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The hyperdynamic circulation of cirrhosis participates in the pathophysiology of portal hypertension. P450-dependent epoxyeicosatrienoic acids (EET) are potent vasodilators. We evaluated plasma levels of EETs in cirrhotic patients and the effect of epoxygenase and nitric oxide synthase (NOS) inhibition on skin blood flow, measured by laser Doppler flowmetry, in normal subjects and cirrhotic patients with and without ascites. Free plasma EETs were increased in cirrhotic patients compared to normal subjects, while the ratio between 8,9-, 11,12-, and 14-15-EET was the same. In cirrhotic patients without ascites, skin blood flow was significantly increased compared to normal subjects. In patients with ascites skin blood flow was significantly reduced compared to control subjects and patients without ascites. Inhibition of epoxygenase with miconazole and of NOS with l -NG-Nitroarginine methyl ester ( l -NAME) decreased basal skin flow in normal subjects and in cirrhotic patients, the effect being higher in cirrhotic patients. Miconazole caused a further decrease in flow when administered with l -NAME, both in normal subjects and in cirrhotic patients. In conclusion, EETs participate in the control of peripheral circulation of normal subjects and in the pathophysiology of peripheral vasodilatation of cirrhotic patients with ascites.

Splenic Doppler impedance indices are measurements of splenic congestion in chronic liver disease. It is not known whether they can also assess splenic congestion in patients affected by right-sided or congestive heart failure. We analyzed splanchnic hemodynamics with Doppler ultrasound and systemic hemodynamics with right-sided heart catheterization in patients with heart failure. Splenic pulsatility index (PI) was higher in patients with heart failure (48 patients) compared with healthy subjects (39 patients) (1.19 ± 0.41 vs. 0.73 ± 0.11, p0.0001) and was related to hepatic vein diameter (p = 0.02). Splenic PI was not related to systemic arterial pressure, cardiac output, systemic vascular resistance or splenic arterial resistance, whereas it was related to right atrial mean pressure (p = 0.0003) and to right ventricle end-diastolic pressure (p = 0.011) (34 patients). In conclusion, splenic PI is a measurement of splenic congestion caused by an increase in venous outflow resistance. It can estimate splenic congestion in patients with right-sided or congestive heart failure.

Background Abdominal ultrasound can detect non-invasively the presence of abdominal portal-systemic collaterals in patients with liver cirrhosis. Abdominal portal-systemic collaterals may be protective from the formation and growth of oesophageal varices, but available data are inconclusive. Aim We aimed at investigating the relationship between abdominal portal-systemic collaterals and variceal formation and growth. Methods We studied 126 cirrhotic patients without (n = 43) or with small (n = 83) oesophageal varices who entered a protocol of serial ultrasonographic and endoscopic examinations for a median of 55 months. Presence and kind of abdominal portal-systemic collaterals was recorded on first ultrasonography and on each control thereafter. Results At inclusion, abdominal portal-systemic collaterals were found in 19/43 patients without varices and in 23/83 patients with small varices (NS). There was no difference in variceal formation and growth between patients with and without abdominal portal-systemic collaterals at inclusion. However, patients developing new abdominal portal-systemic collaterals during follow-up had a significantly higher rate of variceal formation (56.2% vs. 22.2%; p = 0.024) and growth (52.9% vs. 30.6%; p = 0.041) compared with patients with unchanged ultrasonography. Conclusions Abdominal collaterals are not protective from the formation or growth of oesophageal varices. Conversely, new abdominal portal-systemic collaterals emergence is a non-invasive clue of formation and progression of varices. Therefore, endoscopy is probably indicated whenever new abdominal portal-systemic collaterals are detected in cirrhotic patients.

Objective Nonalcoholic fatty liver disease is very frequent in both type 2 diabetes mellitus (T2DM) and the metabolic syndrome (MS), which share clinical and metabolic characteristics. Whether and to which extent these characteristics can predict the degree of liver steatosis are not entirely clear. Patients and methods We determined liver fat (divided into four classes) by standard sonographic images, and clinical and biochemical variables, in 60 consecutive patients with T2DM and with features of the MS. We examined both simple and multiple correlations between the degree of liver steatosis and the variables measured. Results Increased liver fat (defined as >5% of liver mass) was detected in 88% of the participants. Using simple regression analysis, the class of steatosis correlated positively with BMI, waist, number of factors of the MS, sex (female > male), diastolic blood pressure, insulin resistance, metabolic control, inflammation, C-reactive protein, fibrinogen, and leptin, whereas it correlated negatively with high-density lipoprotein-cholesterol. Using multiple regression analysis, only metabolic control, insulin resistance and/or plasma insulin, and waist, remained correlated significantly with the degree of steatosis. Using an ordered probit statistical model, metabolic control, waist, and insulin concentration predicted the steatosis class in 58% of the cases (¡Ü97% with allowance for one class in either excess or deficit). Conclusion In patients with T2DM, the extent of liver steatosis is correlated with variables associated with metabolic control and features of the MS. The combination of metabolic control, visceral obesity, and insulin resistance may reasonably predict the degree of liver steatosis in T2DM. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

