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Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis…
Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis
CLINICAL FEATURES OF NAFLD
Most asymptomatic.
Obesity
present in 50–90% of subjects;
Most
also have other features of
metabolic syndrome
;
Some
have subtle
stigmata of chronic liver disease
(spider angiomata, palmer erythema, or splenomegaly);
small
minority w/ advanced NAFLD:
complications of end-stage liver disease
(jaundice, features of portal HTN) may be
initial findings
A. w/
obesity, diabetes, hyperTG, HTN, and cardiovascular disease,
(Other associations:
chronic fatigue, mood alterations, obstructive sleep apnea, thyroid dysfunction, and chronic pain syndrome
)
an independent
RF
for
metabolic syndrome
presence also
independently a. w/ endothelial dysfunction, incr carotid intimal thickness, number of plaques in carotid and coronary arteries
GLOBAL HEALTH CONSIDERATIONS
advanced NAFLD (cirrhosis and primary liver cancer) can occur in children + might follow a more aggressive course
certain environmental pollutants seem to exacerbate NAFLD.
INCIDENCE, PREVALENCE, AND NATURAL HISTORY: NAFLD
most common chronic liver
disease
pxs deny hazardous levels of alcohol consumption (>1 drink/day in women or 2 drinks/day in men) (bc serum aminotransferase incr when exceeding these levels)
strongly a. w/
overweight/obesity + insulin resistance
; can also occur in lean individuals (partic common in those w/ a paucity of adipose depots (i.e., lipodystrophy))
Ethnic/racial factors
(prevalence low to high: African As, white As, Hispanic As)
a
spectrum
of liver pathology w/ different clinical prognoses:
most
clinically
benign
extreme: simple accumulation of TG within hepatocytes (
hepatic steatosis
)
most
clinically
ominous
extreme:
cirrhosis + primary liver cancer
risk of developing
cirrhosis extremely low
in
chronic hepatic steatosis
, but
incr
as steatosis becomes complicated by histologically conspicuous
hepatocyte death and inflammation
(i.e.,
nonalcoholic steatohepatitis
[
NASH
]: a heterogeneous condition: sometimes improves to
steatosis
or
normal
histology, sometimes remains
relatively stable
for years, sometimes results in progressive accumulation of fibrous scar that eventuates in
cirrhosis
)
Once NAFLD-related
cirrhosis
develops: annual
incidence of primary liver cancer: 1%.
Abdominal imaging
not able to determine which ppl w/ NAFLD have
NASH
, and
specific blood tests
to diagnose
not available
Studies: serum ALT elevations that cannot be explained by etc + bc prevalence of such “
cryptogenic” ALT elevations
incr w/ BMI--> presumed that they are due to NASH-->NASH present in 25% of NAFLD--> cirrhosis develops in 6% of NAFLD
risk for
advanced liver fibrosis highest
in
NASH
who are
>45–50 yrs of age + overweight/obese or w/ DM2
cirrhosis incr risk for primary liver cancer.
Both hepatocellular carcinoma + intrahepatic cholangiocarcinoma (ICC) reported to occur in NAFLD w/o cirrhosis
--> NAFLD may be a premalignant condition.
NAFLD, NASH, and NAFLD-related cirrhosis not limited to adults
;
obesity + insulin resistance
main RFs for pediatric NAFLD
PATHOGENESIS
hepatic
steatosis
:
TG synth overwhelms disposal
--> accumulation of fat within hepatocytes.
Obesity
-->
alter
intestinal
microbiota
-->
enhance energy harvest
from dietary sources +
intestinal permeability
-->
incr hepatic exposure
to gut-derived products-->
liver cells generate infl
mediators-->
inhibit insulin
actions.
Obese
adipose depots
-->
excessive
soluble factors (
adipokines
)-->
inhibit tissue insulin sensitivity
1 +2-->
hyperglycemia
-->
hyperinsulinemia
--> promotes
lipid uptake, fat synth, and fat storage
-->
steatosis
TG
precursors
+ metabolic
by-products hepatotoxic
-->
hepatocyte lipotoxicity
--> generation of other
factors
(e.g., infl cytokines, hormonal mediators)-->
deregulate systems
maintaining hepatocyte
viability
-->
incr
hepatocyte
death
--> release various
factors
that trigger
wound healing responses
that aim to replace (regenerate) lost hepatocytes: transient expansion of other cell types (ex myofibroblasts and progenitor cells) that make and degrade matrix, remodel vasculature, and generate replacement hepatocytes, as well as recruitment of immune cells that release factors that modulate liver injury and repair-->
NASH
(morphologic manifestation of lipotoxicity and resultant wound healing responses)
Cirrhosis and liver cancer: potential outcomes of chronic NASH.
futile repair
, i.e., progressive accumulation of wound healing cells, fibrous matrix, and abnormal vasculature (scarring)-->
cirrhosis
current strategies focus on circumventing misrepair by preventing and/or reducing lipotoxic liver injury.
