Portal hypertension is the most common complication of liver cirrhosis and is considered the key point for the triggering of ascites, encephalopathy and esophageal varices and, in this way, it is considered a milestone for decision making, with its diagnosis being fundamental in the follow-up of cirrhotic patients.

How can we diagnose portal hypertension?

The gold standard for defining portal hypertension is the measurement of the hepatic venous pressure gradient (HPVG). Values above 5mmHG define portal hypertension. When this gradient exceeds 10mmHg, we consider that portal hypertension is clinically significant (HPCS), with the patient prone to the appearance of decompensations. The presence of esophageal varices in patients diagnosed with cirrhosis also implies the presence of clinically significant portal hypertension regardless of the venous gradient measurement.

As the measurement of the hepatic venous pressure gradient is not a routine practice, in addition to being an invasive examination, it is admitted that, liver stiffness values ? 25 kPa obtained through transient hepatic elastography, are defining of HPCS, with specificity and positive predictive value > 90%. As it is a non-invasive examination, capable of providing such information, transient hepatic elastography has been increasingly used in the follow-up of compensated cirrhotic patients in order to provide data so that the pharmacological treatment of portal hypertension can be instituted early, without the need for serial endoscopies or even the measurement of the hepatic venous pressure gradient.

And what is the role of beta-blockers in the treatment of patients with liver cirrhosis?

Non-selective beta-blockers (propranolol, nadolol and carvedilol), have been used routinely, with proven benefits in the primary prophylaxis of bleeding from risk varices and as an adjunct in the secondary prophylaxis of varicose bleeding.

Patients at high risk for bleeding are those with thin-caliber esophageal varices with red color signs, medium and large caliber varices, gastric varices and decompensated patients in ascites with varices of any size.

Carvedilol is a non-selective beta-blocker, with alpha-1 blocking activity and appears to be more effective than traditional beta-blockers in reducing portal hypertension, having been recommended in the last Baveno VII consensus, as the beta-blocker of choice in the treatment of portal hypertension. Its currently recommended dose is 12.5mg/day, divided into two doses and patients should be monitored for their main adverse effects such as asthenia, dyspnea and low blood pressure (SBP< 90mmHG).

The PREDESCI study showed that the use of beta-blockers, especially carvedilol, in cirrhotic patients with clinically significant portal hypertension (HPVG> 10mmHG) reduced the chance of decompensation in ascites by up to 40% in a subgroup of patients with thin-caliber varices without red color signs, implying an improvement in survival.

The use of beta-blockers in patients with portal hypertension without varices has no clearly proven benefits. Pre-primary prophylaxis, that is, the use of this medication in compensated cirrhotic patients, did not show benefit in the appearance of varices, however, the use in patients with HPCS, even in the absence of varices, has been an increasingly routine practice, suggested in the latest consensuses, with the aim of reducing long-term decompensation.

In summary…

In patients diagnosed with liver cirrhosis, the use of beta-blockers, preferably carvedilol, is indicated in:

• patients without ascites with thin-caliber esophageal varices without red color signs – for prevention of decompensation in ascites;
• decompensated patients in ascites with thin-caliber esophageal varices without red color signs – for primary prophylaxis of bleeding;
• thin-caliber varices with red color signs, medium and large caliber varices and gastric varices– as primary prophylaxis;
• thin-caliber varices with red color signs, medium and large caliber varices and gastric varices – as secondary prophylaxis associated with elastic ligation;
• recurrent bleeding from portal hypertensive gastropathy;
• patients with clinically significant portal hypertension ( LMS ? 25 kPa).

