Urea for long-term treatment of syndrome of inappropriate secretion of antidiuretic hormone.

The efficacy of oral urea in producing a sufficiently high osmotic diuresis was tested in seven patients with the syndrome of inappropriate secretion of antidiuretic hormone. In all patients urea corrected the hyponatraemia despite a normal fluid intake. Five patients were controlled (serum sodium concentration greater than 128 mmol(mEq)/1) with a dose of 30 g urea daily, and two with 60 g daily. The patients who needed 30 g drank 1-2 1 of fluid daily, while those who needed 60 g drank up to 3.1 per day. No major side effects were noted, even after treatment periods of up to 270 days. These findings suggest that urea is a safe and efficacious treatment of the syndrome of inappropriate secretion of antidiuretic hormone.     

Coma Associated with Vincristine Therapy

Three cases of coma after vincristine therapy are described. One patient had hyponatraemia and other features of inappropriate secretion of antidiuretic hormone. The effects were temporary, and full recovery occurred in all three patients.     

Influence of the CXCL1 rs4074 A Allele on Alcohol Induced Cirrhosis and HCC in Patients of European Descent

Background and Aims

CXCL1 (CXC chemokine-ligand-1) is a ligand for CXC chemokine receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. In the present study, we investigated the influence of the CXCL1 rs4074 polymorphism on the occurrence of alcohol induced liver cirrhosis and hepatocellular carcinoma (HCC).

Methods

The study involved 458 patients with alcoholic cirrhosis (170 with HCC), 115 alcoholics without liver disease and 342 healthy controls. All subjects were genotyped for the CXCL1 rs4074 polymorphism and CXCL1 serum levels of 132 patients were measured. In vitro CXCL1 secretion in TLR-transfected cell lines were studied by ELISA.

Results

Distribution of the CXCL1 genotypes (GG/GA/AA) was 159/219/80 in patients with alcoholic cirrhosis, 52/44/19 in alcoholic controls and 158/140/44 in healthy controls. Patients with alcohol-induced cirrhosis were significantly more often carriers of the CXCL1 rs4074 A allele (65.3%) than alcoholics without liver disease (54.8%, OR=1.55; 95%CI=1.025-2.350; p=0.04) and healthy controls (53.8%, OR=1.62; 95%CI=1.212-2.151; p=0.001). Accordingly, the frequency of the CXCL1 rs4074 A allele was significantly higher in the cirrhotic patients than in the subjects without cirrhosis (41.4% vs. 33.9%, OR=1.38, 95% CI:1.14–1.66, p=0.001). Furthermore cirrhotic carriers of the CXCL1 rs4074 A allele had significantly higher CXCL1 serum levels than carriers of the GG genotype. In contrast to sera from healthy controls, sera from patients with alcoholic cirrhosis induced CXCL1 secretion in TLR2- (p=0.016) and TLR4- (p=0.008) transfected HEK293 cells. This finding indicates that sera from patients with alcoholic cirrhosis contain soluble ligands that can induce CXCL1 production via stimulation of TLRs.

Conclusion

The enhanced CXCL1 serum levels in carriers of the rs4074 A allele together with their increased frequency in patients with alcohol induced cirrhosis suggest the CXCL1 rs4074 A allele as a genetic risk factor for alcoholic cirrhosis.     

Hypoalbuminaemic hyponatraemia: a new syndrome?

Six patients with severe hyponatraemia had neurological features of hyponatraemia and pronounced hypoalbuminaemia. All had biochemical features typical of the syndrome of inappropriate secretion of antidiuretic hormone with low serum osmolality and an inappropriately high urinary osmolality. All were given infusions of whole plasma or albumin solution, or both, to restore their plasma albumin concentrations to normal, which led to a dramatic increase in plasma sodium concentrations and serum osmolality, with a concomitant fall in urinary osmolality in all patients. Neurological features were reversed in four patients. It is suggested that severe hypoalbuminaemia is an important cause of appreciable hyponatraemia; infusions of plasma and albumin in such patients may reverse the biochemical and clinical features and should form the basis of management.     

