Natalizumab-induced hepatic injury: A case report and review of literature.

Natalizumab is an α4-integrin monoclonal antibody used for treatment of relapsing multiple sclerosis (MS). At least and nearly 30 cases of liver failure in natalizumab-treated patients are listed in the post-marketing FDA adverse event reporting system (FAERS) and twelve patients with severe liver injury, including several after the first infusion, have been reported (Lisotti et al., 2012; Bezabeh et al., 2010; Martinez-Lapiscina et al., 2013; Michael et al., 2007; Hillen et al., 2015). Herein, we describe a case of a young woman with relapsing MS who developed acute liver injury after the second infusion of natalizumab. Liver biopsy demonstrated a mixed pattern of medication-induced injury or partially treated auto-immune hepatitis. Liver function normalized after natalizumab discontinuation and a subsequent liver biopsy showed resolution of hepatitis. The patient's MS has since been successfully treated with rituximab for over a year. We review the published cases of liver injury associated with natalizumab and those in the post-marketing FDA adverse event reporting system (FAERS).

Pulmonary hypertension in high-altitude chronic hypoxia: response to nifedipine.

Permanent residents at high altitude may develop excessive polycythaemia (H-Hb) and pulmonary hypertension, which often leads to cardiac failure. Inhibitors of calcium channels have been shown to reverse pulmonary hypertension in respiratory diseases and in primary pulmonary hypertension, but their efficiency has not been evaluated in high-altitude-induced pulmonary hypertension. Systolic pulmonary arterial pressure (Ppa) was studied by Doppler echocardiography, at rest and after sublingual nifedipine, in 31 asymptomatic residents at 3,600 m. Individuals were separated into two groups according to resting Ppa: a group with low Ppa (< or =4.7 kPa, n=17) and a group with high Ppa (>4.7 kPa, n=14). Individuals were also split into two groups according to haemoglobin (Hb) concentration: a normocythaemic (L-Hb) group ([Hb] < or =180 g.L(-1), n=17) and a H-Hb group ([Hb] >180 g.L.(-1), n=14). No significant difference in Ppa was observed between the L-Hb and H-Hb groups. There was no correlation between [Hb] and Ppa. Nifedipine induced a decrease of >20% in Ppa in two-thirds of the subjects. This response was correlated with higher levels of basal Ppa (p<0.001) and was inversely correlated with age in the L-Hb group (p<0.05). Pulmonary vasoreactivity to nifedipine was independent of the degree of H-Hb. Pulmonary hypertension secondary to chronic altitude hypoxia may be reversible, despite a possible remodelling of the pulmonary arterioles.

Hormonal changes in normal and polycythemic high-altitude natives.

Acute and chronic exposure to high-altitude (HA) hypoxia inhibits the renin-angiotensin-aldosterone system and may modify the release of atrial natriuretic peptide (ANP) in sea-level (SL) natives. In HA natives, the release of these hormones could be influenced by changes in blood volume or pulmonary arterial pressure. Twenty-four men residing in La Paz, Bolivia, at 3,600 m were separated into two groups: one normocythemic (HAN; with hematocrit < 57%; n = 13) and the other polycythemic (HAP; with hematocrit > 57%; n = 11). A control group of 9 SL residents was studied in normoxia (SLN) as well as after 4 days spent at 4,350 m (SLH). The groups were tested for plasma active renin (PAR), plasma aldosterone concentration, ANP, and potassium and norepineprine concentrations at rest and after a maximal exercise. Pulmonary arterial systolic pressure was assessed by a Doppler technique. It was observed that PAR and plasma aldosterone concentration at rest and after exercise were lower in the SLH than in the SLN group. PAR and norepineprine concentration were higher among highlanders than in the SLN group. Renin response to exercise was normal among the HAN group and slightly decreased among the HAP group, and an exercise-induced increase in aldosterone was attenuated in both HA groups. Aldosterone response to renin was maintained among the SLH group but was attenuated in the HA groups, possibly owing to a protective mechanism against salt and water retention. Resting and exercise ANP was lower in the HA groups than in the SLN group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic status of humans during prolonged exposure to the altitude of 6,542 m.

