Non-alcoholic fatty liver disease medical therapy: Difference between revisions

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{{Non alcoholic fatty liver disease}}
{{Non alcoholic fatty liver disease}}
{{CMG}}; {{AE}} {{VKG}}
{{CMG}}; {{AE}} {{MKK}}


==Overview==
==Overview==
Trials are presently being conducted to optimize treatment of NASH. No standard treatment has yet emerged as the gold standard. General recommendations include improving metabolic risk factors - [[weight loss]], treating [[diabetes]], managing [[lipids]] - and reducing [[alcohol]] intake.
[[Clinical practice guideline]]s from NICE<ref name="nice">NICE (2016). Non-alcoholic fatty liver disease (NAFLD): assessment and management. Available at https://www.nice.org.uk/guidance/ng49</ref> and the American Association for the Study of Liver Diseases (AASLD)<ref name="pmid28714183">{{cite journal| author=Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M | display-authors=etal| title=The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. | journal=Hepatology | year= 2018 | volume= 67 | issue= 1 | pages= 328-357 | pmid=28714183 | doi=10.1002/hep.29367 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28714183  }} </ref> direct management. The available guidelines have been compared and summarized<ref name="pmid30122876">{{cite journal| author=Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L| title=Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. | journal=World J Gastroenterol | year= 2018 | volume= 24 | issue= 30 | pages= 3361-3373 | pmid=30122876 | doi=10.3748/wjg.v24.i30.3361 | pmc=6092580 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30122876  }} </ref>.
 
[[Weight loss]], withdrawal of [[Hepatotoxicity causes|hepatotoxic agents]], and management of underlying [[insulin resistance]]/[[metabolic syndrome]] is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).


==Medical Therapy==
==Medical Therapy==
* There is no one FDA approved specific treatment for NAFLD. Multiple trails are going on to obtain specific and effective treatment for NAFLD.
There is no [[Food and Drug Administration|FDA]] approved specific treatment for NAFLD. [[Weight loss]], withdrawal of [[Hepatotoxicity causes|hepatotoxic agents]], and management of underlying [[insulin resistance]]/[[metabolic syndrome]] is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).
* One of the largest trials of NAFLD/NASH therapy evaluated [[rosiglitazone]], an insulin-sensitizing [[thiazolidinedione]].<ref name="pmid18503774">{{cite journal |vauthors=Ratziu V, Giral P, Jacqueminet S, Charlotte F, Hartemann-Heurtier A, Serfaty L, Podevin P, Lacorte JM, Bernhardt C, Bruckert E, Grimaldi A, Poynard T |title=Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT) Trial |journal=Gastroenterology |volume=135 |issue=1 |pages=100–10 |year=2008 |pmid=18503774 |doi=10.1053/j.gastro.2008.03.078 |url=}}</ref>.
 
