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Lean Fatty Liver Disease & Visceral Afiposity
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"The risk of mortality in NAFLD can be affected by the presence of visceral obesity, especially in the lean BMI group......it is highly plausible that assessment of visceral adiposity can be an important predictor of long-term outcome among those with NAFLD, even those who are considered lean by BMI classification."
Individuals with NAFLD who were lean by BMI but obese by WC had higher risk of all-cause mortality. Individuals with NAFLD with normal BMI but obese WC had a higher risk of cardiovascular mortality (hazard ratio 2.63 [95% CI: 1.15-6.01]) as compared with overweight (by BMI) NAFLD with normal WC. Conclusion: The risk of mortality in NAFLD can be affected by the presence of visceral obesity, especially in the lean BMI group. These data have important management implications for patients with NAFLD.
As noted, components of metabolic syndrome (visceral obesity, insulin resistance, type 2 diabetes [T2DM], dyslipidemia, and HTN) not only increase the risk of NAFLD but also lead to increased risk for developing nonalcoholic steatohepatitis (NASH), advanced hepatic fibrosis, and experiencing liver-related mortality.(7, 8) Although NAFLD is strongly associated with obesity and metabolic syndrome, a portion of patients with NAFLD are not obese. The prevalence of lean NAFLD can range from 7% to 10% in the United States and up to 19% in some Asian countries.(9-12) The definition of lean NAFLD can vary based on the use of body mass index (BMI) or waist circumference (WC) thresholds.(9, 13) It has also been suggested that BMI reflects the total body fat and may not accurately reflect the presence of visceral obesity, which is more relevant for patients with NAFLD.(14) Despite the importance of visceral obesity according to waist circumference in NAFLD, most long-term studies could not provide consistent WC data. Nevertheless, the importance of visceral obesity as a predictor of long-term outcomes has been established.(15) In this context, it is highly plausible that assessment of visceral adiposity can be an important predictor of long-term outcome among those with NAFLD, even those who are considered lean by BMI classification. Therefore, the aim of the current study was to determine the effect of different combinations of abdominal adiposity (WC) and overall adiposity (BMI) on the prevalence and mortality of NAFLD in the United States.
Hispanics & Liver Disease/Fatty Liver, Liver Cancer & Mortality Rates Increasing Particularly Among Blacks & Hispanics
Among the Hispanic population, injection drug use has been identified as the most common risk factor for HCV infection.....Studies measuring hepatic triglyceride content by magnetic resonance spectroscopy identified steatosis in 45% of the Hispanic population, making NAFLD 1.4 times more frequent in Hispanic than in NHW and 1.9 times more common than in African American persons.....Similar to previous reports, Hispanic persons had the highest prevalence of NAFLD (58.3%), followed by Caucasian (44.4%), and African American (35.1%) .....Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in Hispanic persons followed by chronic alcoholic liver disease and viral hepatitis C and B.12, 13, 14, 15 Among Hispanic persons, hepatocellular carcinoma also has a higher incidence and worse prognosis than NHW or African American persons.
This disease is now recognized as the most frequent etiology of elevated serum aminotransferase levels in the United States.....Multiple studies have shown that NAFLD is more common in Hispanic than in NHW or African American persons of the same age with an even distribution among Hispanic men and women.....The most commonly accepted explanation for these epidemiologic variations reflects ethnic differences in prevalence of the metabolic syndrome......In general, Hispanic individuals have higher incidence rates of HCC compared with African American and NHW persons (5.7 vs 4.2 vs 2.6 per 100,000, respectively)....the mean yearly age-adjusted incidence rate of HCC is 2.7 times higher in Hispanic than in NHW individuals.....Data from the SEER database also revealed that Hispanic persons have a 9% higher mortality risk from HCC than NHW persons and, similar to African American persons, they have the shortest 1- and 3-year survival rates amongst all ethnic groups in the United States, even after adjusting for time of diagnosis, receipt of therapy, age, and gender.
