European Review for Medical and Pharmacological Sciences 2005; 9: 285-290 Steatosis and portal hypertension C. PUOTI, L. BELLIS Department of Gastroenterology and Internal Medicine, Ospedale di Genzano – Rome (Italy) Abstract. – Non Alcoholic Fatty Liver Dis- chronic viral hepatitis (mainly HCV), alco- ease (NAFLD) is characterized by histologically hol, drugs, diabetes, overweight, total par- macrovesicular steatosis in the absence of al- enteral nutrition, disorders of lipid metabo- cohol consumption. Portal hypertension (PH) is a severe complication of liver cirrhosis leading lism, etc. Traditionally, steatosis of the liver is to a higher risk to develop gastro-esophageal classified as alcoholic or non alcoholic. The varices, ascites, hepatorenal syndrome, and term Non Alcoholic Fatty Liver Disease hepatic encephalopathy. The definition of por- (NAFLD) represents a spectrum of condi- tal hypertension is based on a pressure mea- tions characterized by histologically surement. It may be performed directly through macrovesicular hepatic steatosis in the ab- portal vein punction or by subtracting the free sence of alcohol consumption. In this context, hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP). The two different histological patterns exist: fatty hepatic venous pressure gradient (HVPG) re- liver alone and Non Alcoholic SteatoHepati- flects the degree of PH in the majority of liver tis (NASH)1. diseases. The hepatic vein catheterization with The main histologic feature of NAFLD is measurement of the HVPG is considered the the presence of macrovesicular fatty change golden standard for portal pressure evaluation. in hepatocytes with displacement of the nu- The mechanisms by which steatosis could in- duce PH are not fully understood. It is not clear cleus to the edge of the cell, additional pres- whether the degree of PH differs between pa- ence of Mallory bodies, ballooning degenera- tients with viral and alcoholic cirrhosis, and be- tion, predominantly lobular neutrophilic in- tween patients with mild vs severe steatosis, In flammation, and Rappaport zone III perisi- the majority of the studies subjects with alco- nusoidal fibrosis1. It has been postulated that holic cirrhosis were included. Among patients steatosis may lead to more severe degree of with NASH, the portal hypertensive syndrome fibrosis and cirrhosis via increased lipid per- appears only in those with advanced cirrhosis. Further, although weight reduction decreas- oxidation and subsequent stellate cell activa- 2 es steatosis grade and fibrosis score, it is not tion and collagen synthesis . Although an ac- clear whether it improves PH in patients with cepted staging system is not still available, the cirrhosis. In contrast, other studies found a fibrosis in patients with NAFLD scored as correlation between the severity of steatosis stage 1 (zone III perisinusoidal or pericellular and clinical or lab parameters of PH. We can fibrosis focally present); stage 2 (zone III conclude that up to now it is not actually clear whether steatosis in itself might affect portal perisinusoidal or pericellular fibrosis focally pressure. with focal or extensive periportal fibrosis); stage 3 (zone III perisinusoidal or pericellular Key Words: fibrosis with portal fibrosis and focal or ex- Steatohepatitis, Portal hypertension, Stellate cells, tensive periportal fibrosis); stage 4 Variceal bleeding. (cirrhosis)1. Portal Hypertension (PH) Non Alcoholic Fatty Liver Disease (NAFLD) To date, it is not clear whether liver steato- sis per se (i.e., in the absence of severe fibro- Steatosis of the liver is a usually mild and sis or liver cirrhosis) might increase portal benign disease, due to several causes, as pressure and trigger the portal hypertensive 285 C. Puoti, L. Bellis syndrome. Further, the mechanisms by which (∆P = Q × R), where DP is the portal pres- steatosis could induce portal hypertension sure gradient, Q is portal blood flow and R is (PH) are not fully understood. Leptin seems the vascular resistance5. to play a role in the profibrogenic responses Increased resistance is due to: in the liver3. Activated hepatic stellate cells, the main hepatic fibrogenic cell type, express 1) liver architectural disturbance, with dis- leptin as well as its receptor, Ob-RL. When tortion of vascular architecture by fibro- treated with leptin these cells show an in- sis, scarring, regenerative nodules, creased a2(I) collagen gene expression. In- thrombosis (mechanical or fixed compo- jected leptin leads to a greater expression of nent, not modifiable by pharmacological procollagen type 1, TGF-β1, and a smooth treatment), and muscle actin in rats treated with CCl4 or 2) functional hepatic microcirculation alter- thioacetamide3. However, activated stellate