F. Nevens

GC–MS analysis of breath odor compounds in liver patients

BACKGROUND Liver diseases can cause a sweet, musty aroma of the breath, called fetor hepaticus. Even in a stage of cirrhosis, the disease can be asymptomatic for many years. Breath analysis might be helpful to detect occult liver pathology. STUDY OBJECTIVE This study examined whether specific breath odor compounds can be found in liver patients, suffering from cirrhosis, which might be useful for diagnosis. MATERIALS AND METHODS Fifty-two liver patients and 50 healthy volunteers were enrolled. Alveolar air was analyzed by gas chromatography-mass spectrometry. Using discriminant analysis a model for liver disease was built. RESULTS Dimethyl sulfide, acetone, 2-butanone and 2-pentanone were increased in breath of liver patients, while indole and dimethyl selenide were decreased. Sensitivity and specificity of the model were respectively 100% and 70%. CONCLUSIONS Fetor hepaticus is caused by dimethyl sulfide and to a lower extent by ketones in alveolar air. Breath analysis by GC-MS makes it possible to discriminate patients with breath malodor related to hepatic pathologies.

In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats

Background: Portal hypertension in cirrhosis results from enhanced intrahepatic resistance to an augmented inflow. The former is partly due to an imbalance between intrahepatic vasoconstriction and vasodilatation. Enhanced endothelin-1 and decreased activity of hepatic constitutive endothelial nitric oxide synthase (NOS 3) was reported in carbon tetrachloride (CCl4) cirrhotic rat liver. Aims: To study whether an increase in hepatic NOS 3 could be obtained in the CCl4 cirrhotic rat liver by in vivo cDNA transfer and to investigate a possible effect on portal pressure. Methods: Hepatic NOS 3 immunohistochemistry and western blotting were used to measure the amount of NOS 3 protein. Recombinant adenovirus, carrying cDNA encoding human NOS 3, was injected into the portal vein of CCl4 cirrhotic rats. Cirrhotic controls received carrier buffer, naked adenovirus, or adenovirus carrying the lac Z gene. Results: NOS 3 immunoreactivity and amount of protein (western blotting) were significantly decreased in CCl4 cirrhotic livers. Following cDNA transfer, NOS 3 expression and the amount of protein were partially restored. Portal pressure was 11.4 (1.6) mm Hg in untreated cirrhotic (n=9) and 11.8 (0.6) in lac Z transfected (n=4) cirrhotic rats but was reduced to 7.8 (1.0) mm Hg (n=9) five days after NOS 3 cDNA transfer. No changes were observed in systemic haemodynamics, in liver tests or urinary nitrates, or in NOS 3 expression in lung or kidney, indicating a highly selective transfer. Conclusions: NOS 3 cDNA transfer to cirrhotic rat liver is feasible and the increase in hepatic NOS 3 leads to a marked decrease in portal hypertension without systemic effects. These data indicate a major haemodynamic role of intrahepatic NOS 3 in the pathogenesis of portal hypertension in CCl4 cirrhosis.

Congenital veno-venous malformations of the liver: widely variable clinical presentations.

Background and Aim:  Congenital portosystemic veno‐venous malformations are rare abnomalities that often remain undiagnosed. Typically they are classified by their anatomical characteristics according to Morgan (extrahepatic, Abernethy malformations type Ia,b and II) and Park (intrahepatic, types 1–4). However, their clinical presentation is less dependent on the anatomical type.

Assessment of variceal pressure by continuous non-invasive endoscopic registration: a placebo controlled evaluation of the effect of terlipressin and octreotide.

