Non-alcoholic fatty liver disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Ludwig was the first physician to describe the non-alcoholic fatty liver disease as a separate medical entity from other fatty liver diseases.

• In 1980, Ludwig was the first physician to describe non-alcoholic fatty liver disease as a separate medical entity from other fatty liver diseases.^[1][2][3]
• In 1983, Adler & Schaffner described the association between obesity and non-alcoholic fatty liver disease.
• In 1984, Andersen & Gluud conducted numerous experiments with extensive documentation of the liver biopsies in patients with non-alcoholic fatty liver disease.
• In 1985, Bockus was the first to coin the term non-alcoholic fatty liver.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]Parth Vikram Singh, MBBS[3]

Non-alcoholic fatty liver (NAFLD) disease may be classified based on clinical presentation into non-alcoholic fatty liver and non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease may be classified based on clinical presentation into non-alcoholic fatty liver and non-alcoholic steatohepatitis.^[1][2][3]

Steatotic liver disease may be subclassified according to the presence of cardiometabolic risk factors, alcohol intake, and other causes of hepatic steatosis.^[4]

One standard drink is approximately equivalent to 10 g of alcohol, corresponding approximately to 12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof distilled spirits.

Histological classification of NAFLD includes grading and staging.

• Grade: Depending on degree of steatosis and necro-inflammatory activity
• Stage: Depending on degree of fibrosis.

NAFLD activity score is employed for grading steatohepatitis of NASH. NAS represents the sum of scores for steatosis, lobular inflammation, and ballooning.^[5]

Based on liver biopsy histology, liver fibrosis in MASLD is scored using a 5-stage scale:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2] Parth Vikram Singh, MBBS[3]

The pathogenesis of MASLD is multifactorial. The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors such as obesity, Insulin resistance, and metabolic syndrome. Hepatic steatosis develops due to increased hepatic uptake of free fatty acids, increased de novo hepatic lipogenesis, decreased hepatic fatty acid oxidation, and reduced hepatic export of triglycerides into very low-density lipoproteins. Systemic insulin resistance promotes adipose tissue lipolysis and hepatic de novo lipogenesis, thereby increasing hepatic lipid accumulation. Progression from isolated steatosis to MASH is associated with lipotoxicity, in which accumulation of triglycerides, free cholesterol, saturated fatty acids, and ceramides contributes to hepatic inflammation, cellular dysfunction, and cell death. Metabolic factors, diet, genetic susceptibility, adipose tissue inflammation, and the gut microbiome may also contribute to disease progression. Dietary factors, including high intake of glucose, fructose, saturated fats, and processed foods, may promote low-grade inflammation in the liver and extrahepatic organs. Excess adipose tissue contributes to systemic inflammation through increased release of proinflammatory cytokines and recruitment and activation of immune cells, particularly macrophages.^[1]

Pathogenesis of non-alcoholic liver disease was previously explained by 2 hit hypothesis. The first hit is steatosis. The second hit is controversial and is likely cause changes that leads from hepatic steatosis to hepatic inflammation and fibrosis by way of lipid peroxidation. The older two-hit hypothesis should be regarded as historical background. Current evidence supports a broader multifactorial model in which insulin resistance, lipotoxicity, diet, adipose tissue inflammation, genetics, and gut microbiome-related pathways act together to promote progression from steatosis to MASH and fibrosis.

The exact pathogenesis of NAFLD is not fully understood but is believed due to the interaction of multiple factors.

Pathogenesis of non-alcoholic liver disease can be summarized by 2 hit hypothesis. According to 2 hit hypothesis:

• The first hit results in increased fat accumulation especially triglycerides within the hepatocyte and increases the risk of liver injury.
• On the second hit inflammatory cytokines causes mitochondrial dysfunction and oxidative stress which in turn lead to steatohepatitis and/or fibrosis.^[2]

• Free fatty acids (FFA) play very crucial role in damaging the liver indirectly by either undergoing β-oxidation or are esterified with glycerol to form triglycerides, leading to hepatic fat accumulation.^[3][4][5]
• By upregulating TNF-alpha expression via lysosomal pathway, free fatty acids make the liver susceptible to oxidative stress.^[6]

