The Ketogenic Diet and Non-alcoholic Fatty Liver Disease

Keto4Life

Well-known member
May 24, 2021
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Old dogmas die hard. One that comes up from time to time is that the high levels of fat consumed on a ketogenic diet will give you a fatty liver. Is this true? What does the science have to say about this? I took a deep dive to find out and here is what I found.

When most of us think about liver damage we think in terms alcoholic cirrhosis of the liver. The progression can vary but a common path starts with fatty liver (hepatic steatosis) advancing to alcoholic hepatitis and then finally to alcoholic liver cirrhosis. However, the abuse of alcohol is not the only way to damage the liver. Our choice of diet can create a similar progression, but or choice of diet can also reverse this path!

Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases and affects up to 33.6% of the adult population in the United States. It is usually found in overweight or obese individuals. Similar to alcoholic fatty liver, it can start as a fairly benign accumulation of fat in the liver and, when left unchecked, it can progress to a serious condition called Non-alcoholic steatohepatitis (NASH). NAFLD is now the second most prevalent cause of liver transplant in the United States.

NASH is referred to as a “lifestyle disease” and often found in conjunction with obesity, pre-diabetes and diabetes. “The symptoms of NASH are often invisible until the liver is damaged beyond repair. While patients remain unaware of their liver condition, NASH can progress to more serious disease stages, such as advanced fibrosis, cirrhosis, liver failure, or liver cancer, driven by hepatocellular ballooning and inflammation.” * The inception of “simple” fatty liver can be relatively easily identified via a physical examine (i.e. palpation), blood tests (i.e. elevated liver enzymes) and imaging (i.e. ultrasound exam). However, NASH can only be found through a liver biopsy.

The progression to NASH with fibrosis (scarring/cirrhosis of the liver) is variable but is most closely linked with obesity and type-2 diabetes. Sadly, the growing problem of fatty liver and NASH is becoming a common problem in the pediatric population as well with an ever-increasing high rate of obesity in children in the United States.

A paper published in March of 2020 (Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: A comprehensive review of the literature) by group in Rome, Italy conducted a review of the available data “aimed at providing an accurate revision of current literature on KDs (ketogenic diets) and NAFLD, focusing on clinical evidence, metabolic pathways involved, and strict categorization of dietary interventions.” During their review they found a need to clearly define what a low-carbohydrate and ketogenic diet were. Consequently, their exploration included studies with ketogenic diets (KDs) classified “as those with a CHO (carbohydrate) content below 50 g and LCDs (low-carb diets) as those with one of 50–130 g/day. We did not include in this revision studies involving diets defined as LCD (Low-Carbohydrate Diet) by the authors but with a content >130 g/day in order to limit heterogeneity.”

The authors note that in the earlier studies in mice models it was found that the “KD may promote hepatic steatosis and, in some cases, inflammation.” However, they also revealed that the rodent models do not translate well to humans as the KDs consumed by the mice were significantly different from what humans typically consume on a ketogenic diet. The KD the rodents consumed compared to the typical KD consumed by humans “is extremely high in saturated fats (lard and butter), markedly low in protein content (8.6%), and insufficient in choline, as opposed to the latter, that is moderately high in lipids with unsaturated fat consumption usually encouraged, it has a normal protein content, and it does not lack in choline.” It was also noted that some studies, in epileptic children implementing a high-fat KD to control seizures, exhibited elevated liver enzymes. However, this was not observed in all the patients and a confounding variable for this observation was in part explained by the anti-epileptic drug valproate.

During the authors review they pointed out that the use of the ketogenic diet is probably best known in the general public for the goal of weight loss, but that “significant evidence suggests a hepatoprotective, role when applied to the fields of obesity and the metabolic syndrome”, as well. In that vein, NAFLD “has been linked to insulin resistance, increased oxidative stress, and inflammation, and it can comprise significant fibrosis.” Some of the relevant effects observed of the KD that suggest it has liver protecting attributes were delineated in this review as:
  • decrease insulin levels, with subsequent reduction in lipogenesis (formation of fat) and increase in FA (fatty acid) oxidation rate
  • Recent evidence also reports that such a drastic reduction of dietary carbohydrates leads to a gut microbiota shift that in turn induces folate production ameliorating lipid metabolism and limiting oxidative stress and inflammation
  • Ketone bodies, produced in response to carbohydrate restriction, have also been proven to induce satiety, which leads to total calorie intake limitation and weight loss facilitation
  • Shimazu et al. reported that βOHB increased global histone acetylation with subsequent transcriptional changes in mouse models, including genes encoding oxidative stress resistance factors, suggesting that βOHB expression may promote oxidative stress resistance
  • βOHB is an endogenous activator of GPR109A, abundantly expressed by many immune system cells, including macrophages or monocytes. 46 Anti‐inflammatory roles of GPR109A ligands in atherosclerosis, obesity, inflammatory bowel disease, neurological disease, and cancer have been reported
  • βHB has also been linked to inhibition of inflammasomes, in particular NLRP3, 15 a key signaling platform that activates proinflammatory cytokines, in particular IL‐1β and IL‐18, strongly associated with obesity and the pathogenesis of IR and T2DM
The researchers combed through 1,386 studies and whittled them down to just 21 studies meeting these six requirements:
  • observational prospective and retrospective studies, case–control studies, cohort studies, randomized clinical trials (RCTs)
  • reported biochemical, histological, or imaging signs relative to outcome measures of NAFLD
  • female only, male only, and both genders enrolled
  • no age limitation
  • sufficient detail about nutritional intervention reported
  • studies written in English
The diets reviewed fell into five different categories that included:
  • High-Fat Ketogenic Diets (HFKD) - HFKD imply a carbohydrate (CHO) content of <20–50 g/day and may be mildly hypocaloric, normocaloric, or unrestricted, with a progressive increase in fat content.
  • Very Low Calorie Ketogenic Diets (VLCKD) – these studies varied in method but contained 45 g/day or less of carbohydrates ranging down to 15g/day while maintaining a low calorie intake.
  • Low‐Carbohydrate non‐Ketogenic Diets (LCD) – these diets included a carbohydrate consumption of 50-130 g/day
  • Very-Low Calorie Diets (VLCD) – these diets included a calorie intake of 800 kcal/day.
  • Intermittent Fasting Regimens (IFR) – these studies included a variety of fasting strategies.
Results
The results in each of these categories were summarized as:

High-Fat Ketogenic Diets (HFKD)
“Altogether, these data suggest a positive effect of HFKDs on NAFLD both in the short and medium term, independent of calorie and fat intake. In particular, HFKDs appear to have greater and faster impact on liver fat content compared with isocaloric high CHO diets and to hypocaloric high CHO diets in the short term, with a possible flattening of the discrepancies as time progresses.”

Very Low Calorie Ketogenic Diets (VLCKD)
“The majority of the studies evaluating the effects of VLCKDs are prospective and short term, as VLCKDs are intrinsically hard to maintain for longer periods of time. Moreover, given the extreme caloric restriction, VLCKD steps only last 2–3 weeks, and most often, outcome measures are assessed at the end of the study rather than at the end of the most restricted first step, making overall results challenging to interpret. Paoli et al. and Bruci et al. do not report significant biochemical improvement in liver function, conversely to what reported by all other studies. This could be due to the relatively low baseline BMI and AST/ALT levels of the study cohort, suggesting that the enrolled patients might not have had NAFLD to start with.”

Low Carbohydrate non-Ketogenic Diets (LCD)
“Evidence on hepatic outcomes in LCDs is extremely heterogeneous, most likely due to the great variety in dietary composition and study duration, together with different means of assessment. However, most studies suggest that, among LCD and LFD, calorie intake is primarily responsible in determining liver pathology improvement, and a relatively small difference in macronutrient distribution might not be sufficient to observe differential effects.”

Very-Low Calorie Diets (VLCD)
“Altogether, available evidence suggests that such an extreme caloric restriction is effective in improving liver conditions in subjects with obesity, although the studies conducted so far are only short term, and dietary interventions are incompletely described and potentially leading to ketosis, which was unassessed, making the interpretation of results potentially misleading.”

Intermittent Fasting Regimen (IFR)
“Evidence on the hepatic effects of IFRs are too few and controversial to draw definitive conclusions. However, recent evidence suggests that IFRs leads to ketosis and metabolic improvement likely to cause amelioration of NAFLD. Targeted clinical studies are therefore needed to confirm whether the equal ability versus simple caloric restriction observed regarding body composition and glucometabolic outcomes is also true regarding liver function and pathology.”

Conclusions
In this review of all the available literature in 2020 the authors found that low-carbohydrate and ketogenic diets do not result in the accumulation of fat in the liver and in fact the science reveals just the opposite is true. In the past it has been observed that weight loss results in the reduction of a fatty liver, however this study found that ketosis itself, independent of a reduction of calories, proves beneficial. They further elucidate that even the consumption of exogenous ketones in conjunction with a normal diet may prove beneficial in treating a fatty liver and should be examined in future studies to assess this a potential novel application.

Some highlights from the conclusion of this review include:
  • Virtually, all reviewed studies assessing liver fat content report positive results after VLCDs, VLCKDs, and HFKDs, with inconclusive results after LCDs diets and IFRs.
  • The common belief that increasing dietary fat intake invariably leads to fatty liver and prevents fat mass loss has been recently proven wrong by an elegant experiment, showing that a normocaloric HFKD inhibits de novo lipogenesis and induces FA oxidation, leading to weight loss and reduced hepatic fat content.*
  • On the contrary, a hypercaloric balanced diet decreases intrahepatic FA oxidation and increases de novo lipogenesis primarily from carbohydrate, and not lipid substrates, leading to NAFLD development.*
  • This finding suggests that ketosis might exert beneficial effects independent of dietary composition and therefore warrants studies aiming at identifying the specific role played by ketone bodies in NAFLD pathophysiology, possibly paving the way for new therapeutic targets and strategies.