Letter to the Editor Liver steatosis induces portal hypertension regardless of fibrosis in patients with NAFLD: A proof of concept case report To the Editor: controlled transient elastography (VCTE) and controlled attenu- Non-alcoholic fatty liver disease (NAFLD) affects 25-35% of adults in ation parameter values were 7.8 kPa and 333 dB/m, respectively, the general population, and it is closely related to metabolic dis- suggestive of severe steatosis without significant fibrosis. ALT eases, particularly obesity and type 2 diabetes. The hallmark of and AST values were 102 and 82 IU/L, respectively, and liver NAFLD is the accumulation of lipid droplets in hepatocytes (so function parameters (bilirubin, albumin) were within the normal called steatosis). The pathophysiology of NAFLD is complex, and the range, as was platelet count (Table S1). clinical course is widely variable. The bulk of patients present with During follow-up, an upper gastrointestinal endoscopy (or- a mild non-progressive disease. However, in about 20-30%, lipid dered for gastroesophageal reflux disease symptoms) showed accumulation will promote cell death and oxidative stress, which small esophageal varices. The imaging techniques (ultrasound will activate the cytokine cascade, promoting liver inflammation and contrast-enhanced scan) ruled out vascular disease and no (non-alcoholic steatohepatitis [NASH]) that could trigger liver architectural abnormalities in the liver or radiological signs of fibrosis and eventually cirrhosis and hepatocellular carcinoma.1 portal hypertension were found (spleen size 10.5 cm). Portal hypertension (PH) is the main driver of hepatic Due to the mismatch between endoscopic findings and imaging decompensation in advanced liver disease. It is defined as a plus laboratory results, measurement of the hepatic venous pres- multifactorial condition due to hemodynamic abnormalities of sure gradient (HVPG) and a transjugular liver biopsy were carried the portal venous system, related to increased intrahepatic out. HVPG confirmed the presence of portal hypertension vascular resistance and altered splanchnic blood flow. None- (6 mmHg) and the histological evaluation demonstrated an archi- theless, several studies have suggested that PH can be present in tectural lobular alteration due to severe steatosis and an increased the early stages of NASH, when fibrosis is far less advanced or hepatocyte size due to the accumulation of lipid droplets. The even absent.2–8 NAFLD activity score was 7/8 (steatosis 3; lobular inflammation 2; We present the case of a 60-year-old Hispanic female with no ballooning 2) with fibrosis stage 1a (Fig. 1A-B). The timeframe from alcohol consumption, a body mass index of 31.2 kg/m2 and a endoscopy to VCTE and HVPG measurement/liver biopsy was 5 and waist circumference of 102 cm. The patient received proton- 10 months, respectively. Of note, the patient had a stable weight, pump inhibitors due to gastroesophageal reflux disease and and no medication was added during that period. did not present any other medical history of interest. She was PH plays a key role in the natural history of patients with liver referred to our liver unit in 2020 due to a persistent alteration of disease. HVPG remains the gold standard, with a well- liver enzymes and the presence of steatosis on abdominal ul- established threshold to define PH (> −6 mmHg) and clinically trasound. After excluding other potential causes of liver disease, significant PH (CSPH; > − 10 mmHg), which is strongly associated NAFLD was diagnosed. Liver stiffness measurement by vibration- with the presence of gastroesophageal varices and liver-related A B C Fig. 1. Liver biopsy from a human with NAFLD and a rat model of NASH. (A,B) Individual with NAFLD and (C) rat model. Courtesy of Salcedo M. and Barberá A, respectively. Representative images showing NASH features in absence of fibrosis, stained with (A) H&E and (B) picrosirius red. (C) Representative image showing liver parenchyma stained with H&E in the murine model after 36 weeks of dietary intervention. NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. Keywords: Non-alcoholic fatty liver disease; Liver steatosis; Portal hypertension; Sinusoidal area; Non-alcoholic steatohepatitis. Received 15 August 2022; received in revised form 21 September 2022; accepted 10 October 2022; ; available online 29 October 2022 Letter to the Editor complications. Moreover, it has been shown that liver stiffness substances)2,3 and structural sinusoidal disturbances secondary 9 measurement < −15 kPa + platelet count >−150x10 rules out CSPH to fatty liver changes could promote PH, even in the absence of 9 in compensated advanced liver disease. Nevertheless, some fibrosis.4,5 Our group reported that steatosis was the main studies yielded unexpected results regarding the role of PH and determinant of PH in a 36-week dietary NASH rat model.5 The the ability of HVPG and VCTE to address CSPH in NAFLD. On the main mechanism was the architectural distortion of the sinu- one hand, it seems that the HVPG threshold to define CSPH is not soid area caused by accumulation of lipid droplets and specific enough for individuals with NAFLD,10 with liver events morphological changes in hepatocytes, which led to sinusoidal registered also at HVPG <10 mmHg within this population.11 On compression and increased intrahepatic vascular resistance the other hand, the diagnostic accuracy of VCTE to rule in CSPH (Fig. 1C) significantly decreases in individuals with obesity and NAFLD In summary, the present clinical case provides proof-of- despite the utilization of the XL probe.12 This gap was reflected in concept of the major influence of liver steatosis on the