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FATTY LIVER (3) Darien Liew Daojuin


NON ALCOHOLIC FATTY LIVER DISEASE 16 May 2017
OVERVIEW
NAFLD represents a spectrum of disorders that have in common the
presence of hepatic steatosis (fatty liver) in individuals who do not
consume alcohol or do so in very small quantities (less than 20 g of
ethanol/week).

The term nonalcoholic steatohepatitis (or its common acronym NASH)


is often used to denote overt clinical features of liver injury, such as
elevated serum transaminases, but the designation NAFLD is
preferred, with steatohepatitis reserved for histologic features of
hepatocyte injury already described in the section on alcoholic liver
disease. The histologic hallmarks of NAFLD are most consistently
associated with the metabolic syndrome.
OVERVIEW
NAFLD contributes to the progression of other liver diseases such as
HCV and HBV infection. Increasingly, NAFLD is found to increase the
risk for hepatocellular carcinoma, although, unlike in chronic viral
hepatitis and alcoholic liver disease, it may often do so in the absence
of significant scarring.

Currently available data suggests a two hit model for NAFLD.


Insulin resistance gives rise to hepatic steatosis.
Hepatocellular oxidative injury resulting in liver cell necrosis and the
inflammatory reactions to it.
PATHOGENESIS (1)
INITIATING EVENTS

The initiating events in NAFLD are based on the development of


obesity and insulin resistance, leading to increased hepatic free fatty
acid flux.
This imbalance between the rate of import/synthesis and the rate of
export/catabolism of fatty acids in the liver leads to the development
of steatosis. This may be an adaptive response through which
hepatocytes store potentially toxic lipids as relatively inert
triglyceride.
PATHOGENESIS (2)
METABOLIC SYNDROME

In patients with
metabolic syndrome, the
presence of type 2
diabetes and obesity is
the best predictor of
severe fibrosis and
disease progression.
PATHOGENESIS (3)
INSULIN RESISTANCE
Insulin resistance results in the accumulation of triglycerides in hepatocytes
by at least three mechanisms:
Impaired oxidation of fatty acids
Increased synthesis and uptake of fatty acids
Decreased hepatic secretion of very-low-density lipoprotein cholesterol

The end result of insulin resistance is steatosis, which can then progress to
steatohepatitis.

In individuals with established insulin resistance and metabolic syndrome,


the visceral adipose tissue not only increases, but also becomes
dysfunctional, with reduced production of the lipid hormone, adiponectin,
and increased production of inflammatory cytokines such as TNF- and
IL-6.
PATHOGENESIS (4)
OXIDATIVE STRESS

Fat-laden hepatocytes are highly sensitive to lipid peroxidation


products generated by oxidative stress, which can damage
mitochondrial and plasma membranes, causing apoptosis.
Either as a consequence of oxidative stress or through release from
visceral adipose tissue, levels of TNF, IL-6, and of the MCP-1
chemokine increase, contributing to liver damage and inflammation.
Important roles are emerging for adiponectin and leptin in regulating
these processes as well.
PATHOGENESIS (5)
CELLULAR DAMAGE

Two hit model for NAFLD: Cellular damages:


oxidative stress due to free
Insulin resistance gives rise radicals produced during
to hepatic steatosis. fatty acid oxidation
Hepatocellular oxidative direct lipotoxicity
injury resulting in liver cell gut-derived endotoxin
necrosis and the cytokine release (TNF- etc.)
inflammatory reactions to it. endoplasmic reticulum stress.

Cellular damage triggers a mixture of immune-mediated


hepatocellular injury and cell death, which leads to stellate cell
activation and hepatic fibrosis
PATHOGENESIS OVERVIEW
NAFLD AND ALD
NASH almost completely overlaps in its histologic features with alcoholic
hepatitis.
In NASH, compared with alcoholic hepatitis, mononuclear cells may be
more prominent than neutrophis and Mallory-Denk bodies are often less
prominent.
Steatofibrosis in NAFLD shows precisely the same features and
progression as it does in alcoholic liver disease, although portal fibrosis
may be more prominent.
Cirrhosis may develop, is often subclinical for years, and, when
established, the steatosis or steatohepatitis may be reduced or absent.
Greater than 90% of previously described cryptogenic cirrhosis (i.e.,
cirrhosis of unknown cause) is now thought to represent such burned out
NAFLD.
NATURAL HISTORY
INVESTIGATION
Exclusion of excess alcohol consumption and other liver disease
(autoimminue, virus etc).
Then, confirm the presence of NAFLD, discriminating simple steatosis from
NASH and determining the extent of any hepatic fibrosis that is present.
Imaging
Ultrasound liver appears bright due to increase echogenicity; sensitivity is limited when
steatotic hepatocytes <33%
CT
MRI
MR Spectroscopy

Liver Biopsy
Gold standard to assess the degree of inflammation and extent of fibrosis
MANAGEMENT
Non-Pharmacological Treatment
Lifestyle intervention weight loss, diet and physical exercise

Pharmacological Treatment treatment is directed at metabolic


disorders
Specific insulin-sensitising agents, in particular glitazones, may help selected patients,
while positive results with high-dose vitamin E (800 U/day) have been tempered by
evidence that high doses may be associated with an increased risk of prostate cancer
and all-cause mortality, which has limited its use.
REFERENCES
1. Davidsons Principles and Practice of Medicine, 22nd Edition
2. Robbins Basic Pathology, 9th Edition
3. Robin and Cotrans Pathologic Basis of Diease, 9th Edition
4. Kumar and Clarks Clinical Medicine 8th Edition
5. http://bestpractice.bmj.com.ezproxy.lib.monash.edu.au/best-
practice/monograph/796/treatment.html