NON-ALCOHOLIC FATTY
LIVER DISEASE
Dr. Anuj Satarkar
JR-1
MD Pharmacology

INTRODUCTION
• Global Obesity Pandemic: Increased prevalence of NAFLD
• Most common cause of CLD in western
• Associated with :
• CVD
• Type 2 DM
• Manifestations of Metabolic Syndrome.
• Obstructive Sleep Apnoea
• Vitamin D Deficiency
• NAFLD/NASH: Hepatic manifestation of Metabolic Syndrome
• Clinically relevant subset in terms of liver-specific outcome: NASH

CONTD…
• Ludwig and his colleagues coined the term NAFLD: 1980
• Cohort of middle aged patients: raised level of serum enzymes; evidence of alcoholic
hepatitis on liver biopsy without alcohol consumption.
• Subsequent studies: “Two-hit hypothesis”
• 1st hit: Sequential progression of Isolated fatty liver to NASH: Initial lesion of hepatic
steatosis.
• 2nd hit: Oxidative stress leading to liver injury.

SPECTRUM OF NAFLD
Steatosis NASH Cirrhosis HCC
14 years 7 years

DEFINITIONS
• Nonalcoholic fatty liver is defined as the presence of hepatic steatosis without evidence of
hepatocellular injury in absence of secondary causes of steatosis.
• Macrovesicular fat accumulation in more than 5% hepatocytes.
• Requires biopsy: invasive procedure.
• Alternatively, presence of hepatic steatosis, determined by imaging in the absence of secondary
causes of hepatic fat accumulation
• USG
• MRI
• TE
• NASH is defined as the presence of hepatic steatosis and inflammation with evidence of
hepatocyte injury (ballooning) with or without fibrosis.
• Biopsy in mandatory for defining NASH.

EPIDEMIOLOGY
• Estimated prevalence worldwide: 2.8 to 46%.
• Prevalence is increasing with increased rates of Obesity and type II DM.
• 33.8 % population worldwide is obese; (75 % have NAFLD)
• 10.6 % have type II DM (30-60 % have NAFLD)
• The community prevalence of NAFLD in India varies from 5% to 28%.
• The first population-based study from India showed overall prevalence of NAFLD as
9% and around 19% in adult population*.
• NAFLD is more common in men.
* Amarapurkar D, et. al. Prevalence of non-alcoholic fatty liver disease: population-based study. Annals of
hepatology. 2007 Jul 1;6(3):161-3

ETIOLOGY
• Acquired Metabolic Disorders
• Obesity
• Diabetes
• Dyslipidemia
• Kwashiorkor
• Drugs
• Amiodarone
• Tetracyclines
• Methotrexate
• Long term use of Steroids
• Tamoxifen

• Metals
• Antimony
• Mercury
• Phosphorous
• Uranium compounds
• Thallium Compounds
• Inborn errors of metabolism
• Familial Hepatosteatosis
• Galactosemia
• Glycogen Storage Disease
• Wilson’s Disease
• Surgical Procedures:
• Biliopancreatic diversion
• Extensive Small Bowel Bypass
• Misc. Conditions
• IBD, Industrial Exposure to Petrochemicals.

RISK FACTORS
• Obesity, Dyslipidemia, Type 2 Diabetes and Metabolic Syndrome are established
risk factors
• Hypothyroidism
• Polycystic ovary syndrome
• Obstructive sleep apnoea
• Hypopituitarism
• Hypogonadism
Have been described in western
countries; yet to be studied in
Asia-Pacific region

PATHOGENESIS
STAGES OF LIVER DAMAGE

DIAGNOSIS
• Most patients are asymptomatic.
• Some: RUQ pain, fatigue and malaise
• Hepatomegaly commonly seen; physical estimation is difficult due to obesity.
• Usually discovered incidentally:
• Hepatic steatosis on imaging.
• Elevated liver biochemical test levels
• Rule out significant alcohol consumption.

