Hepatic cirrhosis associated with arterial pulmonary hypertension

The association between hepatic cirrhosis and arterial pulmonary hypertension is mentioned in the literature. The authors report the case of a patient with hepatic cirrhosis, who developed in time an arterial pulmonary hypertension with a fatal outcome. They discuss the pathogenesis of arterial pulmonary hypertension in patients with hepatic diseases, and the therapeutic options in these patients.     

Renal response to atrial natriuretic peptide in patients with advanced liver cirrhosis

Sodium retention in liver cirrhosis is thought to be due to, among other things, lack of a natriuretic factor or failure to respond to one. alpha-Human-atrial natriuretic peptide is a peptide that accounts partly or entirely for the circulating natriuretic activity in man. In the present study, we have evaluated the effects of the bolus administration of synthetic alpha-human-atrial natriuretic peptide (1 microgram per kg) to patients with liver cirrhosis and variable degrees of sodium retention. alpha-Human-atrial natriuretic peptide induced rapid and marked increases of diuresis and natriuresis in patients without sodium retention or with moderate retention. The results were comparable to those obtained in six healthy control subjects. Conversely, the diuretic and natriuretic effects of alpha-human-atrial natriuretic peptide were attenuated or completely blunted in patients with avid sodium retention. The two groups of patients differed not only in basal sodium excretion, but also in plasma renin activity and in plasma aldosterone levels, suggesting that the reduced responsiveness to atrial natriuretic peptide might be due to excessive antagonism by antinatriuretic factors. The direct relationship between baseline sodium excretion rate and that stimulated by human-atrial natriuretic peptide administration was consistent with this interpretation. In none of the subjects did plasma renin activity peptide and cortisol levels change after human-atrial natriuretic peptide, while plasma aldosterone slightly declined in cirrhotics. Blood pressure fell after the administration of the peptide, with the drug greater in cirrhotic than in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic arterial pulsatility index in cirrhosis: correlation with portal pressure.

BACKGROUND/AIMS: Determination of the pulsatility index by means of duplex sonography provides the opportunity to evaluate the vascular resistance of the hepatic artery noninvasively. The aim of this study was to investigate the relationship between the hepatic arterial pulsatility index and the hepatic venous pressure gradient in cirrhosis. METHODS: In 50 patients with cirrhosis, hepatic venous pressure gradient was determined in the fasting state. Immediately thereafter, hepatic arterial pulsatility index and portal blood flow velocity were measured by duplex sonography with no knowledge of hepatic venous pressure values. In addition, the duplex parameters were determined in 20 controls. RESULTS: Hepatic arterial pulsatility index was significantly higher in patients with cirrhosis than in controls (0.92+/-0.1 vs. 1.14+/-0.18; p<0.001) and directly correlated with the hepatic venous pressure gradient (r = 0.7; p<0.001). Furthermore, weak correlations were found between hepatic arterial pulsatility index and Child-Pugh score (r = 0.49; p<0.01) and between portal blood flow velocity and hepatic venous pressure gradient (r = -0.48; p<0.01). CONCLUSION: In cirrhosis the hepatic arterial vascular resistance seems to increase parallel to the rise of the portal pressure. Therefore, duplex sonographic determination of the hepatic arterial pulsatility index may contribute to the noninvasive evaluation of portal hypertension.     

Hepatic arterial flow volume and reserve in patients with cirrhosis: use of intra-arterial Doppler and adenosine infusion

BACKGROUND & AIMS: In cirrhosis, liver blood flow becomes increasingly dependent on the hepatic artery. The aim of this study was to investigate hepatic arterial blood flow volume and resistance and hepatic arterial flow reserve in relation to liver function and systemic hemodynamic alterations in patients with cirrhosis. METHODS: In 38 patients with cirrhosis, liver function, cardiac output, and systemic vascular resistance were studied, and hepatic arterial blood flow velocity, flow volume, and pulsatility index at baseline and during intra-arterial administration of adenosine (2-40 microg. min-1. kg body wt-1) were assessed by angiography combined with intravascular Doppler flowmetry. RESULTS: Hepatic arterial flow velocity was 21 +/- 11, 31 +/- 17, and 41 +/- 27 cm/s; flow volume was 266 +/- 246, 342 +/- 289, and 417 +/- 220 mL/min; and pulsatility index was 2.2 +/- 0.7, 1.7 +/- 0.6, and 1.5 +/- 0.5 in Child-Pugh classes A, B, and C, respectively (differences not statistically significant). Adenosine-induced changes in these parameters were more marked in Child-Pugh class A (68 +/- 15 cm/s, 1246 +/- 486 mL/min, and -1.14 +/- 0.5) than in class C (45 +/- 23, P < 0.05; 704 +/- 492, P = 0.02; and -0.58 +/- 0.38, P < 0.05). Using analysis of variance, cardiac index, systemic vascular resistance, and ascites, but not Child-Pugh class, were related to baseline values and adenosine-induced changes. CONCLUSIONS: Adenosine is a potent dilator of the hepatic artery in humans. The data suggest that hepatic arterial blood flow and adenosine-dependent flow reserve in patients with cirrhosis are under systemic hemodynamic or neurohormonal control.     