Octreotide has been proposed for the treatment of variceal bleeding. The effects on portal pressure, however, have been variable in published studies. As bleeding is more directly related to pressure in the varices, this study investigated the effect on variceal pressure of octreotide and terlipressin, a vasoactive drug with a well established effect. Variceal pressure was measured during four to eight minutes by a continuous non-invasive endoscopic registration method. Thirty patients in whom a stable variceal pressure recording had been obtained during at least one minute, were randomised to receive either 2 mg terlipressin, 50 micrograms octreotide or an identical volume of saline, as a single intravenous injection given over 60 seconds. For the final analysis three patients had to be excluded because of lack of a satisfactory recording. There were no significant clinical differences between the three groups of patients. Placebo administration did not induce significant changes, but a mean decrease in variceal pressure of -27% was noted with terlipressin, starting from two minutes onwards. Variceal pressure changes after injection of octreotide were variable and the mean change in pressure did not reach statistical significance. Seven of 10 patients showed a temporary increase in variceal pressure. In conclusion, terlipressin induces a significant and progressive decrease in variceal pressure but inconsistent variations of variceal pressure changes were seen after octreotide administration. This is probably related to its effect on central venous pressure. This study also shows that continuous variceal pressure recording with the non-invasive endoscopic registration technique detects in an accurate way the effect of vasoactive drugs on variceal pressure, because placebo injection did not produce significant changes.

Clinical aspects of incomplete septal cirrhosis in comparison with macronodular cirrhosis.

BACKGROUND/AIMS Incomplete septal cirrhosis (ISC) is a form of macronodular cirrhosis characterized by slender, incomplete septa that demarcate inconspicuous nodules. Its clinical features have not been investigated in a large series. The aims of this study were to review the clinical symptoms and evolution of ISC in 42 patients. METHODS Forty-two patients with at least one liver biopsy strongly suggestive of ISC were selected for the study covering a period between 1968 and 1987. Data for these patients were compared with the evolution of 49 patients with classical macronodular cirrhosis after chronic active hepatitis type B or C. RESULTS Possible etiological factors for ISC were alcohol abuse, arsenic treatment, and hepatitis B infection. In three cases, a genetic factor could not be excluded. Patients with ISC had significantly lower serum concentrations of transaminases and bilirubin at diagnosis. Compared with macronodular cirrhosis, bleeding varices were more frequent (57% vs. 22%) in ISC. Ten-year survivals in the ISC and the macronodular cirrhosis groups were 54% and 57%, respectively. CONCLUSIONS ISC represents a relatively stable burnt-out form of macronodular cirrhosis with an unusually high incidence of variceal bleeding. This could be explained by a superimposed insufficiency of the portal vascular supply.

Low NO bioavailability in CCl4 cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: A comparison of two portal hypertensive rat models with healthy controls

BackgroundIn cirrhotic livers, the balance of vasoactive substances is in favour of vasoconstrictors with relatively insufficient nitric oxide. Endothelial dysfunction has been documented in cirrhotic rat livers leading to a lower activity of endothelial nitric oxide synthase but this might not be sufficient to explain the low nitric oxide presence. We compared the amount of all nitric oxide synthase isoforms and other factors that influence nitric oxide bioavailability in livers of two portal hypertensive rat models: prehepatic portal hypertension and carbon tetrachloride induced cirrhosis, in comparison with healthy controls.ResultsEndothelial nitric oxide synthase was the solely detected isoform by Western blotting in all livers. In cirrhotic livers, the amount of endothelial nitric oxide synthase protein was lower than in healthy controls, although an overlap existed. Levels of caveolin-1 messenger RNA were within the normal range but endothelin-1 messenger RNA levels were significantly higher in cirrhotic livers (p < 0.05). A markedly lower superoxide dismutase activity was observed in cirrhotic livers as compared to healthy controls (p < 0.05).ConclusionsIn contrast to prehepatic portal hypertension, cirrhotic livers had decreased endothelial nitric oxide synthase protein and enhanced endothelin-1 messenger RNA amount. We hypothesise that a vasodilator/vasoconstrictor imbalance may be further aggravated by the reduced activity of superoxide dismutase. Decreased activity allows enhanced superoxide action, which may lead to breakdown of nitric oxide in liver sinusoids.