To evaluate the prevalence, severity, and hemodynamic features of nonalcoholic fatty liver disease (NAFLD) in nonobese diabetics.We studied 100 consecutive nonobese (body mass index [BMI] 30) patients with type 1 (n = 17) or type 2 (n = 83) diabetes and no known causes of liver disease. Steatosis was diagnosed and graded with ultrasonography. Digital sonographic images of the liver and right kidney were analyzed with dedicated software (HDI-Lab), and the liver/kidney ratio of grey-scale intensity was calculated as an index of the severity of the steatosis. Severity scores ranging from 0 (none) to 5 (severe) were compared with sonographic and Doppler findings (right liver size, portal vein diameter and flow velocity, hepatic and splenic arterial pulsatility indices, hepatic-vein flow profile and A- and S-wave velocities).The prevalence of steatosis was 24% in type I and 80% in type II diabetes (grade 1 in 17%, grade 2 in 34%, grade 3 in 33%, grade 4 in 9%, grade 5 in 7%). In patients with steatosis (especially those with grades 4-5 disease), hepatic volume was increased (p 0.005). Portal vein diameter was increased in grade 5 steatosis. The hepatic artery pulsatility index was significantly increased, particularly in grades 4 and 5 (p 0.0001); portal and A-wave velocities were significantly reduced in grades 3-5 (p 0.001); and the hepatic vein flow profile was altered in 27% (biphasic: 20%, flat: 7%) patients with steatosis, although there was no correlation with severity.NAFLD is very frequent in nonobese diabetics with type 2 but not type 1 disease, and it is associated with hepatomegaly and liver hemodynamic alterations only when it is severe.Sommario SCOPO: Valutare la prevalenza e la gravità della steatosi nei pazienti diabetici non-obesi e le alterazioni emodinamiche epatiche associate. METODI: Sono stati studiati 100 pazienti diabetici non-obesi (BMI 30 kg/m), 17 di tipo I e 83 di tipo II, privi di cause note di epatopatia. Mediante eco-color-Doppler sono stati valutati: un'immagine digitale di confronto tra fegato e corticale del rene destro, analizzata tramite un programma dedicato per la valutazione del grado di steatosi (rapporto fegato/rene dell'intensità dei grigi), le dimensioni del lobo epatico destro, il calibro della vena porta (PV), la velocità della vena porta (PBV), gli indici di pulsatilità arteriosa epatica (PI-L) e splenica (PI-S), il profilo flussimetrico e la velocità delle onde a (HV-a) e s (HV-s) delle vene sovraepatiche. RISULTATI: La prevalenza di steatosi è stata del 24% nel diabete di tipo I e dell'80% nel tipo II ed è risultata prevalentemente di grado lieve-moderato. Nella steatosi il volume epatico è risultato aumentato (p 0,005), in particolare nei gradi superiori a 3, e il diametro della vena porta è risultato aumentato nel grado 5. Il PI-L è risultato aumentato in tutti i gradi di steatosi, in particolare in quelli di grado 4 e 5 (p 0,0001); la PBV è risultata ridotta nei gradi 3, 4 e 5 (p 0,001); la HV-a è risultata ridotta nei pazienti con grado 3, 4 e 5. Il profilo flussimetrico delle vene sovraepatiche è risultato alterato nel 27% (20% bifasico, 7% appiattito). CONCLUSIONI: La steatosi epatica è un reperto molto frequente nel diabete di tipo II senza obesità ed è associata a epatomegalia e alterazioni emodinamiche epatiche nelle forme più gravi.

Experimental studies show that the heme oxygenase/carbon monoxide system (HO/CO) plays an important role in the homeostasis of circulation and in the pathophysiology of hypertension. No data are available on its role in the control of peripheral circulation in humans. We evaluated the effects of inhibition of HO with stannous mesoporphyrin IX (SnMP) (200 𝜇 M) locally administered by iontophoresis, on human skin blood flow, evaluated by laser-Doppler flowmetry, in the presence and absence of nitric oxide synthase (NOS) inhibition with L-NG-Nitroarginine methyl ester (L-NAME) (100 𝜇 M). We also evaluated the effect of HO inhibition on vasodilatation induced by acetylcholine (ACh) and vasoconstriction caused by noradrenaline (NA). SnMP and L-NAME caused a similar 20–25% decrease in skin flow. After nitric oxide (NO) inhibition with L-NAME, HO inhibition with SnMP caused a further 20% decrease in skin perfusion. SnMP decreased vasodilatation induced by ACh by about 70%, while it did not affect vasoconstriction to NA. In conclusion, HO/CO participates in the control of peripheral circulation, independently from NO, and is involved in vasodilatation to ACh.

