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Liver steatosis induces portal hypertension regardless of fibrosis in patients with NAFLD: A proof of concept case report

  • Jesús Rivera-Esteban
    Affiliations
    Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut of Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Universitat Autònoma de Barcelona, Bellaterra, Spain
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  • Aurora Barberá
    Affiliations
    Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut of Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Universitat Autònoma de Barcelona, Bellaterra, Spain
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  • Maria Teresa Salcedo
    Affiliations
    Universitat Autònoma de Barcelona, Bellaterra, Spain

    Pathology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
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  • Maria Martell
    Affiliations
    Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut of Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Universitat Autònoma de Barcelona, Bellaterra, Spain

    CIBEREHD, ISCIII, Madrid, Spain
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  • Joan Genescà
    Correspondence
    Corresponding author. Joan Genescà, MD, PhD, 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,
    Affiliations
    Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut of Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Universitat Autònoma de Barcelona, Bellaterra, Spain

    CIBEREHD, ISCIII, Madrid, Spain
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  • Juan M. Pericàs
    Correspondence
    Corresponding author. Juan M Pericàs, MD, PhD, 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,
    Affiliations
    Liver Unit, Vall d’Hebron Hospital Universitari, Vall d’Hebron Institut of Research (VHIR), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain

    Universitat Autònoma de Barcelona, Bellaterra, Spain

    CIBEREHD, ISCIII, Madrid, Spain
    Search for articles by this author
Open AccessPublished:October 28, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100618

      Abstract

      Portal hypertension (PH) is the main driver of hepatic decompensation in advanced liver disease. Nonetheless, increasing evidence suggests that PH can be present at the early stages of NASH.
      We present a case of a 60-year-old obese female with oesophageal varices without signs of advanced liver disease or vascular abnormalities at imaging plus laboratory tests. The hepatic venous pressure gradient confirmed the presence of PH (6 mmHg) and the histological evaluation demonstrated an architectural lobular alteration due to severe steatosis, leading to sinusoid compression without concomitant significant fibrosis.
      This proof-of-concept case reflects the influence of liver steatosis in PH physiopathology on NAFLD patients. Further research is needed to elucidate the precise mechanisms of PH and to refine the diagnostic approach in NAFLD obese subjects.

      Keywords

      Abbreviations:

      ALT (alanine aminotransferase), AST (aspartate aminotransferase), CAP (controlled attenuation parameter), NAFLD (non-alcoholic fatty liver disease), LSM (liver stiffness measurements), VCTE (vibration-controlled transient elastography)
      Non-alcoholic fatty liver disease (NAFLD) affects 25-35% of adults in the general population, and it is closely related to metabolic diseases, particularly obesity and type 2 diabetes. The hallmark of NAFLD is the accumulation of lipid droplets in the hepatocytes or steatosis. NAFLD physiopathology is complex, and the clinical course is widely variable. The bulk of patients would present a mild non-progressive disease. However, in about 20-30%, lipid accumulation will promote cell death and oxidative stress, which will activate the cytokine cascade, promoting liver inflammation (steatohepatitis or NASH) that could trigger liver fibrosis and eventually cirrhosis and hepatocellular carcinoma.
      • Singh S.
      • Allen A.M.
      • Wang Z.
      • Prokop L.J.
      • Murad M.H.
      • Loomba R.
      Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies.
      Portal hypertension (PH) is the main driver of hepatic decompensation in advanced liver disease. It is defined as a multifactorial condition due to hemodynamic abnormalities of the portal venous system, related to increased intrahepatic vascular resistance and altered splanchnic blood flow. Nonetheless, several studies have suggested that PH can be present at the early stages of NASH, when fibrosis is far less advanced or even absent.
      • Francque S.
      • Laleman W.
      • Verbeke L.
      • Van Steenkiste C.
      • Casteleyn C.
      • Kwanten W.
      • et al.
      Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture.
      • van der Graaff D.
      • Chotkoe S.
      • De Winter B.
      • De Man J.
      • Casteleyn C.
      • Timmermans J.P.
      • et al.
      Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD.
      • Francque S.
      • Verrijken A.
      • Mertens I.
      • Hubens G.
      • Van Marck E.
      • Pelckmans P.
      • et al.
      Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis.
      • Barberá A.
      • Raurell I.
      • García-Lezana T.
      • Torres-Arauz M.
      • Bravo M.
      • Hide D.
      • et al.
      Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model.
      • Baffy G.
      • Bosch J.
      Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it?.
      • Rodrigues S.G.
      • Montani M.
      • Guixé-Muntet S.
      • De Gottardi A.
      • Berzigotti A.
      • Bosch J.
      Patients With Signs of Advanced Liver Disease and Clinically Significant Portal Hypertension Do Not Necessarily Have Cirrhosis.
      • Moga L.
      • Laroyenne A.
      • Larrue H.
      • Bureau C.
      • Rautou P.E.
      Patients with NAFLD do not have severe portal hypertension in the absence of cirrhosis.
      We present a case of a 60-year-old Hispanic female with no alcohol consumption, a body mass index of 31.2 kg/m2, and a waist circumference of 102 cm. The patient received proton-pump inhibitors due to a gastroesophageal reflux disease (GERD) and did not present any other medical history of interest. She was referred to the Liver Unit clinic in 2020 due to a persistent alteration of liver enzymes and the presence of steatosis on abdominal ultrasound. After excluding other potential causes of liver disease, NAFLD was diagnosed. Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) values were 7.8 kPa and 333 dB/m, respectively, suggestive of severe steatosis without significant fibrosis. ALT and AST values were 102 and 82 UI/L, respectively, and liver function parameters (bilirubin, albumin) were within the normal range, as well as platelet count (Supplementary Table 1).
      During follow-up, an upper gastrointestinal endoscopy (ordered for GERD symptoms) showed small esophageal varices. The imaging techniques (ultrasound and contrast-enhanced scan) ruled out vascular disease and no architectural abnormalities in the liver or radiological signs of portal hypertension were found (spleen size 10.5 cm).
      Due to the mismatch between endoscopic findings and imaging plus laboratory results, measurement of the hepatic venous pressure gradient (HVPG) and a transjugular liver biopsy were carried out. HVPG confirmed the presence of portal hypertension (6 mmHg) and the histological evaluation demonstrated an architectural lobular alteration due to severe steatosis and an increased hepatocyte size due to the accumulation of lipid droplets. The NAS-CRN score was 7/8 (Steatosis 3; Lobular inflammation 2; Ballooning 2) with fibrosis stage 1a (Figure 1 A-B). The timeframe from endoscopy to VCTE and HVPG measurement/liver biopsy was 5 and 10 months, respectively. Of note, the patient had a stable weight and no medication was added during that period.
      Figure thumbnail gr1
      Figure 1Liver biopsy of the NAFLD patient (A, B) and a rat model (C). Courtesy of Salcedo M. and Barberá A, respectively. Representative images showing NASH features in absence of fibrosis, stained with hematoxylin and eosin (A) and picrosirius red (B). (C) Representative image showing liver parenchyma stained with hematoxylin and eosin in the murine model after 36 weeks of diet intervention.
      PH plays a key role in the natural history of patients with liver disease. HVPG remains the gold standard, with a well-established threshold to define PH (≥6 mmHg) and clinically significant PH (CSPH; ≥ 10mmHg), which is strongly associated with the presence of gastroesophageal varices and liver-related complications. Moreover, it has been shown that LSM ≤15 kPa + platelet count ≥150x10E9 rules out CSPH in compensated advanced liver disease.
