• Credits

  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

• Q. Give a broad outline of the terms NAFLD, NAFL, NASH

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• Q. What is NAFLD?

  • (1) Evidence of hepatic steatosis (HS), either by imaging or histology
  • (2) lack of secondary causes of hepatic fat accumulation such as significant alcohol consumption, long-term use of a steatogenic medication, or monogenic hereditary disorders.
  • (3) no significant alcohol consumption (defined as ongoing or recent alcohol consumption of >21 drinks/week for men and >14 drinks/week for women)

• Q. What is NASH?

  • NAFLD is subdivided into the nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH).
  • NAFL, hepatic steatosis is present without evidence of significant inflammation
  • NASH, hepatic steatosis is associated with hepatic inflammation that may be histologically indistinguishable from alcoholic steatohepatitis

• Q. How do you differentiate NASH from NAFL?

  • Liver biopsy is the only method to differentiate NAFL from NASH #ClinicalPearl

• Q. What is MAFLD?

  • Metabolic dysfunction-associated fatty liver disease (MAFLD)
  • Recently, based on insights gained from the past two decades, an international panel of experts from 22 countries has taken the initiative to propose a new name and definition for NAFLD in adult individuals - that is, metabolic dysfunction-associated fatty liver disease .
  • Idea is to make it a diagnosis of inclusion rather than the diagnosis of exclusion

• Q. Give the direction in which the etiology for transplant is moving.

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• Applying Wilson and Junger criteria for nash/NAFLD screening

• Q. The condition sought should be an important health problem. Is NAFLD an important health problem?

  • Yes
  • NASH is 2nd most common etiology for Liver transplant and will be number one soon.
  • Risk of Liver cancer is increased 2 folds in patients with NAFLD

• Q. What is the prevalence of NAFLD in patients with type 2 diabetes?

  • Depending on the screening methodology used, as much as 65-70% of patients with Type 2 Diabetes have NAFLD

• Q. There should be an accepted treatment for patients with recognized diseases. Can we prevent the progression of Fibrosis in patients with NASH?

  • Yes
  • Drugs like Pioglitazone, Empagliflozin, and Liraglutide have been shown to prevent the progression of fibrosis in NASH
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  • Weight loss is an effective option for preventing progress in patients with NASH.

• Q. How do we screen for NAFLD/NASH?

  • 2/3rd of patients with NAFLD/NASH have normal liver enzymes
    • Typically ALT >AST
    • Newer Cut-offs are 30 in males and 19 in females
  • USG shows increased echogenicity
  • A meta-analysis found that the sensitivity and specificity for ultrasound were 85 and 94 percent, respectively, when using liver biopsy as the gold standard
  • The fatty liver index (FLI), is an algorithm based on waist circumference, body mass index (BMI), triglyceride, and gamma-glutamyl-transferase (GGT) used for recognizing fatty liver
    • Cutoff of 30 has a sensitivity of 87%
    • Cutoff of 60 has a specificity of 86%
  • Other tests like Transient elastography, MR spectroscopy, MR elastography, and liver biopsy are more useful for the assessment of fibrosis rather than mere screening

• Q. Does the AST/ALT (SGOT/SGPT) ratio help in the diagnosis of NASH?

  • AST/ALT ratio in NASH/NAFLD is <1 (SGOT/SGPT) while in Alcoholic liver disease, it is more than 2

• Q. Does the degree of ALT elevation correlate with the severity of the disease?

  • the degree of AST/ALT elevation does not correlate with the severity of the disease

• Q What happens to the ALP levels?

  • ALP may be elevated 2-3 times the ULN

• Q. What is the importance of serum ferritin levels in this disease?

  • Serum ferritin has an important role in NASH/NAFLD #ClinicalPearl
    • Value >1.5 times the ULN is likely to be associated with greater progression of the liver disease

• Q. What are the diagnostic criteria for MAFLD ?

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• Q. Do we have an early stage here?

  • Yes. NASH is an early precursor of Cirrhosis or End stage liver disease which is what we are trying to prevent.
  • There should be a suitable test or examination and the test should be acceptable to the population
  • Liver enzymes and ultrasound are acceptable tests for the population

• Q. Upto what stage can the disease be reversed?

  • Upto the Fibrosis stage

• Q. The natural history of the condition, including development from latent to declared disease, should be adequately understood. Do we understand the natural history of NAFLD/NASH?

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• Q. There should be an agreed policy on whom to treat as patients. What to do once NAFLD is recognized?

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• FIBROSIS BIOMARKERS AND SCORES

• Q. Is screening for NAFLD cost-effective?