physio- the Baveno VII expert consensus,9 where no specific recom- pathology of PH in individuals with NAFLD. Further research is mendation in individuals with obesity and NAFLD was provided needed to elucidate the precise mechanisms of PH and to refine to rule in CSPH through non-invasive tests. the diagnostic approach in obese individuals with NAFLD. Be- Interestingly, murine models suggested that both sides, the real prevalence of PH unrelated to fibrosis in in- functional (i.e. endothelial dysfunction, imbalance in vasoactive dividuals with NAFLD remains to be determined. Financial support [2] Francque S, Laleman W, Verbeke L, Van Steenkiste C, Casteleyn C, No financial support was received for data analysis or writing assistance. Kwanten W, et al. Increased intrahepatic resistance in severe steatosis: JRE is a PhD student at Universitat Autònoma de Barcelona, Spain. JMP endothelial dysfunction, vasoconstrictor overproduction and altered reports having received consulting fees from Boehringer Ingelheim, MSD microvascular architecture. Lab Invest 2012;92(10):1428–1439. and Novo Nordisk. He has received speaking fees from Gilead, Intercept, [3] van der Graaff D, Chotkoe S, De Winter B, De Man J, Casteleyn C, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, Timmermans JP, et al. Vasoconstrictor antagonism improves functional MSD, CUBICIN, and Novo Nordisk. He has received educational and and structural vascular alterations and liver damage in rats with early NAFLD. JHEP Rep 2021;4(2):100412. research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, [4] Francque S, Verrijken A, Mertens I, Hubens G, Van Marck E, Pelckmans P, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA et al. Noncirrhotic human nonalcoholic fatty liver disease induces portal IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898 (PI22/ hypertension in relation to the histological degree of steatosis. Eur J 01770). JG has received consulting fees from Boehringer Ingelheim, Gastroenterol Hepatol 2010;22(12):1449–1457. speaking fees from Echosens and travel expenses from Gilead and Abbie. [5] Barberá A, Raurell I, García-Lezana T, Torres-Arauz M, Bravo M, Hide D, Funds from ISCIII PI18/00947 and PI21/00691. All other authors: nothing et al. Steatosis as main determinant of portal hypertension through a to disclose. restriction of hepatic sinusoidal area in a dietary rat nash model. Liver Int 2020;40(11):2732–2743. Conflict of interest [6] Baffy G, Bosch J. Overlooked subclinical portal hypertension in The authors declare no conflicts of interest that pertain to this work. non-cirrhotic NAFLD: is it real and how to measure it? J Hepatol 2022; Please refer to the accompanying ICMJE disclosure forms for further 76(2):458–463. details. [7] Rodrigues SG, Montani M, Guixé-Muntet S, De Gottardi A, Berzigotti A, Bosch J. Patients With Signs of Advanced Liver Disease and Clinically Authors’ contributions Significant Portal Hypertension Do Not Necessarily Have Cirrhosis. Clin Study concept and design; JRE, JMP, JG; Patient enrolment and acquisition Gastroenterol Hepatol 2019;17(10):2101–2109.e1. of data JR, AB, MTS; Analysis and interpretation of data, JRE, AB, MTS; [8] Moga L, Laroyenne A, Larrue H, Bureau C, Rautou PE. Patients with NAFLD do not have severe portal hypertension in the absence of cirrhosis. Drafting of the manuscript, JRE, JMP; Critical revision of the manuscript: J Hepatol 2021;74(5):1269–1270. JRE, AB, MTS, MM, JG, JMP. JRE is the guarantor of the article. All the [9] de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, Baveno VII authors approved the final draft which is being submitted. Faculty. Baveno VII - renewing consensus in portal hypertension. J Hepatol 2022;76(4):959–974. Data availability statement [10] Ferrusquía-Acosta J, Bassegoda O, Turco L, Reverter E, Pellone M, The data that support the findings of this study are available from the Bianchini M, et al. Agreement between wedged hepatic venous pressure corresponding author upon reasonable request. and portal pressure in non-alcoholic steatohepatitis-related cirrhosis. J Hepatol 2021;74(4):811–818. Supplementary data [11] Bassegoda O, Olivas P, Turco L, Mandorfer M, Serra-Burriel M, Tellez L, et al. Supplementary data to this article can be found online at https://doi. Decompensation in advanced nonalcoholic fatty liver disease may occur at org/10.1016/j.jhepr.2022.100618. lower hepatic venous pressure gradient levels than in patients with viral disease. Clin Gastroenterol Hepatol 2021. S1542–3565(21)1136-1138. [12] Pons M, Augustin S, Scheiner B, Guillaume M, Rosselli M, Rodrigues SG, References et al. Noninvasive diagnosis of portal hypertension in patients with Author names in bold designate shared co-first authorship. compensated advanced chronic liver disease. Am J Gastroenterol 2021;116:723–732. [1] Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a Jesús Rivera-Esteban1,2 systematic review and meta-analysis of paired-biopsy studies. Clin Gas- Aurora Barberá1,2 troenterol Hepatol 2015;13(4):643–654.e1-9. JHEP Reports 2023 vol. 5 j 100618 2 Maria Teresa Salcedo2,4 1 Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut of Maria Martell1,2,3 Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Joan Genescà1,2,3,* Spain; Juan M. Pericàs1,2,3,* 2 Universitat Autònoma de Barcelona, Bellaterra, Spain; 3 CIBEREHD, ISCIII, Madrid, Spain; 4 Pathology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain * Corresponding authors. Address: Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d’Hebron 119- 129, 08035 Barcelona, Spain. E-mail address: juanmanuel.pericas@vallhebron.cat (J.M. Pericàs); joan.genesca@vall- hebron.cat (J. Genescà). JHEP Reports 2023 vol. 5 j 100618 3