* Rosiglitazone is recommended among all patients who develop NAFLD. Long term treatment with rosiglitazone in patients with NAFLD shows significant improvement.<ref name="urlLong-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial - Ratziu - 2009 - Hepatology - Wiley Online Library">{{cite web |url=http://onlinelibrary.wiley.com/doi/10.1002/hep.23270/pdf |title=Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial - Ratziu - 2009 - Hepatology - Wiley Online Library |format= |work= |accessdate=}}</ref>
[[Systematic review]]s, using network analyses, by the Cochrane Collaboreation<ref name="pmid28358980">{{cite journal| author=Lombardi R, Onali S, Thorburn D, Davidson BR, Gurusamy KS, Tsochatzis E| title=Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis. | journal=Cochrane Database Syst Rev | year= 2017 | volume= 3 | issue= | pages= CD011640 | pmid=28358980 | doi=10.1002/14651858.CD011640.pub2 | pmc=6464620 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28358980  }} </ref> made no conclusion, whereas a non-Cochrane review<ref name="pmid34435378">{{cite journal| author=Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S | display-authors=etal| title=Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH. | journal=Aliment Pharmacol Ther | year= 2021 | volume= 54 | issue= 7 | pages= 880-889 | pmid=34435378 | doi=10.1111/apt.16583 | pmc=8711247 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34435378  }} </ref> made the following conclusions:
* Patients with NAFLD shows benifits when using ursodeoxycholic acid (UDCA) in combination with vitamin E improved laboratory values and hepatic steatosis of patients with NASH.<ref name="pmid17162245">{{cite journal |vauthors=Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A |title=Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis |journal=Clin. Gastroenterol. Hepatol. |volume=4 |issue=12 |pages=1537–43 |year=2006 |pmid=17162245 |doi=10.1016/j.cgh.2006.09.025 |url=}}</ref>
* ≥1 stage of fibrosis improvement: "Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively.
* Pharmacologic medical therapies for NAFLD also include vitamin E with vitamin C which shows statstically significant improvement without any side effects in fibrosis score (p=0.002).<ref name="pmid14638353">{{cite journal |vauthors=Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S |title=Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis |journal=Am. J. Gastroenterol. |volume=98 |issue=11 |pages=2485–90 |year=2003 |pmid=14638353 |doi=10.1111/j.1572-0241.2003.08699.x |url=}}</ref>
* NASH resolution: "semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively."
**  Vitamin E 800 mg PO /OD.<ref name="pmid15537682">{{cite journal |vauthors=Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E |title=Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality |journal=Ann. Intern. Med. |volume=142 |issue=1 |pages=37–46 |year=2005 |pmid=15537682 |doi= |url=}}</ref>
 
** Avoid high dose of vitamin E which increases the fatality rate.
The combination of [[vitamin E]]  (400 IU b.i.d.) and [[pioglitazone]] has been studies in one trial<ref name="pmid31332029">{{cite journal| author=Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J | display-authors=etal| title=Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial. | journal=Diabetes Care | year= 2019 | volume= 42 | issue= 8 | pages= 1481-1488 | pmid=31332029 | doi=10.2337/dc19-0167 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31332029  }} </ref>.
* ''Moringa Oleifera'' (''MO''), a plant from the family Moringacea is a major crop in Asia and Africa, the leaves of these plant have been studied extensively and it has shown to be beneficial in NAFLD and in prevention and alleviation of NAFLD.<ref name="urlpdfs.semanticscholar.org">{{cite web |url=https://pdfs.semanticscholar.org/3198/7b349e2bbce24f2cbcdd4c5a67d940b186b4.pdf |title=pdfs.semanticscholar.org |format= |work= |accessdate=}}</ref>
 
=== Resmetirom ===
Resmetirom, in the MAESTRO-NASH randomized controlled trial, was better than placebo at causing resolution of NASH and improvement in fibrosis (improvement in fibrosis stage 24% versus 14 for placebo)<ref name="pmid38324483">{{cite journal| author=Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R | display-authors=etal| title=A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. | journal=N Engl J Med | year= 2024 | volume= 390 | issue= 6 | pages= 497-509 | pmid=38324483 | doi=10.1056/NEJMoa2309000 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38324483  }} </ref>.
 
=== Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA) ===
Randomized controlled trials have been executed of:
* Liraglutide in the LEAN trial in 2016<ref name="pmid26608256">{{cite journal| author=Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R | display-authors=etal| title=Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. | journal=Lancet | year= 2016 | volume= 387 | issue= 10019 | pages= 679-690 | pmid=26608256 | doi=10.1016/S0140-6736(15)00803-X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26608256  }} </ref>
** "Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04)"
* Semaglutide in the Newsome trial in 2021<ref name="pmid33185364">{{cite journal| author=Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V | display-authors=etal| title=A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. | journal=N Engl J Med | year= 2021 | volume= 384 | issue= 12 | pages= 1113-1124 | pmid=33185364 | doi=10.1056/NEJMoa2028395 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33185364  }} </ref>:
** "An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48)" over 6 years of treatment.
* Semaglutide in the Loomba trial in 2023<ref name="pmid36934740.pdf">{{cite journal| author=Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N | display-authors=etal| title=Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. | journal=Lancet Gastroenterol Hepatol | year= 2023 | volume= 8 | issue= 6 | pages= 511-522 | pmid=36934740.pdf | doi=10.1016/S2468-1253(23)00068-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=36934740  }} </ref>
** "Improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06–1·24; p=0·087)."
* Semaglutide in the Romero trial in 2023<ref name="pmid37328931">{{cite journal| author=Romero-Gómez M, Armstrong MJ, Funuyet-Salas J, Mangla KK, Ladelund S, Sejling AS | display-authors=etal| title=Improved health-related quality of life with semaglutide in people with non-alcoholic steatohepatitis: A randomised trial. | journal=Aliment Pharmacol Ther | year= 2023 | volume= 58 | issue= 4 | pages= 395-403 | pmid=37328931 | doi=10.1111/apt.17598 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=37328931  }} </ref>
** Fibrosis change results were not included in their journal article, but are available at in the trial registration at https://classic.clinicaltrials.gov/ct2/show/NCT02970942. The results do not show a dose-response relationship.
 
