Non-alcoholic fatty liver disease (NAFLD) is characterized by fat accumulation in the liver in the absence of excessive alcohol use. It ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD affects 25% of Americans and its prevalence is increasing worldwide. Risk factors include obesity, diabetes, and metabolic syndrome. Diagnosis involves blood tests and imaging, while biopsy is needed to diagnose NASH. Treatment focuses on lifestyle changes like weight loss and exercise. Medications being investigated include antioxidants, diabetes medications, cytoprotective agents, and lipid lowering drugs, but more research is still needed to determine the optimal pharmacotherapy.

1. NON ALCOHOLIC
FATTY LIVER DISEASE
DR. HARITHA
M.D. GENERAL MEDICINE

2. Introduction
• NAFLD is macrovesicular fat
accumulation in >5 percent of
hepatocytes encompassing a spectrum
of hepatic changes from steatosis alone
to NASH to cirrhosis to primary liver
cancer in the absence of hazardous
levels of alcohol consumption or any
other secondary cause.

3. INCIDENCE
AND
PREVALENCE
NAFLD is most common cause of Chronic Liver Disease in most
parts of the world. Fatty liver is present in 25% of American
population, 25% of individuals with NAFLD have NASH and 25%
nash progress to advanced fibrosis or cirrhosis.
In India 5 to 28% of the adult population have NAFLD.
Since gold standard for diagnosis of NASH is liver
biopsy prevalece of NASH is underestimated
Nafld was initially thought to be more common among men.
woman had a late peak of the disease suggesting a role of sex
hormones and menopause in NAFLD

4. Nafld is considered to
be the
hepatic manifestation
of metabolic syndrome
consisting of 3 or more
of the following
Hypertension
High fasting plasma
glucose levels
Hypertriglyceridemia Abdominal obesity
Decreased levels of
HDL

5. Spectrum of NAFLD

6. Risk factors and
associations
• Well known associations:
• Obesity
• DM
• Hypertension
• Cardiovascular disease
Other associations
• Chronic fatigue
• Mood alterations
• OSA
• Thyroid dysfunction
• Chronic pain syndrome

7. genetics
PNPLA GENE MBOAT7 TM6SF2

8. ADIPONECTIN

9. Progression
of NAFLD

10. Clinical features
• 48 to 100 percent of people are asymptomtic
• Uncommonly: vague right upper quadrant
pain Fatigue and malaise
• Signs:
common is hepatomegaly
Rarely: splenomegaly, ascitis, spider telengectasias,
palmar erythema

11. DIAGNOSIS
LABORATORY Increase in serum ALT levels(1.5 to 4 times) and AST
levels but ALT>AST.
Serum alkaline phosphatase and GGTP levels may be
elevated.
Bilirubin, albumin and PT are typically normal.
ANA is positive in low titers(1:320).
Serum ferritin levels are increased in 50 percent of
patients with NAFLD.
Clinical and lab findings do not correlate with the
severity of NAFLD, including cirrhosis which can be
seen in near normal aminotransferase levels.

12. Imaging studies
• Hepatic ultrasound: bright liver
of high echogenicity consistent
with hepatic steatosis.
• In abdominal CT a fatty liver is
lower in density than spleen
• In MRI fat appears bright on T1
weighted images
• US and CT have sensitivity
rates 100% and 93 % for
detecting hepatic fat
involving greater than 33% of
the liver
• NO IMAGING MODALITIES CAN
DISTINGUISH SIMPLE STEATOSIS
FROM NASH OR PREDICT ITS
SEVERITY.

13. ROLE OF LIVER
BIOPSY
• A LIVER BIOPSY IS REQUIRED TO MAKE THE
DIANOSIS OF NASH
• It is not widely done as it is invasive and causes
hemorrhage or rarely even death when
undergoing the biopsy.
• Ideal way: select patients who are high risk with
advanced imaging techniques and then perform
a liver biopsy.

15. Treatment of NAFLD
The optimal therapy for NAFLD has not been established
A 2-point improvement in the NAS, with 1 of the points coming from a reduction in hepatocyte ballooning
degeneration, may indicate a successful intervention
Improvement in fibrosis (which is not part of the NAS) is also desirable, although it is difficult to conduct
trials of adequate length to allow improvement in fibrosis.
Standard treatment of NAFLD has consisted of weight loss, removal of potentially offending drugs and
toxins, and control of associated metabolic disorders, including diabetes mellitus and hyperlipidemia

16. Lifestyle
modifications
◦ Lifestyle modification is often divided into
calorie reduction with a goal of weight loss,
macronutrient modification, and physical
activity, including aerobic and resistance
activity.
◦ Preliminary evidence has suggested that low-
carbohydrate, calorie-restricted approaches
improve insulin sensitivity and decrease
hepatic TG content more than high-
carbohydrate caloric restriction, despite
comparable weight .