• Oxidative stress inhibits the replication process in the mature hepatocytes.
• Inhibition of hepatocyte replication results in the proliferation of progenitor cell population which can also differentiates into hepatocyte-like cells.
• Progenitor cells along with hepatocyte-like cells are responsible for fibrosis and carcinogenesis in non alcoholic fatty liver.^[2]

• Obese patients who underwent jejuno-ileal bypass surgery has the risk of developing bacterial endotoxins in the portal circulation due to small intestinal deformity.
• Increase in small bowel bacterial overgrowth due to decreased gastric motility.
• Bacterial toxins released by this bacteria overgrowth stimulate an elevation of intra-hepatic levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha.
• Expression of TNF-alpha begins the cascade of events making liver susceptible for free radical injury.

• Adiponectin is an anti-atherogenic, insulin sensitizing cytokine whose secretion is decreased in obesity.^{[10][11][12][13]}
• There is an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor.
• Any conditions that cause low production of adiponectin ( consuming high amounts of poly unsaturated fatty acids) results in production of TNF alpha.

• Alteration of purinergic metabolism is another important pathway responsible for development of non-alcoholic liver disease.
• Adenosine receptor A2A is a major factor in the pathogenesis of cirrhosis.
• CD39 is the dominant vascular ectonucleotidase in the liver that hydrolyzes extracellular ATP and ADP to AMP which can then be converted to adenosine via ecto-5’-nucleotidase/CD73.^[15]
• Alterations in purinergic signaling induced by altered CD39 mutation have major impacts upon hepatic metabolism, repair mechanisms, regeneration and associated immune responses.
• Adenosine forms a supportive link in the cell’s cascade healing response to inflammation.
  • Adenosine suppresses inflammation by enhancing fibrosis.
• CD39 deletion shifts the local population of cytokines to produce TNF alpha.

• Fibroblast growth factor 21 (FGF21) is an important metabolic regulator of glucose and lipid metabolism.
• FGF21 moderates or induces the hepatic response to a fasting state by gluconeogenesis, fatty acid oxidation, and ketogenesis.
• Moreover, it is a crucial component of the hepatic lipid oxidation machinery, as proliferator-activated receptor activation.
• FGF21 is responsible for normal blood glucose, insulin, and lipid levels in normal individuals.
• Low levels of FGF21 are closely associated with the obesity, insulin resistance, type two diabetes mellitus and hyperlipidemia.

• Most patients have associated features of the metabolic syndrome including obesity, diabetes mellitus type 2, hyperlipidemia (hypertriglyceridemia), and hypertension
• MASLD is a multisystem metabolic disease associated with cardiovascular disease, chronic kidney disease, heart failure, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers, particularly gastrointestinal, breast, and gynecologic cancers.
• Patients may suffer from complications of obesity such as obstructive sleep apnea , orthopedic complications, and polycystic ovary syndrome.

On microscopic histopathological analysis, characteristic findings of the non-alcoholic liver disease include:

• Macrovesicular steatosis

• Predominant lobular inflammation in form of spotty necrosis in cases where steatosis is associated with inflammation.

• Ballooning degeneration (hallmark of steatohepatitis)
  • Characterized by cellular swelling, rarefaction of the hepatocytic cytoplasm and clumped strands of intermediate filaments.
• Mallory-Denk bodies (MDB)
• Fibrosis
• Perivenular and pericellular (peri-sinusoidal) fibrosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Parth Vikram Singh, MBBS[3]

Common causes in the development of nonalcoholic fatty liver disease is related to obesity which will result in insulin resistance and metabolic syndrome. Less commonly patients with hypertension and dyslipidemia are also associated with developing nonalcoholic fatty liver disease.

