Propranolol for portal hypertension. Evaluation of therapeutic response by direct measurement of portal vein pressure.

Portal vein pressure was measured before and after a week of oral propranolol hydrochloride therapy in 27 patients with alcoholic liver disease. Mean net portal pressure fell (14.5 +/- 3.3 to 12.5 +/- 4.5 mm Hg), but there was wide variation in individual response to the drug. Simultaneous transhepatic portal vein pressure and wedged hepatic vein pressure were similar before and one hour after a single oral dose of 40 mg of propranolol hydrochloride in six additional patients. Arterial, portal, and hepatic vein oxygen content did not change significantly. Propranolol hydrochloride appears not to dissociate portal and wedged hepatic vein pressure or to impair liver oxygenation. Because of variability of response, the portal hypotensive effect of propranolol should be documented before beginning therapy with the drug.

'Diuretic-resistant' ascites. Observations on pathogenesis.

Hepatic sinusoidal hydrostatic-oncotic balance was measured in 25 patients with alcoholic liver disease and varying severity of sodium retention. Eight patients had diuretic-responsive ascites and 17 patients had diuretic-resistant ascites. Net "transfer pressure," the force theoretically favoring fluid transudation across the hepatic sinusoids, was similar in the diuretic-responsive and diuretic-resistant groups and was unrelated to the fractional excretion of sodium after intravenous administration of furosemide. Fractional sodium excretion was significantly less in resistant than in responsive patients, but kaliuresis after furosemide was similar. Baseline creatinine clearance was similar in the two groups, but maximal oral diuretic therapy caused a significantly steeper rise in serum creatinine concentration in resistant than in responsive patients, despite less weight loss. More marked hepatic sinusoidal hydrostatic-oncotic imbalance was not present in patients with diuretic-resistant ascites. Similar kaliuretic response despite reduced natriuretic response to furosemide suggested that the proximal tubule is the site of enhanced sodium resorption in these patients. Renal insufficiency developing during long-term diuretic treatment is an important factor limiting natriuresis in patients with diuretic-resistant ascites.

Propranolol in the treatment of cirrhotic ascites.

Propranolol hydrochloride is reported to lower portal pressure and inhibit renin secretion in patients with chronic liver disease, actions that might lessen the tendency to ascites formation. We compared the effect of diuretics with that of the same dose of diuretics plus propranolol on natriuresis, urine output, and daily weight loss in 13 hospitalized patients with stable chronic liver disease, sodium retention, and ascites. The propranolol hydrochloride dose was 20 to 160 mg four times a day, titrated to reduce resting pulse by 25% or systolic BP 10 mm Hg. Diuretics given were furosemide, 80 to 160 mg, and triamterene, 100 or 200 mg/day. Periods of time when each regimen was received ranged from one to four days. Creatinine excretion documented complete urine collections. Compared with diuretics alone, diuretics plus propranolol substantially reduced resting pulse, systolic BP, and urine sodium excretion, although not creatinine clearance. This antinatriuretic effect may limit the proposed usefulness of propranolol for prevention of variceal bleeding in patients with cirrhosis and ascites.

Nonketotic hyperglycemia appearing as choreoathetosis or ballism.

A number of focal neurologic abnormalities may accompany severe, nonketotic hyperglycemia, but extrapyramidal movement disorders have not previously been described. We evaluated the conditions of three patients with marked hyperglycemia in whom hemichorea or ballism developed that resolved completely with normalization of the blood glucose level. Potential pathogenetic mechanisms include relative dopaminergic hypersensitivity, impaired synthesis of acetylcholine or gamma-aminobutyric acid, or an undefined effect of hyperosmolarity, perhaps unmasking a previously subclinical lesion of the basal ganglia. Serum glucose level should be determined in anyone with the new onset of choreoathetosis or ballism, as hyperglycemia is a rapidly reversible cause of these conditions.

Membranous obstruction of the inferior vena cava in the United States.