Plasma norepinephrine (NE) concentration increases with altitude exposure while maximal heart rate (HR) and chronotropic response to isoproterenol (IP) are blunted. Downregulation of cardiac beta-adrenergic receptors (beta-AR) has been evoked to explain this phenomenon. Chronotropic response was studied at extreme altitude in 10 subjects (4 women, 6 men; aged 35 +/- 6 yr). Observations were made in normoxia (N) and after 1 (H1) and 3 (H3) wk at 6,542 m. Acclimatization was accomplished by gradual climbing from 4,000 to 6,542 m over 10 days. Plasma NE was obtained at rest and during submaximal exercise. Successive doses of IP (0.02, 0.04, and 0.06 microgram/kg-1.min-1) were infused for 5 min each. Density and affinity of lymphocyte beta 2-AR were also measured. Increase in HR for maximal dose of IP decreased from 57 +/- 12 to 34 +/- 7 and 37 +/- 10 min-1 in H1 and H3, respectively (P < 0.001 for both). IP dose for which HR rises by 25 min-1 (I25) increased from 27 +/- 5 in N to 42 +/- 10 and 43 +/- 17 ng.kg-1.min-1 in H1 and H3, respectively (P < 0.001 for both). Arterial O2 saturation at rest was 98 +/- 2% in N, 72 +/- 6% in H1 (P < 0.001), and 79 +/- 5% in H3 (P < 0.001). The chronotropic response was neither restored nor further attenuated after 3 wk at 6,542 m. Plasma NE levels at rest and during exercise were higher at 6,542 m than values obtained in previous studies at 4,350 and 4,800 m.(ABSTRACT TRUNCATED AT 250 WORDS)

Control of erythropoiesis in humans during prolonged exposure to the altitude of 6,542 m.

Altitude hypoxia induces an increase in erythropoiesis. Some of the factors involved in the control of altitude polycythemia were studied. Ten subjects (4 women, 6 men) were exposed for 3 wk to extreme altitude (6,542 m). Blood was withdrawn in normoxia (N) and after 1 wk (H1), 2 wk (H2), or 3 wk (H3) at 6,542 m for the measurement of serum erythropoietin (EPO), blood hemoglobin (Hb), hematocrit (Hct), intraerythrocyte folate (Fol), and plasma ferritin (Fer) concentrations. Renal blood flow (RBF) and absolute proximal reabsorption rate (APR) were measured by the p-aminohippuric acid and lithium clearance, respectively, in N and H2 conditions. O2 supply to the kidneys was calculated using RBF and arterial O2 content (CaO2). After an initial sharp increase in EPO, it decreased at H2 and H3. Hct and Hb increased from N to H1 and H2 and then unexpectedly decreased from H2 to H3. Mean corpuscular Hb content (MCHC = Hb/Hct) was lower in all H than in N conditions. Increase in EPO at H1 varied from 3- to 134-fold among individuals. Women showed a smaller increase in Hct and Hb and a greater decrease in MCHC. Two women showed a large increase in EPO without increase in Hb. Fol was not modified by altitude hypoxia. Fer showed a marked decrease in H1 and H3 compared with N. Hb was positively related to Fer in hypoxia. Iron intake in food was markedly decreased during the 2-wk ascent to 6,542 m. EPO was inversely related to CaO2 and positively related to APR.(ABSTRACT TRUNCATED AT 250 WORDS)

Sistema adrenérgico en los residentes de grandes alturas / Adrenergic system at high altitude population

Heart rate (FC) response to perfusion with isoprenaline is decreased in sealevel natives on expuser to high altitude hypoxia. Since noredraline concentration in plasma is elevated under these condition as phenomenon of downregulation of the betareceptors (BAR) cuold be evoked. For the fisrt time, this aspect was explored in a population native from and residing at 3600 m consisting of normocythemics (HAN) and polycythemics (HAP). the results were compared to those obtained from a sealevel population, exmined in normoxia (SLN) at 4800 m (J. Appl. Physiol. 65:1975-61, 1988). The dose necessary to increase FC by 25 beats per min (125) was identical for HAN and HAP as well as SLN. This iondicates that the chronotropic responses is igual in the two populations when they are studied in their habitual environment; to the contrary, this response is diminished in SLH, thus correlating to the phenomenon of downregulation.

Sleep apneas and high altitude newcomers.

Sleep and respiration data from two French medical high altitude expeditions (Annapurna 4,800 m and Mt Sajama 6,542 m) are presented. Difficulties in maintaining sleep and a SWS decrease were found with periodic breathing (PB) during both non-REM and REM sleep. Extent of PB varied considerably among subjects and was not correlated to the number of arousals but to the intercurrent wakefulness duration. There was a positive correlation between the time spent in PB and the individual hypoxic ventilatory drive. The relation between PB, nocturnal desaturation, and mountain sickness intensity are discussed. Acclimatization decreased the latency toward PB and improved sleep. Hypnotic benzodiazepine intake (loprazolam 1 mg) did not worsen either SWS depression or apneas and allowed normal sleep reappearance after acclimatization.

The control of cardiac chronotropic function in hypobaric hypoxia.