Postprandial vascular response in patients with cirrhosis

Systemic and portal hemodynamic parameters were evaluated in eight cirrhotic patients in basal conditions and after food intake and placebo. Following seven days of oral propranolol administration, hemodynamic parameters were reevaluated in the fasting and postprandial states under similar conditions. Cardiac output and portal blood flow were measured by Doppler technique. Intraobserver variability of repeated measurements was less than 10%. Food intake caused a significant increase of portal blood flow (+28%,P<0.05). No significant changes were observed in the other hemodynamic parameters studied. Propranolol at doses achieving effective beta blockade (84±14 mg/day) (mean±sd) reduced portal blood flow (?24%,P<0.05). Food intake caused a significant increase in portal blood flow (+35%,P<0.05) in propranolol treated patients. However, in absolute values, postprandial portal blood flow during propranolol treatment was significantly lower (986±402 ml/min) than that obtained after the initial food intake (1214±537 ml/min,P<0.05). Placebo administration had no significant hemodynamic effects in either group. This study demonstrates that chronic propranolol administration could protect from portal hemodynamic changes following food intake. Doppler technique is a reliable technique to evaluate changes on portal and systemic hemodynamic parameters during a short period of time in patients with cirrhosis.     

Hepatic and splanchnic nitric oxide activity in patients with cirrhosis

BACKGROUND: In animal models of cirrhosis, altered activity of nitric oxide (NO) has been implicated in the pathogenesis of increased intrahepatic portal vascular resistance and abnormal mesenteric vasodilatation. AIMS: To investigate NO activity in the liver and splanchnic vascular bed of patients with cirrhosis. METHODS: Activity of the calcium dependent constitutive and calcium independent inducible isoforms of NO synthase (cNOS and iNOS, respectively) was assayed biochemically in biopsy specimens of liver and a vascular portion of the greater omentum (representative of mesenteric vasculature) obtained from patients with cirrhosis undergoing liver transplantation (n=14) and non-cirrhotic control patients undergoing liver resection for metastases (n=9). The concentration of NO metabolites (NO2 + NO3) in portal and peripheral venous plasma was measured. RESULTS: The activity of cNOS was lower in cirrhotic compared with non-cirrhotic subjects for both liver and omentum. Hepatic and omental iNOS activities did not differ significantly between the two groups. Portal (NO2 + NO3) was threefold higher in cirrhotic than non-cirrhotic patients, but no differences were observed in systemic venous samples from the two groups. CONCLUSIONS: The activity of cNOS is diminished in the cirrhotic human liver. The resultant decrease in constitutive NO release may promote an increase in the intrahepatic portal vascular resistance. Elevated portal venous (NO2 + NO3) indicates enhanced splanchnic vascular release of NO in cirrhotic patients, but the absence of increased NOS activity in the mesenteric vasculature suggests differential regulation of NO synthesis within the splanchnic vascular bed.     

Hepatic decompensation in patients with cirrhosis during infection with influenza A

BACKGROUND: Patients with chronic liver disease can develop hepatic decompensation during systemic infections. Although gram-negative and gram-positive bacteria are well recognized as causes of decompensation, the effect of influenza virus infection on patients with chronic liver disease is poorly documented. METHODS: Retrospective analysis of patients with positive viral cultures who were seen at a liver transplantation clinic in a tertiary care referral center during the 1997-1998 influenza A (H3N2) epidemic in San Diego, Calif. RESULTS: Three patients with end-stage liver disease (1 with Wilson disease and 2 with alcoholic liver disease) developed hepatic decompensation and required hospitalization during infection with influenza A. Two patients had biochemical and clinical evidence of hepatic decompensation, including ascites, hepatic encephalopathy, and peripheral edema, and the third had acute hepatocellular damage, with elevated levels of aminotransferases. Viral hepatitis serologic test results, acetaminophen levels, drug and alcohol screening findings, and bacterial and fungal cultures were negative in all 3 patients. Hepatic decompensation resolved without the need for transplantation in the 2 patients with liver failure, and all patients recovered to their baseline liver function levels within 1 month of onset of acute illness. CONCLUSIONS: Influenza A infection can cause hepatic decompensation and hospitalization in patients having cirrhosis or who are awaiting liver transplantation. Effective prevention with vaccination and early recognition and treatment of influenza are strongly recommended in these individuals.     

