Epidemiology and Natural History of Non-Alcoholic Steatohepatitis
Section snippets
Prevalence of NAFLD in adults
NAFLD is one of the most common liver disorders in industrialized countries,1, 2, 3, 4, 5, 6, 7 with type 2 diabetes, obesity, hyperlipidemia, and cardiovascular disease being the most frequently evaluated and cited risk factors for the presence of NAFLD and accelerated disease.8 The estimated prevalence in the general population ranges between 2.8% and 46% depending on the screening test used (Fig. 1).9 Clearly, no single marker or test has sufficient positive or negative predictive value for
Classical phenotype of NAFLD
NAFLD and metabolic syndrome (central obesity, hypertriglyceridemia, hypertension, impaired glucose tolerance, and low high-density lipoprotein [HDL] cholesterol) commonly coexist, with over 90% of NAFLD patients having at least one of these characteristics. NAFLD prevalence increases as the severity and number of metabolic syndrome parameters increases.19
The prevalence of NAFLD has accelerated in the last 20 years, paralleling the substantial increase in rates of overweight and obesity in the
NAFLD in bariatric surgery patients/morbid obesity
Because of the ease of performing intraoperative liver biopsy in bariatric surgery patients (BMI greater than or equal to 40 kg/m2 or BMI greater than or equal to 35 kg/m2 with medical comorbidities), the high prevalence of NAFLD in this population is well-established. In pooled analysis, the rate of steatosis from studies of this population is 61%, with a rate of NASH of 36%. Fibrosis is present in 16% of patients, and cirrhosis is present in approximately 2%.9 These studies have demonstrated
Nonclassical phenotype of NAFLD: Normal weight patients
Although NAFLD and NASH are more common among obese patients, it is recognized widely that a fraction of NAFLD patients do not meet weight criteria of obesity. Not surprisingly, this is more common among Asian patients (even with adjusted criteria), although it is recognized increasingly in Western countries.5 In China, it has been reported that up to 40% of patients with NASH do not meet ethnicity-adjusted BMI for overweight or obesity.13, 38, 39 Most lower BMI NAFLD/NASH patients, however,
Familial associations, genetics, and ethnicity in NAFLD
There have been three studies reporting clustering of NASH and cryptogenic cirrhosis in one or more first-degree relatives of index cases of NASH.42, 43, 44 In the two earlier studies, an association with obesity, diabetes, and features of metabolic syndrome were evident as a common thread.45 From this group of studies, a case-control aggregation analysis revealed a possible maternal linkage supporting a genetic predisposition. Although it previously was estimated that about 20% of index cases
Mitochondriopathies and lipodystrophies associated with NAFLD
The evident histologic abnormalities involving mitochondria in NAFLD have fueled speculation that manifestations usually associated with primary mitochondriopathies may occur in NAFLD patients.82, 83 Several isolated elements of systemic mitochondrial disease have been observed in NASH patients, including opthalmoplegia, deafness, depression, gut dysmotility, lipomatosis, and neurodegenerative diseases.84 Concerted investigation of these phenomena has not occurred, but Al-Osaimi and colleagues85
NAFLD in pediatric patients
Just as the worldwide epidemic of obesity in adults has been mirrored in children, determining the prevalence of NAFLD in the pediatric population has been difficult because of the lack of reliable disease markers, the invasiveness of liver biopsy, and a relative lack population-based studies. As a result, secondary surrogates such as aminotransferases and ultrasound imaging have been the basis for diagnosis in most studies estimating prevalence to date.
Some population-based prevalence studies
Cryptogenic cirrhosis
Based on a number of epidemiologic studies of cryptogenic cirrhosis patients after transplant and more recent serial histologic studies, it is estimated that antecedent NASH underlies two thirds to three fourths of cryptogenic cirrhosis cases. The epidemiologic association was compiled recently in a review of six prior studies.109 Compared with cirrhotic control groups, the prevalence of obesity was increased among cryptogenic cirrhosis in all six series examined, and diabetes was increased in
Liver transplantation and de novo and recurrent NAFLD
The proportion of orthotopic liver transplants occurring secondary to NASH cirrhosis is increasing rapidly. In data from United Network for Organ Sharing, 3.5% of transplants occurred in patients with confirmed NASH cirrhosis in 2005 compared with only 0.1% of transplants in 1996.119 Over the same period, transplants for cryptogenic cirrhosis decreased from 9.6% in 1996 to 6.6% in 2005, which most likely represents greater acceptance of the diagnosis of NASH-related late-stage cirrhosis. NAFLD
Drug- and toxin-associated NASH
Environmental exposures have been associated with NASH, although the relative prevalence and relationship to underlying genetic or other risks remain uncertain. Petrochemical workers have been the best characterized such group.128 Typical features of common NASH including insulin resistance are less apparent in these patients, although progressive disease has been observed.129 More recently, NASH has been observed in nonobese chemical workers with high-level exposure to vinyl chloride.130
Natural history of NAFLD
Much work is ongoing to elucidate the mechanisms for progression of NAFLD to cirrhosis, but the overall body of literature suffers from lack of controlled, longitudinal studies, use of nonstandard definitions of the condition, variable collection of clinical parameters, and referral and publication bias. Although many potential predictors have been investigated, histology at initial presentation appears to have the best predictive value. Benign fatty liver appears to have very little likelihood
Histologic spectrum and progression of NAFLD
Cross-sectional and longitudinal biopsy studies constitute the best available evidence for establishing the probability of developing progressive fibrosis caused by NAFLD. Cross-sectional studies are naturally substantially limited by lack of follow-up. Longitudinal studies with paired biopsies carry the obvious benefit of providing firm follow-up data on which to establish long-term predictors, but they are limited by referral, selection, and ascertainment biases and tend to portray patients
Survival and long-term outcomes in NAFLD
The long-term clinical outcome in patients with NAFLD has been controversial, although it long has been recognized that the prognosis varies with the presence or absence of histologic injury (ie, NASH versus simple steatosis) and that the outcomes are tied closely into other conditions associated with metabolic syndrome. For example, variable clinical outcomes were evident in one of the early publications classifying NAFLD into histologic types wherein the risk of liver disease-related death
Cryptogenic cirrhosis in the patient with metabolic syndrome
For many years, the overall impact of NASH was obscured further by its relationship to cryptogenic cirrhosis.45 Although originally used to describe the occurrence of unexplained steatohepatitis, Ludwig's 1980 description of NASH is equally applicable to many cases of cryptogenic cirrhosis
“…we have encountered patients who did not drink, who had not been subject to bypass surgery, and who had not taken drugs that may produce steatohepatitis, yet had in their liver biopsy specimens changes that
Occult morbidity and changing epidemiology of NAFLD
Existing natural history studies draw from populations encountered in the 1980s and 1990s and cannot account for the changing epidemiology that has occurred in the interval because of the increasing prevalence of obesity in the general population, in pediatric patients, and in groups not traditionally thought of as having significant obesity such as the Asian population. These changing patterns raise the probability that what has been seen in the past 10 to 15 years is a harbinger of problems
Summary
NAFLD will present increasingly greater challenges over the next decade. The prevalence of this disorder shows no signs of slowing in any region of the world, and many predict it eventually may overtake all other forms of liver disease as the most common reason for liver transplantation and liver disease-related death in some regions. NAFLD undoubtedly is aligned closely with obesity, insulin resistance, and the metabolic syndrome, but differences according to age, ethnicity, and medical
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