Altitude hypoxia induces an increase in adrenergic activity in humans. However, a decrease in maximal heart rate is observed after a few days of exposure to altitudes above 3500 m, as well as a decrease in chronotropic response to isoproterenol infusion. This phenomenon has been linked to a desensitization of beta-adrenoceptors (beta AR), and/or an increase in parasympathetic activity. A decrease in the density of beta AR in chronic hypoxia has been found in rat left ventricle and in human lymphocytes, without modification of the affinity of beta AR for an agonist or antagonist, and a decreased adenylate cyclase activity in the right ventricle. In the same conditions, the density of adenosine A1 receptors is decreased by 46% in rat myocardium, without alteration in the coupling between hormone, receptor and Gi protein. The density of muscarinic receptors is increased by 40%, with an increase in the affinity for an agonist, suggesting an augmented parasympathetic effect. Hypoxia probably acts on all the receptors involved in the modulation of cardiac chronotropic activity; the combined effects of chronic hypoxia on these receptors tend to a beneficial limitation of myocardial oxygen consumption, especially during heavy exercise.

Adrenergic system in high altitude residents.

Heart rate (HR) response to isoproterenol (ISO) infusion (IP) is decreased in normal sea level (SL) natives exposed to high altitude (HA). Since norepinephrine plasma concentration is higher in HA hypoxia, a downregulation of beta-adrenoceptors (beta AR) was evoked. We explored this phenomenon at 3600 m in a HA normal population (HAN) and in polycythemic subjects (HAP). Results are compared to SL natives in normoxia (SLN), and during chronic hypoxia at 4800 m (SLH) (J Appl Physiol 65:1957-1961, 1988). ISO dose required to raise HR by 25 min-1 (I 25) is not different in HAN or HAP group when compared to SLN. Density of beta AR on lymphocytes was 39% and 25% lower in HAN and HAP than in SLN group, respectively. Chronotropic response to IP is similar in SL and HA subjects under their usual environmental conditions, while SL natives show a blunted response under hypoxia, probably due to a decrease in beta AR density. No adrenergic desensitization was found in highlanders. Lower beta AR density in HA groups could be an adaptive mechanism to chronic hypoxia. Polycythemia does not affect this responsiveness.

Ecocardiografia modo "M" y bidimensional en cardiopatias congenitas en la altura (3.500 m) / Echocardiography mode \"M\" and bidimensional in heart defects, congenital in height (3.500 m)

Para evaluar la experiencia, alcances y limitaciones de la ecocardiografia en la valoracion de las cardiopatias congenitas, se reviso la casuistica de los ultimos 5 anos (1982-87) en el IBBA. De un total de 1736 ecocardiografias efectuadas 137 correspondieron a pacientes con diagnostico clinico de cardiopatia congenita. Grupo I (menores de 15 anos) 102 pacientes con cardiopatia congenita siendo la mas frecuentes CIV-CIA-PCA entre las cardiopatias acianoticas y la enfermedad de Ebstein(13 casos -76%). Grupo II (mayores de 15 años) 35 pacientes con cardiopatias congenitas siendo la mas frecuente la CIA (22%) entre las acianoticas y la enfermedad de Ebstein (8%) entre las cianoticas. Se discuten las aportaciones y las limitaciones que la ecocardiografia modo "M" presenta en la evaluacion de las alteraciones anatomicas de las cardiopatias congenitas asi como las ventajas sobre la misma de la acocardiografia bidimensional. Se analizan los hallazgos ecocardiograficos en las cardiopatias congenitas mas frecuentesl. Se concluye que la ecocardiografia constituye un adelanto significativo en la evaluacion y diagnostico de las cardiopatias.

Diagnostico ecocardiografico de la enfermedad de Ebstein / Ultrasonographic diagnosis of Ebstein disease

Se analizaron los hallazgos Eccocardiograficos en siete pacientes con diagnostico clinico, Radiologico y Electrocardiografico de Enfermedad de Ebstein, tres de estos pacientes fueron sometidos a Cateterismo Cardiaco y Cineangiocardiografia. Las alteraciones Ecocardiograficas encontradas e interpretadas como criterios diagnosticos de Enfermedad de Ebstein en vigencia del examen clinico, fueron: 1) Retraso del cierre de la Valvula Tricuspide respecto a laValvula Mitral, mayor a 50 miliseg. b) Registro simultaneo de la Valvula Mitral Tricuspide desde posiciones alejadas del borde esternal izq. c) Amplitud incrementada del movimiento diatolico de la valva anterior de la Tricuspide, d) Morfologia alterada de la valva anterior de la Tricuspide, e) incremento aparente de las dimensiones de Ventriculo derecho, f) Movimiento anormal del Neptum Intraventricular. Se concluye que la Ecocardiografia incrementa las posibilidades diagnosticas de esta Cardiopatia compleja, asimismo se llama la atencion sobre la elevada incidneica de la Enfermedad de Ebstein en nuestra casuistica.