• The most common cause of NAFLD are conditions associated with obesity such as insulin resistance and metabolic syndrome. It is estimated that approximately 80% of the obese people suffer from NAFLD.^[1][2][3]

• Less common causes of non-alcoholic fatty liver disease include hypertension and dyslipidemia.
• The risk of developing MASLD and progressing to MASH increases with the number of metabolic syndrome features, including abdominal obesity, hypertension, hypertriglyceridemia, low HDL cholesterol, and elevated blood glucose.^[4] Cardiometabolic risk factors used in the classification of MASLD include body mass index of 25 or greater, or 23 or greater in Asian individuals; waist circumference of 80 cm or greater in women and 94 cm or greater in men; fasting glucose level of 5.6 mmol/L or greater, 2-hour postload glucose level of 7.8 mmol/L or greater, hemoglobin A1c level of 5.7% or greater, established type 2 diabetes, or use of glucose-lowering medication; blood pressure of 130/85 mm Hg or greater or use of antihypertensive medication; plasma triglyceride level of 1.70 mmol/L or greater or use of triglyceride-lowering medication; and low HDL cholesterol.
• Other contributors include older age, male sex, postmenopausal status, PNPLA3 and TM6SF2 genetic variants, sedentary lifestyle, smoking, high fructose intake, alcohol consumption above MASLD thresholds, and high-calorie diets rich in saturated fats, sugars, and processed foods.
• Other known causes of hepatic steatosis that should be excluded include use of corticosteroids, methotrexate, or tamoxifen; hepatitis C virus infection; iron overload; celiac disease; HIV infection; malnutrition; Wilson disease; lysosomal acid lipase deficiency; hypobetalipoproteinemia; and inborn errors of metabolism.

Secondary non-alcoholic fatty liver disease can also be defined as injury to liver caused by either medications, surgery and other diseases.

• Amiodarone
• Antiviral drugs (nucleoside analogues)
• Aspirin / NSAIDS
• Corticosteroids
• Methotrexate
• Nifedipine
• Perhexiline
• Tamoxifen
• Tetracycline
• Valproic acid

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Parth Vikram Singh, MBBS[3]

Usually, NAFLD presents with no or few symptoms but if symptomatic NAFLD must be differentiated from other diseases that cause jaundice and abdominal pain which include Wilson’s disease, hemochromatosis, alcoholic hepatitis and cholestatic jaundice.

NAFLD must be differentiated from other diseases that cause jaundice and abdominal pain like including alcohol-associated liver disease, metabolic dysfunction and alcohol-related liver disease, drug-induced liver injury, hepatitis C virus infection, iron overload, celiac disease, HIV infection, malnutrition, Wilson disease, lysosomal acid lipase deficiency, hypobetalipoproteinemia, and inborn errors of metabolism.^[1][2]

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Parth Vikram Singh, MBBS[3]

The estimated annual incidence of non alcoholic liver disease with steatosis in the United States is approximately 9,255 per 100,000 individuals. The prevalence of non-alcoholic liver disease in the United States is estimated to be 10,000 to 24,000 cases per 100,000 individuals annually. Non-alcoholic fatty liver disease may occur at any age, but is diagnosed most commonly in patients aged 50 to 60 years. Hepatic steatosis is more prevalent in the hispanics.

One estimate of prevalence is 30% from a systematic review^[1]. A similar estimate comes from the Global Burden of Disease (GBD) 2019 study^[2].

• The estimated annual incidence of non alcoholic liver disease with steatosis in the United States is approximately 9,255 per 100,000 individuals.
• The estimated annual incidence of non alcoholic liver disease with steatohepatitis in the United States is approximately 265 per 100,000 individuals .

• About 1/3 of america population is expected to have non alcoholic fatty liver disease.^{[3][4][5][6][7]}

• MASLD is the most common chronic liver disease worldwide. Approximately 30% to 40% of adults worldwide have MASLD. The prevalence is substantially higher among individuals with type 2 diabetes and obesity, affecting approximately 60% to 70% of individuals with type 2 diabetes and approximately 70% to 80% of individuals with obesity.^[8]
• In a systematic review of 92 population-based studies from 1990 to 2019, the highest prevalence of ultrasound-detected MASLD was observed in Latin America and the lowest in Western Europe. By 2040, the global prevalence of MASLD among adults is projected to exceed 55%. In 2021, the global age-standardized prevalence of MASLD was 15,018 per 100,000 population, and the annual incidence was 608 per 100,000 population. The prevalence was higher in men than women and peaked at 45 to 49 years of age in men and 50 to 54 years of age in women.
• Among individuals with type 2 diabetes, the global pooled prevalence of MASLD based on ultrasonography was 65.3%. Among individuals with type 2 diabetes who had liver biopsy data, the global histological prevalence of MASH was 66.4%, stage F2 fibrosis was present in 40.8%, and advanced fibrosis, defined as stage F3 or F4, was present in 15.5%.
• The prevalence of non-alcoholic liver disease in the United States is estimated to be 10,000 to 24,000 cases per 100,000 individuals annually.

