Non alcoholic fatty liver disease

1. Nonalcoholic fatty liver disease
(NAFLD)
Dr.Rajesh K. Mandal
MD, Internal Medicine
Bir Hospital,Nepal

2. • Nonalcoholic fatty liver disease (NAFLD) refers to
the presence of hepatic steatosis when no other
causes for secondary hepatic fat accumulation
(eg, heavy alcohol consumption) are present.
• NAFLD may progress to cirrhosis and is likely an
important cause of cryptogenic cirrhosis
• Patients with nonalcoholic fatty liver disease
(NAFLD) have hepatic steatosis, with or without
inflammation and fibrosis. In addition, no
secondary causes of hepatic steatosis are
present.

3. • NAFLD is subdivided into nonalcoholic fatty liver
(NAFL) and nonalcoholic steatohepatitis (NASH).
• In 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.
• Other terms that have been used to describe
NASH include pseudoalcoholic hepatitis, alcohol-
like hepatitis, fatty liver hepatitis, steatonecrosis,
and diabetic hepatitis

4. EPIDEMIOLOGY
• Prevalence — Nonalcoholic fatty liver disease (NAFLD)
is seen worldwide and is the most common liver
disorder in Western industrialized countries.
• Major risk factors for NAFLD, central obesity, type 2
diabetes mellitus, dyslipidemia, and metabolic
syndrome are common.
• In the United States, studies report a prevalence of
NAFLD of 10 to 46 percent, with most biopsy-based
studies reporting a prevalence of NASH of 3 to 5
percent.
• Worldwide, NAFLD has a reported prevalence of 6 to
35 percent (median 20 percent).

5. • High rates of NAFLD and NASH among obese persons
were subsequently confirmed in a study of patients
undergoing bariatric surgery, in which the prevalence
rates of NAFLD and NASH were as high as 91% and
37%, respectively.
• The Dallas Heart Study used MR spectroscopy in more
than 2200 adults to identify a 31% prevalence of
NAFLD in a cohort of asymptomatic persons.7,8
Subsequent population base
• cohort studies from China, Japan, and Korea
havereported a prevalence of NAFLD ranging from 10%
to 24%

6. • Most relevant studies have reported NAFLD to
be more common in men than women and
have described a later peak in prevalence in
women
• Dallas Heart Study, among others, suggested
that ethnicity was important, with Hispanics
showing the highest prevalence of NAFLD
(45%) compared with Caucasians (33%) and
African Americans (24%).

7. • Patients with NAFLD (particularly those with
NASH) often have one or more components of
the metabolic syndrome .("The metabolic
syndrome (insulin resistance syndrome or
syndrome X)".):
• ●Obesity
• ●Systemic hypertension
• ●Dyslipidemia
• ●Insulin resistance or overt diabetes

8. • Increased consumption of high-fructose corn
syrup and sugar-containing sodas, coupled with a
sedentary lifestyle, has been associated with
higher rates of NAFLD and specifically NASH.
• Genetic influences on the development of NAFLD
may prove to be equally important.
• Single nucleotide polymorphisms (SNPs) from
specific genes have been found to be associated
with an increased risk of NAFLD.

9. • The first of these SNPs to be identifie was in the
patatin-like phospholipase domain–containing
protein-3 (PLPLA3) gene located on chromosome
22q13 and known to encode adiponutrin, a 481–
amino acid protein that mediates triacylglycerol
synthesis.
• The allelic variant rs738409 results in a change
from isoleucine to methionine at position 148
(I148M) and was shown to be associated with
increased hepatic steatosis as well as
inflammation.

10. • Alternative causes of hepatic steatosis — There are multiple causes of hepatic
steatosis that should be considered in a patient with suspected nonalcoholic
fatty liver disease (NAFLD). Causes of hepatic steatosis in addition to NAFLD
include
●Alcoholic liver disease
• ●Hepatitis C (particularly genotype 3)
• ●Wilson disease
• ●Lipodystrophy
• ●Starvation
• ●Parenteral nutrition
• ●Abetalipoproteinemia
• ●Medications (amiodarone, methotrexate, tamoxifen, glucocorticoids,
valproate, anti-retroviral agents for HIV)
• ●Reye syndrome
• ●Acute fatty liver of pregnancy
• ●HELLP (hemolytic anemia, elevated liver enzymes, low platelet count)
syndrome
• ●Inborn errors of metabolism (LCAT deficiency, cholesterol ester storage
disease, Wolman disease)