The syndrome of inappropriate antidiuretic hormone secretion

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the commonest form of normovolaemic or dilutional hyponatraemia. The diagnosis of SIADH should be considered if the five cardinal criteria are fulfilled (hypotonic hyponatraemia, natriuresis, urine osmolality in excess of plasma osmolality, absence of oedema and volume depletion, normal renal and adrenal function). The clinical features are principally neuro-muscular and gastro-intestinal, the severity of which is related to both the absolute serum sodium concentration and its rate of fall, particularly if greater than 0.5 mmol/1/h. The dilutional hyponatraemia of SIADH develops due to persistent detectable or elevated plasma arginine vasopressin (AVP) concentrations in the presence of continued fluid intake. Osmoregulated inhibition of thirst failures to curb fluid intake. The major groups of causes of SIADH are: (i) neoplasia, (ii) neurological diseases, (iii) lung diseases and (iv) a wide variety of drugs. Inappropriate infusion of hypotonic fluids in the post-operative state remains a common cause. Four categories of osmoregulated AVP secretion have been described: (i) erratic AVP release, (ii) reset osmostat, (iii) persistent AVP release at low plasma osmolality and (iv) normal osmoregulated AVP secretion. For symptomatic patients with chronic SIADH, the mainstay of therapy remains fluid restriction. New antagonists to the antidiuretic action of AVP offer a new therapeutic approach.     

Rate of cirrhosis progression reduced in HIV/HCV co-infected non-responders to anti-HCV therapy

This is a retrospective longitudinal follow-up study of 25 HIV/HCV positive cirrhotic patients not responding to peg-IFN plus ribavirin, and 25 untreated controls matched for age (+/-5 years), gender and Child-Pugh score. The primary endpoint of the study was the incidence of cirrhosis progression (CP) defined as the occurrence of at least one of the following events: death, ascites, jaundice, encephalopathy, gastrointestinal bleeding and hepatocellular carcinoma (HCC). During the median follow-up of 54 months (34-89), four treated (16%) and 13 untreated patients (52%) experienced CP (p = 0.02). Poisson's regression model showed that the independent predictors of CP were Peg-IFN therapy (p = 0.016), positive HIV-RNA (p = 0.024), and altered ALP values (p = 0.012). Peg-IFN therapy seems to slow down the rate of cirrhosis progression also in HIV/HCV co-infected patients nonresponders to anti-HCV therapy, in comparison with untreated patients.     

Resetting of osmoreceptor response as cause of hyponatraemia in acute idiopathic polyneuritis.

In a patient with hyponatraemia associated with acute idiopathic polyneuritis plasma concentrations of antidiuretic hormone increased when hypertonic saline was infused intravenously, and urine osmolality rose concomitantly. A water load was excreted normally, while the plasma remained extremely hypo-osmolal. It is concluded that osmoregulation was functioning normally but was set abnormally low, possibly owing to a disturbance of the peripheral volume receptors.     

Inappropriate secretion of antidiuretic hormone treated with frusemide.

Seven out of nine patients with chronic inappropriate secretion of antidiuretic hormone were successfully treated with 40 mg frusemide daily. One patient needed 80 mg, and the remaining patient achieved only a small increase in diuresis after 40 mg frusemide; this was probably related to his low creatinine clearance. In order to maintain a salt intake high enough to compensate for the loss of urine electrolytes 3 to 6 g sodium chloride was added as tablets to the sodium-free diet in six patients. Hypokalaemia occurred in five patients but was easily corrected with either supplements of potassium chloride or a potassium-sparing diuretic. These findings add further weight to evidence that Frusemide is a good alternative for the treatment of patients with inappropriate secretion of antidiuretic hormone who cannot tolerate water restriction.     

Predictive value of early virological response to treatment with different interferon-based regimens plus ribavirin in patients with chronic hepatitis C

