestation of sickle cell disease (SCD) and a leading cause of death among adults with SCD. Chronic intravascular hemolysis is a central pathologic event with release of hemoglobin into plasma and leads to nitric oxide consumption. A resulting NO deficiency state is hypothesized to produce vasoconstriction within the pulmonary vasculature, ultimately becoming manifest as symptomatic PH. We have hypothesized that genetic factors may influence the risk for developing PH in SCD. As an initial step in identifying PH susceptibility loci, the allelic spectrum of mutations and polymorphisms in the hemoglobin genes have been examined with respect to PH in adults with SCD. Echocardiography was used to phenotype 261 unrelated subjects for PH, where cases were prospectively defined by a triscuspid regurgitant jet velocity > 2.5 m/s. The entire HBB gene was sequenced, and genotypes for SNPs flanking the β and α-globin loci were determined. HBB sequence analysis identified 66 (25.3%) compound heterozygotes for 1 of 13 different mutations (16.1% Hb SC or 9.2% β+ thalassemia, β0 thalassemia, or another hemoglobinopathy). A significant difference in genotype distributions between PH cases and cohort controls (3 x 2 table, P=0.026) suggested that individual mutations within the locus may be associated with PH. When analyzed individually, the prevalence of HbSC between cases (7.4%) and controls (21.1%) suggested that the HbC allele is associated with protection from PH (Odds Ratio=0.35, 95% CI 0.15–0.78, P=0.009). HbSS is only a mild risk factor (OR=2.01, 95% CI 1.07–3.78, P=0.026). In contrast, there was no association between 5′ or 3′ β globin locus haplotypes defined by combinations of 16 common SNPs and PH in patients with either SCD or HbSS. When the α-globin locus was examined using 3 haplotype tagged SNPs flanking the HBA2 and HBA1 genes, no PH associations were observed. An analysis of α-thalassemia mutations has not yet been completed, thus no definitive conclusions can be made for the influence of the α-globin locus on PH. Finally, the HbSC association was explored further by comparing laboratory markers of hemolysis and survival data within the HbSC group. Between SC PH cases and controls, anemia was the only significant characteristic of PH (P=0.0027) without other labs suggestive of excessive hemolysis. In contrast, other clinical findings observed in association with SCD PH, including hepatic congestion, iron overload and renal insufficiency, were present in HbSC PH group. While an overall association with protection from PH was observed for HbSC, a preliminary 40 month survival analysis suggests that PH in SC patients remains a significant marker associated with a risk for death (Hazard Ratio=7.89, P=0.007) which is comparable to overall SCD survival with PH. We conclude that the HbSC genotype is associated with protection from the development of PH in SCD, possibly due a smaller relative contribution of intravascular hemolysis. However, this diagnosis remains a strong predictor for death in SCD independent of HBB genotype. Further study of large populations of HbSC patients are warranted for defining optimal PH therapies and may be useful for elucidating the genetic basis for the non-hemolytic mechanisms contributing to secondary PH in SCD.
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