https://www.natap.org/2014/HCV/061614_04.htm
Nonalcoholic Fatty Liver Disease
NAFLD refers to fat deposition in hepatocytes, or steatosis, in individuals with little or no alcohol use. When accompanied by inflammation and fibrosis, it is referred to as nonalcoholic steatohepatitis (NASH). The prevalence of NAFLD in the U.S. population ranges from 17%–33%, and risk factors include obesity, hyperglycemia, diabetes mellitus, and hyper-triglyceridemia.73 Recently, mounting evidence suggests that the prevalence of hepatic steatosis in HIV-infected patients is high, especially in patients with chronic HCV or on NRTIs.61 Most of the prevalence data come from studies in HIV-HCV coinfected individuals, with rates of steatosis in this population ranging from 40%– 69%.33,74 However, in a recent study of 216 HIV-infected patients without viral hepatitis coinfection, 31% had NAFLD diagnosed, although most were diagnosed with ultrasound rather than the gold standard of liver biopsy.75
Metabolic abnormalities are extremely common in HIV-infected persons on ART, especially NRTI-PI combinations. These include insulin resistance, dyslipidemia, hypertriglyceridemia, and lipodystrophy, a disorder of peripheral fat distribution resulting in lipotrophy and visceral adiposity. 76 NRTIs can also lead to hepatic steatosis via inhibition of mitochondrial DNA replication, resulting in triglyceride accumulation in the liver. 77 Hypertriglyceridemia, low high-density lipoprotein, and low total cholesterol have also been independently associated with HIV infection and might be mediated by cytokines like interferon alfa. 78 These metabolic abnormalities have been associated with the development of NASH in HIV-infected patients.79
The natural history of NAFLD in HIV infection is unknown. In the general population, approximately 10%–15% of patients with simple steatosis progress to NASH, and 15%–20% of these patients progress to cirrhosis. 80 In general, steatosis alone is not concerning for liver damage, but it might exacerbate underlying chronic liver disease. In HCV-monoinfected patients, steatosis is associated with faster progression of fibrosis and decreased response to treatment.81 Similarly, in cohorts of HIV-HCV coinfection, hepatic steatosis has been associated with more advanced liver fibrosis.33,74 With continued investigation and research into NAFLD, its impact on liver disease progression in HIV-infected individuals will likely be further elucidated.
https://www.natap.org/2010/HCV/PIIS2.pdf
NAFLD Is Increasingly Affecting Patients With HIV
Risk factors, diabetes, lipids, metabolic syndrome
NASH is a histological diagnosis characterized by inflammation, ballooning of hepatocytes and fibrosis or nonalcoholic fatty liver that is not associated with hepatocellular damage. Worldwide, the prevalence of NAFLD in the general population is rising and estimated to be 25%.2 This mirrors the rising prevalence of obesity, type 2 diabetes (T2DM), and metabolic syndrome. The disease is most prevalent in the Middle East and South America, whereas it is lowest in Africa. Patients with NAFLD experience increased morbidity and mortality, which are most commonly attributed to cardiovascular disease when compared with matched controls.3 In the United States, NAFLD is the third most common cause of hepatocellular carcinoma, with up to 13% of cases occurring in absence of cirrhosis.4
https://www.natap.org/2022/HCV/051122_01.htm
With longer life expectancy and declining AIDS-associated mortality, non-AIDS-related comorbidities have emerged as diagnostic and treatment problems in persons with HIV (PWH). Chronic liver disease is the second most common cause of non-AIDS-related mortality in PWH.5 Results of a US study of 47,062 PWH from 2006 to 2016 showed that 22% had some form of liver disease. The increased prevalence of liver disease is multifactorial and attributable to NAFLD, alcohol use, and viral hepatitis.6 In a meta-analysis of PWH, the prevalence of NAFLD, biopsy-proven NASH, and fibrosis were 35%, 42% and 22% respectively, which is significantly higher than that of the general population.7
General Pathogenesis and Risk Factors
Insulin resistance (IR) is a key factor in pathogenesis of hepatic steatosis. Dietary factors, including high consumption of fats and sugars, have been linked to NAFLD development.8 IR causes triglycerides to mobilize from the adipose tissue to the liver, whereas IR-associated hyperinsulinemia promotes hepatic de novo lipogenesis.9 Hepatic steatosis is a benign condition that can progress to NASH in certain individuals, and NASH can progress to cirrhosis and liver cancer. Mitochondrial dysfunction plays an important role in dysregulation of the liver's lipid environment. Enhanced mitochondrial fatty acid oxidation induces production of reactive oxygen species, which results in oxidative stress and development of NASH.10
Pathogenesis and Risk Factors Specific to HIV Infection
There are multiple complex mechanisms by which HIV infection increases the risk of NAFLD. These are incompletely understood and include comorbid risk factors, direct viral effects, and adverse effects of antiretroviral therapy (ART).