• In obese children the prevalence of non-alcoholic liver disease is estimated to be 20,000 to 50,000 cases per 100,000 individuals annually.^[9]

• Prevalence of non-alcoholic fatty liver disease increases nearly five fold in obese individuals.

• Non-alcoholic fatty liver disease may occur at any age, but is diagnosed most commonly in patients aged 50 to 60 years.

• Men are more commonly affected by non-alcoholic liver disease than women. In global 2021 estimates, prevalence peaked at 45 to 49 years of age in men and at 50 to 54 years of age in women.
• Among women it is more common in post-menopausal women than pre-menopausal.

• Hepatic steatosis is more prevalent in the hispanics (45%) race and followed by caucasians (42% of men, 24% of women) and african-american (24%)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Parth Vikram Singh, MBBS[3]

The most potent risk factor in the development of NAFLD is obesity. Other risk factors include insulin resistance and metabolic syndrome.

Risk factors in the development of non-alcoholic fatty liver disease include:^[1][2][3][4]

• Viral hepatitis
• Rapid weight loss
• Malnutrition
• Hypertriglyceridemia
• Low HDL cholesterol
• Sleep apnea
• Hypothyroidism
• Abdominal overweight or Obesity
• Hypopituitarism
• Prediabetes or Diabetes mellitus type 2
• Insulin resistance
• Hypertension
• PCOS (polycystic ovarian syndrome)
• Older age
• Male sex
• Postmenopausal status
• PNPLA3 and TM6SF2 genetic variants
• Sedentary lifestyle
• Smoking
• High intake of fructose, especially from sugar-sweetened beverages
• High-calorie diets rich in saturated fats, sugars, and processed foods
• Alcohol intake above MASLD thresholds
• Medications like tamoxifen, corticosteriods, methotrexate

Cardiometabolic risk factors used in the classification of MASLD include body mass index of 25 or greater, or 23 or greater in Asian individuals; waist circumference of 80 cm or greater in women and 94 cm or greater in men; fasting glucose level of 5.6 mmol/L or greater, 2-hour postload glucose level of 7.8 mmol/L or greater, hemoglobin A1c level of 5.7% or greater, established type 2 diabetes, or use of glucose-lowering medication; blood pressure of 130/85 mm Hg or greater or use of antihypertensive medication; plasma triglyceride level of 1.70 mmol/L or greater or use of triglyceride-lowering medication; and low HDL cholesterol.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]Parth Vikram Singh, MBBS[3]

There is insufficient evidence to recommend routine screening for NAFLD in general population. However, screening is recommended in high-risk population groups(obesity, insulin resistance and patients with metabolic syndrome) as more than 50 million Americans have been estimated to have metabolic syndrome and about 80% of them have NAFD.

• There is insufficient evidence to recommend routine screening for NAFLD in general population.^[1][2][3]
• However, American Gastroenterological Association Technical Review recommends screening for non-alcoholic fatty liver disease in population at high risk such as obesity, insulin resistance, and metabolic syndrome.
• Screening is however complicated by the lack of accurate, noninvasive diagnostic tools for NAFLD and the lack of clear treatment that can be proposed to the patient.
• Current guidelines summarized in the JAMA review^[4] recommend a 2-tier testing approach to screen for advanced liver fibrosis in high-risk populations, including individuals with prediabetes or type 2 diabetes, obesity, 2 or more cardiometabolic risk factors, imaging-detected hepatic steatosis, or persistently elevated serum aminotransferase levels.
  • The first step is calculation of the Fibrosis-4 index, usually performed in primary care. Patients with a Fibrosis-4 index greater than 1.3 should undergo vibration-controlled transient elastography or another noninvasive test, such as the enhanced liver fibrosis test. Patients with liver stiffness greater than 8.0 kPa or an enhanced liver fibrosis test score greater than 9.8 should be referred to a hepatologist.
  • Patients with a FIB-4 score less than 1.3 should undergo lifestyle modification, avoidance of alcohol intake, and treatment of type 2 diabetes, obesity, dyslipidemia, and hypertension. Repeat FIB-4 testing may be performed every 1 to 3 years. Patients with indeterminate or high-risk findings should undergo additional noninvasive fibrosis assessment and may require hepatology referral.