The pathogenesis of membranous obstruction of the inferior vena cava (MOVC) is unclear. Although the lesion is rare in the United States compared to Japan, India, and black South Africa, it has been responsible for 23% of cases of hepatic outflow obstruction we have encountered in the ethnically heterogeneous indigent population of Los Angeles. Most patients with MOVC are male. In contrast, recent series of patients with Budd-Chiari Syndrome (BCS) have demonstrated a female predominance. Compared to BCS without involvement of the inferior vena cava (IVC), patients with MOVC have more chronic symptoms. Large truncal collaterals, particularly on the back, strongly suggest MOVC. In patients without this sign, a high index of diagnostic suspicion is required. Chronic hepatitis B infection occurs with increased frequency in these patients. Chest radiograph may show an enlarged azygous shadow. Liver-spleen scan is not helpful, and the liver biopsy is frequently nondiagnostic. A useful screening procedure for hepatic outflow block is transhepatic portal pressure measurement demonstrating aberrant hepatic veins with pressures higher than in the portal vein and, occasionally, hepatofugal portal flow. Transcardiac membranotomy appears to be symptomatically effective in patients with MOVC and at least one patent hepatic vein. It is not known whether this operation will prolong life and prevent the development of hepatocellular cancer, which may occur in up to 48% of these patients. The correct therapeutic approach has not been established for those patients whose lesion is not amenable to surgery because of extensive IVC occlusion or absence of patent hepatic veins.

Superiority of the serum-ascites albumin difference over the ascites total protein concentration in separation of "transudative" and "exudative" ascites.

The serum-ascites albumin difference, an index of the serum-ascites oncotic pressure difference, correlates directly with the pressure gradient between the portal capillaries and the peritoneal cavity. This test was compared with the ascites total protein concentration in the separation of "transudative" and "exudative" ascites. The serum-ascites albumin difference was large in patients with transudative ascites (1.6 +/- 0.5 g/dl) and small in patients with exudative ascites (0.6 +/- 0.4 g/dl, p less than 0.001) and provided significantly better discrimination of these categories than did the ascites total protein concentration. The serum-ascites albumin difference was especially useful in the separation of cardiac ascites, which usually has a high total protein concentration, from high protein exudative ascites. The serum-ascites albumin difference did not provide perfect discrimination of any category, however; in patients with mixed causes of ascites, this difference tended to be large, resembling ordinary transudative ascites, a potential source of diagnostic error. Nevertheless, the serum-ascites albumin difference has superior discriminatory power and should replace the ascites total protein concentration in the routine diagnostic examination of ascites.

Plasma renin activity in alcoholic liver disease.

PURPOSE AND PATIENTS AND METHODS: The relationship of plasma renin activity (PRA) to indices of circulatory filling and other possible determinants of renin secretion was studied in 31 men with alcoholic liver disease. Characteristics of patients with normal and increased PRA values were examined. Significant differences guided subsequent simple and multiple regression analysis. RESULTS: Supine PRA was increased (greater than 2.4 ng/mL/h on a 200 mEq/d intake of sodium, ranging as high as 33 ng/mL/h) in 14 of 57 studies. Nonascitic patients with elevated PRA values were significantly younger than those with normal PRA values. Among patients without ascites, the plasma atrial natriuretic factor concentration correlated inversely with PRA. Ascitic patients with elevated PRA values had a significantly reduced serum sodium concentration, urinary sodium excretion, creatinine clearance, and arterial pressure. Systemic vascular resistance, plasma norepinephrine and caffeine concentrations, and left atrial volume were similar in patients with and without increased PRA values. Univariate followed by multiple regression analysis identified age and plasma atrial natriuretic factor concentration as significant independent correlates of PRA in patients without ascites (R2 = 0.54). Serum sodium concentration and urinary sodium excretion were significant correlates of PRA in patients with ascites (R2 = 0.80). CONCLUSION: The associates of PRA in alcoholic liver disease are diverse and potentially complex. Age and plasma atrial natriuretic factor concentration are important in patients without ascites. In patients with ascites, tubular delivery of sodium to the macula densa, as modified by the filtered load and proximal reabsorption, appeared to be a principal association of PRA. Indices of circulatory filling did not emerge as clearly independent associations of PRA. Increased PRA values in patients with ascites may be an effect of sodium retention rather than part of its cause.

Arterial underfilling does not cause sodium retention in cirrhosis.

