Overall Bottom Line
- NAFLD encompasses a spectrum of disease conditions ranging from simple steatosis to NASH which may progress to cirrhosis and hepatocellular carcinoma. Many patients who previously were labeled as having cryptogenic cirrhosis actually have NAFLD-induced cirrhosis.
- Pathogenesis of NAFLD is closely associated with metabolic syndrome and insulin resistance.
- NASH is characterized histologically by steatosis, features of cellular injury (hepatocyte ballooning, necrosis, apoptosis, Mallory-Denk bodies), inflammation, and variable degrees of fibrosis.
- Liver biopsy is the only investigation at this time that can differentiate NASH from bland steatosis.
- The mainstay of treatment is lifestyle modification (diet, exercise, weight loss). No widely approved pharmacologic treatment exists to date.
Section 1: Background
Definition of disease
- NAFLD refers to a spectrum of liver diseases that resemble/mimic alcohol-induced liver injury in patients who do not consume significant amounts of alcohol (women ≤20 g/day; men ≤40 g/day).
Disease classification
- Simple steatosis is defined by >5% of hepatocytes containing fat in the absence of histologic features of NASH.
- Definite NASH is defined by hepatic steatosis (macrovesicular > microvesicular) plus additional features of histologic liver injury (inflammation, Mallory-Denk bodies, ballooned hepatocytes) and fibrosis.
- Borderline NASH is defined by no hepatocyte ballooning, no Mallory-Denk bodies.
Incidence/prevalence
- NAFLD is the most common chronic liver disease in Western countries with a prevalence of about 30% in the adult population and 9% in children and adolescents. Approximately 55 million Americans have NAFLD.
- Prevalence of NASH in Western countries is estimated around 2.5%.
Economic impact
- The economic impact of NAFLD is unknown. However, rising obesity trends will lead to continued importance of NAFLD as a major cause of chronic liver disease.
Etiology
- The exact etiology of NAFLD is unclear and remains an area of active investigation; however, there is a strong association with obesity, metabolic syndrome and insulin resistance.
Pathology/pathogenesis
Hepatic steatosis
- Hepatic steatosis may result from several factors including:
- Increased circulating free fatty acids due to dietary fat.
- Increased release of free fatty acids from adipose tissue due to increased stores found in obesity and insulin resistance.
- Increased de novo lipogenesis in the liver.
- Impaired fatty acid oxidation in the liver.
- Decreased export of lipids from the liver as VLDL. Another theory is that hepatic steatosis is in fact a protective and adaptive mechanism in response to excess fat intake.
- Increased circulating free fatty acids due to dietary fat.
Steatohepatitis
- One theory is the “two hit” hypothesis which proposes a stepwise process where steatosis is the first “hit” and inflammation/fibrosis is the second “hit”. Several possible mechanisms may be involved in the “second hit” that leads to additional features of liver injury found in NASH.
- Possible mediators of inflammation are:
- Gut-derived endotoxin.
- Proinflammatory cytokines TNF-α, IL-6 released by adipose tissue.
- Endoplasmic reticulum stress.
- Gut-derived endotoxin.
Genetic predictors
- Genome wide association studies have found a single nucleotide polymorphism variant in the gene encoding PNPLA3 that is associated with NAFLD. PNPLA3 encodes a protein that belongs to the patatin-like phospholipase domain-containing family. Its function remains unclear; however, it appears to be involved in hydrolysis of triglycerides. Interestingly, the association between the PNPLA3 variant and NAFLD is independent of insulin resistance.
Predictive/risk factors
| Risk factor | Odds ratio |
|---|---|
| Metabolic syndrome | 4.68 |
| Type 2 diabetes mellitus | 3.37 |
| Hypertension | 2.21 |
| Obesity | 1.10–1.12 |
| PNPLA3 rs738409 gene variant | 3.26 |
Section 2: Prevention
- No specific interventions have been shown to prevent the development of the disease.
Screening
- No widely accepted screening methods exist. Prevalence rates of NAFLD are highest in patients with obesity, metabolic syndrome, type 2 diabetes mellitus, and dyslipidemia. Therefore, a targeted screening approach might be to screen these patients with ALT and/or ultrasound. This has not been studied and is not endorsed by guidelines.
Section 3: Diagnosis
Clinical Pearls
- Careful history taking to exclude alcohol-associated liver disease is important in making the diagnosis, although some patients may have both alcoholic and non-alcoholic (metabolic/insulin resistance-associated) liver disease.
- Physical examination findings may include increased BMI, increased waist circumference, hypertension and acanthosis nigricans associated with insulin resistance.
- Laboratory findings are ALT > AST (usually 1–2 × ULN and are rarely >5 × ULN), elevated GGT, elevated ferritin (in approximately 50% of cases). AST and ALT can be normal even in cases of advanced fibrosis. Low titer ANA (≤1:320) can be found in up to 25% of patients with NAFLD.
- Abdominal imaging (US, CT scan or MRI) may demonstrate evidence of steatosis. US findings include increased echogenicity to detect 30% or more of fatty infiltration.
- There are no well-validated non-invasive biomarkers or imaging methods that can differentiate NASH from simple steatosis.
Differential diagnosis
| Differential diagnosis | Features |
|---|---|
| Alcoholic liver disease | AST > ALT, elevated MCV, leukocytosis History of excessive alcohol intake (>40 g/day in men, >20 g/day in women) |
| Wilson disease | Low ceruloplasmin, elevated 24 hour urine copper, Kayser–Fleischer rings, neurologic symptoms |
| Viral hepatitis (HBV, HCV) | +HBsAg, +HCV Ab and RNA |
| Drug-induced liver injury | Recent new medications/herbal use Tamoxifen, amiodarone, valproic acid, antiretroviral agents and TPN have been associated with steatohepatitis on biopsy |
Typical presentation
- Most patients are asymptomatic and present with incidentally noted liver enzyme elevation on routine blood tests or incidental fatty liver on imaging ordered for unrelated symptoms (such as abdominal US to rule out cholelithiasis). A subset of patients present with end stage complications of cirrhosis or hepatocellular carcinoma. This highlights the “silent nature” of NASH during the early stages of disease (much like chronic viral hepatitis).
Clinical diagnosis
History
- Careful assessment of alcohol intake is important in excluding alcoholic liver disease, which can cause identical or similar histologic findings to NASH.
- Assessment of a family history of metabolic syndrome is important in supporting a diagnosis of NASH. A review of systems assessment should include inquiry about associated conditions: diabetes mellitus, dyslipidemia, hypertension, obstructive sleep apnea, polycystic ovary syndrome, chronic hepatitis C. Medications associated with secondary NASH including amiodarone, TPN and antiretroviral drugs should be reviewed.
- The patient should be asked about weight gain and lifestyle factors including exercise and diet, with particular attention to intake of high fructose corn syrup containing foods and foods high in trans fats. Extreme degrees of rapid weight loss can also cause NASH. Therefore recent weight reduction surgery or other causes of weight loss may be revealed.
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