The AGA also recommends screening^[5].

Workflows to promote screening may increase treatment^[6].

• Serum tests of liver function

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2] Parth Vikram Singh, MBBS[3]

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.

• 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
• Approximately 15% to 40% of patients with isolated hepatic steatosis progress to MASH. Fibrosis progression is usually slow, with progression of approximately 1 fibrosis stage over 14 years among patients with isolated steatosis and approximately 1 fibrosis stage over 7 years among patients with MASH. More advanced fibrosis is the strongest risk factor for progression to cirrhosis, hepatic decompensation, and liver-related mortality.^[1]
• In a systematic review and meta-analysis of patients with histologically confirmed MASLD, 2% to 3% of patients with isolated steatosis developed advanced fibrosis over 15 to 20 years, while approximately 25% to 30% of patients with MASH developed advanced fibrosis within 8 to 10 years. Among patients with biopsy-confirmed MASH and F3 fibrosis, 22% progressed to cirrhosis over 2 years.
• Cirrhosis is associated with hepatic decompensation events, including ascites, hepatic encephalopathy, and variceal bleeding, which occur at rates of about 10% annually. Up to nearly 2.5% of patients with cirrhosis develop incident hepatocellular carcinoma annually.
• 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.^[2]

Patients progress about 1 stage per 7 years^[3].

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.^[4]
• NAFLD with normal liver enzyme levels (n = 3,522) after 8 years of monitoring^[5].

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^[6].

The fatty liver index (FLI) is based on the following findings from a cohort study^[7]:

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:

• e^y / (1 + e^y) × 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^[8].

Online calculators are available:

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

The NIH Cohort found that any state of Fibrosis increases overall mortality or liver transplantation^[9].

Elastography can help determine prognosis^[10].

• Common complications of NAFLD include:^[11][12]
  • 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
  • Hepatic decompensation events include ascites, hepatic encephalopathy, and variceal bleeding.

• Other complications of MASLD include hepatocellular carcinoma, cardiovascular disease, chronic kidney disease, heart failure, atrial fibrillation, incident type 2 diabetes, and certain extrahepatic cancers.

Non-alcoholic fatty liver disease, especially if with cirrhosis, may be associated with thrombocytopenia^[13][14].

• Cardiovascular disease is the leading cause of death in patients with noncirrhotic MASLD, followed by extrahepatic cancer and liver-related complications. In patients with MASLD-related cirrhosis, liver-related and cardiovascular disease-related deaths are the predominant causes of mortality.^[15]
• In a cohort study of patient who had biopsy-proven NAFLD, 6% developed death, hepatocellular carcinoma, or death with 5 years^[16].

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^[5].

• 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^[17]:
  • 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.
  • Fibrosis stage is the strongest prognostic factor for liver-related morbidity and mortality. Compared with patients with no fibrosis, patients with cirrhosis have substantially higher risks of liver-related events, liver-related mortality, liver transplantation, and all-cause mortality.
  • The presence of fibrosis and cirrhosis is associated with a particularly poor prognosis among patients with NAFLD. ^[18]
  • Depending on the extent of the fibrosis and cirrhosis at the time of diagnosis, the prognosis may vary.^[19]

A simulation study has estimated prognoses^[20]

Randomized controlled trials have been executed of:

• Semaglutide^[21]:
  • “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^[21] 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[21])
 x 
14% (approximate absolute increase in risk of ESLD from fibrosis 3/4 versus fibrosis 1/2 per Nasr et al[17])

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

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