Nonalcoholic Fatty Liver Diseases and Nonalcoholic Steatohepatitis
CLINICAL FEATURES OF NAFLD
GLOBAL HEALTH CONSIDERATIONS
INCIDENCE, PREVALENCE, AND NATURAL HISTORY: NAFLD
PATHOGENESIS
DIAGNOSIS
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
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 variable (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.
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
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.
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
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)
steatosis: managed conservatively
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
Diet and Exercise:
(2) treatment of NAFLD-associated comorbidities
(3) treatment of complications of advanced NAFLD: management of complications of cirrhosis + portal HTN, including primary liver cancers
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.
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.
advanced NAFLD (cirrhosis and primary liver cancer) can occur in children + might follow a more aggressive course
certain environmental pollutants seem to exacerbate NAFLD.