==== Weight management ====
* Lifestyle modifications to achieve [[weight loss]] is a central aspect of management of NAFLD in [[Obesity|obese patients]].
 
===== Bariatric surgery =====
In a non-randomized cohort study of patients with liver fibrosis (histological stages 1-3) and he prevention of "major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality)"<ref name="pmid34762106">{{cite journal| author=Aminian A, Al-Kurd A, Wilson R, Bena J, Fayazzadeh H, Singh T | display-authors=etal| title=Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis. | journal=JAMA | year= 2021 | volume= 326 | issue= 20 | pages= 2031-2042 | pmid=34762106 | doi=10.1001/jama.2021.19569 | pmc=8587225 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34762106  }} </ref>:
* Bariatric surgery: 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01).
 
* No surgery:  9.6% (95% CI, 6.1%-12.9%)
 
...resulting in an adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01).
 
==== Management of hyperlipidemia ====
* The direct effect of anti-lipid agents on NAFLD and liver histology has not been clearly understood; however, trials suggest no harm<ref name="pmid21109302">{{cite journal| author=Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K | display-authors=etal| title=Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. | journal=Lancet | year= 2010 | volume= 376 | issue= 9756 | pages= 1916-22 | pmid=21109302 | doi=10.1016/S0140-6736(10)61272-X | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21109302  }}  [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=21901179 Review in: J Fam Pract. 2011 Sep;60(9):536-8] </ref> and observational studies suggest benefit<ref name="pmid28585556">{{cite journal| author=Kamal S, Khan MA, Seth A, Cholankeril G, Gupta D, Singh U | display-authors=etal| title=Beneficial Effects of Statins on the Rates of Hepatic Fibrosis, Hepatic Decompensation, and Mortality in Chronic Liver Disease: A Systematic Review and Meta-Analysis. | journal=Am J Gastroenterol | year= 2017 | volume= 112 | issue= 10 | pages= 1495-1505 | pmid=28585556 | doi=10.1038/ajg.2017.170 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28585556  }} </ref>.
* [[Statin|Statins]]&nbsp;are the drugs of choice, however statins should not be administered as primary treatment of NAFLD, but rather as treatment of hyperlipidemia.
* The goal is to get the&nbsp;[[LDL]]&nbsp;down to < 100 mg/dl.
** '''Preferred regimen''': [[Atorvastatin]] 40 mg PO q24h.
 
==== Management of Insulin resistance ====
* [[Rosiglitazone]] is recommended among all patients who develop NAFLD.
* Long term treatment with [[rosiglitazone]] in patients with NAFLD shows significant improvement.
** '''Preferred regimen''': [[Rosiglitazone]] 4 mg PO/OD q24h .<ref name="pmid21430606">{{cite journal |vauthors=Saryusz-Wolska M, Szymańska-Garbacz E, Jabłkowski M, Białkowska J, Pawłowski M, Kwiecińska E, Omulecka A, Borkowska A, Ignaczak A, Loba J, Czupryniak L |title=Rosiglitazone treatment in nondiabetic subjects with nonalcoholic fatty liver disease |journal=Pol. Arch. Med. Wewn. |volume=121 |issue=3 |pages=61–6 |year=2011 |pmid=21430606 |doi= |url=}}</ref>
** '''Alternative regimen''': [[Pioglitazone]] 4mg PO/OD.<ref name="pmid29223443">{{cite journal |vauthors=Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, Orsak B, Tio F, Cusi K |title=Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes |journal=Clin. Gastroenterol. Hepatol. |volume= |issue= |pages= |year=2017 |pmid=29223443 |doi=10.1016/j.cgh.2017.12.001 |url=}}</ref>
** '''Alternative regimen''':&nbsp;[[Liraglutide]]&nbsp;1.2 mg PO/OD.
 
