Non-alcoholic fatty liver disease natural history, complications and prognosis: Difference between revisions

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__NOTOC__
__NOTOC__
{{Non alcoholic fatty liver disease}}
{{Non alcoholic fatty liver disease}}
{{CMG}}; {{AE}} {{VKG}}
{{CMG}}; {{AE}} {{MKK}}
   
   
==Overview==
==Overview==
[[NASH]] may progress to [[fibrosis]] and, later, [[cirrhosis]]. Studies of serial [[liver biopsies]] estimate a 26-37% rate of [[hepatic]] [[fibrosis]] and 2-15% rate of [[cirrhosis]] in less than 6 years.The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies.The natural history of nonalcoholic fatty liver disease:a clinical histopathological study.Long-term follow-up of patients with NAFLD and elevated liver enzymes. In 2001, [[NASH]] represented 2.9% of the indications of [[liver transplantation]].The frequency of Nonalcoholic Steatohepatitis as a Cause of Advanced Liver Disease. The impact of [[NAFLD]] is manifest at each step along the spectrum of the disease. Studies in the United States and Sweden have revealed that both simple [[steatosis]] as well as [[steatohepatitis]] significantly reduce life expectancy, even when the diagnosis is made in children.The natural history of the non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.  
If left untreated non-alcoholic fatty liver disease may progress to [[fibrosis]] and, later [[cirrhosis]]. Studies of serial [[liver biopsies]] estimate a 26-37% rate of [[hepatic]] [[fibrosis]] and 2-15% rate of [[cirrhosis]] in less than 6 years. Common complications of NAFLD include fibrosis, cirrhosis, internal bleeding, encephalopathy. The presence of [[fibrosis]] and [[cirrhosis]] associated with a particularly poor prognosis among patients with NAFLD.


==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
{{see also|Non-alcoholic fatty liver disease Noninvasive scores}}


===Natural History===
===Natural History===
*The symptoms of NAFLD usually develop in the 40th decade of life, And usually asymptomatic at first.  
*The symptoms of NAFLD usually develop in the 40th decade of life, and usually asymptomatic at first.  
*After following NAFLD patients for long-term the outcome of the disease is as follows <ref name="urlThe Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology - Gastroenterology">{{cite web |url=http://www.gastrojournal.org/article/S0016-5085(12)00494-5/fulltext?referrer=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2F#sec5 |title=The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology - Gastroenterology |format= |work= |accessdate=}}</ref>
*After following NAFLD patients for long-term the outcome of the disease is as follows  
**1) Patients with [[Non-alcoholic fatty liver disease|NAFLD]] has overall high morbidity and mortality rate and the common cause of death in NAFLD patients is cardiovascular disease.  
**1) Patients with [[Non-alcoholic fatty liver disease|NAFLD]] has overall high [[morbidity]] and [[mortality]] rate and the common cause of death in NAFLD patients is cardiovascular disease.  
**2) Patients with [[NASH]] has more liver-related mortality rate   
**2) Patients with [[NASH]] has more liver-related mortality rate   
* If left untreated, Patients with NAFLD may progress to develop hepato cellular carcinoma (HCC). But it is directly propotional to the degree of fibrosis and advanced cirrhosis
* If left untreated, patients with NAFLD may progress to develop hepato-cellular carcinoma ([[HCC]]). But it is directly propotional to the degree of [[fibrosis]] and advanced [[cirrhosis]]
* Children who are positive with NAFLD are also prone to short lifespan when compared to general population.<ref name="urlNonalcoholic Fatty Liver Disease">{{cite web |url=http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/nonalcoholic-fatty-liver-disease/ |title=Nonalcoholic Fatty Liver Disease |format= |work= |accessdate=}}</ref>
* Children who are positive with NAFLD are also prone to short lifespan when compared to general population.<ref name="pmid27213358">{{cite journal| author=Calzadilla Bertot L, Adams LA| title=The Natural Course of Non-Alcoholic Fatty Liver Disease. | journal=Int J Mol Sci | year= 2016 | volume= 17 | issue= 5 | pages=  | pmid=27213358 | doi=10.3390/ijms17050774 | pmc=4881593 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27213358  }} </ref>