PURPOSE: To test the peripheral arterial vasodilation hypothesis of sodium retention in cirrhosis. This states that sodium retention is triggered by arterial underfilling and predicts that development of sodium retention will be associated with significant and related declines in indices of arterial filling that reverse when sodium retention resolves. DESIGN: Longitudinal evaluation of a cohort of patients with alcoholic liver disease. PATIENTS AND METHODS: Eighteen men, 8 of whom were studied twice, 3 three times, 2 four times, and 5 five times (40 between-study comparisons). Between 23 studies, the patients were ascites-free (Group NN). Ascites spontaneously disappeared between seven studies (Group YN), appeared between six studies (Group NY), and remained present between four studies (Group YY). Between-study changes in blood volume, arterial blood pressure, cardiac output, systemic vascular resistance, left atrial volume, left ventricular diastolic diameter, aortic root diameter, aortic blood velocity, plasma norepinephrine and atrial natriuretic factor concentrations, plasma renin activity, and urinary sodium excretion were evaluated by paired t-tests. These changes were also compared among groups by analysis of variance. In addition, correlations among the changes were sought. RESULTS: Systolic, diastolic, and mean arterial pressures, left ventricular diastolic diameter, aortic root diameter, stroke volume, cardiac output, plasma norepinephrine concentration, and systemic vascular resistance were unchanged between studies. Left atrial volume increased between studies in Group NY. Pulse pressure fell more in Group NY than in Groups NN and YN, principally as a result of a decline in systolic blood pressure. Plasma norepinephrine concentration, plasma renin activity, and blood volume rose more in Group NY than in Groups NN, YN, and YY. Changes in both systolic and pulse pressures were directly correlated with the change in sodium excretion but unrelated to the change in plasma norepinephrine concentration. Changes in plasma norepinephrine concentration and plasma renin activity were unrelated to changes in blood pressure, systemic vascular resistance, and urinary sodium excretion. CONCLUSIONS: None of the indices of arterial filling tested except pulse pressure were related to sodium retention. Reduced pulse pressure is inconsistent with arterial underfilling, as peripheral vasodilation instead increases pulse pressure by increasing diastolic run-off. These data do not support the hypothesis that arterial underfilling is the stimulus for sodium retention in alcoholic cirrhosis.

Morbidity and mortality of portal hypertension.

Portal hypertension occurs in several aetiologically distinct disease states associated with either increased flow or increased resistance in the portal venous system. The morbidity and mortality observed are the result of ascites formation, impaired hepatic metabolism, encephalopathy and, most ominously, variceal haemorrhage. Patients with conditions in which there is relatively little hepatic parenchymal damage (non-cirrhotic portal hypertension) tend to have fewer episodes of encephalopathy and are better able to tolerate bleeding episodes than those patients with underlying cirrhosis. Similarly, the development of ascites varies with respect to the aetiology of the portal hypertension. This chapter discusses the natural history of the various disease states that manifest portal hypertension, thus allowing critical evaluation of the various therapeutic modalities used in its treatment.

Serum magnesium and copper levels in myocardial infarction.

The serum levels and urinary excretion of magnesium and copper were studied in 66 patients with either acute myocardial ischemia or myocardial infarction. Serum for magnesium and copper determinations was obtained daily for three days. The initial serum magnesium levels were normal in patients with ischemia but were low in some patients with myocardial infarction. Patients developing ventricular arrhythmias with myocardial infarction showed the lowest levels of serum magnesium. Copper in the serum appeared elevated in patients developing acute congestive heart failure but the elevation was not statistically significant. These data indicate that a decrease in serum magnesium as evaluated may be associated with ventricular arrhythmias in patients with myocardial infarction; thus continued observations of magnesium levels in the myocardial infarction patient is warranted.

Incidence and predictors of bleeding or thrombosis after polypectomy in patients receiving and not receiving anticoagulation therapy.

BACKGROUND AND AIMS: To assess the effect of warfarin anticoagulation therapy (AC) on the incidence of colon bleeding after elective colonoscopy with polypectomy and to identify independent predictors of post-polypectomy colon bleeding. METHODS: This was a retrospective cohort analysis. Patients interrupting warfarin AC therapy for polypectomy (AC group) were matched on age (+/- 3 years) with up to two patients who underwent polypectomy but were not receiving AC (non-AC group). Data were extracted from electronic medical, pharmacy and laboratory claims and records and manual medical chart review. Incidence rates of colon bleeding requiring hospitalization, other gastrointestinal bleeding, thrombosis and death in the 30 days post-polypectomy were compared between groups. Multivariate regression techniques were used to identify independent predictors of post-polypectomy colon bleeding. RESULTS: A total of 425 AC group patients were matched to 800 non-AC group patients. Post-polypectomy colon bleeding occurred more often in AC group patients (2.6% vs. 0.2%, P = 0.005). There were no differences in the rates of other outcomes (P > 0.05). Independent predictors of colon bleeding included AC group status [adjusted odds ratio (AOR) = 11.6; 95% confidence interval (CI) = 2.3-57.3], number of polyps removed (AOR = 1.2; 95% CI = 1.1-1.4) and male gender (AOR = 9.2, 95% CI = 1.1-74.9). CONCLUSIONS: The incidence of post-polypectomy colon bleeding was higher in patients receiving AC even although warfarin was interrupted for the procedure. Independent predictors of colon bleeding were identified as: receiving AC, removal of multiple polyps and male gender. Our findings suggest that additional methods to reduce the likelihood of post-polypectomy colon bleeding in AC patients should be investigated.