  • NAFLD is a reversible condition, particularly in the early stages.
  • Failing to detect the disease at an early stage can have detrimental clinical effects for some high-risk patients who are in danger of developing liver cirrhosis and related complications such as jaundice, ascites, variceal bleeding, hepatic encephalopathy, and hepatocellular carcinoma.
  • NAFLD was considered cost-effective at a cost-effectiveness threshold of £20,000 per QALY gained.
  • Fatty liver index is the most cost-effective screening test

• Q. Give a broad outline of the treatment of NASH/NAFLD.

  • Vaccination
    • Hepatitis A
    • Hepatitis B
    • Pneumococcal vaccine
  • Weight loss - 0.5-1 kg/week
  • Biopsy proven NASH and fibrosis with stage ≥2 and not having diabetes - Vitamin E - 800 IU/day (C. EVION- 400 IU - twice a day)
  • Diabetes patients
    • Metformin
    • Pioglitazone
    • Liraglutide
  • If after weight loss - repeat ALT/AST after 3 months
    • if it has not come to normal - look for other causes

• Q. Give some important notes on weight loss and NASH/NAFLD.

  • Weight loss to be done to the tune of 0.5- 1 kg/week
  • weight loss can reverse all stages except cirrhosis
  • Liver function test can be normal in 30% of patients with NASH/NAFLD #ClinicalPearl
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• Q. In which cases is Pharmacotherapy used?

  • Early ­stage NASH at high risk for disease progression (age > 50 years, metabolic syndrome, diabetes mellitus, or increased ALT)
  • Active NASH with high necroinflammatory activities
  • Progressive NASH (brid­ging fibrosis and cirrhosis)

• Q. What is the main purpose of any medication used?

  • It should be able to prevent the fibrosis stage
  • This can be gauged by a reduction of the NAS score (NAFLD Activity score)

• Q. Give an outline of various legacy drugs and their use in NASH/NAFLD.

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• Q. Is Saroglitazar approved in India for use in NASH/NAFLD?

  • Yes

• Q. What is the mechanism of action of Saroglitazar?

  • Saroglitazar is a dual PPAR α and γ agonist and through activation of these transcriptional factors PPAR α & γ :
    • Reduces TG (predominantly through PPAR α agonism)
    • Reduces Insulin resistance and controls blood sugar level (predominantly through PPAR γ agonism)

• Q. How does Saroglitazar compare with other drugs like OCA and UDCA?

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• Q. Does Saroglitazar reduce (NAFLD Activity score)?

  • Yes

• Q. What is the role of Semaglutide in NASH/NAFLD?

  • This is from a trial published in the NEJM
    • Nonalcoholic steatohepatitis (NASH) is a common disease that is associated with increased morbidity and mortality, but treatment options are limited. The efficacy and safety of the glucagon-like peptide-1 receptor agonist semaglutide in patients with NASH are not known
    • This phase 2 trial involving patients with NASH showed that treatment with semaglutide resulted in a significantly higher percentage of patients with NASH resolution than placebo.
    • However, the trial did not show a significant between-group difference in the percentage of patients with an improvement in fibrosis stage

• Q. What is the most common cause of death in patients with NASH/NAFLD?

  • The most common cause of death in patients with NASH/NAFLD is heart disease - need to screen and monitor for the same

• Q. What is MAFLD?

  • Metabolic dysfunction-associated fatty liver disease (MAFLD)
  • "Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease in many parts of the world, causing considerable liver-related (steatohepatitis, cirrhosis, liver failure, and hepatocellular carcinoma) and extra-hepatic morbidity and mortality (mainly cardiovascular disease, chronic kidney disease or certain types of extra-hepatic cancers).
  • Recently, based on insights gained from the past two decades, an international panel of experts from 22 countries has taken the initiative to propose a new name and definition for NAFLD in adult individuals - that is, metabolic dysfunction-associated fatty liver disease .
  • This proposed change in nomenclature is not simply a semantic revision, but may facilitate improved diagnosis of this common liver disease for health promotion, case identification, patient awareness, ongoing clinical trials, and health services delivery"
  • Until now the exclusion of other chronic liver diseases, including “excess” alcohol intake, was necessary for the diagnosis of MAFLD.
  • As the pathogenic process leading to MAFLD is now better understood and is seen to originate from an underlying state of systemic metabolic dysfunction, MAFLD is perceived as a standalone disease that warrants a positive diagnosis, rather than a “none”-disease rubric.
  • Moreover, the rising prevalence of MAFLD makes its coexistence with other chronic liver diseases quite possible, further negating a diagnosis based on the exclusion of concomitant diseases.
  • It is therefore our belief that this disease needs to be defined by its own set of positive criteria, rather than by exclusion criteria.

  • Idea is to make it a diagnosis of inclusion rather than the diagnosis of exclusion

• Q. What are the diagnostic criteria for MAFLD ?

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• Q. What is Hepatic hypothyroidism?