Screening for hepatocellular carcinoma in patients with advanced cirrhosis

OBJECTIVE: Most available data on screening for hepatocellular carcinoma (HCC) in patients with cirrhosis originate from Asia and Europe. These data may not be applicable to patients from the United States because of geographic variation in the underlying etiology and other factors. Our aim was to assess the risk of HCC in U.S. patients with cirrhosis undergoing standardized screening. METHODS: All cirrhotic patients evaluated for liver transplantation at our institution from January 1, 1994-December 31, 1997 were included in this study. The screening strategy included initial screening, which was offered to all patients and consisted of alpha-fetoprotein (AFP), abdominal ultrasound, and computed tomography (CT) scan, and extended screening, which was performed only on transplant-eligible patients and consisted of semiannual AFP and ultrasound. RESULTS: During the study period, 285 patients with cirrhosis were evaluated for transplantation and underwent initial screening. Of these, 166 were eligible for transplantation and underwent extended screening during a median follow-up of 15 months (range 6-42 months). Twenty-seven HCC were found, 22 during initial screening and five during extended screening. The cancer-free proportions of the cohort who underwent extended screening at 1, 2, and 3.5 yr were 98.6% +/- 1.4%, 96.4 +/- 1.8%, and 77.1% +/- 1.7%, respectively (mean +/- SE). Hepatitis C, either alone or in part, was the etiology in 63% of patients with HCC. The sensitivity of CT scan (88%) was significantly higher than AFP >20 ng/ml (62%) and ultrasound (59%) for detecting HCC (p < 0.001). CONCLUSIONS: In patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening (7%). Hepatitis C was the most common etiology for cirrhosis in study. In U.S. patients with established cirrhosis, CT scan exhibited higher sensitivity for detecting HCC than ultrasound or AFP.     

Intestinal permeability is increased in patients with advanced cirrhosis

BACKGROUND/AIMS: The dysfunction of the intestinal barrier is a factor that has been related to bacterial translocation from lumen to extra-intestinal sites and consequently to the development of spontaneous bacterial peritonitis. The aim of this study was to investigate if the alterations of the intestinal barrier in cirrhosis are related with the degree of liver failure and associated with other clinical complications. METHODOLOGY: Intestinal permeability was assessed by means of the lactulose/mannitol test in 79 cirrhotic and 25 controls subjects. They received 10 g of lactulose and 5 g of mannitol. Lactulose and mannitol were measured in a five-hour urinary volume. RESULTS: Lactulose/mannitol ratio was significantly higher in cirrhotic patients than in controls (p = 0.03). This was more evident in end-stage cirrhosis. Patients with ascites, or encephalopathy showed a statistically significant increase in lactulose/mannitol ratio when compared to patients without these complications. CONCLUSIONS: The increased intestinal permeability is related to the progression of the liver disease and is more relevant with overt clinical complications. This is due to an increased absorption of lactulose. However, as liver disease progresses, mannitol absorption is progressively reduced, probably due to a reduced surface of absorption, and these events are more relevant in patients with overt clinical complications.     