Urinary prostaglandin E2 excretion, sodium retention, and diuretic responsiveness in patients with chronic liver disease.

It has been postulated that diminished renal prostaglandin E2 (PGE2) production, whether basal or in response to stimulation by diuretic treatment, determines the intensity of sodium retention in cirrhosis. Urinary PGE2 excretion (as an index of renal PGE2 production) as well as urine volume, urinary sodium and potassium excretion, and creatinine clearance were examined in 19 patients with cirrhosis and either no ascites, diuretic-responsive ascites, or diuretic-resistant ascites. Measurements were made both before (all patients) and after (ascitic patients) stimulation of renal PGE2 synthesis by 80 mg of furosemide intravenously. Urinary PGE2 excretion was similar in the three groups both before and after furosemide. Baseline urine volume and creatinine clearance were similar in all groups but were significantly less after furosemide in patients with diuretic-resistant ascites as compared to the other two groups. The natriuretic response to intravenous furosemide was significantly less in patients with diuretic-resistant ascites. Insertion of the peritoneovenous shunt to aid in the management of diuretic-resistant ascites resulted in a marked, immediate increase in urine volume and urinary PGE2 excretion in the four patients who were serially evaluated, but natriuresis occurred in only two. Overall, urinary PGE2 excretion correlated with urine volume but not with sodium excretion or creatinine clearance. Diminished renal PGE2 production, as reflected by urinary PGE2 excretion, does not appear to be a determinant of the severity of renal sodium retention in cirrhosis.

Ascites kinetics in cirrhosis: effects of rapid volume expansion and diuretic administration.

I examined whether the rate of ascites formation in cirrhosis is increased by volume expansion and whether this rate is related to the intensity of renal sodium retention, and I examined the mechanisms by which ascites is mobilized during diuresis. The plasma-ascites filtration rate (PFR) of intravenously injected iodine 125-labeled albumin (the rate of ascites formation by the liver) after volume expansion with normal saline solution in seven patients was similar to that observed in 14 patients who had not received infusions (0.010 +/- 0.003 vs. 0.013 +/- 0.006 L/hr/m2) and was unrelated to natriuresis both before and after intravenous administration of 80 mg furosemide the previous day (r = 0.04 and -0.36). Diuresis of seven patients who had not received infusions reduced PFR (from 0.679 +/- 0.267 to 0.411 +/- 0.198 L/day, P less than 0.05) and total ascites formation rate (from 3.029 +/- 1.620 to 1.465 +/- 1.053 L/day, P less than 0.02) but not plasma volume (from 3.464 +/- 0.646 to 3.391 +/- 0.775 L). Increases occurred in ascites albumin concentration (from 7 +/- 4 to 9 +/- 4 gm/L, P less than 0.05) and in the ascites/serum albumin ratio (from 0.26 +/- 0.12 to 0.35 +/- 0.13, P less than 0.05) but not in the serum-ascites albumin gradient (portal pressure). Fractional changes in ascites volume and albumin concentration were unrelated (r = 0.20). The calculated rate of ascites reabsorption decreased in five patients during diuresis, indicating that ascites was mobilized by decreased formation. Ascites reabsorption increased in two patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Pica: its frequency and significance in patients with iron-deficiency anemia due to chronic gastrointestinal blood loss.

PURPOSE: Pica, particularly ice-eating (pagophagia), is a recognized symptom of iron deficiency. The value of pica as a clue to the etiology of blood loss has never been studied. PATIENT POPULATION: Fifty-five unselected patients with iron-deficiency anemia due to gastrointestinal blood loss evaluated by a gastroenterology referral service at a city hospital. RESULTS: The patients' mean hematocrit was 26 +/- 15% (SD). Thirty two (58%) had pica, and in 28 (88%) it manifested as pagophagia. Pica was present significantly more often in women (19/32, 68%) than in men (9/23, 39%, p less than 0.05). Pica occurred less frequently in patients with malignancy (2/9 vs. 30/46), but this difference was not significant. CONCLUSION: Pica, a frequent symptom in patients with iron-deficiency anemia due to gastrointestinal blood loss, particularly women, is not of value in predicting the cause of bleeding.

Spontaneous chylous ascites of cirrhosis.