DIAGNOSIS
can be accomplished by HX + P/E, liver imaging (ultrasound ok, CT or MRI added expense), and blood tests to
exclude other causes
liver
may
not
be
enlarged
+
tests
may be completely
normal
--> confidence in Dx of NAFLD incr by identification of NAFLD RFs (incr BMI, insulin resistance/DM2,
other parameters indicative of metabolic syndrome
(ex hyperuricemia/gout, cardiovascular disease) in px / family members)
Establishing severity
goal of staging: identify NASH from simple steatosis + which NASH have advanced fibrosis.
NASH: more intensive follow-up + therapy
NASH w/ advanced fibrosis: most intensive scrutiny and intervention
steatosis: managed conservatively
Staging approaches
noninvasive testing
blood
testing:
evidence of hepatic dysfunction
(ex hyperbilirubinemia, hypoalbuminemia, prothrombin time prolongation) or portal HTN (ex thrombocytopenia)--> advanced NAFLD
P/E
:
stigmata of portal HTN
(ex spider angiomata, palmar erythema, splenomegaly, ascites, clubbing, encephalopathy)--> advanced NAFLD
imaging
invasive approaches: liver
biopsy: gold standard
seldom complicated by serious adverse sequelae (ex significant bleeding, pain, or inadvertent puncture of other organs)-->
relatively safe.
suffers from
potential sampling error
unless tissue cores of 2 cm or longer acquired
examination
of tissue
at a single point in time not reliable
for determining whether processes are progressing or regressing but risk of serial liver biopsies within short time unacceptable
research
to identify superior markers of liver injury:
Serum levels of keratin 8 and 18
(epithelial cytoskeletal prs that undergo cleavage during apoptosis--> released into blood as hepatocytes die + appear to parallel severity of liver fibrosis)
TREATMENT OF NAFLD
(1) specific therapy of NAFLD-related liver disease: no therapies for treatment--> improve RFs for NASH
Pharmacologic Therapies: only patients w/ NASH or those w/ features of hepatic fibrosis on biopsy considered currently for targeted pharmacologic therapies
No agent approved
Metformin: not currently recommended as a treatment for NASH.
thiazolidinediones
(pioglitazone and rosiglitazone): Pioglitazone may be safer but
caution
when considering its use in
impaired myocardial function.
Antioxidants:
vitamin E
should only be considered as a first-line pharmacotherapy for
nondiabetic
NASH; potentially
negative effects on cardiovascular
health
Ursodeoxycholic acid (a bile acid ) + betaine (metabolite of choline) : no benefit
omega-3 Fas: no
Statins
: do not cause liver failure in any chronic liver disease-->
use of statins to treat dyslipidemia in NAFLD/NASH.
Bariatric Surgery: safe in well-compensated chronic liver disease + improves hepatic steatosis and necroinflammation (i.e., features of NAFLD/NASH); however, effects on
hepatic fibrosis v
ariable (
might progress
); pxs w/ NAFLD-related cirrhosis and portal HTN should be excluded;
not contraindicated in otherwise eligible patients with NAFLD or NASH.
Liver Transplantation: NAFLD in whom end-stage liver disease develops;
NAFLD may recur
after transplantation.
RFs
for recurrent or de novo NAFLD after liver transplantation multifactorial:
hyperTG, obesity, DM, and immunosuppressive therapies, partic glucocorticoids.
Diet and Exercise:
Lifestyle changes + dietary modification: foundation for NAFLD treatment
loss of min
3–5% of body weight
improving
steatosis
, but greater weight loss (
up to 10%
) necessary to improve
steatohepatitis
.
benefits of different dietary macronutrient contents
exercise that improve fitness may be sufficient to reduce hepatic steatosis (not others though)
pharmacologic therapies (orlistat, topiramate, and phentermine) to facilitate weight loss experimental.
(2) treatment of NAFLD-associated comorbidities
(3) treatment of complications of advanced NAFLD: management of complications of cirrhosis + portal HTN, including primary liver cancers