CME INDIA Presentation by Dr. N.K. Singh, MD, FICP, Director, Diabetes and Heart Research Centre, Dhanbad, Jharkhand, India. Editor,

Vision 2023

New studies strongly unfold about dysregulation of hepatic glucose and lipid metabolism as primary factor underlying the pathogenesis of type 2 diabetes mellitus (T2DM) and T1DM.
In India we need to Implement a “FIB-4 First” Strategy.
In a recent study a FIB-4 (Fibrosis-4 index) threshold of 1.3 has been found acceptable for excluding the presence of advanced fibrosis (assessed by VCTE vibration-controlled transient elastography (VCTE).
So, a staged risk-stratification model using FIB-4 and VCTE could save up to 87% of further assessments.
This model could improve accessibility by moving the initial fibrosis evaluation by primary care physician helping to prioritize patients for further specialized care.

Very Grim Scenario

  • Liver disease affects up to 70% of people with type 2 diabetes, and is common in people with prediabetes, and in those with type 1 diabetes who also have obesity.
  • The global prevalence of NASH among individuals with T2DM was found 37.3% in a systematic review published in 2019. In US similar numbers have been reported (estimated prevalence of NASH in this setting being 35%).
  • A great proportion of NASH patients have comorbid obesity (as high as 80%).
  • Most NAFLD & NASH patients are asymptomatic, and only a small fraction of patients with NAFLD progress to NASH. This is the reason diagnosis becomes difficult.

FIB-4 – ADA 2023, Revised recommendations in June 2023

Adults with type 2 diabetes or prediabetes, particularly those with obesity or cardio-metabolic risk factors/established cardiovascular disease, should be screened/risk stratified for non-alcoholic fatty liver disease with clinically significant fibrosis (defined as moderate fibrosis to cirrhosis) using a calculated fibrosis-4 index even if they have normal liver enzymes. Level of evidence B.
Adults with diabetes or prediabetes with persistently elevated plasma aminotransferase levels for >6 months and low fibrosis-4 index should be evaluated for other causes of liver disease. Level of evidence B.
Adults with type 2 diabetes or prediabetes with an indeterminate or high fibrosis-4 index should have additional risk stratification by liver stiffness measurement with transient elastography, or the blood biomarker enhanced liver fibrosis. Level of evidence B.
Adults with type 2 diabetes or prediabetes with indeterminate results or at high risk for significant liver fibrosis (i.e., by fibrosis-4 index, liver stiffness measurement, or enhanced liver fibrosis) should be referred to a gastroenterologist or hepatologist for further workup. Multidisciplinary care is recommended for long-term management. Level of evidence B.

What are the recommendations by RSSDI (2022) (Research Society for study of Diabetes in India)?

Universal FIB-4 Score Screening in Diabetes - What Physicians Must Know?

Why to screen universally all diabetics?

  • Diabetes is a major risk factor for developing NASH, disease progression, and worse liver outcomes.
  • Clinicians underestimate its prevalence and do not consistently implement appropriate screening strategies. It leads to missing the diagnosis of the potentially progressive form of NAFLD in high-risk groups, such as those having obesity or type 2 diabetes.
  • The underdiagnosis is compounded by sparse referral to specialists. The inadequate prescription of medications with proven efficacy in NASH is detrimental.

What’s the Goal of screening for NAFLD?

  • It is to identify patients at risk for adverse health outcomes associated with NASH such as cirrhosis, HCC, and death from liver disease.
  • We must be aware that this risk is higher in people who have central obesity and cardiometabolic risk factors or insulin resistance, are >50 years of age, and/or have persistently elevated plasma aminotransferases (AST and/or ALT >30 units/L for >6 months).


  • There is consensus that the fibrosis-4 index (FIB-4) is the most cost-effective strategy for the initial screening of people with prediabetes and cardiometabolic risk factors or with type 2 diabetes in primary care and diabetes clinical settings.

How to calculate?

  • The FIB-4 estimates the risk of hepatic cirrhosis and is calculated from the computation of age, plasma aminotransferases (AST and ALT), and platelet count.
  • It is recommended by ADA to download it from here.
Universal FIB-4 Score Screening in Diabetes - What Physicians Must Know?

Interpretation of FIB-4

A value of <1.3 is considered low risk of having advanced fibrosis (F3–F4) and for developing adverse liver outcomes.
A value of >2.67 is considered as having a high probability of advanced fibrosis (F3–F4) and increased risk of adverse liver outcomes.
FIB-4 predicts changes over time in hepatic fibrosis and allows risk stratification of individuals in terms of future liver-related morbidity and mortality.
FIB-4 has reasonable specificity but low sensitivity, hence a negative result rules out fibrosis while a positive result requires confirmatory testing.
  • It has a reasonable specificity.
  • It has reasonable negative predictive value to rule out advanced fibrosis but lacks adequate sensitivity and positive predictive value to establish presence of advanced fibrosis in many cases as many people with diabetes often fall in the “indeterminate” (or intermediate) risk group for advanced fibrosis and adverse liver outcomes (when FIB-4 is between 1.3 and 2.67).
  • Its low cost, simplicity, and good specificity make it the initial test of choice.