SIGNIFICANT ALCOHOL CONSUMPTION
• More than 210 gm alcohol per week for men = 30 gm / day
• More than 140 gm alcohol per week for women = 20 gm / day

LFT
• Normal or mildly elevated Aspartate aminotransferase(AST) and Alanine Transaminase(ALT);
with ALT more than AST.
• Normal AST: 8-33 U/L
• Normal ALT: 7-56 U/L
• AST/ALT Ratio:
• Normal- <1
• NAFLD- <1 (0.8); if >0.8, indicates severe disease
• Alcoholic disease > 1.5
• ALP(Alkaline Phosphatase)
• Normal: 44-147 IU/L
• In NAFLD, Isolated rise in ALP may be seen.

CONTD…
FIB-4 SCORE:
• Takes into consideration
• Age
• Platelet count
• AST
• ALT
• Calculation requires Fib-4 calculator.
• Provides immediate results.
• Rules out advanced fibrosis.
• < 1.30 = F0 – F1
• > 2.67 = F3 – F4

CONTD…
LIPID PROFILE
• Total cholesterol
• Normal: <200 mg/dL; 200-239 mg/dL: borderline high; 240 or more: High
• Low-density lipoprotein (LDL) Cholesterol: Normal: <110 mg/dL
• High-density lipoprotein (HDL) Cholesterol: Normal >60 mg/dL
• Triglycerides
• Normal: <150 mg/dL
• NAFLD: Raised

OTHER
INVESTIGATIONS
• Fasting Plasma Glucose
• Post Prandial Glucose
• HbA1c
• HBsAg
• HCV Ab
• TSH

IMAGING
USG
• Can detect fatty liver only if the liver fat is >12%.
• Useful only for advanced fatty liver;
• Sensitivity: 84.8%; Specificity: 93.6% for detecting ≥20–30% steatosis.
• Easily available.
• Inexpensive without any radiation risk.

USG GRADING OF FATTY LIVER

FIBROSCAN
• Novel, non-invasive technique to assess hepatic fibrosis and steatosis.
• Vibration-controlled transient elastography.
• Works by measuring shear wave velocity; delivered using a handheld probe (M or
XL), in the intercostal space over the right lobe of liver.
• Returning shear wave velocities are used to generate the liver stiffness
measurement (LSM): Higher the velocity, higher is the stiffness.

CONTD…
• Controlled attenuation parameter (CAP): detects amount of fat
• Many patients: with fatty liver on conventional imaging; significant fibrosis on
Fibroscan
• Limitations
• Difficult in patients with morbid obesity and patients with ascites.
• Cannot detect necroinflammation.

MRI-PROTON DENSITY FAT FRACTION
• Measures fat content
• Compares proton signals arising out of fat, relative to those arising out of water.
• Noninvasive standard of care for quantification of liver fat.
• MRI-PDFF declines over time;
• co-relates with reduction in liver fat content.
• Surrogate marker for improvement in necroinflammation.
• Advantage:
• Sensitivity is higher
• Can assess complete liver.
• Disadvantage:
• Not patient friendly
• Costly

LIVER BIOPSY
• Current gold standard method used in diagnosis and prognosis.
• Expensive and invasive procedure.
• High sampling error.
• Risk of complications:
• Pain
• Bleeding
• Death (very rare)

TREATMENT
• Lifestyle modification and weight reduction in obese subjects: cornerstone of therapy
• Improve liver histology, transaminitis and quality of life.
• As little as 5% weight loss may result in regression of fibrosis.
• Weight loss goals: Rarely achieved by lifestyle modifications alone.
• Lifestyle changes alone are insufficient to stop disease progression

CONTD…
• Pharmacological treatment of NAFLD remains elusive.
• In last 12 years, after vitamin E and pioglitazone, seven other drugs have shown
promise as a drug treatment for NASH in phase 2 – 3 trials:
• Obeticholic acid
• Cenicriviroc
• Lanifibranor
• Resmetirom
• Liraglutide
• Saroglitazar
• Latest being semaglutide
• However, till now, none of these drugs have received FDA approval.