*Common complications of NAFLD include:<ref name="urlNonalcoholic Fatty Liver Disease Symptoms, Causes, and More">{{cite web |url=https://www.healthline.com/health/nonalcoholic-fatty-liver-disease#symptoms |title=Nonalcoholic Fatty Liver Disease Symptoms, Causes, and More |format= |work= |accessdate=}}</ref>
Patients progress about 1 stage per 7 years<ref name="pmid24768810">{{cite journal| author=Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R| title=Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. | journal=Clin Gastroenterol Hepatol | year= 2015 | volume= 13 | issue= 4 | pages= 643-54.e1-9; quiz e39-40 | pmid=24768810 | doi=10.1016/j.cgh.2014.04.014 | pmc=4208976 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24768810  }} </ref>.
**[[Fibrosis]]
 
**[[Cirrhosis]]
==== NAFLD with normal liver enzymes ====
**Internal bleeding
Two cohort studies suggest no increased risk of cirrhosis among patients with steatosis by imaging but normal liver transaminases"
**Encepholopathy
* NAFLD with normal liver enzyme levels (n = 41,461) after 6 years of monitoring.<ref name="pmid35124270">{{cite journal| author=Huang YH, Chan C, Lee HW, Huang C, Chen YJ, Liu PC | display-authors=etal| title=Influence of Nonalcoholic Fatty Liver Disease With Increased Liver Enzyme Levels on the Risk of Cirrhosis and Hepatocellular Carcinoma. | journal=Clin Gastroenterol Hepatol | year= 2023 | volume= 21 | issue= 4 | pages= 960-969.e1 | pmid=35124270 | doi=10.1016/j.cgh.2022.01.046 | pmc=9349477 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35124270  }} </ref>
* NAFLD with normal liver enzyme levels (n = 3,522) after 8 years of monitoring<ref name="pmid32022277">{{cite journal| author=Natarajan Y, Kramer JR, Yu X, Li L, Thrift AP, El-Serag HB | display-authors=etal| title=Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes. | journal=Hepatology | year= 2020 | volume= 72 | issue= 4 | pages= 1242-1252 | pmid=32022277 | doi=10.1002/hep.31157 | pmc=8318072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32022277  }} </ref>.
 
==== NAFLD with high FIB-4 ====
In a cohort study of uncertain duration, 8% of patients had a high FIB-4 and 3% had one of cirrhosis, hepatocellular carcinoma, and liver transplantation<ref name="pmid36814048">{{cite journal| author=Schreiner AD, Zhang J, Moran WP, Koch DG, Livingston S, Bays C | display-authors=etal| title=Real-World Primary Care Data Comparing ALT and FIB-4 in Predicting Future Severe Liver Disease Outcomes. | journal=J Gen Intern Med | year= 2023 | volume= 38 | issue= 11 | pages= 2453-2460 | pmid=36814048 | doi=10.1007/s11606-023-08093-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=36814048  }} </ref>.


==NAFLD Activity Score (NAS)==
==== NAFLD and fatty liver index ====
The fatty liver index (FLI) is based on the following findings from a cohort study<ref name="pmid17081293">{{cite journal| author=Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A | display-authors=etal| title=The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. | journal=BMC Gastroenterol | year= 2006 | volume= 6 | issue=  | pages= 33 | pmid=17081293 | doi=10.1186/1471-230X-6-33 | pmc=1636651 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17081293  }} </ref>:


{| class="wikitable"
{| class="wikitable"
!STEATOSIS
|+ Parameters of the fatty liver index<ref name="pmid17081293"/>
!S SCORE
! Parameter !! Regression coefficient]
!COMMENT
|-
|<5%
|0
|Refers to the quantity of surface area involved by means of steatosis as evaluated on low to medium power examination; minimum steatosis (<5%) gets a rating of 0 to keep away from giving excess weight to biopsies with little or no fatty change.<ref name="pmid28507929">{{cite journal |vauthors=Vizuete J, Camero A, Malakouti M, Garapati K, Gutierrez J |title=Perspectives on Nonalcoholic Fatty Liver Disease: An Overview of Present and Future Therapies |journal=J Clin Transl Hepatol |volume=5 |issue=1 |pages=67–75 |year=2017 |pmid=28507929 |pmc=5411359 |doi=10.14218/JCTH.2016.00061 |url=}}</ref>
|-
|5–33%
|1
|
|-
|34–66%
|2
|
|-
|>66%
|3
|
|-
|'''Lobular Inflammation'''
|    '''L SCORE'''
|
|-
|None
|0
|Acidophil bodies are not protected by this evaluation, neither is the portal irritation.<ref name="urlTransplant Pathology Internet Services">{{cite web |url=http://tpis.upmc.com/changebody.cfm?url=/tpis/schema/NAFLD2006.jsp |title=Transplant Pathology Internet Services |format= |work= |accessdate=}}</ref>
|-
|<2 foci
|1
|
|-
|2–4 foci
|2
|
|-
|-
|>4 foci
| Log<sub>e</sub> (triglycerides, mg*dL<sup>-1</sup>) || style="text-align: right;"| 0.953
|3
|
|-
|-
|'''Hepatocyte                          Balloning'''
| BMI (kg*m<sup>2-1</sup>)|| style="text-align: right;"| 0.139
|   '''B score'''
|
|-
|-
|None
| Log<sub>e</sub> (GGT, U*L<sup>-1</sup>) || style="text-align: right;"| 0.718
|0
|
|-
|-
|Few ballooned cells
| Waist circumference (cm) || style="text-align: right;"| 0.053
|1
|The term "few" means rare however specific ballooned hepatocytes as well as cases which are diagnostically borderline.
|-
|-
|Many ballooned cells
| Constant || style="text-align: right;"| -15.745
|2
|Maximum cases with distinguished ballooning additionally had Mallory's hyaline, howeverMallory's hyaline isn't scored one after the other for the NAS
.
|}
|}
This leads to the equation:
FLI = (e <sup>0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745</sup>) / (1 + e <sup>0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745</sup>) * 100
Or the equation may be expressed as:
*  e<sup>y</sup> / (1 + e<sup>y</sup>) × 100
* Note that in both the numerator and denominator the exponent is: y = 0.953 × ln(triglycerides, mg/dL) + 0.139 × BMI + 0.718 × ln (GGT, U/L) + 0.053 × waist circumference, cm – 15.745
This equation has been used to prognosticate<ref name="pmid38350680">{{cite journal| author=Kim KS, Hong S, Han K, Park CY| title=Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study. | journal=BMJ | year= 2024 | volume= 384 | issue=  | pages= e076388 | pmid=38350680 | doi=10.1136/bmj-2023-076388 | pmc=10862140 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38350680  }} </ref>.
Online calculators are available:
* Diagnosis of fatty liver. [https://www.mdcalc.com/calc/10001/fatty-liver-index MDCALC]
* Distinguishing alchoholic and nonalcoholic fatty liver disease, [https://www.mayoclinic.org/medical-professionals/transplant-medicine/calculators/the-alcoholic-liver-disease-nonalcoholic-fatty-liver-disease-index-ani/itt-20434726 Mayo Clinic]