The spontaneous development of chylous ascites in patients with cirrhosis is documented, but its clinical features are not well defined. The incidence of this complication of chronic liver disease was 0.5% in ascitic patients in our liver unit. These patients were older than a control group with nonchylous cirrhotic ascites and, despite better liver tests, appeared to have a higher diuretic requirement. Several had disabling, recurrent spontaneous encephalopathy. The mechanism of chylous ascites in cirrhosis is probably portal hypertension causing lymphatic rupture; however, the fact that serum-to-ascites albumin gradients were similar in the two groups, indicating similar degrees of portal hypertension, suggests that other factors also play a role. Spontaneous transformation of previously clear ascites appeared to be associated with a poor prognosis. In contrast, the appearance of chylous ascites de novo in a cirrhotic patient appeared to have a more favorable outcome. Conservative management is recommended for most patients, as the degree of their liver disease appears to be the most important factor determining prognosis.

Fever, shock and chills in gram-negative bacillemia: clinical correlations in 100 cases.

Patterns of fever, shock, and chills in 100 episodes of febrile, Gram-negative bacillemia were retrospectively analyzed to determine features predictive of the site of infection, organism, and prognosis. Pneumonias most often produced morning temperature rises, whereas infections in other sites were usually associated with an afternoon or evening peak. Peritonitis (usually due to Bacteroides fragilis) tended to cause an indolent temperature rise (over a day or more), whereas pyelonephritis and cholangitis typically produced an abrupt "spike." Relatively low fevers characterized Enterobacter pneumonias while very high fevers were noted in Pseudomonas aeruginosa infections in patients with leukemia. Chills occurred with unusually high frequency in cholangitis and in Klebsiella bacteremia. Patients going into shock had higher fevers than those who did not. More importantly, the development of shock was shown to be related to severity of underlying disease. Shock never developed if the disease was not serious, unless the bacteremia was caused by instrumentation, but occurred in 73% of patients with leukemia or lymphoma. The clinical setting, pattern of fever, and presence or absence of a chill can in many cases usefully guide diagnosis and therapy in patients with Gram-negative bacillemia.

Portal hypertension: a permissive factor only in the development of ascites and variceal bleeding.

It is controversial whether the occurrence of ascites and gastrointestinal bleeding in cirrhosis is related to the severity of portal hypertension. Portal pressure was examined in 124 unselected patients with portal hypertension due to chronic liver disease to evaluate this issue. Portal pressure was less in patients without complications of chronic liver disease (11.7 +/- 3.0 mmHg, n = 16) as compared to patients who had bled from varices or erosive gastritis (16.6 +/- 3.4 mmHg, p less than 0.001, n = 49), who had ascites (16.2 +/- 3.0 mmHg, p less than 0.001, n = 78) or both (16.5 +/- 3.0 mmHg, p less than 0.001, n = 19). Portal pressure was similar in patients bleeding from varices and erosive gastritis (16.7 +/- 3.4 mmHg, n = 43; vs 16.2 +/- 4.0 mmHg, n = 6, respectively) and in patients with refractory and nonrefractory ascites (16.2 +/- 3.5, n = 21; vs 16.2 +/- 3.5 mmHg, n = 57). The lowest portal pressure recorded in a patient with variceal bleeding was 9.0 mmHg. The lowest portal pressure recorded in a patient with ascites was 8.0 mmHg. Esophageal varices (graded 0-4 at endoscopy) were larger in patients with a history of bleeding from esophageal varices as compared to patients without such a history (3.2 +/- 0.7 vs 2.0 +/- 0.9, p less than 0.001). Serum albumin concentration was greater in patients without ascites as compared to patients with ascites (33 +/- 5 vs 26 +/- 5 g/l p less than 0.001) but was similar in patients with refractory and nonrefractory ascites (25 +/- 7 vs 26 +/- 5 g/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Drug therapy for portal hypertension.

Drugs used to treat portal hypertension cause constriction of mesenteric arterioles, reducing inflow to the portal venous system, portal pressure, and flow through portasystemic collaterals (such as esophageal varices). Vasopressin and somatostatin are direct vasoconstrictors. Propranolol acts by blocking vasodilatory beta 1 receptors and reducing cardiac output. A major side effect of vasopressin therapy is impaired cardiac performance secondary to coronary vasoconstriction and increased work against high arterial pressure. Infusion of vasopressin together with a cardiac inotrope or a vasodilator, and administration of vasopressin as an inactive "hormonogen" which is slowly released in vivo, may lessen adverse effects. Somatostatin appears to act selectively in the mesenteric circulation. Controlled trials indicate that vasopressin may be useful for controlling hemorrhage from esophageal varices and that somatostatin works at least as well as vasopressin. Propranolol treatment has been used to prevent variceal bleeding; however, controlled trials of its effectiveness have produced conflicting results.