Early virological response (EVR) to different interferon-based regimens plus ribavirin and its ability to predict the outcome of therapy in patients with chronic hepatitis C were investigated. The study design was as follows: 64 naive patients were considered, 32/64 received pegylated interferon alpha-2b (Peg-IFN-alpha2b) plus ribavirin and the remaining 32 received leucocyte interferon alpha (IFN-alpha) plus ribavirin. At week 4 of treatment, EVR was present in 68.7% and 37.5% of patients treated with Peg-IFN-alpha2b plus ribavirin, and with leucocyte interferon alpha (IFN-alpha) plus ribavirin, respectively (p = 0.024). At week 12, the cumulative EVR rates did not differ between the two groups (71.9% vs 56.2%, p >0.05) because a higher proportion of patients achieved EVR for the first time after more than 4 weeks of therapy in the standard IFN-alpha group. Sustained virological response (SVR) rates, however, resulted significantly higher in the Peg-IFN-alpha2b group (65.6% vs 37.5%; p = 0.045) since a higher proportion of patients who received standard IFN-alpha relapsed during the follow-up. In the standard IFN-alpha group, HCV genotype 1 (p = 0.035), high baseline viral load (p = 0.035) and the presence of bridging fibrosis/cirrhosis (p = 0.011) were closely associated with significantly lower SVR rates. In the Peg-IFN-alpha2b group, only bridging fibrosis/cirrhosis (p = 0.02) negatively influenced the outcome of treatment. Overall, 33/41 (80.5%) patients with EVR at week 12 were sustained responders, yielding a positive predictive value (PPV) of 0.80. However, when SVR was related to the time taken to reach EVR, 32/34 (94.1%) patients with EVR at week 4 of therapy (PPV = 0.94) versus 1/7 (14.3%) patients who had EVR after more than 4 weeks of therapy (PPV = 0.14) resulted sustained responders (p = 0.000057). In conclusion, EVR at week 4 of treatment is strongly associated with the likelihood of achieving SVR, regardless of the therapeutic regimen. However, when compared with standard IFN-alpha plus ribavirin, treatment with Peg-IFN-alpha2b plus ribavirin significantly increases the probability of viral clearance within the first 4 weeks of treatment. Finally, patients who do not clear the virus within the first 12 weeks of treatment have no chance of achieving SVR, justifying discontinuation of therapy in these patients.     

Frequency of Strongyloides stercoralis infection in alcoholics

Several studies have shown that chronic alcoholics have increased susceptibility to infections due to higher exposure to infectious agents as well as breakdown in their immune defenses. As Strongyloides stercoralis infection is usually more relevant in immunocompromised patients, the aim of this study was to evaluate the frequency of S. stercoralis infection in alcoholics. Thus, coproparasitological examination was carried out in 145 subjects, from which 45 were chronic alcoholics (mean age of 45.7 +/- 11.0 years), 10 were nonalcoholic cirrhotic patients (mean age of 50.2 +/- 13.1 years), and 90 were asymptomatic nonalcoholic subjects (mean age of 46.7 +/- 10.1 years), which served as controls. From the alcoholics, 9 had hepatic cirrhosis, 9 had chronic pancreatitis and 27 had neither cirrhosis nor pancreatitis. For the diagnosis of strongyloidiasis, the Baermann-Moraes and Lutz methods were used in three fecal samples from each subject. Samples were collected at alternated days, and three slides of each sample were analyzed for each method, thus totalizing 2,610 slides examined. The frequency of strongloidiasis in the total alcoholic group (33.3%) and in the subgroups of alcoholics, i.e., patients with hepatic cirrhosis (44.4%), with chronic pancreatitis (33.3%), and those with no cirrhosis or pancreatitis (29.6%) was statistically higher than that found in the control group (5.5%). None of the individuals with nonalcoholic hepatic cirrhosis had S. stercoralis infection. Our results showed that the chronic alcoholism itself is an important factor that predisposes to strongyloidiasis.     

Gastric acid secretion in streptozotocin-diabetic rats--different responses to various secretagogues.

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)), pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(-1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.     

Effect of repeated alcohol administration on urine secretion and antidiuretic hormone in rats]

The administration of ehtanol by gavage immediately produced a maintened hyperdiuresis, a transient decrease of urinary osmolality and antidiuretic hormone secretion, followed by increased plasmatic and urinary antidiuretic hormone concentrations. Chronic intoxication enhanced these effects probably due to central disturbance.     

Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease.

Increasing evidence indicates the involvement of immune reactions in the pathogenesis of alcoholic liver disease. We have investigated whether ethanol-induced oxidative stress might contribute to immune response in alcoholics. Antibodies against human serum albumin modified by reaction with malondialdehyde (MDA), 4-hydroxynonenal (HNE), 2-hexenal, acrolein, methylglyoxal, and oxidized arachidonic and linoleic acids were measured by ELISA in 78 patients with alcoholic cirrhosis and/or hepatitis, 50 patients with nonalcoholic cirrhosis, 23 heavy drinkers with fatty liver, and 80 controls. Titers of IgG-recognizing epitopes derived from MDA, HNE, and oxidized fatty acids were significantly higher in alcoholic as compared to nonalcoholic cirrhotics or healthy controls. No differences were instead observed in the titers of IgG-recognizing acrolein-, 2-hexenal-, and methylglyoxal-modified albumin. Alcoholics showing high IgG titers to one adduct tended to have high titers to all the others. However, competition experiments showed that the antigens recognized were structurally unrelated. Anti-MDA and anti-HNE antibodies were significantly higher in cirrhotics with more severe disease as well as in heavy drinkers with cirrhosis or extensive fibrosis than in those with fatty liver only. We conclude that antigens derived from lipid peroxidation contribute to the development of immune responses associated with alcoholic liver disease.     