==== NAFLD with any fibrosis ====
The NIH Cohort found that any state of Fibrosis increases overall mortality or liver transplantation<ref name="pmid25935633">{{cite journal| author=Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P | display-authors=etal| title=Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. | journal=Gastroenterology | year= 2015 | volume= 149 | issue= 2 | pages= 389-97.e10 | pmid=25935633 | doi=10.1053/j.gastro.2015.04.043 | pmc=4516664 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25935633  }} </ref>.
==== NAFLD imaging ====
Elastography can help determine prognosis<ref name="pmid38512249">{{cite journal| author=Lin H, Lee HW, Yip TC, Tsochatzis E, Petta S, Bugianesi E | display-authors=etal| title=Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease. | journal=JAMA | year= 2024 | volume=  | issue=  | pages=  | pmid=38512249 | doi=10.1001/jama.2024.1447 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38512249  }} </ref>.
===Complications===
*Common complications of NAFLD include:<ref name="pmid27063276">{{cite journal| author=Chacko KR, Reinus J| title=Extrahepatic Complications of Nonalcoholic Fatty Liver Disease. | journal=Clin Liver Dis | year= 2016 | volume= 20 | issue= 2 | pages= 387-401 | pmid=27063276 | doi=10.1016/j.cld.2015.10.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27063276  }} </ref><ref name="pmid26378641">{{cite journal| author=Vanni E, Marengo A, Mezzabotta L, Bugianesi E| title=Systemic Complications of Nonalcoholic Fatty Liver Disease: When the Liver Is Not an Innocent Bystander. | journal=Semin Liver Dis | year= 2015 | volume= 35 | issue= 3 | pages= 236-49 | pmid=26378641 | doi=10.1055/s-0035-1562944 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26378641  }} </ref>
**[[Fibrosis]]
**[[Cirrhosis]]. Amon patients with both [[hepatic steatosis]] and elevated [[liver function tests]], the incidence rate of cirrhosis is 3.37 (95% CI: 2.34-4.86) per 1000 1000 person-years.
**[[Internal bleeding]]
**Encepholopathy
[[Non-alcoholic fatty liver disease]], especially if with cirrhosis, may be associated with [[thrombocytopenia]]<ref name="pmid34312112">{{cite journal| author=Rivera-Álvarez M, Córdova-Ramírez AC, Elías-De-La-Cruz GD, Murrieta-Álvarez I, León-Peña AA, Cantero-Fortiz Y | display-authors=etal| title=Non-alcoholic fatty liver disease and thrombocytopenia IV: its association with granulocytopenia. | journal=Hematol Transfus Cell Ther | year= 2021 | volume=  | issue=  | pages=  | pmid=34312112 | doi=10.1016/j.htct.2021.06.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34312112  }} </ref><ref name="pmid31575467">{{cite journal| author=Panke CL, Tovo CV, Villela-Nogueira CA, Cravo CM, Ferreira FC, Rezende GFM | display-authors=etal| title=Evaluation of thrombocytopenia in patients with non-alcoholic fatty liver disease without cirrhosis. | journal=Ann Hepatol | year= 2020 | volume= 19 | issue= 1 | pages= 88-91 | pmid=31575467 | doi=10.1016/j.aohep.2019.05.011 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31575467  }} </ref>.