17. A reduction in the intake of high-fructose corn syrup and an increase
in the intake of omega-3 fatty acids and caffeinated coffee are
adjuvants to a multidisciplinary approach that includes caloric
reduction and increased physical activity.
AASLD and ACG recommend weight loss of at least 3% to 5%, either
with a hypocaloric diet or in conjunction with increased physical
activity, and note that weight loss of up to 10% may be required to
improve hepatic necroinflammation in patients with NAFLD
Moderate calorie restriction; aim to reduce daily calories by 500-750
kcal and achieve weight loss of 7%-10%
Moderate exercise 4-5 times weekly for 30-45 minutes each
time.Resistance training 3 times weekly; total exercise time ≈ 45
minutes

18. PHARMACOTHERAPY
1.Weight loss
medications
2.Antioxidants
3.Diabetes
medications
4.Cytoprotective
Agents
5.Lipid lowering
agents
6.Other therapies

19. Weight loss medications
◦ Limited study is available for weight loss and the most studied agent is ORLISTAT.
◦ It is a reversible inhibitor of pancreatic and gastric lipase, leading to intestinal fat maldigestion
causing modest weight loss.
◦ Casse reports showing cholelithiasis,cholestasis and hepatocyte injury has limited the use of this
drug, so FDA issued a post markting warning for this drug.
◦ Newer agents are going to come to market such as LORCASERIN.

20. Antioxidants
Medications that reduce the generation of reactive oxygen species in the liver and reduce oxidative stress are
another potential avenue for therapy.
The most studied antioxidants are vitamin E, vitamin C, and betaine.
Vitamin E, an inexpensive yet potent antioxidant, has been examined as an agent for the treatment of
NAFLD with varying results. In all studies, vitamin E was well tolerated, and most studies showed modest
improvements in serum aminotransferase levels and the US appearance of the liver, but infrequently histologic
findings.
Although a pilot trial showed a benefit to vitamin E and C together for hepatic fibrosis, a larger randomized
controlled trial did not show improvement in hepatic fibrosis despite significant improvement in steatosis,
inflammation, and ballooning degeneration.

21. The tri-society practice guidelines recommend vitamin E 800 IU/day as a first-line
therapy in nondiabetic adults with biopsy-proved NASH but caution against use of
vitamin E in diabetic patients or patients with NAFLD without a liver biopsy.
Betaine, a metabolite of choline that raises S-adenosyl methionine levels and decreases
cellular oxidative damage, has shown promise in mouse models. A pilot study showed
only improvement in mouse models.
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22. Diabetes mediations
◦ The association between
hyperinsulinemic insulin resistance and
NAFLD provides a logical target for
treatment. Metformin,
thiazolidinediones (TZDs), and incretin
mimetics are all diabetes medications
that have been investigated in the
treatment of NASH
◦ METFORMIN
◦ The use of metformin has showed
benefits in mice not in humans. It's use
is not recommended in NAFLD

23. ◦ TZDs are potent PPAR-γ agonists.
◦ PPAR-γ is a nuclear receptor that is expressed in adipose tissue, muscle, and
liver. In adipocytes, PPAR-γ promotes cell differentiation and decreases
lipolysis and FFA release. TZDs improve insulin resistance by increasing
glucose disposal in muscle and decreasing hepatic glucose output
◦ Rosiglitazone and pioglitazone are TZDs with low rates of hepatotoxicity. It is
associated with improvement in insulin resistance, normalization of liver
biochemical test levels, and histologic improvement in most patients.
◦ Continued treatment appears to be necessary, because subsequent
studies demonstrated recurrence of NASH off therapy.
◦ Long-term therapy with either agent is problematic because of an associated
average weight gain of 3 to 4 kg. Rosiglitazone has been linked to increased
rates of myocardial infarction. METAPLASIA is a known complication.
◦ The tri-society guidelines agree that pioglitazone can be used to treat biopsy-
proved NASH but emphasize that the long-term safety and efficacy have not
been established in this population

24. Exenatide and liraglutide are glucagon-like protein-1
receptor agonists that improve insulin sensitivity and
serum glucose levels and promote modest weight loss.
Incretins mimetics

25. Cytoprotective agents
Cytoprotective agents are thought to prevent apoptosis and
down-regulate the inflammatory cascade.
Ursodeoxycholic acid (UDCA) is a cytoprotective agent that
has been investigated with mixed results
• The largest placebo-controlled trial demonstrated equal improvement in
patients receiving UDCA and placebo
• The tri-society practice guidelines do not recommend routine use of UDCA

26. Pentoxifylline (PTX) is another cytoprotective agent studied in NASH that has been
shown to inhibit proinflammatory cytokines, including TNF-α, leading to reduced
production of reactive oxygen species
It is said to improve NASH and fibrosis. A 1.6-point improvement in the NAS is seen.

27. Lipid lowering agents
The most commonly prescribed agents for hyperlipidemia are statins
(HMG CoA reductase)
Pilot studies and large trials have both shown benefit
For now, statins can be recommended to treat concomitant
hyperlipidemia in patients with NASH, but further study is needed before
statins can be recommended as primary therapy for NASH

30. THANK YOU
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