==== Anti-oxidants ====
* [[Antioxidants]] offer [[hepatocyte]] protection from free [[Radical (chemistry)|radical]] damage.
 
* Patients with NAFLD are recommended to use [[ursodeoxycholic acid]] (UDCA) in combination with [[vitamin E]].<ref name="pmid17162245">{{cite journal |vauthors=Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A |title=Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis |journal=Clin. Gastroenterol. Hepatol. |volume=4 |issue=12 |pages=1537–43 |year=2006 |pmid=17162245 |doi=10.1016/j.cgh.2006.09.025 |url=}}</ref>
* [[Vitamin E]]  alone or in combination with [[vitamin C]] is also recommended in patients without any side effects in [[fibrosis]] score.<ref name="pmid14638353">{{cite journal |vauthors=Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S |title=Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis |journal=Am. J. Gastroenterol. |volume=98 |issue=11 |pages=2485–90 |year=2003 |pmid=14638353 |doi=10.1111/j.1572-0241.2003.08699.x |url=}}</ref>
** '''Preferred regimen (1) :'''&nbsp;[[Vitamin&nbsp;E]] 800 mg PO /OD.<ref name="pmid15537682">{{cite journal |vauthors=Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E |title=Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality |journal=Ann. Intern. Med. |volume=142 |issue=1 |pages=37–46 |year=2005 |pmid=15537682 |doi= |url=}}</ref>
** '''Preferred regimen (1) :''' [[Vitamin C]]  30 mg/Kg/PO/OD.
** '''Note:''' Avoid high dose of [[vitamin E]] which increases the [[Fatality rate|fatality]] rate.
 
The combination of [[vitamin E]] (400 IU b.i.d.) and [[pioglitazone]] has been studies in one trial<ref name="pmid31332029">{{cite journal| author=Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J | display-authors=etal| title=Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial. | journal=Diabetes Care | year= 2019 | volume= 42 | issue= 8 | pages= 1481-1488 | pmid=31332029 | doi=10.2337/dc19-0167 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31332029  }} </ref>.
 
==== Miscellaneous ====
* ''Moringa Oleifera''&nbsp;(''MO''), a plant from the family Moringacea is a major crop in Asia and Africa, the leaves of these plant have been studied extensively and it has shown to be beneficial in NAFLD and in prevention and alleviation of NAFLD.<ref name="pmid29144438">{{cite journal |vauthors=Vergara-Jimenez M, Almatrafi MM, Fernandez ML |title=Bioactive Components in Moringa Oleifera Leaves Protect against Chronic Disease |journal=Antioxidants (Basel) |volume=6 |issue=4 |pages= |year=2017 |pmid=29144438 |doi=10.3390/antiox6040091 |url=}}</ref>


==References==
==References==

Latest revision as of 04:55, 29 March 2024

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Overview

Clinical practice guidelines from NICE[1] and the American Association for the Study of Liver Diseases (AASLD)[2] direct management. The available guidelines have been compared and summarized[3].

Weight loss, withdrawal of hepatotoxic agents, and management of underlying insulin resistance/metabolic syndrome is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).

Medical Therapy

There is no FDA approved specific treatment for NAFLD. Weight loss, withdrawal of hepatotoxic agents, and management of underlying insulin resistance/metabolic syndrome is the mainstay of treatment in non-alcoholic fatty liver disease (NAFLD).