What to do in Paediatric and people with age <35 and >65?

  • FIB-4 has not been well validated in Paediatric populations and does not perform as well in those aged <35 years.
  • In people with diabetes ≥65 years of age, higher cut-offs for FIB-4 have been recommended (1.9–2.0 rather than >1.3).
Universal FIB-4 Score Screening in Diabetes - What Physicians Must Know?

Does it impact the way you treat?

  • Yes.
  • The early diagnosis and treatment of NAFLD offers the best opportunity for cirrhosis prevention.
  • Pioglitazone and some glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to be effective to treat steatohepatitis. It may slow fibrosis progression and decrease cardiovascular disease.
  • Based on current evidence and consensus statements, a GLP-1 RA would be preferred in patients with obesity, since this drug class has shown efficacy in patients with NASH and also is approved for the treatment of type 2 diabetes, as well as they also have the potential to induce meaningful weight loss.
Universal FIB-4 Score Screening in Diabetes - What Physicians Must Know?

Dr. Sanjeev Thakur, DM Gastro, Patna comments (CME INDIA Discussion):

How to adjust FIB-4 for persons aged over >65?

  • Age is incorporated as it suggests the duration of risk factors/ disease. Age is negatively associated with ALT. Both these factors falsely increase the FIB4 value.
  • A cut off of 2.0 has been suggested which raises the specificity from 30 to 70%.

Why Platelet count is incorporated?

  • Platelet count is incorporated as its levels fall with increasing fibrosis especially Cirrhosis.

CME INDIA Learning Points

  • The American Diabetes Association (ADA) now advises universal screening of people with type 2 diabetes and prediabetes for fatty liver disease.
  • It provides new recommendations for management in those with the condition, or who are at risk for it.
  • Liver disease affects up to 70% of people with type 2 diabetes, and is common in people with prediabetes, and in those with type 1 diabetes who also have obesity.
  • Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease in people with diabetes. It can lead to cirrhosis and liver cancer and is associated with an increased risk for cardiovascular disease and death. The condition includes non-alcoholic steatohepatitis (NASH).
  • The new ADA guidance aligns with those of other professional societies, including the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Society, and the American Association of Clinical Endocrinology (AACE). RSSDI also recommends the same.
  • So, what’s message START USING FIB-4:
    • Easy Calculation.
    • The ADA now advises screening all adults with type 2 diabetes or prediabetes, particularly those with obesity or cardiometabolic risk factors or established cardiovascular disease — even those with normal liver enzyme levels.
    • People with type 1 diabetes who have obesity and/or cardiovascular risk factors are also to be screened for NAFLD.
    • You need 3 parameters the patient’s age, liver enzyme levels, and platelet counts.
    • A score of 1.3 or higher is considered high risk for clinically significant fibrosis, and above 2.6 is very high-risk.
    • The FIB-4 is a simple, great screening test because it is essentially free. But be cautioned that it has some limitations.
    • It is a good test for ruling out advanced liver disease but can have false positives and false negatives.
    • DO REMEMBER- The FIB-4 cut-offs need to be adjusted for persons over 65 years old and is not to be used for persons under 30 years old.

CME INDIA Tail-Piece

Universal FIB-4 Score Screening in Diabetes - What Physicians Must Know?

Courtesy: Cusi, S. Isaacs, D. Barb et al. Endocrine Practice 28 (2022) 528e562


  1. Comprehensive Medical Evaluation and Assessment of Comorbidities: Standards of Care in Diabetes—2023. Diabetes Care 2023;46(Suppl. 1):S49–S67
  2. Garvey WT, Mechanick JI, Brett EB, et al.; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016;22(Suppl. 3):1 –203
  3. Castera L, Cusi K. Diabetes and cirrhosis: current concepts on diagnosis and management. Hepatology 2023;77:2128 –2146
  4. Younossi, Zobair M., et al. “The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis.” Journal of hepatology 71.4 (2019): 793-801.
  5. Harrison, Stephen A., et al. “Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort.” Journal of hepatology 75.2 (2021): 284-291.
  6. Cotter, Thomas G., and Mary Rinella. “Nonalcoholic fatty liver disease 2020: the state of the disease.” Gastroenterology 158.7 (2020): 1851-1864.
  7. Kanwal, Fasiha, et al. “Preparing for the NASH epidemic: a call to action.” Metabolism 122 (2021): 154822.
  8. Cusi, Kenneth, et al. “American Association of Clinical Endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD).” Endocrine Practice 28.5 (2022): 528-562.
  9. Tracy Davyduke, Puneeta Tandon, Mustafa Al-Karaghouli, Juan G. Abraldes, Mang M. MaTracy Davyduke, Puneeta Tandon, Mustafa Al-Karaghouli, Juan G. Abraldes, Mang M. Ma.Impact of Implementing a “FIB-4 First” Strategy on a Pathway for Patients With NAFLD Referred From Primary Care.hepatology communications Volume3, Issue10October 2019.Pages 1322-1333.

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