Severe Hyponatre mia Due to Rosiglita zone Use in an Elderly Woman With Diabetes Mellitus: A Rare Cause of Syndrome of Inappropriate Antidiuretic Hormone Secretion

ObjectiveTo describe the first case of syndrome of inappropriate antidiuretic hormone secretion with lifethreatening hyponatremia due to rosiglitazone therapy.MethodsWe describe the clinical, laboratory, and imaging findings of the study patient.ResultsAn 89-year-old woman with a 5-year history of type 2 diabetes mellitus was admitted to the emergency department because of unconsciousness. She had reported generalized weakness for 15 days and nausea and vomiting for 3 days. Findings from laboratory analysis showed severe hyponatremia (sodium, 110 mEq/L). She had normal renal, cardiac, and adrenal function, and she did not have edema or volume depletion. The cause of hyponatremia was syndrome of inappropriate antidiuretic hormone secretion. We did not find any cause for her condition other than rosiglitazone, an antihyperglycemic drug that is increasingly being used in patients with type 2 diabetes mellitus. According to her medical history, rosiglitazone was prescribed 1 month previously after withdrawal of gliclazide. We stopped the rosiglitazone and administered hypertonic saline infusion to treat the hyponatremia. Saline infusion was stopped and blood sodium levels were stabilized in the normal range after 2 days. The patient’s plasma sodium concentration has remained in the reference range at follow-up visits.ConclusionsThis is the first reported case of syndrome of inappropriate antidiuretic hormone secretion as an adverse effect of rosiglitazone, and this drug should possibly be considered for addition to the list of drugs that cause this condition. (Endocr Pract. 2008;14:1017-1019)     

Bombesin microinjected into the dorsal vagal complex inhibits vagally stimulated gastric acid secretion in the rat

Medullary sites of action for bombesin-induced inhibition of gastric acid secretion were investigated in urethane-anesthetized rats with gastric fistula. Unilateral microinjection of bombesin or vehicle into the dorsal vagal complex was performed using a glass micropipet and pressure ejection of 100 nl volume; gastric acid output was measured every 10 min by flushing the stomach. Microinjection of vehicle into the dorsal vagal complex did not alter gastric acid secretion (1.9 +/- mumol/10) from preinjection levels (2.9 +/- 0.8 mumol/10 min). Microinjection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, at a 77 pmol dose into the dorsal vagal complex stimulated gastric acid secretion for 100 min with a peak response at 40 min (24.1 +/- 3.2 mumol/10 min). Concomitant microinjection of RX 77368 (77 pmol) with bombesin (0.6-6.2 pmol) into the dorsal vagal complex dose dependently inhibited by 35-86% the gastric acid response to the TRH analog. Bombesin (6.2 pmol) microinjected into the dorsal vagal complex inhibited by 17% pentagastrin infusion-induced stimulation of gastric acid secretion (13.2 +/- 0.8 mumol/10 min) whereas intracisternal injection induced a 69% inhibition of the pentagastrin response. These results demonstrate that the dorsal motor complex is a sensitive site of action for bombesin-induced inhibition of vagally stimulated gastric secretion. However, other medullary sites must be involved in mediating the inhibitory effect of intracisternal bombesin on pentagastrin-stimulated gastric acid secretion.     

Renin-Aldosterone System in Osmoregulatory Reactions of Healthy Subjects in Response to Desmopressin

Systemic regulation of osmotic and ionic homeostasis was studied in healthy male volunteers after oral administration of desmopressin. Endogenous secretion of the antidiuretic hormone was inhibited by a water load (WL, 2% of the body mass). Desmopressin exerted an antidiuretic effect. In addition, the WL portion excreted during 4 h decreased and the urine osmolality at peak diuresis increased with the absence of osmotically free water. At maximum diuresis, the ratio between concentrations of osmotically active substances in the urine and in the blood was high, which reflected an intense antidiuretic effect. Desmopressin progressively decreased the rate of sodium excretion owing to a change of sodium reabsorption in the kidneys. The WL increased the level of aldosterone and the activity of renin in blood plasma 1.5 h after its administration. Contrary to the control series, desmopressin stimulated the renin-angiotensin-aldosterone system only by the end of the 4-h observation period. A significant negative correlation between the aldosterone level and the rate of sodium excretion was observed 3 h after the beginning of testing (r = ?0.76). Thus, under conditions of water loading, desmopressin had a specific antidiuretic effect involving systemic mechanisms of ion regulation.     