13. • Macrovesicular fat accumulation in more than
5% of hepatocytes is the defining feature of
NAFLD.
• The majority of patients with NAFLD have IFL,
which is defined as hepatic steatosis in the
absence of significant necroinflammation or
fibrosis

14. Pathogenesis
• The pathogenesis of nonalcoholic fatty liver disease has
not been fully elucidated.
• The most widely supported theory implicates insulin
resistance as the key mechanism leading to hepatic
steatosis, and perhaps also to steatohepatitis.
• Others have proposed that a "second hit", or
additional oxidative injury, is required to manifest the
necroinflammatory component of steatohepatitis
• Hepatic iron, leptin, antioxidant deficiencies, and
intestinal bacteria have all been suggested as potential
oxidative stressors.

16. Clinical features
• Most patients with NAFLD NAFLD usually is discovered
incidentall because of elevated liver biochemical test
levels or the finding of hepatic steatosis on imaging.
• Asymptomatic
• Vague right upper quadrant pain, fatigue, and malaise.
Hepatomegaly is commonly seen
• Difficult to appreciate on physical examination
because of obesity.
• Stigmata of chronic liver disease, such as
splenomegaly, spider telangiectasias, and ascites, are
limited to those patients with cirrhosis.

17. • Stigmata of chronic liver disease, such as spider
angiomata, palmer erythema, or splenomegaly.
• In a small minority of patients with advanced NAFLD,
complications of end-stage liver disease (e.g., jaundice,
features of portal hypertension such as ascites or
variceal hemorrhage)
• The association of NAFLD with obesity, diabetes,
hypertriglyceridemia,hypertension, and cardiovascular
disease is well known.
• Other associations include chronic fatigue, mood
alterations, obstructive sleep apnea, thyroid
dysfunction, and chronic pain syndrome.

19. Diagnosis
• The diagnosis of nonalcoholic fatty liver
disease (NAFLD) requires all of the following
• ●Demonstration of hepatic steatosis by
imaging or biopsy
• ●Exclusion of significant alcohol consumption
• ●Exclusion of other causes of hepatic steatosis

21. Diagnosis
• Patients with NAFLD may have mild or moderate
elevations in the aspartate aminotransferase (AST) and
alanine aminotransferase (ALT)
• Normal aminotransferase levels do not exclude NAFLD.
• When elevated, the AST and ALT are typically two to
five times the upper limit of normal, with an AST to ALT
ratio of less than one (unlike alcoholic fatty liver
disease, which typically has a ratio greater than two)
• A mild to moderate (1.5- to 4-fold) elevation of the
serum AST or ALT level, or both, is common,
• Although levels seldom exceed 10 times the upper limit
of normal.

22. • To establish a diagnosis of NAFLD, alcoholic
liver disease must be excluded
• Diagnosis of NAFLD should be entertained
only in the absence of significant alcohol use
(consumption of < 20 to 40 g of alcohol per
day in most clinical studies).

23. • significant alcohol consumption as an average
consumption of >210 grams of alcohol per week
in men or >140 grams of alcohol per week in
women over at least a two-year period
• A standard drink in the United States
• (12 oz [360 mL] of beer,
• 5 oz [150 mL] of wine,
• 1.5 oz [45 mL] of 80-proof spirits)
• contains approximately 14 grams of alcohol , so
the limits above roughly translate to >15 drinks
per week for men and >10 drinks per week for
women.

25. • Serum alkaline phosphatase and GGTP levels may
be elevated
• Serum bilirubin level, prothrombin time, and
serum albumin level are typically normal, except
in patients with cirrhosis
• The degree of aminotransferase elevation does
not predict the degree of hepatic inflammation or
fibrosis
• Normal alanine aminotransferase does not
exclude clinically important histologic injury

26. Other causes of liver fat accumulation
(particularly exposure to certain drugs and liver
injury (e.g., viral hepatitis, autoimmune liver
disease, iron or copper overload, α1 antitrypsin
deficiency) must also be excluded

27. Imaging Study
• liver imaging (ultrasound is an acceptable first-
line test)
• computed tomography [CT] or magnetic
resonance imaging [MRI] enhances sensitivity for
liver fat detection but adds expense
• Blood tests to exclude other liver diseases.
• liver may not be enlarged, and serum
aminotransferases and liver function tests (e.g.,
bilirubin, albumin, prothrombin time) may be
completely normal, in individuals with NAFLD