===Prognosis===
===Prognosis===
* Histology is the most reliable means to grade the severity of the disease and thus estimate prognosis because the diagnostic criteria for NAFLD  as of now is low.
* In a cohort study of patient who had biopsy-proven NAFLD, 6% developed death, hepatocellular carcinoma, or death with 5 years<ref name="pmid37290471">{{cite journal| author=Mózes FE, Lee JA, Vali Y, Alzoubi O, Staufer K, Trauner M | display-authors=etal| title=Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis. | journal=Lancet Gastroenterol Hepatol | year= 2023 | volume=  | issue=  | pages=  | pmid=37290471 | doi=10.1016/S2468-1253(23)00141-3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=37290471  }} </ref>.
* The initial biopsy at the time of the diagnosis appears to be very valuable to predict the diagnosis.<ref name="urlNonalcoholic Fatty Liver Disease">{{cite web |url=http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/nonalcoholic-fatty-liver-disease/ |title=Nonalcoholic Fatty Liver Disease |format= |work= |accessdate=}}</ref>
 
* Depending on the extent of the [[fibrosis]] and [[cirrhosis]] at the time of diagnosis, the prognosis may vary.<ref name="urlComplications of Non-Alcoholic Fatty Liver Disease - Journal of Hepatology">{{cite web |url=http://www.journal-of-hepatology.eu/article/S0168-8278(16)00798-4/abstract |title=Complications of Non-Alcoholic Fatty Liver Disease - Journal of Hepatology |format= |work= |accessdate=}}</ref>
In a cohort of patients with steatosis by imaging but did not have liver biopsies, after 8 years of follow-up, liver function tests predicted clinical outcomes only if LFTs abnormal<ref name="pmid32022277">{{cite journal| author=Natarajan Y, Kramer JR, Yu X, Li L, Thrift AP, El-Serag HB | display-authors=etal| title=Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes. | journal=Hepatology | year= 2020 | volume= 72 | issue= 4 | pages= 1242-1252 | pmid=32022277 | doi=10.1002/hep.31157 | pmc=8318072 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32022277  }} </ref>.
* The presence of [[fibrosis]] and [[cirrhosis]] associated with a particularly poor prognosis among patients with NAFLD.
 
* The rate of ESLD (fibrosis stage 3/4 with symptoms) among patients with fibrosis stage 1/2 over 20 years is per Nasr et al<ref name="pmid29404527">{{cite journal| author=Nasr P, Ignatova S, Kechagias S, Ekstedt M| title=Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies. | journal=Hepatol Commun | year= 2018 | volume= 2 | issue= 2 | pages= 199-210 | pmid=29404527 | doi=10.1002/hep4.1134 | pmc=5796332 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29404527  }} </ref>:
** 11% (6 of 53) (Supplementary table 1)
** 25% (4 of 16) (Supplementary table 1)
* Histology is the most reliable means to grade the severity of the disease and thus estimate prognosis.
** The presence of [[fibrosis]] and [[cirrhosis]] is associated with a particularly poor prognosis among patients with NAFLD. <ref name="pmid22102440">{{cite journal| author=Jepsen P, Grønbæk H| title=Prognosis and staging of non-alcoholic fatty liver disease. | journal=BMJ | year= 2011 | volume= 343 | issue=  | pages= d7302 | pmid=22102440 | doi=10.1136/bmj.d7302 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102440  }} </ref>
** Depending on the extent of the [[fibrosis]] and [[cirrhosis]] at the time of diagnosis, the prognosis may vary.<ref name="SumanKhullar2016">{{cite journal|last1=Suman|first1=A.|last2=Khullar|first2=V.|last3=Limaye|first3=A.|title=Complications of Non-Alcoholic Fatty Liver Disease|journal=Journal of Hepatology|volume=64|issue=2|year=2016|pages=S473|issn=01688278|doi=10.1016/S0168-8278(16)00798-4}}</ref>
 
A simulation study has estimated prognoses<ref name="pmid36098969">{{cite journal| author=Chhatwal J, Dalgic OO, Chen W, Samur S, Bethea ED, Xiao J | display-authors=etal| title=Analysis of a Simulation Model to Estimate Long-term Outcomes in Patients with Nonalcoholic Fatty Liver Disease. | journal=JAMA Netw Open | year= 2022 | volume= 5 | issue= 9 | pages= e2230426 | pmid=36098969 | doi=10.1001/jamanetworkopen.2022.30426 | pmc=9471976 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=36098969  }} </ref>
 
==== Prognosis estimated based on treatment ====
Randomized controlled trials have been executed of:
* Semaglutide<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.
 