ations (active contraction of portal/septal cells are the most important dynamic compo- myofibroblasts, activated stellate cells, nent leading to the increase of portal pres- portal venules – the so-called dynamic sure in patients with cirrhosis4. component, modifiable by drugs). This active intrahepatic vascular contraction is a consequence of an unbalance be- tween vasoconstrictor substances (en- Relations between NASH and PH dothelin, angiotensin II, vasopressin, tromboxane A2, leukotrienes, etc) and Thus, several questions about the relation- vasodilators (nitric oxide-NO, CO, ship between steatosis and portal hyperten- prostacycline, etc)4,5. sion remain to be answered: Portal blood flow in its turn increases be- • Does steatosis per se increase portal cause of enhanced production of vasodilators, pressure? increased eNOS activity and NO release, sys- • Does a “steatosis-related” portal hyper- temic and splanchnic vasodilatation, hyperki- tension exists (i.e., in the absence of fi- netic circulation, hyposensitivity to vasocon- brosis/cirrhosis)? strictors5. • Does portal hypertension correlate with The definition of portal hypertension is the presence/severity of steatosis? based on a pressure measurement4. Portal • Does portal hypertension differ accord- pressure measurement may be performed di- ing to the etiology of cirrhosis (viral vs rectly through portal vein punction, although alcohol vs NASH vs cryptogenic)? it is usually determined indirectly, by sub- tracting the free hepatic venous pressure PH is a severe complication of liver cirrho- (FHVP) from the wedged hepatic venous sis. Patients with PH are at risk to develop pressure (WHVP). In liver cirrhosis, WHVP gastro-esophageal varices and massive gas- equals portal (sinusoidal) pressure, and trointestinal bleeding, ascites, hepatorenal FHVP equals inferior vena cava pressure. syndrome, and hepatic encephalopathy4. This gradient, the so-called hepatic venous pressure gradient (HVPG), accurately re- Hepatic Venous Pressure Gradient flects the degree of PH in the majority of liv- (HVPG) er diseases4. The technique of hepatic vein The portal pressure gradient is the differ- catheterization with measurement of the ence between portal pressure and the pres- HVPG is safe and reproducible. The HVPG sure at the hepatic veins/inferior vena cava evaluation can be performed by catheteriza- level; it represents the hepatic perfusion pres- tion of hepatic veins with a balloon-tipped sure5. In patients with cirrhosis, portal pres- catheter and represents the pressure in the sure increases because of increased intrahep- hepatic sinusoids. In fact, the catheter in the atic vascular resistance and increased portal occluded position forms a continuous column blood flow. The interaction between portal of fluid between the catheter itself and the blood flow and the vascular resistance that blood in the hepatic vein, the sinusoids and opposes that flow is defined by the Ohm’s law the portal vein5. Several studies have shown a 286 Steatosis and portal hypertension good correlation between direct portohepatic Furthermore, HVPG measurement could measurements and HVPG measurements have a prognostic value. It has been shown (using a balloon catheter) both in alcoholic that the HVPG at different cut-off levels is a and viral cirrhosis4,5. Thus, the HVPG mea- predictor of long-term survival in cirrhotic surement using a balloon catheter is now con- patients without previous variceal bleeding at sidered the golden standard for portal pres- inclusion in the study4. Several studies have sure evaluation. found a significant higher survival in patients in whom HVPG levels were below the cut-off Clinical Picture of PH than in those with HVPG above the cut-off5. PH is a clinical syndrome defined by a The predictive HVPG value was identified pathological increase of the HVPG values between 12 and 20.8 mmHg. Further, it has above the normal upper limit of 5 mmHg, been found that early measurement of while clinically significant PH (CSPH) is de- HVPG in patients with acute variceal bleed- fined by an increase in HVPG values to a ing could have a negative prognostic value if threshold above approximately 10-12 mmHg. > 20 mmHg. Varices do not bleed when the HVPG is be- low 12 mmHg1-4,8,12-14. HVPG determination is a safe and reliable tool to measure the degree of portal hyperten- NASH and Viral Hepatitis sion, with a very low rate of complications. Conscious sedation with low dose midazolam In patients with chronic viral hepatitis, (0.02 mg/kg) increases patient comfort and steatosis is more frequent in hepatitis C willingness to undergo repeated measure- (52%) than in hepatitis B (22%) (p = 0.03). ments, without hepatic pressure modifica- The severity of steatosis in hepatitis