28. • confidence in the diagnosis of NAFLD is increased
by identification of NAFLD risk factors.
• Increased body mass index, insulin
resistance/type 2 diabetes mellitus
• parameters indicative of the metabolic syndrome
(e.g., systemic hypertension, dyslipidemia,
hyperuricemia/gout, cardiovascular disease) in
the patient or family members

29. • Up to one fourth of patients with NAFLD may have
antinuclear antibodies (ANA) in low titers (<1 : 320)
• laboratory tests for other chronic liver disease are negative.
• NAFLD can exist in concert with HCV, although HCV
infection by itself can promote hepatic steatosis
• Serum and hepatic iron levels may be elevated in patients
with NAFLD.
• In particular, the serum ferritin level may be elevated in 20
to 50% of patients with NAFLD and may be a marker of
more advanced disease.
• A serum ferritin level more than 1.5 times the upper limit
of normal has been independently associated

30. • Hepatic US may reveal a “bright” liver of
increased echogenicity, consistent with hepatic
steatosis .
• Fatty liver also can be documented by abdominal
CT (a fatty liver is lower in density than the
spleen) an by MRI, with which fat appears bright
on T1-weighted imaging. Areas of relative sparing
of fat may be seen on imaging studies.
• A study that assessed the sensitivities of MRI,
abdominal CT, and US for distinguishing advanced
NASH from simple steatosis showed that US and
CT had sensitivity rates of 100% and 93%,
respectively, for detecting hepatic fat involving
greater than 33% of the liver, with positive
predictive values of 62% and 76%, respectively

32. Biopsy
• liver biopsy is the gold standard for diagnosing
NAFLD
• Many cases a presumptive diagnosis can be made
based upon the patient's history, laboratory tests,
and imaging findings, provided other disorders
have been excluded.
• Some patients will continue to have an unclear
diagnosis following a noninvasive evaluation. In
such cases, a liver biopsy is indicated

33. • Liver biopsy is an invasive procedure
associated with rare but severe complications,
including hemorrhage and even death
• Taking liver biopsies in 20% to 30% of the
general population is not feasible.

35. • Imaging to Detect Fibrosis
• The most studied and widely available has
been transient elastography (Fibroscan;
Echosens, Paris, France), which uses a low
amplitude shear wave that propagates
through the liver parenchyma.

36. • Acoustic radiation force impulse (ARFI)
elastography. This technology measures the
velocity of a short-duration, high-intensity
acoustic pushing pulse in the liver.
• Pilot trials have suggested accuracy similar to
that of US elastography

37. • MR elastography (MRE) combines MRI with
elastography and has been accurate in staging
NAFLD fibrosis in studies.
• MRE appears to be better than transient
elastography in differentiating mild from
moderate to severe fibrosis, with a sensitivity
of 86% and a specificity of 85%

38. Biomarkers
• The most studied single marker for identifying
NASH is cytokeratin-18 (CK-18), a marker of
apoptosis.
• Other biomarkers that have been studied
include the apoptosis markers CK-18
fragments and soluble Fas.

39. Clinical Scores
• Clinical scoring systems have also been
investigated for the ability to predict either
NASH or advanced fibrosis.
• The major clinical scoring systems studied in
NAFLD include FibroSURE (FibroTest),
Fibrometer, NAFLD fibrosis score, Fib-4, AST-
to-platelet ratio index (APRI), BARD, European
Liver Fibrosis Score (ELF), NASHTest, and
AST/ALT ratio.

42. • Additional histologic findings of NASH include
• ●Apoptotic (acidophil) bodies
• ●Mild chronic portal inflammation (inflammation that is severe or is
disproportionate to the acinar lesions is suggestive of concurrent
hepatitis C)
• ●Perisinusoidal collagen deposition that may result in zone 3
accentuation in a "chicken wire" pattern (related to the deposition
of collagen and other extracellular matrix fibers along the sinusoids
of zone 3 and around hepatocytes)
• ●Portal fibrosis without perisinusoidal or pericellular fibrosis
• ●Cirrhosis, which is typically macronodular or mixed
• ●Mallory-Denk bodies (previously called Mallory bodies or
Mallory's hyaline)
• ●Megamitochondria
• ●Glycogenated (vacuolated) nuclei in periportal hepatocytes (rarely
seen in alcoholic steatohepatitis)
• ●Lobular lipogranulomas
• ●PAS-diastase-resistant Kupffer cells
• ●Hepatic siderosis (typically mild) involving periportal hepatocytes
or panacinar reticuloendothelial cells