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - Renewing consensus in portal hypertension.
      Nevertheless, some studies yielded unexpected results regarding the role of PH and the ability of HVPG and VCTE to address CSPH in NAFLD. On the one hand, it seems that the HVPG threshold to define CSPH is not specific enough for NAFLD patients,
      • Ferrusquía-Acosta J.
      • Bassegoda O.
      • Turco L.
      • Reverter E.
      • Pellone M.
      • Bianchini M.
      • et al.
      Agreement between wedged hepatic venous pressure and portal pressure in non-alcoholic steatohepatitis-related cirrhosis.
      with liver events registered also at HVGP <10mmHg within this population.
      • Bassegoda O.
      • Olivas P.
      • Turco L.
      • Mandorfer M.
      • Serra-Burriel M.
      • Tellez L.
      • et al.
      Decompensation in Advanced Nonalcoholic Fatty Liver Disease May Occur at Lower Hepatic Venous Pressure Gradient Levels Than in Patients With Viral Disease.
      On the other hand, the diagnostic accuracy of VCTE to rule in CSPH significantly decreases in patients with obesity and NAFLD despite the utilization of the XL probe.
      • Pons M.
      • Augustin S.
      • Scheiner B.
      • Guillaume M.
      • Rosselli M.
      • Rodrigues S.G.
      • et al.
      Noninvasive Diagnosis of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease.
      This gap was reflected in the Baveno VII expert consensus,
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - Renewing consensus in portal hypertension.
      where no specific recommendation in patients with obesity and NAFLD was provided to rule in CSPH through non-invasive tests.
      Interestingly, murine models suggested that both functional (i.e. endothelial dysfunction, vasoactive substances imbalance)
      • Francque S.
      • Laleman W.
      • Verbeke L.
      • Van Steenkiste C.
      • Casteleyn C.
      • Kwanten W.
      • et al.
      Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture.
      ,
      • van der Graaff D.
      • Chotkoe S.
      • De Winter B.
      • De Man J.
      • Casteleyn C.
      • Timmermans J.P.
      • et al.
      Vasoconstrictor antagonism improves functional and structural vascular alterations and liver damage in rats with early NAFLD.
      and structural sinusoidal disturbances secondary to fatty liver changes could promote PH even in the absence of fibrosis.
      • Francque S.
      • Verrijken A.
      • Mertens I.
      • Hubens G.
      • Van Marck E.
      • Pelckmans P.
      • et al.
      Noncirrhotic human nonalcoholic fatty liver disease induces portal hypertension in relation to the histological degree of steatosis.
      ,
      • Barberá A.
      • Raurell I.
      • García-Lezana T.
      • Torres-Arauz M.
      • Bravo M.
      • Hide D.
      • et al.
      Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model.
      Our group reported that steatosis was the main determinant of portal hypertension in a 36-week dietary NASH rat model.
      • Barberá A.
      • Raurell I.
      • García-Lezana T.
      • Torres-Arauz M.
      • Bravo M.
      • Hide D.
      • et al.
      Steatosis as main determinant of portal hypertension through a restriction of hepatic sinusoidal area in a dietary rat nash model.
      The main mechanism was the architectural distortion of the sinusoid area by the accumulation of lipid droplets and the morphological changes in the hepatocyte, which led to sinusoidal compression and increased intrahepatic vascular resistance (Figure 1C)
      In summary, the present clinical case provides proof-of-concept of the capital influence of liver steatosis in the physiopathology of PH on NAFLD patients. Further research is needed to elucidate the precise mechanisms of PH and to refine the diagnostic approach in obese subjects with NAFLD. Besides, the real prevalence of PH unrelated to liver fibrosis in NAFLD patients remains to be determined.

      Financial disclosure

      No financial support was received for data analysis or writing assistance. JRE is a PhD student at Universitat Autònoma de Barcelona, Spain. JMP reports having received consulting fees from Boehringer Ingelheim, MSD and Novo Nordisk. He has received speaking fees from Gilead, Intercept, and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk. He has received educational and research support from Madrigal, Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD. Funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898. JG has received consulting fees from Boehringer Ingelheim, speaking fees from Echosens and travel expenses from Gilead and Abbie. Funds from ISCIII PI18/00947 and PI21/00691. All other authors: nothing to disclose.

      Data Availability Statement

      The data that support the findings of this study are available from the corresponding author upon reasonable request.

      Permission to reproduce material from other sources

      The material in this paper is original and does not come from other sources.

      Specific author contributions

      Study concept and design; JRE, JMP, JG; Patient enrolment and acquisition of data JR, AB, MTS; Analysis and interpretation of data, JRE, AB, MTS; Drafting of the manuscript, JRE, JMP; Critical revision of the manuscript: JRE, AB, MTS, MM, JG, JMP.

      Authorship Statement

      JRE is the guarantor of the article. All the authors approved the final draft which is being submitted.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

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