PPAR
• Peroxisome Proliferator-Activated Receptors
• A group of nuclear receptor proteins that function as transcription factors regulating the
expression of genes.
• Essential roles in the regulation of cellular differentiation, development,
and metabolism (carbohydrate, lipid, protein)
• Regulates many functions that are disturbed in NAFLD, including glucose and lipid metabolism,
as well as inflammation.
• Represent relevant clinical targets for NAFLD

• Three types of PPARs have been identified: alpha, gamma, and delta (beta)
• α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
• β/δ (beta/delta) - expressed in many tissues, especially in brain, adipose tissue, and skin
• γ (gamma) - although transcribed by the same gene, this PPAR, by way of alternative splicing, is
expressed in three forms:
• γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
• γ2 - expressed mainly in adipose tissue; it is 30 amino acids longer than γ1
• γ3 - expressed in macrophages, large intestine, white adipose tissue

SAROGLITAZAR
• Given approval for treatment of NASH by the Drug Controller General of India
(DCGI) in March 2020.
• A novel dual peroxisome proliferator-activated receptors (PPAR) alfa/gamma agonist
• Used for diabetic dyslipidaemia; targets some pathogenic mechanisms of NASH.
• PPAR alfa agonism: lipid accumulation
• PPAR gamma agonism: hepatic inflammation
• Dose: 4 mg/day

MECHANISM OF ACTION

ADVERSE EFFECTS OF SAROGLITAZAR
• Gastritis (stomach inflammation)
• Nausea.
• Vomiting.
• Asthenia (weakness)
• Flatulence
• Dyspepsia
• Bloating
• Chest discomfort.
• Dizziness.
• Pyrexia

PIOGLITAZONE
• PPAR Gamma Agonist
• Decreases Insulin resistance and hepatic steatosis up-regulation of Adiponectin.
• Recommended in treatment of both diabetic and non-diabetics with biopsy-proven
NASH.
• Dose: 30 mg
• Adverse effects:
• Increase in body weight
• Osteoporosis
• Association with bladder cancer has been suggested.

LANIFIBRANOR
• a pan-PPAR (peroxisome proliferator–activated receptor) agonist that modulates key
metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.
• MoA: anti-fibrotic, anti-inflammatory as well as beneficial metabolic changes in the body
by activating each of the three PPAR isoforms, known as PPARα, PPARδ and PPARɣ.
• Still under investigation in phase 2-3 clinical trial

VITAMIN E
• A key fat-soluble antioxidant
• Has the most evidence for its ability to provide a therapeutic benefit.
• Efficacy of Vitamin E. in NAFLD is unclear.
• Has the ability to reduce the oxidative stress
• Retards the pathogenesis of NASH
• Therefore provide a therapeutic benefit
• Dose: 800 IU/day

CONTD…
• Antioxidant Effect of Vitamin E
• Oxidative stress is created when the production of reactive oxygen species (ROS)
overwhelms antioxidative pathways.
• Vitamin E is one of the most powerful chain-breaking antioxidants in the human body.
• alpha-tocopherol form is the most prevalent and active in tissue and human plasma.
• Anti-Inflammatory and Anti-Apoptotic Properties of Vitamin E
• Vitamin E supplementation: Increased adiponectin mRNA and protein levels.
• Adiponectin: Important molecule;works by suppressing hepatic fatty acid synthesis and
reducing inflammation in patients with NASH.
• Vitamin E is also a powerful player in cell death and apoptosis pathways

ADVERSE EFFECTS OF VIT. E
• Cardiovascular risk in Diabetic patients.
• Modest increase in prostrate cancer rates

OBETICHOLIC ACID
• Semi-synthetic bile acid analogue.
• Chemical structure 6α-ethyl-chenodeoxycholic acid.
• MoA: Highly potent FXR agonist.
• FXR receptors are expressed in Liver and Intestines.
• Selectively binds and activates the FXRs of the enterocytes and the hepatocytes, thereby reducing
the risk to liver and bile ducts due to toxic levels of bile acids.
• Uses:
• Primary Biliary Cholangitis
• NASH
• Portal Hypertension
• Bile acid diarrhoea

CENICRIVIROC
• Experimental drug candidate for the treatment of HIV infection and in combination
with Tropifexor for non-alcoholic steatohepatitis.
• CCR-2 and CCR-5: Chemokine Receptor 2 and Chemokine Receptor 5.
• Expressed on various cell populations including macrophages, dendritic cells and memory T cells
in the immune system
• MoA: Cenicriviroc is an inhibitor of CCR2 and CCR5 receptors, allowing it to function as
an entry inhibitor which prevents the virus from entering into a human cell. Inhibition of CCR2
may have an anti-inflammatory effect.

THANK YOU!