References

1. Turco L, Reiberger T, Vitale G, La Mura V. Carvedilol as the new non-selective beta-blocker of choice in patients with cirrhosis and portal hypertension. Liver Int. 2023 Jun;43(6):1183-1194. doi: 10.1111/liv.15559. Epub 2023 Apr 17. PMID: 36897563.
2. Wong YJ, Zhaojin C, Tosetti G, Degasperi E, Sharma S, Agarwal S, Chuan L, Huak CY, Jia L, Xiaolong Q, Saraya A, Primignani M. Baveno-VII criteria to predict decompensation and initiate non-selective beta-blocker in compensated advanced chronic liver disease patients. Clin Mol Hepatol. 2023 Jan;29(1):135-145. doi: 10.3350/cmh.2022.0181. Epub 2022 Sep 5. PMID: 36064306; PMCID: PMC9845679.
3. Gralnek IM, Camus Duboc M, Garcia-Pagan JC, Fuccio L, Karstensen JG, Hucl T, Jovanovic I, Awadie H, Hernandez-Gea V, Tantau M, Ebigbo A, Ibrahim M, Vlachogiannakos J, Burgmans MC, Rosasco R, Triantafyllou K. Endoscopic diagnosis and management of esophagogastric variceal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2022 Nov;54(11):1094-1120. doi: 10.1055/a-1939-4887. Epub 2022 Sep 29. PMID: 36174643.
4. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30. Erratum in: J Hepatol. 2022 Apr 14;: PMID: 35120736.
5. Katarey D, Jalan R. Non-selective beta blockers in cirrhosis: time to extend the indications? Ann Transl Med. 2019 Dec;7(Suppl 8):S355. doi: 10.21037/atm.2019.09.56. PMID: 32016073; PMCID: PMC6976476.
6. Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja JL, Aracil C, Bañares R, Morillas RM, Poca M, Peñas B, Augustin S, Abraldes JG, Alvarado E, Torres F, Bosch J. ? blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2019 Apr 20;393(10181):1597-1608. doi: 10.1016/S0140-6736(18)31875-0. Epub 2019 Mar 22. Erratum in: Lancet. 2019 Jun 22;393(10190):2492. PMID: 30910320.
7. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017 Jan;65(1):310-335. doi: 10.1002/hep.28906. Epub 2016 Dec 1. Erratum in: Hepatology. 2017 Jul;66(1):304. PMID: 27786365

How to cite this article

Ramos JSD, When is the use of beta-blockers recommended in patients with liver cirrhosis? Gastropedia 2023 Vol 2. Available at: gastropedia.com.br/gastroenterology/when-is-the-use-of-beta-blockers-recommended-in-patients-with-liver-cirrhosis/

When we come across an ultrasound (USG) describing a focal liver lesion, we should organize the reasoning of when and how to investigate the described lesion: is it a focal cystic lesion, with regular walls, anechoic content and without signs of complexity (septa, calcifications, irregular margins)?

If yes and the exam is done by an experienced radiologist, no further investigation is necessary. However, if there is a complex cystic focal lesion or a solid focal lesion, these have an indication for investigation with contrasted imaging exam (computed tomography or upper abdomen magnetic resonance).

Figure 1. Abdominal ultrasound showing a solid, hyperechoic nodule, measuring approximately 1.0 cm, circumscribed, located in the right lobe, hepatic segment VII. Source: personal file.

It is essential to order the exam correctly, that is, to describe in the exam order that it is directed to the investigation of focal liver lesion. This will be fundamental to align the correct protocol on the day of the exam, especially, of abdominal tomography with intravenous contrast (iodine) with triphasic protocol – in addition to the pre-contrast phase, there will be the arterial, portal and balance phases.

The abdominal resonance exam with intravenous contrast (gadolinium) performs the contrasted phases (arterial, portal, balance) usually, in addition to having additional sequences that assist in the evaluation of the focal lesion (T1 pre-contrast sequences; in-phase and out-of-phase for fat evaluation; T2 and diffusion).

It is strongly recommended to mention in the exam order the most significant clinical data of the patient, such as age, symptoms, absence/presence of chronic liver disease and/or liver cirrhosis, use of anabolic steroids or contraceptives and previous or current oncological disease.

Note 1: The presence of liver cirrhosis is the most relevant clinical data and the most significant risk factor for the development of hepatocellular carcinoma (HCC), so that cirrhosis is present in approximately 90% of patients with HCC. Therefore, a hepatic nodule in cirrhotic liver, the main suspicion will be of HCC; already a hepatic nodule in non-cirrhotic liver, there will be a greater chance of benign focal lesion.

Among the benign focal liver lesions, the following stand out: hemangioma, focal nodular hyperplasia and adenoma. Such lesions present different echogenicity patterns to USG, being able to be hyperechoic, isoechoic or hypoechoic and their particularities will be themes of future posts

A differential diagnosis to be remembered is the possibility of area spared from steatosis, when the liver as a whole becomes hyperechoic due to fat deposition and a specific area is spared from this, generating the false impression of hypoechoic nodular focal lesion. There are also cases of focal steatosis, when fat deposition occurs locally, simulating a hyperechoic nodule.

Note 2: Except for simple hepatic cysts, solid hepatic focal lesions deserve dynamic investigation with intravenous contrasted exam for the evaluation of their behavior in the different phases of filling and vascular emptying, even if they are suggestive of benign lesion to abdominal ultrasound.

            Most of the time, the identification of benign focal liver lesion will be incidental, in routine exams, without clinical repercussion (symptoms or complications) and without laboratory alterations. After the initial contrasted exam (CT/MRI), selected cases will be candidates for abdominal resonance with hepatospecific contrast (gadoxetic acid – Primovist), biopsy of the hepatic nodule or even referred for surgical approach.