Systematic reviews, using network analyses, by the Cochrane Collaboreation[4] made no conclusion, whereas a non-Cochrane review[5] made the following conclusions:

  • ≥1 stage of fibrosis improvement: "Lanifibranor and obeticholic acid had the highest probability of being ranked the most effective intervention for achieving ≥1 stage of fibrosis improvement (SUCRA 0.78) and (SUCRA 0.77), respectively.
  • NASH resolution: "semaglutide, liraglutide and vitamin E plus pioglitazone had the highest probability of being ranked the most effective intervention for achieving NASH resolution (SUCRA 0.89), (SUCRA 0.84) and (SUCRA 0.83), respectively."

The combination of vitamin E (400 IU b.i.d.) and pioglitazone has been studies in one trial[6].

Resmetirom

Resmetirom, in the MAESTRO-NASH randomized controlled trial, was better than placebo at causing resolution of NASH and improvement in fibrosis (improvement in fibrosis stage 24% versus 14 for placebo)[7].

Glucagon-like Peptide-1 Receptor Agonists (GLP1-RA)

Randomized controlled trials have been executed of:

  • Liraglutide in the LEAN trial in 2016[8]
    • "Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04)"
  • Semaglutide in the Newsome trial in 2021[9]:
    • "An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48)" over 6 years of treatment.
  • Semaglutide in the Loomba trial in 2023[10]
    • "Improvement in liver fibrosis of one stage or more without worsening of NASH (five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group; odds ratio 0·28 [95% CI 0·06–1·24; p=0·087)."
  • Semaglutide in the Romero trial in 2023[11]

Weight management

Bariatric surgery

In a non-randomized cohort study of patients with liver fibrosis (histological stages 1-3) and he prevention of "major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality)"[12]:

  • Bariatric surgery: 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01).
  • No surgery: 9.6% (95% CI, 6.1%-12.9%)

...resulting in an adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01).

Management of hyperlipidemia

  • The direct effect of anti-lipid agents on NAFLD and liver histology has not been clearly understood; however, trials suggest no harm[13] and observational studies suggest benefit[14].
  • Statins are the drugs of choice, however statins should not be administered as primary treatment of NAFLD, but rather as treatment of hyperlipidemia.
  • The goal is to get the LDL down to < 100 mg/dl.

Management of Insulin resistance

Anti-oxidants

The combination of vitamin E (400 IU b.i.d.) and pioglitazone has been studies in one trial[6].

Miscellaneous

  • Moringa Oleifera (MO), a plant from the family Moringacea is a major crop in Asia and Africa, the leaves of these plant have been studied extensively and it has shown to be beneficial in NAFLD and in prevention and alleviation of NAFLD.[20]

