[Lance Sherriff assisted in the transcription and compilation of this article.]
Fatty liver disease (hepatic steatosis) was found to be very common among people living with HIV in a cross-sectional study involving 160 people on antiretroviral treatment, according to data presented at the 9th International HIV and Aging Workshop last week in New York City.
“The prevalence of hepatic steatosis was 39% for those ≥ 50 [years of age and] 49% percent for those < 50 [years of age],” said Dr. Jordan Lake of the University of Texas, Houston, though she added that the difference in percentages might not be significant. “I would probably take the average and say we have about 45% fatty liver disease.”
Nevertheless, it was a very high prevalence in the younger subset (which had a mean age of 42) of what is typically a comorbidity seen at older ages — underlining the harmful effects that either HIV, its treatment, or both together are having on metabolism.
Overall, these prevalence rates were similar, if not somewhat higher, than rates of fatty liver disease previously reported in people living with HIV using non-invasive diagnostic techniques (rates using liver biopsy can be higher). It is important to note, however, that this cohort included people that have typically been under-represented in most of the previously described cohorts: The study population was mostly uninsured, non-white (~ 95%) and also included a higher proportion of cisgender women and trans women (31% and 11%, respectively) than typically included in HIV trials.
Obesity was the major driver of hepatic steatosis in this population. However, Dr. Lake noted that some of the metabolic profiles in the individuals with fatty livers were divergent. “Quite a few of these folks had lean nonalcoholic fatty liver disease, which is a whole different metabolic disorder,” she said.
“When hepatocytes are stuffed full of lipid, they become angry,” said Dr. Lake.
Fatty liver disease is defined as having > 5% of extra fat in the liver, traditionally on biopsy, however, with more advanced imaging techniques such as magnetic resonance imagery (MRI), the same criteria are applied.
The root cause of fatty liver disease is the excess deposition/accumulation of triglycerides in the liver — which leads to impaired insulin signaling and glycolysis of excess hepatic glucose (increasing the risk of hyperglycemia). This in turn causes more local ‘lipotoxicity’ — a metabolic syndrome which elevates circulating fatty acids leading to the accumulation of lipids where they don’t belong in non-adipose (or non-fat) tissue — which causes additional hepatocyte stress and death. All of these together lead to inflammation and oxidative stress.
If this all sounds a bit circular, it is. Once it gets started, it’s something of a vicious cycle.
In short, fatty liver disease is a metabolic and inflammatory condition — and though it could progress to further liver complications such as liver cancer, cirrhosis or end stage liver disease, most of the morbidity and mortality associated with it is due to cardiovascular disease, at least in the general population.
In the HIV population, it is much more common however, with up to about 40% of people with HIV having non-alcoholic fatty liver disease (NAFLD).
“When you start layering on top of that [fatty liver due to] alcohol use, viral hepatitis co-infection, it quickly gets to probably more than half of the adults being affected by fatty liver disease,” said Dr. Lake.
Data suggest that HIV infection uniquely contributes to the development of fatty liver disease most likely in a number of ways, including:
- Chronic inflammation and immune activation
- Dyslipidemias associated with antiretroviral therapy and HIV itself
- Mitochondrial dysfunction
- Persistent microbial translocation (people living with HIV have mucosal impairment, and increased gut permeability that allows for intestinal microbes to spread into the bloodstream, causing even more chronic inflammation)
“With translocation of bacterial products – the drainage from the gut goes straight to the liver and the surrounding fat and creates a local inflammatory response that is pretty significant,” Dr. Lake said.
Despite these compelling hypotheses, Dr. Lake believes that the prevalence, risk factors and biomarkers for fatty liver disease are not well defined, including differences by age, in people living with HIV, which led her to establish this observational cohort.
Fatty liver disease is gravely under-diagnosed in clinical practice. Although liver function tests (LFTs) may be elevated, fatty liver disease is often present in the absence of higher LFTs. Liver biopsy and magnetic resonance imaging (MRI) tends to be the gold standard for diagnosing fatty liver disease, but as noted elsewhere on this website, tissue biopsies are painful and MRI is expense, so more convenient, less invasive diagnostic methodologies need to be developed to study organ and tissue diseases.
In this study, after enrollment, participants underwent a FibroScan, a portable ultrasound machine designed specifically for liver scans, with controlled attenuation parameter (CAP) — a scanning methodology to identify the liver’s fat content — and trans elastography (another scanning method that assesses the liver’s stiffness — as a healthy organ should be more flexible). Blood specimens were also collected to look at number of experimental biomarkers that may one day help diagnose and monitor fatty liver disease. The participants clinical characteristics were collected from a medical chart review. The study’s subset analysis, comparing participants by younger or older (50 and above) age was planned from the offset.