Atrial natriuretic hormone secretion in patients with renal failure

To study the effects of volume overload and renal failure on plasma levels of immunoreactive atrial natriuretic hormone (IR-ANH), we measured levels of this hormone in normal subjects, in patients with advanced chronic renal failure (CRF) with and without clinically evident volume overload, and in patients with end-stage renal disease (ESRD) treated with chronic hemodialysis. The levels were 13 +/- 2 pmol/l in normal volunteers, 77 +/- 24 pmol/l in patients with CRF without volume overload, and 219 +/- 50 pmol/l in patients with CRF and clinically evident volume overload (analysis of variance, p less than 0.001, alpha = 0.05 compared to normals). In patients with ESRD, the levels of IR-ANH were 145 +/- 46 pmol/l before dialysis and decreased to 87 +/- 31 after dialysis (p less than 0.025). No correlation was found between the decrease in IR-ANH levels and the decrease in weight during dialysis. A significant positive correlation was found between the IR-ANH levels and blood urea nitrogen in patients with CRF (r = 0.658, p less than 0.01). Volume overload appears to be the most important stimulatory factor for ANH secretion in renal failure patients but other mechanisms, especially a decrease in metabolic clearance, may also contribute to elevated plasma levels. The increased secretion of ANH in patients with renal failure may be an important adaptive response to volume overload and hypertension.     

Electrically evoked synaptosomal amino acid transmitter release in human brain in alcohol misuse

Severe chronic alcohol misuse leads to neuropathological changes in human brain, with the greatest neuronal loss in the dorsolateral prefrontal cortex. In this region, GABA(A) receptors are selectively upregulated, and show altered subunit expression profiles only in alcoholics without comorbid disease, whereas glutamate(NMDA) subunit expression profiles are selectively downregulated only in alcoholics with comorbid cirrhosis of the liver. To determine whether these outcomes might be conditional on synaptic transmitter levels, evoked release was studied in well-characterized synaptosome suspensions preloaded with L-[(3)H]glutamate and [(14)C]GABA and stimulated electrically (±10 V contiguous square waves, 0.4 ms, 100 Hz, 1.5 min) with and without Ca(2+). Stimulation elicited brief peaks of both radioisotopes that were larger in the presence of Ca(2+) ions (p < 0.01). A repeat stimulus evoked a second, smaller (p < 0.01) peak. Ca(2+)-dependent L-[(3)H]glutamate release, but not [(14)C]GABA release, was higher overall in alcoholics than in controls (p < 0.05). With comorbid cirrhosis, L-[(3)H]glutamate release showed a graded response, whereas [(14)C]GABA release was lowest in noncirrhotic alcoholics. Release patterns did not differ between cortical regions, or between males and females. Neither age nor postmortem interval was a significant confounder. The released transmitters may differentially alter receptor profiles on postsynaptic cells.     

Serum concentration of zinc, copper, manganese and magnesium in patients with liver cirrhosis

The role of trace elements in the pathogenesis of liver cirrhosis and its complications is still not clearly understood. Serum concentrations of zinc, copper, manganese and magnesium were determined in 105 patients with alcoholic liver cirrhosis and 50 healthy subjects by means of plasma sequential spectrophotometer. Serum concentrations of zinc were significantly lower (median 0.82 vs. 11.22 micromol/L, p < 0.001) in patients with liver cirrhosis in comparison to controls. Serum concentrations of copper were significantly higher in patients with liver cirrhosis (median 21.56 vs. 13.09 micromol/L, p < 0.001) as well as manganese (2.50 vs. 0.02 micromol/L, p < 0.001). The concentration of magnesium was not significantly different between patients with liver cirrhosis and controls (0.94 vs. 0.88 mmol/L, p = 0.132). There were no differences in the concentrations of zinc, copper, manganese and magnesium between male and female patients with liver cirrhosis. Only manganese concentration was significantly different between Child-Pugh groups (p = 0.036). Zinc concentration was significantly lower in patients with hepatic encephalopathy in comparison to cirrhotic patients without encephalopathy (0.54 vs. 0.96 micromol/L, p = 0.002). The correction of trace elements concentrations might have a beneficial effect on complications and maybe progression of liver cirrhosis. It would be recommendable to provide analysis of trace elements as a routine.