References

  1. ↑ NICE (2016). Non-alcoholic fatty liver disease (NAFLD): assessment and management. Available at https://www.nice.org.uk/guidance/ng49
  2. ↑ Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M; et al. (2018). "The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases". Hepatology. 67 (1): 328–357. doi:10.1002/hep.29367. PMID 28714183.
  3. ↑ Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L (2018). "Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis". World J Gastroenterol. 24 (30): 3361–3373. doi:10.3748/wjg.v24.i30.3361. PMC 6092580. PMID 30122876.
  4. ↑ Lombardi R, Onali S, Thorburn D, Davidson BR, Gurusamy KS, Tsochatzis E (2017). "Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis". Cochrane Database Syst Rev. 3: CD011640. doi:10.1002/14651858.CD011640.pub2. PMC 6464620. PMID 28358980.
  5. ↑ Majzoub AM, Nayfeh T, Barnard A, Munaganuru N, Dave S, Singh S; et al. (2021). "Systematic review with network meta-analysis: comparative efficacy of pharmacologic therapies for fibrosis improvement and resolution of NASH". Aliment Pharmacol Ther. 54 (7): 880–889. doi:10.1111/apt.16583. PMC 8711247 Check |pmc= value (help). PMID 34435378 Check |pmid= value (help).
  6. ↑ 6.0 6.1 Bril F, Biernacki DM, Kalavalapalli S, Lomonaco R, Subbarayan SK, Lai J; et al. (2019). "Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial". Diabetes Care. 42 (8): 1481–1488. doi:10.2337/dc19-0167. PMID 31332029.
  7. ↑ Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R; et al. (2024). "A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis". N Engl J Med. 390 (6): 497–509. doi:10.1056/NEJMoa2309000. PMID 38324483 Check |pmid= value (help).
  8. ↑ Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R; et al. (2016). "Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study". Lancet. 387 (10019): 679–690. doi:10.1016/S0140-6736(15)00803-X. PMID 26608256.
  9. ↑ Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V; et al. (2021). "A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis". N Engl J Med. 384 (12): 1113–1124. doi:10.1056/NEJMoa2028395. PMID 33185364 Check |pmid= value (help).
  10. ↑ Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N; et al. (2023). "Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial". Lancet Gastroenterol Hepatol. 8 (6): 511–522. doi:10.1016/S2468-1253(23)00068-7. PMID 36934740.pdf Check |pmid= value (help).
  11. ↑ Romero-Gómez M, Armstrong MJ, Funuyet-Salas J, Mangla KK, Ladelund S, Sejling AS; et al. (2023). "Improved health-related quality of life with semaglutide in people with non-alcoholic steatohepatitis: A randomised trial". Aliment Pharmacol Ther. 58 (4): 395–403. doi:10.1111/apt.17598. PMID 37328931 Check |pmid= value (help).
  12. ↑ Aminian A, Al-Kurd A, Wilson R, Bena J, Fayazzadeh H, Singh T; et al. (2021). "Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis". JAMA. 326 (20): 2031–2042. doi:10.1001/jama.2021.19569. PMC 8587225 Check |pmc= value (help). PMID 34762106 Check |pmid= value (help).
  13. ↑ Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K; et al. (2010). "Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis". Lancet. 376 (9756): 1916–22. doi:10.1016/S0140-6736(10)61272-X. PMID 21109302. Review in: J Fam Pract. 2011 Sep;60(9):536-8
  14. ↑ Kamal S, Khan MA, Seth A, Cholankeril G, Gupta D, Singh U; et al. (2017). "Beneficial Effects of Statins on the Rates of Hepatic Fibrosis, Hepatic Decompensation, and Mortality in Chronic Liver Disease: A Systematic Review and Meta-Analysis". Am J Gastroenterol. 112 (10): 1495–1505. doi:10.1038/ajg.2017.170. PMID 28585556.
  15. ↑ Saryusz-Wolska M, Szymańska-Garbacz E, Jabłkowski M, Białkowska J, Pawłowski M, Kwiecińska E, Omulecka A, Borkowska A, Ignaczak A, Loba J, Czupryniak L (2011). "Rosiglitazone treatment in nondiabetic subjects with nonalcoholic fatty liver disease". Pol. Arch. Med. Wewn. 121 (3): 61–6. PMID 21430606.
  16. ↑ Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, Orsak B, Tio F, Cusi K (2017). "Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes". Clin. Gastroenterol. Hepatol. doi:10.1016/j.cgh.2017.12.001. PMID 29223443.
  17. ↑ Dufour JF, Oneta CM, Gonvers JJ, Bihl F, Cerny A, Cereda JM, Zala JF, Helbling B, Steuerwald M, Zimmermann A (2006). "Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis". Clin. Gastroenterol. Hepatol. 4 (12): 1537–43. doi:10.1016/j.cgh.2006.09.025. PMID 17162245.
  18. ↑ Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S (2003). "Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis". Am. J. Gastroenterol. 98 (11): 2485–90. doi:10.1111/j.1572-0241.2003.08699.x. PMID 14638353.
  19. ↑ Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E (2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality". Ann. Intern. Med. 142 (1): 37–46. PMID 15537682.
  20. ↑ Vergara-Jimenez M, Almatrafi MM, Fernandez ML (2017). "Bioactive Components in Moringa Oleifera Leaves Protect against Chronic Disease". Antioxidants (Basel). 6 (4). doi:10.3390/antiox6040091. PMID 29144438.

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