CYP450-dependent epoxyeicosatrienoic acids (EETs) are potent arterial vasodilators, while 20-hydroxyeicosatatraenoic acid (20-HETE) is a vasoconstrictor. We evaluated their role in the control of portal circulation in normal and cirrhotic (CCl(4) induced) isolated perfused rat liver. Phenylephrine (PE) and endothelin-1 (ET-1) increased portal perfusion pressure, as did arachidonic acid (AA), 20-HETE, and 11,12-EET. Inhibition of 20-HETE with 12,12-dibromododecenoic acid (DBDD) did not affect basal pressure nor the responses to PE, ET-1, or AA. However, inhibition of epoxygenase with miconazole caused a significant reduction in the response to ET-1 and to AA, without affecting neither basal pressure nor the response to PE. Hepatic vein EETs concentration increased in response to ET-1, and was increased in cirrhotic, compared to control, livers. 20HETE levels were non-measurable. Miconazole decreased portal perfusion pressure in cirrhotic livers. In conclusion, 20HETE and EETs increase portal resistance; EETs, but not 20-HETE, mediate in part the pressure response to ET-1 in the portal circulation and may be involved in pathophysiology of portal hypertension.

Portal vein thrombosis (PVT) is a rare cause of portal hypertension. Its diagnosis has been facilitated by improvements in imaging techniques, in particular Doppler sonography. The prevalence is about 1% in the general population, but much higher rates are observed in patients with hepatic cirrhosis (7%, range 0.6-17%), particularly those who also have hepatocellular carcinoma (HCC) (35%). The most common causes of PVT are myeloproliferative disorders, deficiencies of anticoagulant proteins, prothrombotic gene mutations, cirrhosis with portal hypertension, and HCC. Its development often requires the presence of two or more risk factors (local and/or systemic), e.g., a genetically determined thrombophilic state plus an infectious episode or abdominal surgery. It is clinically useful to distinguish between cirrhotic and noncirrhotic forms. Portal vein thrombosis is also traditionally classified as acute or chronic, but this distinction is often difficult. Color Doppler ultrasound is the first-line imaging study for diagnosis of PVT; magnetic resonance angiography and CT angiography are valid alternatives. The main complications are ischemic intestinal necrosis (in acute PVT) and esophageal varices (in chronic cases); the natural history of the latter differs depending on whether or not the thrombosis is associated with cirrhosis. The treatment of choice for PVT has never been adequately investigated. It is currently based on the use of anticoagulants associated, in some cases, with thrombolytics, but experience with the latter agents is too limited to draw any definite conclusions. In chronic thrombosis (even forms associated with cirrhosis), anticoagulant therapy is recommended and possibly, beta-blockers as well. Naturally, treatment of the underlying pathology is essential.SommarioLa trombosi portale rappresenta una causa rara di ipertensione portale che oggi viene diagnosticata con maggior facilità per l'affinamento delle metodiche di imaging, in particolare quelle ecografiche. La prevalenza è dell'1% circa, del 7% (0,6–17%) nella cirrosi epatica, del 35% circa nell'epatocarcinoma. Le cause più comuni di trombosi portale sono: i disordini mieloproliferativi, il deficit di proteine anticoagulanti, le mutazioni geniche protrombotiche, la cirrosi con ipertensione portale, l'epatocarcinoma. Per lo sviluppo di trombosi portale è spesso necessaria la presenza di due o più fattori, locali e sistemici, come uno stato trombofilico su base genetica e un episodio infettivo o un intervento chirurgico addominale. È utile clinicamente dividere la trombosi portale in cirrotica e non-cirrotica. La trombosi portale è inoltre tradizionalmente classificata in acuta e cronica, ma spesso è difficile distinguerle. L'indagine di primo livello per la diagnosi di trombosi portale è rappresentata dall'eco-color-Doppler; in alternativa possono essere usate angio-RM e angio-TC. Le conseguenze della trombosi portale sono rappresentate principalmente dalla necrosi intestinale ischemica nelle forme acute e dalle varici esofagee, che hanno una storia naturale diversa a seconda della presenza o meno di cirrosi, nelle forme croniche. Non vi sono studi adeguati sulla terapia della trombosi portale, che attualmente consiste nell'anticoagulazione, a cui può essere associata la trombolisi, sulla quale non vi è però casistica adeguata. Nella trombosi cronica è indicata l'anticoagulazione, probabilmente anche nella cirrosi, ed eventualmente il beta-bloccante. Ovviamente importante è la terapia della patologia di base.

Bright Times for Patients With Cirrhosis and Delayed Sleep Habits: A Case Report on the Beneficial Effect of Light Therapy