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Liver disease

Absence of OSA could protect patients from liver disease

Study supports the notion of an interaction between sleep apnoea and NAFLD

In a study that aimed to identify factors predictive of normal liver histology in a bariatric cohort, researchers have found that the absence of obstructive sleep apnoea (OSA) was strongly associated with normal histology.

Writing in the online journal Plos One, the authors note that non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and its progressive form, nonalcoholic steatohepatisis (NASH), will be the leading indication for liver transplant by 2020. While risk factors for steatohepatitis have been identified, little work has been performed to identify factors protective against NAFLD development.

“The identification of protective factors, most importantly the absence of OSA, offers a unique insight into the forces that ameliorate or modulate the driving forces underlying NAFLD,” the authors write. “Identification of the mediators of protection, in time could lead to rational approaches to prevention or treatment of patients at high risk of NAFLD.”

NAFLD is associated with obesity, and up to 91% of obese adults have some form of fatty liver disease, although NAFLD is common in patients with obesity, it is not universal. A standard of care liver biopsy is performed at the time of weight loss surgery because of the high prevalence of NAFLD. And some studies evaluating the prevalence of NAFLD and paired biopsy studies have shown that NASH regresses after bariatric surgery in up to 69.5% of patients and up to a 22% prevalence of normal liver histology.

However, the factors associated with normal liver histology in patients at high risk for NAFLD are unknown.

Previous studies have found a high prevalence of elevated non-HDL cholesterol (non-HDL-C) in patients with NASH, compared to those with NAFLD and the researchers hypothesized that high levels of HDL and low levels of triglyceride and non-HDL-C levels will be predictive of the absence of NAFLD.

They also hypothesised that race is predictive of the likelihood of having NAFLD, as radiographic NAFLD has been shown to have the highest prevalence in Hispanic patients and lowest prevalence in African Americans.

As a result, the study investigators sought to evaluate these and other factors to determine their combined ability to predict normal liver histology in patients with obesity undergoing weight loss surgery.


A total of 159 patients were included in the study; 49 patients (30.8%) had normal liver histology, while 110 patients met criteria for NAFLD. The mean age of patients with normal liver histology was 40.3 years, patients with NAFLD was significantly higher at 47.8 years (p=0.0007). Gender and body mass index were not significantly different between the two groups. Black patients accounted for 57.5% of the normal group but only 19.3% of the NAFLD group (p<0.0001). Among the NAFLD patients, 31.0% (n=34) had a NAS score of 3–4 and 25.5% (n=28) had a NAS score >=5. The majority of NAFLD patients had stage 0 or stage 1 fibrosis (n=97, 88%) and grade 1 steatosis (n=61. 55.5%).

Patients with normal histology were less likely to have obstructive sleep apnoea, diabetes mellitus or hyperlipidemia and less likely to be on lipid lowering medications.

Patients in the normal group had lower mean ALT, glucose, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR) than those in the NAFLD group and a higher mean HDL than the NAFLD group (49.5 vs. 42.3, p=0.009) and a higher proportion of patients in the normal group had HDL>50mg/dL than in the NAFLD group (p=0.0098). There were no differences in total cholesterol, LDL, triglycerides, or non-HDL-C between the groups.

Predictive factors

The investigators reported that black race was the strongest predictor of the absence of NAFLD and was associated with an odds ratio (OR) of 6.8 (95% confidence interval [CI] 2.4–18.9) for normal histology. Insulin resistance (measured by fasting insulin, fasting glucose, diagnosis of diabetes mellitus and HOMA-IR) were also predictive of normal histology. A low HOMA-IR had the strongest association with the presence of normal histology (OR 1.4, 95% CI 1.03–1.9).

This indicates that for each unit decrease in HOMA-IR, the risk of having normal liver histology increases 1.4 fold. In addition, a low HDL was associated with a decreased likelihood of normal liver histology (OR 0.38, 95% CI 0.05–0.83). No other lipid values were predictive of normal histology, including non-HDL cholesterol.

Finally, a low ALT was associated with an increased prevalence of normal liver histology with an OR of 1.06 (95% CI1.01–1.1).

“While black race and a favourable metabolic profile have previously been associated with normal liver histology, we identified the absence of obstructive sleep apnoea, as a novel factor associated with normal liver histology,” the researcher write.

Obstructive sleep apnoea was present in only nine subjects (18%) with normal liver histology, compared to 65 subjects (59.1%) with NAFLD (p=<0.001). The absence of obstructive sleep apnoea was also strongly associated with the presence of normal histology, with an OR of 5.6, (95% CI 2.0–16.1). Self-reported use of continuous positive airway pressure (CPAP) for OSA was not significantly different between groups but formal compliance was not assessed.

The researcher then used clinical and metabolic factors that differed between the normal and NAFLD groups, and constructed a weighted score to predict the presence of normal liver histology.

A score of 0 or greater maximised the combined sensitivity and specificity for predicting normal liver histology with a sensitivity of 59.5% and specificity of 92.7%.

They noted that while this score has a relatively low sensitivity, the high specificity minimises the risk of falsely predicting normal liver histology, suggesting its value as a tool to refer patients for NAFLD screening.

We also determined the positive predictive value (PPV) and negative predictive value (NPV) of the Healthy Liver Score, which was defined as a high NPV of 99.2% at 1% prevalence and 92.8% at 15% prevalence. This indicates that a score of “not normal” or less than 0 has a high probability of correctly identifying patients with NAFLD (or those without normal liver histology). The PPV was 14% at 1% prevalence and 56.2% at 15% prevalence of normal histology. Therefore, patients without NAFLD will be placed in the screening group, but the researchers explained that a screening score the inclusion of normal patients is preferable to the exclusion of abnormal (or NAFLD) patients.

The Healthy Liver Score was evaluated in 92 subjects undergoing weight loss surgery, 27 had normal liver histology and 65 had NAFLD on liver biopsy. Using a cut-off of >=0 for normal liver, the Healthy Liver Score had similar performance characteristics with a 44.4% sensitivity and a 96.9% specificity, replicating the researchers findings in the initial cohort.

The results suggest that suggest that OSA is associated with liver injury and although the exact mechanism/s are unclear the researchers note that hypoxia induced by sleep apnoea has been shown to increase expression of lipogenic genes and decrease expression of genes regulating mitochondrial beta oxidation in murine models leading to increased hepatic triglyceride storage.

Hypoxia has also been associated with increased lipid peroxidation and increased pro-inflammatory cytokines resulting in increased inflammation.

“Our study lends further support to the notion of an important interaction between sleep apnoea and NAFLD by demonstrating that the absence of sleep apnoea may protect not only from the development of steatohepatitis but also steatosis itself,” the researcher s conclude. “Further study is required to determine the impact of sleep apnoea on the development of NAFLD and the impact of effective treatment of sleep apnoea (CPAP) on NAFLD regression.”

Next article: Genes predict weight loss post gastric bypass

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