As already noted, the finding of a higher prevalence of fatty liver among the younger population was a bit of a surprise. Dr. Lake said that according to the literature in the general population, for every decade over 40, there is generally an increase in prevalence of fatty liver disease. The findings may be a fluke, or due to some other ethnicity or gender differences between the older and younger populations. Another feature that might merit investigation was whether the presence of lean NAFLD was different between the two age subsets or added complexity to the data. However, among those who did have fatty liver, there also did not appear to be any great difference in liver stiffness as a consequence of the disease between the young and older participants.
There was some discussion about this point after the presentation, with one researcher suggesting that there may be a mortality bias — older individuals with fatty liver disease might have passed away from associated cardiovascular disease or some other comorbidity and simply never made it into the cohort. A competing possibility is that older people who have been on treatment longer may also have been already advised for other reasons to make changes to their diet, behavior or regimens may have kept their fatty liver disease in check.
Other findings such as a greater level of obesity and hypertriglyceridemia among those with fatty liver disease were to be expected. Of note, the study did not observe any differences due to the anchor HIV drug (non-nucleoside reverse transcriptase inhibitors, protease inhibitors or integrase inhibitors). However, one wonders whether there might be a difference between individuals who have taken specific drugs, such as ritonavir or cobicistat, which are known to cause hypertriglyceridemia, versus those who have not. The study also did not detect as great of a higher prevalence of fatty liver disease in women than in men, in contrast to what is seen in the general population.
The esoteric bit
However, Dr. Lake said the study was meant to be exploratory and hypothesis-generating, and that the data and p-values were “nothing to hang your hat on.” This may have pertained particularly to the experimental biomarkers for fatty liver disease, which included adiponectin, IL-6, PCSK-9 (proprotein convertase subtilisin/kexin type 9), FGF-21 (Fibroblast Growth Factor 21), Fetuin A (this sole marker stood out as significantly elevated in those with fatty liver disease compared to those without it in this cohort), and FABP4 (fatty acid-binding protein 4). Some of these biomarker appear to behave much differently in people living with HIV than in the general population — with abnormal measurements regardless of whether there was fatty liver disease.
For instance, PCSK-9 is an enzyme that plays a key role in lipoprotein homeostasis. When levels are elevated, it potently interferes with the ability of the liver to clear low-density lipoprotein cholesterol — which is why in recent years, drugs that inhibit PCSK-9 have been approved to lower cholesterol in people who do not have an adequate response to statins. Levels of PCSK-9 are elevated in people with fatty liver disease in the general population. But in people living with HIV — and particularly on protease inhibitors — levels of PCSK-9 seem to be much higher generally. And this was also observed in this cohort study, and there was not as much of a difference between those with fatty liver disease and those without as seen in the general population.
This is significant, because there is considerable interest in using PCSK-9 inhibitors in people living with HIV. However, some advocates, such as Jules Levin of NATAP, fear that clinicians may see these new drugs, alirocumab and evolocumab, as potential magic bullets, and rush to administer them before there is clear data that they will be effective in people living with HIV. In fact, he said at one point during the meeting, “There are reasons to believe that they may not work as effectively in HIV-positives.”
During the discussion, Levin asked Dr. Lake about whether she thought PCSK-9 inhibitors might be able to specifically affect fatty liver disease in people living with HIV.
“Yes,” she responded. “Just because of its hepatic pathway – and I’ve asked the two drug companies that have an agent to consider studying that specifically in our patient population as a therapeutic agent for fatty liver disease.”
“And what did they say?” Jules asked?
“I will hopefully receive an enthusiastic response any day now,” she replied, though she noted that one of the companies just wanted to focus on cardiovascular outcomes.
The primary intervention mentioned by Dr. Lake to reduce the prevalence of fatty liver disease would be to target obesity — as it appears to be the most powerful driver of the condition in most of the subjects.
“Obesity prevention keeps coming up in multiple metabolic disease stages of HIV infection, and so we would just like to highlight the need for obesity prevention,” Dr. Lake concluded.
Lake J, Feng H, Miao H et al. Hepatic Steatosis Is Common in Both Younger and Older Adults Living with HIV and Associated with Divergent Immuno-Metabolic Profiles. 9th International Workshop on HIV and Aging, September 13-14, 2018, New York. Abstract 7.
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