Local arterial vasoconstriction induced by octreotide in patients with cirrhosis

Peripheral vasodilation initiates the hyperdynamic circulation in cirrhosis. Somatostatin and its analogues, such as octreotide, have a vasoconstrictive effect in cirrhotic patients and experimental animals with portal hypertension. The exact mechanism of octreotide-induced vasoconstriction remains unknown. To investigate whether octreotide produces vasoconstriction through suppression of vasodilatory peptides, such as glucagon, or through a local effect, we evaluated the effect of an intra-arterial dose on forearm blood flow (FBF), while measuring systemic glucagon levels. FBF was measured in 10 cirrhotic patients by venous occlusion plethysmography. The brachial artery of the nondominant arm was catheterized, and vasoactive drugs were administered: methacholine 4 microg/min; octreotide 20 microg/h, and octreotide 20 microg/h + methacholine 4 microg/min. Each infusion, lasting 5 minutes, was followed by saline for washout. FBF was measured in both arms during the last minute of each infusion and at the end of washout, with the uninfused arm acting as the control. Nitrates and nitrites, octreotide, and glucagon blood levels were determined at baseline and after each infusion. Percent change in flow (%triangle up) was obtained by comparing the flow during drug administration to that during the preceding saline infusion. Saline infusion did not alter FBF, but octreotide infusion resulted in a 34% +/- 7.7 (P <.005) reduction in FBF in the infused arm. FBF in the control arm was unchanged despite a significant decrease in systemic glucagon levels. Methacholine infusion increased FBF around 300%, which was not altered by the concomitant infusion of octreotide. Octreotide has a local vasoconstrictive effect that seems nitric oxide (NO)-independent. Octreotide probably has a facilitating effect over vasoconstrictors increased in chronic liver diseases.     

Hepatic arterial and portal venous oxygen content and extraction in liver cirrhosis

ABSTRACT— We examined the oxygen content in the hepatic arterial, hepatic venous and portal venous blood to evaluate the oxygen supply to the liver and hepatic oxygen extraction in cirrhosis. The arterial-portal venous difference of the oxygen content was within the normal range in cirrhosis patients, although the oxygen content of the hepatic artery and portal vein was lower than in the control patients. The hepatic venous oxygen content was normal in the cirrhosis patients. The oxygen tension and saturation were always higher in the splenic vein than in the other branches of the portal system. Oxygen was supplied chiefly by the hepatic artery, and arterial oxygen extraction was normal in cirrhosis. In addition, there was no change in arterial extraction during oxygen inhalation by cirrhosis patients. Portal venous oxygen extraction was decreased in cirrhosis and was increased by oxygen inhalation. These findings indicate the autoregulation of hepatic oxygen through a mutual relationship between the hepatic arterial and the portovenous oxygen supply.     

Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumours

Liver metastases, in patients with gastroenteropancreatic endocrine tumours, are present in 25-90%, depending on the nature of the primary tumour. Surgical resection is indicated only for localised liver metastasis, whereas in most cases with diffuse liver involvement other therapeutic modalities such as intravenous chemotherapy, embolization or hepatic arterial chemoembolization, ligation or intra-arterial chemotherapy are currently available. Hepatic arterial chemoembolization is specifically indicated for progressive tumours (mainly carcinoids) confined to the liver especially after unsuccessful systemic chemotherapy. A mixture of cytotoxic drug and iodised oil followed by gelatine sponge particles are injected in the branches of the hepatic artery supplying the tumours. 66-100% positive results of this treatment have been reported in the carcinoid syndrome with a 50-91% decrease in 5-HIAA secretion. Variation of tumour size (WHO criteria) has been reported in 33-80% of the cases, even if no direct comparison between chemoembolization and other therapeutic modalities are currently available. Extensive follow-up of the treated patients and additional studies will clarify the role of chemoembolisation in advanced digestive neuroendocrine tumours.     

Elevated arterial compliance in patients with cirrhosis is not related to arterial endothelin-1

BACKGROUND: Patients with cirrhosis and portal hypertension have a hyperkinetic systemic circulation. A number of circulating vasoactive peptides, including endothelin-1 (ET-1), are elevated and, recently, increased arterial compliance has been described in these patients. The aim of the present study was to investigate a potential relation between altered arterial compliance and arterial ET-1 in patients with cirrhosis. As ET-1 may be manipulated by somastostatin, the study includes infusion of octreotide in a subset of patients. METHODS: A total of 67 patients with cirrhosis and 27 controls were studied during a haemodynamic investigation. Arterial ET-1 was determined by two different radioimmunoassays and arterial compliance was determined as the stroke volume/pulse pressure index. RESULTS: Arterial compliance was elevated by 32%-40% in the cirrhotic patients as compared to the controls (P < 0.005). Arterial ET-1 was elevated by 26%-170% in the cirrhotic patients (P<0.001). No significant relationships could be established between arterial compliance and arterial ET-1 (r = -0.15 to 0.23, ns). Intravenous bolus injection and infusion of octreotide (100 pg + 100 microg/h, n = 9) did not significantly change either arterial compliance or arterial ET-1. CONCLUSION: Both arterial compliance and arterial ET- I are substantially elevated in patients with cirrhosis, but there is no significant relation between arterial compliance and arterial ET- I in these patients.     

Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumors

The management of advanced digestive endocrine tumors is often challenging. Liver metastases are usually diffuse at the time of diagnosis, and surgical resection is rarely feasible. Objective response rates with systemic chemotherapy are disappointing. Arterial hypervascularization of most liver metastases from digestive endocrine tumors argues in favor of hepatic arterial chemoembolization (HACE). It is assumed that embolization-induced ischemia sensitizes tumor cells to cytotoxic drugs, whose tumor concentrations are increased by blood flow slowing down. The aims of HACE are: (1) to control otherwise untractable hormone-related symptoms, particularly the carcinoid syndrome (>50% urinary 5-HIAA decrease: 57-91%) and insulinoma-related life-threatening hypoglycemias; (2) to inhibit tumor growth (objective response rates: 33-80%; mean duration: 6-42.5 months), and (3) to improve patients' survival. The postembolization syndrome, usually mild and transient, is the commonest side effect. Major extrahepatic complications are rare. In conclusion, HACE seems to be an attractive alternative treatment for diffuse (unresectable) and progressive metastases confined to the liver in patients with digestive endocrine tumors, mainly following unsuccessful systemic chemotherapy. Further studies assessing the long-term results of HACE and comparing it to other treatments, particularly systemic chemotherapy, are needed.     

Hepatic perfusion changes in patients with liver metastases: comparison with those patients with cirrhosis.

Previous studies using dynamic scintigraphy have shown that the measurement of changes in hepatic perfusion may be exploited to detect liver metastases. Similar hepatic haemodynamic changes also occur in cirrhosis, however, thereby reducing the diagnostic power of the technique. The ability of duplex colour Doppler sonography (DCDS) to differentiate between the changes in liver perfusion in patients with cirrhosis and those with hepatic metastases was assessed. Hepatic arterial and portal venous blood flows were measured in 30 control subjects, 20 patients with cirrhosis, and 55 patients with overt liver metastases. The Doppler perfusion index (DPI) (the rate of hepatic arterial to total liver blood flow) and the congestive index (ratio of the cross sectional area of the vessel to time averaged velocity of blood flow in the vessel) of the hepatic artery (HCI) and portal vein (PCI) were calculated. The hepatic arterial blood flow of the cirrhotic and metastatic groups was significantly raised compared with that of controls, and the portal venous blood flow of the former groups were reduced (p < 0.0001). The DPIs of the cirrhotic and metastatic groups were therefore significantly raised compared with those of controls (p < 0.0001). No significant difference was noted in HCI values between the three groups. The PCI values of the cirrhotic group, however, were significantly raised compared with those of controls and patients with metastases (p < 0.0001). The data suggest that DCDS measurement of PCI may be of value in differentiating between the hepatic perfusion changes caused by cirrhosis and those resulting from hepatic metastases, thereby increasing the diagnostic power of this technique.     

Hepatic arterial chemoembolization with streptozotocin in patients with metastatic digestive endocrine tumours

BACKGROUND: Hepatic arterial chemoembolization (CE) with anthracyclines is an effective treatment for progressive liver metastases of digestive endocrine tumours. Streptozotocin (STZ) is widely used for systemic chemotherapy, but its efficacy by the hepatic arterial route has not been evaluated. PATIENTS AND METHODS: Fifteen consecutive patients, mean age 57.8 years, were prospectively included between July 1993 and January 1997. All patients had progressive liver metastases from either a carcinoid tumour (eight patients) or an islet cell carcinoma (ICC) (seven patients) that had increased in size (> or = 25%) before CE. Five patients had the carcinoid syndrome. STZ was administered, as an emulsion with iodized oil, into the hepatic artery before embolization with gelatin sponge particles. Two to six procedures (median, 3) were performed in 12 patients (one in three patients). Changes in the size of the liver metastases were evaluated by CT scan or MRI according to WHO criteria. The median follow-up was 15 months (1-50). RESULTS: An objective response was achieved in 8/15 patients (53%; median duration of 10.5 months) whatever the primary tumour (carcinoid or ICC). The carcinoid syndrome disappeared in 3/5 patients for 10, 11 and 17 months, respectively. CE effectively controlled hypoglycaemic attacks (decrease of > 50%) in the patient with insulinoma. The biological response was complete in four patients for a median duration of 7 months. CE induced minor side effects, namely nausea, fever and abdominal pain. Acute and reversible tubular necrosis due to CE was observed in one patient who had previously undergone a nephrectomy. CONCLUSION: Hepatic arterial chemoembolization with STZ is an effective treatment for patients with liver metastases caused by digestive endocrine tumours.