  • Effects of Resmetirom on Noninvasive Endpoints in a 36‐Week Phase 2 Active Treatment Extension Study in Patients With NASH - PMC
    • Evidence suggests that NASH may be, in part, a condition of diminished liver thyroid hormone levels or hepatic hypothyroidism and that the incidence of clinical and subclinical hypothyroidism is higher in patients with NAFLD/NASH relative to age‐matched controls. Tag: NASH/NAFLD; NASH
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• December 14th, 2022 - Updates from ADA 2023 Guidelines

• Q. What is the grading for hepatic fibrosis?

  • 1. F0- No fibrosis
  • 2. F1- Mild
  • 3. F2- Moderate
  • 4. F3- Severe
  • 5. F4- Cirrhosis

• Q. Patients with type 2 diabetes generally have what level of fibrosis?

  • 20% of patients with type 2 diabetes have ≥F2 level of fibrosis

• Q. What is the link between NAFLD and CKD?

  • Patients with NAFLD have an increased risk of developing CKD

• Q. Should Type 1 diabetes patients be screened for NAFLD?

  • The prevalence of NAFLD/NASH is lower in type 1 diabetes
  • Hence routine screening for type 1 diabetes is not recommended

• Q. Which is the most effective screening tool for screening for NASH/NAFLD in patients with type 2 diabetes and prediabetes?

  • FIB-4 score is the most effective screening tool for screening for patients

• Q. Is it okay to screen patients having ALT >40?

  • No
  • Significant patients have ≥F2 by the time they have ALT >40

• Q. What are the ALT cut-off's given by the American college of Gastroenterology?

  • More than 29-33 male
  • More than 19-25 female

• Q. What FIB-4 score is suggestive of high risk?

  • <1.3- lower risk
  • 1.3-2.67- moderate risk
  • More than 2.67- high risk of fibrosis
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• Q. What is the problem with FIB-4 score?

  • 1. It has good specificity but low sensitivity
    • A lot of type 2 diabetes fall in intermediate-risk and hence may be missed out
    • hence a confirmation test is often required
  • 2. It is not recommended for pediatric patients
  • 3. It is less reliable for ages <35 years
  • 4. For ages > 65 years- a higher cutoff of 1.9-2.0 is suggested in place of 1.3

• Q. Which is a good confirmatory test?

  • Transient elastography

• Q. What are the cut-off used in transient elastography?

  • <8.0 kPA- has good negative predictive value to rule out advanced fibrosis- ≥ F3/F4 levels
  • More than 12 KPA - must be referred to a hepatologist

• Q. Which test has good use in early fibrosis?

  • MR elastography

• Q. Give the clinical care pathway for NASH/NAFLD as suggested by several guidelines.

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• Q. What type of diet has the best evidence for improving outcomes in NASH?

  • Mediterranean diet

• Q. Is obesity surgery helpful?

  • Yes
  • It is known to reduce all parameters in NASH including fibrosis

• Q. Can obesity surgery lead to decompensation in patients with compensated cirrhosis?

  • The risk is no greater compared to other surgeries
  • However in patients already having decompensated cirrhosis, it is not recommended

• Q. Can Pioglitazone reduce fibrosis in NASH?

  • Yes

• Q. Does GLP-1 receptor agonist reduce fibrosis ?

  • It delays fibrosis as observed in two trials involving liver biopsies
  • The evidence is for liraglutide and semaglutide

• Q. What about SGLT2i?

  • It is known to reduce steatosis
  • But the impact on steatohepatitis and fibrosis is unknown

• Q. Is currently any drug FDA-approved for NASH?

  • No

• Q. What about Vitamin E?

  • Vitamin E is useful in non-diabetic patients with NASH
  • No clear evidence of benefit in patients with diabetes

• Q. Summarize the treatment option for NASH based on the new guidelines.

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Some notes from UptoDate
- Most cases are diagnosed in the 40-the 50s
- Some reports suggest that NASH/NAFLD may be more common after cholecystectomy (but not in patients having gallstones) #ClinicalPearl
- AST/ALT ratio in NASH/NAFLD is <1 (SGOT/SGPT) while in Alcoholic liver disease it is more than 2 #ClinicalPearl
- the degree of AST/ALT elevation does not correlate with the severity of the disease #ClinicalPearl
- ALP may be elevated 2-3 times the ULN
- Serum ferritin has important role in NASH/NAFLD #ClinicalPearl
- Value >1.5 times the ULN is likely to be associated with greater progression of the liver disease
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- Treatment of NASH/NAFLD
- Vaccination
- Hepatitis A
- Hepatitis B
- Pneumococcal vaccine
- Weight loss - 0.5-1 kg/week
- Biopsy proven NASH and fibrosis with stage ≥2 and not having diabetes - Vitamin E - 800 IU/day (C. EVION- 400 IU - twice a day)
- Diabetes patients
- Metformin
- Pioglitazone
- Liraglutide
- If after weight loss - repeat ALT/AST after 3 months
- if it has not come to normal - look for other causes
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