Components of metabolic syndrome are more common among PWH. T2DM is 4 times more prevalent in PWH, and dyslipidemia and hypertension are also more common.11-13 Results of a US outpatient study revealed that nearly half of patients were obese at the time of starting ART, and in the next 2 years, 20% moved up to a higher BMI category.14 Achhra et al showed that weight gain in the first year after initiation of ART was associated with increased risk of cardiovascular disease and diabetes.15 NAFLD, which is called lean NAFLD when it affects patients with a BMI of less than 25 kg/m2, occurs in 1 in 4 lean PWH. Lean patients with NAFLD had more metabolic derangements, such as higher triglyceride and ALT levels and lower HDL levels, than lean patients without NAFLD. They had longer duration of HIV infection and higher CD4 lymphocyte counts, and they were more likely to maintain viral suppression. This clinical phenotype may be related to genetic factors, change in gut microbiota, dysfunctional adipose tissue, and improved ability to adapt to an excess intake of calories. However, the exact mechanism is not completely understood.16 Direct viral effects also may contribute to NAFLD. Depletion of CD4+ lymphocytes in the gut causes disruption of the gut epithelial barrier, facilitating microbial translocation into the portal and systemic translocation. This promotes liver fibrosis by activation of hepatic Kupffer cells and induction of proinflammatory cytokines, including tumor necrosis factor, interleukin (IL)-1, and IL-6.17,18 HIV-induced mitochondrial dysfunction results in production of reactive oxygen species, which causes oxidative stress that is known to increase fat accumulation in hepatocytes.19
Finally, certain ARTs may contribute to the pathogenesis of NAFLD. Older nucleoside reverse transcriptase inhibitors, (eg, stavudine, zidovudine, and didanosine) inhibit mitochondrial RNA and have been associated with liver fibrosis. Although these drugs are no longer recommended, associated adverse effects may be irreversible.7,20 Protease inhibitors increase central adiposity, decrease hepatic clearance of very-low-density lipoproteins, increase hepatic triglyceride production, and potentially contribute to NAFLD.21,22 ART in the current era, particularly integrase strand transfer inhibitors, is associated with weight gain with metabolic consequences that are not yet known.23
Fatty Liver in HIV+ Young Adults
The prevalence of NAFLD was high (28.9%) among PHIV, and only partially explained by overweight and metabolic syndrome defining factors.
In this exploratory study using noninvasive imaging techniques, the prevalence of NAFLD among youths living with HIV since childhood was surprisingly high (28.9%) compared to an uninfected cohort. The fact that no clear relation to overweight and the metabolic syndrome defining factors could be established, together with the extremely poor performance of the scores based on clinical and analytical parameters, are worrisome, as
identification of patients at risk remains extremely challenging among youths.
https://www.natap.org/2022/HCV/Prevalence_of_nonalcoholic_fatty_liver_disease.6(1).pdf
Fatty liver disease associated with metabolic dysfunction has emerged as an important NCD in SSA and available data suggest that this region has one of the fastest growing burden worldwide. The prevalence of NAFLD in Africa was estimated to be about 13% [5], although apparently there is underestimation partly due to an under diagnoses and under recording. Cirrhosis-related deaths doubled in SSA between 1980 and 2010, and the underlying aetiology of cirrhosis was unknown in 31% of cases [6]. Similarly, 10% of the underlying aetiology for hepatocellular carcinoma in Africa was unknown [6], suggesting potentially a major contributing role of NAFLD.
Management of NAFLD in SSA faces unique challenges in contrast to high-income countries, where these life-style changes occurred over several decades, allowing health systems to adapt. The changes in sub-Saharan African countries are occurring abruptly and involving massive populations that have rapidly outstripped health care systems, which are already fragile, fragmented, under-resourced, and limited in terms of infrastructure and capacity to be able to cope [3]. Hence, SSA countries do not have the option to simply copy the protocols that have emerged in high-income countries and examining the existing NAFLD guidelines through the contextualisation lens reveals gaps between policy and implementation.
https://www.natap.org/2021/HCV/012021_01.htm
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