European Review for Medical and Pharmacological Sciences 2005; 9: 285-290 Steatosis and portal

C. PUOTI, L. BELLIS

Department of and Internal Medicine, Ospedale di Genzano – Rome (Italy)

Abstract. – Non Alcoholic Fatty Dis- chronic viral (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 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, , , and term Non Alcoholic Fatty . 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 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- , Portal hypertension, Stellate cells, tensive periportal fibrosis); stage 4 Variceal bleeding. (cirrhosis)1.

Portal Hypertension (PH) Non Alcoholic (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- (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- , 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 (-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- 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 /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 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 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 C is not tions1. However, it is an invasive technique, correlated with metabolic features, suggesting not inexpensive, which requires well-experi- a direct role of HCV6,7. The score of steatosis enced hepatologists, specific equipments and correlates with the level of HCV RNA in expensive disposable materials. serum and liver, but only in patients with Thus, due to these methodological and genotype 3. In these subjects, virological re- technical difficulties, the measurement of PH sponse to alfa-IFN is associated with the dis- is not immediate and is performed only in a appearance of the steatosis, which recurs at limited number of specialized centers4. It de- the time of virological relapse. Finally, steato- rives that available informations on the rela- sis grades 3-4 seem to be associated with a tionship between levels of PH and clinical higher annual rate of fibrosis progression, re- consequences are substantially limited, and gardless of HCV type8. Further, the progres- present knowledge on PH is mainly based on sion of fibrosis and of portal hypertension is the relationship between its clinical manifes- influenced by the severity of steatosis and by tations, namely gastro-esophageal varices, the presence of obesity and diabetes. In par- and clinical outcomes such as bleeding and ticular, in patients with hepatitis C fibrosis is death1,4. associated with the BMI and the severity of steatosis9. Indeed, it has been shown that Clinical application of obese patients with HCV related CH and HVPG measurement steatosis and diabetes show a fibrosis progres- In clinical practice, HVPG measurement sion significantly higher than those with could have several applications, such as: steatosis and obesity but without diabetes, and those with steatosis but without obesity. 1. Evaluation of the risk of variceal hemor- rhage 2. Assessment of hemodynamic response to pharmacological therapy Clinical Picture of NAFLD and NASH 3. Definition of prognosis (cirrhosis and acute variceal bleeding) Steatosis of the liver and NAFLD repre- 4. Pre-operative evaluation of cirrhotic pa- sent the most common causes of ALT eleva- tients candidates to hepatic resection. tion once other causes of liver damage have

287 C. Puoti, L. Bellis been excluded (virus, alcohol, drugs, etc). In and alcoholic cirrhosis, and between patients the majority of the patients the disease ap- with mild vs severe steatosis. In the majority pears to be symptomless. In other subjects of the studies mainly subjects with alcoholic non-specific symptoms occur, such as fatigue, cirrhosis were included. vague right upper quadrant discomfort or In a recent study, we found that the severi- pain, malaise. Obesity and hepatomegaly rep- ty of portal hypertension, evaluated through resent the most common findings in patients HVPG measurement, does not differ by the with steatosis or NAFLD. Only a smaller rate etiology of cirrhosis (Figure 1). Further, in of subjects show signs of chronic liver disease. patients with HCV related cirrhosis, no cor- In a minority of patients, the presence of as- relation was found between HVPG and HCV cites, variceal bleeding, anasarca indicates a genotype. Finally, the severity of steatosis decompensated liver cirrhosis. (US or histological steatosis) did not corre- late with the degree of the HVPG10. Other investigators11 found that alcoholic patients with non cirrhotic chronic liver dis- Degree of PH in Patients with ease and mild to severe steatosis have normal Alcoholic or non Alcoholic Etiology baseline HVPG, and no correlations were found between the HVPG and fibrosis, degree To date it is not clear whether the architec- of steatosis and necroinflammatory activity. In tural and functional alterations seen in pa- these patients however, ethanol infusion sig- tients with steatosis might induce a significant nificantly increased HVPG values11. Thus, the increase of portal pressure. In particular, authors did conclude that alcoholic patients when dealing with steatosis and PH, several without cirrhosis have normal portal pressure, other issues might be solved: despite liver steatosis, and that ethanol infu- sion increases HVPG, irrespective of steatosis, • Does the severity of PH differ between fibrosis and clinical or lab parameters. Other patients with alcohol-related and viral- studies reported that HVPG did not correlate related steatosis? with steatosis and that alcohol ingestion • Does the degree of PH correlate with the markedly increased the HVPG in cirrhotic pa- entity of steatosis? tients with already established PH12. • Does the severity of PH differ between Thus, it has been suggested that patients patients with alcoholic or HCV related with NASH but without cirrhosis have no ev- liver cirrhosis? idence of PH13. Among patients with NASH, • Does the severity of PH differ by the the portal hypertensive syndrome appears HCV type? only in those with advanced cirrhosis1. Fur- ther, although weight reduction decreases Indeed, it is not yet clear whether the de- steatosis grade and fibrosis score, it is not gree of PH differs between patients with viral clear whether it improves PH in patients with

Figure 1. HVPG levels in patients with HCV-related and alcoholic cirrhosis. No significant differences in portal pressure where seen according to the etiology of cirrhosis. (From Bellis L, Castellacci R, Montagnese F, et al, ref. 10).