Thus, doctors from different specialties should have the discernment to investigate appropriately the finding of hepatic nodule in routine exam or choose to refer the patient for specialized evaluation with gastro-hepatologist.

Learn more about the evaluation of liver lesions in this other article

How to cite this article

Oti, KST. Hepatic nodule detected by ultrasound: step by step of when and how to investigate. Gastropedia 2022. Available at: https://gastropedia.com.br/gastroenterologia/figado/nodulo-hepatico-detectado-pela-ultrassonografia-passo-a-passo-de-quando-e-como-investigar/

References

1. Haring MPD, Cuperus FJC, Duiker EW, de Haas RJ, de Meijer VE. Scoping review of clinical practice guidelines on the management of benign liver tumours. BMJ Open Gastroenterol. 2021 Aug;8(1):e000592. doi: 10.1136/bmjgast-2020-000592. PMID: 34362758; PMCID: PMC8351490.
2. Strauss E, Ferreira AdeSP, França AVC, et al. Diagnosis and treatment of benign liver nodules: Brazilian Society of hepatology (SBH) recommendations. Arq Gastroenterol 2015;52:47–54.
3. Marrero JA, Ahn J, Rajender Reddy K, Reddy RK, et al. Acg clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol 2014;109:1328–47.
4. European Association for the Study of the Liver (EASL). EASL clinical practice guidelines on the management of benign liver tumours. J Hepatol 2016;65:386–98.

Non-alcoholic steatohepatitis (NASH) corresponds to the group of patients with non-alcoholic fatty liver disease (NAFLD) who present, in addition to predominantly macrovesicular steatosis, with hepatocyte ballooning, lobular inflammation, liver fibrosis, cirrhosis and risk of progression to hepatocellular carcinoma (HCC). Learn more in this other article.

About 30-40% of adults have NAFLD and of these, 3-12% evolve with NASH, with prevalence in progression in recent years, especially due to the strong association with metabolic factors such as obesity. Thus, NASH has become in recent years the main cause of liver transplantation in the world

In the evaluation of patients with NAFLD, it is essential to assess which non-invasive tests (NIT) can contribute to the investigation. Although abdominal ultrasound is the first-line examination in the initial evaluation of patients with NAFLD, it is operator-dependent and has low sensitivity for mild hepatic steatosis: typically, steatosis needs to affect more than 30% of hepatocytes to be detectable by this method.

Among the NITs available in our environment, transient hepatic elastography (FibroScan®, Echosens, Paris, France; TE) is the most commonly used by hepatologists. The technology was approved in 2013 by the Food and Drug Administration in the United States and quickly incorporated in the evaluation of patients with hepatopathy of different etiologies, including those with NAFLD.

Advantages of the method

Through the appropriate selection of one of the probes (Small, Medium and XL) by age, physical type and skin-liver distance, the examination is performed non-invasively and quickly, allowing the quantification of liver fat by CAP (controlled attenuation parameter) and liver fibrosis by assessing liver stiffness (liver stiffness measurement; LSM).

The reference point is guided by anatomical markers (meeting of the mid-axillary line with transverse and parallel line to the costal margins, at the level of the xiphoid appendix).

LSM

Through vibrations of low amplitude and low frequency (50Hz) emitted by the probe at the reference point, a shear wave propagates through the liver tissue at a certain speed (m/s): the stiffer the tissue, the faster the propagation of the wave. The LSM ranges from 1.5 to 75 kilopascals (kPa) and assesses liver stiffness in a volume 100 times larger than a liver biopsy.

The values of LSM vary according to the etiology of the hepatopathy, with the values of AUROC for F1, F2, F3 and F4 of 0.82, 0.85, 0.94 and 0.96, respectively, being reported in NAFLD. For advanced fibrosis (F3-F4), the cut-offs range from 8-12kPa, with a sensitivity of 84-100% and specificity of 83-97%.

Note 1: Some cross-sectional studies and head-to-head comparison indicated better accuracy of MR elastography in the evaluation of liver fibrosis compared to TE, in the identification of fibrosis (F1-F4) with specificity (F4, 94.5% vs 75.9%), however, the factors cost, availability and examination time (duration) are limiting factors of elastoRM in clinical practice.

CAP

An AUROC of 81-84% ?E1 (steatosis in at least 5-10% of hepatocytes); 85-88% for ?E2 (33%) and 86-91% for E3 (66%), with sensitivity for ?E1, ?E2 and E3 of 60-75%, 69-84% and 77-96%, respectively. The cut-offs for CAP is 248 dB/m for E1, 268 dB/m for E2 and 280 dB/m for E3.