Assuming that
* The 14% improvement above found be Newsome et al<ref name="pmid33185364"/> would be significant in larger trials
* An improvement in fibrosis state has the same clinical significance as regression from advanced fibrosis (stage 3 or 4) to non-advanced fibrosis (Stage 1 or 2)
 
The reduction in progression to end-stage liver disease (ESLD; fibrosis stage 3 or 4 with symptoms) by treating is 1.4% over twenty years. The estimate is based on:
 
10% (the absolute reduction in advanced fibrosis due to treatment according to Newsome et al<ref name="pmid33185364"/>)
  x
14% (approximate absolute increase in risk of ESLD from fibrosis 3/4 versus fibrosis 1/2 per Nasr et al<ref name="pmid29404527"/>)
 
Thus, the number needed to treat (NNT) is about 70 (100/1.4).


==References==
==References==

Latest revision as of 23:53, 21 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

If left untreated non-alcoholic fatty liver disease may progress to fibrosis and, later cirrhosis. Studies of serial liver biopsies estimate a 26-37% rate of hepatic fibrosis and 2-15% rate of cirrhosis in less than 6 years. Common complications of NAFLD include fibrosis, cirrhosis, internal bleeding, encephalopathy. The presence of fibrosis and cirrhosis associated with a particularly poor prognosis among patients with NAFLD.

Natural History, Complications and Prognosis

See also: Non-alcoholic fatty liver disease Noninvasive scores

Natural History

  • The symptoms of NAFLD usually develop in the 40th decade of life, and usually asymptomatic at first.
  • After following NAFLD patients for long-term the outcome of the disease is as follows
    • 1) Patients with NAFLD has overall high morbidity and mortality rate and the common cause of death in NAFLD patients is cardiovascular disease.
    • 2) Patients with NASH has more liver-related mortality rate
  • If left untreated, patients with NAFLD may progress to develop hepato-cellular carcinoma (HCC). But it is directly propotional to the degree of fibrosis and advanced cirrhosis
  • Children who are positive with NAFLD are also prone to short lifespan when compared to general population.[1]

Patients progress about 1 stage per 7 years[2].

NAFLD with normal liver enzymes

Two cohort studies suggest no increased risk of cirrhosis among patients with steatosis by imaging but normal liver transaminases"

  • NAFLD with normal liver enzyme levels (n = 41,461) after 6 years of monitoring.[3]
  • NAFLD with normal liver enzyme levels (n = 3,522) after 8 years of monitoring[4].

NAFLD with high FIB-4

In a cohort study of uncertain duration, 8% of patients had a high FIB-4 and 3% had one of cirrhosis, hepatocellular carcinoma, and liver transplantation[5].

NAFLD and fatty liver index

The fatty liver index (FLI) is based on the following findings from a cohort study[6]:

Parameters of the fatty liver index[6]
Parameter Regression coefficient]
Loge (triglycerides, mg*dL-1) 0.953
BMI (kg*m2-1) 0.139
Loge (GGT, U*L-1) 0.718
Waist circumference (cm) 0.053
Constant -15.745

This leads to the equation: FLI = (e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) / (1 + e 0.953*loge (triglycerides) + 0.139*BMI + 0.718*loge (ggt) + 0.053*waist circumference - 15.745) * 100

Or the equation may be expressed as:

  • ey / (1 + ey) × 100
  • Note that in both the numerator and denominator the exponent is: y = 0.953 × ln(triglycerides, mg/dL) + 0.139 × BMI + 0.718 × ln (GGT, U/L) + 0.053 × waist circumference, cm – 15.745

This equation has been used to prognosticate[7].

Online calculators are available:

  • Diagnosis of fatty liver. MDCALC
  • Distinguishing alchoholic and nonalcoholic fatty liver disease, Mayo Clinic

NAFLD with any fibrosis

The NIH Cohort found that any state of Fibrosis increases overall mortality or liver transplantation[8].

NAFLD imaging

Elastography can help determine prognosis[9].