Tolerance of Liver Transplant Patients to Strenuous Physical Activity in High-Altitude

Physical functioning is improved after liver transplantation but studies comparing liver transplant recipients with normal healthy people are lacking. How liver (and other organ) transplant recipients tolerate strenuous physical activities is unknown. There are no data on the tolerance of transplant patients at high altitude. Six liver transplant subjects were selected to participate in a trek up Mount Kilimanjaro 5895m, Tanzania. Physical performance and susceptibility to acute mountain sickness were prospectively compared with fifteen control subjects with similar profiles and matched for age and body mass index. The Borg‐scale (a rating of perceived exertion) and cardiopulmonary parameters at rest were prospectively compared with six control subjects also matched for gender and VO2max. Immunosuppression in transplant subjects was based on tacrolimus. No difference was seen in physical performance, Borg‐scales and acute mountain sickness scores between transplant and control subjects. Eight‐three percent of transplant subjects and 84.6% of control subjects reached the summit (p = 0.7). Oxygen saturation decreased whereas arterial blood pressure and heart rate increased with altitude in both groups. The only difference was the development of arterial hypertension in transplant subjects at 3950 m (p = 0.036). Selected and well‐prepared liver transplant recipients can perform strenuous physical activities and tolerate exposure to high altitude similar to normal healthy people.

HEPATIC FIBRIN-RING GRANULOMAS IN GRANULOMATOUS HEPATITIS : REPORT OF FOUR CASES AND REVIEW OF THE LITERATURE

BACKGROUND The differential diagnosis of hepatic fibrin-ring granulomas includes infective agents (Coxiella burneti, CMV, EBV,....), hypersensitivity to medication (allopurinol) and malignancy. METHODS During a period of 6 months, four patients presented at our university hospital with a similar clinical picture of fever and abnormal liver tests, and fibrin-ring granulomas on liver biopsy. Clinical course, laboratory and imaging findings, and histopathological features were compared. RESULTS Clinical manifestations, and laboratory and imaging findings were similar. Histopathological assessment of the hepatic fibrin-ring granulomas appeared not to be helpful in identifying the causative agent. Other histopathological features (e.g. sinusoidal rows of lymphocytes, eosinophilic polymorphonuclear infiltrate) were suggestive for the causative agent, yet conclusive identification was obtained by either serology (Q fever, CMV, EBV), or by exclusion with concomitant stop of medication (allopurinol). CONCLUSIONS In the differential diagnosis of hepatic fibrin-ring granulomas, serologic titers remain the determining factor, since an infective agent is the most common cause. When hepatic fibrin-ring granulomas are present, other histopathological features may be helpful in making the differential diagnosis.

Blood antioxidant levels in patients with alcoholic liver disease correlate with the degree of liver impairment and are not specific to alcoholic liver injury itself

Enhanced production of reactive oxygen species may play a pathogenic role in alcoholic liver injury.

ADP-degrading enzymes inhibit platelet activation in bile duct-ligated rats

Summary.  Background: The effect of cholestatic liver disease on primary hemostasis function remains ill‐defined. Objectives: To determine platelet function and identify the mechanisms involved in the observed platelet function in cholestatic rats. Methods: Platelet function was studied in a model of 2‐week bile duct ligation and compared to that in sham‐operated rats with and without a storage pool defect. Results: ADP‐induced and collagen‐induced platelet aggregation were clearly impaired following bile duct ligation (P < 0.01 for areas under the curve). Crossover experiments, with sham platelets in bile duct‐ligated plasma and vice versa, demonstrated that this is due to inhibition by a plasmatic factor, as sham platelets aggregated less in cholestatic plasma (P < 0.03) and to an equal extent as platelets from bile duct‐ligated rats when they were in the same sham or cholestatic plasma. Moreover, in bile duct‐ligated rats, platelet ultrastructure was unaffected and platelet aggregation was similar to that of sham platelets when resuspended in the same plasma (P‐value not significant). Aditionally, studies in storage pool‐deficient rats showed no role of platelet exhaustion. The plasmatic factor causing impaired aggregation was shown to be increased total activity of ADP‐degrading enzymes upon bile duct ligation (P < 0.01), as there was no decreased aggregation with a stable ADP analog in bile duct‐ligated rats (P‐value not significant vs. sham‐operated rats). Furthermore, preincubation of plasma from bile duct‐ligated rats with ADP decreased aggregation more than was seen with sham plasma (P < 0.01). Conclusions: Bile duct ligation does not affect intrinsic platelet function, but impairs platelet activation via release of ADP‐degrading enzymes in the circulation.