49. • FORMULA
• NAFLD Score = -1.675 + (0.037*age [years]) +
(0.094*BMI [kg/m2]) + (1.13*IFG/diabetes
[yes = 1, no = 0]) + (0.99*AST/ALT ratio) –
(0.013*platelet count [×109/L]) –
(0.66*albumin [g/dl])

52. Natural History

53. Associated Disorders
• In addition to the metabolic syndrome, diabetes
mellitus, and vitamin D deficiency, cardiovascular
disease, obstructive sleep apnea, colonic
adenomas, hypothyroidism, polycystic ovary
syndrome, pancreatic steatosis, and elevated
serum uric acid levels have been reported to be
associated with NAFLD.
• Cardiovascular disease has been shown to be the
primary cause of death

54. Treatment
• Treatment of NAFLD can be divided into three
components:
• (1) specific therapy of NAFLD-related liver
disease;
• (2) treatment of NAFLDassociated
comorbidities; and
• (3) treatment of the complications of
NAFLD.

55. • Lifestyle changes and dietary modification are
the foundation for NAFLD treatment
• The benefits of different dietary
macronutrient contents (e.g., low-
carbohydrate vs low-fat diets, saturated vs
unsaturated fat diets) and different intensities
of calorie restriction appear to be comparable.

58. • Metformin, an agent that mainly improves
hepatic insulin sensitivity
• Ursodeoxycholic acid (a bile acid that improves
certain cholestatic liver diseases)
• UDCA are thought to prevent apoptosis and
down-regulate the inflammatory cascade.
• choline that raises SAM levels and decreases
cellular oxidative damage
• omega-3 fatty acids

59. • Statins are an important class of agents to
treat dyslipidemia and decrease
cardiovascular risk.
• Bariatric surgery as a treatment for NAFLD
exists, a recently published Cochrane review
concluded that lack of randomized clinical
trials or adequate clinical studies prevents
definitive assessment of benefits and harms of
bariatric surgery as a treatment for NASH

60. • Most studies of bariatric surgery have shown that
bariatric surgery is generally safe in individuals
with wellcompensated chronic liver disease and
improves hepatic steatosis and
necroinflammation (i.e., features of
NAFLD/NASH); however, effects on hepatic
fibrosis have been variable
• General agreement that patients with
NAFLDrelate cirrhosis and portal hypertension
should be excluded as candidate for bariatric
surgery

61. Liver Transplant
• Patients with NAFLD in whom end-stage liver
disease develops should be evaluated for liver
transplantation
• The outcomes of liver transplantation in well-
selected patients with NAFLD are generally good,
but comorbid medical conditions associated with
NAFLD, such as diabetes mellitus, obesity, and
cardiovascular disease, often limit transplant
candidacy.
• NAFLD may recur after liver transplantation.

62. • NASH cirrhosis is currently the third most
common indication for liver transplantation
after cirrhosis caused by HCV and alcoholic
liver disease

63. Hepatic steatosis in donor grafts is common
Transplanted steatotic livers have been
associated with primary graft nonfunction and
poorer overall outcomes.
• Grafts with less than 30% steatosis are
acceptable for use, and those with more than
60% fat are generally considered unacceptable

64. • The risk factors for recurrent or de novo
NAFLD after liver transplantation are
multifactorial and include
hypertriglyceridemia, obesity, diabetes
mellitus, and immunosuppressive therapies,
particularly glucocorticoids

65. Focal Fatty Liver
• Focal fatty liver is a localized or patchy process that
simulates a space-occupying lesion in the liver on imaging
studies.
• Increasingly in adults and children as a result of the
improved sensitivity of abdominal imaging
• No evidence exists to suggest that the pathogenesis of focal
fatty liver is similar to that of NAFLD. In fact, the
pathogenesis of focal fatty liver is uncertain and may
involve altered venous blood flow to the liver, tissue
hypoxia, or intestinal malabsorption of lipoprotein.
• In the absence of accompanying liver disease, the lesion
often regresses. No specific treatment is necessary.

67. References
• Sleisengers 10th ed
• Harrisons principles of Int Med.19th ed
• Uptodate