288 Steatosis and portal hypertension

Figure 2. Postprandial changes in HVPG in cirrhotic patients pretreated with placebo or simvastatin. The brisk postprandial increase in HVPG caused by post- prandial hyperemia seen in patients treated with place- bo is significantly attenuated in those receiving simvas- tatin. (From Zafra C, Abraldes JC, Turnes J, et al, ref. 16).

cirrhosis1. Indeed, it has been shown that his- sponse. For example, the brisk postprandial tological improvement might occur, with a increase in HVPG due to volume load caused decrease in and even in perisi- by postprandial hyperemia is markedly atten- nusoidal fibrosis. uated in patients pretreated with simvastatin In contrast with these findings, other stud- but not in those receving placebo (Figure 2). ies found a correlation between the severity In conclusion, given these discrepancies it of steatosis and clinical or lab parameters of is not actually clear whether steatosis in itself PH, as patients with grade II/III steatosis might affect portal pressure. However this have significantly higher frequency of hy- possibility, that has been already suggested poalbuminemia, thrombocitopenia and over 30 years ago17-19, cannot be ruled out. , the clinical evidence of portal hypertension14,15.

References Pathway and Portal Pressure 1) AGA TECHNICAL REVIEW ON NONALCOHOLIC FATTY LIVER Disease. Gastroenterology 2002; 123: 1705- 1725. Recently, a relationship between choles- terol pathway and portal pressure has been 2) IOANNU GN, WEISS NS, KOWDLEY KW, et al. Is obesi- 16 ty a risk factor for cirrhosis-related death or hospi- suggested . Indeed, it has been found that talization? A population-based cohort study. Gas- cholesterol increases caveolin-1, a inhibitory troenterology 2003; 125: 1053-1059. protein of endothelial nitric oxide synthase 3) ANGULO P, A LBA LM, PETROVIC LM, et al. Leptin, in- activity (eNOS), thus decreasing eNOS ac- sulin resistance, and liver fibrosis in human non- tivity. Further, farnesyl-PP activates RAS, a alcoholic fatty liver disease. J Hepatol 2004; 41: protein implicated in cell proliferation, ad 943-949. thus proliferation. In its turn, geranylgeranyl- 4) BOSCH J, ABRALDES JG, GROSZMANN R. Current man- PP downregulates eNOS expression (Figure agement of portal hypertension. J Hepatol 2003; 2). Taken together, the biological actions of 38: S54-58. cholesterol and isoprenoid intermediate path- 5) BOSCH J, GARCIA PAGAN JC. Complications of cirrho- way induce a decrease of NO production, sis. I. Portal hypertension. J Hepatol 2000; 32 (1 thus increasing intrahepatic resistance, which Suppl): 141-156. is the first phenomenon leading to portal hy- 6) RUBBIA-BRANDT L, QUADRI R, ABID K, et al. Hepato- pertension. Simvastatin, an inhibitor of cyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol 2000; 33: 106-115. HMG-CoA reductase, counteracts these ac- tions, increasing eNOS activity and eNOS ex- 7) ADINOLFI LE, GAMBARDELLA M, ANDREANA A, et al. Steatosis accelerates the progression of liver pression and improving NO bioavailability damage of chronic hepatitis C patients and corre- into the liver, thus decreasing intrahepatic re- lates with specific HCV genotype and visceral sistance and restoring a vasorelaxing re- obesity. 2001; 33: 1358-1364.

289 C. Puoti, L. Bellis

8) MONTO A, ALONZO J, WATSON JJ, et al. Steatosis in 14) RATZIU V, B ONYHAY L, DI MARTINO V, et al. Survival, chronic hepatitis C: contribution of obesity, dia- and in obe- betes mellitus and alcohol. Hepatology 2002; 36: sità-related cryptogenic cirrhosis. Hepatology 729-736. 2002; 35: 1485-1492.

9) HOURIGAN LF, MACDONALD GA, PURDIE D, et al. Fi- 15) HU KQ, KYULO NL, ESRAELIAN E, et al. Overweight brosis in chronic hepatitis C correlates significant- and obesity, hepatic steatosis, and progression of ly with body mass index and steatosis. Hepatol- chronic hepatitis C: a retrospective study on a ogy 1999; 29: 1215-1219. large cohort of patients in the United States. J 10) BELLIS L, CASTELLACCI R, MONTAGNESE F, e t al. Hepatic Hepatol 2004; 40: 147-154. venous pressure gradient determination in pa- 16) ZAFRA C, ABRALDES JC, TURNES J, et al. Simvastatin tients with hepatitis C virus-related and alcoholic enhances hepatic nitric oxide production and cirrhosis. Eur J Gastroenterol Hepatol 2003; 15: decreases the hepatic vascular tone in patients 1085-1089. with cirrhosis. Gastroenterology 2004; 126: 11) SILVA G, FLUXA F, B RESKY G, et al. Splanchnic and 749-755. systemic hemodynamics in early abstinence and 17) CHIANDUSSI L, GRECO F, I NDOVINA D. Hepatic steato- after ethanol administration in non-cirrhotic alco- sis and portal hypertension with presinusoidal ob- holic patients. J Hepatol 1994; 20: 494-499. struction. Report of a case. Gastroenterology 12) LUCA A, GARCIA-PAGAN JC, BOSCH J, et al. Effects of 1963; 44: 532-535. ethanol consumption on hepatic hemodynamics in patients with alcoholic cirrhosis. Gastroenterol- 18) MADORE P. Variceal hemorrhage in a case of he- ogy 1997; 112: 1284-1289. patic steatosis. Am J Gastroenterol 1970; 54: 267-271. 13) AGARWAL SR, MALHOTRA V, S AKHUJA P, et al. Clinical, biochemical and histological profile of nonalco- 19) MINO G, MURO J, ACOSTA J, et al. Portal hyperten- holic steatohepatitis. Indian J Gastroenterol 2001; sion in hepatic steatosis. Rev Clin Esp 1969; 15: 20: 183-186. 112: 77-84.

290