Complications

Non-alcoholic fatty liver disease, especially if with cirrhosis, may be associated with thrombocytopenia[12][13].

Prognosis

  • In a cohort study of patient who had biopsy-proven NAFLD, 6% developed death, hepatocellular carcinoma, or death with 5 years[14].

In a cohort of patients with steatosis by imaging but did not have liver biopsies, after 8 years of follow-up, liver function tests predicted clinical outcomes only if LFTs abnormal[4].

  • The rate of ESLD (fibrosis stage 3/4 with symptoms) among patients with fibrosis stage 1/2 over 20 years is per Nasr et al[15]:
    • 11% (6 of 53) (Supplementary table 1)
    • 25% (4 of 16) (Supplementary table 1)
  • Histology is the most reliable means to grade the severity of the disease and thus estimate prognosis.
    • The presence of fibrosis and cirrhosis is associated with a particularly poor prognosis among patients with NAFLD. [16]
    • Depending on the extent of the fibrosis and cirrhosis at the time of diagnosis, the prognosis may vary.[17]

A simulation study has estimated prognoses[18]

Prognosis estimated based on treatment

Randomized controlled trials have been executed of:

  • Semaglutide[19]:
    • "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.

Assuming that

  • The 14% improvement above found be Newsome et al[19] would be significant in larger trials
  • An improvement in fibrosis state has the same clinical significance as regression from advanced fibrosis (stage 3 or 4) to non-advanced fibrosis (Stage 1 or 2)

The reduction in progression to end-stage liver disease (ESLD; fibrosis stage 3 or 4 with symptoms) by treating is 1.4% over twenty years. The estimate is based on: 

10% (the absolute reduction in advanced fibrosis due to treatment according to Newsome et al[19])
 x 
14% (approximate absolute increase in risk of ESLD from fibrosis 3/4 versus fibrosis 1/2 per Nasr et al[15])

Thus, the number needed to treat (NNT) is about 70 (100/1.4).