Note 2: Although abdominal resonance with proton density fat fraction (MR-PDFF) has better sensitivity and specificity for the quantification of liver fat fraction compared to CAP, the factors cost and availability are the major limitations in clinical practice.

Reliability criteria

According to the manufacturer’s recommendations, during TE, 10 valid measurements should be obtained, with a success rate >60% and an interquartile range (IQR) ?30%.
Some studies have shown that IQR > 40 dB/m of CAP with M probe was associated with lower reliability for the diagnosis of liver steatosis, but additional studies are needed for validation as a criterion.

Limitations and considerations of the method

One of the biggest challenges of TE is the lower success rate in obese patients. While the M probe is indicated for adults with normal weight (BMI <25kg/m²) and the S probe for children and adolescents, the XL probe is indicated for obese patients or those with skin-liver distance greater than 3.5cm, as this probe allows greater depth in the evaluation of liver stiffness (35-75 vs 25-65mm) and CAP.

Prospective studies indicate that the XL probe estimates higher liver stiffness value than the M probe when applied in the same patient, however, high BMI tends to overestimate the LSM, thus, the effects of obesity and the XL probe tend to cancel each other out.

Other factors that impair LSM are: liver congestion, biliary obstruction, amyloidosis, focal liver lesions, increased transaminases (1-5xLSN) and ascites.

It is essential to instruct the patient to fast for 3-4 hours before the examination, as increased portal flow can increase the LSM by 1-5kPa (peak at 20-40 minutes, with duration of up to 180 minutes, on average).

Clinical application

In addition to the evaluation of liver stiffness and quantification of steatosis, TE has an important role in predicting complications of compensated advanced chronic liver disease (cACLD), such as esophageal varices (EV), HCC and liver-related death.

According to Baveno VII, in general:

1. LSM ?15kPa and platelets ? 150,000 excludes clinically significant portal hypertension (CSPH, sensitivity and negative predictive value >90%) in patient with cACLD;
2. LSM <20kPa and platelets > 150,000 allows to avoid performing EDA screening of EV;
3. In patients of viral, alcoholic and non-obese NASH etiology (BMI <30kgm/²), LSM ? 25 is sufficient to exclude CSPH (sensitivity and positive predictive value >90%).
4. In patients with cACLD due to NASH, the ANTECIPATE model can be used to predict the risk of CSPH, but additional validation is needed.

Guidelines Recommendations

TE is a validated NIT and recommended by the AASLD and EASL guidelines and, according to its availability, should be incorporated as a tool in the evaluation of patients with NAFLD in clinical practice.

References

1. Zhang X, Wong GL, Wong VW. Application of transient elastography in nonalcoholic fatty liver disease. Clin Mol Hepatol. 2020 Apr;26(2):128-141. doi: 10.3350/cmh.2019.0001n. Epub 2019 Nov 8. PMID: 31696690; PMCID: PMC7160347.
2. Younossi ZM, Loomba R, Anstee QM, Rinella ME, Bugianesi E, Marchesini G, Neuschwander-Tetri BA, Serfaty L, Negro F, Caldwell SH, Ratziu V, Corey KE, Friedman SL, Abdelmalek MF, Harrison SA, Sanyal AJ, Lavine JE, Mathurin P, Charlton MR, Goodman ZD, Chalasani NP, Kowdley KV, George J, Lindor K. Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis. Hepatology. 2018 Jul;68(1):349-360. doi: 10.1002/hep.29721. PMID: 29222917; PMCID: PMC6511364.
3. Park CC, Nguyen P, Hernandez C, Bettencourt R, Ramirez K, Fortney L, Hooker J, Sy E, Savides MT, Alquiraish MH, Valasek MA, Rizo E, Richards L, Brenner D, Sirlin CB, Loomba R. Magnetic Resonance Elastography vs Transient Elastography in Detection of Fibrosis and Noninvasive Measurement of Steatosis in Patients With Biopsy-Proven Nonalcoholic Fatty Liver Disease. Gastroenterology. 2017 Feb;152(3):598-607.e2. doi: 10.1053/j.gastro.2016.10.026. Epub 2016 Oct 27. PMID: 27911262; PMCID: PMC5285304.
4. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII – Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30. Erratum in: J Hepatol. 2022 Apr 14;: PMID: 35120736.

How to cite this file

Oti KST., What should we know about transient hepatic elastography and its application in non-alcoholic fatty liver disease?. Gastropedia, 2022. Available at: https://gastropedia.com.br/gastroenterologia/figado/o-que-devemos-saber-sobre-a-elastografia-hepatica-transitoria-e-sua-aplicacao-na-doenca-hepatica-gordurosa-nao-alcoolica/