References

  1. ↑ Calzadilla Bertot L, Adams LA (2016). "The Natural Course of Non-Alcoholic Fatty Liver Disease". Int J Mol Sci. 17 (5). doi:10.3390/ijms17050774. PMC 4881593. PMID 27213358.
  2. ↑ Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R (2015). "Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies". Clin Gastroenterol Hepatol. 13 (4): 643-54.e1-9, quiz e39-40. doi:10.1016/j.cgh.2014.04.014. PMC 4208976. PMID 24768810.
  3. ↑ Huang YH, Chan C, Lee HW, Huang C, Chen YJ, Liu PC; et al. (2023). "Influence of Nonalcoholic Fatty Liver Disease With Increased Liver Enzyme Levels on the Risk of Cirrhosis and Hepatocellular Carcinoma". Clin Gastroenterol Hepatol. 21 (4): 960–969.e1. doi:10.1016/j.cgh.2022.01.046. PMC 9349477 Check |pmc= value (help). PMID 35124270 Check |pmid= value (help).
  4. ↑ 4.0 4.1 Natarajan Y, Kramer JR, Yu X, Li L, Thrift AP, El-Serag HB; et al. (2020). "Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes". Hepatology. 72 (4): 1242–1252. doi:10.1002/hep.31157. PMC 8318072 Check |pmc= value (help). PMID 32022277 Check |pmid= value (help).
  5. ↑ Schreiner AD, Zhang J, Moran WP, Koch DG, Livingston S, Bays C; et al. (2023). "Real-World Primary Care Data Comparing ALT and FIB-4 in Predicting Future Severe Liver Disease Outcomes". J Gen Intern Med. 38 (11): 2453–2460. doi:10.1007/s11606-023-08093-8. PMID 36814048 Check |pmid= value (help).
  6. ↑ 6.0 6.1 Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A; et al. (2006). "The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population". BMC Gastroenterol. 6: 33. doi:10.1186/1471-230X-6-33. PMC 1636651. PMID 17081293.
  7. ↑ Kim KS, Hong S, Han K, Park CY (2024). "Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study". BMJ. 384: e076388. doi:10.1136/bmj-2023-076388. PMC 10862140 Check |pmc= value (help). PMID 38350680 Check |pmid= value (help).
  8. ↑ Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P; et al. (2015). "Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease". Gastroenterology. 149 (2): 389–97.e10. doi:10.1053/j.gastro.2015.04.043. PMC 4516664. PMID 25935633.
  9. ↑ Lin H, Lee HW, Yip TC, Tsochatzis E, Petta S, Bugianesi E; et al. (2024). "Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease". JAMA. doi:10.1001/jama.2024.1447. PMID 38512249 Check |pmid= value (help).
  10. ↑ Chacko KR, Reinus J (2016). "Extrahepatic Complications of Nonalcoholic Fatty Liver Disease". Clin Liver Dis. 20 (2): 387–401. doi:10.1016/j.cld.2015.10.004. PMID 27063276.
  11. ↑ Vanni E, Marengo A, Mezzabotta L, Bugianesi E (2015). "Systemic Complications of Nonalcoholic Fatty Liver Disease: When the Liver Is Not an Innocent Bystander". Semin Liver Dis. 35 (3): 236–49. doi:10.1055/s-0035-1562944. PMID 26378641.
  12. ↑ Rivera-Álvarez M, Córdova-Ramírez AC, Elías-De-La-Cruz GD, Murrieta-Álvarez I, León-Peña AA, Cantero-Fortiz Y; et al. (2021). "Non-alcoholic fatty liver disease and thrombocytopenia IV: its association with granulocytopenia". Hematol Transfus Cell Ther. doi:10.1016/j.htct.2021.06.004. PMID 34312112 Check |pmid= value (help).
  13. ↑ Panke CL, Tovo CV, Villela-Nogueira CA, Cravo CM, Ferreira FC, Rezende GFM; et al. (2020). "Evaluation of thrombocytopenia in patients with non-alcoholic fatty liver disease without cirrhosis". Ann Hepatol. 19 (1): 88–91. doi:10.1016/j.aohep.2019.05.011. PMID 31575467.
  14. ↑ Mózes FE, Lee JA, Vali Y, Alzoubi O, Staufer K, Trauner M; et al. (2023). "Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis". Lancet Gastroenterol Hepatol. doi:10.1016/S2468-1253(23)00141-3. PMID 37290471 Check |pmid= value (help).
  15. ↑ 15.0 15.1 Nasr P, Ignatova S, Kechagias S, Ekstedt M (2018). "Natural history of nonalcoholic fatty liver disease: A prospective follow-up study with serial biopsies". Hepatol Commun. 2 (2): 199–210. doi:10.1002/hep4.1134. PMC 5796332. PMID 29404527.
  16. ↑ Jepsen P, Grønbæk H (2011). "Prognosis and staging of non-alcoholic fatty liver disease". BMJ. 343: d7302. doi:10.1136/bmj.d7302. PMID 22102440.
  17. ↑ Suman, A.; Khullar, V.; Limaye, A. (2016). "Complications of Non-Alcoholic Fatty Liver Disease". Journal of Hepatology. 64 (2): S473. doi:10.1016/S0168-8278(16)00798-4. ISSN 0168-8278.
  18. ↑ Chhatwal J, Dalgic OO, Chen W, Samur S, Bethea ED, Xiao J; et al. (2022). "Analysis of a Simulation Model to Estimate Long-term Outcomes in Patients with Nonalcoholic Fatty Liver Disease". JAMA Netw Open. 5 (9): e2230426. doi:10.1001/jamanetworkopen.2022.30426. PMC 9471976 Check |pmc= value (help). PMID 36098969 Check |pmid= value (help).
  19. ↑ 19.0 19.1 19.2 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).

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